https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61889-4.pdf

The war against heart failure: the Lancet lecture

Despite declines in heart failure morbidity and mortality with current therapies, rehospitalization rates remain distressingly high, substantially affecting individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. Because these events are highly interrelated, targeting a single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling.

Pathological Ventricular Remodeling Mechanisms: Part 1 of 2

Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

/pdf/expert-consensus-document-mitochondrial-function-as-a-59a2a3971g.pdf

Expert consensus document: Mitochondrial function as a therapeutic target in heart failure

Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

https://science.sciencemag.org/content/sci/351/6273/617.full.pdf

A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice

J-STAGE Advance Publication released online September 10, 2019 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: meeting@j-circ.or.jp This English language document is a revised digest version of Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure (JCS 2017/JHFS 2017) reported at the Japanese Circulation Society Joint Working Groups performed in 2017 (Website: http://www.j-circ.or.jp/guideline/pdf/JCS2017_tsutsui_d.pdf). Joint Working Groups: The Japanese Circulation Society; the Japanese Heart Failure Society; the Japanese Association for Thoracic Surgery; the Japanese Society of Hypertension; the Japanese Society of Echocardiography; the Japanese Society for Cardiovascular Surgery; the Japanese College of Cardiology; the Japanese Association of Cardiac Rehabilitation; the Japan Society of Ultrasonics in Medicine; the Japan Diabetes Society; the Japanese Heart Rhythm Society; “the Study Group on Idiopathic Cardiomyopathy” supported by the Health and Labor Sciences Research Grant on Intractable Diseases; and “the Study Group on the Multi-center Observational Study of Dilatedphase Hypertrophic Cardiomyopathy”, supported by the “Practical Research Project for Rare/ intractable Diseases by the Japan Agency for Medical Research and Development”. ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure ― Digest Version ―

/pdf/jcs-2017-jhfs-2017-guideline-on-diagnosis-and-treatment-of-2ndrq4hiod.pdf

JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure ― Digest Version ―

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

/pdf/cardiac-myosin-activation-a-potential-therapeutic-approach-4quxm43glb.pdf

Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure

High‐throughput, image‐based cell assays are rapidly emerging as valuable tools for the pharmaceutical industry and academic laboratories for use in both drug discovery and basic cell biology research. Access to commercially available assay reagents and automated microscope systems has made it relatively straightforward for a laboratory to begin running assays and collecting image‐based cell assay data, but doing so on a large scale can be more challenging. Challenges include process bottlenecks with sample preparation, image acquisition, and data analysis as well as day‐to‐day assay consistency, managing unprecedented quantities of image data, and fully extracting useful information from the primary assay data. This chapter considers many of the decisions needed to build a robust infrastructure that addresses these challenges. Infrastructure components described include integrated laboratory automation systems for sample preparation and imaging, as well as an informatics infrastructure for multilevel image and data analysis. Throughout the chapter we describe a variety of strategies that emphasize building processes that are scaleable, highly efficient, and rigorously quality controlled.

An infrastructure for high-throughput microscopy: instrumentation, informatics, and integration.

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Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure

An infrastructure for high-throughput microscopy: instrumentation, informatics, and integration.