井澤 英夫

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11β-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs. © 2006 American Heart Association, Inc.

OBJECTIVES The relation between the occurrence of pacing-induced mechanical alternans and prognosis in patients with mild-to-moderate idiopathic dilated cardiomyopathy (IDCM) in sinus rhythm was investigated prospectively. The myocardial expression of genes for Ca2+-handling proteins in such patients was also examined. BACKGROUND Mechanical alternans occurs in some patients with severe heart failure, but the relation between the occurrence of mechanical alternans and prognosis in patients with IDCM has remained unknown. METHODS Left ventricular (LV) pressure was measured during atrial pacing, and LV endomyocardial biopsy specimens were collected in 36 IDCM patients and 8 controls. Idiopathic dilated cardiomyopathy patients were divided into two groups consisting of 22 individuals who did not develop mechanical alternans at heart rates up to 140 beats/min (group A) and of 14 individuals who did (group B). The patients were followed up for a mean of 3.7 years. RESULTS There was no significant difference in LV ejection fraction or the plasma concentration of brain natriuretic peptide between groups A and B. The myocardial abundance of ryanodine receptor 2 messenger ribonucleic acid (mRNA) was significantly lower in groups A and B than in controls, whereas that of sarcoplasmic reticulum Ca2+-ATPase mRNA was significantly lower in group B than in group A or controls. Stepwise multivariate analysis identified pacing-induced mechanical alternans as the strongest predictor of cardiac events. Event-free survival in group A was significantly greater than that in group B. CONCLUSIONS The occurrence of pacing-induced mechanical alternans is a potentially useful indicator of poor prognosis in patients with mild-to-moderate IDCM in sinus rhythm.

Aldosterone promotes vascular smooth muscle cell proliferation and endothelial dysfunction, suggesting the contribution to in-stent restenosis (ISR). This study evaluated any relation between plasma aldosterone levels and ISR 6 months after successful coronary stenting. We enrolled 156 consecutive patients with stable angina who underwent coronary bare metal stenting. Plasma aldosterone levels and other serum markers known to influence cardiovascular events were measured in all patients at baseline. Patients with restenosis were found to have significantly higher plasma aldosterone levels than their counterparts without restenosis (162 +/- 60 vs 122 +/- 60 pg/ml, p = 0.007). On logistic regression analysis, even after adjusting for clinical, angiographic, and other confounding variables, plasma aldosterone level per 10 pg/ml (odds ratio 1.34, 95% confidence interval 1.10 to 1.63, p = 0.006) proved to be the independent predictor of ISR. The area under the receiver-operating characteristic curve for plasma aldosterone level was 0.75, and the optimal cut-off value identified by receiver-operating characteristic analysis was 141.9 pg/ml, which had a predictive accuracy of 69%. In conclusion, the present findings indicate that plasma aldosterone levels at baseline are independent predictors of ISR and may constitute a potential therapeutic target. (c) 2006 Elsevier Inc. All rights reserved.

Background The presence of intracoronary large thrombus burden (LTB) in the infarct-related artery increases the risk of distal embolization and no-reflow during percutancous coronary intervention (PCI). Evaluation of whether the distal protection (DP) during primary PCI reduces adverse effects of LTB on myocardial reperfusion and infarct size was investigated. Methods and Results A consecutive series of 88 patients with acute myocardial infarction undergoing primary PCI using DP were compared with 81 consecutive patients treated by primary PCI alone. The DP use showed similar post-procedural myocardial blush grade (MBG)-3 and infarct size, but improved corrected thrombolysis in myocardial infarction frame count (cTFC) (29 +/- 11 vs 35 +/- 20, p=0.011) and the incidence of ST-segment resolution (80.7% vs 66.7%, p=0.038). In patients with LTB present, however, the DP use reduced occurrences of no-reflow (0% vs 11.8%, p=0.036) and distal embolization (4.8% vs 17.6%, p=0.129), resulting in higher occurrences of MBG-3 (61.9% vs 35.3%, p=0.021) and ST-segment resolution (78.6% vs 50.0%, p=0.009), lower cTFC values (30 8 vs 40 22, p=0.012) and smaller infarct size (12.2 +/- 11.2 vs 18.7 +/- 11.1, p=0.015). Conclusions With an improved myocardial reperfusion and smaller infarct size in patients with LTB, the DP during primary PCI might be a better strategy in this particular setting compared with conventional strategy.

Aldosterone promotes vascular smooth muscle cell proliferation and endothelial dysfunction, suggesting the contribution to in-stent restenosis (ISR). This study evaluated any relation between plasma aldosterone levels and ISR 6 months after successful coronary stenting. We enrolled 156 consecutive patients with stable angina who underwent coronary bare metal stenting. Plasma aldosterone levels and other serum markers known to influence cardiovascular events were measured in all patients at baseline. Patients with restenosis were found to have significantly higher plasma aldosterone levels than their counterparts without restenosis (162 +/- 60 vs 122 +/- 60 pg/ml, p = 0.007). On logistic regression analysis, even after adjusting for clinical, angiographic, and other confounding variables, plasma aldosterone level per 10 pg/ml (odds ratio 1.34, 95% confidence interval 1.10 to 1.63, p = 0.006) proved to be the independent predictor of ISR. The area under the receiver-operating characteristic curve for plasma aldosterone level was 0.75, and the optimal cut-off value identified by receiver-operating characteristic analysis was 141.9 pg/ml, which had a predictive accuracy of 69%. In conclusion, the present findings indicate that plasma aldosterone levels at baseline are independent predictors of ISR and may constitute a potential therapeutic target. (c) 2006 Elsevier Inc. All rights reserved.

Background The presence of intracoronary large thrombus burden (LTB) in the infarct-related artery increases the risk of distal embolization and no-reflow during percutancous coronary intervention (PCI). Evaluation of whether the distal protection (DP) during primary PCI reduces adverse effects of LTB on myocardial reperfusion and infarct size was investigated. Methods and Results A consecutive series of 88 patients with acute myocardial infarction undergoing primary PCI using DP were compared with 81 consecutive patients treated by primary PCI alone. The DP use showed similar post-procedural myocardial blush grade (MBG)-3 and infarct size, but improved corrected thrombolysis in myocardial infarction frame count (cTFC) (29 +/- 11 vs 35 +/- 20, p=0.011) and the incidence of ST-segment resolution (80.7% vs 66.7%, p=0.038). In patients with LTB present, however, the DP use reduced occurrences of no-reflow (0% vs 11.8%, p=0.036) and distal embolization (4.8% vs 17.6%, p=0.129), resulting in higher occurrences of MBG-3 (61.9% vs 35.3%, p=0.021) and ST-segment resolution (78.6% vs 50.0%, p=0.009), lower cTFC values (30 8 vs 40 22, p=0.012) and smaller infarct size (12.2 +/- 11.2 vs 18.7 +/- 11.1, p=0.015). Conclusions With an improved myocardial reperfusion and smaller infarct size in patients with LTB, the DP during primary PCI might be a better strategy in this particular setting compared with conventional strategy.

68歳男.高血圧,高脂血症を指摘されたが放置した.労作性狭心症が出現し,胸痛が持続し救急搬送された.心拍数は55/min,心電図でST上昇,陰性T波を認め,胸部X線でCTR63%で中等度鬱血を認めた.又,緊急心臓カテーテルでKillip II度の心原性プレショック状態の急性下壁心筋梗塞と診断し,緊急冠動脈造影を施行した.LADに対してはPCIを施行した.心電図におけるST上昇部位と灌流域の大きさより右冠動脈に対しPCIを行い,ガイディングワイヤー,ガイディングカテーテルを使用したが,冠動脈造影上,責任病変は動脈硬化主体で,血栓量は多くないと判断し,バルーンカテーテルで前拡張し,良好な拡張を確保した.完全血行再建を目的とする一期的PCIは症例によっては,多枝病変の虚血性疾患に対する方法として有用な可能性があると思われた

The possible role of calcineurin in cardiac hypertrophy induced by calmodulin (CaM) overexpression in the heart was investigated. CaM transgenic (CaM-TG) mice developed marked cardiac hypertrophy and exhibited up-regulation of atrial natriuretic factor (ANF) and P-myosin heavy chain gene expression in the heart during the first 2 weeks after birth. The activity of calcineurin in the heart was also significantly increased in CaM-TG mice compared with wild-type littermates. Treatment of CaM-TG mice with the calcineurin inhibitor FK506 (1 mg/kg per day) prevented the increase in the heart-to-body weight ratio as well as that in cardiomyocyte width. FK506 also inhibited the induction of fetal-type cardiac gene expression in CaM-TG mice. Overexpression of CaM in cultured rat cardiomyocytes activated the ANF gene promoter in a manner sensitive to FK506. Activation of a calcineurin-dependent pathway thus contributes to the development of cardiac hypertrophy induced by CaM overexpression in the heart. (c) 2005 Elsevier Inc. All rights reserved.

OBJECTIVES We investigated the relationship between iodine-123-metaiodobenzylguanidine (I-123-MIBG) findings and myocardial contractile reserve in patients with mild to moderate dilated cardiomyopathy (DCM). BACKGROUND Little is known regarding the relationship between cardiac sympathetic nervous function and myocardial contractile reserve in DCM. METHODS Twenty-four DCM patients who showed sinus rhythm underwent echocardiography, biventricular catheterization, and myocardial I-123-MIBG scintigraphy. Left ventricular (LV) pressures were measured using a micromanometer-tipped catheter. The myocardial contractile function (LV dP/dt(max)) was determined at rest and during atrial pacing. The messenger ribonucleic acid (mRNA) expressions of intracellular Ca2+-regulatory proteins were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. Myocardial I-123-MIBG accumulation was quantified as a heart-mediastinum ratio (HMR). RESULTS A significant correlation was observed between the delayed I-123-MIBG HMR and the percentage change in LV dP/dt(max) from the baseline to the peak or critical heart rate (r = 0.64; p < 0.001). The delayed I-123-MIBG HMR was significantly lower in patients showing a worsening change in LV dP/dt(max) than in those showing a favorable change (p < 0.005). The maximum LV dP/dt(max) during pacing and the sarcoplasmic reticulum Ca2+-ATPase (SERCA2) mRNA levels were significantly more reduced in patients with a delayed HMR than in those with a delayed HMR > 1.8 (p < 0.05, respectively). CONCLUSIONS Abnormal myocardial I-123-MIBG accumulation is related to an impaired myocardial contractile reserve and down-regulation of SERCA2 mRNA in DCM. Myocardial I-123-MIBG scintigraphy can be useful in noninvasively evaluating myocardial contractile reserve in patients with mild to moderate DCM.

The possible role of calcineurin in cardiac hypertrophy induced by calmodulin (CaM) overexpression in the heart was investigated. CaM transgenic (CaM-TG) mice developed marked cardiac hypertrophy and exhibited up-regulation of atrial natriuretic factor (ANF) and P-myosin heavy chain gene expression in the heart during the first 2 weeks after birth. The activity of calcineurin in the heart was also significantly increased in CaM-TG mice compared with wild-type littermates. Treatment of CaM-TG mice with the calcineurin inhibitor FK506 (1 mg/kg per day) prevented the increase in the heart-to-body weight ratio as well as that in cardiomyocyte width. FK506 also inhibited the induction of fetal-type cardiac gene expression in CaM-TG mice. Overexpression of CaM in cultured rat cardiomyocytes activated the ANF gene promoter in a manner sensitive to FK506. Activation of a calcineurin-dependent pathway thus contributes to the development of cardiac hypertrophy induced by CaM overexpression in the heart. (c) 2005 Elsevier Inc. All rights reserved.

OBJECTIVES We investigated the relationship between iodine-123-metaiodobenzylguanidine (I-123-MIBG) findings and myocardial contractile reserve in patients with mild to moderate dilated cardiomyopathy (DCM). BACKGROUND Little is known regarding the relationship between cardiac sympathetic nervous function and myocardial contractile reserve in DCM. METHODS Twenty-four DCM patients who showed sinus rhythm underwent echocardiography, biventricular catheterization, and myocardial I-123-MIBG scintigraphy. Left ventricular (LV) pressures were measured using a micromanometer-tipped catheter. The myocardial contractile function (LV dP/dt(max)) was determined at rest and during atrial pacing. The messenger ribonucleic acid (mRNA) expressions of intracellular Ca2+-regulatory proteins were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. Myocardial I-123-MIBG accumulation was quantified as a heart-mediastinum ratio (HMR). RESULTS A significant correlation was observed between the delayed I-123-MIBG HMR and the percentage change in LV dP/dt(max) from the baseline to the peak or critical heart rate (r = 0.64; p < 0.001). The delayed I-123-MIBG HMR was significantly lower in patients showing a worsening change in LV dP/dt(max) than in those showing a favorable change (p < 0.005). The maximum LV dP/dt(max) during pacing and the sarcoplasmic reticulum Ca2+-ATPase (SERCA2) mRNA levels were significantly more reduced in patients with a delayed HMR than in those with a delayed HMR > 1.8 (p < 0.05, respectively). CONCLUSIONS Abnormal myocardial I-123-MIBG accumulation is related to an impaired myocardial contractile reserve and down-regulation of SERCA2 mRNA in DCM. Myocardial I-123-MIBG scintigraphy can be useful in noninvasively evaluating myocardial contractile reserve in patients with mild to moderate DCM.

Background-Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM). Methods and Results-Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide ( PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (<= 35, group A, n = 12; > 35, group B, n = 13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone. Conclusions-Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.

Long-term administration of vasodilators increases shear stress, which is thought to be important for vascular growth in the heart. Nicorandil, an activator of ATP-sensitive potassium channels with a nitrate-like action, is a potent vasodilator. We have now investigated the effects of nicorandil on vascular growth and gene expression in the failing heart of Dahl salt-sensitive (DS) hypertensive rats. DS rats fed a high-salt diet from 6 weeks of age develop concentric cardiac hypertrophy secondary to hypertension at I I weeks, followed by heart failure at IS weeks. DS rats on such a diet were treated with a nonantihypertensive oral dose of nicorandil (6 mg/kg per day) or vehicle from I I to 18 weeks of age. Treatment of DS rats with nicorandil improved cardiac function and attenuated the development of heart failure. Myocardial capillary and arteriolar densities did not differ between vehicle-treated DS rats and age-matched controls. The abundance of mRNAs for endothelial NO synthase (eNOS), vascular endothelial growth factor (VEGF), the VEGF receptor Flt-1, and basic fibroblast growth factor (bFGF) in the myocardium was markedly reduced in vehicle-treated DS rats compared with controls. Treatment of DS rats with nicorandil greatly increased capillary and arteriolar densities and inhibited the downregulation of eNOS, VEGF, fms-like tyrosin kinase-1. and bFGF gene expression. This, nicorandil stimulates coronary capillary and arteriolar growth and thereby likely suppresses the development of heart failure in DS rats. Nicorandil may prove beneficial for the treatment of hypertensive heart failure as well as of ischemic heart disease.

Little is known about the relation between left ventricular (LV) functional reserve in response to exercise and cardiac sympathetic nervous function in patients with nonobstructive hypertrophic cardiomyopathy (HCM). We investigated whether an assessment of cardiac sympathetic nervous function by myocardial I-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy might provide a sign of an abnormal LV functional reserve in response to exercise-induced P-adrenergic stimulation in patients with HCM. Methods: Thirty HCM patients underwent I-123-MIBG scintigraphy and echocardiography at rest and subsequent biventricular cardiac catheterization at rest and during dynamic exercise. LV pressures were measured using a micromanometer-tipped catheter system. The,early and delayed I-123-MIBG images were quantified as a heart-to-mediastinum ratio (H/M). The plasma levels of brain natriuretic peptide (BNP) and norepinephrine (NE) were also measured. Results: Patients were divided into 2 groups according to the delayed I-123-MIBG H/M: group I consisted of 12 patients with a delayed H/M of <= 1.8 and group II had 18 patients with a delayed H/M of > 1.8. Both the percentage increase from rest to exercise in LV isovolumic contraction (LV dP/dt(max)) and the percentage shortening of LV pressure half-time (T-1/2) as an index of isovolumic relaxation were significantly less in group I than in group II (P < 0.05, respectively). A significant linear correlation was observed between the percentage increase in LV dP/dt(max) and I-123-MIBG H/Ms (early H/M: r = 0.49, P < 0.01; delayed H/M: r = 0.54, P < 0.005, respectively). A significant linear correlation was also observed between the percentage shortening in T1/2 and I-123-MIBG H/Ms (early H/M: r = 0.58, P < 0.001; delayed H/M: r = 0.64, P < 0.0005, respectively). The plasma NE levels were significantly higher in group I than in group If (P < 0.01), whereas the plasma BNP levels were comparable in the 2 HCM groups. Conclusion: beta-Adrenergic enhancement of LV function during exercise may depend on the extent of cardiac sympathetic nervous innervation in HCM patients. Resting myocardial I-123-MIBG scintigraphy can noninvasively evaluate LV functional reserve in response to exercise in patients with nonobstructive HCM.

Little is known about the relation between left ventricular (LV) functional reserve in response to exercise and cardiac sympathetic nervous function in patients with nonobstructive hypertrophic cardiomyopathy (HCM). We investigated whether an assessment of cardiac sympathetic nervous function by myocardial I-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy might provide a sign of an abnormal LV functional reserve in response to exercise-induced P-adrenergic stimulation in patients with HCM. Methods: Thirty HCM patients underwent I-123-MIBG scintigraphy and echocardiography at rest and subsequent biventricular cardiac catheterization at rest and during dynamic exercise. LV pressures were measured using a micromanometer-tipped catheter system. The,early and delayed I-123-MIBG images were quantified as a heart-to-mediastinum ratio (H/M). The plasma levels of brain natriuretic peptide (BNP) and norepinephrine (NE) were also measured. Results: Patients were divided into 2 groups according to the delayed I-123-MIBG H/M: group I consisted of 12 patients with a delayed H/M of <= 1.8 and group II had 18 patients with a delayed H/M of > 1.8. Both the percentage increase from rest to exercise in LV isovolumic contraction (LV dP/dt(max)) and the percentage shortening of LV pressure half-time (T-1/2) as an index of isovolumic relaxation were significantly less in group I than in group II (P < 0.05, respectively). A significant linear correlation was observed between the percentage increase in LV dP/dt(max) and I-123-MIBG H/Ms (early H/M: r = 0.49, P < 0.01; delayed H/M: r = 0.54, P < 0.005, respectively). A significant linear correlation was also observed between the percentage shortening in T1/2 and I-123-MIBG H/Ms (early H/M: r = 0.58, P < 0.001; delayed H/M: r = 0.64, P < 0.0005, respectively). The plasma NE levels were significantly higher in group I than in group If (P < 0.01), whereas the plasma BNP levels were comparable in the 2 HCM groups. Conclusion: beta-Adrenergic enhancement of LV function during exercise may depend on the extent of cardiac sympathetic nervous innervation in HCM patients. Resting myocardial I-123-MIBG scintigraphy can noninvasively evaluate LV functional reserve in response to exercise in patients with nonobstructive HCM.

Background-The differentiation of hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) on the basis of morphological information obtained by conventional echocardiography is occasionally problematic. We investigated whether strain rate (SR) imaging derived from tissue Doppler imaging (TDI) is able to discriminate HCM from H-LVH. Methods and Results-Conventional echocardiography and TDI were performed with 34 patients with LVH and 16 reference subjects. Mean values of systolic strain (εsys), peak systolic SR, and early diastolic SR obtained from 8 left ventricular (LV) segments were calculated. LV pressures were recorded simultaneously in the patients. Patients were diagnosed with HCM (n=20) or H-LVH (n=14) on the basis of conventional echocardiography and endomyocardial biopsy findings. Multivariate analysis revealed that septum/posterior wall thickness ratio (P=0.00013) and εsys (P&lt 0.0001) were each able to discriminate HCM from H-LVH. A εsys cutoff value of - 10.6% discriminated between HCM and H-LVH with a sensitivity of 85.0%, specificity of 100.0%, and predictive accuracy of 91.2%. The combination of the septum/posterior wall thickness ratio and εsys discriminated HCM from H-LVH with a predictive accuracy of 96.1%. The εsys parameter was significantly correlated with pulmonary arterial wedge pressure, LV end-diastolic pressure, the peak positive first derivative of LV pressure, and the time constant of LV pressure decay. Conclusions-SR imaging is able to discriminate HCM from H-LVH, with εsys reflecting myocardial contractile and lusitropic properties.