Postcardiac transplant survival in the current era in patients receiving continuous-flow left ventricular assist devices

ObjectivesContinuous-flow left ventricular assist devices have become the standard of care for patients with heart failure requiring mechanical circulatory support as a bridge to transplant. However, data on long-term post-transplant survival for these patients are limited. We evaluated the effect of continuous-flow left ventricular assist devices on postcardiac transplant survival in the current era.MethodsAll patients who received a continuous-flow left ventricular assist device as a bridge to transplant at a single center from June 2005 to September 2011 were evaluated.ResultsOf the 167 patients who received a continuous-flow left ventricular assist device as a bridge to transplant, 77 (46%) underwent cardiac transplantation, 27 died before transplantation (16%), and 63 (38%) remain listed for transplantation and continued with left ventricular assist device support. The mean age of the transplanted patients was 54.5 ± 11.9 years, 57% had an ischemic etiology, and 20% were women. The overall mean duration of left ventricular assist device support before transplantation was 310 ± 227 days (range, 67-1230 days). The mean duration of left ventricular assist device support did not change in patients who had received a left ventricular assist device in the early period of the study (2005-2008, n = 62) compared with those who had received a left ventricular assist device later (2009-2011, n = 78, 373 vs 392 days, P = NS). In addition, no difference was seen in survival between those patients supported with a left ventricular assist device for fewer than 180 days or longer than 180 days before transplantation (P = NS). The actuarial survival after transplantation at 30 days and 1, 3, and 5 years by Kaplan-Meier analysis was 98.7%, 93.0%, 91.1%, and 88.0%, respectively.ConclusionsThe short- and long-term post-transplant survival for patients bridged with a continuous-flow left ventricular assist device in the current era has been excellent. Furthermore, the duration of left ventricular assist device support did not affect post-transplant survival. The hemodynamic benefits of ventricular unloading with continuous-flow left ventricular assist devices, in addition to their durability and reduced patient morbidity, have contributed to improved post-transplant survival

Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation

Human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are based on ground-breaking technology that has significantly impacted cardiovascular research. They provide a renewable source of human cardiomyocytes for a variety of applications including in vitro disease modeling and drug toxicity testing. Cardiac calcium regulation plays a critical role in the cardiomyocyte and is often dysregulated in cardiovascular disease. Due to the limited availability of human cardiac tissue, calcium handling and its regulation have most commonly been studied in the context of animal models. hiPSC-CMs can provide unique insights into human physiology and pathophysiology, although a remaining limitation is the relative immaturity of these cells compared to adult cardiomyocytes Therefore, this field is rapidly developing techniques to improve the maturity of hiPSC-CMs, further establishing their place in cardiovascular research. This review briefly covers the basics of cardiomyocyte calcium cycling and hiPSC technology, and will provide a detailed description of our current understanding of calcium in hiPSC-CMs

Modeling and rescue of Duchenne muscular dystrophy cardiomyopathy using human induced pluripotent-derived cardiomyocytes

University of Minnesota Ph.D. dissertation. January 2021. Major: Integrative Biology and Physiology. Advisor: Daniel Garry. 1 computer file (PDF); x, 214 pages.Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and affects 1:5000 boys born in the United States. DMD is a result of mutations in the dystrophin (DMD) gene that leads to the absence of the full length cytoskeletal protein dystrophin, which is expressed in skeletal muscle, brain, and heart. The absence of dystrophin leads to weakness of not only the skeletal muscle but also the heart. With advances in treatment for DMD, patients are living longer but a cardiomyopathic phenotype has been uncovered. DMD associated cardiomyopathy is nearly ubiquitous and is the leading cause of death with adults with DMD. There have been limited studies and therapies for dystrophic heart failure thus far, and there is a critical need to identify the pathophysiology and develop effective therapeutic regimens. In this thesis, I hypothesized that DMD cardiomyopathy could be modeled using DMD patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs) to identify physiological changes and future drug therapies. To explore and define therapies for DMD cardiomyopathy, we used DMD patient-specific and dystrophin null isogenic hiPSC-derived CMs to examine the physiological response to adrenergic agonists and -blocker treatment. We further examined these agents in vivo using wildtype and the mdx mouse model. At baseline and following adrenergic stimulation, DMD hiPSC-derived CMs had a significant increase in arrhythmic calcium traces compared to isogenic controls. Further, these arrhythmias were significantly decreased with propranolol treatment. Using telemetric monitoring, we observed that mdx mice, which lack dystrophin, and were stimulated with isoproterenol had an arrhythmic death and the lethal arrhythmias were rescued, in part, by propranolol pretreatment. Using single cell and bulk RNA-seq, we compared DMD and control hiPSC-derived CMs, mdx mice and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized following propranolol treatment in the mdx model. We also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived CMs have similar dysregulated pathways as the human DMD heart. We further determined that relatively few DMD patients see a cardiovascular specialist or receive β-blocker therapy. The results of these experiments highlight important mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. Importantly, these results may serve as a platform to elucidate further mechanisms of DMD cardiomyopathy and serve as a platform for testing novel therapies. Our results also provide a rationale for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies

Intermittent antegrade cardioplegia: isolated heart preservation with the Asporto heart preservation device

Background—A major problem in procurement of donor hearts is the limited time a donor heart remains viable. After cardiectomy, ischemic hypoxia is the main cause of donor heart degradation. The global myocardial ischemia causes a cascade of oxygen radical formation that cumulates in an elevation in hydrogen ions (decrease in pH), irreversible cellular injury, and potential microvascular changes in perfusion. Objective—To determine the changes of prolonged storage times on donor heart microvasculature and the effects of intermittent antegrade perfusion. Materials and Methods—Using porcine hearts flushed with a Ribosol-based cardioplegic solution, we examined how storage time affects microvascular myocardial perfusion by using contrast-enhanced magnetic resonance imaging at a mean (SD) of 6.1 (0.6) hours (n=13) or 15.6 (0.6) hours (n=11) after cardiectomy. Finally, to determine if administration of cardioplegic solution affects pH and microvascular perfusion, isolated hearts (group 1, n=9) given a single antegrade dose, were compared with hearts (group 2, n=8) given intermittent antegrade cardioplegia (150 mL, every 30 min, 150 mL/min) by a heart preservation device. Khuri pH probes in left and right ventricular tissue continuously measured hydrogen ion levels, and perfusion intensity on magnetic resonance images was plotted against time. Results—Myocardial perfusion measured via magnetic resonance imaging at 6.1 hours was significantly greater than at 15.6 hours (67% vs 30%, P= .00008). In group 1 hearts, the mean (SD) for pH at the end of 6 hours decreased to 6.2 (0.2). In group 2, hearts that received intermittent antegrade cardioplegia, pH at the end of 6 hours was higher at 6.7 (0.3) (P=.0005). Magnetic resonance imaging showed no significant differences between the 2 groups in contrast enhancement (group 1, 62%; group 2, 40%) or in the wet/dry weight ratio. Conclusion—Intermittent perfusion maintains a significantly higher myocardial pH than does a conventional single antegrade dose. This difference may translate into an improved quality of donor hearts procured for transplantation, allowing longer distance procurement, tissue matching, improved outcomes for transplant recipients, and ideally a decrease in transplant-related costs