Amir H. Sepehripour

SERCA2a Gene Transfer Decreases Sarcoplasmic Reticulum Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure

Background—Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart. Methods and Results—We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action. Conclusions—SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.

SERCA2a Gene Transfer Decreases SR Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure

Background—Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart. Methods and Results—We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action. Conclusions—SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.

Beating-Heart Versus Conventional On-Pump Coronary Artery Bypass Grafting: A Meta-Analysis of Clinical Outcomes

BACKGROUNDnBeating-heart on-pump coronary artery bypass grafting (BH-ONCAB) offers a hybrid coronary revascularization technique that may confer the benefits of an off-pump operation while maintaining the hemodynamic stability and mechanical support of conventional on-pump CABG (C-ONCAB). This study aimed to identify whether BH-ONCAB confers a morbidity or mortality benefit over C-ONCAB in the immediate and midterm postoperative period.nnnMETHODSnA systematic literature review identified 13 studies incorporating 3,930 patients (937 BH-ONCAB; 2,993 C-ONCAB) fulfilling our inclusion criteria. Outcomes were meta-analyzed using random-effects modelling. Between-study heterogeneity was investigated through quality assessment, subgroup, and risk of bias analysis.nnnRESULTSnNo difference was seen in overall 30-day mortality (13 studies; odds ratio, 0.60; 95% confidence interval, 0.32 to 1.14; p = 0.12), or midterm survival (5 studies; hazard ratio, 0.65; 95% confidence interval, 0.22 to 1.88; p = 0.43) between BH-ONCAB and C-ONCAB. BH-ONCAB was associated with significantly fewer postoperative myocardial infarction events (odds ratio, 0.32; 95% confidence interval, 0.11 to 0.92; p = 0.03); however, no significant difference was observed in other postoperative morbidity outcomes. Intraoperatively, BH-ONCAB resulted in significantly less intraaortic balloon pump use, shorter cardiopulmonary bypass time, and less blood loss. The number of anastomoses and vessels grafted were not significantly different between BH-ONCAB and C-ONCAB.nnnCONCLUSIONSnBH-ONCAB is a safe and comparable alternative to C-ONCAB in terms of early mortality and late survival. Furthermore, BH-ONCAB may confer a particular advantage in preventing perioperative myocardial infarction and reducing overall blood loss. Future work should focus on larger matched studies and multicenter randomized controlled trials that risk-stratify patients according to preoperative ventricular function and renal insufficiency to allow us to optimize our surgical revascularization strategy in these high-risk patients.

Does off-pump coronary revascularization reduce mortality in re-operative coronary artery surgery? A meta-analysis of observational studies.

Background: Re-operative coronary artery bypass grafting (CABG) is a challenging operation that is often performed in a high-risk patient group. Avoiding cardiopulmonary bypass (CPB) in these patients is hypothesised to be advantageous due to the reduced invasiveness and physiological stress of off-pump coronary artery bypass grafting (OPCAB). The aims of this study were to assess whether OPCAB may improve outcomes in patients undergoing re-operative CABG. Methods: Twelve studies, incorporating 3471 patients, were identified by systematic literature review. These were meta-analysed using random-effects modelling. Primary endpoints were 30-day and mid-term mortality. Secondary endpoints were completeness of revascularization, mean number of grafts per patient and the effect of intra-operative conversion on mortality. Results: A significantly lower rate of 30-day mortality was observed with OPCAB (OR 0.51, 95% CI [0.35, 0.74]), however, no difference was demonstrated in mid-term mortality. Significantly less complete revascularization and mean number of grafts per patient were observed in the OPCAB group. Meta-regression revealed no change in 30-day mortality when the effect of conversion from one technique to the other was assessed. Conclusions: Off-pump techniques may reduce early mortality in selected patients undergoing re-operative CABG; however, this does not persist into mid-term follow-up. OPCAB may also lead to intra-operative conversion and, although this did not affect outcomes in this study, these results are constrained by the limited data available. Furthermore, OPCAB may increase target vessel revascularization and, consequently, incomplete revascularization which, whilst not reflected in the short-term outcomes, requires longer-term follow-up in order to be fully assessed.

How revascularization on the beating heart with cardiopulmonary bypass compares to off-pump? A meta-analysis of observational studies

Off-pump coronary artery bypass surgery has been a controversial area of debate and the outcome profile of the technique has been thoroughly investigated. Scepticism regarding the reported outcomes and the conduct of the randomized trials comparing this technique with conventional on-pump coronary artery bypass surgery has been widely voiced, and the technique of off-pump surgery remains as an infrequently adopted approach to myocardial revascularization worldwide. Criticisms of the technique are related to lower rates of complete revascularization and its unknown long-term consequences, the significant detrimental effects on mortality and major adverse events when emergency conversion is required, and the significant lack of long-term survival and morbidity data. The hybrid technique of myocardial revascularization on the beating heart with the use of cardiopulmonary bypass may theoretically provide the beneficial effects of off-pump surgery in terms of myocardial protection and organ protection, while providing the safety and stability of on-pump surgery to allow complete revascularization. Large randomized comparison to support evidence-based choices is currently lacking. In this article, we have meta-analysed the outcomes of on-pump beating heart surgery in comparison with off-pump surgery focusing on major adverse cardiovascular and cerebrovascular adverse events (MACCE) including mortality, stroke and myocardial infarction and the degree of revascularization and number of bypass grafts performed. It was demonstrated that the beating heart on-pump technique allows a significantly higher number of bypass grafts to be performed, resulting in significantly higher degree of revascularization. We have also demonstrated a slightly higher rate of 30-day mortality and MACCE with the technique although not at a statistically significant level. These results should be considered alongside the population risk profile, where a significantly higher risk cohort had undergone the beating heart on-pump technique. Long-term survival and morbidity figures are required to assess the impact of these findings in the coronary surgery patient population.

Off-pump or on-pump beating heart: which technique offers better outcomes following coronary revascularization?

A best evidence topic was written according to a structured protocol. The question addressed was whether on-pump beating heart coronary artery bypass (BH-ONCAB) surgery has a different outcome profile in comparison to off-pump coronary artery bypass (OPCAB). A total of 205 papers were found by systematic search of which 7 provided the largest and most recent outcome analysis comparing BH-ONCAB with OPCAB, and represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results were tabulated. Reported outcome measures included mortality, stroke, myocardial infarction, renal failure, myocardial damage, change in ejection fraction, number of bypass grafts and completeness of revascularization. With the exception of one study that favoured the off-pump technique, our review did not demonstrate a statistically significant difference in terms of mortality between the groups. We did not identify a statistically significant difference in any reported morbidity outcomes. However, there was a trend towards better outcomes for the on-pump beating heart technique, despite a higher risk profile in terms of age, ejection fraction and burden of coronary disease in this group. Consistent statistically significant differences between the groups were the mean number of grafts performed and the completeness of revascularization, both of which were higher with the on-pump beating heart technique. Limitations to the current evidence include the finding that most of the current data arise from specialist off-pump surgeons or centres that would usually only carry out BH-ONCAB in the higher risk patients where the added safety of cardiopulmonary bypass is desired.

Is the evidence from first time off-pump coronary artery bypass graft surgery transferable to re-operative off-pump surgery?

On-pump coronary artery surgery remains the gold standard treatment for multi-vessel disease. The technique of off-pump surgery has evolved since its first use; however, currently less than 20% of all cases worldwide are performed this way. This poor uptake has been both the cause and the effect of widespread scepticism regarding the validity of the data on the technique, as well as criticism regarding the conversion-related adverse outcomes, graft patency and completeness of revascularisation. Consequently, there has been focus on patient selection from subgroups most likely to benefit from the technique. Re-operative patients, by virtue of their advanced age, complex co-morbidities and the technical challenges of re-operation, fall into this category. In this review, the authors will discuss the outcomes of off-pump surgery in comparison to on-pump, explore the potential beneficial effects of off-pump in re-operative surgery and formulate a decision-making strategy in patients undergoing reoperative coronary artery surgery.

Do selective serotonin reuptake inhibitors increase the risk of bleeding or mortality following coronary artery bypass graft surgery? A meta-analysis of observational studies

Introduction: Depressive illness has a high prevalence in patients undergoing coronary artery bypass graft surgery (CABG). The first line treatment for depression are selective serotonin reuptake inhibitors (SSRIs) which inhibit serotonin reuptake in the presynaptic neuronal membrane and uptake by platelets, inhibiting subsequent serotonin-mediated platelet activation. This presents a theoretically increased risk of bleeding and subsequent postoperative mortality. This review aims to investigate the effects of SSRIs on postoperative bleeding, defined as the need for transfusions and re-operation for bleeding, as well as 30-day mortality in patients undergoing CABG. Method: Four hundred and thirty-seven papers were screened with seven meeting the full inclusion criteria. Results: Meta-analysis demonstrated that SSRI use increased the risk of red blood cell transfusion (odds ratio (OR) = 1.15; 95% confidence interval (CI): 1.06-1.26), but resulted in no difference in the rate of re-operation for bleeding (OR = 1.07; 95% CI: 0.66-1.74). SSRI use had no effect on the rates of platelet (OR = 0.93; 95% CI: 0.79-1.09) or fresh frozen plasma (OR = 0.96; 95% CI: 0.74-1.24) transfusion nor on the mortality rate (OR =1.03; 95 CI: 0.90-1.17). Conclusion: This review demonstrates that SSRIs are largely safe in cardiac surgery as no increase in mortality was observed. However, there is a significantly raised chance of red blood cell transfusion. The heterogeneous nature of the current evidence base highlights the need for further research into SSRIs and whether any effect on patient outcomes in cardiac surgery occurs.

Robotics in cardiac surgery

&NA; A summary of its uses in mitral valve surgery and coronary artery revascularisation

SERCA2a Gene Transfer Decreases Sarcoplasmic Reticulum Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart FailureClinical Perspective

Background—Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart. Methods and Results—We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action. Conclusions—SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.