More than a year has passed and the Corona pandemic still has us firmly in its grip. Familiar habits, vacations, conferences, trade fairs and meetings, and even the usual daily routine in the office—many things have been cancelled, and even more now take place purely digitally, currently with a still vague prospect of a return to normality. Compared to the state of digitization we had just a year ago, however, a lot has happened, and what was still the exception rather than the rule for many in the past has become the habit. However, the ubiquitous digitization of work and private life also shows us how vulnerable society is and that citizens must be able to rely on the supply of critical services and goods. If all resources function as normal, no one worries—but it is a different story if the Internet or telephone fail for half a day or, even worse, the electricity, gas or district heating supply stops working. At a time when people are increasingly retreating into the private sphere to live and work as a result of the pandemic, it must be ensured that this sphere offers all the resources needed for society and the economy to continue to function “remotely.”However, this is not always the case, as the massive blackout in the USA in February of this year made clear: In the middle of winter, hundreds of thousands of households were cut off from the power supply and, in some cases, also from the water supply, since the transport systems and control electronics no longer functioned properly due to the extreme cold. Europe was also affected by power outages and significant voltage fluctuations at the beginning of 2021, with the real danger of a total blackout. Political demands were quickly made during this time to ensure security of supply for the population. However, this issue is not just about the power supply, but more generally about the protection of critical infrastructures—those facilities that are a mandatory prerequisite for the functioning of public life. This primarily includes the sectors of energy, food, finance and insurance, health, information technology and telecommunications, media and culture, government and administration, transport and traffic, as well as public water supply and wastewater disposal.More and more—and not just since the start of the Corona pandemic—such essential facilities are connected to the digital data network and are therefore increasingly vulnerable from a cybersecurity perspective. Years ago, for example, simulated waterworks were operated that could be found on the Internet , which were deliberately compromised by attackers within just a few minutes. In this context, it was also proven, for example, that small and medium-sized water supply companies in particular have massive problems in adequately securing their critical systems against cyberattacks.This is where the legislator comes into play, since guaranteeing not only the water and energy supply, but also the proper operation of all critical infrastructures is a central task of state regulation. For several years now, various approaches to this issue have been advocated in legislation around the world, many of which have similarities in terms of technical and organizational aspects, but which are often quite different in terms of their legal policy objectives. Since the end of last year, German and European legislators in particular have once again turned their attention to the legal regulation of IT security and especially of critical infrastructures. The European Union, for example, published its new cybersecurity strategy, “The EU’s Cybersecurity Strategy for the Digital Decade,” on December 16, 2020, and the draft for the new German IT Security Act 2.0 (IT-SiG 2.0) was the subject of considerable criticism by various experts in the committee meeting of the German Bundestag on March 1, 2021. All the more reason to take an in-depth look at the German draft law in this issue of the International Cybersecurity Law Review.In addition to this article on the IT-SiG 2.0, the ICLR once again features numerous papers that shed light on cybersecurity regulation around the globe: An introduction to Korean cybersecurity law, the historical development of the cybersecurity framework in Japan, an introduction to Indian cybersecurity law, the regulation of digital space using China as an example, dealing with cybersecurity legislation in the United Kingdom for the post-Brexit period, the data security implications of the annulment of the EU–US Privacy Shield, and an assessment of the German implementation of the EU Digital Services Directive. Other interesting topics in this issue include dealing with COVID-19 and cybercrime from a practical perspective, the legal requirements for establishing an “open search engine,” how cybersecurity and outsourcing can be contractually coordinated, and the contractual requirements to be applied to pen testing. Also worth reading is the proposal for a new, comparative law concept of a “Cybersecurity Governance Triangle” in a European–US legal comparison.With this issue of the ICLR, I would like to wish you many exciting and important insights as you start your legal journey around the world—and please do not hesitate to get in touch should you have feedback on any of the articles or an interesting topic of your own that you would like to write about!With best wishes,Dennis-Kenji Kipkermittlerweile ist mehr als ein Jahr vergangen, und die Coronapandemie hat uns immer noch fest im Griff. Liebgewonnene Gewohnheiten, Urlaubsreisen, Konferenzen, Messen und Meetings und selbst der gewöhnliche Alltag im Büro – vieles wurde abgesagt, noch mehr findet mittlerweile rein digital statt – gegenwärtig mit einer noch unbestimmten Aussicht auf eine Rückkehr zur Normalität. Verglichen mit dem Stand der Digitalisierung, den wir noch vor einem Jahr hatten, ist jedoch viel geschehen, und das, was für viele in der Vergangenheit noch eher Ausnahme denn Regel war, wurde zur Gewohnheit. Die allgegenwärtige Digitalisierung von Beruf und Privatleben zeigt uns aber auch, wie verletzlich die Gesellschaft ist, und dass die Bürgerinnen und Bürger sich auf die Versorgung mit kritischen Diensten und Gütern verlassen können müssen. Wenn dabei alle Ressourcen wie im Regelfall funktionieren, macht sich niemand Gedanken – ganz anders jedoch, wenn einmal das Internet oder das Telefon für einen halben Tag ausfallen, oder, schlimmer noch, die Strom‑, Gas- oder Fernwärmeversorgung nicht mehr funktionieren. Wo man sich zum Leben und Arbeiten pandemiebedingt mehr und mehr in den privaten Raum zurückzieht, muss sichergestellt sein, dass dieser alle Ressourcen bietet, damit Gesellschaft und Wirtschaft weiterhin „remote“ funktionieren können.Dass dies aber nicht immer der Fall ist, verdeutlichte jüngst, im Februar dieses Jahres, der massive Blackout in den USA: Inmitten des Hochwinters wurden Hunderttausende Haushalte von der Stromversorgung und teils auch von der Wasserversorgung abgeschnitten, weil aufgrund der massiven Kälte Transportsysteme und Steuerungselektronik nicht mehr richtig funktionierten. Auch Europa war zu Jahresbeginn 2021 von Stromausfällen und erheblichen Spannungsschwankungen betroffen, mit der realen Gefahr eines totalen Blackouts. Schnell wurden in dieser Zeit politische Forderungen laut, die Versorgungssicherheit der Bevölkerung zu gewährleisten. Bei diesem Thema geht es aber nicht nur um die Stromversorgung, sondern generell um den Schutz kritischer Infrastrukturen – also solcher Einrichtungen, die für das Funktionieren des öffentlichen Lebens zwingende Voraussetzung sind. Hierzu gehören vornehmlich die Sektoren Energie, Ernährung, Finanz- und Versicherungswesen, Gesundheit, Informationstechnik und Telekommunikation, Medien und Kultur, Staat und Verwaltung, Transport und Verkehr sowie die öffentliche Wasserver- und Abwasserentsorgung.Mehr und mehr – und nicht erst seit Beginn der Coronapandemie – sind solche wesentlichen Einrichtungen an das digitale Datennetz angebunden und damit auch unter Gesichtspunkten der Cybersicherheit zunehmend vulnerabel. Schon vor Jahren wurden beispielsweise simulierte Wasserwerke betrieben, die im Internet auffindbar waren (sog. Honeypots), die schon nach wenigen Minuten vorsätzlich von Angreifern kompromittiert wurden. Nachgewiesen wurde in diesem Zusammenhang z. B. auch, dass gerade kleine und mittelständische Betriebe der Wasserversorgung massive Probleme haben, ihre kritischen Systeme hinreichend gegen Cyberangriffe abzusichern.„The EU’s cybersecurity strategy for the digital decade“ am 16.12.2020, und der Entwurf für das neue deutsche IT-Sicherheitsgesetz 2.0 (IT-SiG 2.0) wurde in der Ausschusssitzung des Deutschen Bundestages am 01.03.2021 von verschiedenen Sachverständigen erheblich kritisiert. Umso mehr ein Grund dafür, in dieser Ausgabe des „International Cybersecurity Law Review“ einen vertieften Blick in den deutschen Gesetzentwurf zu wagen.An dieser Stelle tritt der Gesetzgeber auf den Plan, denn nicht nur die Wasser- und Energieversorgung, sondern die Gewährleistung des ordnungsgemäßen Betriebs sämtlicher kritischer Infrastrukturen ist eine zentrale Gewährleistungsaufgabe staatlicher Regulierung. Bereits seit mehreren Jahren werden hierzu in der Gesetzgebung weltweit verschiedene Ansätze vertreten, die in technisch-organisatorischer Hinsicht vielfach Ähnlichkeiten aufweisen, aber in ihrer rechtspolitischen Zielsetzung nicht selten durchaus verschieden sind. Vor allem der deutsche und der europäische Gesetzgeber wandten sich seit dem Ende des vergangenen Jahres wieder verstärkt der gesetzlichen Regulierung von IT-Sicherheit (IT: Informationstechnologie) und speziell von kritischen Infrastrukturen zu. Die EU (Europäische Union) beispielsweise veröffentlichte ihre neue Cybersicherheitsstrategie ICLR auch dieses Mal wieder zahlreiche Beiträge, die die Regulierung der Cybersicherheit rund um den Globus beleuchten: eine Einführung in das koreanische Recht der Cybersicherheit, die historische Entwicklung des „cybersecurity framework“ in Japan, eine Einführung in das indische Recht der Cybersicherheit, die Regulierung des digitalen Raums am Beispiel von China, der Umgang mit Cybersicherheitsgesetzgebung im „United Kingdom“ für die Zeit nach dem Brexit, die datensicherheitsrechtlichen Folgen der Nichtigerklärung des „EU-US Privacy Shield“ und eine Bewertung der deutschen Umsetzung der Richtlinie für digitale Dienste der EU. Interessante Themen dieser Ausgabe sind darüber hinaus der Umgang mit COVID-19 („coronavirus disease 2019“) und Cyberkriminalität aus praktischer Sicht, welche rechtlichen Anforderungen für die Etablierung einer „open search engine“ gelten, wie Cybersicherheit und Outsourcing vertraglich abgestimmt werden können und welche vertraglichen Anforderungen an Pentesting anzulegen sind. Lesenswert ist außerdem der Vorschlag für ein neues, rechtsvergleichendes Konzept eines „cybersecurity governance triangle“ im europäisch-US-amerikanischen (US: „United States“) Rechtsvergleich.Neben diesem Beitrag zum IT-SiG 2.0 finden sich im ICLR wünsche ich Ihnen viele spannende und wichtige Erkenntnisse bei der juristischen Reise rund um die Welt – und zögern Sie nicht, den Kontakt aufzunehmen, sollten Sie Feedback zu einem der Beiträge oder selbst ein interessantes Thema haben, über das Sie gerne schreiben möchten!Auch für diese Ihnen vorliegende Ausgabe des Mit den besten Wünschen und alles Gute,Dennis-Kenji Kipker


Em uso de warfarina e enalapril.Paciente evoluiu sem sintomas desde o nascimento até a juventude, ocasião do advento de hipóxia discreta mas progressiva, que requereu a feitura de anastomose com PTFe de 8 mm entre o tronco braquiocefálico e o tronco pulmonar com 32 anos de idade. Desde então, mantém-se estável com saturação de oxigênio acima de 80 vol. OExame físico: Bom estado geral, eupneico, cianose discreta de extremidades, baqueteamento digital moderado, pulsos normais nos quatro membros. Peso: 67 Kg, Alt.: 170 cm, PAMSD: 140x90 mmHg, FC: 105 bpm, saturação O2= 83%, Hg= 22,1 g/l, Hct= 66%.Precórdio: Abaulamento torácico à esquerda, ictus cordis palpado para fora da linha hemiclavicular esquerda, com impulsões sistólicas nítidas na borda esternal esquerda (BEE). Bulhas cardíacas hiperfonéticas, estalido protossistólico, 2º ruído desdobrado constante, sopro sistólico discreto e suave ao longo da BEE e sopro sistólico moderado na área mitral. Fígado não palpado e pulmões limpos.Eletrocardiograma: Ritmo sinusal, sinais de sobrecarga ventricular direita, com com onda P apiculada a + 70° e complexo QRS com predomínio das ondas S de V4 a V6 e eixo desviado para a direita (AQRS= +110º). A onda T se mostra negativa nas derivações precordiais com alterações difusas da repolarização ventricular em todas as outras derivações . A trama vascular pulmonar aumentada no hilo direito se afila nos campos inferiores na expressão da hipertensão arterial pulmonar deste lado e nitidamente diminuída à esquerda com vasos finos distribuídos pelos vários lobos  cavalgando em mais de 50% o septo interventricular. O átrio direito é muito dilatado  assim como o átrio esquerdo . O ventrículo direito (39 mm) é dilatado e hipertrófico com disfunção discreta, com hipocinesia apical. O ventrículo esquerdo (60 mm) apresenta disfunção com fração de ejeção de 47% mas sem hipertrofia (septo=parede posterior= 10 mm). Arco aórtico à direita com a aorta abdominal à esquerda. Visualiza-se a imagem de shunt da anastomose entre o tronco braquiocefálico e o tronco pulmonar. A artéria pulmonar direita nasce da aorta ascendente e a esquerda é hipoplásica.Cateterismo cardíaco: Mostrou a anatomia de dupla via de saída das grandes artérias do ventrículo direito com fluxo anterógrado pulmonar exíguo (considerada como atresia pulmonar) em continuidade da artéria pulmonar esquerda hipoplásica com o tronco pulmonar também hipoplásico, artéria pulmonar direita dilatada e com hipertensão sistêmica, emergindo da aorta ascendente . Hyperphonetic heart sounds, protosystolic click, constant split 2nd heart sound, discrete and mild systolic murmur along the LSB and moderate continuous murmur in the mitral region. The liver was not palpable, and the lungs were clear.Electrocardiogram: Sinus rhythm, signs of right cavity overload, with apiculate P wave + 70º, QRS complex showing predominance of S waves from V4 to V6 and axis deviated to the right (AQRS= +110°). The T wave was negative in the precordial leads with diffuse ventricular repolarization changes in all other leads . The increased pulmonary vascular network in the right hila tapers off towards the lower lobes, in pulmonary artery hypertension expression, and is clearly reduced on the left side with thin blood vessels coursing through several lobes  and single outflow tract with aorta (50 mm), overriding the interventricular septum for more than 50%. The right atrium is very dilated (RAV=67.2 ml/m2), as well as the left atrium (62.1 ml/m2). The right ventricle (39 mm) is dilated and hypertrophic, with moderate dysfunction and apical hypokinesia. The left ventricle (60 mm) shows dysfunction with ejection fraction of 47%, but without hypertrophy . Right-sided aortic arch with left-sided abdominal aorta. Shunt anastomosis between the brachiocephalic trunk and the pulmonary trunk is visualized. The right pulmonary artery originates from the ascending aorta, and the left one is hypoplastic.Cardiac catheterization: It revealed the anatomy of a double outlet of the great arteries from the right ventricle with minimal antegrade pulmonary blood flow (considered as pulmonary atresia), hypoplastic left pulmonary artery in continuity, associated with hypoplasia of the pulmonary trunk, dilated right pulmonary artery and systemic hypertension originating from the ascending aorta ( g aorta   .Clinical diagnosis: Pulmonary atresia, interventricular communication, anomalous origin of the right pulmonary artery from the ascending aorta, right-sided pulmonary artery hypertension and anastomosis between the brachiocephalic trunk and the pulmonary trunk, with left pulmonary hypoplasia, biventricular dysfunction and signs of chronic progressive hypoxia in later adulthood.Clinical reasoning: There were clinical elements leading to a diagnosis of cyanogenic congenital heart disease with decreased pulmonary flow, with arterial malposition considering the hyperphonetic heart sounds and pulmonary atresia in association with interventricular communication. The right ventricular overload on the electrocardiogram demonstrates the predominance of this ventricle, given the marked pulmonary obstruction. The diagnosis of anomalous origin of the right pulmonary artery from the ascending aorta, leading to ipsilateral pulmonary artery hypertension, could be considered by means of the appreciation and adequate analysis of the markedly dilated pulmonary vascular network. The discrete degree of hypoxia with oxygen saturation of approximately 80% is associated with this increased pulmonary vascular network on the chest X-ray, despite the pulmonary vascular disease. Still, even in adults, it provides a considerable increase in red blood cells and their levels in relation to that of serum. The diagnosis of the anomaly was well established by the echocardiography and mainly by the angiography.Differential diagnosis: Other heart diseases that accompany interventricular communication and pulmonary atresia show other features that differentiate them in the usual complementary exams, such as the double inlet left or right ventricle, in atrioventricular valve atresia, corrected transposition of the great arteries and in rarer diseases. The contrasts in the two pulmonary circulations, more marked on the right and reduced on the left, could orient towards the presence of stenosis on this side and hyperflow due to collateral circulation on the other side. However, in this condition there would be a clear continuous murmur, mainly at the right back. Thus, origin of the right pulmonary artery from the ascending aorta could be clinically considered, even before the anatomical diagnosis.Conduct: Despite the balance of the pulmonary and systemic flows over time, with signs of hypoxemia and myocardial dysfunction, the need to increase pulmonary flow to improve quality of life with better physical tolerance is presumed. In face of the anatomical complexity, right-sided pulmonary artery hypertension and biventricular dysfunction, the consideration of the expectant conduct was not ruled out, despite the development risks involved.Comments: The natural evolution of this patient until the adult age highlights unfavorable elements, related to right-sided pulmonary vascular disease, given the anomalous origin of the right pulmonary artery from the ascending aorta, with clear transmission of systemic blood pressure. Furthermore, chronic hypoxia induced biventricular dysfunction, in addition to other injuries responsible for the greatest ventricular hypertrophy, such as pulmonary atresia and even aortic dextroposition. There was clinical improvement after the performance of systemic-pulmonary anastomosis, which was a useful strategy for hypoxia mitigation. However, in face of the other parameters, a quicker deterioration is expected, with the emergence of thrombosis, embolism, arrhythmias, heart failure complications and even sudden events. On the other hand, the expectant conduct considered was the most plausible in view of the high and considerable surgical risk in this age group, in addition to right-sided pulmonary arterial hypertension, and no adequate functional solution.12The question is, in similar cases in childhood, whether it would be more convenient to attempt an earlier correction. Undoubtedly, it should always be considered at different conditions to create an anatomic shape that is adequate and favorable to blood dynamics.3The combination of these defects is extremely rare since in the literature three similar cases are described, all of them involving the anomalous origin of the left pulmonary artery from the ascending aorta.


Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor . In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes. Angioedema is characterized by non-inflammatory, localized, asymmetric, disfiguring, and self-limited swelling of the deep dermis, subcutaneous, and/or submucosal tissue, resulting from vasodilation and an increase in vascular permeability.,3Due to potential severity, especially when angioedema affects the airways, the therapeutic approach in emergency department is often initiated soon after admission, before taking the medical history and possible identification of the etiology. However, the recognition and differentiation of the different etiologies and pathogenesis of angioedema are important for an efficacious treatment in the emergency department.The mechanism involved in angioedema without urticaria can be mediated by histamine or bradykinin. The most common causes of histaminergic angioedema are food, medication, insect bites, and idiopathic. In bradykinin-mediated angioedema, the most frequent triggers are angiotensin-converting enzyme inhibitors (ACEi) and factors related to hereditary angioedema (HAE) or acquired angioedema (AAE). Although less common, AAE and HAE are relevant because of the possibility of a fatal outcome, if not properly treated. Intestinal wall edema is frequent and disabling, and abdominal pain may be the only manifestation during an attack. Abdominal angioedema attack may be misdiagnosis of acute abdomen leading to unnecessary surgery.Hereditary angioedema is a rare, potentially fatal, and still underdiagnosed disease. Its attacks can affect both the dermis and subcutaneous, as well as internal organs - predominantly the gastrointestinal tract and upper airways - the most feared outcome being laryngeal angioedema. It is estimated that 25% to 40% of HAE attacks lead to death by asphyxia, when untreated. In the cases studied by Bork et al.,the cause of death in one third of patients was asphyxia, those with no confirmed diagnosis being most at risk.In the emergency department, HAE attacks can be mistaken with other types of angioedema, mainly histaminergic. A Brazilian study showed that 29% of patients with HAE reported deaths in family members due to asphyxia.In an Italian study, 0.37% of patients admitted to the emergency department during a six month period presented with angioedema of varyng causes. In Canada, 0.1% of emergency care was due to angioedema of different etiologies, and more than one third of patients reported previous visits for the same cause. No data is avaiable in Brazil on the number of visits to emergency department caused by angioedema attacks.Data from the United States show that approximately 110 thousand emergency department visits per year are due to HAE or AAE. These patients have a higher hospital admission rate than those treated for allergy-caused angioedema.There is an urgent need to inform health professionals, especially those working in emergency department about HAE as well as relevant aspects for the care of angioedema attacks. The authors aim to address these questions.® (PubMed®), Cochrane, and Scientific Electronic Library Online (SciELO) databases, and considered the consensus and guidelines previously published, with the purpose of using practices already approved by experts on the subject, including Brazil, over the last 10 years. The Health Sciences Descriptors (DeCS) “hereditary angioedema”, “emergency” and “bradykinin,” the Boolean operator “AND” and their correspondents in Portuguese were used.We evaluated publications that addressed the topic HAE through revision of MEDLINEi.e., histamine, or bradykinin. This classification allows the identification of the type of angioedema and its appropriate treatment , or by alteration in arachidonic acid metabolism, typified by cases induced by nonsteroidal anti-inflammatory drugs (NSAIDs).Histaminergic angioedema is the most common. It progresses rapidly,Bradykinin-mediated cases are clinically characterized by the absence of urticaria and include HAE, C1-inhibitor AAE (C1-INH), and drug-induced: ACEi, angiotensin II receptor blocker, and glyptins.,12The genetic inheritance of HAE-C1-INH is autosomal dominant, resulting from mutations in the SERPING1 gene, which encodes a serinoprotease, C1-INH, with several sites of action. Such mutations result in quantitative and/or functional deficiency of C1-INH, which causes the exaggerated production of bradykinin, with a consequent increase in vascular permeability and the onset of angioedema. Hereditary angioedema with normal C1-INH is associated with other mutations, and also lead to bradykinin overproduction.,14 Cases of coagulation factor XII (FXII) mutation are the most common.,14Other recently described mutations occur in plasminogen (HAE-PLG),angiopoietin-1 (HAE-ANGPT1), and kininogen-1 (KNG1) genes.There are two subtypes of HAE: due to deficiency of C1-inhibitor (HAE-C1-INH) and with normal C1-INH .The clinical picture is similar to HAE, but the onset of symptoms is later, and the family history is negative.,12AAE-C1-INH results from C1-INH consumption, and the most common causes being lymphoproliferative and autoimmune diseases. Attacks can occur regardless of the length of use, and the ACEi most frequently related to the occurrence of angioedema are captopril, enalapril, and lisinopril. Medications of the group of gliptins, sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin, used to treat type 2 diabetes mellitus, are also potential triggers of angioedema. These drugs inhibit the enzyme dipeptidyl peptidase 4 (DPP4i), which is important in the degradation of bradykinin and substance P.Antihypertensive agents in the ACEi group represent 0.1% to 0.5% of angioedema cases seen in emergency department .Data on the prevalence of bradykinin-mediated angioedema are scarce, and studies show that ACEi angioedema is more common than HAE, and the latter being more common than AAE-C1-INH.Some clinical characteristics, such as age of onset of symptoms, positive family history, the association of urticaria, location of the attack, and speed of onset and progression, permit differentiating five main phenotypes of angioedema .,22 , leading to the release of bradykinin. This kinin binds to its B2 receptor, constitutively expressed in endothelial cells, and interferes with endothelial junctions, increasing vascular permeability and causing angioedema. In C1-INH deficiency, the lack of control of the contact system activation is more relevant to the release of bradykinin. On the other hand, by activation of the complement system, the plasma C4 levels decrease due to lack of C1-INH, and the dosage of C4 is used as a screening test for HAE,22 .,14 Thus, FXII mutant activates rapidly after cleavage by plasmin and escapes from C1-INH inhibition. In cases of HAE with mutations in PLG, ANGPT1, or KNG1 genes, other mechanisms are involved. The PLG, eg., is a circulating zymogen, which is converted into the active plasmin enzyme by cleavage of a peptide bond. Plasmin, the main enzyme of fibrinolysis seems to be involved in the pathogenesis of HAE with normal C1-INH, but the role of the fibrinolytic system in HAE has yet to be fully clarified. In case of mutations in the ANGPT1 gene, the loss of protein function is described, with consequent reduction in the angiopoietin-1 receptor activation capacity, expressed in endothelial cells. This, in turn, would influence vascular permeability. In KNG1 gene mutation, an aberrant bradykinin formation occurs, with a longer half-life and, consequently, more active.In HAE with normal C1-INH, the mutations in FXII result in greater activation of FXII by plasmin, generating the activated factor XII, which acts on pre-kallikrein.When treating patients with angioedema, a detailed medical history, physical examination, and response to conventional treatment with antihistamines (anti-H1), corticosteroids (EC), and epinephrine may indicate the possible etiology. This type of angioedema evolves rapidly, and the most common triggers being medication, food, insect venom, physical , and even idiopathic factors. In these situations, the removal of the trigger and conventional treatment are effective.The presence of urticaria associated with angioedema, both in the current episode and in previous attacks, strongly suggests histaminergic angioedema. High tryptase does not occur in bradykinin-induced angioedema, such as HAE, AAE-C1-INH, or ACEi-induced.When other organs or systems are involved, configuring anaphylaxis, the serum tryptase dosage may corroborate this hypothesis. This test is generally not available in the Brazilian emergency departments, and the delay for the result does not help assistance in the emergency setting. High level of tryptase during the attack will confirm degranulation of mast cells. On the other hand, the normal dosage of tryptase during the attack does not exclude anaphylaxis. In addition, they do not present associated urticaria and do not respond to conventional treatment.,17Although angioedema attacks induced by ACEi, AAE-C1-INH, and HAE, all mediated by bradykinin, usually take hours to become full blown, there are reports of sudden events. In some cases, prodrome signs and symptoms may occur, such as erythema marginatum, characterized by serpinginous erythematous and non-pruritic lesions, which may be confuses with urticaria. A family history of HAE is an important warning sign, but is absent in approximately 25% of cases.The diagnosis of HAE is generally not made in emergency department. Diagnosis requires clinical data such as family history of angioedema, edema persisting for 3 to 5 days, no response to conventional treatment, recurrent airway edema, and abdominal pain episodes with no apparent cause, sometimes with a history of unnecessary abdominal surgeries. Hereditary angioedema with normal C1-INH levels is more associated with estrogen, being even more frequent in women.Another relevant aspect of women with HAE is the higher frequency and/or severity of attacks in periods of a higher estrogen level, either endogenous , or under exogenous administration (contraceptives or hormone replacement) among women.In patients with no other cause of angioedema, but who present any of these indicators, a diagnosis of HAE should be presumed, especially if there is no clinical response to conventional treatment with epinephrin, anti-H1, and CE.The diagnosis of HAE C1-INH is confirmed by quantitative and/or functional evaluation of C1-INH. Laboratory tests are often not available for diagnosis in the emergency department. Nevertheless, the dosage of C4 during the attack may contribute to the diagnosis. It is estimated that almost 100% of these patients have reduced C4 levels during the attack, so, if the level of C4 is normal HAE C1-INH can be ruled out.AAE-C1-INH can be differentiated from HAE-C1-INH as the former, in most cases has low levels of C1q concentration, in addition to the reduction of C4, and quantitative and functional C1-INH. elected the main warning signs for HAE, based on pathophysiology, signs, and symptoms, laboratory tests, and response to specific therapies. To facilitate memorization, the signs were listed in alphabetical order and are called the ABC of angioedema.Grumach et al., All these signs are listed in With the same objective, the Brazilian Group for the Study of Hereditary Angioedema (Gebraeh) created a mnemonic rule with the warning signs for diagnosis of HAE: HAAAAE. Identification of the triggering factor may contribute towards the diagnosis and future follow-up.Hereditary angioedema attacks can be spontaneous or triggered by factors identified by means of a detailed medical history. The following have been described as triggers: trauma, stress, infection, surgical and dental procedures, menses, gestation, alcohol consumption, extreme change in temperature, physical exercise, use of ACEi, exposure to estrogen, among others.  should not be delayed . It is i  pdC1-INH (Berinert®) and icatibant (Firazyr®),27,28 , recombinant human C1-inhibitor (Rh C1-INH), bradykinin B2 receptor antagonist (icatibant), and kallikrein inhibitor .®),27,28 .,29,30 Berinert®, approved in Brazil, is indicated for intravenous administration at a dose of 20IU/kg, regardless of the severity of the attack. Another concentrate of nano-filtrated pdC1-INH (Cinryze®), has been used in fixed doses , in lower severity attacks, such as angioedema of limbs and abdominal pain episodes. However, there is evidence that fixed doses may not be sufficient to control the attacks, and that the 20IU/kg dose is more effective. Bork et al., observed that more than 60% of patients with a laryngeal edema who received fixed doses of C1-INH concentrate required another dose of the drug.C1-INH concentrates for intravenous use have been shown to be efficacious and safe in the treatment, both of children and adults, of all forms of HAE attacks due to C1-INH deficiency.®) is obtained from the purification of transgenic rabbit milk. Studies have demonstrated its efficacy and safety, with no adverse thrombotic events, though it should be used with care in those with allergy to rabbits. It is not available in Brazil, and the established dose is from 60IU to 100IU per kg of body weight, per dose.The recombinant human C1-INH (Ruconest®) is a synthetic molecule, similar to bradykinin, and acts as a competitive and selective antagonist to the bradykinin B2 receptor. The safety and efficacy of icatibant have been demonstrated in three clinical trials - phases I, II, and III.,33 Hereditary angioedema attacks are resolved more quickly with the early, rather than later use of icatibant, therefore, administration is recommended in the first 6 hours after onset of symptoms.It is licensed in Brazil, including for administration at home. Home use is safe, and patients report only erythema and pain at the injection site, with spontaneous resolution. The recommended dose is 30mg for adults and 0.4mg/kg in the age range of 2 to 17 years, subcutaneously, exclusively in the abdominal region. Additional injections may be administered every 6 hours, up to a maximum of three injections in 24 hours.Icatibant (Firazyr®), approved for use in the United States and not available in Brazil. The recommended dose is 30mg subcutaneously, but it is not approved for home administration, since anaphylaxis has been observed in approximately 3% of patients.To date, there are no studies comparing the efficacy of these drugs in randomized clinical trials. We therefore suggest, for greater efficacy, using the available option, as soon as possible after the onset of the attack.The fourth class of drugs to treat attacks is kallikrein inhibitors, such as Ecallantide  and pdC1-INH concentrate (Berinert®) are classified as Category C by the Food and Drug Administration (FDA) for use in pregnancy and lactation. However, these drugs have been used during pregnancy in situations of neccessity, proving to be effective and safe, with no adverse effect for pregnant women and neonates.Icatibant . Some drugs used for treatment of attacks can also be used in prophylaxis, such as pdC1-INH concentrate. Recently, an immunobiological agent has been approved that blocks kallikrein, and consequent bradykinin formation, indicated for long-term prophylaxis..Hereditary angioedema attacks are unusual causes of angioedema in the emergency department. Restricted knowledge of hereditary angioedema by healthcare professionals can lead to incorrect diagnoses, especially when these attacks manifest in internal organs. Although rare, due to its potential for fatality, physicians acting in the emergency department should be aware of the warning signs of hereditary angioedema, especially when there is no response to treatment with usual drugs, such as antihistamines and corticosteroids. The correct and immediate management of these patients prevents unnecessary surgeries and, above all, fatal outcomes. O angioedema caracteriza-se por edema localizado, não inflamatório, assimétrico, desfigurante e autolimitado da derme profunda, tecidos subcutâneo e/ou submucoso, decorrente da vasodilatação e do aumento da permeabilidade vascular.,3Devido a potencial gravidade, principalmente quando o angioedema acomete as vias aéreas, a abordagem terapêutica na emergência é, muitas vezes, realizada logo após a admissão, antes da anamnese e da possível identificação da etiologia. Entretanto, o reconhecimento e a diferenciação das diversas etiologias e patogênese do angioedema são importantes para um tratamento eficaz na emergência.O mecanismo envolvido no angioedema sem urticas pode ser mediado por histamina ou bradicinina. As causas mais comuns de angioedema histaminérgico são alimentos, medicamentos, ferroada de insetos e idiopática. No angioedema mediado por bradicinina, os desencadeantes mais frequentes são os inibidores da enzima conversora de angiotensina (iECA) e fatores relacionados ao angioedema hereditário (AEH) ou angioedema adquirido por deficiência do inibidor de C1 (AEA). Embora menos comuns, o AEA e o AEH são relevantes, pela possibilidade de desfecho fatal, caso uma terapêutica inapropriada seja adotada. O edema de alças intestinais é frequente e incapacitante, e a dor abdominal pode ser a única manifestação durante a crise. Pode ocorrer o diagnóstico equivocado de abdome agudo ocasionando cirurgia desnecessária.O AEH é uma doença rara, potencialmente fatal e ainda subdiagnosticada, cujas crises podem acometer tanto a derme e o subcutâneo, quanto órgãos internos – predominantemente o trato gastrintestinal e as vias aéreas superiores –, sendo o desfecho mais temido o angioedema laríngeo. Estima-se que 25% a 40% das crises de AEH evoluem para óbito por asfixia, quando não tratadas. Na casuística de Bork et al., em um terço dos pacientes que foram a óbito, a causa foi asfixia, sendo o risco maior naqueles sem diagnóstico confirmado.Na emergência, as crises de AEH podem ser confundidas com outros tipos de angioedema, principalmente o histaminérgico. Estudo brasileiro mostrou que 29% dos pacientes com AEH relataram óbitos em familiares por asfixia.Em estudo italiano, 0,37% dos pacientes admitidos nas emergências durante 6 meses foram diagnosticados com angioedema por causas diversas.No Canadá, 0,1% dos atendimentos nas emergências foram por angioedema de diferentes etiologias, e mais de um terço dos pacientes relataram visitas prévias pela mesma causa. No Brasil, não há dados disponíveis sobre o número de atendimentos por crises de angioedema nas emergências.Dados dos Estados Unidos mostram que, anualmente, ocorrem aproximadamente 110 mil visitas às emergências por AEH ou AEA, e esses pacientes apresentam taxa de admissão hospitalar maior em relação aos atendidos por angioedema de causa alérgica.Considerando-se a necessidade de melhorar o conhecimento sobre o AEH por parte dos profissionais de saúde, especialmente os que atuam em emergências, os autores abordam os aspectos relevantes para o atendimento das crises de angioedema.® (PubMed®), Cochrane e Scientific Electronic Library Online (SciELO), e considerados os consensos e diretrizes previamente publicados, com a finalidade de utilizar práticas já aprovadas por experts no assunto, inclusive em nosso país, nos últimos 10 anos. Foram utilizados os Descritores em Ciências da Saúde (DeCS) “hereditary angioedema”, “emergency” e “bradykinin”, o operador booleano AND e suas correspondentes em português.Foram avaliadas publicações que abordassem o tema AEH por meio de revisão em bases de dados MEDLINE , ou por alteração no metabolismo do ácido araquidônico, como nos casos induzidos por anti-inflamatórios não esteroidais (AINEs).O angioedema histaminérgico é o mais frequente. Tem evolução rápida,Os casos mediados por bradicinina caracterizam-se clinicamente pela ausência de urticas e incluem o AEH, o AEA-inibidor de C1 (C1-INH) e o induzido por iECA, bloqueador do receptor de angiotensina II e gliptinas.,12 A herança genética do AEH C1-INH é autossômica dominante, decorrente de mutações no gene SERPING1, que codifica uma serinoprotease, o C1-INH, com vários locais de atuação. Tais mutações resultam em deficiência quantitativa e/ou funcional de C1-INH, o que ocasiona a produção exagerada de bradicinina, com consequente aumento da permeabilidade vascular e surgimento de angioedema. O AEH com C1-INH normal está associado a outras mutações, e também resulta da produção exagerada de bradicinina.,14 O maior número de casos descritos é de mutação no fator XII da coagulação (FXII).,14 Outras mutações recentemente descritas são nos genes do plasminogênio (AEH-PLG), da angiopoietina-1 (AEH-ANGPT1), e do cininogênio 1 (KNG1).O AEH tem dois subtipos: por deficiência do inibidor de C1 (AEH C1-INH) e com C1-INH normal .O quadro clínico é semelhante ao AEH, mas o início dos sintomas é tardio, e a história familiar é negativa.,12O AEA-C1-INH ocorre devido ao consumo de C1-INH, e as causas mais comuns são as doenças linfoproliferativas e autoimunes. As crises podem ocorrer independentemente do tempo de uso, e os iECA mais relacionados à ocorrência de angioedema são o captopril, o enalapril e o lisinopril. Os medicamentos do grupo das gliptinas, sitagliptina, vildagliptina, saxagliptina, alogliptina e linagliptina, utilizados no tratamento do diabetes mellitus tipo 2, também são potenciais desencadeantes de angioedema. Esses fármacos inibem a enzima dipeptidil peptidase 4 (DPP-4), que é importante na degradação da bradicinina e da substância P.Os anti-hipertensivos do grupo de iECA são causa frequente de atendimentos por angioedema nas emergências e representam 0,1% a 0,5% desses casos.Dados sobre a prevalência de angioedema mediado por bradicinina são escassos, e estudos mostram que o angioedema por iECA é mais comum que o AEH, e, por sua vez, este é mais comum que o AEA-C1-INH.Algumas características clínicas, como, por exemplo, idade de início dos sintomas, história familiar positiva, urticas associadas, localização da crise e velocidade de instalação, permitem diferenciar os cinco principais fenótipos de angioedema .,22 , levando à liberação da bradicinina. Essa cinina liga-se ao seu receptor B2, que é constitutivamente expresso em células endoteliais e interfere nas junções endoteliais, aumentando a permeabilidade vascular e provocando angioedema. Na deficiência do C1-INH, a falta de controle da ativação do sistema de contato é mais relevante para a liberação da bradicinina. Por outro lado, por ativação do sistema complemento, o nível plasmático de C4 diminui por falta do C1-INH, sendo a dosagem de C4 utilizada como exame de triagem para o AEH,22 .,14 Dessa forma, o FXII mutante ativa-se rapidamente após clivagem pela plasmina e escapa da inibição de C1-INH. Nos casos de AEH com mutações nos genes PLG, ANGPT1ou KNG1, outros mecanismos estão envolvidos. O PLG, por exemplo, é um zimogênio circulante, que é convertido na enzima ativa plasmina por clivagem de uma ligação peptídica. A plasmina é a principal enzima da fibrinólise, que parece estar envolvida na patogênese do AEH com C1-INH normal, mas o papel do sistema fibrinolítico no AEH ainda não está totalmente esclarecido. No caso das mutações no gene da ANGPT1, é descrita a perda da função da proteína, com consequente redução da capacidade da ativação do receptor tirosina-quinase 2 (TIE2), expresso em células endotelais. Este, por sua vez, atuaria na menor permeabilidade vascular. Na mutação no gene do KNG1, ocorre formação de uma bradicinina aberrante, com meia-vida mais prolongada e, consequentemente, mais ativa.Em relação ao AEH com C1-INH normal, as mutações no FXII resultam em ativação maior do FXII pela plasmina, gerando o fator XII ativado, que atua na pré-calicreína.Na abordagem do paciente com angioedema, a história clínica detalhada, os aspectos do exame físico e a resposta ao tratamento convencional com anti-histamínicos (anti-H1), corticosteroides (CE) e adrenalina podem indicar a possível etiologia. Esse tipo de angioedema evolui rapidamente, e os desencadeantes mais comuns são medicamentos, alimentos, veneno de insetos, fatores físicos  ou, ainda, idiopáticos. Nessas situações, a remoção do fator desencadeante e o tratamento convencional são eficazes.A presença de urticas associadas ao angioedema, tanto no episódio atual como em crises prévias, sugere fortemente angioedema histaminérgico. A triptase elevada não ocorre no angioedema induzido por bradicinina, como AEH, AEA-C1-INH ou induzido por iECA.Quando houver acometimento de outros órgãos ou sistemas, configurando anafilaxia, a dosagem da triptase sérica pode corroborar essa hipótese. Esse exame geralmente não está disponível nos serviços de emergência brasileiros, e a demora para o resultado não permite auxiliar a abordagem na emergência, porém, um nível elevado de triptase durante a crise confirma desgranulação dos mastócitos. Por outro lado, a dosagem normal de triptase na crise não exclui anafilaxia. Além disso, não apresentam urticas associadas e não respondem ao tratamento convencional.,17As crises de angioedema induzidas por iECA, AEA-C1-INH e AEH, todas mediadas por bradicinina, costumam levar horas até a instalação completa, mas existe descrição de quadros súbitos. Em alguns casos, podem ocorrer sinais e sintomas prodrômicos, como o eritema marginado, caracterizado por lesões eritematosas, serpinginosas e não pruriginosas, que podem ser confundidas com urticas. A história familiar de AEH é um sinal de alerta importante, mas está ausente em aproximadamente 25% dos casos.Quanto ao AEH, o diagnóstico geralmente não é feito no atendimento da emergência. Alguns dados clínicos contribuem para o diagnóstico, como antecedente familiar de angioedema, edemas que persistem por 3 a 5 dias, não resposta ao tratamento convencional, edema de via aérea recorrente, crises de dor abdominal sem causa aparente, por vezes, com história de cirurgias abdominais não terapêuticas (“laparotomias brancas”). O AEH com níveis normais de C1-INH está mais associado ao estrógeno, sendo ainda mais frequente em mulheres.Outro dado que chama a atenção nos portadores de AEH é que as mulheres costumam ter maior frequência e/ou gravidade de crises em fases de maior nível estrogênico, seja endógeno , seja sob administração exógena .Pacientes sem outra causa de angioedema, com algum desses achados, devem ser abordados como possíveis portadores de AEH, principalmente se não houver resposta clínica ao tratamento convencional com adrenalina, anti-H1 e CE.O diagnóstico do AEH C1-INH é confirmado por avaliação quantitativa e/ou funcional do C1-INH. Exames laboratoriais não são indispensáveis para o diagnóstico na emergência. Entretanto, a dosagem de C4 durante a crise pode contribuir para o diagnóstico. Estima-se que quase 100% desses pacientes tenham redução dos níveis de C4 durante a crise, ou seja, o C4 normal na crise permite excluir AEH C1-INH.O AEA-C1-INH pode ser diferenciado do AEH C1-INH por meio da dosagem de C1q, que se encontra em níveis baixos, além da redução de C4, C1-INH quantitativo e funcional. elegeram os principais sinais de alerta para o AEH, baseados na fisiopatologia, sinais e sintomas, exames laboratoriais e resposta a terapias específicas. Para facilitar a memorização, os sinais foram listados em ordem alfabética e chamados de ABC do angioedema.Grumach et al., Todos esses sinais estão listados na Ainda, com o mesmo objetivo, o Grupo de Estudos Brasileiro em Angioedema Hereditário (Gebraeh) criou uma regra mnemônica com os sinais de alerta para o diagnóstico do AEH: HAAAAE. A identificação do fator desencadeante pode contribuir para o diagnóstico e seguimento futuro.As crises de AEH podem ser espontâneas ou desencadeadas por fatores identificados por meio de história clínica detalhada. São descritos como desencadeantes: trauma, estresse, infecção, procedimento cirúrgico e dentário, menstruação, gestação, consumo de bebida alcoólica, mudança extrema de temperatura, exercício físico, uso de iECA, exposição ao estrógeno, entre outros.  . É impor: o pdC1-INH (Berinert®) e o icatibanto (Firazyr®),27,28 , inibidor de C1 recombinante humano, (Rh C1-INH), antagonista do receptor B2 da bradicinina (icatibanto) e inibidor da calicreína .®),27,28 .,29,30 O Berinert®, aprovado no Brasil, é indicado para administração por via intravenosa na dose de 20UI/kg, independente da gravidade da crise. Outro concentrado de pdC1-INH nanofiltrado (Cinryze®), foi utilizado em doses fixas (500UI ou 1.000UI), em crises de menor gravidade, como no angioedema de extremidades e nas crises abdominais. Entretanto, existem evidências de que doses fixas podem não ser suficientes para controlar as crises, e a dose de 20UI/kg é mais eficaz. Bork et al., observaram que mais de 60% dos pacientes com crise de edema de laringe que receberam doses fixas de concentrado de C1-INH necessitaram de nova dose do medicamento.Os concentrados de C1-INH para uso intravenoso demonstraram ser eficazes e seguros no tratamento de todas as formas de crises de AEH por deficiência do C1-INH em crianças e adultos.®) é obtido a partir da purificação de leite de coelhas transgênicas. Estudos demonstraram sua eficácia e segurança, sem eventos adversos trombóticos, com recomendação de cuidado para seu uso em alérgicos a coelhos. Não está disponível no Brasil, e a dose estabelecida é de 60UI a 100UI por kg de peso corporal, por dose.O C1-INH recombinante humano (Ruconest®) é uma molécula sintética, semelhante à bradicinina, e age como antagonista competitivo e seletivo do receptor B2 da bradicinina. A segurança e a eficácia do icatibanto foram demonstradas em três ensaios clínicos de fases I, II e III.,33 As crises de AEH são resolvidas mais rapidamente com o uso precoce do icatibanto em comparação com o uso tardio. Por isso, recomenda-se a administração nas primeiras 6 horas após o início dos sintomas. No Brasil, está licenciado, inclusive para autoadministração domiciliar. O uso domiciliar é seguro, e os pacientes relatam apenas eritema e dor no local da injeção, com resolução espontânea. A dose preconizada é de 30 mg para adultos e de 0,4mg/kg na faixa etária de 2 a 17 anos, por via subcutânea, exclusivamente na região abdominal, podendo ser administradas injeções adicionais, a cada 6 horas, até o máximo de três injeções em 24 horas.O icatibanto (Firazyr®), aprovado para utilização nos Estados Unidos e indisponível no Brasil. A dose recomendada é de 30mg por via subcutânea, e não está aprovado para autoadministração domiciliar, pois a anafilaxia foi observada em aproximadamente 3% dos pacientes. Até o momento, não existem estudos comparando a eficácia desses fármacos em ensaios clínicos randômicos. Portanto, sugerimos usar a opção disponível, e com menor tempo possível entre o início da crise e sua aplicação, para melhor eficácia.A quarta classe de drogas para tratamento das crises é a dos inibidores da calicreína, cujo representante é o Ecallantide  e o icatibanto (Firazyr®) são classificados como categoria C do Food and Drug Administration (FDA) para uso na gravidez e na lactação. Entretanto, esses medicamentos têm sido usados durante a gestação em situações nas quais se fazem necessários, mostrando-se eficazes e seguros, sem qualquer consequência para as gestantes e os neonatos.O concentrado do C1-INH . Alguns medicamentos utilizados para o tratamento das crises também podem ser usados na profilaxia, como, por exemplo, o concentrado do pdC1-INH. Recentemente, foi aprovado um imunobiológico que bloqueia a calicreína e, consequentemente, a formação de bradicinina, indicado para profilaxia de longo prazo.As crises de angioedema hereditário são causas pouco comuns de angioedema na emergência. O conhecimento restrito sobre o angioedema hereditário por parte dos profissionais de saúde pode levar ao diagnóstico incorreto, principalmente quando essas crises se manifestam em órgãos internos. Apesar de raro, devido ao seu potencial de gravidade, os médicos que atuam na emergência devem estar atentos aos sinais de alerta do angioedema hereditário, principalmente quando não há resposta ao tratamento com drogas usuais, como anti-histamínicos e corticosteroides. O manejo correto e imediato desses pacientes evita cirurgias desnecessárias e, principalmente, desfechos fatais.


Their affiliation should have read as follows: “Instituto de Física Corpuscular (IFIC), CSIC–Universitat de València, Valencia, Spain.” This article has been corrected.1In the Original Investigation titled “Evaluation of Combined Artificial Intelligence and Radiologist Assessment to Interpret Screening Mammograms,”


Reconstruct types of simultaneous stress trajectories in the family and employment domain at different stages of life and estimate their association with cerebrovascular accident (CVA) in old age.We used a retrospective, face-to-face, representative survey of people aged 65 to 75 years in the city of Santiago, Chile, (n = 802). We performed a multichannel sequence analysis to reconstruct family and employment stress trajectory types at various life stages and then used logistic regression models to estimate the association of these trajectory types with CVA in old age, controlled for traditional cardiovascular risk factors.Four representative types of family and employment stress trajectories were identified: (1) Absence of family and employment stress, (2) Absence of family stress, persistent employment stress, (3) Absence of family stress, out of the labor market, and (4) Persistent family stress, absence of employment stress. The 61.7% of the sample followed trajectories marked by the permanent presence of family and/or employment stress. Likewise, 18.3% had a trajectory characterized by prolonged absence from the labor market. Individuals with persistent family or employment stress trajectories, as well as those with extended periods of inactivity, are more at risk of developing CVA.Stress is a risk factor for cardiovascular disease experienced by many people at different stages and domains of life on a prolonged basis. Consequently, prevention systems for this type of chronic diseases should emphasize the highly harmful effects of daily and cumulatively stressful life experiences. This could mitigate the multiple health and financial consequences associated with CVA. Among cardiovascular diseases, cerebrovascular accident (CVA) is the second leading cause of death in men and women (11.9 million deaths)2 and the third leading cause of disability in adults3.Cardiovascular diseases are a group of disorders of the circulatory and coronary systems that occur regularly in adulthood and old age3. Epidemiological evidence indicates that these factors include smoking, high blood pressure, high cholesterol levels, diabetes mellitus, obesity, physical inactivity, alcohol consumption and inadequate dietary patterns4. However, there is also an emphasis on the growing influence of psychosocial, environmental and behavioral factors. Among these, stress is a crucial determinant5, as it is associated with the development of premorbid processes that lead to the occurrence of CVA6. Specifically, acute and long-term stressful experiences can trigger pathological cardiac events and are associated with an increased risk of developing CVA and greater associated mortality9.Approximately 90% of CVA can be attributed to modifiable risk factors12. For example, the accumulation of adverse experiences during childhood, such as parental illness, prolonged family conflict or financial problems showed to have a significantly positive effect on the risk of CVA later in life11. On the other hand, some studies suggest that facing stressful events during adulthood, whether earthquakes13 or family and interpersonal events such as the loss of a partner, as well as isolation of community, are associated with an increase in CVA14.From life course epidemiology, the development of CVA is a result of multiple exposures to adverse social, physical and psychological conditions during different stages of people's lives15.In addition to stressful family experiences, another domain in which people often face stressful situations is the labor market. Evidence suggests that those exposed to multiple employment stressors, such as a high workload and long working hours, are at increased risk of developing CVA, especially when stress exposures are frequent over timeDespite the advances in relation to the effect of family and employment stressors on the risk of CVA, there are at least three aspects that still require further elaboration in this study field. First, most research so far considers measurements of stress and CVA at one or two life stages. This precludes understanding family or employment stress patterns along people's lives, as well as their cumulative effect on CVA.Second, despite the growing evidence on the consequences of family and employment stressors on CVA, most studies focused on only one domain separately to measure the presence of stress. Consequently, the studies have been ignored the simultaneous impact of experiencing family and employment stress on this type of pathology. The simultaneous effect of family and employment stress is relevant because the harmful effect of the presence of stress in one of these domains could be compensated by the absence of stress in the other; or the effect on CVA could be greater due to the presence of stress in both life domains.15. After an exhaustive review of the current evidence, we did not find any studies on trajectories of employment or family stress and CVA in developing or middle-income countries, such as those in the Latin American. Understanding the relationship between stress trajectories and CVA could allow us to reorient public policies for the prevention of this type of disease in Latin American countries as well, directing efforts towards stress mitigation in different domains and stages of people's lives.Third, the growing research in this field almost exclusively occurs in high-income countries with better health promotion and disease prevention-oriented health systems, such as Finland and the United KingdomConsidering these knowledge gaps, the present study has two main objectives: reconstruct different types of simultaneous stress trajectories in the family and employment domains during the life of individuals in Chile; and estimate the association of these types of trajectories on the presence of CVA in old age.Curso de vida y vulnerabilidad en personas mayores en Santiago, Chile” , which collected retrospective information on multiple life domains, such as residential, educational and occupational histories, health risk habits, marital and fertility patterns, financial vulnerabilities, and health status in old age. The survey was face-to-face, conducted between March and August 2019, obtaining representative information from 802 people aged 65 to 75 years old residing in Santiago, Chile.This study used data from the survey “16. The selection of the sample of individuals was random, with a maximum variance (p = 0.5), a confidence level of 95%, and an estimated error of ± 3.5 points for an infinite population. To mitigate possible non-response bias in the sample selection, we adjusted the database by a weighting factor that corrects our estimates for known population characteristics of this age group in Santiago, such as areas of residence, educational level and sex.We conducted the data collection following the quality standards defined by the American Association for Public Opinion Research18 was used to collect the data, specially designed to help the interviewees remember and chronologically organize the episodes of their lives with approximate dates of occurrence. 18.A retrospective instrument called “life course calendar”felt stress due to family causes”; in the employment domain we asked them to answer “yes” or “no” to the question “Was it generally a stressful employment?” for each of the jobs they had during their life. From these questions, we first created the variable “employment stress”, which measured the categories “presence of stress”, “absence of stress” or “out of the labor market” in the case of a year in which the person was outside the labor force. Secondly, we created the variable “family stress”, which similarly identified for each year of people's lives the categories: “presence of stress” and “absence of stress”.To reconstruct types of family and employment stress trajectories, we considered life course calendar questions in which we asked to each participant to identify periods in their lives when they experienced family and employment stress according to their own criteria. Specifically, while for the family domain we asked each participant to mark the years in which they “Has a doctor ever told you that you have or had any of the health problems listed on this card? Remember that they may be health problems that you currently have or had in the past.” Among the options was “Stroke or cerebral vascular disease”.The dependent variable in our study corresponds to having experienced a cerebrovascular accident or not. Following international standards, the participants were asked: “Considering studies conducted in high-income countries, the analyses were first adjusted for the following four sociodemographic variables: age, sex , educational level , and health coverage . The latter variable is a proxy indicator of the socioeconomic level of the respondent, since people with a better financial situation have access to private health coverage. Our analyses were also adjusted for traditional CVA risk factors, such as body mass index ; physical activity (one or more times per week / once a month or less); frequency of consumption of (1) dairy, (2) legumes, beans or eggs and (3) meat, fish or poultry (one or more times per week / less than once a week); current smoking (presence/absence); and diagnosis of hypertension (presence/absence).21 to reconstruct representative types of simultaneous trajectories of family and employment stress during the life course. Multichannel sequence analysis allows comparing similarities and differences between life trajectories in two or more life domains (in this case employment stress and family stress), by estimating the distance between these trajectories. Distance is the cost of transforming the trajectory of an individual in a specific domain to the trajectory of another individual in that domain, through two specific operations: status substitution from which trajectories are measured, and insertion or elimination of this status22.First, we employed multichannel sequence analysis23, which allowed us to group trajectories similar to each other (with less distance between them) into different clusters or representative types of family and employment stress trajectories. Finally, to determine the most robust number of trajectory types representative of the diversity of possible trajectories in the sample, we used four statistical selection criteria: average silhouette width (ASW), point biserial correlation (PBS), Hubert's gamma (HG) and Hubert's C (HC)24. The scores of these criteria ranges from −1 to 1, or from 0 to 1. To ensure comparability between the criteria, their scores were standardized. In the case of ASW, PBC and HG, higher values mean a better solution, while lower values in HC indicate a better solution.Once the distances between all individual trajectories are obtained, they are inserted into a distance matrix, on which a hierarchical cluster analysis is performed using Ward's method25, specifically with the statistical package TraMineR22 to estimate multichannel sequence analyses, and the statistical package survey26 to work with a weighted database.After identifying the most robust number of family and employment stress trajectory types, this became the main independent variable in a logistic regression model in which we measure its association with CVA, adjusting for the control variables indicated previously. We conducted the analyses in this study in the statistical software RThe estimated weighted univariate proportions of the dependent and control variables are in The first type, “Absence of family stress, persistent employment stress”, includes 54.8% of the sample and corresponds to people who mostly described not having felt stress due to family causes, but permanently due to employment causes. This group reports having experienced employment stress mostly from the age of 20 years old constantly, which decreases after the age of 50 years when the leaving from the labor market begins to increase progressively.The second type of trajectory, “Absence of family stress, out of the labor market”, gathers 18.3% of the sample, characterized by people who most of the time in their lives were without a paid work, and who did not report having felt stress due to family causes. In this group, some people report having suffered employment stress in early adulthood (from 18 to 30 years of age), but then left the labor market.The third type of trajectory, “Persistent family stress, absence of employment stress”, included 6.9% of the sample and was composed of individuals who mostly reported no employment stress, but reported family stress. In this type, even some people are classified as having felt family stress since early childhood, increasing markedly after the age of 18 and remaining constant until after 60 years old.Finally, the fourth type of trajectory “Absence of family and employment stress” includes 20% of the sample and consists of people who mostly described not having felt stress due to family or employment stress in their lives.The model that considers adjustments for all control variables shows that the possibility of suffering a CVA is significantly higher in all types of stress trajectories, compared to those subjects grouped in the “Absence of family and employment stress” trajectory. Specifically, in those subjects that compose the trajectory “Absence of family stress, persistent employment stress”, the probability of suffering a CVA is more than twice higher . While for those classified in the “Absence of family stress, out of the labor market” trajectory, the probability is more than seven times higher , and for those who followed the trajectory “Persistent family stress, absence of employment stress” the probability is more than ten times higher . In relation to the control factors, having private health coverage, as well as the consumption of legumes, beans or eggs more than once a week, reduces the risk of CVA.27, we conducted a sensitivity analysis including interaction effects between trajectory types and sex on CVA risk  followed trajectories marked by the permanent presence of family and/or employment stress. Likewise, a not smaller proportion (18.3%) had a trajectory characterized by prolonged absence from the labor market.28.In terms of the association with CVA, we observed that trajectories characterized by permanent exposure to stressful family and/or employment situations during life are significantly associated with the presence of this cardiovascular disease. These findings are consistent with previous cross-sectional studies. For example, in a meta-analysis of 14 studies involving 10,130 patients diagnosed with CVA, a 33% increased risk of this disease was estimated among those who reported experiencing family, employment, or financial stress29. In addition, our sensitivity analysis . This result is in line with previous studies that have observed a relevant effect on the presence of CVA in those individuals facing stressful marital and interpersonal relationshipsanalysis  show tha31. In addition, other studies in Latin America indicate a higher mortality associated with CVA in inactive subjects.32. One possible explanation for this association is that, especially in countries such as Chile, having a continuous work implies obtaining a financial income that allows satisfying individual needs such as access to better preventive health services and pharmacological treatments35.On the other hand, our study evidences a strong association with CVA among people who report not having suffered stress due to family causes, but were out of the labor market for prolonged periods of time. These results are also consistent with previous cross-sectional studies, which show that those who stop working for pay have more than twice the risk of CVA , especially if the inactivity occurs involuntarilyThis study has some limitations that should be considered when interpreting findings. First, due to inevitable memory bias, respondents may have inaccurately reported early life experiences. To mitigate this bias, the life course calendar employed in this study incorporated methodological innovations aimed at strengthening autobiographical memory, such as the decomposition of life domains into different subcategories, the use of illustrative visual supports, and the orientation of a properly trained interviewer in the process of filling out the questionnaire. Second, in relation to the sample, it is relevant to consider that it is representative of the capital, but not of all of Chile. This is important, since the centralized nature of the country means that access to health services is greater and of better quality in the capital than in the rest of the regions. A final relevant limitation refers to the fact that the report of stress by the participants depends closely on their perception of the concept of “stress”. We know, however, that there is no single definition of this term, as it encompasses psychological, emotional, motivational and cognitive aspects. Likewise, when identifying employment stress, participants may have considered different aspects than when reporting family stress.This study has relevant implications for the field of cardiovascular diseases. CVA are highly prevalent pathologies, with catastrophic health consequences and highly associated with modifiable risk factors, including stress. In order to reduce mortality and the consequences that these pathologies have on the population, it is essential to consider these risk factors and strengthen health systems with a promotional and preventive approach, focusing on reducing health inequities, and not only on optimizing medical technologies for treatment and rehabilitation.As this study suggests, stress is a risk factor experienced on a prolonged basis by a high proportion of people at different stages and domains of life. Consequently, it is necessary to adopt a promotional and preventive approach that emphasizes the adverse effects of experiencing daily and cumulatively stressful situations. The formulation of public policies aimed at reducing stress could contribute to mitigating the risk of CVA in traditionally susceptible populations. 1, y representan actualmente la principal causa de muerte en el mundo, alcanzando 17,8 millones de muertes2. Entre las enfermedades cardiovasculares, el accidente cerebrovascular (ACV) es la segunda causa de muerte en hombres y mujeres 2, y la tercera causa de discapacidad en adultos3.Las enfermedades cardiovasculares son un grupo de desórdenes del sistema circulatorio y coronario que se manifiestan regularmente en la adultez y la vejez3. La evidencia epidemiológica ha destacado que entre estos factores se encuentran el hábito tabáquico, presión arterial elevada, niveles nocivos de colesterol, diabetes mellitus, obesidad, inactividad física, consumo de alcohol y patrones dietéticos inadecuados4. Sin embargo, también se ha enfatizado la creciente influencia de factores de tipo psicosocial, del entorno y del comportamiento. Entre ellos, el estrés se considera un determinante crucial5, pues se asocia al desarrollo de procesos premórbidos que conducen a la aparición de ACV6. Específicamente, las experiencias estresantes agudas y de larga duración pueden desencadenar eventos cardíacos patológicos y se asocian a un mayor riesgo de desarrollar ACV y a una mayor mortalidad asociada9.Se estima que aproximadamente el 90% de los ACV pueden ser atribuidos a factores de riesgo modificables12. Por ejemplo, la acumulación de experiencias adversas durante la niñez, tales como enfermedades de los padres, conflictos familiares prolongados o problemas financieros, han mostrado un efecto significativamente positivo sobre el riesgo de ACV en etapas posteriores de la vida11. Por otra parte, algunas investigaciones sugieren que enfrentar eventos estresantes durante la adultez, ya sea terremotos13 o eventos familiares e interpersonales como la pérdida de la pareja, así como el aislamiento comunitario, inciden en un aumento de ACV14.Desde la epidemiología de curso de vida, el desarrollo de ACV se ha entendido como el resultado de múltiples exposiciones a condiciones sociales, físicas y psicológicas adversas durante distintas etapas de la vida de las personas15.Además de las experiencias familiares estresantes, se ha descrito que otro de los dominios en el que las personas suelen enfrentar situaciones de estrés es el mercado laboral. La evidencia sugiere que aquellas personas expuestas a múltiples estresores laborales, por ejemplo una alta carga laboral y jornadas extensas de trabajo, presentarían mayor riesgo de desarrollar ACV, especialmente cuando las exposiciones a estrés son frecuentes en el tiempoA pesar de los avances en relación al efecto de estresores familiares y laborales sobre el riesgo de ACV, existen al menos tres aspectos que aún requieren mayor elaboración en este campo de estudio. En primer lugar, hasta el momento la mayoría de las investigaciones consideran mediciones del estrés y de ACV en una o dos etapas de la vida. Esto impide entender patrones de estrés de tipo familiar o laboral a lo largo de la vida de las personas, así como su efecto acumulativo sobre el ACV.En segundo lugar, pese a la creciente evidencia sobre las consecuencias de estresores familiares y laborales sobre ACV, la mayoría de los estudios se han centrado en uno u otro dominio por separado para medir la presencia de estrés. En consecuencia, se ha ignorado el impacto simultáneo de experimentar estrés familiar y laboral sobre este tipo de patologías. El efecto simultáneo de estrés por causas familiares y laborales es relevante por cuanto el efecto nocivo de la presencia de estrés en uno de estos dominios podría ser compensado por la ausencia de estrés en el otro; o por el contrario, el efecto sobre el ACV podría verse aumentado por la interacción de la presencia de estrés en ambos dominios de vida.15. Luego de revisar exhaustivamente la evidencia actual, no se encontraron estudios sobre trayectorias de estrés laboral o familiar y ACV en países en desarrollo o de ingresos medios, como aquellos de la región latinoamericana. Comprender la relación entre trayectorias de estrés y ACV podría permitir reorientar las políticas públicas de prevención de este tipo de enfermedades también en los países latinoamericanos, dirigiendo esfuerzos hacia la mitigación del estrés en diferentes dominios y etapas de la vida de las personas.En tercer lugar, la creciente investigación en este campo ha sido conducida casi únicamente en países de altos ingresos, los que cuentan con sistemas sanitarios mejores y orientados a la promoción de la salud y prevención de enfermedades, tales como Finlandia y Reino UnidoConsiderando estas brechas de conocimiento, el presente estudio se plantea dos objetivos principales: Reconstruir diferentes tipos de trayectorias de estrés simultáneo en el dominio familiar y laboral durante la vida de las personas en Chile; y estimar la asociación de dichos tipos de trayectorias sobre la presencia de ACV en la vejez.Este estudio utilizó datos de la encuesta “Curso de vida y vulnerabilidad en personas mayores en Santiago, Chile”, la cual recolectó información retrospectiva en múltiples dominios de la vida, tales como historias residenciales, educacionales y ocupacionales, hábitos de riesgo para la salud, patrones maritales y de fertilidad, vulnerabilidades financieras, y estados de salud en la vejez. La encuesta fue cara a cara, aplicada entre marzo y agosto del año 2019, y obtuvo información representativa de 802 personas de 65 a 75 años de edad que residían en Santiago de Chile.16. La selección de la muestra de individuos fue aleatoria, con una varianza máxima , un nivel de confianza del 95%, y un error estimado de ± 3,5 puntos para una población infinita. Para mitigar los posibles sesgos de no respuesta en la selección de la muestra, la base de datos fue ajustada por un factor de ponderación que corrige nuestras estimaciones por características poblacionales conocidas de este tramo de edad en Santiago, tales como zonas de residencia, nivel educacional y género.La recopilación de datos se realizó siguiendo los estándares de calidad definidos por la Asociación Americana de Investigación de Opinión Pública18, diseñado especialmente para ayudar a los entrevistados a recordar y organizar cronológicamente los episodios a lo largo de sus vidas con fechas aproximadas de ocurrencia. En la 18.Para recopilar los datos se utilizó el instrumento retrospectivo llamado “calendario de curso de vida”sintió estrés por causas familiares”, en el dominio laboral se le pidió que para cada uno de los trabajos en los que se había desempeñado durante su vida respondiera “sí” o “no” a la pregunta “¿En general fue un trabajo estresante?”. A partir de estas preguntas, se creó en primer lugar la variable “estrés laboral”, que midió para cada año de vida de las personas las categorías “presencia de estrés”, “ausencia de estrés” o “fuera del mercado laboral” en caso de ser un año en el que la persona no se encontrara empleada. En segundo lugar, se creó la variable “estrés familiar”, la cual de modo similar identificó para cada año de vida de las personas las categorías: “presencia de estrés” y “ausencia de estrés”.Para reconstruir tipos de trayectorias de estrés familiar y laboral, se consideraron preguntas del calendario de curso de vida en las que los participantes debieron identificar períodos de sus vidas en que experimentaron estrés por motivos familiares y laborales de acuerdo a su propio criterio. Específicamente, mientras que para el dominio familiar a cada participante se le solicitó marcar los años en que “¿Alguna vez un médico le ha dicho que tiene o tenía alguno de los problemas de salud que figuran en esta tarjeta? Recuerde que pueden ser problemas de salud que tiene actualmente, o tuvo anteriormente”. Entre las opciones se encontraba “Derrame cerebral o enfermedad vascular cerebral”.La variable dependiente de nuestro estudio corresponde a haber experimentado o no un accidente cerebrovascular. Siguiendo estándares internacionales, a los participantes se les consultó “proxy de nivel socioeconómico del entrevistado por cuanto las personas con mejor situación financiera acceden a cobertura privada de salud. Nuestros análisis se ajustaron también por factores de riesgo tradicionales de ACV, tales como índice de masa corporal ; actividad física ; frecuencia de consumo de (1) lácteos, (2) legumbres, alubias o huevos y (3) carne, pescado o ave (una o más veces por semana / menos de una vez por semana); hábito tabáquico actual (presencia/ausencia); y diagnóstico de hipertensión (presencia/ausencia).Tomando en cuenta estudios realizados en países de altos ingresos, los análisis fueron ajustados primero por las siguientes cuatro variables sociodemográficas: edad, género , nivel educacional , y cobertura de salud . Esta última variable se considera un indicador 21 para reconstruir tipos representativos de trayectorias simultáneas de estrés familiar y laboral a lo largo de la vida. El análisis de secuencia multicanal permite comparar similitudes y diferencias entre trayectorias de vida en dos o más dominios de la vida , por medio del cálculo de la distancia entre dichas trayectorias. La distancia se entiende como el costo de transformar la trayectoria de un individuo en un dominio específico a la trayectoria de otro individuo en dicho dominio, mediante dos operaciones concretas: substitución de estatus a partir de los que se miden las trayectorias, e inserción o eliminación de estos estatus22.En primer lugar, empleamos un análisis de secuencia multicanal23, que nos permitió agrupar trayectorias similares entre sí  en diferentes conglomerados o tipos representativos de trayectorias de estrés familiar y laboral. Finalmente, para determinar el número más robusto de tipos de trayectorias representativos de la diversidad de trayectorias posibles en la muestra, se utilizaron cuatro criterios estadísticos de selección: average silhouette width (ASW), point biserial correlation (PBS), Hubert's gamma (HG) y Hubert's C (HC)24. Los puntajes de estos índices varían de −1 a 1, o de 0 a 1. Para asegurar la comparación entre los criterios, sus puntajes fueron estandarizados. En el caso de ASW, PBC y HG, valores mayores significan una mejor solución, mientras que valores menores en HC indican una mejor solución.Cuando se obtienen las distancias entre las distintas trayectorias individuales, estas son introducidas en una matriz de distancias, sobre la cual se realiza un análisis de conglomerados jerárquico usando el método de Wardsoftware estadístico R25, específicamente con el paquete estadístico TraMineR22 para estimar análisis de secuencia multicanal, y el paquete estadístico survey26 para trabajar con base de datos ponderada.Una vez identificado el número de tipos más robusto de trayectoria de estrés familiar y laboral, este se convirtió en la principal variable independiente para medir la asociación con ACV en un modelo de regresión logística, el cual fue ajustado por las variables de control indicadas previamente. Los análisis de este estudio fueron conducidos en el Las proporciones univariadas ponderadas de las variables dependientes y de control se muestran en la La En las El primer tipo, “Ausencia de estrés familiar, estrés laboral persistente”, incluye al 54,8% de la muestra y corresponde a personas que mayoritariamente describieron no haber sentido estrés por causas familiares, pero sí permanentemente por causas laborales. Este grupo manifiesta haber percibido estrés laboral mayoritariamente a partir de los 20 años de edad de forma constante, lo que disminuye después de los 50 años cuando comienza a aumentar progresivamente la salida del mercado laboral.El segundo tipo de trayectoria, “Ausencia de estrés familiar, fuera del mercado laboral”, reúne al 18,3% de la muestra y se caracteriza por personas que la mayoría del tiempo en sus vidas se encontraron sin un empleo remunerado, y que no reportaron haber sentido estrés por causas familiares. En este grupo algunas personas reportan haber sufrido estrés laboral en etapas tempranas de la adultez , pero luego salieron del mercado laboral.El tercer tipo de trayectoria, “Estrés familiar persistente, ausencia de estrés laboral”, comprende el 6,9% de la muestra y está compuesto por individuos que mayoritariamente casi no reportaron estrés por causas laborales, pero sí por causas familiares. En este tipo, se clasifican incluso algunas personas que indicaron haber sentido estrés familiar desde la primera infancia, aumentando notoriamente después de los 18 años y manteniéndose constante hasta después de los 60 años.Por último, el cuarto tipo de trayectoria “Ausencia de estrés familiar y laboral” incluye al 20% de la muestra y se compone de personas que mayoritariamente describieron no haber sentido estrés ni por causas familiares ni laborales en sus vidas.odds ratios (OR) con sus respectivos intervalos de confianza y niveles de significancia estadística.La Como se observa en el modelo que considera los ajustes de todas las variables de control, la posibilidad de sufrir ACV es significativamente mayor en todos los tipos de trayectorias de estrés, en comparación a aquellos sujetos agrupados en la trayectoria “Ausencia de estrés familiar y laboral”. Específicamente, en aquellos sujetos que componen la trayectoria “Ausencia de estrés familiar, estrés laboral persistente”, la probabilidad de sufrir ACV es más de dos veces mayor . Mientras que para aquellos clasificados en la trayectoria “Ausencia de estrés familiar, fuera del mercado laboral” la probabilidad es más de siete veces mayor , y para aquellos que siguieron la trayectoria “Estrés familiar persistente, ausencia de estrés laboral” la probabilidad es más de diez veces mayor . En relación a los factores de control, se observa que el hecho de tener cobertura privada de salud, así como el consumo de legumbres, alubias o huevos más de una vez a la semana, reduce el riesgo de ACV.27, condujimos un análisis de sensibilidad incluyendo efectos de interacción entre los tipos de trayectorias y género sobre el riesgo de ACV  siguieron trayectorias marcadas por la presencia permanente de estrés familiar y/o laboral. Asimismo, una proporción no menor  tuvo una trayectoria caracterizada por la ausencia prolongada del mercado laboral.28.En términos de la asociación con ACV, observamos que trayectorias caracterizadas tanto por la exposición permanente a situaciones familiares y/o laborales estresantes a lo largo de la vida, se asocian significativamente con la presencia de esta enfermedad cardiovascular. Estos hallazgos son coherentes con estudios transversales o cros-seccionales previos. Por ejemplo, en un metaanálisis de 14 estudios que involucró 10.130 pacientes con diagnóstico de ACV, se estimó un aumento del riesgo del 33% en esta patología entre aquellos que reportaron sentir estrés por motivos familiares, laborales o financieros29. Además, nuestros análisis de sensibilidad . Este resultado se ajusta adecuadamente a estudios previos que han observado un efecto relevante sobre la presencia de ACV en aquellas personas que enfrentan relaciones maritales e interpersonales estresantesibilidad  nos mues31. Además, otros estudios en Latinoamérica indican una mayor mortalidad asociada a ACV en sujetos inactivos32. Una posible explicación de esta asociación corresponde a que, sobre todo en países como Chile, tener un empleo de manera continua implica obtener a un ingreso financiero que permite satisfacer necesidades individuales tales como el acceso a mejores servicios preventivos de salud y a tratamientos farmacológicos35.Por otro lado, nuestro estudio evidencia una fuerte asociación con ACV entre personas que reportan no haber sufrido estrés por causas familiares, pero estaban fuera del mercado laboral durante períodos prolongados. Estos resultados también coinciden con estudios transversales previos, que muestran que aquellas personas que dejan de trabajar remuneradamente tienen más del doble de riesgo de padecer ACV , especialmente si la pérdida del empleo se produce de forma involuntariaEste estudio tiene ciertas limitaciones que deben ser consideradas. En primer lugar, debido al ineludible sesgo de memoria, los encuestados podrían haber reportado de forma inexacta experiencias tempranas de su vida. Para mitigar este sesgo, el calendario de curso de vida empleado en este estudio incorporó innovaciones metodológicas orientadas a fortalecer la memoria autobiográfica, tales como la descomposición de los dominios de vida en diferentes subcategorías, el uso de ayudas visuales y la orientación de un encuestador debidamente capacitado en el proceso de rellenado del cuestionario. En relación a la muestra, es relevante considerar que esta es representativa de la capital, pero no de todo Chile. Esto es importante, por cuanto el centralismo del país genera que el acceso a los servicios de salud sea mayor y de mejor calidad en la capital que en el resto de las regiones. Una última limitación relevante refiere a que el reporte de estrés por parte de los encuestados depende estrechamente de su percepción del concepto “estrés”. Sabemos, sin embargo, que no existe una definición única de este término, pues abarca aspectos psicológicos, emocionales, motivacionales y cognitivos. Asimismo, al momento de identificar estrés laboral, los participantes pueden haber considerado aspectos diferentes que cuando reportaron estrés familiar.Este estudio tiene implicancias relevantes para el campo de enfermedades cardiovasculares. Los ACV son patologías de alta prevalencia, con consecuencias catastróficas en la salud y altamente asociadas a factores de riesgo modificables, entre ellos el estrés. Para disminuir la mortalidad y las secuelas que estas patologías tienen en la población, es fundamental considerar dichos factores de riesgo y fortalecer los sistemas sanitarios con un enfoque promocional, preventivo, con eje en la disminución de las inequidades en salud, y no solo en la optimización de tecnologías médicas de tratamiento y rehabilitación.Como sugiere este estudio, el estrés es un factor de riesgo que experimenta de manera prolongada una alta proporción de personas en distintas etapas y dominios de la vida. En consecuencia, es necesario adoptar un enfoque promocional y preventivo que enfatice los efectos adversos de experimentar cotidiana y acumulativamente situaciones estresantes. La formulación de políticas públicas orientadas a reducir el estrés podría contribuir a mitigar el riesgo de ACV en poblaciones tradicionalmente susceptibles.