Mapping the Progression to HFpEF in the Elderly through Longitudinal Changes in Cardiac Function

通过心功能的纵向变化绘制老年人 HFpEF 的进展情况

• 批准号: 9383642
• 负责人: Amil M Shah
• 金额: $ 88.84万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383642
• 关键词: Accounting; Activities of Daily Living; Address; Affect; Age; Anemia; Atherosclerosis Risk in Communities; Atrial Fibrillation; Biological Markers; Biological Preservation; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiovascular system; Characteristics; Clinical; Clinical assessments; Communities; Comorbidity; Coronary heart disease; Cyclic GMP; Data; Databases; Depressed mood; Development; Diabetes Mellitus; EFRAC; Echocardiography; Elderly; Epidemiology; Fibrosis; Functional disorder; Funding; Future; Genes; Goals; Guidelines; Heart; Heart failure; Hospitalization; Hypertension; Hypertrophy; Image; Impairment; Incidence; Inflammation; Inflammatory; Intervention Studies; Kidney; Knowledge; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Life; Link; Lung; Measures; Mediating; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Natriuretic Peptides; Nitric Oxide; Obesity; Outcome; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Physical activity; Plasma; Population; Positioning Attribute; Prevention; Preventive Intervention; Pump; Resources; Risk; Risk Behaviors; Risk Factors; Role; Sampling; Structure; Symptoms; Techniques; Time; Tissues; Translating; Ultrasonography; Visit; Walking; Weight; age related; biomarker panel; biracial; blood-based biomarker; cardiogenesis; cardiovascular visualization; clinical predictors; cohort; cost; defined contribution; effective intervention; effective therapy; follow-up; genetic variant; glycemic control; heart function; high risk; human data; hypertensive heart disease; innovation; mortality; novel; physical inactivity; pressure; prevent; prospective

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 76±5 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 ~82±5 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) 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 76±5 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 ~82±5 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.