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Objectives—To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment. Methods—For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the USinduced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant-bearing nude mice were treated by tumor-regional USmediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel-infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days). Results—Combination therapy experiments with xenotransplant-bearing nude mice significantly increased the antitumor activity of tTF-NGR by regional low-energy US destruction of vascular microbubbles in tumor vessels shortly before application of tTF-NGR (P < .05). Mechanistic studies proved the upregulation of anionic PS on the outer leaflet of the lipid bilayer of endothelial cell membranes by low-energy US and a consecutive higher potential of these preapoptotic endothelial cells to activate coagulation via tTF-NGR and coagulation factor X as being a basis for this synergistic activity. Conclusions—Combining retargeted tTF to tumor vessels with proapoptotic stimuli for the tumor vascular endothelium increases the antitumor effects of tumor vascular infarction. Ultrasound treatment may thus be useful in this respect for regional tumor therapy. Key Words—low-energy ultrasound treatment; regional cancer therapy; truncated tissue factor; vascular infarction; vascular targeting; vascular ultrasound

Reports on third-generation centrifugal intrapericardial pumps (HeartWare International, Inc., Framingham, MA, USA) have shown better survival results than the previous-generation devices. However, outcomes depending on the preoperative level of stability can substantially differ, resulting in a limited analysis of potentialities and drawbacks of a given device. In the present study we sought to compare in our single-center experience the survival results of this third-generation device with previous left ventricular systems taking into account the different preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels. Between February 1993 and March 2012, 287 patients underwent assist device implantation in our university hospital (INTERMACS Level 1-2 = 158 patients; INTERMACS Level 3-4-5 = 129 patients). Assist devices implanted were: Group A (HVAD HeartWare, n = 52), group B (previous continuous-flow ventricular assist device [VAD], InCor [Berlin Heart, Berlin, Germany], n = 37; VentrAssist [VentraCor, Inc., Chatswood, NSW, Australia], n = 7; DeBakey [MicroMed Cardiovascular, Inc., Houston, TX, USA], n = 32), and group C (pulsatile systems, n = 159). After cumulative support duration of 54 436 days and a mean follow-up of 6.21 ± 7.46 months (range 0-45.21 months), log-rank analysis revealed a survival for group A of 82.0%, 70.4%, and 70.4%; for group B of 84.0%, 48.2%, 33.7%; and for group C of 71.6%, 46.1%, 33.8%, at 1, 12, and 24 months respectively, with a significantly (P = 0.013) better outcome for group A. When stratifying the survival on the basis of INTERMACS level, no significant survival improvement was observed among all patients who underwent VAD implantation in INTERMACS 1-2 (P = 0.47). However, among patients who underwent elective VAD implantation (INTERMACS 3-4-5), group A had a significantly better outcome (P = 0.005) compared with the other INTERMACS-matched groups (B,C) with a survival rate of 88.8% in group A versus 34.2% in group B and 45.6% in group C at 24 months, respectively. Elective HVAD system implantation shows improved survival benefit over the other INTERMACS-matched devices. Moreover, preoperative unstable hemodynamics resulted in a poor prognosis independently from the pump generation.

Aims Ranolazine (RAN) was reported to be effective and safe in converting atrial fibrillation (AF) to sinus rhythm by administration of a single dose (‘pill in the pocket’) to patients with structural heart disease. This study examines the underlying mechanisms for the antiarrhythmic benefit of RAN application in chronic heart failure (CHF). Methods and results In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1 µM) and isoproterenol (1 µM) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of RAN (10 µM) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. RAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, RAN application moderately increased interatrial conduction time. Conclusion RAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to development of atrial post-repolarization refractoriness and a moderate increase in conduction time. The described electrophysiological mechanisms remain preserved in the setting of CHF.

BACKGROUND: Statins have been suggested to improve cardiac function, but the evidence underlying beneficial effects of statins in heart failure (HF) is insufficient. We analyzed plasma N‐terminal prohormone brain natriuretic peptide (NT‐proBNP) levels and cardiac function in patients with HF of various etiologies, and who were treated with or without statins. HYPOTHESIS: Statin treatment is associated with improved cardiac function in HF. METHODS: The study cohort consisted of 139 consecutive male patients receiving atorvastatin (n = 44), simvastatin (n = 29), pravastatin (n = 19), or no statin (n = 47). The NT‐proBNP levels were measured using electroluminescence immunoassay. Left ventricular end‐diastolic diameter (LVEDD), fractional shortening (FS), and ejection fraction (EF) were determined by echocardiography. RESULTS: Patients receiving atorvastatin presented with reduced NT‐proBNP levels (1,552 ± 3,416 versus 3,771 ± 6,763 pg/mL; p < 0.01), and improved values of LVEDD (65.2 ± 8.9 versus 70.7 ± 10.9 mm; p < 0.05) and EF (33.2 ± 12.6 versus 28.2 ± 9.6%; p < 0.05). By contrast, plasma NT‐proBNP and cardiac parameters in patients treated with statins other than atorvastatin did not significantly differ from control. Atorvastatin treatment was equally effective in patients with ischemic and nonischemic HF. CONCLUSIONS: Atorvastatin treatment is associated with improved cardiac function in HF, and may represent an additional option for patients with this disease. Copyright © 2008 Wiley Periodicals, Inc.

Background Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via I(Kr) blockade in an intact heart model of proarrhythmia. Methods and results In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 microM to 1,000 microM were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP(90/50)) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. Conclusion Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP.

To dissect the tissue-specific functions of atrial natriuretic peptide (ANP), we recently introduced loxP sites into the murine gene for its receptor, guanylyl cyclase-A (GC-A), by homologous recombination (tri-lox GC-A). For either smooth-muscle or cardiomyocyte-restricted deletion of GC-A, floxed GC-A mice were mated to transgenic mice expressing Cre-recombinase under the control of the smooth-muscle SM22 or the cardiac αMHC promoter. As shown in these studies, Cre-mediated recombination of the floxed GC-A gene fully inactivated GC-A function in a cell-restricted manner. In the present study we show that αMHC-Cre, but not SM22-Cre, with high frequency generates genomic recombinations of the floxed GC-A gene segments which were transmitted to the germline. Alleles with partial or complete deletions were readily recovered from the next generation, after segregation of the Cre-transgene. We took advantage of this strategy to generate a new mouse line with global, systemic deletion of GC-A. Doppler-echocardiographic and physiological studies in these mice demonstrate for the first time the tremendous impact of ANP/GC-A dysfunction on chronic blood volume homeostasis. genesis 39:288–298, 2004. © 2004 Wiley-Liss, Inc.

Background: Heart transplantation is the most effective treatment for well-selected patients with endstage heart failure. Unfortunately, transplant candidates with pulmonary hypertension (PHT) are often not considered for heart transplantation. This study was performed to assess the value of prostaglandin E1 (PG-E1) for reduction of PHT and to predict the postoperative outcome, compared to patients without PHT. Patients and methods: We studied a group of 151 consecutive heart transplant candidates using right heart catheterization. In patients with PHT (pulmonary vascular resistance, PVR≥2.5 Wood-Units (WU) and/or transpulmonary gradient (TPG)≥12 mmHg) a short-term treatment protocol with PG-E1 was performed, to achieve PVR

Aim: This study investigated the value of epicardial mapping immediately before CABG in the differentiation of hibernating from scarred myocardium in correlation to the noninvasive gold standard 18F-FDG PET. Methods and Results: In 35 patients with CAD, myocardial perfusion (99mTc-Tetrofosmin-SPECT), viability (18F-FDG-PET), and function (LVangiography) were assessed before CABG. 102 bipolar epicardial electrograms per patient (n = 3570 electrograms) were recorded simultaneously with a ventricular jacket array. Based on the scintigraphic and LV angiographic data at the site of each electrode with good myocardial contact (n = 1963), segments (n = 492, 14.1 ± 5.6 per patient; mean ± SD) were classified into three groups: hibernating (n = 139), scarred (n = 104), and control (n = 249). Regional mean bipolar voltage values were calculated for Receiver Operating Characteristic (ROC) analysis. Mean bipolar voltage was significantly lower in scarred when compared to hibernating myocardium. ROC curve analysis (area under the curve of O.92 ± 0.47, mean ± SE) for mean bipolar voltage to discriminate between hibernating and scarred myocardium revealed a sensitivity of 94% with a specificity of 83% at a cut-off value of 8.75 mV. Conclusion: Hibernating myocardium can be differentiated correctly from scarred myocardium by direct epicardial mapping. In the future, hibernating myocardium may be detectable by body surface mapping techniques using inverse solutions. A.N.E. 2002;7(4):349–356