Abstract
Context:
Individuals with HIV have an elevated risk for developing cardiovascular disease compared to controls, particularly in relationship to abnormal deposition of lipid within various body compartments. Dysregulation of lipolysis may contribute to abnormal deposition of lipid in non-adipose tissues such as the heart, leading to untoward health consequences.
Objective:
To evaluate potential relationships between rates of whole-body lipolysis and intramyocardial lipid content in HIV-infected subjects compared to healthy controls.
Design:
Cross-sectional study.
Setting:
National Institutes of Health Clinical Research Center in Bethesda, Maryland.
Participants:
Forty-six HIV-infected adults and 12 controls without known cardiovascular disease.
Main Outcome Measure:
Intramyocardial lipid content quantified by MRI and rates of lipolysis determined using stable isotope tracer techniques.
Results:
We observed a significant positive correlation between the rate of appearance of glycerol and intramyocardial lipid overall (r = 0.323; P = .014) and among the HIV group separately (r = 0.361; P = .014). Multivariate regression analyses including HIV, lipid-lowering therapy, and diabetes identified both rate of appearance of glycerol and age as independent significant predictors of intramyocardial lipid (P = .01 and P = .03, respectively), but these were not significant with inclusion of visceral adipose in the analyses.
Conclusions:
To our knowledge, this study is among the first in humans to characterize the relationship between lipid deposition in the myocardium and direct measurement of whole-body fatty acid metabolism. Our current findings contribute to the growing understanding of factors that promote myocardial steatosis, such as visceral adiposity, and implicate lipolysis as a potential target for interventions to optimize myocardial health.
HIV is now managed as a chronic infection, and patients with access to antiretroviral therapy (ART) have significantly improved life expectancies. However, individuals living with HIV have an elevated risk for developing cardiovascular disease compared to controls, particularly in relationship to abnormal deposition of lipid within various body compartments such as abdominal and pericardial fat (1–6). Although the etiology of alterations in lipid metabolism is attributable in part to ART, hypertriglyceridemia and low plasma high-density lipoprotein cholesterol levels were observed in HIV-infected subjects before the widespread introduction of ART (7–9). There remain significant knowledge deficits in the characterization of the extent of abnormal lipid partitioning in HIV and the long-term health impact of these disturbances.
One component of the metabolic disturbances associated with HIV and its therapy has been recognition of inappropriately elevated lipolysis. Hadigan et al and others (10, 11) have shown increased rates of appearance (Ra) of glycerol, an index of total body lipolysis, among HIV-infected individuals compared to healthy controls. Dysregulation of lipolysis may contribute to abnormal deposition of lipid in nonadipose tissues such as liver, heart, and muscle, leading to untoward health consequences.
Advances in magnetic resonance spectroscopy (MRS) now permit reliable noninvasive quantification of the fat content of myocardial tissue (12). In metabolic conditions, such as diabetes and obesity, MRS demonstrates increased accumulation of intramyocardial lipid, also referred to as cardiac steatosis, in association with impaired myocardial function (13–18). Although there is no well-established normative value for intramyocardial lipid content, two previous studies of nonobese healthy adults, without known cardiovascular disease, observed myocardial triglyceride measurements of 0.76 and 0.43%, respectively (19, 20). We applied the novel techniques of cardiac MRS to quantify intramyocardial triglyceride content in a large cohort of HIV-infected subjects and found that it was increased compared to healthy controls and was associated with subclinical impairment in myocardial function (21). Furthermore, we hypothesized that abnormal lipid deposition in the myocardium associated with HIV infection may be related to abnormal lipolysis. Therefore, we employed stable isotope tracer techniques to measure lipid kinetics and evaluated potential relationships between rates of lipolysis and intramyocardial lipid content in HIV-infected subjects compared to healthy controls.
Subjects and Methods
Subjects
We prospectively evaluated 46 HIV-infected adults and 12 age-, sex-, and race-matched controls from April 2010 to May 2013 at the National Institutes of Health (NIH) Clinical Research Center in Bethesda, Maryland. Partial data from these subjects were included in a previous report of a larger cohort (95 HIV-infected and 30 matched controls) (21). Participation in the stable isotope study was based on time of enrollment, and stable isotope studies were analyzed on the first 65 subjects to enroll. Seven subjects did not have usable data for either MRS imaging or stable isotope sample testing, yielding a total sample size of 58. Subjects were recruited through self-referral and in response to local advertisements. Participants were excluded if they had a known history of cardiovascular disease or a contraindication to magnetic resonance imaging (MRI). There were no restrictions regarding ART medication use or CD4 count. Controls were documented HIV-negative and were required to be healthy with no known significant medical conditions, including cardiovascular disease. Targeted recruitment of control subjects was performed to match the HIV-infected group on the relative distribution of age, sex, and race. Written informed consent was obtained from each participant, and the protocol was approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases of the NIH.
Study evaluations
A medical history, physical examination, and laboratory tests were obtained from each participant, including a detailed review of ART exposures and cardiovascular disease risk factors, as well as a fasting lipid panel, CD4 T-cell count, and HIV viral load. Whole body and regional lean mass and fat distribution were assessed with dual-energy x-ray absorptiometry, and standard anthropometric measurements including waist-to-hip ratio, height, weight, and body mass index (BMI) were obtained.
Intramyocardial, intrahepatic, and intramuscular lipid and visceral adipose by MRS/MRI
To quantify intramyocardial, hepatic, and skeletal triglyceride content, each participant underwent myocardial 1H-MRS. All studies were performed on a 3.0-T MR scanner (Verio; Siemens) with a 32-channel phased-array torso coil (Invivo Corp) and combined with posterior coil elements as previously described (21). The distribution of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by a single-shot fast spin echo sequence (slice thickness, 10 mm). Three transverse images were acquired at the level of the fifth lumbar vertebrae during one breath hold. VAT and SAT were identified by selecting the region of interest and thresholding the pixel signal intensity, using QMASS (QMass 7.2; Medis).
Isotope infusion
Participants completed a 3-hour stable isotope tracer infusion for assessment of lipolysis in the NIH Clinical Center Metabolic Unit. They were instructed to abstain from any strenuous physical exercise 24 hours before this study and were admitted to the Clinical Center the night before the stable isotope tracer infusion study. In addition, to limit any confounding effects, morning doses of antidiabetic and lipid-lowering drugs were withheld until isotope study completion. Shortly after waking and after a 12-hour overnight fast, resting energy expenditure and respiratory quotient were determined using a standard indirect calorimetry measure taken over 20–30 minutes. Next, iv access was established with the placement of two peripheral iv. Baseline blood samples, including fasting free fatty acid, insulin, glucose concentrations, background enrichment, and a complete lipid panel were obtained. A tracer infusion of 2H5-glycerol, dissolved in normal saline, was then administered at a rate of 0.11 μmol/kg/min for 180 minutes after a priming dose of 1.6 μmol/kg over 1–2 minutes. Blood samples were collected from an iv catheter in a heated hand vein, maintained by a warming pad at 60–68°C to approximate arterialized blood. Samples were obtained every 20 minutes for 160 minutes, and then every 10 minutes for the last three samples. Samples were placed on ice and stored at −80°C until they were later processed.
Ra glycerol calculations
Ra of glycerol offers an index of whole-body lipolytic rate and quantifies the rate at which glycerol is released in the systemic circulation, mostly from hydrolysis of adipose tissue and intramuscular plasma triglycerides (22). The Ra of glycerol was calculated at steady state using the average of two to three samples obtained from 160 to 180 minutes. Calculations were based on estimates using the following formula: Ra glycerol = F/(rsa − rbk) (1–0.00015)5 where F = infusion rate of tracer, rsa = enrichment in the sample at steady state, and rbk = background enrichment of the sample before tracer administration (23).
Statistical analyses
Group comparisons were performed using Wilcoxon nonparametric comparisons or χ2 statistics, as appropriate. Non-normally distributed variables were log transformed to approximate a normal distribution. Two-sided P values of P < .05 were used to determine statistical significance. Univariate and multivariate linear regression analyses were calculated to identify variables associated with fatty acid turnover (Ra glycerol) in the entire study population and in the subset with HIV infection. Statistical analyses were completed using SAS JMP version 11.0 (SAS Institute).
Results
The demographic characteristics are summarized in Table 1, and body composition, labs, and energy expenditure parameters of the subjects are summarized in Table 2. Seven individuals in the HIV cohort were diagnosed with type II diabetes mellitus (T2DM), but none of the control subjects. All subjects with T2DM were well controlled, with five on oral insulin-sensitizing agents (two on pioglitazone and three on metformin), two on insulin, and one diet controlled. The mean fasting glucose of this subset was 107 ± 18 mg/dL. Of the 46 HIV-infected participants, 35% were currently on lipid-lowering therapy, all but one were on a statin, and the other was taking a fibrate. Furthermore, two HIV-infected participants and one control were on combined statin and fibrate regimens. No subjects were on acipimox or niacin. The prevalence of hypoglycemic and hypolipidemic agent use in the HIV cohort may explain the lower percentage of intrahepatic triglyceride content observed relative to the control population (Table 2).
Table 1.
Demographic and Clinical Characteristics Among Subjects With HIV Infection and Controls Without HIV
| HIV Subjects | Controls | P Value | |
|---|---|---|---|
| n | 46 | 12 | |
| Age, y | 47.8 ± 8.9 | 46.0 ± 8.3 | .64 |
| Sex | .71 | ||
| Male | 32 (70) | 9 (75) | |
| Female | 14 (30) | 3 (25) | |
| Ethnicity | .84 | ||
| White | 11 (24) | 3 (25) | |
| Black | 30 (65) | 7 (58) | |
| Hispanic | 5 (11) | 2 (17) | |
| Diabetes | 7 (15) | 0 (0) | .15 |
| Currently on lipid-lowering therapy | 16 (35) | 1 (8) | .04 |
| HIV-specific characteristics | |||
| Years with HIV | 14.7 ± 7.1 | — | — |
| Years of exposure | 8.8 ± 5.9 | — | — |
| Currently on PI | 22 (48) | — | — |
| Current CD4 T-cell count (cells/μL) | 655 ± 277 | 987 ± 397 | .016 |
| Undetectable HIV viral load (<50 copies/mL) | 43 (93.5) | — | — |
Abbreviation: PI, protease inhibitor. Values represent number (percentage) or mean ± standard deviation unless stated otherwise. —, not available.
Table 2.
Body Composition and Metabolic Parameters Among Subjects With HIV Infection and Controls Without HIV
| HIV Subjects | Controls | P Value | |
|---|---|---|---|
| n | 46 | 12 | |
| BMI, kg/m2 | 29.7 ± 6.2 | 28.0 ± 5.2 | .29 |
| Body fat, % | 32.5 ± 8.9 | 31.8 ± 7.2 | .99 |
| Total body mass, kg | 87.1 ± 19.1 | 84.6 ± 17.2 | .74 |
| Lean body mass, kg | 54.8 ± 9.9 | 54.1 ± 8.6 | .97 |
| Resting energy expenditure, kcal/d | 1772 ± 319 | 1665 ± 150 | .32 |
| Respiratory quotient | 0.81 ± 0.05 | 0.79 ± 0.05 | .15 |
| Ra glycerol, μmol/kg/min | 3.8 ± 2.2 | 3.6 ± 1.7 | .83 |
| Fasting glucose, mg/dL | 97.0 ± 16 | 93.5 ± 9.3 | .77 |
| Fasting insulin, μIU/mL | 10.0 ± 9.5 | 8.1 ± 6.9 | .62 |
| 7.5 [3.1–13.5]a | 6.2 [2.5–11.9]a | ||
| Free fatty acid, μEq/L | 0.50 ± 0.22 | 0.55 ± 0.18 | .36 |
| Total cholesterol, mg/dL | 172 ± 33 | 181 ± 46 | .44 |
| Triglycerides, mg/dL | 130 ± 73 | 154 ± 82 | .38 |
| 114 [87–153]a | 167 [68–209]a | ||
| HDL cholesterol, mg/dL | 50 ± 14 | 41 ± 11 | .11 |
| LDL cholesterol, mg/dL | 97 ± 32 | 109 ± 34 | .22 |
| MRI measures | |||
| Subcutaneous adipose tissue, mL | 659 ± 438 | 604 ± 349 | .89 |
| VAT, mL | 573 ± 212 | 492 ± 141 | .34 |
| Skeletal muscle fat, % | 2.1 ± 2.5 | 1.6 ± 1.4 | .74 |
| 1.1 [0.5–2.3]a | 1.2 [0.5–2.0]a | ||
| Liver fat, % | 7.5 ± 12.3 | 16.2 ± 19.2 | .03 |
| 3.6 [1.1–8.3]a | 11.4 [3.0–16.7] | ||
| Intramyocardial lipid, % | 1.5 ± 1.4 | 1.4 ± 1.3 | .56 |
| 1.3 [0.5–2.0]a | 0.7 [0.5–2.3]a |
Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein. Values represent mean ± standard deviation, unless stated otherwise.
Median [interquartile range].
On average, the HIV cohort was diagnosed with HIV for 14.7 ± 7.1 years and was on ART for an average of 8.8 ± 5.9 years, with 48% currently on protease inhibitors. In the HIV group, 93% of the subjects had an HIV viral load below the limit of detection. Only one HIV-infected participant had a clinical diagnosis of lipodystrophy. Ra glycerol was similar between the HIV and control groups (HIV vs control, 3.8 ± 2.2 vs 3.6 ± 1.7 μmol/kg/min; P = .83). The median intramyocardial triglyceride content for the HIV group was 1.3%, whereas the control median was 0.7% (P = .56). We observed a significant positive correlation between measured Ra glycerol and intramyocardial lipid content in the whole cohort (r = 0.323; P = .014), and this correlation was also present when the HIV group was evaluated separately (r = 0.361; P = .014). We did not identify a correlation between these two factors when analyzing the control group independently (r = 0.35; P = .73).
The association between intramyocardial lipid and Ra glycerol persisted in subanalyses accounting for other potential cofounding variables. For example, in a subanalysis of the HIV-infected subjects excluding those with diabetes, the correlation between intramyocardial lipid and Ra glycerol remained significant (P = .012). Furthermore, a multivariate regression analysis, which included HIV status, current lipid-lowering therapy, and diabetes, identified both Ra glycerol and age as independent significant predictors of intramyocardial lipid content (P = .01 and P = .03, respectively; Table 3). Although VAT was not directly correlated with Ra glycerol (r = 0.14; P = .33), it was correlated with intramyocardial lipid (r = 0.28; P = .046). In fact, when added to the multivariate analysis, VAT became the only factor significantly associated with intramyocardial lipid content (Table 3). There was no interaction effect between Ra glycerol and intramyocardial lipid. Furthermore, there were no significant differences between HIV-infected subjects and controls with respect to measures of body composition, resting energy expenditure, or measures of glucose, insulin, and lipids (Table 2).
Table 3.
Multivariate Regression of Characteristics Potentially Associated With Intramyocardial Lipid Content (n = 58)
| Variable | Model 1 |
Model 2 |
||
|---|---|---|---|---|
| β-Estimate | P Value | β-Estimate | P Value | |
| Ra glycerol, μmol/kg/min | 0.234 | .01 | 0.155 | .17 |
| Age, y | 0.045 | .03 | 0.031 | .10 |
| HIV status (uninfected vs infected) | −0.023 | .92 | 0.059 | .77 |
| Lipid-lowering therapy (no vs yes) | −0.038 | .87 | 0.052 | .81 |
| Diabetes (no vs yes) | 0.020 | .95 | −0.095 | .73 |
| VAT, mL | — | — | 0.002 | .03 |
Bold text indicates a significant P value (P < .05).
Discussion
To investigate the potential relationship between fatty acid metabolism and abnormal lipid deposition in the myocardium observed in HIV, we examined intramyocardial lipid content using MRS in a cohort of HIV-infected adults and quantified fatty acid metabolism through stable isotope tracer techniques. Ra glycerol, a measure of whole-body lipolysis, was found to be positively correlated with intramyocardial lipid content in the HIV cohort and the cohort overall, indicating a relationship between fatty acid metabolism and fat present in the myocardium. After adjusting for HIV status, as well as potential confounders such as current lipid-lowering therapy and diabetes, both Ra glycerol and age were significant independent predictors of intramyocardial lipid content.
Using larger cohorts of HIV-infected adults, we and others have shown that intramyocardial lipid is increased in HIV compared to uninfected controls (21, 24). Furthermore, this increase in myocardial lipid appears to be associated with subclinical abnormalities in myocardial function. In the present study, we used detailed stable isotope tracer techniques in a subset of our original cohort to better characterize the relationship between fatty acid metabolism and cardiac steatosis in this setting.
Previous studies evaluating lipolysis in HIV-infected subjects focused on lipodystrophy and/or observed increased rates of lipolysis relative to healthy controls (10, 11, 25). For example, Sekhar et al (25) observed elevated rates of lipolysis among HIV-infected men with lipodystrophy compared to healthy controls. The current study was not designed to evaluate lipodystrophy, and whereas one HIV-infected participant presented with clinical lipodystrophy, we found no observed difference in the overall rates of lipolysis between controls and those with HIV. Furthermore, past studies have implicated specific antiretroviral therapies, in particular protease inhibitors, as contributing factors in abnormal rates of lipolysis (26). The effects of protease inhibitors, as well as other components of ART, on lipid metabolism have changed in recent years because newer agents generally have more favorable side effect profiles. In our study, rates of lipolysis did not differ according to years on, or current use of, protease inhibitors.
To our knowledge, this study is among the first in humans to characterize the relationship between lipid deposition in the myocardium measured with MRS techniques and direct measurement of whole-body fatty acid metabolism. The relationship between whole-body lipid turnover and abnormalities in lipid deposition in the heart may represent a physiological connection linking lipolysis to myocardial function and cardiovascular disease.
An increase in myocardial lipid content has been demonstrated in diabetic as well as obese populations. Myocardial steatosis is abnormal and likely represents subclinical myocardial injury that may ultimately lead to myocardial dysfunction (13–18). Studies have identified a significant correlation between myocardial triglyceride content and left ventricular diastolic dysfunction in T2DM patients (14–16). Rijzewijk et al (14) specifically determined that myocardial steatosis is increased in uncomplicated T2DM and associated with impaired left ventricular diastolic function independent of age, BMI, blood pressure, and heart rate. Furthermore, after adjusting for diabetic state, Rijzewijk et al observed both visceral fat volume and hepatic triglyceride content to be increased and correlated to myocardial lipid content.
The relationship between visceral abdominal fat volume and myocardial lipid content has been well observed in obese populations (17, 18). Granér et al (18) demonstrated that increased intramyocardial triglyceride content, which correlates with the visceral fat, is inversely associated with stroke volume in non-HIV-infected obese individuals. Although our larger study established VAT as a strong independent predictor of myocardial steatosis, specifically in HIV-infected individuals, our present study also links lipolysis to abnormal lipid deposition in the myocardium and may play an integral role in its development. Of note, there was no correlation between VAT volume and Ra glycerol, suggesting that each may influence intramyocardial lipid content through independent mechanisms. However, when VAT was included in the multivariate model, the strength of the relationship between VAT and intramyocardial lipid significantly attenuated the observed relationship between Ra glycerol and intramyocardial lipid content. VAT may represent a more stable persistent physiological effect on intramyocardial lipid, whereas lipolysis may reflect the influence of recent fatty acid metabolism. Although visceral adiposity remains a key component of cardiovascular health, lipolysis may also be a useful target for interventions developed to address myocardial steatosis and its downstream effects on myocardial function.
There are several limitations to the current study. The cross-sectional design identifies an association between whole-body lipolysis and intramyocardial lipid but cannot establish causality. HIV-infected and control subjects were allowed to self-refer, which may have introduced bias to the sample selection; however, subjects with known cardiovascular disease were excluded. Furthermore, the study sample size was relatively small, and this may limit our ability to identify possible differences between study groups as well as potential relationships between antiretroviral agents or other factors that may influence lipolysis and myocardial steatosis in HIV infection.
Given the already known increased risk of cardiovascular disease in persons living with HIV (27), it is important to continue to characterize the underlying pathophysiology leading to these untoward health consequences. Our current findings contribute to the growing understanding of factors that promote cardiac steatosis and constitute a presumed new quantitative target to interrupt early pathogenesis and preserve myocardial function in this context. Future investigation is necessary to further elucidate the mechanistic links between lipolysis and myocardial lipid in patients with HIV, as well as the larger population of individuals with T2DM and obesity also at risk for these cardiac abnormalities.
Acknowledgments
This research was supported by intramural funding from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- ART
- antiretroviral therapy
- BMI
- body mass index
- MRI
- magnetic resonance imaging
- MRS
- magnetic resonance spectroscopy
- Ra
- rate of appearance
- T2DM
- type II diabetes mellitus
- VAT
- visceral adipose tissue.
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