Matthew J. Feinstein

Contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization: a new surrogate marker of atherosclerosis?

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 Spearmans 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.

Patterns of Cardiovascular Mortality for HIV-Infected Adults in the United States: 1999 to 2013.

With widespread availability and the use of antiretroviral therapy, patients with human immunodeficiency virus (HIV) in the United States are living long enough to experience non-AIDS-defining illnesses. HIV is associated with an increased risk for cardiovascular disease (CVD) because of traditional CVD risk factors, residual virally mediated inflammation despite HIV treatment, and side effects of antiretroviral therapy. No United States population-wide studies have evaluated patterns of CVD mortality for HIV-infected subjects. Our central hypothesis was that the proportionate mortality from CVD (CVD mortality/total mortality) in the HIV-infected population increased from 1999 to 2013. We used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research online database of the United States public health data to assess proportionate CVD mortality from 1999 to 2013 in the HIV-infected, general, and inflammatory polyarthropathy populations; the inflammatory polyarthropathy population was included as a positive control group. Total mortality in the HIV-infected population decreased from 15,739 in 1999 to 8,660 in 2013; however, CVD mortality increased from 307 to 400 during the same period. Thus, proportionate CVD mortality for the HIV-infected population increased significantly from 1999 to 2013 (p <0.0001); this pattern was consistent across races, particularly for men. In contrast, proportionate CVD mortality decreased for the general and inflammatory polyarthropathy populations from 1999 to 2013. In conclusion, CVD has become an increasingly common cause of death in HIV-infected subjects since 1999; understanding evolving mortality risks in the HIV-infected population is essential to inform routine clinical care of HIV-infected subjects as well as CVD prevention and treatment.

Racial Differences in Risks for First Cardiovascular Events and Noncardiovascular Death The Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis

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. # CLINICAL PERSPECTIVE {#article-title-33}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.

Burden of Cardiovascular Risk Factors, Subclinical Atherosclerosis, and Incident Cardiovascular Events Across Dimensions of Religiosity: The Multi-Ethnic Study of Atherosclerosis

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 Institutes 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.

A Systematic Review of the Usefulness of Statin Therapy in HIV-Infected Patients

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.

Assessing and refining myocardial infarction risk estimation among patients with human immunodeficiency virus: A study by the Centers for AIDS Research Network of Integrated Clinical Systems

Importance Persons with human immunodeficiency virus (HIV) that is treated with antiretroviral therapy have improved longevity but face an elevated risk of myocardial infarction (MI) due to common MI risk factors and HIV-specific factors. Despite these elevated MI rates, optimal methods to predict MI risks for HIV-infected persons remain unclear. Objective To determine the extent to which existing and de novo estimation tools predict MI in a multicenter HIV cohort with rigorous MI adjudication. Design, Setting, and Participants We evaluated the performance of standard of care and 2 new data-derived MI risk estimation models in 5 Centers for AIDS Research Network of Integrated Clinical Systems sites across the United States where a multicenter clinical prospective cohort of 19 829 HIV-infected adults received care in inpatient and outpatient settings since 1995. The new risk estimation models were validated in a separate cohort from the derivation cohort. Exposures Traditional cardiovascular risk factors, HIV viral load, CD4 lymphocyte count, statin use, antihypertensive use, and antiretroviral medication use were used to calculate predicted event rates. Main Outcomes and Measures We observed MI rates over the course of follow-up that were scaled to 10 years using the Greenwood-Nam-D’Agostino Kaplan-Meier approach to account for dropout and loss to follow-up before 10 years. Results Of the 11 288 patients with complete baseline data, 6904 were white and 9250 were men. Myocardial infarction rates were higher among black men (6.9 per 1000 person-years) and black women (7.2 per 1000 person-years) than white men (4.4 per 1000 person-years) and white women (3.3 per 1000 person-years), older participants (7.5 vs 2.2 MI per 1000 person-years for adults 40 years and older vs < 40 years old at study entry, respectively), and participants who were not virally suppressed (6.3 vs 4.7 per 1000 person-years for participants with and without detectable viral load, respectively). The 2013 Pooled Cohort Equations, which predict composite rates of MI and stroke, adequately discriminated MI risk (Harrell C statistic = 0.75; 95% CI, 0.71-0.78). Two data-derived models incorporating HIV-specific covariates exhibited weak calibration in a validation sample and did not discriminate risk any better (Harrell C statistic = 0.72; 95% CI, 0.67-0.78 and 0.73; 95% CI, 0.68-0.79) than the Pooled Cohort Equations. The Pooled Cohort Equations were moderately calibrated in the Centers for AIDS Research Network of Clinical Systems but predicted consistently lower MI rates. Conclusions and Relevance The Pooled Cohort Equations discriminated MI risk and were moderately calibrated in this multicenter HIV cohort. Adding HIV-specific factors did not improve model performance. As HIV-infected cohorts capture and assess MI and stroke outcomes, researchers should revisit the performance of risk estimation tools.

Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual‐level reanalysis of CORONA and GISSI‐HF

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.

Types of Myocardial Infarction Among Human Immunodeficiency Virus-Infected Individuals in the United States

Importance The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. Type 1 MIs result spontaneously from instability of atherosclerotic plaque, whereas type 2 MIs occur in the setting of a mismatch between oxygen demand and supply, as with severe hypotension. Type 2 MIs are uncommon in the general population, but their frequency in human immunodeficiency virus (HIV)–infected individuals is unknown. Objectives To characterize MIs, including type; identify causes of type 2 MIs; and compare demographic and clinical characteristics among HIV-infected individuals with type 1 vs type 2 MIs. Design, Setting, and Participants This longitudinal study identified potential MIs among patients with HIV receiving clinical care at 6 US sites from January 1, 1996, to March 1, 2014, using diagnoses and cardiac biomarkers recorded in the centralized data repository. Sites assembled deidentified packets, including physician notes and electrocardiograms, procedures, and clinical laboratory tests. Two physician experts adjudicated each event, categorizing each definite or probable MI as type 1 or type 2 and identifying the causes of type 2 MI. Main Outcomes and Measures The number and proportion of type 1 vs type 2 MIs, demographic and clinical characteristics among those with type 1 vs type 2 MIs, and the causes of type 2 MIs. Results Among 571 patients (median age, 49 years [interquartile range, 43-55 years]; 430 men and 141 women) with definite or probable MIs, 288 MIs (50.4%) were type 2 and 283 (49.6%) were type 1. In analyses of type 1 MIs, 79 patients who underwent cardiac interventions, such as coronary artery bypass graft surgery, were also included, totaling 362 patients. Sepsis or bacteremia (100 [34.7%]) and recent use of cocaine or other illicit drugs (39 [13.5%]) were the most common causes of type 2 MIs. A higher proportion of patients with type 2 MIs were younger than 40 years (47 of 288 [16.3%] vs 32 of 362 [8.8%]) and had lower current CD4 cell counts (median, 230 vs 383 cells/µL), lipid levels (mean [SD] total cholesterol level, 167 [63] vs 190 [54] mg/dL, and mean (SD) Framingham risk scores (8% [7%] vs 10% [8%]) than those with type 1 MIs or who underwent cardiac interventions. Conclusions and Relevance Approximately half of all MIs among HIV-infected individuals were type 2 MIs caused by heterogeneous clinical conditions, including sepsis or bacteremia and recent use of cocaine or other illicit drugs. Demographic characteristics and cardiovascular risk factors among those with type 1 and type 2 MIs differed, suggesting the need to specifically consider type among HIV-infected individuals to further understand MI outcomes and to guide prevention and treatment.

Monoclonal Antibodies for Lipid Management

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.

Clinical characteristics of HIV-infected patients with adjudicated heart failure:

Aims HIV-infected persons may have elevated risks for heart failure, but factors associated with heart failure in the modern era of HIV therapy are insufficiently understood. Despite substantial disagreement between physician-adjudicated heart failure and heart failure diagnosis codes, few studies of HIV cohorts have evaluated adjudicated heart failure. We evaluated associations of HIV viremia, immunosuppression, and cardiovascular risk factors with physician-adjudicated heart failure. Methods and results We analyzed clinical characteristics associated with heart failure in a cohort of 5041 HIV-infected patients receiving care at an urban hospital system between 2000 and 2016. We also evaluated characteristics of HIV-infected patients who screened negative for heart failure, screened positive for possible heart failure but did not have heart failure after adjudication, and had adjudicated heart failure. HIV-infected patients with heart failure (N = 216) were older and more likely to be black, hypertensive, and have diabetes than HIV-infected patients without heart failure; heart failure with reduced ejection fraction was more common than heart failure with preserved ejection fraction. In our primary analyses restricted to HIV-infected patients whose heart failure diagnoses did not precede their HIV diagnoses (N = 149), peak HIV viral load ≥100,000 copies/mL (odds ratio (OR) 2.12, 1.28–3.52) and nadir CD4 T-cell count <200 cells/mm3 (OR 2.35, 1.04–5.31) were associated with significantly elevated odds of heart failure. Overall, 30.6% of patients with any diagnosis code of heart failure had adjudicated heart failure. Conclusion Higher peak HIV viremia and lower CD4 cell nadir are associated with significantly elevated odds of heart failure for HIV-infected persons. Physician adjudication of heart failure may be helpful in HIV cohorts.