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BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) with multigrees, vessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown. METHODS: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year. RESULTS: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCL A primary end-point event occurred in 35 patients (8.590) in the immediate group as compared with 68 patients (16.396) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P< 0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.090) and 17 patients (4.1°6), respectively, in the immediate group and in 22 patients (5.3°6) and 39 patients (9.3°6), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event. CONCLUSIONS: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. [ABSTRACT FROM AUTHOR]

Objectives: To compare vascular closure devices (VCD) with manual compression (MC) in patients on chronic oral anticoagulation (OAC) who undergo diagnostic coronary angiography in terms of vascular access-site complications., Methods: This is a subanalysis of 604 patients that had undergone transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either VCDs (intravascular FemoSeal VCD or extravascular EXOSEAL VCD) or MC within the large scale, randomized ISAR-CLOSURE trial. Primary endpoint was the composite of access-site-related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat MC., Results: Vascular access-site complications were similar in patients assigned to VCDs compared to MC (8.2% vs 10.6%; P=.33). There was no interaction of treatment effect and OAC (P interaction = 0.59). Rates of pseudoaneurysms were lower with VCDs (0.8% vs 3.2%; P=.02). Time to hemostasis was significantly shortened with VCDs compared to MC (1 [IQR 0.5-2.0] min vs 12 [IQR 10-15] min; P<.001). There was no difference regarding repeat MC in both groups (VCD 1.5% vs MC 0.5%; P=.23). Time to hemostasis (0.5 [0.2-1.0] min, vs 2.0 [1.75-2.0] min; P<.001) and closure device failure (3.7% vs 17.2%; P<.001) were lower with the intravascular VCD, compared with the extravascular VCD., Conclusions: In patients on chronic OAC undergoing transfemoral diagnostic coronary angiography, the use of VCDs was comparable to MC regarding the primary combined endpoint of vascular access-site related complications. VCDs reduced the occurrence of pseudoaneurysms and time to hemostasis.

Introduction: Transradial access (TRA) has become the primary route for coronary angiography (CAG) and percutaneous coronary interventions (PCI). Recently a new puncture site more distally in the area of the anatomical snuffbox has been described. With this multicenter registry, we wish to demonstrate the feasibility and safety of the distal radial access (dRA)., Methods: Between December 2018 and May 2019 all patients with a planned CAG or PCI via dRA in three cardiology centers in Germany were entered into this registry. Procedural data, puncture success, crossover rate and complications were registered. Proximal and distal radial artery patency were examined by ultrasound within 48 h., Results: A total of 327 patients were enrolled (mean age: 69 ± 12 years, 69% male gender, 49% PCI), in 5 cases bilateral distal puncture was performed. Puncture success, defined as completed sheath placement was high (N = 316/332, 95%) and the crossover rate was low (27/332, 8%). The rate of proximal radial artery occlusion after 1-48 h was low (2/332 1%), the rate of occlusion at the distal puncture site was also very low (3/332, 1%). Major complications were not encountered., Conclusion: Coronary angiography and interventions via the distal transradial access in the area of the anatomical snuffbox can be performed with a high rate of success and safety. This data suggests a reduced rate of radial artery occlusion compared to previously reported data after cannulation via the standard forearm radial artery puncture site. Randomized studies are needed to further investigate these results., Trial Registration: This study was registered in the German registry for clinical trials: DRKS00017110, retrospectively on 07.May 2019.

Background: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain., Methods: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding., Results: A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46)., Conclusions: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: The value of vascular closure devices (VCD) in women undergoing transfemoral catheterization has not been sufficiently investigated., Methods and Results: This is a sex-specific analysis of 1395 women enrolled in a large-scale, randomized, multicenter trial, in which patients undergoing transfemoral diagnostic coronary angiography were randomly assigned in a 1:1:1 ratio to arteriotomy closure with an intravascular VCD, extravascular VCD, or manual compression (MC). Primary objective was to assess the safety and efficacy of 2 different VCD compared with MC regarding vascular access-site complications at 30 days. A secondary comparison was between 2 different types of contemporary VCD. Overall, women were at higher risk for vascular access-site complications compared with men (9.0% versus 6.4%; P=0.002). Vascular access-site complications were comparable in women assigned to VCD and MC (8.6% versus 9.8%; P=0.451). There was no interaction of treatment effect and sex ( P interaction =0.970). Time to hemostasis was significantly shortened with VCD compared with MC (1 [interquartile range, 0.5-2.0] minutes) versus 11 [interquartile range, 10-15] minutes; P<0.001); however, more women with VCD required repeat MC (2.4% versus 0.6%; P=0.018). The use of the intravascular compared with the extravascular VCD was associated with a numerical reduction in vascular access-site complications (6.6% versus 10.7%; P=0.027) and significant reductions in time to hemostasis and VCD failure., Conclusions: In women undergoing diagnostic coronary angiography via the common femoral artery, VCD and MC provided comparable safety, while time to hemostasis was reduced with VCD., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01389375.

Objectives: To assess the safety and efficacy of arteriotomy closure with the intravascular FemoSeal vascular closure device (VCD; St. Jude Medical) compared to manual compression in patients undergoing diagnostic cardiac catheterization via the common femoral artery., Background: There is limited evidence on the performance of individual contemporary VCDs compared to manual compression., Methods: This is a subanalysis of 3018 patients who underwent transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either the intravascular FemoSeal VCD or manual compression within the investigator-initiated, large-scale, randomized, multicenter, open-label ISAR-CLOSURE trial. Primary endpoint was the composite of access-site related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat manual compression., Results: Vascular access-site complications were lower in patients assigned to the FemoSeal VCD compared to manual compression (6.0% vs 7.9%; P=.04), driven by a lower incidence of hematomas in the FemoSeal group (4.3% vs 6.8%; P<.01). Pseudoaneurysm rates were comparable in both groups (1.5% vs 1.5%; P=.88). Time to hemostasis was significantly shortened with the FemoSeal VCD compared to manual compression (0.5 min [IQR, 0.2-1.0 min] vs 10 min [IQR, 10-15 min]; P<.001). However, repeat manual compression was increased with the FemoSeal VCD (1.5% vs 0.7%; P=.03)., Conclusion: In patients undergoing transfemoral diagnostic coronary angiography, the use of the FemoSeal VCD is associated with shortened time to hemostasis and a reduction in vascular access-site complications driven by fewer hematomas when compared to manual compression.

Importance: The role of vascular closure devices (VCD) for the achievement of hemostasis in patients undergoing transfemoral coronary angiography remains controversial., Objective: To compare outcomes with the use of 2 hemostasis strategies after diagnostic coronary angiography performed via transfemoral access-a VCD-based strategy with 2 types of devices, an intravascular device and an extravascular device, vs standard manual compression. The primary hypothesis to be tested was that femoral hemostasis achieved through VCD is noninferior to manual compression in terms of vascular access-site complications. A secondary objective was the comparison of the 2 types of VCD., Design, Setting, and Participants: Randomized, large-scale, multicenter, open-label clinical trial. We enrolled 4524 patients undergoing coronary angiography with a 6 French sheath via the common femoral artery from April 2011 through May 2014 in 4 centers in Germany. Last 30-day follow-up was performed in July 2014., Interventions: After angiography of the access site, patients were randomized to hemostasis with an intravascular VCD, extravascular VCD, or manual compression in a 1:1:1 ratio., Main Outcomes and Measures: Primary end point: the composite of access site-related vascular complications at 30 days after randomization with a 2% noninferiority margin. Secondary end points: time to hemostasis, repeat manual compression, and VCD failure. An α-level of .025 was chosen for primary and secondary comparisons., Results: Of the 4524 enrolled patients, 3015 were randomly assigned to a VCD group (1509 received intravascular VCD and 1506 received extravascular VCD) and 1509 patients were randomly assigned to the manual compression group. Before hospital discharge, duplex sonography of the access site was performed in 4231 (94%) patients. The primary end point was observed in 208 patients (6.9%) assigned to receive a VCD and 119 patients (7.9%) assigned to manual compression (difference, -1.0% [1-sided 97.5% CI, 0.7%]; P for noninferiority<.001). Time to hemostasis was significantly shorter in patients with VCD (1 minute [interquartile range {IQR}, 0.5-2.0]), vs manual compression (10 minutes [IQR, 10-15]; P < .001). Time to hemostasis was significantly shorter among patients with intravascular VCD (0.5 minute [IQR, 0.2-1.0]), vs extravascular VCD (2.0 minutes [IQR, 1.0-2.0]; P <.001) and closure device failure was also significantly lower among those with intravascular vs extravascular VCD (80 patients [5.3%], vs 184 patients [12.2%]; P < .001)., Conclusions and Relevance: In patients undergoing transfemoral coronary angiography, VCDs were noninferior to manual compression in terms of vascular access-site complications and reduced time to hemostasis., Trial Registration: clinicaltrials.gov Identifier: NCT01389375.

Background: Regular student evaluations at the Technical University Munich indicate the necessity for improvement of the clinical examination course. The aim of this study was to examine if targeted measures to restructure and improve a clinical examination course session lead to a higher level of student satisfaction as well as better self-assessment of the acquired techniques of clinical examination., Methods: At three medical departments of the Technical University Munich during the 2010 summer semester, the quantitative results of 49 student evaluations (ratings 1-6, German scholastic grading system) of the clinical examination course were compared for a course before and a course after structured measures for improvement. These measures included structured teaching instructions, handouts and additional material from the Internet., Results: 47 evaluations were completed before and 34 evaluations after the measures for improvement. The measures named above led to a significant improvement of the evaluative ratings in the following areas: short introduction to the topic of each clinical examination course (from 2.4±1.2 to1.7±1.0; p=0.0020) and to basic measures of hygiene (from 3.8±1.9 to 2.5±1.8; p=0.004), structured demonstration of each clinical examination step (from 2.9±1.5 to 1.8±1.0; p=0.001), sufficient practice of each clinical examination step (from 3.1±1.8 to 2.2±1.4; p=0.030) structured feedback on each clinical examination step (from 3.0±1.4 to 2.3±1.0; p=0.0070), use of handouts (from 5.2±1.4 to 1.8±1.4; p<0.001), advice on additional learning material (from 5.0±1.4 to 3.4±2.0; p<0.001), general learning experience (from 2.4±0.9 to 1.9±0.8; p=0.017), and self-assessment of the acquired techniques of clinical examination (from 3.5±1.3 to 2.5±1.1; p<0.01)., Conclusion: Structured changes led to significant improvement in the evaluative ratings of a clinical examination course session concerning preparation of the tutors, structure of the course, and confidence in performing physical examinations.

Background: Post-implantation therapies to optimize cardiac resynchronization therapy (CRT) focus on adjustments of the atrio-ventricular (AV) delay and ventricular-to-ventricular (VV) interval. However, there is little consensus on how to achieve best resynchronization with these parameters. The aim of this study was to examine a novel combination of doppler echocardiography (DE) and three-dimensional echocardiography (3DE) for individualized optimization of device based AV delays and VV intervals compared to empiric programming., Methods: 25 recipients of CRT (male: 56%, mean age: 67 years) were included in this study. Ejection fraction (EF), the primary outcome parameter, and left ventricular (LV) dimensions were evaluated by 3DE before CRT (baseline), after AV delay optimization while pacing the ventricles simultaneously (empiric VV interval programming) and after individualized VV interval optimization. For AV delay optimization aortic velocity time integral (AoVTI) was examined in eight different AV delays, and the AV delay with the highest AoVTI was programmed. For individualized VV interval optimization 3DE full-volume datasets of the left ventricle were obtained and analyzed to derive a systolic dyssynchrony index (SDI), calculated from the dispersion of time to minimal regional volume for all 16 LV segments. Consecutively, SDI was evaluated in six different VV intervals (including LV or right ventricular preactivation), and the VV interval with the lowest SDI was programmed (individualized optimization)., Results: EF increased from baseline 23±7% to 30±8 (p<0.001) after AV delay optimization and to 32±8% (p<0.05) after individualized optimization with an associated decrease of end-systolic volume from a baseline of 138±60 ml to 115±42 ml (p<0.001). Moreover, individualized optimization significantly reduced SDI from a baseline of 14.3±5.5% to 6.1±2.6% (p<0.001)., Conclusions: Compared with empiric programming of biventricular pacemakers, individualized echocardiographic optimization with the integration of 3-dimensional indices into the optimization protocol acutely improved LV systolic function and decreased ESV and can be used to select the optimal AV delay and VV interval in CRT.

The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10(-8) M (30 µg/l), 6 · 10(-7) M (300 µg/l) or 2-chloro-N(6)-cyclopentyladenosine (CCPA) 10(-6) M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/-87 pmol/g vs. 173+/-18 pmol/g, p<0.01). Capadenoson led to a concentration-dependent decrease of the stimulation-induced NE release in SHR (S2/S1  =  0.90 ± 0.08 with capadenoson 6 · 10(-8) M, 0.54 ± 0.02 with 6 · 10(-7) M), but not in Wistar hearts (S2/S1  =  1.05 ± 0.12 with 6 · 10(-8) M, 1.03 ± 0.09 with 6 · 10(-7) M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35)S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/-2% A(1)-receptor stimulation). These results suggest that partial adenosine A(1)-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.

Background: Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier I(Ks) current., Methods: We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes., Results: Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a “ventricular,” “atrial,” or “nodal” phenotype, as evidenced by the expression of cell-type–specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in “ventricular” and “atrial” cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q–KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype., Conclusions: We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.)

Objectives: The aim of this study was to test whether the left ventricular assist device (LVAD) Impella LP2.5 (Abiomed Europe GmbH, Aachen, Germany) provides superior hemodynamic support compared with the intra-aortic balloon pump (IABP)., Background: Cardiogenic shock caused by left ventricular failure is associated with high mortality in patients with acute myocardial infarction (AMI). An LVAD may help to bridge patients to recovery from left ventricular failure., Methods: In a prospective, randomized study, 26 patients with cardiogenic shock were studied. The primary end point was the change of the cardiac index (CI) from baseline to 30 min after implantation. Secondary end points included lactic acidosis, hemolysis, and mortality after 30 days., Results: In 25 patients the allocated device (n = 13 IABP, n = 12 Impella LP2.5) could be safely placed. One patient died before implantation. The CI after 30 min of support was significantly increased in patients with the Impella LP2.5 compared with patients with IABP (Impella: DeltaCI = 0.49 +/- 0.46 l/min/m(2); IABP: DeltaCI = 0.11 +/- 0.31 l/min/m(2); p = 0.02). Overall 30-day mortality was 46% in both groups., Conclusions: In patients presenting with cardiogenic shock caused by AMI, the use of a percutaneously placed LVAD (Impella LP 2.5) is feasible and safe, and provides superior hemodynamic support compared with standard treatment using an intra-aortic balloon pump. (Efficacy Study of LV Assist Device to Treat Patients With Cardiogenic Shock [ISAR-SHOCK]; NCT00417378).

Apoptosis--programmed cell death--has been implicated in a variety of cardiac diseases, including myocardial infarction and chronic heart failure. This study was conducted to quantify the amount of apoptotic markers in human end-stage heart failure and to correlate the results to clinical parameters of heart failure. Myocardial samples from 44 patients with end-stage heart failure and 5 controls were collected at the time of heart transplantation. Lysates of tissue samples were analysed for cleavage of alpha actin, alpha actinin, troponin T, tropomyosin, essential myosin light chain-1 (MLC-1v), and gelsolin. We observed cleavage of alpha actin, and alpha actinin. Troponin I, tropomyosin, and MLC-1v were not detectably cleaved. The amount of active caspase-3 was low in all samples (1.10+/-0.1 ng/ml). The same applied for DNA histone fragments (0.61+/-0.04). In patients with acutely decompensated heart failure we observed a striking increase in caspase-3 activity, but not DNA fragmentation. When calculated for the entire group there was no correlation between caspase-3 activity, DNA fragmentation and haemodynamic or echocardiographic variables. Relevant increases in apoptosis were only observed in patients with acute decompensated heart failure.

Platelet aggregation and secretion play a crucial role in acute coronary syndromes. In Galpha(q) knock-out mice (Galpha(q)(-/-)) platelet function is eliminated in terms of aggregation and secretion of cytokines. We investigated whether restricted platelet aggregation and secretion reduces myocardial infarct size in vivo. Thirty minute regional myocardial ischemia was followed by 24 h reperfusion (I/R) in vivo. Infarct size was determined by counterstaining. Left ventricular function was measured by ultrasound. Infarct size to area at risk ratio was significantly smaller in Galpha(q)(-/-) mice (5.6+/-1.6%) compared to wild-type (WT) mice (27.2+/-3.0%, p<0.01). Fractional shortening was improved in Galpha(q)(-/-) mice compared to WT (42.2+/-1.4% versus 30.5+/-1.4%, respectively, p<0.01). WT mice, transplanted with Galpha(q)(-/-) bone marrow showed a significant reduction in infarct size compared to control (7.8+/-2.2% versus 18.4+/-2.7%, respectively, p<0.01). Platelets of Galpha(q)(-/-) mice had an impaired aggregation and secretion phenotype. In the in vivo model of ischemia and reperfusion, beyond impaired platelet aggregation, platelet secretion plays an additional role in myocardial infarct extension. Blocking platelet aggregation in combination with secretion might be a promising supplementary therapeutic strategy in acute myocardial infarction.

Myocardial infarction and subsequent reperfusion lead to the activation of apoptosis, and the final destruction of the cell. The aim of this study was to show that broad-scale inhibition of caspases, the main executioners of apoptosis, improves functional outcome after ischemia and reperfusion in an in vivo model. Twenty male Wistar rats were directly injected with an adenovirus, encoding the baculoviral protein p35. Nineteen rats served as controls, and were injected with a virus only encoding green fluorescent protein (GFP). After 3 days, 12 animals were used for Langendorff perfusion experiments, the other 27 animals were submitted to in vivo infarction. Myocardial infarction was induced by ligation of the left anterior descending artery (LAD) for 30 min, and reperfusion for 24 h. Echocardiographic and hemodynamic measurements were made 24 h after infarction. Infarct size was assessed in all animals histologically. In both, in vivo and Langendorff perfused hearts, myocardial infarct size was significantly reduced in the p35 group (for in vivo experiments: 0.11+/-0.03 vs 0.33+/-0.03 in the GFP group, p<0.01), as was the ratio of infarct size to area at risk (6 vs 17%, p<0.01). Left ventricular function was similar in both groups prior to infarction, but was significantly less compromised after infarction in the p35 group. The left ventricular systolic pressure after infarction was higher in the p35 group (107+/-5 vs 92+/-4 mmHg, p<0.05), as was the maximal rate of rise of left ventricular systolic pressure dp/dt (5,659+/-585 vs 4,634+/-256 mmHg s(-1), p<0.05). Adenoviral gene transfer of the caspase inhibitor p35 leads to a significant reduction of the myocardial infarct size after ischemia and reperfusion. Hemodynamic variables were significantly improved by treatment with p35. Cardiac restricted inhibition of apoptosis seems to be a promising approach for ameliorating the effects of ischemia and reperfusion.

Programmed cell death involves the activation of caspase proteases that can mediate the cleavage of vital cytoskeletal proteins. We have recently reported that, in failing cardiac myocytes, caspase-3 activation is associated with a reduction in contractile performance. In this study we used a modified yeast two-hybrid system to screen for caspase-3 interacting proteins of the cardiac cytoskeleton. We identified ventricular essential myosin light chain (vMLC1) as a target for caspase-3. By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. Adenoviral gene transfer of the caspase inhibitor p35 in vivo prevented caspase-3 activation and vMLC1 cleavage, with positive impact on contractility. These data suggest that direct cleavage of vMLC1 by activated caspase-3 may contribute to depression of myocyte function by altering cross-bridge interaction between myosin and actin molecules. Therefore, activation of apoptotic pathways in the heart may lead to contractile dysfunction before cell death.