Author + information
- Received January 29, 2015
- Revision received February 24, 2015
- Accepted March 3, 2015
- Published online August 1, 2015.
- Eric A. Secemsky, MD∗,
- Rebecca Scherzer, PhD†,
- Elaine Nitta, MPH‡,
- Alan H.B. Wu, PhD§,
- David C. Lange, MD‖,
- Steven G. Deeks, MD¶,
- Jeffrey N. Martin, MD#,
- James Snider, PhD∗∗,
- Peter Ganz, MD‡ and
- Priscilla Y. Hsue, MD‡∗ ()
- ∗Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- †Department of Medicine, Veteran’s Affairs Medical Center, San Francisco, University of California-San Francisco, San Francisco, California
- ‡Division of Cardiology, Department of Medicine, San Francisco General Hospital, University of California-San Francisco, San Francisco, California
- §Laboratory Medicine, San Francisco General Hospital, University of California-San Francisco, San Francisco, California
- ‖Division of Cardiology, Department of Medicine, Cedars-Sinai Hospital, Los Angeles, California
- ¶San Francisco General Hospital HIV/AIDS Division, Department of Medicine, University of California-San Francisco, San Francisco, California
- #Department of Epidemiology and Biostatistics, University of California-San Francisco and San Francisco General Hospital HIV/AIDS Division, San Francisco, California
- ∗∗Critical Diagnostics, San Diego, California
- ↵∗Reprint requests and correspondence:
Dr. Priscilla Y. Hsue, Cardiology Division, San Francisco General Hospital, University of California-San Francisco, 1001 Potrero Avenue, SFGH 5G20, Box 0846, San Francisco, California 94143-0846.
Objectives This study sought to determine whether biomarkers ST2, growth differentiation factor (GDF)-15, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I are elevated in patients infected with human immunodeficiency virus (HIV) and are associated with cardiovascular dysfunction and all-cause mortality.
Background HIV-infected patients have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information.
Methods Biomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and sex-matched control subjects. Left ventricular systolic dysfunction was defined as ejection fraction <50%, diastolic dysfunction (DD) as stage 1 or higher, and pulmonary hypertension as pulmonary artery systolic pressure ≥35 mm Hg. Mortality data were obtained from the National Death Index.
Results Patients with HIV had a median age of 49 years, and 80% were male. Compared with control subjects, HIV-infected patients had higher adjusted percent estimates of all biomarkers except ST2 and interleukin-6. Among HIV-infected patients, 45% had DD; only ST2 was associated with DD (relative risk [RR]: 1.36; p = 0.047). Left ventricular systolic dysfunction was rare in this cohort (5%). Pulmonary hypertension was present in 27% of HIV-infected patients and was associated with GDF-15 (RR: 1.18; p = 0.04), NT-proBNP (RR: 1.18; p = 0.007), and cystatin C (RR: 1.54; p = 0.03). Thirty-eight deaths occurred among HIV-infected patients over a median of 6.1 years. In adjusted analysis, all-cause mortality was independently predicted by ST2 (hazard ratio [HR]: 2.04; p = 0.010), GDF-15 (HR: 1.42; p = 0.0054), high-sensitivity C-reactive protein (HR: 1.25; p = 0.023), and D-dimer (HR: 1.49; p = 0.029). Relationships were unchanged when analyses were restricted to virally suppressed HIV-infected patients receiving antiretroviral therapy.
Conclusions Among HIV-infected patients, ST2 and GDF-15 were associated with both cardiovascular dysfunction and all-cause mortality, and these variables may be useful at identifying those at risk for developing cardiovascular events and death.
Through the evolution of the human immunodeficiency virus (HIV) epidemic, cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality among HIV-infected patients. In contemporary observational studies of patients with HIV, the proportion of total deaths caused by CVD ranges from 6.5% to 15%, with HIV infection alone conferring a 61% increased risk compared with uninfected subjects (1,2).
Previously, this elevated risk of CVD, present even among treated and virally suppressed subjects, was largely attributed to the consequences of antiretroviral therapy (ART) use and the increased burden of traditional risk factors. However, in the SMART (Strategies for Management of Antiretroviral Therapy) trial, chronic inflammation and viral replication were identified as causative factors, which prompted further investigation into the role of HIV-induced inflammation and immune activation as possible mediators of cardiovascular risk (1,3).
An important step in establishing a relationship between HIV-associated immunologic perturbations and CVD is demonstrating that specific markers of these pathways predict subsequent events. However, most studied biomarkers, including high-sensitivity C-reactive protein (hsCRP), D-dimer, interleukin (IL)-6, and cystatin C, are predominantly released outside of the myocardium and may not represent a direct relationship between HIV infection and CVD.
Among subjects without HIV, novel biomarkers primarily expressed or secreted by cardiovascular tissue in response to pathological stress have been predictive of cardiovascular events and mortality. These include soluble ST2, growth differentiation factor (GDF)-15, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I (hsTnI) (4). However, only NT-proBNP has been evaluated in the HIV population (5).
The purpose of the present study was to determine whether ST2, GDF-15, NT-proBNP, and hsTnI are elevated in HIV-infected patients compared with uninfected control subjects and if these factors are associated with cardiovascular dysfunction and mortality. We also sought to establish whether these cardiac biomarkers provide independent assessment of risk compared with the previously studied biomarkers hsCRP, IL-6, D-dimer, and cystatin C.
Subjects with HIV infection were consecutively enrolled between September 2004 and March 2011 from SCOPE (Study of the Consequences of the Protease Inhibitor Era), a large clinic-based cohort at San Francisco General Hospital. All participants of SCOPE were documented to be HIV infected. The cohort included: 1) untreated patients, defined as no ART in the preceding 6 months; 2) treated patients with detectable viremia, defined as >24 weeks of ART with the most recent 2 HIV ribonucleic acid levels >75 copies/ml; and 3) treated patients who achieved full viral suppression, defined as >24 weeks of ART with 2 most recent HIV ribonucleic acid levels <75 copies/ml. The only inclusion criterion was HIV infection, and there were no exclusion criteria. Enrollment of the uninfected control group was targeted toward subjects with similar age, sex, and smoking status as the SCOPE population. Control subjects were not known to have CVD at the time of enrollment and tested negative for HIV. Written informed consent was provided by all study participants, and the study was approved by the University of California-San Francisco Committee on Human Research.
Clinical and sociodemographic characteristics
At enrollment, all participants completed a detailed interview, and information on traditional risk factors, medication use, and sociodemographic factors were collected. HIV-related disease characteristics collected included ART, duration of infection, history of opportunistic infections, and nadir CD4 count.
As described previously (6), a 2-dimensional transthoracic echocardiogram was performed on each participant within 6 months of enrollment by a single sonographer blinded to the participant’s HIV status. The presence of diastolic dysfunction (DD) was determined by using the guidelines from the American Society of Echocardiography (7). Left ventricular end-diastolic and end-systolic volumes and left ventricular ejection fraction (LVEF) were assessed by using the modified Simpson’s rule and indexed to body surface area. Pulmonary artery systolic pressure was quantified by using the modified Bernoulli equation to obtain the calculated pressure gradient and then added to the mean right atrial pressure, which was estimated from the diameter of the inferior vena cava, degree of inspiratory collapse, and hepatic vein Doppler profile (8). All calculations and interpretations were performed offline by 2 cardiologists who were blinded to participants’ HIV infection and clinical status.
Eight biomarkers were selected because of reported associations with CVD or death in either the general population and/or HIV-infected patients. The biomarkers included: ST2 (fibrosis); GDF-15 (apoptosis); NT-proBNP (myocyte stretch); hsTnI (myocardial injury); hsCRP and IL-6 (inflammation); cystatin C (renal dysfunction); and D-dimer (thrombosis) (4,5,9–12). Thresholds of risk for ST2, GDF-15, and NT-proBNP were pre-defined based on earlier studies associating values exceeding these cutpoints with CVD. These thresholds were: ST2 >35 ng/ml, GDF-15 >1,200 pg/ml, and NT-proBNP >300 pg/ml (13–16). Detectable troponin was defined as ≥0.006 ng/ml, which is the minimal detection limit. Details regarding assay brands, ranges and sensitivities are shown in Online Table 1.
Follow-up and outcomes
All patients were followed up as part of the SCOPE study. The main echocardiographic outcomes were DD, defined as stage 1 or higher findings, and pulmonary hypertension (PHTN), classified as pulmonary artery systolic pressure ≥35 mm Hg (8). Systolic dysfunction, defined as an LVEF <50%, was not considered a primary outcome because of the low prevalence in the HIV population (17). For all-cause mortality, participants were followed up through December 2012 or until time of death as determined by the National Death Index. Two independent physicians adjudicated cardiovascular death by using patient International Classification of Diseases-Ninth Revision (ICD-9) codes provided by the National Death Index. To be considered a cardiovascular death, patients had to have an ICD-9 code related to cardiovascular pathology in ≥1 of the first 3 ICD-9 codes reported on the death document.
Covariates of interest included demographic characteristics, CVD risk factors, and HIV-related risk factors. Multiple imputation with the Markov chain Monte Carlo method was used to impute missing covariates, with 5 imputations to yield ∼95% relative efficiency.
Demographic and clinical characteristics were compared between groups by using the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. Spearman coefficients were used to evaluate correlations between biomarkers.
We used multivariable linear regression to evaluate the associations of HIV infection and other factors with each candidate biomarker, with separate models for each outcome. We used Huber-White SEs, which are designed to be robust to nonnormally distributed residuals. Because of the high percentage of below-detectable values, Tobit regression was used to evaluate associations with hsTnI. Because the biomarkers were right-skewed, each outcome was log-transformed for analysis; results were back-transformed to produce estimated percent differences. To determine whether HIV infection was independently associated with each biomarker, multivariable models were adjusted for age, sex, and estimated glomerular filtration rate, calculated by using the Modification of Diet in Renal Disease formula. Poisson regression with a robust variance estimator was used to assess the associations of biomarkers with the dichotomous outcomes of DD and PHTN, and Cox proportional hazards regression was used to obtain hazard ratios for all-cause mortality. We also used unadjusted generalized additive models to produce a spline plot depicting the probability of mortality over the range of each biomarker.
To determine whether each biomarker was independently associated with the outcome, multivariable models were sequentially adjusted for: 1) demographic characteristics; and 2) cardiovascular and HIV-related risk factors. Factors forced in the full model included age, sex, and race/ethnicity. Stepwise backward selection was used with a significance level of α = 0.05 to remove candidate biomarkers that were not associated with each outcome. As an alternative approach, Bayesian model averaging was used and predictors with posterior probabilities >35% were retained. We constructed receiver-operating characteristic curves and calculated Harrell’s C-index of concordance for survival models to assess model discrimination.
Bayesian model averaging was performed by using the BMA package for the R statistical computing language (R Development Core Team, Vienna, Austria). All other analyses were conducted by using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina).
Study group characteristics
A total of 332 HIV-infected patients and 50 age- and sex-matched control subjects were studied. Baseline characteristics are shown in Table 1. HIV-infected patients were more often African American and had a higher prevalence of hypertension, hepatitis C infection, and previous intravenous drug use. Among HIV-infected participants, the median duration of infection was 14 years, 79% were currently on ART, and 60% had undetectable viral loads. The median current CD4 count was 469 cells/mm3, and the median nadir CD4 count was 160 cells/mm3.
Echocardiographic parameters and study outcomes
Echocardiographic measures and study outcomes are summarized in Table 2. Median LVEF was 61% in both HIV-infected patients and control subjects. Fourteen HIV-infected patients, compared with no control subjects, had an LVEF <50% (p = 0.23). DD was present in 45% of HIV-infected participants versus 28% of control subjects (p = 0.02). The median left ventricular mass was greater in patients with HIV compared with control subjects (77.3 g/m2 vs. 66.4 g/m2; p < 0.001). Eighty-nine HIV-infected patients, compared with 1 control subject, met the criteria for PHTN (p < 0.001). Pulmonary artery systolic pressure was significantly higher in HIV-infected patients compared with control subjects (31.0 mm Hg vs 22.5 mm Hg; p < 0.001). Results were similar when the analysis was restricted to treated, virally suppressed HIV-infected patients (Online Table 2).
Thirty-eight deaths occurred in the HIV-infected cohort over a median follow-up of 6.1 years (interquartile range [IQR]: 3.0 to 7.9 years), and 3 deaths occurred in the control group over a median follow-up of 7.7 years (IQR: 7.6 to 7.8 years), corresponding to a 5-year mortality rate of 10.3% in HIV-infected patients and 4.0% in control subjects (p = 0.094). HIV-infected patients who died compared with those who survived had a higher prevalence of hepatitis C and opportunistic infections, longer duration of HIV infection, lower current CD4 counts, and higher HIV viral loads (Online Table 3).
Compared with control subjects, HIV-infected patients had higher levels of all biomarkers with the exception of ST2, IL-6, and the prevalence of detectable hsTnI (Table 3). After controlling for age, sex, and estimated glomerular filtration rate, HIV infection was associated with greater percent estimates of all candidate biomarkers except ST2 and IL-6. In addition, more HIV-infected patients compared with control subjects exceeded pre-defined CVD risk thresholds for ST2 (31% vs. 14%; p = 0.01), GDF-15 (40% vs. 0%; p<0.001), and NT-proBNP (9.5% vs. 0%; p = 0.02) (13–16). Biomarker levels were only moderately intracorrelated (r ≤ 0.35 for all) (Online Table 4). Results were similar when the analysis was restricted to treated, virally suppressed HIV-infected patients (Online Table 5).
Association of biomarkers with study outcomes in HIV-infected patients
ST2 was the only biomarker significantly associated with DD after adjustment for demographics, with each doubling of ST2 conferring a 43% increased risk (Table 4). ST2 remained independently related to DD after adjustment for CVD and HIV-related risk factors (36%; p = 0.047), whereas other biomarkers exhibited weaker associations that were not statistically significant.
In demographic-adjusted analyses, each doubling of NT-proBNP was associated with a 15% increased risk of PHTN (p = 0.004), and each doubling of GDF-15 was associated with a 19% increased risk (p = 0.02). Both NT-proBNP and GDF-15 remained independently related to PHTN after multivariable adjustment (Table 4). Cystatin C was associated with PHTN only in the fully adjusted analysis (relative risk: 1.54 [95% confidence interval: 1.04 to 2.29]; p = 0.03). No combination of biomarkers strengthened the association with PHTN.
In the fully adjusted analysis, ST2, GDF-15, hsCRP, and D-dimer were each associated with all-cause mortality (Table 4). ST2 demonstrated the strongest association with all-cause mortality, with each doubling of ST2 conferring a 104% increased risk of death. No combination of biomarkers was simultaneously associated with mortality. When controlling for ST2, GDF-15, hsCRP, and D-dimer simultaneously, the hazard ratios for each marker were attenuated, and no associations with mortality remained statistically significant. Graphical examination of the association of ST2 and GDF-15 with all-cause mortality is shown in Figure 1. A strong linear association was seen for GDF-15 (p < 0.001), with increasing GDF-15 levels associated with a greater probability of mortality. Increasing ST2 was also associated with all-cause mortality (p = 0.0024), but the slope appeared steeper at higher values of ST2 (test for nonlinearity: p = 0.035), with an inflection point occurring near 50 ng/ml.
For all-cause mortality, model discrimination was modest in the unadjusted analysis for ST2 (c = 0.61 [95% confidence interval: 0.51 to 0.71]) and GDF-15 (c = 0.67 [95% confidence interval: 0.58 to 0.76]). Fully adjusted models that included demographic and clinical variables demonstrated strong discrimination for all-cause mortality (c = 0.85 [95% confidence interval: 0.79 to 0.91]), with no change in area under the curve when either biomarker was added (Online Figure 1).
Of the 38 HIV-infected patients who died, 12 died of cardiovascular causes. Among these patients, the median ST2 level was 38.1 ng/ml (IQR: 26.6 to 51.2 ng/ml), and the median GDF-15 level was 1,777.4 pg/ml (IQR: 942.8 to 4,528.4 pg/ml). Nine of the 12 patients with cardiovascular death exceeded pre-defined CVD risk thresholds for either ST2 and/or GDF-15 (13–16), with 5 of these patients having elevated levels of both ST2 and GDF-15.
Association of biomarkers with study outcomes in treated, virally suppressed HIV-infected patients
For each study outcome, we assessed for the interaction between individual biomarkers and detectable viremia and ART use. The only significant interaction occurred between ST2 and detectable viral load for the outcome of mortality (p = 0.049) (Online Table 6). When the analysis was restricted to HIV participants on ART and with undetectable viral loads, there was no significant change in the associations between biomarkers and study outcomes (Online Table 7).
In the current study, we examined the relationship between cardiovascular dysfunction and all-cause mortality in ambulatory HIV-infected patients by using 4 cardiac biomarkers (ST2, GDF-15, NT-proBNP, and hsTnI) and 4 nonspecific biomarkers previously associated with HIV-related cardiovascular events (hsCRP, IL-6, D-dimer, and cystatin C). Of these, ST2 was the only biomarker associated with DD, a finding that was independent of traditional and HIV-related risk factors, whereas GDF-15, NT-proBNP, and cystatin C were independently associated with PHTN. In addition, ST2, GDF-15, hsCRP, and D-dimer were each predictive of all-cause mortality. Only ST2 and GDF-15 were associated with both cardiovascular dysfunction and all-cause mortality, and they were elevated in the majority of HIV-infected patients who experienced cardiovascular death. Importantly, the associations between biomarkers and outcomes were unchanged when restricted to treated, virally suppressed patients with HIV.
CVD in the HIV population accounts for a large proportion of morbidity and mortality, and as HIV-infected patients continue to live longer, the burden of CVD will simultaneously rise (1). As such, CVD has become an important health issue for primary providers, and the ability to identify HIV-infected patients who are at risk is now an essential component in their ongoing management. The pathophysiology of CVD in HIV, however, is complex and multifactorial, likely involving the interplay between an increased burden of traditional risk factors, adverse effects of ART, immune activation, and chronic viral-mediated inflammation. As a result, traditional cardiovascular risk algorithms developed for the non–HIV-infected population do not accurately predict cardiovascular risk in HIV-infected patients because they fail to account for factors unique to HIV infections (18).
Incorporating serum biomarkers reflecting specific disease pathways into risk-stratification algorithms has previously demonstrated improvements in the ability to predict cardiovascular events among non–HIV-infected subjects beyond established risk factors (4). For example, hsCRP has shown the ability to strengthen the prediction of cardiovascular risk in the general population and is associated with subclinical atherogenesis, cardiovascular events, and mortality in HIV-infected patients (9,10). However, hsCRP is primarily secreted by the liver and likely reflects an indirect mechanism involved in the development of CVD.
In contrast, cardiac-specific biomarkers represent more terminal pathways in the pathophysiology of CVD and may improve the prediction of cardiovascular-related outcomes. For example, among ambulatory subjects from the Framingham Heart Study, ST2, GDF-15, hsTnI, and BNP were each associated with incident heart failure, major cardiovascular events, and death, whereas hsCRP only showed an association with death (4).
ST2 is a member of the IL-1 receptor family and is induced in cardiac myocytes and fibroblasts in response to mechanical strain. Signaling between IL-33 and ST2 is thought to be cardioprotective, primarily through inhibiting the development of cardiac fibrosis. Circulating ST2 is a sensitive marker of cardiac stress and has prognostic value in patients with myocardial infarction and heart failure (13,19). To date, the only published analysis of ST2 in HIV-infected patients was from a small study comparing ST2 levels in 26 HIV-infected patients versus noninfected control subjects either with or without active atopic dermatitis (20).
Although ST2 levels in HIV-infected patients were similar to that of control subjects in our study, HIV-infected patients were more likely to exceed a ST2 risk threshold associated with adverse events in patients with heart failure (13,14). In addition, despite our HIV cohort having a younger age, more optimal lipid profiles, and a lower prevalence of diabetes, median ST2 levels among HIV-infected patients were higher than levels seen in the Framingham population (28.5 ng/ml vs. 21.05 ng/ml) (4).
More impressive, however, was the relationship between ST2 with DD and all-cause mortality in HIV-infected patients. In a previous study by our group, we determined that HIV-infected patients have a higher prevalence of DD and increased left ventricular mass indices compared with noninfected subjects, independent of traditional risk factors (6). These findings have been replicated in subsequent studies among different HIV populations (17). Furthermore, a high prevalence of cardiac steatosis and fibrosis as shown by cardiac magnetic resonance imaging has been reported in treated HIV-infected patients compared with noninfected control subjects (21). Myocardial fibrosis and DD are known risk factors for mortality in the general population, and in a separate study by our group, HIV-infected patients who experienced sudden cardiac death were ∼8 times more likely to have DD compared with those experiencing death related to acquired immune deficiency syndrome (22). Thus, it is plausible that elevated ST2 in HIV-infected patients is a mediator of fibrosis, DD, and possibly death. Further investigation is needed to more completely delineate this association.
GDF-15 is strongly induced in cardiac myocytes in response to cardiovascular inflammation, tissue injury, and pressure-overload states and is involved in the regulation of cell differentiation and tissue repair. Among subjects without HIV, levels of GDF-15 are markedly elevated in the setting of acute coronary syndromes and heart failure, and correlate with disease severity and mortality risk (23,24). In addition, GDF-15 levels identify ambulatory patients with and without CVD at risk for future events and are predictive of the development of PHTN (15,25).
To our knowledge, GDF-15 has not been described in the HIV population. In the present study, HIV-infected patients had GDF-15 concentrations significantly greater than that of control subjects and remained independently associated with PHTN, increasing pulmonary artery systolic pressure and mortality after controlling for traditional and HIV-related variables.
GDF-15 is up-regulated in pulmonary vascular endothelial cells in response to hypoxia and laminar stress and is thought to be involved in the regulation of apoptosis, cellular proliferation, and the development of PHTN (26). Because PHTN is a well-recognized complication of HIV infection that heightens the risk of mortality, it is plausible that increased GDF-15 expression in HIV-infected patients mediates this disease process.
This study is also the first to assess an hsTnI assay in HIV-infected patients and expands upon limited existing data investigating the association between other troponin assays and HIV-related CVD (27). Although the current study did not find a significant relationship between hsTnI levels and cardiovascular dysfunction or mortality, HIV-infected patients were more likely to have detectable hsTnI levels compared with control subjects. It is possible that detection of hsTnI in our study reflects subclinical coronary artery disease, which we were unable to assess.
Levels of NT-proBNP were associated with PHTN in the current study but not with DD or mortality after full adjustment. Unlike the other cardiac-specific biomarkers, the relationship between NT-proBNP and CVD in HIV-infected patients has been previously evaluated. In the SMART trial, NT-proBNP was independently associated with cardiovascular events after adjustment for baseline covariates, traditional risk factors, IL-6, hsCRP, and D-dimer (5). Other studies have also explored the relationship between natriuretic peptides and cardiovascular function in HIV-infected patients with conflicting results (28). In a previous study, we found no association between BNP and DD in HIV-infected patients but a similar positive relationship with pulmonary artery systolic pressure (6). Thus, at this time, the association between NT-proBNP and HIV-related CVD remains unclear.
Our study demonstrated significant associations between D-dimer and hsCRP with all-cause mortality, consistent with results of previous studies (9–11). However, neither of these biomarkers was associated with cardiovascular dysfunction. Importantly, few prior studies have evaluated whether a relationship exists between these nonspecific biomarkers and cardiovascular function as determined by echocardiography in HIV-infected patients. In a previous study by our group, hsCRP was not found to be significantly associated with the presence of DD in HIV-infected patients (6). In addition, a recent meta-analysis of 2,242 HIV-infected patients from 11 studies found no association between hsCRP and DD (17). Therefore, these nonspecific biomarkers may only be a global marker of risk for all-cause mortality but not useful for identifying patients with occult cardiovascular dysfunction.
This is the first study to determine levels of GDF-15 and hsTnI in HIV-infected patients and the first to examine whether cardiac biomarkers are associated with echocardiographic determinants of cardiovascular dysfunction and all-cause mortality. Although only a single assessment of each biomarker was used for the prediction of the study outcomes, previous studies have shown that baseline biomarker measurements in HIV-infected patients are stable over time and remain strongly and independently associated with future events (12). Due to the small number of deaths, only a descriptive analysis of cardiovascular mortality was performed. In addition, the diagnosis of PHTN was made by using echocardiographic measurements, which lack specificity compared with invasive hemodynamic studies and cannot discriminate between the etiologies of PHTN. Although we found similar results when we restricted our analysis to patients on ART with undetectable viremia, our results do not exclude the possibility that certain ART agents or classes may have important associations with the development of CVD. Lastly, we cannot exclude the possibility that associations between biomarkers and outcomes may be due in part to residual confounding or unmeasured confounders.
Our study showed that ST2 and GDF-15 were associated with both cardiovascular dysfunction and all-cause mortality in ambulatory HIV-infected patients. Future studies are necessary to elucidate the potential role of ST2 and GDF-15 in identifying patients with subclinical cardiovascular dysfunction and those at risk of developing cardiovascular events, including death.
COMPETENCY IN MEDICAL KNOWLEDGE: With the advent of highly active ART, the HIV population is now growing older, and in parallel with this trend, CVD has emerged as an important health concern. Novel biomarkers of myocardial stress have identified at-risk patients for cardiovascular events in the general population and may provide additional prognostic information for patients with HIV infection.
TRANSLATIONAL OUTLOOK: Because methods to better identify HIV-infected patients at risk for cardiovascular events are needed, further investigation into the role of cardiac biomarkers such as ST2 and GDF-15 for the risk-stratification of these patients is warranted.
For supplemental tables and a figure, please see the online version of this article.
Dr. Scherzer has received honorarium from Merck for participating in an HIV Renal Expert Input Forum; the honorarium was donated to the Northern California Institute for Research and Education to support kidney research. Dr. Wu has a patent with and receives speaker fees from Singulex. Dr. Hsue has received honoraria from Gilead and Pfizer; and grant support from the National Heart, Lung, and Blood Institute (RO1 HL095130 and RO1 HL091526). Dr. Snider is an employee of Critical Care Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- antiretroviral therapy
- cardiovascular disease
- diastolic dysfunction
- growth differentiation factor
- human immunodeficiency virus
- high-sensitivity C-reactive protein
- high-sensitivity troponin I
- International Classification of Diseases-Ninth Revision
- interquartile range
- left ventricular ejection fraction
- N-terminal pro–B-type natriuretic peptide
- pulmonary hypertension
- Received January 29, 2015.
- Revision received February 24, 2015.
- Accepted March 3, 2015.
- American College of Cardiology Foundation
- Boccara F.,
- Lang S.,
- Meuleman C.,
- et al.
- Wang T.J.,
- Wollert K.C.,
- Larson M.G.,
- et al.
- Hsue P.Y.,
- Hunt P.W.,
- Ho J.E.,
- et al.
- De Luca A.,
- de Gaetano Donati K.,
- Colafigli M.,
- et al.
- Neuhaus J.,
- Jacobs D.R.,
- Baker J.V.,
- et al.
- Rehman S.U.,
- Mueller T.,
- Januzzi J.L.
- Ky B.,
- French B.,
- McCloskey K.,
- et al.
- Januzzi J.L.,
- van Kimmenade R.,
- Lainchbury J.,
- et al.
- Cerrato E.,
- D’Ascenzo F.,
- Biondi-Zoccai G.,
- et al.
- Holloway C.J.,
- Ntusi N.,
- Suttie J.,
- et al.
- Wollert K.C.,
- Kempf T.,
- Peter T.,
- et al.
- Kempf T.,
- von Haehling S.,
- Peter T.,
- et al.
- Jain N.,
- Reddy D.H.,
- Verma S.P.,
- et al.