Cardiopoietic Stem Cell Therapy in Heart Failure Bartunek, Jozef, MD, PhD; Behfar, Atta, MD, PhD; Dolatabadi, Dariouch, MD ...
Journal of the American College of Cardiology,
06/2013, Letnik:
61, Številka:
23
Journal Article
Recenzirano
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Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in ...patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238 ).
Several meta-analyses have focused on determination of the effectiveness of aspirin (acetylsalicylic acid) in primary prevention of cardiovascular (CV) events. Despite these data, the role of aspirin ...in primary prevention continues to be investigated. Nine randomized trials have evaluated the benefits of aspirin for the primary prevention of CV events: the British Doctors' Trial (BMD), the Physicians' Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary Prevention Project (PPP), the Women's Health Study (WHS), the Aspirin for Asymptomatic Atherosclerosis Trial (AAAT), the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial. The combined sample consists of about 90,000 subjects divided approximately evenly between those taking aspirin and subjects not taking aspirin or taking placebo. A meta-analysis of these 9 trials assessed 6 CV end points: total coronary heart disease, nonfatal myocardial infarction (MI), total CV events, stroke, CV mortality, and all-cause mortality. No covariate adjustment was performed, and appropriate tests for treatment effect, heterogeneity, and study size bias were applied. The meta-analysis suggested superiority of aspirin for total CV events and nonfatal MI, (p <0.05 for each), with nonsignificant results for decreased risk for stroke, CV mortality, and all-cause mortality. There was no evidence of a statistical bias (p >0.05). In conclusion, aspirin decreased the risk for CV events and nonfatal MI in this large sample. Thus, primary prevention with aspirin decreased the risk for total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease.
Resting Heart Rate in Cardiovascular Disease Fox, Kim, MD, FESC; Borer, Jeffrey S., MD, FACC; Camm, A. John, MD, FESC, FACC ...
Journal of the American College of Cardiology,
08/2007, Letnik:
50, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Resting Heart Rate in Cardiovascular Disease Kim Fox, Jeffrey S. Borer, A. John Camm, Nicolas Danchin, Roberto Ferrari, Jose L. Lopez Sendon, Philippe Gabriel Steg, Jean-Claude Tardif, Luigi Tavazzi, ...Michal Tendera, for the Heart Rate Working Group Recent large epidemiologic studies have confirmed earlier studies that showed resting heart rate (HR) to be an independent predictor of cardiovascular and all-cause mortality in men and women with and without cardiovascular disease. Clinical trial data suggest that HR reduction is an important mechanism of benefit of beta-blockers and other HR lowering drugs. Pathophysiological studies indicate that a relatively high HR has direct detrimental effects on the progression of coronary atherosclerosis, on the occurrence of myocardial ischemia and ventricular arrhythmias, and on left ventricular function. Studies have found a continuous increase in risk with HR above 60 beats/min.
Acute and Late Outcomes of Unprotected Left Main Stenting in Comparison With Surgical Revascularization Pawel E. Buszman, Stefan R. Kiesz, Andrzej Bochenek, Ewa Peszek-Przybyla, Iwona Szkrobka, ...Marcin Debinski, Bozena Bialkowska, Dariusz Dudek, Agata Gruzka, Aleksander Zurakowski, Krzysztof Milewski, Miroslaw Wilczynski, Lukasz Rzeszutko, Piotr Buszman, Jan Szymszal, Jack L. Martin, Michal Tendera Unprotected left main coronary artery (ULMCA) stenting is the subject of intense investigation as a potential alternative to bypass surgery. We randomly assigned 105 patients with ULMCA stenosis to receive percutaneous coronary intervention (PCI) (52 patients) or coronary artery bypass grafting (CABG) (53 patients). Patients treated with PCI had favorable early outcomes in comparison with the CABG group. At 1 year, the ejection fraction improved significantly only in the PCI group. Target vessel failure was similar in both groups. After more than 2 years, major adverse cardiac and cerebrovascular event-free survival was similar in both groups with a trend toward improved survival after PCI.
Abstract Background Anemia is a predictor of adverse outcomes in acute myocardial infarction. We studied the relationship of hemoglobin, or its change over time, and outcomes in patients with stable ...coronary artery disease. Methods CLARIFY is a prospective, cohort study of outpatients with stable coronary artery disease (32,901 in 45 countries 2009-2010); 21,829 with baseline hemoglobin levels. They were divided into hemoglobin quintiles and anemia status (anemic A or normal N) at baseline/follow-up: N/N; A/N; N/A; A/A. All-cause mortality, cardiovascular events, and major bleeding at 4-year follow-up were assessed. Results Low baseline hemoglobin was an independent predictor of all-cause, cardiovascular, and noncardiovascular mortality, the composite of cardiovascular death/myocardial infarction or stroke and major bleeds (all P <.001; unadjusted models). Anemia at follow-up was independently associated with all-cause mortality (hazard ratio HR, 1.90; 95% confidence interval CI, 1.55-2.33 for A/A; 1.87; 1.54-2.28 for N/A; both P <.001), noncardiovascular mortality ( P <.001), and cardiovascular mortality ( P = .001). Patients whose baseline anemia normalized (A/N) were not at increased risk of death (HR, 1.02; 95% CI, 0.77-1.35), although risk of major bleeding was greater (HR, 2.06; 95% CI, 1.23-3.44; P = .013) than in those with normal hemoglobin throughout. Sensitivity analyses excluding patients with heart failure and chronic kidney disease at baseline yielded qualitatively similar results. Conclusion In this large stable coronary artery disease population, low hemoglobin was an independent predictor of mortality, cardiovascular events, and major bleeds. Persisting or new-onset anemia is a powerful predictor of cardiovascular and noncardiovascular mortality.
Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological ...intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.
Abstract Background Elevated resting heart rate is associated with increased cardiovascular risk, particularly in patients with left ventricular systolic dysfunction. Heart rate is not monitored ...routinely in these patients. We hypothesized that routine monitoring of heart rate would increase its prognostic value in patients with left ventricular systolic dysfunction. Methods We analyzed the relationship between heart rate measurements and a range of adverse cardiovascular outcomes, including hospitalization for worsening heart failure, in the pooled placebo-treated patients from the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial and Systolic Heart failure treatment with the If inhibitor ivabradine (SHIFT) Trial, using standard and time-varying covariate Cox proportional hazards models. By adjusting for other prognostic factors, models were fitted for baseline heart rate alone or for time-updated heart rate (latest heart rate) alone or corrected for baseline heart rate or for immediate previous time-updated heart rate. Results Baseline heart rate was strongly associated with all outcomes apart from hospitalization for myocardial infarction. Time-updated heart rate increased the strengths of associations for all outcomes. Adjustment for baseline heart rate or immediate previous time-updated heart rate modestly reduced the prognostic importance of time-updated heart rate. For hospitalization for worsening heart failure, each 5 beats/min increase in baseline heart rate and time-updated heart rate was associated with a 15% (95% confidence interval, 12-18) and 22% (confidence interval, 19-40) increase in risk, respectively. Even after correction, the prognostic value of time-updated heart rate remained greater. Conclusions In patients with left ventricular systolic dysfunction, time-updated heart rate is more strongly related with adverse cardiovascular outcomes than baseline heart rate. Heart rate should be measured to assess cardiovascular risk at all assessments of patients with left ventricular systolic dysfunction.
Background Although significant efforts have been made to improve ST-segment elevation myocardial infarction (STEMI) outcomes by reducing symptom-onset-to-reperfusion times, strategies to decrease ...the clinical impact of ischemic reperfusion injury have demonstrated limited success. Bendavia, an intravenously administered mitochondrial targeting peptide, has been shown to reduce myocardial infarct size and attenuate coronary no-reflow in experimental modelswhen given before reperfusion. Design The EMBRACE STEMI study is a phase 2a, randomized, double-blind, placebo-controlled trial enrolling 300 patients with a first-time anterior STEMI and an occluded proximal or mid–left anterior descending artery undergoing primary percutaneous coronary intervention (PCI) within 4 hours of symptom onset. Patients will be randomized to receive either Bendavia at 0.05 mg/kg per hour or an identically appearing placebo administered as an intravenous infusion at 60 mL/h. The primary end point is infarct size measured by the area under the creatine kinase–MB enzyme curve calculated from measurements from the central clinical chemistry laboratory obtained over the initial 72 hours after the primary PCI procedure, and the major secondary end point is infarct size calculated by the volume of infarcted myocardium (late contrast gadolinium enhancement) on the day 4±1 cardiac magnetic resonance imaging. Summary EMBRACE-STEMI is testing the hypothesis that Bendavia, in conjunction with standard-of-care therapy, is superior to placebo for the reduction of myocardial infarction size among patients with first time, acute, anterior wall STEMI who undergo successful reperfusion with primary PCI and stenting.
Background Elevated heart rate in stable coronary artery disease (CAD) is associated with worse outcomes, particularly increased risk of myocardial infarction. Heart rate reduction with the If ...inhibitor ivabradine confers symptomatic benefits in angina pectoris and reduces coronary events in patients with stable CAD and left ventricular (LV) systolic dysfunction, with a resting heart rate of ≥70 beats/min. The SIGNIFY trial is testing the hypothesis that heart rate reduction using ivabradine reduces mortality and cardiovascular events in patients with stable CAD, but without clinical heart failure. Methods The SIGNIFY trial is a randomized, double-blind, parallel-group, placebo-controlled, event-driven study in patients with stable CAD (1,139 centers, 51 countries). Participants are 55 years or older, with stable CAD and an LV ejection fraction >40%, in sinus rhythm, with a baseline resting heart rate of ≥70 beats/min, and with at least 1 additional cardiovascular risk factor. At inclusion, patients receive ivabradine 7.5 mg twice a day or matching placebo, which is adjusted at every visit to a heart rate target of 60 beats/min. Participants should receive the best possible background treatment for stable CAD. The primary end point is a composite of cardiovascular death or nonfatal myocardial infarction. Results Recruitment lasted from October 2009 to April 2012. The SIGNIFY trial has recruited 19,102 patients (age 65.0 ± 7.2 years, resting heart rate 77.2 ± 7.0 beats/min, 72% male) with no evidence for LV dysfunction (ejection fraction 56.5% ± 8.6%). Conclusion The SIGNIFY trial will shed further light on the role of heart rate lowering with ivabradine in patients with stable CAD without clinical heart failure. The study is expected to end in 2014.
Objectives This study sought to assess of the mobilization of nonhematopoietic very small embryonic-like stem cells (VSELs) in acute myocardial infarction (MI). Background Acute MI induces ...mobilization of bone marrow stem cells. Recently, a rare population of VSELs, expressing markers of embryonic pluripotent stem cells (PSCs), was identified in adult murine bone marrow and human umbilical cord blood. Methods Thirty-one patients with acute MI and 30 healthy subjects were enrolled. Blood was sampled on admission, after 24 h, and 5 days later. Erythrocytes were lysed and lin− CD45− VSELs were isolated using a live cell sorting system (FACSAria, Beckton Dickinson, San Jose, California). Results In healthy subjects the median number of circulating VSELs was very low (median 0.8 range 0 to 1.3) cells/μl. In acute MI, VSELs were mobilized early (median 2.7 range 0.2 to 3.9 cells/μl; p < 0.001) and remained elevated after 24 h and 5 days (median 4.7 range 0.2 to 6.4 cells/μl; p < 0.003, and median 2.6 range 0.3 to 3.6 cells/μl; p < 0.03, respectively). The mobilization of VSEL was significantly reduced in patients older than 50 years and with diabetes in comparison with younger and nondiabetic patients. Circulating VSELs were small (7 to 8 μm) and enriched in the messenger ribonucleic acid of PSC markers (Oct-4, Nanog), cardiac lineage (GATA-4, Nkx2.5/Csx, MEF2C), and endothelial (VE-cadherin) markers. The presence of PSC markers (Oct-4, SSEA-4) and the chemokine receptor CXCR4 in circulating VSELs was confirmed at the protein level by immunofluorescent staining and ImageStream system (Amnis Corporation, Seattle, Washington) analysis. Conclusions Acute MI induced mobilization of VSELs expressing pluripotent markers, early cardiac and endothelial markers, and chemokine receptor CXCR4.
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