Coronary Vasculature and Myocardial Structure in HIV: Physiologic Insights From the Renin-Angiotensin-Aldosterone System

Abstract

The landscape of HIV medicine dramatically changed with the advent of contemporary antiretroviral therapies, which has allowed persons with HIV (PWH) to achieve good virologic control, essentially eliminating HIV-related complications and increasing life expectancy. As PWH are living longer, noncommunicable diseases, such as cardiovascular disease (CVD), have become a leading cause of morbidity and mortality in PWH with rates that are 50% to 100% higher than in well-matched persons without HIV. In this review, we focus on disease of the coronary microvasculature and myocardium in HIV. We highlight a key hormonal system important to cardiovascular endocrinology, the renin-angiotensin-aldosterone system (RAAS), as a potential mediator of inflammatory driven-vascular and myocardial injury and consider RAAS blockade as a physiologically targeted strategy to reduce CVD in HIV.

Keywords: HIV; coronary flow reserve; eplerenone; myocardial dysfunction; renin-angiotensin-aldosterone system; sacubitril/valsartan.

Figure 1.

Representative myocardial tissue sections stained with hematoxylin and eosin from (A) a mouse treated with Ang II/L-NAME and (B) a control mouse. Ang II/L-NAME-treated mice show areas of organizing myocardial necrosis with granulation tissue. Representative micrographs of a coronary artery section stained with hematoxylin and eosin from (C) a mouse treated with Ang II/L-NAME and (D) a control mouse. Coronary arteries from the Ang II/L-NAME-treated mouse show fibrinoid necrosis of the vessel wall with intimal thickening, a mixed inflammatory response. Effect of spironolactone on (E) myocardial damage and (F) vascular injury in mice treated with Ang II/L-NAME, Ang II/L-NAME/spironolactone (50 mg·100 g⁻¹ day⁻¹), or control group. *P < 0.05, **P < 0.005 vs control. Adapted from Oestreicher et al (30).

Figure 2.

Comparison of RAAS parameters (A) urinary aldosterone excretion (mcg/24 h), (B) serum aldosterone (ng/dL), and (C) plasma renin activity (ng/mL/h) during the low-sodium diet (simulating RAAS activation) among persons with HIV with low VAT vs high VAT. Adapted from Srinivasa et al (36) with permission from the Endocrine Society.

Figure 3.

Left figure: Study of RAAS activation. Comparison of the serum aldosterone (ng/dL) and MCP-1 (pg/mL), marker of immune activation during ad libitum and low-sodium diets in persons with (A and C) and persons without (B and D) HIV. Box plot represents the 25th and 75th percentiles, and lines within the boxes represents medians. Adapted from Srinivasa et al (44). Right figure: Study of RAAS blockade. Absolute between-group change of MCP-1 (pg/mL) after 6 months treatment of eplerenone vs placebo among PWH. Adapted from Srinivasa et al (82) with permission from the Endocrine Society.

Figure 4.

Hypothesized mechanisms and potential treatment targets of RAAS-mediated cardiovascular disease in HIV. Potential mediators of RAAS dysfunction may include direct viral effects, antiretroviral therapy effects, or the adipose depot. Increased RAAS activation activates the mineralocorticoid receptor, which may potentiate metabolic dysregulation, increased inflammation, and immune activation. Adverse cardiovascular sequalae of metabolic disease and inflammation may include coronary microvascular and myocardial dysfunction. US Food and Drug Administration–approved medications acting along the RAAS pathway, such as ACEi, ARB, and mineralocorticoid receptor blockers, are physiologically based treatment targets, which may be useful for CVD risk reduction based on strong data that RAAS blockade may reduce BP, decrease inflammation, and improve metabolic indices in PWH.