Cardiac regulatory mechanisms

Heart failure is a systemic disease in which neuroendocrine activation, inflammation and metabolic changes can impair cardiac function. In addition, variants in genes encoding sarcomeric proteins can predispose individuals to develop heart failure. The 2022 Gordon Research Conference on Cardiac Regulatory Mechanisms aims to identify novel treatment targets by applying high-resolution approaches to complex cardiac disorders.

Variants in genes encoding sarcomeric proteins can cause hypertrophic or dilated cardiomyopathy. In this Review, the authors discuss therapeutic strategies to target the cardiac sarcomere, focusing on four small molecules that have been developed that inhibit or activate the myosin motor protein to decrease or increase contractile force, respectively.

The microtubule network of cardiomyocytes has unique architectural and biophysical features. In this Review, Caporizzo and Prosser discuss the contribution of microtubules to cardiac mechanics, the drivers of microtubule network remodelling in heart failure and the therapeutic potential of targeting cardiac microtubules in acquired heart diseases.

In this Review, the authors summarize the latest advances in cardioimmunology and discuss experimental tools and strategies that are currently available for the study of immune cells, guiding readers through case-based examples to provide recommendations for the use of immunological tools and strategies in the study of immune cells in cardiac disease.

The autonomic nervous system profoundly affects the function of the cardiovascular and immune systems. In this Review, Carnevale summarizes how the neural regulation of immunity and inflammation participates in the onset and progression of cardiovascular disease and explores promising opportunities for therapeutic strategies.

In this Review, the authors explore metabolic dysregulation as an important theme in cardio-oncology. They discuss metabolic reprogramming in cardiovascular disease and cancer and the possibility that therapeutically targeting metabolic and immunometabolic changes in patients with cancer might also reduce their risk of cardiovascular disease.

Paradigm-shifting studies have revealed that the heart contains heterogeneous and dynamic immune and stromal cell populations that are crucial determinants of health and disease. Advances in molecular imaging now make it possible to non-invasively visualize the cardiac cellular landscape in humans, providing a means to guide precision therapies.

Dietary supplementation with NAD⁺ precursors or ketone esters has been shown to improve mitochondrial function in preclinical models of heart failure with either reduced or preserved ejection fraction. Both supplementation approaches hold promise but are in the early stages of development as clinical therapies for heart failure.

In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and disease progression. In this Review, Bertero and Maack describe the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus, and discuss promising treatments targeting substrate utilization or oxidative stress in mitochondria.

In this Review, Foo and colleagues summarize the benchmark studies that have mapped the role of enhancers in cardiac disease and development, highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis and consider how enhancer targeting might soon be developed for heart disease.

Mutations in genes that encode components of desmosomes are the predominant cause of arrhythmogenic cardiomyopathy, a genetic disorder characterized by fibrofatty replacement of myocardial tissue and the risk of life-threatening arrhythmias. In this Review, the authors discuss the molecular mechanisms underlying the pathogenesis of this condition.

Activated cardiac fibroblasts in adult hearts participate in the healing response after acute myocardial infarction and during chronic disease states. In this Review, Tallquist and Molkentin discuss insights gained from the use of genetically engineered mice that allow a systematic evaluation of fibroblast identity, origins, and response during cardiac disease and ventricular remodelling.