Usefulness of acute pulmonary vasoreactivity test of sildenafil in treatment of portopulmonary hypertension. A case report

SummaryA 50-year-old man diagnosed with liver cirrhosis type C was referred to our hospital because of right heart failure with pulmonary hypertension. Echocardiography revealed enlargement of the right atrium and ventricle with severe tricuspid regurgitation. The peak flow velocity of tricuspid regurgitation by continuous wave Doppler echocardiography was 452cm/s. Right heart catheterization demonstrated severe pulmonary hypertension [pulmonary arterial pressure (PAP) systolic/diastolic/mean=73/20/41mmHg and pulmonary vascular resistance (PVR)=509dynscm–5] with portal hypertension. We diagnosed the patient as having portopulmonary hypertension (PoPH). Although we treated the patient with a prostacyclin analog, tricuspid regurgitation velocity was increased to 480cm/s four years after the start of the therapy. To select drugs for the treatment of PoPH, we performed an acute vasoreactivity test of sildenafil during right heart catheterization. Since single administration of sildenafil (20mg) decreased PAP (93/30/55–77/27/44mmHg) and PVR (908–833dynscm–5), we added sildenafil (20mg, t.i.d.) to the prostacyclin analog. Tricuspid regurgitation velocity decreased to 403cm/s one year after the addition of sildenafil. An acute vasoreactivity test of sildenafil during right heart catheterization was useful for the decision of the drug to be used in the treatment of PoPH

Hepatocyte growth factor gene therapy reduces ventricular arrhythmia in animal models of myocardial ischemia.

It was recently reported that gene therapy using hepatocyte growth factor (HGF) has the potential to preserve cardiac function after myocardial ischemia. We speculated that this HGF gene therapy could also prevent ventricular arrhythmia. To investigate this possibility, we examined the antiarrhythmic effect of HGF gene therapy in rat acute and old myocardial infarction models. Myocardial ischemia was induced by ligation of the left descending coronary artery. Hemagglutinating virus of Japan (HVJ)-coated liposome containing HGF genes were injected directly into the myocardium fourteen days before programmed pacing. Ventricular fibrillation (VF)was induced by programmed pacing. The VF duration was reduced and the VF threshold increased after HGF gene therapy ( p&#60; 0.01). Histological analyses revealed that the number of vessels in the ischemic border zone was greatly increased after HGF gene injection. These findings revealed that HGF gene therapy has an anti-arrhythmic effect after myocardial ischemia.</p

Usefulness of body surface mapping to differentiate patients with Brugada syndrome from patients with asymptomatic Brugada syndrome.

We attempted to determine the usefulness of body surface mapping (BSM) for differentiating patients with Brugada syndrome (BS) from patients with asymptomatic Brugada syndrome (ABS). Electrocardiograms (ECG) and BSM were recorded in 7 patients with BS and 35 patients with ABS. Following the administration of Ic antiarrhythmic drugs, BSM was recorded in 5 patients with BS and 16 patients with ABS. The maximum amplitudes at J0, J20, J40 and J60 were compared between the 2 groups, as were 3-dimensional maps. The maximum amplitudes at J0, J20 and J60 under control conditions were larger in patients with BS than in patients with ABS (P < 0.05). A three-dimensional map of the ST segments under control conditions in patients with BS showed a higher peak of ST elevation in the median precordium compared to that for patients with ABS. Increases in ST elevation at J20, J40 and J60 following drug administration were greater in patients with BS than in patients with ABS (P < 0.05). Evaluation of the change in amplitude of the ST segment at E5 caused by Ic drug administration was also useful for differentiating between the 2 groups. In conclusion, BSM was useful for differentiating patients with BS from those with ABS.</p

Attenuation of conduction delay by ischemic preconditioning reduces ischemia-induced ventricular arrhythmias.

Ischemic preconditioning has been acknowledged as a powerful method of decreasing ischemic injury. However, the antiarrhythmic mechanism of ischemic preconditioning during ischemia is unclear. We studied the effects of ischemic preconditioning on arrhythmias and cardiac electrophysiology during ischemia in Langendorff rat hearts (n = 44). In the non-preconditioned group (PC(-); n = 24), the hearts underwent 5-min zero-flow global ischemia without any prior ischemic preconditioning. In the preconditioned group (PC(+); n = 20), the hearts were preconditioned by three cycles of 3-min zero-flow global ischemia and 5-min reperfusion before undergoing 5-min global ischemia. Ischemic preconditioning reduced the incidence of ischemia-induced arrhythmias (PC(-); 38.9%, PC(+): 8.3%, p < 0.05), shortened monophasic action potential duration (MAPD, P < 0.05), attenuated conduction delay (conduction time; PC(-): 234.2%, PC(+): 173.4%, P < 0.05) and increased the ventricular fibrillation threshold. Although the shortening of MAPD in PC(-) hearts was not influenced by the presence or absence of arrhythmias, conduction time prolongation at 3-min was more obvious in PC(-) hearts with arrhythmia than in PC(-) hearts without arrhythmia (PC(-) with arrhythmia: 220.2%, PC(-) without arrhythmia: 190.7%, P < 0.05). We concluded that ischemic preconditioning could protect the rat hearts from ischemia-induced arrhythmias and postulated that attenuation of conduction delay during ischemia might be an important factor in the antiarrhythmic action of ischemic preconditioning.</p

Expression of monocyte chemoattractant protein-1 in idiopathic dilated cardiomyopathy

Immunological factors have been involved in the pathogenesis of dilated cardiomyopathy (DCM). The cytotoxic action of macrophages is one of the main factors causing cardiac myocyte damage. Monocyte chemoattractant protein-1 (MCP-1) is a major signal for the accumulation of monocytes/macrophages. We examined whether MCP-1 was expressed in the myocardium of DCM patients and whether the expression level was correlated with the degree of impairment of cardiac function. The expression of MCP-1 in the myocardium was determined by immunohistochemistry in endomyocardial biopsy samples from 13 patients. The expression of MCP-1 was found in all myocardial samples from DCM patients but not in those from control subjects. Positive staining for MCP-1 was distinct in cardiac myocytes, interstitium and infiltrating cells. Semi-quantitative analysis revealed that the expression of MCP-1 was inversely correlated with left ventricular ejection fraction. In conclusion, the expression level of MCP-1 in the myocardium was correlated with the degree of impairment of cardiac function in patients with DCM.</p

Circulating KCNH2 Current-Activating Factor in Patients with Heart Failure and Ventricular Tachyarrhythmia

It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K(+) current (I(Kr)) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I(Kr) increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF.We examined the effects of serum of HF patients on recombinant I(Kr) recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I(Kr) tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia.Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF

Arterial Stiffening is Associated with Exercise Intolerance and Hyperventilatory Response in Patients with Coronary Artery Disease

Exercise intolerance is a common feature of patients with coronary artery disease (CAD). Arterial stiffness is increased in CAD patients; however, the association between arterial stiffness and exercise capacity of CAD patients has not been fully clarified. In this study, we investigated the association between arterial stiffness and the exercise capacity of 62 CAD patients (67 ± 7 yo, 49 men). The patients underwent symptom-limited cardiopulmonary exercise testing and measurement of pulse wave velocity (PWV). The patients were divided into the high-PWV group (n = 31) and the low-PWV group (n = 31), according to the median PWV (1622 cm/sec). In exercise testing, the peak VO 2 was lower in the high-PWV group than in the low-PWV group. VE/VCO 2 slope was higher and the time to ST depression was shorter in the high-PWV group than in the low-PWV group. Multivariate analysis results showed that PWV significantly correlated with peak VO 2 as well as sex. PWV also significantly correlated with time to ST depression and VE/VCO 2 slope. In conclusion, patients with high PWV had lower exercise capacity than patients with low PWV. A low myocardial ischemia threshold, as well as an enhancement of the ventilatory response to exercise, was also found in patients with high PWV