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Transition from Risk Factors to Early HF: Prevalence, Pathogenesis, and Phenomics

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? DESCRIPTION (provided by applicant): Heart failure (HF) is a major public health problem: it affects >6 million people in the U.S., it is the #1 cause of hospitalization and readmission in older adults, and 5-year survival after HF hospitalization is a dismal 35%, regardless of underlying ejection fraction (EF). These statistics highlight the urgent need for prevention of HF and better understanding of how and why HF develops in high-risk individuals. However, a critical limitation of prior population-based studies is the ascertainment of incident HF based on hospitalizations for HF and/or signs of overt volume overload. Many older individuals may suffer from early HF: breathlessness, fatigue, and exercise intolerance (without overt volume overload) due to underlying cardiac structure/function abnormalities, typically with a preserved EF (i.e. early HFpEF). Thus, the current epidemiology of HF is most likely missing a major form of prevalent HF. In this ancillary study of the Multi-Ethnic Study of Atherosclerosis (MESA, Year-15 Exam, n=3500), we will define early HF in a contemporary, multi-ethnic, elderly cohort; we will utilize cutting- edge indices of cardiac mechanics and ventricular-arterial interactions, including Lagrangian strain and time- varying pressure-stress analyses; and we will perform novel phenomics analyses to better characterize the interplay of risk factors and cardiac structure/function abnormalities (i.e., multi-dimensional phenotypic signatures) as they relate to early and overt HF. The aims of our study are to: (1) determine the prevalence of early HF using a combination of validated symptom surveys, 6-minute walk test, NTproBNP, and echocardiography, with validation using cardiopulmonary exercise testing (CPEX); (2) better understand the pathophysiology of early HF, particularly HFpEF; and (3) delineate the key phenotypic signatures associated with early and overt HF. The proposed exam will include anthropometry, blood pressure, symptom surveys, functional status (6-minute walk test), physical activity, laboratory measures (NTproBNP, fasting glucose, renal function), and comprehensive echocardiography (with tissue Doppler and speckle-tracking at rest and during physiologic maneuvers) in all participants. In sub-samples we will also measure arterial tonometry, novel biomarkers, and fitness (CPEX). We will utilize the wealth of data collected during the 5 prior MESA exams to perform longitudinal analyses (including latent class trajectory and statistical learning analyses) to determine the extent to which risk factors are associated with early HF, particularly early HFpEF. By the end of our 4-year study, we will accomplish the following key goals, each of which will have a lasting impact on the field of HF: (1) we will establish the prevalence of early HF in the community; (2) we will have a standardized method for the screening/diagnosis of early HFpEF, validated by CPEX, and readily applicable to the clinical setting; (3) we will define novel mechanisms by which risk factors, alone and in combination, relate to abnormalities in cardiac mechanics and ventricular-arterial coupling in the general population; and (4) we will have defined phenotypic signatures of HF development that will inform future clinical trials for HF prevention and treatment.
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