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Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.

ABSTRACT: Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.

SUBMITTER: Hu YF

PROVIDER: S-EPMC4949602 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.

Hu Yu-Feng YF Dawkins James Frederick JF Cho Hee Cheol HC Marbán Eduardo E Cingolani Eugenio E

Science translational medicine 20140701 245

Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyo ...[more]

PMID: 25031269

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Project description:BackgroundBilateral thoracoscopic stellectomy has antiarrhythmic effects, but the procedure is invasive with associated morbidity. Sympathetic nerves from both stellate ganglia form the deep cardiac plexus (CP) in the aortopulmonary window, anterior to the trachea.ObjectiveThe purpose of this study was to demonstrate a novel and minimally invasive transtracheal approach to block the CP in porcine models.MethodsIn 12 Yorkshire pigs, right (RSG) and left (LSG) stellate ganglia were electrically stimulated and sympathetic baseline response recorded (hemodynamic parameters and T-wave pattern). Aortopulmonary window was accessed transtracheally with endobronchial ultrasound guidance, and local stimulation of CP confirmed the location. Injection of 1% lidocaine (n = 10) or saline solution (n = 2) was performed, and RSG and LSG responses were re-evaluated and compared with baseline.ResultsTranstracheal lidocaine injection into the CP successfully blocked bilateral sympathetic induced changes (%) in T-wave amplitude (282.8% ± 152.2% vs 20.1% ± 16.5%; P <.001 [LSG]; 338.9% ± 189.8% vs 28% ± 18.3%; P <.001 [RSG]), Tp-Te interval (87.9% ± 37.2% vs 6.9% ± 6.7%; P <.001 [LSG]; 32.6% ± 27.4% vs 6.9% ± 4.7%; P <.035 [RSG]), and left ventricular dP/dTmax (148.3% ± 108.5% vs 16.5% ± 13.4%; P <.001 [LSG]; 243.1% ± 105.2% vs 19.0% ± 12.4%; P <.001 [RSG]). RSG-induced elevations of systemic, left ventricular, and pulmonary arterial pressures were blocked by lidocaine injection into CP (P <.005 for all comparisons). Stellate ganglia response was not affected in sham studies. No complications were observed during the procedures.ConclusionMinimally invasive transtracheal injection of lidocaine into the CP blocked the sympathetic response of either RSG and LSG. Transtracheal assessment of CP may allow for minimally invasive and selective ablation of cardiac innervation, extending the cardiac sympathectomy denervation benefits to those not suitable for surgery.

Project description:IntroductionIntercostal cryo nerve block has been shown to enhance pulmonary function recovery and pain management in post-thoracotomy procedures. However, its benefit have never been demonstrated in minimal invasive thoracotomy heart valve surgery (Mini-HVS). The purpose of the study was to determine whether intraoperative intercostal cryo nerve block in conjunction with standard of care (collectively referred to hereafter as CryoNB) provided superior analgesic efficacy in patients undergoing Mini-HVS compared to standard-of-care (SOC).MethodsFROST was a prospective, 3:1 randomized (CryoNB vs. SOC), multicenter trial in patients undergoing Mini-HVS. The primary endpoint was the 48-h postoperative forced expiratory volume in 1 s (FEV1) result. Secondary endpoints were visual analog scale (VAS) scores for pain at the surgical site and general pain, intensive care unit and hospital length-of-stay, total opioid consumption, and allodynia at 6 months postoperatively.ResultsA total of 84 patients were randomized to the two arms of the trial CryoNB (n = 65) and SOC (n = 19). Baseline Society of Thoracic Surgeons Predictive Risk of Mortality (STS PROM) score, ejection fraction, and FEV1 were similar between cohorts. A higher 48-h postoperative FEV1 result was demonstrated in the CryoNB cohort versus the SOC cohort (1.20 ± 0.46 vs. 0.93 ± 0.43 L; P = 0.02, one-sided two-sample t test). Surgical site VAS scores were similar between the CryoNB and SOC cohorts at all postoperative timepoints evaluated, but VAS scores not related to the surgical site were lower in the SOC group at 72, 94, and 120 h postoperatively. The SOC cohort had a 13% higher opioid consumption than the CryoNB cohort. One of 64 CryoNB patients reported allodynia that did not require pain medication at 10 months.ConclusionsThe results of FROST demonstrated that intercostal CryoNB provided enhanced FEV1 score at 48 h postoperatively with optimized analgesic effectiveness versus SOC. Future larger prospective randomized trials are warranted to determine whether intercostal CryoNB has an opioid-sparing effect in patients undergoing Mini-HVS.Trial registrationClinicaltrials.gov identifier: NCT02922153.

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Project description:Minimally invasive esophagectomy is increasingly performed for the treatment of esophageal cancer, but it is unclear whether hybrid minimally invasive esophagectomy (HMIE) or totally minimally invasive esophagectomy (TMIE) should be preferred. The objective of this study was to perform a meta-analysis of studies comparing HMIE with TMIE. A systematic literature search was performed in MEDLINE, Embase, and the Cochrane Library. Articles comparing HMIE and TMIE were included. The Newcastle-Ottawa scale was used for critical appraisal of methodological quality. The primary outcome was pneumonia. Sensitivity analysis was performed by analyzing outcome for open chest hybrid MIE versus total TMIE and open abdomen MIE versus TMIE separately. Therefore, subgroup analysis was performed for laparoscopy-assisted HMIE versus TMIE, thoracoscopy-assisted HMIE versus TMIE, Ivor Lewis HMIE versus Ivor Lewis TMIE, and McKeown HMIE versus McKeown TMIE. There were no randomized controlled trials. Twenty-nine studies with a total of 3732 patients were included. Studies had a low to moderate risk of bias. In the main analysis, the pooled incidence of pneumonia was 19.0% after HMIE and 9.8% after TMIE which was not significantly different between the groups (RR: 1.46, 95% CI: 0.97-2.20). TMIE was associated with a lower incidence of wound infections (RR: 1.81, 95% CI: 1.13-2.90) and less blood loss (SMD: 0.78, 95% CI: 0.34-1.22) but with longer operative time (SMD:-0.33, 95% CI: -0.59--0.08). In subgroup analysis, laparoscopy-assisted HMIE was associated with a higher lymph node count than TMIE, and Ivor Lewis HMIE was associated with a lower anastomotic leakage rate than Ivor Lewis TMIE. In general, TMIE was associated with moderately lower morbidity compared to HMIE, but randomized controlled evidence is lacking. The higher leakage rate and lower lymph node count that was found after TMIE in sensitivity analysis indicate that TMIE can also have disadvantages. The findings of this meta-analysis should be considered carefully by surgeons when moving from HMIE to TMIE.

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Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.

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Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.

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