Shaul Atar

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

The mitochondria as a target for cardioprotection in acute myocardial ischemia

The ischemic heart suffers from nutrient deprivation, lack of oxygen, metabolic acidosis, hyperkalemia and Ca(2+) overload as well as high level of reactive oxygen species (ROS) generation; these risk factors endanger the cardiomyoctes and may cause their demise. Nevertheless, the treatment of acute myocardial infarction includes reperfusion, although it can exacerbate the effects of ischemia since resumption of blood supply to the ischemic myocardium is associated with increased ROS production. In the past 20 years, preconditioning and postconditioning were revealed, directing research efforts at finding pharmacological agents that can mimic these techniques. Soon thereafter, the involvement of several molecular pathways such as the reperfusion injury salvage kinase, the ATP-sensitive K(+) channel, the survivor-activating factor enhancement and the adenosine mono phosphate activated protein kinase pathways were discovered. Further, studies have shown that these pathways convey the adverse effects of ischemia, reperfusion and the combination thereof to the mitochondria, suggesting that the death signals during ischemia and reperfusion are controllable, and can therefore be partially inhibited or even reversed. Hence, the aim of this review is to describe these signaling pathways, the established pre-clinical means to manipulate them, and their current application status in the clinic.

Fatal Association of Mechanical Valve Thrombosis With Dabigatran: A Report of Two Cases

Several new oral anticoagulants have been approved for thromboembolism prevention in patients with nonvalvular atrial fibrillation. However, they are not yet approved for anticoagulation use in patients with prosthetic mechanical valves, and no randomized data have been published so far on their safety of use in these patients. We present two cases of patients with prosthetic mechanical mitral valves who were switched from warfarin and acenocoumarol to dabigatran and within 1 month experienced severe valve complications resulting in death. One patient experienced stroke and later cardiogenic shock and death, and the other experienced pulmonary edema, cardiogenic shock, and subsequent death.

Hemodynamic Effect and Safety of Intermittent Sequential Pneumatic Compression Leg Sleeves in Patients With Congestive Heart Failure

BACKGROUND Pneumatic leg sleeves are widely used after prolonged operations for prevention of venous stasis. In healthy volunteers they increase cardiac function. We evaluated the hemodynamic effects and safety of intermittent sequential pneumatic compression (ISPC) leg sleeves in patients with chronic congestive heart failure (CHF). METHODS AND RESULTS We studied 19 patients with systolic left ventricular dysfunction and CHF. ISPC leg sleeves, each with 10 air cells, were operated by a computerized compressor, exerting 2 cycles/min. Hemodynamic and echocardiographic parameters were measured before, during, and after ISPC activation. The baseline mean left ventricular ejection fraction was 29 ± 9.2%, median 32%, range 10%-40%. Cardiac output (from 4.26 to 4.83 L/min; P = .008) and stroke volume (from 56.1 to 63.5 mL; P = .029) increased significantly after ISPC activation, without a reciprocal increase in heart rate, and declined after sleeve deactivation. Systemic vascular resistance (SVR) decreased significantly (from 1,520 to 1,216 dyne-s/cm5; P = .0005), and remained lower than the baseline level throughout the study. There was no detrimental effect on diastolic function and no adverse clinical events, despite increased pulmonary venous return. CONCLUSIONS ISPC leg sleeves in patients with chronic CHF do not exacerbate symptoms and transiently improve cardiac output through an increase in stroke volume and a reduction in SVR.

Prevention of contrast‐induced nephropathy with single bolus erythropoietin in patients with diabetic kidney disease: A randomized controlled trial

Contrast‐induced‐nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue‐protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease.

Etiology and characteristics of large symptomatic pericardial effusion in a community hospital in the contemporary era.

BACKGROUND The etiology and laboratory characteristics of large symptomatic pericardial effusion (LSPE) in the Western world have evolved over the years, and vary between regions, community and tertiary hospitals. METHODS We reviewed data of 86 consecutive patients who underwent pericardiocentesis or pericardial window due to LSPE in a community hospital from 2001 to 2010. The characteristics of the PE including chemistry, hematology, bacteriology, serology and cytology have been analyzed. We correlated the etiologies of PE with age, gender and clinical presentation. RESULTS The most frequent etiology of LSPE was idiopathic [36% (77% with a clinical diagnosis of pericarditis)], followed by malignancy (31.4%), ischemic heart disease (16.3%), renal failure (4.6%), trauma (4.6%) and autoimmune disease (4.6%). The average age of all the etiological groups excluding trauma was over 50 years. Laboratory tests did not modify the pre-procedure diagnosis in any of the patients. The most frequent presenting symptom was dyspnea (76.6%). Chest pain was mostly common in patients with idiopathic etiology (58.06%). The most frequent medical condition associated with LSPE was the use of anticoagulant or antiplatelet drugs (31.40%), especially aspirin, and in those, the PE tended to be bloody (73%, P = 0.11). Most of the effusions were exudates (70.9%). PE due to renal failure was the largest (1467 ± 1387 ml). CONCLUSION The spectrum of etiologies of LSPE in a community hospital in the Western world in the contemporary era is continuously evolving. The most frequent etiology is now idiopathic, followed by malignancy. Routine laboratory testing still rarely modifies the pre-procedure diagnosis.

Clinical outcomes of patients with acute coronary syndrome and moderate or severe chronic anaemia undergoing coronary angiography or intervention

Background: There are limited data on the impact of chronic moderate or severe anaemia on the clinical outcomes of patients with acute coronary syndrome undergoing coronary angiography or percutaneous coronary intervention. Methods: We retrospectively compared two groups of consecutive patients with acute coronary syndrome according to their haemoglobin level on admission. The research group (n=89) had a haemoglobin level of 10.9 g/dl or less and a control group (n=79) of age-matched patients had a haemoglobin level greater than 10.9 g/dl. We studied drug therapy before, during and after intervention, and performed 1-year follow-up of bleeding complications according to the Bleeding Academic Research Consortium criteria, all-cause mortality and re-infarction, as well as haemoglobin level on discharge, 6 and 12 months after admission. Results: Compared to controls, a haemoglobin level less than 10.9 g\dl on admission is associated with a higher rate of major bleeding: 26 patients (32%) versus none in the control group (P<0.001); and the use of packed red blood cell (RBC) transfusion: nine patients (11.7%) versus none in the control group (P=0.003) within the first 6 months post-catheterisation. However, the re-infarction rate and mortality were similar in the study and control groups: 9.2% versus 9.7% (P=0.915) and 12.6% versus 8.9% (P=0.434), accordingly. Conclusions: Chronic moderate or severe anaemia in patients with acute coronary syndrome undergoing coronary angiography or percutaneous coronary intervention is associated with a substantially increased risk of bleeding in the first 6 months. However, rates of mortality and re-infarction were similar.

Impact of mobile intensive care unit use on total ischemic time and clinical outcomes in ST-elevation myocardial infarction patients – real-world data from the Acute Coronary Syndrome Israeli Survey

Background: Ischemic time has prognostic importance in ST-elevation myocardial infarction patients. Mobile intensive care unit use can reduce components of total ischemic time by appropriate triage of ST-elevation myocardial infarction patients. Methods: Data from the Acute Coronary Survey in Israel registry 2000–2010 were analyzed to evaluate factors associated with mobile intensive care unit use and its impact on total ischemic time and patient outcomes. Results: The study comprised 5474 ST-elevation myocardial infarction patients enrolled in the Acute Coronary Survey in Israel registry, of whom 46% (n=2538) arrived via mobile intensive care units. There was a significant increase in rates of mobile intensive care unit utilization from 36% in 2000 to over 50% in 2010 (p<0.001). Independent predictors of mobile intensive care unit use were Killip>1 (odds ratio=1.32, p<0.001), the presence of cardiac arrest (odds ratio=1.44, p=0.02), and a systolic blood pressure <100 mm Hg (odds ratio=2.01, p<0.001) at presentation. Patients arriving via mobile intensive care units benefitted from increased rates of primary reperfusion therapy (odds ratio=1.58, p<0.001). Among ST-elevation myocardial infarction patients undergoing primary reperfusion, those arriving by mobile intensive care unit benefitted from shorter median total ischemic time compared with non-mobile intensive care unit patients (175 (interquartile range 120–262) vs 195 (interquartile range 130–333) min, respectively (p<0.001)). Upon a multivariate analysis, mobile intensive care unit use was the most important predictor in achieving door-to-balloon time <90 min (odds ratio=2.56, p<0.001) and door-to-needle time <30 min (odds ratio=2.96, p<0.001). One-year mortality rates were 10.7% in both groups (log-rank p-value=0.98), however inverse propensity weight model, adjusted for significant differences between both groups, revealed a significant reduction in one-year mortality in favor of the mobile intensive care unit group (odds ratio=0.79, 95% confidence interval (0.66–0.94), p=0.01). Conclusions: Among patients with ST-elevation myocardial infarction, the utilization of mobile intensive care units is associated with increased rates of primary reperfusion, a reduction in the time interval to reperfusion, and a reduction in one-year adjusted mortality.

Outcomes of Patients Presenting With Clinical Indices of Spontaneous Reperfusion in ST‐Elevation Acute Coronary Syndrome Undergoing Deferred Angiography

Background Few data are available regarding the optimal management of ST‐elevation myocardial infarction patients with clinically defined spontaneous reperfusion (SR). We report on the characteristics and outcomes of patients with SR in the primary percutaneous coronary intervention era, and assess whether immediate reperfusion can be deferred. Methods and Results Data were drawn from a prospective nationwide survey, ACSIS (Acute Coronary Syndrome Israeli Survey). Definition of SR was predefined as both (1) ≥70% reduction in ST‐segment elevation on consecutive ECGs and (2) ≥70% resolution of pain. Of 2361 consecutive ST‐elevation–acute coronary syndrome patients in Killip class 1, 405 (17%) were not treated with primary reperfusion therapy because of SR. Intervention in SR patients was performed a median of 26 hours after admission. These patients were compared with the 1956 ST‐elevation myocardial infarction patients who underwent primary reperfusion with a median door‐to‐balloon of 66 minutes (interquartile range 38–106). Baseline characteristics were similar except for slightly higher incidence of renal dysfunction and prior angina pectoris in SR patients. Time from symptom onset to medical contact was significantly greater in SR patients. Patients with SR had significantly less in‐hospital heart failure (4% versus 11%) and cardiogenic shock (0% versus 2%) (P<0.01 for all). No significant differences were found in in‐hospital mortality (1% versus 2%), 30‐day major cardiac events (4% versus 4%), and mortality at 30 days (1% versus 2%) and 1 year (4% versus 4%). Conclusions Patients with clinically defined SR have a favorable prognosis. Deferring immediate intervention seems to be safe in patients with clinical indices of spontaneous reperfusion.

High-Intensity Training Improves Global and Segmental Strains in Severe Congestive Heart Failure

BACKGROUND High-intensity training (HIT) is superior to moderate aerobic training (MAT) for improving quality of life in congestive heart failure (CHF) patients. Speckle-tracking echocardiography (STE) has recently been suggested for estimation of left ventricle global and regional function. We evaluated the utility of STE for characterizing differences in cardiac function following MAT or HIT in a CHF rat model. METHODS AND RESULTS After baseline physiologic assessment, CHF was induced by means of coronary artery ligation in Sprague-Dawley rats. Repeated measurements confirmed the presence of CHF (ejection fraction 52 ± 10%, global circumferential strain (GCS) 10.5 ± 4, and maximal oxygen uptake (V˙O2max) 71 ± 11 mL⋅min-1⋅kg-1; P < .001 vs baseline for all). Subsequently, rats were divided into training protocols: sedentary (SED), MAT, or HIT. After the training period, rats underwent the same measurements and were killed. Training intensity improved V˙O2max (73 ± 13 mL⋅min-1⋅kg-1 in MAT [P < .01 vs baseline] and 82 ± 6 mL⋅min-1⋅kg-1 in HIT [P < .05 vs baseline or SED] and ejection fraction (50 ± 21% in MAT [P < .001 vs baseline] and 66 ± 7% in HIT [P > .05 vs baseline]). In addition, strains of specific segments adjacent to the infarct zone regained basal values (P > .05 vs baseline), whereas global cardiac functional parameters as assessed with the use of 2-dimensional echocardiography did not improve. CONCLUSIONS High-intensity exercise training improved function in myocardial segments remote from the scar, which resulted in compensatory cardiac remodeling. This effect is prominent, yet it could be detected only with the use of STE.