Carsten Wunderlich

Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction.

Objective:Cardiogenic shock is the leading cause of death in patients hospitalized for acute myocardial infarction. The objectives were to investigate the effects of levosimendan, a novel inodilator, compared with the phosphodiesterase-III inhibitor enoximone in refractory cardiogenic shock complicating acute myocardial infarction, on top of current therapy. Design:Prospective, randomized, controlled single-center clinical trial. Setting:Medical and coronary intensive care unit in a university hospital. Patients:Thirty-two patients with refractory cardiogenic shock for at least 2 hrs requiring additional therapy. Interventions:Infusion of either levosimendan (12 &mgr;g/kg over 10 min, followed by 0.1 &mgr;g/kg/min over 50 min, and of 0.2 &mgr;g/kg/min for the next 23 hrs) or enoximone (fractional loading dose of 0.5 mg/kg, followed by 2–10 &mgr;g/kg/min continuously) after initiation of current therapy, always including revascularization, intra-aortic balloon pump counterpulsation, and inotropes. Measurements and main results:Survival rate at 30 days was significantly higher in the levosimendan-treated group (69%, 11 of 16) compared with the enoximone group (37%, 6 of 16, p = 0.023). Invasive hemodynamic parameters during the first 48 hrs were comparable in both groups. Levosimendan induced a trend toward higher cardiac index, cardiac power index, left ventricular stroke work index, and mixed venous oxygen saturation. In addition, lower cumulative values for catecholamines at 72 hrs and for clinical signs of inflammation were seen in the levosimendan-treated patients. Multiple organ failure leading to death occurred exclusively in the enoximone group (4 of 16 patients). Conclusions:In severe and refractory cardiogenic shock complicating acute myocardial infarction, levosimendan, added to current therapy, may contribute to improved survival compared with enoximone.

High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest.

INTRODUCTION After cardiac arrest due to acute coronary syndromes (ACS) therapeutic hypothermia (HT) is the standard care to reduce neurologic damage. Additionally, the concomitant medical treatment with aspirin and a P2Y12 receptor inhibitor like clopidogrel (Cl), prasugrel (Pr) or ticagrelor (Ti) is mandatory. The platelet inhibitory effect of these drugs under hypothermia remains unclear. METHODS 164 patients with ACS were prospectively enrolled in this study. 84 patients were treated with HT, 80 patients were under normothermia (NT). All patients were treated with aspirin and one of the P2Y12 receptor inhibitors Cl, Pr or Ti. 24h after the initial loading dose the platelet reactivity index (PRI/VASP-index) was determined to achieve the platelet inhibitory effect. RESULTS In the HT-group the PRI/VASP-index was significantly higher compared to the NT-group (54.86%±25.1 vs. 28.98%±22.8; p<0.001). In patients under HT receiving Cl, the platelet inhibition was most markedly reduced (HT vs. NT: 66.39%±19.1 vs. 33.36%±22.1; p<0.001) compared to Pr (HT vs. NT: 37.6%±25.0 vs. 27.04%±25.5; p=0.143) and Ti (HT vs. NT: 41.5%±21.0 vs. 17.83%±14.5; p=0.009). The rate of non-responder defined as PRI/VASP-index>50% was increased in HT compared to NT (60.7% vs. 22.5%; p<0.001) with the highest rates in the group receiving Cl (CL: 82% vs. 26%, p<0.001; Pr: 32% vs. 23%; n.s.; Ti: 30% vs. 8%, n.s.). CONCLUSION The platelet inhibitory effect in patients treated with HT after cardiac arrest is significantly reduced. This effect was most marked with the use of Cl. The new P2Y12-inhibitors Pr and Ti improved platelet inhibition in HT, but could not completely prevent non-responsiveness.

Chronic NOS inhibition prevents adverse lung remodeling and pulmonary arterial hypertension in caveolin-1 knockout mice

Recently generated caveolin-1 deficient mice (cav-1 ko) suffer from severe lung fibrosis with marked pulmonary hypertension and arterial hypoxemia and may therefore serve as an useful animal model of this devastating human disorder. Accumulating evidence strongly supports the negative regulatory influence of caveolin-1 on endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO) pathway in cav-1 ko. We therefore hypothesized that a disturbed NO signaling is implicated in the evolution of the adverse lung phenotype of cav-1 ko. For this purpose, cav-1 ko of 2 months age were compared with knockout counterparts experiencing 2-month postnatal NO synthase inhibition by NG-nitro-l-arginine methyl ester (L-NAME) treatment. Chronic l-NAME administration prevented adverse lung remodeling in cav-1 ko. Furthermore, l-NAME donation led to a normalized oxygen saturation (91.5+/-1.8% vs. 98.5+/-2.3%, P<0.01, n=10-12), a marked decrease in right ventricular hypertrophy (LV/RV ratio: 4.0+/-0.3 vs. 2.7+/-0.3, P<0.01, n=10-12) and reductions of the elevated pulmonary artery pressure (40.2+/-3.1 mmHg vs. 26.3+/-4.6 mmHg, P<0.01, n=6). Collectively, these improvements resulted in an enhanced exercise capacity of l-NAME-treated cav-1 ko. Finally, we found evidence for enhanced oxidative stress in untreated cav-1 ko which was substantially reduced by chronic l-NAME administration to cav-1 ko. In view of these data, we speculate that a perturbation of NO signaling, together with enhanced O2(-) production originating from NO synthases, may play a pivotal role in the pathogenesis of the adverse pulmonary phenotype seen in cav-1 ko.

The adverse cardiopulmonary phenotype of caveolin-1 deficient mice is mediated by a dysfunctional endothelium

Recently generated caveolin-1 deficient mice (cav-1(-/-)) display several physiological alterations such as severe heart failure and lung fibrosis. The molecular mechanisms how the loss of caveolin-1 (cav-1) mediates these alterations are currently under debate. A plethora of studies support a role of cav-1 as a negative regulator of endothelial nitric oxide synthase (eNOS). Accordingly, constitutive eNOS hyperactivation was observed in cav-1(-/-). Given the hyperactivated eNOS enzyme we hypothesized that disturbed eNOS function is involved in the development of the cardiopulmonary pathologies in cav-1(-/-). The present study argues that loss of cav-1 results in enhanced eNOS activity but not in increased vascular tetrahydrobiopterin (BH(4)) levels (which acts as an essential eNOS cofactor) thereby causing a stoichiometric discordance between eNOS activity and BH(4) sufficient to cause dysfunctional eNOS signaling. The resultant oxidative stress is largely responsible for major cardiac and pulmonary defects observed in cav-1(-/-). BH(4) donation to cav-1(-/-) led to a normalized BH(4)/BH(2) ratio, to reduced oxidant stress, to substantial improvements of both systolic and diastolic heart function and to marked amelioration of the impaired lung phenotype. Notably, the antioxidant tetrahydroneopterin which is not essential for eNOS function showed no relevant effect. Taken together these novel findings indicate that dysfunctional eNOS is of central importance in the genesis of the cardiopulmonary phenotype of cav-1(-/-). Additionally, these findings are generally of paramount importance since they underline the deleterious role of an uncoupled eNOS in cardiovascular pathology and they additionally suggest BH(4) as an effective cure.

Correlation of heart-type fatty acid–binding protein with mortality and echocardiographic data in patients with pulmonary embolism at intermediate risk

BACKGROUND The management strategy in patients presenting with pulmonary embolism at intermediate risk still remains controversial. Our aim was to determine the role of heart-type fatty acid-binding protein (H-FABP) in this patient population. METHODS One hundred one consecutive patients with confirmed pulmonary embolism and echocardiographic signs of right ventricular overload but without evidence for hypotension or shock, referred to as pulmonary embolism at intermediate risk, were included in the study. Heart-type fatty acid-binding protein and other biomarkers were measured in all patients upon arrival in the emergency department. RESULTS Of the included 101 patients, 14 had positive H-FABP tests. Ten patients with positive H-FABP (71%) had clinical deterioration during the hospital course and required inotropic support and 8 of these patients died. None of the 87 patients with a negative test worsened or needed inotropic support or died during hospital stay (P < .005). In the H-FABP-positive group, right ventricular function on echocardiography was more impaired (tricuspid annular plane systolic excursion 13 +/- 4 vs 18 +/- 4 mm, RV/LV ratio 1.1 +/- 0.2 vs 0.9 +/- 0.2, presence of paradoxical septal movement 79% vs 46%, presence of McConnell sign 100% vs 60%, respectively, all P < .05) compared to the H-FABP-negative group. After adjusting for potential confounding parameters, in multivariate analysis, H-FABP was the only independent predictor of mortality. CONCLUSIONS Heart-type fatty acid-binding protein significantly predicts mortality in patients with pulmonary embolism at intermediate risk. Furthermore, it is significantly associated with impaired right ventricular function and shows better correlation with mortality than troponin I. It may be a novel prognostic parameter enabling the optimization of management strategy in the very difficult population of pulmonary embolism at intermediate risk.

Fluoroscopy integrated 3D mapping significantly reduces radiation exposure during ablation for a wide spectrum of cardiac arrhythmias

AIMS Despite the use of established 3D-mapping systems, invasive electrophysiological studies and catheter ablation require high radiation exposure of patients and medical staff. This study investigated whether electroanatomic catheter tracking in prerecorded X-ray images on top of an existing 3D-mapping system has any impact on radiation exposure. METHODS AND RESULTS Two hundred and ninety-five consecutive patients were either ablated with the guidance of the traditional CARTO-3 system (c3) or with help of the CARTO-UNIVU system (cU): [typical atrial flutter (AFL) n = 58, drug refractory atrial fibrillation (AF) n = 81, ectopic atrial tachycardia (EAT) n = 37, accessory pathways (APs) n = 22, symptomatic, idiopathic premature ventricular complexes (PVCs) n = 56, ventricular tachycardias (VTs) n = 41]. The CARTO-UNIVU allowed a reduction in radiation exposure: fluoroscopy time: AFL c3: 8.6 ± 0.8 min vs. cU: 2.9 ± 0.3 min, P < 0.001; AF c3: 16.0 ± 1.3 min vs. cU: 6.4 ± 0.9 min, P < 0.001; EAT c3: 23.4 ± 3.1 min vs. cU: 9.7 ± 1.7 min, P < 0.001; AP c3: 7.1 ± 1.2 min vs. cU: 6.0 ± 1.5 min, P = 0.59; PVCs c3: 17.6 ± 2.3 min vs. cU: 15.2 ± 2.8 min, P = 0.52; VT c3: 31.4 ± 3.4 min vs. cU: 17.5 ± 2.4 min, P = 0.003. Corresponding to the fluoroscopy time the fluoroscopy dose was also reduced significantly. These advantages were not at the cost of increased procedure times, periprocedural complications, or decreased acute ablation success rates. CONCLUSION In a wide spectrum of cardiac arrhythmias, and especially in AF and VT ablation, fluoroscopy integrated 3D mapping contributed to a dramatic reduction in radiation exposure without prolonging procedure times and compromising patients safety. That effect, however, could not be maintained in patients with APs and PVCs.

Chronic angiotensin ii receptor blockade induces cardioprotection during ischemia by increased PKC-ε expression in the mouse heart

This study was performed to investigate the role of chronic pretreatment with angiotensin II type 1 receptor antagonists (ARB) and angiotensin converting enzyme inhibitors (ACE-I) in myocardial infarction (MI) and ischemic preconditioning (iPC). Little is known about molecular mechanisms of MI and iPC, especially about protein kinase C (PKC) isozyme levels induced by chronic pharmacologic pretreatment with ARB and ACE-I. To address one of the most important signal molecules in iPC, the PKC system was investigated in an ischemia/reperfusion model using isolated mouse hearts. Methods: C57/BL6 mice were treated orally with candesartan cilexetil or ramipril for 2 weeks. Isolated perfused hearts were subjected to 60 minutes of left anterior descending occlusion and 30 minutes of reperfusion. IPC was performed by 3 cycles of 5 minutes of ischemia prior to the infarct ischemia. Infarct size was measured using the propidium iodide method, and PKC isoenzymes were detected by immunoblotting in the membrane and cytosolic fraction. Results: In the control group, iPC reduced infarct size from 59.8 ± 4.2% to 24.5 ± 1.7%. ARB pretreatment itself reduced the infarct size significantly (38.1 ± 3.0%) in hearts without iPC. This protection could neither be enhanced by additional iPC (40.3 ± 3.4%) nor blocked by the AT2-receptor antagonist PD123.319 (40.7 ± 3.7%). The ARB-induced cardio protection, however, was abolished by chelerythrine (5 μmol/L) (71.7 ± 6.6%, n = 11, P < 0.001). Furthermore, PKC-epsilon (PKC-ϵ) was significantly increased in the particulate fraction of ARB-pretreated mice. On the contrary, chronic treatment with ACE-I completely blocked iPC (57.7 ± 3.9%, n = 12, P < 0.001) without any effect on infarct size itself (51.5 ± 3.0%, n = 12). PKC-ϵ expression was significantly reduced. Conclusion: Chronic AT1-receptor antagonism is capable of protecting the heart against myocardial infarction in a PKC-ϵ-dependent way. Furthermore, chronic treatment with ACE-I is suggested to have suppressing effects on iPC, possibly caused by reduced PKC-ϵ expression.

Reduction of radiation exposure during atrial fibrillation ablation using a novel fluoroscopy image integrated 3-dimensional electroanatomic mapping system: A prospective, randomized, single-blind, and controlled study

OBJECTIVE We explored whether the use of a novel fluoroscopy image integrated 3-dimensional electroanatomic mapping (F-EAM) system could result in a reduction of overall fluoroscopy time and radiation doses during the whole procedure of atrial fibrillation (AF) ablation. METHODS Eighty patients (44 men (55%); mean age 63 ± 10 years) who underwent catheter ablation due to paroxysmal AF were recruited consecutively in the present study. Patients were randomized (1:1) into 2 arms for AF ablation: one using a conventional 3-dimensional electroanatomical mapping (EAM) system and the other using the F-EAM system. RESULTS Fluoroscopy time (10:42 [interquartile range {IQR} 8:45-12:46] minutes:seconds vs 1:45 [IQR 1:05-2:22] minutes:seconds; P < .001) and radiation doses (2440 [IQR 1593-3091] cGy·cm(2) vs 652 [IQR 326-1489] cGy·cm(2); P < .001) in the EAM group were significantly greater than those in the F-EAM group. The majority of reduction of radiation exposure was achieved after transseptal puncture, which was near-zero fluoroscopic exposure. In total, approximately 84% of fluoroscopy time and 73% of radiation doses have been reduced during the AF ablation procedure using the F-EAM system compared to using the conventional EAM system. However, procedure time did not differ significantly (1:39 [IQR 1:18-2:10] hours:minutes vs 1:37 [IQR 1:17-1:50] hours:minutes; P = .362). During follow-up (5.9 ± 1.3 months), 61 patients (76.3%) had no recurrence of atrial arrhythmias. The recurrence rate between the 2 groups did not differ. CONCLUSION AF catheter ablation using the F-EAM system was safe and resulted in a significant reduction of radiation exposure to patients and staff without complicating the workflow of the procedure. A near-zero fluoroscopic catheter ablation procedure could be performed without compromising acute/mid-term efficacy and safety.

Nitric oxide synthases are crucially involved in the development of the severe cardiomyopathy of caveolin-1 knockout mice.

Targeted ablation of caveolin-1 (cav-1) results in a severe cardiomyopathy. How the loss of cav-1 mediates these abnormalities is currently under investigation. Mounting evidence indicates that cav-1 acts as a negative regulator of endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO)-pathway in cav-1 knockout mice (cav-1 ko). In this context we hypothesized that disturbed NO signalling is implicated in these changes. To explore this question cav-1 ko were compared with knockout counterparts experiencing 2 month postnatal NO synthase inhibition by N(G)-nitro-l-arginine methyl ester (l-NAME) treatment. Chronic l-NAME treatment resulted in significant improvements in heart function and exercise capacity in cav-1 ko. Furthermore, we found evidence for an enhanced radical stress in hearts of cav-1 ko which was markedly reduced by l-NAME treatment. Collectively, these findings suggest that NO synthases play a crucial role in the evolution of heart failure evident in cav-1 ko.

Local inhibition of hypoxia-inducible factor reduces neointima formation after arterial injury in ApoE-/- mice.

OBJECTIVE Hypoxia plays a pivotal role in development and progression of restenosis after vascular injury. Under hypoxic conditions the hypoxia-inducible factors (HIFs) are the most important transcription factors for the adaption to reduced oxygen supply. Therefore the aim of the study was to investigate the effect of a local HIF-inhibition and overexpression on atherosclerotic plaque development in a murine vascular injury model. METHODS AND RESULTS After wire-induced vascular injury in ApoE-/- mice a transient, local inhibition of HIF as well as an overexpression approach of the different HIF-subunits (HIF-1α, HIF-2α) by adenoviral infection was performed. The local inhibition of the HIF-pathway using a dominant-negative mutant dramatically reduced the extent of neointima formation. The diminished plaque size was associated with decreased expression of the well-known HIF-target genes vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and Flk-1. In contrast, the local overexpression of HIF-1α and HIF-2α further increased the plaque size after wire-induced vascular injury. CONCLUSIONS Local HIF-inhibition decreases and HIF-α overexpression increases the injury induced neointima formation. These findings provide new insight into the pathogenesis of atherosclerosis and may lead to new therapeutic options for the treatment of in stent restenosis.