Hypercholesterolemia in midlife increases risk for Alzheimer’s disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD.
In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound.
At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p<0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo.
In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD.
Alzheimer’s disease; cerebral blood flow; dementia; MRI perfusion; prevention; statins
The long-term effects of smoking and smoking cessation on markers of cardiovascular disease (CVD) prognosis obtained during treadmill stress testing (TST) are unknown. The purpose of this study was to evaluate the long-term effects of smoking cessation and continued smoking on TST parameters that predict CVD risk.
In a prospective, double-blind, randomized, placebo-controlled trial of 5 smoking cessation pharmacotherapies, symptom-limited TST was performed to determine peak METs, rate-pressure product (RPP), heart rate (HR) increase, HR reserve, and 60-second HR recovery, before and 3 years after the target smoking cessation date. Relationships between TST parameters and treatments among successful abstainers and continuing smokers were evaluated using multivariable analyses.
At baseline, the 600 current smokers (61% women) had a mean age of 43.4 (SD 11.5) years and smoked 20.7 (8.4) cigarettes per day. Their exercise capacity was 8.7 (2.3) METs, HR reserve was 86.6 (9.6)%, HR increase was 81.1 (20.9) beats/min, and HR recovery was 22.3 (11.3) beats. Cigarettes per day and pack-years were independently and inversely associated with baseline peak METs (P < .001), RPP (P < .01, pack-years only), HR increase (P < .05), and HR reserve (P < .01). After 3 years, 168 (28%) had quit smoking. Abstainers had greater improvements than continuing smokers (all P < .001) in RPP (2,055 mm Hg beats/min), HR increase (5.9 beats/min), and HR reserve (3.7%), even after statistical adjustment (all P < .001).
Smokers with a higher smoking burden have lower exercise capacity, lower HR reserve, and a blunted exercise HR response. After 3 years, TST improvements suggestive of improved CVD prognosis were observed among successful abstainers.
HIV-infected patients have low vitamin D levels as well as an increase in cardiovascular (CVD) risk. We examined the relationship between vitamin D and three markers of arterial dysfunction among HIV-infected individuals on stable antiretroviral (ARV) therapy. Levels of 25-hydroxyvitamin D [25(OH)D] were assessed by chemiluminescent immunoassay (DiaSorin) in 100 enrollees into the Hawaii Aging with HIV-Cardiovascular Cohort Study, a cohort of HIV-infected subjects age ≥40 years on stable (≥6 months) ARV therapy. The relationships between 25(OH)D levels and brachial artery flow-mediated dilation (FMD), right common carotid artery intima-media thickness (cIMT), and coronary artery calcium (CAC) were examined. Analytical methods included Pearson's correlations, Kruskal–Wallis tests, relative risks, and linear regression models. The cohort was 86% male and 60% white with a median age of 52 years and CD4 of 510 cells/mm3. The median (Q1, Q3) level of 25(OH)D was 27.9 ng/ml (21.8, 38.3). There were 72 FMD, 50 cIMT, and 90 CAC measurements available for analyses. A significant correlation was observed between 25(OH)D levels and FMD (r=0.30, p=0.01) but not with cIMT (r=−0.05, p=0.76). In a linear regression model, Framingham risk score attenuated the relationship between FMD and 25(OH)D. Those with lower 25(OH)D levels were at slightly higher risk of having CAC (RR=1.02, p=0.04). Among those with CAC, lower 25(OH)D levels were not associated with higher CAC scores (p=0.36). Lower vitamin D levels are associated with evidence of subclinical arterial dysfunction in HIV-infected individuals. The significance of these findings warrants further investigation.
To evaluate associations between traditional cardiovascular disease (CVD) risk factors, inflammatory markers, and markers of HIV disease activity with ultrasonographic measures of CVD risk in patients with HIV who are not receiving antiretroviral therapy (ART).
Cross-sectional, baseline evaluation of ART-naïve HIV-infected individuals without known CVD or diabetes mellitus enrolled in a randomized ART treatment trial.
Prior to ART initiation, carotid artery intima-media thickness (CIMT) and brachial artery flow-mediated dilation (FMD) were measured. Additional parameters included CD4 cell count, HIV viral load, body composition, lipoproteins, and inflammatory markers. Associations with common CIMT, bifurcation CIMT, presence of carotid artery lesions, and brachial artery FMD were evaluated.
The 331 enrolled subjects were a median (1st–3rd quartile) of 36 (28–45) years old. Common and bifurcation CIMT values were higher and lesions more prevalent with older age (p <0.001). FMD was lower with older age (p =0.009). Those with a Framingham Risk Score >6%/10 years (N =44) had higher common and bifurcation CIMT (p <0.001), carotid lesion prevalence (p <0.001), and lower FMD (p =0.035). Independent associations with common CIMT were identified for increasing age, height, weight, small LDL particles, and black race; these were similar for bifurcation CIMT. Presence of carotid artery lesions was associated with increasing age, presence of metabolic syndrome, interleukin-6, and lower HIV-1 RNA.
In a contemporary cohort of ART-naive HIV-infected individuals, ultrasonographic measures of CVD risk were more strongly associated with traditional risk factors than CD4 cell counts, HIV replication, or inflammatory markers.
atherosclerosis; carotid arteries; endothelial function; human immunodeficiency virus; inflammation
atherosclerosis; carotid arteries; carotid intima-media thickness; human immunodeficiency virus
Atherosclerosis; Carotid arteries; Risk factors; Ultrasound
Carotid ultrasound screening (CUS) has been recommended for cardiovascular disease (CVD) risk prediction; however, its effectiveness in clinical practice is unknown. The purpose of this study was to prospectively determine the effects of office-based CUS on physician decision-making and patient health-related behaviors (HRBs).
Physicians from 5 non-academic, community practices recruited patients ≥40 years old with ≥1 CVD risk factor. Abnormal carotid ultrasound screening (AbnlCUS) was defined as carotid intima-media thickness >75th percentile or carotid plaque presence. Subjects completed questionnaires before and immediately after CUS, then 30 days later to determine self-reported behavioral changes. Odds ratios (OR) for changes in physician management and patient HRBs were determined from multivariate hierarchical logistic regression models.
There were 355 subjects (mean [standard deviation] 53.6 [7.9] years old, 2.3 [0.9] risk factors, 58% women); 266 (74.9%) had AbnlCUS. Presence of AbnlCUS altered physicians’ prescription of aspirin (p<0.001) and cholesterol medications (p<0.001). Immediately after CUS, subjects reported increased ability to change HRBs (p=0.002), regardless of their test results. Subjects with AbnlCUS reported increased CVD risk perception (OR 4.14, p<0.001), intentions to exercise (OR 2.28, p=0.008), make dietary changes (OR 2.95, p<0.001), and quit smoking (OR 4.98, p=0.022). After 30 days, 34% increased exercise frequency and 37% reported weight loss; but these changes were not predicted by the CUS results. AbnlCUS modestly predicted reduced dietary sodium (OR 1.45, p=0.002) and increased fiber (OR 1.55, p=0.022) intake.
Finding abnormal results on CUS had major effects on physician but not patient behaviors.
Atherosclerosis; Carotid arteries; Risk factors; Ultrasound
This study characterized the determinants of carotid atherosclerosis in a large, contemporary sample of current smokers. Associations between risk factors, carotid intima-media thickness (CIMT) and carotid plaque presence were determined by multivariable regression. Subjects included 1,504 current smokers (58% female) who were a median (interquartile range) of 44.7 (38–53) years old and smoked 25 (15–40) pack-years; 55% had plaque. Pack-years, age, male sex, non-white race, body-mass index, systolic blood pressure, small low-density lipoproteins (LDL), and total high-density lipoproteins were independently associated with CIMT (model R2=0.434, p<0.001). Pack-years (OR 1.14 per 10 pack-years, p=0.001), age (OR 1.75 per 10 years, p<0.001), body-mass index (OR 0.91 per 5 kg/m2, p =0.035), and small LDL (OR 1.11 per 100 nmol/L, p<0.001), were independently associated with carotid plaque presence (model X2=210.7, p<0.001). The association between pack-years and carotid plaque was stronger in women (OR 1.09 per 10 pack-years, pinteraction=0.018).
atherosclerosis; carotid; arteries; lipoproteins; smoking
Research shows that certain antihypertensives taken during midlife confer Alzheimer’s disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including CSF amyloid β levels (Aβ) and ACE activity, arterial function and cognition in participants with a parental history of AD.
This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier (BBB) crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ1–42 and ACE activity, arterial function and cognition.
Participants were middle-aged (mean 54yrs) highly educated (mean 15.4yrs), and included 50% men and 50% APOEε4 carriers. While results did not show a treatment effect on CSF Aβ1–42 (p=0.836), data revealed that ramipril can inhibit CSF ACE activity (p=0.009) and improve blood pressure (BP), however there were no differences between groups in arterial function or cognition.
In this study, ramipril therapy inhibited CSF ACE activity and improved BP, but did not influence CSF Aβ1–42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of Angiotensin II-mediated inhibition of acetylcholine.
Alzheimer’s disease; Hypertension; Blood Pressure; Clinical Trial; Vascular Risk; Cognition; Angiotensin Converting Enzyme; Antihypertensive; Arterial Function; Prevention
The effects of smoking and smoking cessation on lipoproteins have not been studied in a large contemporary group of smokers. This study was designed to determine the effects of smoking cessation on lipoproteins.
One-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained before and 1-year after the target smoking cessation date. The effects of smoking cessation and predictors of changes in lipoproteins after one year were identified by multivariable regression.
The 1,504 current smokers were mean (standard deviation) 45.4 (11.3) years old and smoked 21.4 (8.9) cigarettes/day at baseline. Of the 923 adult smokers who returned at 1 year, 334 (36.2%) had quit smoking. Despite gaining more weight (4.6 kg [5.7] vs. 0.7 kg [5.1], p<0.001], abstainers had increases in high-density lipoprotein cholesterol (HDL-C) (2.4 [8.3] vs. 0.1 [8.8] mg/dL, p<0.001], total HDL (1.0 [4.6] vs. −0.3 mcmol/L [5.0], p<0.001) and large HDL (0.6 [2.2] vs. 0.1 [2.1] mcmol/L, p=0.003) particles, compared with continuing smokers. Significant changes in low-density lipoprotein (LDL) cholesterol and particles were not observed. After adjustment, abstinence from smoking (p<0.001) was independently associated with increases in HDL-C and total HDL particles. These effects were stronger in women.
Despite weight gain, smoking cessation improved HDL-C, total HDL and large HDL particles, especially in women. Smoking cessation did not affect LDL or LDL size. Increases in HDL may mediate part of the reduced cardiovascular disease risk observed after smoking cessation.
Clinical Trial; High-density lipoprotein cholesterol; Lipoproteins; Low-density lipoprotein cholesterol; Risk Factors; Smoking
Cigarette smoking has been associated with increases in C-reactive protein (CRP) and leukocyte counts (WBC); however, the effects of smoking intensity and smoking cessation on inflammatory markers have not been evaluated prospectively in a large, modern cohort of current smokers.
WBC count and high-sensitivity CRP were measured in current smokers enrolled in a randomized, prospective clinical trial of five smoking cessation pharmacotherapies. Smoking intensity parameters included: cigarettes/day, pack-years, Fagerstrom Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels. CRP also was measured after 1 year with assessment of abstinence status.
The 1,504 current smokers (58% female) were mean (standard deviation): 44.7 (11.1) years old, smoked 21.4 (8.9) cigarettes/day and had a smoking burden of 29.4 (20.4) pack-years. Log (CRP) was not associated with any marker of smoking intensity, except for a weak correlation with pack-years (r=0.05, p=0.047). In contrast, statistically significant correlations were observed between all 4 markers of smoking intensity and WBC count (all p≤0.011). In multivariable models, waist circumference (p<0.001) and triglycerides (p<0.05), but no markers of smoking intensity, were associated with log(CRP). However, pack-years (p=0.002), cigarettes/day (p=0.013), CO (p<0.001), and FTND (p<0.001) were independently associated with WBC count. After 1 year, log(CRP) (p=0.296) and changes in log(CRP) (p=0.455) did not differ between abstainers and continuing smokers.
Smoking intensity is associated with increased WBC count, but not CRP levels. Smoking cessation does not reduce CRP. The relationship between CRP and smoking intensity may be masked by CRP’s stronger relationship with adiposity.
C-reactive protein; Inflammation; Leukocytes; Risk factors; Smoking
To determine if smoking cessation improves flow-mediated dilation (FMD) of the brachial artery (BA).
The long-term effects of continued smoking and smoking cessation on endothelial function have not been described previously.
This was a one-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. FMD was measured by B-mode ultrasound before and 1-year after the target smoking cessation date. Cessation was verified by exhaled carbon monoxide levels. ΔFMD was compared among study arms and between subjects that successfully quit and those who continued to smoke. Predictors of baseline FMD and ΔFMD were identified by multivariable regression.
The 1,504 current smokers (58% female, 84% white) were mean (standard deviation): 44.7 (11.1) years old and smoked 21.4 (8.9) cigarettes/day. Baseline FMD was similar in each treatment arm (p=0.499) and was predicted by BA diameter (p<0.001), reactive hyperemia blood flow (p<0.001), high-density lipoprotein cholesterol (p=0.001), and carbon monoxide (p=0.012) levels. After one year, 36.2% quit smoking. FMD increased by 1% [6.2% (4.4%) to 7.2% (4.2%)] after 1 year (p=0.005) in those who quit, but did not change (p=0.643) in those who continued to smoke. Improved FMD among quitters remained significant (p=0.010) after controlling for changes in BA diameter, reactive hyperemia, low-density lipoprotein cholesterol, and presence of a home smoking ban.
Despite weight gain, smoking cessation leads to prolonged improvements in endothelial function, which may mediate part of the reduced cardiovascular disease risk observed after smoking cessation.
Endothelial dysfunction; Clinical Trial; Risk Factors; Smoking
Smoking is associated with decreased high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides.
To evaluate the effects of five markers of smoking intensity on lipoprotein concentrations and particle sizes in a large, modern cohort of current smokers.
Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained in a large cohort of current smokers enrolled in a smoking cessation trial. Multivariate linear regression models were constructed to determine predictors of lipoprotein fractions. Models included age, sex, race, waist circumference, level of physical activity and alcohol consumption. Smoking intensity parameters included: current cigarettes smoked/day, pack-years, the Fagerström Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels.
The 1,504 subjects (58% women, 84% white) had a mean (standard deviation) age of 45 (11.0) years. They smoked 21.4 (8.9) cigarettes/day (29.4 [20.4] pack-years). HDL-C (42.0 [13.5] mg/dL) and total HDL particles (30.3 [5.9] μmol/L) were low. Cigarettes smoked/day independently predicted higher total cholesterol (p=0.009), low-density lipoprotein cholesterol (p=0.023), and triglycerides (p=0.002). CO levels predicted lower HDL-C (p=0.027) and total HDL particles (p=0.009). However, the incremental R2 for each marker of smoking intensity on each lipoprotein was small. Relationships between the FTND score and lipoproteins were weak and inconsistent. Participants in the lowest quintiles of current smoking, pack-years, and CO had more favorable lipoproteins (all p<0.04).
Among current smokers, increased smoking burden is associated with small increases in total cholesterol, LDL-C, and triglycerides. Increased recent smoke exposure is associated with small decreases in HDL-C and HDL particles.
High-density lipoprotein cholesterol; Low-density lipoprotein cholesterol; Lipoproteins; Risk factors; Smoking; Triglycerides
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
Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk.
The mechanisms by which smoking cessation reduces cardiovascular disease risk are unclear. We evaluated longitudinal changes in carotid intima-media thickness among current smokers enrolled in a prospective, randomized smoking cessation clinical trial.
Subjects were enrolled in a randomized, double-blind, placebo-controlled trial of 5 smoking cessation pharmacotherapies and underwent carotid ultrasonography with carotid intima-media thickness measurement. Subjects were classified as continuously abstinent (biochemically confirmed abstinence at 6 months, 1 year, and 3 years post-quit attempt), intermittently abstinent (reported smoking at one of the three time points), or smoked continuously (reported smoking at all three time points). The primary endpoint was the absolute change (mm) in carotid intima-media thickness (ΔCIMTmax) before randomization and 3 years after the target quit date. Pearson correlations were calculated and multivariable regression models (controlling for baseline CIMTmax and research site) were analyzed. Among 795 subjects (45.2±10.6 years old, 58.5% female), 189 (23.8%) were continuously abstinent, 373 (46.9%) smoked continuously, and 233 (29.3%) were abstinent intermittently. There was a greater increase in carotid intima-media thickness among subjects who were continuously abstinent than among those who smoked continuously (p = 0.020), but not intermittently (p = 0.310). Antihypertensive medication use (p = 0.001) and research site (p<0.001) independently predicted ΔCIMTmax – not smoking status. The greatest increase in carotid intima-media thickness among continuous abstainers was related to increases in body-mass index (p = 0.043).
Smoking status did not independently predict ΔCIMTmax; increasing body-mass index and antihypertensive medication use were the most important independent predictors. The rapid reduction in cardiovascular disease events observed with smoking cessation is unlikely to be mediated by changes in subclinical atherosclerosis burden.
The role of strength training in peripheral arterial disease (PAD) is unclear. Benefits of supervised treadmill exercise in PAD patients without intermittent claudication (IC) are not established.
To determine whether supervised treadmill exercise and lower extremity resistance training, respectively, improve functional performance compared to a control group in PAD persons with and without IC.
Randomized controlled clinical trial performed between 4/1/04 and 8/19/08.
156 people with PAD (ankle brachial index ≤ 0.95), including 81.4% without IC.
Primary outcomes were six-minute walk performance and the short physical performance battery (SPPB). Additional outcomes were brachial artery flow-mediated dilation (FMD), treadmill walking performance, the Walking Impairment Questionnaire (WIQ), and the Short-Form 36 Physical Functioning score (SF-36 PF).
Three parallel arms: supervised treadmill exercise, supervised lower extremity resistance training, and a control group.
Compared to control, the treadmill exercise group increased six-minute walk distance (+35.9 meters, 95% confidence interval (CI), +15.3 to +56.5; P <0.001), while the resistance trained group did not improve (+12.4 meters, 95% CI, −8.42 to +33.3; P=0.24). Neither exercise group improved the SPPB. Compared to control, treadmill exercise improved brachial artery FMD (+1.53%, 95% CI, +0.35 to +2.70, P=0.018), time on treadmill (+3.44 minutes, 95% CI, +2.05 to +4.84; P<0.001), the WIQ distance score P=0.015), and the SF-36 PF score (P=0.02). Compared to control, resistance training improved time on treadmill (+1.98 minutes, 95% CI, +0.56 to +3.39; P=0.007), the WIQ distance score (P=0.02), the WIQ stair climbing score (P=0.02), and the SF-36 PF score (P=0.04).
Supervised treadmill exercise improved six-minute walk distance, treadmill walking performance, brachial artery FMD, and quality of life, but not the SPPB, in PAD participants with and without classic IC symptoms. Resistance training improved treadmill walking performance, quality of life, and stair climbing ability in patients with PAD.
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
To assess the short-term effects of extended-release niacin (ERN) on endothelial function in HIV-infected patients with low high-density lipoprotein-cholesterol (HDL-c) levels.
Randomized controlled study to determine the short-term effects of ERN on endothelial function, measured by flow-mediated vasodilation (FMD) of the brachial artery, in HIV-infected adults with low HDL-c. Participants on stable HAART with fasting HDL-c less than 40 mg/dl and low-density lipoprotein-cholesterol less than 130 mg/dl were randomized to ERN or control arms. ERN treatment started at 500 mg/night and titrated to 1500 mg/night for 12 weeks. Controls received the same follow-up but were not given ERN (no placebo). Participants were excluded if they had a history of cardiac disease, uncontrolled hypertension, diabetes mellitus, or were on lipid-low-ering medications such as statins and fibrates. Change in FMD was compared between arms with respect to baseline HDL-c.
Nineteen participants were enrolled: 89% men, median age 50 years, 53% white/non-Hispanic, median CD4 cell count 493 cells/μl, and 95% of them had HIV RNA below 50 copies/ml. Participants receiving ERN had a median HDL-c (interquartile range) increase of 3.0 mg/dl (0.75 to 5.0) compared with −1.0 mg/dl in controls (−6.0 to 2.5), a P value is equal to 0.04. The median change in FMD was 0.91% (−2.95 to 2.21) for ERN and −0.48% (−2.65 to 0.98) for controls (P=0.67). However, end of study FMD for ERN was significantly different from controls after adjusting for baseline differences in FMD and HDL-c, 6.36% (95% confidence interval 4.85–7.87) and 2.73% (95% confidence interval 0.95–4.51) respectively, a P value is equal to 0.048.
This pilot study demonstrated that short-term niacin therapy could improve endothelial function in HIV-infected patients with low HDL-c.
endothelial function; flow-mediated vasodilation; niacin
Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized.
To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins.
This was a substudy of a prospective, multicenter study treatment-naïve HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy.
Among the 82 participants, total and small low-density lipoprotein concentrations increased (median, interquartile range) by 152 (-49 - +407, p<0.01) and 130 (-98 - +417, p<0.01) nmol/L, respectively, especially in the arms containing lopinavir/ritonavir (pKW<0.04). Very low-density lipoproteins also increased (p<0.01), with a larger increase in the arms that contained lopinavir/ritonavir (p=0.022). High-density lipoproteins increased by 6.0 nmol/L (2.8 - 10.4, p<0.01), but differences between arms were not significant (pKW=0.069). Changes were not related to changes in markers of insulin/glucose metabolism.
Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.
Antiretroviral therapy; Cardiovascular risk; Clinical trial; Human immunodeficiency virus; Lipids; Lipoproteins
Dyslipidemia is very common in patients with human immunodeficiency virus (HIV) infection but current therapies are often suboptimal. Because niacin may cause insulin resistance and hepatotoxicity, it has generally been avoided in this setting.
Non-diabetic male subjects (N=33) who had well-controlled HIV infection on antiretroviral therapy, fasting triglycerides ≥ 2.26 mmol/L and non-high density lipoprotein cholesterol (non-HDL-C) ≥ 4.66 mmol/L received escalating doses of extended-release niacin up to 2000 mg nightly for up to 44 weeks.
Fourteen subjects (42%) had prediabetes at entry. Twenty-three subjects (70%) received the maximum dose, eight (24%) received 1500 mg. Niacin was well-tolerated. Only four subjects (12%) discontinued study treatment. There were small increases in fasting glycemia and insulin resistance estimated by the homeostasis model assessment, but insulin resistance measures from the two-hour oral glucose tolerance test only transiently worsened. No subject developed persistent fasting hyperglycemia; one had persistently elevated 2-hour glucose > 11.1 mmol/L. There were no significant changes in serum transaminases or uric acid. At week 48, the median change in fasting lipid levels in mmol/L (interquartile range) were: total cholesterol −0.21 (−1.35, −0.05), HDL-C +.013 (−0.03, +0.28), non-HDL-C −0.49 (−1.37, +0.08), triglycerides −1.73 (−3.68, −0.72). Favorable changes in large HDL and large very low density lipoprotein particle concentration were observed by nuclear magnetic resonance spectroscopy.
Extended-release niacin in doses up to 2000 mg daily was safe, well-tolerated, and efficacious in HIV-infected subjects with atherogenic dyslipidemia. Increases in glycemia and insulin resistance tended to be transient.
HIV; niacin; dyslipidemia; cholesterol; triglycerides; insulin resistance; oral glucose tolerance
The effects of hypercapnia on coronary arteries in humans are not known. We used transthoracic Doppler echocardiography (TTDE) to evaluate coronary blood flow velocity (CFV) changes in response to hypercapnia in healthy adults.
Methods and Results
Twenty adults underwent TTDE of the left anterior descending coronary artery while breathing room air, 40% FiO2, and 40% FiO2 with CO2 supplemented to end-tidal tensions of +5, +7.5, and +10 mmHg above baseline. Mean (standard deviation) diastolic peak CFV values for these conditions were 23.1(9.1), 23.0(9.0), 25.5(9.3), 27.9(11.5), and 31.5(13.0) cm/s. Significant overall differences between conditions (p<0.001) and progressive levels of hypercapnia (p≤0.01) were observed. CFV increases remained significant after adjusting for increases in cardiac output (p=0.038).
CFV increases with hypercapnia. This is the first report of human coronary artery flow responses to hypercapnia. TTDE methodology is feasible for measuring CFV and the effects of hypercapnia on the coronary circulation.
Blood flow; Coronary arteries; Carbon dioxide; Echocardiography
Cardiovascular disease (CVD) can be detected and quantified by analysis of the electrocardiogram (ECG); however the effects of smoking and smoking cessation on the ECG have not been characterized.
Standard 12-lead ECGs were performed at baseline and 3 years after subjects enrolled in a prospective, randomized, placebo-controlled clinical trial of smoking cessation pharmacotherapies. ECGs were interpreted using the Minnesota Code ECG Classification. The effects of (i) smoking burden on the prevalence of ECG findings at baseline, and (ii) smoking and smoking cessation on ECG changes after 3 years were investigated by multivariable and multinomial regression analyses.
At baseline, 532 smokers were (mean [SD]) 43.3 (11.5) years old, smoked 20.6 (7.9) cigarettes/day, with a smoking burden of 26.7 (18.6) pack-years. Major and minor ECG criteria were identified in 87 (16.4%) and 131 (24.6%) of subjects, respectively. After adjusting for demographic data and known CVD risk factors, higher pack-years was associated with major ECG abnormalities (p = 0.02), but current cigarettes/day (p = 0.23) was not. After 3 years, 42.9% of subjects were abstinent from smoking. New major and minor ECG criteria were observed in 7.2% and 15.6% of subjects respectively, but in similar numbers of abstinent subjects and continuing smokers (p>0.2 for both). Continuing smokers showed significant reduction in current smoking (–8.4 [8.8] cigarettes/day, p<0.001) compared to baseline.
In conclusion, major ECG abnormalities are independently associated with lifetime smoking burden. After 3 years, smoking cessation was not associated with a decrease in ECG abnormalities, although cigarettes smoked/day decreased among continuing smokers.
Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.
We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.
The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.
PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.
Previous studies have demonstrated gaps in achievement of low-density lipoprotein-cholesterol (LDL-C) goals among U.S. individuals at high cardiovascular disease risk; however, recent studies in selected populations indicate improvements.
We sought to define the longitudinal trends in achieving LDL-C goals among high-risk United States adults from 1999–2008.
Methods We analyzed five sequential population-based cross-sectional National Health and Nutrition Examination Surveys 1999–2008, which included 18,656 participants aged 20–79 years. We calculated rates of LDL-C goal achievement and treatment in the high-risk population.
The prevalence of high-risk individuals increased from 13% to 15.5% (p = 0.046). Achievement of LDL-C <100 mg/dL increased from 24% to 50.4% (p<0.0001) in the high-risk population with similar findings in subgroups with (27% to 64.8% p<0.0001) and without (21.8% to 43.7%, p<0.0001) coronary heart disease (CHD). Achievement of LDL-C <70 mg/dL improved from 2.4% to 17% (p<0.0001) in high-risk individuals and subgroups with (3.4% to 21.4%, p<0.0001) and without (1.7% to 14.9%, p<0.0001) CHD. The proportion with LDL-C ≥130 mg/dL and not on lipid medications decreased from 29.4% to 18% (p = 0.0002), with similar findings among CHD (25% to 11.9% p = 0.0013) and non-CHD (35.8% to 20.8% p<0.0001) subgroups.
The proportions of the U.S. high-risk population achieving LDL-C <100 mg/dL and <70 mg/dL increased over the last decade. With 65% of the CHD subpopulation achieving an LDL-C <100 mg/dL in the most recent survey, U.S. LDL-C goal achievement exceeds previous reports and approximates rates achieved in highly selected patient cohorts.