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Aims Despite its high incidence and mortality risk, there is no evidence-based treatment for non-ischaemic cardiogenic shock (CS). The aim of this study was to evaluate the use of mechanical circulatory support (MCS) for non-ischaemic CS treatment.Methods and results In this multicentre, international, retrospective study, data from 890 patients with non-ischaemic CS, defined as CS due to severe de-novo or acute-on-chronic heart failure with no need for urgent revascularization, treated with or without active MCS, were collected. The association between active MCS use and the primary endpoint of 30-day mortality was assessed in a 1:1 propensity-matched cohort. MCS was used in 386 (43%) patients. Patients treated with MCS presented with more severe CS (37% vs. 23% deteriorating CS, 30% vs. 25% in extremis CS) and had a lower left ventricular ejection fraction at baseline (21% vs. 25%). After matching, 267 patients treated with MCS were compared with 267 patients treated without MCS. In the matched cohort, MCS use was associated with a lower 30-day mortality (hazard ratio 0.76, 95% confidence interval 0.59-0.97). This finding was consistent through all tested subgroups except when CS severity was considered, indicating risk reduction especially in patients with deteriorating CS. However, complications occurred more frequently in patients with MCS; e.g. severe bleeding (16.5% vs. 6.4%) and access-site related ischaemia (6.7% vs. 0%).Conclusion In patients with non-ischaemic CS, MCS use was associated with lower 30-day mortality as compared to medical therapy only, but also with more complications. Randomized trials are needed to validate these findings. [GRAPHICS] Open Access funding enabled and organized by Projekt DEAL. Conflict of interest: B.S. reports speaker fees from Abiomed and AstraZeneca, outside of the submitted work. B.N.B. reports honoraria from Siemens Healthineers, outside of the submitted work. S.B. reports grants and personal fees from Abbott Diagnostics, Bayer, Siemens, Thermo Fisher, grants from Singulex, personal fees from Abbott, AstraZeneca, Amgen, Medtronic, Pfizer, Roche, Siemens Diagnostics, Novartis, outside of the submitted work. D.E. reports speaker fees from Abiomed, Bayer, Daiichi Sankyo, outside of the submitted work. P.H. reports travel compensation from Abiomed, outside of the submitted work. P.K. reports research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK) and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. He is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783; unrelated to the submitted work). S.K. reports research support from Cytosorbents and Daiichi Sankyo. He also received lecture fees from Astra, Bard, Baxter, Biotest, Cytosorbents, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Philips and Zoll. He received consultant fees from Fresenius, Gilead, MSD and Pfizer, outside of the submitted work. P.L. reports speaker fees from AstraZeneca, Bayer, EdwardsLifesciences, Medtronic and Pfizer outside the submitted work. N.M. reports lecture fees Pfizer/Bristol-Myers Squibb and grant research from Getinge Global USA and Italfarmaco, outside of the submitted work. M.O. reports speaker honoraria from Abbott Medical, AstraZeneca, Abiomed, Bayer vital, Biotronik, Bristol-Myers Squibb, CytoSorbents, Daiichi Sankyo Deutschland, Edwards Lifesciences Services, Sedana Medical, outside of the submitted work. A.P. reports an unrestricted educational grant from Abbott Vascular, outside of the submitted work. T.R. reports speaker fees from AstraZeneca, Daiichy, Bayer, Novartis, Abiomed outside the submitted work. D.W. reports speaker fees from Abiomed, AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Novartis and Medtronic, outside of the submitted work. All other authors have nothing to disclose.

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score–matched cohort. Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63–0.98]; P =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site–related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

Die Prognose der Herzinsuffizienz hat sich in den letzten Jahren durch die Einfuhrung verschiedener neuer Therapien stetig verbessert, dennoch ist die 5‑Jahres-Mortalitat mit >50 % sowohl der systolischen auch der diastolischen Herzinsuffizienz immer noch sehr hoch. Mogliche Therapieoptionen sind die medikamentose Therapie, die Device-Therapie sowie die interventionelle Therapie der chronischen Herzinsuffizienz.

ObjectiveTo assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy.MethodsPRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist’s referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early.ResultsIn total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients’ adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation.ConclusionsPREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit.

The COVID-19 pandemic is placing a heavy burden on healthcare systems worldwide with the risk that acute cardiovascular diseases are treated too late. The present study aims to analyze patients with acute coronary syndrome in the current pandemic. A total of 966 patients (2019 n = 463, 2020 n = 503) can be evaluated. A comparison of patient care during and before the COVID-19 pandemic was made in terms of patient characteristics and pre- and in-hospital processes. Another aim is to show how many patients seek clinical care at a late stage of the disease. After Lockdown in Germany at week 12, 2020, there was a significant decrease in patients with an acute coronary syndrome (ACS), significant for STEMI cases in the first weeks after Lockdown (calendar week 13–16 2019 n = 43, 2020 n = 30; p = 0.02). The time from pain to first medical contact (time to FMC) is significantly extended during Lockdown, while internal clinical processes are unchanged. The rate of subacute myocardial infarction is numerically, but not significantly increased in calendar weeks 15, 2020 (p = 0.40) and 16 (p = 0,19). In addition, elderly patients avoid treatment for multifactorial reasons, and the longer overall pain to FMC may impact long-term mortality.

Background: The vascular access in transcatheter aortic valve replacement (TAVR) was initially dominated by a surgical approach. Meanwhile, percutaneous closure systems became a well-established alternative. The aim of this study was to compare the clinical outcome between the two approaches. Methods: In this retrospective study, we observed 787 patients undergoing a TAVR-Procedure between 2013 and 2019. Of those, 338 patients were treated with surgical access and 449 with the Perclose ProGlide™-System (Abbott, Chicago, IL, USA). According to the Bleeding Academic Research Consortium (BARC) and Valve Academic Research Consortium (VARC) criteria, the primary combined endpoints were defined. Results: Overall hospital mortality was 2.8% with no significant difference between surgical (3.8%) and percutaneous (2.2%) access (p = 0.182). Major vascular complications or bleeding defined as the primary combined endpoint was not significantly different in either group (Surgical group 5.3%, ProGlide group 5.1%, p = 0.899). In the ProGlide group, women with pre-existing peripheral artery disease (PAD) were significantly more often affected by a vascular complication (p = 0.001 for female sex and p = 0.03 for PAD). Conclusions: We were able to show that the use of both accesses is safe. However, the surgical access route should also be considered in case of peripheral artery disease.

Background Cardiogenic shock (CS) in patients (pts) with acute ST elevation myocardial infarction (STEMI) is the strongest predictor of hospital mortality. Radial in contrast to femoral access in STEMI pts might be associated with a lower mortality. However, little is known on radial access in CS pts. Methods We retrospectively analysed all STEMI pts between 2009 and 2015 who sufferend from CS and who were included into the ALKK PCI registry. Pts treated via a radial access were compared to those treated via a femoral access. Results Between 2009 and 2015 23796 STEMI pts were included in the registry. 1763 (7.4%) of pts were in CS. The proportion of radial access was 6.6%: in 2009 4.0% and in 2015 19.6%, p for trend Conclusions Radial access was only used in 6.6% of STEMI pts presenting in CS. However, a significant increase in the use of radial access was observed over time (2009: 4%, 2015 19.6%, p Funding Acknowledgement Type of funding source: None

Aims Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long‐time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)‐induced myocarditis. Methods and results SWR/J mice were infected with 5 × 104 plaque‐forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8‐fold (P

Background Determination of the Fractional Flow Reserve (FFR) has become part of routine clinical practice. Contemporary clinical use, consequences as well as complications in consecutive, large cohorts have not been thoroughly investigated. We report the results of the prospective Fractional Flow Reserve Fax Registry F (FR2) conducted in Germany. Purpose To systematically analyze indications, procedural parameters, complications and consequences of intracoronary pressure measurements in a large contemporary cohort. Methods Data of 2000 consecutive patients undergoing clinically indicated FFR, iFR or pd/pa measurements in 8 interventional centres in Germany were prospectively collected in a systematic fashion. Data included basic patient characteristics, procedural aspects of intracoronary pressure measurements, associated complications, visual stenosis degree, measurement results and treatment decisions. Results Mean patient age was 68±11 years, 73% of patients were male. Of all patients, 300 patients (15%) had an acute coronary syndrome (STEMI: 9; NSTEMI: 94; unstable angina: 197) and 1002 patients (50%) had undergone previous revascularization. A mean of 1.7±0.9 measurements were performed per patient, for which an average of 1.02 pressure wires were required (more than 1 wire in 64 patients). For all 3373 interrogated lesions, median stenosis degree was 60%. Vasodilator-free measurements were performed in 415/3373 cases (12%, iFR: 346; pd/pa: 69). For vasodilation, i.v. adenosine was used in 396 cases (13%), i.c. adenosine in 2628 cases (87%), and other drugs in 10 cases (0.3%). Measurement was performed before potential revascularization in 3232 cases (96%) and during or following PCI in 141 cases. In 2958 lesions analyzed by FFR, mean FFR was 0.87, with 588 FFR measurements ≤0.80 (19.8%). Median FFR values were higher for i.c than i.v. adenosine administration (0.88 vs. 0.84), but not significantly different after adjustment for stenosis degree. In 735 cases (20.2%), intracoronary pressure measurement was followed by revascularization measures, while in 2637 cases (79.8%), no revascularization or no further revascularization was performed. In 36 out of 117 stenoses visually estimated to be ≥90%, revascularization was deferred following pressure measurement (31%). In 75 out of 2958 lesions analyzed by FFR, revascularization was performed even though FFR was >0.80 (3%). Severe complications (vessel dissection or occlusion) occurred in 5 out of 2000 patients as a consequence of intracoronary pressure measurement, resulting in death of 1 patient. Conclusion In clinical practice, the majority of intracoronary pressure measurements are performed in stenoses of intermediate angiographic severity and revascularization is deferred in approximately 80% of lesions. Vasodilator-free measurements are infrequent and route of adenosine administration has no effect on results. Complication rate is low but not negligible. Acknowledgement/Funding Abbott Vascular

Background Veno-arterial extracorporeal membrane oxygenation therapy (VA-ECMO) is increasingly used for treatment of severe cardiogenic shock, although it causes an increase in left ventricular (LV) afterload and might therefore hamper myocardial recovery. Recently, the addition of catheter-based left ventricular assist device (cLVAD) on top of VA-ECMO has been used to unload the LV and to improve outcome measures. However, there is limited data on predictors of outcome in this high-risk population. Aim The aim of this study was to evaluate predictors of 30-day survival in a multicentre cohort of severe cardiogenic shock patients treated with cLVADon top of VA-ECMO. Material and methods We report on consecutive patients from six tertiary care centers being treated with cLVAD in addition to VA-ECMO for treatment of cardiogenic shock. The primary endpoint is 30-day all-cause mortality. To identify predictors of the primary endpoint, multivariate analysis using an “elastic net” variable selection algorithm was done after imputation of missing variables. Results A total of 220 patients treated with cLVAD on top of VA-ECMO were included in the analysis. Of these, 79.1% were male with a median age of 55.5 (25thpercentile 48.0, 75thpercentile 65.6) years. In 60.5% of the patients, acute myocardial infarction was the underlying cause of cardiogenic shock and in 44.6% VA-ECMO was used for refractory cardiac arrest (eCPR). In the multivariable analysis, the following baseline parameters were significantly associated with the primary endpoint: Age (odds ratio of 1.68 per standard deviation), duration of cardiopulmonary resuscitation (OR 2.08 per SD), lactate (OR 1.04 per SD) and time from onset of shock to VA-ECMO (OR 1.30 per SD). Conclusion and outlook In this large-scale multicentre analysis of severe cardiogenic shock patients treated with VA-ECMO plus additional cLVAD unloading, age, duration of cardiopulmonary resuscitation, lactate and time from onset of shock to VA-ECMO were significantly associated with 30-day all-cause mortality. To further investigate this topic, we will evaluate predictors of outcome in distinct patient populations such as acute myocardial infarction vs. acute heart failure and patients without vs. patients with prior cardiopulmonary association.

In der Abb. 1 des Beitrags wurden 2 Felder vertauscht. „Sinusrhythmus, Herzfrequenz ≥70 bmp“ folgt richtigerweise „Ivabradin“. „Sinusrhythmus, QRS-Intervall ≥130 msec“ folgt richtigerweise „Indikation fur CRT evaluieren“. Wir bitten Sie, die korrigierte Abb. 1 zu beachten und den Fehler zu …

Background: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. Methods: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. Results: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P =0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P P =0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results. Conclusions: In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03313687.

Ferdinand Vogt,1 Susanne Wicklein,2 Markus Gosch,2 Jürgen Jessl,3 Wolfgang Hitzl,4 Theodor Fischlein,1 Matthias Pauschinger,3 Steffen Pfeiffer,1 Dennis Eckner3 1Department of Cardiac Surgery, Paracelsus Medical University, Nuremberg, Germany; 2Department of Geriatric Medicine, Paracelsus Medical University, Nuremberg, Germany; 3Department of Cardiology, Paracelsus Medical University, Nuremberg, Germany; 4Research Office – Biostatistics, Paracelsus Medical University, Salzburg, Austria Background: Frailty is a geriatric syndrome that can influence mortality and functional recovery after treatment of severe aortic stenosis (AS). The integration of standardized geriatric assessment (GA) in clinical practice is limited by a lack of consensus on how to measure it. Objectives: This study aims to compare the incremental predictive value of different frailty scales to predict the outcomes following surgical aortic valve replacement, transcatheter aortic valve implantation, and conservative treatment of severe AS. Methods: A prospective cohort of 300 older adults with severe AS will be assembled after standard clinical examinations and a comprehensive GA, including 18 different tests and values. Primary outcome parameters are overall mortality, cardiovascular mortality, quality of life, and functionality. Secondary parameters are overall complications, cardiovascular complications, and costs. Results: Expected results will contribute to the growing body of evidence on frailty based on parameters that influence clinical and functional outcome in elderly patients independent of the method of treatment. The pre-procedural assessment is expected to be valuable in discriminating new post-procedural complications from simple exacerbations of pre-existing conditions. Therefore, a new frailty test which is simple and feasible for application in a clinical routine by most medical professionals, may help in identifying patients for whom further GA should be considered. Finally, such a frailty score could support heart teams to find the right treatment for patients suffering from AS. Conclusion: Comparison of different frailty scales has not only the goal of finding a predictive value of mortality but also to bring in a meaningful improvement for each individual patient and to avoid disability or fatal outcomes. Keywords: frailty, aortic valve, geriatric assessment, transcatheter aortic valve implantation, TAVI, aortic valve replacement, AVR

Aims Oesophagogastroduodenoscopy (OGD) after catheter ablation (CA) of atrial fibrillation (AF) revealed a high rate of procedure related oesophageal lesions. We hypothesized that magnetically guided CA with careful radiofrequency energy titration at the posterior left atrial (LA) wall limits the incidence of oesophageal tissue damage. Methods and results As a part of the prospective "Remote MAGNetic catheter Ablation for Atrial Fibrillation" (MAGNA-AF) registry, 251 out of 266 consecutive patients underwent OGD after magnetically guided single-CA for AF. All detected pathologies were analysed. Simultaneous pacing and ablation from the tip of the magnetically guided catheter was found to be a safe and feasible method for energy titration. Post-interventional OGD documented midoesophageal tissue damage in four (1.6%) patients. Although a thermal origin of these injuries must be discussed, none of them was located at the anterior oesophageal wall. Risk factors for midoesophageal lesions were female gender and concomitant acetylsalicylic acid (ASA) treatment. Mechanical lesions in 16 patients were attributed to periprocedural transoesophageal echocardiography (TOE). There was no atrio-oesophageal fistula (AOF). Five hundred and one incidental pathologies were found endoscopically, most frequent axial oesophageal herniation (71%), oesophagitis (22%), and gastritis (57%). Conclusion Magnetically guided CA for AF with careful energy titration at the posterior LA wall and no oesophageal temperature monitoring is not associated with an increased incidence of oesophageal thermal injury. The routine use of periprocedural TOE may cause a low rate of mechanical oesophageal lesions but reliably prevents major complications like transient ischaemic attack, stroke, or cardiac tamponade. An observed high prevalence of upper digestive system inflammation (63%) may further support the recommendation for a routine post-interventional treatment with a proton-pump-inhibitor.

Objective To assess risk factors for paravalvular leak (PVL) after transcatheter aortic valve implantation in a large single-center cohort, including measurement of aortic valve calcification using a reproducible method. Methods We retrospectively analyzed preoperative contrast-enhanced multidetector computed tomography scans of patients who underwent transcatheter aortic valve implantation in our center between 2009 and 2016. Calcium volume was calculated for each aortic cusp in the aortic valve, left ventricular outflow tract, and device landing zone. Results Overall, 539 patients were included in the study who had experience with 4 prothesis types (SapienXT [Edwards Lifesciences, Irvine, Calif] [n = 192], Sapien3 [Edwards Lifesciences] [n = 206], CoreValve EvolutR [Medtronic, Minneapolis, Minn] [n = 44], and Acurate [Symetis, Ecublens, Switzerland] [n = 97]). Median calcium volume in the device landing zone was 757 mm3, with no significant differences among the 4 prosthesis groups. None of the patients had severe PVL. The overall incidence of mild-to-moderate PVL was 15.8% (95% confidence interval [CI], 12.8%-19.1%). On multivariate logistic regression, device landing zone calcification (P = .00006; odds ratio for an increase of 100 mm3, 1.08; 95% CI, 1.04-1.13) and use of the CoreValve (P = .0028; odds ratio, 4.1; 95% CI, 1.6-10 with SapienXT as reference) prosthesis were found to be associated with mild or greater PVL. In contrast, degree of oversizing (P = .002; odds ratio, 0.97; 95% CI, 0.95-0.99), and use of Sapien3 (P = .00005; odds ratio, 0.23; 95% CI, 0.11-0.47 with SapienXT as reference) were associated with a lower incidence of mild or greater PVL. Conclusions Aortic calcification volume in the device landing zone is associated with residual PVL after transcatheter aortic valve implantation. When taking calcification into account, the balloon-expandable prosthesis Sapien3 seems to be associated with a lower incidence of PVL.

Objective: Postoperative thrombocytopenia after aortic valve replacement has been reported in the literature for many years, often associated with specific types of prosthetic valve models. Several...

Background— The prognostic significance of papillary muscle infarction (PapMI) on hard clinical outcomes has not been investigated in patients with reperfused ST-segment–elevation myocardial infarction. Noninvasive investigation by gadolinium-enhanced cardiac MRI enables the detection of PapMI with high spatial resolution. The aim of our study was (1) to assess the incidence, determinants, and clinical characteristics of PapMI in a large multicenter cohort of patients with ST-segment–elevation myocardial infarction and (2) to assess the prognostic significance of PapMI at 1-year follow-up. Methods and Results— We enrolled 738 patients with ST-segment–elevation myocardial infarction reperfused by primary angioplasty (P P P P =0.02). Patients with PapMI had a significantly higher mortality (8 [7.7%] versus 12 [1.9%]) and major adverse cardiac events (21 [20.2%] versus 31 [4.9%]) rate at 12-month follow-up ( P P Conclusions— The presence of PapMI is associated with decreased myocardial salvage, larger infarcts, and more pronounced reperfusion injury with subsequent significantly increased major adverse cardiac event rates. Consequently, our data underscore the importance of PapMI as a marker of poor outcome in patients with ST-segment–elevation myocardial infarction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00712101.

Objectives The aim of the AIDA STEMI (Abciximab i.v. Versus i.c. in ST-elevation Myocardial Infarction) cardiac magnetic resonance (CMR) substudy was to investigate potential benefits of intracoronary versus intravenous abciximab bolus administration on infarct size and reperfusion injury in ST-segment elevation myocardial infarction. Background The AIDA STEMI trial randomized 2,065 patients to intracoronary or intravenous abciximab and found similar rates of major adverse cardiac events at 90 days with significantly less congestive heart failure in the intracoronary abciximab group. CMR can directly visualize myocardial damage and reperfusion injury, thereby providing mechanistic and pathophysiological insights. Methods We enrolled 795 patients in the AIDA STEMI CMR substudy. CMR was completed within 1 week after ST-segment elevation myocardial infarction. Central core laboratory–masked analyses for quantified ventricular function, volumes, infarct size, microvascular obstruction, hemorrhage, and myocardial salvage were performed. Results The area at risk (p = 0.97) and final infarct size (16% [interquartile range: 9% to 25%] versus 17% [interquartile range: 8% to 25%], p = 0.52) did not differ significantly between the intracoronary and the intravenous abciximab groups. Consequently, the myocardial salvage index was similar (52 [interquartile range: 35 to 69] versus 50 [interquartile range: 29 to 69], p = 0.25). There were also no differences in microvascular obstruction (p = 0.19), intramyocardial hemorrhage (p = 0.19), or ejection fraction (p = 0.95) between both treatment groups. Patients in whom major adverse cardiac events occurred had significantly larger infarcts, less myocardial salvage, and more pronounced ventricular dysfunction. Conclusions This largest multicenter CMR study in ST-segment elevation myocardial infarction patients to date demonstrates no benefit of intracoronary versus intravenous abciximab administration on myocardial damage and/or reperfusion injury. Infarct size determined by CMR was significantly associated with major adverse cardiac events. (Abciximab i.v. Versus i.c. in ST-elevation Myocardial Infarction [AIDA STEMI]; NCT00712101 )

Recently, a new device for noninvasive assessment of central systolic blood pressure (cSBP) (BPro device with A-Pulse) was approved by the US Food and Drug Administration, but available data are limited. In 52 patients undergoing invasive elective cardiac evaluation, central hemodynamics were measured invasively. Immediately thereafter, radial artery waveforms were sampled by two noninvasive techniques, the BPro and, as a comparator, the SphygmoCor System. Then, central hemodynamics were measured invasively for a second time. The invasively recorded cSBP (137 ± 27 mm Hg) did not differ with both noninvasively assessed cSBP by BPro (136 ± 21 mm Hg, P = .627 vs invasive cSBP) and by SphygmoCor (136 ± 23 mm Hg, P=.694 vs invasive cSBP) and correlated highly between invasively recorded and both noninvasively assessed cSBP. However, using Bland-Altman plots, spreading of compared data of both devices can be found (BPro: 0.87 ± 13 mm Hg vs invasive cSBP; SphygmoCor: 0.77 ± 14 mm Hg vs invasive cSBP). There was an excellent correlation of both noninvasive devices for the calculation of cSBP (r=0.961, P

The innate antiviral response is mediated, at least in part, by Toll-like receptors (TLRs). TLR3 signaling is activated in response to viral infection, and the absence of TLR3 in mice significantly increases mortality after infection with enteroviruses that cause myocarditis and/or dilated cardiomyopathy. We screened TLR3 in patients diagnosed with enteroviral myocarditis/cardiomyopathy and identified a rare variant in one patient as well as a significantly increased occurrence of a common polymorphism compared with controls. Expression of either variant resulted in significantly reduced TLR3-mediated signaling after stimulation with synthetic double-stranded RNA. Furthermore, Coxsackievirus B3 infection of cell lines expressing mutated TLR3 abrogated activation of the type I interferon pathway, leading to increased viral replication. TLR3-mediated type I interferon signaling required cellular autophagy and was suppressed by 3-methyladenine and bafilomycin A1, by inhibitors of lysosomal proteolysis, and by reduced expression of Beclin 1, Atg5, or microtubule-associated protein 1 light chain 3beta (MAP1LC3beta). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3beta fusion protein refractory to RNA interference. These data suggest that individuals harboring these variants may have a blunted innate immune response to enteroviral infection, leading to reduced viral clearance and an increased risk of cardiac pathology.

Zusammenfassung {! Fragestellung:} In dieser Pilotstudie wurde der spontane Verlauf von Depressivitat und Angstlichkeit uber einen Zeitraum von eineinhalb Jahren bei Patienten mit koronarer Herzerkrankung erhoben. Weiterhin wurden das Teilnahmeinteresse an einer psychotherapeutischen Gruppenintervention und die Effektivitat dieser Intervention bei der Reduktion der Beschwerden in einer Subgruppe untersucht. {! Methode:} Erhebung von Depressivitat und Angstlichkeit (HADS) zu drei Zeitpunkten bei N = 58 Koronarpatienten (t1 nach einem, t2 nach 1,5 Jahren). Durchfuhrung einer halbjahrigen psychotherapeutischen Intervention bei neun Patienten und Vergleich mit einer unbehandelten Kontrollgruppe (N = 14). {! Ergebnis:} 79% der belasteten Patienten waren an der Teilnahme an einer psychotherapeutischen Gruppenintervention interessiert. Es zeigte sich eine hohe Stabilitat der psychischen Belastung ohne psychotherapeutische Behandlung. Die Intervention fuhrte zu einer signifikanten Reduktion der Beschwerden von im...

Background— An unequivocal diagnosis of myocarditis and cardiac virus persistence is based on histological, immunohistological, and molecular biological analyses of endomyocardial biopsies (EMBs). Biopsy-based diagnosis of myocarditis has become increasingly important because recent studies have demonstrated the beneficial effects of biopsy-based causal treatment strategies (immunosuppressive or antiviral). Because the risks of major complications caused by EMB procedures have not yet been well defined, we evaluated the incidence of major and minor complications of right ventricular EMB procedures in this retrospective and prospective single-center study. Methods and Results— With the use of a modified Cordis bioptome, 1919 patients underwent 2505 EMB procedures retrospectively over a 9-year period (January 1995 to December 2003), and 496 patients underwent 543 EMB procedures prospectively between January 2004 and December 2005. A total of 2415 patients had 3048 EMB procedures via the right femoral vein approach under biplane fluoroscopic control to evaluate unexplained left ventricular dysfunction (retrospective left ventricular ejection fraction, 49.8±18.8%; prospective, 48.8±19.7%) after exclusion of secondary causes. During each EMB procedure, an average of 8.2±0.8 EMBs were obtained retrospectively and 10.1±0.6 specimens prospectively for a total of 26 025 specimens. No patient died or required emergency cardiac surgery. Other major complications like cardiac tamponade requiring pericardiocentesis or complete atrioventricular block requiring permanent pacing were very rare: 0.12% in the retrospective study and 0% in the prospective study. Minor complications such as pericardial effusion, conduction abnormalities, or arrhythmias occurred in 0.20% of the EMB procedures in the retrospective study and 5.5% in the prospective study. Conclusions— The EMB procedure via the femoral vein approach under fluoroscopic guidance has a very low complication rate when performed by experienced operators.

Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cδ and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p < 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.

Background— Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results— Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. Conclusions— Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.

Cardiac autoantibodies play a pathogenic role in dilated cardiomyopathy (DCM). Removal of antibodies by immunoadsorption (IA) induces hemodynamic improvement in DCM patients. The present study investigated the effects of IA on myocardial gene expression of the intermediate cytoskeletal filament desmin, which is upregulated in heart failure. RNA was isolated from five explanted non-failing hearts and five explanted failing hearts of DCM patients, and myocardial gene expression of desmin was estimated by real-time polymerase chain reaction (PCR). In a case-control study in six DCM patients (LVEF

Background— Various conventional and tissue Doppler echocardiographic indexes were compared with pressure–volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF). Methods and Results— Diastolic dysfunction was confirmed by pressure–volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (τ, dP/dt min ), LV end-diastolic pressure, and LV end-diastolic pressure–volume relationship (stiffness, b [dP/dV], and stiffness constant, β) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, τ (E/A: r =−0.36, P =0.013; isovolumic relaxation time: r =0.31, P =0.040) and b (deceleration time: r =0.39, P =0.012) but not with β, in contrast to the tissue Doppler imaging indexes E’/A’ lateral ( r =−0.37, P =0.008) and E/E’ lateral ( r =0.53, P lateral , and E/E’ lateral , respectively. Conclusions— Of all echocardiographic parameters investigated, the LV filling index E/E’ lateral was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.

Objective Despite the success of antiproliferative therapies, restenosis remains a common problem after percutaneous transluminal coronary angioplasty (PTCA). Longer-term clinical results of brachytherapy (intracoronary radiation), the lack of long-term clinical results after implantation of drug eluting stents, and the occurrence of late thrombosis after both procedures leave room for skepticism. Neointimal proliferation is not substantially inhibited at late time points after brachytherapy, and late lumen loss with a “catch-up” proliferation can occur. We hypothesized that the transcription factors nuclear factor-{kappa}B (NF-κB) and activator protein-1 (AP-1) are involved in these processes. We addressed the role of these mediators in a porcine model of coronary restenosis. Methods Thirty-nine pigs underwent PTCA in two major coronary arteries. One of the two balloon-injured arteries was randomly assigned to receive immediate 20 Gy beta-irradiation (Brachy group) using a noncentered source train (90Sr/Y Beta-Cath, Novoste). Animals were sacrificed after 1 day, 14 days, or 28 days. Proliferating cells were labeled prior to euthanasia. Results At late time points, lumen area was significantly smaller and the inflammatory response was more pronounced in the Brachy group than in the PTCA group. These findings coincided with sustained activation of MMP-9 and transcription factors like NF-κB and AP-1. Initially, cell proliferation was reduced in the Brachy group; however, at late time points, differences between the two treatment groups were no longer significant. Conclusions Brachytherapy initially inhibits cell proliferation; however, cellular and molecular inflammatory processes (e.g. activation of NF−κB) are enhanced within the arterial wall. This proinflammatory side effect may be responsible for the observed delayed proliferation and the resulting lumen loss.

We investigated the effect of the angiotensin type 1 (AT-1) receptor antagonist, irbesartan, on matrix metalloproteinase (MMP) activity and cardiac cytokines in an animal model of diabetic cardiomyopathy. Diabetes was induced in 20 C57/bl6 mice by injection of streptozotocin (STZ). These animals were treated with irbesartan or placebo and were compared with nondiabetic controls. Left ventricular (LV) function was measured by pressure-volume loops with parameters for systolic function (end systolic elastance [Ees]) and diastolic function (cardiac stiffness) 8 weeks after STZ treatment. The cardiac protein content of interleukin (IL)1β and transforming growth factor (TGF)β1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemestry, and MMP-2 activity was measured by gelatin zymography. LV dysfunction was documented by impaired Ees and diastolic stiffness in STZ mice compared with controls. This was accompanied by increased TGFβ, IL1β, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1β, TGFβ, and cardiac fibrosis compared with untreated diabetic animals and normalized MMP activity. These findings present evidence that AT-1 receptor antagonists attenuate cardiac failure by decreasing cardiac inflammation and normalizing MMP activity, leading to normalized cardiac fibrosis in STZ-induced diabetic cardiomyopathy.

We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy.Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-alpha, IL6, IL1-beta, and TGF-beta1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining.Left ventricular dysfunction was documented by impaired ESPVR and EDPVR. Cardiac cytokine levels and cardiac fibrosis were increased in diabetic animals compared to controls. Treatment with the p38 inhibitor normalised cardiac cytokine levels and improved systolic function, but did not change cardiac fibrosis and diastolic dysfunction compared to placebo.Pharmacological inhibition of p38 MAPK prevents cardiac inflammation and attenuates left ventricular dysfunction in diabetic cardiomyopathy.

Coxsackie adenovirus receptor (CAR) is involved in immunological processes, and its soluble isoforms have antiviral effects on coxsackievirus B3 (CVB3) infection in vitro. We explored in this study the impact of CAR4/7, a soluble CAR isoform, on CVB3-induced myocarditis in BALB/c mice. BALB/c mice were treated daily with recombinant CAR4/7, beta-galactosidase (beta-Gal; as control protein) or buffer for 9 days. Half of each group was infected with CVB3 on day 3, and all mice were killed on day 9. Myocardial CVB3 titer, histology, and serology were analyzed. Treatment with CAR4/7 led to a significant reduction of myocardial CVB3 titer, whereas the application of beta-Gal had no detectable effect on the myocardial virus load. CAR4/7 application, however, resulted in increased myocardial inflammation and tissue damage in CVB3-infected hearts, whereas beta-Gal caused a degree of cardiac inflammation and injury similar to that in buffer-treated CVB3-infected control animals. CAR4/7 and beta-Gal treatment induced the production of antibodies against the respective antigens. CAR4/7-, but not beta-Gal-specific, virus-negative sera reacted against myocardial tissue and cellular membranous CAR, and significantly inhibited CVB3 infection in vitro. Thus, CAR4/7 suppressed CVB3 infection in vivo, supporting the concept of receptor analog in antiviral therapy. However, CAR4/7 treatment also leads to an aggravation of myocardial inflammation and injury most likely secondary to an autoimmune process.

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by impaired contractility and dilation of the ventricles. In a subset of DCM patients, classical inheritance patterns occur (familial DCM), which have led to the identification of specific genomic loci and gene defects causing monogenic DCM subtypes. In the majority of DCM patients, however, there is no evidence for a monogenic etiology of the disorder (sporadic DCM), and in the absence of other recognizable etiological factors, these cases were classified as "idiopathic". Recent research suggests that cardiotropic viruses are important environmental factors in the pathogenesis of "idiopathic" cases and that DCM commonly results from interactions between genetic and environmental factors, whereas "pure" genetic forms are rather rare. Regarding genetics, the clinical cardiomyopathic phenotype associated with single gene defects may be highly variable for unknown reasons. Furthermore, a novel class of genetic defects was identified recently which provide a molecular basis for abnormal reactions of cardiomyocytes to environmental stress. These defects are paradigms of specific molecular links between genome and environment during the pathogenesis of DCM. Regarding environmental factors, a recent molecular virological study based on myocardial biopsies in a large series of sporadic DCM patients has detected cardiac viral infections in the majority of patients, with a broad spectrum of virus species being involved. Apparently, DCM does not only occur as a late sequela of acute viral myocarditis, but also in patients without clinical history of cardiac viral disease. Cardiotropic viruses thus emerge as prevalent environmental factors which may cause or influence the course of DCM in a large fraction of cases. Synopsis of current data suggests that a comprehensive picture of DCM pathogenesis can only be drawn if both genetic and environmental pathogenetic factors are considered. The course of cardiac viral infections depends strongly on genetic host factors and may range from rapid and complete virus elimination or silencing without clinical symptoms, to rapidly progressive or fatal disease. Viruses interact not only with genetically heterogenous host systems of virus uptake, migration, and antiviral immunity, but, due to their prevalence in DCM hearts, are also likely to encounter multiple structural proteins of cardiac cells known to be defective in familial DCM. The combined knowledge on DCM-associated gene defects and viruses therefore suggests in-depth studies on genome-environment interactions in DCM pathogenesis which may underlie the high clinical variability observed both in monogenic and virus-associated DCM and have implications for the clinical management of DCM patients.

ObjectivesWe investigated the myocardial localization and expression of tissue factor (TF) and alternatively spliced human tissue factor (asHTF) in patients with dilated cardiomyopathy (DCM).BackgroundTissue factor is expressed in cardiac muscle and may play a role in maintaining myocardial structure.MethodsMyocardial biopsies were obtained from patients with a normal or mildly impaired ejection fraction (EF) (≥50%) and moderate to severely reduced EF (

Objectives The purpose of this study was to analyze cardiac tissue and blood for viral genomes using polymerase chain reaction (PCR) to define the common viral etiologies of myocarditis by age group. Background Enteroviruses are considered the most common cause of myocarditis at all ages. Diagnosis relies on viral cultures, serology, and cardiac histology, which lack sensitivity, as well as PCR. However, in many cases enteroviruses are not detected. Methods Cardiac samples were obtained for PCR analysis from patients with myocarditis (n = 624) and dilated cardiomyopathy (DCM) (n = 149). Patients were analyzed by age group, including neonates (n = 116), infants (n = 191), toddlers (n = 87), children (n = 110), adolescents (n = 92), and adults (n = 177). After nucleic acids had been extracted from an endomyocardial biopsy, an explant, or autopsy samples, PCR and reverse transcription PCR were performed to detect the genomic sequences of enterovirus, adenovirus, cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), parvovirus, respiratory syncytial virus (RSV), and influenza A virus. Results Viral genome was amplified (adenovirus = 142, enterovirus = 85, CMV = 18, parvovirus = 6, influenza A = 5, HSV = 5, EBV = 3, RSV = 1) from 239 (38%) of the 624 samples from myocarditis patients, including 26 patient samples in which dual infection was found. Virus was detected in 30 (20%) of 149 DCM patient samples; only adenovirus (n = 18) and enterovirus (n = 12) were detected. Conclusions Polymerase chain reaction identified adenovirus as the most common virus in the myocardium of children and adults with myocarditis and DCM. Although enteroviruses are also found in these patients, they appear to be a less common cause of myocarditis than adenovirus.

Background— Viral infections are important causes of myocarditis and may induce cardiac dysfunction and finally lead to dilated cardiomyopathy. We investigated whether interferon (IFN)-β therapy is safe and may achieve virus clearance and prevent deterioration of left ventricular (LV) function in patients with myocardial virus persistence. Methods and Results— In this phase II study, 22 consecutive patients with persistence of LV dysfunction (history of symptoms, 44±27 months) and polymerase chain reaction–proven enteroviral or adenoviral genomes were treated with 18×10 6 IU/week IFN-β (Beneferon) subcutaneously for 24 weeks. Histological and immunohistological analysis of endomyocardial biopsies was used to characterize myocardial inflammation. LV diameters and ejection fraction were assessed by echocardiography and angiography, respectively. During the treatment period, IFN-β was well tolerated by all patients. No patient deteriorated. Clearance of viral genomes was observed in 22 of 22 of patients after antiviral therapy. Virus clearance was paralleled by a significant decrease of LV end diastolic and end systolic diameters, decreasing from 59.7±11.1 to 56.5±10.0 mm ( P P P Conclusions— A 6 months, IFN-β treatment was safe in patients with myocardial enteroviral or adenoviral persistence and LV dysfunction and resulted in elimination of viral genomes (22 of 22 patients) and improved LV function (15 of 22 patients).