Hypertension and Atrial Fibrillation: Doubts and Certainties From Basic and Clinical Studies.

Verdecchia P, Angeli F, Reboldi G
Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin-angiotensin-aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin-angiotensin-aldosterone system to reduce the risk of AF. Finally, it examines the impact of non-vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.

Circ Res: 18 Jan 2018; 122:352-368

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling.

Dell\'Italia LJ, Collawn JF, Ferrario CM
Chymase is the most efficient Ang II (angiotensin II)-forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin-angiotensin system blockade.

Circ Res: 18 Jan 2018; 122:319-336

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift.

Chamuleau SAJ, van der Naald M, Climent AM, Kraaijeveld AO, ... Bolli R,
The international consortium TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) has recently addressed key priorities in the field of cell-based therapy for cardiac repair, identifying the efficacy of translational research as one of the main challenges to ultimately improve the quality of life of patients with ischemic disease. Much of the controversy and confusion surrounding cardiac regenerative therapy stems from insufficient rigor in the conduct of preclinical studies, and there is an increasing recognition of a number of problems that undermine its quality that may contribute to translational failure. Here, we introduce well defined stages for preclinical research, and put forth proposals that should promote more rigorous preclinical work, in an effort to improve its quality and translatability. To augment the utility of preclinical research and its translation, it is necessary to (1) improve the quality of preclinical research, (2) promote collaborative efforts, and (3) enhance the sharing of knowledge and protocols. In particular, confirmatory (stage III) preclinical studies should be considered as a preamble to clinical studies and therefore must adhere to their standards of quality (including internal validity, standardization of protocols, and multicenter design). To increase transparency and minimize bias, these studies should be prospectively registered in an independent, open database. Ultimately, these recommendations should be implemented in the daily routine of investigators and in the policies of institutions, journals, and funding agencies.

Circ Res: 18 Jan 2018; 122:310-318

Emerging Role of Precision Medicine in Cardiovascular Disease.

Leopold JA, Loscalzo J
Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual\'s genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein-drug or drug-drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease.

Circ Res: 26 Apr 2018; 122:1302-1315

Biomedical Informatics on the Cloud: A Treasure Hunt for Advancing Cardiovascular Medicine.

Ping P, Hermjakob H, Polson JS, Benos PV, Wang W
In the digital age of cardiovascular medicine, the rate of biomedical discovery can be greatly accelerated by the guidance and resources required to unearth potential collections of knowledge. A unified computational platform leverages metadata to not only provide direction but also empower researchers to mine a wealth of biomedical information and forge novel mechanistic insights. This review takes the opportunity to present an overview of the cloud-based computational environment, including the functional roles of metadata, the architecture schema of indexing and search, and the practical scenarios of machine learning-supported molecular signature extraction. By introducing several established resources and state-of-the-art workflows, we share with our readers a broadly defined informatics framework to phenotype cardiovascular health and disease.

Circ Res: 26 Apr 2018; 122:1290-1301

Taking Systems Medicine to Heart.

Trachana K, Bargaje R, Glusman G, Price ND, Huang S, Hood LE
Systems medicine is a holistic approach to deciphering the complexity of human physiology in health and disease. In essence, a living body is constituted of networks of dynamically interacting units (molecules, cells, organs, etc) that underlie its collective functions. Declining resilience because of aging and other chronic environmental exposures drives the system to transition from a health state to a disease state; these transitions, triggered by acute perturbations or chronic disturbance, manifest as qualitative shifts in the interactions and dynamics of the disease-perturbed networks. Understanding health-to-disease transitions poses a high-dimensional nonlinear reconstruction problem that requires deep understanding of biology and innovation in study design, technology, and data analysis. With a focus on the principles of systems medicine, this Review discusses approaches for deciphering this biological complexity from a novel perspective, namely, understanding how disease-perturbed networks function; their study provides insights into fundamental disease mechanisms. The immediate goals for systems medicine are to identify early transitions to cardiovascular (and other chronic) diseases and to accelerate the translation of new preventive, diagnostic, or therapeutic targets into clinical practice, a critical step in the development of personalized, predictive, preventive, and participatory (P4) medicine.

Circ Res: 26 Apr 2018; 122:1276-1289

Defining the Human Envirome: An Omics Approach for Assessing the Environmental Risk of Cardiovascular Disease.

Riggs DW, Yeager RA, Bhatnagar A
Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility.

Circ Res: 26 Apr 2018; 122:1259-1275

Cardiovascular Metabolomics.

McGarrah RW, Crown SB, Zhang GF, Shah SH, Newgard CB
Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field.

Circ Res: 26 Apr 2018; 122:1238-1258

Precision Profiling of the Cardiovascular Post-Translationally Modified Proteome: Where There Is a Will, There Is a Way.

Fert-Bober J, Murray CI, Parker SJ, Van Eyk JE
There is an exponential increase in biological complexity as initial gene transcripts are spliced, translated into amino acid sequence, and post-translationally modified. Each protein can exist as multiple chemical or sequence-specific proteoforms, and each has the potential to be a critical mediator of a physiological or pathophysiological signaling cascade. Here, we provide an overview of how different proteoforms come about in biological systems and how they are most commonly measured using mass spectrometry-based proteomics and bioinformatics. Our goal is to present this information at a level accessible to every scientist interested in mass spectrometry and its application to proteome profiling. We will specifically discuss recent data linking various protein post-translational modifications to cardiovascular disease and conclude with a discussion for enablement and democratization of proteomics across the cardiovascular and scientific community. The aim is to inform and inspire the readership to explore a larger breadth of proteoform, particularity post-translational modifications, related to their particular areas of expertise in cardiovascular physiology.

Circ Res: 26 Apr 2018; 122:1221-1237

Calcium Signaling and Reactive Oxygen Species in Mitochondria.

Bertero E, Maack C
In heart failure, alterations of Na and Ca handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca During physiological variations of workload, mitochondrial Ca uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca via the mitochondrial Ca uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca and Na handling hampers mitochondrial Ca uptake and the ensuing Krebs cycle-induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation-contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation-contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Circ Res: 10 May 2018; 122:1460-1478

Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors.

Scheen AJ
Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

Circ Res: 10 May 2018; 122:1439-1459

PCSK9: From Basic Science Discoveries to Clinical Trials.

Shapiro MD, Tavori H, Fazio S
Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery. The PCSK9 saga is unfolding quickly but is far from complete. Here, we review major scientific understandings as they relate to the role of PCSK9 in lipoprotein metabolism and atherosclerotic cardiovascular disease and the impact that therapies designed to inhibit its action are having in the clinical setting.

Circ Res: 10 May 2018; 122:1420-1438

Metabolic Coordination of Physiological and Pathological Cardiac Remodeling.

Gibb AA, Hill BG
Metabolic pathways integrate to support tissue homeostasis and to prompt changes in cell phenotype. In particular, the heart consumes relatively large amounts of substrate not only to regenerate ATP for contraction but also to sustain biosynthetic reactions for replacement of cellular building blocks. Metabolic pathways also control intracellular redox state, and metabolic intermediates and end products provide signals that prompt changes in enzymatic activity and gene expression. Mounting evidence suggests that the changes in cardiac metabolism that occur during development, exercise, and pregnancy as well as with pathological stress (eg, myocardial infarction, pressure overload) are causative in cardiac remodeling. Metabolism-mediated changes in gene expression, metabolite signaling, and the channeling of glucose-derived carbon toward anabolic pathways seem critical for physiological growth of the heart, and metabolic inefficiency and loss of coordinated anabolic activity are emerging as proximal causes of pathological remodeling. This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling. Adoption of conceptual frameworks based in relational biology may enable further understanding of how metabolism regulates cardiac structure and function.

Circ Res: 21 Jun 2018; 123:107-128

NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis.

Grebe A, Hoss F, Latz E
Inflammation is an important driver of atherosclerosis, the underlying pathology of cardiovascular diseases. Therefore, therapeutic targeting of inflammatory pathways is suggested to improve cardiovascular outcomes in patients with cardiovascular diseases. This concept was recently proven by CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated the therapeutic potential of the monoclonal IL (interleukin)-1β-neutralizing antibody canakinumab. IL-1β and other IL-1 family cytokines are important vascular and systemic inflammatory mediators, which contribute to atherogenesis. The NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome, an innate immune signaling complex, is the key mediator of IL-1 family cytokine production in atherosclerosis. NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic lesions, such as oxidized low-density lipoprotein and cholesterol crystals. Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression. Here, we review the mechanisms of NLRP3 inflammasome activation and proinflammatory IL-1 family cytokine production in the context of atherosclerosis and discuss treatment possibilities in light of the positive outcomes of the CANTOS trial.

Circ Res: 07 Jun 2018; 122:1722-1740

Sleep Apnea and Cardiovascular Disease: An Enigmatic Risk Factor.

Floras JS
Synchronization of molecular, metabolic, and cardiovascular circadian oscillations is fundamental to human health. Sleep-disordered breathing, which disrupts such temporal congruence, elicits hemodynamic, autonomic, chemical, and inflammatory disturbances with acute and long-term consequences for heart, brain, and circulatory and metabolic function. Sleep apnea afflicts a substantial proportion of adult men and women but is more prevalent in those with established cardiovascular diseases and especially fluid-retaining states. Despite the experimental, epidemiological, observational, and interventional evidence assembled in support of these concepts, this substantial body of work has had relatively modest pragmatic impact, thus far, on the discipline of cardiology. Contemporary estimates of cardiovascular risk still are derived typically from data acquired during wakefulness. The impact of sleep-related breathing disorders rarely is entered into such calculations or integrated into diagnostic disease-specific algorithms or therapeutic recommendations. Reasons for this include absence of apnea-related symptoms in most with cardiovascular disease, impediments to efficient diagnosis at the population level, debate as to target, suboptimal therapies, difficulties mounting large randomized trials of sleep-specific interventions, and the challenging results of those few prospective cardiovascular outcome trials that have been completed and reported. The objectives of this review are to delineate the bidirectional interrelationship between sleep-disordered breathing and cardiovascular disease, consider the findings and implications of observational and randomized trials of treatment, frame the current state of clinical equipoise, identify principal current controversies and potential paths to their resolution, and anticipate future directions.

Circ Res: 07 Jun 2018; 122:1741-1764

Epithelial Properties of the Second Heart Field.

Cortes C, Francou A, De Bono C, Kelly RG
The vertebrate heart tube forms from epithelial progenitor cells in the early embryo and subsequently elongates by progressive addition of second heart field (SHF) progenitor cells from adjacent splanchnic mesoderm. Failure to maximally elongate the heart results in a spectrum of morphological defects affecting the cardiac poles, including outflow tract alignment and atrioventricular septal defects, among the most common congenital birth anomalies. SHF cells constitute an atypical apicobasally polarized epithelium with dynamic basal filopodia, located in the dorsal wall of the pericardial cavity. Recent studies have highlighted the importance of epithelial architecture and cell adhesion in the SHF, particularly for signaling events that control the progenitor cell niche during heart tube elongation. The 22q11.2 deletion syndrome gene Tbx1 regulates progenitor cell status through modulating cell shape and filopodial activity and is required for SHF contributions to both cardiac poles. Noncanonical Wnt signaling and planar cell polarity pathway genes control epithelial polarity in the dorsal pericardial wall, as progenitor cells differentiate in a transition zone at the arterial pole. Defects in these pathways lead to outflow tract shortening. Moreover, new biomechanical models of heart tube elongation have been proposed based on analysis of tissue-wide forces driving epithelial morphogenesis in the SHF, including regional cell intercalation, cell cohesion, and epithelial tension. Regulation of the epithelial properties of SHF cells is thus emerging as a key step during heart tube elongation, adding a new facet to our understanding of the mechanisms underlying both heart morphogenesis and congenital heart defects.

Circ Res: 04 Jan 2018; 122:142-154

Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function.

Sallam T, Sandhu J, Tontonoz P
Despite significant improvements during the past 3 decades, cardiovascular disease remains a leading worldwide health epidemic. The recent identification of a fascinating group of mediators known as long noncoding RNAs (lncRNAs) has provided a wealth of new biology to explore for cardiovascular risk mitigation. lncRNAs are expressed in a highly context-specific fashion, and multiple lines of evidence implicated them in diverse biological processes. Indeed, abnormalities of lncRNAs have been directly linked with human ailments, including cardiovascular biology and disease. Of particular interest to the cardiovascular research community, dysregulation in lncRNA regulatory circuits have been associated with cardiac pathological hypertrophy, vascular disease, cell fate programming and development, atherosclerosis, dyslipidemia, and metabolic syndrome. Although techniques in interrogating noncoding RNAs are rapidly evolving, a major challenge in studying lncRNAs remains navigating through multiple technical constraints. In this review, we provide a road map for lncRNA discovery and interrogation in biological systems relevant to cardiovascular disease and highlight approaches to decipher their modes of action.

Circ Res: 04 Jan 2018; 122:155-166

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling.

Mayourian J, Ceholski DK, Gonzalez DM, Cashman TJ, ... Hajjar RJ, Costa KD
Cardiac excitation-contraction coupling (ECC) is the orchestrated process of initial myocyte electrical excitation, which leads to calcium entry, intracellular trafficking, and subsequent sarcomere shortening and myofibrillar contraction. Neurohumoral β-adrenergic signaling is a well-established mediator of ECC; other signaling mechanisms, such as paracrine signaling, have also demonstrated significant impact on ECC but are less well understood. For example, resident heart endothelial cells are well-known physiological paracrine modulators of cardiac myocyte ECC mainly via NO and endothelin-1. Moreover, recent studies have demonstrated other resident noncardiomyocyte heart cells (eg, physiological fibroblasts and pathological myofibroblasts), and even experimental cardiotherapeutic cells (eg, mesenchymal stem cells) are also capable of altering cardiomyocyte ECC through paracrine mechanisms. In this review, we first focus on the paracrine-mediated effects of resident and therapeutic noncardiomyocytes on cardiomyocyte hypertrophy, electrophysiology, and calcium handling, each of which can modulate ECC, and then discuss the current knowledge about key paracrine factors and their underlying mechanisms of action. Next, we provide a case example demonstrating the promise of tissue-engineering approaches to study paracrine effects on tissue-level contractility. More specifically, we present new functional and molecular data on the effects of human adult cardiac fibroblast conditioned media on human engineered cardiac tissue contractility and ion channel gene expression that generally agrees with previous murine studies but also suggests possible species-specific differences. By contrast, paracrine secretions by human dermal fibroblasts had no discernible effect on human engineered cardiac tissue contractile function and gene expression. Finally, we discuss systems biology approaches to help identify key stem cell paracrine mediators of ECC and their associated mechanistic pathways. Such integration of tissue-engineering and systems biology methods shows promise to reveal novel insights into paracrine mediators of ECC and their underlying mechanisms of action, ultimately leading to improved cell-based therapies for patients with heart disease.

Circ Res: 04 Jan 2018; 122:167-183

Trials and Tribulations of CETP Inhibitors.

Tall AR, Rader DJ
The development of CETP (cholesteryl ester transfer protein) inhibitors has had a long and difficult course with 3 compounds failing in phase III clinical trials. Finally, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid modification) trial has shown that the CETP inhibitor anacetrapib decreased coronary heart disease when added to statin therapy. Although the result is different to earlier studies, this is likely related to the size and duration of the trial. The benefit of anacetrapib seems to be largely explained by lowering of non-HDL-C (high-density lipoprotein cholesterol), rather than increases in HDL-C. Although the magnitude of benefit for coronary heart disease appeared to be moderate, in part this may have reflected aspects of the trial design. Anacetrapib treatment was associated with a small increase in blood pressure, but was devoid of major side effects and was also associated with a small reduction in diabetes mellitus. Treatment with CETP inhibitors, either alone or in combination with statins, could provide another option for patients with coronary disease who require further reduction in LDL (low-density lipoprotein) and non-HDL-C.

Circ Res: 04 Jan 2018; 122:106-112

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease.

Honold L, Nahrendorf M
Macrophages are ubiquitous cells that reside in all major tissues. Counter to long-held beliefs, we now know that resident macrophages in many organs are seeded during embryonic development and self-renew independently from blood monocytes. Under inflammatory conditions, those tissue macrophages are joined and sometimes replaced by recruited monocyte-derived macrophages. Macrophage function in steady state and disease depends on not only their developmental origin but also the tissue environment. Here, we discuss the ontogeny, function, and interplay of tissue-resident and monocyte-derived macrophages in various organs contributing to the development and progression of cardiovascular disease.

Circ Res: 04 Jan 2018; 122:113-127

Is Optimism Associated With Healthier Cardiovascular-Related Behavior? Meta-Analyses of 3 Health Behaviors.

Boehm JK, Chen Y, Koga H, Mathur MB, Vie LL, Kubzansky LD
Optimistic people have reduced risk for cardiovascular disease and cardiovascular-related mortality compared with their less optimistic peers. One explanation for this is that optimistic people may be more likely to engage in healthy behavior like exercising frequently, eating fruits and vegetables, and avoiding cigarette smoking. However, researchers have not formally determined the extent or direction of optimism\'s association with health behaviors. Moreover, it is unclear whether optimism temporally precedes health behaviors or whether the relationship is because of shared common causes. We conducted random effects meta-analyses examining optimism\'s association with 3 health behaviors relevant for the prevention of cardiovascular disease. PubMed and PsycINFO databases were searched for studies published through November 2017 reporting on optimism\'s relationship with physical activity, diet, and cigarette smoking. We identified 34 effect sizes for physical activity (n=90 845), 15 effect sizes for diet (n=47 931), and 15 effect sizes for cigarette smoking (n=15 052). Findings suggested that more optimistic individuals tended to engage in healthier behaviors compared with less optimistic individuals, but effect sizes were modest (=0.07, <0.0001; =0.12, <0.0001; and =0.07, =0.001). Most evidence was cross-sectional (≥53% of effect sizes) and did not consider sociodemographic characteristics (<53% of effect sizes) or psychological distress (<27% of effect sizes) as potential confounders. Optimism is associated with healthier behaviors that protect against cardiovascular disease, although most evidence was relatively low quality. Additional longitudinal and experimental research is required to determine whether optimism causally contributes to healthy behaviors and whether optimism could be an effective target for preventing cardiovascular disease.

Circ Res: 12 Apr 2018; 122:1119-1134

Epigenomes in Cardiovascular Disease.

Rosa-Garrido M, Chapski DJ, Vondriska TM
If unifying principles could be revealed for how the same genome encodes different eukaryotic cells and for how genetic variability and environmental input are integrated to impact cardiovascular health, grand challenges in basic cell biology and translational medicine may succumb to experimental dissection. A rich body of work in model systems has implicated chromatin-modifying enzymes, DNA methylation, noncoding RNAs, and other transcriptome-shaping factors in adult health and in the development, progression, and mitigation of cardiovascular disease. Meanwhile, deployment of epigenomic tools, powered by next-generation sequencing technologies in cardiovascular models and human populations, has enabled description of epigenomic landscapes underpinning cellular function in the cardiovascular system. This essay aims to unpack the conceptual framework in which epigenomes are studied and to stimulate discussion on how principles of chromatin function may inform investigations of cardiovascular disease and the development of new therapies.

Circ Res: 24 May 2018; 122:1586-1607

Steroid Hormone Vitamin D: Implications for Cardiovascular Disease.

Demer LL, Hsu JJ, Tintut Y
Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.

Circ Res: 24 May 2018; 122:1576-1585

Mechanisms of Cardiac Repair and Regeneration.

Broughton KM, Wang BJ, Firouzi F, Khalafalla F, ... Fernandez-Aviles F, Sussman MA
Cardiovascular regenerative therapies are pursued on both basic and translational levels. Although efficacy and value of cell therapy for myocardial regeneration can be debated, there is a consensus that profound deficits in mechanistic understanding limit advances, optimization, and implementation. In collaboration with the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes), this review overviews several pivotal aspects of biological processes impinging on cardiac maintenance, repair, and regeneration. The goal of summarizing current mechanistic understanding is to prompt innovative directions for fundamental studies delineating cellular reparative and regenerative processes. Empowering myocardial regenerative interventions, whether dependent on endogenous processes or exogenously delivered repair agents, ultimately depends on mastering mechanisms and novel strategies that take advantage of rather than being limited by inherent myocardial biology.

Circ Res: 12 Apr 2018; 122:1151-1163

The Vasculature in Prediabetes.

Wasserman DH, Wang TJ, Brown NJ
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.

Circ Res: 12 Apr 2018; 122:1135-1150

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis.

Koupenova M, Clancy L, Corkrey HA, Freedman JE
Platelets, non-nucleated blood components first described over 130 years ago, are recognized as the primary cell regulating hemostasis and thrombosis. The vascular importance of platelets has been attributed to their essential role in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism. Increasing knowledge on the platelets\' role in the vasculature has led to many advances in understanding not only how platelets interact with the vessel wall but also how they convey changes in the environment to other circulating cells. In addition to their well-described hemostatic function, platelets are active participants in the immune response to microbial organisms and foreign substances. Although incompletely understood, the immune role of platelets is a delicate balance between its pathogenic response and its regulation of thrombotic and hemostatic functions. Platelets mediate complex vascular homeostasis via specific receptors and granule release, RNA transfer, and mitochondrial secretion that subsequently regulates hemostasis and thrombosis, infection, and innate and adaptive immunity.

Circ Res: 18 Jan 2018; 122:337-351

Elixir of Life: Thwarting Aging With Regenerative Reprogramming.

Beyret E, Martinez Redondo P, Platero Luengo A, Izpisua Belmonte JC
All living beings undergo systemic physiological decline after ontogeny, characterized as aging. Modern medicine has increased the life expectancy, yet this has created an aged society that has more predisposition to degenerative disorders. Therefore, novel interventions that aim to extend the healthspan in parallel to the life span are needed. Regeneration ability of living beings maintains their biological integrity and thus is the major leverage against aging. However, mammalian regeneration capacity is low and further declines during aging. Therefore, modalities that reinforce regeneration can antagonize aging. Recent advances in the field of regenerative medicine have shown that aging is not an irreversible process. Conversion of somatic cells to embryonic-like pluripotent cells demonstrated that the differentiated state and age of a cell is not fixed. Identification of the pluripotency-inducing factors subsequently ignited the idea that cellular features can be reprogrammed by defined factors that specify the desired outcome. The last decade consequently has witnessed a plethora of studies that modify cellular features including the hallmarks of aging in addition to cellular function and identity in a variety of cell types in vitro. Recently, some of these reprogramming strategies have been directly used in animal models in pursuit of rejuvenation and cell replacement. Here, we review these in vivo reprogramming efforts and discuss their potential use to extend the longevity by complementing or augmenting the regenerative capacity.

Circ Res: 04 Jan 2018; 122:128-141

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways.

Mozaffarian D, Wu JHY
A growing body of nutritional science highlights the complex mechanisms and pleiotropic pathways of cardiometabolic effects of different foods. Among these, some of the most exciting advances are occurring in the area of flavonoids, bioactive phytochemicals found in plant foods; and in the area of dairy, including milk, yogurt, and cheese. Many of the relevant ingredients and mechanistic pathways are now being clarified, shedding new light on both the ingredients and the pathways for how diet influences health and well-being. Flavonoids, for example, have effects on skeletal muscle, adipocytes, liver, and pancreas, and myocardial, renal, and immune cells, for instance, related to 5\'-monophosphate-activated protein kinase phosphorylation, endothelial NO synthase activation, and suppression of NF-κB (nuclear factor-κB) and TLR4 (toll-like receptor 4). Effects of dairy are similarly complex and may be mediated by specific amino acids, medium-chain and odd-chain saturated fats, unsaturated fats, branched-chain fats, natural trans fats, probiotics, vitamin K1/K2, and calcium, as well as by processing such as fermentation and homogenization. These characteristics of dairy foods influence diverse pathways including related to mammalian target of rapamycin, silent information regulator transcript-1, angiotensin-converting enzyme, peroxisome proliferator-activated receptors, osteocalcin, matrix glutamate protein, hepatic de novo lipogenesis, hepatic and adipose fatty acid oxidation and inflammation, and gut microbiome interactions such as intestinal integrity and endotoxemia. The complexity of these emerging pathways and corresponding biological responses highlights the rapid advances in nutritional science and the continued need to generate robust empirical evidence on the mechanistic and clinical effects of specific foods.

Circ Res: 18 Jan 2018; 122:369-384

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease.

Lezoualc\'h F, Fazal L, Laudette M, Conte C
cAMP is a universal second messenger that plays central roles in cardiovascular regulation influencing gene expression, cell morphology, and function. A crucial step toward a better understanding of cAMP signaling came 18 years ago with the discovery of the exchange protein directly activated by cAMP (EPAC). The 2 EPAC isoforms, EPAC1 and EPAC2, are guanine-nucleotide exchange factors for the Ras-like GTPases, Rap1 and Rap2, which they activate independently of the classical effector of cAMP, protein kinase A. With the development of EPAC pharmacological modulators, many reports in the literature have demonstrated the critical role of EPAC in the regulation of various cAMP-dependent cardiovascular functions, such as calcium handling and vascular tone. EPAC proteins are coupled to a multitude of effectors into distinct subcellular compartments because of their multidomain architecture. These novel cAMP sensors are not only at the crossroads of different physiological processes but also may represent attractive therapeutic targets for the treatment of several cardiovascular disorders, including cardiac arrhythmia and heart failure.

Circ Res: 03 Mar 2016; 118:881-97

The Transcription Factor GATA-6 Regulates Pathological Cardiac Hypertrophy.

van Berlo JH, Elrod JW, van den Hoogenhof MM, York AJ, ... Duncan SA, Molkentin JD
Rationale: The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown. Objective: To determine the role of GATA-6 in cardiac hypertrophy and homeostasis. Methods and results: Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with beta-myosin heavy chain-cre (betaMHC-cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload-induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes. Conclusions: These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4.

Circ Res: 13 Aug 2010; epub ahead of print

Cardiovascular Disease in Women: Clinical Perspectives.

Garcia M, Mulvagh SL, Bairey Merz CN, Buring JE, Manson JE
Cardiovascular disease continues to be the leading cause of death among women in the United States, accounting for ≈1 of every 3 female deaths. Sex-specific data focused on cardiovascular disease have been increasing steadily, yet is not routinely collected nor translated into practice. This comprehensive review focuses on novel and unique aspects of cardiovascular health in women and sex differences as they relate to clinical practice in the prevention, diagnosis, and treatment of cardiovascular disease. This review also provides current approaches to the evaluation and treatment of acute coronary syndromes that are more prevalent in women, including myocardial infarction associated with nonobstructive coronary arteries, spontaneous coronary artery dissection, and stress-induced cardiomyopathy (Takotsubo Syndrome). Other cardiovascular disease entities with higher prevalence or unique considerations in women, such as heart failure with preserved ejection fraction, peripheral arterial disease, and abdominal aortic aneurysms, are also briefly reviewed. Finally, recommendations for cardiac rehabilitation are addressed.

Circ Res: 14 Apr 2016; 118:1273-93

Cardiac Fibrosis: The Fibroblast Awakens.

Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC
Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.

Circ Res: 17 Mar 2016; 118:1021-40

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease.

Blenck CL, Harvey PA, Reckelhoff JF, Leinwand LA
Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men, leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole-heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. Although endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically and in common animal models of CVD.

Circ Res: 14 Apr 2016; 118:1294-312

Imaging Atherosclerosis.

Tarkin JM, Dweck MR, Evans NR, Takx RA, ... Fayad ZA, Rudd JH
Advances in atherosclerosis imaging technology and research have provided a range of diagnostic tools to characterize high-risk plaque in vivo; however, these important vascular imaging methods additionally promise great scientific and translational applications beyond this quest. When combined with conventional anatomic- and hemodynamic-based assessments of disease severity, cross-sectional multimodal imaging incorporating molecular probes and other novel noninvasive techniques can add detailed interrogation of plaque composition, activity, and overall disease burden. In the catheterization laboratory, intravascular imaging provides unparalleled access to the world beneath the plaque surface, allowing tissue characterization and measurement of cap thickness with micrometer spatial resolution. Atherosclerosis imaging captures key data that reveal snapshots into underlying biology, which can test our understanding of fundamental research questions and shape our approach toward patient management. Imaging can also be used to quantify response to therapeutic interventions and ultimately help predict cardiovascular risk. Although there are undeniable barriers to clinical translation, many of these hold-ups might soon be surpassed by rapidly evolving innovations to improve image acquisition, coregistration, motion correction, and reduce radiation exposure. This article provides a comprehensive review of current and experimental atherosclerosis imaging methods and their uses in research and potential for translation to the clinic.

Circ Res: 18 Feb 2016; 118:750-69

Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies: What Can Systematic Reviews Tell Us About Cell Therapies for Ischemic Heart Disease?

Martin-Rendon E
Controversies from basic science, discrepancies from clinical trials, and divergent results from meta-analyses have recently arisen in the field of cell therapies for cardiovascular repair and regeneration. Noticeably, there are almost as many systematic reviews and meta-analyses published as there are well-conducted clinical studies. But how do we disentangle the confusion they have raised? This article addresses why results obtained from systematic reviews and meta-analyses of human cell-based cardiac regeneration therapies are still valid to inform the design of future clinical trials. It also addresses how meta-analyses are not free from limitations and how important it is to assess the quality of the evidence and the quality of the systematic reviews and finally how stronger conclusions can be drawn when several pieces of evidence converge.

Circ Res: 14 Apr 2016; 118:1264-72

Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

Patel VB, Zhong JC, Grant MB, Oudit GY
Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

Circ Res: 14 Apr 2016; 118:1313-26

Brain-Gut-Bone Marrow Axis: Implications for Hypertension and Related Therapeutics.

Santisteban MM, Kim S, Pepine CJ, Raizada MK
Hypertension is the most prevalent modifiable risk factor for cardiovascular disease and disorders directly influencing cardiovascular disease morbidity and mortality, such as diabetes mellitus, chronic kidney disease, obstructive sleep apnea, etc. Despite aggressive attempts to influence lifestyle modifications and advances in pharmacotherapeutics, a large percentage of patients still do not achieve recommended blood pressure control worldwide. Thus, we think that mechanism-based novel strategies should be considered to significantly improve control and management of hypertension. The overall objective of this review is to summarize implications of peripheral- and neuroinflammation as well as the autonomic nervous system-bone marrow communication in hematopoietic cell homeostasis and their impact on hypertension pathophysiology. In addition, we discuss the novel and emerging field of intestinal microbiota and roles of gut permeability and dysbiosis in cardiovascular disease and hypertension. Finally, we propose a brain-gut-bone marrow triangular interaction hypothesis and discuss its potential in the development of novel therapies for hypertension.

Circ Res: 14 Apr 2016; 118:1327-36

Vascular Smooth Muscle Cells in Atherosclerosis.

Bennett MR, Sinha S, Owens GK
The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.

Circ Res: 18 Feb 2016; 118:692-702

Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.

Griendling KK, Touyz RM, Zweier JL, Dikalov S, ... Bhatnagar A, American Heart Association Council on Basic Cardiovascular Sciences
Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.

Circ Res: 14 Jul 2016; epub ahead of print

From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk.

Shapiro MD, Fazio S
The introduction of statins ≈30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels. Although the utility of triglyceride-lowering therapies remains uncertain, 2 large clinical trials are testing the influence of omega-3 polyunsaturated fatty acids on atherosclerotic events in hypertriglyceridemia. Novel antisense therapies targeting apolipoprotein C-III (for triglyceride reduction) and apo(a) (for lipoprotein(a) reduction) are showing a promising trajectory. Finally, 2 large clinical trials are formally putting the inflammatory hypothesis of atherosclerosis to the test and may open a new avenue for cardiovascular disease risk reduction.

Circ Res: 18 Feb 2016; 118:732-49

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Paynter NP, Ridker PM, Chasman DI
In this review, we lay out 3 areas currently being evaluated for incorporation of genetic information into clinical practice related to atherosclerosis. The first, familial hypercholesterolemia, is the clearest case for utility of genetic testing in diagnosis and potentially guiding treatment. Already in use for confirmatory testing of familial hypercholesterolemia and for cascade screening of relatives, genetic testing is likely to expand to help establish diagnoses and facilitate research related to most effective therapies, including new agents, such as PCSK9 inhibitors. The second area, adding genetic information to cardiovascular risk prediction for primary prevention, is not currently recommended. Although identification of additional variants may add substantially to prediction in the future, combining known variants has not yet demonstrated sufficient improvement in prediction for incorporation into commonly used risk scores. The third area, pharmacogenetics, has utility for some therapies today. Future utility for pharmacogenetics will wax or wane depending on the nature of available drugs and therapeutic strategies.

Circ Res: 18 Feb 2016; 118:607-19

Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association.

Murphy E, Ardehali H, Balaban RS, DiLisa F, ... Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology
Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.

Circ Res: 28 Apr 2016; epub ahead of print

MicroRNA Regulation of Atherosclerosis.

Feinberg MW, Moore KJ
Atherosclerosis and its attendant clinical complications, such as myocardial infarction, stroke, and peripheral artery disease, are the leading cause of morbidity and mortality in Western societies. In response to biochemical and biomechanical stimuli, atherosclerotic lesion formation occurs from the participation of a range of cell types, inflammatory mediators, and shear stress. Over the past decade, microRNAs (miRNAs) have emerged as evolutionarily conserved, noncoding small RNAs that serve as important regulators and fine-tuners of a range of pathophysiological cellular effects and molecular signaling pathways involved in atherosclerosis. Accumulating studies reveal the importance of miRNAs in regulating key signaling and lipid homeostasis pathways that alter the balance of atherosclerotic plaque progression and regression. In this review, we highlight current paradigms of miRNA-mediated effects in atherosclerosis progression and regression. We provide an update on the potential use of miRNAs diagnostically for detecting increasing severity of coronary disease and clinical events. Finally, we provide a perspective on therapeutic opportunities and challenges for miRNA delivery in the field.

Circ Res: 18 Feb 2016; 118:703-20

Cardiac Progenitor Cell Cycling Stimulated by Pim-1 Kinase.

Cottage CT, Bailey B, Fischer KM, Avitable D, ... Muraski J, Sussman MA
Rationale: Cardioprotective effects of Pim-1 kinase have been previously reported but the underlying mechanistic basis may involve a combination of cellular and molecular mechanisms that remain unresolved. The elucidation of the mechanistic basis for Pim-1 mediated cardioprotection provides important insights for designing therapeutic interventional strategies to treat heart disease. Objective: Effects of cardiac-specific Pim-1 kinase expression on the cardiac progenitor cell (CPC) population were examined to determine whether Pim-1 mediates beneficial effects through augmenting CPC activity. Methods and results: Transgenic mice created with cardiac-specific Pim-1 overexpression (Pim-wt) exhibit enhanced Pim-1 expression in both cardiomyocytes and CPCs, both of which show increased proliferative activity assessed using 5-bromodeoxyuridine (BrdUrd), Ki-67, and c-Myc relative to nontransgenic controls. However, the total number of CPCs was not increased in the Pim-wt hearts during normal postnatal growth or after infarction challenge. These results suggest that Pim-1 overexpression leads to asymmetrical division resulting in maintenance of the CPC population. Localization and quantitation of cell fate determinants Numb and alpha-adaptin by confocal microscopy were used to assess frequency of asymmetrical division in the CPC population. Polarization of Numb in mitotic phospho-histone positive cells demonstrates asymmetrical division in 65% of the CPC population in hearts of Pim-wt mice versus 26% in nontransgenic hearts after infarction challenge. Similarly, Pim-wt hearts had fewer cells with uniform alpha-adaptin staining indicative of symmetrically dividing CPCs, with 36% of the CPCs versus 73% in nontransgenic sections. Conclusions: These findings define a mechanistic basis for enhanced myocardial regeneration in transgenic mice overexpressing Pim-1 kinase.

Circ Res: 15 Jan 2010; epub ahead of print

Endocardial Notch Signaling in Cardiac Development and Disease.

de Luxán G, D\'Amato G, MacGrogan D, de la Pompa JL
The Notch signaling pathway is an ancient and highly conserved signaling pathway that controls cell fate specification and tissue patterning in the embryo and in the adult. Region-specific endocardial Notch activity regulates heart morphogenesis through the interaction with multiple myocardial-, epicardial- and neural crest-derived signals. Mutations in NOTCH signaling elements cause congenital heart disease in humans and mice, demonstrating its essential role in cardiac development. Studies in model systems have provided mechanistic understanding of Notch function in cardiac development, congenital heart disease and heart regeneration. Notch patterns the embryonic endocardium into prospective territories for valve and chamber formation, and later regulates the signaling processes leading to outflow tract and valve morphogenesis and ventricular trabeculae compaction. Alterations in NOTCH signaling in the endocardium result in congenital structural malformations that can lead to disease in the neonate and adult heart.

Circ Res: 03 Dec 2015; epub ahead of print

Microdomains, Inflammation, and Atherosclerosis.

Sorci-Thomas MG, Thomas MJ
Elevated levels of cholesteryl ester (CE)-enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of low-density lipoprotein cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can be either re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP-binding cassette transporter A1-mediated efflux. Because cholesterol is an essential component of all cellular membranes, some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ATP-binding cassette transporter A1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor apolipoprotein AI (apoAI) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified, CE droplets accumulate and microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor oversensitization. The availability of apoAI or other amphipathic α-helix-rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation.

Circ Res: 18 Feb 2016; 118:679-91

The Success Story of LDL Cholesterol Lowering.

Pedersen TR
We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence.

Circ Res: 18 Feb 2016; 118:721-31

Distinct Roles for Cell-Autonomous Notch Signaling in Cardiomyocytes of the Embryonic and Adult Heart.

Kratsios P, Catela C, Salimova E, Huth M, ... Rosenthal N, Mourkioti F
Rationale: The Notch signaling pathway is important for cell-cell communication that controls tissue formation and homeostasis during embryonic and adult life, but the precise cell targets of Notch signaling in the mammalian heart remain poorly defined. Objective: To investigate the functional role of Notch signaling in the cardiomyocyte compartment of the embryonic and adult heart. Methods and results: Here, we report that either conditional overexpression of Notch1 intracellular domain (NICD1) or selective silencing of Notch signaling in the embryonic cardiomyocyte compartment results in developmental defects and perinatal lethality. In contrast, augmentation of endogenous Notch reactivation after myocardial infarction in the adult, either by inducing cardiomyocyte-specific Notch1 transgene expression or by intramyocardial delivery of a Notch1 pseudoligand, increases survival rate, improves cardiac functional performance, and minimizes fibrosis, promoting antiapoptotic and angiogenic mechanisms. Conclusions: These results reveal a strict requirement for cell-autonomous modulation of Notch signaling during heart morphogenesis, and illustrate how the same signaling pathway that promotes congenital heart defects when perturbed in the embryo can be therapeutically redeployed for the treatment of adult myocardial damage.

Circ Res: 16 Dec 2009; epub ahead of print

Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis.

Musunuru K, Kathiresan S
Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.

Circ Res: 18 Feb 2016; 118:579-85

Macrophage Phenotype and Function in Different Stages of Atherosclerosis.

Tabas I, Bornfeldt KE
The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for >50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to high-density lipoprotein; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and proresolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge.

Circ Res: 18 Feb 2016; 118:653-67

Platelet-Mediated Thrombosis: From Bench to Bedside.

Gurbel PA, Jeong YH, Navarese EP, Tantry US
The pivotal role that platelets play in thrombosis and resultant ischemic event occurrences in patients with high-risk coronary artery disease is well established. This role provides the fundamental basis for the current wide implementation of dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor. The development of user friendly point-of-care methods to assess platelet reactivity to adenosine diphosphate has increased the frequency of platelet function testing in clinical practice. Recent large observational studies have established an independent relation between the results of point-of-care platelet function testing and clinical event occurrence in patients undergoing coronary artery stenting. However, prospective, randomized trials have failed to demonstrate that personalized antiplatelet therapy based on point-of-care assessment of platelet function is effective in reducing ischemic event occurrences. Important limitations were associated with these trials. In addition, the concept of a therapeutic window of P2Y12 receptor reactivity with an upper threshold associated with ischemic event occurrence and a lower threshold associated with bleeding has also been proposed. In the absence of strong prospective evidence to support personalized antiplatelet therapy, clinical decision making about antiplatelet therapy rests on the large body of observational data and the fundamental importance of platelet physiology in catastrophic event occurrence in patients with high-risk coronary artery disease.

Circ Res: 28 Apr 2016; 118:1380-91

From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease.

Nurnberg ST, Zhang H, Hand NJ, Bauer RC, ... Reilly MP, Rader DJ
Genome-wide association studies have provided a rich collection of ≈58 coronary artery disease (CAD) loci that suggest the existence of previously unsuspected new biology relevant to atherosclerosis. However, these studies only identify genomic loci associated with CAD, and many questions remain even after a genomic locus is definitively implicated, including the nature of the causal variant(s) and the causal gene(s), as well as the directionality of effect. There are several tools that can be used for investigation of the functional genomics of these loci, and progress has been made on a limited number of novel CAD loci. New biology regarding atherosclerosis and CAD will be learned through the functional genomics of these loci, and the hope is that at least some of these new pathways relevant to CAD pathogenesis will yield new therapeutic targets for the prevention and treatment of CAD.

Circ Res: 18 Feb 2016; 118:586-606

Insulin Signaling and Heart Failure.

Riehle C, Abel ED
Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed.

Circ Res: 31 Mar 2016; 118:1151-69

CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation.

Neef S, Dybkova N, Sossalla S, Ort KR, ... Hasenfuss G, Maier LS
Rationale: Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak. Objective: We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF. Methods and results: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current. Conclusion: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.

Circ Res: 08 Jan 2010; epub ahead of print

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease.

Fuster JJ, Ouchi N, Gokce N, Walsh K
Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines.

Circ Res: 26 May 2016; 118:1786-807

The genomic architecture of sporadic heart failure.

Dorn GW
Common or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20% and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease-common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies used a candidate gene approach focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data supports risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin-converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene-centric subgenome single nucleotide polymorphism array identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects.

Circ Res: 13 May 2011; 108:1270-83

Fractional Flow Reserve and Coronary Computed Tomographic Angiography: A Review and Critical Analysis.

Hecht HS, Narula J, Fearon WF
Invasive fractional flow reserve (FFR) is now the gold standard for intervention. Noninvasive functional imaging analyses derived from coronary computed tomographic angiography (CTA) offer alternatives for evaluating lesion-specific ischemia. CT-FFR, CT myocardial perfusion imaging, and transluminal attenuation gradient/corrected contrast opacification have been studied using invasive FFR as the gold standard. CT-FFR has demonstrated significant improvement in specificity and positive predictive value compared with CTA alone for predicting FFR of ≤0.80, as well as decreasing the frequency of nonobstructive invasive coronary angiography. High-risk plaque characteristics have also been strongly implicated in abnormal FFR. Myocardial computed tomographic perfusion is an alternative method with promising results; it involves more radiation and contrast. Transluminal attenuation gradient/corrected contrast opacification is more controversial and may be more related to vessel diameter than stenosis. Important considerations remain: (1) improvement of CTA quality to decrease unevaluable studies, (2) is the diagnostic accuracy of CT-FFR sufficient? (3) can CT-FFR guide intervention without invasive FFR confirmation? (4) what are the long-term outcomes of CT-FFR-guided treatment and how do they compare with other functional imaging-guided paradigms? (5) what degree of stenosis on CTA warrants CT-FFR? (6) how should high-risk plaque be incorporated into treatment decisions? (7) how will CT-FFR influence other functional imaging test utilization, and what will be the effect on the practice of cardiology? (8) will a workstation-based CT-FFR be mandatory? Rapid progress to date suggests that CTA-based lesion-specific ischemia will be the gatekeeper to the cardiac catheterization laboratory and will transform the world of intervention.

Circ Res: 07 Jul 2016; 119:300-16

Relative Roles of Direct Regeneration Versus Paracrine Effects of Human Cardiosphere-Derived Cells Transplanted Into Infarcted Mice.

Chimenti I, Smith RR, Li TS, Gerstenblith G, ... Giacomello A, Marbán E
Rationale: Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair. Objective: Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells. Methods and results: In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects. Conclusions: Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as "role models," recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration.

Circ Res: 29 Jan 2010; epub ahead of print

Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics.

Cheng H, Force T
In 2002, Hoshijima and Chien drew largely theoretical parallels between the dysregulation of the signaling pathways driving cancer and those driving cardiac hypertrophy (Hoshijima M, Chien KR. J Clin Invest. 2002;109:849-855). On the surface, this statement appeared to stretch the limits of reason, given the fact that cancer cells are known for their proliferative capacity, and adult cardiomyocytes are, except under unusual circumstances, terminally differentiated and incapable of re-entering the cell cycle. However, on closer examination, there are numerous parallels between signaling pathways that drive tumorigenesis and signaling pathways that regulate hypertrophic responses and survival in cardiomyocytes. Indeed, this issue appears to be at the core of the cardiotoxicity (often manifest as a dilated cardiomyopathy) that can result from treatment with agents typically referred to as "targeted therapeutics," which target specific protein kinases that are dysregulated in cancer. Herein, we examine the cardiotoxicity of targeted therapeutics, focusing on the underlying molecular mechanisms, thereby allowing an understanding of the problem but also allowing the identification of novel, and sometimes surprising, roles played by protein kinases in the heart.

Circ Res: 08 Jan 2010; 106:21-34

MicroRNAs for Restenosis and Thrombosis After Vascular Injury.

Gareri C, De Rosa S, Indolfi C
Percutaneous revascularization revolutionized the therapy of patients with coronary artery disease. Despite continuous technical advances that substantially improved patients\' outcome after percutaneous revascularization, some issues are still open. In particular, restenosis still represents a challenge, even though it was dramatically reduced with the advent of drug-eluting stents. At the same time, drug-eluting stent thrombosis emerged as a major concern because of incomplete or delayed re-endothelialization after vascular injury. The discovery of microRNAs revealed a previously unknown layer of regulation for several biological processes, increasing our knowledge on the biological mechanisms underlying restenosis and stent thrombosis, revealing novel promising targets for more efficient and selective therapies. The present review summarizes recent experimental and clinical evidence on the role of microRNAs after arterial injury, focusing on practical aspects of their potential therapeutic application for selective inhibition of smooth muscle cell proliferation, enhancement of endothelial regeneration, and inhibition of platelet activation after coronary interventions. Application of circulating microRNAs as potential biomarkers is also discussed.

Circ Res: 31 Mar 2016; 118:1170-84

Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes.

Standl E, Schnell O, McGuire DK
Prevalent and incident heart failure (HF) is increased in people with type 2 diabetes mellitus, with risk directly associated with the severity of hyperglycemia. Furthermore, in patients with type 2 diabetes mellitus, mortality is increased ≈10-fold in patients with versus without HF. Reducing HF with antihyperglycemic therapies, however, has been unsuccessful until recently. In fact, HF as an important outcome in patients with type 2 diabetes mellitus seems to be heterogeneously modulated by antihyperglycemic medications, as evidenced by results from cardiovascular outcome trials (CVOTs) and large observational cohort studies. Appropriately powered and executed CVOTs are necessary to truly evaluate cardiovascular safety and efficacy of new antihyperglycemic medications, as reflected by the guidance of the US Food and Drug Administration and other regulatory agencies since 2008. In light of the best available evidence at present, metformin and the sodium-glucose-co-transporter 2-inhibitor empagliflozin seem to be especially advantageous with regard to HF effects, with their use associated with reduced HF events and improved mortality. Acarbose, the dipeptidyl-peptidase 4-inhibitor sitagliptin, the glucagon-like peptide 1-receptor agonist lixisenatide based on presently available CVOT results comprise reasonable additional options, as significant harm in terms of HF has been excluded for those drugs. Additions to this list are anticipated pending results of ongoing CVOTs. Although no HF harm was seen in CVOTs for insulin or sulfonylureas, they should be used only with caution in patients with HF, given their established high risk for hypoglycemia and some uncertainties on their safety in patients with HF derived from epidemiological observations. Pioglitazone is contraindicated in patients with HF>New York Heart Association I, despite some benefits suggested by CVOT subanalyses.

Circ Res: 26 May 2016; 118:1830-43

Advances in Echocardiographic Imaging in Heart Failure With Reduced and Preserved Ejection Fraction.

Omar AM, Bansal M, Sengupta PP
Echocardiography, given its safety, easy availability, and the ability to permit a comprehensive assessment of cardiac structure and function, is an indispensable tool in the evaluation and management of patients with heart failure (HF). From initial phenotyping and risk stratification to providing vital data for guiding therapeutic decision-making and monitoring, echocardiography plays a pivotal role in the care of HF patients. The recent advent of multiparametric approaches for myocardial deformation imaging has provided valuable insights in the pathogenesis of HF, elucidating distinct patterns of myocardial dysfunction and events that are associated with progression from subclinical stage to overt HF. At the same time, miniaturization of echocardiography has further expanded clinical application of echocardiography, with the use of pocket cardiac ultrasound as an adjunct to physical examination demonstrated to improve diagnostic accuracy and risk stratification. Furthermore, ongoing advances in the field of big data analytics promise to create an exciting opportunity to operationalize precision medicine as the new approach to healthcare delivery that aims to individualize patient care by integrating data extracted from clinical, laboratory, echocardiographic, and genetic assessments. The present review summarizes the recent advances in the field of echocardiography, with emphasis on their role in HF phenotyping, risk stratification, and optimizing clinical outcomes.

Circ Res: 07 Jul 2016; 119:357-74

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival.

Otterbein LE, Foresti R, Motterlini R
Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.

Circ Res: 09 Jun 2016; 118:1940-59

Isoform-Selective Physical Coupling of TRPC3 Channels to IP3 Receptors in Smooth Muscle Cells Regulates Arterial Contractility.

Adebiyi A, Zhao G, Narayanan D, Thomas CM, Bannister JP, Jaggar JH
Rationale: Inositol 1,4,5-trisphosphate (IP3)-induced vasoconstriction can occur independently of intracellular Ca(2+) release and via IP3 receptor (IP3R) and canonical transient receptor potential (TRPC) channel activation, but functional signaling mechanisms mediating this effect are unclear. Objectives: Study mechanisms by which IP3Rs stimulate TRPC channels in myocytes of resistance-size cerebral arteries. Methods and results: Immunofluorescence resonance energy transfer (immuno-FRET) microscopy using isoform-selective antibodies indicated that endogenous type 1 IP3Rs (IP3R1) are in close spatial proximity to TRPC3, but distant from TRPC6 or TRPM4 channels in arterial myocytes. Endothelin-1 (ET-1), a phospholipase C-coupled receptor agonist, elevated immuno-FRET between IP3R1 and TRPC3, but not between IP3R1 and TRPC6 or TRPM4. TRPC3, but not TRPC6, coimmunoprecipitated with IP3R1. TRPC3 and TRPC6 antibodies selectively inhibited recombinant channels, but only the TRPC3 antibody blocked IP3-induced nonselective cation current (ICat) in myocytes. TRPC3 knockdown attenuated immuno-FRET between IP3R1 and TRPC3, IP3-induced ICat activation, and ET-1 and IP3-induced vasoconstriction, whereas TRPC6 channel knockdown had no effect. ET-1 did not alter total or plasma membrane-localized TRPC3, as determined using surface biotinylation. RT-PCR demonstrated that C-terminal calmodulin and IP3R binding (CIRB) domains are present in myocyte TRPC3 and TRPC6 channels. A peptide corresponding to the IP3R N-terminal region that can interact with TRPC channels activated ICat. A TRPC3 CIRB domain peptide attenuated IP3- and ET-1-induced ICat activation and vasoconstriction. Conclusions: IP3 stimulates direct coupling between IP3R1 and membrane-resident TRPC3 channels in arterial myocytes, leading to ICat activation and vasoconstriction. Close spatial proximity between IP3R1 and TRPC3 establishes this isoform-selective functional interaction.

Circ Res: 09 Apr 2010; epub ahead of print

Therapeutic Targeting of Mitochondrial Superoxide in Hypertension.

Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, ... Harrison DG, Dikalov SI
Rationale: Superoxide (O2(-)) has been implicated in the pathogenesis of many human diseases including hypertension; however, commonly used antioxidants have proven ineffective in clinical trials. It is possible that these agents are not adequately delivered to the subcellular sites of superoxide production. Objective: Because the mitochondria are important sources of reactive oxygen species, we postulated that mitochondrial targeting of superoxide scavenging would have therapeutic benefit. Methods and results: In this study, we found that the hormone angiotensin (Ang II) increased endothelial mitochondrial superoxide production. Treatment with the mitochondrial targeted antioxidant mitoTEMPO decreased mitochondrial O2(-), inhibited the total cellular O2(-), reduced cellular NADPH oxidase activity, and restored the level of bioavailable NO. These effects were mimicked by overexpressing the mitochondrial MnSOD (SOD2), whereas SOD2 depletion with small interfering RNA increased both basal and Ang II-stimulated cellular O2(-). Treatment of mice in vivo with mitoTEMPO attenuated hypertension when given at the onset of Ang II infusion and decreased blood pressure by 30 mm Hg following establishment of both Ang II-induced and DOCA salt hypertension, whereas a similar dose of nontargeted TEMPOL was not effective. In vivo, mitoTEMPO decreased vascular O2(-), increased vascular NO2(-) production and improved endothelial-dependent relaxation. Interestingly, transgenic mice overexpressing mitochondrial SOD2 demonstrated attenuated Ang II-induced hypertension and vascular oxidative stress similar to mice treated with mitoTEMPO. Conclusions: These studies show that mitochondrial O2(-) is important for the development of hypertension and that antioxidant strategies specifically targeting this organelle could have therapeutic benefit in this and possibly other diseases.

Circ Res: 07 May 2010; epub ahead of print

Systems Analysis of Thrombus Formation.

Diamond SL
The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient-specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High-dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. In addition, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs.

Circ Res: 28 Apr 2016; 118:1348-62

Global Burden of Thrombosis: Epidemiologic Aspects.

Wendelboe AM, Raskob GE
Thromboembolic conditions were estimated to account for 1 in 4 deaths worldwide in 2010 and are the leading cause of mortality. Thromboembolic conditions are divided into arterial and venous thrombotic conditions. Ischemic heart disease and ischemic stroke comprise the major arterial thromboses and deep-vein thrombosis and pulmonary embolism comprise venous thromboembolism. Atrial fibrillation is a major risk factor for stroke and systemic arterial thromboembolism. Estimates of the global burden of disease were obtained from Global Burden of Disease Project reports, recent systematic reviews, and searching the published literature for recent studies reporting measures of incidence, burden, and disability-adjusted life-years. Estimates per 100 000 of the global incidence rate (IR) for each condition are ischemic heart disease, IR=1518.7; myocardial infarction, IR=139.3; ischemic stroke, IR=114.3; atrial fibrillation, IR=77.5 in males and 59.5 in females; and venous thromboembolism, IR=115 to 269. Mortality rates (MRs) for each condition are ischemic heart disease, MR=105.5; ischemic stroke, MR=42.3; atrial fibrillation, MR=1.7; and venous thromboembolism, MR=9.4 to 32.3. Global public awareness is substantially lower for pulmonary embolism (54%) and deep-vein thrombosis (44%) than heart attack (88%) and stroke (85%). Over time, the incidence and MRs of these conditions have improved in developed countries, but are increasing in developing countries. Public health efforts to measure disease burden and increase awareness of symptoms and risk factors need to improve, particularly in low- and middle-income regions to address this leading cause of morbidity and mortality.

Circ Res: 28 Apr 2016; 118:1340-7

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

Shah MS, Brownlee M
The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

Circ Res: 26 May 2016; 118:1808-29

Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation.

Walker RG, Poggioli T, Katsimpardi L, Buchanan SM, ... Wagers AJ, Lee RT
Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

Circ Res: 31 Mar 2016; 118:1125-42

Myocardin-Related Transcription Factor-A Controls Myofibroblast Activation and Fibrosis in Response to Myocardial Infarction.

Small EM, Thatcher JE, Sutherland LB, Kinoshita H, ... Kuwahara K, Olson EN
Rationale: Myocardial infarction (MI) results in loss of cardiac myocytes in the ischemic zone of the heart, followed by fibrosis and scar formation, which diminish cardiac contractility and impede angiogenesis and repair. Myofibroblasts, a specialized cell type that switches from a fibroblast-like state to a contractile, smooth muscle-like state, are believed to be primarily responsible for fibrosis of the injured heart and other tissues, although the transcriptional mediators of fibrosis and myofibroblast activation remain poorly defined. Myocardin-related transcription factors (MRTFs) are serum response factor (SRF) cofactors that promote a smooth muscle phenotype and are emerging as components of stress-responsive signaling. Objective: We aimed to examine the effect of MRTF-A on cardiac remodeling and fibrosis. Methods and results: Here, we show that MRTF-A controls the expression of a fibrotic gene program that includes genes involved in extracellular matrix production and smooth muscle cell differentiation in the heart. In MRTF-A-null mice, fibrosis and scar formation following MI or angiotensin II treatment are dramatically diminished compared with wild-type littermates. This protective effect of MRTF-A deletion is associated with a reduction in expression of fibrosis-associated genes, including collagen 1a2, a direct transcriptional target of SRF/MRTF-A. Conclusions: We conclude that MRTF-A regulates myofibroblast activation and fibrosis in response to the renin-angiotensin system and post-MI remodeling.

Circ Res: 18 Jun 2010; epub ahead of print

Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications.

Bhupathiraju SN, Hu FB
Obesity and diabetes mellitus have reached epidemic proportions in the past few years. During 2011 to 2012, more than one-third of the US population was obese. Although recent trend data indicate that the epidemic has leveled off, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes mellitus incidence with an increasing number of type 2 diabetes mellitus cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes mellitus. In general, in both adults and children, non-Hispanic blacks and Mexican Americans seem to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the diabesity epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an obesogenic one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes mellitus raise the risk of cardiovascular disease by ≈2-fold. Among those with type 2 diabetes mellitus, significant sex differences occur in the risk of cardiovascular disease such that diabetes mellitus completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes mellitus, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases.

Circ Res: 26 May 2016; 118:1723-35

Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

Harper SC, Brack A, MacDonnell S, Franti M, ... Rudnicki MA, Houser SR
This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.

Circ Res: 31 Mar 2016; 118:1143-50

Modulation of Angiotensin II-Mediated Cardiac Remodeling by the MEF2A Target Gene Xirp2.

McCalmon SA, Desjardins DM, Ahmad S, Davidoff KS, ... Gavras H, Naya FJ
Rationale: The vasoactive peptide angiotensin II (Ang II) is a potent cardiotoxic hormone whose actions have been well studied, yet questions remain pertaining to the downstream factors that mediate its effects in cardiomyocytes. Objective: The in vivo role of the myocyte enhancer factor (MEF)2A target gene Xirp2 in Ang II-mediated cardiac remodeling was investigated. Methods and results: Here we demonstrate that the MEF2A target gene Xirp2 (also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart. Xirp2 belongs to the evolutionarily conserved, muscle-specific, actin-binding Xin gene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized the Xirp2 promoter and demonstrate that Ang II activates Xirp2 expression by stimulating MEF2A transcriptional activity. To further characterize the role of Xirp2 downstream of Ang II signaling we generated mice harboring a hypomorphic allele of the Xirp2 gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adult Xirp2 hypomorphic mice displayed cardiac hypertrophy and increased beta myosin heavy chain expression. Strikingly, Xirp2 hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis. Conclusions: These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart.

Circ Res: 22 Jan 2010; epub ahead of print

Time to Give Up on Cardioprotection? A Critical Appraisal of Clinical Studies on Ischemic Pre-, Post-, and Remote Conditioning.

Heusch G, Rassaf T
The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-of-concept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection.

Circ Res: 18 Aug 2016; 119:676-95

T1 Mapping in Characterizing Myocardial Disease: A Comprehensive Review.

Puntmann VO, Peker E, Chandrashekhar Y, Nagel E
Cardiovascular magnetic resonance provides insights into myocardial structure and function noninvasively, with high diagnostic accuracy and without ionizing radiation. Myocardial tissue characterization in particular gives cardiovascular magnetic resonance a prime role among all the noninvasive cardiovascular investigations. Late gadolinium enhancement imaging is an established method for visualizing replacement scar, providing diagnostic and prognostic information in a variety of cardiac conditions. Late gadolinium enhancement, however, relies on the regional segregation of tissue characteristics to generate the imaging contrast. Thus, myocardial pathology that is diffuse in nature and affecting the myocardium in a rather uniform and global distribution is not well visualized with late gadolinium enhancement. Examples include diffuse myocardial inflammation, fibrosis, hypertrophy, and infiltration. T1 mapping is a novel technique allowing to diagnose these diffuse conditions by measurement of T1 values, which directly correspond to variation in intrinsic myocardial tissue properties. In addition to providing clinically meaningful indices, T1-mapping measurements also allow for an estimation of extracellular space by calculation of extracellular volume fraction. Multiple lines of evidence suggest a central role for T1 mapping in detection of diffuse myocardial disease in early disease stages and complements late gadolinium enhancement in visualization of the regional changes in common advanced myocardial disease. As a quantifiable measure, it may allow grading of disease activity, monitoring progress, and guiding treatment, potentially as a fast contrast-free clinical application. We present an overview of clinically relevant technical aspects of acquisition and processing, and the current state of art and evidence, supporting its clinical use.

Circ Res: 07 Jul 2016; 119:277-99

Pharmacological Strategies to Retard Cardiovascular Aging.

Alfaras I, Di Germanio C, Bernier M, Csiszar A, ... Lakatta EG, de Cabo R
Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health.

Circ Res: 12 May 2016; 118:1626-42

Mitochondrial Metabolism in Aging Heart.

Lesnefsky EJ, Chen Q, Hoppel CL
Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.

Circ Res: 12 May 2016; 118:1593-611

Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.

Priori SG, Chen SR
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life-threatening arrhythmias elicited by stress and emotion. In 2001, the ryanodine receptor was identified as the gene that is linked to CPVT; shortly thereafter, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca(2+) regulation could profoundly disrupt the electrophysiological properties of the heart. In this article, we discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.

Circ Res: 01 Apr 2011; 108:871-83

Chronic Heart Failure and Inflammation: What Do We Really Know?

Dick SA, Epelman S
As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established-which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

Circ Res: 23 Jun 2016; 119:159-76

A Peptide Mimetic of the Connexin43 Carboxyl Terminus Reduces Gap Junction Remodeling and Induced Arrhythmia Following Ventricular Injury.

O\'Quinn MP, Palatinus JA, Harris BS, Hewett KW, Gourdie RG
Rationale: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia. Objectives: A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ)-binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic αCT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether αCT1 affected arrhythmic propensity; and (3) the mechanism of αCT1 effects on arrhythmogenicity and GJ remodeling. Methods and results: A cryoinjury model generating a reproducible wound and injury border zone (IBZ) in the LV was used. Adherent methylcellulose patches formulated to locally release αCT1 (<48 hours) were placed on cryoinjuries. Relative to controls, Cx43/ZO-1 colocalization in the IBZ was reduced by αCT1 by 24 hours after injury. Programmed electric stimulation ex vivo and optical mapping of voltage transients indicated that peptide-treated hearts showed reduced inducible arrhythmias and increased ventricular depolarization rates 7 to 9 days after injury. At 24 hours and 1 week after injury, αCT1-treated hearts maintained Cx43 in intercalated disks (IDs) in the IBZ, whereas by 1 week after injury, controls demonstrated Cx43 remodeling from IDs to lateralized distributions. Over a postinjury time course of 1 week, αCT1-treated IBZs showed increased Cx43 phosphorylation at serine368 (Cx43-pS368) relative to control tissues. In biochemical assays, αCT1 promoted phosphorylation of serine368 by protein kinase (PK)C-ε in a dose-dependent manner that was modulated by, but did not require ZO-1 PDZ2. Conclusions: αCT1 increases Cx43-pS368 in vitro in a PKC-ε-dependent manner and in the IBZ in vivo acutely following ventricular injury. αCT1-mediated increase in Cx43-pS368 phosphorylation may contribute to reductions in inducible-arrhythmia following injury.

Circ Res: 28 Jan 2011; epub ahead of print

Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel.

Wilde AA, Brugada R
Variations in the gene encoding for the major sodium channel (Na(v)1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the α-subunit Na(v)1.5 and modifying its function. Based on detailed studies of genotype-phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities.

Circ Res: 01 Apr 2011; 108:884-97

Treatment of Obesity: Weight Loss and Bariatric Surgery.

Wolfe BM, Kvach E, Eckel RH
This review focuses on the mechanisms underlying, and indications for, bariatric surgery in the reduction of cardiovascular disease (CVD), as well as other expected benefits of this intervention. The fundamental basis for bariatric surgery for the purpose of accomplishing weight loss is the determination that severe obesity is a disease associated with multiple adverse effects on health, which can be reversed or improved by successful weight loss in patients who have been unable to sustain weight loss by nonsurgical means. An explanation of possible indications for weight loss surgery as well as specific bariatric surgical procedures is presented, along with review of the safety literature of such procedures. Procedures that are less invasive or those that involve less gastrointestinal rearrangement accomplish considerably less weight loss but have substantially lower perioperative and longer-term risk. The ultimate benefit of weight reduction relates to the reduction of the comorbidities, quality of life, and all-cause mortality. With weight loss being the underlying justification for bariatric surgery in ameliorating CVD risk, current evidence-based research is discussed concerning body fat distribution, dyslipidemia, hypertension, diabetes mellitus, inflammation, obstructive sleep apnea, and others. The rationale for bariatric surgery reducing CVD events is discussed and juxtaposed with impacts on all-cause mortalities. Given the improvement of established obesity-related CVD risk factors after weight loss, it is reasonable to expect a reduction of CVD events and related mortality after weight loss in populations with obesity. The quality of the current evidence is reviewed, and future research opportunities and summaries are stated.

Circ Res: 26 May 2016; 118:1844-55

The Coronary Circulation as a Target of Cardioprotection.

Heusch G
The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available.

Circ Res: 12 May 2016; 118:1643-58

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator.

Vanhoutte PM, Zhao Y, Xu A, Leung SW
Endothelial cells control vascular tone by releasing nitric oxide (NO) produced by endothelial NO synthase. The activity of endothelial NO synthase is modulated by the calcium concentration and by post-translational modifications (eg, phosphorylation). When NO reaches vascular smooth muscle, soluble guanylyl cyclase is its primary target producing cGMP. NO production is stimulated by circulating substances (eg, catecholamines), platelet products (eg, serotonin), autacoids formed in (eg, bradykinin) or near (eg, adiponectin) the vascular wall and physical factors (eg, shear stress). NO dysfunction can be caused, alone or in combination, by abnormal coupling of endothelial cell membrane receptors, insufficient supply of substrate (l-arginine) or cofactors (tetrahydrobiopterin), endogenous inhibitors (asymmetrical dimethyl arginine), reduced expression/presence/dimerization of endothelial NO synthase, inhibition of its enzymatic activity, accelerated disposition of NO by reactive oxygen species and abnormal responses (eg, biased soluble guanylyl cyclase activity producing cyclic inosine monophosphate) of the vascular smooth muscle. Major culprits causing endothelial dysfunction, irrespective of the underlying pathological process (aging, obesity, diabetes mellitus, and hypertension), include stimulation of mineralocorticoid receptors, activation of endothelial Rho-kinase, augmented presence of asymmetrical dimethyl arginine, and exaggerated oxidative stress. Genetic and pharmacological interventions improve dysfunctional NO-mediated vasodilatations if protecting the supply of substrate and cofactors for endothelial NO synthase, preserving the presence and activity of the enzyme and reducing reactive oxygen species generation. Common achievers of such improvement include maintained levels of estrogens and increased production of adiponectin and induction of silent mating-type information regulation 2 homologue 1. Obviously, endothelium-dependent relaxations are not the only beneficial action of NO in the vascular wall. Thus, reduced NO-mediated responses precede and initiate the atherosclerotic process.

Circ Res: 07 Jul 2016; 119:375-96

Epigenetic Changes in Diabetes and Cardiovascular Risk.

Keating ST, Plutzky J, El-Osta A
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.

Circ Res: 26 May 2016; 118:1706-22

Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels.

Shimizu W, Horie M
Since 1995, when a potassium channel gene, hERG (human ether-à-go-go-related gene), now referred to as KCNH2, encoding the rapid component of cardiac delayed rectifier potassium channels was identified as being responsible for type 2 congenital long-QT syndrome, a number of potassium channel genes have been shown to cause different types of inherited cardiac arrhythmia syndromes. These include congenital long-QT syndrome, short-QT syndrome, Brugada syndrome, early repolarization syndrome, and familial atrial fibrillation. Genotype-phenotype correlations have been investigated in some inherited arrhythmia syndromes, and as a result, gene-specific risk stratification and gene-specific therapy and management have become available, particularly for patients with congenital long-QT syndrome. In this review article, the molecular structure and function of potassium channels, the clinical phenotype due to potassium channel gene mutations, including genotype-phenotype correlations, and the diverse mechanisms underlying the potassium channel gene-related diseases will be discussed.

Circ Res: 24 Jun 2011; 109:97-109

Chromatin remodeling in cardiovascular development and physiology.

Han P, Hang CT, Yang J, Chang CP
Chromatin regulation provides an important means for controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease.

Circ Res: 04 Feb 2011; 108:378-96

Aging and Autophagy in the Heart.

Shirakabe A, Ikeda Y, Sciarretta S, Zablocki DK, Sadoshima J
The aging population is increasing in developed countries. Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

Circ Res: 12 May 2016; 118:1563-76

Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation.

Feaver RE, Gelfand BD, Wang C, Schwartz MA, Blackman BR
Rationale: The extracellular matrix protein fibronectin (FN) is focally deposited in regions of atherosclerosis, where it contributes to inflammatory signaling. Objective: To elucidate the mechanism by which FN deposition is regulated by local shear stress patterns, its dependence on platelet-endothelial cell adhesion molecule (PECAM)-1 mechanotransduction and the role this pathway plays in sustaining an atheroprone/proinflammatory phenotype. Methods and results: Human endothelial cells were exposed in vitro to atheroprone or atheroprotective shear stress patterns derived from human carotid arteries. Onset of atheroprotective flow induced a transient increase in FN deposition, whereas atheroprone flow caused a steady increase in FN expression and integrin activation over time, leading to a significant and sustained increase in FN deposition relative to atheroprotective conditions. Comparing FN staining in ApoE(-/-) and ApoE(-/-)PECAM(-/-) mice showed that PECAM-1 was essential for FN accumulation in atheroprone regions of the aortic arch. In vitro, small interfering RNA against PECAM-1 blocked the induction of FN and the activation of nuclear factor (NF)-kappaB by atheroprone flow, which was rescued by the addition of exogenous FN. Additionally, blocking NF-kappaB activation attenuated the flow-induced FN expression. Small interfering RNA against FN significantly reduced NF-kappaB activity, which was rescued by the addition of exogenous FN. Conclusions: These results indicate that FN gene expression and assembly into matrix fibrils is induced by atheroprone fluid shear stress. This effect is mediated at least in part by the transcription factor NF-kappaB. Additionally, because FN promotes activation of NF-kappaB, atheroprone shear stress creates a positive feedback to maintain inflammation.

Circ Res: 09 Apr 2010; epub ahead of print

Mechanical Regulation of Cardiac Aging in Model Systems.

Sessions AO, Engler AJ
Unlike diet and exercise, which individuals can modulate according to their lifestyle, aging is unavoidable. With normal or healthy aging, the heart undergoes extensive vascular, cellular, and interstitial molecular changes that result in stiffer less compliant hearts that experience a general decline in organ function. Although these molecular changes deemed cardiac remodeling were once thought to be concomitant with advanced cardiovascular disease, they can be found in patients without manifestation of clinical disease. It is now mostly acknowledged that these age-related mechanical changes confer vulnerability of the heart to cardiovascular stresses associated with disease, such as hypertension and atherosclerosis. However, recent studies have aimed at differentiating the initial compensatory changes that occur within the heart with age to maintain contractile function from the maladaptive responses associated with disease. This work has identified new targets to improve cardiac function during aging. Spanning invertebrate to vertebrate models, we use this review to delineate some hallmarks of physiological versus pathological remodeling that occur in the cardiomyocyte and its microenvironment, focusing especially on the mechanical changes that occur within the sarcomere, intercalated disc, costamere, and extracellular matrix.

Circ Res: 12 May 2016; 118:1553-62