Gregor Simonis

Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy

ObjectivesProtein kinase C (PKC) is a central enzyme in the regulation of growth and hypertrophy. Little was known on PKC isoform regulation in human heart. Goal of this study was to characterize the isoforms of protein kinase C in human heart, their changes during ontogenesis, and their regulation in myocardial hypertrophy and heart failure.MethodsIn left ventricular and atrial samples from adults with end-stage dilated cardiomyopathy (DCM), from adults with severe aortic stenosis (AS), from small infants undergoing repair of ventricular septal defects, and from healthy organ donors (CO), activity of protein kinase C and the expression of its isozymes were examined.ResultsIn the adult human heart, the isoforms PKC-α, PCK-β, PKC-δ, PKC-ε, PKC-λ/-ι, and PKC-ζ were detected both on protein and on mRNA level. All isozymes are subjected to downregulation during ontogenesis. No evidence, however, exists for an isoform shift from infancy to adulthood. DCM leads to a pronounced upregulation of PKC-β. Severe left ventricular hypertrophy in AS, however, recruits a distinct isoform pattern, i.e., isoforms PKC-α, PKC-δ, PKC-ε, PKC-λ/-ι, and PKC-ζ are upregulated, whereas PKC-β is not changed under this condition.ConclusionThis work gives evidence for a differential recruitment of human PKC isoforms in various forms of myocardial hypertrophy and heart failure.

Transcatheter closure of atrial septal defects improves right ventricular volume, mass, function, pulmonary pressure, and functional class: a magnetic resonance imaging study

Objective: To characterise prospectively by magnetic resonance imaging (MRI) changes in right ventricular (RV) volume, function, and mass after transcatheter closure of atrial septal defects (ASDs) and to evaluate the course of pulmonary pressure and functional class criteria. Methods: In 20 patients with secundum-type ASD and dilated RV diameter, MRI was performed to quantify RV end diastolic (RVEDV) and end systolic volumes (RVESV), RV mass, tricuspid annular diameter, and RV ejection fraction before and 6 and 12 months after transcatheter closure of the ASD. RV systolic pressure was measured during follow up by transthoracic echocardiography. Results: Functional class improved in the majority of patients after ASD closure. RVESV (from 81 (18) ml/m2 to 53 (15) ml/m2, p < 0.001), RVEDV (from 127 (17) ml/m2 to 99 (18) ml/m2, p < 0.001), and RV mass (from 79 (10) g to 63 (8) g, p < 0.01) decreased significantly during follow up, although tricuspid annular diameter did not. RV ejection fraction improved (by 9% compared with baseline, p < 0.05) and RV systolic pressure decreased significantly (from 33 (8) mm Hg to 24 (6) mm Hg, p < 0.001) after closure. Conclusion: MRI studies showed significant improvement of RV volumes, mass, and function after transcatheter closure of ASDs. Restoration of the RV leads to decreased pulmonary pressure resulting in a better functional class in the majority of patients.

Transapical Transcatheter Valve-in-Valve Implantation for Deteriorated Mitral Valve Bioprostheses

BACKGROUND The transcatheter valve-in-valve concept has been described for patients requiring redo valve surgery. We report our experience with transapical mitral valve-in-valve implantation. METHODS Since 2008, 301 patients were treated with transapical transcatheter valve implantation. Seven of these patients presented with a deteriorated mitral valve bioprosthesis and underwent transapical mitral valve-in-valve implantation. Median age was 79 years. Preoperatively, all patients presented in New York Heart Association functional class III. For risk estimation, The Society of Thoracic Surgeons and European System for Cardiac Operative Risk scores were used and predicted high mortality (mean ± standard error of mean: Society of Thoracic Surgeons mortality, 12.3% ± 2.1%; European System for Cardiac Operative Risk mortality, 58.0% ± 7.0%). Mean follow-up time was 93 ± 29 days, with a total of 21.6 patient-months. RESULTS Preoperatively, all patients who had deteriorated bioprostheses presented with severe regurgitation and increased transvalvular pressure gradients (maximal pressure gradient, 23.9 ± 0.9 mm Hg; mean pressure gradient, 11.3 ± 1.0 mm Hg). One patient was identified with mitral valve stenosis (effective orifice area, 0.25 cm(2)). All patients underwent successful transapical mitral valve-in-valve implantation. Sizes of previously implanted bioprostheses were 27, 29, and 31 mm; Edwards SAPIEN valves at sizes 26 and 29 mm were implanted. Postoperatively, echocardiography revealed excellent hemodynamics with no remaining mitral regurgitation in 5 patients and minimal regurgitation in 2 patients. Transvalvular pressure gradients decreased significantly (maximal pressure gradient, 13.8 ± 2.1 mm Hg; mean pressure gradient 5.7 ± 0.8 mm Hg, p < 0.05). One patient had fatal pneumonia on postoperative day 34. No patient died during further follow-up, and all patients remained in New York Heart Association class I or II. CONCLUSIONS Our results demonstrate the feasibility of transapical mitral valve-in-valve implantation for treatment of a degenerated bioprosthesis (size range, 27 to 31 mm) using the Edwards SAPIEN valve in sizes 26 and 29 mm.

Valvular heart disease in Parkinson's disease patients treated with dopamine agonists: a reader-blinded monocenter echocardiography study.

Fibrotic valvular heart disease (VHD) has been reported in association with ergot dopamine agonists (DAs), but the current database is insufficient regarding clinical relevance and comparison to data on non‐ergot DAs. We evaluated the effects of four DAs (pergolide, cabergoline, ropinirole, pramipexole) on morphology and function of heart valves in patients with Parkinsons disease (PD) to determine the frequency and clinical relevance of DA‐induced VHD. A total of 85 patients treated with ergot or non‐ergot DAs and 38 age‐matched controls were evaluated by transthoracic echocardiography. Valvular pathology was assessed by established criteria of valvular regurgitation and a VHD scoring system. Both grading systems revealed increased frequency of VHD in ergot DA patients compared to both non‐ergot DA patients and controls with 22% of ergot DA patients having moderate VHD versus 3% of non‐ergot DA patients and none of controls (P = 0.001). We did not find correlations of echocardiographic findings with duration/cumulative dose of treatment, age, or vascular risk factors. Our data suggest that ergot DAs are associated with higher prevalence of VHD compared to non‐ergot DAs and controls. Standard echocardiography seems sufficient to detect VHD in PD patients treated with DAs.

Transapical transcatheter aortic valve implantation vs conventional aortic valve replacement in high-risk patients with previous cardiac surgery: a propensity-score analysis

OBJECTIVES The present analysis compared clinical and mid-term outcomes of patients with previous cardiac surgery undergoing transapical transcatheter aortic valve implantation (TAVI) with propensity-matched patients undergoing conventional redo aortic valve replacement (cAVR). METHODS Since 2008, 508 patients were treated with TAVI. Fifty-three of these patients presented with a history of cardiac surgery and underwent transapical TAVI using the Edwards SAPIEN bioprosthesis. A propensity-matched control group of 53 patients receiving cAVR was generated out of the hospitals database. The mean age for all the patients was 77.8 ± 4.5 years. The logistic EuroSCORE was 28.4 ± 13.6% in mean, and mean EuroSCORE II was 8.56 ± 3.93%. The mean follow-up time was 245 ± 323 days, which equated to a total of 700 patient-months. RESULTS The observed hospital mortality did not differ significantly between TAVI and cAVR (TAVI: 9.4% and cAVR: 5.7%; P = 0.695). Six-month survival was 83.0% for the TAVI and 86.8% for the cAVR patients (P = 0.768). Postoperative bleedings (TAVI: 725 ± 1770 ml and cAVR: 1884 ± 6387; P = 0.022), the need for transfusion (TAVI: 1.7 ± 5.3 vs cAVR: 6.2 ± 13.7 units packed red blood cells (PRBC); P = 0.030), consecutive rethoracotomy (TAVI: 1.9% vs cAVR: 16.9%; P = 0.002) and postoperative delirium (TAVI: 11.5% vs cAVR: 28.3%; P = 0.046) were more common in the cAVR patients. The TAVI patients suffered more frequently from respiratory failure (TAVI: 11.3% vs cAVR: 0.0%; P = 0.017) and mean grade of paravalvular regurgitation (TAVI: 0.8 ± 0.2 vs cAVR: 0.0; P = 0.047). Although primary ventilation time (P = 0.020) and intensive care unit stay (P = 0.022) were shorter in the TAVI patients, mean hospital stay did not differ significantly (P = 0.108). CONCLUSIONS Transapical TAVI as well as surgical aortic valve replacement provided good clinical results. The pattern of postoperative morbidity and mortality was different for both entities, but the final clinical outcome did not differ significantly. Both techniques can be seen as complementary approaches by means of developing a tailor-made and patient-orientated surgery.

Meta-analysis of heart valve abnormalities in Parkinson's disease patients treated with dopamine agonists

Valvular heart disease in patients being treated with ergot‐derivative dopamine agonists (Ergot‐DA) for Parkinsons disease has been reported to occur as a consequence of serotonine receptor stimulation. Goal of this analysis was to estimate the incidence of those changes from recently published studies and to determine its clinical relevance. Medline searches were performed to identify cross‐sectional, echocardiographic studies comparing patients treated with dopamine agonists or controls, in terms of valvular changes. Observational studies of valve changes in Parkinsonian patients were used to estimate the incidence of severe valvulopathy. The results from 7 cross‐sectional studies including 477 patients treated with Ergot‐DA, 127 patients with non‐Ergot‐DA, and 364 control patients were analyzed. Moderate‐to‐severe valvular changes were detected in 26% of patients treated with Ergot‐DA, 10% of patients treated with non‐Ergot DA, and 10% of control patients. Severe valvulopathy was less than 1% both in cross‐sectional and observational studies. The high rate of moderate valvular changes in patients treated with Ergot‐DA suggests that close surveillance of the patients is required. Severe valvulopathy was less than 1% in the studies analyzed.

Continuous mechanical chest compression during in-hospital cardiopulmonary resuscitation of patients with pulseless electrical activity

UNLABELLED Survival after in-hospital pulseless electrical activity (PEA) cardiac arrest is poor and has not changed during the last 10 years. Effective chest compressions may improve survival after PEA. We investigated whether a mechanical device (LUCAS™-CPR) can ensure chest compressions during cardiac arrest according to guidelines and without interruption during transport, diagnostic procedures and in the catheter laboratory. METHODS We studied mechanical chest compression in 28 patients with PEA (pulmonary embolism (PE) n=14; cardiogenic shock/acute myocardial infarction; n=9; severe hyperkalemia; n=2; sustained ventricular arrhythmias/electrical storm; n=3) in a university hospital setting. RESULTS During or immediately after CPR, 21 patients underwent coronary angiography and or pulmonary angiography. Successful return of a spontaneous circulation (ROSC) was achieved in 27 out of the 28 patients. Ten patients died within the first hour and three patients died within 24h after CPR. A total of 14 patients survived and were discharged from hospital (13 without significant neurological deficit). Interestingly, six patients with PE did not have thrombolytic therapy due to contraindications. CT-angiography findings in these patients showed fragmentation of the thrombus suggesting thrombus breakdown as an additional effect of mechanical chest compressions. No patients exhibited any life-threatening device-related complications. CONCLUSION Continuous chest compression with an automatic mechanical device is feasible, safe, and might improve outcomes after in-hospital-resuscitation of PEA. Patients with PE may benefit from effective continuous chest compression, probably due to thrombus fragmentation and increased pulmonary artery blood flow.

The iron-regulatory peptide hepcidin is upregulated in the ischemic and in the remote myocardium after myocardial infarction

Recent evidence suggests that iron metabolism contributes to the ischemic damage after myocardial infarction. Hepcidin, a recently discovered peptide hormone, regulates iron uptake and metabolism, protecting the body from iron overload. In this study we analyzed the regulation of hepcidin in the heart and blood of rats after myocardial infarction. To induce a myocardial infarction in the rats, left anterior descending coronary artery ligation was performed. After 1-24h, biopsies from the ischemic and the non-ischemic myocardium were taken. In these biopsies, the mRNA levels and the protein expression of hepcidin were analyzed by quantitative RT-PCR and immunoblot analysis, respectively. In parallel, the serum levels of prohepcidin were measured by ELISA. Six hours after myocardial infarction, the hepcidin mRNA expression was temporally upregulated in the ischemic and in the non-ischemic myocardium. The upregulation was specific for hepcidin, since other iron-related genes (hemojuvelin, IREG-1) remained unchanged. Furthermore, the alteration of the hepcidin protein expression in the ischemic area was connected to the level of hepcidin in the serum of the infarcted rats, where hepcidin also raised up. Angiotensin receptor blockade with candesartan did not influence the mRNA regulation of hepcidin. Together, these data show a particular upregulation of the iron-regulatory peptide hepcidin in the ischemic and the non-ischemic myocardium after myocardial infarction. It is speculated that upregulation of hepcidin may reduce iron toxicity and thus infarct size expansion in an infarcted heart.

Apoptosis at a distance: remote activation of caspase-3 occurs early after myocardial infarction.

AbstractObjective: After an acute myocardial infarction, the viable myocardium remote from the infarct zone is subjected to ventricular remodeling. Besides hypertrophy, processes of apoptosis may contribute to these remodeling processes. Reports on apoptosis in this area have been doubted because they were mainly based on in-situ nick-end DNA labeling (TUNEL) measurements, with questionable specifity. Moreover, the time course of initiation of these processes has not been characterized. Therefore the goals of this study were to (1) reliably determine if in the remote area of the infarcted heart apoptosis may be initiated using highly specific biochemical markers and (2) evaluate the time course of such an activation. Methods: A well-defined model, regional myocardial infarction induced by ligation of the left anterior coronary artery in rats in vivo, was used. Heart and lung wet weights, the left ventricular end-diastolic pressure (LVEDP), and the serum level of the atrial natriuretic propeptide (proANP) were determined from 1 day up to 4 weeks as indicators of developing heart failure. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, the activation of caspase-3, the bcl-2/bax ratio (Western blot analysis), and the DNA laddering (LM-PCR) were determined. Results: Although heart- and lung weights did not increase before 1 week after infarction, proANP levels were elevated already 1 day after myocardial infarction suggesting early sub-clinical heart failure. The activity of caspase-3 increased significantly to 160± 20% compared to sham operated controls as early as 1 day after ligation and remained elevated over the entire time course. In parallel, the bcl-2/bax ratio shifted toward the pro-apoptotic bax. Moreover, these clear and specific biochemical indicators of apoptosis in the remote area of the infarcted heart were paralleled by the fragmentation of genomic DNA. Conclusion: These data demonstrate that apoptotic markers are activated in the surviving zone of the heart remote from the infarct area as early as 1 day after myocardial infarction with persistence for up to 4 weeks. This activation coincides with early markers of heart failure. The exact regulation of this apoptotic process remains to be elucidated.

Regulation of the isozymes of protein kinase c in the surviving rat myocardium after myocardial infarction: Distinct modulation for PKC-α and for PKC-δ

Objective The goal of this study was to clarify the regulation of the isozymes of protein kinase C (PKC) in the process of remodeling after myocardial infarction. Methods An in vivo model of regional myocardial infarction induced by ligation of the left anterior coronary artery in rats was used. Hemodynamic parameters and the heart and lung weights were determined 1 week and 1, 2 and 3 months after operation. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, PKC activity (ELISA) and the expression of its major isozymes, PKC-α, PKC-δ and PKC-ε (Westernblot analysis) were determined. Results As early as one week after myocardial infarction, heart weight and left ventricular enddiastolic pressures were significantly increased. Lung weights increased after 2 – 3 months, indicating progressive pulmonary congestion. The activity of PKC was significantly increased about 1.8-fold after 1 week, decreasing progressively in the later time course. Whereas the expression of PKC-ε did not change, PKC-α was increased after 1 month (157 %) and then returned to baseline values. In contrast, PKC-δ expression was significantly augmented after 2 and 3 months of myocardial infarction (187 %). Conclusions These data demonstrate for the first time that in the remodeling heart after myocardial infarction, a subtype-selective regulation of the PKC isozymes occurs: The upregulation of PKC-α coincides with the development of hypertrophy, whereas the extensive upregulation of PKC-δ outlasts the process of developing hypertrophy and persists in the failing heart. The trigger mechanisms for this newly characterized process remains to be elucidated.