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.

Technical complications during veno-venous extracorporeal membrane oxygenation and their relevance predicting a system-exchange--retrospective analysis of 265 cases.

OBJECTIVES: Technical complications are a known hazard in veno-venous extracorporeal membrane oxygenation (vvECMO). Identifying these complications and predictive factors indicating a developing system-exchange was the goal of the study. METHODS: Retrospective study on prospectively collected data of technical complications including 265 adult patients (Regensburg ECMO Registry, 2009-2013) with acute respiratory failure treated with vvECMO. Alterations in blood flow resistance, gas transfer capability, hemolysis, coagulation and hemostasis parameters were evaluated in conjunction with a system-exchange in all patients with at least one exchange (n = 83). RESULTS: Values presented as median (interquartile range). Patient age was 50(36-60) years, the SOFA score 11(8-14.3) and the Murray lung injury Score 3.33(3.3-3.7). Cumulative ECMO support time 3411 days, 9(6-15) days per patient. Mechanical failure of the blood pump (n = 5), MO (n = 2) or cannula (n = 1) accounted for 10% of the exchanges. Acute clot formation within the pump head (visible clots, increase in plasma free hemoglobin (frHb), serum lactate dehydrogenase (LDH), n = 13) and MO (increase in pressure drop across the MO, n = 16) required an urgent system-exchange, of which nearly 50% could be foreseen by measuring the parameters mentioned below. Reasons for an elective system-exchange were worsening of gas transfer capability (n = 10) and device-related coagulation disorders (n = 32), either local fibrinolysis in the MO due to clot formation (increased D-dimers [DD]), decreased platelet count; n = 24), or device-induced hyperfibrinolysis (increased DD, decreased fibrinogen [FG], decreased platelet count, diffuse bleeding tendency; n = 8), which could be reversed after system-exchange. Four MOs were exchanged due to suspicion of infection. CONCLUSIONS: The majority of ECMO system-exchanges could be predicted by regular inspection of the complete ECMO circuit, evaluation of gas exchange, pressure drop across the MO and laboratory parameters (DD, FG, platelets, LDH, frHb). These parameters should be monitored in the daily routine to reduce the risk of unexpected ECMO failure.

Panel of emerging cardiac biomarkers contributes for prognosis rather than diagnosis in chronic heart failure.

BACKGROUND: As complex disease, heart failure is associated with various pathophysiological and biochemical disorders. No single biomarker is able to display all these characteristics. Therefore, we evaluated a multimarker panel together with the biochemical gold-standard NT-proBNP. Part of the panel are markers for angiogenesis (Endostatin, IBP-4, IBP-7, sFlt-1 as antiangiogenetic factors and PLGF as angiogenectic factor), myocyte stress (GDF-15), extracellular matrix remodelling (galectin-3, mimecan and TIMP-1), inflammation (galectin-3) and myocyte injury (hs-TnT). METHODS: All markers (Roche Diagnostics, Penzberg, Germany) were assessed in a cohort of 149 patients with chronic heart failure and 84 healthy controls. RESULTS: All markers were positively correlated with ln NT-proBNP (each p < 0.05). Furthermore, they were significantly elevated in patients with chronic heart failure (each p < 0.05). All markers increased significantly with severity of LV dysfunction and severity of New York Heart Association class (each p < 0.05), except for PLGF and Mimecan (each p = NS). With the exception of endostatin, mimecan and PLGF, all other markers were further significant predictors for all-cause mortality in a 3-year follow-up. In a multimarker approach of the five biomarkers with the best performance (NT-proBNP, hs-TnT, TIMP-1, GDF-15 and IBP-4), the event rate was superior to NT-proBNP alone and increased significantly and progressively with the number of elevated biomarkers. CONCLUSION: All emerging markers increased stepwise with the severity of symptoms and LV dysfunction and offer important prognostic information in chronic heart failure, except for PLGF and mimecan. Five biomarkers with different pathophysiological background incorporated additive prognostic value in heart failure. Prognostication in heart failure may be further improved through a multimarker approach.

Interatrial differences of basal molecular set-up and changes in tachycardia-induced heart failure-a proteomic profiling study.

AIMS: Left and right atria show compelling differences regarding organogenesis and specific clinical diseases. In congestive heart failure (CHF), remodelling of the atria occurs leading to increased arrhythmogenic susceptibility and deterioration of clinical symptoms. We aimed to assess the basal left and right atrial molecular set-up and different chamber-specific atrial changes in heart failure. METHODS AND RESULTS: We combined an animal model of rapid ventricular pacing induced heart failure in the rabbit and a gel-based proteomic screening of left and right atrial specimen. A gene ontology over-representation analysis was performed for biological function. Ultrastructural adaptations were evaluated using transmission electron microscopy. Comparing left and right atria of healthy control animals (CTRL), 39 proteins displayed significant expression differences involving various biological functions. Upon further statistical analyses, four pathways of energy metabolism were confirmed to be significantly over-represented beneath the other biological processes. Rapid ventricular pacing induced severe left ventricular systolic dysfunction, symptomatic heart failure and a macroscopic atrial remodelling. In CHF versus CTRL, metabolic and antioxidative enzymes were differentially expressed and showed chamber-specific bidirectional alterations. Transmission electron microscopy visualized a remarkable and again chamber-specific ultrastructural disturbance of mitochondrial morphology. CONCLUSIONS: Our data indicate a diverging basal left and right atrial molecular set-up in the adult healthy heart. In addition, metabolic and antioxidative enzymes are profoundly and chamber-specifically altered during atrial remodelling in progressive heart failure.

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.

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.

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.

Prognostic impact of sleep duration and sleep efficiency on mortality in patients with chronic heart failure.

BACKGROUND: Both short and long self-reported sleep duration (SDSR) has been linked to increased mortality. Our analysis tested the hypothesis that long SDSR is paralleled by impaired objective sleep efficiency (SEPSG) measured by polysomnography (PSG) and that impaired SEPSG is a risk factor for death in patients with chronic heart failure (CHF). METHODS: SDSR and SEPSG were assessed by standardized questionnaire and PSG in 188 consecutive CHF patients (age range, 63±10 year; left ventricular ejection fraction, 34±10%) admitted to the Sleep Center of the University Hospital Regensburg between 1/2002 and 12/2009. The mean follow-up period was 44±26 months. RESULTS: SEPSG in CHF patients from the highest quintile of SDSR (≥9h) was significantly lower compared with the middle quintile (7.25-8h; 71±15% vs 77%±11%; p=0.032) and similar to the lowest quintile (≤5.75h; 71±15% vs 71±16%, p=0.950). SEPSG is an independent predictor for death in the multivariable model after accounting for the significant confounders age, left ventricular ejection fraction, cause of CHF, and NYHA class (hazard ratio [HR] per 5% increase, 0.85; 95% confidence interval [CI], 0.77-0.93; p<0.001). CONCLUSIONS: Data indicate that subjective long sleepers with CHF have poor sleep efficiency. Objectively measured SEPSG strongly predicts mortality in CHF patients, underscoring the importance of objective assessment of sleep.

Tumor marker carbohydrate antigen 125 predicts adverse outcome after transcatheter aortic valve implantation.

OBJECTIVES: This study sought to predict the value of tumor marker carbohydrate antigen 125 (CA125) before and after transcatheter aortic valve implantation (TAVI) for all-cause death and a composite endpoint of death, admission for heart failure, myocardial infarction, and stroke (major adverse cardiac events [MACE]). BACKGROUND: Risk stratification after TAVI remains challenging. The use of biomarkers in this setting represents an unmet need. METHODS: CA125 was measured in 228 patients before and after TAVI. The association with outcomes was assessed using parametric Cox regression and joint modeling for baseline and longitudinal analyses, respectively. CA125 was evaluated as logarithm transformation and dichotomized by its median value (M1 ≤15.7 U/ml vs. M2 >15.7 U/ml). RESULTS: At a median follow-up of 183 days (interquartile range: 63 to 365) and 144 days (interquartile range: 56 to 365), 50 patients (22%) died and 75 patients (33%) experienced MACE. A 3-fold increase in the rates for death and MACE was observed in patients above the median (M2 vs. M1) of CA125 (5.2 vs. 1.6 per 10 person-years and 8.3 vs. 3.3 per 10 person-years, respectively; p for both <0.001). In a multivariable analysis adjusted for logistic EuroSCORE, New York Heart Association functional class III/IV, and device success, baseline values of CA125 (M2 vs. M1) independently predicted death (hazard ratio [HR]: 2.18; 95% confidence interval [CI]: 1.11 to 4.26; p = 0.023) and MACE (HR: 1.77; 95% CI: 1.05 to 2.98; p = 0.031). In the longitudinal analysis, lnCA125 as a time-varying exposure, was highly associated with both endpoints: HR: 1.47; 95% CI: 1.01 to 2.14; p = 0.043 and HR: 2.26; 95% CI: 1.28 to 3.98; p = 0.005, for death and MACE, respectively. CONCLUSIONS: Serum levels of CA125 before and after TAVI independently predict death and MACE.

Prosthesis sizing for transcatheter aortic valve implantation--comparison of three dimensional transesophageal echocardiography with multislice computed tomography.

BACKGROUND: The complex anatomy of the aortic annulus warrants the use of three dimensional (3D) modalities for prosthesis sizing in transcatheter aortic valve implantation (TAVI). Multislice computed tomography (MSCT) has been used for this purpose, but its use may be restricted because of contrast administration. 3D transesophageal echocardiography (3D-TEE) lacks this limitation and data on comparison with MSCT is scarce. We compared 3D-TEE with MSCT for prosthesis sizing in TAVI. METHODS: Aortic annulus diameters in the sagittal and coronal plane and annulus areas in 3D-TEE and MSCT were compared in 57 patients undergoing TAVI. Final prosthesis size was left at the operator's discretion and the agreement with 3D-TEE and MSCT was calculated. RESULTS: Sagittal diameters on 3D-TEE and MSCT correlated well (r=.754, p<.0001) and means were comparable (22.3±2.1 vs. 22.5±2.3 mm; p=0.2; mean difference: -0.3 mm [-3.3-2.8]). On 3D-TEE, coronal diameter and annulus area were significantly smaller (p<.0001 for both) with moderate correlation (r=0.454 and r=0.592). Interobserver variability was comparable for both modalities. TAVI was successful in all patients with no severe post-procedural insufficiency. Final prosthesis size was best predicted by sagittal annulus diameters in 84% and 79% by 3D-TEE and MSCT, respectively. Agreement between both modalities was 77%. CONCLUSIONS: Annulus diameters and areas for pre-procedural TAVI assessment by 3D-TEE are significantly smaller than MSCT with exception of sagittal diameters. Using sagittal diameters, both modalities predicted well final prosthesis size and excellent procedural results were obtained. 3D-TEE can thus be a useful alternative in patients with contraindications to MSCT.

Cardiac workload in patients with sleep-disordered breathing early after acute myocardial infarction.

BACKGROUND: Sleep-disordered breathing (SDB) may promote an increase in cardiac workload early after acute myocardial infarction (AMI). We tested the hypothesis that in the early phase after AMI, SDB is associated with increased 24-h arterial BP, heart rate (HR), and, thus, cardiac workload. METHODS: In this prospective study, 55 consecutive patients with AMI and subsequent percutaneous coronary intervention (78% men; mean age, 54 ± 10 y; mean BMI, 28.3 ± 3.6 kg/m²; mean left ventricular ejection fraction [LVEF], 47% ± 8%) underwent polysomnography and 24-h ambulatory BP and heart rate monitoring within 5 days after MI. Cardiac workload was calculated as systolic BP multiplied by HR. The presence of SDB was defined as ≥ 10 apneas and hypopneas per hour of sleep. RESULTS: Fifty-five percent of the patients had SDB, of which 40% was predominantly central in nature. Patients with SDB had higher 24-h HR and systolic and diastolic BP compared with those without SDB (115 vs 108 mm Hg, P = .029; 71 vs 67 mm Hg, P = .034; 69 vs 64 beats/min, P = .050, respectively). Use of antihypertensive medication and ß-receptor blockers was similar in both groups. In a multivariate linear regression analysis, SDB was significantly associated with an increased 24-h cardiac workload (ß-coefficient, 0.364; 95% CI, 0.071-0.657; P = .016), independently of age, sex, BMI, LVEF, and antihypertensive medication. CONCLUSION: Patients with AMI and SDB have significantly increased 24-h BP, HR, and cardiac workload. Treatment of SDB may be a valuable nonpharmacologic approach to lower cardiac workload in these patients.

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.

Extracorporeal pulmonary support in severe pulmonary failure in adults: a treatment rediscovered.

BACKGROUND: Severe, acute respiratory failure in adults still carries a high mortality. In recent years, improved pulmonary support techniques have been used increasingly alongside conventional treatment. About 1000 such treatments are performed in Germany annually, and the number is rising rapidly. The two types of systems currently in use involve venovenous extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide elimination. METHODS: The underlying principles, technical implementation, efficacy, and adverse effects of the new techniques are summarized in the light of a selective review of the literature, supplemented by the authors' personal experience. Recommendations are given for clinical use. RESULTS: Currently, only limited high-quality data (from prospective randomized trials) are available to support the use of either of these techniques in adults. Veno-venous ECMO systems can effectively secure gas exchange in patients with severe respiratory failure, with experienced centers reporting survival rates from 63% to 75%. Either pump-free arteriovenous systems or low-flow ECMO systems can be used for extracorporeal carbon dioxide elimination. Complications can be serious or life-threatening and must, therefore, be rapidly recognized and treated: these include vascular injury during cannulation, venous thrombosis in a cannulated vessel, an increased hemorrhagic tendency, and thrombocytopenia. CONCLUSION: Modern miniaturized pulmonary support systems enable protective mechanical ventilation with low tidal volumes, reduce ventilator-associated lung injury, and can improve survival rates in critically ill patients with a manageable adverse effect profile.

Cardiovascular magnetic resonance-derived intramyocardial hemorrhage after STEMI: Influence on long-term prognosis, adverse left ventricular remodeling and relationship with microvascular obstruction.

BACKGROUND: T2 weighted cardiovascular magnetic resonance (CMR) can detect intramyocardial hemorrhage (IMH) after ST-elevation myocardial infarction (STEMI). The long-term prognostic value of IMH beyond a comprehensive CMR assessment with late enhancement (LE) imaging including microvascular obstruction (MVO) is unclear. The value of CMR-derived IMH for predicting major adverse cardiac events (MACE) and adverse cardiac remodeling after STEMI and its relationship with MVO was analyzed. METHODS: CMR including LE and T2 sequences was performed in 304 patients 1 week after STEMI. Adverse remodeling was defined as dilated left ventricular end-systolic volume indexes (dLVESV) at 6 months CMR. RESULTS: During a median follow-up of 140 weeks, 47 MACE (10 cardiac deaths, 16 myocardial infarctions, 21 heart failure episodes) occurred. Predictors of MACE were ejection fraction (HR .95 95% CI [.93-.97], p=.001, per %) and IMH (HR 1.17 95% CI [1.03-1.33], p=.01, per segment). The extent of MVO and IMH significantly correlated (r=.951, p<.0001). dLVESV was present in 40% of patients. CMR predictors of dLVESV were: LVESV (OR 1.11 95% CI [1.07-1.15], p<.0001, per ml/m(2)), infarct size (OR 1.05 95% CI [1.01-1.09], p=.02, per %) and IMH (OR 1.54 95% CI [1.15-2.07], p=.004, per segment). Addition of T2 information did not improve the LE and cine CMR-model for predicting MACE (.744 95% CI [.659-.829] vs. .734 95% CI [.650-.818], p=.6) or dLVESV (.914 95% CI [.875-.952] vs. .913 95% CI [.875-.952], p=.9). CONCLUSIONS: IMH after STEMI predicts MACE and adverse remodeling. Nevertheless, with a strong interrelation with MVO, the addition of T2 imaging does not improve the predictive value of LE-CMR.

Predictors of cardiovascular magnetic resonance-derived microvascular obstruction on patient admission in STEMI.

BACKGROUND: Early stratification of patients according to the risk for developing microvascular obstruction (MVO) after ST-segment elevation myocardial infarction (STEMI) is desirable. We aimed to identify predictors of cardiovascular magnetic resonance (CMR)-derived MVO from clinical+ECG, laboratory and angiographic parameters available on admission. METHODS: Characteristics available on admission were documented in 97 STEMI patients referred for primary angioplasty. MVO was determined using contrast-enhanced CMR. RESULTS: MVO was present in 44 patients (45%). The C-statistic for predicting MVO was: clinical+ECG (.832), laboratory (.743), and angiographic parameters (.669). Adding laboratory to clinical+ECG information did not improve the C-statistic (.873 vs. .832, p=.2). Further addition of angiographic data (.904) improved the C-statistic of clinical+ECG (p=.04) but not of clinical+ECG and laboratory (p=.2). Independent predictors of MVO using clinical and ECG parameters were: Killip class >1 (OR 15.97 95%CI [1.37-186.76], p=.03), diabetes (OR 6.15 95%CI [1.49-25.39], p=.01), age <55years (OR 4.70 95%CI [1.56-14.17], p=.006), sum of ST-segment elevation >10mm (OR 4.5 95%CI [1.58-12.69], p=.005) and delayed presentation >3h (OR 3.80 95%CI [1.19-12.1], p=.02). A score was constructed assigning Killip class >1 2 points and the remaining indexes 1 point. The incidence of MVO increased with the score: 0 point: 8.7%; 1 point: 28.1%; 2 points: 71.4%; and 3+ points: 93% (p<.0001). CONCLUSIONS: MVO can be predicted using parameters already available on patient admission. We developed a clinical-ECG score allowing for early and reliable classification of STEMI patients according to the risk of MVO.

Equal performance of novel N-terminal proBNP (Cardiac proBNP®) and established BNP (Triage BNP®) point-of-care tests.

BACKGROUND: Recently, a novel point-of-care test (POCT) for N-terminal proBNP (NTproBNP) has been introduced (Cardiac proBNP®, Roche). AIM: The aim was to compare the novel POCT for NTproBNP with the established POCT for BNP. METHODS: NTproBNP and BNP were assessed in 222 individuals with chronic heart failure (n = 151) or controls (n = 71) with both POCTs. RESULTS: NTproBNP and BNP were closely correlated upon regression analysis (r = 0.93; p < 0.01). NTproBNP and BNP were both correlated with ejection fraction and New York Heart Association stage. Receiver operating characteristic analysis yielded satisfying and equivalent predictive values for the detection of left ventricular dysfunction (ejection fraction <40%; NTproBNP: area under the curve 0.97; BNP: area under the curve 0.96; p > 0.05) and presence of New York Heart Association stage >2 (area under the curve 0.92 vs 0.91 for NT-proBNP and BNP, respectively; p > 0.05). CONCLUSION: The NTproBNP POCT allows biochemical detection of heart failure with satisfactory predictive values, is equivalent to the BNP POCT and will improve near-patient testing.

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.

Antihypertrophic effects of combined inhibition of the renin-angiotensin system (RAS) and neutral endopeptidase (NEP) in progressive, tachycardia-induced experimental heart failure.

Vasopeptidase inhibition (VPI), a therapeutic strategy by dual inhibition of both ACE and neutral endopeptidase 24.11, has not shown a prognostic benefit over ACE inhibition in chronic severe heart failure (CHF). Nevertheless, the effects of early treatment by VPI on cardiac remodelling have not been well assessed. We analysed the effects of early chronic VPI (50 mg/kg/day Omapatrilat) on cardiac remodelling and neurohumoral function during the progression of rapid ventricular pacing-induced heart failure in rabbits (early left ventricular dysfunction [ELVD]: 10 days at 330 bpm, CHF: further 10 days at 360 bpm). VPI-treated animals (ELVD-VPI n = 6; CHF-VPI n = 8) and placebo treated animals (ELVD n = 6; CHF n = 7) were compared with control rabbits (CTRL n = 5). LV fractional shortening (FS) and enddiastolic diameter (LVEDD) were assessed by echocardiography (12 MHz probe). LV BNP- and LV IL-6 gene expression was analysed quantitatively by real time PCR. Neurohumoral function was assessed by ANP, cGMP, plasma renin activity (PRA) and Aldosterone. In ELVD, LVEDD and atrial mass were significantly increased (both p < 0.05). This increase was markedly attenuated by VPI (both p < 0.05 vs. placebo). CHF was associated with a further increase in atrial mass and an increase in LV mass (both p < 0.05), which was again attenuated by VPI (atrial mass, p < 0.05 vs. untreated). LV BNP mRNA was significantly increased in CHF (p < 0.05 vs. control), and chronic VPI completely abolished this increase in ELVD and significantly attenuated it in CHF (p < 0.05 vs. CHF-placebo). Beyond that, the increase of cGMP was augmented by chronic VPI (p < 0.05 vs. placebo in CHF) in heart failure and that of Aldosterone was attenuated (p < 0.05 vs. placebo in ELVD), whereas PRA was temporarily increased (p < 0.05 vs. placebo in ELVD). Combined inhibition of ACE and NEP by VPI significantly inhibits early cardiac remodelling and LV BNP gene expression. If initiated early enough, it may slow down cardiac remodelling and represents a promising therapeutic strategy in progressive heart failure.

Growth-differentiation factor-15 improves reclassification for the diagnosis of heart failure with normal ejection fraction in morbid obesity.

AIMS: This study aimed to examine the incremental value of growth-differentiation factor-15 (GDF-15) to N-terminal pro brain natriuretic hormone (NT-proBNP) levels for the diagnosis of left ventricular diastolic dysfunction (LVDD) and possible heart failure (HF) in morbidly obese patients. Method and results We analysed data from 207 obese subjects [body mass index (BMI) 41 ± 8 kg/m(2)] with normal ejection fraction, LVDD, and symptoms and/or signs of HF (referred to as 'LVDD with possible HF', n = 88) and with normal left ventricular function (n = 119) before participating in a medical weight loss programme, in addition to the study of healthy lean subjects (n = 51). Median NT-proBNP (interquartile range) for obese subjects with 'LVDD and possibe HF' and with normal LV function was 52 (29-96) and 42 (25-66) pg/mL, respectively (P = 0.12). There was no correlation of NT-proBNP with parameters of left ventricular filling pressure, i.e. E/E' (r(2) = 0.002, P = 0.63) or E' velocity (r(2) = 0.02, P = 0.24). In contrast, GDF-15 was 665 (496-926) with 'LVDD and possible HF' and 451 (392- 679) pg/mL without (P < 0.0001). GDF-15 was significantly correlated to E/E', E' velocity, E/A ratio, isovolumetric relaxation time, duration of reversed pulmonary vein atrial systolic flow, and left atrial size. The area under the receiver operating characteristic curve that defines LVDD with possible HF was 0.56 for NT-proBNP and 0.74 for GDF-15 (P < 0.0001). The addition of GDF-15 to a multivariate predicition model increased the net reclassification improvement (NRI) by 9% (P= 0.022). CONCLUSION: In morbidly obese individuals, GDF-15 levels seem to better correlate with diastolic dysfunction than NT-proBNP levels. GDF-15 significantly improves reclassification for the diagnosis of 'LVDD with possible HF' and, thus, adds incremental value to NT-proBNP.

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.