Creighton W. Don

Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

Trends in Coronary Revascularization in the United States From 2001 to 2009 Recent Declines in Percutaneous Coronary Intervention Volumes

Background— There is speculation that the volume of percutaneous coronary interventions (PCIs) has been decreasing over the past several years. Published studies of PCI volume have evaluated regional or hospital trends, but few have captured national data. This study describes the use of coronary angiography and revascularization methods in Medicare patients from 2001 to 2009. Methods and Results— This retrospective study used data from the Centers for Medicare & Medicaid Services from 2001 to 2009. The annual number of coronary angiograms, PCI, intravascular ultrasound, fractional flow reserve, and coronary artery bypass graft (CABG) surgery procedures were determined from billing data and adjusted for the number of Medicare recipients. From 2001 to 2009, the average year-to-year increase for PCI was 1.3% per 1000 beneficiaries, whereas the mean annual decrease for CABG surgery was 5%. However, the increase in PCI volume occurred primarily from 2001 to 2004, as there was a mean annual rate of decline of 2.5% from 2004 to 2009; similar trends were seen with diagnostic angiography. The use of intravascular ultrasound and fractional flow reserve steadily increased over time. Conclusions— This study confirms recent speculation that PCI volume has begun to decrease. Although rates of CABG have waned for several decades, all forms of coronary revascularization have been declining since 2004.

Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital.

Objective: To evaluate whether implementation of a therapeutic hypothermia protocol on arrival in a community hospital improved survival and neurologic outcomes in patients initially found to have ventricular fibrillation, pulseless electrical activity, or asystole, and then successfully resuscitated from out-of-hospital cardiac arrest. Design: A retrospective study of patients who presented after implementation of a therapeutic hypothermia protocol compared with those who presented before the protocol was implemented. Setting: Harborview Medical Center, Seattle, WA. Patients: A total of 491 consecutive adults with out-of-hospital, nontraumatic cardiac arrest who presented between January 1, 2000 and December 31, 2004. Interventions: An active cooling therapeutic hypothermia protocol, using ice packs, cooling blankets, or cooling pads to achieve a temperature of 32°C to 34°C was initiated on November 18, 2002 for unconscious patients resuscitated from cardiac arrest. Measurements and Main Results: Demographics and outcomes were obtained from medical records and an emergency medical database. The primary outcomes were survival and favorable neurologic outcome at discharge associated with the therapeutic hypothermia protocol. An adjusted analysis was performed, using a multivariate regression. During the therapeutic hypothermia period, 204 patients were brought to the emergency department; of these 204 patients, 132 (65%) ultimately achieved temperatures of <34°C. Of the 72 patients who did not achieve goal temperatures: 40 (20%) died in the emergency department or shortly after being admitted to the hospital, 15 (7%) regained consciousness, four (2%) had contraindications, 13 (6%) had temperature increase or did not have documented use of the therapeutic hypothermia protocol. In the prior period, none of the 287 patients received active cooling. Patients admitted in the therapeutic hypothermia period had a mean esophageal temperature of 34.1°C during the first 12 hrs compared with 35.2°C in the pretherapeutic hypothermia period (p < .01). Survival to hospital discharge improved in the therapeutic hypothermia period in patients with an initial rhythm of ventricular fibrillation (odds ratio, 1.88, 95% confidence interval, 1.03–3.45), however not in patients with nonventricular fibrillation (odds ratio, 1.17, 95% confidence interval, 0.66–2.05). In adjusted analysis, ventricular fibrillation patients during the therapeutic hypothermia period trended toward improved survival (odds ratio, 1.71, 95% confidence interval, 0.85–3.46) and had favorable neurologic outcome (odds ratio, 2.62, 95% confidence interval, 1.1–6.27) compared with the earlier period. This benefit was not observed in patients whose initial rhythm was pulseless electrical activity or asystole. Conclusions: The therapeutic hypothermia period was associated with a significant improvement in neurologic outcomes in patients whose initial rhythm was ventricular fibrillation, but not in patients with other rhythms.

Systematic Review and Cost–Benefit Analysis of Radial Artery Access for Coronary Angiography and Intervention

Background— Radial artery access for coronary angiography and interventions has been promoted for reducing hemostasis time and vascular complications compared with femoral access, yet it can take longer to perform and is not always successful, leading to concerns about its cost. We report a cost–benefit analysis of radial catheterization based on results from a systematic review of published randomized controlled trials. Methods and Results— The systematic review added 5 additional randomized controlled trials to a prior review, for a total of 14 studies. Meta-analyses, following Cochrane procedures, suggested that radial catheterization significantly increased catheterization failure (OR, 4.92; 95% CI, 2.69–8.98), but reduced major complications (OR, 0.32; 95% CI, 0.24–0.42), major bleeding (OR, 0.39; 95% CI, 0.27–0.57), and hematoma (OR, 0.36; 95% CI, 0.27–0.48) compared with femoral catheterization. It added approximately 1.4 minutes to procedure time (95% CI, −0.22 to 2.97) and reduced hemostasis time by approximately 13 minutes (95% CI, −2.30 to −23.90). There were no differences in procedure success rates or major adverse cardiovascular events. A stochastic simulation model of per-case costs took into account procedure and hemostasis time, costs of repeating the catheterization at the alternate site if the first catheterization failed, and the inpatient hospital costs associated with complications from the procedure. Using base-case estimates based on our meta-analysis results, we found the radial approach cost

Impact of rapid ventricular pacing during percutaneous balloon aortic valvuloplasty in patients with critical aortic stenosis: Should we be using it?

275 (95% CI, −

Improving survival and efficacy of pluripotent stem cell–derived cardiac grafts

374 to −

Coronary Artery Perforations in the Contemporary Interventional Era

183) less per patient from the hospital perspective. Radial catheterization was favored over femoral catheterization under all conditions tested. Conclusions— Radial catheterization was favored over femoral catheterization in our cost–benefit analysis.

Retrograde versus antegrade percutaneous aortic balloon valvuloplasty: Immediate, short- and long-term outcome at 2 years†

Background: Rapid ventricular pacing (RP) during percutaneous balloon aortic valvuloplasty (BAV) facilitates balloon positioning by preventing the “watermelon seeding” effect during balloon inflation. The clinical consequences of RP BAV have never been compared with standard BAV in which rapid pacing in not used. We evaluated the immediate results and in‐hospital adverse events of patients with severe aortic stenosis (AS) undergoing BAV with and without RP. Methods: This is a retrospective study of patients with severe AS undergoing retrograde BAV. Patients who underwent BAV with RP were compared to those who did not receive RP during BAV. Procedural outcomes, complications, and in‐hospital adverse events were compared between both groups. Stratified analyses were performed to evaluate RP in pre‐specified subsets for confounding and effect modification. Results: Between January 2005 and December 2008, 111 consecutive patients underwent retrograde BAV at Massachusetts General Hospital. Sixty‐seven patients underwent BAV with RP. Nearly 90% of patients were NYHA class III or IV and the mean AVA was 0.64 cm2. Baseline characteristics and balloon sizes were similar in the two groups. The average post‐BAV AVA was smaller in the RP group compared to the no‐RP group (0.87 v. 1.02 cm2, p = 0.02). Pre and post‐cardiac output, in‐hospital mortality, myocardial infarction, stroke, frequency of cardiopulmonary arrest, vasopressor use, and major complications were similar in the two groups. Conclusions: 1) RP allows precise balloon placement during BAV. 2) RP BAV is associated with lower post‐BAV AVA. 3) RP BAV may be safely performed in patients with high‐risk cardiac features.

Comparison of Procedural and In-Hospital Outcomes of Percutaneous Balloon Aortic Valvuloplasty in Patients >80 Years Versus Patients <80 Years

Human embryonic stem cells (hESCs) can be differentiated into structurally and electrically functional myocardial tissue and have the potential to regenerate large regions of infarcted myocardium. One of the key challenges that needs to be addressed towards full‐scale clinical application of hESCs is enhancing survival of the transplanted cells within ischaemic or scarred, avascular host tissue. Shortly after transplantation, most hESCs are lost as a result of multiple mechanical, cellular and host factors, and a large proportion of the remaining cells undergo apoptosis or necrosis shortly thereafter, as a result of loss of adhesion‐related signals, ischaemia, inflammation or immunological rejection. Blocking the apoptotic signalling pathways of the cells, using pro‐survival cocktails, conditioning hESCs prior to transplant, promoting angiogenesis, immunosuppressing the host and using of bioengineered matrices are among the emerging techniques that have been shown to optimize cell survival. This review presents an overview of the current strategies for optimizing cell and host tissue to improve the survival and efficacy of cardiac cells derived from pluripotent stem cells.

Outcomes in Nonagenarians Undergoing Transcatheter Aortic Valve Replacement in the PARTNER-I Trial

BACKGROUND Coronary perforations represent a serious complication of percutaneous coronary intervention (PCI). METHODS We performed a retrospective analysis of documented coronary perforations at Massachusetts General Hospital from 2000 to 2008. Medical records review and detailed angiographic analysis were performed in all patients. RESULTS Sixty-eight cases of coronary perforation were identified from a total of 14,281 PCIs from March 2000 to March 2008 representing an overall incidence of 0.48%. The study cohort was predominantly male (61.8%), mean age 71+/-11 years with 78% representing acute cases (unstable angina: 36.8%, NSTEMI: 30.9%, STEMI: 10.3%). Coronary artery perforation occurred as a complication of wire manipulation in 45 patients (66.2%) with 88.9% of this group being hydrophilic wires, of coronary stenting in 11 (16.2%), of angioplasty alone in 6 (8.8%), and of rotational atherectomy in 8 (11.8%). The perforation was sealed with an angioplasty balloon alone in 16 patients (23.5%), and with stents in 14 patients (20.6%) (covered stents: 11.8% and noncovered stents: 8.8%). Emergency CABG was performed in 2 patients (2.9%). Five patients (7.4%) developed periprocedural MI. The in-hospital mortality rate was 5.9% in the study cohort. CONCLUSION Coronary artery perforation as a complication of PCI is still rare as demonstrated in our series with an incidence of 0.48%. The predominant cause of coronary perforations in the current era of PCI is wire injury.