Mehdi H. Shishehbor

Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways

Background—The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide–derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. Methods and Results—As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P <0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P <0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P >0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. Conclusions—Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide–derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans

Background—In vitro and animal studies demonstrate that myeloperoxidase catalytically consumes nitric oxide as a substrate, limiting its bioavailability and function. We therefore hypothesized that circulating levels of myeloperoxidase would predict risk of endothelial dysfunction in human subjects. Methods and Results—Serum myeloperoxidase was measured by enzyme-linked immunoassay, and brachial artery flow–mediated dilation and nitroglycerin-mediated dilation were determined by ultrasound in a hospital-based population of 298 subjects participating in an ongoing study of the clinical correlates of endothelial dysfunction (age, 51±16; 61% men, 51% with cardiovascular disease). A strong inverse relation between brachial artery flow–mediated dilation and increasing quartile of serum myeloperoxidase level was observed (11.0±6.0%, 9.4±5.3%, 8.6±5.8%, and 6.4±4.5% for quartiles 1 through 4, respectively; P<0.001 for trend). Using the median as a cut point to define endothelial dysfunction, increasing quartile of myeloperoxidase predicted endothelial dysfunction after adjustment for classic cardiovascular disease risk factors, C-reactive protein levels, prevalence of cardiovascular disease, and ongoing treatment with cardiovascular medications (OR, 6.4; 95% CI, 2.6 to 16; P=0.001 for highest versus lowest quartile). Conclusions—Serum myeloperoxidase levels serve as a strong and independent predictor of endothelial dysfunction in human subjects. Myeloperoxidase-mediated endothelial dysfunction may be an important mechanistic link between oxidation, inflammation, and cardiovascular disease.

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Prognosis on Chronic Dobutamine or Milrinone Infusions for Stage D Heart Failure

Background—There are no published clinical trials comparing dobutamine with milrinone in outpatients with stage D heart failure on continuous inotropes. Methods and Results—In a retrospective analysis of 112 inotrope-dependent patients with stage D heart failure who were not transplant candidates at enrollment, we investigated the relationship between choice of dobutamine or milrinone and mortality. Half the patients were on dobutamine (mean dose, 5.4±2.5 &mgr;g/kg per minute) and half on milrinone (mean dose, 0.4±0.2 &mgr;g/kg per minute). Those on dobutamine tended to be older (63 years old versus 54 years old), male (86% versus 79%), and fewer had implantable cardioverter-defibrillators (57% versus 74%). During a median follow-up time of 130 days (range, 2 to 2345 days), there were 85 deaths (76% of cohort) and 55 rehospitalizations. Use of dobutamine compared with milrinone was associated with higher all-cause mortality in an unadjusted analysis (hazard ratio [HR], 1.63; 95% CI, 1.06 to 2.52; P<0.03). However, this association was not significant after adjustment for baseline characteristics in the full cohort (N=112; HR, 0.99; 95% CI 0.5 to 1.97; P=0.98) or propensity-matched cohort (N=70; HR, 0.94; 95% CI 0.48 to 1.85; P=0.86). Conclusions—In this single-center retrospective study, there were no mortality differences between chronic intravenous dobutamine or milrinone in patients with stage D heart failure being discharged from the hospital. The high mortality in this group selected for inotrope dependence warrants careful consideration of all options and priorities for further care.

β-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials

Context The mechanisms by which -blockers prevent recurrent myocardial infarction are not clear. Contribution This pooled analysis of individual patient data examines changes in coronary atheroma volume as measured by serial intravascular ultrasonography in 4 randomized trials. The trials followed 1515 patients with coronary artery disease for 18 to 24 months. Atheroma volume decreased in patients who were receiving -blockers but stayed the same in those not receiving -blockers. Cautions The trials tested other interventions (such as statins) that could have affected atheromas. We do not know whether changes in atheroma volume predict cardiovascular outcomes. Implication -Blockers probably slow progression of coronary atherosclerosis. The Editors Clinical trials conducted in the 1980s (16) showed that -adrenergic blockers effectively reduce recurrent myocardial infarction, sudden cardiac death, and total mortality in patients with myocardial infarction. Researchers have attributed these effects to many properties of -adrenergic blockers, including reduced myocardial oxygen consumption, sympathetic blockade, decreased blood pressure, and potential antiatherosclerotic effects. Although the first 3 of these actions are well established, antiatherosclerotic effects in human coronary arteries have not been shown. On the other hand, whether -blockers still provide benefit in the current era of aggressive reperfusion for myocardial infarction, in which the beneficial effects of these drugs on preserving ventricular function is seemingly less important, is not known. Intravascular ultrasonography (IVUS) is increasingly used to assess the possible coronary antiatherosclerotic effects of various classes of drugs. Four major trials used IVUS to assess this effect: REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) (7), CAMELOT IVUS (Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis Intravascular Ultrasound) substudy (8), ACTIVATE (Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation) (9), and ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden) (10). The REVERSAL study evaluated the effects of moderate versus intensive lipid-lowering therapy with statins, the CAMELOT IVUS substudy examined the effects of a calcium-channel blocker (amlodipine) and an angiotensin-converting enzyme (ACE) inhibitor (enalapril), ACTIVATE evaluated the effect of the acyl coenzyme A (CoA)cholesterol acyltransferase inhibitor pactimibe, and ASTEROID evaluated the effect of very-high-intensity lipid-lowering therapy with rosuvastatin on the progression rate of coronary atherosclerosis. However, no study has evaluated the potential coronary antiatherosclerotic effects of -blockers by using IVUS or any other technique that allows direct quantification of plaque volume. Thus, we aimed to determine the relationship between concomitant -blocker treatment and the progression rate of coronary atherosclerosis in the combined samples of REVERSAL, CAMELOT IVUS, ACTIVATE, and ASTEROID. Methods Study Samples The samples of the 4 trials included in our analysis are fully described elsewhere (711) (Table 1). The studies enrolled patients with a clinical indication for coronary angiography (stable or unstable angina or positive results on a stress test) who had luminal narrowing of more than 20% in at least 1 vessel on angiography. Table 1. Characteristics of the Included Trials* The 4 trials assessed vital signs, use of concomitant medications, and fasting plasma lipid and glucose levels every 3 months. Because of study protocols, all patients in REVERSAL and ASTEROID were considered to have continuously received statins. -Blocker use was defined as receipt of a -blocker at any time during the trial period. The Cleveland Clinic institutional review board approved the research by using the databases of these 4 trials. Intravascular Ultrasonography The same acquisition and measurement method was used in all 4 studies (711). The IVUS catheter was inserted into the target vessel, and the transducer was positioned distal to a side branch. A motor drive unit withdrew the transducer at a constant speed. External elastic membrane (EEM) and lumen area measurements were obtained every 1 mm starting at the distal branch site and ending at a proximal branch site, in accordance with the standards of the American College of Cardiology and the European Society of Cardiology (12, 13). At the end of the trial, a follow-up IVUS was performed in the same arterial segments. All IVUS interrogations were analyzed in the same core laboratory at the Cleveland Clinic. The reproducibility of IVUS measurements was excellent for both intraobserver and interobserver variability (correlation coefficient, 0.99 for EEM measurements and 0.98 for lumen area measurements) (7). Atheroma volume was calculated as (EEM arealumen area), corresponding to the sum of the atheroma areas in slices spaced 1 mm apart. Because volume calculations are dependent on the length of the imaged segment, normalized atheroma volume was calculated for each patient, which corresponded to: Statistical Analysis We report the quantitative data as mean (SD) and categorical data as number (percentage), unless stated otherwise. Average blood pressure, plasma lipid levels, and glucose levels during treatment were calculated by averaging all of the available data collected during follow-up visits that were performed every 3 months. The characteristics of patients who received and did not receive -blocker treatment were compared by using the chi-square test or the unpaired t test, except for the nonnormally distributed characteristics of average triglyceride levels during treatment and baseline atheroma volume, for which the MannWhitney test was used. The prespecified primary outcome measure was the comparison of changes in atheroma volume of patients who received and those who did not receive -blocker treatment, after controlling for histories of hypertension, angina, and myocardial infarction (the major indications for -blocker treatment). We constructed additional multivariable models to evaluate the effect of other possible confounders, including heart rate, plasma lipid levels, other concomitant medications, and the specific trials in which the patients were enrolled. We evaluated the outcome measures by using linear mixed-effects models and estimated annual changes in atheroma volume from these models (14). In addition, we developed a propensity score by using a logistic regression model to determine the predicted probability of -blocker use (15). Covariates that we entered into the logistic model included demographic characteristics (age, sex, race, and body mass index), medical history (hypertension, angina, myocardial infarction, heart failure, and diabetes), hemodynamic variables (baseline blood pressure and heart rate), and concomitant use of other medications (aspirin, ACE inhibitors, calcium-channel blockers, and nitrates). Concomitant use of other medications referred to any use of these medications during the trial period. We entered the predicted probability from this model as a covariate in the linear mixed-effects models to help reduce the bias of the baseline differences. We did not include patients with missing data in the multivariable analyses. We performed a sensitivity analysis by using multiple imputation methods to assign missing end point data for patients who did not complete the original trials and those with missing covariate information. We considered 2-sided P values less than 0.05 to be statistically significant. We performed analyses by using SPSS, version 11.5 for Windows (SPSS, Chicago, Illinois), and SAS software, version 8.2 (SAS Institute, Cary, North Carolina). Role of the Funding Sources The sponsors of the original trials, Pfizer (REVERSAL and CAMELOT IVUS), Sankyo (ACTIVATE), and AstraZeneca (ASTEROID), contributed to the data collection for our pooled analysis. The sponsors had no role in the study design, data interpretation, writing of the manuscript, or decision to submit the paper for publication. Results -Blocker Use A total of 2129 patients were randomly assigned in the 4 trials, and 1533 patients completed the trials. -Blocker use could not be determined in 18 patients, leaving 1515 patients for our analysis. Of these patients, 1154 (76%) received concomitant -blocker treatment during the trials (Table 2); 993 (86%) received treatment continuously and 161 (14%) received treatment intermittently. Patients who received any concomitant -blocker treatment received these drugs on average for 91% of the trial durations. The treatment groups in individual studies did not significantly differ in frequency of concomitant -blocker treatment (P= 0.82 for REVERSAL, P= 0.44 for CAMELOT IVUS, and P= 0.98 for ACTIVATE; ASTEROID had 1 group). Metoprolol was the most commonly used -blocker in all studies (46.2% in REVERSAL, 50.2% in CAMELOT IVUS, 53.4% in ACTIVATE, and 41.1% in ASTEROID), followed by atenolol (25.2%, 31.9%, 18.5%, and 26.7%, respectively). Table 2. -Blocker Use during the 4 Trials* Patient Characteristics Table 3 shows the characteristics of patients according to -blocker treatment. Patients who received -blocker treatment had lower average diastolic blood pressure (P= 0.063). They were also more likely to have histories of hypertension, angina, and myocardial infarction. Average high-density lipoprotein cholesterol levels during treatment were lower and triglyceride levels were higher in patients who received -blockers. Patients who received -blockers were also more likely to receive aspirin and nitrate therapy. The use of other medications was similar between patients who did and did not receive -blocker treatment. The consistency of treatment status throughout the study period (that is, no intermittent therapy) was high for all

Prevalence, awareness, treatment, and risk factors associated with hypertension in the Iranian population: the national survey of risk factors for noncommunicable diseases of Iran.

BACKGROUND The prevalence of hypertension in the Middle East is not well defined. We examined the prevalence, awareness, treatment, and control of hypertension in Iran. METHODS The Survey of Risk Factors of Noncommunicable Diseases was conducted in 2005 and contains a representative sample of the Iranian adult population. Of 70,981 participants, the data of 68,250 adults aged 25-64 years who had two valid blood pressure (BP) readings were analyzed to estimate the total prevalence of hypertension (systolic BP >or= 140 mm Hg, diastolic BP >or= 90 mm Hg, or the concurrent use of antihypertensive agents) in the Iranian adult population. RESULTS Approximately 25% or 6.6 million Iranians aged 25-64 years had hypertension; additionally 46% or 12 million Iranians aged 25-64 years had prehypertension. Among hypertensive patients, 34% were aware of their elevated BP; 25% were taking antihypertensive medications; and of these treated subjects, only 24% had BP values <140/90 mm Hg. Hypertension and prehypertension were associated with age, male gender, obesity, central obesity, hypercholesterolemia, and diabetes. CONCLUSIONS The prevalence of hypertension and prehypertension is high, and the rates of awareness, treatment, and control are unacceptably low. These results underscore the urgent need to develop national strategies to improve prevention, detection, and treatment of hypertension in Iran.

Characterization and outcome of patients with severe symptomatic aortic stenosis referred for percutaneous aortic valve replacement

OBJECTIVE Many high-risk patients with severe symptomatic aortic stenosis are not referred for surgical aortic valve replacement. Although this patient population remains ill-defined, many of these patients are now being referred for percutaneous aortic valve replacement. We sought to define the characteristics and outcomes of patients referred for percutaneous aortic valve replacement. METHODS Between February 2006 and March 2007, 92 patients were screened for percutaneous aortic valve replacement. Clinical and echocardiographic characteristics of patients undergoing surgical aortic valve replacement, percutaneous aortic valve replacement, balloon aortic valvuloplasty, or no intervention were compared. The primary end point was all-cause mortality. RESULTS Nineteen patients underwent successful surgical aortic valve replacement, 18 patients underwent percutaneous aortic valve replacement, and 36 patients had no intervention. Thirty patients underwent balloon aortic valvuloplasty, and of these, 8 patients were bridged to percutaneous aortic valve replacement and 3 were bridged to surgical aortic valve replacement. Of the remaining 19 patients undergoing balloon aortic valvuloplasty, bridging to percutaneous aortic valve replacement could not be accomplished because of death (n = 9 [47%)], exclusion from the percutaneous aortic valve replacement protocol (n = 6 [32%]), and some patients improved after balloon aortic valvuloplasty and declined percutaneous aortic valve replacement (n = 4 [21%]). The most common reasons for no intervention included death while awaiting definitive treatment (n = 10 [28%]), patient uninterested in percutaneous aortic valve replacement (n = 10 [28%]), and questionable severity of symptoms or aortic stenosis (n = 9 [25%]). Patients not undergoing aortic valve replacement had higher mortality compared with those undergoing aortic valve replacement (44% vs 14%) over a mean duration of 220 days. CONCLUSION Symptomatic patients with severe aortic stenosis have high mortality if timely aortic valve replacement is not feasible. Twenty percent of the patients referred for percutaneous aortic valve replacement underwent surgical aortic valve replacement with good outcome. Patients undergoing balloon aortic valvuloplasty alone or no intervention had unfavorable outcomes.

The nutcracker syndrome

Left renal vein (LRV) compression, commonly referred to as the nutcracker syndrome or renal vein entrapment syndrome, is a rare and often overlooked condition. Anatomically, the LRV traverses the space between the superior mesenteric artery and the aorta in close proximity to the origin of the artery. In affected individuals, the LRV is subjected to compression between these two structures, resulting in renal venous hypertension. A review of published data on this condition reveals either case reports or small case series. The classic symptoms of nutcracker syndrome include left flank pain with gross or microscopic hematuria. Patients are often children or young adults, with a slight predisposition for women who may also present with pelvic congestion symptoms such as pelvic pain and dyspareunia. Most patients have disease symptoms for many years and nondiagnostic investigations before proper diagnosis can be made. Appropriate diagnostic work-up and treatment may help alleviate patient morbidity from this chronic condition. Although surgical repair has been the standard of care, more recently endovascular intervention has become the first line of therapy. This tabular review compiles published cases in the adult population during the period between 1980 and 2009.

Xuezhikang, an Extract of Cholestin, Protects Endothelial Function Through Antiinflammatory and Lipid-Lowering Mechanisms in Patients With Coronary Heart Disease

Background—Endothelial dysfunction is associated with inflammation and postprandial hypertriglyceridemia. Xuezhikang, an extract of Cholestin, a dietary supplement, has lipid-modulating and antiinflammatory effects. We explored the effects of xuezhikang on endothelial function and high-sensitivity C-reactive protein (hs-CRP) in patients with coronary heart disease (CHD). Methods and Results—We prospectively randomized 50 CHD patients to xuezhikang 1200 mg/d or placebo for 6 weeks. Fasting hs-CRP concentrations, flow-mediated vasodilation (FMD) at 0 and 4 hours, and lipid parameters at 0, 2, 4, and 6 hours were monitored after a high-fat meal (800 calories; 50 g fat) in all patients. All patients underwent a high-fat meal test at the beginning of the study and after 6 weeks of treatment. Postprandial FMD was significantly worse at 4 hours after a high-fat meal (P<0.05), and this was associated with the area under the triglyceride curve (TG-AUC) (r=0.345, P<0.01). After 6 weeks of xuezhikang, fasting hs-CRP levels and TG-AUC (P<0.001 for each) decreased. Furthermore, preprandial and postprandial FMD significantly improved (P<0.001). There were no significant changes in serum lipids and FMD in the placebo arm. In multivariable regression analysis, changes in TG-AUC and fasting hs-CRP levels were predictive of improvement in preprandial FMD (P<0.05). Conclusions—Xuezhikang effectively improved preprandial and postprandial endothelial function through its potent antiinflammatory and lipid-lowering effects.

Endovascular Treatment of Resistant and Uncontrolled Hypertension: Therapies on the Horizon

The treatment of resistant hypertension has undergone remarkable advancements in recent years. Endovascular radio frequency renal sympathetic denervation (RSD) has shown initial success in treating resistant hypertension by targeting the connection between the brain and renal sympathetic nerves. However, the encouraging results of first-generation RSD have been tempered by important procedural limitations and a need for long-term results of safety and efficacy. In an effort to build on early clinical success, several second-generation RSD technologies are now being developed that may improve procedural safety and efficacy. Preliminary evidence for some of the latest technologies is now available. In this review, we summarize the current evidence in support of RSD and consider unique features of several new technologies that are likely to refine the endovascular treatment of resistant hypertension.