A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
HIV infection leads to activation of coagulation, which may increase the risk for atherosclerosis and venous thromboembolic disease. We hypothesized that HIV replication increases coagulation potentially through alterations in extrinsic pathway factors.
Methods and Results
Extrinsic pathway factors were measured among a subset of HIV participants from the Strategies for Management of Anti‐Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross‐sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short‐term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons.
HIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV‐related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00027352.
antiretroviral therapy; coagulation; HIV infection; HIV replication; inflammation; thrombin generation
The prevalence of hypertension in African Americans in the United States is amongst the highest in the world and increasing. The identification of genes and pathways regulating blood pressure in African Americans has been challenging. An early predictor of hypertension is arterial stiffness. The prevalence of arterial stiffness is significantly higher in African Americans compared to Caucasians. Approximately 20% of the variance in arterial stiffness is estimated to be heritable. Identifying genes and biological pathways regulating arterial stiffness may provide insight into the genetics underlying the increased risk of hypertension in African Americans. This paper reviews the genetic findings to date in the area of arterial stiffness and blood pressure in African Americans with an emphasis on the current limitations and new efforts to move the field forward.
African Americans; arterial stiffness; arterial elasticity; compliance; genetics; DNA; variants; SNP; elastin; collagen; health and medicine
Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.
The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors.
Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p=0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p=0.60). Percent emphysema was associated with neither measure.
FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
To compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no PI) regimen.
2998 participants (average age 44 years, 28% females) enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial.
Primary outcome measures
Heart rate and two heart rate variability measures (the SD of all filtered RR intervals over the length of the recording (SDNN) and the root mean square of successive differences in normal RR intervals (rMSSD)).
At study entry, 869 participants were taking a boosted PI (PI/r), 579 a non-boosted PI and 1550 an NNRTI-no PI. Median values (IQR) of heart rate, SDNN and rMSSD were: 68 (60–75) beats/min (bpm), 21 (13–33) ms, 22 (13–35) ms in the PI/r group, 68 (60–75) bpm, 21 (13–33) ms and 21 (14–33) ms in the non-boosted PI group and 69 (62–77) bpm, 20 (13–31) ms and 21(13–33) ms in the NNRTI-no PI group. After adjustment for baseline factors, for those given PI/r and non-boosted PI, heart rate was 2.2 and 2.8 bpm, respectively, lower than the NNRTI-no PI group (p<0.001 for both). On the other hand, compared with the NNRTI-no PI group, log SDNN and log rMSSD were significantly greater for those in the non-boosted PI (p values for baseline adjusted differences in log-transformed SDNN and rMSSD were 0.004 and 0.001) but not for those in the PI/r group at the 0.01 α-level.
Compared to an NNRTI-no PI regimen, heart rate was lower for those taking a PI/r or non-boosted PI and heart rate variability was greater, reflecting better cardiac autonomic function, for those taking a non-boosted PI regimen but not PI/r.
Virology; Cardiology; Clinical Pharmacology
Lung function studies in middle-aged subjects predict cardiovascular disease (CVD) mortality. We studied if greater loss of forced vital capacity (FVC) early in life predicted incident hypertension (HTN). The sample was 3205 black and white men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) study examined between 1985-86 (CARDIA year 0, ages 18-30 years) and 2005-06 and who were not hypertensive by year 10. FVC was assessed at years 0, 2, 5, 10, and 20. Proportional hazard ratios (HR) and linear regression models predicted incident HTN at years 15 or 20 (n=508) from the change in FVC (FVC at year 10 – peak FVC, where peak FVC was estimated as the maximum across years 0, 2, 5 and 10). Covariates included demographics, center, systolic blood pressure, FVC max, smoking, physical activity, asthma and BMI. Unadjusted cumulative incident HTN was 25% in the lowest FVC loss quartile (Q1, median loss=370ml) compared to 12% cumulative incident HTN in those who achieved peak FVC at year 10 (Q4). Minimally adjusted HR for Q1 vs. Q4 was 2.21 (95% CI: 1.73-2.83) and this association remained significant in the fully adjusted model (1.37, 95% CI: 1.05-1.80). Decline in FVC from average age at peak (29.4 years) to 35 years old predicted incident hypertension between average ages 35 and 45. The findings may represent a common pathway that may link low normal FVC to cardiovascular disease morbidity and mortality.
forced vital capacity; hypertension; CARDIA; adults; cohort
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
It remains debated whether to include resting electrocardiogram (ECG) in the routine care of patients infected with Human immunodeficiency virus (HIV). This is largely because data are limited regarding the prevalence and prognostic significance of ECG abnormalities in HIV-infected patients.
This analysis included 4518 HIV-infected patients (28% females and 29% blacks) from The Strategies for Management of Antiretroviral Therapy (SMART) study, a clinical trial aimed to compare two HIV treatment strategies. ECG abnormalities were classified using the Minnesota Code. Multivariable adjusted Cox proportional hazards analysis was used to examine the association between baseline ECG abnormalities and incident cardiovascular disease.
More than half of the participants (N=2325, 51.5%) had either minor or major ECG abnormalities. Minor ECG abnormalities (48.6%) were more common than major ECG abnormalities (7.7%). During a median follow-up of 28.7 months, 155 (3.4%) participants developed incident cardiovascular disease. After adjusting for the study treatment arms, the presence of major, minor, and either minor or major ECG abnormalities were significantly predictive of incident cardiovascular disease [Hazard ratio (95% Confidence Interval): 2.76 (1.74, 4.39), p<0.001; 1.58 (1.14, 2.20), p=0.006; 1.57 (1.14, 2.18), p=0.006, respectively]. However, after adjusting for demographics, common cardiovascular risk factors and HIV characteristics (full model), presence of major ECG abnormalities was still significantly predictive of cardiovascular disease [1.83 (1.12, 2.97), p=0.015)], but not minor or minor or major abnormalities taken together [1.26 (0.89, 1.79), p=0.18; 1.25 (0.89, 1.76), p=0.20, respectively]. Individual ECG abnormalities that significantly predicted cardiovascular disease in the fully adjusted model included major isolated ST/T abnormalities, major prolongation of QT interval, minor isolated ST/T and minor isolated Q/QS abnormalities.
Nearly one in two of the HIV-infected patients in SMART study had ECG abnormalities; one in thirteen had major ECG abnormalities. Presence of ECG abnormalities, especially major ECG abnormalities was independently predictive of incident cardiovascular disease. These results suggest that the ECG could provide a convenient risk screening tool in HIV-infected patients.
HIV/AIDS; ECG; Cardiovascular Disease; SMART Study
African-Americans have a disproportionate burden of hypertension compared to Caucasians, while data on Hispanics is less well-defined. Mechanisms underlying these differences are unclear, but could be due in part to ancestral background and vascular function.
Methods and Results
660 African-Americans and 635 Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) with complete data on genetic ancestry, pulse pressure (PP), and large and small arterial elasticity (LAE, SAE) were studied. LAE and SAE were obtained using the HDI PulseWave CR-2000 Research CardioVascular Profiling Instrument. Among African-Americans higher European ancestry was marginally associated with higher LAE (p=0.05) and lower PP (p=0.05) among African-Americans; results for LAE were attenuated after adjustment for potential mediators (p=0.30). Ancestry was not associated with SAE in African-Americans. Among Hispanics, higher Native American ancestry was associated with higher SAE (p=0.0006); higher African ancestry was marginally associated with lower SAE (p=0.07). Ancestry was not significantly associated with LAE or PP in Hispanics.
Among African-Americans, higher European ancestry may be associated with less large artery damage as measured by LAE and PP, although these associations warrant further study. Among Hispanics, ancestry is strongly associated with SAE. Future studies should consider information on genetic ancestry when studying hypertension burden in race/ethnic minorities, particularly among Hispanics.
large artery elasticity; small artery elasticity; admixture; pulse pressure
Treatments that reduce inflammation and cardiovascular disease (CVD) risk among individuals with HIV infection receiving effective antiretroviral therapy (ART) are needed.
Design and Methods
We conducted a 2×2 factorial feasibility study of lisinopril (L) (10 mg daily) vs L-placebo in combination with pravastatin (P) (20 mg daily) vs P-placebo among participants receiving ART with undetectable HIV RNA levels, a Framingham 10 year risk score (FRS) ≥3%, and no indication for ACE-I or statin therapy. Tolerability and adherence were evaluated. Longitudinal mixed models assessed changes in blood pressure (BP), blood lipids, and inflammatory biomarkers from baseline through months 1 and 4.
Thirty-seven participants were randomized and 34 [lisinopril/pravastatin (n = 9), lisinopril/P-placebo (n = 8), L-placebo/pravastatin (n = 9), L-placebo/P-placebo (n = 8)] attended at least one follow-up visit. Participants were 97% male, 41% white, 67% were current smokers, and 65% were taking a protease inhibitor. Median age was 48 years, CD4 count 483 cells/mm3, FRS 7.79%, total cholesterol 184 mg/dL, and LDL-C 95 mg/dL. There was no treatment difference for pravastatin vs P-placebo in total cholesterol, LDL-C, or any of the inflammatory biomarkers. Participants randomized to lisinopril vs. L-placebo had significant declines in diastolic BP (−3.3 mmHg, p = 0.05), hsCRP (−0.61 µg/mL, p = 0.02) and TNF-α (−0.17 pg/mL, p = 0.04). Participants taking lisinopril vs L-placebo were more likely to report missed doses (88 vs 35%; p = 0.001) and have adherence <90% by pill count (42 vs. 0%; p = 0.02). Few participants from either group reported side effects (n = 3 vs. n = 1).
The modest BP changes and decreased adherence with lisinopril and absence of lipid differences with pravastatin suggest future studies of these drug classes should consider a run-in period to assess adherence and use a different statin. Our results also indicate that ACE-I therapy may have anti-inflammatory benefits for ART-treated persons with HIV infection and this should be further evaluated.
The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.
A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.
There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).
In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
arteries; cardiovascular diseases; elasticity; risk factors
HIV infection is associated with premature development of cardiovascular disease (CVD). Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce CVD risk.
A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy (SMART) study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40L and P-selectin levels.
At study entry, median (IQR) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n=114), participants randomized to immediate ART (n=134) had 10.3% lower ADMA levels (p=0.003) at 12 months; treatment differences in sCD40L (95% CI:-17 to 44%; p=0.53) and P-selectin (95% CI:-10 to 10%; p=0.95) were not significant. The difference in ADMA for those assigned immediate ART compared to those assigned ART deferral was greater among younger patients and those with higher levels of hsCRP and D-dimer (p≤0.05 for interaction for both), but not HIV RNA level at baseline (p=0.51).
ART initiation leads to declines in ADMA levels, a marker of nitric-oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that up-regulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
HIV infection; antiretroviral therapy; inflammation; endothelial dysfunction; asymmetric dimethylarginine (ADMA); CD40 ligand; P-selectin
The inferior vena cava (IVC) diameter and degree of inspiratory collapse are used as echocardiographic indices in the estimation of right atrial pressure. Brain-natriuretic peptides (BNPs) are established biomarkers of myocardial wall stress. There is no information available regarding the association between the IVC diameter and BNPs in patients with heart failure and various degrees of systolic performance. The purpose of this investigation is to quantify the degree to which natriuretic peptides (BNP and N-terminal pro-B natriuretic peptide [NT-ProBNP]) and echocardiographic-derived indices of right atrial pressure correlate in this patient population.
We examined 77 patients (mean age 61 ± 17 years, 44% male) with decompensated heart failure who underwent transthoracic echocardiography and, within a timeframe of 24 hours, determination of BNP and NT-ProBNP levels in venous blood. BNP and NT-ProBNP were analyzed after log transformation. The degree of association was measured by the correlation coefficient using the Pearson’s method.
The mean ejection fraction was 50% ± 20%, and 33% of the study cohort had a remote history of heart failure. The mean IVC diameter was 1.85 cm ± 0.5, the mean BNP was 274 pg/mL, the confidence interval (CI) was 95% (95% CI: 197–382), and the mean NT-ProBNP was 1994 pg/mL (95% CI: 1331–2989). There was a positive, albeit small, association between IVC diameter and BNP (r = 0.24, 95% CI: 0.01–0.44; P = 0.03) and NT-ProBNP (r = 0.27, 95% CI: 0.05–0.47; P = 0.01). Among patients with different degrees of IVC collapse in response to inspiration, values for BNP and NT-ProBNP did not differ substantially (P = 0.36 and 0.46 for BNP and NT-ProBNP, respectively).
Natriuretic peptides correlate weakly with IVC size and do not predict changes in response to intrathoracic pressure.
heart failure; inferior vena cava; natriuretic peptides
The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high- and low-density lipoprotein particle concentrations (HDL-P and LDL-P) and apolipoprotein (Apo) levels are not well described.
In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) to immediately initiate ART (‘VS group’) or to defer it (‘DC group’), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization.
Compared to DC group (n=126), HDL-P and ApoA1 levels increased among VS participants (n=128) after starting ART. At 6 months, VS participants had 13% higher total HDL-P (p < 0.001) and 9% higher ApoA1 (p < 0.001). LDL-P, VLDL-P, and ApoB did not differ significantly between the VS and DC groups. Among VS participants, predictors of HDL-P and ApoA1 increases included baseline levels of hsCRP and IL-6, but not HIV RNA level, CD4 count or traditional CVD risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (p=0.001 and 0.08, respectively, for interaction) or hsCRP (p=0.01 and 0.04, respectively, for interaction).
HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.
HIV infection; antiretroviral therapy; high-density lipoprotein; apolipoprotein A1; inflammation
There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.
This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett’s (QTcB) and Fredericia’s (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group.
Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P <0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P <0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P <0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P <0.01).
Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.
electrocardiogram; HIV/AIDS; PR; protease inhibitors; QTc
Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (≥6 months) at study entry, risk of AIDS and serious non-AIDS events was increased for participants who deferred ART compared to those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART.
Stored specimens for 254 participants (126 DC and 128 VS) who were naïve to ART or off ART (≥6 months) were analyzed for interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP) and D-dimer at baseline and months 2 and 6.
At month 6, 62% of VS group had HIV RNA <400copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 vs. 400 cells/mm3). Compared with DC, the VS group had 32% (95%CI: 19 to 43%) lower D-dimer levels at month 6 (p<0.001); differences were not significant for hsCRP or IL-6 levels.
In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not IL-6 and hsCRP, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease, and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.
Stage 2 hypertension often requires combination antihypertensive therapy. Ambulatory blood pressure monitoring (ABPM) is a useful tool for assessing antihypertensive drugs and their combinations.
To compare the effect of a moderate dose of angiotensin receptor blocker/calcium channel blocker (ARB/CCB) combined with a diuretic versus a maximal dose of ARB with a diuretic on 24-hour ambulatory blood pressure monitoring (ABPM) and other derived ambulatory blood pressure (ABP) parameters.
The EXforge As compared to Losartan Treatment ABPM substudy was a randomized, double-blind, parallel-group, active-control, forced-titration study of patients with Stage 2 hypertension that compared the efficacy of initial treatment with valsartan/amlodipine 160/5 mg (n = 48) or losartan 100 mg (n = 36). At week 3, hydrochlorothiazide (HCTZ) 25 mg was added in both treatment groups. ABP was measured at baseline and at week 6. Additionaly, 24-hour ABP, nighttime (10 pm to 6 am) and daytime (6 am to 10 pm) ABP, and ABP load (percentage of readings above 140/90 mmHg) were determined.
Eighty-four patients (48 ARB/CCB/HCTZ, 36 ARB/HCTZ) had ABPM at baseline and at week 6. Reductions of systolic/diastolic ABP were greater in the ARB/CCB/ HCTZ group than in the ARB/HCTZ group for 24-hour mean ABP (−22.0/−13.3 versus −17.4/−8.1 mmHg), as well as nighttime ABP (−22.2/−13.3 versus −16.2/−7.4 mmHg), daytime ABP (−21.9/−13.0 versus −18.1/−8.6 mmHg), ABP in the last 4 hours of the dosing period (−21.5/−13.5 versus −17.0/−7.7 mmHg), and ABP load (21.7%/12.8% versus 30.8%/20.0%).
Initiating antihypertensive treatment with moderate doses of ARB/CCB with a diuretic is more effective in lowering nighttime and daytime ABP and reducing ABP load than a maximal dose of an ARB with a diuretic.
antihypertensive drugs; ambulatory blood pressure; ambulatory blood pressure monitoring; combination therapy; valsartan; amlodipine; hydrochlorothiazide; losartan
HIV-infection; inflammation; coagulation; endothelial dysfunction; arterial elasticity; cardiovascular disease
The effect of interruption of antiretroviral therapy (ART) on lipoprotein particle subclasses has not been studied. We examined short-term changes in lipids and lipoprotein particles among 332 HIV-infected individuals randomized to interrupt or continue ART in the “Strategies for Management of Antiretroviral Therapy” trial.
Lipids and lipoprotein particles measured by nuclear magnetic resonance spectroscopy were compared between randomized groups at month 1; associations with inflammatory and coagulation markers (high sensitivity C-reactive protein; interleukin 6; amyloid A; amyloid P; D-dimer; prothrombin fragment 1 + 2) were assessed.
Compared with continuation of ART, treatment interruption resulted in substantial declines in total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglyceride, at month 1 but had little net effect on total/HDL cholesterol ratio [baseline-adjusted mean difference [95% confidence interval (CI)] interruption versus continuation arms: −0.10 (−0.59 to 0.38); P = 0.67]. ART interruption resulted in declines in total, large, and medium very low density lipoprotein (VLDL) particle concentrations (VLDL-p) and total and medium HDL-p. However, there was no change in small HDL-p [baseline-adjusted percentage difference between arms: −4.6% (−13.1%, +5.1% ); P = 0.35], small LDL-p [−5.0% (−16.9%, +8.6%); P = 0.45], or other LDL-p subclasses. Changes in lipid parameters on ART interruption did not differ according to baseline ART class (protease inhibitor versus non-nucleoside reverse transcriptase inhibitor) but were negatively associated both with changes in HIV viral load and with changes in inflammatory and coagulation markers, particularly D-dimer.
These results suggest that ART interruption does not favorably influence overall lipid profile: there was little net effect on total/HDL cholesterol ratio, and no change in small LDL-p or small HDL-p, the lipoprotein particle subclasses most consistently linked to coronary risk. Short-term declines in lipid parameters after ART interruption were not associated with class of ART and may be linked to increases in viral replication, inflammation and coagulation.
antiretroviral therapy interruption; coagulation markers; inflammatory markers; lipids; lipoprotein particle subclasses
HIV replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers for those with and without HIV infection.
For those aged 45–76, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), D-dimer, and cystatin C were compared for 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study with 5,386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). For those aged 33–44, hsCRP and IL-6 were compared for 287 participants in SMART with 3,231 participants in the Coronary Artery Development in Young Adults (CARDIA) Study.
hsCRP and IL-6 were 55% (p<0.001) and 62% (p<0.001) higher among HIV-infected participants compared to CARDIA. Compared to MESA, hsCRP, IL-6, D-dimer and cystatin C were 50%, 152%, 94%, and 27% higher (p<0.001 for each). For HIV-infected participants on ART with HIV-RNA levels ≤400 copies/mL, levels were higher (p<0.001) than the general population for all biomarkers (by 21% to 60%).
hsCRP, IL-6, D-dimer and cystatin C are elevated with HIV infection and remain so even after HIV-RNA levels are suppressed with ART. Further research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways in order to guide potential interventions.
Inflammation; coagulation; renal function; HIV infection; cardiovascular disease
Cardiovascular disease (CVD) is increasing in HIV-infected patients. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population. We aimed to quantify the risk of CVD events associated with NT-proBNP at baseline in the Strategies for Management of Anti-Retroviral Therapy study.
In a nested case–control study, NT-proBNP was measured at baseline in 186 patients who experienced a CVD event over an average of 2.8 years of follow-up and in 329 matched controls. Odds ratios (ORs) associated with baseline levels of NT-proBNP for CVD were estimated using conditional logistic regression.
At baseline median NT-proBNP [interquartile range (IQR)] was 48.1 (18.5, 112.9) pg/ml in patients who developed a CVD event and 25.7 (12.4, 50.2) pg/ml in controls. The unadjusted OR for the highest versus the lowest quartile was 3.7 [95% confidence interval (CI) 2.1–6.5, P < 0.0001]. After adjustment for baseline covariates and CVD risk factors, OR was 2.8 (95% CI 1.4–5.6, P = 0.003); with additional adjustment for IL-6, high-sensitivity C-reactive protein and D-dimer, OR was 2.3 (95% CI 1.1–4.9, P = 0.02).
Higher levels of NT-proBNP are associated with increased risk of CVD in HIV patients after considering established CVD risk factors and markers for inflammation and thrombosis.
AIDS; antiretroviral therapy; cardiovascular disease events; HIV; NT-proBNP; SMART
Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial.
SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT).
Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met “confirmed” and 13% “probable” criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached.
HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication.
clinical trials; cardiovascular disease; endpoint review committees; HIV; serious non-AIDS events