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Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35–0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups—they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17–0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22–0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25–0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38.Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies.Dr Falk Pharma GmbH.

Aims Apical rocking (ApRock) and septal flash (SF) are often observed phenomena in asynchronously contracting ventricles. We investigated the relationship of visually assessed ApRock and SF, reverse remodelling, and long-term survival in cardiac resynchronization therapy (CRT) candidates. Methods and results A total of 1060 patients eligible for CRT underwent echocardiographic examinations before and 12 ± 6 months after device implantation. Three blinded physicians were asked to visually assess the presence of ApRock and SF before device implantation and also their correction by CRT 12 ± 6 months post-implantation. Patients with a left ventricular (LV) end-systolic volume decrease of ≥15% during the first year of follow-up were regarded as responders. Patients were followed for a median period of 46 months (interquartile range: 27–65 months) for the occurrence of death of any cause. If corrected by CRT, visually assessed ApRock and SF were associated with reverse remodelling with a sensitivity of 84 and 79%, specificity of 79 and 74%, and accuracy of 82 and 77%, respectively. ApRock (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.30–0.53, P < 0.0001) and SF (HR 0.45 [CI 0.34–0.61], P < 0.001) were independently associated with lower all-cause mortality after CRT and had an incremental value over clinical variables and QRS width for identifying CRT responders. Both the absence of ApRock/SF and unsuccessful correction of ApRock/SF despite CRT were associated with a high risk for non-response and an unfavourable long-term survival. Conclusion A specific LV mechanical dyssynchrony pattern, characterized by ApRock and SF, is associated with a more favourable long-term survival after CRT. Both parameters are also indicators of an effective therapy. [10.1093/ehjci/jev324][1] [1]: /lookup/doi/10.1093/ehjci/jev324

OBJECTIVES The aim of this study was to compare the volumetric response and the long- term survival after cardiac resynchronization therapy (CRT) in patients with intrinsic left bundle branch block (LBBB) versus chronic right ventricular pacing (RVP) with respect to the presence of mechanical dyssynchrony (MD). BACKGROUND Chronic RVP induces an iatrogenic LBBB and asynchronous left ventricular contraction that is potentially reversible by upgrading to CRT. METHODS A total of 914 patients eligible for CRT (117 with conventional pacemakers and 797 with intrinsic LBBB) were included in the study. MD was visually assessed before CRT and was defined as the presence of either apical rocking and/or septal flash on baseline echocardiograms. Patients with a left ventricular end-systolic volume decrease of >= 15% during the follow-up were considered responders. Patients were followed for all-cause mortality during the median follow-up of 48 months (interquartile range: 29 to 66 months). RESULTS MDwas observed in 51% of patientswithRVP versus 77% in patients with intrinsic LBBB( p< 0.001). Patients with RVP and MD had a similar likelihood of volumetric response as did patients with intrinsic LBBB and MD (adjusted odds ratio: 0.71; 95% confidence interval: 0.33 to 1.53; p - 0.385). There was no significant difference in long-term survival between patients with RVP and intrinsic LBBB (adjusted hazard ratio: 1.101; 95% confidence interval: 0.658 to 1.842; p = 0.714). Patients with visual MD and either intrinsic LBBB or RVP had a more favorable survival than those without MD (p < 0.001). CONCLUSIONS The likelihood of volumetric response and a favorable long-term survival of patients with RVP was similar to those of patients with intrinsic LBBB and were mainly determined by the presence of MD and not by the nature of LBBB. (C) 2017 by the American College of Cardiology Foundation.

Aims Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT. Methods and results In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 +/- 3 months postimplantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 +/- 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction >= 15%), and LV volume expansion (ESV increase >= 5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P

Hypertrophic Cardiomyopathy (HCM) confers a 4-5 %/year-risk for sudden cardiac death. Intramyocardial fibrosis (IF) is associated with this risk. The gold standard of IF visualization is cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE-CMR). In view of a number of CMR-limitations the hypothesis of this study was that late enhanced multi-slice computed tomography (leMDCT) enables demonstration of late enhancement (LE) indicating IF. In a prospective single-center validation study leMDCT research-scans were exclusively performed for IF-imaging in HCM-patients not including non-invasive coronary angiography during first-pass (64-slice; 80 kV; Iopromide, 150 mL, injected 7 min before scanning). Applying a 17-segment-polar-map short cardiac axis views (multiplanar reformations; 5 mm slice thickness) were analysed in order to exclude/detect, localize and measure LE practicing the manual quantification method if present. Finally, leMDCT and LGE-CMR data were unblinded for intermodal correlation. We included n = 24 patients consecutively (64.0 ± 14.5 years of age). LE was demonstrated by LGE-CMR in n = 14/24 patients (prevalence 58 %). Patient- and segment-based sensitivity in leMDCT was 100 and 68 %, respectively. In leMDCT tissue density of LE was 142 ± 51 versus 89.9 ± 19.3 HU in remote myocardium (p0.001). Signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) appeared to be 7.3 ± 3.3 and 2.3 ± 1, respectively. Sizing of LE-area gave 2.2 ± 1.4 cm(2) in leMDCT versus 2.9 ± 2.4 cm(2) in LGE-CMR (r = 0.93). Intra-/interobserver variability was assessed with an accuracy of 0.36 cm(2) (r = 0.91) and 0.47 cm(2) (r = 0.82), respectively. In consecutive HCM patients leMDCT can reliably detect intramyocardial fibrosis marked by LE. In view of a comparatively low SNR and CNR leMDCT may alternatively be applied in case of CMR contraindications.

To analyze whether left ventricular dyssynchrony (LVD) at baseline is predictive for long-term outcome in heart failure (CHF) patients with left ventricular (LV) dysfunction and conduction disturbances treated with cardiac resynchronization therapy (CRT).In 535 consecutive individuals with CHF scheduled for implantation of a CRT device, LVD was assessed by tissue Doppler imaging (TDI), defined as an electromechanical delay (EMD) difference of ≥40 ms in 2 opposed left ventricular wall regions (septal vs. lateral, anterior vs. inferior). All-cause mortality, heart transplantation, or assist device implantation was defined as combined primary end point. Secondary end points were measures of reverse LV remodeling and of symptomatic improvement.Mean follow-up was 68 ± 36 [range: 4-150] months. LVD at baseline was present in 308 patients (61%). Of these, 24% reached the combined primary endpoint in contrast to 58% of patients without LVD (p0.001). Furthermore, patients with LVD showed pronounced improvement of all secondary end point parameters. In our cohort LVD was an independent predictor for outcome (hazard ratio [95% CI]: 0.30 [0.21-0.42], p0.001).LVD at baseline as assessed by TDI is associated with a more pronounced clinical improvement and is a predictor for transplant-free long-term survival in CRT recipients.

We examined the prevalence of sleep-disordered breathing (SDB) in patients with severe aortic valve stenosis (AS) and the impact of transfemoral aortic valve implantation (TAVI) on SDB.79 patients underwent cardiorespiratory polygraphy (PG) before TAVI (CoreValve™), 62 of them a second PG after the procedure.Forty-nine (62 %) patients had obstructive sleep apnea (OSA), 25 (32 %) central sleep apnea (CSA), and 5 (6 %) presented without significant SDB (apnea-hypopnea index (AHI)5/h). Among the 62 patients evaluated before and after TAVI, 36 (58 %) had OSA, 22 (36 %) CSA, and 4 patients (7 %) no SDB. AHI was significantly higher in CSA patients than in OSA patients (34.5 ± 18.3 vs. 18.0 ± 12.6/h, p0.001). Successful TAVI had a significant impact on CSA but not on OSA: CSA patients with optimal TAVI results experienced a significant reduction in central respiratory events (AHI 39.6 ± 19.6-23.1 ± 16.0/h, p = 0.035), while no changes were detected in OSA patients (AHI 18.8 ± 13.0-20.25 ± 13.4/h, p = 0.376). In contrast, in patients who developed at least moderate periprosthetic aortic regurgitation (ARI), CSA increased significantly (AHI 26.3 ± 13.2-39.2 ± 18.4/h, p = 0.036), whereas no acute change was seen in patients with OSA (AHI 10.5 ± 7.8-12.5 ± 5.0/h, p = 0.5).OSA and CSA are prevalent in more than 90 % of patients undergoing TAVI for severe aortic valve stenosis. Successful TAVI had no significant impact on OSA but improved CSA. In case of an acute change from pressure overload (aortic stenosis) to acute volume overload (aortic regurgitation after TAVI), central, but not obstructive, sleep apnea deteriorated.

BackgroundLeft ventricular rotation is physiologically affected by acute changes in preload. We investigated the acute effect of preload changes in chronically underloaded and overloaded left ventricles in children with shunt lesions.MethodsA total of 15 patients with atrial septal defects (Group A: 7.4 ± 4.7 years, 11 females) and 14 patients with patent arterial ducts (Group B: 2.7 ± 3.1 years, 10 females) were investigated using 2D speckle-tracking echocardiography before and after interventional catheterisation. The rotational parameters of the patient group were compared with those of 29 matched healthy children (Group C).ResultsMaximal torsion (A: 2.45 ± 0.9°/cm versus C: 1.8 ± 0.8°/cm, p < 0.05), apical peak systolic rotation (A: 12.6 ± 5.7° versus C: 8.7 ± 3.5°, p < 0.05), and the peak diastolic torsion rate (A: −147 ± 48°/second versus C: −110 ± 31°/second, p < 0.05) were elevated in Group A and dropped immediately to normal values after intervention (maximal torsion 1.5 ± 1.1°/cm, p < 0.05, apical peak systolic rotation 7.2 ± 4.1°, p < 0.05, and peak diastolic torsion rate −106 ± 35°/second, p < 0.05). Patients in Group B had decreased maximal torsion (B: 1.8 ± 1.1°/cm versus C: 3.8 ± 1.4°/cm, p < 0.05) and apical peak systolic rotation (B: 8.3 ± 6.1° versus C: 13.9 ± 4.3°, p < 0.05). Defect closure was followed by an increase in maximal torsion (B: 2.7 ± 1.4°/cm, p < 0.05) and the peak diastolic torsion rate (B: −133 ± 66°/second versus −176 ± 84°/second, p < 0.05).ConclusionsPatients with chronically underloaded left ventricles compensate with an enhanced apical peak systolic rotation, maximal torsion, and quicker diastolic untwisting to facilitate diastolic filling. In patients with left ventricular dilatation by volume overload, the peak systolic apical rotation and the maximal torsion are decreased. After normalisation of the preload, they immediately return to normal and diastolic untwisting rebounds. These mechanisms are important for understanding the remodelling processes.

Cheyne-Stokes Respiration and Arrhythmias ObjectiveThis study aimed to investigate whether adequate treatment of Cheyne-Stokes respiration (CSR) reduces the risk of arrhythmic events in patients with chronic heart failure (CHF). MethodsA cohort of 403 registry patients with CHF (LVEF45%, NYHA-class2) and implanted cardioverter-defibrillator devices (ICD) was studied. They underwent overnight polygraphy, with 221 having mild or no CSR (apnea-hypopnea index [AHI] 15/h). Latter ones were offered therapy with adaptive servoventilation (ASV), which 96 patients accepted and 86 rejected. During follow-up (21 15 months) defibrillator therapies were recorded in addition to clinical and physiologic measures of heart failure severity. ResultsEvent-free survival from (a) appropriate cardioverter-defibrillator therapies and (b) appropriately monitored ventricular arrhythmias was shorter in the untreated CSR group compared to the treated CSR and the no CSR group. Stepwise Cox proportional hazard regression analysis showed untreated CSR (a: hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.46-2.72, P < 0.001; b: HR 2.19, 95%CI 1.42-3.37, P < 0.001), but not treated CSR (a: HR 1.06, 95%CI 0.74-1.50; P = 0.77; b: HR 1.21, 95%CI 0.75-1.93, P = 0.43) was an independent risk factor. The treated CSR group showed improvements in cardiac function and respiratory stability compared to the untreated CSR group. ConclusionThis study demonstrates a decrease of appropriate defibrillator therapies by ASV treated CSR in patients with CHF and ICD. A reduced exposure to hyperventilation, hypoxia, and improvement in indices of CHF severity and neurohumoral disarrangements are potential causative mechanisms.

Electromyostimulation (EMS) of thigh and gluteal muscles is a strategy to increase exercise capacity in patients with chronic heart failure (CHF). The aim of this non-randomised pilot study was to investigate the effects of different stimulation strategies in CHF patients using a newly developed stimulation suit also involving trunk and arm muscles [extended electromyostimulation (exEMS)] in comparison with EMS therapy limited to gluteal and leg muscles (limEMS). 60 individuals joined the EMS training programme. Stable CHF patients (NYHA class II–III) received either exEMS (22 patients, 15 males, mean age 59.95 ± 13.16 years) or limEMS (12 patients, 9 males, 62.75 ± 8.77 years). 26 participants served as healthy control group (CG) receiving exEMS. Training was performed for 10 weeks twice weekly for 20 min, and the level of daily activity remained unchanged. Effects on exercise capacity, oxygen uptake, left ventricular function (EF) and biomarkers were evaluated. There was a significant increase of oxygen uptake at aerobic threshold in all groups (exEMS: 13.7 ± 3.9–17.6 ± 5.1 ml/kg/min (+28.46 %, p

Until now, there is no consensus regarding the definition of a clinical response to cardiac resynchronization therapy (CRT) in patients with chronic heart failure (CHF) and systolic left ventricular (LV) dysfunction. The aim of this study was to evaluate if echocardiography is predictive for an objective improvement in exercise capacity during long-term follow-up of CRT.Each patient underwent echocardiography and spiroergometry both at baseline and at last follow-up. Left ventricular dyssynchrony (LVD) before CRT was defined by tissue Doppler imaging (TDI) as intra-LV delay ≥40 msec (septal-lateral or anterior-posterior). Clinical response to CRT was defined as increase of peakVO2 or as increase of maximal workload10% as compared to baseline.Mean follow-up was 69 ± 37 months. From the 238 consecutive patients included in the study, 141 (59%) were classified as clinical responders and 97 (41%) as nonresponders. Baseline data of responders and nonresponders were comparable. However, clinical responders showed more often LVD (64%) than nonresponders (42%, P = 0.004). On multivariate regression analysis, nonischemic origin of CHF (β-coefficient in the final model 0.1, P = 0.04) and LVD at baseline (β-coefficient in the final model 0.2, P 0.001) were independently associated with clinical response during long-term follow-up. Patients with LVD at baseline had significant more often an improvement of left ventricular ejection fraction10% (P = 0.02) and a reduction of left ventricular end-diastolic diameter (LVEDD)10% (P 0.01) than patients without LVD at baseline.LVD at baseline as assessed by a straightforward echocardiographic approach predicts the long-term clinical response to CRT and is associated with a more pronounced reverse LV remodeling.

Background The purpose of our study was to correlate the incidence of adequate implantable cardioverter-defibrillator (ICD) interventions in hypertrophic cardiomyopathy (HCM) patients with risk markers (RMs) for sudden cardiac death (SCD) plus myocardial fibrosis as detected by late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging. Methods In all, 87 patients with HCM underwent LGE-CMR imaging prior to ICD implantation, performed for secondary (n = 2; 2%) or primary SCD prophylaxis (n = 85; 98%). Fibrosis was graded with a 17-segment left ventricular model (0 = absent, 1=point-shaped, 2=limited to 1 left ventricular segment, 3=involving ≥ 2 segments). During follow-up, ICD memories were read out by a physician blinded to the individual patient data. Results The number of RMs per patient was 1.9 ± 0.8. Myocardial fibrosis was present in 78 patients (90%); 26 (30%) had a fibrosis score of 3. During follow-up (3.5 ± 2.6 [range, 0.2-11.4 years]), 15 patients had 50 appropriate ICD interventions. Episodes of atrial fibrillation were found in 28 patients. Fibrosis severity correlated with occurrence of ventricular tachycardia (Cramer's V, or φc = 0.4, P 0.001) and atrial fibrillation (φc = 0.6, P 0.001). On multivariate regression analysis, an independent association between myocardial fibrosis (s = 0.6, P 0.01) and sustained ventricular tachycardia was found. Conclusions In HCM patients treated with ICD implantation because of a high SCD risk by traditional RM assessment, a high rate of arrhythmic events was observed during long-term follow-up. In a cohort of patients with clinical markers for high risk of SCD, severity of myocardial fibrosis as detected by an easy LGE-CMR scoring system was associated with future arrhythmic events and appropriate ICD therapies.

Bei symptomatischen Patienten mit chronischen erworbenen Herzklappenfehlern kann eine Intervention indiziert sein, um Beschwerden und die Lebensqualitat zu verbessern. Interventionsziel bei asymptomatischen Patienten ist die Prognoseverbesserung durch Pravention typischer Komplikationen, insbesondere von Herzinsuffizienz und Arrhythmien. Leitliniengerecht ist es unerlasslich, Symptome zuverlassig zu erfassen und u. a. mithilfe der Spiroergometrie zu objektivieren. Bei zweifelsfrei asymptomatischen Patienten mit hamodynamisch fortgeschrittenen Klappenfehlern muss zudem gepruft werden, ob das Myokard an die chronische Druck- und/oder Volumenbelastung auch unter Belastungsbedingungen adaptiert ist (Kontraktilitatsreserve). Nach den klassischen Symptomen der diastolischen und systolischen Herzinsuffizienz zu fragen, ist dabei nicht ausreichend, da die Leitlinien ein abwartendes Vorgehen nur fur Patienten empfehlen, die frei von jedweder kausalen Symptomatik sind. Bei allen anderen Patienten ist grundsatzlich die Intervention indiziert. In Anbetracht des zunehmend alteren Patientenkollektivs mit Herzklappenfehlern – insbesondere mit degenerativer Aortenklappenstenose – gilt es zu berucksichtigen, dass der Lebensstil der Patienten oftmals durch die Vermeidung korperlicher Belastungen charakterisiert ist. Dementsprechend sind Fragen zur Belastungsintoleranz oft wenig hilfreich. Bei einer erschopften myokardialen Kontraktilitatsreserve ist eine Klappenintervention auch indiziert, wenn der Patient im Alltagsleben asymptomatisch ist.

Background and objective: The study determined growth factor gene expression obtained from patients undergoing curative total mesorectal excision (TME) between 2009 and 2016 at the Helios Klinikum Wuppertal; Germany (total of n=44). Methods: Rectal cancers were grouped according to Lauren’s classification (UICC I-IV stages); overall survival (OS) and progression free survival (PFS). 25 patients were in UICC III/IV stages, while 19 patients were in UICC I/II stages. VEGF-A/B/C/D, PDGF-A, EGF, IGF-1/2, and corresponding receptor subtypes 1/2 mRNA enrichment was determined using quantitative real-time PCR. Data were correlated to clinical outcome. Results: The obtained results show that VEGF-B and IGF-2 mRNA were significantly higher expressed in rectal adenocarcinoma than adjacent normal tissues, while other GF genes were not significantly affected. IGF-2 levels were further upregulated in advanced stages UICC III/IV where patients received radiotherapy. Patients with good response to neoadjuvant radiotherapy (as determined by the histological Dworak regression score) had significant better overall survival. Expression of microRNA miR-483 (a known microRNA molecule previously associated with IGF-2 expression) was evaluated by TaqMAN PCR, but no significant correlation to IGF-2 levels was detected. Conclusions: IGF-2 appears as a biomarker of rectal adenocarcinoma, but does not serve as predictive parameter for tumor progression or survival. The results encourage further development of biomarkers targeting IGF-2 molecules in blood or urine. Furthermore, IGF-2 levels are increased in patients undergoing radiotherapy and thus, IGF related molecules might also serve as predictors for response to neoadjuvant therapy in rectal adenocarcinoma.

The aims of this study were to assess the influence of left bundle branch block (LBBB)-like conduction abnormalities on left ventricular (LV) blood flow patterns and to characterize their potential impact on LV efficiency by measuring the changes in vortex formation and energy dissipation in the left ventricle using echocardiographic particle image velocimetry.Thirty-six subjects were prospectively studied, including 20 patients with pacemakers, six patients with LBBB, and 10 healthy control subjects, all of whom had normal ejection fractions (50%). In patients with pacemakers, data were acquired in both DDD and AAI modes. Standard grayscale, tissue Doppler myocardial imaging, and contrast-enhanced echocardiographic particle image velocimetric data were acquired, and LV flow patterns were analyzed using dedicated software. Dyssynchrony was quantified by measuring apical transverse motion.Apical transverse motion was significantly higher in patients with LBBB compared with normal control subjects (mean, 4.9 ± 1.9 vs 1.0 ± 0.7 mm; P .001). Quantitative measures of vortex energy dissipation (relative strength, vortex relative strength, and vortex pulsation correlation) were significantly higher in patients with LBBB (2.05 ± 0.54, 0.53 ± 0.13, and 0.87 ± 0.47, respectively) compared with control subjects (1.48 ± 0.28, 0.33 ± 0.05, and 0.24 ± 0.51, respectively) (P .02 for all). Vortex duration time in relation to the entire cardiac cycle was shorter in patients with LBBB than in control subjects (28% vs 44%). All findings in both groups were comparable with DDD and AAI.LV flow pattern analysis by echocardiographic particle image velocimetry reveals that conduction delay due to LBBB or pacemaker stimulation in the right ventricle (DDD) disturbs the transfer of kinetic energy during the cardiac cycle and causes less efficient LV function. These data contribute to a better understanding of hemodynamic consequences of conduction delays and may help in the optimization of therapeutic approaches.

OBJECTIVE Cardiac adaptation to sports activity in endurance athletes is considerably different from that in power athletes. The effects of a high-level team sport like handball, one of the most popular sports in the world, performed at a younger age, on cardiac rhythm in individuals above the age of 50 have not been investigated to date. METHODS Thirty-three former top-level handball players from the first German league (6 former world champions and numerous Olympians) (57.5 +/- 5.5 y) joined our screening programme for former athletes and underwent electrocardiography, echocardiography and spiroergometry. Data were compared to 24 sedentary healthy controls. RESULTS Ten of the 33 athletes suffered from atrial fibrillation (AF). Left ventricular diameter was 53.68 +/- 4.88 mm in the athletes group and 50.58 +/- 4.12 mm in the healthy controls. Analysing the subgroups of handball players ('AF group' and 'non-AF group'), spiroergometry showed oxygen consumption at the anaerobic threshold of 27.54 +/- 6.77 ml/kg/min in the AF group and 31.24 +/- 10.33 ml/kg/min in the non-AF group (P = 0.228). Absolute left atrial diameter was 44.34 +/- 4.41 mm in the AF group (non-AF group 38.94 +/- 3.77 mm, P < 0.001) (healthy controls 37.54 +/- 4.34 mm, compared with all athletes P = 0.015). In all individuals left ventricular wall thickness was within normal limits. However, myocardial walls were thicker in the AF group (11.28 +/- 1.83 mm) than in the non-AF group (9.44 +/- 1.26 mm, P = 0.002). Athletes in the AF group (187.6 +/- 6.42 cm) were significantly taller than in the non-AF group (180.91 +/- 7.31 cm, P = 0.018). CONCLUSION Not only endurance training, but also sports activity with a relevant static component, like team handball, might predispose for AF above the age of 50. LA size, height and myocardial wall thickness seem to affect the risk of developing AF. More data in non-endurance sports are mandatory to confirm this hypothesis.

The aim of this study was to assess LA function by two-dimensional speckle-tracking echocardiography and its relation with myocardial fibrosis in hypertrophic cardiomyopathy (HCM).We enrolled 30 consecutive HCM-patients in our study (20 males; age: 49.7 +/- 10.4 years, NYHA-class: 1.9 +/- 0.7). Echocardiography was performed with assessment of global longitudinal LV strain (epsilon) and LA epsilon and strain-rate parameters (systolic, early diastolic, and late diastolic during atrial contraction). Each patient received delayed-enhancement magnetic resonance imaging (DE-MRI) to check for myocardial fibrosis. We divided the patients into two groups. Patients of group 1 had no fibrosis, group 2 demonstrated moderate or severe fibrosis inor = 2 segments using a 17 segment-model of the LV.Moderate and severe fibrosis was observed in 20 patients (group 2: 66.7%). Global longitudinal LV epsilon (-13.0 +/- 2.4 vs -20.6 +/- 3.2%, P0.001) and peak LA epsilon (-0.2 +/- 3.9 vs 17.9 +/- 6.7%, P0.001) were reduced in group 2 in comparison with patients without myocardial fibrosis. In all patients peak LA epsilon correlated with global longitudinal LV epsilon (r = -0.78, P0.001). Patients with considerable myocardial fibrosis (group 2) had a higher indexed left atrial volume (35.7 +/- 12.8 ml/m2 vs 24.1 +/- 8.6 ml/m2, P = 0.016). New York Heart Association class (NYHA) was higher in patients with severe myocardial fibrosis (2.2 +/- 0.7 vs 1.3 +/- 0.5) and correlated with peak LA (r = -0.5, P = 0.008) and global LV epsilon (r = 0.5, P = 0.005).Occurrence of myocardial fibrosis in hypertrophic cardiomyopathy is associated with left atrial and ventricular dysfunction as well as with the severity of heart failure symptoms.

Aims: To assess left (LV) and right ventricular (RV) function by two-dimensional (2D) speckle tracking echocardiography and its relation to myocardial fibrosis in hypertrophic cardiomyopathy (HCM). Methods: We enrolled 50 HCM patients (30 male; 47.3 ± 9.9 years) in our study. Each patient received echocardiography with modern high-end scanners. For speckle tracking analysis of LV and RV function the dedicated software was used. The presence of myocardial fibrosis was detected by cardiac magnetic resonance imaging (MRI). Results: For intraobserver variability of RV global longitudinal strain, we found a correlation of r = 0.89 (p < 0.001) with a minor bias of 4.9 ± 2.9%. On cardiac MRI 30 patients (60%) demonstrated late gadolinium-enhancement (LGE) of the LV. Of these patients only 7% showed LGE of the RV. HCM patients with myocardial fibrosis had less global longitudinal LV strain in comparison to patients without myocardial fibrosis (−12.8 ± 2.2 vs −21.1 ± 2.6, P < 0.001), thicker interventricular septums (23.7 ± 4.0 vs 19.2 ± 5.1, P < 0.001), larger left atria (34.9 ± 7.1 vs 23.9 ± 5.1, P < 0.001), and impaired diastolic function (E/A-ratio: 1.02 ± 0.22 vs 1.15 ± 0.18, P < 0.01). Comparable results were found for RV function. LV and RV strain correlated with r = 0.85 (p < 0.001). Conclusions: HCM is not only a disease of the LV. LGE in HCM is associated with both LV and RV dysfunction. Although RV LGE occurs only in a minority of patients with HCM and LV fibrosis, speckle tracking echocardiography is feasible for evaluating LV and RV dysfunction in these patients. (Echocardiography 2012;29:438-444)

Predictors of AF Recurrence After Cryoballoon PVI. Introduction: In patients with atrial fibrillation (AF) undergoing pulmonary vein isolation, cryoballoon technique (cryoPVI) has been adopted in many centers. This study aimed to evaluate predictors of AF recurrence including impact of sleep-disordered breathing (SDB). Methods and Results: In 82 patients consecutively assigned to cryoPVI cardiorespiratory screening for SDB, assessment of medical history, ECG, echocardiography, standard laboratory measurement, and blood gas analysis were performed prior to intervention. After a 3-month blanking period, a 7-day Holter ECG was performed at 3, 6 and then every 6 months to determine AF recurrence. Seventy-five patients (69 paroxysmal AF, 6 persistent AF, 22 female, age 60 ± 9 years) completed at least 6-month follow-up. Median follow-up of 12 months (interquartile range 6–18 months) confirmed maintenance of sinus rhythm in 69.4% of these patients. Stepwise forward regression model revealed moderate to severe SDB (cut-off apnea-hypopnea-index (AHI) ≥ 15 per hour; Hazard Ratio (HR) 2.95, P = 0.04), early recurrence of AF (HR 8.74, P < 0.001), persistent AF (HR 7.16, P < 0.001), preprocedural class III-antiarrhythmic drug treatment (HR 3.63, P = 0.02), but not SDB per se (AHI ≥ 5 per hour) as independent predictors for AF recurrence. Conclusion: Moderate to severe SDB is a treatable condition that independently predicts AF recurrence in patients undergoing cryoPVI. Screening for SDB and adequate treatment may improve long-term success of cryoPVI. (J Cardiovasc Electrophysiol, Vol. 23, pp. 18-25, January 2012)

The authors investigated the prevalence of sleep-disordered breathing (SDB) together with its clinical correlations in patients with hypertrophic cardiomyopathy (HCM). A total of 113 consecutive patients including 63 patients with HCM (40 men; mean age, 59.5±13.0 years; New York Heart Association class, 2.0±0.9) underwent cardiorespiratory polygraphy in addition to their clinical work-up including echocardiography. Patients with an apnea-hypopnea-index (AHI) ≥5/h were considered to have SDB. If thoracic and abdominal inspiration efforts were documented, SDB was considered to be obstructive sleep apnea (OSA), otherwise SDB was considered to be central sleep apnea (CSA). The age- and sex-matched control group of 50 patients had exclusion of coronary artery disease by angiography, and normal left ventricular (ejection fraction ≥55%) and valvular function. SDB was diagnosed in 52 patients (82.5% vs 72% in the control group; P =not significant) with a mean AHI of 23.0±17.8/h. Severity of SDB was higher in patients with HCM than in the control group (AHI 12.2±7.6/h; P =.003). OSA was documented in 39 patients (AHI 21.2±16.5/h) and CSA in 13 (AHI 28.4±20.9/h). The severity of SDB correlated with New York Heart Association functional class (η=0.9, η(2) =0.811) and with left ventricular end-diastolic (r=0.6, P

OBJECTIVES: In patients with unresectable pancreatic cancer, estimation of individual prognosis is essential to provide the most suitable biliary stent (self-expanding metal stent or plastic stent). The aim of the current study was to determine prognostic factors for survival in patients with unresectable pancreatic cancer after initial biliary drainage. PATIENTS AND METHODS: The current study included 278 patients with unresectable pancreatic cancer. Prognostic factors for survival were analyzed using the Cox proportional hazards model, the Kaplan-Meier survival estimator, and the Wilcoxon test for difference in survival. RESULTS: In univariate analysis, advanced T stage according to the TNM classification (P = 0.021, Wald test) and the presence of distant metastases (P = 0.001, Wald test) were predictive factors for shorter survival. However, in multivariate analysis, the presence of distant metastasis was the only independent prognostic factor. The median survival time after initial biliary drainage was 3.1 and 6.6 months in patients with and without the presence of distant metastases, respectively. CONCLUSIONS: The presence of distant metastases was identified as the only independent prognostic factor for survival after initial biliary drainage. A self-expanding metal stent should be systematically chosen for patient without distant metastases, whereas polyethylene plastic stents should be preferred in patients with distant metastases.

Often, equivocal pancreatic cystic masses in a patient cannot be clearly identified. We report on a 74-year-old patient who consulted us with size-gaining multi-cystic lesions located at the pancreatic head and tail as well as with an increased CA 19-9 level. By using diagnostic methods as ultrasound, radiological images and innovative endoscopic techniques an intraductal papillary mucinous neoplasm (IPMN) was diagnosed. Evaluation of equivocal cystic lesions requires developing of further strategies as well as integration of new concepts: We present a diagnostic algorithm basedon endoscopy that enables us to perform an adapted therapy by having a more accurate evaluation and the opportunity to gain samples where unclear lesions are given.

Aims The aim of this first large-scale long-term study was to investigate whether obstructive sleep apnoea (OSA) and/or central sleep apnoea (CSA) are associated with an increased risk of malignant cardiac arrhythmias in patients with congestive heart failure (CHF). Methods and results Of 472 CHF patients who were screened for sleep disordered breathing (SDB) 6 months after implantation of a cardiac resynchronization device with cardioverter-defibrillator, 283 remained untreated [170 with mild or no sleep disordered breathing (mnSDB) and 113 patients declined ventilation therapy] and were included into this study. During follow-up (48 months), data on appropriately monitored ventricular arrhythmias as well as appropriate cardioverter-defibrillator therapies were obtained from 255 of these patients (90.1%). Time period to first monitored ventricular arrhythmias and to first appropriate cardioverter-defibrillator therapy were significantly shorter in patients with either CSA or OSA. Forward stepwise Cox models revealed an independent correlation for CSA and OSA regarding monitored ventricular arrhythmias [apnoea-hypopnoea index (AHI) >= 5 h(-1): CSA HR 2.15, 95% CI 1.40-3.30, P < 0.001; OSA HR 1.69, 95% CI 1.64-1.75, P = 0.001; AHI >= 15 h(-1): CSA HR 2.06, 95% CI 1.40-3.05, P < 0.001; OSA HR 1.69, 95% CI 1.14-2.51, P = 0.02] and appropriate cardioverter-defibrillator therapies (AHI >= 5 h(-1): CSA HR 3.24, 95% CI 1.86-5.64, P < 0.001; OSA HR 2.07, 95% CI 1.14-3.77, P = 0.02; AHI >= 15 h(-1): CSA HR 3.41, 95% CI 2.10-5.54, P < 0.001; OSA HR 2.10, 95% CI 1.17-3.78, P = 0.01). Conclusion In patients with CHF, CSA and OSA are independently associated with an increased risk for ventricular arrhythmias and appropriate cardioverter-defibrillator therapies.

Speckle tracking echocardiography (STE) or two-dimensional (2D) strain imaging is a novel ultrasound method to assess myocardial deformation. Peak systolic longitudinal strain (PSLS) of the basal septum (IVS) and the opposite lateral (LVFW) wall were measured in addition to standard echocardiography in 88 consecutive patients (pts) with obstructive hypertrophic cardiomyopathy (HOCM) who underwent a septal ablation procedure (PTSMA) and who were re-evaluated 12 ± 12 after months. At baseline, PSLS was substantially reduced both in basal regions. While PSLS remained unchanged in the basal IVS, i.e. the target region for PTSMA (baseline: −5.3 ± 4.1%; follow-up: −6.0 ± 4.3%; P = 0.06), it improved in the opposite LVFW (from −9.4 ± 4.7 to −12.4 ± 4.8%; P < 0.0001). Wall thickness decreased in both regions (Septum: from 20 ± 4 to 17 ± 4 mm; P < 0.0001; LV free wall: from 13 ± 2 to 12 ± 2 mm; P = 0.001). PSLS correlated significantly with wall thickness, both at baseline and at follow-up. NYHA functional class (from 2.9 ± 0.4 to 1.6 ± 0.6; P < 0.0001) and objective exercise capacity (from 96 ± 42 to 114 ± 42 W; P = 0.001) improved together with the reduction of outflow obstruction (LVOTO: from 62 ± 30 to 11 ± 19 mm Hg at rest, from 121 ± 26 to 43 ± 40 mm Hg with provocation; P < 0.0001). During the 12 months of observation, no patient had a severe adverse event. Regional myocardial deformation can be assessed quantitatively by STE. Reduction of LV afterload by elimination of the outflow gradient following a successful PTSMA with low doses of alcohol results in improvement of systolic lateral longitudinal function.

Background & Aims Ablation of gastric inlet patches (GIP) in the cervical esophagus by argon plasma coagulation (APC) can alleviate chronic globus sensations in the throat. We investigated the efficacy of this therapy in a randomized, controlled multicenter trial. Methods Patients with chronic globus sensations and GIP were randomly assigned 1:1 to groups that were treated with APC or a sham procedure (controls). Patients and their referring physicians were blinded to therapy. All patients completed a standardized questionnaire about symptoms before and 3 months after the procedure. Thereafter, control patients were eligible for cross-over therapy. Long-term efficacy was assessed in all patients ≥6 months after APC. Results Improvement of symptoms was reported in 9 (82%) of 11 patients who received APC, compared with 0 (0%) of 10 patients in the control group ( P = .002). Nine (90%) of 10 patients treated with APC had per protocol healing, compared with 0 (0%) of 9 controls ( P Conclusions Ablation of gastric inlet patches appears to be an effective therapy for alleviation of associated globus sensations. This new treatment modality might change the paradigm for treatment of these patients.

This guideline updates a prior concensus recommendation of the German Society for Digestive and Metabolic Diseases (DGVS) from 1996. It was developed by an interdisciplinary cooperation with representatives of the German Society for Microbiology, the Society for Pediatric Gastroenterology and Nutrition (GPGE) and the German Society for Rheumatology. The guideline is methodologically based on recommendations of the Association of the Scientific Medical Societies in Germany (AWMF) for providing a systematic evidence-based consensus guideline of S 3 level and has also implemented grading criteria according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Clinical applicability of study results as well as specifics for Germany in terms of epidemiology, antibiotic resistance status, diagnostics and therapy were taken into account.

Helicobacter pylori strains harboring the vacAs1, cagA and babA2 have been associated with ulcer disease (UD). We compared the prevalence of these different genotypes and adhesive properties in H. pylori infected patients with UD in four European countries. Genomic DNA was isolated from 314 H. pylori strains: Germany (GER; n=92), Sweden (SWE, n=74), Portugal (POR, n=91) and Finland (FIN, n=57). The frequencies of babA2 genotype varied from 35% to 60%. Triple-positive strains (vacAs1+, cagA+ and babA2+) were significantly associated with UD in GER and POR and were closely correlated with UD in FIN, but not in SWE. Classification as triple-positive strains had a higher specificity for detection of UD in GER, POR and FIN than type1 or cagA+ strains. In vitro adhesion assays revealed that Swedish strains showed high adhesion properties and were thus correlated with the diagnosis of UD, although PCR detected the babA2 gene at lower frequencies and failed to show a correlation with UD. This finding appears to reflect allelic variations of the babA2 gene in SWE, although adhesive properties of the strains are retained.

Background: Despite its high prevalence, data on the course of gastroesophageal reflux disease (GERD) are still sparse. There is also an ongoing debate on the natural history of its various manifestations, i. e., non-erosive reflux disease (NERD) vs. erosive reflux disease (ERD) vs. Barrett's esophagus (BE). Patients and Methods: This study was conducted within the framework of a prospective multicenter study on the course and prevalence of intestinal metaplasia at the gastroesophageal junction. 1014 dyspeptic patients were screened by the means of upper GI endoscopy. Clinical data were recorded by the use of a questionnaire. At least 15 months after the initial examination, all patients were invited for follow-up (FU) examination. Patients were analyzed separately with respect to their clinical and endoscopic findings. For the latter, only patients without any treatment with proton-pump-inhibitors (PPI) prior to initial and follow-up examinations were included. Patients were categorized as GERD positive if typical symptoms were present and/or proton pump inhibitors were used. Results: Sufficient clinical and/or endoscopic data were available in 590 GERD patients with heartburn at least once a week. Follow-up data could be obtained in 320 patients (clinical FU: n=304; endoscopic FU: n=52) after a mean follow-up period of 35 months (18-48 months). 96 of 144 previously asymptomatic patients (67%) remained asymptomatic at follow-up, the rest (n = 48) were symptomatic. 143 of 304 previously symptomatic patients (47%) were symptom-free at follow-up, and only 161 patients (53%) remained symptomatic or had concomitant therapy with proton-pump-inhibitors (PPI). For follow-up endoscopy in patients off PPI (n = 52), ERD was no longer confirmed in 7/12 ERD patients (58%), whereas progress to ERD was found in 3/34 patients (9%) in the NERD group. BE was newly diagnosed in two NERD patients but could no longer be detected in 2 of 6 patients with an initial diagnosis of BE. Conclusions: With respect to its clinical as well as its endoscopic manifestations, gastroesophageal reflux disease does not appear to be very stable over time. However, in most cases this is due to regression rather than progression of the disease.

Gastric enterochromaffin-like (ECL) cells are histamine-producing cells in the gastric epithelium which are responsible for the peripheral regulation of acid secretion. The gastric mucosa is frequently infected with Helicobacter pylori, leading to increased levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). The aim of our current study was to identify the effect of TNF-α on programmed cell death. ECL cells were isolated from the rat corpus mucosa to a purity >90%. TNF receptor and adapter protein presence were determined using RT-PCR, Western blot and immunocytochemistry. Apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and by DNA fragmentation based ELISA. Isolated ECL cells were found to express the TNF receptor p55 and IFN-γ receptor, but not the TNF receptor p75 or CD95. TNF-α (25 ng/ml) increased apoptosis in ECL cells approximately 4-fold, IFN-γ had no effect. Western blot analysis revealed that TNF-α caused degradation of IĸBα within 10 min. EMSA demonstrated that TNF-α led to increased DNA-binding activity of NFĸB and that proteasome inhibitors counteracted NFĸB activation. Proteasome inhibitors, specific antisense oligodeoxynucleotides against the p65 subunit of the NFĸB complex and the NO synthase inhibitor NG-monomethyl-L-arginine completely prevented TNF-α-induced apoptosis. Our data suggest that TNF-α induces apoptosis of isolated gastric ECL cells via activation of NFĸB and the generation of NO.

Supraventricular tachyarrhythmias are a major cause of inappropriate defibrillator shocks. Sleep-disordered breathing (SDB) is a known risk factor for atrial fibrillation (AF). We hypothesized that Cheyne–Stokes respiration (CSA) and obstructive sleep apnea (OSA) have an impact on inappropriate defibrillator discharges in patients witch chronic heart failure (CHF) and cardiac resynchronization therapy with defibrillator (CRT-D). In this study, 172 patients with CHF (LVEF ≤ 45 %, NYHA-class ≥ 2) and CRT-D underwent overnight polygraphy; 54 had no SDB (apnea–hypopnea index

Gastric enterochromaffin-like cells produce histamine in response to the antral hormone gastrin and accumulate the biogenic amine in secretory organelles via vesicular monoamine transporter subtype 2. The putative effects of gastrin on vesicular monoamine transporter subtype 2 expression and promoter activity are poorly understood. In the present study we used highly enriched rat enterochromaffin-like cells (purity, >90%) and rat pheochromocytoma cells stably transfected with a gastrin/cholecystokinin B receptor to investigate the expression and transcriptional regulation of vesicular monoamine transporter subtype 2. Stimulation of vesicular monoamine transporter subtype 2 mRNA and protein expression was observed in isolated enterochromaffin-like cells after 3- to 7-h incubation with gastrin (10(-7) M), forskolin (10(-5) M), or ionomycin (10(-5) M). Deletion analysis of the rat vesicular monoamine transporter subtype 2 promoter defined the minimal promoter sequence necessary for full basal activity as a -121 bp segment upstream of exon 1 containing two Sp1 sites (-97 to -88 bp and -68 to -59 bp) and a cAMP-responsive element (-44 to -35 bp). Gastrin (10(-7) M) stimulated extracellular signal related kinase1/2 phosphorylation, activated Sp1 and cAMP-responsive element-binding protein, and further induced activity of the complete rat vesicular monoamine transporter subtype 2 promoter (-800 bp) in gastrin/cholecystokinin B receptor cells. The -121-bp fragment was able to confer full gastrin responsiveness, and site-directed mutagenesis of the Sp1 and cAMP-responsive element motifs demonstrated their crucial importance for basal and inducible activities. Comparison of promoter activity of histidine decarboxylase, chromogranin A, or vesicular monoamine transporter subtype 2 in transfected cell lines revealed significant differences in basal and gastrin-stimulated activities. Our current study provides the first evidence that gastrin directly stimulates the expression and promoter activity of vesicular monoamine transporter subtype 2. Sp1 and cAMP-responsive element-binding protein recognition motifs located within 121 bp upstream of exon 1 appear to be indispensable for full basal and inducible promoter activities. Diverging effects of gastrin on histidine decarboxylase, chromogranin A, and vesicular monoamine transporter subtype 2 promoter may account for the coordinated synthesis and storage of histamine in this neuroendocrine cell type.

History. We report about the course of central sleep apnea (CSA) in 3 patients ( years) with severe aortic stenosis (AS) ( cm2, NYHA ).Investigations. Every patient received echocardiography, left/right-heart catheterization, and cardiorespiratory polygraphy before and 6 months after surgical aortic valve replacement (without right-heart catheterization during follow up).Course. Preoperatively all patients demonstrated reduced systolic left ventricular function (EF ). They had elevated pulmoraryarterialy pressures and severe CSA. After valve replacement left ventricular function and exercise capacity improved, as well as the severity of CSA.Conclusion. Patients with severe AS can develop CSA, which seems to improve after surgery. Patients with severe AS should be screened for CSA, because CSA might be an additional risk factor and hint that myocardial adaptation is exhausting.

Aims To use particle image velocimetry (PIV) echocardiography for the evaluation of diastolic dysfunction (DD) in patients with hypertrophic nonobstructive cardiomyopathy (HNCM). Methods This study included 50 individuals, thereof 30 patients with DD due to HNCM and 20 healthy individuals who served as controls. HNCM patients were divided into 3 groups according to DD severity. All subjects underwent clinical assessment, exercise testing, and standard as well as PIV echocardiography. Results Energy dissipation was higher in DD patients than in the control group. The severity of flow pattern disturbance corresponded to the degree of DD. In a subgroup of 20 HNCM patients we found significant correlations between invasive measured left ventricular end-diastolic pressure and noninvasive PIV parameters for intraventricular pressure differences and filling. Inter-observer variability (mean difference ± 1.96 SD) for all tested PIV measurements was good. Conclusion According to DD severity, patients with HNCM have disturbed intraventricular flow and reduced intraventricular pressure differences, consistent with a reduced intraventricular suction. PIV echocardiography appears to be feasible for detailed analysis of ventricular vortex flow in DD conditions. Further research using PIV echocardiography in different cardiac pathologies seems warranted.

A 65-year-old German woman was admitted to our hospital with signs and symptoms of an acute coronary syndrome (NSTEMI). On admission, she reported progressive cervical and chest pain, since a few hours. On physical examination, there was a non-specific cardiac murmur with punctum maximum at Erb0s point. Lung sounds were normal, and blood pressure was 115/70 mmHg. The following laboratory data were obtained: creatine kinase of 282 U/L (reference level \171 U/L), troponin I 4.5 lg/L (reference level \0.04 lg/L), lactate dehydrogenase of 250 U/L (reference level \248 U/L), creatinine of 0.82 mg/dL (reference level 0.7–1.2 mg/dL) and C-reactive protein of 0.29 mg/dL (reference level \0.5 mg/dL). The ECG demonstrated repolarization abnormalities in leads I, II, III, aVF and V4-V6 (Fig. 1a). Cardiac catheterization excluded a significant macroangiopathy. A transthoracic echocardiogram was consistent with hypertrophic cardiomyopathy of the apical type without significant LV outflow obstruction (Fig. 2a) prompting routine screening to exclude secondary origin of LVH. A decreased a-galactosidase A activity was found and triggered further molecular genetic workup. A Fabry-specific mutation C.559.A[G (M187V) in the a-galactosidase gene was identified. In addition to symptomatic medical treatment, and in cooperation with a regional center for Fabry’s disease, the patient received continuous enzymereplacement therapy with Agalsidase-b [1]. After 1 year, the clinical status of the patient was stable. Both regression of the ST segment abnormalities (Fig. 1b) on ECG, and improvement of regional LV function (Fig. 2b) by speckle tracking echocardiography was documented [2, 3]. This report illustrates the potential of a causal therapy in patients with cardiac manifestations of Fabry’s disease.

Enterochromaffin-like (ECL) cells play a pivotal role in the peripheral regulation of gastric acid secretion as they respond to the functionally important gastrointestinal hormones gastrin and somatostatin and neural mediators such as pituitary adenylate cyclase-activating peptide and galanin. Gastrin is the key stimulus of histamine release from ECL cells in vivo and in vitro. Voltage-gated K+and Ca2+channels have been detected on isolated ECL cells. Exocytosis of histamine following gastrin stimulation and Ca2+entry across the plasma membrane is catalyzed by synaptobrevin and synaptosomal-associated protein of 25 kDa, both characterized as a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein. Histamine release occurs from different cellular pools: preexisting vacuolar histamine immediately released by Ca2+entry or newly synthesized histamine following induction of histidine decarboxylase (HDC) by gastrin stimulation. Histamine is synthesized by cytoplasmic HDC and accumulated in secretory vesicles by proton-histamine countertransport via the vesicular monoamine transporter subtype 2 (VMAT-2). The promoter region of HDC contains Ca2+-, cAMP-, and protein kinase C-responsive elements. The gene promoter for VMAT-2, however, lacks TATA boxes but contains regulatory elements for the hormones glucagon and somatostatin. Histamine secretion from ECL cells is thereby under a complex regulation of hormonal signals and can be targeted at several steps during the process of exocytosis.

Enterochromaffin-like (ECL) cells are histamine-containing endocrine cells in the gastric epithelium that show increased density during chronic atrophic gastritis. The current study determined cell number and apoptosis of isolated rat ECL cells in response to several growth factors. Isolated ECL cells from fundic mucosa (enrichment >90%) were grown in serum-free medium over 2-5 days. Cell number was determined by mitochondrial formazan production; apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and DNA fragmentation-based enzyme-linked immunosorbent assay. Immunocytochemistry and RT-PCR demonstrated the presence of epidermal growth factor receptor, neuronal growth factor receptor (type 1), and fibroblast growth factor (FGF) receptor (type 1). Gastrin (EC50, approximately 2 pM), transforming growth factor-alpha (TGF alpha; 10-30 ng/ml), and basic FGF (bFGF; 1-10 ng/ml) increased the total number of cultured ECL cells. bFGF augmented the gastrin (1 pM)-induced response. Beta-neuronal growth factor (10 ng/ml) and bFGF (2 ng/ml) decreased the programed death of ECL cells. Interleukin-1beta (100 pg/ml, 24 h) stimulated apoptosis 2- to 3-fold in ECL cells, and simultaneous incubation with TGF alpha (20 ng/ml) or bFGF (2 ng/ml) significantly inhibited this effect. ECL cells express specific receptors for gastrin, epidermal growth factor, neuronal growth factor, and FGF. bFGF prolonged ECL cell survival by inhibiting spontaneous apoptosis. Our data further indicate that TGF alpha and bFGF increase ECL cell number by inhibiting cytokine-induced programed cell death.

BACKGROUND & AIMS: Histamine-producing enterochromaffin-like (ECL) cells play an integrative role in the regulation of acid secretion. Decreased mucosal histamine concentrations and increased levels of interleukin (IL) 1 beta, IL-6, and IL-8 have been detected in the gastric mucosa inflamed with Helicobacter pylori. The aim of this study was to investigate the response of isolated ECL cells to these cytokines. METHODS: Enriched rat gastric ECL cells (85%-95%) were cultured for 2-4 days. RESULTS: Polymerase chain reaction showed IL-1 and IL-6, but not IL-8 receptors, in ECL cell complementary DNA. Positive receptor staining with biotinylated IL-1 beta corresponded to ECL cell enrichment (92%). IL-6 and IL-8 had no effect on histamine secretion. IL-1 beta (2 U/mL) stimulated basal histamine secretion and nitric oxide production within 60 minutes and cyclic guanosine monophosphate production within 20 minutes. Pretreatment for 20 minutes with IL-1 beta (2 U/mL) attenuated gastrin-stimulated histamine secretion by 40%-50%, reversed by the IL-1 receptor antagonist (10 U/ mL). Pretreatment for 20 minutes with IL-1 beta (2 U/mL) completely inhibited gastrin-stimulated (1 nmol/L) histidine decarboxylase activity. IL-1 beta (2 U/mL, 60 minutes) increased lactate dehydrogenase release to 25% of cell content. Cells pretreated with IL- 1 beta did not respond to gastrin after a further 48-hour culture and showed decreased histamine content. CONCLUSIONS: ECL cells appear to express IL-1 receptors. IL-1 beta causes sustained functional impairment of ECL cells in vitro. (Gastroenterology 1997 Feb;112(2):364-75)

Type 2 diabetes and obstructive sleep apnoea (OSA) are diseases with high prevalence and major public health impact. There is evidence that OSA is independently associated with alterations in glucose metabolism. Furthermore, OSA is a significant risk factor for the development of type 2 diabetes. Possible causes might be intermittent hypoxaemia and sleep fragmentation with increased oxidative stress and sympathetic activity, which are typical features of OSA. OSA might also be a reason for ineffective treatment of type 2 diabetes. There is further evidence that the treatment of OSA by continuous positive airway pressure (CPAP) therapy might improve glucose metabolism. On the other hand, there are also hints in the literature that type 2 diabetes might induce sleep apnoea, especially in patients with autonomic neuropathy, but that OSA also facilitates the development of neuropathy in terms of mutual interactions between OSA, type 2 diabetes and diabetic neuropathy. Based on the current scientific data, clinicians have to be aware of the relations between OSA and type 2 diabetes, both from the sleep medical and the diabetological point of view.

The infarction induced by alcohol septal ablation (ASA) may predispose to arrhythmia and sudden cardiac death (SCD).To assess survival, incidence of SCD after ASA and effects of ASA on the traditional risk factors (RFs) for SCD.An observational cohort-study (follow-up 8.4±4 years).A dual-centre cohort.470 consecutive patients (age 56±14 years) with obstructive hypertrophic cardiomyopathy (HCM) (1996-2010).Clinically applied echo-contrast-guided ASA treatments.All-cause mortality, SCD and RFs for SCD before and after ASA.The 10-year survival was 88% (annual all-cause death rate 1.2%) after ASA compared with 84% (p=0.06) in a matched background population. The 10-year survival free of SCD was 95% (annual SCD rate 0.5%). ASA reduced the prevalence of abnormal blood pressure response (from 23% to 9%, p0.001), syncope (26% to 2%, p0.001), non-sustained ventricular tachycardia (NSVT) (23% to 17%, p0.05) and maximal wall thickness ≥30 mm (7% to 2%, p0.001). There was a family history of SCD in 19% of the patients. The proportion of patients at high risk-that is, two or more RFs (n=89), was reduced from 25% to 8% (p0.001). A RF score ≥2 before ASA was not associated with SCD (n=361, p=0.31).Survival in ASA-treated patients was similar to that in the background population. The number of RFs, including the prevalence of NSVT, was markedly reduced by ASA and the incidence of SCD was correspondingly low. Thus, clinically applied ASA was safe.

Fibroblast activity within the heart may be considered a basically constructive process. Hyperactivity of fibroblasts, however, may result in the accumulation of extracellular matrix proteins with adverse effects on cardiac structure and function including electrical instability and increased risk of arrhythmogenic cardiac death. The detection of cardiac fibrosis by dedicated imaging techniques, mainly gadolinium-enhanced MRI, holds promise to refine patient management in a variety of cardiac conditions. This review aims to summarize the current knowledge regarding fibrosis in hypertrophic cardiomyopathy.

Previous studies confirmed Cheyne-Stokes respiration (CSA) and obstructive sleep apnea (OSA) to be independently associated with adequate implanted cardioverter-defibrillator (ICD) therapies in patients with chronic heart failure (CHF) to prevent sudden cardiac death. This study aims to clarify the

Patients (pts) with hypertrophic cardiomyopathy (HCM) may present with a variety of symptoms, including sudden cardiac death. Sudden cardiac death due to ventricular fibrillation correlates with the extent of intramural fibrosis (IF). IF can be detected using cardiac magnetic resonance (CMR) by