Calcium cycling proteins and heart failure: mechanisms and therapeutics

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Abstract

Ca²⁺-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca²⁺ cycling refers to the release and reuptake of intracellular Ca²⁺ that drives muscle contraction and relaxation. In failing hearts, Ca²⁺ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca²⁺ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca²⁺ storage organelle in muscle. Defects in the regulation of Ca²⁺ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/Ca²⁺ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in “leaky” channels in failing hearts. These leaky RyR2s contribute to depletion of Ca²⁺ from the SR, and the leaking Ca²⁺ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca²⁺ reuptake that conspires with leaky RyR2 to deplete SR Ca²⁺. Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca²⁺-release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca²⁺ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca²⁺ cycling in the heart.

Authors

Andrew R. Marks

Cardiovascular science: opportunities for translating research into improved care

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Abstract

Cardiovascular research is progressing on many fronts, as highlighted in the collection of Reviews in this issue of the JCI. MicroRNAs that regulate cardiac function have been implicated in cardiac disorders, and efforts to develop therapeutic antagomirs are underway. The genetic bases of several cardiac disorders, including cardiomyopathies that cause heart failure and channelopathies that underlie cardiac arrhythmias, have been elucidated. Genetic testing can identify asymptomatic individuals at risk, potentially leading to effective preventative measures. Growing evidence supports the role of chronic inflammation in atherosclerosis, providing new opportunities for therapeutic intervention. For heart failure, recent work suggests that cardiac regeneration using stem/progenitor cells, gene transfer, new drugs that restore normal Ca²⁺ cycling, and agents that reduce reperfusion injury following myocardial infarction are all viable new approaches to managing disease. Cumulatively, it seems likely that the clinical advances emerging from ongoing research will, in the foreseeable future, reduce the number of deaths in the industrialized world from cardiovascular disease.

Authors

Eugene Braunwald

Genetic mutations and mechanisms in dilated cardiomyopathy

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Abstract

Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.

Authors

Elizabeth M. McNally, Jessica R. Golbus, Megan J. Puckelwartz

Molecular and genetic basis of sudden cardiac death

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Abstract

The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

Authors

Alfred L. George Jr.

Regenerating new heart with stem cells

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Abstract

This article discusses current understanding of myocardial biology, emphasizing the regeneration potential of the adult human heart and the mechanisms involved. In the last decade, a novel conceptual view has emerged. The heart is no longer considered a postmitotic organ, but is viewed as a self-renewing organ characterized by a resident stem cell compartment responsible for tissue homeostasis and cardiac repair following injury. Additionally, HSCs possess the ability to transdifferentiate and acquire the cardiomyocyte, vascular endothelial, and smooth muscle cell lineages. Both cardiac and hematopoietic stem cells may be used therapeutically in an attempt to reverse the devastating consequences of chronic heart failure of ischemic and nonischemic origin.

Authors

Piero Anversa, Jan Kajstura, Marcello Rota, Annarosa Leri

Potential of gene therapy as a treatment for heart failure

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Abstract

Advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, make gene-based therapy a promising treatment option for heart conditions. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design, and delivery modalities. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Advances in understanding of the molecular basis of myocardial dysfunction, together with the development of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the cardiac sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase pump (SERCA2a) has the potential to open a new era for gene therapy for heart failure.

Authors

Roger J. Hajjar

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

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Abstract

The discovery of the genetic basis of inherited arrhythmias has paved the way for an improved understanding of arrhythmogenesis in a wide spectrum of life-threatening conditions. In vitro expression of mutations and transgenic animal models have been instrumental in enhancing this understanding, but the applicability of results to the human heart remains unknown. The ability to differentiate induced pluripotent stem cells (iPSs) into cardiomyocytes enables the potential to generate patient-specific myocytes, which could be used to recapitulate the features of inherited arrhythmias in the context of the patient’s genetic background. Few studies have been reported on iPS-derived myocytes obtained from patients with heritable arrhythmias, but they have demonstrated the applicability of this innovative approach to the study of inherited arrhythmias. Here we review the results achieved by iPS investigations in arrhythmogenic syndromes and discuss the existing challenges to be addressed before the use of iPS-derived myocytes can become a part of personalized management of inherited arrhythmias.

Authors

Silvia G. Priori, Carlo Napolitano, Elisa Di Pasquale, Gianluigi Condorelli

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

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Abstract

Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

Authors

Andrew H. Lichtman, Christoph J. Binder, Sotirios Tsimikas, Joseph L. Witztum

S-nitrosylation: integrator of cardiovascular performance and oxygen delivery

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Abstract

Delivery of oxygen to tissues is the primary function of the cardiovascular system. NO, a gasotransmitter that signals predominantly through protein S-nitrosylation to form S-nitrosothiols (SNOs) in target proteins, operates coordinately with oxygen in mammalian cellular systems. From this perspective, SNO-based signaling may have evolved as a major transducer of the cellular oxygen-sensing machinery that underlies global cardiovascular function. Here we review mechanisms that regulate S-nitrosylation in the context of its essential role in “systems-level” control of oxygen sensing, delivery, and utilization in the cardiovascular system, and we highlight examples of aberrant S-nitrosylation that may lead to altered oxygen homeostasis in cardiovascular diseases. Thus, through a bird’s-eye view of S-nitrosylation in the cardiovascular system, we provide a conceptual framework that may be broadly applicable to the functioning of other cellular systems and physiological processes and that illuminates new therapeutic promise in cardiovascular medicine.

Authors

Saptarsi M. Haldar, Jonathan S. Stamler

Molecular pathogenesis of pulmonary arterial hypertension

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Abstract

Recent clinical and experimental studies are redefining the cellular and molecular bases of pulmonary arterial hypertension (PAH). The genetic abnormalities first identified in association with the idiopathic form of PAH — together with a vast increase in our understanding of cell signaling, cell transformation, and cell-cell interactions; gene expression; microRNA processing; and mitochondrial and ion channel function — have helped explain the abnormal response of vascular cells to injury. Experimental and clinical studies now converge on the intersection and interactions between a genetic predisposition involving the BMPR2 signaling pathway and an impaired metabolic and chronic inflammatory state in the vessel wall. These deranged processes culminate in an exuberant proliferative response that occludes the pulmonary arterial (PA) lumen and obliterates the most distal intraacinar vessels. Here, we describe emerging therapies based on preclinical studies that address these converging pathways.

Authors

Marlene Rabinovitch