Outcomes of implantable cardioverter-defibrillator implantation in HIV-infected patients: A single-center retrospective cohort study.

BACKGROUND: HIV-infected individuals have a known increased risk of sudden cardiac death (SCD) compared to uninfected individuals. Implantable cardioverter-defibrillators (ICDs) are standard therapy for preventing SCD; however, there is limited data on the outcomes of ICDs in HIV-infected individuals. HYPOTHESIS: HIV-infected subjects receive a higher number of appropriate ICD therapies than uninfected controls. METHODS: This is a retrospective cohort study of 35 consecutive HIV-Infected patients and 36 uninfected controls matched by age, race, and gender who were treated at the University of North Carolina Medical Center in the outpatient or inpatient setting from 2014 to the present and had undergone ICD implantation. For HIV-infected subjects, a multivariate Poisson regression analysis was performed to evaluate the association between covariates and ICD therapies. RESULTS: Among HIV-infected subjects, the mean CD4 count was 582.5 cells/mm3 and 69% had an undetectable viral load. The median follow-up was 6.4 years. HIV-infected subjects had both a higher number of appropriate ICD shocks or antitachycardia pacing (ATP) therapy per person-year as well as a higher number of inappropriate ICD shocks per person-year than uninfected controls (1.512 vs. 0.590 and 0.122 vs. 0.0166, respectively, p < .001 for both comparisons). After multivariate adjustment, the presence of detectable/unsuppressed viral load at the time of ICD implantation was an independent predictor of both of the following in HIV-infected subjects: (1) appropriate ICD discharge (p = .004), and (2) appropriate ICD discharge or appropriate ATP therapy (p < .001). CONCLUSION: HIV-infected subjects had a higher number of appropriate ICD discharge or ATP therapy per person-year than matched uninfected controls.

Sudden cardiac death in HIV-infected patients: A contemporary review.

HIV-infected individuals have an increased risk of sudden cardiac death compared to the general population; yet the mechanisms underlying this increased risk remain unclear. The mechanisms underlying the heightened sudden cardiac death risk in HIV-infected individuals is likely multifactorial. We reviewed the literature to elucidate and summarize the potential mechanisms contributing to sudden cardiac death in the HIV patient population. There is biologic plausibility that the following mechanisms may be contributing to the significantly heightened risk of sudden cardiac death in HIV to varying degrees: ventricular arrhythmias, myocardial fibrosis and scar, prolonged QTc interval (both as a direct effect of HIV on repolarization as well as a result of concurrent medications/antiretroviral therapies), substance abuse, structural heart disease, and premature atherosclerosis. Further understanding of the mechanisms underlying the increased sudden cardiac death risk in HIV can lead to identification of modifiable risk factors, implementation of public health programs, and potential revision of ICD implantation guidelines to ultimately reduce the incidence of sudden cardiac death in HIV-infected patients. Further studies are needed to assess the relative contribution of each of these mechanisms and risk factors.

Unique Circulating MicroRNA Profiles in HIV Infection.

OBJECTIVE: MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression. We aimed to determine the association between extracellular miRNAs and HIV infection. DESIGN: Single-center, cross-sectional study. METHODS: We analyzed the expression of 192 plasma-derived miRNAs in 69 HIV-infected individuals and 24 uninfected controls using TaqMan miRNA assays and a high-throughput Real-Time PCR instrument (Fluidigm). False discovery rate (FDR) was applied. RESULTS: HIV-infected individuals and controls were similar in age, sex, and traditional risk factors. Among those with HIV, 72.5% were on antiretroviral therapy (ARVs) and 64% had an undetectable viral load. Twenty-nine miRNAs were differentially expressed in the plasma of HIV-infected individuals compared with controls (P < 0.05, FDR < 0.15). Nineteen miRNAs were differentially expressed among HIV+ subjects on ARVs, HIV+ subjects not on ARVs, and HIV- subjects (P < 0.05 and FDR < 0.15). Thirty-four miRNAs were differentially expressed between HIV- subjects and elite controllers (ie, suppressed viral loads despite the absence of ARVs; P < 0.05 and FDR < 0.15). These 34 miRNAs included miRs-29c, 146b, 223, and 382, which were previously reported to have intracellular roles in HIV latency, as well as miRs-126, 145, and let-7, which were previously shown to be differentially expressed in coronary artery disease among uninfected individuals. CONCLUSIONS: We demonstrate a unique expression profile of 29 miRNAs in HIV+ subjects and 34 miRNAs in elite controllers as compared to HIV- subjects. These miRNA signatures may be useful in further elucidating mechanisms of viral and immunological control and may have diagnostic or prognostic value in HIV-associated coronary artery disease.

A novel minimally-invasive method to sample human endothelial cells for molecular profiling.

OBJECTIVE: The endothelium is a key mediator of vascular homeostasis and cardiovascular health. Molecular research on the human endothelium may provide insight into the mechanisms underlying cardiovascular disease. Prior methodology used to isolate human endothelial cells has suffered from poor yields and contamination with other cell types. We thus sought to develop a minimally invasive technique to obtain endothelial cells derived from human subjects with higher yields and purity. METHODS: Nine healthy volunteers underwent endothelial cell harvesting from antecubital veins using guidewires. Fluorescence-activated cell sorting (FACS) was subsequently used to purify endothelial cells from contaminating cells using endothelial surface markers (CD34/CD105/CD146) with the concomitant absence of leukocyte and platelet specific markers (CD11b/CD45). Endothelial lineage in the purified cell population was confirmed by expression of endothelial specific genes and microRNA using quantitative polymerase chain reaction (PCR). RESULTS: A median of 4,212 (IQR: 2161-6583) endothelial cells were isolated from each subject. Quantitative PCR demonstrated higher expression of von Willebrand Factor (vWF, P<0.001), nitric oxide synthase 3 (NOS3, P<0.001) and vascular cell adhesion molecule 1 (VCAM-1, P<0.003) in the endothelial population compared to similarly isolated leukocytes. Similarly, the level of endothelial specific microRNA-126 was higher in the purified endothelial cells (P<0.001). CONCLUSION: This state-of-the-art technique isolates human endothelial cells for molecular analysis in higher purity and greater numbers than previously possible. This approach will expedite research on the molecular mechanisms of human cardiovascular disease, elucidating its pathophysiology and potential therapeutic targets.

Association between resting heart rate and inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-6, and fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis).

Heart rate (HR) at rest is associated with adverse cardiovascular events; however, the biologic mechanism for the relation is unclear. We hypothesized a strong association between HR at rest and subclinical inflammation, given their common interrelation with the autonomic nervous system. HR at rest was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis, a cohort of 4 racial or ethnic groups without cardiovascular disease at baseline and then divided into quintiles. Subclinical inflammation was measured using high-sensitivity C-reactive protein, interleukin-6, and fibrinogen. We used progressively adjusted regression models with terms for physical activity and atrioventricular nodal blocking agents in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables using the clinical cut point of ≥3 mg/L for high-sensitivity C-reactive protein and the upper quartiles of fibrinogen (≥389 mg/dl) and interleukin-6 (≥1.89 pg/ml). Participants had a mean age of 62 years (SD 9.7), mean resting heart rate of 63 beats/min (SD 9.6) and were 47% men. Increased HR at rest was significantly associated with higher levels of all 3 inflammatory markers in both continuous (p for trend <0.001) and categorical (p for trend <0.001) models. Results were similar among all 3 inflammatory markers, and there was no significant difference in the association among the 4 racial or ethnic groups. In conclusion, an increased HR at rest was associated with a higher level of inflammation among an ethnically diverse group of subjects without known cardiovascular disease.

Compensatory responses to age-related decline in odor quality acuity: cholinergic neuromodulation and olfactory enrichment.

The perceptual differentiation of odors can be measured behaviorally using generalization gradients. The steepness of these gradients defines a form of olfactory acuity for odor quality that depends on neural circuitry within the olfactory bulb and is regulated by cholinergic activity therein as well as by associative learning. Using this system as a reduced model for age-related cognitive decline, we show that aged mice, while maintaining almost the same baseline behavioral performance as younger mice, are insensitive to the effects of acutely elevated acetylcholine, which sharpens generalization gradients in young adult mice. Moreover, older mice exhibit evidence of chronically elevated acetylcholine levels in the olfactory bulb, suggesting that their insensitivity to further elevated levels of acetylcholine may arise because the maximum capacity of the system to respond to acetylcholine has already been reached. We propose a model in which an underlying, age-related, progressive deficit is mitigated by a compensatory cholinergic feedback loop that acts to retard the behavioral effects of what would otherwise be a substantial age-related decline in olfactory plasticity. We also treated mice with 10-day regimens of olfactory environmental enrichment and/or repeated systemic injections of the acetylcholinesterase inhibitor physostigmine. Each treatment alone sharpened odor quality acuity, but administering both treatments together had no greater effect than either alone. Age was not a significant main effect in this study, suggesting that some capacity for acetylcholine-dependent plasticity is still present in aged mice despite their sharply reduced ability to respond to acute increases in acetylcholine levels. These results suggest a dynamical framework for understanding age-related decline in neural circuit processing in which the direct effects of aging can be mitigated, at least temporarily, by systemic compensatory responses. In particular, a decline in cholinergic efficacy can precede any breakdown in cholinergic production, which may help explain the limited effectiveness of cholinergic replacement therapies in combating cognitive decline.

Coronary artery calcification and inflammation according to various metabolic syndrome definitions.

A number of metabolic syndrome (MS) definitions exist, and one's cardiovascular disease risk may depend on the definition used. The authors compared the association of subclinical atherosclerosis (coronary artery calcification [CAC] score >0] and inflammation (white blood cell [WBC] count greater than or equal to the highest quartile) with 3 definitions of MS (those of the National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III], the American Heart Association/National Heart, Lung and Blood Institute [AHA/NHLBI], and the International Diabetes Federation [IDF]) in 458 asymptomatic men (mean age, 46+/-7 years). MS was present in 28%, 29%, and 34% according to NCEP ATP III, AHA/NHLBI, and IDF criteria, respectively. CAC was observed in 40% and high WBC count in 24%. After adjustment for age, smoking, and low-density lipoprotein cholesterol, the odds ratios for CAC scores >0 with MS by NCEP ATP III, AHA/NHLBI, and IDF definitions were 1.67 (95% confidence interval [CI], 1.02-2.72), 1.67 (95% CI, 1.03-2.70), and 1.63 (95% CI, 1.03-2.57), respectively. The multivariate odds ratios for high WBC count with MS by NCEP ATP III, AHA/NHLBI, and IDF definitions were 1.69 (95% CI, 1.04-2.73), 1.84 (95% CI, 1.14-2.95), and 1.66 (95% CI, 1.05-2.62), respectively. MS is associated with increased subclinical atherosclerosis and inflammation irrespective of various definitions.

Multiple learning parameters differentially regulate olfactory generalization.

Sensory representations depend strongly on the descending regulation of perceptual processing. Generalization among similar stimuli is a fundamental cognitive process that defines the extent of the variance in physical stimulus properties that becomes categorized together and associated with a common contingency, thereby establishing units of meaning. The olfactory system provides an experimentally tractable model system in which to study the interactions of these physical and psychological factors within the framework of their underlying neurophysiological mechanisms. The authors here show that olfactory associative learning systematically regulates gradients of odor generalization. Specifically, increasing odor-reward pairings, odor concentration, or reward quality--each a determinant of associative learning--significantly transformed olfactory generalization gradients, each narrowing the range of variance in odor quality perceived as likely to share the learned contingency of a conditioned odor stimulus. However, differences in the qualitative features of these three transformations suggest that these different determinants of learning are not necessarily theoretically interchangeable. These results demonstrate that odor representations are substantially shaped by experience and descending influences.

The JUPITER and AURORA clinical trials for rosuvastatin in special primary prevention populations: perspectives, outcomes, and consequences.

Statins have emerged at the forefront of preventive cardiology and have significantly reduced cardiovascular events and mortality. Nonetheless, cardiovascular disease remains the leading cause of death in the United States and in other developed countries, as well as the etiology of significant morbidity and health-care expenditure. In an attempt to reduce potentially missed opportunities for instituting preventive therapy, the JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and the AURORA study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) examined the effect of statins in two specific patient populations who currently do not meet the guidelines for statin treatment, but nonetheless, are at high cardiovascular risk. This review outlines the JUPITER and AURORA trials, interprets the data and significance of the results, analyses the drawbacks and impact of both trials and delineates the potential for further clinical trials.

Favorable cardiovascular risk factor profile is associated with reduced prevalence of coronary artery calcification and inflammation in asymptomatic nondiabetic white men.

Middle-aged individuals with favorable levels of all major cardiovascular risk factors (CVRFs) have much lower age-specific risks for incident cardiovascular disease (CVD). However, the relationship of the absence of CVRFs with subclinical CVD and inflammation is not well described. We classified 440 asymptomatic Brazilian men (aged 46+/-7 years) based on the number of CVRFs (smoking, systolic blood pressure > or =130 mm Hg, low-density lipoprotein cholesterol > or =130 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, triglycerides > or =150 mg/dL, fasting glucose > or =100 mg/dL, and waist circumference >102 cm). Only 7% had no CVRFs, whereas 1, 2, 3, and > or =4 CVRFs were observed in 18%, 24%, 21%, and 29%, respectively. In age-adjusted analysis, each lower CVRF profile was associated with lower odds of prevalent coronary artery calcium (odds ratio, 0.75; P=.002) and elevated white blood cell count (odds ratio, 0.70; P<.001). Our study supports the notion that a favorable CVD profile is associated with less underlying atherosclerosis and inflammation and further highlights the importance of primary prevention of CVRFs.

Real and virtual mobility performance in simulated prosthetic vision.

Wayfinding is an important activity that can be performed with limited visual resources, and thus may be an important application of early visual prostheses. In a pair of experiments we explored minimal visual resolution requirements of a simulated retinal electrode array for mobility in real and virtual environments, experienced by normally sighted subjects in video headsets. In experiment 1, inexperienced and experienced subjects traveled similar routes around a suite of offices with simulated implants of 4 x 4, 6 x 10 and 16 x 16 dots. In experiment 2, the effects of adding dynamic noise and removing a subset of 'phosphenes' from a 6 x 10 dot array on the mobility of experienced subjects through a series of different virtual 10-room buildings were determined. Performance was quantified in terms of time and navigation errors in both experiments, and wall contacts in the real environment; a compound score was also computed for trials in experiment 1. In experiment 1, inexperienced subjects required 16 x 16 dots for adequate performance, while experienced subjects reached similar levels with 6 x 10 dots. In experiment 2, dot removal up to 30% led to modest yet significant performance deterioration, and noise addition to slight but non-significant improvement, while practice led to a reduction in travel time by 50% over the 28-trial experiment. Error counts in experiment 2 were fairly high, but largely randomly distributed, and attributable to the high risk of becoming disoriented in the sparse visual environment. Substantial performance level differences were found between subjects, spanning a threefold range even after practice. The findings suggest that a retinal implant with as few as 60 electrodes may provide independent wayfinding abilities to the adventitiously blind, but that substantial practice and supervision will be required in learning this task.

Intensity modulation of olfactory acuity.

Acuity is fundamental to sensory systems, establishing the foundation for detectable differences in stimulus quality and consequently shaping animals' sensory capacities. In the olfactory system, which samples intrinsically high-dimensional chemical information, acuity for odor quality is measurable by means of ad hoc dimensions based on behaviorally confirmed sets of sequentially similar odorants. The authors measure olfactory acuity in mice using a rewarded forced-choice odor generalization task and show that mice exhibit greater olfactory acuity in response to higher concentration (1,0 Pa) odorants than to lower concentration (0.01 Pa) odorants. Results suggest that the dynamic modulation of sensory acuity--not necessarily its maximization--is an important component of olfactory processing and reflects the salience of odorant stimuli.