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Subclinical Heart Dysfunction/Belly Fat - Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV
 
 
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"visceral adiposity in HIV-infected individuals may increase the risk for clinical cardiac dysfunction through cardiac steatosis."
 
HIV infection is associated with increased central adiposity which conveys a two-fold increased risk in 5-year mortality [9], but the present study is among the first to characterize the relationship between visceral adipose tissue (VAT) and intramyocardial steatosis in HIV-infected individuals. VAT, in part due to side effects of ARV exposure, was the strongest independent predictor of intramyocardial lipid. This suggests that the altered metabolic activity of the visceral fat compartment may be a driving force of observed myocardial effects. Studies of non-HIV-infected obese populations have shown that increased intramyocardial triglyceride content, which correlates with VAT, is inversely associated with stroke volume [16]. Therefore, visceral adiposity in HIV-infected individuals may increase the risk for clinical cardiac dysfunction through cardiac steatosis."
 
"The cross-sectional design of the present study limits the interpretation of observed associations and cannot establish causality. HIV-infected and control subjects were allowed to self-refer which may have introduced bias to the sample selection. Subjects with known cardiovascular disease, though, were excluded and therefore the abnormalities identified in cardiac steatosis and function are subclinical in nature. Prospective longitudinal studies evaluating these characteristics in patients initiating ARVs, as well as studies with clinical cardiovascular disease endpoints are needed to fully appreciate the etiology and significance of cardiac steatosis, fibrosis, and impaired cardiac strain in HIV. Females were relatively underrepresented in the study population. Further studies focusing on cardiovascular disease in women are needed to better examine the relationship between HIV infection and cardiac steatosis.
 
Our study identified increased subclinical cardiac dysfunction in association with cardiac steatosis and fibrosis in HIV-infected adults. Given the known increased risk of cardiovascular disease in persons living with HIV [36], it is important to identify risk factors and create targeted strategies to prevent progression of global cardiac dysfunction. We demonstrate that increased visceral adipose tissue is a strong independent predictor of myocardial steatosis, and as such, reducing visceral adiposity should be a target for strategies of lifestyle modification and cardiovascular risk reduction. Further, impaired cardiac strain tracked with markers of chronic inflammation and immune activation, which may serve as targets for the development of therapeutic strategies to optimize long-term cardiovascular health in persons living with HIV."
 
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Impaired Cardiac Strain and Biomarkers of Immune Activation in HIV - (10/10/14)
 
Hadigan et al
16th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV 6 October 2014, Philadelphia USA
 
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Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV
 
Journal of Infectious Diseases Advance Access published May 11, 2015 Diana K. Thiara1, Liu Chia Ying2, Fabio Raman2,3, Sabrina Mangat1, Julia B. Purdy4, Horacio A. Duarte5, Nancyanne Schmidt1, Jamie Hur1, Christopher T. Sibley6, David A. Bluemke2, Colleen Hadigan1 1Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 2Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda MD 3Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL 4Critical Care Medicine Department, National Institutes of Health, Bethesda MD 5Department of Pediatrics, Seattle Children's Hospital/University of Washington School of Medicine, Seattle WA 6Oregon Health and Science University, Knight Cardiovascular Institute, Portland OR
 
Abstract
 
Background. Impaired cardiac function persists in the era of effective HIV therapy, though the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid and fibrosis as possible contributors to HIV-associated myocardial dysfunction.
 
Methods. Cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid, myocardial fibrosis, and cardiac function measured by strain were quantified by MRI.
 
Results. Systolic function was significantly decreased in HIV-infected subjects compared to controls (radial strain 21.78.6% vs 30.514.2%, p=0.004).
 
Intramyocardial lipid and fibrosis were both increased in HIV compared to controls (p0.04 for both) and correlated with degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein-1 levels (r=0.396, p=0.0002) and lipopolysaccharide binding protein (r=0.25, p=0.02).
 
Conclusions. HIV-infected adults have reduced myocardial function compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV.
 
DISCUSSION
 
To investigate the potential relationship between subclinical cardiac dysfunction and myocardial lipid and fibrosis, this study evaluated subjects with a broad range of exposure to HIV and its therapies, but without clinical cardiovascular disease. Despite normal ejection fraction, we identified significantly reduced systolic function (27% relative reduction in radial strain), greater intramyocardial lipid content (by 38%), and evidence of diffuse myocardial fibrosis (by 8%) in HIV-infected individuals compared to age, sex, and race-matched controls. Impaired myocardial function as measured by strain parameters was associated with increased myocardial lipid and fibrosis in this cohort.
 
One brief report and one cohort study have used MRI/MRS to examine subjects with HIV infection receiving antiretroviral therapy [27, 28]. In the U.K. cohort, subjects had more overt cardiac disease than those in the current study (e.g. 76% of the U.K. HIV cohort had overt, focal myocardial scar on MRI vs. only 8% in the current study). Focal myocardial scar represents macroscopic replacement of myocardium by collagen; the most common cause of focal scar is myocardial infarction but other conditions (e.g. myocarditis, hypertension, diabetes) are also associated with focal scar. Although our U.S. HIV cohort had very little focal myocardial scar, our cohort did have evidence of expanded extracellular volume (ECV) index that is associated with diffuse myocardial fibrosis. Diffuse myocardial fibrosis may represent a sequelae of subclinical myocarditis and, in the general population, is a histologic finding in the failing heart associated with adverse cardiac outcomes [29, 30]. ECV remained increased in HIV compared to controls after controlling for variables known to increase fibrosis index, such as age and lower hematocrit. Further, myocardial fibrosis index was positively correlated with intramyocardial lipid content but not with duration of ARV exposure, HIV viremia, or inflammatory markers in the HIV subjects. Our findings suggest cardiac fibrosis may be secondary to downstream metabolic effects of HIV infection. Similar to the U.K. cohort, we found that the relationship between HIV and increased cardiac steatosis persisted when adjusted for potential confounders, such as smoking.
 
Myocardial strain was lower in HIV-infected subjects compared to control subjects. Holloway et al.[27] proposed their observed cardiac dysfunction in HIV-infected subjects was due to cardiac steatosis and fibrosis, but did not report a correlation between myocardial strain and these parameters. We, however, observed overall correlations between cardiac steatosis and fibrosis with depressed cardiac strain in subjects with a minor degree of focal scar that did not differ from age and gender matched controls (8-9%). Our findings strongly suggest that diffuse, rather than focal myocardial injury, may be the sequelae of HIV infection and myocardial steatosis.
 
The relationship between visceral abdominal fat volume and myocardial lipid content has been well-established in obese populations [16, 31]. HIV infection is associated with increased central adiposity which conveys a two-fold increased risk in 5-year mortality [9], but the present study is among the first to characterize the relationship between visceral adipose tissue (VAT) and intramyocardial steatosis in HIV-infected individuals. VAT, in part due to side effects of ARV exposure, was the strongest independent predictor of intramyocardial lipid. This suggests that the altered metabolic activity of the visceral fat compartment may be a driving force of observed myocardial effects. Studies of non-HIV-infected obese populations have shown that increased intramyocardial triglyceride content, which correlates with VAT, is inversely associated with stroke volume [16]. Therefore, visceral adiposity in HIV-infected individuals may increase the risk for clinical cardiac dysfunction through cardiac steatosis.
 
Monocyte chemoattractant protein-1 (MCP-1) is a chemokine important in monocyte and macrophage migration and is a marker of chronic inflammation and immune activation. In patients with chronic heart failure, elevated MCP-1 levels are associated with decreased left ventricular ejection fraction and, in one study, higher MCP-1 levels predicted subsequent cardiac events [32]. We found that increased MCP-1 levels were strongly associated with degree of impairment in cardiac strain. Lipopolysaccharide binding protein, a marker of chronic inflammation and an acute phase protein made in response to lipopolysaccharide (LPS), was also associated with impaired cardiac strain in the HIV-infected cohort. In a case-control study, Sandler and colleagues [33] found sCD14, a marker of LPS mediated monocyte activation, though not associated with cardiovascular events, was a predictor of mortality in HIV. Therapeutic interventions targeted at attenuating immune activation in chronic HIV infection are under active investigation. Our data support this as an approach that may modify or reduce end organ injury that accumulates through this process.
 
Previously uncharacterized differences related to sex in both cardiac steatosis and cardiac fibrosis indices were observed. Female sex was an independent predictor of intramyocardial lipid content in both HIV and controls. Earlier data in HIV-infected populations suggest that women may be more susceptible than their male counterparts to the metabolic effects of ARVs [34]. In the general population, female sex independently predicts higher myocardial fatty acid esterification and lower percent fatty acid oxidation in the left ventricle of the heart [35], suggesting cardiomyocytes may have an increased fatty acid deposition-to-utilization ratio in females. Therefore, HIV-infected women on ARVs may be particularly susceptible to abnormal cardiac lipid deposition. As seen in large population studies[30], female sex was independently associated with greater myocardial fibrosis indices compared to males.
 
The cross-sectional design of the present study limits the interpretation of observed associations and cannot establish causality. HIV-infected and control subjects were allowed to self-refer which may have introduced bias to the sample selection. Subjects with known cardiovascular disease, though, were excluded and therefore the abnormalities identified in cardiac steatosis and function are subclinical in nature. Prospective longitudinal studies evaluating these characteristics in patients initiating ARVs, as well as studies with clinical cardiovascular disease endpoints are needed to fully appreciate the etiology and significance of cardiac steatosis, fibrosis, and impaired cardiac strain in HIV. Females were relatively underrepresented in the study population. Further studies focusing on cardiovascular disease in women are needed to better examine the relationship between HIV infection and cardiac steatosis.
 
Our study identified increased subclinical cardiac dysfunction in association with cardiac steatosis and fibrosis in HIV-infected adults. Given the known increased risk of cardiovascular disease in persons living with HIV [36], it is important to identify risk factors and create targeted strategies to prevent progression of global cardiac dysfunction. We demonstrate that increased visceral adipose tissue is a strong independent predictor of myocardial steatosis, and as such, reducing visceral adiposity should be a target for strategies of lifestyle modification and cardiovascular risk reduction. Further, impaired cardiac strain tracked with markers of chronic inflammation and immune activation, which may serve as targets for the development of therapeutic strategies to optimize long-term cardiovascular health in persons living with HIV.

 
 
 
 
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