Unmasking the dormant pulmonary vein conduction with adenosine administration after pulmonary vein isolation with laser energy.

AIMS: The isolation of the pulmonary veins (PVs) is the mainstay of atrial fibrillation (AF) ablation, which with current ablation techniques can be achieved in almost all cases. Reconnection of PVs constitutes the most frequent cause of AF recurrence. Visually guided laser balloon ablation (VGLA) is a novel system with very high rate of persistence of pulmonary vein isolation (PVI) three months after the first procedure shown in preclinical and clinical studies. We aimed to determine the acute efficiency of the laser energy during PVI with the help of adenosine provocation. METHODS AND RESULTS: Twenty-six patients (19 male; mean age 64 ± 9 years) with symptomatic paroxysmal AF were included in the study. Pulmonary vein isolation was performed using the VGLA system. After successful PVI, we studied the effects of intravenous adenosine (18 mg) on activation of each PV at least 20 min after PVI. A total of 104 PVs were targeted. The balloon catheter could not be placed in two PVs. Of the remaining 102 PVs 99 (97% of the ablated PVs) could be successfully isolated. Adenosine was administered for each isolated PV in 25 patients. Only six PVs (6.7%) in five patients (20%) showed a PV reconnection during adenosine provocation. CONCLUSION: Pulmonary vein isolation with VGLA is a feasible technique for PVI with a very effective acute lesion formation. The clinical significance of this low reconnection rate has to be determined.

Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction.

AIMS: Sleep-disordered breathing (SDB) may be a risk factor for expansion of infarct size early after acute myocardial infarction (MI) by exposing the heart to repetitive oxygen desaturations and increased cardiac afterload. The objective of this study was to assess the impact of SDB on myocardial salvage and infarct size within 3 months after acute MI. METHODS AND RESULTS: Patients with acute MI and percutaneous coronary intervention were enrolled in this prospective observational study. All patients underwent cardiovascular magnetic resonance (CMR) to define salvaged myocardium and infarct size within three to five days and at 3 months after acute MI. Patients were stratified according to apnoea-hypopnoea index (AHI) assessed by polysomnography at baseline into those with (AHI ≥ 15/h) and without (AHI < 15/h) SDB. Of the 56 patients included, 29 (52%) had SDB. The area at risk between both groups was similar (40 ± 12% vs. 40 ± 14%, P = 0.925). Patients with SDB had significantly less salvaged myocardium (myocardial salvage index 52% vs. 77%, P < 0.001), smaller reduction in infarct size (0.3% vs. 6.5%, P < 0.001) within 3 months after acute MI, a larger final infarct size (23% vs. 12%, P < 0.001), and a lower final left ventricular ejection fraction (48% vs. 54%, P = 0.023). In a multivariate analysis, including established risk factors for large MI, AHI was independently associated with less myocardial salvage and a larger infarct size 3 months after acute MI. CONCLUSIONS: Sleep-disordered breathing was associated with less myocardial salvage and a smaller reduction in infarct size. These findings suggest a contribution of SDB to impaired healing of MI.

Experimental heart failure induces alterations of the lung proteome--insight into molecular mechanisms.

BACKGROUND: Heart failure (CHF) is characterized by dyspnea and pulmonary changes. The underlying molecular adaptations are unclear, but might provide targets for therapeutic interventions. We therefore conceived a study to determine molecular changes of early pulmonary stress failure in a model of tachycardia-induced heart failure. METHODS: CHF was induced in rabbits by progessive right ventricular pacing (n=6). Invasive blood pressure measurements and echocardiography were repeatedly performed. Untreated animals served as controls (n=6). Pulmonary tissue specimens were subjected to two-dimensional gel electrophoresis, and differentially expressed proteins were identified by mass spectrometry. Selected proteins were validated by Western Blot analysis and localized by immunohistochemical staining. RESULTS: CHF animals were characterized by significantly altered functional, morphological, and hemodynamic parameters. Upon proteomic profiling, a total of 33 proteins was found to be differentially expressed in pulmonary tissue of CHF animals (18 up-regulated, and 15 down-regulated) belonging to 4 functional groups: 1. proteins involved in maintaining cytoarchitectural integrity, 2. plasma proteins indicating impaired alveolar-capillary permeability, 3. proteins with antioxidative properties, and 4. proteins participating in the metabolism of selenium compounds CONCLUSION: Experimental heart failure profoundly alters the pulmonary proteome. Our results supplement the current knowledge of pulmonary stress failure by specifying its molecular fundament.

A unique access for the ablation catheter to treat electrical storm in a patient with extracorporeal life support.

AIMS: Extracorporeal membrane oxygenation (ECMO) is a very effective bridging therapy in patients with cardiogenic shock. To perform coronary angiography in these patients our group developed an unique system to get urgent vascular access with minimal additional vascular complication risk. The 6 Fr coronary catheters are introduced through a standard Y-connector, which is inserted into the arterial cannula of the ECMO-line close to the patient, the blind end of which is then equipped with a haemostatic valve (Check-Flo Performer accessory adapter, Cook Medical, USA). To the best of our knowledge, we here present the first patient, in whom this system had been used to insert an 8 Fr radiofrequency ablation catheter to treat incessant ventricular fibrillation. METHODS AND RESULTS: A 66-year-old patient had been transferred with electrical storm 5 days after an acute MI. After failed interventional and medical therapies an ECMO system had been inserted (right femoral artery cannula 15 Fr, left femoral vein cannula 21 Fr) and an electrophysiological study had been performed because of incessant ventricular fibrillation episodes, which always were induced by the same ventricular premature beat (VPB). During this first EP study over the left femoral artery the VPB could be targeted and successfully ablated. Unfortunately the VPB recovered again after some days so a second EP study had to be performed. This time the left femoral artery could not be used because of a postinterventional complication so we used the arterial cannula of the ECMO system as the access for the ablation catheter using a Y-connector. Using this way again a successful ablation procedure could be performed, after getting familiar with manipulation the ablation catheter over the ECMO cannula and with the help of different curved ablation catheters. The issue of compromising of the effective lumen of the arterial cannula by the ablation catheter`s cross sectional area could be overcome with increasing the rotational speed of the V-A ECMO. CONCLUSION: Ablation of ventricular arrhythmias using a Y-connector to insert the ablation catheter into the arterial cannula is feasible in patients with a V-A ECMO system avoiding additional arterial puncture with potentially major vascular complications in critically ill patients. Manipulation of the catheter is not as easy as using a standard sheath but can well be performed after a short habituation.

Emergency and prophylactic use of miniaturized veno-arterial extracorporeal membrane oxygenation in transcatheter aortic valve implantation.

OBJECTIVES: To report our center's experience using veno-arterial extracorporeal membrane oxygenation (vaECMO) in transcatheter aortic valve implantation (TAVI). BACKGROUND: In TAVI, short-term mortality closely relates to life threatening procedural complications. VaECMO can be used to stabilize the patient in emergency situations. However, for the prophylactic use of vaECMO in very high-risk patients undergoing TAVI there is no experience. METHODS: From January 2009 to August 2011, we performed 131 TAVI. Emergency vaECMO was required in 8 cases (7%): ventricular perforation (n = 3), hemodynamic instability/cardiogenic shock (n = 4), hemodynamic deterioration due to ventricular tachycardia (n = 1). Since August 2011, during 83 procedures, prophylactic vaECMO was systematically used in very high-risk patients (n = 9, 11%) and emergency ECMO in one case (1%) due to ventricular perforation. RESULTS: Median logistic EuroScore in prophylactic vaECMO patients was considerably higher as compared to the remaining TAVI population (30% vs. 15%, P = 0.0003) while in patients with emergency vaECMO it was comparable (18% vs. 15%, P = 0.08). Comparing prophylactic to emergency vaECMO, procedural success and 30-day mortality were 100% vs. 44% (P = 0.03) and 0% vs. 44% (P = 0.02), respectively. Major vascular complications and rate of life threatening bleeding did not differ between both groups (11% vs. 11%, P = 0.99 and 11% vs. 33%, P = 0.3) and were not vaECMO-related. CONCLUSIONS: Life-threatening complications during TAVI can be managed using emergency vaECMO but mortality remains high. The use of prophylactic vaECMO in very high-risk patients is safe and may be advocated in selected cases.

A comprehensive linkage analysis for myocardial infarction and its related risk factors.

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Natural course of sleep-disordered breathing after acute myocardial infarction.

The aim of this study was to test whether an improvement of left ventricular ejection fraction (EF) in the early phase after acute myocardial infarction is associated with a reduction of the severity of central and obstructive sleep apnoea. 40 consecutive patients with acute myocardial infarction underwent polysomnography and cardiovascular magnetic resonance imaging within 5 days and 12 weeks after the event to assess sleep apnoea and cardiac function. We stratified the sample in patients who improved their left ventricular EF within 12 weeks by ≥ 5% (improved EF group, ΔEF 9 ± 1%, n=16) and in those who did not (unchanged EF group, ΔEF -1 ± 1%, n=24). Prevalence of sleep apnoea (≥ 15 apnoea and hypopnoea events·h(-1)) within ≤ 5 days after myocardial infarction was 55%. Apnoea and hypopnoea events·h(-1) were significantly more reduced in the improved EF group compared with the unchanged EF group (-10 ± 3 versus 1 ± 3 events·h(-1); p=0.036). This reduction was based on a significant alleviation of obstructive events (-7 ± 2 versus 4 ± 3 events·h(-1); p=0.009), while the reduction of central events was similar between groups (p=0.906). An improvement of cardiac function early after myocardial infarction is associated with an alleviation of sleep apnoea. This finding suggests that re-evaluation of treatment indication for sleep apnoea is needed when a change in cardiac function occurs.

Proteomic profiling implies mitochondrial dysfunction in tachycardia-induced heart failure.

BACKGROUND/OBJECTIVES: Molecular mechanisms of congestive heart failure as reflected by alterations of protein expression patterns are still incompletely analyzed. We therefore investigated intraventricular (ie, left ventricular congestive heart failure [LV-CHF] vs. LV-control [CTRL], and right ventricular [RV]-CHF vs. RV-CTRL) and interventricular (ie, LV-CHF vs. RV-CHF, and LV-CTRL vs. RV-CTRL) protein expression differences in an animal model. METHODS: The model of rapid ventricular pacing in rabbits was combined with a proteomic approach using 2-dimensional gel electrophoresis. Identification of proteins was done by matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS). RESULTS: Rapid ventricular pacing-induced heart failure was characterized by LV dilatation, dysfunction, and hypotension as well as by increased BNP gene expression. By comparing LV-CHF vs. LV-CTRL, proteins were found to be underexpressed at 3 crucial points of cellular energy metabolism. In RV-CHF vs. RV-CTRL, proteins belonging to respiratory chain complexes were underexpressed, but additionally a disturbance in the nitric oxide-generating enzymatic apparatus was seen. Regarding the interventricular analyses, a stronger expression of energetic pathways was accompanied by an underexpression of contractile and stress response proteins in failing left vs. right ventricles. Finally, significant protein expression differences were found in LV-CTRL vs. RV-CTRL reflecting a higher expression of contractile, stress response, and respiratory chain proteins in LV tissue. CONCLUSIONS: In tachycardia-induced heart failure, significant inter- and intraventricular protein expression patterns were found with a predominance of proteins, which are involved in cellular energy metabolism.

Increased myocardial SERCA expression in early type 2 diabetes mellitus is insulin dependent: In vivo and in vitro data.

BACKGROUND: Calcium (Ca2+) handling proteins are known to play a pivotal role in the pathophysiology of cardiomyopathy. However little is known about early changes in the diabetic heart and the impact of insulin treatment (Ins). METHODS: Zucker Diabetic Fatty rats treated with or without insulin (ZDF ± Ins, n = 13) and lean littermates (controls, n = 7) were sacrificed at the age of 19 weeks. ZDF + Ins (n = 6) were treated with insulin for the last 6 weeks of life. Gene expression of Ca2+ ATPase in the cardiac sarcoplasmatic reticulum (SERCA2a, further abbreviated as SERCA) and phospholamban (PLB) were determined by northern blotting. Ca2+ transport of the sarcoplasmatic reticulum (SR) was assessed by oxalate-facilitated 45Ca-uptake in left ventricular homogenates. In addition, isolated neonatal cardiomyocytes were stimulated in cell culture with insulin, glucose or triiodthyronine (T3, positive control). mRNA expression of SERCA and PLB were measured by Taqman PCR. Furthermore, effects of insulin treatment on force of contraction and relaxation were evaluated by cardiomyocytes grown in a three-dimensional collagen matrix (engineered heart tissue, EHT) stimulated for 5 days by insulin. By western blot phosphorylations status of Akt was determed and the influence of wortmannin. RESULTS: SERCA levels increased in both ZDF and ZDF + Ins compared to control (control 100 ± 6.2 vs. ZDF 152 ± 26.6* vs. ZDF + Ins 212 ± 18.5*# % of control, *p < 0.05 vs. control, #p < 0.05 vs. ZDF) whereas PLB was significantly decreased in ZDF and ZDF + Ins (control 100 ± 2.8 vs. ZDF 76.3 ± 13.5* vs. ZDF + Ins 79.4 ± 12.9* % of control, *p < 0.05 vs control). The increase in the SERCA/PLB ratio in ZDF and ZDF ± Ins was accompanied by enhanced Ca2+ uptake to the SR (control 1.58 ± 0.1 vs. ZDF 1.85 ± 0.06* vs. ZDF + Ins 2.03 ± 0.1* µg/mg/min, *p < 0.05 vs. control). Interestingly, there was a significant correlation between Ca2+ uptake and SERCA2a expression. As shown by in-vitro experiments, the effect of insulin on SERCA2a mRNA expression seemed to have a direct effect on cardiomyocytes. Furthermore, long-term treatment of engineered heart tissue with insulin increased the SERCA/PLB ratio and accelerated relaxation time. Akt was significantly phosphorylated by insulin. This effect could be abolished by wortmannin. CONCLUSION: The current data demonstrate that early type 2 diabetes is associated with an increase in the SERCA/PLB ratio and that insulin directly stimulates SERCA expression and relaxation velocity. These results underline the important role of insulin and calcium handling proteins in the cardiac adaptation process of type 2 diabetes mellitus contributing to cardiac remodeling and show the important role of PI3-kinase-Akt-SERCA2a signaling cascade.

Impact of three-dimensional transesophageal echocardiography on prosthesis sizing for transcatheter aortic valve implantation.

OBJECTIVES: To compare aortic annulus diameters obtained by 3D transesophageal echocardiography (TEE) with 2D-TEE and the impact on prosthesis size selection in transcatheter aortic valve implantation (TAVI). BACKGROUND: In TAVI the aortic annulus diameter determines prosthesis size. The ideal modality for annulus assessment has not been defined yet. METHODS: Annulus diameters in 2D-TEE (long-axis view) and in 3D-TEE (long-axis view in multiple-plane-reconstruction) were compared in consecutive patients with aortic stenosis screened for TAVI. Prosthesis size was selected according to industry guidelines, integrating data from 3D-TEE, angiography and computed tomography. The percentage of cases in which 2D-TEE and 3D-TEE correctly predicted final prosthesis size was calculated. RESULTS: Forty-nine patients were studied (Age 80 ± 5, 39% male, logistic EuroScore 17 ± 11%). Annulus diameters from 2D- and 3D-TEE correlated (r = 0.808, P < 0.0001). Mean diameters were significantly larger on 3D- vs. 2D-TEE (23.4 ± 2.2 vs. 22.1 ± 2.6 mm, P < 0.001) with a mean difference of 1.2 mm (limits of agreement: -1.8 to 4.3). The interobserver variability of 2D- and 3D-TEE was 3.5 ± 5.6% and 0.9 ± 5.1%, respectively. Thirty-nine patients underwent TAVI (27 CoreValve™, 12 Edwards Sapien™). The procedure was successful in 37 (95%) patients. Postprocedural regurgitation was none or mild in 89% of the cases with no severe insufficiency. Final prosthesis size was correctly predicted by 2D-TEE in 67% while in 80% by 3D-TEE. Overall, 3D-TEE suggested a different prosthesis size in 26% of all cases compared to 2D-TEE. CONCLUSIONS: Aortic annulus measurement by 3D-TEE yields significantly larger diameters than 2D-TEE. This impacts prosthesis size selection in a considerable percentage of cases.

Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report.

BACKGROUND: Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet. METHODS: After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed. RESULTS: Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content. CONCLUSION: Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.

High-sensitive troponin T in chronic heart failure correlates with severity of symptoms, left ventricular dysfunction and prognosis independently from N-terminal pro-b-type natriuretic peptide.

BACKGROUND: Troponin T is an established marker of myocardial ischemia. We speculated that the role of the new high-sensitive troponin T (hs-cTnT) might expand towards non-ischemic myocardial disease, indicate disease severity and allow for prognostication in chronic heart failure. METHODS: Hs-cTnT (Roche Diagnostics, Mannheim, Germany) was assessed in 233 individuals with chronic heart failure (n=149) or healthy controls (n=84). RESULTS: Hs-cTnT was significantly elevated in patients with chronic heart failure [0.018 ng/mL, interquartile range (IQR) 0.009-0.036 ng/mL, vs. controls 0.003 ng/mL, 0.003-0.003 ng/mL, p<0.001] and positively correlated with N-terminal pro-b-type natriuretic peptide (NT-proBNP) (r=0.79, p<0.001). Hs-cTnT increased stepwise and signitificantly according to clinical (NYHA stage) as well as functional (LV ejection fraction, fluid retention) severity (each p<0.001). At a binary cutpoint of 0.014 ng/mL, hs-TropT was a significant predictor of all-cause mortality and all-cause mortality or rehospitalization for congestive heart failure (each p≤0.01). Of note, the prognostic value of hs-TropT was independent and additive to that of NT-proBNP. CONCLUSIONS: Hs-cTnT increases stepwise with the severity of symptoms and LV dysfunction and offers important prognostic information in chronic heart failure, independently from and additive to NT-proBNP. The utility of hs-cTnT expands beyond acute myocardial ischemia and towards chronic heart failure.

Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA).

BACKGROUND: Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. METHODS AND FINDINGS: Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. CONCLUSIONS: We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).

Contractile reserve and extent of transmural necrosis in the setting of myocardial stunning: comparison at cardiac MR imaging.

PURPOSE: To perform a comparison of cardiac magnetic resonance (MR) imaging-derived ejection fraction (EF) during low-dose dobutamine infusion (EF(D)) with the extent of segments with transmural necrosis in more than 50% of their wall thickness (ETN) for the prediction of major adverse cardiac events (MACEs) and late systolic recovery soon after a first ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: Institutional ethics committee approval and written informed consent were obtained. One hundred nineteen consecutive patients with a first STEMI, a depressed left ventricular EF, and an open infarct-related artery underwent MR imaging at 1 week after infarction. EF(D) and ETN (by using a 17-segment model) were determined, and the prediction of MACEs and systolic recovery at follow-up was assessed by using area under the receiver operating characteristic curve (AUC) and multivariable regression analysis. RESULTS: During follow-up (median, 613 days; range, 312-1243 days), 18 MACEs (five cardiac deaths, six myocardial infarctions, seven readmissions for heart failure) occurred. MACEs were associated with a lower EF(D) (43% +/- 12 [standard deviation] vs 49% +/- 10, P = .02) and a larger ETN (seven segments +/- three vs four segments +/- three, P < .001). Patients with systolic recovery (increase in EF of >5% at follow-up compared with baseline EF, n = 44) displayed a higher EF(D) (51% +/- 10 vs 47% +/- 9, P = .04) and a smaller ETN (three segments +/- two vs five segments +/- three, P = .002) at 1 week. ETN and EF(D) both related to MACEs (AUC: 0.78 vs 0.67, respectively, P = .1) and systolic recovery (AUC: 0.68 vs 0.62, respectively, P = .3). According to multivariable analysis, ETN was the only MR variable associated with time to MACEs (hazard ratio, 1.38; 95% confidence interval: 1.19, 1.60; P < .001) and systolic recovery (odds ratio, 0.76; 95% confidence interval: 0.64, 0.92; P = .004) independent of baseline characteristics. CONCLUSION: ETN is as useful as EF(D) for the prediction of MACEs and systolic recovery soon after STEMI.

Dynamic changes in N-terminal pro-brain natriuretic peptide in acute coronary syndromes treated with percutaneous coronary intervention: a marker of ischemic burden, reperfusion and outcome.

BACKGROUND: Whereas N-terminal pro-brain natriuretic peptide (NT-proBNP) is approved for risk stratification of patients with acute coronary syndromes (ACS), short-term temporal changes in NT-proBNP concentrations and the optimal time points for sampling are not clear. The purpose of this study was to better define the short-term changes in NT-proBNP in relation to clinical presentation, reperfusion and prognostic value in patients with ACS, as well as to identify the optimum time points for sampling. METHODS: We studied daily plasma concentrations of NT-proBNP in 133 unselected patients with myocardial infarction (n=65), stable coronary artery disease (CAD, n=46) and no CAD (n=22) who underwent coronary angiography. RESULTS: Patients with non-ST-elevation myocardial infarction (NSTEMI) presented with markedly higher NT-proBNP than patients with ST-elevation myocardial infarction (STEMI) [1305 (741-3208) ng/L vs. 170 (70-424) ng/L, p<0.001]. Also, time to presentation from onset of pain was much longer in NSTEMI as compared to STEMI (>48 h vs. <6 h, p<0.001). Patients with NSTEMI also presented with higher NT-proBNP as compared with CAD [224 (98-732) ng/L] and no CAD [47 (26-102) ng/L; p<0.001, NSTEMI vs. both]. Following successful percutaneous coronary intervention [thrombolysis in myocardial infarction (TIMI) 3-flow established], NT-proBNP increased markedly within 24 h in patients with STEMI [718 (379-1338) ng/L, p<0.01 vs. 0 h], whereas no change in NT-proBNP was noted in patients with NSTEMI [1190 (1010-2024) ng/L, p=0.88 vs. 0 h]. In both STEMI and NSTEMI, NT-proBNP decreased significantly 96 h after successful reperfusion [STEMI -52%, 372 (189-610) ng/L, p<0.05; NSTEMI -52%, 613 (365-724) ng/L, p<0.05]. Unsuccessful reperfusion (TIMI<3) was associated with unchanged or increased NT-proBNP. NT-proBNP at 96 h and peak NT-proBNP further displayed a strong correlation with cardiac troponin T (r=0.64 and r=0.54, p<0.001), a marker of infarct size, and NT-proBNP at 96 h was a strong predictor of long-term prognosis (hazard ratio 7.29, p=0.025). CONCLUSIONS: In patients with NSTEMI, NT-proBNP may be increased as high as concentrations usually associated with acute congestive heart failure despite the absence of clinical signs. In contrast, patients with STEMI and short time to presentation may present with completely normal NT-proBNP, but dramatic short-term increases following reperfusion. NT-proBNP reflects ischemic burden, reperfusion success and prognosis, and the current data support repetitive sampling in patients with ACS.

Safe and rapid isolation of pulmonary veins using a novel circular ablation catheter and duty-cycled RF generator.

BACKGROUND: Ablation of atrial fibrillation (AF) has been one of the most difficult and time-consuming electrophysiological procedures. Due to the rapidly increasing demand for ablation procedures, technical advances would be helpful to reduce complexity and procedure time in AF ablation. Therefore, we investigated the feasibility of a single-catheter technique for pulmonary vein (PV) isolation utilizing a decapolar catheter combined with a duty-cycled, unipolar-bipolar radiofrequency (RF) generator. METHODS: AF mapping and ablation was performed in 21 consecutive patients (mean age 59 +/- 12 years, 9 males) with paroxysmal AF (n = 17) and persistent AF (n = 4). The ablation catheter was forwarded to the LA via single-transseptal puncture. All electrodes were energized in 2 to 5 applications per vein, followed by segmental RF applications, as needed, to achieve electrical isolation. To assess left atrial anatomy for purposes of catheter manipulation, and later evaluate the possibility of asymptomatic PV-stenosis, CT or MR imaging was performed both prior to ablation and at 6-month follow-up. RESULTS: Isolation could be achieved in 85/86 veins (99%). Procedure time for ablation was 81 +/- 13 minutes, and fluoroscopy time was 30 +/- 11 minutes. There were no procedural complications. Success rate at 6 months was 86% (18/21). MR or CT imaging excluded asymptomatic PV-stenosis. CONCLUSION: Mapping and ablation of PVs can be performed in a safe and efficient manner using a single-catheter technique, with short procedure times and minimal learning curve. Thus, this system may be of high interest not only for high volume but all centers performing AF ablation.

Time course of continuous positive airway pressure effects on central sleep apnoea in patients with chronic heart failure.

Continuous positive airway pressure (CPAP) causes a variable immediate reduction in the frequency of central apnoeas and hypopnoeas in patients with congestive heart failure (CHF) and central sleep apnoea (CSA), but has beneficial mid-term effects on factors known to destabilize the ventilatory control system. We, therefore, tested whether CPAP therapy leads, in addition to its short-term effects on CSA, to a significant further alleviation of CSA after 12 weeks of treatment on the same CPAP level in such patients. CPAP therapy was initiated in 10 CHF patients with CSA. During the first night on CPAP, the pressure was stepwise increased to a target pressure of 8-12 cmH(2)O or the highest level the patients tolerated (<12 cmH(2)O). Throughout the second night (baseline CPAP), the achieved CPAP of the first night was applied. After 12 weeks of CPAP treatment, we performed a follow-up polysomnography (12 weeks CPAP) on the same CPAP level (8.6 +/- 1.1 cmH(2)0). We found a significant reduction of the apnoea-hypopnoea index (AHI) between the diagnostic polysomnography and baseline CPAP night (41.8 +/- 19.2 versus 22.2 +/- 12.6 events per hour; P = 0.005). The AHI further significantly decreased between the baseline CPAP night and the 12 weeks CPAP night on the same CPAP level (22.2 +/- 12.6 versus 12.8 +/- 11.0 events per hour; P = 0.028). We conclude that, in addition to its immediate effects, CPAP therapy leads to a time-dependent alleviation of CSA in some CHF patients, indicating that in such patients neither clinical nor scientific decisions should be based on a short-term trial of CPAP.

A new miniaturized system for extracorporeal membrane oxygenation in adult respiratory failure.

INTRODUCTION: Mortality of severe acute respiratory distress syndrome in adults is still unacceptably high. Extracorporeal membrane oxygenation (ECMO) could represent an important treatment option, if complications were reduced by new technical developments. METHODS: Efficiency, side effects and outcome of treatment with a new miniaturized device for veno-venous extracorporeal gas transfer were analysed in 60 consecutive patients with life-threatening respiratory failure. RESULTS: A rapid increase of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) from 64 (48 to 86) mmHg to 120 (84 to 171) mmHg and a decrease of PaCO2 from 63 (50 to 80) mmHg to 33 (29 to 39) mmHg were observed after start of the extracorporeal support (P < 0.001). Gas exchange capacity of the device averaged 155 (116 to 182) mL/min for oxygen and 210 (164 to 251) mL/min for carbon dioxide. Ventilatory parameters were reduced to a highly protective mode, allowing a fast reduction of tidal volume from 495 (401 to 570) mL to 336 (292 to 404) mL (P < 0.001) and of peak inspiratory pressure from 36 (32 to 40) cmH2O to 31 (28 to 35) cmH2O (P < 0.001). Transfusion requirements averaged 0.8 (0.4 to 1.8) units of red blood cells per day. Sixty-two percent of patients were weaned from the extracorporeal system, and 45% survived to discharge. CONCLUSIONS: Veno-venous extracorporeal membrane oxygenation with a new miniaturized device supports gas transfer effectively, allows for highly protective ventilation and is very reliable. Modern ECMO technology extends treatment opportunities in severe lung failure.

High osmolality induces the kidney-specific chloride channel CLC-K1 by a serum and glucocorticoid-inducible kinase 1 MAPK pathway.

The kidney-specific chloride channels CLC-K1/2 and their functionally important subunit barttin, by mediating solute transport in medulla, contribute to the osmotic gradient. We sought to determine whether they themselves are regulated by variations of osmolality. The expression of CLC-K1 and barttin mRNA and protein was significantly increased in a distal convoluted tubule cell line after a shift to high osmolar medium. This upregulation paralleled that of serum and glucocorticoid-inducible kinase 1 (SGK1), a gene known to be upregulated by cell shrinkage. Specific knockdown of SGK1 or addition of the p38 MAPK pathway inhibitor SB203580 abolished the induction of SGK1, CLC-K1 and barttin by high osmolarity suggesting that a functional MAPK pathway is required to mediate osmotic-driven induction of all three genes. The physiological relevance of our in vitro data was confirmed by water deprivation of male C57BL6 mice, which caused a significant increase in serum osmolality along with induction of CLC-K1, barttin and SGK1. Our study shows that change in intracellular volume, because of high osmolality, result in SGK1 upregulation and the subsequent increase of CLC-K1/barttin expression in distal renal tubular cells in vivo and in vitro.