Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices.

BACKGROUND: Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. METHODS AND RESULTS: In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. CONCLUSIONS: In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.

A critical analysis of clinical outcomes reported in stem cell trials for acute myocardial infarction: some thoughts for design of future trials.

The purpose of stem cell therapy for myocardial infarction is to improve clinical outcomes, and detailed information on clinical outcomes is critical to appropriate planning of phase III trials. We have examined data from select phase II trials using autologous bone-marrow-derived stem cells in patients with acute myocardial infarction. We have extracted available definitions and outcome data, and have generated standardized estimates of events to permit summary comparisons. Nine trials (1,040 patients) with results for 6 months to 5 years were evaluated. Adverse outcomes differed widely, and there was a general lack of details in the definitions of these outcomes. Heart-failure-related hospitalizations occurred in only 16 patients (1.5 %) and death occurred in only 43 patients (4.1 %). Ischemia-related outcomes outnumbered heart failure outcomes more than tenfold. Uniform criteria need to be developed to better define clinical outcomes of interest. Furthermore, a refocus from heart failure outcomes to ischemia-related outcomes seems appropriate.

Systolic blood pressure, heart rate, and outcomes in patients with coronary disease and heart failure.

AIMS: Data regarding the optimal systolic blood pressure (SBP) and heart rate (HR) for coronary artery disease (CAD) patients with hypertension and a history of heart failure (HF) are limited. Accordingly, using data from a large clinical trial, we investigated the association between SBP and heart rate and subsequent adverse outcomes in CAD patients with a history of HF, and we aimed to better understand how pre-existing HF impacts outcomes among patients with CAD. METHODS AND RESULTS: Among 22 576 CAD patients enrolled in the INternational VErapamil SR-Trandolapril STudy (INVEST), 1256 were identified with a history of physician-diagnosed HF New York Heart Association (NYHA) Class 1-3 at entry. The primary outcome was the first occurrence of all-cause death, myocardial infarction (MI), or stroke. Cox proportional-hazards models adjusted for pre-specified covariates were constructed to estimate risk among the HF cohort compared with a case-matched sample from the non-HF cohort. At a mean 2.5 years' follow-up, those with prior HF had a higher risk of the primary outcome (hazard ratio (HR) 2.55, 95% confidence interval 2.30-2.83, P < 0.0001). Among those with history of HF, a low (<120 mmHg) or high (>140 mmHg) SBP and heart rate ≥ 85 b.p.m. were associated with increased risk for adverse outcomes, which persisted after covariate adjustment. CONCLUSIONS: In patients with CAD, a physician diagnosis of HF at baseline portended a higher risk for death, MI, or stroke than in those without an HF history. Achieving SBP of 120-140 mmHg and heart rate < 85 b.p.m. was associated with a better outcome in patients with known HF and CAD.

Unanticipated Cardiotoxicity Associated with Targeted Anticancer Therapy in Patients with Hematologic Malignancies Patients: Natural History and Risk Factors.

Our aim is to study unanticipated cardiotoxicity associated with the use of anticancer targeted agents, a problem that remains poorly understood. Using diagnosis codes, we retrospectively identified patients with both hematologic malignancies (HM) and cardiovascular diseases (n = 820 patients). Cardiotoxicity was defined per published criteria. The targeted agents of interest included tyrosine kinase inhibitors, proteasome inhibitors, monoclonal antibodies, and immunomodulatory agents. Patients found with cardiotoxicity (n = 29) were compared with 70 case-matched reference subjects. Median time from targeted therapy exposure to cardiotoxicity was 132 days. A higher percentage of patients had prior exposure to anthracyclines in study versus reference group (65.5 vs. 42.8%, P = 0.04), however, did not stay significant in multivariate analysis. Two variables were significant predictors, prior of DVT/PE and Karnofsky score of ≥ 80% (P ≤ 0.011). Only 2 study group patients died of cardiac causes. Most cardiotoxicity patients (23/29) had remained stable or improved, while 21 patients received further chemotherapy. OS was lower in the study group (P = 0.018) versus the reference group. In conclusion, a small number patients with HM experience unanticipated cardiotoxicity with low related mortality. Risk of cardiotoxicity was significantly associated with history of DVT/PE. Most patients do well, but despite that, their OS is significantly poorer.

Suspected autoimmune myocarditis and cardiac conduction abnormalities with nivolumab therapy for non-small cell lung cancer.

Checkpoint inhibitors such as nivolumab represent a novel class of agents that are being increasingly used in the treatment of various cancers. Their toxicities represent unique challenges to the oncologists prescribing them, patients' primary care physicians and other specialists who may encounter these patients during consultations. It is important for physicians to remain vigilant and include autoimmune toxicities in the list of potential differential diagnoses in patients receiving novel cancer therapeutics who present with unusual toxicities. We report the unusual case of a 68-year-old woman with advanced lung cancer on the novel chemotherapeutic Nivolumab whom we suspect developed autoimmune myocarditis with significant cardiac conduction disease as an unintended, and as of yet unrecognised, side effect from this medication.

Cardiovascular Events in a Physical Activity Intervention Compared With a Successful Aging Intervention: The LIFE Study Randomized Trial.

IMPORTANCE: Whether sustained physical activity prevents cardiovascular disease (CVD) events in older adults is uncertain. OBJECTIVE: To test the hypothesis that cardiovascular morbidity and mortality would be reduced in participants in a long-term physical activity program. DESIGN, SETTING, AND PARTICIPANTS: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial. Participants were recruited at 8 centers in the United States. We randomized 1635 sedentary men and women aged 70 to 89 years with a Short Physical Performance Battery (SPPB) score of 9 or less but able to walk 400 m. INTERVENTIONS: The physcial activity (PA) intervention was a structured moderate-intensity program, predominantly walking 2 times per week on site for 2.6 years on average. The successful aging intervention consisted of weekly health education sessions for 6 months, then monthly. MAIN OUTCOMES AND MEASURES: Total CVD events, including fatal and nonfatal myocardial infarction, angina, stroke, transient ischemic attack, and peripheral artery disease, were adjudicated by committee, and silent myocardial infarction was assessed by serial electrocardiograms. A limited outcome of myocardial infarction, stroke, and CVD death was also studied. Outcome assessors and adjudicators were blinded to intervention assignment. RESULTS: The 1635 LIFE study participants were predominantly women (67%), with a mean (SD) age of 78.7 (5.2) years; 20% were African-American, 6% were Hispanic or other race or ethnic group, and 74% were non-Latino white. New CVD events occurred in 121 of 818 PA participants (14.8%) and 113 of 817 successful aging participants (13.8%) (HR, 1.10; 95% CI, 0.85-1.42). For the more focused combined outcome of myocardial infarction, stroke, or cardiovascular death, rates were 4.6% in PA and 4.5% in the successful aging group (HR, 1.05; 95% CI, 0.67-1.66). Among frailer participants with an SPPB score less than 8, total CVD rates were 14.2% in PA vs 17.7% in successful aging (HR, 0.76; 95% CI, 0.52-1.10), compared with 15.3% vs 10.5% among those with an SPPB score of 8 or 9 (HR, 1.59; 95% CI, 1.09-2.30) (P for interaction = .006). With the limited end point, the interaction was not significant (P = .59), with an HR of 0.94 (95% CI, 0.50-1.75) for an SPPB score less than 8 and an HR of 1.20 (95% CI, 0.62-2.34) for an SBBP score of 8 or 9. CONCLUSIONS AND RELEVANCE: Among participants in the LIFE Study, an aerobically based, moderately intensive PA program was not associated with reduced cardiovascular events in spite of the intervention's previously documented ability to prevent mobility disability. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116194.

A training program in cardiovascular cell-based therapy: from the NHLBI Cardiovascular Cell Therapy Research Network.

Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician-scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs.

Diuretics in heart failure: a critical appraisal of efficacy and tolerability.

Heart failure is a significant cause of morbidity and mortality worldwide. While the aetiology varies and there are a wide variety of treatment options, a large amount of the morbidity related to heart failure is due to fluid retention and the symptoms of volume overload. Multiple neurohormonal pathways are activated in heart failure, and contribute to the symptoms of fluid retention and volume overload. Although not ideal, diuretic therapy is one of the mainstays of treatment of fluid overload in patients with heart failure. This review focuses on the pathophysiology of heart failure leading to volume overload, the different classes of diuretics used in alleviating the symptoms of fluid retention, their mechanisms of action within the kidney, and strategies for using them in ways that minimize their deleterious effects in patients with heart failure.