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.

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.

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.

Vascular inflammation plays an important role in the development of myocardial infarction (MI). Lymphotoxin α (LTA) is a cytokine with multiple functions in regulation of the immune system and inflammatory reactions. The aim of this study was to examine whether polymorphisms of the LTA gene are associated with the risk of MI in Japanese men and women. A case-control association study was performed for the 252A→G and 804C→A polymorphisms of the LTA gene and the prevalence of MI. The study population comprised 3,689 unrelated Japanese individuals (2,486 men, 1,203 women), including 1891 patients with MI (1,493 men, 398 women) and 1798 control subjects (993 men, 805 women). Among the control subjects 257 individuals (108 men, 149 women) who had none of the conventional risk factors for coronary artery disease (CAD) were defined as low-risk controls. Genotypes for the two polymorphisms were determined with a fluorescence-based allele-specific DNA primer assay system. Among all study subjects the 252A→G and 804C→A polymorphisms exhibited linkage disequilibrium. No association of either polymorphism with MI was detected in men or in women in comparisons with total control or low-risk control subjects. However, each of the two polymorphisms was associated with the prevalence of type 2 diabetes mellitus both in men with MI and in those without MI in a recessive genetic model. No association was detected between the polymorphisms and other conventional risk factors for CAD. The LTA gene thus does not appear to be a susceptibility locus for MI in Japanese men or women, although it might affect susceptibility to type 2 diabetes in Japanese men. © Springer-Verlag 2004.

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Given that a substantial proportion of individuals with coronary artery disease (CAD) also have type 2 diabetes, it is important to identify genes that confer susceptibility to CAD independently in subjects with type 2 diabetes and in those without this condition. A large-scale association study was performed to identify genes that confer susceptibility to CAD in either the absence or presence of type 2 diabetes. The study population comprised 5207 unrelated Japanese individuals, including 3085 subjects with CAD and 2122 controls. Among all subjects, 1704 individuals had type 2 diabetes and 3503 individuals did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, hypercholesterolemia, and hyperuricemia revealed that the following polymorphisms were significantly (P < 0.005) associated with CAD: the 1019C → T of the connexin 37 gene for men with type 2 diabetes; the 2445G → A in the fatty acid-binding protein 2 gene for women with this condition; the -863C → A in the tumor necrosis factor-α gene, the -219G → T in the apolipoprotein E gene, the 1019C → T in the connexin 37 gene for men without type 2 diabetes; and the -482C → T in the apolipoprotein C-III gene for women without this condition. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for CAD in the absence or presence of type 2 diabetes. (C) 2004 Elsevier Inc. All rights reserved.

Given that a substantial proportion of individuals with coronary artery disease (CAD) also have type 2 diabetes, it is important to identify genes that confer susceptibility to CAD independently in subjects with type 2 diabetes and in those without this condition. A large-scale association study was performed to identify genes that confer susceptibility to CAD in either the absence or presence of type 2 diabetes. The study population comprised 5207 unrelated Japanese individuals, including 3085 subjects with CAD and 2122 controls. Among all subjects, 1704 individuals had type 2 diabetes and 3503 individuals did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, hypercholesterolemia, and hyperuricemia revealed that the following polymorphisms were significantly (P < 0.005) associated with CAD: the 1019C → T of the connexin 37 gene for men with type 2 diabetes; the 2445G → A in the fatty acid-binding protein 2 gene for women with this condition; the -863C → A in the tumor necrosis factor-α gene, the -219G → T in the apolipoprotein E gene, the 1019C → T in the connexin 37 gene for men without type 2 diabetes; and the -482C → T in the apolipoprotein C-III gene for women without this condition. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for CAD in the absence or presence of type 2 diabetes. (C) 2004 Elsevier Inc. All rights reserved.

Objective: The mammalian heart contains specific growth hormone-releasing peptide (GHRP) binding sites whose physiological significance is unknown. We sought to compare the effects of GHRP and GH on progressive left ventricular (LV) dysfunction in the TO-2 hamster model of dilated cardiomyopathy. Methods: TO-2 hamsters (8 weeks old) were injected with GHRP-6 (100 mug/kg day), GH (2 mg/ kg day), or saline for 4 weeks; F1B hamsters served as controls. LV functional and structural changes were evaluated by echocardiography and pathology. Results: The increase in body weight of GH-treated TO-2 hamsters was greater than that of animals in the other two groups. Plasma GH and insulin-like growth factor-1 (IGF-1) concentrations were not increased by GHRP-6. LV fractional shortening (LVFS) decreased from 42.0 +/- 2.6% to 25.4 +/- 1.8% and the LV end-diastolic dimension (LVDd) increased from 4.0 +/- 0.1 to 5.0 +/- 0.1 mm in untreated TO-2 hamsters between 8 and 12 weeks. LVFS was substantially improved by treatment with GHRP-6 (33.4 +/- 2.0%) or GH (32.0 +/- 2.1%). The LVDd was significantly smaller in animals treated with GHRP-6 than in those treated with GH. The cross-sectional LV myocyte area and the amount of atrial natriuretic peptide mRNA in the LV were increased by GH but not by GHRP-6. Treatment woth GH at a lower dose (0.2 mg/(kg day)) exerted minimal cardiac and systematic growth effects without improving LV function. Conclusion: GHRP can ameliorate the development of progressive LV dysfunction independently of the GH-IGF-1 axis, suggesting a potential new approach to the heart failure. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men. 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Va1279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Objective: The mammalian heart contains specific growth hormone-releasing peptide (GHRP) binding sites whose physiological significance is unknown. We sought to compare the effects of GHRP and GH on progressive left ventricular (LV) dysfunction in the TO-2 hamster model of dilated cardiomyopathy. Methods: TO-2 hamsters (8 weeks old) were injected with GHRP-6 (100 mug/kg day), GH (2 mg/ kg day), or saline for 4 weeks; F1B hamsters served as controls. LV functional and structural changes were evaluated by echocardiography and pathology. Results: The increase in body weight of GH-treated TO-2 hamsters was greater than that of animals in the other two groups. Plasma GH and insulin-like growth factor-1 (IGF-1) concentrations were not increased by GHRP-6. LV fractional shortening (LVFS) decreased from 42.0 +/- 2.6% to 25.4 +/- 1.8% and the LV end-diastolic dimension (LVDd) increased from 4.0 +/- 0.1 to 5.0 +/- 0.1 mm in untreated TO-2 hamsters between 8 and 12 weeks. LVFS was substantially improved by treatment with GHRP-6 (33.4 +/- 2.0%) or GH (32.0 +/- 2.1%). The LVDd was significantly smaller in animals treated with GHRP-6 than in those treated with GH. The cross-sectional LV myocyte area and the amount of atrial natriuretic peptide mRNA in the LV were increased by GH but not by GHRP-6. Treatment woth GH at a lower dose (0.2 mg/(kg day)) exerted minimal cardiac and systematic growth effects without improving LV function. Conclusion: GHRP can ameliorate the development of progressive LV dysfunction independently of the GH-IGF-1 axis, suggesting a potential new approach to the heart failure. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men. 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Va1279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

The anti-anginal drug nicorandil has been shown to inhibit apoptosis by activating mitochondrial ATP-sensitive potassium (K-ATP) channels. The possible contribution of the nitrate moiety of this drug to its anti-apoptotic effect has now been investigated in neonatal rat ventricular myocytes subjected to oxidative stress. Exposure of cultured myocytes to 100 mumol/l hydrogen peroxide (H2O2) increased the number of nuclei stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique as well as induced internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspases-3 and -9, all of which are characteristics of apoptosis. Pretreatment of cells with nicorandil (100 mumol/l) inhibited these effects of H2O2. Both the mitochondrial K-ATP channel antagonist 5-hydroxydecanoate (5-HD) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, attenuated the anti-apoptotic effect of nicorandil in concentration-dependent manners. Coapplication of ODQ (10 mumol/l) and 5-HD (500 mumol/l) completely abolished nicorandil-induced cytoprotection. The effect of nicorandil was also reduced by an inhibitor of cGMP-dependent protein kinase (KT5823, 1 mumol/l). The nitric oxide donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 50 mumol/l) mimicked the protective effect of nicorandil in a manner sensitive to ODQ but not to 5-HD. A cell-permeable cGMP analog, 8-bromo-cGMP. also reduced H2O2-induced apoptosis. The inhibition of the H2O2-induced activation of caspase-3, but not that of caspase-9, by nicorandil in the presence of 5-HD or by SNAP was reversed by the addition of dithiothreitol to the enzyme assay. Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through a nitric oxide/cGMP-dependent mechanism as well as by activating mitochondrial K-ATP channels. (C) 2003 Elsevier Ltd. All rights reserved.

The anti-anginal drug nicorandil has been shown to inhibit apoptosis by activating mitochondrial ATP-sensitive potassium (K-ATP) channels. The possible contribution of the nitrate moiety of this drug to its anti-apoptotic effect has now been investigated in neonatal rat ventricular myocytes subjected to oxidative stress. Exposure of cultured myocytes to 100 mumol/l hydrogen peroxide (H2O2) increased the number of nuclei stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique as well as induced internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspases-3 and -9, all of which are characteristics of apoptosis. Pretreatment of cells with nicorandil (100 mumol/l) inhibited these effects of H2O2. Both the mitochondrial K-ATP channel antagonist 5-hydroxydecanoate (5-HD) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, attenuated the anti-apoptotic effect of nicorandil in concentration-dependent manners. Coapplication of ODQ (10 mumol/l) and 5-HD (500 mumol/l) completely abolished nicorandil-induced cytoprotection. The effect of nicorandil was also reduced by an inhibitor of cGMP-dependent protein kinase (KT5823, 1 mumol/l). The nitric oxide donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 50 mumol/l) mimicked the protective effect of nicorandil in a manner sensitive to ODQ but not to 5-HD. A cell-permeable cGMP analog, 8-bromo-cGMP. also reduced H2O2-induced apoptosis. The inhibition of the H2O2-induced activation of caspase-3, but not that of caspase-9, by nicorandil in the presence of 5-HD or by SNAP was reversed by the addition of dithiothreitol to the enzyme assay. Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through a nitric oxide/cGMP-dependent mechanism as well as by activating mitochondrial K-ATP channels. (C) 2003 Elsevier Ltd. All rights reserved.

Many studies have demonstrated that reduced left ventricular (LV) diastolic distensibility plays a key role in the pathophysiology of hypertrophic cardiomyopathy (HCM). However, the relationship between myocardial ischemia and reduced LV distensibility in HCM remains unclear. We aimed to clarify the relationship between exercise-induced ischemia and reduced LV distensibility in patients with HCM. Methods: Twenty patients with HCM and 5 age-matched control subjects underwent stress-redistribution Tl-201 myocardial scintigraphy and biventricular cardiac catheterization and echocardiography at rest and during exercise. Scintigraphic defect analysis was interpreted using Berman's 20-segment model. The summed stress score (SSS) was calculated as the sum of scores of the 20 LV segments and the summed difference score (SDS) was calculated as the sum of differences between each of the 20 LV segments on stress and rest images. Results: Patients were divided into 2 groups according to the Tl-201 defect as follows: 9 patients with an SSS on Tl-201 of greater than or equal to10 and an SDS on Tl-201 of greater than or equal to5 (ischemic group) and 11 patients with an SSS of <10 or an SDS of <5 (nonischemic group). The absolute increases from rest to peak exercise in LV end-diastolic pressure (LVEDP) and pulmonary artery wedge pressure were significantly greater (15.5 +/- 5.2 vs. 7.6 +/- 5.5 mm Hg and 17.3 +/- 5.0 vs. 8.9 +/- 5.0 mm Hg, P < 0.01, respectively), and the percentage changes from rest to peak exercise in the maximum first derivative of LV pressure and LV pressure half-time were significantly smaller in the ischemic HCM group compared with the nonischemic HCM group (70% +/- 24% vs. 123% +/- 43% and -32% +/- 6.4% vs. -44% +/- 9.4%, P < 0.01, respectively). However, the end-diastolic dimensions did not differ between the 2 HCM groups. One of the 9 patients in the ischemic group, as revealed by fill-in on Tl-201 scintigraphy, showed increased F-18-FDG uptake in the anteroseptal wall. Conclusion: Some HCM patients show a significant increase in LVEDP without chamber dilatation, indicating reduced LV diastolic distensibility. Myocardial ischemia may at least in part contribute to this condition.

Many studies have demonstrated that reduced left ventricular (LV) diastolic distensibility plays a key role in the pathophysiology of hypertrophic cardiomyopathy (HCM). However, the relationship between myocardial ischemia and reduced LV distensibility in HCM remains unclear. We aimed to clarify the relationship between exercise-induced ischemia and reduced LV distensibility in patients with HCM. Methods: Twenty patients with HCM and 5 age-matched control subjects underwent stress-redistribution Tl-201 myocardial scintigraphy and biventricular cardiac catheterization and echocardiography at rest and during exercise. Scintigraphic defect analysis was interpreted using Berman's 20-segment model. The summed stress score (SSS) was calculated as the sum of scores of the 20 LV segments and the summed difference score (SDS) was calculated as the sum of differences between each of the 20 LV segments on stress and rest images. Results: Patients were divided into 2 groups according to the Tl-201 defect as follows: 9 patients with an SSS on Tl-201 of greater than or equal to10 and an SDS on Tl-201 of greater than or equal to5 (ischemic group) and 11 patients with an SSS of <10 or an SDS of <5 (nonischemic group). The absolute increases from rest to peak exercise in LV end-diastolic pressure (LVEDP) and pulmonary artery wedge pressure were significantly greater (15.5 +/- 5.2 vs. 7.6 +/- 5.5 mm Hg and 17.3 +/- 5.0 vs. 8.9 +/- 5.0 mm Hg, P < 0.01, respectively), and the percentage changes from rest to peak exercise in the maximum first derivative of LV pressure and LV pressure half-time were significantly smaller in the ischemic HCM group compared with the nonischemic HCM group (70% +/- 24% vs. 123% +/- 43% and -32% +/- 6.4% vs. -44% +/- 9.4%, P < 0.01, respectively). However, the end-diastolic dimensions did not differ between the 2 HCM groups. One of the 9 patients in the ischemic group, as revealed by fill-in on Tl-201 scintigraphy, showed increased F-18-FDG uptake in the anteroseptal wall. Conclusion: Some HCM patients show a significant increase in LVEDP without chamber dilatation, indicating reduced LV diastolic distensibility. Myocardial ischemia may at least in part contribute to this condition.

Background Relaxation-frequency relations (RFR) during demand ischemia have not been fully examined in patients with effort angina pectoris (AP). We sought to clarify the effects of pacing and exercise on RFR in patients with AP. Methods We recorded left ventricular (LV) pressures during rapid atrial pacing and symptom-limited supine bicycle exercise. RFR were analyzed in 24 patients with AP and 10 controls. Results LV pressure half-time (T-1/2) in controls was gradually shortened with an increase in heart rate (HR) during pacing (-19% +/- 6% at peak HR). The changes in T-1/2 during pacing were biphasic with initial shortening (-12% +/- 5% at the critical HR) followed by prolongation (-3% +/- 7% at peak HR) in all patients with AP. The critical HR, at which T-1/2 was minimum, preceded the HR at 0.1-mV ST-segment depression, and finally chest pain occurred. The critical HR was correlated negatively with the severity of ischemia as assessed by thallium-201 scintigraphy. T-1/(2) was remarkably shortened during exercise in controls (-41% - 10% at peak exercise). In patients with AP, 2 distinct patterns of RFR were observed during exercise. T-1/2 was shortened progressively (-37% +/- 8% at peak exercise) in 15 patients, whereas RFR remained biphasic (-21% +/- 10% at the critical HR and - 11% +/- 11% at peak exercise) in the other 9 patients. Coronary angiography and exercise scintigraphy suggested more severe ischemia in patients with biphasic RFR during exercise. Conclusions Impaired RFR might be the most sensitive parameter of pacing-induced ischemia. The critical HR was closely related with severity of ischemia. Adverse effects of ischemia on IV relaxation may be alleviated by exercise.

Aims Impaired coronary microcirculation is thought to contribute to myocardial ischaemia, causing an abnormal increase in left ventricular end-diastolic pressure during exercise in individuals with hypertrophic cardiomyopathy. The effects of nicorandil on left ventricular end-diastolic pressure during exercise were examined in patients with this condition. Methods and results Left ventricular pressures and dimensions were measured simultaneously during supine bicycle exercise in 23 patients with nonobstructive hypertrophic cardiomyopathy, before and after intravenous injection of either nicorandil (0.1 mg/kg) or propranolol (0.15 mg/kg). Exercise thallium-201 scintigraphy was also performed. Patients were grouped according to the changes in left ventricular end-diastolic pressure during exercise before treatment. Group I comprised 13 patients in whom left ventricular end-diastolic pressure increased progressively to abnormal values during exercise; group 11 comprised 10 patients in whom left ventricular end-diastolic pressure changed biphasically. The extents of both left ventricular hypertrophy and ischemic burden during exercise were greater in group I than in group II. Of the eight group I patients who received nicorandil, four individuals exhibited biphasic changes in left ventricular end-diastolic pressure during exercise after its administration whereas four subjects showed no such effect of the drug. Left ventricular end-diastolic pressure increased progressively during exercise after propranolol treatment in all 6 group II patients given this drug. Conclusion Nicorandil has a salutary effect on the changes in left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy. (C) 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

ORJECTIVES We investigated the utility of the peak negative myocardial velocity gradient (MVG) derived from tissue Doppler imaging (TDI) for evaluation of diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is characterized by impaired diastolic function with abnormal stiffness and prolonged relaxation. However, it remains difficult to evaluate these defects noninvasively. METHODS Both TDI and conventional echocardiography were performed in 36 patients with HCM and in 47 control subjects. Left ventricular (LV) pressure was measured simultaneously in all HCM patients and in 26 controls. RESULTS The peak negative MVG occurred soon after the isovolumic relaxation period during the initial phase of rapid filling (auxotonic relaxation). It was significantly smaller in HCM patients than in control subjects (2.32 +/- 0.52/s vs. 4.82 +/- 1.15/s, p < 0.0001); the cutoff value for differentiation between all HCM patients and 47 normal individuals was determined as 3.2/s. Both the left ventricular end-diastolic pressure (LVEDP) (19.6 +/- 6.1 mm Hg vs. 6.5 +/- 1.7 mm Hg, p < 0.0001) and the time constant of LV pressure decay during isovolumic diastole (tau) (44.0 +/- 6.7 ms vs. 32.1 +/- 5.5 ms, p < 0.0001) were increased in HCM patients compared with controls. The peak negative MVG was negatively correlated with both LVEDP (r = -0.75, p < 0.0001) and tau (r = -0.58, p < 0.0001). CONCLUSIONS A reduced peak negative MVG reflects both prolonged relaxation and elevated LVEDP. The peak negative MVG might thus provide a noninvasive index of diastolic function, yielding unique information about auxotonic relaxation in patients with HCM. (C) 2003 by the American College of Cardiology Foundation.

Background Relaxation-frequency relations (RFR) during demand ischemia have not been fully examined in patients with effort angina pectoris (AP). We sought to clarify the effects of pacing and exercise on RFR in patients with AP. Methods We recorded left ventricular (LV) pressures during rapid atrial pacing and symptom-limited supine bicycle exercise. RFR were analyzed in 24 patients with AP and 10 controls. Results LV pressure half-time (T-1/2) in controls was gradually shortened with an increase in heart rate (HR) during pacing (-19% +/- 6% at peak HR). The changes in T-1/2 during pacing were biphasic with initial shortening (-12% +/- 5% at the critical HR) followed by prolongation (-3% +/- 7% at peak HR) in all patients with AP. The critical HR, at which T-1/2 was minimum, preceded the HR at 0.1-mV ST-segment depression, and finally chest pain occurred. The critical HR was correlated negatively with the severity of ischemia as assessed by thallium-201 scintigraphy. T-1/(2) was remarkably shortened during exercise in controls (-41% - 10% at peak exercise). In patients with AP, 2 distinct patterns of RFR were observed during exercise. T-1/2 was shortened progressively (-37% +/- 8% at peak exercise) in 15 patients, whereas RFR remained biphasic (-21% +/- 10% at the critical HR and - 11% +/- 11% at peak exercise) in the other 9 patients. Coronary angiography and exercise scintigraphy suggested more severe ischemia in patients with biphasic RFR during exercise. Conclusions Impaired RFR might be the most sensitive parameter of pacing-induced ischemia. The critical HR was closely related with severity of ischemia. Adverse effects of ischemia on IV relaxation may be alleviated by exercise.

Aims Impaired coronary microcirculation is thought to contribute to myocardial ischaemia, causing an abnormal increase in left ventricular end-diastolic pressure during exercise in individuals with hypertrophic cardiomyopathy. The effects of nicorandil on left ventricular end-diastolic pressure during exercise were examined in patients with this condition. Methods and results Left ventricular pressures and dimensions were measured simultaneously during supine bicycle exercise in 23 patients with nonobstructive hypertrophic cardiomyopathy, before and after intravenous injection of either nicorandil (0.1 mg/kg) or propranolol (0.15 mg/kg). Exercise thallium-201 scintigraphy was also performed. Patients were grouped according to the changes in left ventricular end-diastolic pressure during exercise before treatment. Group I comprised 13 patients in whom left ventricular end-diastolic pressure increased progressively to abnormal values during exercise; group 11 comprised 10 patients in whom left ventricular end-diastolic pressure changed biphasically. The extents of both left ventricular hypertrophy and ischemic burden during exercise were greater in group I than in group II. Of the eight group I patients who received nicorandil, four individuals exhibited biphasic changes in left ventricular end-diastolic pressure during exercise after its administration whereas four subjects showed no such effect of the drug. Left ventricular end-diastolic pressure increased progressively during exercise after propranolol treatment in all 6 group II patients given this drug. Conclusion Nicorandil has a salutary effect on the changes in left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy. (C) 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

ORJECTIVES We investigated the utility of the peak negative myocardial velocity gradient (MVG) derived from tissue Doppler imaging (TDI) for evaluation of diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is characterized by impaired diastolic function with abnormal stiffness and prolonged relaxation. However, it remains difficult to evaluate these defects noninvasively. METHODS Both TDI and conventional echocardiography were performed in 36 patients with HCM and in 47 control subjects. Left ventricular (LV) pressure was measured simultaneously in all HCM patients and in 26 controls. RESULTS The peak negative MVG occurred soon after the isovolumic relaxation period during the initial phase of rapid filling (auxotonic relaxation). It was significantly smaller in HCM patients than in control subjects (2.32 +/- 0.52/s vs. 4.82 +/- 1.15/s, p < 0.0001); the cutoff value for differentiation between all HCM patients and 47 normal individuals was determined as 3.2/s. Both the left ventricular end-diastolic pressure (LVEDP) (19.6 +/- 6.1 mm Hg vs. 6.5 +/- 1.7 mm Hg, p < 0.0001) and the time constant of LV pressure decay during isovolumic diastole (tau) (44.0 +/- 6.7 ms vs. 32.1 +/- 5.5 ms, p < 0.0001) were increased in HCM patients compared with controls. The peak negative MVG was negatively correlated with both LVEDP (r = -0.75, p < 0.0001) and tau (r = -0.58, p < 0.0001). CONCLUSIONS A reduced peak negative MVG reflects both prolonged relaxation and elevated LVEDP. The peak negative MVG might thus provide a noninvasive index of diastolic function, yielding unique information about auxotonic relaxation in patients with HCM. (C) 2003 by the American College of Cardiology Foundation.