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Transendocardial CD34+ Cell Therapy does not Increase the Risk of Ventricular Arrhythmias in Patients with Chronic Heart Failure.

ABSTRACT: Ventricular arrhythmias (VA) are of major concern in the field of cell therapy, potentially limiting its safety and efficacy. We sought to investigate the effects of CD34+ cell therapy on VA burden in patients with chronic heart failure (CHF). We performed registry data analysis of patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34+ cell therapy. Demographic, echocardiographic, and biochemical parameters were analyzed. Device records were reviewed and the number and type of VA 1 year prior to and 1 year after cell therapy were analyzed. All patients underwent electroanatomical mapping, and myocardial scar was defined as unipolar voltage (UV) <8.3 mV and linear local shortening (LLS) <6%. Of 209 patients screened, 48 met inclusion criteria. The mean age of the patients was 52 years and 88% were male. Nonischemic and ischemic cardiomyopathy were present in 55% and 45% of patients. The average serum creatinine was 91±26 µmol/L, serum bilirubin 18±9 µmol/L, NT-proBNP 1767 (468, 2446) pg/mL, LVEF 27±9% and 6' walk test 442±123 m. The average scar burden in patients with nonischemic and ischemic DCM was 58±15% and 51±25% (P=0.48). No significant difference in VA burden was observed before and after cell therapy (48% vs. 44%; P=0.68). ICD activation occurred in 19% and 27% of patients before and after cell therapy (P=0.33). According to our results, transendocardial CD34+ cell therapy does not appear to increase the risk of VA in chronic heart failure patients.

SUBMITTER: Poglajen G

PROVIDER: S-EPMC6719496 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Transendocardial CD34+ Cell Therapy does not Increase the Risk of Ventricular Arrhythmias in Patients with Chronic Heart Failure.

Poglajen Gregor G Zemljič Gregor G Cerar Andraž A Frljak Sabina S Jaklič Martina M Androcec Vesna V Vrtovec Bojan B

Cell transplantation 20190502 7

Ventricular arrhythmias (VA) are of major concern in the field of cell therapy, potentially limiting its safety and efficacy. We sought to investigate the effects of CD34<sup>+</sup> cell therapy on VA burden in patients with chronic heart failure (CHF). We performed registry data analysis of patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34<sup>+</sup> cell therapy. Demographic, echocardiographic, and biochemical parameters were analyzed. Device records were re ...[more]

PMID: 31046425

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Project description:BACKGROUND:Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. METHODS:Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. RESULTS:After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. CONCLUSIONS:Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.

Project description:BackgroundBeneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (G?(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated G?(q) (G?(q)-TG).Methodology/principal findingsNicorandil (6 mg/kg/day) or vehicle was chronically administered to G?(q)-TG from 8 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic nicorandil administration prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis in G?(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated G?(q)-TG but not in nicorandil-treated G?(q)-TG. eNOS gene expression was also increased in nicorandil-treated G?(q)-TG compared with vehicle-treated G?(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated G?(q)-TG but in none of 10 nicorandil-treated G?(q)-TG. The QT interval was significantly shorter in nicorandil-treated G?(q)-TG than vehicle-treated G?(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused G?(q)-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal K(ATP) channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the G?(q)-TG heart.Conclusions/significanceThese findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of GPCR signaling through the shortening of the QT interval, action potential duration, the normalization of SERCA2 gene expression. Nicorandil may also improve the impaired coronary circulation during HF.

Project description:Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.clinicaltrials.gov Identifier: NCT00824005.

Dataset Information

Transendocardial CD34+ Cell Therapy does not Increase the Risk of Ventricular Arrhythmias in Patients with Chronic Heart Failure.

Publications

Transendocardial CD34+ Cell Therapy does not Increase the Risk of Ventricular Arrhythmias in Patients with Chronic Heart Failure.

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