P682Preserved contractile function of unloaded cardiomyocytes despite diminished sarcomere size is associated with troponin I activation

Objective: Myocardial unloading with ventricular assist devices in patients with severe heart failure (HF) can lead to reversal of certain aspects of pathological remodeling. However, these effects do not translate into recovery of myocardial function in the human heart, possibly due to detrimental atrophic processes also elicited through unloading. We have studied the effects of long-term unloading on sarcomeric morphology and function in a small animal model of ventricular unloading, heterotopic heart transplantation (HTX) in rats. Methods: Native rat hearts were unloaded via HTX for 30 days, CMs from control and unloaded hearts were isolated (n=8 hearts/>250 individual cells/group). CM overall size was determined, sarcomere length/contractility assessed and Calcium transients as well as E-C coupling gain analyzed in patch-clamped CMs. Additionally, phosphorylation of Troponin I, indicative of sarcomere activation, was measured with western blotting. Results: CM cross-sectional area was diminished in unloaded cells by about one third (2787±345 vs 1993±230 μm2) as was cell capacitance in patched cells. Accordingly, baseline sarcomere length was significantly reduced by ~0.2μm (Figure). However, this reduction did not diminish contractile function: fractional shortening was significantly higher in unloaded CMs (8.0 ± 3 % vs 6.6 ± 2.5 % in CTR, p = 0.01). Departure velocity of the transients was similar (-135.2 ± 48 vs -119.4 ± 40 dL/dt), and return velocity was slightly increased in unloaded cells (120.7 ± 54 vs 94.0 ± 46 dL/dt, p < 0.05), indicating preserved relaxation. Calcium transient amplitudes and current-voltage relationship under basal condition and isoproterenol stimulation was not changed. Troponin I phosphorylation was elevated and may contribute to the maintenance of sarcomeric function in long-term unloaded CMs. Conclusion: Although there are limitations regarding assessment of contractility in isolated cells, we may conclude that the considerable size reduction in CMs induced by unloading does not translate into diminished contractile function or E-C couplin

Glucose-Insulin Therapy, Plasma Substrate Levels and Cardiac Recovery After Cardiac Ischemic Events

INTRODUCTION: The potential usefulness of glucose-insulin therapy relies to a large extent on the premise that it prevents hyperglycemia and hyperlipidemia following cardiac ischemic events. METHODS: In this review we evaluate the literature concerning plasma glucose and free fatty acids levels during and following cardiac ischemic events. RESULTS: The data indicate that hyperlipidemia and hyperglycemia most likely occur during acute coronary ischemic syndromes in the conscious state (e.g. acute myocardial infarction) and less so during reperfusion following CABG reperfusion. This is in accordance with observations that glucose-insulin therapy during early reperfusion post CABG may actually cause hypolipidemia, because substantial hyperlipidemia does not appear to occur during that stage of cardiac surgery. DISCUSSION: Considering recent data indicating that hypolipidemia may be detrimental for cardiac function, we propose that free fatty acid levels during reperfusion post CABG with the adjunct glucose-insulin therapy need to be closely monitored. CONCLUSION: From a clinical point of view, a strategy directed at monitoring and thereafter maintaining plasma substrate levels in the normal range for both glucose (4-6 mM) and FFA (0.2-0.6 mM) as well as stimulation of glucose oxidation, promises to be the most optimal metabolic reperfusion treatment following cardiac ischemic episodes. Future (preclinical and subsequently clinical) investigations are required to investigate whether the combination of glucose-insulin therapy with concomitant lipid administration may be beneficial in the setting of reperfusion post CAB

Heart Transplantation With Donation After Circulatory Death.

Heart transplantation remains the preferred option for improving quality of life and survival for patients suffering from end-stage heart failure. Unfortunately, insufficient supply of cardiac grafts has become an obstacle. Increasing organ availability with donation after circulatory death (DCD) may be a promising option to overcome the organ shortage. Unlike conventional donation after brain death, DCD organs undergo a period of warm, global ischemia between circulatory arrest and graft procurement, which raises concerns for graft quality. Nonetheless, the potential of DCD heart transplantation is being reconsidered, after reports of more than 70 cases in Australia and the United Kingdom over the past 3 years. Ensuring optimal patient outcomes and generalized adoption of DCD in heart transplantation, however, requires further development of clinical protocols, which in turn require a better understanding of cardiac ischemia-reperfusion injury and the various possibilities to limit its adverse effects. Thus, we aim to provide an overview of the knowledge obtained with preclinical studies in animal models of DCD heart transplantation, to facilitate and promote the most effective and efficient advancement in preclinical research. A literature search of the PubMed database was performed to identify all relevant preclinical studies in DCD heart transplantation. Specific aspects relevant for DCD heart transplantation were analyzed, including animal models, graft procurement and storage conditions, cardioprotective approaches, and graft evaluation strategies. Several potential therapeutic strategies for optimizing graft quality are identified, and recommendations for further preclinical research are provided