Mohamed Khayata

Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.

IMPORTANCE Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01041417.

Oxidative Stress Is Associated With Increased Pulmonary Artery Systolic Pressure in Humans

Oxidative stress contributes to the development of pulmonary hypertension in experimental models, but this association in humans is unknown. We investigated the relationship between pulmonary artery systolic pressure measured by echocardiography and plasma aminothiol oxidative stress markers, with the hypothesis that oxidative stress will be higher in those with pulmonary hypertension. A group of 347 patients aged 65±12 years from the Emory Cardiovascular Biobank underwent echocardiographic assessment of left ventricular ejection fraction and pulmonary artery systolic pressure. Plasma aminothiols, cysteine, its oxidized form, cystine, glutathione, and its oxidized disulphide were measured and the redox potentials (Eh) of cysteine/cystine and glutathione/oxidized glutathione couples were calculated. Non-normally distributed variables were log transformed (Ln). Univariate predictors of pulmonary artery systolic pressure included age (P<0.001), sex (P=0.002), mitral regurgitation (P<0.001), left ventricular ejection fraction (P<0.001), left atrial size (P<0.001), diabetes mellitus (P=0.03), plasma Ln cystine (&bgr;=9.53; P<0.001), Ln glutathione (&bgr;=−5.4; P=0.002), and Eh glutathione (&bgr;=0.21; P=0.001). A multivariate linear regression model adjusting for all confounding variables demonstrated that Ln cystine (&bgr;=6.56; P=0.007), mitral regurgitation (&bgr;=4.52; P<0.001), statin use (&bgr;=−3.39; P=0.03), left ventricular ejection fraction (&bgr;=−0.26; P=0.003), and age (&bgr;=0.17; P=0.003) were independent predictors of pulmonary artery systolic pressure. For each 1% increase in plasma cystine, pulmonary artery systolic pressure increased by 16%. This association persisted in the subgroup with preserved left ventricular ejection fraction (≥50%) and no significant mitral regurgitation. Whether treatment of oxidative stress will improve pulmonary hypertension requires further study.

Differential effects of nebivolol and metoprolol on arterial stiffness, circulating progenitor cells, and oxidative stress

Unlike traditional beta receptor antagonists, nebivolol activates nitric oxide. We hypothesized that therapy with nebivolol compared with metoprolol would improve arterial stiffness, increase levels of circulating progenitor cells (PC), and decrease oxidative stress (OS). In a randomized, double-blind, cross-over study, 30 hypertensive subjects received either once daily nebivolol or metoprolol succinate for 3 months each. Pulse wave velocity and augmentation index were measured using tonometry. Flow cytometry was used to measure circulating PC. OS was measured as plasma aminothiols. Measurements were performed at baseline, and repeated at 3 and 6 months. No significant differences were present between the levels of OS, arterial stiffness, and PC numbers during treatment with metoprolol compared with nebivolol. In subgroup analyses of beta-blocker naïve subjects (n = 19), nebivolol reduced pulse wave velocity significantly compared with metoprolol (-1.4 ± 1.9 vs. -0.1 ± 2.2; P = .005). Both nebivolol and metoprolol increased circulating levels of CD34+/CD133 + PC similarly (P = .05), suggesting improved regenerative capacity.

Time to Change Our Focus: Defining, Promoting, and Impacting Cardiovascular Population Health

Despite numerous groundbreaking advances in the field, cardiovascular disease remains the leading cause of mortality in the United States, accounting for more than 787,000 deaths per year. Already leading the world in per capita healthcare expenditure, U.S. medical costs related to cardiovascular disease are projected to triple by 2030, to over

Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death

800 billion annually. The medical communitys traditional disproportionate focus on treating cardiovascular disease, relative to promoting cardiovascular health, is an important contributor to these expenses. To ensure continued reductions in the burden of cardiovascular disease, as well as the overall sustainability of the healthcare system, a paradigm shift that places more emphasis on cardiovascular health promotion throughout the life course is required. This review will discuss the current definitions of cardiovascular health, as well as strategies for promoting and impacting cardiovascular health at both the local and national level.

A DISTINCT PERIPHERAL BLOOD GENE EXPRESSION PROFILE IS ASSOCIATED WITH ACUTE MYOCARDIAL INFARCTION AND PREDICTS RISK OF CARDIOVASCULAR DEATH

Background— Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. Methods and Results— C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden’s index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43–2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. Conclusions— SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

Coronary and Peripheral Vasomotor Responses to Mental Stress

Recent advances in gene expression analysis have led to discoveries of signatures that are associated with presence and severity of coronary artery disease (CAD) and the risk of future outcomes in non-diabetics with CAD. We sought to identify signatures associated with acute myocardial infarction (

STROMAL CELL-DERIVED FACTOR 1- AND CIRCULATING PROGENITOR CELL LEVELS AS PREDICTORS OF ADVERSE CARDIOVASCULAR OUTCOMES IN PATIENTS WITH CORONARY ARTERY DISEASE

Background Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress (MS). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow (CBF) responses during MS remains understudied. We hypothesized that coronary vasomotion during MS is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation. Methods and Results In 38 patients aged 59±8 years undergoing coronary angiography, endothelium‐dependent and endothelium‐independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after MS induced by mental arithmetic testing. Peripheral microvascular tone during MS was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio). MS increased the rate‐pressure product by 22% (±23%) and constricted epicardial coronary arteries by −5.9% (−10.5%, −2.6%) (median [interquartile range]), P=0.001, without changing CBF. Acetylcholine increased CBF by 38.5% (8.1%, 91.3%), P=0.001, without epicardial coronary diameter change (0.1% [−10.9%, 8.2%], P=not significant). The MS‐induced CBF response correlated with endothelium‐dependent CBF changes with acetylcholine (r=0.38, P=0.03) but not with the response to nitroprusside. The peripheral arterial tonometry ratio also correlated with the demand‐adjusted change in CBF during MS (r=−0.60, P=0.004), indicating similarity between the microcirculatory responses to MS in the coronary and peripheral microcirculation. Conclusions The coronary microvascular response to MS is determined by endothelium‐dependent, but not endothelium‐independent, coronary microvascular function. Moreover, the coronary microvascular responses to MS are reflected in the peripheral microvascular circulation.

SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR IS AN INDEPENDENT PREDICTOR OF CARDIOVASCULAR OUTCOMES IN PATIENTS WITH LEFT VENTRICULAR SYSTOLIC DYSFUNCTION

We have shown that levels of circulating progenitor cells (PCs) predict future outcomes in patients with CAD. SDF-1a is a biomarker responsible for homing of PCs to ischemic tissues. We investigated the relationship between circulating levels of SDF1a and PCs and whether they enhance prediction of

Plasma Stromal Cell-Derived Factor 1α/CXCL12 Level Predicts Long-Term Adverse Cardiovascular Outcomes in Patients with Coronary Artery Disease

Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. Recent studies have associated suPAR with presence and severity of coronary artery disease (CAD). However, the prognostic implication of suPAR in patients with left ventricular systolic dysfunction (