Michihiko Ueno

Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors

Endothelin (ET)-1 has potent positive inotropic and chronotropic activity in the heart and induces cardiac hypertrophy. The production of ET-1 in the heart is reported to be increased under some conditions. In normal circulation, the pressure load to the left ventricle (LV) is much greater than that to the right ventricle (RV). In this study, we investigated the gene expression of the myocardial ET-1 system (ET-1, ETA receptor, and ETB receptor) in the RV and LV of normal rats and also investigated these genes in hypertrophied RV due to pathological pulmonary hypertension (PH). Normal rats showed no differences between the RV and LV in the gene expression of either ET-1, ETA receptor, or ETB receptor in either the adult stage (11 wk old) or the neonatal stage (1 and 8 days old). On the other hand, the expression of both atrial natriuretic peptide (ANP) mRNA and B-type natriuretic peptide (BNP) mRNA was significantly greater in the LV than in the RV in adult rats. Gene expression of ET-1, ETA receptor, and ETB receptor in the RV was markedly higher in rats with monocrotaline-induced (pathological) PH than that in control rats. The expression of ANP mRNA and BNP mRNA in the RV was also markedly higher in the rats with PH. In conclusion, the data suggest that gene expression of the ET-1 system in the myocardium is not affected by physiological pressure load in either the adult stage or neonatal stage; however, it is enhanced by pathological pressure overload such as that in PH.Endothelin (ET)-1 has potent positive inotropic and chronotropic activity in the heart and induces cardiac hypertrophy. The production of ET-1 in the heart is reported to be increased under some conditions. In normal circulation, the pressure load to the left ventricle (LV) is much greater than that to the right ventricle (RV). In this study, we investigated the gene expression of the myocardial ET-1 system (ET-1, ET(A) receptor, and ET(B) receptor) in the RV and LV of normal rats and also investigated these genes in hypertrophied RV due to pathological pulmonary hypertension (PH). Normal rats showed no differences between the RV and LV in the gene expression of either ET-1, ET(A) receptor, or ET(B) receptor in either the adult stage (11 wk old) or the neonatal stage (1 and 8 days old). On the other hand, the expression of both atrial natriuretic peptide (ANP) mRNA and B-type natriuretic peptide (BNP) mRNA was significantly greater in the LV than in the RV in adult rats. Gene expression of ET-1, ET(A) receptor, and ET(B) receptor in the RV was markedly higher in rats with monocrotaline-induced (pathological) PH than that in control rats. The expression of ANP mRNA and BNP mRNA in the RV was also markedly higher in the rats with PH. In conclusion, the data suggest that gene expression of the ET-1 system in the myocardium is not affected by physiological pressure load in either the adult stage or neonatal stage; however, it is enhanced by pathological pressure overload such as that in PH.

Endothelin-A-receptor antagonist and oral prostacyclin analog are comparably effective in ameliorating Pulmonary hypertension and right ventricular hypertrophy in rats

Pulmonary hypertension (PH) has a poor prognosis and is a drug-resistant disease. Recently, it has been reported that continuous intravenous prostacyclin (PGI2) administration is effective for PH. In this study, we compared the effects of chronic treatment with an endothelin-A- (ETA) receptor antagonist with an oral PGI2 analog on PH in rats. We administered the ETA-receptor antagonist TA-0201 or beraprost sodium (BPS), which is an orally active PGI2 analog, to monocrotaline- (MCT) induced PH rats. Each drug was given orally for 19 days. The rats were divided into the following four groups: (1) normal rats with vehicle (control); (2) PH rats with vehicle treatment (PH + vehicle); (3) PH rats with TA-0201 treatment (0.5 mg/kg/day) (PH + TA-0201); (4) PH rats with BPS treatment (100 microg/kg/day) (PH + BPS). Nineteen days after MCT injection, Pp/Ps [the ratio of right ventricular (RV) systolic pressure to systemic systolic blood pressure) and the ratio of the RV weight to the body weight (RV/BW), indicators of PH and RV hypertrophy. were markedly higher in the PH + vehicle group than in the control (healthy) group. The increase in Pp/Ps and RV/BW was significantly depressed in the PH + TA-0201 group and PH + BPS group to a similar extent. The expression of beta-myosin heavy chain (MHC) mRNA, a molecular marker for cardiac hypertrophy, in the RV was greatly increased in the PH + vehicle group and this increase was inhibited in the PH + TA-0201 group and PH + BPS group to a similar effect. In conclusion, treatment with an ETA-receptor antagonist or an oral PGI2 analog is comparably effective in the prevention of progression of PH and RV hypertrophy.

Aortic pressure wave reflection in children.

Aortic pressure wave reflection is one of the risk factors for developing cardiovascular disease in adults, and the degree of pressure wave reflection increases with aging. However, enhanced pressure wave reflection has also been reported in infants and children. The purpose of this study was to clarify pressure wave reflection during childhood and to determine the reference for the augmentation index, which is one of the most useful parameters used to represent the degree of aortic pressure wave reflection in children. This study enrolled 72 patients with normal aortic circulation. The aortic pressure waveform was recorded using a pressure sensor-mounted catheter, and the augmentation index was thus calculated. The augmentation index tended to decrease with increasing age until around 15 years of age and then increased thereafter. For children below 15 years of age, multiple regression analysis revealed a significant negative correlation between body height and augmentation index. In children, increases in aortic pressure wave reflection are probably attributable to changes in body height.

Endothelin-1 and right-sided heart failure in rats: effects of an endothelin receptor antagonist on the failing right ventricle.

The development of pulmonary hypertension (PH) causes right-sided heart failure. We investigated whether chronic treatment with the endothelin-A- (ETA) receptor antagonist BMS-193884 in rats with monocrotaline- (MCT) induced PH improves right-sided heart failure. Administration of BMS-193884 (100mg/kg) was commenced on the day before treatment with MCT. At 19 days, hemodynamics were measured under anesthesia and hearts were removed. The right ventricular systolic pressure (RVSP), an indicator for pulmonary hypertension, was remarkably elevated in the PH group compared with the normal control group. BMS-193884 effectively prevented this elevation. The central venous pressure, an indicator for right-sided heart failure, was markedly increased in the PH group. This increase was reduced to the normal level by BMS-193884. In the failing right ventricle of the PH group, the expression of atrial natriuretic peptide (ANP) mRNA, which is a molecular marker for the failing heart, was markedly increased. BMS-193884 greatly prevented this increase. The present study suggests that ET-1 contributes to the right-sided heart failure caused by PH and that an ETA-receptor antagonist is a beneficial drug which improves both hemodynamics and cardiac gene expression in the failing right ventricle.

Abnormal neurohumoral responses to exercise in patients with heart disease : Inhibition of an increase in endothelin-1 production during exercise

We have reported that the plasma endothelin-1 (ET-1) level is significantly increased by exercise in healthy athletes and that it is elevated in the circulation of the non-working leg but not the working leg, suggesting that ET-1 plays an important role in redistribution of blood during exercise. This study was designed to compare alterations of neurohumoral substances by exercise in normal subjects and patients with heart disease. Study patients comprised three groups: eight patients with congestive heart failure (CHF) due to Ebsteins anomaly or single-ventricle heart after Fontan operation; six patients with complete transposition of the great arteries (TGA) after an anatomic surgical correction who may be candidates for ischemic heart disease; and five age-matched normal subjects. All patients were in New York Heart Association functional class I. All subjects performed symptom-limited treadmill exercise. It is suggested that patients with CHF or TGA have a manifest or latent exercise intolerance, respectively. In failed to increase plasma ET-1 level, although it caused a greater increase in norepinephrine, angiotensin II, and arginine vasopressin than in the controls. Exercise also caused a delay in the increased response of plasma ET-1 levels in patients with TGA after an anatomic surgical repair. On the other hand, plasma brain natriuretic peptide (BNP) level was augmented by exercise in patients with CHF and patients with TGA but not in the controls. The present results suggest that an increase in ET-1 production during exercise is absent in patients with heart disease. The mechanisms of inhibition of ET-1 production during exercise in patients with heart disease remain to be elucidated. However, the present study suggests that ET-1 plays an important role in redistribution of blood during exercise, and proposes the possibility that failure of an increase in ET-1 production results in exercise intolerance in patients with heart disease.

Clinical features of adult patients with Eisenmenger's syndrome in Japan and Korea

BACKGROUND There are few articles on mortality and morbidity of adult patients with Eisenmengers syndrome (ES) in the current era when disease targeting therapy (DTT) has been available. METHODS AND RESULTS 198 patients (a median age 35 years, 64% female) with ES who visited the 16 participating institutes in Japan and Korea from 1998 to 2009 were enrolled. Clinical data during adulthood were collected from each institutional chart and analyzed centrally. During a median follow-up of 8 years, 30 patients died including 14 sudden deaths. 89 patients took oral medication of DTT and clinical improvement was observed in 54 of them. However, survival rate in patients taking DTT was not different from those without (87% vs 84%, p=0.55). When the clinical data in between first and last clinic visits were compared in 85 patients, the patients with NYHA >/=III increased from 24% to 48% (p<0.001), SpO2 decreased from 89% to 85% (p=0.008) and hematocrit increased from 51.4% to 52.9% (p=0.04). Non-survivors had poorer NYHA function class, lower body weight (BW), lower body mass index (BMI), and higher serum level of Cr at the first visits than survivors. CONCLUSIONS Long term survival and clinical status of adult patients with ES remains unsatisfactory even in the current era of DTT. Poor NYHA functional class, low BW, low BMI and high serum level of Cr were related to mortality. DTT therapy improved clinical status in many patients with Eisenmengers syndrome, but no significant impact on survival could be shown.

Idiopathic reentrant right ventricular outflow tract tachycardia with presystolic potential of central pathway.

Idiopathic Reentrant RVOT VT With Presystolic Potential. A 12‐year‐old girl with recurrent palpitation due to idiopathic ventricular tachycardia (VT) with a left bundle branch block configuration and inferior axis was referred to our hospital. During the VT, a spiky presystolic potential (SP) was recorded at the septum of right ventricular outflow tract (RVOT) just below pulmonary valve. The SP was entrained with a decremental property by pacing from right ventricular apex. Concealed entrainment was observed by pacing where the SP was recorded. Delivery of radiofrequency current targeting the SP abolished the VT. The SP with the decremental property could represent the central pathway of this idiopathic RVOT reentrant VT. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1174‐1177)

Multiple Coronary Stenosis in Infantile Moyamoya Disease

A 3-year-old girl was referred to our institution for evaluation of mitral valve regurgitation. A heart murmur was observed when she visited a pediatrician for treatment of a respiratory infection, and it was diagnosed as mitral valve regurgitation. The regurgitation gradually became worse and she was referred to the hospital. An echocardiographic examination showed moderate mitral valve regurgitation. Because her ECG demonstrated a slight ST depression on the left chest leads, dipyridamole stress thallium imaging was performed. However, it …