Hajnalka Vágó

Bosentan the mixed endothelin-A- and -B-receptor antagonist suppresses intrapericardial endothelin-1-induced ventricular arrhythmias

We observed that heterozygous knockout (+/-, KO) of either endothelin-A- (ET(A)) or -B- (ET(B)) receptors significantly reduced the pressor responses to systemically administered endothelin-1 (ET-1) in ET(A) or ET(B) (+/-) KO mice when compared to wild-type (WT) mice (data not shown). Also, we observed that basal mean arterial pressure (MAP) is significantly higher in ET(B) (+/-) (92.7 +/- 1.2 mmHg) (n = 53, p < 0.05) but not ET(A) (+/-) KO mice (70.6 +/- 1.8 mmHg) (n = 23) when compared to their anaesthetized WT littermates (70.1 +/- 0.7 mmHg) (n = 118). A 90 min treatment with either BQ-123 (10 mg/kg), an ET(A)-selective antagonist, or BQ-928 (10 mg/kg), a mixed ET(A)/ET(B) antagonist, administered intraperitoneally, significantly reduced basal MAP of ET(B) (+/-) KO mice almost to the level of their WT treated counterparts (94.9 +/- 4.9 mmHg) (n = 6) vs (+ BQ-123: 59.7 +/- 0.3 mmHg, n = 8); (+ BQ-928: 72.4 +/- 2.6 mmHg, n = 5). It is worthy of note that BQ-123 significantly reduced basal MAP in WT mice but to a lesser extent than in ET(B) (+/-) KO mice (69.6 +/- 2.3 mmHg, n = 8) vs (+ BQ-123: 57.3 +/- 1.4 mmHg, n = 8). In contrast, the ET(B)-selective antagonist, BQ-788 (10 mg/kg i.p.), had no significant effect on MAP even after 90 min of treatment (ET(B) (+/-) KO: (92.3 +/- 2.3 mmHg, n = 6) vs (+ BQ-788: 89.7 +/- 3.1 mmHg, n = 6); WT: (70.5 +/- 3.7 mmHg, n = 7) vs (+ BQ-788: 71.2 +/- 2.0 mmHg, n = 6). Therefore heterozygous KO of either ET(A)- or ET(B)-receptors significantly alters the phenotypic pressor properties of ET-1. We also suggest that there is less ET clearance in ET(B) (+/-) KO mice than in WT mice, which can explain the ET(A)-dependent hypertensive state of the former strain.We evaluated the role of endothelin-B- (ET(B)) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting lethal (sl) rat which carries a naturally occurring deletion in the ET(B)-receptor gene. Homozygous (sl/sl) rats exhibit abnormal development of the neural crest-derived epidermal melanocytes and the enteric nervous system (ENS), and do not live beyond 1 month because of intestinal aganglionosis and resulting intestinal obstruction. Therefore, the dopamine-beta-hydroxylase (D betaH) promoter was used to direct ET(B) transgene expression in sl/sl rats to support normal ENS development. D betaH-ET(B) sl/sl rats live into adulthood and are healthy, expressing ET(B)-receptor in adrenals and other adrenergic neurons. When homozygous (sl/sl) and wild-type (WT) (+/+) rats, all of which were transgenic, were treated with DOCA and salt for 4 weeks, the homozygous rats exhibited significantly earlier and higher increases in systolic blood pressure than WT rats. The daily oral administration of ABT-627, a selective ET(A)-receptor antagonist, almost completely suppressed the DOCA-salt-induced hypertension in both groups. Renal dysfunction and histological damage induced by DOCA-salt treatment were more severe in homozygous than in WT rats. Increased and marked vascular hypertrophy of the aorta was also observed in homozygous rats, compared with WT rats. Renal and vascular injuries induced by DOCA and salt were significantly improved by ABT-627 administration. We propose that ET(B)-receptor-mediated actions are protective factors in the pathogenesis of DOCA-salt-induced hypertension. ET(A)-mediated actions are at least partly responsible for the increased susceptibility to DOCA-salt-induced hypertension and related tissue injuries in ET(B)-receptor-deficient rats.

Severe mitral regurgitation and heart failure due to caseous calcification of the mitral annulus

Caseous calcification is a rare form of mitral annular calcification. Echocardiography reveals an echodense mass in the inferior mitral annulus with smooth borders and an echolucent inner core. We present a case where caseous calcification of the mitral annulus caused severe mitral regurgitation, atrial fibrillation and heart failure. Transthoracic echocardiography, transesophageal echocardiography, cardiac mag- netic resonance and computed tomography were performed and ensured the diagnosis. The mass was surgically removed and a prosthetic valve was implanted. We conclude that caseous calcification of the mitral annulus should be considered not only in the differential diagnosis of cardiac masses but also in the background of mitral regurgitation, atrial fibrillation and heart failure. This case also represents the usefulness of multimodal imaging in identifying cardiac masses.

Images in cardiovascular medicine. Cardiac contusion in a professional soccer player: visualization of acute and late pathological changes in the myocardium with magnetic resonance imaging.

We report here the case of a 30-year-old professional soccer player who presented to our hospital after sustaining a blunt chest trauma. To the best of our knowledge, this is the first reported case of cardiac contusion when acute myocardial edema and subsequent chronic myocardial injury were visualized with cardiac magnetic resonance (CMR) imaging. A professional soccer player presented to our hospital with persistent chest pain and fatigue after being hit in the chest by a soccer ball during a national league game. The hospital admission was 10 hours after the accident and onset of symptoms. The patient had no medical history and no recent history of infectious disease. The initial workup revealed elevated cardiac troponin T of 0.576 μg/L (normal range, 0.00 to 0.03 μg/L) and creatine kinase-MB levels of 25.4 U/L (normal range, 0 to 25 U/L); the markers of inflammation proved to be negative (C-reactive protein level, 0.9 mg/L [normal range, 0 to 5.0 mg/L]; white blood cell count, 7.0×103/μL [normal range, 4 to 10×103/μL]). The patient underwent a performance-enhancing drug screening 8 days before the event as part of the regular doping control protocol of professional soccer players, which proved to be negative. Furthermore, the toxicology panel testing for 7 drugs (phencyclidine, barbiturates, cannabinoids, amphetamines, benzodiazepines, …

Mesenteric vascular dysfunction after cardiopulmonary bypass with cardiac arrest is aggravated by coexistent heart failure.

Although patients suffering from heart failure (HF) have an increased incidence of nonocclusive mesenteric ischemia after opened heart surgery, the impact of cardiopulmonary bypass with cardiac arrest (CPB) on mesenteric vascular circulation in such situation remains unexplored. Therefore, the present study investigates the effects of CPB on mesenteric vascular reactivity, regional metabolism, and oxidative stress in an experimental model of HF. Volume-overload HF was induced in six dogs by bilateral femoral arteriovenous fistula. Six sham-operated dogs were used as controls. Eight weeks later, the short-term effects of 90 min of CPB were assessed in vivo during acute experiments. The significant increase in left ventricular end-diastolic volume in HF animals did not influence the vasodilator response of the superior mesenteric artery to acetylcholine (ACH) and nitroprusside (SNP) under baseline conditions. However, reduced mesenteric oxygen delivery, increased oxygen extraction, and lactate release were found during CPB in the HF group. In addition, an increased free radical production was assessed in the HF group during (89 ± 23 x 106 relative light units [RLU]) and after CPB (93 ± 15 x 106 RLU) compared with controls (45 ± 15 and 49 ± 7 x 106 RLU, respectively). Finally, 90 min of CPB led to a more pronounced decrease of ACH- (−22% ± 5% vs. −42% ± 9%, P < 0.05) and SNP- (−14% ± 4% vs. −50% ± 7%, P < 0.002) induced mesenteric vasodilatations in the HF group compared with controls. We conclude that coexistent HF significantly enhances the pathological effects of CPB on the mesenteric vascular circulation by additionally altering endothelial and smooth muscle vascular function consequent to augmented oxidative stress.

Changes of endothelin-1 and big endothelin-1 levels and action potential duration during myocardial ischemia-reperfusion in dogs with and without ventricular fibrillation.

Myocardial ischemia-reperfusion is associated with increased production of endothelin-1 (ET-1). Moreover, exogenous ET-1 has arrhythmogenic properties. Our aim was to investigate the correlation between endogenous ET-1, big ET-1 levels and epicardial monophasic action potential duration during myocardial ischemia-reperfusion in anesthetized dogs. Thirty-minute myocardial ischemia was followed by a 90-minute reperfusion period in 18 mongrel dogs. The total incidence of ventricular fibrillation (VF) during ischemia and reperfusion was 11.1% and 33.3%, respectively. During ischemia, the monophasic action potential duration at 90% repolarization (MAPD90) decreased significantly (control versus ischemia, 30 minutes, 224.7 ± 7.1 ms versus 173.8 ± 7.6 ms; P < 0.05), while during reperfusion a significant prolongation of MAPD90 was observed (ischemia, 30 minutes versus reperfusion, 30 minutes, 173.8 ± 7.6 ms versus 249.7 ± 9.9 ms, P < 0.05). During reperfusion ET-1 and big ET-1 levels increased significantly in the coronary sinus and femoral artery (control versus reperfusion, 90 minutes: coronary sinus ET-1, 15.1 ± 1.4 fmol/mL versus 22.3 ± 1.1 fmol/mL; big ET-1, 14.7 ± 1.9 fmol/mL versus 27.4 ± 2.3 fmol/mL; P < 0.05). The ET-1 concentration increased to a higher level during ischemia in dogs with VF compared with dogs surviving ischemia-reperfusion (non-VF versus VF: control, 15.1 ± 1.3 versus 15.2 ± 1.3; ischemia, 30 minutes, 17.6 ± 1.2 fmol/mL versus 22 ± 1.6 fmol/mL; P < 0.05), demonstrating a trend of correlation between endothelin levels and development of VF (P = 0.07). ET-1 and big ET-1 levels increased during reperfusion and in the VF group during ischemia; however, there was no correlation between endothelin levels and MAPD90.

Endothelin gene expression during ischemia and reperfusion

Endothelin-1 (ET-1) probably plays an important role in myocardial damage in acute ischemia. Coronary sinus ET-1 and its precursor big endothelin-1 (big ET-1) levels and also tissue levels of preproendothelin-1 mRNA (ET-1 mRNA) were investigated in an in vivo canine ischemia-reperfusion model in nine consecutive mongrel dogs, surviving 30-minute ligation of the left descending coronary artery followed by a 90-minute reperfusion period. Samples were collected before and at the end of ischemia and during reperfusion. ET-1 and big ET-1 were obtained by immunoprecipitation and detected by western blotting. The ET-1 mRNA level was assessed by reverse transcription-polymerase chain reaction. During ischemia the plasma ET-1 levels and big ET-1 levels did not change significantly, while the myocardial ET-1 mRNA level decreased to 57.8%. During reperfusion an increase of the coronary sinus ET-1 and big ET-1 levels was observed (control versus reperfusion, 90 minutes; ET-1, 15.2 ± 4.18 fmol/mL versus 23.2 ± 5.23 fmol/mL, P < 0.01; big ET-1, 14.7 ± 5.9 fmol/mL versus 27.2 ± 7.1 fmol/mL, P < 0.001). Simultaneously, the ET-1 mRNA level increased by 322% relative to the ischemic and by 214% relative to the baseline level. The decrease of ET-1 mRNA during ischemia may be due to degradation and decreased metabolism in the hypoxic cells locally. The elevation of the ET-1 mRNA level during reperfusion indicates rapid big ET-1 synthesis. This was confirmed by the increases in big ET-1 and ET-1 plasma levels. This latter can be associated with the generation of reperfusion arrhythmias or other complications of acute myocardial infarction.

The ETA receptor antagonist LU 135252 has no electrophysiological or anti-arrhythmic effects during myocardial ischaemia/reperfusion in dogs

The anti-arrhythmic effects of ET(A) receptor antagonists during myocardial ischaemia and reperfusion remain controversial. Moreover, the electrophysiological mechanism has not yet been identified. The aim of this study was to investigate the potential anti-arrhythmic and electrophysiological effects of the ET(A) receptor antagonist LU 135252 (LU) during myocardial ischaemia and reperfusion in a canine model. A bolus of LU (1 mg/kg; n=10) or saline (control; n=10) was injected into the left anterior descending coronary artery before ligation of this vessel for 30 min, which was followed by a 90-min reperfusion period. LU bolus administration (0.5 mg/kg) was repeated every 30 min. There were no differences in mean arterial blood pressure or coronary blood flow between the two groups. The determined left ventricular ischaemic mass was 25.5+/-1.8% and 27.8+/-2.2% of the total left ventricular mass in the control and LU groups respectively. The total incidence of ventricular fibrillation during ischaemia and reperfusion was 40% in the control and 50% in the LU group (not significantly different). The incidence of non-sustained and sustained ventricular tachycardias during ischaemia, reperfusion and over the whole period (ischaemia plus reperfusion) in the control group was 50%, 50% and 70% respectively, and that in the LU group was 80%, 70% and 100% respectively (no significant differences between groups). The number of ventricular premature beats was not decreased by LU during either ischaemia or reperfusion [median (25th-75th percentile): ischaemia, 20 (13-37) and 56 (32-130) for LU and control groups respectively; reperfusion, 15 (2-21) and 39 (7-74) respectively; ischaemia+reperfusion, 16 (4-35) and 43 (10-82) respectively; no significant differences between groups]. During ischaemia, the monophasic action potential duration at 90% repolarization (MAPD(90)) decreased significantly, while during reperfusion a significant prolongation of MAPD(90) was observed in the left anterior descending region that was similar in the two groups. In conclusion, LU did not affect repolarization changes and did not have anti-arrhythmic effects during either ischaemia or reperfusion in this model.

Multimodality Imaging of Giant Right Coronary Aneurysm and Postsurgical Coronary Artery Inflammation

A 52-year-old former recreational marathon runner with a history of permanent atrial fibrillation was referred to our institution because of fatigue and shortness of breath. His 12-lead ECG indicated atrial fibrillation with incomplete right bundle-branch block and inferolateral T-wave inversions (Figure 1). The chest x-ray showed an abnormal structure with a circular silhouette at the projection of the right atrium in the anterior-posterior view (Figure 2). Transthoracic echocardiography revealed a vascular tubular structure adjacent to the atrioventricular groove (Figure 3A and 3B and Movies I and II in the online-only Data Supplement). Subsequently, we performed a coronary computed tomography angiography (CCTA) using a 256-slice multidetector-row CT (Philips Brilliance iCT, Best, The Netherlands) with a tube voltage of 100 kV and a tube current of 300 mA. Because of the atrial fibrillation (mean heart rate, 57 bpm; range, 45–110 bpm), an arrhythmia detection algorithm was used during the prospective ECG-triggered image acquisition. The CCTA depicted a normal left coronary system with no signs of atherosclerosis. The ostium of the right coronary artery (RCA) was dilated (10×8 mm), and the proximal segment of the vessel formed a giant aneurysm (Figure 4A and 4B). The location of the aneurysm was noted to be anterior to the right atrium, adjacent to the atrioventricular groove, and its size measured 62×60×86 mm (Figure 4D–4F). Distal to the aneurysm, the extremely tortuous RCA remained enlarged (12–14 mm) and showed a fistulous communication with the coronary sinus (Figure 4C). The length of the whole RCA was ≈80 cm along its centerline. Subsequent invasive coronary angiography confirmed the CCTA findings (Movies III and IV in the online-only Data Supplement). Surgery was performed to repair the RCA and to stop …

Parasympathetic Cardiac Nerve Stimulation with Implanted Coronary Sinus Lead

A patient with drug‐refractory paroxysmal atrial fibrillation associated with rapid ventricular rate underwent biatrial pacemaker implantation. During elective replacement of the pacemaker, a significant voltage‐ and frequency‐dependent decrease in ventricular rate was achieved by high‐frequency electrical stimulation (17 Hz) of parasympathetic cardiac nerves innervating the AV node with the implanted bipolar coronary sinus electrode. The negative dromotropic effect of parasympathetic stimulation was eliminated by intravenous administration of 1‐mg atropine. (J Cardiovasc Electrophysiol, Vol. 15, pp. 588‐590, May 2004)

Right Ventricular Adaptation Is Associated with the Glu298Asp Variant of the NOS3 Gene in Elite Athletes

Nitric oxide (NO), an important endogenous pulmonary vasodilator is synthetized by the endothelial NO synthase (NOS3). Reduced NO bioavailability and thus the Glu298Asp polymorphism of NOS3 may enhance right ventricular (RV) afterload and hypertrophic remodeling and influence athletic performance. To test this hypothesis world class level athletes (water polo players, kayakers, canoeists, rowers, swimmers, n = 126) with a VO2 maximum greater than 50ml/kg/min were compared with non-athletic volunteers (n = 155). Cardiopulmonary exercise tests and cardiac magnetic resonance imaging (cMRI) were performed to determine structural or functional changes. Genotype distribution of the NOS3 Glu298Asp polymorphism was not affected by gender or physical performance. Cardiac MRI showed increased stroke volume with eccentric hypertrophy in all athletes regardless of their genotype. However, the Asp allelic variant carriers had increased RV mass index (32±6g versus 27±6g, p<0.01) and larger RV stroke volume index (71±10ml versus 64±10ml, p<0.01) than athletes with a Glu/Glu genotype. Genotype was not significantly associated with athletic performance. In the non-athletic group no genotype related differences were detected. The association between the NOS3 Glu298Asp polymorphism and RV structure and dimension in elite athletes emphasizes the importance of NOS3 gene function and NO bioavailability in sport related cardiac adaptation.