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Principal Investigator: Suman Srinivasa
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $840,829
Funding agency: National Heart Lung and Blood Institute
Project Summary: Heart disease is a leading cause of non-communicable disease-related morbidity and
mortality in the well-treated HIV population, and heart failure with preserved ejection fraction (HFpEF) is rising
in prevalence. There are no FDA-approved therapeutics directed at HFpEF that effectively reduce morbidity
and mortality in HIV or the general population, which highlights an expanding population of patients with a
significant unmet clinical need. Early changes in myocardial structure and function are well-recognized among
asymptomatic persons with HIV (PWH), affecting 50-60% of the population. The exact mechanism precipitating
antecedent myocardial dysfunction, related to altered relaxation and increased stiffness and filling pressures of
the left ventricle, and subsequent progression to symptomatic HFpEF in HIV is unclear. Myocardial
inflammation and fibrosis are postulated to be substantial mediators of HFpEF and are mechanistically relevant
among PWH whom demonstrate chronic systemic inflammation and immune activation and metabolic disease
regardless of immunological control. Rigorous hormonal testing from our group among PWH show increased
renin-angiotensin-aldosterone system (RAAS) activation is relation to reduced natriuretic peptide (NP) and
increased inflammation and monocyte/macrophage activation. NPs have cardioprotective effects, and relatively
reduced NPs could impair activities related to natriuresis, vasodilation, myocyte hypertrophy, and fibroblast
proliferation, altering stability of the myocardium. We further postulate relatively reduced NP, a phenotype
shown in highly metabolic groups and now demonstrated for the first time in HIV, may allow permissive RAAS
activation leading to downstream inflammation and myocardial damage. We aim to investigate the cardiac
phenotype associated with reduced NP among PWH compared to uninfected individuals utilizing advanced CV
imaging techniques (cardiac MRI, cardiac TTE) and circulating myocardial biomarkers to comprehensively
assess myocardial inflammation, structure, and function. This novel proposal represents a substantial
departure from the typically well-studied HF patients with relatively higher NP and may uncover a large class of
newly-identified inflammatory-prone or metabolically-deranged patients deserving of more clinical attention in
the HF realm. We will also determine the effect of sacubitril/valsartan, a dual angiotensin II receptor antagonist
and neprilysin inhibitor, vs. placebo on longitudinal changes in myocardial inflammation, structure and function
among PWH in a 6-month randomized controlled trial. These studies apply a novel concept in studying PWH,
among whom we postulate a therapy to simultaneously increase NP and decrease RAAS activation may be
beneficial for heart disease based on unique RAAS-NP physiology in HIV. These studies led by an early stage
investigator and team of experts in HIV-associated CVD, CV imaging, HFpEF phenotyping, CV biomarker
science, and CV endocrinology will provide key insight on two neurohormonal systems critical to CV health,
RAAS-NP, and test whether targeted manipulation of these systems can reduce subclinical HFpEF risk in HIV.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Aldosterone><Angiotensin II Receptor><Angiotensin Receptor><Atrial><Attention><BNP Gene Product><BNP-32><Biological Markers><Blood Vessels><Blood monocyte><Brain Natriuretic Peptide-32><Brain natriuretic peptide><CD10 Antigens><Cardiac><Cardiac Atrium><Cardiac Diseases><Cardiac Disorders><Cardiomyopathies><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Chronic><Chronic Disease><Chronic Illness><Clinical><Coupled><Data><Deposit><Deposition><Development><Disease><Disorder><Dysfunction><EFRAC><Echocardiogram><Echocardiography><Ejection Fraction><Endocrine Gland Secretion><Endocrinology><Enkephalinase><FDA approved><Failure><Fats><Fatty acid glycerol esters><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Functional disorder><GDF15><GDF15 gene><General Population><General Public><Groups at risk><HIV><Health><Heart><Heart Atrium><Heart Diseases><Heart Vascular><Heart failure><Hormonal><Hormones><Human Immunodeficiency Viruses><Hypertrophy><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune Cell Activation><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impairment><Individual><Inflammation><Inflammatory><Insulin Resistance><Investigators><Knowledge><LAV-HTLV-III><LVEF><Left><Left Ventricles><Left Ventricular Ejection Fraction><Left Ventricular Hypertrophy><Left ventricular structure><Link><Liver><Lymphadenopathy-Associated Virus><MIC-1 gene product><MIC1><Macrophage Activation><Macrophage Inhibitory Cytokine-1><Marrow monocyte><Measures><Mediator><Membrane Metalloendopeptidase><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolism and Endocrinology><Morbidity><Morbidity - disease rate><Muscle Cells><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial depression><Myocardial dysfunction><Myocardiopathies><Myocardium><Myocytes><NAG-1 protein><NAG1><NSAID activated gene-1 product><NSAID-Activated Protein 1><NSAID-Regulated Protein 1><Natriuresis><Natriuretic Factor-32><Natriuretic Peptide Hormones><Natriuretic Peptides><Neprilysin><Nesiritide><Neutral Endopeptidase><Nonsteroidal Anti-Inflammatory Drug-Activated Protein 1><PLAB><PLAB Protein><PTGF-Beta><Patients><People at risk><Persons><Persons at risk><Phenotype><Physiologic><Physiological><Physiology><Physiopathology><Placebos><Placental Bone Morphogenic Protein><Placental TGF-Beta><Population><Populations at Risk><Prevalence><Proliferating><Prostate Differentiation Factor><Public Health><Randomized, Controlled Trials><Relaxation><Renin-Angiotensin-Aldosterone System><Research Personnel><Researchers><Risk><Science><Sham Treatment><Structure><System><TIMP-1><Testing><Therapeutic><Therapeutic Hormone><Thesaurismosis><Time><Tissue Inhibitor of Metalloproteinase-1><Transthoracic Echocardiography><Type-B Natriuretic Peptide><Vasodilatation><Vasodilation><Vasorelaxation><Ventricle Remodeling><Ventricular Cardiac Remodeling><Ventricular Myocardial Remodeling><Ventricular Remodeling><Virus-HIV><Visceral><antagonism><antagonist><atrium><bio-markers><biologic marker><biomarker><brain Natriuretic factor><cardiac MRI><cardiac disease risk><cardiac disorder risk><cardiac dysfunction><cardiac failure><cardiac fibrosis><cardiac function><cardiac magnetic resonance imaging><cardiac muscle><cardiometabolic><cardiometabolism><cardioprotectant><cardioprotection><cardioprotective><cardiovascular health><chronic disorder><circulatory system><coronary fibrosis><developmental><disease model><disorder model><extracellular><fibrotic heart><function of the heart><growth differentiation factor 15><heart disease risk><heart disorder><heart disorder risk><heart dysfunction><heart fibrosis><heart function><heart muscle><heart sonography><hepatic body system><hepatic organ system><imaging><immune activation><improved><indexing><inhibitor><injury to tissue><insight><insulin resistant><insulin tolerance><metabolism disorder><monocyte><mortality><myocardial damage><myocardial fibrosis><myocardial remodeling><myocardium disease><myocardium disorder><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><patient population><permissiveness><pharmacologic><preservation><pressure><randomized control trial><sham therapy><sudden cardiac death><systemic inflammation><systemic inflammatory response><tissue injury><treatment strategy><valsartan><vascular>