Anticoagulation Strategies in Patients With Cancer: JACC Review Topic of the Week

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.     

Risk Factor Variability and Cardiovascular Outcome: JACC Review Topic of the Week

Until recently, intraindividual visit-to-visit variability of cardiovascular risk factors has been dismissed as random fluctuation. This simplistic concept was challenged by demonstrating that visit-to-visit blood pressure variability, independent of average blood pressure, was a powerful risk factor for stroke. Subsequently, variability of other cardiovascular risk factors such as cholesterol, glycemia, and body weight was documented to increase risk independent of their absolute values. Variability of these risk factors has been demonstrated to be a powerful predictor for all-cause and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease, and dementia. With the notable exception of heart rate, cardiovascular risk factors must now be defined by 2 components: the magnitude and duration of sustained risk factor elevation and, equally important, the variability of the same risk factor over time.     

Moving Beyond the Sarcomere to Explain Heterogeneity in Hypertrophic Cardiomyopathy: JACC Review Topic of the Week

Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ～70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.     

Long-Term Cardiovascular Risks Associated With Adverse Pregnancy Outcomes: JACC Review Topic of the Week

Adverse pregnancy outcomes (APOs)—including pre-term birth, pre-eclampsia, and intrauterine growth restriction—are common interrelated disorders caused by placental dysfunction and maternal vascular abnormalities (endothelial activation, inflammation, and vasospasm) that occur in approximately 10% to 20% of pregnancies. Women who experience APOs are at increased risk for future cardiovascular disease (CVD). APOs are associated with increased risk of development of hypertension, left ventricular hypertrophy/dysfunction, vascular dysfunction, and renal dysfunction. The vascular abnormalities that are present during an APO also underlie common, difficult-to-treat forms of CVD in women as they age (e.g., cardiac microvascular dysfunction, heart failure with preserved ejection fraction), suggesting shared mechanistic pathways for APOs and CVD. Here, the authors synthesize the current information and knowledge gaps regarding the progression from APO to CVD. Understanding the risk factors for and pathogenesis of APO-related cardiovascular dysfunction is a critical unmet need that could inform efforts to prevent and more effectively treat CVD in women.     

von Willebrand Factor and Management of Heart Valve Disease: JACC Review Topic of the Week

For decades, numerous observations have shown an intimate relationship between von Willebrand factor (VWF) multimer profile and heart valve diseases (HVD). The current knowledge of the unique biophysical properties of VWF helps us to understand the longstanding observations concerning the bleeding complications in patients with severe HVD. Not only does the analysis of the VWF multimer profile provide an excellent evaluation of HVD severity, it is also a strong predictor of clinical events. Also of importance, VWF responds within minutes to any significant change in hemodynamic valve status, making it an accurate marker of the quality of surgical and transcatheter therapeutic interventions. The authors provide in this review a practical, comprehensive, and evidence-based framework of the concept of VWF as a biomarker in HVD, advocating for its implementation into the clinical decision-making process besides usual clinical and imaging evaluation. They also delineate critical knowledge gaps and research priorities to definitely validate this concept.     

Interventional Cardiology and Acute Stroke Care Going Forward: JACC Review Topic of the Week

Stroke is a catastrophic event for patients and their families. Given the frequency of approximately 750,000 events annually with their associated morbidity and mortality, stroke has assumed increasing importance. Scientific study has identified several diseases categorized under the broad term of “stroke” that form the rationale for current treatment strategies. This paper reviews new information, especially on ischemic stroke (particularly large-vessel occlusions), which identifies the potential for new approaches that can dramatically improve outcome but will require the need to enhance and embrace the care team required to deliver optimal care and address current unmet clinical needs.     

Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100–containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.     

Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week

Many treatments have been identified that confer robust cardioprotection in experimental animal models of acute ischemia and reperfusion injury. However, translation of these cardioprotective therapies into the clinical setting of acute myocardial infarction (AMI) for patient benefit has been disappointing. One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells. Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities. In this regard, emerging data suggest that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This review will present an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of cardioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies. This paper emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.     

PCI and CABG for Treating Stable Coronary Artery Disease: JACC Review Topic of the Week

Percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are considered revascularization procedures, but only CABG can prolong life in stable coronary artery disease. Thus, PCI and CABG mechanisms may differ. Viability and/or ischemia detection to guide revascularization have been unable to accurately predict treatment effects of CABG or PCI, questioning a revascularization mechanism for improving survival. By contrast, preventing myocardial infarction may save lives. However, the majority of infarcts are generated by non–flow-limiting stenoses, but PCI is solely focused on treating flow-limiting lesions. Thus, PCI cannot be expected to significantly limit new infarcts, but CABG may do so through providing flow distal to vessel occlusions. All comparisons of CABG to PCI or medical therapy that demonstrate survival effects with CABG also demonstrate infarct reduction. Thus, CABG may differ from PCI by providing “surgical collateralization,” prolonging life by preventing myocardial infarctions. The evidence is reviewed here.     

Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease

Background

Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events.

Anatomy,Function, and Dysfunction of the Right Ventricle: JACC State-of-the-Art Review

There is increasing recognition of the crucial role of the right ventricle (RV) in determining functional status and prognosis in multiple conditions. The normal RV is anatomically and functionally different from the left ventricle, which precludes direct extrapolation of our knowledge of left-sided physiopathology to the right heart. RV adaptation is largely determined by the level of exposure to hemodynamic overload (both preload and afterload) as well as its intrinsic contractile function. These 3 processes (pressure overload, volume overload, and RV cardiomyopathy) are associated with distinct clinical course and therapeutic approach, although in reality they often coexist in various degrees. The close relationship between the RV and left ventricle (ventricular interdependence) and its coupling to the pulmonary circulation further modulate RV behavior in different clinical scenarios. In this review, the authors summarize current knowledge of RV anatomic, structural, metabolic, functional, and hemodynamic characteristics in both health and disease.     

Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are both manifestations of end-organ damage of the metabolic syndrome. Through multiple pathophysiological mechanisms, CVD and NAFLD are associated with each other. Systemic inflammation, endothelial dysfunction, hepatic insulin resistance, oxidative stress, and altered lipid metabolism are some of the mechanisms by which NAFLD increases the risk of CVD. Patients with NAFLD develop increased atherosclerosis, cardiomyopathy, and arrhythmia, which clinically result in cardiovascular morbidity and mortality. Defining the mechanisms linking these 2 diseases offers the opportunity to further develop targeted therapies. The aim of this comprehensive review is to examine the association between CVD and NAFLD and discuss the overlapping management approaches.     

Use of Medication for Cardiovascular Disease During Pregnancy: JACC State-of-the-Art Review

Cardiovascular disease complicating pregnancy is rising in prevalence secondary to advanced maternal age, cardiovascular risk factors, and the successful management of congenital heart disease conditions. The physiological changes of pregnancy may alter drug properties affecting both mother and fetus. Familiarity with both physiological and pharmacological attributes is key for the successful management of pregnant women with cardiac disease. This review summarizes the published data, available guidelines, and recommendations for use of cardiovascular medications during pregnancy. Care of the pregnant woman with cardiovascular disease requires a multidisciplinary team approach with members from cardiology, maternal fetal medicine, anesthesia, and nursing.     

Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review

Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a “bystander-phenomenon”), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels.     

Screening and Management of Depression in Patients With Cardiovascular Disease: JACC State-of-the-Art Review

Depression is a common problem in patients with cardiovascular disease (CVD) and is associated with increased mortality, excess disability, greater health care expenditures, and reduced quality of life. Depression is present in 1 of 5 patients with coronary artery disease, peripheral artery disease, and heart failure. Depression complicates the optimal management of CVD by worsening cardiovascular risk factors and decreasing adherence to healthy lifestyles and evidence-based medical therapies. As such, standardized screening pathways for depression in patients with CVD offer the potential for early identification and optimal management of depression to improve health outcomes. Unfortunately, the burden of depression in patients with CVD is under-recognized; as a result, screening and management strategies targeting depression have been poorly implemented in patients with CVD. In this review, the authors discuss a practical approach for the screening and management of depression in patients with CVD.     

Primary Prevention With Statins in the Elderly

The burden of atherosclerotic cardiovascular disease (ASCVD) in high-income countries is mostly borne by the elderly. With increasing life expectancy, clear guidance on sensible use of statin therapy to prevent a first and potentially devastating ASCVD event is critically important to ensure a healthy aging population. Since 2013, 5 major North American and European guidelines on statin use in primary prevention of ASCVD have been released by the American College of Cardiology/American Heart Association, the UK National Institute for Health and Care Excellence, the Canadian Cardiovascular Society, U.S. Preventive Services Task Force, and the European Society of Cardiology/European Atherosclerosis Society. Guidance on using statin therapy in primary ASCVD prevention in the growing elderly population (>65 years of age) differs markedly. The authors discuss the discrepant recommendations, place them into the context of available evidence, and identify circumstances in which uncertainty may hamper the appropriate use of statins in the elderly.     

New Concepts in Sudden Cardiac Arrest to Address an Intractable Epidemic: JACC State-of-the-Art Review

Sudden cardiac arrest (SCA) is one of the largest causes of mortality globally, with an out-of-hospital survival below 10% despite intense research. This document outlines challenges in addressing the epidemic of SCA, along the framework of respond, understand and predict, and prevent. Response could be improved by technology-assisted orchestration of community responder systems, access to automated external defibrillators, and innovations to match resuscitation resources to victims in place and time. Efforts to understand and predict SCA may be enhanced by refining taxonomy along phenotypical and pathophysiological “axes of risk,” extending beyond cardiovascular pathology to identify less heterogeneous cohorts, facilitated by open-data platforms and analytics including machine learning to integrate discoveries across disciplines. Prevention of SCA must integrate these concepts, recognizing that all members of society are stakeholders. Ultimately, solutions to the public health challenge of SCA will require greater awareness, societal debate and focused public policy.     

Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of HF, affecting over 3 million adults in the United States alone. HFpEF is a heterogenous syndrome. One important phenotype may be related to comorbid conditions, including diabetes mellitus (DM). DM has a prevalence of approximately 45% in HFpEF, but characteristics and outcomes of this population are poorly understood. In this review, the authors summarize data from several clinical trials of HFpEF therapeutics and provide original data from a large cohort using the Get With The Guidelines-HF registry, which together suggest that DM is associated with increased morbidity and long-term mortality in HFpEF. The authors then discuss several common pathological mechanisms in HFpEF and DM, including sodium retention, metabolic derangements, impaired skeletal muscle function, and potential therapeutic targets. As the understanding of comorbid HFpEF and DM improves, it is hoped clinicians will be better equipped to offer effective, patient-centered treatments.