iconstar paper   HIV Articles  
Back grey arrow rt.gif
 
 
Increased pericardial fat accumulation is associated with increased intramyocardial lipid content and duration of highly active antiretroviral therapy exposure in patients infected with human immunodeficiency virus: a 3T cardiovascular magnetic resonance feasibility study
 
 
  Download the PDF her
 
"first, that increased pericardial fat at the level of the LM [left main coronary artery] origin, measured quickly and reproducibly from a standard CMR sequence, is significantly higher in HIV (+) patients treated with HAART. Second, this increase in pericardial fat is significantly associated with increased intramyocardial lipid content (i.e. cardiac steatosis). To our knowledge, this is the first report of this correlation of pericardial fat with cardiac steatosis. Third, we extend the existing literature [13, 14, 17] by showing that each of these markers are also associated with HIV history (i.e. years of infection), duration of HAART exposure, as well as the clinical presence of lipo-accumulation secondary to HAART. Remarkably, these results persist despite rigorous screening for cardiovascular risk factors in our HIV+ subjects, including family history of cardiovascular disease. That HAART exposure was found to be related to derangements in fat metabolism, reinforces the hypothesis that HAART itself contributes to cardiac alterations.
 
.....Pericardial fat volume at the level of LM [left main coronary artery] origin was higher in HIV (+).....We found that HAART exposure was strongly associated with pericardial fat deposition, providing important mechanistic insight. .....Pericardial fat content is increased in HIV (+) subjects on chronic HAART (>5 years), who demonstrate HAART-related lipo-accumulation and prolonged HIV duration of infection. Further investigation is warranted to determine whether increased pericardial fat is associated with higher cardiovascular risk leading to premature cardiovascular events in this patient population......That HAART exposure was found to be related to derangements in fat metabolism, reinforces the hypothesis that HAART itself contributes to cardiac alterations.....indeed, HAART is known to cause both lipodystrophy and hyperlipidemia [5-7] and in the present investigation, was associated with lipo-accumulation......Routine clinical qualitative screening for external lipodystrophy may serve as a useful screening tool for further CVD screening in this patient population......pericardial fat, measured at the origin of LM [left main coronary artery], can be done both quickly and reproducibly and is highly correlated with intramyocardial lipid content, years of HIV infection"
 
Journal of Cardiovascular Magnetic Resonance
 
(2015)
Mariana Diaz-Zamudio1, Damini Dey2, Troy LaBounty4, Michael Nelson5,6, Zhaoyang Fan2, Lidia S. Szczepaniak2,5,
Bill Pei-Chin Hsieh1, Ronak Rajani1, Daniel Berman2, Debiao Li2, Rohan Dharmakumar2, W. David Hardy3 and Antonio Hernandez Conte7*
 
Abstract
 
Background

 
The aim of the current study was to examine whether the use of highly active antiretroviral therapy (HAART) in patients with HIV is associated with changes in pericardial fat and myocardial lipid content measured by cardiovascular magnetic resonance (CMR).
 
Methods
 
In this prospective case-control study, we compared 27 HIV seropositive (+) male subjects receiving HAART to 22 control male subjects without HIV matched for age, ethnicity and body mass index. All participants underwent CMR imaging for determination of pericardial fat [as volume at the level of the origin of the left main coronary artery (LM) and at the right ventricular free wall] and magnetic resonance spectroscopy (MRS) for evaluation of intramyocardial lipid content (% of fat to water in a single voxel at the interventricular septum). All measurements were made by two experienced readers blinded to the clinical history of the study participants. Two-sample t-test, Spearman's correlation coefficient or Pearson's correlation coefficient and multivariable logistic regression were used for statistical analysis.
 
Results
 
Pericardial fat volume at the level of LM origin was higher in HIV (+) subjects (33.4 cm3 vs. 27.4 cm3, p = 0.03). On multivariable analysis adjusted for age, Framingham risk score (FRS) and waist/hip ratio, pericardial fat remained significantly associated to HIV-status (OR 1.09, p = 0.047). For both HIV (+) and HIV (-) subjects, pericardial fat volume showed strong correlation with intramyocardial lipid content (r = 0.58, p < 0.0001) and FRS (r = 0.53, p = 0.0002). Among HIV (+) subjects, pericardial fat was significantly higher in patients with lipo-accumulation (37 cm3 vs. 27.1 cm3, p = 0.03) and showed significant correlation with duration of both HIV infection (r = 0.5, p = 0.01) and HAART (r = 0.46, p = 0.02).
 
Conclusions
 
Pericardial fat content is increased in HIV (+) subjects on chronic HAART (>5 years), who demonstrate HAART-related lipo-accumulation and prolonged HIV duration of infection. Further investigation is warranted to determine whether increased pericardial fat is associated with higher cardiovascular risk leading to premature cardiovascular events in this patient population.
 
Discussion
 
HIV-related cardiovascular disease is an emerging contributor to morbidity and mortality. Imaging biomarkers such as pericardial or myocardial adiposity may serve as markers of cardiovascular risk in this population. Computed tomography is commonly used to quantify pericardial fat deposition; however, computed tomography remains limited by its need for ionizing radiation. CMR provides a safe, reliable means of serial cardiac evaluation without the hazards associated with ionizing radiation. In our study, we utilized CMR to demonstrate several important findings: first, that increased pericardial fat at the level of the LM origin, measured quickly and reproducibly from a standard CMR sequence, is significantly higher in HIV (+) patients treated with HAART. Second, this increase in pericardial fat is significantly associated with increased intramyocardial lipid content (i.e. cardiac steatosis). To our knowledge, this is the first report of this correlation of pericardial fat with cardiac steatosis. Third, we extend the existing literature [13, 14, 17] by showing that each of these markers are also associated with HIV history (i.e. years of infection), duration of HAART exposure, as well as the clinical presence of lipo-accumulation secondary to HAART. Remarkably, these results persist despite rigorous screening for cardiovascular risk factors in our HIV+ subjects, including family history of cardiovascular disease. That HAART exposure was found to be related to derangements in fat metabolism, reinforces the hypothesis that HAART itself contributes to cardiac alterations.
 
The exact mechanism responsible for pericardial fat deposition remains unclear. We found that HAART exposure was strongly associated with pericardial fat deposition, providing important mechanistic insight. Indeed, HAART is known to cause both lipodystrophy and hyperlipidemia [5-7] and in the present investigation, was associated with lipo-accumulation. Triglyceride infiltration into the myocardium has previously been associated with derangements in both diastolic relaxation and systolic contractility in both rodents [26-29] and humans [30, 31] One explanation for this observation is that ectopic fat accumulation contributes to the generation of lipotoxic intermediates, such as ceramide, which can trigger myocellular apoptosis [32]. Lipid vacuole infiltration can also dissemble the myocardial contractile apparatus, which could independently lead to contractile dysfunction [8, 33]. Thus, while our data cannot prove causality, we hypothesize that chronic exposure to HAART produces a metabolic-type derangement (clinically or non-clinically evident) leading to myocardial and pericardial fat accumulation. Taken together, we speculate that disturbances in the metabolic milieu, secondary to HAART exposure, leads to ectopic fat accumulation in HIV+ patients.
 
Clinical relevance
 
Identification of multiple risk factors in the development of pericardial fat or myocardial triglyceride accumulation in HIV+ patients on HAART is paramount in developing clinical algorithms for appropriate cardiac screening and risk reduction implementation. Factors such as duration of HAART exposure, specific exposure to "cardiotoxic" antiretroviral agents, or overall duration of HIV infection may guide the clinician in screening maneuvers. Chronologic age alone cannot be the sole criteria for routine cardiovascular screening and assessment, as many individuals become infected with HIV at a relatively young age and have been on HAART for over a decade by the time they reach their early 30's or 40's. Thus, the concept of chronologic age as a cardiovascular screening indictor may be irrelevant, especially in younger HIV+ patients. As such, defining "HIV-infection-age" and "HAART-exposure" may be more informative to the clinician for CVD screening and assessment.
 
Ectopic fat deposition is emerging as an independent marker of cardiovascular risk in HIV-infected patients as demonstrated via computed tomography [34, 35]. In a study by Guaraldi et al. [14], epicardial adipose tissue was strongly associated with coronary artery calcium (an established marker of atherosclerosis) in patients with HIV infection on HAART. In our study, we show that pericardial fat deposition is related to HIV history, duration of HAART exposure, as well as the clinical presence of lipo-accumulation secondary to HAART. While these two fat depots are not entirely the same, both have been implicated in the development of coronary artery disease [36]. Further investigation is therefore warranted to determine whether pericardial fat content, measured by routine CMR, will be equally predictive for cardiovascular risk in HIV.
 
Although our study did not find specific protease inhibitors or nucleoside reverse transcriptase inhibitors (which are known to have cardiotoxic effects) to be more predictive of cardiac steatosis or pericardial fat accumulation, compared to other medications, the present investigation was not specifically powered to detect such differences. However caution must continue to be exercised when these medications are prescribed, and during routine CVD risk stratification.
 
Routine clinical qualitative screening for external lipodystrophy may serve as a useful screening tool for further CVD screening in this patient population. Indeed, this study utilized a straightforward method of evaluating lipodystrophy that can be performed by a general or subspecialist physician during a regular outpatient office consultation. Importantly, traditional indicators for CVD such as body mass index were not found to be associated with increased cardiac steatosis in HIV-infected patients on HAART, whereas waist/hip circumference ratio and lipodystrophy screening were found to be highly correlated with cardiac alterations.
 
Limitations
 
There were several limitations to this study. First, our study population was small, however, both the patient and control groups were highly homogeneous with regard to multiple demographic parameters. Our selection process of HIV (-) control subjects closely approximated the HIV (+) subjects, therefore, the two study groups were very similar aside from HIV status and use of HAART. Second, our measurements provide information about pericardial fat and not exclusively epicardial fat, which has been proposed as the best marker for cardiovascular risk among thoracic fat deposits [8, 12]. Furthermore, our measurements of pericardial fat are obtained from a single slab in order to propose a practical fast approach to pericardial fat quantification, nevertheless a full volumetric assessment is more desirable and could be introduced in the future. Third, this was a cross-sectional study of HIV (+) patients on multiple HAART regimens, therefore, associations between specific classes of HAART and pericardial fat and intramyocardial lipid content were limited due to small groups of patients on particular medication regimens. Larger cohorts of HIV (+) patients on specific HAART regimens are necessary to determine medication class-induced risk profiles. This study did not include a group of HIV-infected patients without history of HAART exposure, thus preventing us from completely partitioning the independent role of HIV infection (without HAART) per se. In the United States, HAART is immediately implemented once the patient is able to make a decision to accept the risks and benefits of therapy, therefore, it would be extremely difficult to recruit a subset of HIV+ subjects without history of HAART. Finally, this study was limited to male subjects due to its sample size and significant reported differences in patient characteristics by gender among patients with HIV. As a result, these findings may not be generalizable to women, and future research in women is warranted. Studies in non-HIV-infected individuals have implicated pericardial fat accumulation with increasing cardiovascular risk and events [10-12]. Further studies are therefore warranted to investigate the relationship between pericardial fat accumulation and cardiovascular events in HIV-infected subjects.
 
Conclusions
 
Our study show that pericardial fat, measured at the origin of LM, can be done both quickly and reproducibly and is highly correlated with intramyocardial lipid content, years of HIV infection, duration of HAART exposure and the clinical presence of lipo-accumulation. Pericardial fat by CMR therefore represents a viable biomarker for assessing cardiovascular risk in this population.

 
 
 
 
  iconpaperstack View Older Articles   Back to Top   www.natap.org