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HIV-infected persons develop coronary artery disease (CAD) more commonly and earlier than uninfected persons; however, the role of non-invasive testing to stratify CAD risk in HIV is not well defined. Patients were selected from a single-center electronic cohort of HIV-infected patients and uninfected controls matched 1:2 on age, sex, race, and type of cardiovascular testing performed. Patients with abnormal echocardiographic or nuclear stress testing who subsequently underwent coronary angiography were included. Logistic regressions were used to assess differences by HIV serostatus in two co-primary endpoints: (1) severe CAD (≥70% stenosis of at least one coronary artery) and (2) performance of percutaneous coronary intervention (PCI). HIV-infected patients (N = 189) were significantly more likely to undergo PCI following abnormal stress test when compared with uninfected persons (N = 319) after adjustment for demographics, CAD risk factors, previous coronary intervention, and stress test type (OR 1.85, 95% CI 1.12-3.04, P = 0.003). No associations between HIV serostatus and CAD were statistically significant, although there was a non-significant trend toward greater CAD for HIV-infected patients. HIV-infected patients with abnormal cardiovascular stress testing who underwent subsequent coronary angiography did not have a significantly greater CAD burden than uninfected controls, but were significantly more likely to receive PCI.

In recent years, biochemical and genetic studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a major mediator of low-density lipoprotein cholesterol (LDL-c) levels and thereby a potential novel target for reducing risk of coronary heart disease (CHD). These observations led to the development of PCSK9 inhibitors, which lower LDL-c levels more than any other non-invasive lipid-lowering therapy presently available. The PCSK9 inhibitors furthest along in clinical trials are subcutaneously injected monoclonal antibodies. These PCSK9 inhibitors have demonstrated LDL-c-lowering efficacy with acceptable safety in phase III clinical trials and may offer a useful therapy in addition to maximally tolerated HMG-CoA reductase inhibitors (statins) in certain patient groups. Longer-term data are required to ensure sustained efficacy and safety of this new class of medications. This review provides an overview of the biology, genetics, development, and clinical trials of monoclonal antibodies designed to inhibit PCSK9.

Background: Persons living with human immunodeficiency virus (HIV) have greater risks for myocardial infarction (MI) than uninfected persons. These elevated MI risks, which are associated with both traditional and HIV-specific risk factors, may limit the applicability of cardiovascular risk prediction models for HIV-infected persons. Methods: We evaluated the ACC/AHA atherosclerotic cardiovascular disease (ASCVD) Risk Estimator’s Pooled Cohort Equations (PCEs) and a new model incorporating HIV-specific variables using the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) multi-center U.S.-based cohort of HIV-infected adults. CNICS has rigorous central adjudication of type I and II myocardial infarction (MI), which may be distributed differently in HIV-infected versus uninfected populations. Because adjudicated stroke data were not available, ASCVD risks predicted by the PCEs were scaled to determine predicted MI rates using race-sex-specific proportions. MI rates predicted by the PCEs and the new model were compared with observed MI rates in CNICS. Harrell’s C-statistic and Hosmer-Lemeshow chi-square were used to determine discrimination and calibration of these models. Results: Of 11,901 HIV-infected persons in CNICS with baseline data required for the PCEs, 180 experienced MIs over a mean follow-up of 4.3 years. The PCEs were poorly calibrated for white men and black women (Hosmer-Lemeshow chi-square = 25.3 and 42.9, respectively) and had inadequate discrimination for black men (Harrell’s C statistic = 0.65). A modified, data-derived model had excellent discrimination (Harrell’s C-statistic for men = 0.81; for women = 0.83) and was well calibrated (Figure). Conclusions: A data-derived ASCVD risk estimator that incorporates HIV-specific coefficients had excellent discrimination and calibration in a large multi-center U.S. HIV cohort. Future studies are needed to validate this model in other HIV cohorts and evaluate the contributions of type I versus II MI to ASCVD risk.

Religious involvement has been associated with improved health outcomes but greater obesity in older adults. No longitudinal study of young adults has examined the prospective association of religious involvement with incident cardiovascular risk factors (RFs) and subclinical disease (subCVD).We included 2433 participants of the CARDIA study, aged 20 to 32 in 1987 when religiosity was assessed, who were followed for 18 years. Multivariable-adjusted regression models were fitted to assess prospective associations of frequency of religious participation at baseline with incidence of RFs and prevalence of subCVD after 18 years' follow up.The high frequency of religious participation was associated with a significantly greater incidence of obesity in unadjusted models (RR 1.57, 95% CI 1.14-1.73) and demographic-adjusted models (RR 1.34, 95% CI 1.09-1.65) but not after additional adjustment for baseline RFs (RR 1.17, 95% CI .97-1.41). When religious participation was treated dichotomously, any religious participation, compared with none, was associated with significantly lower subCVD.Frequent religious participants are more likely to become obese between young adulthood and middle age; this association is confounded by demographic and other factors. Nonetheless, young adults with frequent participation may represent an opportunity for obesity prevention.

Background: Human immunodeficiency virus (HIV)-infected individuals are at elevated risk for cardiovascular disease (CVD) due to an interplay between traditional CVD risk factors, chronic inflammation persisting despite HIV viral suppression, and side effects of antiretroviral therapy. Previous studies evaluating CVD risk prediction models in HIV populations have generally been small in size and assessed non-U.S. cohorts. The 2013 ACC/AHA ASCVD Risk Estimator has not been evaluated in a large, multi-center HIV cohort. Hypothesis: Our primary hypothesis was that the ACC/AHA ASCVD Risk Estimator would underestimate ASCVD risk across risk strata for HIV-infected patients. Methods: We evaluated this risk prediction tool in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) multi-center U.S.-based cohort of approximately 30,000 HIV-infected adults with rigorous central adjudication of myocardial infarction (MI) and differentiation between type I and II MI. We compared MI and ASCVD risks predicted by the ASCVD Risk Estimator to actual rates of MI observed in the CNICS cohort. Results: A total of 132 MIs were observed during follow-up, compared with 103 MIs that would have been expected based on the ASCVD risk estimator. Observed MI rates were higher than expected across most predicted risk levels, particularly among black participants and those with low ( Conclusions: These data suggest that the ACC/AHA Risk Estimator under-predicts MI risk among HIV-infected individuals. The under-prediction was relatively uniform across risk strata for white men. These data highlight the need for accurate HIV-specific CVD risk prediction tools.

Introduction: Due to the success of antiretroviral therapy, Human Immunodeficiency Virus (HIV)-infected individuals live longer and are at risk for cardiovascular disease (CVD). Whether the proportion of deaths due to CVD in the HIV-infected population has increased over time is unknown. Hypothesis: Our hypothesis was that proportionate mortality from CVD in the HIV-infected population has increased significantly since 1999. Methods: Using the publicly available CDC Wonder database of U.S. national mortality data, we assessed proportionate CVD mortality among adults aged ≥25 years with HIV. We compared these data to proportionate CVD mortality in two control groups: the general population and people with underlying inflammatory disease (i.e., inflammatory polyarthropathies (IPA)). For each group, we calculated proportionate CVD mortality by dividing deaths attributed to circulatory causes (based on ICD10 coding) by all causes of death for each year from 1999 to 2013. Results: Proportionate CVD mortality increased among HIV+ individuals from 1.9% of deaths in 1999 to 4.6% in 2013 (Figure 1); this pattern of increasing proportionate mortality was highly significant for men and women (P Conclusions: Proportionate CVD mortality appears to have increased substantially in the HIV-infected population since 1999. Further studies are needed to guide risk assessment and prevention in this unique population.

Background Human Immunodeficiency Virus-Infected (HIV+) persons have elevated risks for various manifestations of cardiovascular disease (CVD). No studies to our knowledge have compared atrial fibrillation (AF) and atrial flutter (AFL) prevalence and associated characteristics for HIV+ persons and matched uninfected controls. Methods and findings Persons with diagnoses of HIV receiving care at a large urban academic medical center were frequency-matched 1:2 on age, sex, race, zip code, and clinic location with uninfected persons. Possible AF/AFL was screened for using administrative codes and diagnoses of AF/AFL were subsequently adjudicated using electrocardiography and physician notes; adjudication was performed given the inconsistent validity of administrative code-derived AF diagnoses found in previous studies. There were 101 confirmed AF/AFL cases (2.00%) among 5,052 HIV+ patients and 159 confirmed AF/AFL cases (1.57%) among 10,121 uninfected controls [Odds Ratio (OR) 1.27, 95% Confidence Interval (CI) 0.99–1.64; p = 0.056]. The association between HIV serostatus and AF/AFL was attenuated after adjustment for demographics and CVD risk factors. Among HIV+ persons, nadir CD4+ T cell count

An atherosclerotic plaque requires a nutrient blood supply, which is predominantly derived from arterial vasa vasorum. A variety of factors (environmental and genetic) contribute to the initiation and growth of atherosclerosis within vessel walls. Chemotactic factors, such as tissue ischemic and hypoxic factors, stimulate the release of vascular endothelial growth factor (VEGF) proteins, resulting in vessel wall angiogenesis. These developments often precede the formation of the luminal plaque. In this report, we describe the use of contrast-enhanced carotid ultrasound (CECU) imaging for the detection and quantification of intra-plaque neovascularization. The efficacy of CECU was measured against the neovascular density observed within the tissue specimens obtained at the time of carotid endarterectomy surgery. The objective of this study was to provide a histologic correlation between CECU and carotid artery atherosclerotic plaque neovascularization. Fifteen patients with significant atherosclerotic carotid artery disease received a CECU examination prior to undergoing a carotid endarterectomy (CEA). Two patients received bilateral endarterectomies, resulting in a total of 17 cases. At the time of surgery, carotid plaque samples were surgically removed and stained with specific vascular markers (CD31, CD34, von Willebrand factor, and hemosiderin) designed to identify the presence and degree of neovascularization. The intra-plaque neovascularization recorded on preoperative CECU was correlated with the degree of neovascularization noted in the tissue specimens. The CECU neovascularization was correlated to CD31-stained tissue specimens. This correlation value was 0.68 using Spearman's rank method. When CECU results were correlated with the other histologic markers (CD34, von Willebrand factor, and hemosiderin), a correlation of 0.50 was obtained. In conclusion, contrast-enhanced carotid ultrasound correlated to the presence and degree of intra-plaque neovascularization as determined from histology specimens.

HIV-infected patients have a greater prevalence of dyslipidemia, earlier incidence and progression of atherosclerosis, and a nearly twofold increased risk for myocardial infarction compared with those not infected with HIV. Pre-existing cardiovascular risk factors, viral replication, and antiviral treatments all contribute to this accelerated and increased risk for cardiovascular disease in HIV-infected subjects. Given this risk and the proven benefit of statins reducing cardiovascular events across numerous patient groups, statin therapy might be particularly beneficial for patients with HIV. However, safety concerns and a dearth of quality trial data evaluating clinical outcomes in HIV-infected patients on simultaneous antiretroviral therapy (ART) and statin therapy have likely limited statin use in HIV-infected patients chronically taking ART. We performed a systematic review evaluating 18 clinical trials of statins in HIV-infected subjects receiving ART. Simvastatin is contraindicated in the setting of protease inhibitor use because of toxic drug-drug interactions when the 2 drugs are taken concomitantly. Meanwhile, atorvastatin appears to be relatively safe at submaximal doses if monitored. Pravastatin, rosuvastatin, and pitavastatin appear to have the most benign safety profiles among statins when co-administered with ART and may not require dose adjustment. In conclusion, clinicians should be mindful of the elevated risk for atherosclerotic cardiovascular disease in HIV-infected patients when assessing the need for lifestyle interventions and statin therapy.

Current guidelines do not explicitly recommend statin use in heart failure (HF). Relatively low numbers of atherothrombotic events among HF patients, in the context of their elevated competing risks for non-atherothrombotic causes of death, may have prevented previous analyses of clinical trials from detecting a benefit for statins. We pooled data from two landmark trials of HF patients not on statin therapy randomized to rosuvastatin 10 mg daily vs. placebo, CORONA and GISSI-HF, in order to improve our power to detect statistically significant differences in atherothrombotic events. We also accounted for competing risks from other causes of death.We used competing risks analyses to evaluate atherothrombotic events in the context of death from other cardiovascular and non-cardiovascular causes. We also performed traditional Cox survival analyses of the same data with the intention that these statistical approaches would be complementary. CORONA participants (n = 5011, median follow-up 32.8 months) were older and sicker than GISSI-HF participants (n = 4574, median follow-up 46.9 months) by design. Rosuvastatin decreased risk for myocardial infarction (MI) among CORONA and GISSI-HF participants with ischaemic aetiology of HF (hazard ratio 0.81, 95% confidence interval 0.66-0.99, P 0.05). There were no significant differences between rosuvastatin and placebo in risks for stroke or death from other causes.This individual-level reanalysis of two landmark trials demonstrates a small but statistically significant decreased risk for MI among patients with ischaemic HF randomized to rosuvastatin vs. placebo. Rosuvastatin appears to be effective in preventing MI in ischaemic HF patients not already on statins.

Diabetes mellitus and the metabolic syndrome (MS) are reaching epidemic proportions in the United States, and cardiovascular disease continues to be the leading cause of death among patients with diabetes. A range of noninvasive screening tools may help reduce the morbidity and mortality of patients with diabetes because of early detection of subclinical cardiovascular disease and active monitoring of the effectiveness of therapy. Surrogate markers of subclinical disease include conventional and contrast-enhanced ultrasound imaging of carotid artery intima-media thickness (c-IMT), 2-dimensional echocardiography, coronary artery calcium imaging, cardiac magnetic resonance imaging, ankle-brachial indices, and brachial artery reactivity testing. Because these noninvasive imaging tools are relatively comfortable and entail relatively low risk to the patient, they are ideal for initial screening and for the repeated imaging that is required for monitoring the effectiveness of therapy. Moreover, when used in large numbers of patients with diabetes, prediabetes, and the MS, these imaging tools may be useful in developing and validating thresholds for the use of lipid-lowering therapy as well as clear therapeutic goals for this population. In addition, contrast-enhanced c-IMT scans now produce real-time images of the vasa vasorum and neovascularization of atherosclerotic plaque, potentially causing a paradigm shift in our view of the genesis of atherosclerosis and affecting treatment options for all populations. Thus, surrogate markers may not only help improve individual patient outcomes, they also may help direct scarce medical resources to maximize medical benefits, improve overall medical care, and minimize costs and untoward side effects.

Noninvasive surrogate markers of atherosclerosis allow the physician to identify subclinical disease before the occurrence of adverse cardiovascular events, thereby limiting the need to perform invasive diagnostic procedures. Imaging modalities, such as carotid artery ultrasound, two-dimensional echocardiography, coronary artery calcium imaging, cardiac magnetic resonance imaging, ankle-brachial indices, brachial artery reactivity testing, and epicardial coronary flow reserve measurements, provide information that may improve the predictive value of a person's risk of developing clinically significant atherosclerotic disease. Newer imaging modalities have also emerged to bring insight into the pathophysiology and treatment of atherosclerosis.

Persons with HIV are surviving longer than ever before due to effective antiretroviral therapy (ART) and are increasingly at risk for chronic, non-communicable diseases.1–3 Data from large cohorts in North America and Europe have demonstrated that HIV-infected persons have roughly 50% greater risks for myocardial infarction (MI) than uninfected persons, as well as greater risks for other cardiovascular diseases such as heart failure and stroke.4 ,5 These elevated risks for MI persist even after accounting for cardiovascular risk factors and ART regimens and are thought to result from HIV-associated inflammation, immune activation and atherosclerosis—even in the setting of successful viral suppression with ART.6 To inform efforts to prevent MI in this emerging at-risk population, several studies have evaluated both MI and atherosclerotic cardiovascular disease (ASCVD, which includes MI and stroke) risk prediction models in the setting of HIV. These studies have generally been fairly small and some have assessed surrogate endpoints. Perhaps the best known of these studies, the Data collection on Adverse Effects of Anti-HIV Drugs (D:A:D) Study, used a European and Australian cohort of patients infected with HIV to derive risk prediction equations incorporating HIV-specific treatment exposures; however, the clinical utility of these equations may be limited due to their incorporation of ART medications no longer commonly used.7 Accordingly, the degree to which HIV-specific and general population cardiovascular risk models—such as the 2013 American College of Cardiology/American Heart Association (ACC/AHA) ASCVD Risk Calculator—may apply in the setting of HIV remains unclear. In sub-Saharan Africa, which is home to the substantial majority of the global HIV-infected population, cardiovascular risk estimation is particularly complicated due to the relative dearth of mature cohorts evaluating cardiovascular complications of HIV. Although some studies in sub-Saharan Africa HIV cohorts have evaluated the prevalence of ASCVD risk factors and subclinical …

Background: HIV+ persons appear to have elevated risks for HF. However, few studies have evaluated clinical characteristics of HF in HIV and none has adjudicated HF diagnoses. Thus, the extent to which traditional and HIV-specific risk factors contribute to HF in HIV remains unclear. We hypothesized

Background: HIV+ persons have elevated risks for various manifestations of cardiovascular disease (CVD), but no studies to our knowledge have evaluated AF and AFL for HIV+ persons and matched uninfected controls. Methods: Patients from an electronic cohort of 5,052 HIV+ patients and 10,121

Persons with human immunodeficiency virus (HIV) have greater risks for myocardial infarction and sudden cardiac death (SCD) than the general population. Associations between coronary artery disease (CAD) and myocardial fibrosis - a mediator of SCD - in the setting of HIV are unknown. We hypothesized

Background— No studies have compared first cardiovascular disease (CVD) events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously. Methods and Results— We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in 3 multicenter, National Heart, Lung, and Blood Institute–sponsored cohorts. Of 14 569 Atherosclerosis Risk in Communities (ARIC) study participants aged 45 to 64 years with mean follow-up of 10.5 years, 11.6% had CVD and 5.0% had non-CVD death as first events; among 4237 Cardiovascular Health Study (CHS) study participants aged 65 to 84 years and followed for 8.5 years, these figures were 43.2% and 15.7%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for Multi-Ethnic Study of Atherosclerosis (MESA) participants. Traditional Cox and competing risks models yielded different results for coronary heart disease risk. Black men appeared somewhat more likely than white men to experience coronary heart disease with use of a standard Cox model (hazard ratio 1.06; 95% CI 0.90, 1.26), whereas they appeared less likely than white men to have a first coronary heart disease event with use of a competing risks model (hazard ratio, 0.77; 95% CI, 0.60, 1.00). Conclusions— CVD affects blacks at an earlier age than whites; this may be attributable in part to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.

Background—Religious involvement has been associated with improved health practices and outcomes; however, no ethnically diverse community-based study has examined differences in cardiac risk factors, subclinical cardiovascular disease, and cardiovascular disease (CVD) events across levels of religiosity.Methods and Results—We included 5474 white, black, Hispanic, and Chinese participants who attended examination 2 of the National Heart, Lung, and Blood Institute’s Multi-Ethnic Study of Atherosclerosis (MESA). We compared cross-sectional differences in cardiac risk factors and subclinical CVD and longitudinal CVD event rates across self-reported levels of religious participation, prayer/meditation, and spirituality. Multivariable-adjusted regression models were fitted to assess associations of measures of religiosity with risk factors, subclinical CVD, and CVD events. MESA participants (52.4% female; mean age, 63) with greater levels of religious participation were more likely to be female and black. After adjustment for demographic covariates, participants who attended services daily, compared with never, were significantly more likely to be obese (adjusted odds ratio 1.57, 95% confidence interval [CI] 1.12 to 1.72) but less likely to smoke (adjusted odds ratio 0.39, 95% CI 0.26 to 0.58). Results were similar for those with frequent prayer/meditation or high levels of spirituality. There were no consistent patterns of association observed between measures of religiosity and presence/extent of subclinical CVD at baseline or incident CVD events during longitudinal follow-up in the course of 4 years.Conclusions—Our results do not confirm those of previous studies associating greater religiosity with overall better health risks and status, at least with regard to CVD. There was no reduction in risk for CVD events associated with greater religiosity.

BACKGROUND Transthoracic Doppler echocardiography is a valuable tool to measure coronary flow reserve (CFR) and detect in-stent restenosis (ISR) after percutaneous coronary angioplasty in selected series of patients. OBJECTIVES To assess the usefulness of coronary flow reserve measured by echocardiography in detecting significant (> or =70%) ISR of the left anterior descending coronary artery in a large unselected population. METHODS Two hundred and twenty-three patients (age 61 +/- 10 years; 168 men) treated with left anterior descending stenting underwent CFR measurement by transthoracic Doppler echocardiography and venous adenosine infusion 24-72 h before control coronary angiography. Coronary-active drugs were continued, and patients with multiple risk factors and old anterior-apical myocardial infarction were included. RESULTS Significant ISR occurred in 56 patients (25%). Patients with ISR had higher basal coronary flow velocity (27 +/- 10 cm/s vs. 24 +/- 7 cm/s; P < 0.002) and lower CFR (1.5 +/- 0.5 vs. 2.7 +/- 0.6; P < 0.0001) than those without ISR. A linear relation was found between ISR and CFR (r = -0.73; P < 0.0001) and remained significant after adjustment for blood pressure and heart rate (r = -0.74; P < 0.0001). A CFR less than two identified significant ISR (sensitivity 88%, specificity 88%, area under the curve = 0.943; P < 0.001). In a multivariate model of CFR prediction, myocardial infarction and heart rate were slightly contributory (ss = -0.19, P < 0.01; ss = -0.16, P < 0.03, respectively), whereas ISR had a large influence (ss = -0.66; P < 0.0001). The inverse correlation between ISR and CFR persisted in patients with myocardial infarction (r = -0.64; P < 0.0001) and in those treated with beta-blockers (r = -0. 71; P < 0.0001). CONCLUSION Echocardiographic measurement of CFR detects significant left anterior descending ISR in unselected patients with multiple risk factors, old anterior-apical myocardial infarction, and taking beta-blockers.