Cardiovascular Disease Risk Factors in Women: The Impact of Race and Ethnicity: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading cause of death in women, yet differences exist among certain racial and ethnic groups. Aside from traditional risk factors, behavioral and environmental factors and social determinants of health affect cardiovascular health and risk in women. Language barriers, discrimination, acculturation, and health care access disproportionately affect women of underrepresented races and ethnicities. These factors result in a higher prevalence of cardiovascular disease and significant challenges in the diagnosis and treatment of cardiovascular conditions. Culturally sensitive, peer-led community and health care professional education is a necessary step in the prevention of cardiovascular disease. Equitable access to evidence-based cardiovascular preventive health care should be available for all women regardless of race and ethnicity; however, these guidelines are not equally incorporated into clinical practice. This scientific statement reviews the current evidence on racial and ethnic differences in cardiovascular risk factors and current cardiovascular preventive therapies for women in the United States.

Design and rationale of the social determinants of the risk of hypertension in women of reproductive age (SAFE HEART) study: An American Heart Association research goes red initiative.

BACKGROUND: Cardiovascular health literacy (CVHL) and social determinants of health (SDoH) play interconnected and critical roles in shaping cardiovascular health (CVH) outcomes. However, awareness of CVH risk has declined markedly, from 65% of women being aware that cardiovascular disease (CVD) is the leading cause of death for women in 2009 to just 44% being aware in 2019. The American Heart Association Research Goes Red (RGR) initiative seeks to develop an open-source, longitudinal, dynamic registry that will help women to be aware of and participate in research studies, and to learn about CVD prevention. We proposed to leverage this platform, particularly among Black and Hispanic women of reproductive age, to address CVHL gaps and advance health equity. METHODS: The primary objective of the study is to evaluate the cross-sectional association of CVHL, SDoH using a polysocial score, and CVH in women of reproductive age at increased risk of developing hypertension (HTN). To achieve this we will use a cross-sectional study design, that engages women already enrolled in the RGR registry (registry-enrolled). To enhance the racial and ethnic/social economic diversity of the cohort, we will additionally enroll 300 women from the Baltimore and Washington D.C. community into the Social Determinants of the Risk of Hypertension in Women of Reproductive Age (SAFE HEART) Study. Community-enrolled and registry-enrolled women will undergo baseline social phenotyping including detailed SDoH questionnaire, CVH metrics assessment, and CVHL assessment. The secondary objective is to assess whether a 4-month active health education intervention will result in a change in CVHL in the 300 community-enrolled women. DISCUSSION: The SAFE HEART study examines the association between CVHL, SDoH, and CVH, with a focus on racial and ethnic minority groups and socioeconomically disadvantaged women of reproductive age, and the ability to improve these parameters by an educational intervention. These findings will inform the future development of community-engaged strategies that address CVHL and SDoH among women of reproductive age.

Beyond the Agatston calcium score: role of calcium density and other calcified plaque markers for cardiovascular disease prediction.

PURPOSE OF REVIEW: To review the current evidence and highlight future strategies regarding consideration of coronary artery calcium (CAC) density in cardiovascular disease (CVD) risk stratification. RECENT FINDINGS: Expressed as the product of plaque area and a peak calcium density weighting factor, the Agatston method is the gold-standard for measuring CAC on noncontrast cardiac computed tomography. Over the last decade, observational data have suggested that calcium density is inversely associated with CVD events and confers additional prognostic information independent of traditional risk factors and Agatston CAC scores. Specific density measures have been assessed including peak calcium density, mean CAC density, and CAC area-density discordance. Beyond calcium density, the number of affected arteries and regional distribution of CAC which may be correlated with CAC density have also improved the predictive utility of the Agatston score. SUMMARY: Calcium density is inversely associated with CVD risk after considering plaque area and/or volume. Calcium markers including density, vessel involvement, and regional distribution confer additional prognostic information for the prediction of incident CVD among those with prevalent subclinical atherosclerosis. A future area of study includes calcium radiomics ('calcium-omics') and whether the artificial intelligence-derived automated measurement of calcium markers beyond the Agatston score may be of value in CVD risk stratification among individuals with early to advanced subclinical atherosclerosis.

Should We Use Aspirin or P2Y12 Inhibitor Monotherapy in Stable Ischemic Heart Disease?

PURPOSE OF REVIEW: To summarize the recent evidence and guideline recommendations on aspirin or P2Y12 inhibitor monotherapy in patients with stable ischemic heart disease and provide insights into future directions on this topic, which involves transition to a personalized assessment of bleeding and thrombotic risks. RECENT FINDINGS: It has been questioned whether the evidence for aspirin as the foundational component of secondary prevention in patients with coronary artery disease aligns with contemporary pharmaco-invasive strategies. The recent HOST-EXAM study randomized patients who had received dual antiplatelet therapy for 6 to 18 months without ischemic or major bleeding events to either clopidogrel or aspirin for a further 24 months, and demonstrated that the patients in the clopidogrel arm had significantly lower rates of both thrombotic and bleeding complications compared to those in the aspirin arm. The patient-level PANTHER meta-analysis showed that in patients with established coronary artery disease, P2Y12 inhibitor monotherapy was associated with lower rates of myocardial infarction, stent thrombosis as well as gastrointestinal bleeding and hemorrhagic stroke compared to aspirin monotherapy, albeit with similar rates of all-cause mortality, cardiovascular mortality and major bleeding. Long-term low-dose aspirin is recommended for secondary prevention in patients with stable ischemic heart disease, with clopidogrel monotherapy being acknowledged as a feasible alternative. Dual antiplatelet therapy for six months after percutaneous coronary intervention remains the standard recommendation for patients with stable ischemic heart disease. However, the duration of dual antiplatelet therapy may be shortened and followed by P2Y12 inhibitor monotherapy or prolonged based on individualized evaluation of the patient's risk profile.

Molecular Mechanisms of Vascular Health: Insights From Vascular Aging and Calcification.

Cardiovascular disease is the most common cause of death worldwide, especially beyond the age of 65 years, with the vast majority of morbidity and mortality due to myocardial infarction and stroke. Vascular pathology stems from a combination of genetic risk, environmental factors, and the biologic changes associated with aging. The pathogenesis underlying the development of vascular aging, and vascular calcification with aging, in particular, is still not fully understood. Accumulating data suggests that genetic risk, likely compounded by epigenetic modifications, environmental factors, including diabetes and chronic kidney disease, and the plasticity of vascular smooth muscle cells to acquire an osteogenic phenotype are major determinants of age-associated vascular calcification. Understanding the molecular mechanisms underlying genetic and modifiable risk factors in regulating age-associated vascular pathology may inspire strategies to promote healthy vascular aging. This article summarizes current knowledge of concepts and mechanisms of age-associated vascular disease, with an emphasis on vascular calcification.

Predictors of incident stroke among individuals without coronary artery calcification: A pooled cohort analysis from the Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study, and Framingham Heart Study.

INTRODUCTION: The absence of coronary artery calcium (CAC = 0) is associated with low risk of stroke events; however, predictors of incident stroke among those with CAC = 0 are not known. METHODS: Individual participant-level data were pooled from three prospective cohorts (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study, and Framingham Heart Study). Multivariable-adjusted Cox proportional hazards models were used to study the association between cardiovascular risk factors and incident adjudicated stroke among individuals with CAC = 0 who were free of clinical atherosclerotic cardiovascular disease at baseline. RESULTS: Among 6180 participants (mean age 53 [SD 11] years, 62% women, and 44% White, 36% Black, and 20% other individuals), over a median (IQR) follow up of 15 (12-16) years, there were 122 strokes (95 ischemic, 27 hemorrhagic) with an overall unadjusted event rate of 2.0 per 1000 person-years. After multivariable adjustment, risk factors associated with overall stroke included (hazard ratio [95% CI]) systolic blood pressure (SBP): 1.19 (1.05-1.36) per 10-mmHg increase and carotid intima-media thickness (CIMT): 1.21 (1.04-1.42) per 0.1-mm increment. Current cigarette smoking: 2.68 (1.11-6.50), SBP: 1.23 (1.06-1.42) per 10-mmHg increase, and CIMT: 1.25 (1.04-1.49) per 0.1-mm increment were associated with ischemic stroke, whereas C-reactive protein was associated with hemorrhagic stroke risk (0.49, 0.25-0.93). CONCLUSION: In a large cohort of individuals with CAC = 0, the rate for incident stroke was low (2.0 per 1000-person years) and was associated with modifiable risk factors.

Vigorous Exercise in Patients with Hypertrophic Cardiomyopathy.

ABSTRACT: Hypertrophic cardiomyopathy is a genetic heart condition occurring in up to 1 in 200 patients in the United States, many of whom are young and otherwise healthy. This condition puts those affected at increased risk for adverse cardiac outcomes, including sudden cardiac arrest and death, with particular concern for this to occur during exercise and other forms of exertion. Recent studies aimed at evaluating the risk of exercise in hypertrophic cardiomyopathy patients have suggested that moderate and even vigorous exercise may be safe for certain patients. Clinical guidelines are changing to reflect this recent information and to encourage a shared decision-making approach, which can allow more hypertrophic cardiomyopathy patients to participate in health-promoting exercise activities.

Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. METHODS: We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes. RESULTS: We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33). CONCLUSIONS: Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Coronary artery calcium and sudden cardiac death: current evidence and future directions.

PURPOSE OF REVIEW: To provide a summary of the current evidence and highlight future directions regarding coronary artery calcium (CAC) and risk of sudden cardiac death (SCD). RECENT FINDINGS: Although up to 80% of all SCD is attributed to coronary heart disease (CHD), the subclinical atherosclerosis markers that help to improve SCD risk prediction are largely unknown. Recent observational data have demonstrated that, after adjustment for traditional risk factors, there is a stepwise higher risk for SCD across increasing CAC burden such that asymptomatic patients without overt atherosclerotic cardiovascular disease (ASCVD) experience a three-fold to five-fold higher SCD risk beginning at CAC at least 100 when compared with CAC = 0. Although the mechanisms underlying increasing CAC and SCD risk have yet to be fully elucidated, risk for myocardial infarction and scar, and/or exercise-induced ischemia may be potential mediators. SUMMARY: High CAC burden is an important risk factor for SCD in asymptomatic middle-aged adults, suggesting that SCD risk stratification can begin in the early stages of CHD via measurement of calcific plaque on noncontrast computed tomography. Despite the clinical inertia for downstream functional cardiac testing after detecting high CAC, comprehensive ASCVD prevention strategies should be the primary focus for SCD risk reduction.

Very High Coronary Artery Calcium (≥1000) and Association With Cardiovascular Disease Events, Non-Cardiovascular Disease Outcomes, and Mortality: Results From MESA.

BACKGROUND: There are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations. METHODS: Our study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). RESULTS: Compared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm2), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63-6.11), 7.57- (5.50-10.42), 4.86-(3.32-7.11), and 1.94-fold (1.57-2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25-2.16), 1.66- (1.22-2.25), 1.51- (1.03-2.23), and 1.34-fold (1.05-1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57-2.41) and 1.43-fold (1.12-1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups. CONCLUSIONS: Individuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.

Rationale and pathways forward in the implementation of coronary artery calcium-based enrichment of randomized trials.

The Food and Drug Administration recommends prognostic enrichment of randomized controlled trials (RCTs), aimed at restricting the study population to participants most likely to have events and therefore derive benefit from a given intervention. The coronary artery calcium (CAC) score is powerful discriminator of cardiovascular risk, and in this review we discuss how CAC may be used to augment widely used prognostic enrichment paradigms of RCTs of add-on therapies in primary prevention. We describe recent studies in this space, with special attention to the ability of CAC to further stratify risk among guideline-recommended candidates for add-on risk-reduction therapies. Given the potential benefits in terms of sample size, cost reduction, and overall RCT feasibility of a CAC-based enrichment strategy, we discuss approaches that may help maximize its advantages while minimizing logistical barriers and other challenges. Specifically, use of already existing CAC data to avoid the need to re-scan participants with previously documented high CAC scores, use of increasingly available, large clinical CAC databases to facilitate the identification of potential RCT participants, and implementation of machine learning approaches to measure CAC in existing computed tomography images performed for other purposes, will most likely boost the implementation of a CAC-based enrichment paradigm in future RCTs.

Diabetes Duration and Subclinical Myocardial Injury: The Atherosclerosis Risk in Communities Study (ARIC).

BACKGROUND: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT). METHODS: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used multinomial logistic regression to determine the association of diabetes duration with increased (≥14 ng/L) or detectable (≥6 ng/L) Visit 4 hs-cTnT, relative to undetectable hs-cTnT, adjusted for demographics and cardiovascular risk factors. RESULTS: The prevalence of increased Visit 4 hs-cTnT was higher in persons with longer diabetes duration, from 12% for those with diabetes 0 to <5 years up to 31% among those with diabetes for ≥15 years (P for trend <0.0001). New onset diabetes at Visit 4 was associated with 1.92× higher relative risk (95% CI, 1.27-2.91) of increased hs-cTnT than no diabetes. Longer diabetes duration was associated with greater myocardial injury, with duration ≥15 years associated with 9.29× higher risk (95% CI, 5.65-15.29) for increased hs-cTnT and 2.07× (95% CI, 1.24-3.16) for detectable hs-cTnT, compared to no diabetes. CONCLUSIONS: Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether the prevention and delay of diabetes onset can mitigate early myocardial damage.

Cardio-Obstetrics: the Next Frontier in Cardiovascular Disease Prevention.

PURPOSE OF REVIEW: Internationally, cardiovascular disease (CVD) is the leading cause of death in women. With risk factors for CVD continuing to rise, early identification and management of chronic diseases such as hypertension, diabetes, and obstructive sleep apnea is necessary for prevention. Pregnancy is a natural stress test for women with risk factors who may be predisposed to CVD and offers a unique opportunity to not only recognize disease but also implement effective and long-lasting strategies for prevention. RECENT FINDINGS: Prevention begins before pregnancy, as preconception screening, counseling, and optimization of chronic diseases can improve maternal and fetal outcomes. Throughout pregnancy, women should maintain close follow-up, continued reevaluation of risk factors, with counseling when necessary. Continued healthcare engagement during the "fourth trimester," 3 months following delivery, allows clinicians to continue monitoring the evolution of chronic diseases, encourage ongoing lifestyle counseling, and connect women with primary care and appropriate specialists if needed. Unfortunately, this postpartum period represents a major care gap, as a significant proportion of most women do not attend their scheduled visits. Social determinants of health including decreased access to care and economic instability lead to increased risk factors throughout pregnancy but particularly play a role in poor compliance with postpartum follow-up. The use of telemedicine clinics and remote monitoring may prove to be effective interventions, bridging the gap between physicians and patients and improving follow-up for at-risk women. While many clinicians are beginning to understand the impact of CVD on women, screening and prevention strategies are not often implemented until much later in life. Pregnancy creates an opportunity to begin engaging women in cardiovascular protective strategies before the development of the disease.

Controversies in the Use of Omega-3 Fatty Acids to Prevent Atherosclerosis.

PURPOSE OF REVIEW: We discuss current controversies in the clinical use of omega-3 fatty acids (FA), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and examine discrepancies between recent trials. Furthermore, we discuss potential side effects reported in these studies and the role of mixed omega-3 FA dietary supplements and concerns about their use. RECENT FINDINGS: REDUCE-IT showed that addition of icosapent ethyl, a highly purified form of EPA, can reduce risk of cardiovascular events among statin-treated individuals with high triglycerides. Additional supportive evidence for EPA has come from other trials and meta-analyses of omega-3 FA therapy. In contrast, trials of mixed EPA/DHA products have consistently failed to improve cardiovascular outcomes. Discrepancies in results reported in RCTs could be explained by differences in omega-3 FA products, dosing, study populations, and study designs including the placebo control formulation. Evidence obtained from highly purified forms should not be extrapolated to other mixed formulations, including "over-the-counter" omega-3 supplements. Targeting TG-rich lipoproteins represents a new frontier for mitigating ASCVD risk. Clinical and basic research evidence suggests that the use of omega-3 FA, specifically EPA, appears to slow atherosclerosis by reducing triglyceride-rich lipoproteins and/or inflammation, therefore addressing residual risk of clinical ASCVD.

THE ABCDE'S OF PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE.

The growing burden of obesity, smoking, elevated cholesterol, diabetes, hypertension, sedentary lifestyle, and unhealthy dietary habits fuels cardiovascular disease. In 2015, the rates of cardiovascular disease in the United States rose for the first time after decades of steady decline. To combat this rising trend, there is a great need to emphasize primary cardiovascular prevention. In this review, we provide a summary of the current primary prevention recommendations using a simplified ABCDE approach. The aim is to help clinicians utilize an easy-to-use, structured approach to primary atherosclerotic cardiovascular disease prevention.

How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol.

Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.

A cohort study and meta-analysis of isolated diastolic hypertension: searching for a threshold to guide treatment.

AIMS: Whether isolated diastolic hypertension (IDH), as defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, is associated with cardiovascular disease (CVD) has been disputed. We aimed to further study the associations of IDH with (i) subclinical CVD in the form of coronary artery calcium (CAC), (ii) incident systolic hypertension, and (iii) CVD events. METHODS AND RESULTS: We used multivariable-adjusted logistic and Cox regression to test whether IDH by 2017 ACC/AHA criteria (i.e. systolic blood pressure <130 mmHg and diastolic blood pressure ≥80 mmHg) was associated with the above outcomes in the Multi-Ethnic Study of Atherosclerosis (MESA). In a random-effects meta-analysis of the association between IDH and CVD events, we combined the MESA results with those from seven other previously published cohort studies. Among the 5104 MESA participants studied, 7.5% had IDH by the 2017 ACC/AHA criteria. There was no association between IDH and CAC [e.g. adjusted prevalence odds ratio for CAC >0 of 0.88 (95% CI 0.66, 1.17)]. Similarly, while IDH was associated with incident systolic hypertension, there was no statistically significant associations with incident CVD [hazard ratio 1.19 (95% CI 0.77, 1.84)] or death [hazard ratio 0.94 (95% CI 0.65, 1.36)] over 13 years in MESA. In a stratified meta-analysis of eight cohort studies (10 037 843 participants), the 2017 IDH definition was also not consistently associated with CVD and the relative magnitude of any potential association was noted to be numerically small [e.g. depending on inclusion criteria applied in the stratification, the adjusted hazard ratios ranged from 1.04 (95% CI 0.98, 1.10) to 1.09 (95% 1.03, 1.15)]. CONCLUSION: The lack of consistent excess in CAC or CVD suggests that emphasis on healthy lifestyle rather than drug therapy is sufficient among the millions of middle-aged or older adults who now meet the 2017 ACC/AHA criteria for IDH, though they require follow-up for incident systolic hypertension. These findings may not extrapolate to adults younger than 40 years, motivating further study in this age group.

Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or Is Reappraisal Warranted?

Four decades have passed since the first trial suggesting the efficacy of aspirin in the secondary prevention of myocardial infarction. Further trials, collectively summarized by the Antithrombotic Trialists' Collaboration, solidified the historical role of aspirin in secondary prevention. Although the benefit of aspirin in the immediate phase after a myocardial infarction remains incontrovertible, a number of emerging lines of evidence, discussed in this narrative review, raise some uncertainty as to the primacy of aspirin for the lifelong management of all patients with chronic coronary syndrome (CCS). For example, data challenging the previously unquestioned role of aspirin in CCS have come from recent trials where aspirin was discontinued in specific clinical scenarios, including early discontinuation of the aspirin component of dual antiplatelet therapy after percutaneous coronary intervention and the withholding of aspirin among patients with both CCS and atrial fibrillation who require anticoagulation. Recent primary prevention trials have also failed to consistently demonstrate net benefit for aspirin in patients treated to optimal contemporary cardiovascular risk factor targets, indicating that the efficacy of aspirin for secondary prevention of CCS may similarly have changed with the addition of more modern secondary prevention therapies. The totality of recent evidence supports further study of the universal need for lifelong aspirin in secondary prevention for all adults with CCS, particularly in stable older patients who are at highest risk for aspirin-induced bleeding.