Mechanisms of Cardiac Dysfunction in HIV and the Effect of Statins

Abstract: Contemporary cohorts of people living with HIV (PLWH) have a ~ 2.5-fold increased relative risk of heart failure versus matched controls. The predominant type of heart failure among PLWH is heart failure with a preserved ejection fraction (HFpEF). This type of heart failure is typically preceded by diastolic dysfunction, a condition in which the left ventricle of the heart stiffens, resulting in delayed relaxation and increased filling pressures. Among PLWH, the prevalence of diastolic dysfunction is strikingly high: 43%. Once diastolic dysfunction has progressed to overt HFpEF, no good therapeutic options exist. Thus, strong imperatives exist to test rational, safe strategies which may preserve diastolic function and prevent progression to overt heart failure among aging PLWH on ART. There are two key processes which likely contribute to the development of diastolic dysfunction in HIV. The first is myocardial fibrosis, a condition in which excess collagen is deposited in the myocardial structural space. The second is myocardial steatosis, a condition in which triglycerides are ectopically deposited within cardiomyocytes. Myocardial fibrosis and myocardial steatosis are both increased among PLWH, in relation to diastolic dysfunction. We postulate that PLWH without overt heart failure, statin therapy will reduce the progression of myocardial fibrosis and myocardial steatosis, preserving cardiac function. Our primary hypothesis is that statin effects to dampen systemic immune activation and inflammation will translate to reduced in situ myocardial inflammation and, in turn, reduced myocardial fibrosis. We will also test an alternate hypothesis that statin effects to improve lipid metabolism will result in reduced ectopic fat deposition in the heart. Cardiac magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) represents a gold-standard approach with which to test our hypotheses. We propose an observational cardiac MRI/MRS-based study, CARDIAC-MR, integrated with an ongoing randomized trial of pitavastatin vs. placebo (REPRIEVE). From 8 REPRIEVE sites, we will co-enroll 130 PLWH aged 40-75 without known heart failure. Outside of REPRIEVE, we will orchestrate additional study visits at entry and 24 months. At these visits, participants will undergo cardiac MRI/MRS, as well as targeted metabolic and immune phenotyping. Our work will answer scientific questions relevant to heart failure prevention in HIV which will not otherwise be addressed in REPRIEVE. If we confirm our hypothesis that statins forestall progression of myocardial fibrosis and/or fat among PLWH, we will have found the first effective strategy to preserve cardiac function in HIV. Even in the case of null statin effects on fibrosis/fat, our baseline characterization of pathologic pathways predisposing to cardiac dysfunction will help identify future targeted strategies geared toward heart failure prevention in HIV. Given that heart failure is a highly morbid, age-related comorbidity to which PLWH are particularly vulnerable, our work will have significant clinical implications to improve the lives of at-risk individuals aging with HIV.

Project Number: 1R01HL137562-01A1