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This review examines key studies published in 2021 that are related to primary prevention of atherosclerotic cardiovascular disease (ASCVD). Major randomized clinical trials (RCTs) concerning traditional risk factors or ASCVD events, meta‐analyses, and key observational studies related to primary prevention of ASCVD were considered. The review includes interventions for weight loss, cardiometabolic and renal disease, blood pressure control, diet, and the occurrence of cardiovascular disease events. A few studies considered both primary and secondary prevention populations. The review is not exhaustive. We did not include studies that focused on heart failure or clinical presentations that may be difficult to classify, such as acute or chronic ischemic cardiovascular disease without myocardial infarction. Our purpose was to highlight recent research that will help the reader stay abreast of the changing field of cardiovascular prevention.

Background There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID‐19. Methods and Results The French National Healthcare Data System database was used to conduct a matched‐cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID‐19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long‐term medications. Its association with in‐hospital death from COVID‐19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID‐19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81–0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low‐ and moderate‐intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71–0.86] and HR, 0.84 [95% CI, 0.80–0.89], respectively), whereas high‐intensity statins did not (HR, 1.01; 95% CI, 0.86–1.18). We found similar results with in‐hospital death from COVID‐19. Conclusions Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID‐19 and of in‐hospital death from COVID‐19.

Background Aspirin is widely administered to prevent cardiovascular disease (CVD). However, appropriate use of aspirin depends on patient understanding of its risks, benefits, and indications, especially where aspirin is available over the counter (OTC). Methods and Results We did a survey of patient‐reported 10‐year cardiovascular risk; aspirin therapy status; form of aspirin access (OTC versus prescription); and knowledge of the risks, benefits, and role of aspirin in CVD prevention. Consecutive adults aged ≥50 years with ≥1 cardiovascular risk factor attending outpatient clinics in America and Europe were recruited. We also systematically reviewed national policies regulating access to low‐dose aspirin for CVD prevention. At each site, 150 responses were obtained (300 total). Mean±SD age was 65±10 years, 40% were women, and 41% were secondary prevention patients. More than half of the participants at both sites did not know (1) their own level of 10‐year CVD risk, (2) the expected magnitude of reduction in CVD risk with aspirin, or (3) aspirin’s bleeding risks. Only 62% of all participants reported that aspirin was routinely indicated for secondary prevention, whereas 47% believed it was routinely indicated for primary prevention ( P =0.048). In America, 83.5% participants obtained aspirin OTC compared with 2.5% in Europe ( P Conclusions Many patients have poor insight into their objectively calculated 10‐year cardiovascular risk and do not know the risks, benefits, and role of aspirin in CVD prevention. Aspirin is mainly obtained OTC in America in contrast to Europe, where most countries restrict access to low‐dose aspirin.

Background The objective of this study was to evaluate the temporal trends in pregnancy‐associated myocardial infarction (PAMI) in the State of California and explore potential risk factors and mechanisms. Methods and Results The California State Inpatient Database was analyzed from 2003 to 2011 for patients with International Classification of Diseases, Ninth Revision ( ICD‐9 ) codes for acute myocardial infarction and pregnancy or postpartum admissions; risk factors were analyzed and compared with pregnant patients without myocardial infarction. A total of 341 patients were identified with PAMI from a total of 5 266 380 pregnancies (incidence of 6.5 per 100 000 pregnancies). Inpatient maternal mortality rate was 7%, and infant mortality rate was 3.5% among patients with PAMI. There was a nonsignificant trend toward an increase in PAMI incidence from 2003 to 2011, possibly attributable to higher incidence of spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome. PAMI, when compared with pregnant patients without myocardial infarction, was significant for older age (aged >30 years in 72% versus 37%, P P P =0.04), higher prevalence of hypertension (26% versus 7%, P P P P P P =0.0001). Conclusions There has been a trend toward an increase in PAMI incidence in California over the past decade, with an increasing trend in spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome as mechanisms. These findings warrant further investigation.

Background There is wide variability in cardiac rehabilitation (CR) dose (ie, number of sessions) delivered, and no evidence‐based recommendations regarding what dose to prescribe. We aimed to test what CR dose impacts major adverse cardiovascular events (MACEs). Methods and Results This is an historical cohort study of all patients who had coronary artery disease and who initiated supervised CR between 2002 and 2012 from a single major CR center. CR dose was defined as number of visits including exercise and patient education. Follow‐up was performed using record linkage from the Rochester Epidemiology Project. MACEs included acute myocardial infarction, unstable angina, ventricular arrhythmias, stroke, revascularization, or all‐cause mortality. Dose was analyzed in several ways, including tertiles, categories, and as a continuous variable. Cox models were adjusted for factors associated with dose and MACE. The cohort consisted of 2345 patients, who attended a mean of 12.5±11.1 of 36 prescribed sessions. After a mean follow‐up of 6 years, 695 (29.65%) patients had a MACE, including 231 who died. CR dose was inversely associated with MACE (hazard ratio, 0.66 [95% CI]; 0.55–0.91) in those completing ≥20 sessions, when compared with those not exposed to formal exercise sessions (≤1 session; log‐rank P =0.007). We did not find evidence of nonlinearity ( P ≥0.050), suggesting no minimal threshold nor ceiling. Each additional session was associated with a lower rate of MACE (fully adjusted hazard ratio, 0.98 [95% CI, 0.97–0.99]). Greater session frequency was also associated with lower MACE risk (fully adjusted hazard ratio, 0.74 [95% CI, 0.58–0.94]). Conclusions CR reduces MACEs, but the benefit appears to be linear, with greater risk reduction with higher doses, and no upper threshold.

Background Atrial fibrillation (AF) screening is endorsed by certain guidelines for individuals aged ≥65 years. Yet many AF screening strategies exist, including the use of wrist‐worn wearable devices, and their comparative effectiveness is not well‐understood. Methods and Results We developed a decision‐analytic model simulating 50 million individuals with an age, sex, and comorbidity profile matching the United States population aged ≥65 years (ie, with a guideline‐based AF screening indication). We modeled no screening, in addition to 45 distinct AF screening strategies (comprising different modalities and screening intervals), each initiated at a clinical encounter. The primary effectiveness measure was quality‐adjusted life‐years, with incident stroke and major bleeding as secondary measures. We defined continuous or nearly continuous modalities as those capable of monitoring beyond a single time‐point (eg, patch monitor), and discrete modalities as those capable of only instantaneous AF detection (eg, 12‐lead ECG). In total, 10 AF screening strategies were effective compared with no screening (300–1500 quality‐adjusted life‐years gained/100 000 individuals screened). Nine (90%) effective strategies involved use of a continuous or nearly continuous modality such as patch monitor or wrist‐worn wearable device, whereas 1 (10%) relied on discrete modalities alone. Effective strategies reduced stroke incidence (number needed to screen to prevent a stroke: 3087–4445) but increased major bleeding (number needed to screen to cause a major bleed: 1815–4049) and intracranial hemorrhage (number needed to screen to cause intracranial hemorrhage: 7693–16 950). The test specificity was a highly influential model parameter on screening effectiveness. Conclusions When modeled from a clinician‐directed perspective, the comparative effectiveness of population‐based AF screening varies substantially upon the specific strategy used. Future screening interventions and guidelines should consider the relative effectiveness of specific AF screening strategies.

Background Sleep variability and social jetlag are associated with adverse cardiometabolic outcomes via circadian disruption. Variable eating patterns also lead to circadian disruption, but associations with cardiometabolic health are unknown. Methods and Results Women (n=115, mean age: 33±12 years) completed a 1‐week food record using the Automated Self‐Administered 24‐Hour Dietary Assessment Tool at baseline and 1 year. Timing of first and last eating occasions, nightly fasting duration, and %kcal consumed after 5 pm (%kcal 5 pm ) and 8 pm (%kcal 8 pm ) were estimated. Day‐to‐day eating variability was assessed from the SD of these variables. Eating jetlag was defined as weekday‐weekend differences in these metrics. Multivariable‐adjusted linear models examined cross‐sectional and longitudinal associations of day‐to‐day variability and eating jetlag metrics with cardiometabolic risk. Greater jetlag in eating start time, nightly fasting duration, and %kcal 8 pm related to higher body mass index and waist circumference at baseline ( P pm SD predicted increased body mass index (β, 0.52; 95% CI, 0.23–0.81) and waist circumference (β, 1.73; 95% CI, 0.58–2.87); greater %kcal 8 pm weekday‐weekend differences predicted higher body mass index (β, 0.25; 95% CI, 0.07–0.43). Every 30‐minute increase in nightly fasting duration SD predicted increased diastolic blood pressure (β, 0.95; 95% CI, 0.40–1.50); an equivalent increase in nightly fasting duration weekday‐weekend differences predicted higher systolic blood pressure (β, 0.58; 95% CI, 0.11–1.05) and diastolic blood pressure (β, 0.45; 95% CI, 0.10–0.80). Per 10% increase in %kcal 5 pm SD, there were 2.98 mm Hg (95% CI, 0.04–5.92) and 2.37mm Hg (95% CI, 0.19–4.55) increases in systolic blood pressure and diastolic blood pressure; greater %kcal 5 pm weekday‐weekend differences predicted increased systolic blood pressure (β, 1.83; 95% CI, 0.30–3.36). For hemoglobin A1c, every 30‐minute increase in eating start and end time SD and 10% increase in %kcal 5 pm SD predicted 0.09% (95% CI, 0.03–0.15), 0.06% (95% CI, 0.001–0.12), and 0.23% (95% CI, 0.07–0.39) increases, respectively. Conclusions Variable eating patterns predicted increased blood pressure and adiposity and worse glycemic control. Findings warrant confirmation in population‐based cohorts and intervention studies.

Background Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex‐specific relations between domains of physical activity (PA; commuting, domestic, and leisure‐time PA, including active sport and occupational PA) with AS were investigated. Methods and Results Stiffness index by digital photoplethysmography was investigated in 12 650 subjects from the GHS (Gutenberg Health Study). Self‐reported PA was evaluated by the “Short Questionnaire to Assess Health‐Enhancing Physical Activity” and reported as activity score peer week, being a combined measure of duration, frequency, and intensity of PA. Multivariable linear regression analysis demonstrated strong beneficial effects of repetitive activities, such as active commuting or leisure‐time PA–related walking on AS in men, but not in women. Lower AS associated with endurance training was also found among men and premenopausal women. In contrast, intense occupational PA was related to stiffer vessels in men ( P P =0.0021) in a fully adjusted model. Combination of both, performing endurance training and having stiffness index values below median, resulted in the best survival. In contrast, subjects with elevated stiffness index at baseline without any endurance activities demonstrated the worst survival. Conclusions In this population representative sample, a differential impact of domains of self‐reported PA on AS was demonstrated. Our data strengthen the importance of regular endurance PA to induce a reduction of AS, which, in turn, may improve cardiovascular prognosis. We also report deleterious effects of intense occupational PA on stiffness index, a finding that needs further confirmation by larger prospective trials.

Background We studied care gap in patients with familial hypercholesterolemia (FH) with respect to lipid‐lowering therapy. Methods and Results We enrolled patients with cardiovascular disease (CVD) or FH and low‐density lipoprotein‐cholesterol >2.0 mmol/L despite maximally tolerated statin therapy. During follow‐up physicians received online reminders of treatment recommendations of 2009 patients (median age, 63 years, 42% women), 52.4% had CVD only, 31.7% FH only, and 15.9% both CVD and FH. Patients with FH were younger and more likely to be women and non‐White with significantly higher baseline low‐density lipoprotein‐cholesterol level (mmol/L) as compared with patients with CVD (FH 3.92±1.48 versus CVD 2.96±0.94, P P =0.0001) at baseline but not ezetimibe (28.1% versus 20.4%, P =0.0003). Among patients with FH only, 45.3% were at low‐density lipoprotein target (≥ 50% reduction from pre‐treatment level or low‐density lipoprotein P P Conclusions There is significant treatment inertia in patients with FH including those with CVD. Education focused on patients with FH should continue to be undertaken.

Background We assessed cases of incidental unruptured intracranial aneurysm (UIA) discovered on screening magnetic resonance angiography to identify hemodynamic and atherosclerotic risk factors. Methods and Results The data of 1376 healthy older subjects (age range, 31–91 years) without cerebro‐ or cardiovascular diseases who underwent brain magnetic resonance angiography as part of a medical checkup program at a health screening center were examined retrospectively. We looked for an increase in classical risk factors for UIAs (age, sex, hypertension, and smoking) and laboratory data related to lifestyle diseases among subjects with UIAs. Brachial‐ankle pulse wave velocity, central systolic blood pressure, radial augmentation index, and carotid flow pulsatility index were also compared between those with and without UIAs. We found UIAs in 79 (5.7%) of the subjects. Mean age was 67.1±9.0 years, and 55 (70%) were women. Of the 79 aneurysms, 75 (95%) were in the anterior circulation, with a mean diameter of 3.1 mm (range, 2.0–8.0 mm). Subjects with UIAs were significantly older and had more severe hypertension. The carotid flow pulsatility index was significantly lower in subjects with UIAs and negatively and independently correlated with UIAs. Tertile analysis stratified by carotid flow pulsatility index revealed that subjects with lower indices had higher levels of low‐density lipoprotein cholesterol. Conclusions The presence of UIAs correlated with lower carotid flow pulsatility index and elevated low‐density lipoprotein cholesterol in the data from a population of healthy older volunteers. A reduced carotid flow pulsatility index may affect low‐density lipoprotein cholesterol elevation by some molecular pathways and influence the development of cerebral aneurysms. This may guide aneurysm screening indications for institutions where magnetic resonance angiography is not routine.

Background Early identification of healthy arterial aging versus premature atherosclerosis is important for optimal atherosclerotic cardiovascular disease risk stratification and prevention. We sought to identify predictors for the long‐term absence of carotid plaque among young adults. Methods and Results We included 508 participants from the Bogalusa Heart Study without clinical atherosclerotic cardiovascular disease who were free of carotid plaque at baseline (2001–2002) and underwent ultrasound imaging at follow‐up (2013–2016). Modified Poisson regression estimated the persistent absence of plaque over 12.8 years. Participants were on average age 36.2 years at baseline, 64% were women, and 29% were Black. Although nearly all participants (97%) had a 10‐year atherosclerotic cardiovascular disease risk

Background Adropin is a peptide hormone that promotes nitric oxide (NO) production via activation of endothelial NO synthase (eNOS) in endothelial cells. Its circulating levels are reduced with aging and increased with aerobic exercise training (AT). Using a mouse model, we hypothesized that AT restores aging‐associated reductions in arterial and circulating adropin and improves adropin‐induced NO‐dependent vasorelaxation. Further, we hypothesized these findings would be consistent with data obtained in elderly humans. Methods and Results In the animal study, 50‐week‐old SAMP1 male mice that underwent 12 weeks of voluntary wheel running, or kept sedentary, were studied. A separate cohort of 25‐week‐old SAMP1 male mice were used as a mature adult sedentary group. In the human study, 14 healthy elderly subjects completed an 8‐week AT program consisting of 45 minutes of cycling 3 days/week. In mice, we show that advanced age is associated with a decline in arterial and circulating levels of adropin along with deterioration of endothelial function, arterial NO production, and adropin‐induced vasodilation. All these defects were restored by AT. Moreover, AT‐induced increases in arterial adropin were correlated with increases in arterial eNOS phosphorylation and NO production. Consistently with these findings in mice, AT in elderly subjects enhanced circulating adropin levels and these effects were correlated with increases in circulating nitrite/nitrate (NOx) and endothelial function. Conclusions Changes in arterial adropin that occur with age or AT relate to alterations in endothelial function and NO production, supporting the notion that adropin should be considered a therapeutic target for vascular aging. Registration URL: https://www.umin.ac.jp ; Unique identifier: UMIN000035520.

BackgroundPrevious studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and ResultsThe temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time‐series analysis with quasi‐Poisson regression models and distributed lag‐nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03–1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09–1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47–0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49–0.57). ConclusionsInfluenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients., This work has been partially funded by unrestricted research grants from the Fundación para la Investigación Biomédica, University Hospital “Príncipe de Asturias” (Servicio Madrileño de Salud, Madrid, Spain) (to Drs García‐Lledó and de Abajo) and funding from Sanofi‐Pasteur S.A., a manufacturer of influenza vaccines (to Dr de Abajo). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing the report. Dr Tobías received support from the Japanese Society for the Promotion of Science in its invitation‐to‐research fellowship program in Japan (S18149).

Background One third of primary prevention implantable cardioverter‐defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter‐defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter‐defibrillator. During a follow‐up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead‐related (n=47) and pocket‐related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter‐defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

Background Epicardial adipose tissue may be associated with the pathogenesis of coronary artery disease (CAD), but its effect on obstructive CAD risk is uncertain. Therefore, we aimed to examine the relationship between epicardial adipose tissue and obstructive CAD in Chinese patients with suspected CAD. Methods and Results The present study enrolled 194 consecutive inpatients with suspected CAD who underwent both noncontrast computed tomography and coronary angiography. We measured epicardial fat volume (EFV) and evaluated its association with obstructive CAD, which was defined as coronary stenosis severity ≥70%. Overall, 44.3% patients had obstructive CAD and tend to have higher EFV. Age, body mass index, triglycerides, incidence of hypertension, and hyperlipidemia were higher across tertiles of EFV ( P for trend P P E ‐value analysis suggested robustness to unmeasured confounding. Conclusions Our results suggested that in Chinese patients with suspected CAD, EFV was significantly and positively associated with the risk of obstructive CAD, independent of traditional risk factors and coronary artery calcium.

Background The optimal method for communicating coronary heart disease (CHD) risk to individual patients is not yet clear. Recent research supports the concept of "coronary age" for more effective risk communication. We defined an individual's coronary age as the age at which an average healthy individual would have an equivalent estimated CHD risk as that calculated for the index individual, building on our previously validated MESA (Multi‐Ethnic Study of Atherosclerosis) 10‐year CHD Risk Score equations with and without coronary artery calcium (CAC). Methods and Results We derived a coronary age by (1) calculating the MESA 10‐year CHD risk; (2) mathematically setting this equal to an equation describing risk of an average healthy MESA participant, as a function of age; and (3) solving for age. The risk discrimination of the resultant coronary age was compared with that of chronological age, the MESA CHD Risk Score, and CAC alone. Approximately 95% of coronary age values ranged from 30 years less to 30 years higher than chronological age. Although the mean chronological age of individuals experiencing CHD events compared with those free of events was 67.4 versus 61.8 years, the difference in coronary age including CAC was larger (80.6 versus 62.8 years). Coronary age with CAC had identical predictive ability to that of MESA CHD Risk Score and outperformed chronological age and CAC alone. Conclusions The newly derived coronary age is a convenient transformation of MESA CHD Risk, retaining very good risk discrimination. This easy‐to‐communicate tool will be available for patients and clinicians, potentially facilitating risk communication in routine care.

Background Restless legs syndrome (RLS) is associated with higher cardiovascular disease (CVD) risk. However, it remains unknown whether treatment of RLS lowers the cardiovascular risk associated with RLS. Methods and Results All data were collected retrospectively, but subjects were prospectively followed forward in time to determine outcomes of interest. We used the Truven Health MarketScan Commercial Claims and Encounters database from January 1, 2006, through December 31, 2014. Participants were 169 393 individuals, which included 24 199 nonpregnant participants with an RLS diagnosis (16 694 receiving treatments for RLS and 7505 without treatment) during 2006 to 2008 and 145 194 age‐ and sex‐matched participants without RLS. All participants were free of CVD before January 1, 2009 (analysis baseline). Incident CVD cases (myocardial infarction, angina, stroke, atrial fibrillation, and heart failure) were identified. We adjusted for potential confounders, such as presence of chronic conditions and medication use. We identified 16 574 incident CVD cases during 2009 to 2014. Relative to the non‐RLS group, the adjusted hazard ratio (HR) for future CVD was 1.26 (95% CI, 1.20–1.32) ( P P P Conclusions RLS was associated with higher future CVD risk. However, RLS was associated with statistically significantly less future cardiovascular risk in RLS patients with treatment than in those without treatment.

Background It is unclear whether reversion from pre–diabetes mellitus to normoglycemia reduces cardiovascular disease (CVD) and all‐cause mortality risk in a Chinese population. We aimed to fill this research gap. Methods and Results The current study included 14 231 Chinese participants (mean age, 58.08 years) who were free from myocardial infarction and stroke at the time of survey participation (2006–2007 and 2008–2009). Participants were divided into 3 categories according to the 2‐year changes in pre–diabetes mellitus, defined by fasting plasma glucose: those with progression to diabetes mellitus, those with reversion from pre–diabetes mellitus to normoglycemia, and those with persistent pre–diabetes mellitus. Cox proportional hazards models were used to calculate hazard ratios (HRs) and their 95% CIs for CVD and all‐cause mortality. After a median follow‐up period of 8.75 years, a total of 879 CVD events (including 180 myocardial infarction events and 713 stroke events) and 941 all‐cause mortality events were recorded. After adjustment for confounding factors, reversion from pre–diabetes mellitus to normoglycemia was associated with decreased risks of CVD (HR, 0.78; 95% CI, 0.64–0.96), myocardial infarction (HR, 0.62; 95% CI, 0.40–0.97), stroke (HR, 0.79; 95% CI, 0.63–0.98), and all‐cause mortality (HR, 0.82; 95% CI, 0.68–0.99) compared with progression to diabetes mellitus. Conclusions Reversion from fasting plasma glucose–defined pre–diabetes mellitus to normoglycemia was associated with a reduction in the future risk of CVD and all‐cause mortality in a Chinese population. Registration URL: https://www.chictr.org ; Unique identifier: ChiCTRTNC‐11001489.

Background Circulating endothelial cells (CECs) reflect early changes in endothelial health; however, the degree to which CEC number and activation is related to adiposity and cardiovascular risk factors in youth is not well described. Methods and Results Youth in this study (N=271; aged 8–20 years) were classified into normal weight (body mass index [BMI] percentage P >0.05). Youth with severe obesity had a higher degree of CEC activation compared with normal weight youth (8.3%; 95% CI, 1.1–15.6 [ P =0.024]). Higher CEC number was associated with greater body fat percentage (0.02 per percentage; 95% CI, 0.00–0.03 [ P =0.020]) and systolic blood pressure percentile (0.01 per percentage; 95% CI, 0.00–0.01 [ P =0.035]). Higher degree of CEC activation was associated with greater visceral adipose tissue (5.7% per kg; 95% CI, 0.4–10.9 [ P =0.034]) and non–high‐density lipoprotein cholesterol (0.11% per mg/dL; 95% CI, 0.01–0.21 [ P =0.039]). Conclusions Methods of CEC quantification are associated with adiposity and cardiometabolic risk factors and may potentially reflect accelerated atherosclerosis as early as childhood.

Background Sex differences in the trends for control of cardiovascular disease (CVD) risk factors have been described, but temporal trends in the age at which CVD and its risk factors are diagnosed and sex‐specific differences in these trends are unknown. Methods and Results We used the Medical Expenditure Panel Survey 2008 to 2017, a nationally representative sample of the US population. Individuals ≥18 years, with a diagnosis of hypercholesterolemia, hypertension, coronary heart disease, or stroke, and who reported the age when these conditions were diagnosed, were included. We included 100 709 participants (50.2% women), representing 91.9 million US adults with above conditions. For coronary heart disease and hypercholesterolemia, mean age at diagnosis was 1.06 and 0.92 years older for women, compared with men, respectively (both P P P P =0.03), it increased by 0.22 years for men ( P =0.02). Conclusions The trend in decreasing age at diagnosis for CVD and its risk factors in the United States appears to be more pronounced among women. While earlier identification of CVD risk factors may provide opportunity to initiate preventive treatment, younger age at diagnosis of CVD highlights the need for the prevention of CVD earlier in life, and sex‐specific interventions may be needed.

Background Severe coronavirus disease 2019 (COVID‐19) is characterized by a proinflammatory state with high mortality. Statins have anti‐inflammatory effects and may attenuate the severity of COVID‐19. Methods and Results An observational study of all consecutive adult patients with COVID‐19 admitted to a single center located in Bronx, New York, was conducted from March 1, 2020, to May 2, 2020. Patients were grouped as those who did and those who did not receive a statin, and in‐hospital mortality was compared by competing events regression. In addition, propensity score matching and inverse probability treatment weighting were used in survival models to examine the association between statin use and death during hospitalization. A total of 4252 patients were admitted with COVID‐19. Diabetes mellitus modified the association between statin use and in‐hospital mortality. Patients with diabetes mellitus on a statin (n=983) were older (69±11 versus 67±14 years; P P P P =0.82). Propensity score matching (hazard ratio, 0.88; 95% CI, 0.83–0.94; P P Conclusions Statin use was associated with reduced in‐hospital mortality from COVID‐19 in patients with diabetes mellitus. These findings, if validated, may further reemphasize administration of statins to patients with diabetes mellitus during the COVID‐19 era.

Venous thromboembolism (VTE) is an important vascular disease and public health problem. Prevention of VTE has focused mainly on using thromboprophylaxis to avoid provoked VTE or recurrent VTE, with little attention paid to the possibility of preventing the one third to one half of VTEs that are unprovoked. We review growing research suggesting that unhealthy lifestyle risk factors may cause a considerable proportion of unprovoked VTE. Using epidemiologic data to calculate population attributable risks, we estimate that in the United States obesity may contribute to 30% of VTEs, physical inactivity to 4%, current smoking to 3%, and Western dietary pattern to 11%. We also review possibilities for VTE primary prevention either through a high‐risk individual approach or a population‐wide approach. Interventions for outpatients at high VTE risk but without VTE provoking factors have not been fully tested; yet, improving patient awareness of risk and symptoms, lifestyle counseling, and possibly statins or direct oral anticoagulants may prove useful in primary prevention of unprovoked VTE. A population approach to prevention would bolster awareness of VTE and aim to shift lifestyle risk factors downward in the whole population using education, environmental changes, and policy. Assuming the epidemiological associations are accurate, causal, and independent of each other, a reduction of obesity, physical inactivity, current smoking, and Western diet by 25% in the general population might reduce the incidence of unprovoked VTE by 12%. We urge further research and consideration that primary prevention of unprovoked VTE may be a worthwhile public health aim.

Background Despite advances in pediatric health care over recent decades, it is not clear whether survival in children with congenital heart disease (CHD) is still increasing. Methods and Results We identified all patients with CHD using nationwide Swedish health registries for 1980 to 2017. We examined the survival trends in children with CHD; we investigated the mortality risk in patients with CHD compared with matched controls without CHD from the general population using Cox proportional regression models and Kaplan–Meier survival analysis. Among 64 396 patients with CHD and 639 012 matched controls without CHD, 3845 (6.0%) and 2235 (0.3%) died, respectively. The mean study follow‐up (SD) was 11.4 (6.3) years in patients with CHD. The mortality risk was 17.7 (95% CI, 16.8–18.6) times higher in children with CHD compared with controls. The highest mortality risk was found during the first 4 years of life in patients with CHD (hazard ratio [HR], 19.6; 95% CI, 18.5–20.7). When stratified by lesion group, patients with non‐conotruncal defects had the highest risk (HR, 97.2; 95% CI, 80.4–117.4). Survival increased substantially according to birth decades, but with no improvement after the turn of the century where survivorship reached 97% in children with CHD born in 2010 to 2017. Conclusions Survival in children with CHD has increased substantially since the 1980s; however, no significant improvement has been observed this century. Currently, >97% of children with CHD can be expected to reach adulthood highlighting the need of life‐time management.

Background Serum levels of vascular cell adhesion molecule‐1 (VCAM‐1) are reflective of endothelial activation. Although VCAM‐1 has been implicated in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), the prospective association of VCAM‐1 with development of clinically overt heart failure (HF) across ejection fraction categories is unclear. Methods and Results In MESA (the Multi‐Ethnic Study of Atherosclerosis), we evaluated the association of VCAM‐1 at examination 2 (2002–2004) with incident HF (HFpEF and HF with reduced ejection fraction) after adjustment for cardiovascular risk factors. Incident HF was independently adjudicated as first hospitalization for symptomatic HF. Among 2297 participants (mean age, 63 years; women, 53%), those with higher VCAM‐1 were more likely to be White race, had higher blood pressure, and had lower kidney function. Over a median of 14.4 years, there were 102 HF events (HFpEF=65; HF with reduced ejection fraction=37). After covariate adjustment, each doubling of VCAM‐1 was associated with incident HF (hazard ratio [HR], 1.94; 95% CI, 1.17–3.23; P =0.01). This association appeared stronger among current/former smokers compared with never smokers. On evaluation of HF subtypes, VCAM‐1 was associated with incident HFpEF (HR, 1.97; 95% CI, 1.04–3.72; P =0.04) but not with incident HF with reduced ejection fraction, although risk estimates were consistent (HR, 1.82; 95% CI, 0.79–4.21; P =0.16). Conclusions In a multiethnic cohort, VCAM‐1 was significantly associated with incident HF over long‐term follow‐up. These findings suggest a potential role for endothelial activation in driving clinical HF, and specifically HFpEF. Therapies that decrease endothelial activation may prevent the progression from cardiovascular risk factors to clinical HF.

Background Sex differences in outcome have been reported in patients with congenital long QT syndrome. We aimed to report on the incidence of time‐dependent life‐threatening events in male and female patients with long QT syndrome with an implantable cardioverter defibrillator (ICD). Methods and Results A total of 60 patients with long QT syndrome received an ICD for primary or secondary prevention indications. Life‐threatening events were evaluated from the date of ICD implant and included ICD shocks for ventricular tachycardia, ventricular fibrillation, or death. ICDs were implanted in 219 women (mean age 38±13 years), 46 girls (12±5 years), 55 men (43±17 years), and 40 boys (11±4 years). Mean follow‐up post‐ICD implantation was 14±6 years for females and 12±6 years for males. At 15 years of follow‐up, the cumulative probability of life‐threatening events was 27% in females and 34% in males (log‐rank P =0.26 for the overall difference). In the multivariable Cox model, sex was not associated with significant differences in risk first appropriate ICD shock (hazard ratio, 0.83 female versus male; 95% CI, 0.52–1.34; P =0.47). Results were similar when stratified by age and by genotype: long QT syndrome type 1 (LQT1), long QT syndrome type 2 (LQT2), and long QT syndrome type 3 (LQT3). Incidence of inappropriate ICD shocks was higher in males versus females (4.2 versus 2.7 episodes per 100 patient‐years; P =0.018), predominantly attributed to atrial fibrillation. The first shock did not terminate ventricular tachycardia/ventricular fibrillation in 48% of females and 62% of males ( P =0.25). Conclusions In patients with long QT syndrome with an ICD, the risk and rate of life‐threatening events did not significantly differ between males and females regardless of ICD indications or genotype. In a substantial proportion of patients with long QT syndrome, first shock did not terminate ventricular tachycardia/ventricular fibrillation.

Improvements in cardiovascular disease (CVD) rates among young adults in the past 2 decades have been offset by increasing racial/ethnic and gender disparities, persistence of unhealthy lifestyle habits, overweight and obesity, and other CVD risk factors. To enhance the promotion of cardiovascular health among young adults 18 to 39 years old, the medical and broader public health community must understand the biological, interpersonal, and behavioral features of this life stage. Therefore, the National Heart, Lung, and Blood Institute, with support from the Office of Behavioral and Social Science Research, convened a 2‐day workshop in Bethesda, Maryland, in September 2017 to identify research challenges and opportunities related to the cardiovascular health of young adults. The current generation of young adults live in an environment undergoing substantial economic, social, and technological transformations, differentiating them from prior research cohorts of young adults. Although the accumulation of clinical and behavioral risk factors for CVD begins early in life, and research suggests early risk is an important determinant of future events, few trials have studied prevention and treatment of CVD in participants

Background It has been widely recognized that obstructive sleep apnea (OSA) is linked to cardiovascular disease. Yet, randomized controlled studies failed to demonstrate a clear cardiovascular benefit from OSA treatment, mainly because of poor adherence to continuous positive airway pressure (CPAP). To date, no prior study has assessed the effect of CPAP treatment on daytime resting heart rate, a strong predictor of adverse cardiovascular outcomes and mortality. Methods and Results We conducted a randomized controlled study in 39 participants with OSA and prediabetes, who received either in‐laboratory all‐night (ie, optimal) CPAP or an oral placebo for 2 weeks. During daytime, participants continued daily activities outside the laboratory. Resting heart rate was continuously assessed over 19 consecutive days and nights using an ambulatory device consisting of a single‐lead ECG and triaxis accelerometer. Compared with placebo, CPAP reduced daytime resting heart rate (treatment difference, −4.1 beats/min; 95% CI, −6.5 to −1.7 beats/min; P =0.002). The magnitude of reduction in daytime resting heart rate after treatment significantly correlated with the magnitude of decrease in plasma norepinephrine, a marker of sympathetic activity ( r =0.44; P =0.02), and the magnitude of decrease in OSA severity (ie, apnea‐hypopnea index [ r =0.48; P =0.005], oxygen desaturation index [ r =0.50; P =0.003], and microarousal index [ r =0.57; P Conclusions This proof‐of‐concept randomized controlled study demonstrates, for the first time, that CPAP treatment, when optimally used at night, reduces resting heart rate during the day, and therefore has positive cardiovascular carry over effects. These findings suggest that better identification and treatment of OSA may have important clinical implications for cardiovascular disease prevention. Registration URL: https:/// www.clini​caltr​ials.gov ; Unique identifier: NCT01156116.

Background It is still unknown whether traditional risk factors may have a sex‐specific impact on coronary artery disease (CAD) burden. Methods and Results We identified 14 793 patients who underwent coronary angiography for acute coronary syndromes in the ISACS‐TC (International Survey of Acute Coronary Syndromes in Transitional Countries; Clini​calTr​ials.gov , NCT01218776) registry from 2010 to 2019. The main outcome measure was the association between traditional risk factors and severity of CAD and its relationship with 30‐day mortality. Relative risk (RR) ratios and 95% CIs were calculated from the ratio of the absolute risks of women versus men using inverse probability of weighting. Estimates were compared by test of interaction on the log scale. Severity of CAD was categorized as obstructive (≥50% stenosis) versus nonobstructive CAD. The RR ratio for obstructive CAD in women versus men among people without diabetes mellitus was 0.49 (95% CI, 0.41–0.60) and among those with diabetes mellitus was 0.89 (95% CI, 0.62–1.29), with an interaction by diabetes mellitus status of P =0.002. Exposure to smoking shifted the RR ratios from 0.50 (95% CI, 0.41–0.61) in nonsmokers to 0.75 (95% CI, 0.54–1.03) in current smokers, with an interaction by smoking status of P =0.018. There were no significant sex‐related interactions with hypercholesterolemia and hypertension. Women with obstructive CAD had higher 30‐day mortality rates than men (RR, 1.75; 95% CI, 1.48–2.07). No sex differences in mortality were observed in patients with nonobstructive CAD. Conclusions Obstructive CAD in women signifies a higher risk for mortality compared with men. Current smoking and diabetes mellitus disproportionally increase the risk of obstructive CAD in women. Achieving the goal of improving cardiovascular health in women still requires intensive efforts toward further implementation of lifestyle and treatment interventions. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT01218776.

BackgroundThe American Heart Association 2020 Impact Goals aimed to promote population health through emphasis on cardiovascular health (CVH). We examined the association between nondietary CVH metrics and patient‐reported outcomes among a nationally representative sample of US adults without cardiovascular disease.Methods and ResultsWe included adults aged ≥18 years who participated in the Medical Expenditure Panel Survey between 2006 and 2015. CVH metrics were scored 1 point for each of the following: not smoking, being physically active, normal body mass index, no hypertension, no diabetes mellitus, and no dyslipidemia, or 0 points if otherwise. Diet was not assessed in Medical Expenditure Panel Survey. Patient‐reported outcomes were obtained by telephone survey and included questions pertaining to patient experience and health‐related quality of life. Regression models were used to compare patient‐reported outcomes based on CVH, adjusting for sociodemographic factors and comorbidities. There were 177 421 Medical Expenditure Panel Survey participants (mean age, 45 [17] years) representing ~187 million US adults without cardiovascular disease. About 12% (~21 million US adults) had poor CVH. Compared with individuals with optimal CVH, those with poor CVH had higher odds of reporting poor patient‐provider communication (odds ratio, 1.14; 95% CI, 1.05–1.24), poor healthcare satisfaction (odds ratio, 1.15; 95% CI, 1.08–1.22), poor perception of health (odds ratio, 5.89; 95% CI, 5.35–6.49), at least 2 disability days off work (odds ratio, 1.39; 95% CI, 1.30–1.48), and lower health‐related quality of life scores.ConclusionsAmong US adults without cardiovascular disease, meeting a lower number of ideal CVH metrics is associated with poor patient‐reported healthcare experience, poor perception of health, and lower health‐related quality of life. Preventive measures aimed at optimizing ideal CVH metrics may improve patient‐reported outcomes among this population.

BACKGROUND Internationally, most atrial fibrillation (AF) management guidelines recommend opportunistic screening for AF in people ≥65 years of age and oral anticoagulant treatment for those at high stroke risk (CHA₂DS₂‐VA≥2). However, gaps remain in screening and treatment. METHODS AND RESULTS General practitioners/nurses at practices in rural Australia (n=8) screened eligible patients (≥65 years of age without AF) using a smartphone ECG during practice visits. eHealth tools included electronic prompts, guideline‐based electronic decision support, and regular data reports. Clinical audit tools extracted de‐identified data. Results were compared with an earlier study in metropolitan practices (n=8) and nonrandomized control practices (n=69). Cost‐effectiveness analysis compared population‐based screening with no screening and included screening, treatment, and hospitalization costs for stroke and serious bleeding events. Patients (n=3103, 34%) were screened (mean age, 75.1±6.8 years; 47% men) and 36 (1.2%) new AF cases were confirmed (mean age, 77.0 years; 64% men; mean CHA₂DS₂‐VA, 3.2). Oral anticoagulant treatment rates for patients with CHA₂DS₂‐VA≥2 were 82% (screen detected) versus 74% (preexisting AF)( P =NS), similar to metropolitan and nonrandomized control practices. The incremental cost‐effectiveness ratio for population‐based screening was AU$16 578 per quality‐adjusted life year gained and AU$84 383 per stroke prevented compared with no screening. National implementation would prevent 147 strokes per year. Increasing the proportion screened to 75% would prevent 177 additional strokes per year. CONCLUSIONS An AF screening program in rural practices, supported by eHealth tools, screened 34% of eligible patients and was cost‐effective. Oral anticoagulant treatment rates were relatively high at baseline, trending upward during the study. Increasing the proportion screened would prevent many more strokes with minimal incremental cost‐effectiveness ratio change. eHealth tools, including data reports, may be a valuable addition to future programs. REGISTRATION URL: https://www.anzctr.org.au . Unique identifier: ACTRN12618000004268.

Background Assessment of atherosclerotic cardiovascular disease (ASCVD) risk is crucial for prevention and management, but the performance of the pooled cohort equations in older adults with frailty and multimorbidity is unknown. We evaluated the pooled cohort equations in these subgroups and the impact of competing risks. Methods and Results In 4249 community‐dwelling adults, aged ≥65 years, from the CHS (Cardiovascular Health Study), we calculated 10‐year risk of hard ASCVD. Frailty was determined using the Fried phenotype. Latent class analysis was used to identify individuals with multimorbidity patterns using chronic conditions. We assessed discrimination using the C‐statistic and calibration by comparing predicted ASCVD risks with estimated risk using cause‐specific and cumulative incidence models, by multimorbidity patterns and frailty status. A total of 917 (21.6%) participants had an ASCVD event, and 706 (16.6%) had a competing event of death. C‐statistic was 0.68 in men and 0.69 in women; calibration was good when compared with cause‐specific and cumulative incidence estimated risks (males, −0.1% and 3.3%; females, 0.6% and 1.4%). Latent class analysis identified 4 patterns: minimal disease, cardiometabolic, low cognition, musculoskeletal‐lung depression. In the cardiometabolic pattern, ASCVD risk was overpredicted compared with cumulative incidence risk in men (7.4%) and women (6.8%). Risk was underpredicted in men (−10.7%) and women (−8.2%) with frailty compared with cause‐specific risk. Miscalibration occurred mostly at high predicted risk ranges. Conclusions ASCVD prediction was good in this cohort of adults aged ≥65 years. Although calibration varied by multimorbidity patterns, frailty, and competing risks, miscalibration was mostly present at high predicted risk ranges and thus less likely to alter decision making for primary prevention therapy.

BackgroundHigh‐density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti‐inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation.Methods and ResultsThe functional capacity of HDL to inhibit oxidation of oxidized low‐density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case‐control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all‐cause mortality compared to 517 age‐ and sex‐matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50–0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, −8.9% to −1.7%;P=0.005) versus 1.3% (95% CI, −6.5% to 4.0%;P=0.63) with placebo (P=0.22 for between‐group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5–1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06–2.21;P=0.02). Furthermore, there was significant (P=0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti‐inflammatory.ConclusionsIn JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti‐inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti‐inflammatory HDL function with risk may account in part for the HDL paradox.RegistrationURL:https://www.clini​caltr​ials.gov; Unique identifier: NCT00239681.

Background Preeclampsia and gestational hypertension are hypertensive disorders of pregnancy (HDP) that identify an increased risk of developing chronic hypertension and cardiovascular disease later in life. Postpartum follow‐up may facilitate early screening and treatment of cardiovascular risk factors. Our objective is to describe patterns of postpartum visits with primary care and women's health providers (eg, family medicine and obstetrics) among women with and without HDP in a nationally representative sample of commercially insured women. Methods and Results We conducted a retrospective cohort study using insurance claims from a US health insurance database to describe patterns in office visits in the 6 months after delivery. We identified 566 059 women with completed pregnancies between 2005 and 2014. At 6 months, 13% of women with normotensive pregnancies, 18% with HDP, and 23% with chronic hypertension had primary care visits ( P P Conclusions Rates of continuity care follow‐up after a pregnancy complicated by hypertension were low. This represents a substantial missed opportunity to provide cardiovascular risk screening and management to women at increased risk of future cardiovascular disease.