Infections and Cardiovascular Disease: JACC Focus Seminar 1/4

The burden of cardiovascular diseases is sharply rising in low- and middle-income countries (LMICs). Along with the increasing rates of cardiovascular risk factors in these regions, there is a growing recognition of the contribution of neglected tropical diseases and other infections. Several cardiac implications of these infections have been reported but have not yet been validated by robust population data. This is in part due to limited access to health care and insufficient data collection infrastructure in many LMICs. Therefore, the true impact of these infections on the cardiovascular system may be underestimated, because of both underdiagnosis and underreporting bias. There is an urgent need to thoroughly delineate the cardiac impact of these conditions with elevated prevalence in LMICs and to propose strategies to reduce the negative consequences of these diseases in health systems with limited resources.     

Takayasu Arteritis: JACC Focus Seminar 3/4

Takayasu arteritis is a rare idiopathic large-vessel vasculitis that typically affects young women. An early "prepulseless" stage is often missed, associated with nonspecific constitutional symptoms (fever, malaise, and weight loss) and elevated inflammatory markers. Unchecked disease progression leads to the "pulseless" stage, manifest clinically by missing pulses, vascular tenderness, and ischemic symptoms (limb claudication, dizziness, angina, and renovascular hypertension), and is characterized pathologically by arterial wall thickening and stenotic/occlusive lesions or aneurysm formation. Vascular complications (stroke, blindness, heart failure, and aneurysm rupture) could follow unless disease progression is halted by immunosuppressive therapy and critical lesions are palliated by timely endovascular therapy or open surgery. Early diagnosis, effective therapy, and lifelong surveillance for disease activity relapses and vascular disease progression are critical to successful long-term outcomes. The outlook for patients has improved significantly in recent years with the establishment of diagnostic and classification criteria, better investigational modalities, and more effective medical and invasive therapy.     

Red Yeast Rice for Hypercholesterolemia: JACC Focus Seminar

The extracts of red yeast rice (RYR) are currently the most effective cholesterol-lowering nutraceuticals. This activity is mainly due to monacolin K, a weak reversible inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, whose daily consumption causes a reduction in low-density lipoprotein (LDL)-cholesterol plasma levels up to 15% to 25% within 6 to 8 weeks. The decrease in LDL-cholesterol is accompanied by a proportional decrease in total and non–high-density lipoprotein cholesterol, plasma apolipoprotein B, and high-sensitivity C-reactive protein. Some trials suggest that RYR use is associated with improvement in endothelial function and arterial stiffness, whereas a long-term study supports its role in the prevention of cardiovascular events. Despite the statin-like mechanism of action, the risk related to 3 to 10 mg monacolin K taken per day is minimal (mild myalgia in previously severely statin-intolerant subjects). RYR could represent a therapeutic tool to support lifestyle improvement in managing mild to moderate hypercholesterolemia in low-risk patients, including those who cannot be treated with statins or other LDL-cholesterol–lowering therapies.     

Framingham Heart Study: JACC Focus Seminar, 1/8

The Framingham Heart Study is the longest-running cardiovascular epidemiological study, starting in 1948. This paper gives an overview of the various cohorts, collected data, and most important research findings to date. In brief, the Framingham Heart Study, funded by the National Institutes of Health and managed by Boston University, spans 3 generations of well phenotyped White persons and 2 cohorts comprised of racial and ethnic minority groups. These cohorts are densely phenotyped, with extensive longitudinal follow-up, and they continue to provide us with important information on human cardiovascular and noncardiovascular physiology over the lifespan, as well as to identify major risk factors for cardiovascular disease. This paper also summarizes some of the more recent progress in molecular epidemiology and discusses the future of the study.     

Nutritional Heart Disease and Cardiomyopathies: JACC Focus Seminar 4/4

This JACC Focus Seminar provides an overview of and highlights recently published research on cardiomyopathies and nutritional heart disease that have a higher prevalence in tropical regions. The development of tropical cardiomyopathies and nutritional cardiovascular disease (CVD) is complicated by high rates of poverty, fragmented health care systems, and suboptimal access to health care because of socioeconomic inequalities, leading to the fact that children, adolescents, and young adults are disproportionally affected. Such tropical cardiomyopathies and nutritional CVD that have not been prevalent in high-income countries in the past decades are now reemerging. When treating migrants or refugees, it is important for attending physicians to consider the burden of endemic diseases in the countries of origin and the likelihood that such patients might be affected. In this review, the authors propose an approach for adequate diagnostic work-up leading to appropriate care for those with suspected or confirmed tropical cardiomyopathies and nutritional CVD.     

Rheumatic Heart Disease: JACC Focus Seminar 2/4

It is a sad reality that although eminently preventable, and despite possessing such knowledge for >70 years, rheumatic heart disease (RHD) remains the most common cause of cardiovascular morbidity and early mortality in young people worldwide. A disease of the poor, RHD is one of the most neglected diseases. Several challenges are unique to the acute rheumatic fever/RHD continuum and contribute to its persistence, including its sequestration among the poorest, its protracted natural history, the erratic availability of penicillin, and the lack of a concerted effort in endemic regions. However, there is cause for optimism following a resurgence in scientific interest over the last 15 years. This review presents the latest advancements in epidemiology, diagnosis, and management. It also discusses pressing research questions on disease pathophysiology, the barriers to implementation of effective management strategies, and pragmatic policy solutions required for translation of current knowledge into meaningful action.     

Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4

Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (～50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid–targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.     

Precision Medicine Approaches to Cardiac Arrhythmias: JACC Focus Seminar 4/5

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies.     

Systematic Coronary Risk Evaluation (SCORE): JACC Focus Seminar 4/8

Clinical estimation of the combined effect of several risk factors is unreliable and this resulted in the development of a number of risk estimation systems to guide clinical practice. Here, after defining general principles of risk estimation, the authors describe the evolution of the European Society of Cardiology’s (ESC) Systematic COronary Risk Evaluation (SCORE) risk estimation system and some learnings from the data. They move on to describe the establishment of the ESC’s Cardiovascular Risk Collaboration and outline its proposed research directions. First among these is the evolution of SCORE 2, which provides updated, calibrated risk estimates for total cardiovascular events for low, moderate, high, and very high-risk regions of Europe. The authors conclude by considering that the future of risk estimation may be to express risk as years of exposure to a cardiovascular risk factor profile rather than risk over a fixed time period, such as 10 years, and how advances in genetics may permit individualized lifetime risk estimation from childhood on.     

Basic Biology of Extracellular Matrix in the Cardiovascular System,Part 1/4: JACC Focus Seminar

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.     

Precision Medicine in Cardiovascular Disease: Genetics and Impact on Phenotypes: JACC Focus Seminar 1/5

Our understanding of the genetic basis of cardiovascular diseases (CVDs) has evolved rapidly. This has resulted from a combination of dedicated research in well phenotyped CVD patients, the sequencing of the human genome, and the ready accessibility and decreasing cost of next-generation sequencing technologies. This increased knowledge of the genetic basis of CVDs has heralded the era of precision medicine. This encompasses many elements including improved diagnosis, family screening, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Furthermore, novel insights into genetic mechanisms, clinical rollout of polygenic risk scores for common CVDs, and the promise of genome editing approaches to effectively cure disease represent some of the exciting future endeavors that will change established clinical approaches. This Part 1 of a 5-part series focuses on the underpinnings and fundamental aspects of precision medicine.     

Coenzyme Q10 for Patients With Cardiovascular Disease: JACC Focus Seminar

Coenzyme Q₁₀ (CoQ₁₀) is a naturally occurring compound that is found in animals and all humans. It has a fundamental role in cellular energy production. Although it is produced in the body, tissue deficiency can occur due to medications such as statins, which inhibit the mevalonate pathway. The clinical syndromes of statin-associated muscle symptoms (SAMS) and some of the features observed in patients with heart failure (HF) may be related to blood and tissue deficiency of CoQ₁₀. Numerous clinical trials of CoQ₁₀ in SAMS have yielded conflicting results. Yet, the weight of evidence as reflected in meta-analyses supports the use of exogenous CoQ₁₀ in SAMS. In patients with HF, large-scale randomized clinical trials are lacking, although one relatively contemporary trial, Q-SYMBIO, suggests an adjunctive role for CoQ₁₀. The possibility that statin-related CoQ₁₀ deficiency may play a role in patients with diastolic HF is an intriguing hypothesis that warrants further exploration.     

Multi-Ethnic Study of Atherosclerosis (MESA): JACC Focus Seminar 5/8

The MESA (Multi-Ethnic Study of Atherosclerosis) is a National Heart, Lung, and Blood Institute–sponsored prospective study aimed at studying the prevalence, progression, determinants, and prognostic significance of subclinical cardiovascular disease in a sex-balanced, multiethnic, community-dwelling U.S. cohort. MESA helped usher in an era of noninvasive evaluation of subclinical atherosclerosis presence, burden, and progression for the evaluation of atherosclerotic cardiovascular disease risk, beyond what could be predicted by traditional risk factors alone. Concepts developed in MESA have informed international patient care guidelines, providing new tools to effectively guide public health policy, population screening, and clinical decision-making. MESA is grounded in an open science model that continues to be a beacon for collaborative science. In this review, we detail the original goals of MESA, and describe how the scope of MESA has evolved over time. We highlight 10 significant MESA contributions to cardiovascular medicine, and chart the path forward for MESA in the year 2021 and beyond.     

Extracellular Matrix in Vascular Disease,Part 2/4: JACC Focus Seminar

Medium-sized and large arteries consist of 3 layers: the tunica intima, tunica media, and tunica adventitia. The tunica media accounts for the bulk of the vessel wall and is the chief determinant of mechanical compliance. It is primarily composed of circumferentially arranged layers of vascular smooth muscle cells that are separated by concentrically arranged elastic lamellae; a form of extracellular matrix (ECM). The tunica media is separated from the tunica intima and tunica adventitia, the innermost and outermost layers, respectively, by the internal and external elastic laminae. This second part of a 4-part JACC Focus Seminar discusses the contributions of the ECM to vascular homeostasis and pathology. Advances in genetics and proteomics approaches have fostered significant progress in our understanding of vascular ECM. This review highlights the important role of the ECM in vascular disease and the prospect of translating these discoveries into clinical disease biomarkers and potential future therapies.     

Diagnostic Cardiovascular Imaging and Therapeutic Strategies in Pregnancy: JACC Focus Seminar 4/5

The prevalence of cardiovascular disease (CVD) in pregnancy, both diagnosed and previously unknown, is rising, and CVD is a leading cause of maternal morbidity and mortality. Historically, women of child-bearing potential have been underrepresented in research, leading to lasting knowledge gaps in the cardiovascular care of pregnant and lactating women. Despite these limitations, clinicians should be familiar with the safety of frequently used diagnostic and therapeutic interventions to adequately care for this at-risk population. This review, the fourth of a 5-part series, provides evidence-based recommendations regarding the use of common cardiovascular diagnostic tests and medications in pregnant and lactating women.     

Biological Versus Chronological Aging: JACC Focus Seminar

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.     

Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed “Mendelian vascular diseases,” which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.     

Management of Intracerebral Hemorrhage: JACC Focus Seminar

Intracerebral hemorrhage (ICH) accounts for a disproportionate amount of stroke-related morbidity and mortality. Although chronic hypertension and cerebral amyloid angiopathy are the underlying cerebral vasculopathies accounting for the majority of ICH, there are a broad range of potential causes, and effective management requires accurate identification and treatment of the underlying mechanism of hemorrhage. Magnetic resonance imaging and vascular imaging techniques play a critical role in identifying disease mechanisms. Modern treatment of ICH focuses on rapid stabilization, often requiring urgent treatment of mass effect, aggressive blood pressure reduction and correction of contributing coagulopathies to achieve hemostasis. We discuss management of patients with ICH who continue to require long-term anticoagulation, the interaction of ICH with neurodegenerative diseases, and our approach to prognostication after ICH. We close this review with a discussion of novel medical and surgical approaches to ICH treatment that are being tested in clinical trials.     

Myocardial Interstitial Fibrosis in Nonischemic Heart Disease,Part 3/4: JACC Focus Seminar

Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins. Furthermore, in addition to an excess of collagen, qualitative changes in collagen fibers also contribute to the detrimental impact of MIF. In this part 3 of a 4-part JACC Focus Seminar, we review the evidence on the complex mechanisms leading to MIF, as well as its contribution to systolic and diastolic cardiac dysfunction and impaired clinical outcomes in patients with nonischemic heart disease.