井澤 英夫

Background: Although epidemiologic studies have suggested that several genetic variants increase the risk of myocardial infarction, large-scale association studies that examine many polymorphisms simultaneously are required to allow reliable prediction of the genetic risk of myocardial infarction. Methods: We used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay system to determine the genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with myocardial infarction (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women). Results: In an initial screening of the 112 polymorphisms for an association with myocardial infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4152 subjects, similar logistic-regression analysis revealed that the risk of myocardial infarction was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the stromelysin-1 gene (P<0.001) in women. Conclusions: Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition.

Background: Although epidemiologic studies have suggested that several genetic variants increase the risk of myocardial infarction, large-scale association studies that examine many polymorphisms simultaneously are required to allow reliable prediction of the genetic risk of myocardial infarction. Methods: We used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay system to determine the genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with myocardial infarction (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women). Results: In an initial screening of the 112 polymorphisms for an association with myocardial infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4152 subjects, similar logistic-regression analysis revealed that the risk of myocardial infarction was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the stromelysin-1 gene (P<0.001) in women. Conclusions: Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition.

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type I (AT,) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT, receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT, receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT, receptor-mediated angiotensin II signaling in vivo.

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type I (AT,) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT, receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT, receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT, receptor-mediated angiotensin II signaling in vivo.

This article aims to clarify the clinical significance of changes in electrocardiographic (ECG) R-wave voltage on chest leads from I to 4 weeks in patients with acute anterior myocardial infarction (MI) in combination with echocardiographic findings and dual scintigraphic findings. Seventy-one patients with acute anterior MI who under-went emergency revascularization were subjected to ECG and echocardiography, at both 1 and 4 weeks, and to thallium-201 (TI) and iodine-123-beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) about I week after the onset of MI. The total sum of ECG R-wave voltage on each chest lead was calculated. The mean defect ratio on TI and that on BMIPP derived from circumferential profile curve analysis were calculated. The percentage defect-discordant ratio of both SPECT images [(%) discordance on TI/BMIPP] was obtained. The percentage increase ratio of ECG R-wave voltage on chest leads [(%) increase of R wave] and the increase of left ventricular ejection fraction (DeltaEF) from 1 to 4 weeks were obtained. There were significant correlations between the (%) increase of R wave and the DeltaEF as well as between the (%) increase of R wave and the (%) discordance on TI/BMIPP (r=.63, P<.001; r=.74, P<.001). The reversibility of ECG R-wave voltage was related to cardiac functional improvement in addition to the discordance on the 2 images. Monitoring of changes in ECG R-wave voltage on chest leads is useful to detect the presence of myocardial viability and to evaluate functional evolution in patients with acute anterior MI.

This article aims to clarify the clinical significance of changes in electrocardiographic (ECG) R-wave voltage on chest leads from I to 4 weeks in patients with acute anterior myocardial infarction (MI) in combination with echocardiographic findings and dual scintigraphic findings. Seventy-one patients with acute anterior MI who under-went emergency revascularization were subjected to ECG and echocardiography, at both 1 and 4 weeks, and to thallium-201 (TI) and iodine-123-beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) about I week after the onset of MI. The total sum of ECG R-wave voltage on each chest lead was calculated. The mean defect ratio on TI and that on BMIPP derived from circumferential profile curve analysis were calculated. The percentage defect-discordant ratio of both SPECT images [(%) discordance on TI/BMIPP] was obtained. The percentage increase ratio of ECG R-wave voltage on chest leads [(%) increase of R wave] and the increase of left ventricular ejection fraction (DeltaEF) from 1 to 4 weeks were obtained. There were significant correlations between the (%) increase of R wave and the DeltaEF as well as between the (%) increase of R wave and the (%) discordance on TI/BMIPP (r=.63, P<.001; r=.74, P<.001). The reversibility of ECG R-wave voltage was related to cardiac functional improvement in addition to the discordance on the 2 images. Monitoring of changes in ECG R-wave voltage on chest leads is useful to detect the presence of myocardial viability and to evaluate functional evolution in patients with acute anterior MI.

OBJECTIVES The purpose of this study, was to determine, by, analyzing the pressure-volume relationship,,in the prognostic value of parameters related to myocardial energetic for predicting mortality patients with dilated cardiomyopathy (DCM) in sinus rhythm. BACKGROUND The relationship between the myocardial energetics and the prognosis of patients with DCM in sinus rhythm remains unclear. METHODS We followed 114 ambulatory, patients with nonischemic DCM in sinus rhythm for a mean period of 5.8 +/- 3.9 years. Over 70% of our patient,, were in New York Heart Association functional class I and class II. pressure-volume data were obtained by the conductance method, and myocardial oxygen consumption per beat (Vo(2)) measurements were obtained. RESULTS The 3-, 5-, and 10-year cumulative survival rates were 88.61%, 80.0%, and 73.9%, respectively. Of the 114 patients, 47 were selected randomly to assess their myocardial energetics. By univariate analysis, the mechanical efficiency, (ME, external work/Vo(2)), left ventricular (LV) ejection fraction and the LV end-diastolic pressure were statistically associated with cardiac death. The ME was the strongest predictor of survival in a Cox proportional-hazards, analysis (p = 0.011). The best cutoff point of ME identified by the receiver-operating Curve was 11%. This value had a sensitivity, of 100%, a specificity of 87% and an overall predictive accuracy of 88% to distinguish survivors from nonsurvivors. CONCLUSIONS This study clearly demonstrates that ME is a powerful clinical predictor for cardiac death in patients with mild to moderate heart failure and with sinus rhythm. Whether these conclusions apply, to patients with more severe heart failure requires further investigations. (C) 2002 by, the American College of Cardiology, Foundation.

OBJECTIVES The purpose of this study, was to determine, by, analyzing the pressure-volume relationship,,in the prognostic value of parameters related to myocardial energetic for predicting mortality patients with dilated cardiomyopathy (DCM) in sinus rhythm. BACKGROUND The relationship between the myocardial energetics and the prognosis of patients with DCM in sinus rhythm remains unclear. METHODS We followed 114 ambulatory, patients with nonischemic DCM in sinus rhythm for a mean period of 5.8 +/- 3.9 years. Over 70% of our patient,, were in New York Heart Association functional class I and class II. pressure-volume data were obtained by the conductance method, and myocardial oxygen consumption per beat (Vo(2)) measurements were obtained. RESULTS The 3-, 5-, and 10-year cumulative survival rates were 88.61%, 80.0%, and 73.9%, respectively. Of the 114 patients, 47 were selected randomly to assess their myocardial energetics. By univariate analysis, the mechanical efficiency, (ME, external work/Vo(2)), left ventricular (LV) ejection fraction and the LV end-diastolic pressure were statistically associated with cardiac death. The ME was the strongest predictor of survival in a Cox proportional-hazards, analysis (p = 0.011). The best cutoff point of ME identified by the receiver-operating Curve was 11%. This value had a sensitivity, of 100%, a specificity of 87% and an overall predictive accuracy of 88% to distinguish survivors from nonsurvivors. CONCLUSIONS This study clearly demonstrates that ME is a powerful clinical predictor for cardiac death in patients with mild to moderate heart failure and with sinus rhythm. Whether these conclusions apply, to patients with more severe heart failure requires further investigations. (C) 2002 by, the American College of Cardiology, Foundation.

Objectives The aim of this study was to clarify the serial changes in left ventricular (LV) end-diastolic pressure (LVEDP) during dynamic exercise in patients with hypertrophic cardiomyopathy (HCM). Background Although HCM is characterized by impaired resting LV diastolic function, serial changes in LVEDP during exercise have not been characterized. Methods We simultaneously measured LV pressure and LV dimensions during symptom-limited supine bicycle exercise in 5 healthy individuals and 20 patients with HCM. Exercise thallium-201 scintigraphic studies were also performed. Results The LVEDP (baseline: 12 +/-5 mm Hg) progressively increased to a maximum value at peak exercise (28 +/-8 mm Hg) in 11 patients with HCM (group I). In the remaining nine patients with HCM (group II), changes in LVEDP during exercise were biphasic, with an initial progressive increase and a subsequent gradual decline up to peak exercise (14 +/-4 mm Hg at baseline, 27 +/-5 mm Hg at the critical heart rate, 16 +/-3 mm Hg at peak exercise). Exorcise-induced changes in LV dimensions and LV peak systolic pressures were similar in both groups. However, the maximum first derivative of LV pressure was greater and the LV pressure half-time was shorter in group II than in group I at a similar peak exercise heart rate. The biphasic changes in LVEDP disappeared by pretreatment with propranolol. The LV hypertrophy scores were higher in group I than in group II. Exercise thallium-201 images showed more severe perfusion defects in group I than in group II patients. Conclusions The biphasic changes in LVEDP seen during exercise may be related to improved coronary microcirculation in response to beta-adrenergic stimulation in patients with mild to moderate HCM. (J Am Coll Cardiol 2001;38:335-43) (C) 2001 by the American College of Cardiology.

Background-The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca2+-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results-We calculated the maximum first derivative of LV pressure (LV dP/dt(max)) and the LV pressure half-time (T-1/2) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction > 55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na+/Ca2+, exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt(max) with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt,,,, relation was biphasic at physiological pacing rates. Both the mean maximal wall thick-ness and the LV hypertrophy score in group B were greater than in group A (20 +/-5 versus 15 +/-3 nun and 7 +/-1 versus 5 +/-2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34 +/-0.15) compared with group A (0.72 +/-0.27) and control subjects (0.85 +/-0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban. calsequestrin, and Na+/Ca2+ exchanger were similar in all groups. Conclusions-These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca2+ handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.

Objectives The aim of this study was to clarify the serial changes in left ventricular (LV) end-diastolic pressure (LVEDP) during dynamic exercise in patients with hypertrophic cardiomyopathy (HCM). Background Although HCM is characterized by impaired resting LV diastolic function, serial changes in LVEDP during exercise have not been characterized. Methods We simultaneously measured LV pressure and LV dimensions during symptom-limited supine bicycle exercise in 5 healthy individuals and 20 patients with HCM. Exercise thallium-201 scintigraphic studies were also performed. Results The LVEDP (baseline: 12 +/-5 mm Hg) progressively increased to a maximum value at peak exercise (28 +/-8 mm Hg) in 11 patients with HCM (group I). In the remaining nine patients with HCM (group II), changes in LVEDP during exercise were biphasic, with an initial progressive increase and a subsequent gradual decline up to peak exercise (14 +/-4 mm Hg at baseline, 27 +/-5 mm Hg at the critical heart rate, 16 +/-3 mm Hg at peak exercise). Exorcise-induced changes in LV dimensions and LV peak systolic pressures were similar in both groups. However, the maximum first derivative of LV pressure was greater and the LV pressure half-time was shorter in group II than in group I at a similar peak exercise heart rate. The biphasic changes in LVEDP disappeared by pretreatment with propranolol. The LV hypertrophy scores were higher in group I than in group II. Exercise thallium-201 images showed more severe perfusion defects in group I than in group II patients. Conclusions The biphasic changes in LVEDP seen during exercise may be related to improved coronary microcirculation in response to beta-adrenergic stimulation in patients with mild to moderate HCM. (J Am Coll Cardiol 2001;38:335-43) (C) 2001 by the American College of Cardiology.

Background-The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca2+-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results-We calculated the maximum first derivative of LV pressure (LV dP/dt(max)) and the LV pressure half-time (T-1/2) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction > 55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na+/Ca2+, exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt(max) with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt,,,, relation was biphasic at physiological pacing rates. Both the mean maximal wall thick-ness and the LV hypertrophy score in group B were greater than in group A (20 +/-5 versus 15 +/-3 nun and 7 +/-1 versus 5 +/-2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34 +/-0.15) compared with group A (0.72 +/-0.27) and control subjects (0.85 +/-0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban. calsequestrin, and Na+/Ca2+ exchanger were similar in all groups. Conclusions-These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca2+ handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.

Objective: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. Design:A prospective, controlled, in vivo animal laboratory study. Setting: Research laboratory at a university. Subjects: Male, Wistar rats (8-9 wks old; n = 83), Interventions: In pentobarbitat-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. Measurements and Main Results:LPS administration immediately induced progressive hypotension, The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p <.001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats, LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine, There was no elevation of concentrations of nitrite and nitrate, Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration, Conclusions:The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thick ness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Objective: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. Design:A prospective, controlled, in vivo animal laboratory study. Setting: Research laboratory at a university. Subjects: Male, Wistar rats (8-9 wks old; n = 83), Interventions: In pentobarbitat-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. Measurements and Main Results:LPS administration immediately induced progressive hypotension, The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p <.001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats, LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine, There was no elevation of concentrations of nitrite and nitrate, Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration, Conclusions:The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thick ness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Plasma platelet-activating factor acetylhydrolase (PAF-AH) acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Deficiency of the activity of this enzyme may thus potentially result in predisposition to myocardial damage. The possible role of the G(994) (Vallele) --> T (F allele) polymorphism of the PAF-AH gene in modulating cardiac function was investigated in 142 Japanese subjects with nonfamilial hypertrophic cardiomyopathy (HCM). Logistic regression analysis adjusted for age, sex, height, and body weight revealed that the frequency of the F allele was significantly higher in HCM patients than in 284 healthy controls. Echocardiographic examination revealed that left ventricular (LV) end-diastolic and end-systolic dimensions were significantly greater in HCM patients with the FF genotype than in those with the FF genotype. Cardiac catheterization revealed that LV end-diastolic pressure was significantly higher, whereas the LV ejection fraction was significantly smaller, for HCM patients with the F allele than for those with the FF genotype. Interstitial fibrosis was significantly more severe in HCM subjects with the FF genotype than in those with the FF genotype. These results suggest that the G(994) --> T (Val(279) --> Phe) polymorphism in the plasma PAF-AH gene may exacerbate cardiac damage in Japanese individuals with nonfamilial HCM, although this polymorphism is unlikely to be a causative factor for this condition.

Background The impaired adrenergic control of both inotropic and lusitropic reserves has been evaluated in patients with hypertrophic cardiomyopathy (HCM) but nor in those with apical HCM (APH). Objectives We examined the influence of increases in heart rate and adrenergic stimulation on inotropic and lusitropic reserves in HCM and APH with normal resting left ventricular (IV) systolic function. Methods We evaluated LV isovolumic contraction and relaxation during atrial pacing and during supine leg exercise in 7 patients with APH and in 8 patients with HCM. Results Heart rate was significantly correlated with IV isovolumic contraction and relaxation during pacing and exercise in all patients. In all patients with APH, the increase in LV isovolumic contraction was greater during exercise (101%) than pacing alone (27%) for similar increase in heart rate. In 5 patients with HCM, the increase in IV isovolumic contraction was greater during exercise (83%) than pacing alone (24%), whereas in 3 patients with HCM the increase in LV isovolumic contraction was similar between during exercise (25%) and during pacing alone (22%). in all patients with APH, relaxation was shorter during exercise (39%) than pacing alone (16%). Conversely, in patients with HCM relaxation was similarly shortened between during pacing alone (20%) and during exercise (19%). Conclusions The force-frequency and the relaxation-frequency relations were well-preserved in all patients. In patients with HCM, the adrenergic enhancement of force-frequency relation and/or relaxation-frequency relation was impaired. In patients with APH, however, adrenergic control of both force-frequency and relaxation-frequency relations was well-preserved, which may indicate a preserved beta-adrenergic signaling pathway.

Background The impaired adrenergic control of both inotropic and lusitropic reserves has been evaluated in patients with hypertrophic cardiomyopathy (HCM) but nor in those with apical HCM (APH). Objectives We examined the influence of increases in heart rate and adrenergic stimulation on inotropic and lusitropic reserves in HCM and APH with normal resting left ventricular (IV) systolic function. Methods We evaluated LV isovolumic contraction and relaxation during atrial pacing and during supine leg exercise in 7 patients with APH and in 8 patients with HCM. Results Heart rate was significantly correlated with IV isovolumic contraction and relaxation during pacing and exercise in all patients. In all patients with APH, the increase in LV isovolumic contraction was greater during exercise (101%) than pacing alone (27%) for similar increase in heart rate. In 5 patients with HCM, the increase in IV isovolumic contraction was greater during exercise (83%) than pacing alone (24%), whereas in 3 patients with HCM the increase in LV isovolumic contraction was similar between during exercise (25%) and during pacing alone (22%). in all patients with APH, relaxation was shorter during exercise (39%) than pacing alone (16%). Conversely, in patients with HCM relaxation was similarly shortened between during pacing alone (20%) and during exercise (19%). Conclusions The force-frequency and the relaxation-frequency relations were well-preserved in all patients. In patients with HCM, the adrenergic enhancement of force-frequency relation and/or relaxation-frequency relation was impaired. In patients with APH, however, adrenergic control of both force-frequency and relaxation-frequency relations was well-preserved, which may indicate a preserved beta-adrenergic signaling pathway.

A recent long-term multicenter trial has shown that pimobendan is more effective when administered in low doses. However, no data are available concerning the effect of a low dose of pimobendan on the systolic and diastolic pressure-volume relations in patients with heart failure. Therefore we examined the effects of a single low dose of oral pimobendan, a calcium sensitizer, on systolic and diastolic hemodynamics in patients with cardiomyopathy and congestive heart failure. We measured the left ventricular (LV) pressure-volume relations using a conductance catheter with a micromanometer tip in 10 patients with chronic congestive heart failure resulting from idiopathic cardiomyopathy before and 45 and 90 min after administration of a single oral dose of 2.5 mg of pimobendan. End-systolic elastance was used as an index of LV contractility and was measured during transient occlusion of the inferior vena cava. End-systolic elastance increased significantly by 25% at 45 min (p < 0.05) and by 55% at 90 min (p < 0.01) without an increase in myocardial oxygen consumption. The inotropic effect was accompanied by improved ventriculoarterial coupling. This effect was attenuated in patients with severely impaired myocardial contractility. LV relaxation, assessed by the time constant of isovolumic pressure decay (T-1/2), was significantly shortened at 90 min (from 47.7 +/- 1.9 to 41.2 +/- 1.7 ms; p < 0.01), although it remained unchanged at 45 min. The diastolic pressure-volume relation showed a leftward and downward shift in all patients. These results indicate that low-dose oral pimobendan had favorable short-term inotropic and lusitropic effects in patients with congestive heart failure caused by idiopathic dilated cardiomyopathy, and may thus be a useful alternative to traditional agents. Further study in a large-scale trial is merited.