Determinants, Trajectories, and Consequences of Abnormal Cardiac Mechanics

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Heart failure (HF), regardless of the underlying ejection fraction (EF), is a major public health problem. The study of the acquired and genetic risk factors for abnormal cardiac mechanics (indices such as Lagrangian strain and tissue velocities) can provide important insights into the pathogenesis of HF syndromes in patients with both preserved and reduced EF (HFpEF and HFrEF, respectively). Abnormalities in both systolic and diastolic cardiac mechanics are present in virtually all patients with HF, regardless of EF. Systole and diastole are closely intertwined, with continual calcium (Ca2+) cycling within cardiomyocytes. Improved understanding of the factors that disrupt normal cardiomyocyte Ca2+ cycling is therefore essential. Speckle-tracking echocardiography has revolutionized the quantitation of cardiac mechanics because it can detect subclinical abnormalities in myocardial function at the earliest stages of disease development, when cardiomyocyte Ca2+ homeostasis first becomes disrupted. Furthermore, indices of cardiac mechanics ascertained by speckle- tracking are heritable traits that appear to map to genetic loci. Thus, speckle-tracking echo provides a unique window into HF development. Despite considerable progress in the understanding of risk factors for abnormal cardiac mechanics, several unanswered questions related to cardiac mechanics and HF remain: (1) What are the risk factors for decline in cardiac mechanics over time? (2) Are abnormal cardiac mechanics independently associated with incident HF? (3) Can whole exome sequencing provide evidence for novel genetic loci that influence cardiac mechanics? and (4) Can induced pluripotent stem cell (iPS)-derived cardiomyocytes provide biologic insight into whole-heart mechanics? The overall goal of the proposed studies is to leverage a unique ability to digitize and speckle-track archived echos from epidemiologic studies with the goal of further understanding determinants, trajectories, and consequences of abnormal cardiac mechanics. Quantification of cardiac mechanics in (1) the Cardiovascular Health Study (CHS) (n=5,888), which has extensive baseline and longitudinal data, including serial echos and 1,962 incident HF events during follow-up; and (2) the HyperGEN Cardiomyocyte iPS (CiPS) study (n=250) will allow for the completion of the following aims: (1) Determine the association of risk factor patterns with decline in cardiac mechanics over time; (2) Determine the association of cardiac mechanics with incident HF (particularly HFpEF); (3) Examine the association between whole exome data and cardiac mechanics, and validate these findings with gene expression profiling in iPS-derived cardiomyocytes; and (4) Correlate abnormalities in whole-heart mechanics with Ca2+ transients in iPS-derived cardiomyocytes. The proposed studies will have a lasting impact on the field of HF by demonstrating the importance of cardiac mechanics in HF pathogenesis; elucidating novel mechanisms underlying abnormal cardiac mechanics; and providing a personalized window (iPS cardiomyocytes) into whole heart mechanics, which could accelerate drug discovery and result in precision medicine for the prevention of HF.