Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. METHODS: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. RESULTS: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. CONCLUSIONS: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Contemporary in-hospital and long-term prognosis of patients with acute ST-elevation myocardial infarction depending on renal function: a retrospective analysis.

BACKGROUND: Cardiovascular disease is often associated with chronic kidney disease (CKD), resulting in an increased risk for poor outcome. We sought to determine short-term mortality and overall survival in ST-elevation myocardial infarction (STEMI) patients with different stages of CKD. METHODS: In our retrospective cohort study with health insurance claims data of the Allgemeine Ortskrankenkasse (AOK), anonymized data of all STEMI patients hospitalized between 2010 and 2017 were analyzed regarding presence and severity of concomitant CKD. RESULTS: A total of 175,187 patients had an index-hospitalisation for STEMI (without CKD: 78.6% patients, CKD stage 1: 0.8%, CKD stage 2: 4.8%, CKD stage 3: 11.7%, CKD stage 4: 2.8%, CKD stage 5: 0.7%, CKD stage 5d: 0.6%). Patients with CKD were older and had more co-morbidities than patients without CKD. With increasing CKD severity, patients received less revascularization therapies (91.2%, 85.9%, 87.0%, 81.8%, 71.7%, 76.9% and 78.6% respectively, p < 0.001). After 1 year, guideline-recommended medications were prescribed less frequently in advanced CKD (83.4%, 79.3%, 81.5%, 74.7%, 65.0%, 59.4% and 53.7%, respectively, p < 0.001). CKD stages 4, 5 and 5d as well as chronic limb threatening ischemia (CLTI) were associated with decreased overall survival [CKD stage 4: hazard ratio (HR) 1.72; 95% CI 1.66-1.78; CKD stage 5: HR 2.55; 95% CI 2.37-2.73; CKD stage 5d: 5.64; 95% CI 5.42-5.86; CLTI: 2.06; 95% CI 1.98-2.13; all p < 0.001]. CONCLUSIONS: CKD is a frequent co-morbidity in patients with STEMI and is associated with a worse prognosis especially in advanced stages. Guideline-recommended therapies in patients with STEMI and CKD are still underused.

Sex-related differences in treatment and outcome of chronic limb-threatening ischaemia: a real-world cohort.

AIMS: The prevalence of chronic limb-threatening ischaemia (CLTI) is increasing and available data often derive from cohorts with various selection criteria. In the present study, we included CLTI patients and studied sex-related differences in their risk profile, vascular procedures, and long-term outcome. METHODS AND RESULTS: We analysed 199 953 unselected patients of the largest public health insurance in Germany (AOK: Local healthcare funds), hospitalized between 2010 and 2017 for a main diagnosis of CLTI. A baseline period of 2 years before index hospitalization to assess comorbidities and previous procedures, and a follow-up period until 2018 were included. Female CLTI patients were older (median 81.4 vs. 73.8 years in males; P < 0.001) and more often diagnosed with hypertension, atrial fibrillation, chronic heart failure, and chronic kidney disease. Male patients suffered more frequently from diabetes mellitus, dyslipidaemia, smoking, cerebrovascular disease, and chronic coronary syndrome (all P < 0.001). Within hospitalized CLTI patients, females represent the minority (43% vs. 57%; P < 0.001) and during index hospitalization, women underwent less frequently diagnostic angiographies (67 vs. 70%) and revascularization procedures (61 vs. 65%; both P < 0.001). Moreover, women received less frequently guideline-recommended drugs like statins (35 vs. 43%) and antithrombotic therapy (48 vs. 53%; both P < 0.001) at baseline. Interestingly, after including age and comorbidities in a Cox regression analysis, female sex was associated with increased overall-survival (OS) [hazard ratio (HR) 0.95; 95% confidence interval (CI) 0.94-0.96] and amputation-free survival (AFS) (HR 0.84; 95% CI 0.83-0.85; both P < 0.001). CONCLUSION: Female patients with CLTI were older, underwent less often vascular procedures, and received less frequently guideline-recommended medication. Nevertheless, female sex was independently associated with better OS and AFS during follow-up.

[Sex Disparities in Treatment and Outcome of Patients with Lower Extremity Arterial Disease: A Secondary Data Analysis]. / Geschlechtsspezifische Unterschiede in der Versorgung und dem Outcome von pAVK Patienten ­ Eine Sekundärdatenanalyse.

AIM OF THE STUDY: The aim of our study was to analyse sex-specific differences in diagnosis and treatment of patients with lower extremity artery disease (LEAD) at Rutherford stage (RF) 1-3, based on secondary data. Furthermore, we focussed on the influence of the biological sex on short- and long-term outcome. METHODS: The GenderVasc project is carried out in cooperation with the AOK Research Institute (WIdO). As data basis, anonymized routine data from all insured patients of the AOK were used. All patients hospitalized due to a main diagnosis of LEAD at RF 1-3 were included and in addition to the multisectoral cross-sectional analysis, longitudinal analysis (follow-up of up to 10 years) of the health claims data was performed and evaluated. RESULTS: Our secondary data analysis of 42,197 patients with intermittent claudication (IC, LEAD at RF 1-3) showed that male patients were more often hospitalized due to LEAD, while women were older at time-point of index hospitalisation (female: 72.6 vs. male: 66.4 years). Fewer vascular procedures (diagnostic angiography and revascularisation) were carried out in females. Moreover, the prescription of guideline-recommended medications (statins and antithrombotic therapy) was lower in women compared to men. Multivariable Cox regression showed, after adjusting for age, cardiovascular risk profile and performed vascular procedure, that female sex was protective with respect to overall survival and progression of LEAD (progress to chronic limb-threatening ischemia or ischemic amputation). CONCLUSION: In Germany, female LEAD patients were older and less likely to receive guideline-recommended therapy, while female sex is protective in terms of overall survival and progression of LEAD. The extent to which increased age or the presence of other comorbidities influence the decision for or against a vascular procedure can only be assumed from a secondary data analysis. Furthermore, the prescription of drugs in multimorbid patients is challenging and the compliance of the patients with prescribed medication intake is not part of our analysis. Nevertheless, targeted analysis, as in the GenderVasc project, are urgently needed to identify and describe differences in the medical care between the sexes.

Impact of Guideline-Directed Drug Therapy after ST-Elevation Myocardial Infarction on Outcome in Young Patients-Age and Sex-Specific Factors.

Background: Specifically young women are at risk for a poor outcome after ST-elevation myocardial infarction (STEMI). We aimed to investigate sex- and age-specific differences in outcome and associate these results with adherence to a guideline-directed optimal medical therapy (OMT). Methods: Administrative insurance data (≈26 million insured) were screened for patients aged 18-60 years with STEMI. Patient demographics, details on in-hospital treatment, adherence to OMT and its effect on mortality were assessed. Adherence to OMT was analyzed using multistate models and an association of those with death was fitted using multivariable Cox regression models with time-dependent co-variables. Results: Overall, 59,401 patients (19.3% women), median age 52 (interquartile range 48, 56) presented with STEMI. Female sex was associated with a poor outcome early after STEMI (90-day mortality: odds ratio 1.22, 95% confidence interval (CI) 1.12-1.32, p < 0.001). Overall survival was reduced in women compared to same-aged men. The ten-year survival rate was 19.7% (18.1-21.2%) versus 19.6% (18.9-20.4%) in men (p < 0.001). Although long-term drug adherence was low, its intake was associated with a better outcome. Specifically younger women showed a markedly lower mortality when on OMT (hazard ratio (HR) 0.22 (95% CI 0.19-0.26) versus HR 0.31 (95% CI 0.28-0.33) in men, pint < 0.001). Conclusions: Specifically young women were at risk for a poor outcome in the early phase after STEMI. Although long-term adherence to OMT was low, it was generally associated with a lower mortality, specifically in women. Our findings emphasize on early and long-term preventive measures in all patients after STEMI.

Uncoupled eNOS annihilates neuregulin-1ß-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction.

Myocardial infarct size can be limited by pharmacological postconditioning (pPC) with cardioprotective agents. Cardioprotective effects of neuregulin-1ß (NRG) via activation of protein kinase B (Akt) and downstream pathways like endothelial nitric oxide synthase (eNOS) have been postulated based on results from cell culture experiments. The purpose of this study was to investigate if eNOS may be involved in pPC with NRG. NRG application in an ex vivo mouse model (C57Bl6) of ischemia-reperfusion injury was analyzed. Unexpectedly, the infarct size increased when NRG was infused starting 5 min prior to reperfusion, even though protective Akt and GSK3ß phosphorylation were enhanced. In eNOS deficient mice, however, NRG significantly reduced the infarct size. Co-infusion of NRG and L-arginine (Arg) lead to a reduction in infarct size in wild type animals. Electron paramagnetic resonance measurements revealed that NRG treatment prior to reperfusion leads to an enhanced release of reactive oxygen species compared to controls and this effect is blunted by co-infusion of Arg. This study documents the cardioprotective mechanisms of NRG signaling to be mediated by GSK3ß inactivation. This is the first study to show that this protection fails in situations with dysfunctional eNOS. In eNOS deficient mice NRG exerts its protective effect via the GSK3ß pathway, suggesting that the eNOS can limit cardioprotection. As dysfunctional eNOS has been described in cardiovascular risk factors like diabetes, hypertension, and hypercholesterolemia these findings can help to explain lack of postconditioning performance in models of cardiovascular co-morbidities.

Survival of Patients with Acute Coronary Syndrome and Hematologic Malignancies-A Real-World Analysis.

BACKGROUND: The impact of the encounter between coronary heart disease (CHD) and cancer, and in particular hematologic malignancies (HM), remains poorly understood. OBJECTIVE: The aim of this analysis was to clarify how HM affects the prognosis of acute coronary syndrome (ACS). We analyzed German health insurance data from 11 regional Ortskrankenkassen (AOK) of patients hospitalized for ACS between January 2010 and December 2018, matched by age, sex and all comorbidities for short- and long-term survival and major adverse cardiac events (MACE). RESULTS: Of 439,716 patients with ACS, 2104 (0.5%) also had an HM. Myelodysplastic/myeloproliferative disorders (27.7%), lymphocytic leukemias (24.8%), and multiple myeloma (22.4%) predominated. These patients were about 6 years older (78 vs. 72 years *). They had an ST-segment elevation myocardial infarction (STEMI, 18.2 vs. 34.9% *) less often and more often had a non-STEMI (NSTEMI, 81.8 vs. 65.1% *). With the exception of dyslipidemia, these patients had more concomitant and previous cardiovascular disease and a worse NYHA stage. They were less likely to undergo coronary angiography (65.3 vs. 71.6% *) and percutaneous coronary intervention (PCI, 44.3 vs. 52.0% *), although the number of bleeding events was not relevantly increased (p = 0.22). After adjustment for the patients' risk profile, the HM was associated with reduced long-term survival. However, this was not true for short-term survival. Here, there was no difference in the STEMI patients, * p < 0.001. CONCLUSION: Survival in ACS and HM is significantly lower, possibly due to the avoidance of PCI because of a perceived increased risk of bleeding.

Contemporary secondary prevention in survivors of ST-elevation myocardial infarction with and without chronic kidney disease: a retrospective analysis.

Background: Survivors of myocardial infarction have an elevated risk of long-term mortality. We sought to evaluate guideline-directed medical treatment and its impact on long-term mortality in survivors of ST-elevation myocardial infarction (STEMI) according to their chronic kidney disease (CKD) stage. Methods: Using German health insurance claims data, 157 663 hospitalized survivors of STEMI were identified. Regarding different CKD stages, we retrospectively analysed the filled prescriptions of platelet inhibitors (PAI)/oral anticoagulation, statins, beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor antagonists (ACE-I/AT1-A) and their association with long-term mortality. Results: Prescription rates for all four guideline-directed drugs were highest in patients without or with mild CKD and lowest in patients on dialysis. They dropped from 73.4% to 39.2% in patients without CKD and from 47.1% to 29% in patients on dialysis within the 5-year follow-up period. Mortality rates were dramatically increased in patients with CKD compared with patients without CKD (5-year mortality: no CKD, 16.7%; CKD stage 3, 47.1%; CKD stage 5d, 69.7%). Filled prescriptions of at least one drug class [one drug: hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.66-0.74; four drugs: HR 0.28, 95% CI 0.27-0.30; P < .001 for both] as well as the distinct drug classes (statins: HR 0.55, 95% CI 0.54-0.56; ACE-I/AT1-A: HR 0.68, 95% CI 0.67-0.70; beta-blocker: HR 0.87, 95% CI 0.85-0.90; PAI/oral anticoagulation: HR 0.97, 95% CI 0.95-1.00; all P < .05) improved long-term mortality. Conclusions: An improved long-term guideline-recommended drug therapy after STEMI regardless of renal impairment might lead to beneficial effects on long-term mortality.

Sex disparities in guideline-recommended therapies and outcomes after ST-elevation myocardial infarction in a contemporary nationwide cohort of patients over an eight-year period.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. METHODS: From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. RESULTS: Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p <0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00-1.04; p=0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p <0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50-0.55; men HR 0.48, 95% CI 0.47-0.50, pint = 0.014). CONCLUSIONS: In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival.

Coronary Artery Disease and Cancer: Treatment and Prognosis Regarding Gender Differences.

Cardiovascular disease and cancer remain the leading causes of hospitalization and mortality in high-income countries. Survival after myocardial infarction has improved but there is still a difference in clinical outcome, mortality, and developing heart failure to the disadvantage of women with myocardial infarction. Most major cardiology trials and registries have excluded patients with cancer. As a result, there is only very limited information on the effects of coronary artery disease in cancer patients. In particular, the outcomes in women with cancer and coronary artery disease and its management remain empiric. We reviewed studies of over 27 million patients with coronary artery disease and cancer. Our review focused on the most important types of cancer (breast, colon, lung, prostate) and hematological malignancies with particular attention to sex-specific differences in treatment and prognosis.

Acute and Long-Term Outcomes of ST-Elevation Myocardial Infarction in Cancer Patients, a 'Real World' Analysis with 175,000 Patients.

BACKGROUND: Acute myocardial infarction (AMI) and cancer are common and serious diseases. As the prognosis and treatment of both diseases has improved, more cancer patients will suffer an AMI. Unfortunately, data on these "double hit" patients is scarce. METHODS: From the largest public German health insurance, anonymized data of all patients with pre-existing cancer who were hospitalized due to ST-elevation MI (STEMI) between 2010 and 2017 were analyzed and followed-up until 2018. RESULTS: Of 175,262 STEMI patients, 27,213 had pre-existing cancer (15.5%). Most frequent were skin (24.9%), prostate (17.0%), colon (11.0%), breast (10.9%), urinary tract (10.6%), and lung cancer (5.2%). STEMI patients with malignancies were older and presented more often with coronary three-vessel disease, atrial arrhythmias, chronic kidney disease, chronic heart failure, cerebrovascular and peripheral artery disease (PAD, each p < 0.001). They showed more often previous AMI, percutaneous coronary interventions (PCI), cardiac surgery, and stroke (all p < 0.001). Acute PCIs were applied between 2 and 6% less frequently compared to those without cancer. In-hospital adverse events occurred more frequently in cancer. Eight-year survival was 57.3% (95% CI 57.0-57.7%) without cancer and ranged between 41.2% and 19.2% in distinct cancer types. Multivariable Cox regression for all-cause mortality found, e.g., lung cancer (HR 2.04), PAD stage 4-6 (HR 1.78), metastasis (HR 1.72), and previous stroke (HR 1.44) to have the strongest impact (all p < 0.001). CONCLUSION: In this large "real world" data, prognosis after STEMI in cancer patients was markedly reduced but differed widely between cancer types. Of note, no withholding of interventional treatments in cancer patients could be observed.

Safety and efficacy of cryoballoon ablation for the treatment of atrial fibrillation in elderly patients.

BACKGROUND: Catheter ablation (CA) is an established therapy for treatment of atrial fibrillation (AF). However, data about AF ablation using the cryoballoon (CB) in the elderly population are sparse. The aim of this single center retrospective study is to evaluate the safety and efficacy of CB ablation in patients ≥ 75 years compared to patients < 75 years. METHODS AND RESULTS: Fifty-five consecutive patients aged ≥ 75 years (elderly group) were compared with 183 patients aged < 75 years (control group). All patients underwent pulmonary vein isolation (PVI) using the second-generation CB. The mean age in the elderly group was 78 ± 2.8 years and 60.8 ± 9.5 in the control group (p < 0.001). During 11.8 ± 5.4 months of follow-up, single procedure success rate for the elderly and the control group was 72.8 and 76%, respectively (p = 0.37). During redo ablation (n = 40), low-voltage areas in the LA were more frequently observed in elderly patients compared to the control group [1.0 (IQR 0-2.0) segments vs 2.0 (IQR 2.0-3.0) segments, respectively, p = 0.03]. The most common complication was transient phrenic nerve palsy, which only occurred in patients < 75 years (0 vs 7, p = 0.33). No severe complication such as procedure-related deaths, atrio-esophageal fistula, or cerebrovascular embolic events occurred. CONCLUSIONS: Our data strengthen the value of CB ablation for the treatment of AF as an effective and safe procedure in elderly patients, with similar success and complication rates when compared with a younger population.

Mechanism, underlying substrate and predictors of atrial tachycardia following atrial fibrillation ablation using the second-generation cryoballoon.

BACKGROUND: Data regarding atrial tachycardia (AT) following second-generation cryoballoon ablation (CBA) of atrial fibrillation (AF) are limited. AIM: To describe the incidence, mechanisms, and clinical predictors of ATs following CBA. METHODS AND RESULTS: In this retrospective single-center study 238 patients undergoing CBA for treatment of paroxysmal (91/238; 38.2%) or persistent AF were analyzed. During a mean follow-up of 11.9 ± 5.5 months recurrence of AF occurred in 49/238 patients (20.6%) and AT in 27/238 (11.3%). Twenty-six patients with AT and 14 with AF only underwent a redo ablation. The prevailing mechanism of AT was macroreentry [typical atrial flutter (AFL) (n = 10), left atrial macroreentry (n = 14), focal left-AT (n = 2)]. Non-cavotricuspid-isthmus-dependent macroreentry right-AT was mapped and ablated in 3 patients after initial AFL ablation. In a multivariate regression model, persistent type of AF (HR = 3.3; CI = 1.2-9.4), cardiomyopathy (HR = 3.5; CI = 1.5-8.4), treatment with beta-blockers (HR = 0.3; CI = 0.1-0.6), and pulmonary vein-abnormality (HR = 4.6; CI = 2.1-10.4) were independent predictors of AT. Substrate analysis revealed a significantly higher number of low voltage areas in the left atrium in patients with left-AT in comparison to patients with AF recurrence only (2.0; IQR=2.0-4.0 vs. 0.5; IQR = 0.0-2.25; p = 0.005). CONCLUSION: In this study, AT after CBA occurred in 11.3% of patients with macroreentry being the prevalent mechanism. All patients with left-AT presented with low voltage areas in the left atrium, suggesting a more progressive underlying fibrotic disease in these patients.

Biventricular Pacing Going Along with Acute Hemodynamic Response in a Patient with Huge Anterior Wall Aneurysm - Importance of Pacing Viable Myocardium.

BACKGROUND Response to cardiac resynchronization therapy (CRT) is variable among patients. Extensive scar tissue burden has been characterized as a negative predictor of significant response. Whereas mid-term and long-term response has been thoroughly investigated in randomized clinical trials; however, little is known about acute hemodynamic effects of biventricular pacing. CASE REPORT We report a case of an elderly female patient with severe ischemic cardiomyopathy and a large anterior wall aneurysm, who received right ventricular and biventricular pacing during ablation of incessant pleomorphic ventricular tachycardia. During the procedure, biventricular pacing was associated with a 20% acute increase in systolic blood pressure compared to right ventricular pacing, although there was no acute or long-term effect on left ventricular function. CONCLUSIONS The acute hemodynamic effect of CRT in our patient suggests an effect of CRT even in patients with negative predictors of CRT response such as severe ischemic cardiomyopathy with a large aneurysm. Although no marked increase in left ventricular function might be observed, the acute effect of CRT might contribute to stabilization of heart failure in these patients.

In situ postconditioning with neuregulin-1ß is mediated by a PI3K/Akt-dependent pathway.

BACKGROUND: The myocardial infarct size can be reduced by pharmacological postconditioning using cardioprotective agents. Neuregulin-1ß is a potential candidate, but previous studies in an isolated heart model of ischemia and reperfusion displayed controversial results. An in situ model of ischemia/reperfusion was used to clarify whether the remote application of neuregulin-1ß can reduce the reperfusion injury. A second aim was to evaluate, if the effects are specific for reperfused tissue or if this is a general antiapoptotic effect. In addition, the contributing molecular mechanisms were investigated. METHODS: In an open chest model, mouse hearts were subjected to a regional ischemia (45-minute) using ligature of the left anterior descending artery. Neuregulin-1ß (80 ng/kg) was given using an intraperitoneal bolus injection 5 minutes before reopening of the ligature followed by a 30-minute reperfusion. RESULTS: Remote application of recombinant neuregulin-1ß protected the heart from reperfusion injury without influencing hemodynamics. This beneficial effect specifically targets reperfusion injury. In contrast, nonreperfused needle trauma was not reduced by neuregulin-1ß when applied remotely. Pharmacological blocking experiments and enzyme activation analysis using Western blot analysis revealed a crucial involvement of the antiapoptotic reperfusion injury salvage kinase cascade. In contrast, contribution of the survivor activating factor enhancement pathways to this early cardioprotection was not observed. CONCLUSIONS: Remote application of neuregulin-1ß protects hearts from early reperfusion injury by activation of the reperfusion injury salvage kinase pathway without relevant effects on intracardiac pressures in myocardial infarction. Besides its potential pharmacological application, neuregulin-1ß might act as an endogenously produced mediator in remote postconditioning.

Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy.

OBJECTIVE: Recent studies in breast cancer patients and Trastuzumab therapy (Herceptin) showed a development of a toxic cardiomyopathy as a severe complication. The aim of this study was to discover early changes in cardiac function and morphology. METHODS: We studied 42 female patients with Her-2/-neu over-expression in breast cancer by echocardiography before, 3, and 6 months after start of the adjuvant Herceptin therapy. All values were mean value ± standard deviation. RESULTS: After 3 or 6 months of a trastuzumab therapy we discovered significant increases in the diastolic and systolic left ventricle volume indices (LV-DVI 32.4 ± 8.5 vs. 38.5 ± 8.7 vs. 40.3 ± 10.3 ml/m², p < 0.001 and LV-SVI 12.6 ± 4.0 vs. 15.7 ± 4.7 vs. 17.2 ± 6.8 ml/m², p < 0.001), an increase of the end-diastolic and end-systolic LV diameter (LVEDD 46.8 ± 4.2 vs. 48.0 ± 4.7 vs. 49.7 ± 4.5 ml/m², p < 0.01; LVESD 28.3 ± 4.2 vs. 31.0 ± 4.7 vs. 32.3 ± 4.9 mm, p < 0.001), a reduced systolic ventricle function determined by the tissue Doppler imaging (TDI) velocity (9.2 ± 2.5 vs. 8.0 ± 1,7 vs. 7.7 ± 1.5 cm/s, p < 0.001), fractional shortening (39,6 ± 7.5 vs. 35.4 ± 7.4 vs. 35.2 ± 7.0%, p < 0.01), and the LV-EF Simpson biplane [62.0 ± 5.1 vs. 60.1 ± 6.3 (p = ns) vs. 58.4 ± 7.9%, p < 0.01] compared to pretreatment values. There was also an increase of the left atrial volume index (21.4 ± 6.2 vs. 26.2 ± 7.9 vs. 29.7 ± 8.8 ml/m², p < 0.001), a decrease of the median TDI atrial velocities (11.9 ± 2.4 vs. 10.5 ± 2.8 vs. 10.1 ± 2.1 cm/s, p < 0.01), an increase of the peak early diastolic filling velocities (73.1 ± 15.4 vs. 83.1 ± 16.4 vs. 82.2 ± 19.4 cm/s, p < 0.05), and an increase of the median mitral valve insufficiency degree (0.64 ± 0.65 vs. 1.03 ± 0.76 vs. 1.11 ± 0.73°, p < 0.001). We could not detect a significant increase in diastolic dysfunction. Also right heart diameters and function did not change significantly. Most patients stayed in an asymptomatic stage of cardiac disease. CONCLUSION: The blockade of Her2/-neu receptors with trastuzumab in patients with breast cancer led to measurable alterations of left ventricular volume, left atrial volume, and systolic function as early as 3 months after start of treatment.

Chronic angiotensin II receptor blockade induces cardioprotection during ischemia by increased PKC-epsilon expression in the mouse heart.

INTRODUCTION: This study was performed to investigate the role of chronic pretreatment with angiotensin II type 1 receptor antagonists (ARB) and angiotensin converting enzyme inhibitors (ACE-I) in myocardial infarction (MI) and ischemic preconditioning (iPC). Little is known about molecular mechanisms of MI and iPC, especially about protein kinase C (PKC) isozyme levels induced by chronic pharmacologic pretreatment with ARB and ACE-I. To address one of the most important signal molecules in iPC, the PKC system was investigated in an ischemia/reperfusion model using isolated mouse hearts. METHODS: C57/BL6 mice were treated orally with candesartan cilexetil or ramipril for 2 weeks. Isolated perfused hearts were subjected to 60 minutes of left anterior descending occlusion and 30 minutes of reperfusion. IPC was performed by 3 cycles of 5 minutes of ischemia prior to the infarct ischemia. Infarct size was measured using the propidium iodide method, and PKC isoenzymes were detected by immunoblotting in the membrane and cytosolic fraction. RESULTS: In the control group, iPC reduced infarct size from 59.8 +/- 4.2% to 24.5 +/- 1.7%. ARB pretreatment itself reduced the infarct size significantly (38.1 +/- 3.0%) in hearts without iPC. This protection could neither be enhanced by additional iPC (40.3 +/- 3.4%) nor blocked by the AT2-receptor antagonist PD123.319 (40.7 +/- 3.7%). The ARB-induced cardio protection, however, was abolished by chelerythrine (5 micromol/L) (71.7 +/- 6.6%, n = 11, P < 0.001). Furthermore, PKC-epsilon (PKC-epsilon) was significantly increased in the particulate fraction of ARB-pretreated mice. On the contrary, chronic treatment with ACE-I completely blocked iPC (57.7 +/- 3.9%, n = 12, P < 0.001) without any effect on infarct size itself (51.5 +/- 3.0%, n = 12). PKC-epsilon expression was significantly reduced. CONCLUSION: Chronic AT1-receptor antagonism is capable of protecting the heart against myocardial infarction in a PKC-epsilon-dependent way. Furthermore, chronic treatment with ACE-I is suggested to have suppressing effects on iPC, possibly caused by reduced PKC-epsilon expression.

Perforation of aortic root as secondary complication after implantation of patent foramen ovale occlusion device in a 31-year-old woman.

Transesophageal echocardiography (TEE) revealed a 3-mm-large patent foramen ovale (PFO). No other reason for these neurological events could be found and the patient underwent percutaneous closure of the PFO with a CARDIA Star 03/30 device without periprocedural complications. Four weeks later, the patient underwent a routine control of device without any adverse clinical symptoms. Surprisingly, echocardiography revealed a perforation of the aortic root by an umbrella strut with a small shunt from the aortic root to the right atrium. Magnetic resonance imaging (MRI) confirmed the diagnosis of device malposition. Consecutively, the patient underwent minimal invasive surgery. After removal of the single perforating strut, the bleeding lesion was closed. The patient remained free of any additional complications during the postoperative course and up until now has had uneventful follow-ups.

Disruption of caveolin-1 leads to enhanced nitrosative stress and severe systolic and diastolic heart failure.

Although caveolin-1 is not expressed in cardiomyocytes, this protein is assumed to act as a key regulator in the development of cardiomyopathy. In view of recent discordant findings we aimed to elucidate the cardiac phenotype of independently generated caveolin-1 knockout mice (cav-1(-/-)) and to unveil causative mechanisms. Invasive hemodynamic measurements of cav-1(-/-) show a severely reduced systolic and diastolic heart function. Additionally, genetic ablation of caveolin-1 leads to a striking biventricular hypertrophy and to a sustained eNOS-hyperactivation yielding increased systemic NO levels. Furthermore, a diminished ATP content and reduced levels of cyclic AMP in hearts of knockout animals were measured. Taken together, these results indicate that genetic disruption of caveolin-1 is sufficient to induce a severe biventricular hypertrophy with signs of systolic and diastolic heart failure. Collectively, our findings suggest a causative role of a sustained nitrosative stress in the development of the pronounced cardiac impairment.