Given the efficacy of newer, effective antiretroviral therapies, life expectancy of PLWH has shown a widespread improvement; on the other hand, following the introduction of cART, CVD and cardiovascular deaths have increased dramatically among this population (7). Several studies conducted in PLWH with CCT angiography, showed an increased presence and extent of coronary artery disease, including non-calcified and high-risk coronary plaques, that were associated with an increase in indicators of systemic immune activation (10, 11).
In a previous work, increased myocardial inflammation has been described in HIV + patients (15). Specifically in an interesting prospective study, Luetkens et al that compared the results of comprehensive CMR studies in HIV + asymptomatic patients and controls and observed an increase in CMR markers of myocardial inflammation in the HIV + group, thus suggesting the presence of subclinical myocardial inflammation in this population, which may in the end lead to the impairment of left ventricular myocardial function. The major limitation of the cited study, as well as of our present study, is that no histological assessment has been carried out. Luetkens et al. suggested that, although direct HIV infection of myocytes is rare, it is possible that HIV itself together with other cardiotropic viral infections may lead to myocarditis and to a subsequent left ventricular dysfunction; this may also explain the high rate, observed among this population, of resting ECG abnormalities that are consistent with myocardial damage. Authors suggested that inflammatory condition and subsequent fibrosis may be responsible of the observed CMR findings. On the other hand, our results show relevant differences in respect to those of Luetkens et al. Firstly, the statistical evaluation carried out by our colleagues is mainly descriptive and no regression analysis was performed due of the limited sample size. Moreover, since the study was conceived for preliminary investigation purposes, no correction analysis was performed, possibly leading to inflated type I errors. This assumption in our work is supported by a significant difference in ECV values between the different patient groups, which are known to represent an indirect measure of diffuse interstitial myocardial fibrosis or most serious heart diseases (17). In addition, the ECV values observed in our study were consistent with previous studies conducted in the HIV- population (18). Lastly, in our study, due to a larger sample size, we were able to perform a multivariate regression analysis.
It has been described previously that amyloid precursor protein (APP) may be an innate antiviral defence factor in macrophages and microglia that restricts HIV-1 release in the neurological environment. Highly expressed in macrophages and microglia, the membrane-associated APP binds the HIV-1 Gag polyprotein and blocks HIV-1 production and spread. To escape this restriction, Gag promotes secretase-dependent cleavage of APP, resulting in the overproduction of toxic Aβ isoforms. From a neuro-physiopathological point of view, this Gag-mediated Aβ production results in increased degeneration of primary cortical neurons. One interesting question is: could this mechanism be involved in the physiopathology of our findings of an increase in ECV? Could amyloid formation as a result of immunological response to virus in cardiovascular tissue explain cardiomyopathy and peripheral obstructive vascular lesions observed in HIV + patients? Urgent studies are clearly needed to better understand the complex dynamic that underlies the multiple peculiar features which are increasingly being observed in people chronically living with HIV, in order to design effective prevention strategies to counteract the increasing burden of cardiovascular events in our patients.
Overall, these data suggest that an increase in systemic inflammation and immune activation may manifest as a premature CVD phenotype, including disease in large and small vascular beds in patients with HIV. Among PLWH, a relevant concern is whether scores that rely on traditional CV risk factors can accurately identify those individuals with a higher probability to develop CVD (9). In this study, we highlight that PLWH with low-ASCVD risk score are likely to suffer from a silent cardiac impairment. In fact, we found a significant difference in ECV levels between PLWH and healthy subjects (p < 0.001), indicating the presence of ECM expansion in patients with HIV infection. More importantly, years of exposure to HIV, and years of antiretroviral therapy significantly correlated with ECV expansion.
Quantification of ECM is an indirect measure of the expansion of extracellular matrix since, in absence of confounding conditions (e.g. oedema or amyloid), it is related to collagen excess in the interstitium. ECM expansion may therefore indicate vulnerable myocardium in PLWH and represent a potential therapeutic target (7). Indeed, abnormal fibrosis may be the underlying pathological finding in many cardiovascular disorders, particularly in sudden cardiac deaths (SCD), an emerging issue in PLWH. Frieberg et al. report that PLWH had a 14% higher risk of SCD, with uncontrolled HIV infection representing a risk factor (13). Recently, a review of the health records from San Francisco between 2011 and 2016 outlined that the cause of death for autopsy-defined sudden arrhythmic death syndrome (SADS) and SCD were 83% and 82% higher respectively in the PLWH than in general population. Interestingly, the histologic exam identified higher rates of cardiac fibrosis in PLWH underling the excess risk of SADS (14). Indeed, specific tools are sought to measure in vivo the CV risk excess of PLWH which cannot be determined by common predictors of CV scores. Quantifying ECM expansion through ECV assessment may ultimately provide a basis to improve care in HIV individuals through a better risk stratification and the possibility of targeted treatment.