Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular (LV) ejection fraction (HFpEF), for which no efficacious therapies exist. We will employ rigorous epidemiologic approaches and serial state-of-the-art cardiac imaging to tackle the critical knowledge gaps enumerated by ACC/AHA & ESC HF guidelines regarding HF in the very elderly, the pathophysiology of HFpEF, and strategies to prevent HF. We will leverage the comprehensive echo data from the Atherosclerosis Risk in Communities (ARIC) study Visit 5 (2011-2013, age 765 years) and conduct an ancillary to the funded Visit 7 (2018-2019), when participants will be ?75 years old. Few data exist regarding longitudinal changes in cardiac function during this period of life when HF incidence is greatest. Performing new follow-up echos in ~3,900 participants at Visit 7 (age ~825 years) is a unique opportunity to evaluate longitudinal changes over 6 years in novel sensitive measures of LV function (strain, tissue Doppler, pressure-volume analysis) not available serially in previous studies. Integrating this with new and planned pathway biomarkers and clinical assessments (including 2 minute walk distance and HF symptoms) and existing outcomes surveillance uniquely positions us to interrogate a novel, promising, and modifiable biologic pathway underlying HFpEF that involves inflammation, nitric oxide (NO) depletion, and altered cGMP activity. While recent translational data suggest an important role in myocyte stiffness, hypertrophy, and fibrosis, little human data exist from broader samples linking this pathway to progressive LV dysfunction and HFpEF. Our central hypothesis is that cardiovascular (hypertension, coronary disease, atrial fibrillation), non-cardiac (diabetes, obesity, renal dysfunction), and non-traditional (pulmonary dysfunction, anemia, physical inactivity) HF risk factors activate inflammatory pathways, promoting progressive diastolic and systolic dysfunction via depressed cGMP, ultimately resulting in HF. We specifically aim to: (1) prospectively determine the clinical predictors of longitudinal worsening of LV function in the elderly; (2) relate inflammatory pathways and natriuretic peptides known to influence cGMP activity to longitudinal changes in LV function; (3) determine the extent to which worsening LV function, related to these pathway biomarkers, predicts incident HF in the very elderly. Our approach is innovative by interrogating non-traditional HF risk factors, longitudinal changes in advanced echo measures of LV function, and novel biologic pathways to understand the progression to HFpEF in an understudied population: the very elderly. This proposal is significant because it will allow us to identify very elderly persons at high risk of progressive LV dysfunction and incident HFpEF, and determine the importance of a promising biologic pathway targeted by several existing agents that could translate rapidly into preventative interventions. This is therefore a critical step towards intervening to prevent HF in the very elderly, and the associated morbidity, mortality, and cost.
Heart failure (HF) without gross weakening of the heart pump (HF with preserved ejection fraction; HFpEF) is common in the elderly, causes substantial morbidity and mortality, and has no effective treatment. This project will quantify changes in heart function over time in a diverse elderly cohort using novel sensitive cardiac ultrasound techniques, and will relate these changes to clinical characteristics, blood-based biomarkers, and risk of incident HF to understand how and why elderly persons develop HFpEF. This is a critical step towards developing strategies to prevent HF and its associated morbidity, mortality, and cost.
| Fernandes-Silva, Miguel M; Shah, Amil M; Claggett, Brian et al. (2018) Adiposity, body composition and ventricular-arterial stiffness in the elderly: the Atherosclerosis Risk in Communities Study. Eur J Heart Fail 20:1191-1201 |
| Nadruz Jr, Wilson; Claggett, Brian; Henglin, Mir et al. (2018) Widening Racial Differences in Risks for Coronary Heart Disease. Circulation 137:1195-1197 |
| Silvestre, Odilson M; Nadruz Jr, Wilson; Querejeta Roca, Gabriela et al. (2018) Declining Lung Function and Cardiovascular Risk: The ARIC Study. J Am Coll Cardiol 72:1109-1122 |
