Ralf Seipelt

CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation

Rationale: Although research suggests that diastolic Ca2+ levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca2+ levels and play a role in triggering or maintaining AF by transient inward currents through Na+/Ca2+ exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca2+/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca2+ leak. Objective: We tested the hypothesis that CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels occurs in atrial myocardium of patients with AF. Methods and Results: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40±14% (P<0.05), as well as CaMKII phosphorylation by 33±12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110±53%. Furthermore, cytosolic Ca2+ levels were elevated during diastole (229±20 versus 164±8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca2+ leak in AF (P<0.05), which was not attributable to higher SR Ca2+ load. Tetracaine experiments confirmed that SR Ca2+ leak through RyR2 leads to the elevated diastolic Ca2+ level. CaMKII inhibition normalized SR Ca2+ leak and cytosolic Ca2+ levels without changes in L-type Ca2+ current. Conclusion: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca2+ leak in human AF, causing elevated cytosolic Ca2+ levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.

Altered Na+Currents in Atrial Fibrillation: Effects of Ranolazine on Arrhythmias and Contractility in Human Atrial Myocardium

OBJECTIVES We investigated changes in Na(+) currents (I(Na)) in permanent (or chronic) atrial fibrillation (AF) and the effects of I(Na) inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. BACKGROUND Electrical remodeling during AF is typically associated with alterations in Ca(2+) and K(+) currents. It remains unclear whether I(Na) is also altered. METHODS Right atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied. RESULTS Patch-clamp experiments in isolated atrial myocytes showed significantly reduced peak I(Na) density ( approximately 16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late I(Na) was significantly increased in myocytes from AF atria by approximately 26%. Ran (10 mumol/l) decreased late I(Na) by approximately 60% (p < 0.05) in myocytes from patients with AF but only by approximately 18% (p < 0.05) in myocytes from SR atria. Proarrhythmic activity was elicited in atrial trabeculae exposed to high [Ca(2+)](o) or isoprenaline, which was significantly reversed by Ran (by 83% and 100%, respectively). Increasing pacing rates from 0.5 to 3.0 Hz led to an increase in diastolic tension that could be significantly decreased by Ran in atria from SR and AF patients. CONCLUSIONS Na(+) channels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of I(Na) with Ran had antiarrhythmic effects and improved diastolic function. Thus, inhibition of late I(Na) may be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction.

Impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip® and lessons learned after the first 75 consecutive patients

Mitral valve regurgitation plays a significant role in the aetiology and course of heart failure. We investigated the impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip.

Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living.

AIMS Transcatheter aortic valve implantation (TAVI) represents a less invasive treatment option for elderly patients. Therefore, we aimed to determine the impact of frailty measured by the Katz Index of activities of daily living (ADL) on short- and long-term mortality after TAVI. METHODS AND RESULTS Our study included 300 consecutive patients (mean age, 82±5 years) who had undergone TAVI at our institution (158 transapical, 142 transfemoral procedures). At baseline, 144 patients were impaired in at least one ADL and therefore defined as frail (Katz Index <6). Regarding in-hospital outcome, all serious complications except for stage 3 acute kidney injury were equally distributed in both groups, but early mortality was significantly higher in frail persons (5.5% vs. 1.3%, p=0.04 for immediate procedural mortality; 17% vs. 5.8%, p=0.002 for 30-day mortality; and 23% vs. 6.4%, p<0.0001 for procedural mortality). The risk-score-based 30-day mortality estimates (29% vs. 24% for log. EuroSCORE I, 9.5% vs. 7.5% for EuroSCORE II, and 8.8% vs. 5.9% for STS score) reflected neither the observed 30-day mortality in both groups nor the threefold risk elevation in frail patients. In contrast, the Katz Index <6 was identified as a significant independent predictor of long-term all-cause mortality by multivariate analysis (HR 2.67 [95% CI: 1.7-4.3], p<0.0001). During follow-up (median observation period 537 days) 56% of frail vs. 24% of non-frail patients died. CONCLUSIONS Frailty status measured by the Katz Index represents a powerful predictor of adverse early and late outcome after TAVI, whereas commonly used risk scores lack calibration and discrimination in a TAVI-specific patient cohort. Therefore, we propose the incorporation of this simple and reproducible measure into pre-TAVI risk assessment.

Indications for reoperation late after correction of tetralogy of Fallot.

OBJECTIVE Correction of tetralogy of Fallot has excellent long-term results. The present retrospective study investigates the indications for reoperation late after corrective surgery. METHODS Data from 914 consecutive cases who underwent correction of tetralogy of Fallot in our department between 1960 and 2002 were retrospectively reviewed and analysed. In 91 patients, a total of 102 reoperations were performed late after repair. RESULTS The mean time interval between corrective surgery and the first reoperation was 12.8 years. The main indication for reoperation was residual ventricular septal defect in nearly half of the cases, mostly isolated, but also in combination with a right ventricular outflow tract aneurysm or pulmonary stenosis. One-fourth of reoperated patients underwent a procedure on their pulmonary artery or pulmonary valve: replacement of pulmonary valve, replacement of primary implanted pulmonary artery conduits with or without concomitant surgery, and surgery for isolated peripheral pulmonary stenosis. The remaining indications were right ventricular outflow tract aneurysms and others. Aneurysms of the right ventricular outflow tract were seen mostly after the use of autologous - untreated - pericardial patch in 18 of 21 cases. CONCLUSION The number of reoperations for residual ventricular septal defect decreased during the study period. The primary use of conduits led to an increased number of reoperations for conduit exchange due to degeneration or failure. Use of an untreated autologous pericardial patch for enlargement of the right ventricular outflow tract should be avoided due to increased risk for aneurysm formation.

Heart team approach for transcatheter aortic valve implantation procedures complicated by coronary artery occlusion.

We report on three out of 270 consecutive patients (1.1%) suffering from coronary artery obstruction or occlusion at the end of transcatheter aortic valve implantation (TAVI). The partial or total obstruction of the coronary artery seen in the post-implantation aortography was accompanied by haemodynamic instability and electrocardiographic changes typical for myocardial ischaemia. Immediate percutaneous coronary intervention with stent implantation was successful in two cases, while in the third case it was not possible to cross the occluded right coronary artery. Emergency coronary artery bypass grafting was performed resulting in uneventful myocardial recovery. All patients were discharged home. These cases highlight the awareness of this rare, life-threatening complication of TAVI, which is in need of a dedicated heart team involved not only in decision-making, but also in the procedure itself.

The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction

OBJECTIVE Renal dysfunction is one of the most serious complications following cardiac surgery with cardiopulmonary bypass. The causes of renal dysfunction following cardiac surgery are poorly understood. We hypothesised that T-786C endothelial NO synthase (eNOS) polymorphism may lead to an increase in the occurrence of postoperative renal dysfunction following cardiac surgery with cardiopulmonary bypass. METHODS A total of 497 patients undergoing cardiac surgery with cardiopulmonary bypass were included in the study. The T-786C eNOS polymorphism was detected by a polymerase chain reaction. The patients were grouped on the basis of whether they were homozygous or heterozygous for the C allele (TC+CC; n=289) or only homozygous for the T allele (TT; n=208). RESULTS No significance was demonstrated in the preoperative risk factors, with the exclusion of smoking habits (p=0.04) for the C-allele carrier. The administration of anti-lipid agents (p=0.01) and anti-arrhythmics (p=0.01) was significantly lower in the TC/CC group. The TC+CC genotype group had a significantly greater decrease in creatine clearance (p=0.024), the lowest creatine clearance (p=0.004) and more C-allele carriers received acute renal replacement therapy (p=0.04). The usage of norepinephrine (p=0.02) and dobutamine (p=0.02) was significantly higher in C-allele carriers. In the TC+CC genotype group, cross-clamp time (p=0.02) and administration of red cell transfusion (p=0.04) achieved statistically significant difference. The overall in-hospital mortality rate was 8.2% for all patients and was not significant between genotypes. CONCLUSIONS The present findings support the hypothesis that the T-786C eNOS polymorphism may play a role in the development of renal dysfunction and increase the occurrence of renal replacement therapy following cardiac surgery with cardiopulmonary bypass. This polymorphism may be useful in stratifying the risk for the development of postoperative renal dysfunction.

A Three-Group Model to Predict Mortality in Emergent Coronary Artery Bypass Graft Surgery

BACKGROUND Emergent coronary artery bypass graft surgery (CABG) for acute myocardial infarction is associated with an increased operative risk. For estimation of mortality risk, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) is appropriate up to a medium risk score (<6 points). To predict mortality risk more accurately in cases of higher EuroSCORE, additional cardiac data can be helpful. METHODS Over a 3-year period, patient data including acute myocardial infarction and emergent CABG were retrospectively reviewed. Univariate and multivariate analysis for in-hospital mortality was performed. The EuroSCORE analysis and follow-up was investigated. RESULTS Overall in-hospital mortality was 18.3%. Preoperative cardiac related predictors for in-hospital mortality were cardiogenic shock (p < 0.001), very poor left ventricular function (p = 0.001), and ST-segment elevation (p = 0.012). In multivariate regression analysis, age, cardiogenic shock, and pulmonary hypertension were independent preoperative risk factors. According to the EuroSCORE, we could define three statistically different groups: intermediate-risk, high-risk, and very high risk, with an observed mortality of 3.3%, 20.0%, and 63.2%, respectively. The EuroSCORE correlates with but overestimates the mortality risk. In subgroup analysis, the creatine kinase-myocardial band/hour ratio for the intermediate-risk group and ST-segment elevation for the high-risk group were additional cardiac risk factors. CONCLUSIONS Patients with an acute myocardial infarction and emergency aortocoronary CABG have an elevated operative risk. Logistic EuroSCORE overestimates the mortality rate. Three different risk groups can be defined, in which creatine kinase-MB/h-ratio and ST-segment elevation can more accurately predict operative risk.

Impact of endothelin-1 Lys198Asn polymorphism on coronary artery disease and endorgan damage in hypertensives.

ObjectiveEndothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages. MethodsIn 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients. ResultsGenotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004). ConclusionHomozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Miniaturized HIA microdiagonal pump as left ventricular assist device in a sheep model.

We evaluated the newly developed miniaturized HIA microdiagonal blood pump (MDP) as a continuous flow left ventricular assist device. In a sheep model (n = 6), the MDP was implanted through left lateral thoracotomy and placed paracorporeally with inflow conduit to left atrium and outflow conduit to descending aorta. The sheep were pumped at a mean flow rate of 2.5 L/min for 7 days. Anticoagulation was applied by intravenous heparin administration. Postoperatively, activated clotting time was held stable with values of 200 seconds. During follow-up, blood samples (creatinine kinase, creatinine, glutamic-oxaloacetic transaminase (aspartate aminotransferase) (GOT), glutamate dehydrogenase (GLDH), gamma-GT, plasma-free hemoglobin, and hemoglobine) were taken daily. After 7 days, the sheep were killed for macroscopic examination. Systemic artery pressures remained stable during the whole test period. Because of operative reasons, the hemoglobin value (7.5 ± 0.61 g/dl) decreased perioperatively, but recovered within the test period, whereas creatinine kinase increased initially after thoracotomy, but decreased to normal within days. Renal and liver functions were slightly impaired perioperatively, indicated by temporarily enhanced values of GOT, gamma-GT, GLDH, and creatinine. The MDP did not produce significant hemolysis as measured by plasma-free hemoglobin levels. Wound infections did not occur. We conclude that the MDP ran successfully as an left ventricular assist device for 7 days in sheep has potential for long-term support, and may serve as an alternative to current technologies. Presented data were not obtained in a clinical trial; however, the results are promising enough to proceed with longer duration animal studies.