Sumário1. Introdução/Highlights 111.1. Introdução 121.2 Destaques deste Posicionamento 121.2.1. Epidemiologia 121.2.2. Bases Fisiopatológicas da Doença Aterotrombótica 121.2.3. Apresentação Clínica, Diagnóstico e Tratamento Clínico 121.2.4. Diagnóstico por Avaliação Funcional Gráfica 131.2.5. Diagnóstico por Imagem Cardiovascular Não Invasiva 131.2.6. Arritmias na Cardiopatia Isquêmica 131.2.7. Aterotrombose na Gravidez, Contracepção, Infertilidade, Síndrome Antifosfolípide 141.2.8. Cardiomiopatia Isquêmica 141.2.9. Intervenção Coronariana Percutânea 141.2.10. Revascularização Miocárdica e Transplante Cardíaco 141.2.11. Reabilitação na Cardiomiopatia Isquêmica 152. Epidemiologia da Doença Isquêmica do Coração nas Mulheres 152.1. Introdução 152.2. Mortalidade 152.3. Prevalência e Incidência 182.4. Carga de Doenças 212.5. Fatores de Risco 212.6. Conclusão 223. Bases Fisiopatológicas da Doença Aterotrombótica 233.1. Introdução 233.2. Ruptura de Placa 233.3. Dissecção Espontânea de Coronária 233.4. Espasmo Coronariano 243.5. Disfunção Microvascular Coronariana 243.6. Embolia e Trombose 243.7. Síndrome de Takotsubo 243.8. Miocardite 244. Apresentação Clínica, Diagnóstico e Tratamento Clínico 254.1. Dor Torácica de Etiologia Isquêmica 254.2. Fatores de Risco Estabelecidos e Modificáveis 264.3. Fatores de Risco Estabelecidos e Não Modificáveis 274.4. Fatores de Risco Específicos da Mulher 274.5. Fatores de Risco Sub-reconhecidos 284.5.1. Recomendações 284.6. Tratamento Medicamentoso nas Diferentes Formas de Manifestação Isquêmica 284.6.1. Recomendações 295. Diagnóstico por Avaliação Funcional Gráfica 295.1. Eletrocardiograma de Repouso 295.2. Teste Ergométrico 295.2.1. Recomendações 305.3. Teste Cardiopulmonar de Exercício 306. Diagnóstico por Imagem Cardiovascular Não Invasiva 326.1. Introdução 326.2. Ecocardiograma de Repouso e sob Estresse 326.3. Ultrassonografia Vascular 336.4. Tomografia Computadorizada 346.5. Ressonância Magnética Cardíaca 346.6. Medicina Nuclear 357. Arritmias na Cardiomiopatia Isquêmica 367.1. Fibrilação Atrial e Doença Isquêmica do Coração 367.2. Arritmias Ventriculares: Morte Súbita, Prevenção e Tratamento 377.3. Terapia de Ressincronização Cardíaca 397.4. Recomendações 408. Aterotrombose na Gravidez, Contracepção, Infertilidade, Síndrome Antifosfolípide 418.1. Introdução 418.2. Período da Gravidez 418.3. Contracepção 418.3.1. Recomendações 448.4. Infertilidade 448.5. Síndrome Antifosfolípide 458.5.1. Recomendações 479. Cardiomiopatia Isquêmica na Mulher 479.1. Introdução 479.2. Tratamento Clínico 489.3. Dispositivos e Insuficiência Cardíaca Avançada 489.4. Cardiodesfibrilador Implantável 519.5. Insuficiência Cardíaca Avançada 519.6. Recomendações 519.6.1. Manejo Clínico e Indicações de Terapias Avançadas 5110. Intervenção Coronariana Percutânea 5110.1. Introdução 5110.2. Acesso Vascular para o Cateterismo Cardíaco e Intervenção Coronariana Percutânea em Mulheres 5110.3. Diagnóstico 5210.3.1. Angiografia Coronária 5210.3.2. Imagem Intravascular 5210.3.3. Testes Invasivos com Guia de Medição 5310.3.3.1. Reserva de Fluxo Fracionada 5310.3.3.2. Razão de Pressão Instantânea Livre de Onda 5310.3.4. Testes Funcionais 5310.4. Tratamento Percutâneo da Doença Aterotrombótica Coronária em Mulheres 5410.4.1. Revascularização para Síndromes Coronarianas Crônicas 5410.4.1.1. Doença do Tronco de Coronária Esquerda 5510.4.1.2. Oclusão Total Crônica 5510.4.2. Revascularização para Infarto do Miocárdio sem Supradesnivelamento do Segmento ST 5510.4.3. Revascularização para Infarto do Miocárdio Com Supradesnivelamento do Segmento ST 5510.4.3.1. Estratégias na Abordagem da Doença Coronariana Múltipla10.4.3.2. Choque Cardiogênico 5510.4.4. Considerações sobre o Dispositivo durante a Revascularização Percutânea 5510.4.4.1. Stents Farmacológicos 5510.4.4.2. Balão Farmacológico 5510.4.4.3. Aterectomia Rotacional e Litotripsia Intravascular 5610.5. Terapia Farmacológica Adjunta 5610.6. Gaps no Conhecimento 5710.7. Recomendações 5811. Intervenção Cirúrgica, Transplante Cardíaco 5811.1. Revascularização do Miocárdio 5811.1.1. Cirurgia de Revascularização do Miocárdio em Mulheres – Recomendações 6011.2. Transplante Cardíaco 6011.2.1. Transplante Cardíaco em Mulheres – Recomendações 6212. Reabilitação na Cardiomiopatia Isquêmica das Mulheres 62Referências 631As diferenças entre os sexos vão além das questões cromossômicas entre homens (XY) e mulheres (XX). Os valores sociais, as percepções e os comportamentos distintos moldam padrões e criam diferentes papéis na sociedade, o que pode gerar diferenças no estilo de vida e comportamento, possivelmente influenciando epidemiologia, manifestação clínica e tratamento.É importante destacar que, do ponto de vista clínico, a doença isquêmica do coração (DIC) ocorre mais precocemente no homem. Contudo, a incidência e a prevalência na mulher aumentam acentuadamente após a menopausa. Enfatiza-se ainda que a maior proporção de mulheres com sintomas anginosos e síndrome coronariana aguda (SCA) tem DIC não obstrutiva.2A DIC em mulheres inclui a aterosclerose coronariana clássica e compreende fisiopatologia variada, como disfunção microvascular coronariana, disfunção endotelial, anormalidades vasomotoras e dissecção espontânea de artéria coronária (DEAC).3Em relação à anatomia, mulheres têm artérias coronárias epicárdicas menores do que homens, mesmo após ajuste para superfície corporal e massa do ventrículo esquerdo (VE). Porém, em comparação com os homens, as mulheres têm menor prevalência de aterosclerose coronariana obstrutiva e características de placa diversas, ainda que em níveis comparáveis de isquemia.4As mulheres que apresentam DIC obstrutiva geralmente são mais velhas do que os homens, têm mais comorbidades cardiovasculares e maior incidência de desfechos cardiovasculares adversos, incluindo mortalidade após infarto agudo do miocárdio (IAM).5As mulheres são menos propensas do que os homens a apresentar ruptura de placa e, nelas, a revascularização da artéria ocluída pode ser mais difícil devido a sangramento no local de acesso e artérias coronárias pequenas e mais tortuosas.6 A maioria das mulheres com IAM apresenta sintomas prodrômicos de falta de ar, fadiga incomum ou desconforto em braço/mandíbula nas semanas anteriores. Angina estável é a apresentação clínica mais frequente em mulheres com DIC em oposição a IAM ou morte súbita.7A dor torácica é o sintoma mais prevalente de IAM em ambos os sexos. No entanto, as mulheres são mais propensas a apresentar sintomas atípicos, incluindo dor na parte superior das costas e pescoço, fadiga, náuseas e vômitos.8 A menor sensibilidade do teste ergométrico (TE) para detecção de doença coronariana obstrutiva em mulheres limita sua utilização no cenário da cardiomiopatia isquêmica (CMI).9 A ecocardiografia sob estresse (exercício ou dobutamina - ESE) tem performance melhor do que o TE, embora inferior à de outros métodos, com estudos mostrando desempenho similar ou inferior em mulheres.11 A incorporação de avaliação por doppler tecidual tem permitido análise quantitativa de viabilidade. A cintilografia miocárdica com imagens obtidas por tomografia computadorizada por emissão de fóton único (SPECT) tem boa performance em mulheres, principalmente quanto à sensibilidade.12 Algumas limitações em mulheres são relacionadas a falsos positivos decorrentes de atenuação mamária e menor acurácia em corações pequenos.13 Para avaliação de estresse miocárdio, a tomografia por emissão de pósitron (PET) é superior ao SPECT em qualidade de imagem e acurácia, tanto em mulheres quanto em homens.14 Dados adicionais caracterizam inflamação e vulnerabilidade das placas, eventos adversos e potencial benefício de revascularização.15Revisão recentemente publicada resume alguns aspectos relacionados a vantagens e desvantagens, bem como valores de sensibilidade e especificidade de acordo com o gênero, dos principais métodos diagnósticos.16O TE e a ESE são considerados seguros na gestação, pois evitam exposição a radiação, enquanto dobutamina e dipiridamol são considerados categoria B. Técnicas de SPECT e PET-CT devem ser evitadas, mas a ressonância magnética cardíaca (RMC) é uma boa opção na gestação.17Nas últimas décadas, têm sido documentadas diferenças na fisiologia e fisiopatologia cardiovascular entre mulheres e homens. Essas diferenças incluem as propriedades eletrofisiológicas da célula cardíaca, o que pode influenciar na ocorrência de arritmias clínicas distintas entre os sexos. Possivelmente, tais diferenças são de origem multifatorial. Entretanto, a ação hormonal e a influência autonômica são fatores importantes no comportamento eletrofisiológico distinto entre mulheres e homens.17 Além disso, foi documentado um menor tempo de recuperação do nó sinusal, menor intervalo HV, maior velocidade de condução ventricular e aumento no intervalo QT em mulheres.18A média da frequência cardíaca (FC) em mulheres é aproximadamente 3 a 5 batimentos/minuto mais alta que a observada em homens.19 Aproximadamente 60% das taquicardias de QRS estreito observadas na prática clínica são secundárias a taquicardia por reentrada nodal, sendo sua prevalência duas vezes maior nas mulheres.20 O período refratário da via lenta é menor no sexo feminino, o que pode aumentar a janela de indutibilidade arrítmica e justificar o maior número de casos em mulheres.21 Entretanto, vale ressaltar que essa característica não interfere no sucesso do tratamento por ablação, que corresponde a 95% dos casos em ambos os sexos. Em contraste, a taquicardia por reentrada atrioventricular predomina no sexo masculino.18 Os homens apresentam mais frequentemente uma via acessória manifesta, com localização lateral esquerda. Por outro lado, nas mulheres, observa-se quase três vezes mais vias à direita.21A prevalência de taquicardia sinusal inapropriada é muito maior em mulheres. Um estudo com 321 pacientes acompanhados por taquicardia sinusal inapropriada mostrou que 92% deles eram do sexo feminino.22 Além disso, as mulheres são mais sintomáticas e apresentam pior qualidade de vida quando comparadas com os homens. Os mecanismos associados às diferenças entre os sexos na FA são inúmeros, mas é importante ressaltar que a DIC, mais observada no sexo masculino, pode corroborar com a maior incidência de FA nesse grupo. Em relação ao tratamento com drogas antiarrítmicas (DAA), as mulheres apresentam mais efeitos adversos. O aumento no intervalo QT basal pode afetar a tolerância ao uso de DAA, especialmente da classe III, exigindo uma monitorização mais cuidadosa nesse grupo de pacientes. Em relação aos resultados da ablação por cateter, estudos observacionais demonstram que as mulheres são submetidas menos frequente e mais tardiamente a ablação, em geral com evolução pior após o procedimento.23A incidência de fibrilação atrial (FA) ajustada para idade é uma vez e meia a duas vezes maior em homens. Entretanto, o risco de FA ao longo da vida é semelhante em ambos os sexos devido à maior expectativa de vida no sexo feminino. Nas mulheres, existe um aumento desproporcional de FA com o avançar da idade, de tal forma que, aos 85 anos, as diferenças na prevalência são discretas.24 Pacientes pré-púberes do sexo masculino com síndrome do QT longo tipo I e pré-púberes do sexo feminino com síndrome do QT longo tipo II apresentam maior risco de arritmia ventricular.25 A ocorrência de morte súbita cardíaca em mulheres é quase a metade da ocorrência em homens, mesmo após ajuste para fatores predisponentes.26As arritmias ventriculares em pacientes com coração normal apresentam características epidemiológicas variáveis entre os sexos. A taquicardia ventricular (TV) de via de saída do ventrículo direito é mais frequente em mulheres, ao passo que as arritmias com origem fascicular ocorrem mais em homens.mellitus (DM) e hipertensão arterial sistêmica (HAS). Vários fatores levam a menor inclusão de mulheres nos estudos sobre DIC. Os relacionados à condição da paciente são (1) necessidade de viajar e se ausentar do trabalho, (2) ausentar-se das responsabilidades com os filhos, a família e o lar, (3) necessidade de elevado nível de compromisso, (4) barreiras socioeconômicas, psicológicas, culturais e de saúde. Os fatores relacionados ao estudo são: (1) baixas taxas de encaminhamento e triagem de elegibilidade, (2) falta de critério de elegibilidade relacionado ao sexo, (3) liderança heterogênea dos estudos, principalmente composta por homens, (4) exclusão de idosos. Ações futuras são importantes para uma maior inclusão de mulheres portadoras de DIC nos grandes estudos.27Este posicionamento, através de ação conjunta das especialidades da cardiologia com expertise na mulher, tem como principal objetivo divulgar informações sobre a DIC sob vários aspectos para um melhor entendimento de suas particularidades, visando melhor tratar essas pacientes e consequentemente reduzir sua morbimortalidade.As mulheres com insuficiência cardíaca (IC) geralmente são mais idosas que os homens e têm maior prevalência de IC com fração de ejeção preservada (ICFEp). Além disso, mostram mais cardiopatia não isquêmica, diabetes 95%, -58,7; -52,3), do que nos homens, -49,5 , nesse mesmo período. Esse declínio foi desigual nas unidades da federação em ambos os sexos, estando relacionado com o envelhecimento da população e com o índice sociodemográfico (SDI) de 2019.• A DIC mantém-se como a principal causa de morte de mulheres e homens no Brasil. Houve diminuição mais pronunciada do percentual da taxa de mortalidade por DIC padronizada nas mulheres entre os anos de 1990 e 2019, -55,5  é maior nas mulheres, com mortalidade semelhante à da DIC obstrutiva, associando-se com risco de eventos maiores.Global Burden of Diseases (GBD) 2019 estimou taxa padronizada de DALYs (anos de vida ajustados por incapacidade) por DIC por 100 mil habitantes de 1.088,4  nas mulheres e de 2.116,5  nos homens. A DIC foi a segunda causa mais comum de DALYs no Brasil nas mulheres (após distúrbios neonatais) e nos homens  em 2019. Essas taxas foram heterogêneas nas regiões geográficas brasileiras e a tendência das taxas de DALYs padronizadas por idade de 1990 a 2019, nas mulheres, assemelhou-se à das taxas de mortalidade.• O estudo do • As mulheres apresentam maior frequência de fatores de risco cardiovascular (FRCV) não tradicionais, como estresse mental e depressão, e sofrem maior consequência das desvantagens sociais devido a raça, etnicidade e renda. As mulheres têm ainda os fatores de risco (FR) inerentes ao sexo, como gravidez, menopausa e menarca, entre outros.A doença coronariana obstrutiva, caracterizada pela presença de placas de aterosclerose nas paredes das artérias coronárias, é o substrato mais frequente de DIC nas mulheres. Entretanto, é reconhecido que a doença coronariana não obstrutiva com evidências de danos ao músculo cardíaco ou outros sinais de enfermidade coronariana afeta desproporcionalmente mais mulheres.• Os mecanismos fisiopatológicos envolvidos na MINOCA incluem ruptura de placa coronariana, DEAC, vasoespasmo coronariano, disfunção microvascular coronariana e embolismo/trombose. Importante destacar as síndromes que mimetizam clinicamente MINOCA, como Takotsubo, miocardite e cardiomiopatia não isquêmica.• As diferenças biológicas e socioculturais específicas do sexo feminino na apresentação da dor torácica da DIC podem explicar as diferenças em sua apresentação clínica, seu diagnóstico e seu manejo, levando a atrasos na conduta e, consequentemente, desfechos desfavoráveis.• Os sintomas isquêmicos das mulheres são mais relacionados ao estresse emocional ou mental e menos frequentemente precipitados pela atividade física, em comparação aos homens. Escore de risco global e caracterização de angina não devem ser usados uniformemente em mulheres e homens, devido ao impacto diferente dos FR e às manifestações clínicas variáveis entre os sexos.• Existem diferentes proporções na relevância dos FR entre os sexos, como HAS, obesidade, DM e tabagismo. Os FR específicos do sexo feminino são relevantes na estratificação de risco: pré-eclâmpsia e diabetes gestacional aumentam o risco cardiovascular (RCV) da mulher por toda a vida.• Mulheres são menos submetidas a coronariografia e tratamento cirúrgico, incluindo suporte circulatório mecânico no choque cardiogênico. No entanto, têm maior mortalidade e complicações pós-operatórias, apesar de menor carga aterosclerótica.• Menos de 50% das pacientes são submetidas a tratamento medicamentoso adequado, além de ser baixa a aderência ao tratamento e existir subutilização de reabilitação cardíaca.• O tratamento da MINOCA e da isquemia do miocárdio sem doença coronariana obstrutiva (INOCA) baseia-se na mudança de estilo de vida, controle dos FR e tratamento antianginoso.• A posição inadequada dos eletrodos no eletrocardiograma (ECG) pode causar diagnóstico equivocado nas mulheres. Mamas volumosas ou próteses mamárias podem gerar complexos de baixa voltagem e reduzem a amplitude da onda R nas derivações V1 e V2, simulando área inativa. O ECG na avaliação de dor torácica utiliza os mesmos critérios diagnósticos descritos para o sexo masculino, exceto para análise de lesão subepicárdica.• O TE é recomendado como método inicial de escolha na avaliação de mulheres sintomáticas de risco intermediário para DIC, com ECG de repouso normal e capazes de se exercitar. Além das alterações do segmento ST, a capacidade de exercício, as respostas cronotrópica e da pressão arterial (PA), a recuperação da FC e a avaliação do escore de Duke (ED) são informações prognósticas que aumentam a acurácia do TE, especialmente nas mulheres. A capacidade funcional é a variável prognóstica mais importante para morbimortalidade por todas as causas em mulheres, incluindo as assintomáticas. A incapacidade de atingir 5 MET é preditora independente de alto risco, com aumento de três vezes na mortalidade em comparação àquelas que atingem mais de 8 MET.2), que permite inferir a disfunção ventricular isquêmica induzida pelo esforço, cujo achado pode ser relevante no diagnóstico da DIC macro e microvascular na mulher.• O teste cardiopulmonar de exercício (TCPE) permite realizar diagnóstico, prognóstico, acompanhamento após intervenção terapêutica e prescrição de exercícios aeróbicos na DIC. O TCPE apresenta maior acurácia diagnóstica na DIC de mulheres do que o TE. Além dos critérios clínicos, hemodinâmicos e eletrocardiográficos, o TCPE fornece a análise do pulso de oxigênio  é útil na detecção de placas carotídeas como modificador de risco em mulheres de probabilidade intermediária e/ou FR não tradicionais, no rastreamento de aneurisma de aorta abdominal em mulheres tabagistas ou ex-tabagistas entre 55 anos e 75 anos e na busca de doença arterial periférica (DAP) silenciosa.• Angiotomografia coronariana (Angio-TC) apresenta boa acurácia diagnóstica e prognóstica na avaliação de DIC em mulheres, caracterizando e quantificando as lesões. Classicamente, mulheres apresentam lesões menos calcificadas e não obstrutivas em relação a homens.• A RMC oferece maiores informações na detecção da DIC na mulher: identifica isquemia por DIC obstrutiva e não obstrutiva, MINOCA, avalia viabilidade miocárdica, distingue a doença isquêmica da inflamatória e define diagnóstico de Takotsubo.• A imagem nuclear avalia todo o espectro da DIC, desde doença coronariana obstrutiva até disfunção microvascular coronariana, sem limitações quanto a função renal, arritmias, obesidade e dispositivos intracardíacos.• As mulheres têm mais taquicardia sinusal inapropriada e taquicardia por reentrada nodal e menos FA, arritmias ventriculares malignas, como TV e fibrilação ventricular (FV), e morte súbita cardíaca do que os homens. A despeito da diferença na prevalência entre os sexos, as mulheres se beneficiam do tratamento das arritmias cardíacas.• As mulheres com FA têm maior prevalência de HAS, obesidade, depressão, ICFEp e doença valvar como causa da arritmia. São também preditores de risco de FA nas mulheres a falta ou escassez de exercício, a monoterapia com estrogênio e a multiparidade. As mulheres com FA têm alto risco de acidente vascular cerebral (AVC), não havendo diferença significativa no risco de AVC ou de embolia sistêmica e sangramento gastrointestinal entre mulheres e homens em uso de anticoagulantes. Foi demonstrada redução significativa de hemorragia intracraniana e mortalidade por todas as causas nas mulheres com FA em uso de anticoagulantes de ação direta (DOACs). As mulheres com FA têm pior qualidade de vida do que os homens e são menos submetidas a procedimentos, como a ablação por cateter ou cardioversão elétrica (CVE).• As mulheres têm menos CMI que os homens e aquelas com DIC e portadoras de cardiodesfibrilador implantável (CDI) apresentam menos episódios de TV/FV e de tempestade elétrica e ainda menos choques pelo CDI do que os homens. As mulheres têm menos CMI e menor carga de fibrose do que os homens submetidos à terapia de ressincronização cardíaca (TRC) e respondem melhor à TRC do que os homens, com maiores intervalos de tempo até a primeira hospitalização e menor mortalidade. As terapias como CDI e TRC trazem benefícios na mortalidade. As mulheres representam em torno de 30% das populações dos estudos com essas terapias.• O percentual de mulheres contempladas nos estudos de ablação de TV na população com DIC é baixo (7-13%). A menor indicação de procedimentos invasivos, a menor indução de TV sustentada e o menor número de choques apropriados são fatores que podem contribuir para esse percentual reduzido.• A doença aterotrombótica é uma das causas mais frequentes de IAM durante a gravidez e o puerpério.• A conduta diante da DIC aguda durante a gravidez deve priorizar a vida materna e seguir as recomendações para a população em geral.• A tríade conjugada  é considerada o fator determinante da manifestação clínica da doença aterotrombótica durante a gravidez e o puerpério.• A queixa de dor torácica durante a gravidez em mulheres que apresentam FR para a doença cardiovascular (DCV) não deve ser subestimada e deve seguir protocolo convencional de investigação para SCA.• Os contraceptivos não estão isentos de efeitos aterotrombóticos, mas a não prescrição incorre no risco de gravidez não planejada, principalmente na adolescência e em mulheres com comorbidades. A seleção do método de contracepção deve ser individualizada, atender à preferência e idade da paciente, assim como à segurança e eficácia do método.• A frequência de distúrbios metabólicos pró-ateroscleróticos, particularmente obesidade e aumento de colesterol total, LDL-colesterol e triglicerídeos, é maior entre as mulheres que sofrem de infertilidade.• A terapêutica da infertilidade é considerada um potencial FR para os distúrbios hipertensivos na gestação subsequente. Contudo, ainda não foi demonstrada correlação entre tratamento para fertilização e eventos cardiovasculares.• Diagnóstico de síndrome antifosfolípide (SAF) deve ser presumido diante da manifestação clínica de trombose vascular e/ou complicações obstétricas recorrentes, sendo sua investigação obrigatória na presença de AVC e IAM em mulheres jovens.• A IC relacionada à CMI é uma importante causa de morbidade e mortalidade em mulheres, que tendem a desenvolvê-la em idade mais avançada que os homens.• A ICFEp é mais comum em mulheres, mas a etiologia isquêmica tende a manifestar-se na forma dilatada e de fração de ejeção reduzida, ainda que com menos fibrose endomiocárdica quando comparada com homens.• As mulheres estão pouco representadas em ensaios clínicos para IC. Apesar disso, as recomendações para terapias medicamentosas e avançadas nas diretrizes não sugerem tratamento individualizado para as mulheres.• No procedimento intervencionista, estratégias para redução no risco de sangramento e de complicações vasculares devem ser adotadas, priorizando a via de acesso radial e a utilização de fármacos adjuntos em doses adequadas ao peso e à função renal.• Avaliação funcional na doença coronariana, através da análise da reserva de fluxo fracionada (FFR), é de grande valia naquelas obstruções intermediárias (40% a 70%), quando não se tem isquemia comprovada por métodos não invasivos. As mulheres parecem ter valores de FFR mais altos para doença coronariana não obstrutiva, ratificando ser ainda mais relevante medir a FFR em mulheres, além de ser também um preditor univariado significativo de prognóstico para esse grupo.stents e estratégia antiplaquetária pós-intervenção personalizada.• Devem-se identificar perfis de alto risco para sangramento e perseguir a excelência nos resultados da intervenção através de seleção criteriosa e preparo adequado das lesões, baixo limiar para utilização de guia de imagem intravascular, implante otimizado dos • Devem-se utilizar estratégias no laboratório de hemodinâmica para otimizar o diagnóstico etiológico nos casos de MINOCA.• Deve-se considerar o diagnóstico de disfunção microvascular coronariana, mais frequente em mulheres, tanto em cenários crônicos como agudos, que pode ser corroborado por métodos fisiológicos invasivos coronarianos.• O uso de enxertos arteriais na revascularização miocárdica (RVM) é menor em mulheres.• Na evolução pós-operatória, as mulheres apresentam maior taxa de complicações.• A indicação cirúrgica retardada tem impacto negativo nos resultados pós-operatórios.• Atualmente 25% dos transplantados cardíacos são realizados em mulheres, que apresentam maior taxa de complicações, principalmente rejeição, e têm melhor sobrevida do que os homens após o transplante cardíaco.• Mulheres evoluem com incidência menor de tumores malignos no pós-operatório.• O encaminhamento à reabilitação cardíaca deve fazer parte da prescrição médica para mulheres com DIC, inclusive nos casos de DEAC e MINOCA.• A avaliação inicial e a prescrição do programa de reabilitação cardíaca devem ser direcionadas pelas especificidades da mulher para que haja maior engajamento e menor desistência.31O crescimento da população e o aumento da expectativa de vida geraram incremento do número total de mortes por DIC no mundo. As taxas de mortalidade por DIC padronizadas por idade em mulheres e homens diminuíram de forma gradual na maioria dos países, provavelmente devido a melhorias no diagnóstico e tratamento, ainda que tenha ocorrido um aumento relevante da obesidade, da elevação da glicose sérica de jejum e da síndrome metabólica.31A DIC mantém-se como a principal causa de morte em mulheres e homens no Brasil. A incidência e a prevalência da DIC vêm diminuindo no Brasil ao longo dos últimos 20 anos em mulheres e homens, embora tenha ocorrido aumento na mortalidade precoce por essa causa, entre 18 anos e 55 anos, especialmente nas mulheres. A DIC também foi a segunda maior causa de DALYs nas mulheres no Brasil no período de 1990 a 2019.32As mulheres apresentam maior impacto dos FRCV tradicionais e têm pior prognóstico, apesar de a carga de risco por DIC e a carga aterotrombótica serem menores. As mulheres apresentam maior frequência de FRCV não tradicionais, como estresse mental e depressão, e sofrem maior consequência das desvantagens sociais devidas a raça, etnicidade e renda.29 Os desfechos são substancialmente piores em comparação aos homens, além disso as mulheres mais jovens (< 55 anos) e os subgrupos de mulheres definidos por raça, etnia, status socioeconômico e escolaridade apresentam disparidades ainda mais marcantes quanto a diagnóstico, tratamento e prognóstico da DIC.32A MINOCA predomina nas mulheres.Este capítulo tem como objetivo sumarizar os achados sobre a epidemiologia da DIC nas mulheres, especialmente as brasileiras.28Dados recentes do projeto GBD de 2021 estimaram para a DCV no Brasil taxas padronizadas de 3.568,0 DALYs  e 162,2 mortes por 100 mil habitantes, com uma taxa de prevalência padronizada de 6.905,6 por 100 mil habitantes. Ainda segundo o GBD 2021, as taxas estimadas para a DIC na América Latina Tropical (Brasil e Paraguai) em 2021 foram as seguintes: prevalência de 1.989,5, mortalidade de 67,7 e 1.439,6 DALYs por 100 mil habitantes. Embora um progresso considerável tenha sido feito na diminuição do número de mortes por DCV desde 1980 até o final de 2021, houve um aumento preocupante da taxa de mortalidade bruta e do número de DALYs nos últimos anos por DCV.29A DCV é a principal causa de morte em mulheres no mundo e foi responsável por aproximadamente um terço do total de mortes em mulheres em 2021. A mortalidade por DCV diminuiu globalmente nos últimos 30 anos, com declínio mais significativo em países com alto SDI . No entanto, em regiões de alta renda, a tendência de redução da mortalidade por DCV diminuiu e, em 2017, aumentou o número de mortes em mulheres de alguns países, como Estados Unidos e Canadá.95%, 138,23; 168,08) para 96,02 , com decréscimo percentual de -2,3 , e nas mulheres, passando de 92,36  para 54,84 , com decréscimo percentual de -2,7 . Nesse mesmo período, as taxas de mortalidade diminuíram significativamente em 24 países. Costa Rica, Canadá e Chile tiveram os maiores decréscimos percentuais, enquanto aumento significativo ocorreu na República Dominicana e em Granada.30Na região das Américas, a taxa de mortalidade por DIC ajustada por idade diminuiu no período de 2000 a 2019 nos homens, passando de 149,08  foi a principal responsável pela morte de mulheres, seguida por DM tipo 2 e AVC, nessa ordem . Esse de95%, 51; 63) e 96  por 100 mil habitantes no Brasil nas mulheres e nos homens, respectivamente. Entre os anos de 1990 e 2019, houve diminuição mais pronunciada do percentual da taxa de mortalidade por DIC padronizada nas mulheres, -55,5 , do que nos homens, -49,5   A. Em tod; -46,6) .3133Estudo com dados do Brasil oriundos do Sistema de Informação sobre Mortalidade (SIM) reportou que o coeficiente de morte relacionada à DIC permaneceu estável para mulheres nas regiões Norte e Centro-Oeste entre 1981 e 2001, enquanto diminuiu no Sul e Sudeste e aumentou no Nordeste. Para homens, houve tendência decrescente nos eventos nas regiões Sul e Sudeste.34Estudo que avaliou 166.514 procedimentos de angioplastia coronariana para tratamento de DIC realizados em 180 hospitais, entre 2005 e 2008, reportou mortalidade hospitalar média de 2,3% , que variou por região geográfica, sendo menor no Sudeste  e maior no Norte . A taxa de mortalidade foi maior entre mulheres e nos pacientes acima de 65 anos.35As mulheres submetidas a RVM têm maior mortalidade e mais complicações pós-operatórias, apesar de menor carga aterosclerótica. O aumento da mortalidade no momento da RVM é maior em idades mais jovens do mais avançadas, estimando-se um risco três vezes maior de morte em mulheres com idade < 50 anos, apesar do ajuste para os FR.garbage code  e subnotificação analisou as tendências da mortalidade por IAM de acordo com sexo, regiões do Brasil e residência na capital versus não capital. Os autores relataram que a taxa de mortalidade por IAM padronizada por idade diminuiu 44% no país, com diferenças regionais significativas . As variações temporais foram mais pronunciadas nas mulheres e nas capitais. A taxa padronizada por idade de mortalidade por IAM corrigida diminuiu 49% e 23% entre as mulheres que viviam nas capitais e em outras municipalidades, respectivamente.36Estudo realizado no período de 1996 a 2016 com dados do SIM corrigidos por 37Outro estudo realizado com dados do SIM observou um declínio de aproximadamente 2,2% nos últimos 20 anos para o IAM nas regiões geográficas com maior desenvolvimento , estabilização na região Norte e aumento na região Nordeste. Os autores também previram que essa tendência se prolongará até o ano 2030. Essas variações foram provavelmente relacionadas às melhorias no desenvolvimento social, nos FRCV, no acesso ao sistema de saúde e sua cobertura e à melhor discriminação nas codificações das declarações de óbito nas regiões Norte e Nordeste.versus 334 homens). As mulheres apresentaram taxas significativamente menores de angioplastia primária  e significativamente maiores de mortalidade hospitalar  do que os homens.38No registro VICTIM, foram avaliados 878 pacientes com diagnóstico de IAM com supradesnivelamento de segmento ST (IAMCSST) admitidos em quatro hospitais com capacidade para realizar angioplastia primária em Sergipe, sendo um público e três privados, no período de dezembro de 2014 a junho de 2018. Desses pacientes, 33,4% eram mulheres. Do total, apenas 53,3% dos pacientes foram submetidos à reperfusão miocárdica , mais frequentemente apresentavam HAS , DM  e dislipidemia , além de serem menos submetidas à intervenção coronariana percutânea (ICP) por acesso radial  do que os homens. A taxa de mortalidade intra-hospitalar foi significativamente maior nas mulheres em comparação com os homens  e sexo feminino mostrou-se um preditor independente de mortalidade intra-hospitalar .39Outro estudo unicêntrico prospectivo realizado em Recife com 709 pacientes consecutivos com IAMCSST , no período de fevereiro de 2018 a fevereiro de 2019, observou que as mulheres eram mais velhas  por 100 mil mulheres e 2.534  por 100 mil homens .31 Houve redução do percentual da taxa padronizada de prevalência de DIC por 100 mil habitantes nas mulheres entre os anos de 1990 e 2019, de -2,4 , mas discreto aumento nos homens, de 1,4 , nesse mesmo período  eventos  no Brasil em 2019. Em todos os grupos etários, a DIC teve maior incidência nos homens do que nas mulheres  por 100 mil mulheres e 148  por 100 mil homens. Houve uma diferença entre as regiões brasileiras na incidência de DIC padronizada por idade nas mulheres, que foi maior nas regiões Sudeste e Sul e menor na região Norte , e nos homens, -11,8 , nesse mesmo período  aumentou de 27% para 32% nas últimas duas décadas, com maior aumento de mulheres jovens (21% a 31%).Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients), realizado entre 2008 e 2012, incluiu prospectivamente 2.690 pacientes com IAM e idades entre 18 anos e 55 anos em 103 hospitais, na proporção de mulheres para homens de 2:1. Nos 2.374 pacientes submetidos a estudo angiográfico coronariano, as mulheres apresentaram cinco vezes mais chances de ter MINOCA do que os homens . As mulheres com obstrução coronariana significativa eram mais propensas a estar na menopausa  ou ter um histórico de diabetes gestacional . Cabe ressaltar que a mortalidade de 1 e 12 meses nos pacientes com MINOCA foi semelhante à mortalidade por obstrução coronariana nos mesmos 1 e 12 meses.30A prevalência de MINOCA é maior nas mulheres. O estudo VIRGO  nos homens  nas mulheres e de 2.116,5 , do que nos homens, -47,3  , 202.072 indivíduos com idade entre 35 anos e 70 anos, de comunidades urbanas e rurais, em 27 países, entre janeiro de 2005 e maio de 2019, foram acompanhados por uma média de 9,5  anos. As mulheres tiveram uma menor carga de FRCV usando dois escores de risco tradicionais diferentes (INTERHEART e Framingham). Estratégias de prevenção primária (estilo de vida saudável e uso de medicamentos comprovados) foram mais frequentes em mulheres, que, por sua vez, apresentaram menor incidência de DCV. No entanto, tratamentos de prevenção secundária para DIC foram menos frequentes em mulheres do que em homens. As diferenças entre mulheres e homens em relação a tratamentos e resultados foram mais marcantes em países de baixa e média renda, com poucas diferenças em países com alta renda, naqueles com ou sem DCV e DIC prévias.42No estudo PURE  em homens]; depressão ; HAS ; tabagismo atual ; história familiar de infarto prematuro do miocárdio ; baixa renda familiar ; hipercolesterolemia . Houve diferenças significativas entre os sexos nas associações de FR: HAS, depressão, DM, tabagismo atual e história familiar de DM tiveram associações mais fortes com IAM em mulheres jovens, enquanto a hipercolesterolemia teve uma associação mais forte em homens jovens.43No estudo caso-controle derivado do estudo VIRGO, com 2.264 pacientes com IAM (18-55 anos) e 2.264 controles pareados, 3.122  eram mulheres, com mediana de idade de 48 (44-52) anos. Os seguintes sete FR representaram coletivamente a maior parte do risco total de IAM em mulheres  e homens : DM , colesterol de lipoproteína de baixa densidade  e glicose , ou ser fisicamente ativas  ou não obesas . Em contraste, as mulheres tiveram melhor controle da PA  e eram mais propensas a não fumar  do que os homens. Os autores concluíram que o controle para prevenção secundária dos FR relacionados com a DIC foi geralmente pior nas mulheres do que nos homens.gaps no diagnóstico e tratamento, além dos desfechos desfavoráveis nas mulheres.A DIC contribui significativamente para a morbimortalidade das mulheres. Embora as taxas de mortalidade, DALYs, prevalência e incidência de DIC tenham diminuído ao longo dos últimos 20 anos, os dados indicam que a mortalidade por DIC nas mulheres jovens entre 35 anos e 54 anos está aumentando. O reconhecimento, a discussão, a educação e o tratamento apropriado da DIC nas mulheres são necessários para reduzir os O reconhecimento de FR tradicionais para a DCV aterosclerótica, bem como de FR emergentes e não tradicionais únicos ou mais frequentes nas mulheres, e de seus diferentes impactos contribui para o novo entendimento dos mecanismos que levam aos piores desfechos nas mulheres . Maior d46 O critério diagnóstico para MINOCA é a presença de IAM sem lesões obstrutivas (> 50%) em qualquer artéria epicárdica e ausência de diagnóstico alternativo.47As apresentações podem ser agudas, como MINOCA, que representa 3% a 15% dos casos, ou estarem relacionadas a casos de INOCA.48Os mecanismos fisiopatológicos envolvidos na MINOCA incluem ruptura de placa coronariana, DEAC, vasoespasmo, disfunção microvascular coronariana e embolismo/trombose. Importante destacar síndromes que mimetizam clinicamente MINOCA, como Takotsubo, miocardite e cardiomiopatia não isquêmica.48 O sexo feminino e tabagismo estão associados à maior incidência de erosão do que de ruptura da placa. As alterações intravasculares podem ser detectadas por ultrassom ou tomografia de coerência óptica (OCT). O Estudo HARP demonstrou que ruptura de placa foi a causa mais frequente de MINOCA, sendo evidenciada em 43% das mulheres com essa condição.49É considerado um termo amplo que envolve ruptura, erosão e nódulos calcificados nas artérias. A ruptura da placa com formação trombótica é a manifestação usual das SCA, mas pode não obstruir a luz do vaso. A erosão é a formação de trombo adjacente à superfície luminal, resultado de apoptose celular e recrutamento de neutrófilos. Os nódulos calcificados usualmente são identificados por imagem intravascular como protrusões na luz do vaso, podendo ocorrer fratura dos nódulos com acúmulo de fibrina na capa fibrosa.inside-out) e outro onde ocorre uma hemorragia intramural com ou sem ruptura da camada íntima (outside-in).48 Os fatores predisponentes são múltiplos, como fatores genéticos, sexo feminino, gestação e terapia com estrógenos, displasia fibromuscular, doenças inflamatórias sistêmicas, além de fatores externos, como estresse emocional, atividade física intensa e uso de drogas estimulantes. Dados de registros internacionais apontam para DEAC como a principal causa de IAM no período perigestacional, ocorrendo mais no terceiro trimestre da gestação e logo após o parto.50A DEAC resulta da formação de um falso lúmen arterial na ausência de doença aterosclerótica significativa. Existem dois mecanismos descritos, um envolvendo laceração da camada íntima e resultando em falso lúmen  e segmento normal proximal e distalmente (tipo 2A) ou estreitamento difuso que se estende até a extremidade distal do vaso (tipo 2B); tipo 3: um segmento curto de estenose (< 20mm) que mimetiza aterosclerose; tipo 4: caracterizado por dissecção com oclusão total abrupta de um segmento coronariano distal. De acordo com as diretrizes internacionais, a DEAC que resulta em obstrução tipo 4 não configura MINOCA, sendo que os demais tipos com lesões não obstrutivas ou não identificadas na angiografia são incluídos nessa classificação.52 Alguns indivíduos têm gatilhos distintos que induzem espasmo, como estresse, hiperventilação, períodos diurnos e ciclos sazonais (clusters), sugerindo alterações intracelulares e pós-receptores relacionados com a hiper-reatividade. O tabagismo e a etnia asiática são descritos como fatores predisponentes, enquanto os demais FR tradicionais não parecem relacionados a maior risco. Alguns estudos sugerem que as mulheres são mais sensíveis a espasmo induzido por acetilcolina que ergonovina.53O espasmo coronariano como causa de isquemia é diagnosticado quando há dor torácica, com ou sem alteração isquêmica no ECG e vasoconstrição > 90% na angiografia, espontânea ou induzida com acetilcolina ou ergonovina. O mecanismo fisiopatológico é uma hiper-reatividade da camada muscular tanto das artérias epicárdicas quanto da microcirculação, embora não completamente elucidado.54A disfunção microvascular coronariana é definida como alteração dessa reserva de fluxo coronariano (RFC) ou o aumento da resistência intramiocárdica na ausência de obstrução de artérias epicárdicas. A avalição da RFC pode ser feita através de medidas não invasivas, com doppler ou termodiluição. A RFC é expressa como a razão entre o fluxo em hiperemia máxima e o fluxo em repouso. Um valor < 2,0 é considerado alterado. O índice de resistência máximo é calculado como o produto da pressão coronariana distal em máxima hiperemia e o tempo do fluxo médio, sendo um valor ≥ 25 indicativo de disfunção da microcirculação. O diagnóstico de doença da microcirculação foi recentemente proposto pelo COVADIS  Group, levando em consideração achados de isquemia, ausência de doença obstrutiva e evidência de função microvascular alterada.54A circulação coronariana microvascular compreende vasos com calibre inferior a 0,5mm de diâmetro, não visualizados na angiografia convencional, embora representem mais de 70% da resistência vascular coronariana.52Do ponto de vista fisiopatogênico, as causas parecem ser diversas e complexas. Dois endótipos são descritos: estrutural e funcional, que muitas vezes coexistem. No aspecto estrutural, existe disfunção endotelial, remodelamento arteriolar e rarefação de capilares, o que leva a uma diminuição do incremento do fluxo coronariano em repouso e aumento da demanda durante esforço. A manifestação funcional está relacionada ao acoplamento cardíaco-coronário ineficiente, resultado do aumento do tônus microvascular durante pico do exercício e durante o repouso, levando a uma maior demanda de oxigênio do miocárdio no cenário de reserva vasodilatadora esgotada saturada.53Vários estudos demonstraram diferenças relacionadas ao sexo na resposta aos testes funcionais, indicando que as mulheres apresentam mais disfunção microvascular coronariana e vasoespasmo epicárdico em comparação com os homens.55 O National Cerebral and Cardiovascular Center Group classifica essa condição como possível quando existe evidência de embolia/trombose em artéria coronária sem aterosclerose, embolização concomitante para outras artérias ou múltiplos locais e/ou na evidência de fatores predisponentes para formação de êmbolos. Várias causas são descritas para fonte de êmbolos, como diretas, paradoxais, iatrogênicas ou mesmo hipercoagulabilidade sistêmica. As fontes diretas incluem trombos formados no apêndice atrial esquerdo (AAE) na vigência de FA, no VE e nas válvulas mitral e aórtica, bem como em segmentos coronarianos proximais. Os êmbolos podem ter origem hematogênica ou de conteúdo tissular outro, como neoplasia e debris valvares. Indivíduos com shunts direito-esquerdo, como a presença de comunicação atrial, forame oval patente, malformações arteriovenosas, podem apresentar embolização paradoxal. O incremento de procedimentos invasivos coronarianos, valvares e de acesso sistêmico também tem sido relacionado com casos de embolização coronariana.55A embolização de artéria epicárdica sem substrato de aterosclerose é uma causa incomum de MINOCA e, usualmente, um diagnóstico de exclusão ou presuntivo.56 Várias apresentações clínicas e fenotípicas são reconhecidas, sendo a típica um perfil de anormalidade de contração ventricular esquerda circunferencial (bi-) que se estende além de um território de suprimento da artéria coronária e parece seguir a inervação simpática cardíaca anatômica. A síndrome afeta predominantemente mulheres na pós-menopausa, sendo, em mais de 70% dos casos, precedida por estresse emocional ou físico. Há um desequilíbrio entre os sexos, com mulheres representando 90% dos casos de síndrome de Takotsubo, responsável por até 10% das mulheres na pós-menopausa com dor torácica aguda. As diferenças de gênero na fisiopatologia permanecem pouco descritas e são uma área para pesquisas futuras. A patogênese da síndrome de Takotsubo é indefinida. Vários mecanismos fisiopatológicos envolvendo isquemia miocárdica , obstrução da via de saída do VE, toxicidade miocárdica por catecolaminas transmitidas pelo sangue, mudança induzida por epinefrina no tráfego de sinal e disfunção do sistema nervoso autônomo (SNA) foram propostos.57A síndrome de Takotsubo é uma entidade cardíaca aguda, com apresentação clínica semelhante à de uma SCA.58A miocardite é uma doença inflamatória do coração que pode ser causada por infecção, ativação do sistema imune ou toxicidade, sendo a causa mais frequente a infecciosa. Uma das apresentações comuns da miocardite é a mimetização de quadro de IAM, com dor precordial e aumento de troponina, usualmente em homens jovens. Os aspectos fisiopatológicos variam de acordo com o agente agressor e a etiologia, mas envolvem degeneração e necrose do cardiomiócito de origem não isquêmica. Em uma série de casos de miocardite por parvovírus B19, a indução de espasmo coronariano epicárdico reproduziu os sintomas, sugerindo que parte da sintomatologia pode ser de origem coronariana e estar relacionada a uma arterite induzida pelo vírus.60 Acomete entre 20% e 40% da população,61 sendo mais frequente nas mulheres. É preciso, entretanto, conhecer as diferenças na apresentação clínica e no diagnóstico e manejo da DIC entre mulheres e homens.60Apenas 5,1% dos pacientes com dor torácica na emergência apresentam SCA e mais da metade mostra etiologia não cardíaca.59A dor torácica é a segunda queixa mais comum nos serviços de emergência, superada apenas pelas causas traumáticas.32 , psicológica , genética (impressão do cromossomo X/cromossomo Y), neuroquímica , organizacional (ação de esteroides no desenvolvimento), ativacional (ação de esteroides na idade adulta), nível de sistemas  e sociocultural .A isquemia desencadeada por estresse mental prediz mortalidade duas vezes maior e a resposta autonômica anormal ao estresse leva ao aumento da reatividade vascular coronariana.63Na história clínica de dor torácica em mulheres, é fundamental incluir, além das manifestações de DCV, os FR clássicos, os FR específicos do sexo feminino e os determinantes psicossociais da saúde, notadamente depressão e estresse. Em geral, a dor isquêmica miocárdica localiza-se no tórax, porém pode ocorrer em qualquer região desde o epigástrio até a mandíbula ou os dentes, entre as omoplatas ou em qualquer dos braços até o pulso e os dedos.versus 7%), irradiação da dor para o braço esquerdo (36% versus 31%), dorso (31% versus 17%) ou pescoço/mandíbula (28% versus 20%) e maior propensão a náusea (34% versus 22%).64As mulheres geralmente apresentam sintomas de dor semelhantes aos dos homens, porém têm maior prevalência de outros sintomas, como palpitações, dispneia, dor maxilar, cervical e no dorso. Um subestudo do ensaio clínico High-STEACS  avaliou a dor torácica de forma prospectiva e com descritores de natureza típica, presença de radiação e de sintomas adicionais mais comuns em mulheres com suspeita da doença. Em comparação aos homens, as mulheres mais frequentemente relataram palpitações como sintoma inicial , mais comuns nas mulheres. Porém, a denominação de dor “atípica” como característica mais feminina deve ser evitada, devendo-se pensar em padronizar a avaliação dos sintomas de isquemia miocárdica na mulher. Além disso, “dor torácica atípica” é um termo problemático, pois, embora tenha a intenção de indicar ausência de sintomas “típicos”, sugere origem não cardíaca, devendo, assim, ser desencorajado o seu uso.59Dispneia pode acompanhar a dor ou desconforto torácico e sintomas menos específicos, como fadiga ou desmaio, náusea, queimação, inquietação ou sensação de morte iminente, podem ocorrer. A duração do desconforto é breve, em geral menos de dez minutos.Uma melhor compreensão dos sintomas femininos de angina e uma estratificação de risco mais adaptada às mulheres permitem o reconhecimento precoce, diagnóstico correto e tratamento ideal, melhorando o prognóstico e a evolução da DIC nas mulheres.66A dor ou desconforto torácico ocorre em mais de 80% de mulheres e homens com SCA, porém as mulheres atribuem mais esse sintoma a condição não cardíaca, como refluxo, estresse ou ansiedade, o que pode prejudicar o diagnóstico.67Nas mulheres, ocorrem mais sintomas adicionais do que nos homens, sendo elas mais propensas a se apresentarem sem dor torácica.“Dor no peito” significa, além disso, dor, pressão, aperto ou desconforto no tórax, ombros, braços, pescoço, costas, parte superior do abdome ou mandíbula, bem como dispneia e fadiga, que devem ser considerados como equivalentes anginosos. Portanto, são sintomas inespecíficos, descritos até mesmo como fraqueza, tontura, diaforese e dispepsia, podendo ocorrer como manifestações de isquemia miocárdica em mulheres.68Por terem as mulheres formas de apresentação da SCA diferentes, elas correm maior risco de diagnóstico incorreto e atraso no diagnóstico e tratamento, o que pode levar a eventos catastróficos, como parada cardíaca. Sabe-se que pacientes com dispneia de origem cardíaca como manifestação única têm risco duas vezes maior de morte súbita.Mulheres com SCA tendem a ser mais idosas e, portanto, têm mais comorbidades do que homens. Apresentam sintomas contínuos, tentam automedicação em casa e informam sintomas semelhantes no passado.67A idade jovem e a ausência de desconforto torácico estão entre os preditores mais fortes de diagnóstico errôneo de SCA e de alta hospitalar de setores de emergência de forma precoce ou inadequada. Mulheres que receberam alta com o diagnóstico de dor torácica inespecífica podem ter duas vezes mais eventos coronarianos subsequentes.12No escore HEART, as considerações clássicas para a estratificação são História, ECG, Idade (Age), Fatores de risco e Troponina, sendo a pontuação a soma dessas cinco variáveis. Como as mulheres têm apresentação clínica variável, alterações ao ECG muitas vezes dúbias e FR específicos do sexo feminino, aquele e muitos outros escores têm potência reduzida para estratificar essas pacientes.68Os escores de risco criados para estratificar pacientes não são perfeitos, notadamente em mulheres, onde fatores emergentes e específicos não são considerados. O escore HEART teve melhor desempenho do que os escores TIMI, GRACE e EDACS na previsão de eventos adversos em pacientes de emergência que apresentaram dor torácica ou equivalentes anginosos, mas 5,7% dos pacientes classificados como baixo risco apresentaram eventos.69No âmbito da cardiologia, conhecer os FR permite ao profissional de saúde exercer estratégias de prevenção que podem, a médio ou longo prazo, alterar prognóstico e desfecho da DCV.70 Relevante se faz abordar FR bem estabelecidos (modificáveis e não modificáveis) e os específicos do sexo feminino. Alguns fatores de impacto na saúde cardiovascular da mulher são sub-reconhecidos, como depressão, violência doméstica e fatores psicossociais, e merecem ser abordados.32 Em geral, os FR manifestam-se conjuntamente, sendo que, quanto mais FR a paciente apresentar, maior é o seu RCV global.29Diante das divergências anatômicas e metabólicas entre os sexos, deve-se, ao estudar grupos de risco, considerar essa distinção. Existem, portanto, diferentes proporções na relevância dos FR, explicitando a importância de estudá-los separadamente.Obesidade/Sobrepeso: A obesidade é uma doença e, para mulheres em idade reprodutiva, é o fator modificável que mais diretamente se associa à presença de HAS. A obesidade na gestação promove maior risco de desenvolver doença hipertensiva da gravidez e/ou diabetes gestacional, que exercem papel importante na mortalidade materno-fetal. No Framingham Heart Study, a obesidade aumentou o risco de doença coronariana em 64% nas mulheres e em 46% nos homens.71• Sedentarismo: É o FR que tem impacto direto na DCV desde a primeira infância.29 Desde os primeiros anos de vida, a mulher tem progressivamente menor participação em atividade física, o que leva a uma cascata de alterações produzidas pela falta de condicionamento físico, com grande relevância clínica no processo de envelhecimento não saudável.67 Em países onde a mulher está sob limitações sociais/religiosas, há piora dos dados cardiovasculares, dificultando a promoção da saúde e promovendo maior prevalência de outros FR, como obesidade.29• Tabagismo: É um hábito que se apresenta de forma epidêmica. Sua prevalência em homens é maior que em mulheres; entretanto, estudos recentes demostram que o RCV associado ao tabagismo é 25% maior em mulheres do que em homens.29 Importante lembrar que o cigarro eletrônico tem se consolidado como prática popular, atingindo internacionalmente cada vez mais mulheres jovens, contribuindo para a formação de lesões endoteliais. Em todas as faixas etárias, exceto dos 30-44 anos, as mulheres têm um risco 25% maior de DIC associada ao tabagismo em comparação aos homens.67• Dislipidemia: É um FR relacionado ao estilo de vida associado a fatores genéticos, mas estudos mostram que há menor atenção à saúde da mulher e às propostas terapêuticas em comparação às do homem. Fator agravante a ser considerado é a menopausa, devido ao aumento relevante nas concentrações de colesterol total e LDL-colesterol e menor efeito protetor do HDL-colesterol, levando assim, a maior predisposição a DCV. As estratégias de tratamento são as bem estabelecidas nas diretrizes, não diferindo das estratégias dos homens. Porém, cabe ressaltar que a regressão do ateroma e o benefício da redução dos níveis de LDL-colesterol parecem maiores em mulheres do que em homens.71• Diabetes mellitus: Mulheres com DM possuem um risco de DIC fatal três vezes maior do que mulheres não diabéticas. O infarto do miocárdio ocorre mais cedo e existe maior mortalidade em mulheres do que em homens com DM. Mulheres diabéticas apresentam risco significativamente maior de desenvolver doença arterial crônica e/ou ICFEp do que homens.67 Considerando o aumento mundial de DM, diretamente relacionado ao aumento da obesidade, mulheres com DM apresentam 44% maior incidência de DIC do que homens.29• Estresse: Saúde mental é tema de grande relevância, principalmente após a pandemia da COVID-19. Dados mostram que a relação entre estresse e RCV é bem estabelecida, onde ansiedade e depressão estão associadas ao aumento de morbimortalidade por DCV.67A ocorrência de violência doméstica, que atinge grande parte da população feminina, é fator desencadeante de estresse crônico importante, levando a sequelas que persistem mesmo após o término do abuso, ocasionando outros transtornos mentais.29• Hipertensão arterial sistêmica: É o FR de maior importância para as mulheres. Hipertensas apresentam maior risco de IAM comparado a homens hipertensos devido à maior velocidade de progressão da doença, maior negligência no diagnóstico e menor aderência ao tratamento.70 Apesar de as diretrizes de HAS serem bem estabelecidas, recentemente tem-se discutido o impacto de se estabelecerem diferentes metas pressóricas por sexo.29• Histórico familiar: Mulheres com menos de 65 anos e história materna de IAM apresentam risco quatro vezes maior de SCA que homens da mesma idade ou mulheres mais velhas.67• Idade: A idade propicia o desenvolvimento de síndrome metabólica, que conceitualmente associa os principais FR, ou seja, DM, HAS, obesidade e dislipidemia,70 e leva ao aumento da resistência insulínica e do estado pró-inflamatório e pró-trombótico, aumentando o risco de DCV.29• Menopausa: O estrogênio é conhecido por seu efeito protetor do endotélio vascular. Na menopausa, a ausência da proteção estrogênica leva a efeitos negativos na função cardiovascular/metabolismo, tais como: alteração da gordura corporal, inflamação vascular, disfunção endotelial, aumento do tônus simpático e maior resistência à insulina.67 Entretanto, a terapia hormonal da menopausa não é indicada para prevenção primária ou secundária de DCV, sendo que seu uso se baseia na reposição em caso de menopausa prematura. Quando existem sintomas vasomotores acentuados, que comprometem a qualidade de vida, a terapia hormonal também pode ser usada, mas há necessidade de avaliação individual de forma interprofissional para segurança e eficácia do tratamento.71• Distúrbios relacionados à gravidez: A mulher está sujeita a complicações como diabetes gestacional e doença hipertensiva da gravidez, o que aumenta em três a quatro vezes o risco de SCA ao longo de toda a sua vida.70 Sendo assim, sua história obstétrica deve ser investigada cuidadosamente e a presença dessas comorbidades dita o acompanhamento contínuo da mulher. Mulheres com pré-eclâmpsia têm um risco 3,7 vezes maior de desenvolver HAS 14 anos mais tarde, 2,16 vezes maior de DIC em 12 anos, 1,8 vez de AVC em 10 anos e 1,78 vez de tromboembolismo venoso em 5 anos. O diabetes gestacional aumenta o risco de DM tipo 2 em sete vezes, o risco de AVC em duas vezes e de infarto do miocárdio em quatro vezes, independentemente de a paciente se tornar ou não diabética.71• Anticoncepcionais hormonais orais: O uso de anticoncepcionais hormonais orais dobra o risco de SCA de etiologia aterotrombótica, sendo potencializado pelo tabagismo, HAS e DM.29• Síndrome do ovário policístico: Esta, por promover excesso de andrógenos e oligoanovulação, leva a maior probabilidade de desenvolver dislipidemia, HAS e DM.29• Distúrbios inflamatórios sistêmicos e autoimunes: A inflamação crônica de patologias como lúpus eritematoso sistêmico e artrite reumatoide leva a disfunção endotelial e maior predisposição a DCV. As mulheres têm mais prevalência de tais distúrbios em relação aos homens. A razão entre mulheres e homens para artrite reumatoide é de 2,5:1 e para lúpus eritematoso sistêmico é de 9:1. O risco de IAM é duas a três vezes maior e de AVC, 50% maior em mulheres com artrite reumatoide. Para lúpus eritematoso sistêmico, o risco de IAM é de 9-50 vezes o da população geral. Os escores de risco habituais subestimam o RCV nas mulheres com artrite reumatoide e lúpus eritematoso sistêmico, sendo sugerido multiplicar por 1,5 o risco absoluto.71• Radiação e Quimioterapia para Tratamento do Câncer de Mama: Radioterapia para tratamento do câncer de mama envolve exposição do coração à radiação ionizante, aumentando o risco de DIC. Esse risco é proporcional à dose, começa poucos anos após a exposição e continua por 20 anos. Existe associação com a presença de FR e é pior na irradiação da mama esquerda comparada à da direita. Pode se manifestar por valvopatias ou cardiomiopatias.69• 69 Importante avaliá-las de forma singular na identificação e controle dos FR, tanto os estabelecidos como os específicos, cruciais no acompanhamento longitudinal da mulher para prevenção de DCV e promoção da saúde.29Pelo menos 20% das mulheres apresentam evento coronariano sem FR para DCV bem estabelecidos.32• Alguns desses fatores, como os distúrbios de ansiedade/depressão e determinantes sociais de saúde, como abuso sexual e violência, privação socioeconômica e baixa escolaridade, são considerados potencializadores de DCV, sendo importante sua investigação na estratificação das mulheres. Ademais, os determinantes sociais de saúde também levam a desfechos negativos, como a inflamação vascular e a disfunção endotelial, principalmente quando associados aos FR clássicos.29• Os distúrbios de ansiedade/depressão aumentam em duas vezes o risco de DIC, por alterarem o eixo hipotálamo-hipofisário-adrenal e SNA, aumentando o estresse oxidativo e a resposta inflamatória, com consequente disfunção endotelial, aterotrombose e DIC. Mulheres jovens têm maior risco de depressão e maior mortalidade após IAM do que homens, além de apresentarem menor declínio nas taxas de morte do que homens.32As recomendações específicas dos fatores de risco cardiovasculares estão descritas no Posicionamento sobre Saúde Cardiovascular da Mulher.72 incluindo suporte circulatório mecânico no choque cardiogênico. Apresentam, portanto, maior probabilidade de óbito intra-hospitalar.Comparadas aos homens, as mulheres, incluindo as mais jovens, têm maior atraso no diagnóstico e tratamento da SCA. Por conseguinte, são menos submetidas a coronariografia e tratamento cirúrgico,72Parece que o menor índice de tratamento cirúrgico nas mulheres se deve à presença de MINOCA, artérias menos calibrosas e doença aterosclerótica menos grave. As mulheres apresentam maior prevalência de outros mecanismos fisiopatológicos da DIC, como cardiomiopatia de Takotsubo (estresse-induzida), disfunção microvascular coronariana, embolia coronariana, vasoespasmo coronariano e DEAC. Porém, esse dado não explica porque as mulheres são menos submetidas a coronariografia e a suporte circulatório no choque cardiogênico.versus 7-17% em homens) e associa-se a risco de desfechos desfavoráveis, como hospitalizações recorrentes, intervenções, pior qualidade de vida, maior mortalidade e cinco a dez vezes mais risco de desenvolver ICFEp. Portanto, seus diagnóstico e prognóstico, assim como a conduta nos casos de INOCA, continuam sendo um desafio para os médicos.73 Apesar de a INOCA se associar a risco de eventos maiores, menos de 50% das pacientes são submetidas a tratamento medicamentoso adequado, além de ser baixa a aderência ao tratamento prescrito e haver subutilização de reabilitação cardíaca.74 Sugere-se que as mulheres são menos submetidas à terapia medicamentosa por não haver evidências sobre seu tratamento, sobretudo quando existe disfunção microvascular coronariana associada.76 Outro fator que limita o consenso sobre seu tratamento é a presença de diferentes fenótipos na doença, ora predominando disfunção microvascular coronariana, ora vasoespasmo coronariano ou ambos. Portanto, as respostas terapêuticas são variadas e incertas.A INOCA predomina em mulheres , têm demonstrado a eficácia do inibidor da enzima conversora da angiotensina (IECA) na RFC e na melhora da angina. Portanto, pacientes hipertensas portadoras de INOCA/MINOCA podem se beneficiar com seu uso.78As estatinas, por seu efeito inibitório sobre o estresse oxidativo e propriedades anti-inflamatórias, atuam na RFC e na disfunção microvascular coronariana, melhorando a tolerância ao esforço e reduzindo isquemia esforço-induzida, principalmente quando associada a diltiazem.77 Em pacientes com disfunção microvascular coronariana, os nitratos de longa ação podem piorar os sintomas, por possível efeito de roubo de fluxo, devendo-se dar preferência aos BCC. Nitratos de curta duração têm eficácia incerta e precisam ser usados repetidas vezes.Drogas antianginosas, como os nitratos, betabloqueadores (BB) e bloqueadores dos canais de cálcio (BCC), são utilizadas na INOCA e MINOCA, porém sua eficácia varia de acordo com o fenótipo predominante, uma vez que podem predominar disfunção microvascular coronariana, vasoespasmo coronariano ou ambos.Os BCC são drogas de primeira escolha em caso de vasoespasmo coronariano, seguido dos nitratos. Em casos de disfunção microvascular coronariana, RFC reduzida e/ou resistência microcirculatória aumentada, sugerindo remodelamento arteriolar, são usados inicialmente BB e, em casos refratários, os BCC. Drogas como a ranolazina e a trimetazidina podem ser consideradas no tratamento da DIC não obstrutiva, principalmente no caso da angina refratária.2) miocárdico. Além disso, melhora a pressão de enchimento do VE e RFC em pacientes com HAS não complicada, possivelmente pela ação do óxido nítrico na microcirculação.78O BB mais utilizado é o nebivolol por sua ação B1 seletiva e efeito vasodilatador via produção de óxido nítrico. Ele tem sido estudado em mulheres com disfunção microvascular coronariana, melhorando a angina e a tolerância ao esforço físico. Seu uso intracoronário melhora a RFC e reduz o consumo de oxigênio . As estatinas atuam na RFC e na disfunção microvascular, melhorando a tolerância ao esforço e reduzindo isquemia esforço-induzida. Como drogas antianginosas, podem-se usar nitratos, BB e BCC; porém, em pacientes com disfunção microvascular coronariana, os nitratos de longa ação podem piorar os sintomas, por possível efeito de roubo de fluxo, devendo-se dar preferência aos BCC. Os BCC são drogas de primeira escolha no vasoespasmo coronariano. Em casos de remodelamento arteriolar , usar inicialmente BB (o mais utilizado é o Nebivolol – ação B1 seletiva e vasodilatação via produção de óxido nítrico) e, em casos refratários, os BCC. Ranolazina e trimetazidina podem ser consideradas na angina refratária.77Baixas doses de antidepressivos tricíclicos podem ajudar na redução dos sintomas em mulheres com estresse mental ou emocional como deflagrador de dor isquêmica.80O ECG das mulheres apresenta diferenças quando comparado ao dos homens, como FC em repouso mais elevada, menor amplitude e maior duração do QRS, maiores intervalos QT e desvios do segmento ST.80Para avaliação da DIC, a posição correta dos eletrodos é fundamental para evitar diagnóstico equivocado. Mamas volumosas ou próteses mamárias geram complexos de baixa voltagem e reduzem a amplitude da onda R nas derivações V1 e V2, simulando área inativa. Em contrapartida, mulheres mastectomizadas geram QRS maiores, simulando hipertrofia ventricular esquerda.80 Outras variáveis, como maior ângulo QRS-T e maior duração do QRS, podem ser consideradas preditores independentes de morte, IC e IAM não fatal.81As anormalidades da repolarização ventricular na menopausa podem ser preditoras importantes de eventos coronarianos e mortalidade por DIC.82O ECG na avaliação de dor torácica em mulheres mantém os critérios diagnósticos descritos para o sexo masculino, exceto para lesão subepicárdica. Nas mulheres, são considerados patológicos valores de elevação do ponto J e segmento ST ≥ 1,5 mm nas derivações precordiais V1 a V3.83O TE é um exame funcional acessível, seguro, reprodutível, de baixo custo, sem radiação, capaz de analisar a resposta cardiovascular ao esforço, propiciando informações clínicas, hemodinâmicas, metabólicas, autonômicas e eletrocardiográficas que auxiliam no diagnóstico, estratificação de risco, avaliação terapêutica e prescrição de exercícios físicos.84A visão multifatorial do TE ampliou sua interpretação ao incluir variáveis prognósticas, sobretudo nas mulheres. É recomendado como método inicial de escolha na avaliação de mulheres sintomáticas de risco intermediário para DIC, com ECG de repouso normal e capazes de se exercitar.versus 70%), assim como a especificidade (72% versus 77%).1 Em mulheres sintomáticas, o valor preditivo positivo da depressão do segmento ST é menor do que nos homens ; no entanto, o valor preditivo negativo é similar (78% versus 81%). Um TE máximo e negativo é útil para afastar a presença de DIC obstrutiva significativa e prever excelente sobrevida livre de eventos.79Em meta-análise de 19 estudos, a sensibilidade média do TE foi menor nas mulheres em comparação aos homens  tendem a não se correlacionar com doença arterial coronariana obstrutiva significativa, ao contrário das alterações ≥ 2,0mm, morfologia horizontal ou descendente, em baixas carga e FC, persistentes por vários minutos na recuperação, sobretudo se acompanhadas de sintomatologia.86A capacidade de atingir ≥ 10 MET é indicador de prevalência muito baixa de isquemia miocárdica significativa, independentemente do gênero.87Entretanto, quando < 7 MET são alcançados, a probabilidade de isquemia é significativamente maior .88 A incapacidade de atingir 5 MET é preditora independente de alto risco, com aumento de três vezes na mortalidade em comparação às mulheres que atingiram > 8 MET.89A capacidade funcional é o maior preditor independente de morte em mulheres, incluindo as assintomáticas.79 A presença de incompetência cronotrópica aumentou em 30% o risco de mortalidade por todas as causas.89 A diminuição da FC no primeiro minuto da recuperação < 12 bpm é outro importante marcador prognóstico, sendo preditor independente de mortalidade por todas as causas.79A incapacidade de alcançar 85% da FC máxima prevista para a idade é preditiva de risco aumentado de mortalidade e DIC obstrutiva em mulheres.89O incremento da PA é menor, principalmente nas mulheres mais jovens, e a não elevação (“platô”) é achado frequente, em geral não relacionado à doença cardíaca, diferentemente do sexo masculino. Sua interpretação deve ser associada às demais variáveis.90As categorias são: baixo risco (ED ≥ 5), risco moderado (ED de −10 a 4) e alto risco (ED ≤ −11).91 Quando baixo, o ED está associado a taxa de mortalidade anual de ≈0,25%, em contraste com ≈ 5% no alto risco, sendo as taxas de mortalidade mais baixas em mulheres. Em coorte de 976 mulheres sintomáticas com TE e angiografia, estenose coronariana ≥ 75% esteve presente em 19%, 35% e 89% daquelas com ED de baixo, moderado e alto risco, respectivamente.92 Mulheres com ED intermediário devem ser encaminhadas para estratificação de risco adicional com imagem sob estresse.79 Essa é uma ferramenta valiosa para prever o risco de eventos  entre as mulheres, mas pode ser menos eficaz naquelas ≥ 75 anos.93Os escores podem ser úteis para aperfeiçoar o diagnóstico de DIC, sendo o Escore de Duke o mais utilizado, com valor diagnóstico e prognóstico, e calculado pelo tempo de exercício (protocolo Bruce) – 5x (desnível do segmento ST) – 4x .A Em situações com maior probabilidade de DCV, doenças ortopédicas, obesidade e sedentarismo, a associação com cintilografia de perfusão miocárdica (CPM) pode ser útil quando comparada com resultados de testes não conclusivos.A avaliação individualizada e as terapias anti-isquêmicas direcionadas após o TE devem ter por base a carga alcançada, os sintomas e o grau de anormalidade do exame.A escolha do método diagnóstico deve ser baseada no perfil clínico da paciente, na probabilidade pré-teste de DCV, nos sintomas, no ECG de repouso e na presença/ausência de condições adequadas para realização de um TE com boa qualidade técnica. A análise deve ser multifatorial para otimizar a abordagem clínica e terapêutica.94O TCPE permite avaliação não invasiva dos sistemas cardiovascular, respiratório e periférico de maneira integrada ao esforço. Embora esteja bem estabelecido na avaliação clínica de pacientes com IC, sua indicação não está bem consolidada pelas diretrizes na investigação da DIC. Em artigo de revisão sobre aplicabilidade do TCPE na DIC, estabeleceram-se as seguintes indicações:Moderada a alta probabilidade pré-teste para DICAcréscimo na acurácia diagnóstica da DIC, quando alguma alteração clínica ou eletrocardiográfica estiver presente, dificultando o diagnóstico pelo TEÁrea isquêmica miocárdica de grande magnitude, comprometendo a função ventricular esquerdaAvaliação evolutiva após RVM mecânica ou cirúrgica.2 < 60% do predito para idade e sexo] e sinais e sintomas de isquemia miocárdica em baixa carga (VO2 < 15 ml.kg-1.min-1) estratificam os pacientes como de alto risco para eventos cardiovasculares.95Além da avaliação dos critérios clínicos, hemodinâmicos e eletrocardiográficos, o TCPE gera informações adicionais dos parâmetros ventilatórios na análise da isquemia, quantifica a capacidade funcional com precisão e estratifica o prognóstico. A baixa capacidade funcional  analyzed the trends of AMI mortality according to sex, Brazilian geographical regions, and place of residence , stabilization in the Northern region, and increase in the Northeastern region. The authors have predicted that the trend will persist up to 2030. Those variations might have been related to improvements in social development, in CVRFs, and in access to the health system and its coverage, as well as to the better coding discrimination in the certificates of death in the Northern and Northeastern regions.versus 334 men). Women had significantly lower primary angioplasty rates  and significantly higher in-hospital mortality rates  than men.38The VICTIM registry has assessed 878 patients diagnosed with ST-elevation myocardial infarction (STEMI) admitted to one public and three private hospitals performing primary angioplasty in the Sergipe state from December 2014 to June 2018. Of those patients, 33.4% were women. Of the total, only 53.3% underwent myocardial reperfusion , most frequently had SAH , DM , and dyslipidemia , and less frequently underwent percutaneous coronary intervention (PCI) through the radial access  than men. The in-hospital mortality rate was significantly higher in women as compared to men , and the female sex was an independent predictor of in-hospital mortality .39Another prospective single-center study conducted in the city of Recife, Pernambuco state, on 709 consecutive patients with STEMI  from February 2018 to February 2019 has reported that women were older , but a slight increase in men, 1.4   per 100 000 women and 2534  per 100 000 men .31The agn region C.31 The .4; 3.3) C.31 The standardized IHD incidence rate per 100 000 inhabitants from 1990 to 2019 had a percent reduction in women, -11.8 , and in men, -11.8   events  in Brazil in 2019. In all age groups, the IHD incidence was higher in men than in women . In 20194.7; -9) D.40The AMI prevalence in women is lower in the younger than in the older age groups, but there has been a worrisome trend in recent years, considering that the proportion attributable to young patients (35-54 years) increased from 27% to 32% in the past two decades, and that increase was higher among young women (21% to 31%).Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study, performed from 2008 to 2012, included prospectively 2690 patients with AMI, aged 18-55 years, from 103 hospitals, at the proportion of 2 women to 1 man. Of the 2374 patients submitted to coronary angiography, women were 5-fold more likely to have MINOCA than men . Women with significant coronary obstruction more often were menopausal  or had a gestational diabetes history . It is worth noting that mortalities from MINOCA at 1 and 12 months were similar to those from coronary obstruction at the same times.30The prevalence of MINOCA is higher in women. The VIRGO  in women and of 2116.5  in men . The secty rates B. The Fety rates .From 1990 to 2019, there was a higher percent reduction in the standardized DALYs rate due to IHD per 100 000 inhabitants in women, -52.7 , than in men, -47.3   Study, 202 072 individuals aged 35-70 years, from urban and rural communities in 27 countries, from January 2005 to May 2019, were followed up for a mean of 9.5 (IQR: 8.5–10.9) years. Women had a lower CVRF burden according to two different traditional risk scores (INTERHEART and Framingham). Primary prevention strategies  were most frequent in women, whose incidence of CVD was lower. However, secondary prevention treatments for IHD were less frequent in women than in men. The differences between women and men with or without previous CVD and IHD regarding treatments and results were more significant in low/middle-income countries, with few differences in high-income countries.42In the PURE (28The IHD attributable RFs are shown in versus 1.76 (1.19-2.60) in men]; depression [OR 3.09  in women versus 1.77 (1.15-2.73) in men]; SAH [OR 2.87  in women versus 2.19 (1.65-2.90) in men]; current smoking [OR 3.28  in women versus 3.28 (2.65-4.07) in men]; family history of early myocardial infarction [OR 1.48  in women versus 2.42 (1.71-3.41) in men]; low family-income [OR 1.79  in women versus 1.35 (0.82-2.23) in men]; hypercholesterolemia [OR 1.02  in women versus 2.16 (1.49-3.15) in men]. There were significant differences between the sexes in RF associations: SAH, depression, DM, current smoking, and family history of DM showed stronger associations with AMI in young women, while hypercholesterolemia showed a stronger association in young men.43In the case-control study derived from the VIRGO study, with 2264 patients with AMI (18-55 years) and 2264 paired controls, 3122 (68.9%) were women, with a median age of 48 (44-52) years. The following seven RFs represent collectively the larger part of the total risk of AMI in women (83.9%) and men (85.1%): DM , LDL-cholesterol [OR 0.57 ], and glucose [OR 0.78 ], or to be physically active [OR 0.74 ] or non-obese [OR 0.82 ]. However, women showed better BP control [OR 1.31 ] and were more likely to not smoke [OR 1.93 ] than men. The authors have concluded that control for secondary prevention of RFs related to IHD was usually worse in women than in men.Ischemic heart disease contributes significantly to women’s morbidity and mortality. Although the IHD mortality, DALYs, prevalence and incidence rates have decreased over the past 20 years, data indicate that mortality from IHD in women aged 35-54 years is increasing. Women’s IHD recognition, discussion, education, and appropriate treatment are necessary to reduce the IHD diagnosis and treatment gaps, and the unfavorable IHD outcomes in women.The recognition of traditional RFs for atherosclerotic CVD, as well as emerging and nontraditional RFs that are specific to or more frequent in women, in addition to their different impacts contribute to the new understanding of the mechanisms that lead to worse outcomes in women . More de46 The diagnostic criterion for MINOCA is the presence of AMI with no obstructive lesion (> 50%) in any epicardial artery and lack of alternative diagnosis.47The presentations of atherosclerotic CVD can be acute, such as MINOCA, which represents 3% to 15% of the cases, or can be related to cases of INOCA.48The pathophysiological mechanisms involved in MINOCA include coronary plaque rupture, SCAD, vasospasm, coronary microvascular dysfunction, and embolism/thrombosis. The syndromes that clinically mimic MINOCA, such as Takotsubo, myocarditis, and nonischemic cardiomyopathy are worth mentioning.48 Female sex and smoking are associated with a higher incidence of erosion than that of plaque rupture. The intravascular changes can be detected by use of ultrasound or optic coherence tomography (OCT). The HARP Study has shown that plaque rupture is the most frequent cause of MINOCA, evidenced in 43% of the women with that condition.49Plaque rupture is a comprehensive term that comprises rupture, erosion, and calcified nodules in the coronary arteries. Plaque rupture with thrombus formation is the usual manifestation of ACS, but it might not obstruct the vessel lumen. Erosion is the formation of a thrombus adjacent to the luminal surface, resulting from cell apoptosis and recruitment of neutrophiles. The calcified nodules are usually identified by use of intravascular imaging as protrusions into the coronary lumen, and they can undergo fracture with fibrin accumulation in the fibrous cap.inside-out), while the other involves intramural hemorrhage with or without rupture of the intimal layer (outside-in).48 There are multiple predisposing factors, such as genetic factors, female sex, pregnancy and estrogen therapy, fibromuscular dysplasia, systemic inflammatory diseases, in addition to external factors, such as emotional stress, intense physical activity, and use of stimulant drugs. Data from international registries point to SCAD as the major cause of AMI in the perigestational period, occurring more frequently in the third gestational trimester and right after delivery.50Spontaneous coronary artery dissection results from the formation of a false arterial lumen in the absence of significant atherosclerotic disease. Two mechanisms have been described, one involving laceration of the intimal layer and resulting in false lumen  and normal proximal and distal segments (type 2A) or diffuse narrowing extending to the distal extremity of the vessel (type 2B); type 3: short segment of stenosis (< 20mm) that mimics atherosclerosis; type 4: characterized by dissection with total abrupt occlusion of a distal coronary segment. According to international guidelines, type 4 SCAD does not constitute MINOCA, while the other types with nonobstructive lesions or lesions not identified on angiography are included in that classification.52 Some individuals have distinct vasospasm triggers, such as stress, hyperventilation, daily periods and seasonal cycles (clusters), suggesting intracellular and post-receptor changes related to hyperreactivity. Smoking and Asian ethnicity are reported as predisposing factors, while the other traditional RFs seem not related to an increased risk. Some studies have suggested that women are more susceptible to spasms induced by acetylcholine than by ergonovine.53Coronary artery spasm as a cause of ischemia is diagnosed in the presence of chest pain with or without ischemic change on ECG and vasoconstriction > 90% on angiography. It can occur spontaneously or be induced by acetylcholine or ergonovine. The pathophysiological mechanism is hyperreactivity of the muscle layer of epicardial arteries and microcirculation, but still not completely clarified.54Coronary microvascular dysfunction is defined as a change in the coronary flow reserve (CFR) or an increase in intramyocardial resistance in the absence of obstruction of epicardial coronary arteries. The CFR can be assessed by using noninvasive measures, with doppler or thermodilution techniques. The CFR is expressed as the ratio between coronary flows at maximal hyperemia and at baseline condition, and a value <2.0 is considered abnormal. The maximum index of microcirculatory resistance is calculated by multiplying the distal coronary pressure during maximal hyperemia by the mean hyperemic transit time, and a value ≥ 25 indicates dysfunction of the microcirculation. The diagnosis of microvascular angina has been recently proposed by the COVADIS  Group in the presence of suggestive findings of ischemia, absence of obstructive coronary disease, and evidence of microvascular dysfunction.54The coronary microvascular circulation comprises vessels with diameter < 0.5mm, not visualized on conventional angiography, although they represent more than 70% of the coronary vascular resistance.52From the pathophysiological viewpoint, the causes seem diverse and complex. Two endotypes have been described, structural and functional, and they often coexist. In the structural aspect, there is endothelial dysfunction, arteriolar remodeling, and capillary rarefaction, which lead to a reduction in the increment of coronary flow at rest and an increase in demand during exertion. The functional manifestation relates to the inefficient cardiac-coronary coupling, resulting from the increased microvascular tonus during peak exercise and at rest, leading to a higher myocardial oxygen demand in the scenario of exhausted coronary vasodilator reserve.53Several studies have shown sex-related differences in response to functional tests, indicating that women more often have coronary microvascular dysfunction and epicardial vasospasm as compared to men.55The National Cerebral and Cardiovascular Center Group classifies this condition as possible when there is evidence of embolism/thrombosis in a coronary artery without atherosclerosis, concomitant embolism to other arteries or multiple sites, and/or in the presence of predisposing factors to embolism. Several causes of embolism, such as direct, paradoxical, and iatrogenic sources, or even systemic hypercoagulability, have been described. The direct sources include thrombi formed in the left atrial appendage (LAA), when AF is present, and in the left ventricle, mitral and aortic valves, and proximal coronary segments. The emboli can have an hematogenic origin or originate from any other tissue content, such as neoplasms and valvular debris. Individuals with right-left shunts, such as atrial communication, patent foramen ovale, and arteriovenous malformations, can have paradoxical embolism. In addition, the increased number of invasive coronary and valvular procedures, as well as of those with systemic access, has been related to cases of coronary embolism.55Epicardial coronary artery embolism without atherosclerotic substrate is an uncommon cause of MINOCA, usually diagnosed by exclusion or presumptively.56Several clinical and phenotypic presentations are known, the typical one being a circumferential left (bi-) ventricular contraction abnormality profile that extends beyond a coronary artery supply territory and seems to follow the anatomical cardiac sympathetic innervation. The syndrome affects predominantly postmenopausal women, being preceded, in more than 70% of the cases, by emotional or physical stress. Regarding incidence, there is an imbalance between sexes, with women representing 90% of the cases of Takotsubo syndrome, responsible for up to 10% of the postmenopausal women with acute chest pain. The gender differences in the pathophysiology of the syndrome remain underreported, thus requiring further investigation. The Takotsubo syndrome pathogenesis remains undefined. Several pathophysiological mechanisms have been proposed, such as myocardial ischemia , LV outflow tract obstruction, blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomic nervous system (ANS) dysfunction.57Takotsubo syndrome is an acute cardiac entity, with clinical presentation similar to that of ACS.58Myocarditis is an inflammatory heart disease that can be caused by an infection, most frequently, or by immune system activation or toxicity. One common presentation of myocarditis is mimicking AMI findings, such as chest pain and increased troponin levels, usually in young men. The pathophysiological aspects vary according to the causing agent and etiology but involve nonischemic degeneration and necrosis of the cardiomyocyte. In a series of cases of myocarditis due to parvovirus B19, the induction of epicardial coronary spasm reproduced the symptoms, suggesting that part of the symptoms can have a coronary origin and be related to a virus-induced arteritis.60 It affects 20% to 40% of the population,61 being more frequent in women. Thus, the differences in IHD clinical presentation, diagnosis, and management between men and women should be known.60Only 5.1% of the patients with chest pain in emergency services have ACS, and more than half of those patients have chest pain of noncardiac etiology.59Chest pain is the second most common complaint in emergency services, after traumatic causes.32 , psychological , genetic (X chromosome imprinting/Y chromosome), neurochemical , organizational (steroid action in development), activational (steroid action in adulthood), systems level , and sociocultural  aspects.Ischemia triggered by mental stress predicts a twice higher mortality, and an abnormal autonomic response to stress leads to an increase in coronary vascular reactivity.63In addition to the CVD manifestations, the clinical history of chest pain in women should include the classic RFs, the female sex-specific RFs, and the psychosocial determinants of health, notably depression and stress. Usually, the myocardial ischemic pain is reported in the chest, but can occur in any region from the epigastrium to the jaw or teeth, between the scapulae, or in an arm radiating to the wrist or fingers.versus 7%), pain radiation to the left arm (36% versus 31%), dorsum (31% versus 17%) or neck/jaw (28% versus 20%), and higher propensity to nausea (34% versus 22%).64Women usually have pain characteristics similar to those of men, but have a higher prevalence of other symptoms, such as palpitations, dyspnea, maxillary, cervical, and dorsal pain. A substudy of the High-STEACS clinical trial  has assessed chest pain prospectively and with descriptors of typical nature, presence of radiation, and additional symptoms more common in women with suspected ACS. As compared to men, women more frequently reported palpitations as the initial symptom , more common in women. However, the denomination “atypical” pain as a female characteristic should be avoided, and the assessment of women’s myocardial ischemia symptoms should be standardized. In addition, “atypical chest pain” is a questionable term because, despite the intention to indicate absence of “typical” symptoms, it suggests a noncardiac origin, and, thus, its use is discouraged.59Dyspnea can accompany pain or chest discomfort, and less specific symptoms, such as fatigue or fainting, nausea, burning, restlessness, or imminent death sensation, can occur. The discomfort duration is short, usually less than 10 minutes.A better understanding of the female anginal symptoms and a more appropriate risk stratification for women enable early recognition, correct diagnosis, and ideal treatment, improving the IHD prognosis and course in women.66Chest pain or discomfort occurs in more than 80% of women and men with ACS; women, however, more often attribute this symptom to noncardiac conditions, such as reflow, stress, or anxiety, hindering the diagnosis.67Women have more additional symptoms than men do, and are more likely to present without chest pain.In addition, “chest pain” means pain, pressure, crushing or discomfort in the thorax, shoulders, arms, neck, dorsum, upper part of the abdomen, jaw, as well as dyspnea and fatigue, which should be considered anginal equivalents. Thus, these are unspecific symptoms, even described as weakness, dizziness, perspiration, and dyspepsia, and can be manifestations of myocardial ischemia in women.68The ACS presentation forms are different in women, who, thus, are at a higher risk for misdiagnosis, as well as for diagnosis and treatment delays, which can lead to catastrophic events, such as cardiac arrest. Patients with dyspnea of cardiac origin as the single manifestation are known to be at a twice higher risk for sudden death.Women with ACS are more likely older, having, thus, more comorbidities than men. In addition, women have continuous symptoms, try self-medication, and usually report similar symptoms in the past.67Young age and absence of chest discomfort are some of the strongest predictors of ACS misdiagnosis and early or inappropriate discharge from the emergency sector. Women discharged with the diagnosis of unspecific chest pain can have twice more subsequent coronary events.12In the HEART score, the classical considerations for stratification are History, ECG, Age, Risk factors, and Troponin, and the score is the addition of those five variables. Women have variable clinical presentations, frequent dubious ECG changes, and female sex-specific RFs, thus, that and other scores have a reduced power to stratify them.68The risk scores created to stratify patients are not perfect, notably for women, whose emerging and specific RFs are not considered. The HEART score performed better than the TIMI, GRACE, and EDACS scores to predict adverse events in emergency patients presenting with chest pain or anginal equivalents, but 5.7% of the patients classified as low risk had events.69Knowing the RFs enables the health professional to use preventive strategies that can, in the medium and long run, change the CVD prognosis and outcome.70 It is worth noting that the well-established RFs (modifiable and nonmodifiable), as well as the female sex-specific RFs, should be considered. Some factors of impact on women’s cardiovascular health, such as depression, domestic violence, and psychosocial factors, are underrecognized and should be assessed.32 Usually, the RFs manifest together, and the higher the number of RFs, the higher the patient’s overall CVR.29The anatomical and metabolic differences between sexes should be considered when studying the risk groups. The relevance of the RFs differs, therefore, studying them separately is important.Obesity/overweight: Obesity is a disease, and, for women at reproductive age, it is the modifiable RF more directly associated with the presence of SAH. Obesity in pregnancy increases the risk of developing hypertensive disease of pregnancy and/or gestational diabetes, which play an important role in maternal and fetal mortality. In the Framingham Heart Study, obesity increased the risk of coronary disease by 64% in women and by 46% in men.71• Sedentary lifestyle: This is the RF with direct impact on CVD since early childhood.29 From the first years of life, women participate less and less in physical activity, which leads to a cascade of changes produced by the lack of physical conditioning, with significant clinical relevance in the unhealthy aging process.67 In countries where women live under social/religious restrictions, the cardiovascular data are worse, hindering health promotion and increasing the prevalence of other RFs, such as obesity.29• Smoking: Is an epidemic habit. Its prevalence in men is higher than in women; however, recent studies have shown that the CVR associated with smoking is 25% higher in women than in men.29 It is worth noting that electronic cigarettes have been consolidated as a popular practice, reaching more and more young women worldwide, contributing to the formation of endothelial lesions. In all age groups, except for the 30-44 year age group, women are at a 25% higher risk of IHD associated with smoking as compared to men.67• Dyslipidemia: Is a RF related to lifestyle and genetic factors, but studies have shown lower attention to women’s health and therapeutic proposals as compared to those of men. An aggravating factor to consider is menopause, because of the relevant increase in total cholesterol and LDL-cholesterol concentrations and smaller protective effect of HDL-cholesterol, thus leading to a higher predisposition to CVD. Treatment strategies are well established in the guidelines, not differing from those for men. However, it is worth emphasizing that atheroma regression and benefit from LDL-cholesterol reduction seem higher in women than in men.71• Diabetes mellitus: Women with DM are at a three-fold higher risk of fatal IHD than women without DM. Myocardial infarction occurs earlier and has higher mortality in women than in men with DM. Women with DM have a significantly higher risk of developing chronic arterial disease and/or HFpEF than men.67 Considering the worldwide increase in DM, directly related to the increase in obesity, women with DM have a 44% higher incidence of IHD than men.29• Stress: Mental health is a subject of great relevance, mainly after the COVID-19 pandemic. The relation between stress and CVR has been well established, and anxiety and depression are associated with an increase in morbidity and mortality from CVD.67Domestic violence, which affects a large part of the female population, is the triggering factor of significant chronic stress, leading to sequelae that persist after the end of the abuse, causing other mental disorders.29• Systemic arterial hypertension: Is the major RF for women. Hypertensive women are at higher risk of AMI as compared to hypertensive men because of the higher velocity of disease progression, higher negligence in diagnosis, and lower adherence to treatment.70 Although the SAH guidelines have been well established, the impact of establishing different BP goals according to sex has been recently discussed.29• Family history: Women under the age of 65 years with maternal history of AMI have a 4-fold higher risk of ACS than men at the same age or older women.67• Age: Age propitiates the development of metabolic syndrome, which conceptually associates with the major RFs – DM, SAH, obesity, and dyslipidemia70 and increases the insulin resistance as well as the pro-inflammatory and prothrombotic status, compounding the risk for CVD.29• Menopause: Estrogen is well known for its protective effect on the vascular endothelium. In menopause, the absence of estrogen protection has negative effects on the cardiovascular function/metabolism, such as: body fat change, vascular inflammation, endothelial dysfunction, sympathetic tonus increase, and higher insulin resistance.67 However, hormone therapy in menopause is not indicated for the primary or secondary prevention of CVD, its use being indicated for replacement in early menopause. In addition, in the presence of important vasomotor symptoms that hinder the quality of life, hormone therapy can be used, but individual interprofessional assessment is required to ensure treatment safety and efficacy.71• Pregnancy-related disorders: Women are subject to complications, such as gestational diabetes and gestational hypertensive disease, which increase the risk of ACS by three to four times throughout life.70 Thus, their obstetric history should be carefully investigated, and the presence of those comorbidities indicates the need for continuous follow-up. Women with preeclampsia are at a 3.7-fold higher risk of developing SAH 14 years later, 2.16-fold higher risk of developing IHD in 12 years, 1.8-fold higher risk for stroke in 10 years, and 1.78-fold higher risk for venous thromboembolism in 5 years. Gestational diabetes increases the risk of type 2 DM by 7 times, the risk of stroke by 2 times, and of myocardial infarction by 4 times, independently of the patient becoming diabetic or not.71• Oral contraceptive hormones: The use of oral contraceptive hormones doubles the risk of ACS of atherothrombotic etiology, which is compounded by smoking, SAH, and DM.29• Polycystic ovary syndrome: By promoting excessive androgens and oligoanovulation, polycystic ovary syndrome (POS) increases the likelihood of developing dyslipidemia, SAH, and DM.29• Systemic inflammatory and autoimmune disorders: The chronic inflammation of some diseases, such as systemic lupus erythematosus and rheumatoid arthritis, leads to endothelial dysfunction and higher predisposition to CVD. Women have a higher prevalence of such disorders as compared to men. The women to men ratio for rheumatoid arthritis is 2.5:1, and for systemic lupus erythematosus, 9:1. For women with rheumatoid arthritis, the risk of AMI is 2-3 times higher, and of stroke, 50% higher. In systemic lupus erythematosus, the risk of AMI is 9-50 times that of the general population. The usual risk scores underestimate the CVR in women with rheumatoid arthritis and systemic lupus erythematosus, suggesting multiplying by 1.5 the absolute risk.71• Radiation and chemotherapy to treat breast cancer: Radiation therapy for breast cancer involves heart exposure to ionizing radiation, increasing the risk of IHD. This risk is proportional to the dose, begins a few years after exposure, and continues for 20 years. It is associated with the presence of RFs and is higher in the left breast radiation as compared to the right one. It can manifest as valvular heart disease or cardiomyopathies.69• 69 Women should be assessed in a particular way to identify and control RFs, both the well-established and specific ones, whose knowledge is crucial for the prevention of CVD and health promotion in women’s longitudinal follow-up.29At least 20% of women have a coronary event with no well-established RF for CVD.32• Some RFs, such as anxiety/depression disorders, and social determinants of health, such as sexual abuse and violence, socioeconomic deprivation, and low education level, are considered CVD enhancers, and their investigation in women’s risk stratification is important. In addition, the social determinants of health lead to negative outcomes, such as vascular inflammation and endothelial dysfunction, mainly when associated with the classic RFs.29• Anxiety/depression disorders increase by two times the risk of IHD, because they change the hypothalamus-pituitary-adrenal axis and ANS, increasing oxidative stress and inflammatory response, with consequent endothelial dysfunction, atherothrombosis, and IHD. Young women have a higher risk for depression and higher mortality after AMI than men, as well as a lower decline in death rates than men.32The specific recommendations on the CVRFs are described in the Position Statement on Women’s Cardiovascular Heath.72 including mechanical circulatory support in cardiogenic shock, and their probability of in-hospital death is higher.As compared to men, women, including the younger ones, have a greater delay in ACS diagnosis and treatment. Therefore, they less often undergo coronary angiography and surgical treatment,72The lower surgical treatment rate in women seems to be due to the presence of MINOCA, small-caliber arteries, and less severe atherosclerotic disease. Women have a higher prevalence of other pathophysiological mechanisms of IHD, such as Takotsubo cardiomyopathy (stress-induced), coronary microvascular dysfunction, coronary embolism, coronary vasospasm, and SCAD. However, this does not explain why women less often undergo coronary angiography and circulatory support in cardiogenic shock.versus 7-17% in men) and associates with the risk of unfavorable outcomes, such as recurrent hospitalizations, interventions, worse quality of life, higher mortality, and 5- to 10-times higher risk of developing HFpEF. Thus, its diagnosis and prognosis, as well as its management, continue to be a challenge for physicians.73 Although INOCA associates with the risk for major events, less than 50% of the female patients undergo appropriate drug treatment, adherence to prescribed treatment is low, and cardiac rehabilitation is underused.74 It has been suggested that women less often undergo drug therapy because of the lack of evidence about their treatment, mainly in the presence of associated coronary microvascular dysfunction.76 Another factor limiting the consensus on INOCA treatment is the presence of different phenotypes of INOCA, either predominating coronary microvascular dysfunction, or coronary vasospasm, or both. Thus, the therapeutic responses are varied and uncertain.INOCA is more common in women , have shown the efficacy of the angiotensin-converting enzyme inhibitor (ACEI) in CFR and in anginal improvement. Thus, hypertensive female patients with INOCA/MINOCA can benefit from its use.78Because of their inhibitory effect on oxidative stress and anti-inflammatory properties, statins act on CFR and coronary microvascular dysfunction, improving tolerance to exertion and reducing exertion-induced ischemia, mainly when associated with diltiazem.77 In patients with coronary microvascular dysfunction, long-acting nitrates can worsen symptoms, because of the possible coronary steal phenomenon, thus, CCB should be preferred. Short-acting nitrates have uncertain efficacy and require repeated doses.Antianginal drugs, such as nitrates, beta-blockers (BB), and calcium-channel blockers (CCB), are used in INOCA and MINOCA, but their efficacy varies according to the predominant phenotype .For coronary vasospasm, CCBs are first-choice drugs, being followed by nitrates. For coronary microvascular dysfunction, reduced CFR and/or increased microcirculatory resistance, suggesting arteriolar remodeling, BBs are used initially, and, for refractory cases, CCBs. Ranolazine and trimetazidine can be considered in the treatment of nonobstructive IHD, mainly for refractory angina.2). In addition, it improves the LV filling pressure and CFR in patients with uncomplicated SAH, possibly because of the nitric oxide action on microcirculation.78Nebivolol is the most often used BB because of its B1-selective action and vasodilator effect via the nitric oxide production. It has been studied in women with coronary microvascular dysfunction, improving angina and tolerance to physical exertion. Its intracoronary infusion improves CFR and reduces myocardial oxygen consumption  should be preferred. Statins act on CFR and coronary microvascular dysfunction, improving tolerance to exertion and reducing exertion-induced ischemia. Nitrates, BBs, and CCBs can be used as antianginal drugs; however, in patients with coronary microvascular dysfunction, long-acting nitrates can worsen symptoms, because of the possible coronary steal phenomenon, thus, CCB should be preferred. For coronary vasospasm, CCBs are first-choice drugs. In cases of arteriolar remodeling , BBs should be initially used (nebivolol is the most often used BB because of its B1-selective action and vasodilator effect via nitric oxide production) and, in refractory cases, the CCBs. Ranolazine and trimetazidine can be considered for refractory angina.77Low doses of tricyclic antidepressants can help reduce symptoms in women with mental or emotional stress as a trigger of ischemic pain.80Women’s ECG have differences as compared to that of men, such as higher HR at rest, QRS with smaller amplitude and longer duration, longer QT intervals, and ST-segment changes.80For IHD assessment, the correct position of electrodes is fundamental to avoid misdiagnosis. Large breasts or breast prostheses generate low-voltage complex and reduce the R-wave amplitude in the V1 and V2 leads, simulating inactive area. In addition, women who underwent mastectomy have QRS widening, simulating LV hypertrophy.80 Other variables, such as greater QRS-T angle and longer QRS duration, can be considered independent predictors of death, HF, and nonfatal AMI.81Postmenopausal ventricular repolarization abnormalities can be important predictors of coronary events and mortality from IHD.82On women’s chest pain assessment, the ECG maintains the diagnostic criteria described in the male sex, except for the subepicardial lesion. In women, J-point elevation and ST-segment values ≥ 1.5mm in the precordial V1 to V3 leads are considered pathological.83The ET is an accessible, safe, reproducible, low-cost, radiation-free functional test that can analyze the cardiovascular response to exertion, providing clinical, hemodynamic, metabolic, autonomic, and electrocardiographic information to support the diagnosis, risk stratification, therapeutic assessment, and physical exercise prescription.84The multifactorial view of the ET has widened its interpretation by including prognostic variables, mainly in women. It is recommended as the first-choice method to assess symptomatic women at intermediate risk for IHD, with normal ECG at rest, and who can exercise.versus 70%), as was its specificity (72% versus 77%).1 In symptomatic women, the positive predictive value of the ST-segment depression was lower than in men ; however, its negative predictive value was similar (78% versus 81%). A maximal and negative ET is useful to rule out the presence of significant obstructive IHD and to predict excellent event-free survival.79In a meta-analysis of 19 studies, the mean sensitivity of ET was lower in women than in men , tend to not correlate with significant obstructive IHD, differently from changes ≥ 2.0mm, with horizontal or descending morphology, low loads and HR, persisting for several minutes in recovery, mainly if accompanied by symptoms.86The ability to reach ≥ 10 MET indicates very low prevalence of significant myocardial ischemia, independently of the gender.87However, when < 7 MET are reached, the probability of ischemia is significantly higher (0.4% versus 7.1%).88 The inability to reach 5 MET is an independent predictor of high risk, with a three-fold increase in mortality as compared to women reaching > 8 MET.89Physical functioning is the major independent predictor of death in women, including the asymptomatic ones.79 The presence of chronotropic incompetence increased by 30% the risk of all-cause mortality.89 A HR reduction in the first minute of recovery < 12 bpm is another important prognostic marker, being an independent predictor of all-cause mortality.79The inability to reach 85% of the predicted maximal HR for age predicts increased risk for mortality and obstructive IHD in women.89The BP increase is smaller, mainly in younger women, and non-elevation (“plateau”) is a frequent finding, usually not related to cardiac disease, which differs in the male sex. Its interpretation should be associated with other variables.90The score categories are: low risk (DTS ≥ 5), moderate risk (DTS ranging from -10 to 4), and high risk (DTS ≤ -11).91 Low DTS is associated with an annual mortality rate of ≈ 0.25% as compared to ≈5% for high risk, and the mortality rates are lower in women. In a cohort of 976 symptomatic women with ET and angiography, coronary stenosis ≥ 75% was present in 19%, 35%, and 89% of those with low-, moderate-, and high-risk DTS, respectively.92 Women with intermediate DTS should be referred for additional risk stratification with stress imaging.79 The DTS is a valuable tool to predict the risk of events  in women, but might be less effective in those aged ≥ 75 years.93Scores can be useful to improve the IHD diagnosis, the Duke treadmill score being the most frequently used, with diagnostic and prognostic value. The DTS is calculated as follows: exercise duration (Bruce protocol) – 5x (ST-segment deviation) – 4x .In situations with high likelihood of CVD, orthopedic diseases, obesity, and sedentary lifestyle, the association with myocardial perfusion scintigraphy (MPS) can be useful in the presence of nonconclusive test results.Individualized assessment and directed anti-ischemic therapies after ET should be based on the load reached, the symptoms, and the test’s grade of abnormality.The choice of the diagnostic method should be based on the patient’s clinical profile, pretest probability of CVD, symptoms, ECG findings at rest, and presence/absence of proper conditions to perform good-quality ET. The analysis should be multifactorial to optimize the clinical management and therapy.94The CPET provides noninvasive and integrated assessment of the cardiovascular, respiratory, and peripheral systems on exertion. Although CPET has been well-established for the clinical assessment of patients with HF, its indication for IHD investigation has not been consolidated in the guidelines. In a review article on the applicability of CPET in IHD, the following indications have been established:Moderate to high pretest probability of IHDTo increase the IHD diagnostic accuracy in the presence of clinical or electrocardiographic changes that hinder the diagnosis on ETLarge myocardial ischemic area that hinders LV functionAssessment of the evolution after mechanical or surgical MRV.2 < 60% of the predicted value for age and sex] and myocardial ischemia signs and symptoms at low load (VO2 < 15ml.kg-1.min-1) stratify patients as at high risk for cardiovascular events.95In addition to the assessment of clinical, hemodynamic, and electrocardiographic criteria, the CPET provides additional information on the ventilatory parameters in the analysis of ischemia, quantifies physical functioning precisely, and stratifies the prognosis. Low physical functioning [VO96In patients with macrovascular IHD and reversible perfusion defects on myocardial perfusion imaging, the assessment of CPET variables, as compared to those of ET, increased sensitivity from 46% to 87% and specificity from 66% to 74%.97 This is particularly important, because, in the myocardial ischemic cascade, changes in the LV diastolic and systolic functions occur before the ischemic changes on ECG.98The CPET identifies the beginning of LV dysfunction induced by ischemia during exertion, and, thus, can improve diagnostic accuracy, mainly in the female sex, reducing the rate of false-positive ET.2 curve and ascension, oxygen pulse, and cardiac work rate (VO2 variation/load variation in Watt), the latter exclusively on cycle ergometer. A linear VO2 increase in parallel with a workload of 10 mL/min/watt under physiological conditions is expected.99The major variables obtained during CPET that evidence LV dysfunction triggered by IHD are: VO99 In the presence of obstructive IHD, the reduced systolic volume causes a compensatory increase in HR that impacts both the cardiac work rate and oxygen pulse. A reduction in the VO2/load curve progression and a decline in or absence of progressive increase in oxygen pulse are seen  because of the limitation of ET in that population. Normal VO2 and oxygen pulse curves could rule out significant coronary stenosis as the cause of LBBB.99Recent studies have assessed the role of CPET in coronary microvascular dysfunction, particularly in women, whose ET is less accurate. A study in postmenopausal women with typical angina and nonobstructive IHD on angiography has shown that ischemia on scintigraphy was associated with LV systolic dysfunction after stress, suggesting microvascular IHD. Considering the CPET potential to infer LV dysfunction in a noninvasive and cost-effective way, the CPET implementation, as compared to that of ET, in the microvascular IHD investigation increases the diagnostic potential.2 , are worth noting.99 The CPET is a valuable tool in daily clinical practice, but further investigations should be directed to a more accurate assessment of its role in IHD diagnosis, prognosis, and treatment efficacy evaluation, mainly in women.Some limitations of CPET, such as restriction of the cardiac work rate assessment to only cycle ergometer, lower sensitivity in single-vessel IHD, and associated clinical conditions that can interfere with VO104 This chapter addresses several cardiovascular imaging modalities, with important information on the assessment of women’s myocardial ischemia symptoms, defining diagnostic performance, female sex-related peculiarities, as well as advantages and limitations of each method  at rest or using several modalities of stress  is useful to detect myocardial ischemia in women.106 In addition, TTE is useful to identify other causes of chest pain, such as pericarditis, aortic dissection, and pulmonary embolism.79Findings compatible with myocardial ischemia include: abnormalities of the segmental LV wall contractility at rest, altered contractile response during stress, reduced microvascular perfusion assessed on contrast echocardiography and/or impairment of the flow of epicardial arteries analyzed by use of Doppler.106 The presence of regional contractile abnormalities can be chronic or acute, an issue better solved if previous studies are available for comparison.106 It is worth noting that the segments with changes due to IHD should be contiguous and correspond to the territories of coronary arteries, because segmental changes can be caused by several conditions other than IHD.106The TTE at rest is recommended for all female patients with suspicion of IHD to assess segmental contractility, as well as the global LV systolic function by use of LV ejection fraction (LVEF).106The LV segmental contractility is assessed visually based on wall thickening during the systole. More recent quantitative methods have been applied, such as the left ventricular global longitudinal strain (LVGLS) analysis. Subendocardial muscle fibers, longitudinally oriented, are more vulnerable to ischemia, and the LVGLS assessment at rest has shown to be more sensitive for the detection of segmental abnormalities as compared to the analysis of wall contractility in ACS.79 When compared to ET, SEC has higher sensitivity and specificity in women.79 A meta-analysis of 14 studies, assessing the sensitivity and specificity of SEC with physical stress for the detection of women’s IHD, has reported values of 79%  and 83% , respectively.107The preferred modality for ischemia assessment on SEC is physical exertion, especially with supine bicycle. In addition to providing additional prognostic data, such as physical functioning, that method comprises more physiological data for ischemia assessment.79Vasodilators, such as dipyridamole or adenosine, have slightly lower sensitivity in women.108In a comparison between SEC with dobutamine and ET for the detection of IHD in symptomatic women, the former showed higher accuracy in women with chest pain, with sensitivity of 70.4% versus 53.7% and specificity of 94.6% versus 73.6% to detect coronary stenosis >50%. The higher accuracy of SEC persisted after excluding the patients who reached HR higher than 85% of that predicted for age before ischemia induction.109 The results are different when comparing the diagnostic performance of SEC between men and women.8 The literature shows that the performance in women is similar or inferior to that in men.109 When compared to SPECT for the investigation of myocardial ischemia, SEC has higher specificity, because it has no false positive due to breast attenuation.8The SEC with dobutamine is preferably indicated for patients who cannot exercise.104 particularly in women, because of the breast tissue. The use of echocardiographic contrast media has become an important tool to properly visualize the endocardium of all LV segments. Thus, in the presence of two or more contiguous segments with limited technical quality, the use of those agents is indicated.110The SEC can be limited by the impossibility of obtaining appropriate acoustic windows in the peak of stress,1In pregnancy, echocardiography with physical or pharmacological stress is considered safe and avoids exposure to radiation; dobutamine and dipyridamole are considered category B. Nuclear medicine techniques should be avoided.111Atherothrombosis is a systemic arterial disease that involves mainly the intima layer of large- and medium-caliber arteries . The VUS is an excellent method for the morphological assessment and severity classification of carotid obstructive disease, abdominal aortic aneurysm, and PAD. In addition, VUS is an important tool to diagnose atherothrombosis in other arterial territories affected simultaneously with the coronary territory, being particularly appealing because of its low cost, wide availability, and noninvasive character.114 The plaque identification and atherosclerotic burden measurement in the carotid and/or peripheral arterial territory can be useful to reclassify the risk, as shown in recent studies.115The analysis of the characteristics and volume of the plaque on 3D seems to significantly improve the atherosclerotic burden estimation and identification of more vulnerable plaques, and can play a role in women’s risk stratification, because women seem to have a higher atherosclerotic burden than men.116 In addition, the use of contrast-enhanced VUS is an attractive tool to assess neovascularization in carotid plaques, because women have more signs of neovascularization.117The detection of subclinical disease and information on the characteristics of the atherosclerotic plaque and burden are useful in some scenarios of women’s atherosclerotic disease. The presence or absence of plaque can re-stratify patients beyond the traditional RFs, while the atherosclerotic burden quantification can personalize even more the risk assessment.118 Recently, the assessment of carotid and femoral atherosclerosis has been suggested to improve the early detection of disease, and the presence of a femoral, rather than a carotid, plaque is more indicative of IHD. In women, the combined femoral and carotid plaque areas have higher sensitivity and can aid in the identification of false-positive stress tests.119Peripheral arterial disease is prevalent in men and women, and its subclinical form is more common in women. Patients with previous preeclampsia, gestational hypertension, and placental insufficiency are three times more likely to develop PAD.120Women have a lower prevalence of abdominal aortic aneurysm and at a more advanced age. However, women are four-times more likely to undergo rupture as compared to men at the same age and have worse results after emergency surgery. The sensitivity of the physical examination is 29% in abdominal aortic aneurysms with diameter of 3-3.9cm; 50% in those with diameter of 4-4.9cm; and 75% in those with diameter over 5cm, justifying that a large part of diagnosis is incidental. Thus, in selected women, screening is indicated: age of 55-75 years; family history of abdominal aortic aneurysm; heavy smokers; and/or history of stroke.Particularities of women’s IHD make noninvasive stratification an important step in the management of those patients. The findings of women’s tests differ from those of men’s regarding anatomy, distribution and extension of the lesions, as well as clinical repercussion. In this scenario, assessment of coronary calcification and obstruction grade on CCTA is important to define the patients’ treatment and follow-up.121Anatomically, epicardial coronary arteries in women are smaller than those in men, even after adjusting for age, body mass, and body surface area. In addition, the vasomotor tonus of those arteries is lower, determining higher coronary flow, which, associated with the reduced size of the arteries, can result in different phenotypes of IHD between the sexes.122 and CCTA, as compared to invasive methods, has excellent accuracy to detect obstructive IHD and characterize plaques.123 The CCTA sensitivity and specificity values to detect IHD are shown in 8Despite the anatomical differences, the diagnostic potential of IHD by use of CCTA is similar between the sexes,125 with high risk for coronary events as compared to that of the general population, being particularly higher in women < 75 years.127 Analyses of the CONFIRM registry that assessed 24 775 patients (12 128 women) have shown an increased mortality risk of patients with obstructive and nonobstructive IHD. In women, the risk increased with the increase in the number of vessels with obstructive disease  as compared to men.128 The presence of atherosclerotic plaques at high risk for thrombosis  is a predictor of cardiac events in women.129In addition, coronary calcification assessed by use of coronary artery calcium score (CAC) differs between the sexes. For patients of the same race and age, CAC quantification is lower in women. Data have consistently shown that the prevalence and severity of coronary calcification increase with age and the male sex, women showing lower prevalence and severity.130The presentation pattern of women’s IHD is predominantly nonobstructive, and the atherosclerotic burden of nonobstructive IHD (defined as stenosis < 50%) affects women more markedly,131New technologies incorporate functional assessment to CCTA, which enables adding the anatomical evaluation to the ischemia investigation. The FFR by computed tomography can increase the diagnostic accuracy in detecting obstructive IHD as compared to CCTA alone. Although promising, the clinical applicability of FFR is reserved to a few centers that provide the technology.132The SCAD, a more frequent complication in women than in men, can be well assessed by CCTA. Pregnant patients have high mortality associated with SCAD. The indication for CCTA in those patients should be individualized, considering the clinical context, and the invasive strategy might be necessary when the clinical suspicion is very relevant.132 The CMRI is a method of high spatial resolution that enables assessment of the morphology, function, and ischemia, in addition to tissue characterization with high accuracy. The fact that it does not have visual limitation due to interposition of the breast tissue, obesity, pulmonary disease, or breast prostheses enables a more detailed assessment of the female heart. In addition, by not using ionizing radiation, it is an innocuous option to the female breast tissue, especially useful for younger women. The female heart has specific morphological characteristics, being relatively smaller than the male heart, with smaller volume, mass and parietal thickness, and can be more accurately assessed by CMRI.134Cardiac magnetic resonance imaging has contributed to a better understanding of the pathophysiological phenomena, structural changes, diagnosis, and prognostic assessment of women’s CVD.137Myocardial perfusion assessment with gadolinium enhancement under pharmacological stress has high sensitivity and has been well-established in both sexes since studies, such as MR-Impact, MR-Impact II, and CE-MARC, have shown high sensitivity to detect ischemia as compared to SPECT, being recommended mainly for the female population.138 and CMRI is useful to identify the subendocardial perfusion defect under pharmacological stress in that population.139 In addition, tissue characterization by use of late enhancement and T1 and T2 maps provides better assessment of the effects of cardiovascular events on the myocardium, more specifically atherothrombotic disease. Thus, myocardial infarction, MINOCA, Takotsubo, and viral or autoimmune myocarditis can be well defined with that methodology.138In women, coronary microvascular dysfunction is a mechanism responsible for the presence of INOCA,in vivo and can differentiate ischemic from nonischemic injury, enabling the differential diagnosis between myocardial infarction and inflammatory conditions. The quantification of the fibrotic involvement of the transmural thickness is determinant to assess the myocardial viability grade and the prognosis.140The late enhancement technique has been established as the best way to identify fibrosis 131Contraindications to the use of CMRI are restricted to situations incompatible with the magnetic field, in addition to the limitations to the use of gadolinium in patients with kidney failure (creatinine clearance below 30 mL/min/BS), because of the risk of nephrogenic systemic fibrosis, and in pregnant patients, because of the risk of fetal exposure to the paramagnetic agent.137 The advance of new myocardial perfusion sequences, quantitative perfusion assessment software, movement correction techniques, and higher availability of parametric maps are perspectives that contribute to the increasing use of the methodology. Therefore, CMRI plays a unique promising role in women’s heart assessment, aggregating a greater amount of diagnostic and prognostic information.132The CMRI enables the diagnostic differentiation of cardiovascular events causing anginal symptoms and ischemia in women, thus it is the preferred method for the functional assessment of that group of patients.141 National and international guidelines emphasize, for IHD assessment, the use of MPS, which can be performed in all patients, regardless of renal function, presence of arrhythmias, obesity, or intracardiac devices.142 The techniques used are SPECT and PET.Nuclear imaging can assess the entire spectrum of IHD, from epicardial obstructive IHD to coronary microvascular dysfunction.143Its is the most commonly used noninvasive imaging technique to assess women at intermediate-high risk for IHD and stable ischemic symptoms.141For over three decades, MPS by the SPECT technique has been widely used in clinical practice because of its wide availability and extensive body of literature that supports its value in the IHD diagnosis and risk stratification.143 The total perfusion deficit and extension can be calculated, being objective parameters of ischemic burden and myocardium at risk that facilitate the definition of therapeutic management and follow-up.142One single test provides information on the extension and severity of perfusion abnormalities, myocardial wall motility, LVEF, and intraventricular synchronism at rest and under stress.142The ET should be chosen for the stress phase when the patient can exercise properly (reach ≥ 5 MET), because it provides important additional diagnostic and prognostic information. For patients who cannot exercise properly, pharmacological stress with a vasodilator  should be chosen. Another option of pharmacological stress is the positive inotropic drug use, such as dobutamine, either sensitized or not with atropine. Women with LBBB and intracardiac devices should always undergo pharmacological stress with a vasodilator, regardless of their physical functioning to avoid imaging artifacts.104The prognostic value of a normal MPS in women is excellent, including elderly women and several racial and ethnic groups, with 99% event-free survival, similarly to that in men, as shown in a large meta-analysis.143 False-positive results can occur because of artifact due to breast attenuation in the anterior LV wall, in addition to possible lower accuracy in women with small hearts.The major disadvantage of MPS is exposure to radiation, although more recent technologies, such as new solid-state CZT gamma-camera detectors, improvement in radionuclides, protocols, and individualized doses of the radiotracer, have reduced that exposure.104 In addition to higher accuracy, PET enables the quantification of myocardial blood flow in milliliters per minute per gram of tissue, and the calculation of CFR, an important prognostic marker of CVR.143 Thus, PET improves the detection of severe multivessel obstructive IHD with balanced ischemia pattern and coronary microvascular dysfunction, which are difficult to identify with SPECT because of its technical limitations.142 Another advantage of PET is the lower exposure to radiation (effective dose of 2-3mSv versus 9-12mSv with SPECT), because it uses short-duration radionuclides, which makes it particularly useful for women of reproductive age.79 Studies with PET have shown that coronary microvascular dysfunction is prevalent in women and men , and regardless of sex, CFR proved to be a powerful incremental predictor of events, a trend maintained even in patients with no coronary calcification.104The new CZT gamma-cameras have shown promising results in the CFR assessment with SPECT, increasing the availability of coronary microvascular dysfunction assessment in regions where the PET technique is not available.142Although less available, the MPS with PET has an excellent diagnostic performance, with sensitivity of 90-92% and specificity of 81-88% to detect angiographically significant stenoses.144In addition, abnormal CFR is associated with diastolic dysfunction. A recent study with 64.7% of women without obstructive IHD has shown an independent association of CFR reduction (defined as < 2) and diastolic dysfunction, and an increase in cardiovascular events or HFpEF. Those findings suggest a pathophysiological relation between coronary microvascular dysfunction and HFpEF.142Imaging protocols with hybrid equipment (PET/CT or SPECT/CT) add the ability of assessing anatomical changes with CAC quantification, thus increasing the test’s sensitivity for IHD diagnosis with a single test.23 Women have more symptoms and worse quality of life as compared to men. There are innumerous mechanisms associated with the differences between sexes in AF, but it is worth noting that the IHD, more commonly observed in the male sex, can contribute to the higher incidence of AF in the group.The age-adjusted incidence of AF is 1.5- to 2-times higher in men, but the risk of AF throughout life is similar in both sexes because of the longer life expectancy of the female sex. At the age of 85 years, the differences in prevalence are mild.24When the rhythm control strategy with AAD is analyzed, women have more adverse events. The increase in the baseline QT interval can affect tolerance to the use of AAD, especially of class III, requiring more careful monitoring in that group of patients. Regarding the results of catheter ablation in the female sex, observational studies have shown that women less often undergo ablation and at a later time, with worse procedural outcome as compared to men.“Atrial Fibrillation Better Care (ABC) pathway” causes significant reductions in the risk of stroke, myocardial infarction, hospitalization, and mortality, with no difference related to sex.145 The ABC strategy comprises three aspects: ‘A’ - to prevent stroke; ‘B’ - to provide better control of symptoms with focus on the patient; and ‘C’ - to prevent and/or treat the CVRFs and comorbidities that contribute to the AF appearance.146Innumerous studies have shown that AF treatment based on 147 Physical activity is another important predictor in women: the higher the exercise intensity, the lower the incidence of AF. Women who practice vigorous physical activity have a 28% reduction in the incidence of AF.148 In a large prospective study with 30 034 women, menopause did not significantly relate to the incidence of AF, while the use of estrogen monotherapy was associated with an increase in its risk, suggesting a pathophysiological relation between estrogen exposure and arrhythmia in women.149 As compared to nulliparity, multiparity was associated with a linear increase in the risk of AF in a large cohort of initially healthy women. The repeated exposure to hormonal, metabolic, and physiological changes during pregnancy can predispose to AF later in life.150Regarding ‘C’, women with AF have a higher prevalence of SAH, obesity, depression, HFpEF, and valvular heart disease as the cause of AF.151 Antithrombotic therapy with oral anticoagulants is indicated for patients with AF and CHA2DS2VASc ≥ 2, but the decision should be individualized.147 Patients with indication of continuous use of anticoagulants require risk assessment of bleeding caused by those drugs before initiating their use. A high risk of bleeding does not contraindicate anticoagulation and indicates the need for higher control of RFs. There are innumerous scores for that purpose, and the HAS-BLED score has been recommended in the last guidelines on AF. Individuals with a score ≥ 3 are considered at higher risk of bleeding.147 Clinical studies on anticoagulation in AF have shown higher safety in the use of DOACs – dabigatran, rivaroxaban, apixaban, edoxaban – in relation to warfarin. The percutaneous occlusion of the LAA has been indicated when there is absolute contraindication to the use of anticoagulants, as occurs in intracranial bleeding of irreversible cause. The surgical occlusion or exclusion of the LAA can be considered when the patient with AF has indication for cardiac surgery.153Regarding ‘A’, women with AF have a higher incidence of stroke than men, and women’s stroke is more severe and causes higher permanent disability, and that is the reason why anticoagulation, based on risk scores, is essential in both sexes.151 Catheter ablation with electrical isolation of the pulmonary veins is currently indicated for the treatment of paroxysmal/persistent AF in patients without graft vascular disease, those with AF-induced tachycardiomyopathy, as well as in those with graft vascular disease and HF to reduce hospitalization and mortality.147Regarding ‘B’, women with AF have more symptoms, worse quality of life, and higher mortality, justifying the need for a proper and early approach regarding HR control with AADs or ablation of the atrioventricular node and, when possible, reversion to sinus rhythm with ECV, chemical cardioversion, or catheter ablation.146 In patients with ACS, the incidence of AF varies from 2% to 23%, being associated with higher in-hospital mortality in the first month and first year, and higher frequency of stroke, with no evidence of sex-related differences. These outcomes are more frequent in individuals who develop AF during hospitalization due to ACS, as compared to those who already had AF previously to the acute ischemic event.154 The hemodynamic instability attributed to AF in the presence of ACS should be treated with synchronized ECV. In stable patients, HR control can be obtained with the intravenous use of BB or CCB. The administration of amiodarone is a proper alternative to control ventricular frequency and can favor the reversion to sinus rhythm. Propafenone should not be used in patients with AF and ACS for reversion to sinus rhythm.147Association between AF and ICM is less frequent in women than in men, but the high risks of that association have no sex-related differences.153 Dual antiplatelet therapy (anticoagulant + antiplatelet) should be maintained for at least 6 months in patients with AF and chronic coronary syndrome and for 12 months in those with AF and ACS.155Recent studies on revascularization in men and women with AF and ACS or chronic coronary syndrome undergoing angioplasty and stent implantation have shown that, in patients with indication for anticoagulation due to AF, the use of dual antiplatelet therapy  is recommended for at least one week for those at lower risk of thrombosis and/or higher risk of bleeding, and can last for four weeks, with acetylsalicylic acid suspension after that period.In acute or chronic ICM associated with AF, there is no evidence that investigation or treatment strategies differ in men and women; thus, those strategies should be equally provided to prevent the innumerous and severe complications related to those diseases.156 Despite all medical advances, sudden cardiac death remains the major cause of cardiovascular death in patients with ICM,157 including acute and chronic IHD and different ventricular arrhythmias.158Women’s representation in clinical trials has increased in recent decades, but is still very low, mainly in cardiology, including studies on arrhythmias.159 In addition, the underrepresentation of women as subjects in clinical trials contributes to the paucity of scientific evidence to develop sex-dependent methods for sudden cardiac death prevention. Despite the scarcity of data on women’s arrhythmia mechanisms, parameters that promote ventricular arrhythmias, such as fibrosis, cardiac hypertrophy, abnormalities of calcium signaling, and electrophysiological changes, differ according to age and sex, stressing the need for further research.159 In the major studies of primary prevention, the percentage of women undergoing ICD implantation has ranged from 8% to 29%, indicating the low representation of women, which hinders the assessment of the procedure’s real benefit on that population. In addition, the individual analyses of those studies on the mortality benefit are not appropriate, because those studies had not been designed with statistical power to answer the question.160A recent review on ventricular arrhythmias in acute myocardial ischemia, focused on the role of age and sex, has concluded that the mechanisms responsible for sex-dependent differences in susceptibility to malignant ventricular arrhythmias during acute ischemia are still misunderstood.Regardless of the sex, the prevention and treatment of ventricular arrhythmias of all etiologies involve the control of modifiable RFs, use of AADs, catheter ablation, and ICD use, the last one as primary or secondary prevention.et al. assessed more than 13 000 patients of the GWTG-HF program (American Heart Association’s Get With the Guidelines – Heart Failure) and concluded that the ICD therapy rates differed in black men, black women, and white women, being 27%, 38%, and 44% lower, respectively, as compared to that of white men.161 The analysis of the GWTG-HF program in 2012 showed an improvement in those rates and the end of the differences, drawing attention to the need to maintain attention and continuing education around the world.162 However, a huge difference persists between the patients who, according to the guidelines, need and those who receive an ICD, especially women.The ICD therapy for patients with indication is another important point. In 2007, Hernandes 163 A subanalysis of the MADIT-CRT study has concluded that women have a lower incidence of VT/VF, suggesting that, in women, non-arrhythmic sudden death is higher than in men. In addition, the presence of appropriate shock therapy by the ICD was a predictor of death, mainly in women.164 In 2022, a study on assessment of ventricular arrhythmias in women  was conducted in individuals with ICD. After pairing for the major comorbidities, indications, concomitant therapy, and demographic data, women remained with a lower risk profile for sustained ventricular arrhythmia than men, except for the subgroup of women with CRT and those with LVEF < 30%.165Regarding individuals with an ICD, there are differences between women and men related to outcomes other than mortality.167 However, in VT ablation studies, the percentage of women in the population with IHD is low (7-13%). The less often indication for invasive procedures, less often induction of sustained VT, and the smaller number of appropriate shocks are factors that might contribute to that reduced percentage.166Catheter ablation is an effective therapy to control ventricular arrhythmias, being recommended in several scenarios in the guidelines.167Those studies were performed in ischemic and nonischemic patients, and ischemia was present in 36% to 69% of the patients studied.173Clinical studies, such as MIRACLE, COMPANION, CARE-HF, MADIT-CRT, RAFT, REVERSE, and MIRACLE, have shown that CRT improves the outcomes in symptomatic patients with reduced LVEF and prolonged QRS duration. Although in those studies the percentage of women has ranged from 17% to 33%, an even greater benefit was demonstrated in women as compared to men .160,167Tversus off, and 33% of the patients were women.173 Woo et al. have analyzed eight pre-specified subgroups in the MIRACLE study, and, when assessing response according to sex, they observed that women receiving CRT had longer times for the first hospitalization or death as compared to the control group, deriving more benefit from CRT than men.174The MIRACLE study has assessed 453 patients with NYHA functional class III or IV HF, LVEF ≤ 35% and QRS duration ≥ 130ms, comparing CRT on versus ICD and showed a favorable HF-free survival curve in the CRT-D group, with a reduction in the composite outcome of HF and death of 34% and 25%, respectively. In the multivariate analysis in both studies for the outcome death and HF, a marked benefit was observed in women. In the MADIT-CRT study, women receiving CRT-D had a more favorable survival curve than women and men not receiving ICD or even men who received CRT-D. There was a 72% reduction in the risk of death when comparing women with CRT-D versus ICD, but there was no difference in the survival curves of men with CRT-D versus ICD.175The MADIT-CRT study has assessed 1820 patients with NYHA functional class I or II HF (25% were women), LVEF ≤ 30%, and QRS duration ≥ 130ms. The RAFT study has assessed 1798 patients with NYHA functional class II or III HF , LVEF ≤ 30%, and QRS duration ≥ 120ms or ≥ 200ms when stimulated by previous pacemaker. Both studies compared cardiac resynchronization therapy with defibrillator (CRT-D) versus ICD in women were found and no difference between men.176A meta-analysis of the MADIT-CRT, RAFT, and REVERSE studies with 4076 patients, 22% of the female sex, has shown, in the analysis of the outcome HF and death, favorable curves for CRT in women. In addition, for the outcome death, the same results with favorable curve to CRT 2, undergoing CRT-D implantation, with randomly assigned atrioventricular interval as either fixed at 120ms, echocardiography-determined, or SmartDelay algorithm-programmed. The composite outcome was death and HF hospitalization and >15% reduction in the end-diastolic diameter at 6 months. The response of both sexes to CRT was similar, and the sex disparities in CRT outcomes were explained by the sex differences in HF substrate, treatment, and comorbidities.177A study has assessed 741 patients aged 66 ± 11 years, 33% women, 78% white, LVEF 28 ± 9%, 58% ICM, 75% with LBBB and LV end-systolic volume of 65 ± 30mL/met al. have investigated to which extent best CRT outcomes could be explained by differences in the baseline characteristics between the sexes. They assessed 1058 patients (24% women) receiving CRT with primary endpoint of all-cause mortality. Women less often had ICM and less fibrosis, more LBBB, and more mechanical dyssynchrony. Considering the baseline characteristics, the survival response was similar in both sexes. The best result found in women was due to the lower ICM rate and smaller scars.179Beela 21 A study with 75 079 patients with NYHA functional class III or IV HF, reduced LVEF (≤ 35%), and QRS duration ≥ 120ms, comparing CRT between women and men, has shown benefit in both sexes. The same occurred in the presence of LBBB, although a more attenuated mortality curve was observed in women. In the group without LBBB, women had a better mortality curve than men for even wider QRS complexes (150-159ms).180 Women with LBBB responded better than men with narrower QRS complexes and a possible reason might be that women have smaller LV mass and narrower QRS complexes than men (approximately 10ms shorter). Thus, any absolute QRS prolongation in women can correspond to a higher grade of dyssynchrony.181The presence of LBBB is a determinant factor of better response to CRT and the same benefit is not observed when LBBB is absent.182 The major differences between women and men receiving CRT are shown in Women have twice the number of major complications related to CRT procedures. This difference can be significant between women and men receiving CRT, the most common complication being pneumothorax/hemothorax. Infection requiring reoperation was more frequent in women. The best predictor of complications in women was a small body mass index (BMI).183Although therapies, such as ICD and CRT, are beneficial regarding mortality, women receive fewer devices than men . This di2DS2VASc score is recommended to identify patients at low risk (CHA2DS2VASc score = 0 for men and 1 for women) who should not receive oral anticoagulants. Antithrombotic therapy with oral anticoagulants is indicated for patients with AF and CHA2DS2VASc ≥ 2, but the decision should be individualized.147For stroke risk assessment, the CHAThe recommendations relative to management of arrhythmias are the same for both sexes.Specific circumstances of women’s biological cycle add risks that contribute to the different course of atherosclerosis and thrombotic disease in women and remain under investigation. This chapter addresses specific topics of reproductive age, such as pregnancy, contraception, infertility, and APS. The APS, prevalent in the female sex, is considered a potential trigger of atherothrombotic disease in women.184Ischemic heart disease is not common during pregnancy. According to data from the World Health Organization, the AMI rate is 3.34 events per 100 000 pregnancies, non-ST-elevation myocardial infarction (NSTEMI) being the most frequent.185 has reported on the most frequent mechanisms related to myocardial infarction during pregnancy and puerperium  and pulmonary thromboembolism (PTE), regardless of the composition or administration route.189 Adolescent or young women often have to face pregnancy without prior counseling about conception planning. Pregnancy, either programmed or not, is a “window of opportunity” to propitiate contraception, for both healthy women and those with some type of comorbidity.190In recent decades, there has been an increasing number of young women with CVD, corroborating North-American registries that have shown an 11.5% prevalence of CVD in women aged 20-29 years.191 The population assigned female at birth receives no reproductive counseling throughout life, although the use of contraceptives might relieve the ovulatory cycle-related symptoms and reduce undesired pregnancy.192In this scenario, it is worth mentioning that self-identification as transgender occurs in 0.69% of the Brazilian population.193, oral and patch, progestin-only contraceptives (POCs), and long-acting contraceptives . The copper intrauterine device is a non-hormonal contraceptive. The failure and efficacy of contraceptives can be calculated by the Pearl index, which considers the number of pregnancies/100 women/year193.194 The effect is due to the action of estrogen, when passing through the liver, to promote changes in the hemostatic pathways that lead to a procoagulant and prothrombotic state. The same does not occur with the POCs, except for medroxyprogesterone acetate, which changes the glycidic and lipidic profiles.195Contraceptives in general and the CHC can be associated with atherothrombotic disease. A meta-analysis has shown that the use of CHC represents a risk 1.7-fold higher of myocardial infarction and ischemic stroke.196  significantly increases the risk of thromboembolism in women on hormonal contraceptives. According to the 2015 WHO-MEC eligibility criteria, in such situations, the CHCs, the patches and ring with combined contraceptives, and the injectable combined contraceptives are contraindicated, while the POCs, the subdermal etonogestrel implant, and the levonorgestrel-releasing intrauterine system can be indicated196 .197In conclusion, although CHCs are the contraceptives most often used worldwide, we emphasize that the subdermal implants and the levonorgestrel-releasing intrauterine system have a smaller impact on atherothrombotic disease. It is worth noting that the selection of a contraceptive method should consider the patient’s intrinsic factors, as well as the safety and efficacy of the contraceptive, in addition to involving a multidisciplinary approach throughout a woman’s reproductive life.193The use of contraceptives in thrombotic and atherothrombotic disease should be guided by the presence or absence of RFs for CVD, in which the following are contraindicated: CHCs, patches and ring with combined contraceptives, and injectable combined contraceptives. In such situations, POCs, subdermal etonogestrel implant, and levonorgestrel-releasing intrauterine system can be indicated.198Infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse. It is estimated to affect 8-12% of couples at reproductive age worldwide. Secondary infertility is the most common type of female infertility, often due to reproductive tract infections. The three major factors influencing the spontaneous likelihood of conception are the time of unwanted non-conception, female partner’s age, and causes related to diseases.199The factors that affect both sexes’ fertility are hypogonadotropic hypogonadism, hyperprolactinemia, ciliary function disorders, cystic fibrosis, infections, systemic diseases, and lifestyle-related factors, while premature ovarian insufficiency, POS, endometriosis, uterine myomas, and endometrial polyps are important causes of female infertility.200In addition to those comorbidities, infertility is often associated with mental disorders, such as depression and anxiety, and has a strong relation to CVD because of the impact of androgenic hormones on CVRFs and on metabolic syndrome.201 comparing groups of women of the same age range, with or without infertility, has shown higher frequency of proatherosclerotic metabolic disorders, mainly obesity and increased total cholesterol, LDL-cholesterol, and triglycerides, in infertile women. In that meta-analysis, an isolated study202 has shown an increase in IHD, stroke, and HF in infertile women in a follow-up of at least 5 years as compared to healthy women .A meta-analysis,203Women with POS are at a higher risk for obesity, SAH, glucose intolerance, dyslipidemia, and sleep obstructive apnea. Regarding metabolic disorders, obesity is present in 50% of the cases. Insulin resistance, present in 60-95% of the cases, causes glucose intolerance in 31-35% and type 2 DM in 7.5-20% of those women. However, the lipid profile changes characterized by low HDL-cholesterol levels, high triglyceride plasma levels, and increased LDL-cholesterol levels are the most frequent metabolic change in POS.th year of the CARDIA prospective study, the analysis of the images of coronary artery calcifications and measures of the carotid intima-media thickness (IMT) has shown a high risk for subclinical CVD  in the presence of hyperandrogenism and anovulation in POS.204 These data have been emphasized in the meta-analysis by Zhang et al., who have reported an increased risk for myocardial infarction, IHD, and stroke  in women with POS.205On the 20206 In endometriosis, there is a chronic inflammatory process mediated by substances, such as intercellular adhesion molecule (ICAM-1), interleukin 1 and 6 (IL-1 and IL-6), tumor necrosis factor (TNF-a), and vascular endothelial growth factor (VEGF), which increase oxidative stress and LDL-cholesterol levels, with subsequent atherogenic effect.207An equally important cause of infertility is endometriosis, with prevalence of almost 10% in the population and associated with chronic diseases, such as asthma, autoimmune diseases, gynecologic cancers, and CVD.208 These observations were in accordance with a prospective study showing the association of endometriosis with an increased risk for myocardial infarction/ coronary ischemia and surgical and percutaneous MRV.209Endometriosis has been shown to associate with well-established RFs for CVD, such as SAH and dyslipidemia, with higher atherogenic profile and increased risk for venous thromboembolism, coronary artery disease, HF, and stroke. A study considering the combination of IHD, HF, and cerebrovascular disease as the primary endpoint has established a positive association of those events with endometriosis , placing endometriosis as a RF for CVD.210 However, a systematic review grouping ACS, stroke, venous thromboembolism, SAH, and DM in women undergoing fertility treatment has shown no increase in the combined events. That analysis, however, with only six very heterogeneous studies, has serious limitations and has not met the statistical criterion to provide more robust evidence.211Fertility therapy is considered a potential RF for hypertensive disorders in pregnancy.In conclusion, the reproductive age is a convenient time to estimate the CVR throughout a woman’s life. In that phase of the female biological cycle, attention should be paid to risks and interventions in clinical pathologies not included in traditional CVR scores, stratifying those women differently for effective prevention of CVD.213 The diagnosis is made in the presence of clinical suspicion of thrombosis in any vascular territory and/or recurring obstetrical complications, such as spontaneous abortions, premature deliveries, and preeclampsia/eclampsia. The APS causes placental insufficiency and restriction of intrauterine growth associated with the persistent presence of antiphospholipid antibodies (aPL): anticardiolipin (aCL), anti-beta2-glycoprotein 1, and/or lupus anticoagulant (LAC) antibodies.213The APS is an autoimmune thrombotic disease that affects mainly young women at the proportion of 5:1.214The aPL are strongly associated with stroke in women aged less than 50 years. The presence of aCL and/or LAC in young patients with ischemic stroke or transient ischemic attack, with no concomitant diagnosis of systemic lupus erythematosus, is frequent. In addition, patients with aPL and cerebral ischemia have a higher frequency of multiple events than patients without those antibodies. A prothrombotic state associated with aPL can be a determinant of recurrent ischemia in women with atherosclerosis.. Considering the different forms of treatment, the distinction between undiagnosed APS patients is fundamental for therapeutic success and prognosis. Although uncommon, APS should be considered in young women with myocardial infarction, especially in the presence of previous unprovoked thrombosis, lower platelet counts, high partial thromboplastin time, and normal coronary arteries or coronary thrombosis. Anticoagulation should be maintained throughout life, even from the first episode. The role of coronary stenting in such patients requires further studies.215The APS is associated with myocardial infarction in approximately 2.8% of patients affected by the disease. The mechanism of myocardial ischemia in APS is considered acute thrombosis of the coronary arteries, which requires anticoagulation therapy, in contrast to atherosclerotic plaque rupture, which is effectively treated with antiplatelet drugs and stenting216The evidence of significantly elevated titles of different aPLs in the initial phase of myocardial infarction suggests that these antibodies are present before the event and are not secondary to it. The disappearance of high aPL levels after 3 months from myocardial infarction can be due to an effect of absorption or possibly to a cyclical phenomenon similar to that found in other autoimmune diseases. The aPL can be an additional RF for myocardial infarction and should be considered especially in younger patients with no apparent CVRF.217The clinical and laboratory criteria for the APS diagnosis should be present concomitantly in a window inferior to 5 years. The progress in the knowledge on the molecular bases of vascular involvement considers APS a multifactorial disease that develops in genetically predisposed individuals. Several mechanisms contribute to the development of thrombosis in patients with APS, mainly the synergistic effect of autoantibodies with prothrombotic molecules, adhesion receptors, inflammatory mediators, oxidative stress, and intracellular signaling molecules.218The presence of aPLs induces a proatherothrombotic state through the expression of prothrombotic and proinflammatory molecules, including tissue factor and VEGF, and induces oxidative stress and mitochondrial dysfunction in monocytes and neutrophils, in addition to increased formation of extracellular “traps” of neutrophils.218 In addition, genetic polymorphisms have been associated with thrombosis in patients with APS, including variants of clotting factors, antithrombotic molecules, and inflammatory mediators.219 The aPLs induce genomic and epigenetic changes that support a prothrombotic state.Genetic predisposition has been shown in associations of human leukocyte antigen (HLA) with the disease and the occurrence of aPLs in patients with APS. The major histocompatibility complex genes seem to influence not only the production of autoantibodies, but disease expression as well.217 MicroRNAs affect the immune system and have an important role in the pathogenesis of autoimmune and inflammatory conditions, acting as the major regulators of several gene targets involved in the APS clinical characteristics, such as immune response, atherosclerosis, and thrombosis.220 Two microRNAs (miR-19b/miR-20a) are known to function as potential modulators of the tissue factor, the major receptor involved in the development of thrombosis in APS. Thus, a specific signature of circulating microRNAs has been recently identified in patients with APS as potential biomarkers221 between 2 and 3. Heparin, administered acutely at the time of the thrombotic event, can have two benefits: first, complement activation blockade (even if only in a prophylactic dose), and second, anticoagulation. Given the high risk of APS recurrence, long-term anticoagulation is recommended, because that risk can reach 24% with anticoagulation suspension, particularly in cases of systemic lupus erythematosus.Continuous progress in the knowledge of genomic bases and epigenetic biomarkers boosts clinical pharmacology and provides more safety to the APS therapy. Thus, although larger studies are needed, the new discoveries provide better understanding of the possibility of new models directed to therapeutic options to prevent the APS thrombosis.222Menopause represents a significant transition in a woman’s life and is characterized by the cessation of the menstrual cycle and the subsequent dramatic reduction in the levels of the sexual hormones, estrogen and progesterone. Although testosterone also decreases in postmenopausal women, that reduction is more gradual and the effects of the androgens in a woman’s health after the menopausal transition have not been totally understood. Hormone replacement therapy is a method by which women can control menopausal symptoms during and after that transition. However, there is no sufficient understanding of the exact effects that different hormone replacement therapy forms have on the woman’s physiology, particularly in the context of risk for CVD. The interaction of advanced age and female sex with CVD in addition to the role of hormone replacement therapy and menopause in the CVD progression leads to future questions to address the gaps in the current understanding of the health of elderly women at risk for CVD.215Antiphospholipid syndrome should be considered in young women with myocardial infarction, in situations of previous unprovoked thrombosis, lower platelet counts, high partial thromboplastin time, and normal coronary arteries or coronary thrombosis. Anticoagulation should be maintained throughout life, even from the first episode, particularly in systemic lupus erythematosus.223In a study involving individuals with ICM undergoing heart transplantation, the assessment of explanted hearts showed an increase in LV mass, myocyte volume, and cellular length in men. This difference was not identified in idiopathic cardiomyopathy, suggesting that gender may influence local myocardial response to ischemic injury.224 In addition, the incidence of symptomatic HF after AMI is higher in the female sex, especially in older women. The increase in risk extends beyond the initial episode of AMI. The female sex is an independent predictor of cardiogenic shock, even in AMI with a less severe IHD.224The evolution after AMI in women is more severe. Higher hospital readmission and mortality rates have been registered in women as compared to men, and they remain higher at 1 (26% x 19%) and 5 years (47% x 36%) after the acute episode.126Despite the better LVEF and lower obstructive IHD burden, women with IHD and ICM have lower physical functioning and quality of life, but similar mortality.7There is more information on ICM regarding men, possibly due to its higher frequency. The SAH and DM play a more significant role in women’s risk for HF, with a distinct phenotypic pattern.2 Somehow, this diagnostic-therapeutic limitation may be influencing the unfavorable outcomes in women.Over the past decade, there was an extension of the debate on inequality in CVD care between genders, especially in AMI treatment; however, the underrepresentation of women in clinical trials and the lower optimization of their treatment currently persist. Men are more promptly taken care of and referred for treatment, and more often receive therapy supported by guidelines.225Regarding remodeling in IHD, the differences seem related to the sexual hormones, in addition to the sexual chromosomes and epigenetics. Several genes related to adverse processes of cardiac remodeling, such as activation of macrophages, apoptosis, and lipidic metabolism, have been shown to be in the chromosome.226 High levels of calcium increase the ischemia-reperfusion injury, and estrogen can reduce the levels of calcium before ischemia, leading to fewer lesions in women.227Female mitochondria have been reported to better tolerate oxygen deprivation and oxidative injury than the male ones, and women seem to be better protected from apoptosis induced by ischemia/reperfusion.228 This has been confirmed in trials with human beings, in whom apoptosis after myocardial infarction follows the same pattern, being more prevalent in men.229In animal models of infarction and fibrosis due to massive apoptosis, necrosis in the infarcted area is larger, with more collagen, in male mice compared to female ones.224Thus, although they seem not to improve mortality and hospitalizations, estrogens can protect against oxidative stress and modulate apoptosis; in addition, estradiol can reduce fibrosis by negatively regulating collagen synthesis, although mortality remains high.230In ICM, recent data have suggested that obesity is more frequent in the female population, correlating with worse prognosis as compared to men.230Regarding the HF symptoms, women tend to be more symptomatic, with complaints of dyspnea and orthopnea across the entire functional class spectrum as compared to men.Several noninvasive methods are available for the diagnosis of women’s ICM and, in many cases, they can aid not only the diagnosis, but the prognostic assessment and therapy definitions as well. The choice of the best modality should consider the diagnostic performance, the gender-related peculiarities, and, sometimes, the presence of special situations, such as pregnancy.231 The addition of technologies for functional assessment enables the identification of hemodynamically significant lesions and helps define therapies. In addition, it aids the diagnosis of SCAD, which affects mainly women. The CMRI has high diagnostic accuracy in both women and men.232 In addition, in cardiomyopathy, different patterns of late enhancement and tissue changes can help the identification of nonischemic etiologies.The CCTA has high sensitivity and similar performance in men and women.Briefly, several noninvasive modalities are available for ICM assessment. Knowing the advantages and disadvantages of each one helps choose the method to be used and interpret the results. It is worth noting, however, that invasive assessment with coronary angiography may be necessary and should not be delayed in case of doubt. In addition, not only in the presence of severe cardiomyopathy and clinical findings, but also of characteristics that increase the probability of ischemic etiology , definitive assessments that exclude or identify the ischemic etiology should be considered.235In recent decades, different clinical trials have reported advances in the treatment of HF with reduced ejection fraction (HFrEF). Thus, the major guidelines recommend the use of quadruple therapy, with ACEI/ARB or angiotensin receptor/neprilysin inhibitor (ARNI) + BB + aldosterone antagonist + SGLT2 inhibitors, for the treatment of patients with HFrEF because of the impact on overall and cardiovascular mortality.7For patients who persist symptomatic, other classes of drugs, such as hydralazine-nitrate, ivabradine, digoxin, and, more recently, guanylate cyclase stimulators, in addition to CRT, can be added. It is worth noting that, in most clinical studies, ischemia has been the most frequent etiology, ranging from 50% to 70% . In addi7Despite recent advances, treating women with ICM is challenging. The first challenge refers to women’s underrepresentation in the major clinical trials of HFrEF. While women represent approximately 50% of the patients in HFpEF trials, their representation in HFrEF trials ranges from 20% to 30% only. Thus, the gender-specific differences are limited, based on analyses of subgroups, and, thus, should be cautiously interpreted.The therapy for ICM and its major supporting studies are as follows:Beta-blockers: a meta-analysis involving the major studies on BB in HFrEF has shown that the reduction in mortality occurs similarly in women and men. Sub-analyses have shown that bisoprolol improved the survival of 515 women studied in the CIBIS-II study , carvedilol reduced the composite outcome of death and hospitalization in 469 women with LVEF < 25% in the COPERNICUS sub-study , and metoprolol succinate reduced the length of hospital stay due to HF in women with LVEF < 25% (p = 0.004), but did not reduce mortality alone.238ACE inhibitors: studies with ACEI, such as SOLVD and CONSENSUS, have shown an impact on mortality reduction of patients with HFrEF and NYHA functional class II/III and IV, respectively; however, when assessing women alone, that benefit was not observed.239Angiotensin-receptor blockers: data from a subanalysis of the CHARM trials (candesartan) have shown no sex-related difference in the primary endpoint of the study on cardiovascular death and HF hospitalization.240Angiotensin receptor-neprilysin inhibitors: analysis of subgroups of the PARADIGM-HF study has suggested no difference between women and men regarding the primary endpoint of cardiovascular death or HF hospitalization. Recently, a real-world study involving 427 patients (29% women) has shown similar tolerability to the use of ARNI in women and men. 241Aldosterone antagonists: analysis of subgroups from studies involving spironolactone (RALES) and eplerenone (EMPHASIS) has revealed that the impact on overall and cardiovascular death/HF hospitalization, respectively, occurred in women and men, with no statistically significant difference.7SGLT2 inhibitors: the studies assessing dapagliflozine (DAPA-HF) or empagliflozine (EMPEROR-Reduced) in patients with HFrEF have shown that the addition of that new class of drugs to triple therapy causes a reduction in the composite outcome of cardiovascular death and HF hospitalization, and that benefit is similar in men and women243, the mortality rate was higher. Thus, lower doses and strict control of digoxin serum levels in women are recommended when that medication is indicated.As previously described, most clinical trials on HFrEF have shown equivalent efficiency of the medicamentous treatment for women and men, and prognosis-modifying drugs should be used in both sexes. However, it is worth noting that those observations result from the analyses of subgroups from studies, and, thus, should be cautiously considered.The advances in electric and mechanical devices have provided substantial benefits to patients’ symptoms, hospitalization, and results, with strong evidence in both sexes.230The range of devices includes ICD, CRT, and defibrillators of CRT. However, recent data have shown that women are less likely to receive ICD, and, when they do, their rates of implantation-related complications, such as pneumothorax and infection, are higher.247As previously mentioned, women less often have IHD as the etiology, and, as remodeling response, less fibrosis, and a lower rate of ventricular arrhythmias, resulting in fewer sudden cardiac deaths. A meta-analysis assessing studies involving patients (n=7229) with ischemic (74%) and nonischemic cardiomyopathy, 22% of women, has shown that the benefit was significantly higher in men  than in women .248However, even after adjusting for age and comorbidities, the female sex had lower probability of receiving an ICD as compared to the male sex.249It is worth noting that women have higher rates of complications related to device implantation, such as pneumothorax, infection, bleeding, and tamponade.170However, because of the less fibrotic profile and even the structural and anatomical characteristics, studies have suggested that women respond more favorably to CRT, which results in improvement of symptoms, quality of life, LVEF, and mortality. Data from the MADIT-CRT study, comparing CRT-D to implantation of ICD alone, have shown a higher benefit in women as shown in versus 41.6% in men) and experienced more complications, such as major bleeding (p = 0.001), arrhythmias (p = 0.02), and right ventricular insufficiency (p < 0.001), with worse 1-year survival (75.5% versus 83.2%).7Ventricular assist devices are already well implemented in the practice of advanced HF services as a bridge or a destination therapy. Women are more likely to be hospitalized due to advanced HF, but less often receive a ventricular assist device. In a recent study analyzing the EUROMACS registry, 966 patients (151 women) have been included. Characteristically, at the time of implantation, women showed worse INTERMACS 1 and 2 profiles  should receive pharmacological treatment according to HF guidelines.235Class I/C – Female patients with ICM and HF with reduced ejection fraction, refractory to pharmacological treatment according to HF guidelines, should be referred for cardiac resynchronization.235Class I/C – Female patients with ICM and advanced HF, refractory to pharmacological and nonpharmacological treatment according to HF guidelines, should be considered for heart transplantation.235250 Despite the increasing evidence of sex-related differences in baseline RFs, coronary anatomy and function, symptoms, comorbidities, treatment efficacy, and outcomes in ACSs, the mechanisms of those differences are not completely known.67 These gaps of knowledge are due to women’s underrepresentation in clinical trials; thus, the scientific community should be encouraged to change this paradigm.Recent studies have reported a significant increase in the mortality rates of acute coronary disease in young women (< 55 years).251Despite the general benefit of MRV, the female sex has been consistently associated with an increased risk of bleeding and vascular complications associated with PCI, evidencing the need to consider the major biological differences, such as the size of the vessels of percutaneous accesses and the prevalence of nonobstructive coronary artery disease in women, in addition to the need to apply the recommendations of current guidelines.252As compared to men, women submitted to PCI are older and have higher prevalence of kidney failure, anemia, and DM. As compared to men, women with ACS have higher mortality and less often undergo the recommended treatments, such as early invasive strategy and antithrombotic therapy.Clinical factors, such as advanced age, kidney failure, cardiogenic shock, and use of major introducers, were specifically identified as predictors of the risk of bleeding in women. However, the female propensity for bleeding persists in addition to those RFs. Sex-specific mechanisms regarding BMI, puncture site anatomy, platelet biology, and PCI-related pharmacotherapy may play an important role.253Mason Sones performed the first selective coronary angiography in 1958 through dissection of the brachial artery. In 1967, Judkins and Amplatz developed the technique of femoral artery puncture and appropriate catheters for that technique, which is still widely used because it provides excellent access in cases of complex angioplasties that require larger introducers and the assessment of bypasses and grafts of patients with previous surgical MRV.255The radial access, described in 1989 by Campeau, is a more complex technique that requires higher ability and experience, in addition to a longer learning curve. A higher proportion of women have more tortuous radial arteries of smaller caliber as compared to men. Patients with chronic kidney disease, DM, low BMI, and elderly have a higher rate of unsuccessful radial access.253The femoral artery access has predominated for decades, because of its significant viability and reproducibility. The radial artery access, however, has shown to be efficient to reduce bleedings and other vascular complications, especially in patients with ACS, thus, becoming the access of choice recently.256 However, the magnitude of the benefit associated with radial access can vary widely, depending mainly on the patient’s risk for femoral access complications. Thus, it is fundamental to ensure the preferential use of the radial access in patients at higher risk for complications from the vascular access, such as women.256In addition, the radial access use can be associated with a better quality of life and lower costs as compared to the femoral one.77Women’s epicardial coronary arteries are significantly smaller than those of men, even after adjusting for age, body structure, and LV mass. The discrepancy in the size of the coronary arteries between women and men is considered an important base of the sex-related differences in the outcomes of the coronary artery disease, despite the smaller atherosclerotic plaque volume of women.77The important implication of the smaller size of the coronary arteries is that the comparatively lower atherosclerotic plaque and thrombus burden can result in obstructive disease. This may be a potential reason for the higher incidence of sudden cardiac death in younger women, despite their lower atherosclerotic plaque burden. In addition, smaller vessels can represent a higher risk of re-stenosis.77 , OCT, and near infrared spectroscopy (NIRS).Providing Regional Observations to Study Predictors of Events in the Coronary Tree) could evaluate the effect of sex on the coronary artery disease extent and characteristics and confirm significant differences between the sexes. Women have less extensive IHD. The morphology and composition of the plaque in women have smaller necrotic nucleus and calcification, for a similar atherosclerotic plaque burden, although smaller minimum luminal area and more lesions with minimum luminal area < 4.0mm2, as compared to men.257The ICUS enables the precise atherosclerotic plaque burden quantification with axial resolution of 70-200 mm and penetration > 5mm. Using that method, the PROSPECT study  adenosine. The ratio between distal coronary pressure and aortic pressure (as registered by the guidewire) during maximum hyperemia is called FFR. The normal value is 1, while values < 0.80 are associated with provocable ischemia with a precision over 90%.261The measurement of FFR consists in the use of angioplasty guidewires with a sensor on their tips, which were developed to measure the pressure and blood flow across a coronary artery stenosis in the catheterization lab. The FFR measures the proximal (aortic pressure) and distal (guidewire pressure) pressures in coronary artery stenosis under maximum blood flow and creates a pressure ratio, representing the proportion of flow through the stenosis. For accurate FFR measures, the pressures should be obtained during hyperemia. Maximum blood flow (hyperemia) is most commonly induced by use of intravenous (140mcg/kg/min) or intracoronary  during the wave-free period (75% in diastole finishing 5ms before the R wave) is called instantaneous wave-free pressure ratio (iFR). It has been shown that, for iFR cut-off points of > 0.93 or < 0.86, there was a strong correlation with normal and abnormal FFR values (using 0.80 as the FFR cut-off point). In the ADVISE II study, iFR was compared to FFR in 690 intermediate stenoses. As compared to FFR (< 0.80), the iFR cut-off of 0.89 classified correctly 83% of the stenoses. The iFR classified correctly those stenoses outside the iFR grey zone from 0.85 to 0.94 with 92% of concordance. Thus, the iFR-FFR hybrid approach for intermediate stenosis can be assessed without the hyperemic stimulus in 65% of the patients.Microvascular coronary vasoconstriction can also be assessed by use of functional tests with intracoronary acetylcholine, which produces coronary vasodilation in the presence of healthy endothelium or paradoxical vasoconstriction in the presence of endothelial dysfunction. Incremental doses are administered for 3 minutes until the response is produced or the target dose is reached.The positive response for epicardial coronary spasm is a focal or diffuse coronary artery diameter reduction > 90% (as compared to the relaxed state). Patients experience the reproduction of angina and ischemic changes on ECG. These patients are considered to have vasospastic angina.The positive response for microvascular vasoconstriction is the absence of epicardial coronary spasm (no diameter reduction or reduction < 90%). Patients experience the reproduction of angina and ischemic changes on ECG (ST-segment depression or elevation).The negative response to the acetylcholine test is the absence of epicardial coronary spasm (no diameter reduction or reduction < 90%), with no angina and no ischemic changes on ECG .260If the test with acetylcholine is negative, there is still the option of testing with intracoronary adenosine. The CFR is calculated based on the coronary flow velocity (CFV), which is the ratio between peak CFV and baseline CFV. A CFR < 2.5 indicates endothelium-independent coronary microvascular dysfunction. These patients with abnormal CFR will also be considered to have changes in the microcirculation.264The objective of MRV in chronic coronary syndromes is to relieve angina rather than reduce mortality. Thus, when considering the medicamentous or PCI treatment options, the higher incidence and frequency of angina in women should be considered. In a subanalysis of the COURAGE study, there was no significant difference in the effect of treatment on the major results between women and men. However, women assigned for PCI have shown a higher benefit, as compared to men, with a reduction in HF hospitalization and in the need for future MRV.265The ISCHEMIA clinical trial has shown that women, as compared to men, have a higher burden of angina symptoms, although their coronary disease is less extensive, and ischemia is less severe.10.4.1.1. Disease of the Left Main Coronary ArteryUntil recently, coronary artery bypass grafting (CABG) was the treatment recommended for left main coronary artery (LMCA) disease, but PCI has been more and more adopted to treat the LMCA disease.266 women undergoing PCI for unprotected LMCA showed a trend towards worse outcomes, a finding related to associated comorbidities and increased periprocedural complications. However, sex was not an independent predictor of post-MRV adverse outcomes, the same conclusion of the NOBLE study.267In the EXCEL trial,10.4.1.2. Total Chronic OcclusionTotal chronic occlusions represent an important subgroup of coronary lesions and are found in as much as 18% of diagnostic angiographies.268A well-succeeded PCI for total chronic occlusion is known to be associated with the symptomatic relief of angina, improvement in LV function and quality of life, as well as mortality reduction. However, several studies have shown that, in women, a well-succeeded PCI for total chronic occlusion has not been associated with a reduced risk for cardiovascular mortality or major adverse coronary events (MACE) as compared to clinical treatment alone, which differs from that in men, who have a significant reduction in the rate of MACE after well-succeeded PCI for total chronic occlusion.269 The benefits of an invasive approach are more pronounced in patients with elevated biomarkers or other findings of high risk, regardless of sex.270A flowchart summarizes the strategy choice and the invasive assessment time , and no benefit regarding cardiac mortality with complete MRV for women.10.4.3.2. Cardiogenic Shock65However, several studies, such as the CULPRIT-SHOCK trial, have shown that sex had no influence on mortality according to different MRV strategies.273Cardiogenic shock, HF and right ventricular infarction occur more frequently in women with STEMI as compared to men. In addition, women have lower BP and cardiac output as compared to men in cardiogenic shock.10.4.4.1. Drug-eluting Stents274In the past two decades, there was an important advance in the technology of drug-eluting stents, such as drug optimization, polymers, and stent design, supporting the safety and efficacy of those most recent devices. Angiographic studies of drug-eluting stents assessing in-stent late loss have shown similar degrees of neointimal hyperplasia in women and men, suggesting that the drug-eluting profiles are effective in both sexes.10.4.4.2. Drug-Coated Balloon277The PCI with drug-eluting stent is the most common mode of revascularization for IHD. However, in-stent restenosis and thin vessels are known limitations. Drug-coated balloon is a balloon coated with antiproliferative agents encapsulated in a polymeric matrix, which are released in the wall during insufflation and contact with the intima. Leaving no metal in the vessel treated is beneficial for thin vessels, in-stent restenosis, and intermediate and distal vessels, where distal stents can be disadvantageous for future MRVs.10.4.4.3. Rotational Atherectomy and Intravascular Lithotripsy278Rotational atherectomy and intravascular lithotripsy are indicated for calcified lesions to prevent stent underexpansion, which is associated with higher restenosis rates. In women, rotational atherectomy is associated with a higher risk of periprocedural complications, but with long-term MACE-free adjusted overall survival rates similar to those in men. However, intravascular lithotripsy has angiographic complications, safety, and efficacy similar in women and men.280 Vulnerability for bleeding is one reason. Women, particularly the elderly and low-weight ones, have higher risk of hemorrhagic complications, which can be related to a smaller body distribution volume, lower glomerular filtration rates, and differences in the activities of hepatic enzymes.269 To mitigate that risk, in addition to the radial access, it is worth noting the need to adjust the doses of anticoagulants and antiplatelet drugs to weight and renal function, whenever pertinent, and to monitor the activated clotting time every 30-60 minutes during the intervention, administering supplementary doses of heparin, if needed, to ensure proper anticoagulation levels.281Although randomized studies have suggested similar benefits of adjunct antithrombotic therapy for coronary disease in both sexes, women less often receive the treatment recommended in the guidelines.155 Clinical presentation, risk of bleeding, ischemic risk, and comorbidities should guide the selection of the P2Y12 inhibitor type, the ideal time to administer its loading dose, and the dual antiplatelet therapy duration, regardless of sex.281 Women, however, have a higher risk of bleeding with any inhibitor.283 Strategies to minimize that risk include to shorten the dual antiplatelet therapy duration, discontinue the acetylsalicylic acid, maintaining monotherapy with a P2Y12 inhibitor after a short period of dual antiplatelet therapy, or de-escalation of the P2Y12 inhibitor, from prasugrel or ticagrelor to clopidogrel.285 The acetylsalicylic acid suspension after a short peri-intervention period  has proven effective to reduce bleedings in individuals with AF requiring oral anticoagulation and undergoing PCI.286 Sex-specific analyses of safety and effectiveness of those strategies can help select or personalize the ideal antiplatelet regimen for women.Regarding oral antiplatelet therapy, the dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 inhibitor  is recommended to prevent post-intervention thrombotic events.• Prevalence of obstructive and nonobstructive coronary disease in the female sex, in different clinical scenarios, acute and chronic.• Clinical validation of the women-specific reference values for the invasive coronary physiological assessment tests (hyperemic and non-hyperemic), regarding the differences in coronary caliber, myocardial mass, and microvascular resistance between sexes.• Different impact of the intravascular imaging method on women, considering its diagnostic role in cases of MINOCA and its value to optimize PCI in the female sex, which typically involves thinner vessels and higher risk of bleeding.versus surgical) in women with LMCA or multivessel lesion, reassessing the influence of sex in current therapeutic outcomes.• Selection of the ideal MRV method , advancing in the pathophysiological understanding, and identification of sex-specific RFs and predictors of recurrence of SCAD and Takotsubo cardiomyopathy.• Particularities of PCI in women in complex scenarios, such as cardiogenic shock, calcified lesions, bifurcations, and chronic coronary occlusions.287Several series have shown that, at the time of surgical indication, women tend to have a higher surgical risk, with more comorbidities associated, such as SAH, DM, HF, ACS, in addition to a higher respiratory function impairment.291Several factors, such as epidemiological, anatomical, and/or operative technique-related ones, make the results of women’s CABG less favorable as compared to those of men.et al. have shown that coronary artery diameters are directly proportional to body surface, being, thus, usually smaller in women than in men.292Since the 1980s, the analyses of the Coronary Artery Surgery Study (CASS) have shown that the coronary artery diameters had a direct influence on the immediate results of CABG.293O’Connor 292 In addition to the coronary artery diameters, the quality and fragility of the grafts influence the decision on the surgical tactic to be used and increase the complexity of the surgical techniques.294When stratified by groups, mortality in patients with large coronary arteries (2.5 – 3.5mm) was 1.5%, increasing to 4.6% in those with intermediate diameter (1.5 – 2.0mm), and reaching 15.8% in individuals whose coronary arteries had a mean diameter of 1mm.155 several studies have shown the underuse of those grafts in female patients.296 Because of the smaller caliber of the mammary arteries and radial arterial grafts, there is an underuse of arterial grafts, which could increase the proportion of revascularized vessels with grafts of higher late permeability.297 The less favorable characteristics of both arterial and venous grafts in women can lead to a higher predisposition to early thrombosis and trend to spasms, increasing the chance of unfavorable results.298 Similarly, although the importance of complete MRV in patients with multivessel lesions has been well established, several studies have shown that women receive a smaller number of grafts, being, thus, not completely revascularized.299Although the 2021 ACC/AHA/SCAI guidelines recommend the preferential use of arterial grafts,301 However, in patients with more advanced cerebrovascular disease, kidney and/or respiratory dysfunction, that technique might be safer. However, because of the anatomical and technical aspects already mentioned, the off-pump CABG in women is frequently more challenging than in men.The benefits of CABG with no cardiopulmonary bypass, off-pump CABG, are still controversial. Some studies have shown similar mortality between the sexes, while others do not confirm those findings.et al., the long-term survival after CABG is worse in women than in men, even after adjusting for differences in RFs.288In recent years, there was a significant increase in the number of women submitted to CABG. However, in most studies, the male sex still predominates in the samples analyzed. There is evidence in the literature that, as compared to men, women have worse outcomes and prognosis after CABG. According to Attia 290 Both in the EXCEL and NOBLE studies, women had a higher prevalence of RFs, such as DM, SAH, and dyslipidemia. However, the anatomical complexity of their coronary lesions was smaller.302Previous analyses have identified the female sex as an independent RF for intra-operative and long-term mortality after CABG, even after adjusting for some variables, such as more advanced age and increased prevalence of comorbidities.et al. have conducted a meta-analysis of studies related to several aspects of CABG: ART TRIAL, CORONARY TRIAL, GOPCABE TRIAL, and PREVENT TRIAL. After the first 5 years from surgery, female patients had worse cardiac and cerebrovascular outcomes, but similar mortality as compared to men. These differences are not evident after the age of 75 years (the difference of these results between the sexes is inversely associated with age). Those studies have reported that women, as compared to men, have a more difficult postoperative recovery from CABG. Between the 6th and 8th postoperative weeks, women reported more physical complaints and side effects than men in the same period. In addition, they had lower physical functioning, more depressive symptoms, and were twice more likely to be readmitted to hospital. These differences remained substantial and statistically significant even after multivariate analysis. In addition, those authors have observed that CABG had a much higher impact on the women’s mood as compared to that of men.303Vaccarino 155 Healthcare providers should know the female sex-related particularities to promote differentiated strategies to improve the healthcare to women undergoing CABG.Despite the gender-related differences, the indications for CABG are well established in current recommendations and guidelines.305Several aspects have been analyzed to identify factors with a negative impact. Of the non-modifiable differences, the smaller body surface most frequently found in the female sex has been studied and considered a factor that can negatively contribute to postoperative results, with no conclusion.306 An important anatomical characteristic regards the aspects of the female coronary circulation, with thinner coronary arteries of smaller caliber, increasing the complexity of the anastomosis technique and the risk of early graft occlusions.307Historically, women have a worse postoperative course as compared to men regarding CABG.305Because of their smaller caliber, fewer arteries receive grafts and, thus, some myocardial areas remain unprotected, increasing the risk of recurrent ischemic events, ventricular dysfunction, and HF in the mid- and long-term postoperative period. The risk of perioperative myocardial infarction and early graft occlusion contributes to a marked higher in-hospital mortality as compared to that observed in men, affecting the late results.308 Even the isolated use of the left internal thoracic artery to revascularize the anterior descending artery, considered gold-standard in CABG, is less frequent in female patients.306 The potential benefit of arterial grafts can be lost in patients of higher risk, which would explain why women with worse baseline risk profiles would not receive as many arterial grafts as men.302Other important data related to unfavorable postoperative course concerns the use of arterial grafts, which is less often in women.309Female patients referred for surgical treatment are more likely to be older, have significantly more severe comorbidities, such as SAH, DM, hyperlipidemia, peripheral arterial and venous disease, and more advanced clinical status of coronary disease with unstable angina, post-infarction angina, HF, and indication for urgent CABG.310 Women most often than men have immediate postoperative complications, but the rates of reoperation due to bleeding are lower in female patients311  assessment. It is reasonable to use the pHM calculation to help the donor-recipient correspondence. A donor-recipient pHM of 0.86 or greater predicts a good prognosis; a pHM between 0.86 and 0.7 can be considered for individual cases; and a pHM lower than 0.7 can be associated with adverse posttransplant results.321 There has been a slight increase in transplants from women to women and a corresponding decline in transplants from women to men, maybe because of the shorter survival observed after donor-recipient sex mismatch transplantations. This can be explained by immune differences291 or the donor-recipient size matching.320The donor-recipient sex correspondence has recently attracted considerable attention.323The sex distribution of heart transplant recipients has changed over time, with an increase in the proportion of female recipients from 19.3% in 1992-2000, to 22.4% in 2001-2009, and to 25.6% in 2010-2018. The reasons why women have reduced representation among heart transplant recipients have not been clearly identified; one would be the HF development and consequent indication for transplant at a more advanced age.325 Anti-HLA antibodies should be detected to reduce the risk of hyperacute rejection. The use of virtual crossmatch, from a data bank, in pre-transplant assessment replaces prospective crossmatch, can increase the pool of donors and reduce the testing time, in addition to helping decide which sensitized patients require treatment before the procedure.326Women are at higher risk of sensitization, pregnancy being one of the major RFs. Transfusions, ventricular assist devices, and previous transplantation are other RFs. Preformed antibodies can cause hyperacute rejection and increase the risk of posttransplant rejection, in addition to predisposing patients to the development of cardiac allograft vasculopathy.319 Desensitization of the recipients can be performed prior to transplantation with venous infusion of immunoglobulin, plasmapheresis isolated or in combination, rituximab, and, in certain very special cases, splenectomy.319 Targeting at the humoral response components, desensitization can be used as a therapeutic option to increase the number of donors and, thus, increase the likelihood of transplantation for sensitized patients , an additional assessment is recommended.patients .319 (1) mechanical circulatory support; (2) high dose of venous corticosteroids; (3) plasmapheresis; (4) venous immunoglobulins; (5) rituximab; (6) cytolytic immunosuppressive therapy; (7) eculizumab; (8) cyclosporin, tacrolimus with increased target levels and inhibitors of the metabolic cycle (mycophenolate); (9) venous inotropic and vasopressors; and (10) heparin.The treatment of hyperacute rejection should be initiated immediately after the diagnosis, even in the operating room. According to the current International Society for the Heart and Lung Transplantation (ISHLT) guidelines, the treatments include:319 Severe acute cellular rejection (ISHLT 3R) diagnosed by use of endomyocardial biopsy should be treated even in the absence of symptoms or evidence of cardiac allograft dysfunction. The significant RFs for the development of cardiac allograft vasculopathy include donor’s death due to stroke and diagnosis of recipient’s ICM and retransplantation. The female sex of both the donor and the recipient has been reported to reduce the risk of developing cardiac allograft vasculopathy.328 Previous studies disagree and have shown either a higher incidence of cardiac allograft vasculopathy in procedures with female donors or recipients or no sex-related difference regarding the development of cardiac allograft vasculopathy.331Cardiac allograft vasculopathy remains highly prevalent and one of the major causes of late death after heart transplantation.332Heart transplantation for peripartum myocarditis remains relatively infrequent. Some studies have shown that, in its late stage, the incidence of cardiac allograft vasculopathy is similar to that of transplantations performed in women due to other etiologies.328 Rudasill et al., in a recent analysis of the United Network for Organ Sharing (UNOS) registry, have shown no association of donor’s malignancy with the recipient’s 10-year survival.333 However, a recipient’s history of pretransplant malignancy has been associated with an increased risk of posttransplant malignancy, especially skin neoplasms. However, that incidence was smaller in women. It is worth noting the need for rigorous surveillance of skin and breast malignancy in the female population and of colon malignancy in the general population.334Malignancy after heart transplantation continues to be a significant cause of morbidity and mortality in recipients. Data from the ISHLT registry have shown a cumulative prevalence of all types of malignancy after heart transplantation in adults of 16% in 5 years and of 28% in 10 years. Skin cancer continues to be the most common posttransplant malignancy.323 In addition to size mismatch, those sex-related differences in survival suggest that hormonal influences on immune response can be associated.319 Hypertrophic cardiomyopathy and congenital heart disease were associated to an increased 1-year mortality. Other variables associated with increased 5-year mortality, conditional on 1-year survival, include restrictive, ischemic, and retransplant cardiomyopathy.According to the 2021 ISHLT report on Adult Heart Transplantation, female donor-recipient had a higher 1-year mortality as compared to the male donor-recipient combination (HR 1.16). The male/female combination increases the 5-year mortality (HR 1.1). However, the female donor-recipient combination is associated with a lower risk (HR 0.90) as compared to the male donor-recipient combination in 5 years.323Indistinctly between genders, the recipient’s panel reactive antibodies and the ischemia duration are associated with 1-year mortality, while the recipient’s chronic characteristics are associated with 5-year mortality. Thus, chronic sequelae of DM, vascular and chronic kidney disease can affect the long-term posttransplant results. Other variables associated with 5-year mortality, conditional on 1-year survival, include recipient’s age, BMI, pulmonary vascular resistance, renal function, donor’s age, and transplant center’s volume of surgeries.335 However, sex has not been shown to be a significant or important variable associated with posttransplant mortality, with few interactions of gender as a mortality predictor, although women live longer than men.336The female gender is a strong predictor of waitlist mortality in heart transplantation.321Despite the increased number of women submitted to heart transplantation, they continue underrepresented. Female recipients have different baseline characteristics when compared to male recipients, and posttransplant survival is equivalent in women and men after adjusting for recipient and donor’s characteristics.330Women tend to have better long-term survival than men after heart transplantation, with smaller risk of developing coronary artery disease, cardiac allograft vasculopathy, and malignancies, but a higher risk of antibody-mediated rejection.330Early posttransplant mortality (< 1 year) is mainly due to graft failure, infection, and multiple organ failure, while late posttransplant mortality (> 5 years) is mainly due to malignancy, graft failure, and cardiac allograft vasculopathy.339Overall survival is emphasized as the primary endpoint after heart transplantation. However, health-related quality of life is important in heart transplant recipients. A recent study using the Short Form with 36 items (SF-36) for quality-of-life assessment, in accordance with the World Health Organization, has shown that 22% of the survivors were employed at 1 year and almost 33% at 2 years following heart transplantation. Neurological and nephrological complications have a negative impact and are important predictors of quality of life after heart transplantation. Gender is a factor related to social determinants of health, as well as race and ethnicity, in addition to socioeconomic and education levels.340In a study cohort to develop and validate machine learning models to increase the predictive accuracy of mortality after heart transplantation, with 18 625 patients, the models demonstrated good predictive accuracy of the posttransplant results, and one of those models was the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score. However, only 27% were female patients.327Chronic humoral rejection and cardiac allograft vasculopathy are the major causes of late morbidity and mortality in patients submitted to heart transplantation, and the diagnosis by use of noninvasive methods has low sensitivity.327The recommendations for heart transplant, which can be found in the guidelines on heart transplant, do not differ between sexes.341 and national95 guidelines. After ACS and percutaneous or surgical MRV and for stable angina, referral for cardiac rehabilitation should be part of the medical prescription. Its efficacy to improve the quality of life and to reduce modifiable RFs and mortality, as well as to prevent readmissions due to new events, has been well established.342The indication of cardiac rehabilitation in IHD is a consensus in international343 Referral to cardiac rehabilitation at hospital discharge has been related to lower mortality, especially in women and ethnical minorities.344 Among women, the likelihood of death, HF or stroke 5 years after AMI is higher than among men, independently of age.345Studies have shown that women less often adhere to cardiac rehabilitation than men. In a sample with 44% of women, only 14.3% used cardiac rehabilitation after AMI as compared to 22.1% of men.346 Other important barriers are lack of social support, low physical functioning, unemployment, more advanced age, fear of physical exercise, high burden of family responsibilities, multiple comorbidities, absence of reimbursement of the sessions, limited accessibility, and diversity of programs.347One of the major barriers to cardiac rehabilitation use is the lack of medical referral for it. In women, cardiac rehabilitation referral and incentive by the physician regarding the importance of cardiac rehabilitation as part of the treatment is a strong predictor of admission to programs.348During the initial assessment for admission to the cardiac rehabilitation program, it is necessary to interrogate women’s specific questions that are related to CVD in that population. Preeclampsia, DM, gestational hypertension, preterm birth, and early menopause are some important additional RFs to be addressed, as are menopause symptoms, presence of urinary incontinence, musculoskeletal questions, and fatigue perception.349 The aim is to achieve moderate intensity with impact on mortality and quality of life, but the prescription should always be individualized  based on a small, randomized study from their group, in which, as compared to moderate training (70-85% of maximum HR), oxygen consumption had a higher increase (23% versus 7%).350 However, further studies are needed to support those findings. Women are more likely to experience musculoskeletal pain and fatigue. To elaborate a program with shared objectives and to offer methods of complementary exercises, such as Yoga, dance, Tai-Chi, might prevent drop out from cardiac rehabilitation programs. However, further studies are necessary to confirm the effectiveness of the methods to reduce CVR, morbidity, and mortality.348In parallel with physical functioning, the reduction in muscle strength associates with an increase in CVD and mortality. Women have less strength in the hand grip test. Khadanga The following situations, more prevalent in the female population, should be considered when addressing cardiac rehabilitation and its role in IHD:Spontaneous coronary dissection: The lack of consensus on exercise practice after SCAD and its possible relation to intense exertion cause uncertainty among health professionals and patients regarding resuming physical activities. However, a Mayo Clinic registry with 354 patients with SCAD, 96% of whom were women, has confirmed the benefits of participating in cardiac rehabilitation programs, without clinical complications.351 A dedicated cardiac rehabilitation program for SCAD survivors was designed at Vancouver General Hospital,352 with improvement in physical functioning and psychological stress, as well as a reduction in the need for MRV during follow-up. Thus, referral to cardiac rehabilitation centers should be encouraged, addressing the concerns about exercise that many patients have after the first SCAD episode.MINOCA: Differently from the unequivocal consensus on the role of cardiac rehabilitation in obstructive coronary disease, data on the efficacy and safety of cardiac rehabilitation in coronary microvascular dysfunction are scarce. However, studies performed in women with microvascular angina have been able to show improvement in physical functioning, metabolic variables, quality of life, and myocardial perfusion after different periods of a cardiac rehabilitation program, and, thus, further studies should be encouraged.354