[Clinical characterization and outcome of patients with noncompaction of ventricular myocardium].

OBJECTIVE: To analyze the clinical features and outcome of patients with noncompaction of ventricular myocardium (NVM). METHODS: Clinical manifestations, electrocardiograms and echocardiographies data were analyzed in 18 patients with NVM. Mean follow-up period was (11 +/- 5) months. RESULTS: The patients aged from 1.5 to 71 years, 66.7% patients were males, familial history was observed in 2 cases, congestive heart failure was present in 14 cases, thromboembolic event occurred in 1 patient, arrhythmia induced syncopes were diagnosed in 2 patients and 1 patient was asymptomatic. Abnormal electrocardiograms were observed in all patients, including premature ventricular beats (7 cases), heart block (4 cases), and atrial fibrillations (4 cases). Echocardiographies showed that noncompaction of ventricular myocardium localized in the left ventricle in 17 patients, and right ventricle in 1 patient. The extension of noncompaction myocardium was predominantly at the apex (72%). N/C was 2.3 - 3.1. EF was less than 50% in 15 patients. Hypokinetic movements were observed in both noncompacted and compacted segments. During the follow-up, 1 patient with congestive heart failure received heart transplantation. ICD was implanted in one patient due to ventricular tachycardia. One patient suffered from sudden cardiac death. CONCLUSIONS: The most common clinical presentations of NVM are congestive heart failure, cardiac arrhythmias, and thromboembolism. Echocardiography is considered as the best tool for the diagnosis of NVM. ICD, heart transplantation and anticoagulation therapy could improve the prognosis of patients with NVM in selected cases.

[Effect of imidapril on the effective refractory period and sodium current of ventricular noninfarction zone in healed myocardial infarction].

AIM: To investigate the effects of imidapril (IMI) on effective refractory period (ERP) and sodium current (I(Na)) of myocytes in ventricular noninfarction zone of healed myocardial infarction (HMI) in rabbit models. METHODS: Rabbits with left coronary artery ligation were prepared and IMI (0.625 mg x kg(-1) x d(-1), 8 weeks) was orally administered. The ERP and sodium current were recorded. RESULTS: The ERP in HMI heart was prolonged. The ERP in IMI group was lower significantly than that of HMI group. The I(Na) density of myocyte in HMI ventricle decreased obviously. V 1/2 of steady state inactivation of I(Na) shifted to hyperpolarization, and time constant (tau) of recovery from inactivation in HMI ventricular myocyte was longer than that of sham ventricular myocyte. I(Na) density in IMI group increased markedly as compared with that of HMI group. CONCLUSION: IMI was shown to reverse the abnormal prolongation of ERP in rabbit heart with the HMI and increase I(Na) density. It may be the mechanism of IMI preventing against antiarrhythmia in healed myocardical infarction.

Effects of transforming growth factor-beta1 and signal protein Smad3 on rat cardiomyocyte hypertrophy.

BACKGROUND: SMAD proteins have recently been identified as the first family of putative transforming growth factor-beta1 (TGF-beta1) signal transducers. This study was to investigate the effects of TGF-beta1 and signal protein Smad3 on rat cardiac hypertrophy. METHODS: The incorporation of [(3)H]-leucine was measured to determine the hypertrophy of cardiomyocyte incubated with different doses of TGF-beta1 in cultured neonatal cardiomyocytes. The model of rat cardiac hypertrophy was produced with constriction of the abdominal aorta. At different times after the operation, rats were killed, and their left ventricular mass index (LVMI) determined. The mRNA expression of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR. The protein expression of Smad3 was assessed by Western blot. RESULTS: In cultured neonatal cardiomyocytes, TGF-beta1 significantly promoted incorporation of [(3)H]-leucine. With the concentration of 3 pg/L, it increased the expression of Smad3 in mRNA and protein levels after 15 minutes, and continued for up to 8 hours of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 (mRNA) and Smad3 (mRNA and protein) of hypertrophic left ventricle were increased by day 3 after the operation and continued to the 4th week. The peak expression of these was in the second week after operation. CONCLUSION: TGF-beta1 has positive effects on rat cardiomyocyte hypertrophy. Signal protein Smad3 could be related to the pathologic progression of rat cardiac hypertrophy.

[Heterogeneity of action potential and ion currents in the left ventricular myocytes of the rabbit].

Experiments were performed to investigate the heterogeneity of the action potential and ion currents in left ventricular myocytes of the rabbit. Myocytes were isolated by enzymatic method. The sub-endocardial (Endo) and sub-epicardium (Epi) tissues were separated from the other region (midmyocardium, M) with a razor. Single cells in each region were obtained by gentle shaking and dispersing in a chamber filled with normal Tyrode's solution. The results showed that the action potential and the ion currents in the three layers were significantly different. M cells had a more pronounced spike-and-dome configuration, with a significantly larger phase 1 magnitude and plateau voltage. Action potential duration (APD) in M cells was longer than that in Epi or Endo cells. I(Ca, L) and I(to) in M cells were higher than those of Epi and Endo. On the contrary, I(K,s) in M cells was the minimum compared with those in the three LV walls. The differences in ion currents may well explain the heterogeneity of action potentials in M layers of the rabbit heart.

Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways.

Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P-450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in bovine aortic endothelial cells. CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-alpha induction of endothelial cell apoptosis as evaluated by morphological analysis of nuclear condensation, DNA laddering, and fluorescent-activated cell sorting (FACS) analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-alpha. The antiapoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-alpha-induced ERK1/2 dephosphorylation in a time-dependent manner and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-alpha. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-alpha. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling.

Effect of imidapril on heterogeneity of slow component of delayed rectifying K+ current in rabbit left ventricular hypertrophic myocytes.

AIM: To investigate the transmural heterogeneous change of slow component of delayed rectifying potassium current in rabbit left ventricular hypertrophic myocytes and the effect of long-term treatment with imidapril (Imi). METHODS: Rabbits were divided into hypertrophy group (left ventricular hypertrophy induced by partial ligation of abdominal aorta), Imi-treated group (surgical treatment as hypertrophy group was treated with Imi), and Sham-operated group as control. Whole-cell patch-clamp technique was used to record potassium currents. RESULTS: (1) Membrane capacitance was larger in hypertrophic cells than in sham-operated and Imi-treated cells. Action potential durations (APD) of epicardium (Epi), midmyocardium (M), and endocardium (Endo) were remarkably longer in hypertrophic cells than those in Imi-treated and sham-operated cells. The prolongation of APD90 of M was the most pronounced in three layer myocytes of hypertrophic group. (2) The densities of I(Ks,tail) of hypertrophic cells were reduced by Epi 25.3 %+/-2.9 %, M 38.0 %+/-3.7 % and Endo 20.3 %+/-4.7 % compared with those of sham-operated cells. The decrease of IKs,tail density was more pronounced in M than in Epi and Endo (n = 13, P<0.01 vs Epi or Endo). (3) The density of I(Kr,tail) in Imi-treated cells was not different from that in sham-operated cells significantly (n=10). CONCLUSION: Imi reduced prolongation of APD and inhibited the heterogeneous change of I(Ks,tail) in rabbit left ventricular hypertrophic myocytes.

Effects of imidapril on heterogeneity of action potential and calcium current of ventricular myocytes in infarcted rabbits.

AIM: To investigate the effects of chronic treatment with imidapril on the electrophysiologic heterogeneous change of the noninfarcted myocardium of rabbits after myocardial infarction and the mechanism of its antiarrhythmic efficacy. METHODS: Rabbits with left coronary artery ligation were prepared and allowed to recover for 8 weeks. Myocytes were isolated from subendocardial, midmyocardial, and subepicardial regions of the noninfarcted left ventricular wall. Action potentials and calcium current were recorded using whole-cell patch clamp technique. RESULTS: The action potential duration of repolarization 90 % (APD90) was more prolonged in midmyocardium rather than in subepicardium and subendocardium with healed myocardial infarction. The transmural dispersion of repolarization (TDR) was increased in the three ventricular regions. The amplitude of I(Ca-L) [was enhanced but its density was decreased in noninfarcted ventricular myocytes due to increased cell membrane capacitance. The increased differences of calcium currents among subepicardium, midmyocardium, and subendocardium were also discovered. Normalization of heterogeneous changes in repolarization after treatment with imidapril was observed and decrease of TDR in noninfarcted area was measured. Early after depolarization (EAD) events of noninfarcted midmyocardium were markedly decreased by imidapril. CONCLUSION: Imidapril reduced the electrophysiologic heterogeneities in noninfarcted area in rabbits after myocardial infarction. This ability of imidapril may contribute to its antiarrhythmic efficacy.

Up-regulation of endothelial nitric-oxide synthase by endothelium-derived hyperpolarizing factor involves mitogen-activated protein kinase and protein kinase C signaling pathways.

Cytochrome P450 (P450)-dependent metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs), are proposed to be endothelium-derived hyperpolarizing factors (EDHF) that affect vascular tone; however, the effects of EDHF on endothelial-derived nitric oxide biosynthesis remain unknown. We examined the regulation of endothelial nitric-oxide synthase (eNOS) by EDHF and investigated the relevant signaling pathways involved. The P450 epoxygenases CYP102 F87V mutant, CYP2C11-CYPOR, and CYP2J2 were transfected into cultured bovine aortic endothelial cells, and the effects of endogenously formed or exogenously applied EETs on eNOS expression and activity were assessed. Transfection with the P450 epoxygenases led to increased eNOS protein expression, an effect that was attenuated by cotreatment with the P450 inhibitor 17-ODYA. Northern analysis demonstrated that P450 transfection led to increased eNOS mRNA levels consistent with an effect at the pretranslational level. P450 epoxygenase transfection resulted in increased eNOS activity as measured by the conversion of L-arginine to L-citrulline. Addition of synthetic EETs (50-200 nM) to the culture media also increased eNOS expression and activity. Treatment with mitogen-activated protein kinase (MAPK), MAPK kinase, and protein kinase C inhibitors apigenin, 2'-amino-3'-methoxyflavone (PD98059), and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), respectively, significantly inhibited the effects of P450 transfection on eNOS expression. Overexpression of P450 epoxygenases or addition of synthetic EETs increased Thr495 phosphorylation of eNOS, an effect that was inhibited by both apigenin and PD98059. Overexpression of P450 epoxygenases in rats resulted in increased aortic eNOS expression, providing direct evidence that EDHF can influence vascular eNOS levels in vivo. Based on this data, we conclude that EDHF up-regulates eNOS via activation of MAPK and protein kinase C signaling pathways.