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Background In the REPAIR-AMI trial, intracoronary infusion of bone marrow-derived cells (BMCs) was associated with a significantly greater recovery of contractile function in patients with acute myocardial infarction (AMI) at 4-month follow-up than placebo infusion. The current analysis investigates clinical outcome and predictors of event-free survival at 5 years. Methods and results In the multicentre, placebo-controlled, double-blind REPAIR-AMI trial, 204 patients received intracoronary infusion of BMCs ( n = 101) or placebo ( n = 103) into the infarct vessel 3–7 days following successful percutaneous coronary intervention. Fifteen patients died in the placebo group compared with seven patients in the BMC group ( P = 0.08). Nine placebo-treated patients and five BMC-treated patients required rehospitalization for chronic heart failure ( P = 0.23). The combined endpoint cardiac/cardiovascular/unknown death or rehospitalisation for heart failure was more frequent in the placebo compared with the BMC group (18 vs. 10 events; P = 0.10). Univariate predictors of adverse outcomes were age, the CADILLAC risk score, aldosterone antagonist and diuretic treatment, changes in left ventricular ejection fraction, left ventricular end-systolic volume, and N-terminal pro-Brain Natriuretic Peptide (all P < 0.01) at 4 months in the entire cohort and in the placebo group. In contrast, in the BMC group, only the basal ( P = 0.02) and the stromal cell-derived factor-1-induced ( P = 0.05) migratory capacity of the administered BMC were associated with improved clinical outcome. Conclusion In patients of the REPAIR-AMI trial, established clinical parameters are associated with adverse outcome at 5 years exclusively in the placebo group, whereas the migratory capacity of the administered BMC determines event-free survival in the BMC-treated patients. These data disclose a potency–effect relationship between cell therapy and long-term outcome in patients with AMI.

Drug-eluting stents (DES) reduce the rate of in-stent restenosis (ISR) and target vessel revascularization significantly when compared with bare metal stents (BMS). Their beneficial effects have been demonstrated in patients with acute myocardial infarction also, but the use of DES in the latter population seems to be still limited in clinical practice. From January 2006 to December 2011, 25,424 patients with ST-elevation myocardial infarction were enrolled in the German ALKK PCI-registry. In 5,467 patients (21.5 %), a DES was implanted in the culprit segment, in 16,911 patients (66.5 %) a BMS, and 2,959 patients (11.6 %) received neither DES nor BMS. The rates of DES for typical subgroups were 31.7 % in patients with diabetes, 36.6 % in unprotected left main stenosis, 32.4 % in ostial lesions, 32.0 % for a stent length >15 mm, 26.2 % for a stent diameter ≤3 mm, and 58.5 % for ISR. There was a wide range in the use of DES between the different ALKK hospitals with a minimum of 2.3 % and a maximum of 58.3 % for the total study period (median 22.0 %, quartiles 14.6 and 37.5 %). Despite convincing data for the use of DES in patients with STEMI, there is still an underuse of DES in this clinical setting in Germany. This is particularly worrying for the subgroups of patients and lesions with a high risk of restenosis. Further efforts are needed to reduce the skepticism about DES and to improve guideline adherent treatment.

Objective To evaluate the acute performance of a novolimus-eluting bioresorbable scaffold (BRS) with different strut thickness (DESolve system 150 and 100) using optical coherence tomography (OCT) in terms of appropriate scaffold deployment. Background Outcome after BRS implantation seen in registries and meta-analyses continue to show a higher rate of scaffold thrombosis than those reported with DES. Thus, second scaffold generations with lower strut thickness might have potential advantages in terms of flow disturbance. However, whether mechanical properties are comparable has to be evaluated. Methods and results Fifty-seven patients undergoing OCT-guided scaffold implantation were enrolled consecutively in this retrospective study. The final pullback after DESolve 150 (n=42) and DESolve 100 (n=15) were compared. The following indices were calculated: mean and minimum area, residual area stenosis, incomplete strut apposition, tissue prolapse, eccentricity and symmetry indexes, strut fracture, and edge dissection. Most patients suffered a multi vessel disease. Maximum pre-dilatation balloon inflation pressure was 13.5±3.2 vs 14.5±2.5atm. OCT analysis showed a minimal lumen area of 6.1±1.9 vs 5.2±1.6mm 2 , p=0.06. Mean residual area stenosis was 15.3% vs 21.3, p=0.22. Mean eccentricity index did not differ significantly (0.8±0.1 vs 0.6±0.1, p=0.61). Prolapse area was 4.5±8.8 vs 5.6±9.8mm 2 . Conclusion OCT showed similar post-procedural scaffold geometry and outcome indicating that both BRS may be implanted with good acute performance. However, the trend towards a smaller MLA and a higher percentage of RAS suggest a decreased radial strength for the 100μm BRS. The attempt to reduce strut thickness should not result in loss of radial strength. Condensed abstract Rates of scaffold thrombosis after bioresorbable scaffold (BRS) implantation are reported to be higher than after metallic stent (DES) implantation. Thus, second scaffold generations with lower strut thickness might have potential advantages in terms of flow disturbance. We aimed to evaluate the acute performance of a novolimus-eluting BRS with different strut thickness (DESolve system 150 and 100) using optical coherence tomography (OCT) in terms of appropriate scaffold deployment. OCT showed similar post-procedural scaffold geometry and outcome indicating that both BRS may be implanted with good acute performance. However, the data suggest a decreased radial strength for the 100μm BRS.

To evaluate safety and efficacy of the everolimus-eluting bioresorbable scaffold (BVS) in patients with ST-segment elevation myocardial infarction (STEMI).According to the current guidelines, drug-eluting stents are the treatment of choice in patients with STEMI. BVS represents a new technology capable to restore the native vessel vasomotion and potentially avoiding long-term limitations such as stent thrombosis.From October 2012 to May 2013, patients with evidence of STEMI eligible for BVS implantation were included in this study. Exclusion criteria were not defined.A total of 25 patients, respectively 31 lesions, were treated. Procedural success was achieved in 97%. Two major adverse cardiac events occurred during hospitalization and follow-up: one patient with cardiogenic shock at the index procedure subsequently died. One patient suffered from instable angina with need for interventional revascularization of a previously untreated vessel. One target vessel failure as a consequence of an intra-procedural dissection was seen. However, no target lesion failure was noted. During 132.7 ± 68.7 days of follow-up none of the patients died.Our findings suggest that implantation of BVS in STEMI patients is feasible in this small cohort of highly selected patients. Further evaluation in randomized-controlled trials is needed.

Background To date, no published data are available regarding long-term follow-up of new generation DES implanted in coronary artery bypass graft (CABG) lesions. Objectives To assess the long-term clinical outcome of patients receiving the new generation Biolimus A9-coated drug-eluting stent (DES) with biodegradable polymer in saphenous vein grafts (SVG). Methods Three thousand sixty-seven patients were included in the NOBORI 2 registry: 71 patients with a total of 117 lesions received at least 1 biolimus A9 DES in SVG lesions and 2,959 patients received percutaneous coronary intervention in other lesions. Clinical follow-up was performed at 1, 6, and 12 months, and annually up to 3 years. Results Compared to the non-CABG group, patients with CABG lesions were older (P

Background: Atrial fibrillation (AF) is a frequent arrhythmia associated with an adverse prognostic value in patients with ACS. Risk stratification as well as diagnosis of ACS is strongly supported by biomarkers. High sensitivity CRP (hs-CRP) is known to be elevated in patients presenting with ACS as well as with AF.Methods: In total, 2034 consecutive patients with an ACS were analysed. The incidence of AF in the setting of ACS, the prognostic value of hs-CRP and the clinical outcome within 6 months were subject of the study. Death after 6 months was considered as primary endpoint. Results: The frequency of AF among patients admitted with suspected ACS was 124 (6.1%). During 6-month follow-up the mortality rate among patients with AF was significantly higher (20 [16.1%] vs 133 [6.9%]; log-rank 13.72; p 0.001) compared to patients without AF. Cox regression analysis revealed an increased risk for ACS patients with AF with an adjusted HR of 2.63 (95% CI 1.48 - 3.78; p 0.001). Patients with AF showed significant higher levels of hs-CRP than patients without AF (6.01mg/dl IQR [1.7 - 17.8] vs 3.3mg/dl IQR [1.37 - 9.83]; p = 0.003). By the use of multivariate Cox regression analysis, risk of mortality was higher when AF patients had higher concentrations of hs-CRP (HR 1.076; 95% CI 1.02 - 1.13; p = 0.002).Conclusions: AF is a strong and independent indicator for increased mortality in patients presenting with ACS. hs-CRP predicts mortality in AF patients and should be considered for risk stratification in clinical routine.

AIMS We aimed to demonstrate the feasibility and investigate the safety of a novel, self-expanding trans-catheter heart valve in a selected patient population with severe aortic stenosis. METHODS AND RESULTS Between January and September 2013, a total of 21 patients with symptomatic severe aortic stenosis were eligible for transcatheter aortic valve implantation (TAVI) with the self-expanding NVT Allegra bioprosthesis (New Valve Technology, Hechingen, Germany) at two cardiovascular centres. Patients were elderly (age 83.8±4 years), predominantly female (95.2%), and all were considered to be at prohibitive risk for surgical aortic valve replacement (logistic EuroSCORE 30.4±11%). Procedural and device success was achieved in 95.2% and 85.7%, respectively. Echocardiographic assessment at discharge showed favourable haemodynamic results with a reduction of the mean transvalvular aortic gradient from 48.0±21 mmHg to 8.9±3 mmHg. In the majority of patients (90.5%), none or trace aortic regurgitation was recorded. Permanent pacemaker implantation was required in 23.8% of patients within the first 30 days of follow-up. Apart from one procedural death, no other serious adverse events were observed during the periprocedural period. TAVI with the NVT Allegra system was highly effective in alleviating symptoms and reducing NYHA functional class at 30-day follow-up. CONCLUSIONS The first-in-human experience with the NVT Allegra transcatheter heart valve prosthesis was associated with a high rate of procedural success. Furthermore, the NVT Allegra bioprosthesis was able to achieve favourable haemodynamic results and effectively alleviate symptoms at 30-day follow-up. The larger, multicentre NAUTILUS study will provide further information on the safety and efficacy of this novel, second-generation transcatheter aortic bioprosthesis.

Hypercholesterolaemia is a major cardiovascular risk factor. A healthy diet and a healthy lifestyle reduces cardiovascular risk. 'Functional foods' supplemented with phytosterols are recommended for the management of hypercholesterolaemia and have become a widely used non-prescription approach to lower plasma cholesterol levels. Two billion euros are spent world-wide each year on various functional foods, which have regulator-approved health claims for the management of elevated cholesterol levels. While international societies, such as the European Atherosclerosis Society or the National Heart Foundation in Australia, still advise phytosterols as an additional dietary option in the management of hypercholesterolaemia, recently released guidelines such as those from the National Institute of Health and Clinical Excellence in the United Kingdom are more critical of food supplementation with phytosterols and draw attention to significant safety issues. This review challenges whether an intervention with phytosterol supplements is beneficial. We summarize the current evidence from genetic diseases, genetic association studies, clinical trial data and data from animal studies.This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Introduction and objectives The implantation of bioresorbable scaffolds (BRS) is an emerging technique used in percutaneous coronary interventions. Their application has been extended to more complex lesions, although evidence is only available for simple lesions. The present study evaluated scaffold implantation in long lesions, focusing on overlapping scaffolds. Methods We retrospectively analyzed all consecutive patients eligible for stenting with everolimus-eluting poly-L-lactic acid-based BRS with a minimum total scaffold length of 28 mm, irrespective of the number of BRS used. The main target parameters were major adverse cardiac events, comprising cardiac death, any myocardial infarction, and target lesion revascularization, and target lesion failure, including cardiac death, target vessel myocardial infarction, and target lesion revascularization. A subgroup analysis included patients with overlapping BRS. Results A total of 250 patients were included. The reason for angiography was stable coronary artery disease in 36.4% (91 of 250), an acute coronary syndrome in 61.6% (154 of 250), and other reasons in 2.0% (5 of 250). Procedural success was achieved in 97.8% (267 of 273) of the lesions. During follow-up, the 12-month rates of major adverse cardiac event, target lesion failure, and scaffold thrombosis were 8.5%, 6.6%, and 2.3%, respectively. Subgroup analysis of 239 patients showed that there were no statistically relevant differences between patients with and without overlapping scaffolds after a 12-month follow-up. Conclusions Long-segment stenting with a single scaffold or with multiple overlapping scaffolds is technically feasible with adequate mid-term outcomes. However, large-scale randomized studies are needed to provide further proof of concept.

Background: Carotid artery stenting (CAS) is increasingly used for treatment of severe carotid artery stenosis, but only few procedural risk factors for complications of CAS are clearly defined yet. A possible impact of the patient's gender on the outcome of patients undergoing CAS has not been investigated properly and only little information about this topic is available so far. Methods: We analysed data of the German prospective, multicenter CAS Registry of the Arbeitsgemeinschaft leitende kardiologische Krankenhausarzte. Results: From July 1996 to May 2009 5130 patients underwent CAS at 35 German hospitals and were enrolled into the prospective ALKK CAS Registry. Therefrom 1443 (28.1%) patients were female. There was no significant time-related difference in the proportion of women undergoing CAS over the years. Women undergoing CAS were significantly older than men (73 years vs. 70 years, p < 0.01) and had a longer in hospital stay in comparison to men (p < 0.01). The majority of patients treated with CAS was between 60 and 80 years of age (∼73%). No significant differences between women and men could be found regarding in-hospital events like death (0.5% vs. 0.5%, p = 0.99), major or minor stroke (1.7% vs. 1.6%, p = 0.97; 1.0% vs. 1.6%, p = 0.12), TIA (2.8% vs. 2.6%, p = 0.64), amaurosis fugax (0.3% vs. 0.5%, p = 0.25) , intracranial bleeding (0.5% vs. 0.3%, p = 0.43), myocardial infarction (0.1% vs. 0.0%, p = 0.48) or all non-fatal strokes and alldeath (3.0% vs. 3.4%, p = 0.47). 30 day event rates did not show gender related differences in the combined endpoint of the outcome of patients undergoing CAS, as well (♀ n = 31/882 [3.5%] vs. ♂ n = 109/2273 [4.8%], p = 0.12). Conclusion: Our results do not suggest any gender-related differences in success rates and complications in CAS. In clinical practice approximately 30% of patients treated with CAS are women. The institutions and people who participated in the ALKK CAS Registry are listed in Zahn et al.16 The authors have no funding, financial relationships, or conflicts of interest to disclose.

Small variations in hydrostatic pressure, as those described in our paper [(1)][1] in relation to anatomic stenosis location, are likely to have a negligible effect on decision making whenever the obtained fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) values are far from their

Aims Aortic stenosis causes cardiac hypertrophy and fibrosis, which often persists despite pressure unloading after aortic valve replacement. The persistence of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. We investigated whether granulocyte colony-stimulating factor (G-CSF) beneficially influences cardiac remodelling after pressure unloading. Methods and results Left ventricular hypertrophy was induced by transverse aortic constriction in C57bl6 mice followed by debanding after 8 weeks. This model closely mimics aortic stenosis and subsequent aortic valve replacement. After debanding, mice were treated with either G-CSF or saline injection. Granulocyte colony-stimulating factor treatment significantly improved systolic (ejection fraction 70.48 ± 1.17 vs. 58.41 ± 1.56%, P < 0.001) and diastolic ( E / E ′ 26.0 ± 1.0 vs. 32.6 ± 0.8, P < 0.05) function. Furthermore, cardiac fibrosis was significantly reduced in G-CSF-treated mice (collagen-I area fraction 7.96 ± 0.47 vs. 11.64 ± 1.22%, P < 0.05; collagen-III area fraction 10.73 ± 0.99 vs. 18.46 ± 0.71%, P < 0.001). Direct effects of G-CSF on cardiac fibroblasts or a relevant transdifferentiation of mobilized bone marrow cells could be excluded. However, a considerable infiltration of neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 β (IL-1β) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of IL-1β in neutrophils after G-CSF treatment. Interleukin-1β directly induced the expression of the gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 in cardiac fibroblasts thereby providing the regression of cardiac fibrosis. Conclusion Granulocyte colony-stimulating factor treatment improves the cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression. Granulocyte colony-stimulating factor might be a potential pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement, although further basic research and clinical trials are required in order to prove beneficial effects of G-CSF in the human organism.

Neue diagnostische Verfahren wie die Druckdrahtmessung (FFR) und optische Koharenztomografie (OCT) wurden bisher trotz ausreichender Datenlage nur wenig eingesetzt. Seit dem Jahreswechsel besteht nun die Moglichkeit einer Vergutung. Somit erscheint zukunftig eine Entscheidung hinsichtlich der Therapie einer koronaren Herzerkrankung bei vorliegender Stenose nicht nur aufgrund einer visuellen Abschatzung moglich, sondern auch auf der Grundlage einer objektiven Messung der hamodynamischen Relevanz. Eine kurzlich vorgestellte Studie konnte belegen, dass eine aufgrund der erhobenen FFR neu festgelegten Therapie gegenuber einer ursprunglich auf rein angiografischen Gesichtspunkten basierenden Therapieentscheidung sicher und fur den Patienten prognostisch gunstig ist.

Aims To assess short-term safety defined as the successful delivery and deployment of the ventricular partitioning device (VPD) implant, as well as 12-month functional, clinical, and haemodynamic effectiveness. Methods and results Ventricular partitioning device implantation was successful in 15/18 (83%) patients with anteroapical regional wall motion abnormalities following myocardial infarction. In one patient, the VPD was removed 3 days post implantation and the patient subsequently died due to extra-cardiac sepsis. When compared with baseline, there was significant improvement at 6 and 12 months following VPD implantation in NYHA class (2.21 ± 0.57 vs. 1.28 ± 0.46 vs. 1.23 ± 0.4.3, respectively, P < 0.001 for both), left ventricular (LV) end-systolic volume (189 ± 45 vs. 142 ± 29 vs. 151 ± 48 mL/m2, respectively, P < 0.001 for both), and LV end-diastolic volume (260 ± 47 vs. 208 ± 33 vs. 222 ± 58 mL/m2, respectively, P < 0.001 for both). After 12 months, an improvement in LV ejection fraction was noted (28 ± 7 vs. 32 ± 7 vs. 33 ± 9%, respectively, P = 0.02) as well as improvement in 6 min walk distance (382 ± 123 vs. 409 ± 7 vs. 425 ± 140 m) when compared with pre-procedural values. Conclusion Our data indicate that VPD implantation is safe and feasible, and that VPD implantation improves LV haemodynamics and functional capacity in the 12 months following the procedure.

Background— The aim of this study was to investigate the clinical outcome 2 years after intracoronary administration of autologous progenitor cells in patients with acute myocardial infarction (AMI). Methods and Results— Using a double-blind, placebo-controlled, multicenter trial design, we randomized 204 patients with successfully reperfused AMI to receive intracoronary infusion of bone marrow–derived progenitor cells (BMC) or placebo medium into the infarct artery 3 to 7 days after successful infarct reperfusion therapy. At 2 years, the cumulative end point of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (hazard ratio, 0.58; 95% CI, 0.36 to 0.94; P =0.025). Likewise, the combined end point death and recurrence of myocardial infarction and rehospitalization for heart failure, reflecting progression toward heart failure, was significantly reduced in the BMC group (hazard ratio, 0.26; 95% CI, 0.085 to 0.77; P =0.015). Intracoronary administration of BMC remained a significant predictor of a favorable clinical outcome by Cox regression analysis when adjusted for classical predictors of poor outcome after AMI. There was no evidence of increased restenosis or atherosclerotic disease progression after BMC therapy nor any evidence of increased ventricular arrhythmias or neoplasms. In addition, regional left ventricular contractility of infarcted segments, as assessed by MRI in a subgroup of patients at 2-year follow-up, was significantly higher in the BMC group compared with the placebo group ( P Conclusions— Intracoronary administration of BMC is associated with a significant reduction of the occurrence of major adverse cardiovascular events maintained for 2 years after AMI. Moreover, functional improvements after BMC therapy may persist for at least 2 years. Larger studies focusing on clinical event rates are warranted to confirm the effects of BMC administration on mortality and progression of heart failure in patients with AMIs. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00279175.

Aims Depressed left ventricular ejection fraction (LVEF) despite successful reperfusion therapy is the single most powerful predictor of progressive LV enlargement after acute myocardial infarction (AMI) and independently determines adverse outcome in these patients. Methods and results We investigated the effect of intracoronary administration of bone marrow-derived mononuclear cells (BMC) within 7 days after successful reperfusion therapy for AMI, on early (within 4 months) LV remodelling processes assessed by quantitative LV angiography. Overall, 95 patients received BMC and 92 patients received placebo. Remodelling was assessed as the changes in either LVEF and end-systolic volume (ESV) or stroke volume and end-diastolic volume (EDV) at 4 months, respectively. Baseline LVEF was inversely correlated with ESV expansion at 4 months in the placebo group, but not in the BMC group. Likewise, EDV expansion was significantly correlated with baseline LVEF in the placebo (r = −0.36, P < 0.001), but not in the BMC group (r = −0.17, P = 1.0). Analysing the interaction between convalescent LV contractile function and LV volumes revealed that the increase in LVEF or stroke volume did not occur at the expense of increases in ESV or EDV, respectively, in the BMC group. Conclusion Intracoronary administration of BMC eliminates the correlation between depressed LVEF after reperfusion therapy and LV expansion during follow-up and, thereby, abrogates early LV remodelling after AMI.

Aims Tako-Tsubo cardiomyopathy (TTC) is characterized by rapid regeneration of contractile dysfunction. From recent studies it is known that excessive catecholamine levels due to emotional or physical stress might play a central role. After sympathetic activation, the PIK3/AKT pathway is a key regulator of many cellular responses, including cytoprotective effects. Thus, the purpose of this study was to investigate whether the PIK3/AKT pathway plays a pivotal role in TTC. Methods and results A total of 16 consecutive patients diagnosed with TTC were studied. Left ventricular biopsies were taken during the acute phase and after functional recovery. Specimens were examined by quantitative RT–PCR and western blotting. Representative genes of the PI3K/AKT pathway (PIK3-R1, PTEN, GSK3β, mTOR, PP2A, eIF4E) were compared with left ventricular controls from non-transplanted healthy hearts. PI3K expression was increased during the acute phase and after functional recovery. AKT protein levels were unaltered, but phosphorylation significantly increased during the acute phase. Both PTEN (PI3K antagonist) and PP2 (unspecific phosphatase) were down-regulated. Phosphorylation of the PI3K/AKT downstream target mTOR was increased, while expression of both GSK3 isoforms was decreased. The Bax/Bcl2 ratio was increased in the acute and recovery phases. Conclusion PI3K/AKT signalling is activated in TTC. This activated cell survival cascade might protect cardiomyocytes from cell death and also contribute to rapid regeneration in TTC.

The development of a collateral circulation (arteriogenesis), bypassing an arterial occlusion, is important for tissue survival, but it remains functionally defective. Micro array data of growing collateral vessels, exposed to chronically elevated fluid shear stress (FSS), showed increased transcription of the transient receptor potential cation channel, subfamily V, member 4 (Trpv4). Thus, the aim of this study was to investigate the role of the shear stress sensitive Trpv4 in transmitting this physical stimulus into an active growth response. qRT-PCR at different time points during the growth of collateral vessels after femoral artery ligature (FAL) in rats showed a strong positive correlation of Trpv4 transcription and the intensity of FSS. An increased protein expression of Trpv4 was localized in the FSS-sensing endothelium by means of confocal immunohistochemistry. Cultured porcine endothelial cells showed a dose-dependent expression of Trpv4 and an increased level of Ki67-positive cells upon treatment with 4alpha-Phorbol 12,13-didecanoate (4alphaPDD), a specific Trpv4 activator. This was also demonstrated by flow culture experiments. These results were confirmed by in vivo application of 4alphaPDD in rabbit hind limb circulation via an osmotic mini-pump after FAL. Trpv4 expression as well as Ki67-positive staining was significantly increased in collateral vessels. Finally, 4alphaPDD treatment after FAL led to a 61% (215.5 ml/min/mmHg versus 350 ml/min/mmHg) recovery of conductance when compared with the non-occluded artery. Cell culture and in vivo studies demonstrate that an FSS- or a 4alphaPDD-induced activation of Trpv4 leads to an active proliferation of vascular cells and finally triggers collateral growth. Trpv4, a well-known FSS-sensitive vasodilator, has hitherto not been implicated in active growth processes of collateral arteries. This new function may lead to new therapeutic strategies for the treatment of arterial occlusive diseases.

The growing incidence of cardiovascular diseases leads to an increase in patients who require treatment with antiplatelet drugs. About 5% of patients who underwent a percutaneous coronary intervention will have to undergo surgery within the first year. In these patients the problem evolves how to handle the antiplatelet therapy in the perioperative period. A continuation of these drugs in order to reduce cardiovascular events is associated with increased perioperative bleeding. Withdrawing antiplatelet agents in order to reduce surgical hemorrhage leads to a significant increase of cardiovascular morbidity and mortality, especially in patients who have been treated with implantation of drug eluting stents. This review balances the specific risks of either approach and offers an algorithm how to manage patients in need for antiplatelet therapy in the setting of (un-)planned surgery.

2-Deoxy-d-glucose (2-DG) is a glucose analogue that has been proposed for cancer therapy due to its cytostatic properties. Its effect on the proliferation of smooth muscle cells and endothelial cells has not been fully clarified. The aims of this study were to investigate the effects of 2-DG on the proliferation of porcine aortic endothelial cells (PAEC) and porcine smooth muscle cells (PSMC), to establish an overview of its dose-dependent inhibitory capacity and to examine whether the short-term incubation of cells with 2-DG has an impact on cell proliferation in culture. Our results showed a dose-dependent significant inhibitory effect on proliferation, which was more pronounced in PSMC than in PAEC. Even after short-term incubation of cells with 2-DG, relevant inhibition of proliferation was documented. The clinical application of 2-DG might be a promising concept by inhibiting cells that show a potentially rapid proliferation in response to non-malignant stimuli, such as smooth muscle cells after intracoronary stenting.

The purpose of this study was to determine the prognostic value of N-terminal B-type natriuretic peptide (NT-proBNP) in two independent samples of patients presenting with acute coronary syndromes (ACS) and normal troponin T (TnT) values.Recently assessment of NT-proBNP has been studied in patients with ACS. However, the clinical relevance in patients who present without troponin elevation is unclear.We included 2,614 patients from two independent registries, one serving as a derivation cohort comprising patients with evident ACS (Bad Nauheim ACS registry, n = 1,131) and the other serving as a validation cohort including chest pain patients (PACS [Prognosis in Acute Coronary Syndromes] registry, n = 1,483). NT-proBNP and TnT were measured upon admission. Clinical outcome has been assessed over a 6-month period.In both cohorts, the mortality rate was significantly lower among TnT negative patients: 3.8% versus 8.2% (p = 0.009) in the Bad Nauheim ACS registry, and 2.8% versus 8.6% (p = 0.009) in the PACS registry. Among TnT negative patients, receiver-operating characteristics curve analysis yielded an optimal cutoff value of 474 pg/ml for NT-proBNP that was able to discriminate patients at higher risk in the Bad Nauheim ACS and PACS registries (mortality rate 12.3% vs. 1.3%, p0.001 and 8.5% vs. 1.5%, p0.001, respectively). By Kaplan-Meier analysis, patients with NT-proBNP values over 474 pg/ml were at higher risk for death in the Bad Nauheim ACS registry (log-rank 19.01, p0.001, adjusted hazard ratio [HR] 9.56 [95% confidence interval (CI) 2.42 to 37.7], p = 0.001) and in the PACS registry (log-rank 23.16, p0.001, adjusted HR 5.02 [95% CI 2.04 to 12.33], p0.001).Among patients with suspected ACS considered to be at low risk because of normal troponin values, NT-proBNP above 474 pg/ml is able to discriminate individuals at higher risk. Because of its incremental prognostic value, NT-proBNP assessment should be considered in clinical routine for risk stratification of patients with normal troponin.

Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction, but its specific pathomechanism remains unknown. Thus, we performed a systematic expression profiling of genes by microarray analysis in the acute phase and after functional recovery. We studied 3 female patients presenting with TTC. Complementary RNA was isolated from left ventricular biopsies taken in the acute phase (group A) and after functional recovery (group B). It was profiled for gene expression using cDNA microarrays. Functionally related genes were determined with the Gene Set Enrichment Analysis (GSEA) bioinformatic tool. Validation of selected genes was performed by means of real-time PCR and immunohistochemistry. In group A, different functional gene sets, such as Nrf2-induced genes , triggered by oxidative stress, and protein biosynthesis were significantly overrepresented among the upregulated targets. Increased transcription of GPX1, CAT, RPS6, and eIF4E was confirmed by RT-PCR. The targets of the Akt/PKB signaling showed significant upregulation in both groups. Immunohistochemistry showed that the downstream targets NF-κB and BcL-X L are upregulated and activated. Gene sets involved in energy metabolism ( oxidative phosphorylation , mitochondrial genes ) showed no differences in group A but were overexpressed in group B. This study demonstrated a significant contribution of oxidative stress to the pathomechanism of TTC; it is possibly triggered by excess catecholamine. Increased protein biosynthesis and an activated cell survival cascade can be interpreted as potential compensatory mechanisms. After functional recovery, processes involved in energy metabolism play a pivotal role, thereby potentially contributing to the normalization of contractile function.

In recent years, a new cardiac syndrome with transient left ventricular dysfunction has been described in Japanese patients. This new entity has been referred to as “tako-tsubo cardiomyopathy” or “apical ballooning”, named for the particular shape of the end-systolic left ventricle in ventriculography.1 To date, tako-tsubo cardiomyopathy has also been reported to occur in the western population. The following clinical characteristics of this phenomenon must be met: (1) transient akinesis or dyskinesis of left ventricular wall motion abnormalities (ballooning) with chest pain; (2) new electrocardiographic changes (either ST elevation or T wave inversion); (3) no significant obstructive epicardial coronary artery disease; (4) absence of recent significant head trauma, intracardial bleeding, phaeochromocytoma, myocarditis, and hypertrophic cardiomyopathy.2 Emotional or physical stress usually precedes this cardiomyopathy. A unifying mechanistic explanation responsible for this acute but rapidly reversible contractile dysfunction is still lacking. Multivessel epicardial coronary artery vasospasm, coronary microvascular dysfunction or spasm, impaired fatty acid metabolism, transient obstruction of the left ventricular outflow, and catecholamine-mediated myocardial dysfunction have been proposed as potential mechanisms.3–6 The optimal treatment of patients presenting with this syndrome depends primarily on the haemodynamic conditions and remains rather symptomatic in nature. This article primarily addresses the clinical setting of tako-tsubo cardiomyopathy and describes a broad spectrum of diagnostic tools. Moreover, currently proposed pathophysiological mechanisms are discussed in detail, providing more insight into this new cardiac entity. Tako-tsubo cardiomyopathy is characterised by acute onset of chest pain and a completely reversible regional contractile dysfunction. In left ventriculography typical wall motion abnormalities, such as apical and mid-ventricular akinesia and a hypercontractile basis, can be documented. Coronary angiography reveals no relevant epicardial coronary artery disease (fig 1). Recently, several cases of transient ballooning involving the mid-ventricular part, sparing the apical and basal segments, have also been documented.7 …

Angiotensin II (Ang II) and endothelin-1 (ET-1) share their effects on growth of myocardial cells but have been shown to elicit different effects on myocardial function. However, these effects vary markedly among species, cardiac regions (atrium or ventricle) and failing or non-failing myocardium. We therefore investigated the effects of both peptides on contractile function of isolated human myocytes from failing and non-failing hearts.Cardiomyocytes were enzymatically isolated and electrically stimulated (15 V, 0.2 Hz). Ang II elicited a positive inotropic effect (PIE) mediated by activation of protein kinase C (PKC) in atrial but no effect in ventricular myocytes. ET-1 (10(-8) M) increased cell-shortening by 146+/-9.3% (p0.05) in atrial myocytes, by 99.1+/-16.5% (p0.05) in non-failing ventricular but only by 40.5+/-6.4% (p0.05) in failing ventricular myocytes. The PIE of ET-1 in failing myocytes was more pronounced at low extracellular pH (+112.6+/-27% at pH 7.0 vs. +40.5+/-6.4% at pH 7.4, p0.05). Amiloride, a sodium-hydrogen-exchange inhibitor, inhibited two thirds of the PIE of ET-1 in failing myocytes. The PKC-inhibitor decreased the PIE by 50% from 113% to 64% in ventricular myocytes under acidotic conditions.Ang II and ET-1 elicited PIE in atrial myocytes, whereas in ventricular myocytes Ang II did not induce PIE in contrast to ET-1. The PIE of ET-1 was markedly attenuated in failing myocytes. Under acidotic conditions, the PIE of ET-1 was more pronounced in failing myocytes, indicating that ET-1 may activate signaling processes in failing myocytes, which are not activated in normal myocytes.

We present our experience with an inflatable, non-metallic, fully retrievable, and repositionable transcatheter aortic valve [Direct Flow® Medical (DFM)] focusing on technical features adopted during implantation.Implantation techniques of new generation percutaneous aortic valves are still developing and with experience implementations are described.The "low pressure" (initial valve inflation at 4 ATM, lower than the recommended 12 ATM) and the "alternate aortic curve" techniques (initial valve pulling either from the wire running on the side of the inner or from the one on the outer aortic curve) are part of our modified protocol for DFM® implantation.Forty-two consecutive patients underwent TAVI with DFM. The "low pressure" technique was used in all patients. In 27 (64.3%) patients the bulkiest calcifications were on the inner aortic curve side, and an inner curve technique was used to initiate valve pulling toward the annular hinge point. In the remaining 15 (35.7%) patients, an outer curve technique was used. Neither pull-through nor re-valving was reported. Valve performance showed mean gradient of 8.9 mm Hg. Mild paravalvular leak was reported in seven (16%) patients. No one experienced moderate or severe aortic insufficiency. Thirty-day mortality was 9.5% (4/42).The "low pressure technique" and the "alternate curve technique" guarantee an anatomy and patient tailored approach to achieve controlled and finely tuned valve seating.

Diabetes is associated with aggressive atherosclerosis, leading to an increased risk of in-stent restenosis and stent thrombosis. Bioresorbable scaffolds (BRS) are a new technology for the treatment of coronary lesions that might be beneficial due to their dissolving character, especially in diabetic patients.This study was designed to evaluate feasibility and mid-term clinical outcome of the implantation of PLLA-based, everolimus-eluting BRS for the treatment of coronary lesions in a diabetic all-comers population.All patients of an all-comers registry with diabetes eligible for BRS implantation were included. Outcome parameters were target vessel failure (TVF), major adverse cardiac events (MACE) including target lesion revascularization (TLR), cardiac death, and myocardial infarction. Follow-up was conducted via telephone and/or office visit.A total of 120 diabetic patients were included. Of all diabetics, 35.0% had insulin-dependent diabetes, and all other patients were treated with oral antidiabetics or dietary modification. The median age was 67 (59-72) years and 26.7% were female. Patients underwent coronary angiography due to acute coronary syndrome in 50.8%. Of 127 lesions, 60.6% were B2/C lesions according to ACC/AHA classification. The 6-month rates of TVF, TLR, and MACE were 8.9, 2.7, and 8.4%, respectively.This evaluation confirms reasonable clinical outcome of bioresorbable vascular scaffold implantation in a high-risk diabetic population with predominately complex lesions during daily clinical practice. Nevertheless, long-term data are required for final evaluation.

Background— To present perioperative and long-term results of percutaneous treatment of adult isthmic coarctation of the aorta by means of a self-expandable closed-web uncovered nitinol stent (Sinus-XL, Optimed, Esslingen, Germany). Methods and Results— Preoperative, perioperative, and long-term clinical and computed tomographic angiography data were collected and analyzed prospectively. A total of 52 consecutive patients were treated with the Sinus-XL stent. Mean age was 36.6 (21–67) years, peak invasive trans–coarctation of the aorta gradient was 54.7±9.9 mm Hg, and upper body hypertension unresponsive to medical treatment was present in all patients. Mean stent diameter and length were 24.2 mm (22–28 mm) and 70.4 mm (40–80 mm), respectively. Eight patients (15.4%) required coarctation of the aorta predilatation. All patients underwent poststent dilatation with a noncompliant balloon. Postoperative peak gradient (3.3±2.5 mm Hg) was reduced significantly ( P P P P Conclusions— Adult coarctation of the aorta treatment by means of a self-expandable uncovered stent is safe and durable. The peculiar stent design maintains adequate localized radial strength over time with minimal trauma on the adjacent aortic wall and negligible device-related complications. Blood pressure control optimization is immediate and persistent even at long-term follow-up.

Unter dem Oberbegriff des akuten Koronarsyndroms werden der ST-Hebungsinfarkt, der Nicht-ST-Hebungsinfarkt, die instabile Angina pectoris und der plotzliche Herztod zusammengefasst. Uber 400 000 akute Koronarsyndrome pro Jahr allein in Deutschland belegen die Notwendigkeit differenzierter Diagnostik- und Behandlungspfade. Diese werden in den gangigen Leitlinien der kardiologischen Gesellschaften aufgefuhrt und erlautert. In der vorliegenden Arbeit wird anhand zweier Fallberichte aus der taglichen Routine die Umsetzung einer leitliniengetreuen Diagnostik und Therapie erlautert.

Background Pilot trials suggest that the intracoronary administration of autologous progenitor cells may improve left ventricular function after acute myocardial infarction. Methods In a multicenter trial, we randomly assigned 204 patients with acute myocardial infarction to receive an intracoronary infusion of progenitor cells derived from bone marrow (BMC) or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy. Results At 4 months, the absolute improvement in the global left ventricular ejection fraction (LVEF) was significantly greater in the BMC group than in the placebo group (mean [±SD] increase, 5.5±7.3% vs. 3.0±6.5%; P = 0.01). Patients with a baseline LVEF at or below the median value of 48.9% derived the most benefit (absolute improvement in LVEF, 5.0%; 95% confidence interval, 2.0 to 8.1). At 1 year, intracoronary infusion of BMC was associated with a reduction in the prespecified combined clinical end point of death, recurrence of myocardial infarction, and any revascularization procedure (P = 0.01). Conclusions Intracoronary administration of BMC is associated with improved recovery of left ventricular contractile function in patients with acute myocardial infarction. Largescale studies are warranted to examine the potential effects of progenitor-cell administration on morbidity and mortality. (ClinicalTrials.gov number, NCT00279175.)

Uber ein neues kardiales Syndrom mit einer reversiblen linksventrikularen Dysfunktion wurde kurzlich in Japan berichtet. Diese neue Entitat, welche ebenfalls in der westlichen Population zu finden ist, wurde aufgrund der typischen Form des endsystolischen Ventrikels in der Lavokardiographie als Tako-Tsubo-Kardiomyopathie oder „apical ballooning“ bezeichnet. Die charakteristischen klinischen Befunde dieses Phanomens sind wie folgt beschrieben: 1. plotzlicher Beginn einer reversiblen linksventrikularen apikalen bis mittventrikularen Wandbewegungsstorung („ballooning“) mit Angina pectoris, 2. EKG-Veranderungen (z.B. ST-Segment- Hebungen), 3. leichter Anstieg der spezifischen myokardialen Marker und 4. keine hamodynamisch relevante Koronarstenosierung. Extremer emotionaler oder korperlicher Stress geht dieser Kardiomyopathie gewohnlich voraus. Der zugrundeliegende pathophysiologische Mechanismus, welcher fur diese akute, jedoch reversible kontraktile Dysfunktion ursachlich ist, ist bislang nicht geklart. Aufgrund einiger Untersuchungen werden eine katecholaminvermittelte Kardiotoxizitat bzw. Koronarspasmen oder Storungen der Mikrozirkulation vermutet. Andere Arbeitsgruppen diskutieren einen gestorten Fettsauremetabolismus sowie eine vorubergehende Obstruktion des linksventrikularen Ausflusstrakts. Die optimale Behandlung dieser Patienten hangt von dem jeweiligen klinischen Bild ab und ist derzeit nicht von allgemein gultigem Charakter, da diesem Krankheitsbild moglicherweise unterschiedliche Pathomechanismen zugrunde liegen.

Background and purpose Computer-assisted teaching and learning tools offer new opportunities for improving education and training of medical professionals. CAMPUS represents a software for computer-based, problem-oriented learning. It is a case-based training system which provides the patient's history within a highly realistic, multimedia format. Thus, the interactive design is expected to challenge, test and improve the medical knowledge and the diagnostic skills of the students. The objective of the present study was to introduce CAMPUS as a computer-based learning tool and to present preliminary results with regard to acceptance and user-friendliness. Methods CAMPUS was evaluated by 52 students regarding quality and experienced learning success. A tutorial was conducted within separate, small-numbered groups of students, each working on one learning case. The virtual case started with a summary of the patient's leading symptoms. The students independently took the patient history and carried out the physical examination. Then, they were asked to suggest differential diagnoses, refer the patient to appropriate diagnostic examinations and were encouraged to choose adequate therapeutic strategies. Subsequently, the quality of CAMPUS and the subjective learning success were evaluated with a standardized questionnaire. Results Nearly all students described the user interface as visually attractive (51/52) and clearly structured (52/52). In particular, the students found the use of videos to be advantageous. A marked learning success was described by most students (46/52) and all students considered learning with CAMPUS to be effective. Conclusion CAMPUS offers an innovative training program to improve medical education and to enhance conventional teaching methods efficiently.

The diabetic patient is at high risk for coronary artery disease. Incidence as well as severity of the disease is highly increased in comparison to non-diabetic patients. The revascularization of the diabetic patient is a great challenge, since the longterm results are disappointing when compared to non-diabetic patients. The success of coronary artery bypass grafting is limited by increased perioperative mortality and a faster occlusion of especially venous bypass grafts. In percutaneous interventions the excessive high restenosis rates worsen longterm results. Several clinical trials investigated the outcome of the two revascularization strategies and could demonstrate at least a tendency towards better results when the operative approach was chosen. Particularly, the BARI trial showed reduced mortality for surgery when compared to percutaneous coronary interventions. However, in this trial, in 87% of patients undergoing bypass surgery all stenoses were successfully treated, whereas in patients undergoing percutaneous coronary intervention only 76% of all stenoses were primarily successfully treated. In addition, no stents were used in this trial.Furthermore, the enrollment of the previous trials dates one decade ago. These trials do therefore not necessarily represent the current standard therapy, especially for percutaneous coronary interventions. The restenosis rate could be decreased in recent years by means of drug-eluting stents and an aggressive antiplatelet therapy from more than 50% to less than 10% leading to considerably improved long-term results. Therefore, percutaneous coronary interventions have developed to be a reasonable alternative to bypass surgery. Different clinical trials are currently underway (BARI 2D, CarDIA, FREEDOM) comparing the outcome of the two approaches.

Background: There is increasing evidence that mitochondria – owning a high degree of autonomy within the cell – might represent the target organelles of the myocardial protection afforded by ischemic preconditioning. It was the aim of the study to investigate a possible subcellular correlate to ischemic preconditioning at the mitochondrial level. In addition, we tested whether this protection depends on mitochondrial ATP-dependent potassium channels (KATP) and an might involve an attenuation of mitochondrial ATP hydrolysis during sustained anoxia.Methods and Results: Sustained anoxia (A, 14 min) and reoxygenation (R) completely inhibited state 3 and state 4 respiration of isolated ventricular mitochondria from Wistar rats. An antecedent brief anoxic incubation (4 min) followed by reoxygenation (2 min) prevented this loss of mitochondrial function. The protection afforded by anoxic preconditioning could be mimicked by the KATP opener diazoxide (30 μmol/l) and was completely inhibited by the KATP blocker 5-hydroxydecanoic acid (300 μmol/l). Structural mitochondrial integrity, as estimated from externalization of the mitochondrial enzymes creatine kinase and glutamateoxalacetate transaminase, remained unchanged between the groups, as did mitochondrial ATP loss during anoxia.Conclusion: For the first time, we provide direct evidence for a subcellular preconditioning-like functional mitochondrial adaptation to sustained anoxia. This effect apparently depends on opening of KATP but is independent of ATP preservation.

Echocardiography is the preferred method for assessment of aortic and mitral valvular lesions. The pressure gradient in aortic stenosis may be misleading in patients with poor left ventricular function. Aortic valve area planimetry by transesophageal echocardiography results in a flow independent anatomic measurement. Low-dose dobutamine stress echocardiography provides important prognostic information. Quantitative Doppler echocardiography allows accurate assessment of mitral regurgitation severity. However, the definition of what is severe mitral regurgitation is different in patients with left ventricular dysfunction.

Durch die Leitlinien „Akutes Koronarsyndrom“ der Deutschen Gesellschaft fur Kardiologie, „Management of acute myocardial infarction in patients presenting with ST-segment elevation“ und „Guidelines for percutaneous coronary interventions“ der Europaischen Gesellschaft fur Kardiologie werden diagnostische Moglichkeiten und Therapieoptionen zur Behandlung des ST-Strecken-Hebungsinfarkt evaluiert und durch evidenzbasierte Empfehlungen das Vorgehen standardisiert, wodurch die Behandlung effizienter wird und konsekutiv die Mortalitat abnimmt. Eine optimale Behandlung eines Patienten mit ST-Strecken-Hebungsinfarkt beinhaltet in der prahospitalen Phase zuerst eine Diagnosestellung anhand der klinischen Symptomatik und der Beurteilung eines Zwolf-Kanal-EKG sowie die intravenose Verabreichung einer Basismedikation aus Aspisol®, Heparin, β-Blocker und Nitrat durch den Notarzt. Durch die etablierten Strukturen eines Herzinfarktnetzwerkes sind die logistischen Ablaufe zu optimieren, und der Patient kann der optimalen Therapie in Form einer primaren perkutanen Koronarintervention (PCI) mit einer adjuvanten medikamentosen Behandlung, die die Gabe eines Glykoprotein-IIb/IIIa-Rezeptor-Antagonisten beinhalten sollte, zugefuhrt werden. Bei einem Symptombeginn 90 min in ein Interventionszentrum sollte die Indikation zur Lysetherapie durch den Notarzt gepruft werden. Bei Versagen der Lysetherapie besteht die Indikation zur „Rescue-PCI“. Jedoch auch nach einer erfolgreichen Fibrinolyse sollte immer eine PCI erfolgen, idealerweise innerhalb von 24 h. Die orale duale Thrombozytenaggregationshemmung, die unmittelbar nach Diagnosestellung durch eine Loading-Dosis von 600 mg Clopidogrel initiiert werden sollte, ist uber 9–12 Monaten mit Clopidogrel 75 mg fortzusetzen. Die Gabe von Acetylsalicylsaure 100 mg erfolgt lebenslang.

A 65-year old patient was admitted after having sustained a ventricular septum rupture 18 days after an anterior myocardial infarction. He developed acute heart failure. Given the extremely high perioperative risk in surgical approaches in this setting, we decided for a transcatheter closure of the defect with an exclusively venous approach. After a complete recovery, the patient underwent open heart surgery with aorto coronary bypass, aneurysmectomy, and removal of the closure device. This case demonstrates that transcatheter closure of a post infarction ventricular septum rupture is a technically feasible and suitable method.

In March 2005, the European Society of Cardiology (ESC) guidelines on percutaneous coronary intervention (PCI) were published, in which the management of patients with acute coronary syndromes (ACSs) was presented in detail for the interventional cardiologist. These guidelines supplement previous guidelines from the ESC on ACS with and without ST-elevation. Patients presenting with non-ST-segment elevation ACS should be treated according to the risk of progressing to myocardial infarction (MI) or death. Immediate ( 3 h after onset of clinical symptoms. Adjunctive therapy should include abciximab. Patients treated with thrombolysis should undergo invasive evaluation within 24 h. If this cannot be achieved, ischaemia-driven angiography is recommended.

An important part of the therapy management of acute coronary syndrome (ACS) consists of antiplatelet drugs. Whereas the administration of acetylsalicylic acid (ASA) is well established, the guidelines recommend the additive use of clopidogrel in patients with ACS without persisting ST-elevation. Clopidogrel should be added to ASA as soon as possible in patients with a non-invasive treatment strategy and continued for more than 1 month (class 1A) and up to 9 months (class 1B). In patients for whom a percutaneous coronary intervention (PCI) is planned, an additional loading-dose of 300 mg clopidogrel should be given on top of ASA (100 mg). These recommendations are based on data recently published in the CURE and CREDO trials, which however should be critically discussed: In these trials, an absolute risk reduction of only 2% could be documented by additive use of clopidogrel. The combined endpoint of cardiovascular death, myocardial infarction and stroke is significantly reduced, but there was no improvement taken the individual endpoints alone. In additional, the data for duration of clopidogrel therapy were determined by taken the mean follow-up of these studies. The efficacy of the dual antiplatelet therapy should be discussed in the context of an increased frequency of major bleedings (in total 1%) and should be considered against a reasonable cost effective background. An adequate therapy with clopidogrel in patients presenting ACS should be confirmed by further trials. Until more detailed data are available, the guideline recommendations should be implemented based on of patient's individual risk.

We have observed increased levels of transforming growth factor-beta1 (TGF-beta1) in human hibernating myocardium (HM). Impaired ventricular function in HM is known to be restored to normal following revascularization implying that myocardial structure in HM is to a certain degree preserved. We have therefore tested whether TGF-beta1 can imitate features of HM by reducing the number and frequency of beating cells (chronotropism) and structural remodeling of cultured adult rat cardiomyocytes (ARC), thus saving substrate, energy, and oxygen. Parameters measured were cell size, protein synthesis, protein degradation, protein content, myofibrillogenesis, and chronotropism. ARC were stimulated for 6 days with sera from patients with coronary heart disease, as this period led to a maximum response of cells. An increase of 90% in cell surface area following such treatment was reduced to a 20% increase of the original size by TGF-beta1. Concomitantly, the rate of protein synthesis dropped from 3.6-fold to 2.4-fold, and myofibrillogenesis was reduced. TGF-beta1 downregulated both the number of contracting cells from 81% to 10% and the frequency from 52 to nine beats per minute. However, TGF-beta1 treatment did not reduce the augmentation of protein content (1.28-fold versus 1.25-fold) indicating that protein degradation was also inhibited. Similar results were obtained with serum from healthy volunteers. The effects of TGF-beta1 were reversible. We conclude that TGF-beta1 constrains protein turnover and beating activity in underperfused myocardium, thus mediating protection by adapting myocytes to shortages in blood supply.

Kardiovaskulare Erkrankungen sind die haufigste Todesursache in den westlichen Industrienationen, und ihre Inzidenz steigt weiter an. Deshalb spielen sowohl die primare als auch die sekundare Pravention eine grose Rolle. Zu den medikamentosen Behandlungsschemata gehoren die antithrombotischen Substanzen Acetylsalicylsaure (ASS) und Clopidogrel. In der Primarpravention profitieren vor allem Patienten mit hohem kardiovaskularem Risiko von ASS. Da die Mortalitat nicht beeinflusst wird, das Blutungsrisiko jedoch durch ASS ansteigt, ist eine kritische Risikostratifizierung wichtig. In der Sekundarpravention hat ASS einen festen Platz, da ein signifikanter Einfluss auf die Letalitat gezeigt werden konnte. Aufgrund der hohen Kosten und fehlender Daten wird Clopidogrel bisher nicht in der Primarpravention eingesetzt. In der Sekundarpravention nach akutem Koronarsyndrom kann Clopidogrel die kardiovaskulare Ereignisrate senken, ohne einen Einfluss auf die Letalitat zu haben.

We report the case of a 39-year-old male with a history of untreated arterial hypertension. He presented to a community hospital with pulmonary edema and anasarca, and was transferred to our heart center for further investigation and therapy. Echocardiography revealed the enlargement of all four heart chambers including a severely compromised systolic function of both ventricles. Coronary angiography ruled out coronary artery disease. Computer tomography of the thorax was performed to exclude pulmonary embolism. Surprisingly, an anomalous left vertical vein was found, connecting left upper pulmonary veins to the left innominate vein as well as to the left atrium (Fig. 1a). Magnetic resonance tomography confirmed the diagnosis of this anatomical large left partial anomalous pulmonary venous connection (PAPVC) with a pulmonary stroke volume of 86 ml and a systemic stroke volume of 68 ml. The resulting left-to-right shunt was relatively small with a pulmonary to systemic cardiac index (Qp:Qs) of just 1.26 and a shunt stroke volume in the vertical vein of 12 ml. Furthermore, a mild coarctation of the aorta and a minimal late enhancement of the left ventricle could be demonstrated, the latter finding was consistent with hypertensive heart disease. Right heart catheterization revealed moderate pulmonary hypertension with a mean pulmonary pressure of 34 mmHg and a mean pulmonary capillary wedge pressure of 29 mmHg. We decided to close the vertical vein percutaneously. After retrograde intubation of the vertical vein, repetitive angiograms at various heights of the vein were performed to define size and target zone of the closure device. Thereby, a further connection to the right atrium via the accessory hemiazygos vein was found, explaining the missing 6 ml of calculated shunt stroke volume (Fig. 2a). Afterwards, this finding of a strictly posterior originating additional connection could be confirmed by re-evaluation of the initial CT scan (Fig. 1b, c). We decided to use an 18-mm Amplatzer vascular plug II (St. Jude Medical, St. Paul, MN, USA) to occlude both anomalous connections. After positioning the Amplatzer TorqVue 2 Delivery Sheath (St. Jude Medical) in the left atrium, the vascular plug II was advanced. While pull-back of the sheath the plug was positioned in the target zone, which was the distal vertical vein at the orifice of the accessory hemiazygos vein, just above the orifice of the left pulmonary veins. After deployment of the device, there was no more washout into the left innominate vein: neither from the accessory hemiazygos vein nor from pulmonary veins (Fig. 2b), and a pulmonary angiogram confirmed successful closure of the anomalous vertical vein also. Fetal venous circulation is very variable and complex. During normal development of the human fetal venous system the left supracardinal vein connects the accessory hemiazygos vein and the left atrium with the left innominate vein. Normally, this vein occludes before birth. However, in cases of left PAPVC, one or more left pulmonary veins can drain into the left innominate vein via a Electronic supplementary material The online version of this article (doi:10.1007/s00392-013-0597-7) contains supplementary material, which is available to authorized users.

IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) demonstrated that intensive lipid-lowering therapy with ezetimibe/simvastatin reduced first and subsequent cardiovascular events compared with placebo/simvastatin. An analysis of the 4S Study (Scandinavian Simvastatin

Background— The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Methods and Results— Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF 1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ in group 2. Cardiomyocyte mitosis was never observed. Conclusions— These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.

Sirs: Coronary artery fistulas are anomalous connections between a coronary artery and a cardiac chamber or great vessel [1]. They are rare abnormalities with a reported incidence of 0.13–0.18% of patients undergoing coronary angiography [2, 3]. The majority of coronary artery fistulas are congenital in origin, but they have been reported as acquired complications of chest trauma and surgery also. Most of them are diagnosed incidentally in asymptomatic patients, but depending on shunt volume, congestive heart failure can develop [1]. Furthermore, myocardial ischemia due to a ‘steal’ from the adjacent myocardium has been reported [4–12], but true existence of this phenomenon is a controversial issue [13]. We present the case of a young female with a large coronary artery fistula originating from the proximal left anterior descending artery (LAD), and evidence of a coronary steal syndrome is provided by fractional flow reserve (FFR). A so far healthy 36-year-old female without cardiovascular risk factors presented in our emergency department with sudden onset chest pain following a long exhausting motorbike trip. Physical examination was unremarkable, and no cardiac murmur was audible. Baseline electrocardiogram showed T inversions in the anterior leads, and the cardiac biomarkers were elevated with a peak high sensitive Troponin T of 0.55 lg/l and a peak creatine kinase of 623 U/l. Subsequent left heart catheterization ruled out coronary artery disease, but a large coronary artery fistula originating from the proximal LAD draining into to the pulmonary trunk was found (Fig. 1). Ventriculography showed a hypokinesis of the anterior segments distal to the origin of the fistula, and magnetic resonance tomography revealed a late enhancement pattern of subendocardial myocardial infarction (Fig. 2). Hypothesizing a coronary steal syndrome due to the fistula, a second procedure with left and right heart catheterization was performed. Hemodynamic and oximetric measurements revealed a systemic blood flow (QS) of 6.0 l/min and a pulmonary blood flow (QP) of 6.7 l/min, leading to a relatively small calculated left-to-right shunt of 0.68 l/min (QP/QS = 1.12), and pulmonary artery pressure was in normal range. FFR in the distal LAD was 0.78 under maximal hyperemia, raising to 0.95 while temporary experimental occlusion of the fistula using a 3.0/15 mm standard balloon catheter. In consideration of this evidence of steal syndrome, coil embolization of the fistula was performed in the same procedure, using 2 Detach embolization coils (Cook Medical, Bloomington, IN, USA) [2–2 and 2–4 (diameter in mm–length in cm)] in each of the two main branches and another two coils (3–4 and 3–6) in the bifurcation of the fistula (Fig. 1). Finally, a FFR of 1.0 was measured in the distal LAD. The patient was discharged free of symptoms the following day. At 3-month follow-up, the patient was free of symptoms, and echocardiography revealed complete recovery of left ventricular function. A coronary artery fistula is a rare but not an exceptional finding on a routine coronary angiogram. Small fistulas need no specific treatment, but if they are hemodynamically important, elective closure is recommended. Coil embolization of coronary artery fistulas is considered as a safe and effective treatment [14–16], and the aim of the procedure is to achieve complete occlusion at as distal a location as possible in the fistulous vessel [1]. Based on case reports, coronary artery fistulas are considered as a rare cause of myocardial infarctions that T. Harle (&) K. Kronberg A. Elsasser Department of Cardiology, Heart Center, Klinikum Oldenburg gGmbH, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany e-mail: t.haerle@gmx.de

Myocardial hibernation represents an adaptation to sustained ischemia to maintain tissue vitality during severe supply–demand imbalance which is characterized by an increased glucose uptake. To elucidate this adaptive protective mechanism, the regulation of anaerobic glycolysis was investigated using human biopsies. In hibernating myocardium showing an increase in anaerobic glycolytic flux metabolizing exogenous glucose, the adjustment of flux through this pathway was analyzed by flux:metabolite co-responses. By this means, a previously unknown pattern of regulation using multisite modulation was found which largely differs from traditional concepts of metabolic control of the Embden–Meyerhof pathway in normal and diseased myocardium.

We report the case of a 69-year-old man with a history of 2,3diphosphoglycerate deficiency and consecutive splenectomy due to hemolytic anemia. He presented in emergency room following a sudden onset of severe pain in the right upper abdomen and mild dyspnea. One week before, he had suffered short-lasting chest pain after cycling. There was no history of congenital heart or lung disease, chest trauma or anticoagulant medication. The ECG was normal, but there were diminished breath sounds and dullness to percussion on the right side of the thorax. Ultrasound showed a right-sided pleural effusion, and surprisingly, thoracentesis revealed a bloody effusion with a hematocrit identical to the peripheral blood. Computer tomography confirmed a large right-sided hemothorax, caused by an ongoing bleeding out of a vascular malformation (Fig. 1). With incipient shock, the patient was transferred to the intensive care unit, and emergency cardiac surgery was initiated. While the pericardial and the left pleural cavity were without pathological findings, the right pleural cavity was filled with blood originating from the right lower lobe. A trial to improve the visibility using a double-lumen endotracheal tube was not tolerated hemodynamically, and cardiopulmonary bypass became necessary. A vascular malformation, a vessel connecting the descending aorta with a pulmonary vessel of the lower lobe could be demonstrated. The bleeding originated from a rupture of this major aorto-pulmonary collateral artery (MAPCA) close to the aortic branch-off. The ligation of this vessel stopped all

Aims Current guidelines recommend immediate multivessel percutaneous coronary intervention (PCI) in patients with cardiogenic shock, despite the lack of randomised trials. We sought to investigate the use and impact on outcome of multivessel PCI in current practice in cardiogenic shock in Germany. Methods and results Between January 2008 and December 2011 a total of 735 consecutive patients with acute myocardial infarction, cardiogenic shock and multivessel coronary artery disease underwent immediate PCI in 41 hospitals in Germany. Of these, 173 (23.5%) patients were treated with immediate multivessel PCI. The acute success of PCI with respect to TIMI 3 flow did not differ between the groups (82.5% versus 79.6%). In-hospital mortality with multivessel PCI and culprit lesion PCI was 46.8% and 35.8%, respectively. In multivariate analysis multivessel PCI was associated with an increased mortality (odds ratio 1.5; 95% confidence interval 1.15-1.84). Conclusions In current clinical practice in Germany multivessel PCI is used only in one quarter of patients with cardiogenic shock treated with primary PCI. We observed an adverse effect of immediate multivessel PCI. Therefore, a randomised trial is needed to determine the definitive role of multivessel PCI in cardiogenic shock.