Atrial fibrillation was searched via the terms primary prevention, hyperthyroidism, Wolff-Parkinson-White syndrome, catheter ablation, surgical ablation, hybrid ablation, stroke prevention, anticoagulation, left atrial occlusion and atrial excision. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. In these two manuscripts, we discuss the current strategies available to prevent AF, then compare noninvasive and invasive treatment strategies to diminish AF recurrence. In addition, we examine the pharmacological, percutaneous device and surgical approaches to prevent stroke as well as other types of thromboembolic events.Atrial fibrillation (AF), is the most common sustained cardiac arrhythmia. It was once thought to be benign as long as the ventricular rate was controlled, however, AF is associated with significant cardiac morbidity and mortality. Increasing life expectancy driven by improved health care and decreased fertility rates has, in most of the world, resulted in the population aged ≥65 years growing more rapidly than the overall population. As the population ages, projections suggest that the burden of AF may increase more than 60% by 2050. Although considerable progress has been made in the treatment and management of AF, primary prevention, secondary prevention, and prevention of thromboembolic complications remain a work in progress. This narrative review was facilitated by a MEDLINE search to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1950 and 2021.  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with significant morbidity and mortality . A 2010 In addition to the aging global population AF's increasing prevalence has been driven by a high burden of risk factors and comorbidities, thereby raising significant issues about the use of healthcare systems and economic costs . This reAF is a complex disorder with shared environmental and genetic factors contributing to its pathogenesis. Three broad genetic approaches, that are not mutually exclusive, have been applied to AF. Linkage analysis uses families with Mendelian forms of AF. Genome-wide association studies (GWAS) use genotyping array data. Analyses of coding variation are gathered from whole-exome or whole-genome sequencing data .TTN as the most common gene associated with mutations in individuals with AF. Future studies will aim to explore application of polygenic risk scores (PRS) to clinical care, building out genetic studies in non-Europeans, and further expand single-cell sequencing and genomic technologies in tissues and cells related to AF. Refinement of AF's genetic basis ultimately will facilitate identification of new therapeutic targets and enable more precise risk stratification for this tachyarrhythmia  play a central role as both ectopic sources and zones of reentry. Disturbances in conduction related to tissue fibrosis and/or connexin-abnormalities predispose to reentry. Abbreviated refractoriness is a potential contributor . Autonomvia rapid pacing led to marked shortening of the atrial effective refractory period (AERP) and development of sustained AF episodes. The authors noted that the presence of multiple wavelets needed to sustain AF would correlate with atrial enlargement because the number of circuits in the atria increases with the square of the atrial diameter  and right atrium 248 ± 27 ms vs. 207 ± 24 ms; P < 0.001. All 4 PVs demonstrated a significantly shorter ERP after the AF exposure compared with their baseline ERP. The mean ERP of all PVs decreased to a significantly greater extent as compared to the atria . The authors suggested that because these changes are significantly more pronounced in the PVs as compared with the atria, they provide evidence that “AF begets AF in the PVs”  , hypertrophic cardiomyopathy/left ventricular hypertrophy, ischemic heart disease, rheumatic/valvular heart disease, hypertension, diabetes, left atrial dilatation, and smoking/pulmonary disease. Obesity  , sleep apresent)  have alspresent) .Hypertensive heart disease (67%–76%) and coronary (ischemic) heart disease are the most common underlying disorders in AF patients from developed nations. Rheumatic heart disease, now uncommon in developed nations, is associated with a much higher incidence of AF .This review will focus on modifiable risk factors for AF, prevention of AF incidence and recurrence , prevention of AF after cardiothoracic surgery, plus special circumstances where treatment/elimination of the underlying condition may reduce or eliminate AF burden and stroke prevention in AF.AF incidence doubles with each decade of adult life ; increasP < 0.001). The prevalence of clinically-detected AF did not differ significantly between Hispanics or Chinese and white patients. Fourteen days of ambulatory ECG monitoring was then performed. The investigators reported episodes of monitor-detected AF lasting over 24 h. The proportions with monitor-detected AF were similar in the four racial/ethnic groups. In analyses limited to those without clinically-detected AF, the proportion with monitor-detected AF was again similar in the four race/ethnic groups. In patients with clinically-detected AF, the proportion with monitor-detected AF was higher in African American and Hispanic participants (42% and 40%) than in white and Chinese participants (28% and 19%). These results supported the hypothesis of differential detection by race/ethnicity in the clinical recognition of AF  participated in an ancillary study . Among 1on of AF . In conton of AF .In Europe, studies performed in the global population between 2007 and 2013 reported an incidence of AF ranging from 0.23 per 1,000 person/years in Iceland to 0.41 in Germany and 0.9 in Scotland . A 2019 Caution should be exercised in evaluation of AF in Europe because the continent is not a homogeneous entity. A temporal (1990–2017) analysis of data from the 2017 Global Burden of Disease Database was performed to evaluate changing trends in AF incidence and mortality in 20 European countries. The analysis identified no across-the-board trend descriptive of all nations. Mortality-to-incidence ratios were calculated for each country. Although AF incidence was higher in men, mortality to incidence ratios were higher in all countries in women .These differences were attributed either to biological differences or health care inequality. Surprisingly, a national low gross domestic product  was related to lower AF incidence and AF-related mortality. The authors speculated that residents in high gross domestic product countries receive better healthcare and live long enough to be diagnosed with and/or suffer from the serious complications of AF (a survivor effect). In addition, the authors speculated that low gross domestic product countries had poorer health systems resulting in underdiagnosis/underreporting of AF and its consequences . Thus, iThe overall prevalence of AF is higher in men than women. However, because women typically live longer than men, there are nearly twice as many women as men aged >75 years. Beyond the age of 75 years (the median onset age for AF), ∼60% of individuals with AF are women , 33. MenThe 2020 ESC Guidelines on the Diagnosis and Management of AF have provided a systematic approach to AF detection, characterization, and management see  7, 40)., 40.7, 4Characterization was initially proposed as a paradigm shift to address specific domains having treatment and prognostic implications. The 4S-AF scheme , a novel pathophysiology-based characterization of AF patients, can be employed in daily practice and supports decision-making regarding prescription of oral anticoagulation (OAC), rate or rhythm control strategies (AF ablation or antiarrhythmic drugs) as well as management of concomitant risk factors and comorbidities .The AF Better Care (ABC) pathway  , 41 streP < 0.001). Rates of rehospitalization were also lower with the mAFA intervention (P < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower hazard ratios for the composite outcome for patients receiving the mAFA intervention compared with usual care   received integrated care based on a mobile AF Application (mAFA) incorporating the ABC  Pathway or usual care (1678). The composite outcome of ischemic stroke/systemic thromboembolism, death, and rehospitalization was lower with the mAFA intervention compared with usual care (s <0.05) . Figure In addition, the benefits of the 4S-AF scheme and ABC pathway adherent care have been clearly demonstrated to be associated with reduction in cardiovascular death, major bleeding, and stroke compared to usual care. The ABC pathway is also recommended in the 2021 Asia-Pacific Heart Rhythm Society Guidelines , 44.Past consensus guidelines stated “AF may be related to acute, temporary causes, including alcohol intake (‘holiday heart syndrome’), surgery, electrocution, MI, pericarditis, myocarditis, pulmonary embolism or other pulmonary diseases, hyperthyroidism, and other metabolic disorders. In such cases, successful treatment of the underlying condition often eliminates AF” .Additional secondary precipitants including fever/infection and acute alcohol consumption were identified among 1,409 Framingham Heart Study patients with new-onset AF. AF recurred in 544 of 846 eligible individuals without permanent AF . Although the 15-year incidence of AF recurrence was significantly lower among participants with secondary precipitants, AF eventually recurred in the majority with of individuals with “reversible causes” .It is commonly assumed that AF related to accessory pathways and hyperthyroidism is reversible. These assumptions are not entirely accurate.Hyperthyroidism is a known precipitant of AF. However, <1% of AF cases are secondary to acute hyperthyroidism , 49. Pha2DS2-VASc score of 0, the risk of ischemic stroke was virtually nil, irrespective of the type of AF (self-limiting or not), thus the use of anticoagulation therapy was deemed inappropriate. However, it also noted that among patients with CHA2DS2-VASc score ≥1, warfarin therapy was associated with a reduced ischemic stroke risk only in those with non–self-limiting AF, not those with self-limiting AF . Nevertheless, atrial premature beats are more frequent in thyrotoxic patients compared to matched controls before and after treatment. This raises the possibility that the risk of AF recurrence and the long-term prognosis are similar in euthyroid and hyperthyroid AF groups , 57.via an accessory pathway (AP) since it may lead to ventricular fibrillation (VF). Patients with APs that only conduct in the retrograde direction may also develop AF  velop AF . Howevervelop AF .Proposed mechanisms of AF initiation in patients with APs include enhanced atrial vulnerability and degeneration of atrioventricular reentrant tachycardia into atrial fibrillation. Although surgical studies have suggested virtually no recurrence of AF after AP resection, radiofrequency catheter ablation has become the treatment of choice for symptomatic patients .P = 0.001). The authors only identified age >50 years as a significant independent predictor of atrial fibrillation recurrence (P = 0.02)  .Primary prevention strategies for AF have not been well-explored. However, individuals with optimal cardiovascular health have a 62% lower risk of AF , 60. ManThe efficacy of beta-blocking agents for AF rate control is well established –64. MostIn short term trials, statin treatment seemed to reduce the odds of an episode of atrial fibrillation however, longer term (mostly larger) trials of statin vs. control treatment were not associated with significant AF reduction , 70. LikOmega-3 fatty acids  exert anti-inflammatory effects similar to statins . In the 3 did not significantly reduce or increase the primary end point of incident AF compared with placebo during a median treatment duration of 5.3 years. There was no evidence of an interaction between the agents employed. The authors concluded their findings did not support use of supplemental EPA-DHA and/or vitamin D3 for primary prevention of AF  study, trandolapril treatment was associated with a 47% lower incidence of new-onset AF in post-MI patients with systolic dysfunction , 82. A sAldosterone creates a substrate susceptible to atrial arrhythmias, characterized by atrial fibrosis, myocyte hypertrophy, and conduction disturbances . Mineraln = 10,186) or known atherosclerotic cardiovascular disease . Dapagliflozin decreased the incidence of reported AF and atrial flutter episodes adverse events in high-risk patients with type 2 diabetes mellitus. This beneficial effect was consistent regardless of the patient's prior history of AF, atherosclerotic cardiovascular disease, or HF  studied the safety and efficacy of dapagliflozin [a sodium-glucose cotransporter (SGLT2) inhibitor] vs. placebo in 17,160 type 2 diabetes mellitus patients with either multiple risk factors for atherosclerotic cardiovascular disease   . An even  0.001) . We beli  0.001) .Based on these (and other) reports, we remain somewhat hesitant to draw a firm conclusion about the benefits of SGLT2 inhibitors in AF prevention . NeverthAddressing and reducing/eliminating risk factors for AF is not an easy task. It requires unique partnerships that are not easily achieved. All caregivers need to be knowledgeable and provide clear goals in a manner that is simultaneously informative, firm, and empathetic. Patients need to be introspective, cooperative and highly motivated.2] is an important, strong risk factor associated with incident AF and persistent AF (Obesity  Chronic Renal Insufficiency Cohort (CRIC) study enrolled 3,267 adult participants. AF was present in 18% of the study participants and >25% of those ≥70 years old . In a 202 compared to those with ≥90 ml/min per 1.73 m2, AF risk was increased . Comparing participants defined by their eGFRcreat levels produced similar results . Individuals with an ACR ≥300 mg/g were compared to those with an ACR < 30 mg/g and, likewise, had an increased incidence of AF   and urinary albumin/creatinine ratio (ACR) were associated with a risk of AF. The study population included 1,840 subjects between the ages 61–82 years. During a follow-up (median 3.7 years), 159 (8.6%) incident AF cases occurred. Reduced eGFR and albuminuria were associated with an increased risk of atrial fibrillation. In subjects with eGFRcys of 15–59 ml/min per 1.73 m< 0.001) . Likewis< 0.001) .2. Incident AF was associated with higher risk of stroke which was similar across all eGFR strata  and death . This was attributed to both ischemic stroke  and intracranial bleeds   Project, 13,412 (12%) developed clinically apparent AF during a mean follow-up of 3.9 years. AF incidence increased across lower eGFR strata: from 29.4 to 46.3 atrial fibrillations per 1,000 person-years in subjects with eGFR = 45–60 and <30 ml/min per 1.73 m42–1.90) .2, respectively. During follow-up, 7,791 subjects (3.3%) developed renal dysfunction  developed proteinuria. AF at entry was associated with development of both renal dysfunction  and proteinuria   developed AF. Baseline serum creatinine and estimated glomerular filtration rate (GFR) were associated with a subsequent risk of AF. The hazard ratios [HRs (95% CI)] for AF were 1.32 (1.08–1.62) and 1.57 (0.89–2.77) for GFRs 30 to 59 and <30 ml/min per 1.73 m2–2.52]) .2 without albuminuria, n = 21,081), stage 1 to 2 CKD , stage 3 CKD  and stage 4 to 5 CKD . The AF prevalence was 1.0% among adults without CKD, and 2.8%, 2.7% and 4.2% among adults with stage 1–2, stage 3 and stage 4–5 CKD, respectively  assessed 1-year outcomes in 2,398 patients with AF in relation to kidney function. Glomerular filtration rate (eGFR) was an independent predictor of stroke/TIA or death, with elevated odds ratios concordant with the severity of renal impairment: eGFR < 30 ml/min/1.73 m 0.0003] .Fauchier and colleagues examined the impact of declining eGFR in 2,653 AF patients with information on worsening of kidney function during a mean of 1,499 days of follow-up. Patients were divided into 4 quartiles based on the slope of their worsening renal function. There was an increased risk of stroke/thromboembolism when the decline in eGFR was more marked  and the risk was markedly increased when patients in the 4th quartile were compared to other patient groups . Likewise, there was an increased bleeding risk when the decline in eGFR was more marked  and the risk was particularly increased when patients in the 4th quartile were compared to other patients . Stroke/thromboembolism and all-cause mortality rates were lower in individuals on oral anticoagulation (OAC), compared with those not on OAC. The effect was not significantly affected by worsening eGFR quartiles. Bleeding rates were higher in individuals on OAC, compared with non-anticoagulated patients. This effect was also not significantly affected by eGFR worsening quartiles .Taken together these findings are consistent with the bidirectional relationship between AF and CKD. The impact of advancing renal disease on AF incidence (AKA the dose-response) and adverse AF related outcomes is clear. DM may predispose to structural, electrical, and autonomic changes and is associated with a higher risk of AF . Data frIn a sample of 3,014 patients from the Non-invasive Monitoring for Early Detection of Atrial Fibrillation (NOMED-AF) study, Polish participants were divided into two groups based on the presence or absence of diabetes mellitus. In the diabetes group, none had type 1, therefore, the analyses comprised solely type 2 diabetics.P  <  0.001). Asymptomatic (“silent”) AF (SAF) was more common among the diabetic group . Likewise, persistent/permanent AF was more common in the diabetic group .AF was noted in 22.6% of the study population. AF prevalence was significantly higher in diabetic individuals compared to those without diabetes ; for A1c >7 but ≤8, 1.48 ; for A1c >8 but ≤9, 1.46 ; and for A1c >9, 1.96  .Two large Taiwanese studies demonstrated that aggressive blood sugar control was associated with a decreased risk of AF incidence and recurrence. A population-based study  revealed that using metformin was associated with a 19% lower risk of AF over 13 years compared with controls . In 12,62DS2-VASc score risk factors, TIA and stroke were significantly more common in both group 3 (P < .001) and group 4 (P < .001) . The remaining 26,182 (69.1%) were not diabetic. The diabetic patients were divided into four group according to their HgbA1c: 1) <6.35%; 2) 6.35%–6.90%; 3) >6.90%–7.70% 4) >7.70%, After adjusting for CHA < .001) .In contrast, data from 1933 diabetic patients in the ATRIA  cohort of AF patients revealed that 46% had a HbA1c < 7.0%, 36% between 7.0% and 8.9%, and 19% ≥9.0% at baseline. Moderate (7.0–8.9%) or poor (≥9.0%) glycemic control was not associated with a significantly increased ischemic stroke rate compared with patients who had HbA1c < 7.0%. A diabetes duration of ≥3 years was associated with an increased ischemic stroke rate compared with a duration <3 years  .Among a cohort of 135,222 Danish patients with AF, 12.4% were identified as having both AF and diabetes mellitus. The diabetic patients were divided  according to diabetes duration into 4 groups . The thromboembolic risk was lowest in the 0 to 4 years duration category , and highest in the longest duration category of ≥15 years  .Most of the studies discussed above were racially and ethnically homogenous. It is important to recognize that large numbers of studies have demonstrated that AF is less prevalent in individuals of African descent compared to those of European ancestry. The risk of AF among blacks, has been independently associated with increasing percentage of European ancestry. In the Candidate-Gene Association Resource Study for every 10% increase in European ancestry, there was a 16% to 20% increased risk of AF. The prevalence of AF in Hispanic and Asians residing in the United States is also lower than in white individuals , 171–173Knowing that pancreatic transplantation is not a standard procedure and is only applicable for type 1 diabetes, addressing the disease duration is difficult. Therefore, despite the conflicting results noted above, we believe that optimal glycemic control is paramount to AF prevention. Use of tobacco has been associated with an increased risk of AF . SmokingIn the prospective, population-based Rotterdam Study, the association between smoking cigarettes and risk of AF development was examined in 5,668 subjects without baseline AF. During a median follow up of 7.2 years, AF was identified in 371 cases. After multivariate adjustment, current and former smokers had an increased relative risk (RR) of AF compared to subjects that never smoked  .In the Atherosclerosis Risk in Communities (ARIC) study, 15,329 participants were available for a smoking status analysis, and 15,078 were available for a cigarette-years and a combined smoking status and amount analyses. Subjects were classified as never, ever, and current smokers. AF incidence was 9.8% in ever smokers and 5.7% in never smokers. Multivariable-adjusted AF hazard ratios were  in former smokers,  in current smokers, and  in ever smokers. Among participants with the highest amounts of cumulative smoking the risk of AF was 2.1 times higher than among those who never smoked .The CHARGE-AF consortium collected and analyzed data from the Framingham Heart Study, ARIC, and the Cardiovascular Health Study [CHS]. AF incidence was 1.44 times higher in current smokers compared with nonsmokers .The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study examined the influence of secondhand exposure to tobacco on the risk of AF. A total of 2,503 participants (21%) reported environmental tobacco smoke exposure. Such exposure was significantly associated with AF  .A meta-analysis of 29 prospective studies suggested that smoking is associated with an increased risk of AF in a dose-dependent manner, but the association was stronger among current smokers compared to former smokers .Although cigar and pipe smoking have been associated with cardiovascular disease, a link to AF has not been reported. In a 22-year follow-up study, both primary and secondary (former cigarette smokers) pipe/cigar smokers showed significantly greater risk of major coronary heart disease and stroke events compared to never smokers. There was little difference between the effects of primary and secondary pipe/cigar smoking after adjustment for differences in lifestyle and biological characteristics . A 2015 The use of alternative products, such as hookah, electronic cigarettes, vapes, e-hookahs, e-pipes and e-cigars is increasing. While use of hookah involves inhalation of flavored tobacco, the battery-operated electronic devices (heat-not-burn products) allow the user to breathe in nicotine through a vapor. The cardiovascular disease risk associated with these entities remains unclear , 184.Smoking cessation counseling and support are recommended as an optimal approach to maintaining cardiovascular health and as an AF prevention strategy . Few smoP = 0.005) as well as a significantly reduced AF burden over 6 months follow up (P = 0.01)  . Moderat = 0.01) . Unfortu = 0.01) .inverse relationship between the amount of alcohol consumed per drinking session and the risk of new-onset AF (Binge drinking (defined as 5 or more drinks on at least one occasion for men or 4 or more drinks for women) is the most common and costly pattern of excessive alcohol use . In the onset AF . Anotheronset AF , 191.P < 0.001). Although no apparent threshold effects existed between the amount of alcohol consumed and risk for a discrete AF event, AF episodes were associated with increased blood alcohol concentration measured via the transdermal alcohol sensor during the previous 12 h  was the most commonly noted trigger . In ordeous 12 h .Therefore, it is clear that alcohol consumption substantially increases the chance of a discrete AF episode within a few hours  and thatA summary of the studies related to alcohol is present in It has been estimated that the global prevalence of obstructive sleep apnea approaches a billion individuals . ObstrucP = 0.002). There was a significant association between mild SAHS and the risk of AF , moderate SAHS , and severe SAHS . These results suggested that the greater the OSAHS severity, the higher the risk of AF   . The met< 0.001) , 200.It is unclear whether treatment of sleep disorders has an impact on AF incidence . HoweverP < 0.009).In a multi-center study 3,000 patients underwent AF catheter ablation. OSA was present in 640 (21.3%). Overall, the OSA group was noted to have more non-pulmonary vein AF triggers . Among the OSA patients, the non-CPAP group had more early recurrences than the CPAP group: 178 (55%) vs. 105 (33%) respectively (P < 0.001). Paroxysmal AF patients who used CPAP had 31 (20%) procedural failures compared with 36 (33%) of the non-CPAP group (P = 0.019). Non-paroxysmal AF patients who used CPAP had 128 (79%) success vs. 150 (68%) in a non-CPAP population (P = 0.032)  .P < 0.02) and similar to that of OSA patients managed without ablation  (Fein and associates reported the results from 426 (62 with OSA) patients who underwent pulmonary vein isolation procedures for AF between 2007 and 2010 and were followed for 1 year. Thirty-two of the 62 (51.6%) with OSA used CPAP and 30 (48.4%) did not. The AF recurrence rate in CPAP users was similar to patients without OSA. In non-users AF recurrence was significantly higher  .During a follow-up period of 18.8 ± 10.3 months, Naruse et al. also reported higher AF recurrence rates post-ablation among 34 untreated OSA patients compared to 82 CPAP users. They concluded that appropriate treatment with CPAP in patients with OSA is associated with reduced recurrence of AF .P = 0.00]. This risk increased by 57% in patients with OSA not receiving CPAP therapy . CPAP users had a risk of AF recurrence similar to that of patients without OSA . This similarity was maintained after the removal of study heterogeneity , individuals with OSA had a 31% greater risk of AF recurrence after catheter ablation compared to those without OSA  within 2 days, 119 [16%] between 3 and 30 days, and 392 [54%] after >30 days. During a mean follow-up of 6.6 years, AF was associated with an increased risk of mortality  compared to patients without AF. The risk of death was highest when AF occurred >30 days post MI  .In a 2003 report, The Global Registry of Acute Coronary Events (GRACE) examined the relationship between AF and acute coronary syndromes (ACS), including ST segment elevation acute MI, non-ST segment elevation acute MI, and unstable angina . AF included both prior and new-onset atrial fibrillation and atrial flutter.Compared with patients without AF, those with new-onset AF were more likely to have had an anterior or any ST-segment elevation MI and cardiac arrest on hospital arrival. While patients with ACS and any AF had worse in-hospital outcomes than those without any AF, all complication rates were higher in patients with ACS and new-onset AF than in those with prior AF. Patients with new AF were significantly more likely to receive temporary pacing, mechanical ventilation, a pulmonary artery catheter, and an intra-aortic balloon pump. Cardiac catheterization rates were similar, coronary artery bypass surgery was more frequent and percutaneous intervention (PCI) less frequent. Among patients with prior AF, cardiac catheterization, PCI, and coronary artery bypass surgery were employed less frequently. Use of temporary pacing, pulmonary artery catheterization, and intra-aortic balloon pumps were statistically less frequent, but percentagewise quite similar to non-AF patients. All AF patients were more likely to experience pulmonary edema, cardiac arrest and death. New AF patients were also more likely to suffer a stroke, reinfarction, major bleeding, and have a longer length of hospital stay .More recently, it has been estimated that 5%–15% of AF patients will require PCI/stenting at some point in their lives. In these individuals, it is pivotal that the risk of bleeding be balanced against the risk of stent occlusion/reinfarction/ACS and/or cerebral infarction. It has been suggested that triple therapy  may be continued for up to 6 months post ACS if the HAS-BLED score is <3. Dual therapy with an a single antiplatelet + oral anticoagulant (a P2Y12 inhibitor is favored over aspirin) should be used over the next 6 months and at 1 year followed by lifelong use of an oral anticoagulant. If the HAS-BLED score is ≥3 a duration of 1 month of triple therapy has been recommended. Dual therapy with an a single antiplatelet + oral anticoagulant is recommended for the next 11 months and at 1 year followed by lifelong use of an oral anticoagulant.After elective PCI, triple therapy is appropriate for 1 month regardless of the HAS-BLED score. If the HAS-BLED score is <3, dual therapy with an a single antiplatelet + oral anticoagulant (a P2Y12 inhibitor is favored over aspirin) is recommended for the next 11 months and at 1 year is followed by lifelong use of an oral anticoagulant. If the HAS-BLED score is ≥3, following 1 month of triple therapy with 5 months of dual therapy is reasonable followed by lifelong use of an oral anticoagulant .AF with a rapid ventricular response may be accompanied by ST segment depression and symptoms suggesting ischemia in the absence of significant obstructive coronary artery disease. Even troponin release may occur in the absence of obstructive CAD. AF has also been independently linked with up to a 3-fold increased risk of cardiac arrest due to VF. The mechanism is likely multifactorial and may result from one or more of the following: a direct proarrhythmic effect of AF, an increased cardiac workload, tachycardia-induced ischemia, or heart failure .Structural heart disease typically refers to non-coronary cardiovascular disease and related interventions. Screening for structural heart disease has an important role in the care of AF patients.Steinberg and associates have described a spectrum of structural heart disease which including valvular heart disease and paravalvular leaks, hypertrophic cardiomyopathy, atrial  and ventricular septal defects, patent ductus arteriosus, the left atrial appendage (as a source of thromboemboli) and left ventricular aneurysm  . A detaiThe consequences of structural heart disease may lead to heart failure (HF). The risk of AF increases 4.5 to 5.9-fold in the presence of HF and AF is present in more than 15% of HF patients. The prevalence of AF increases as HF severity worsens . As many as 25%–35% of individuals with decompensated HF present in AF. Among patients with HF, AF develops at a rate of 6%–8%/year. AF may precipitate HF exacerbation and HF may trigger AF .via AV junction ablation) and evaluating the need for cardioversion and maintenance of sinus rhythm as well as choosing the method to achieve it . Recently, greater emphasis has been placed on using rhythm control  rather than rate control to reduce adverse cardiovascular outcomes. Evidence increasingly supports early rhythm control for AF that has not become long-standing. Early rhythm control may reduce irreversible atrial remodeling and prevent AF-related deaths, heart failure, and strokes in high-risk patients. In patients with HF and AF, catheter ablation may be preferred to AADs due to challenges in optimizing pharmacological strategy in this population  patients with hypertrophic, 90,117 (7.0%) with restrictive, and 37,685 (5.9%) with dilated cardiomyopathy. Significantly higher odds of hospitalization, incident HF, and stroke were noted in all cardiomyopathy subtypes. AF was associated with significantly greater odds of all-cause mortality in hypertrophic  and dilated [1.36 (1.27–1.46)], but not restrictive [0.98 (0.94–1.02)], cardiomyopathy. AF catheter ablation was associated with significantly lower odds of all-cause mortality at 12 months across each of the cardiomyopathy subtypes .The most dramatic example we have seen was of AF's adverse influence on cardiomyopathy was reported in 1986. A 15-year-old male with non-obstructive hypertrophic cardiomyopathy suffered an out of hospital cardiac arrest. He was evaluated with invasive electrophysiologic testing. Although, no ventricular arrhythmias were inducible, we had observed that transient ST elevation occurred during rapid atrial pacing . Near thHe was discharged on a combination of metoprolol and verapamil therapy. During a follow-up period of 5 months, he had one asymptomatic spontaneous AF episode. The ventricular rate was 95 to 100/min, and he was hemodynamically stable. Direct current cardioversion restored sinus rhythm. To the best of our knowledge, this was the first report of AF progressing to VF in the absence of preexcitation .Some individuals with AF, particularly older people, are asymptomatic. Many experience one or more of the following: palpitations , dyspnea, reduced exercise tolerance, lightheadedness, and chest pain. AF is associated with an increased risk of all-cause mortality, stroke, higher medical costs and a reduced quality of life , 233. OdP < .001). Likewise, sole analysis of rehospitalization also revealed significant reduction (P < .001). Analysis of the C component of the pathway (Comorbidities and Risk Factors) demonstrated that, during follow-up, rates of uncontrolled blood pressure, heart failure and acute coronary syndrome were lower in the intervention group (P < .001). Subgroup analyses by age, prior stroke, and sex demonstrated consistently lower hazard ratios for the primary composite outcome and rehospitalization in the intervention patient group (Risk factors often do not occur in isolation. In the (previously noted) mAFA-II Randomized Clinical Trial, 833 AF patients with multiple morbidities used a mobile health  technology that implemented the ABC pathway and 1,057 AF patients with multiple morbidities were allocated to usual care. The composite outcome of stroke or thromboembolism, all-cause death, and rehospitalization was significantly reduced in the ABC intervention group  .Nevertheless, it is important to understand that fluctuations in triggers and/or components of the substrate that occur transiently can result in temporal variability in AF risk. Although speculative, it seems likely that partial/incomplete recovery may from transient disturbances may ultimately lead to an accumulation of progressive AF risk .It has become clear that some risk factors exhibit strong temporal variability. Examples of transiently increased AF risk include heart failure exacerbation and inflammation post-cardiac surgery. Several other AF risk factors may demonstrate a high day-to-day variability  or may occur only during specific conditions such as exercise-induced hypertension .Hence, risk factors contribute to both a progressive AF-promoting substrate and transient changes in AF risk. Components of static risk exposure and transient risk exposure are illustrated in Choosing an optimal pacing mode facilitates primary AF prevention and may play an important role in delaying or preventing progression of paroxysmal AF to persistent or permanent AF. Past studies consistently demonstrated a decreased frequency of AF with atrial-based  vs. single-chamber right ventricular pacing in patients with sinus node dysfunction. Their findings suggested that time might be needed to see potential biological (remodeling) effects of right atrial pacing for AF prevention . Right vThe efficacy of atrial based pacing (AAI or DDD modes) vs. single chamber ventricular pacing (VVI mode) has also been studied extensively with respect to multiple clinical outcomes in addition to new-onset AF, including heart failure hospitalization, stroke incidence, quality of life (QOL) and mortality. The most consistent clinical benefit of dual chamber pacing over single chamber ventricular pacing was reduction of incident AF .AF-preventive algorithms have been designed to increase the baseline atrial pacing rate by overdrive-pacing the atrium, suppressing PACs or preventing pauses. They have not shown unequivocal clinical efficacy, and definitive conclusions about their merit have not been reached .A variety of AF-termination [all are forms of atrial anti-tachycardia pacing (ATP)] algorithms have been tried with variable success. Termination options include Burst ATP, Burst+, Ramp ATP, and Reactive ATP .Reactive ATP , allows multiple deliveries upon detecting changes in rhythm regularity or cycle length, thus allowing additional ATP attempts during long atrial tachycardia/atrial flutter episodes or when AF organizes to either of these entities , 243. ReIn 2015, the MINERVA Investigators demonstrated the efficacy of combining atrial preventive pacing, atrial rATP (DDDRP mode), and managed ventricular pacing (MVP), in preventing progression to persistent or permanent AF patients with bradycardia and prior atrial tachyarrhythmias .P < 0.0001) , ≥7 days (HR 0.64), and ≥30 days (HR 0.56) compared to controls  .P < .001). Upon multivariate analysis, RA pacing quartile remained a significant predictor of post-CRT AF   developed AF. Right atrial pacing percentage was associated with a greater risk of postimplant AF. The incidence of AF increased incrementally within RA pacing quartiles: 44.6%, 64.3%, 79.7%, and 81.6%, respectively ( < .001) .P < 0.001). Multivariable analysis found that atrial pacing above the first quartile was associated with a relative risk of 2.93  , second (32%–66%), third (66%–89%), and fourth (89%–100%) quartiles of %AP was 1.3%, 5.3%, 5.8%, and 8.0%, respectively (= 0.023) . AlgoritIn 2008, De Voogt and Van Hemel discussed technical pitfalls that weakened the accuracy of atrial tachyarrhythmia diagnosis by pacemakers available at that time. These limitations included: (1) inappropriate sensing of AF because of variable and low voltage signals during AF, which might cause inappropriate detection of the onset and/or perpetuation of AF and other atrial arrhythmias; (2) far-field R wave sensing which might be prevented by adaptation of other pacemaker parameters which, in turn, could not only obscure far-field R wave sensing as well as every second beat of an atrial tachycardia; and 3) insufficient memory capacity of the pacemaker to store all atrial tachyarrhythmic episodes , 248.P < 0.001). These investigators also compared 2202 pacemaker recipients to 2202 loop recorder recipients. During the 2-year follow-up, the AF incidence in the groups was 7.9% vs. 8.4% (loop vs. pacemaker). They concluded that pacemaker patients were at increased risk of being diagnosed with AF in comparison to a general cohort, likely due to continuous monitoring  and RVP in 225 patients during long-term follow-up. There were 105 patients in the HBP group and 120 patients in the RVP group. There were 72 patients in the HBP group and 76 patients in the RVP group without a prior AF history .P = 0.006). There was no significant difference between the two groups in the rest of their baseline characteristics. After adjustment for the confounder of age, the risk of new-onset AF remained lower (P = 0.046) in the HBP group. A significantly lower burden of new-onset AF was observed in HBP across all pacing burden subgroups Age was significantly lower (about 4 years) in the HBP group compared with the RVP group (as noted .P = 0.072) which did not reach statistical significance (There were 44 patients in the RVP group and 33 patients in the HBP group who had a prior history of AF. Progression of AF was defined as an increase in AF burden by ≥10%. There was a trend toward lower risk of AF progression with HBP in the patients with His or RV pacing burden ≥40% (ificance .P = 0.022). This finding was significant in 108 patients without a prior history of paroxysmal AF (P = 0.005), but was likely underpowered to reach statistical significance in the 38 patients with a prior history of paroxysmal AF (P = 0.086) . These investigators found that HBP resulted in a lower overall risk of progression to persistent or permanent AF  (P = 0.0= 0.086) .P = 0.035) compared to conventional RVP (Results from the Geisinger-Rush Conduction System Pacing Registry suggest that left bundle branch area pacing (LBBAP) has similar benefits to HBP. In patients with a ventricular pacing burden ≥20% LBBAP was associated with a lower risk of new-onset AF onal RVP .Although AF frequently presents with symptoms, (as noted) it also may be asymptomatic –255. ParAHREs are detected in pacemaker or implantable cardioverter defibrillator (ICD) recipients and often occur in the absence of AF diagnosed by the usual methods of electrocardiography or Holter monitoring , 257. ThBoriani et al. analyzed pooled data from 3 prospective studies in 6,850 patients  with cardiac implanted electronic devices and no history of AF or use of anticoagulants. An AF burden of ≥5 min, was detected during a follow-up period of 2.4 ± 1.7 years in 2,244 (34%) of patients. At 36 months, the cumulative incidence of a daily AF burden of ≥5 min was 40.4% [95% confidence interval (CI): 38.9%–41.9%]. In 53% of cases the first detected AF burden ranged between 5 min and <1 h. Overall, the cumulative incidence of transition to a higher device-detected daily AF burden was 41.0%  in the first 6 months and 57.5%  at 36 months . Figure Pacing primarily has an adjunctive role in AF therapy. In order to take advantage of the therapeutic options, physicians need intricate knowledge of device features so that precision programming can facilitate optimal patient outcomes.AF is classified based on the temporal characteristics of the arrhythmia. When AF is first detected it is designated “recent-onset” (present for <48–72 h) , 268. AFEarly in the first decade of the 21st century, several studies compared rate control and rhythm control strategies for AF. These studies suggested that a rate-control strategy would be an acceptable primary approach for patients with recurrent, persistent AF , 270–275P<0.001) and required fewer follow-up visits. Symptoms and adverse effects were similar in the two groups  or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The composite primary outcome included death from a cardiovascular cause (or causes), heart failure hospitalization, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The overall incidence as well as the components of the primary outcome were similar between the two groups. Significantly more patients in the lenient-control group met the heart-rate target or targets  and, less commonly, digoxin or amiodarone. The largest sample size and longest follow-up comparing rate control agents is a post-hoc analysis from the AFFIRM trial , 279. Bepost hoc analysis of the RACE 4 randomized trial  in patients with vagally mediated paroxysmal AF (see below) –284, theVerapamil was used in 47 patients, beta blockers in 383 and 236 patients were not using rate control drugs. The primary outcome was AF progression, defined as the need for catheter ablation, electrical or chemical cardioversion. Secondary outcomes included the individual components of the primary outcome and a composite of hospital admission for arrhythmias, heart failure, thromboembolic events, major bleeding, acute coronary syndrome, life-threatening drug effects, or cardiovascular death .The verapamil group was significantly younger than the beta blocker group and had fewer men than the no rate control group. After adjustments were made for baseline characteristics, the verapamil group had a significantly lower probability of electrical or chemical cardioversion compared to the beta blocker group as well as the no rate control group. There were no significant differences in catheter ablation between groups. Likewise, there was no significant difference in the multi-component secondary outcome between the groups. The authors concluded that in patients with newly diagnosed paroxysmal AF, verapamil was associated with less progression of AF, compared to beta blockers and no rate control medication. Nevertheless, they characterized the study outcomes as hypotheses generating rather than hypothesis confirming. This cautious interpretation was based on lack of rate control treatment randomization in RACE 4, the small size of the verapamil group and the possibility of confounding factors related to differences in contraindications and adverse effects of the two drugs or after adjusting for baseline characteristics , 281.Although antiarrhythmic drugs reduce AF recurrences, until recently there was little or no evidence of any benefit for other clinical outcomes compared with placebo or no treatment. A meta-analysis of 59 randomized controlled trials  studied the risk and benefits of quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone and sotalol. The outcomes analyzed included all-cause mortality, drug withdrawals due to adverse effects, proarrhythmia, stroke and AF recurrence. The authors considered study limitations, consistency of effect, imprecision, indirectness, and publication bias in order to assess the certainty of a body of evidence .No antiarrhythmic drug produced a benefit on mortality. High-certainty evidence from 5 randomized controlled trials indicated that treatment with sotalol resulted in a higher all-cause mortality rate than placebo or no treatment. Quinidine was associated with a low-certainty increase in all-cause mortality compared with placebo or no treatment. Drugs with no apparent effect on mortality included metoprolol, amiodarone, dofetilide and dronedarone . Howevertime dependent  compared with placebo or no treatment. Quinidine (at higher doses) and sotalol appeared to result in more withdrawals because of adverse events compared to controls and to other antiarrhythmic drugs. Although amiodarone compared favorably with class I agents, it had a very high relative risk (6.70) for increased withdrawal compared to placebo. These results were at 1 year of follow up. It is pivotal to remember that amiodarone's adverse effects are both dose and ependent , 270.Although antiarrhythmic drug therapy (including metoprolol) reduced AF recurrences by 20%–50%, AF still recurred in 43%–67% of participants treated with antiarrhythmics at one year. Amiodarone seems to be the most effective agent  in preveP = 0.007). Overall, 72% of patients with vagal AF were treated with non-recommended medication, especially β-blockers . In vagally mediated paroxysmal AF patients, non-recommended treatment was associated with deterioration to persistent or permanent AF in 19% of patients during 1-year follow-up, compared to none treated with recommended medication, however this difference did not quite reach statistical significance (P = 0.06)  . Per the = 0.06) .or catheter ablation may be an effective approach. The EAST-AFNET 4 Trial Investigators  in improving cardiovascular outcomes in patients with recently diagnosed AF and concomitant cardiovascular conditions. Results were similar in the heart failure subgroup of patients and were irrespective of symptom status. Significant reductions were noted for the primary composite endpoint, as well as for stroke and cardiovascular death. The effectiveness of early rhythm control therapy was mediated by the presence of sinus rhythm at 12 months .A retrospective population-based cohort study including 22,635 Korean AF patients compared groups newly treated with rhythm control (antiarrhythmic drugs or ablation) or rate control from 2011 to 2015. When rhythm control initiated within 1 year of AF diagnosis was compared to rate control it resulted in a decreased risk of stroke. Rhythm control initiated within 6 months of AF diagnosis also reduced the risk of heart failure hospitalization. Risks of myocardial infarction and cardiovascular death did not differ between rate and rhythm control groups regardless of treatment timing .initiating paroxysms of AF. Radiofrequency (RF) catheter ablation was performed at the earliest recorded site of ectopic activity within a main pulmonary vein or one of its proximal branches. The earliest local activity was marked by a “spike”  preceding the onset of the ectopic P wave. During a mean follow-up period of 8 ± 6 months, AF was completely eliminated in 62% of patients without the use of drug therapy  could be recorded at the venous ostia allowed ostial pulmonary vein disconnection by eliminating all ostial potentials in a segmental fashion  , 296.Segmental elimination of all ostial potentials has largely been abandoned in favor of circumferential antral pulmonary vein isolation. The circumferential antral pulmonary vein isolation procedure is easier to perform because it does not require localization of potentials and can be performed during atrial fibrillation. In addition, it reduces the likelihood of pulmonary vein stenosis. It is also more amenable to anatomic variants. Most importantly, it is more effective in preventing arrhythmic recurrence than segmental ostial isolation  and is a preferred ablation strategy for persistent AF  (see belIsolation of only the arrhythmogenic vein(s) has had a limited success rate. The prevalence of multiple arrhythmic pulmonary veins exceeds 70% , 297. AlIn 2000, Pappone and colleagues described an alternate technique to isolate the pulmonary veins. Because all 4 pulmonary veins were viewed as potential sources of AF, the end point was creation of circumferential lines of conduction block around each vein. Contiguous focal lesions were delivered ≥5 mm from the venous ostia. Radiofrequency energy application aimed to reduce bipolar amplitudes at each site by 80%. They used two criteria to define lesion/line continuity, low peak-to-peak bipolar potentials  inside the circumferential lesions and local endocardial activation times during atrial pacing >30 ms between contiguous points lying in the same axial plane on the external and internal sides of lesions encircling each vein. After a follow-up period of 9 ± 3 months of follow-up, 22/26 patients (85%) had stable sinus rhythm  .Although these authors reported no outcome differences between patients with paroxysmal and permanent AF, long term success rates with circumferential left atrial antral ablation have ranged from 59%–89% for paroxysmal AF and 50%–70% for persistent AF .Encircling of the pulmonary veins has been referred to as wide area circumferential ablation , wide anPulmonary vein isolation alone may be insufficient for treatment of patients with persistent AF. The posterior left atrial region encompassed by the LA roof, superiorly, the left and the right PVs, laterally, and the plane extending from the lower borders of the left and the right inferior PVs, form the PV component of the left atrial posterior wall, which has been implicated in genesis and maintenance of persistent AF . Surgicavia pulmonary vein isolation.Catheter-based isolation of the left atrial posterior wall may provide additional benefit over pulmonary vein antral isolation alone in treatment of persistent AF. Posterior wall isolation (PWI) debulks the potential substrate. In addition, posterior wall isolation creates conduction block to prevent potential reentrant circuits and reduces the likelihood of small gaps in the posterior aspect of pulmonary vein isolation lesion sets which may result in AF triggers from conduction recovery. PWI may lead to more reliable ablation of ganglionated plexi . In addiPast clinical guidelines have recommended a minimum of one trial of antiarrhythmic drug therapy before considering ablation therapy for AF. However, the 2014 AHA/ACC/HRS guidelines for the management of AF patients added a class IIa recommendation that, after weighing the outcomes and risks of drug and ablation therapy, catheter ablation is a reasonable initial rhythm-control strategy in symptomatic patients with, recurrent paroxysmal AF .Two recent studies compared cryoablation to drug therapy for initial AF treatment , 307. InAll patients had an implantable cardiac monitor  inserted within 24 h of therapy initiation. The primary end point was the first documented recurrence of any atrial tachyarrhythmia lasting ≥30 seconds between 91 and 365 days (a 90 day “blanking” period was included) after starting antiarrhythmic drug therapy or completing the catheter ablation procedure. Secondary end points included freedom from symptomatic arrhythmia, AF burden, and quality of life. Adverse events were considered serious if they resulted in death or functional disability, warranted an intervention, or resulted in a hospital stay >24 h .P < 0.001). Symptomatic atrial tachyarrhythmia recurred in 11.0% of the ablation cohort and 26.2% of patients assigned to receive antiarrhythmic drugs . The median percentage of total time in AF was 0%  in patients who underwent catheter ablation and 0.13%  in those assigned to the antiarrhythmic drug cohort. Quality of life scores improved more in the ablation group . Serious adverse events occurred in 5 ablation group patients  and 6 patients in the antiarrhythmic drug group , cardioversion, or use of class I or III antiarrhythmic drugs (ablation group only) beyond the 90-day blanking period ; or atrial arrhythmia recurrence  included the following serious procedure-related or cryoballoon system-related adverse events: clinically significant pericardial effusion within 30 days, atrial–esophageal fistula or symptomatic pulmonary vein stenosis within 12 months, phrenic nerve injury that had not recovered at 12 months, transient ischemic attack, stroke, myocardial infarction, major vascular complication, or major bleeding within 7 days post-procedure . PrespecP < 0.001). A post hoc analysis of the 78 patients in the drug-therapy group who took a therapeutic dose of an antiarrhythmic drug throughout this trial revealed treatment success in 40 patients (51%) at 1 year. Although only 1.9% of patients in the ablation group had a primary safety event at 12 months, serious adverse events occurred in 14% of patients in each study group. Quality of life improved significantly from baseline in the ablation group at 12 months. Health care utilization did not differ significantly between the groups , 65.0 to 82.0] in the ablation group and 45.0%  in the drug-therapy group . This significance was maintained in subgroup analyses of 1- and 2-year follow-up (P  <  0.001). Catheter ablation was associated with significantly greater improvement in QoL scores. The incidence of serious adverse events was similar between ablation and AADs group   from five randomized trials revealed that, compared with anti-arrhythmic drugs, catheter as first-line therapy was associated with significantly higher freedom from arrhythmia recurrence  .While the data from Andrade et al. and Wazni is impressive and suggests superiority of catheter ablation as initial therapy, data from the EAST-AFNET 4 Trial Investigators , 290 andIn part 1 of this treatise, we have discussed the pathophysiology, epidemiology, risk factors and comorbidities associated with AF. We have commented on diet, lifestyle modifications, and pharmacological interventions for primary and secondary AF prevention/burden reduction, the benefits of antiarrhythmic drugs for secondary AF prevention/burden reduction, as well as catheter ablation for paroxysmal and persistent AF. We have outlined the benefits of early intervention for secondary AF prevention/burden reduction and reducing the risks of stroke, death, and hospitalization. In part 2, we will discuss the role of AF catheter ablation in heart failure, evolving AF catheter ablation technologies, surgical and hybrid AF ablation, as well as prevention of thromboembolic complications related to AF.HH, PS and RGT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: RGT. Acquisition of data: RGT, HH, PS. Analysis and interpretation of data: RGT, HH, PS. Drafting of the manuscript: RGT. Critical revision of the manuscript for important intellectual content: HH, PS. Administrative, technical, or material support: RGT. Study supervision: RGT. All authors contributed to the article and approved the submitted version.RGT reports serving as an advisor to Boston Scientific/Guidant; receiving research grants from Boston Scientific/Guidant, Medtronic Inc, St Jude Medical (Abbott), Vitatron, and Wyeth-Ayerst/Wyeth Pharmaceuticals; serving as a consultant for Biosense Webster, Alta Thera Pharmaceuticals, and Newron Pharmaceuticals P.s.A.; and receiving speakers fees or honoraria from Boston Scientific/Guidant CRM, Medtronic Inc, Alta Thera Pharmaceuticals, Daichii Sankyo and St Jude Medical (Abbott). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The hyperdense middle cerebral artery sign (HMCAS) is observed in a proportion of patients with acute ischemic stroke (AIS). This sign reflects the presence of an intravascular thrombus rich in red blood cells. Several studies have demonstrated that HMCAS increases the risk of poor outcomes in AIS patients treated with IV thrombolysis or no reperfusion therapy; however, whether HMCAS predicts a poor outcome in patients treated with endovascular thrombectomy (EVT) is less clear. We aimed to evaluate the functional outcome by the modified Rankin scale (mRS) at 90 days and technical challenges in patients with HMCAS undergoing EVT.We studied 143 consecutive AIS patients with middle cerebral artery M1 segment or internal carotid artery + M1 occlusions who underwent EVT.p = 0.038); otherwise, no other baseline difference was observed. No differences in functional outcomes (mRS) at 90  days (p = 0.698), unfavorable outcomes (mRS > 2) (p = 0.929), frequency of symptomatic intracranial hemorrhage (p = 0.924), and mortality (mRS-6) (p = 0.736) were observed between patients with and without HMCAS. In patients with HMCAS, EVT procedures were 9  min longer, requiring a higher number of passes (p = 0.073); however, optimal recanalization scores  were equally achieved by both groups.There were 73 patients (51%) with HMCAS. Patients with HMCAS had a higher frequency of cardioembolic stroke (Patients with HMCAS treated with EVT do not have a worse outcome at 3  months compared with no-HMCAS patients. Patients with HMCAS required a greater number of thrombus passes and longer procedure times. Its eHyperdense middle cerebral artery sign (HMCAS) is defined as a spontaneous visibility of increased density within the first or second segment of the middle cerebral artery (MCA1 or MCA2) with or without internal carotid artery (ICA) involvement on admission non-contrast CT scan  8). Sev. Sev8). 2.2.1.We performed a retrospective analysis of prospectively collected thrombectomy databases from two comprehensive stroke centers, Foshan Sanshui District People’s Hospital, between August 2018 and February 2022, and the First People’s Hospital of Foshan, China, between October 2019 and March 2022. Data were derived from the Bigdata Observatory Platform for Stroke in China2.2.Two vascular neurologists with more than 6 years of practical experience each assessed baseline non-contrast CT scans. HMCAS was determined by visual assessment and by consensus of both experienced stroke neurologists. We collected relevant clinical and demographic data. Clinical features included were age, gender, risk factors, initial premorbid modified Rankin Scale (mRS), National Institute of Health Stroke Scale/Score (NIHSS), and last known normal-to-puncture time (neuroimaging features included: pre-treatment Alberta Stroke Program Early CT Score (ASPECTS)) and occlusion sites. We used the modified thrombolysis in cerebral infarction (mTICI) after thrombectomy to assess the recanalization status . An mTICPatients were followed by trained stroke nurses or vascular neurologists at least twice a month through telephone encounters or in-person consultations. The clinical outcome was assessed by the mRS at 3 months. A favorable outcome was defined as having an mRS of 0–2 while an unfavorable outcome as having an mRS of 3–6. Mortality was defined as an mRS of 6. Symptomatic intracranial hemorrhage (sICH) was defined as any hemorrhage related to transient neurological worsening, manifested by an increase in the NIHSS score of 4 points or higher.2.3.t-test for parametric comparison. The analysis was performed with IBM SPSS version 26 . We considered a value of p of <0.05 as the threshold of statistical significance.Non-normally distributed continuous data were reported as medians along with the interquartile range (IQR). We used the non-parametric Mann–Whitney U-test for non-parametric statistical comparison. Normally distributed variables were reported as means with corresponding standard deviations (SD). We used the student’s 3.p = 0.047); however, there was no other statistically significant difference in risk factors at baseline between groups  presented the HMCAS, while 70 did not (no-HMCAS group). Patients in the no-HMCAS group presented a higher rate of hypertension than those in the HMCAS group . In contrast, those with no-HMCAS had a trend for a higher frequency of atherosclerosis. One hundred and two patients (71.3%) presented with an isolated M1 occlusion (53 with HMCAS vs. 49 with no-HMCAS), while 41 patients (28.7%) presented with a tandem M1 + ICA occlusion (20 with HMCAS vs. 21 with no-HMCAS).According to the TOAST classification, patients with HMCAS presented with a higher rate of cardioembolic stroke  and a higher number of EVT attempts  compared with the no-HMCAS group. However, the proportion of patients achieving successful recanalization (mTICI: 2b-3) was not significantly different between both groups .Intravenous t-PA was administered in 60 patients (41.10% of the HMCAS group vs. 34.1% of the no-HMCAS group). There were no differences between groups in terms of door-to-puncture time and last known normal-to-puncture time. The presence of HMCAS negatively affected some technical outcomes. Indeed, the HMCAS was associated with a longer puncture-to-recanalization time , favorable functional outcome , and mortality  were not different between the two groups (Preoperative NIHSS scores (median 15.00 vs. 13.00) and ASPECTS pre-treatment (median 9.00 vs. 8.00) of the two groups were not statistically different. HMCAS did not affect clinical outcomes. Indeed, rates of sICH , supporting such observation. Moreover, we found that cardioembolic stroke was more frequently observed in patients with HMCAS similar to the study by Kim et al. , the Medical Science and Technology Research Foundation of Guangdong Province (Grant No. 20221027164016611), the Foshan 14th Five-Year Plan Key Discipline Foundation, China, the Guangdong provincial TCM Bureau Key Discipline Foundation, China, and the Foshan Competitive Talent Support Project Fund .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Head (39.0%) accounted for the highest proportion of overall pain locations in subjects with OSA, with 28.8% of OSA patients experiencing headaches. Pain in OSA was associated with impaired HRQoL and psychological problems. Patients with very severe OSA had an increased risk for pain problems . Associated factors for pain intensity in OSA included age, ESS ≥ 9.0, and lowest pulse oximetry (LSpO2) < 80.0%. Pain intensity in OSA decreased significantly after CPAP treatment (p < 0.001). Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment.Pain problems are common in patients with obstructive sleep apnea (OSA), but few studies have thoroughly evaluated pain in these patients. The objective of this study was to examine the prevalence and characteristics of pain in moderate-to-severe OSA patients and the effect of continuous positive airway pressure (CPAP) treatment. Moderate-to-severe OSA patients and healthy controls (HC) completed the Short Form McGill Pain Questionnaire (SF-MPQ) and a portion of the Brief Pain Inventory (BPI) Short Form to assess pain characteristics. The Epworth Sleepiness Scale (ESS), the Short Form-36 (SF-36), and the Hospital Anxiety and Depression Scale (HADS) were used to measure daytime sleepiness, health-related quality of life (HRQoL), and psychological status, respectively. The OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. The subjects' pain intensity was reassessed after 3 months. The prevalence of pain was 57.5% in OSA versus 27.1% in HC ( Moreover, OSA has been associated with various health complications, such as diabetes, hypertension, and cardiovascular disorders2.Obstructive sleep apnea (OSA) is a prevalent condition characterized by complete or partial upper airway obstruction during sleep, leading to fragmented sleep patterns and recurrent nocturnal hypoxia. Individuals with OSA commonly experience psychological difficulties, increased daytime sleepiness and fatigue, impaired concentration and memory, as well as other symptoms3. Numerous painful conditions such as headaches, temporomandibular disorders, and fibromyalgia are influenced by OSA and prone to development and exacerbation4. A recent study revealed that a significant number of patients with high-impact chronic pain, who were referred for specialized pain management also presented with OSA5. The influence of sleep deprivation and intermittent hypoxia has been combined to be the effects of OSA on pain, according to a theory6. Furthermore, OSA patients have also been reported to have greater odds of comorbid moderate and severe pain7. However, the prevalence and characteristics of pain in individuals with obstructive sleep apnea (OSA) remain inadequately understood, with limited studies comparing the experience of pain between OSA patients and healthy individuals. Furthermore, the association between significant clinical features of OSA, such as disrupted sleep structure, hypoxemia, microarousals, daytime drowsiness, and pain, has not been extensively investigated. Therefore, it is imperative to conduct a more detailed examination of the relationship between OSA and pain outcomes.OSA and pain exhibit a strong association8. Research has found that individuals with OSA frequently encounter psychological symptoms such as despair and anxiety in addition to the typical excessive daytime sleepiness9. Moreover, the literature has already reported on the effects of OSA on health-related quality of life (HRQoL)10. A recent study has highlighted the pervasive nature of pain among primary care patients, significantly impacting their overall quality of life8. However, it remains unknown how pain affects the health-related quality of life (HRQoL) and psychological well-being of individuals with obstructive sleep apnea (OSA). To date, no studies have investigated this aspect.Due to the intricate nature of pain, involving both psychological and physical elements, it is often associated with heightened emotional distress and a reduced quality of life11. Therefore, our study aimed to investigate the prevalence, intensity, and location of pain in patients with moderate-to-severe OSA, explore the physiological functioning, psychological symptoms, and quality of life in OSA patients experiencing pain, examine significant clinical features associated with worse pain outcomes in OSA patients, and evaluate the effects of CPAP treatment on pain outcomes among individuals with moderate-to-severe OSA.Continuous positive airway pressure (CPAP) treatment is a well-established therapeutic approach for obstructive sleep apnea (OSA), yet limited research has been conducted on its impact on pain relief11. The exclusion criteria were: (1) AHI (apnoea hypopnea index) < 15 (events/hour); (2) diagnosis of complication except for hypertension, hyperlipemia, hyperuricaemia, and hypercapnia; (3) severe chronic debilitating conditions or pregnancy; (4) concurrent use of painkillers; and (5) inability to complete questionnaires.Consecutive patients referred for suspected OSA at the Sleep Disorders Center of the Second Xiangya Hospital of Central South University were screened from September 2021 to September 2022. The OSA diagnosis was based on the International Classification of Sleep Disorders, third editionHealthy, age-matched control participants were recruited from the Health Management Center of the Second Xiangya Hospital of Central South University. Except for possible obesity, all control subjects had a normal physical examination and laboratory tests. Control subjects were excluded from the study if they (1) were diagnosed with any kind of sleep-disordered breathing through polysomnography; (2) had concurrent use of painkillers; or (3) were unable to complete questionnaires.11.All participants received diagnostic PSG . The monitoring was conducted at a specialized sleep center. Non-OSA, mild OSA, moderate OSA, and severe OSA were defined based on the Apnea–Hypopnea Index (AHI) as < 5, 5–15, 15–30, and ≥ 30 events per hour, respectively. Additionally, within the severe OSA category, a subgroup known as very severe OSA was defined with an AHI ≥ 60 events per hour12. The Short Form McGill Pain Questionnaire (SF-MPQ) was used to evaluate the pain intensity of subjects, which was divided into three parts: the Pain Rating Index (PRI), the Present Pain Intensity (PPI) index and the visual analogue scale (VAS). Based on pain intensity, the PPI is categorized into six levels: 0—no pain, 1—mild, 2—discomforting, 3—distressing, 4—horrible, and 5—unbearable. The three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective, and total descriptors, with a higher score indicating greater pain intensity14. The Brief Pain Inventory (BPI) was used by the subjects to locate the pain on the body chart15.Data on baseline medical history, anthropometric, polysomnographic parameters and common questionnaires were collected. For all of the participants, demographic details  were recorded. All participants completed the Epworth Sleepiness Scale (ESS) questionnaire, and excessive daytime sleepiness was defined as an ESS score ≥ 916. The Short Form-36 (SF-36) was used to evaluate HRQoL. The scores of the SF-36 test are separated into 8 categories , with lower scores indicating worse HRQoL17.The subjects with OSA also completed the following questionnaires: The Hospital Anxiety and Depression Scale (HADS) was used to measure the severity of anxiety and depression, with a higher score indicating greater anxiety or depressionThe OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. Patients undergoing CPAP therapy were telephonically followed up on a weekly basis. The follow-up encompassed assessing patients’ adherence and tolerance to treatment, comfort levels while wearing the ventilator, discomfort experienced, and treatment efficacy in promptly addressing any issues encountered during the course of treatment. Participants adherent to CPAP were defined as those who received CPAP therapy for a minimum of 4 h per night on more than 70% of nights. CPAP compliance data, including device usage and hours of use per night at the prescribed pressure, were automatically recorded by the CPAP device and extracted using the appropriate software. Subsequently, after 3 months, the pain intensity of these participants was reassessed using the Short Form McGill Pain Questionnaire (SF-MPQ).p < 0.05 was considered significant.The statistical analysis was conducted using SPSS software . Descriptive data were presented as percentages. Normally distributed continuous variables were reported as mean values with standard deviations (SD), while non-normally distributed continuous variables were described as medians with interquartile ranges (IQR). Group comparisons for continuous measurements were performed using independent t-tests, Mann–Whitney U tests, paired t-tests or Wilcoxon rank-sum tests. Categorical data were analyzed using the Chi-Square test. A multivariate logistic regression analysis was carried out to identify risk factors for pain by including significant variables from the univariate analysis. The correlations analyses of pain intensity were examined using Spearman’s correlation. Multiple linear regression was employed to assess potential independent factors predicting the most significant factor influencing pain intensity in OSA patients. This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (2019-215). All methods were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects.p < 0.001). The ESS scores, AHI (apnea hypopnea index), REM-AHI (apnea hypopnea index during rapid eye movement stage), NREM-AHI (apnea hypopnea index during non-rapid eye movement stage), LSpO2 (lowest pulse oximetry), MSpO2 (mean pulse oximetry), ODI (oxygen desaturation index), N3 period, sleep efficiency, and arousal index exhibited significant differences between the OSA group and HC group   (Table p < 0.001). The median pain rank index (PRI) score was 4.0 (2.0–5.8) in the OSA group versus 2.0 (1.0–2.0) in the HC group (p < 0.001). The median visual analogue scale (VAS) score was 4.0 (4.0–6.0) in the OSA group versus 2.0 (2.0–4.0) in the HC group (p = 0.011), while the present pain intensity (PPI) score and PPI rank did not show an obvious difference between the two groups  in the OSA group compared to 19 27.1%) in the healthy control group  in the OSA patients with or without pain. The patients with OSA and pain had higher Hospital Anxiety and Depression Scale (HADS) scores than the patients with OSA but without pain. The median HADS anxiety score was 6.0 (4.0–7.0) in OSA patients with pain versus 4.0 (2.3–4.8) in OSA patients without pain (p < 0.001), and the HADS depression score was 5.0 ± 2.4 in OSA patients with pain versus 3.4 ± 2.3 in OSA patients without pain (p = 0.017). From the different dimensions of HRQoL measured by the SF-36, HRQoL was significantly impaired in patients with OSA and pain, which was reflected in the SF total score (106.7 (95.6–124.2) in OSA patients with pain, 129.1 (124.5–133.8) in OSA patients without pain, p < 0.001) and performed in physical functioning (p = 0.014), bodily pain (p < 0.001), general health (p < 0.001), vitality (p = 0.01), social functioning (p = 0.01), role emotional (p = 0.008), mental health (p = 0.002), and health transition (p = 0.015).In the OSA group Table , the aveThe clinical characteristics of patients with obstructive sleep apnea (OSA) were analyzed, comparing those with and without headache. However, no significant variables, including demographics, hypercapnia, comorbidities, and sleep parameters, were found between OSA patients with and without headache Table .Table 3C18, BMI (divided line as 28.0 kg/m2), AHI (divided line as 60 events/hour), LSpO2 (divided line as 80%), arousal index (divided line as 30.0 events/hour), N3 period (divided line as 12.0%), REM period (divided line as 20.0%) and sleep efficiency (divided line as 80.0%)11. After adjusting for ESS and LSpO2, the results of logistic regression analysis revealed that an AHI ≥ 60 events/hour was a risk factor for pain in OSA patients .A multivariate logistic regression analysis was carried out to identify risk factors for pain by including significant variables from univariate analysis, which is presented in Table r = 0.511, p < 0.001), and a negative correlation with LSpO2 levels . Furthermore, the VAS score showed a positive correlation with ESS scores . Additionally, the PPI score demonstrated a negative correlation with LSpO2 levels  , while LSpO2 negatively predicted the PRI score in OSA patients . Regarding the VAS score, ESS positively predicted the VAS score . Therefore, age, ESS, and LSpO2 may be the predictors of the pain intensity in OSA.As is shown in Table p < 0.001), which remained statistically significant only among adherent patients receiving CPAP therapy.All OSA patients experiencing pain were followed up after three months, and the pain intensity in these patients was reassessed. Out of the total, 26 (56.5%) patients demonstrated adherence to CPAP treatment and were categorized as the CPAP-treated group, while 20 (43.5%) patients exhibited non-compliance with CPAP treatment and were classified as the CPAP-untreated group. Table 4. The comprehensive assessment of pain issues in patients with OSA and healthy controls is conducted for the first time in this study.Patients with obstructive sleep apnea (OSA) frequently experience pain-related issues. However, limited research has been conducted in this area. Recent studies have demonstrated that OSA can contribute to the development and exacerbation of various unpleasant conditions, such as headaches, temporomandibular disorders, and fibromyalgia19. The findings of our study demonstrate that pain manifested as a prevalent impairment among individuals with OSA, surpassing its occurrence in healthy controls. According to multivariate logistic regression analysis, we found that very severe OSA had an increased risk for pain problems. Very severe OSA is defined as an Apnea–Hypopnea Index (AHI) ≥ 60 events per hour, which typically exhibits more pronounced nocturnal hypoxemia and symptom burden. According to a research study, individuals with severe OSA reported significantly higher rates of drowsy driving and accidents caused by falling asleep20. Therefore, clinicians should prioritize the management of pain in individuals with very severe OSA.In a recent research, the prevalence of obstructive sleep apnea (OSA) was found to be 13.8% in a retrospective analysis conducted among patients attending a pain management clinic21, and treating OSA resulted in clinically significant improvements in over 30% of patients with undifferentiated headache22. In our study, the head was found to be the most prevalent location for pain in subjects with OSA, accounting for 39% of overall pain locations. Additionally, a significant proportion (28.8%) of patients diagnosed with OSA reported experiencing headaches, suggesting a high prevalence of headache among individuals with OSA. However, upon comparing the clinical characteristics of OSA patients with and without headache, we did not identify any specific factors associated with headache in OSA patients. As reported in the literature, the impact of OSA severity on the prevalence of sleep apnea headache is minimal. The underlying mechanisms behind sleep apnea headache remain elusive, as there are no significant differences in average oxygen desaturation and lowest oxygen saturation between OSA patients with or without headache23.According to earlier research, patients with OSA had considerably more morning headache than patients without OSA10. The findings of a comparative mixed-methods study indicate that individuals experiencing pain exhibit lower health-related quality of life (HRQoL) compared to both the general population and patients with other chronic conditions, owing to the multifaceted adverse effects associated with pain24. We observed that patients with obstructive sleep apnea (OSA) and pain exhibited significantly poorer health-related quality of life (HRQoL) and psychological well-being compared to those without pain. The SF-36 questionnaire revealed substantial impairments in mental health, bodily pain, vitality, and role emotional domains among these patients, which were further supported by the results obtained from the SF-MPQ and HADS assessments. These findings underscore the detrimental impact of pain on HRQoL in individuals with OSA, emphasizing the need for clinicians to prioritize this comorbidity and consider screening for OSA in patients experiencing pain.The term “health-related quality of life” (HRQoL) refers to how one's health, encompassing physical, psychological, and social functions, affects their level of life satisfaction and pleasure6 put forth, OSA’s overall impact on pain is a culmination of the effects of sleep deprivation, inflammatory mediators, and hypoxia markers. These effects increase pain sensitivity, that contributes to neuronal pain sensitivity, and increase spontaneous pain26. The mechanisms in OSA result in sleep fragmentation and nocturnal hypoxemia. These two changes in OSA patients may be involved in the development of a number of OSA comorbidities  and molecular changes 27. We further found that the associated factors for pain intensity in OSA included age, ESS ≥ 9.0 and lowest pulse oximetry (LSpO2) < 80.0%. Many patients with OSA experience excessive daytime sleepiness (EDS), which can negatively affect daily functioning, cognition, mood, and other aspects of well-being. The Epworth Sleepiness Scale (ESS) is an eight-item self-report measure used to assess trait excessive daytime sleepiness (EDS), where patients rate their propensity for dozing off or falling asleep in various scenarios such as reading, watching television, or riding in a car; an ESS score of ≥ 9.0 indicates the presence of excessive daytime sleepiness28. Hypoxemia in OSA has been proven to have a significant impact on increased expression of proinflammatory cytokines influencing the hyperalgesic priming of nociceptors. Moreover, hypoxia markers by themselves are hypothesized to modulate intracellular signal transduction in neurons and have an impact on nociceptive sensitization6. We found that the pain intensity of OSA patients was also related to worse pulse oximetry and severe nocturnal hypoxemia may be one of the predictors of pain intensity in OSA. These results indicated that the degree of daytime sleepiness and nocturnal hypoxia, may play an important role in the development of pain in OSA.It is unclear exactly how OSA and pain are related. According to a theory29. CPAP treatment prevents hypoxia and oxygenation injury and inhibits the cascade of deleterious OSA-induced consequences30. Patients with severe OSA and metabolic syndrome who exhibit good compliance with CPAP treatment may exhibit improved insulin sensitivity and reduced systemic inflammation, and global cardiovascular disease risk31. Previous studies have demonstrated that severe OSA patients are hyperalgesic, their pain sensitivity improves with CPAP treatment, and the improvement disappears immediately with discontinuation of CPAP therapy32. In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQoL over 6–12 months of follow-up, with the largest improvement observed in bodily pain33. The results of this study show that in patients with moderate-to-severe OSA and pain, good compliance with CPAP treatment can improve pain intensity. Therefore, OSA patients should be evaluated for pain and receive timely intervention, and there should be a focus on education for OSA patients with pain to increase compliance with CPAP treatment.The use of continuous positive airway pressure (CPAP) is an effective treatment for OSA because CPAP normalizes sleep architecture, reduces subjective excessive daytime sleepiness and reverses other OSA symptomsTo the best of our knowledge, this study represents the first attempt to investigate the prevalence, distribution, intensity, nature, and associated factors of pain and its severity in patients with OSA. However, it is important to acknowledge certain limitations in our study. Firstly, the study was conducted at a single center with a limited sample size, predominantly consisting of male patients, which may limit the generalizability to the overall OSA population. Secondly, it is important to consider that comorbidities such as hypertension, hyperuricemia, and hypercapnia, which have the potential to influence pain assessment in OSA patients, were not specifically excluded from this study. Lastly, it is worth mentioning that participants' verbal comprehension and subjective experiences might have influenced their responses on the questionnaire ratings, particularly regarding the visual analog scale (VAS) score.Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment.