HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

Abstract

HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015–March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-β1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions.

Do platelets LINE up for aging?

“…Furthermore, eRT in platelets also serves as a novel mechanism of translational control through the formation of RNA-DNA hybrids. Our findings also support published studies of platelets in HIV, where PLHWA have, in general, evidence of increased platelet activation, mitochondrial stress, and reactive oxygenation species generation [2,3].…”

“…Platelets secrete pleiotropic immune and inflammatory mediators that orchestrate heterotypic interactions with endothelial cells, monocytes, neutrophils, and other cells [8]. While still incompletely understood, platelet activation in PLWHA on ART may contribute to premature senescence and an increased cardiovascular risk [2]. Our report [1] adds another facet to this intriguing interplay, demonstrating that platelets possess eRT that functionally serves to regulate platelet activation and protein synthesis.…”

Short Communication: Comparison of Calculated Low-Density Lipoprotein Cholesterol (LDL-C) Values in HIV-Infected and HIV-Uninfected Men Using the Traditional Friedewald and the Novel Martin–Hopkins LDL-C Equations

“…C ompared with uninfected persons, people with HIV (PWH) are 1.5-2 times more likely to develop atherosclerotic cardiovascular disease (ASCVD) and to do so at a younger age. [1][2][3] This increased risk is due to traditional risk factors (e.g., hypertension, diabetes, smoking, and dyslipidemia), but also due to factors related to HIV infection and antiretroviral therapy (ART). 3 Low-density lipoprotein cholesterol (LDL-C) is the predominant atherogenic lipid component and is often used as a target of lipid-lowering therapies, including 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (commonly known as statins) and other nonstatin medications.…”

“…[1][2][3] This increased risk is due to traditional risk factors (e.g., hypertension, diabetes, smoking, and dyslipidemia), but also due to factors related to HIV infection and antiretroviral therapy (ART). 3 Low-density lipoprotein cholesterol (LDL-C) is the predominant atherogenic lipid component and is often used as a target of lipid-lowering therapies, including 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (commonly known as statins) and other nonstatin medications. Even though statin therapy is often underprescribed in PWH, 1 it has proven effective in reducing noncalcified plaque volume in PWH with subclinical atherosclerosis 4 as well as decreasing the risk of cardiovascular events in the general population.…”

The profile of health care utilization among HIV/AIDS patients in Iran from 1987 to 2016: A nationwide study

“…On the other, PLWHA are at the increased risk of developing cardiovascular diseases (CVD) and liver disorders. 12 CVD and TB are common causes of death among PLWHA, 25,30 and the risk of developing CVD is increased with age, based on a study on the assessment of the prevalence and incidence of CVD in Western Australia between 1995 and 2010. The majority of CVD occur in the old age.…”