Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment.

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.

Beneficial effects of torasemide on systolic wall stress and sympathetic nervous activity in asymptomatic or mildly symptomatic patients with heart failure: comparison with azosemide.

Loop diuretics could adversely influence prognosis due to activation of neurohumoral mechanism in the long term. Previous study showed torasemide, a loop diuretic with anti-aldosteronergic properties, was associated with lower mortality in patients with chronic heart failure (CHF). We evaluated the effects of torasemide, in comparison with azosemide, in patients with CHF. Patients received oral diuretic therapy with torasemide (8 mg/d, n = 15) or azosemide (60 mg/d, n = 15) for 3 months. Torasemide and azosemide were then switched, and the patients were treated for another 3 months. Torasemide treatment induced significant decreases in left ventricular (LV) systolic wall stress (from 259 +/- 95 to 232 +/- 80 kdyn/cm2) and the plasma level of aldosterone (from 133 +/- 61 to 95 +/- 50 pg/mL) and was not associated with a change in the plasma level of norepinephrine. In contrast, the plasma level of norepinephrine was significantly increased (from 370 +/- 170 to 481 +/- 247 pg/mL), whereas LV systolic wall stress was unchanged after azosemide treatment. This study indicates that torasemide treatment reduced LV systolic wall stress without activation of the sympathetic nervous system in patients with CHF. The anti-aldosteronergic properties of torasemide may contribute to its favorable effects.

Endomyocardial radial strain imaging and left ventricular relaxation abnormalities in patients with hypertrophic cardiomyopathy or hypertensive left ventricular hypertrophy.

BACKGROUND: Asymmetrical septal hypertrophy and impaired left ventricular (LV) diastolic function are common echocardiographic features of hypertrophic cardiomyopathy (HCM). However, it is difficult to differentiate nonobstructive HCM from hypertensive LV hypertrophy (H-LVH). METHODS AND RESULTS: Standard echocardiography and tissue Doppler imaging were performed in 14 patients with HCM, 16 patients with H-LVH, and 21 control subjects. Endomyocardial radial strain, systolic strain rate (SR), and the early diastolic SR at the posterior and septal segments of the LV short axis were calculated. Endomyocardial peak strain (epsilon) and the absolute value of peak early diastolic SR at the posterior segment were significantly smaller in patients with HCM than in those with H-LVH, whereas the thickness of the LV posterior wall did not differ between these 2 groups. Multivariate analysis of discrimination, including the ratio of interventricular septal thickness and posterior wall thickness (IVST/PWT), epsilon, and SR parameters, between HCM and H-LVH patients revealed that epsilon at the LV posterior segment was the highest discriminant parameter (discriminant coefficient: -14.6, P=0.012). The epsilon at the posterior segment significantly correlated with early diastolic mitral annular velocity. CONCLUSIONS: Endomyocardial radial strain imaging may prove informative for discriminating between HCM and H-LVH.

Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activated protein kinase and inhibition of Akt.

OBJECTIVE: Cardiac hypertrophy is common in diabetes and an independent risk factor for cardiac morbidity and mortality. We investigated the effects of pioglitazone on cardiac hypertrophy and hypertrophic signaling in Dahl salt-sensitive hypertensive rats. METHODS: Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age and treated with pioglitazone (2.5 mg/kg per day) or vehicle from 7 to 11 weeks. RESULTS: The vehicle-treated rats developed left ventricular hypertrophy and fibrosis as well as left ventricular diastolic dysfunction. The serum level of adiponectin and the phosphorylation of AMP-activated protein kinase in the myocardium did not differ between the vehicle-treated rats and control rats maintained on a normal diet. The phosphorylation of Akt, mammalian target of rapamycin, and p70S6 kinase as well as the total protein content were increased in the heart of vehicle-treated rats compared with control rats, and these changes were blocked by treatment with pioglitazone. Pioglitazone treatment also ameliorated left ventricular hypertrophy and fibrosis, improved diastolic function, and increased both the serum adiponectin concentration and the level of AMP-activated protein kinase phosphorylation in the heart. CONCLUSIONS: Long-term administration of pioglitazone attenuated left ventricular hypertrophy and fibrosis as well as inhibited phosphorylation of mammalian target of rapamycin and p70S6 kinase in the heart of hypertensive rats. The beneficial cardiac effects of pioglitazone are likely attributable, at least partly, both to the activation of AMP-activated protein kinase signaling through stimulation of adiponectin secretion and to the inhibition of Akt signaling.

Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome.

Individuals with obstructive sleep apnea syndrome (OSAS) are at high risk for cardiovascular morbidity and mortality. The effects of OSAS severity and nocturnal continuous positive airway pressure (CPAP) on daytime baroreflex sensitivity (BRS) and nitric oxide (NO) production were investigated in OSAS patients. Fifty-one consecutive males with OSAS and 29 age-matched healthy men underwent the Valsalva test and standard polysomnography. Patients with an apnea-hypopnea index (AHI) of >or=20 episodes per hour were randomized to receive CPAP treatment for 3 months (n=14) or no such treatment (n=19). The BRS index measured from the overshoot phase (phase IV) of the Valsalva maneuver and plasma NO concentration were significantly lower, whereas the AHI, oxygen desaturation time, arousal index, percentage of sleep stage 1, and systolic blood pressure were significantly greater, in patients with an AHI of >or=20/h than in those with an AHI of <20/h or in controls. The 24-h urinary excretion of norepinephrine was significantly reduced and the plasma NO concentration was significantly increased after one night of CPAP. The BRS index for phase IV and the Valsalva ratio were significantly increased in the CPAP group after the 3-month treatment period but remained unchanged in the non-CPAP group of OSAS patients. The daytime BRS index and NO production were thus inversely related to the severity of OSAS, and successful CPAP treatment improved these parameters in patients with moderate to severe OSAS. CPAP may therefore reduce the risk of cardiovascular complications due to endothelial dysfunction or increased sympathetic activity.

Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy.

OBJECTIVES: 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.

Prognostic value of mechanical efficiency in ambulatory patients with idiopathic dilated cardiomyopathy in sinus rhythm.

OBJECTIVES: The purpose of this study was to determine, by analyzing the pressure-volume relationship, the prognostic value of parameters related to myocardial energetics for predicting mortality in 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 patients 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 88.6%, 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.

Cardiac 123I-MIBG reflects left ventricular functional reserve in patients with nonobstructive hypertrophic cardiomyopathy.

UNLABELLED: 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 (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy might provide a sign of an abnormal LV functional reserve in response to exercise-induced beta-adrenergic stimulation in patients with HCM. METHODS: Thirty HCM patients underwent (123)I-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 (123)I-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 (123)I-MIBG H/M: group I consisted of 12 patients with a delayed H/M of < or =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 (123)I-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 T(1/2) and (123)I-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 II (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 (123)I-MIBG scintigraphy can noninvasively evaluate LV functional reserve in response to exercise in patients with nonobstructive HCM.

Growth hormone-releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters.

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 microg/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.

Biphasic relaxation-frequency relations in patients with effort angina pectoris: a new marker of myocardial demand ischemia.

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 LV relaxation may be alleviated by exercise.

Validity and application of noninvasive measurement of blood pressure in hamsters.

The aim of this study was to examine both the validity and application of noninvasive measurement of blood pressure (BP) at the brachial artery in hamsters. There were significant correlations between noninvasive and invasive values for systolic BP (SBP), mean BP, and diastolic BP (r = 0.96, r = 0.93, r = 0.88, respectively, all p < 0.0001). Furthermore, SBP appeared to be the most accurate noninvasive BP index because both proportional and constant systematic errors were the least among the three indices. Peripheral vascular resistance calculated by combination with echocardiographic indices actually reflected the prominent alpha 1-adrenergic drive induced by beta-adrenergic blockers. In conclusion, noninvasive BP measurement at the brachial artery can provide useful information regarding the integrated cardiovascular function in hamsters.

Progressive development of pulmonary hypertension leading to right ventricular hypertrophy assessed by echocardiography in rats.

The present study aimed to evaluate the development of pulmonary hypertension by serial echocardiography, including measurements of pulmonary artery (PA) flow velocities, and correlate echocardiographic indices with pathological findings in rats administered monocrotaline (MCT). MCT (60 mg/kg body weight) or physiologic saline was administered to a total of 9 male Wistar rats at the age of 4 weeks (MCT group: n = 4, control group: n = 5, respectively). Echocardiography was performed serially until the age of 8 weeks. The ratio of right ventricular (RV) outflow tract dimensions to aortic dimensions increased progressively in the MCT group and became significantly greater than that of the control group after the age of 6 weeks. Peak PA velocity (Peak V) in the MCT group was significantly less than that of the control group at the ages of 7 and 8 weeks. The ratio of acceleration time to ejection time (AT/ET) in PA flow waveforms declined progressively and was significantly less than that of the control group after the age of 6 weeks. The ratio of RV weight to body weight (RVW/BW) in the MCT group was significantly greater than that of the control group. Both AT/ET ratio and Peak V were significantly inversely correlated with RVW/BW ratio. Furthermore, these echocardiographic findings were also significantly inversely correlated with the mean cross-sectional RV myocyte area. In conclusion, the progressive development of pulmonary hypertension leading to RV hypertrophy can be evaluated appropriately by echocardiography including PA flow Doppler indices in rats.

Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

BACKGROUND: The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF). METHODS AND RESULTS: Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks. Control rats were maintained on a low-salt diet. In vehicle-treated rats, left-ventricular (LV) fractional shortening was preserved but LV end-diastolic pressure was increased, indicative of DHF. Benidipine and nitrendipine had similar antihypertensive effects and reduced both LV weight and cardiomyocyte hypertrophy. Benidipine reduced LV diastolic stiffness and mortality to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight. The extent of interstitial fibrosis and the abundance of mRNAs for prohypertrophic, profibrotic, or proinflammatory genes in the left ventricle were reduced by benidipine and nitrendipine. Benidipine, but not nitrendipine, increased capillary density and restored the expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle. CONCLUSIONS: Benidipine reduced LV diastolic stiffness and increased survival, effects likely attributable predominantly to promotion of coronary angiogenesis rather than to attenuation of interstitial fibrosis. Benidipine may thus be more effective than purely L-type Ca(2+) channel blockers in preventing hypertensive DHF.

Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats.

The Ca2+ channel blocker nifedipine has been reported to reduce the rate of new overt heart failure. We investigated the effects of nifedipine on left ventricular remodeling, oxidative stress, and gene expression in the failing heart of Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet from 7 weeks of age were treated with a non-antihypertensive (1 mg/kg per day, Nif-L) or mild-antihypertensive dose of nifedipine (3 mg/kg per day, Nif-H) or with vehicle (Vehicle) from 12 to 19 weeks. Marked left ventricular hypertrophy and fibrosis were apparent and the ratio of collagen type I to type III mRNA levels and the activity of matrix metalloproteinase (MMP)-2 and its mRNA expression in the myocardium were increased in Vehicle at 19 weeks in comparison with Control. Load-induced left ventricular hypertrophy was reduced in Nif-H, but not in Nif-L, relative to that in Vehicle. Treatment with either dose of nifedipine reduced the extent of fibrosis, the collagen type I to type III mRNA ratio, and MMP-2 activity and its mRNA expression compared with those in Vehicle. The decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in the left ventricle of Vehicle were also inhibited by nifedipine at both doses. Nifedipine thus inhibited the development of left ventricular fibrosis and diastolic heart failure in DS rats, independently of its antihypertensive effect. The overall protective action of nifedipine is likely attributable to its antioxidant effect as well as to its antihypertensive action.

Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats.

The clinical efficacy of exercise training in individuals with heart failure is well established, but the mechanism underlying such efficacy has remained unclear. An imbalance between cardiac hypertrophy and angiogenesis is implicated in the transition to heart failure. We investigated the effects of exercise training on cardiac pathophysiology in hypertensive rats. Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were assigned to sedentary or exercise (swimming)-trained groups at 9 weeks. Exercise training attenuated the development of heart failure and increased survival, without affecting blood pressure, at 18 weeks. It also attenuated left ventricular concentricity without a reduction in left ventricular mass or impairment of cardiac function. Interstitial fibrosis was increased and myocardial capillary density was decreased in the heart of sedentary rats, and these effects were attenuated by exercise. Exercise potentiated increases in the phosphorylation of Akt and mammalian target of rapamycin observed in the heart of sedentary rats, whereas it inhibited the downregulation of proangiogenic gene expression apparent in these animals. The abundance of the p110alpha isoform of phosphatidylinositol 3-kinase was decreased, whereas those of the p110gamma isoform of phosphatidylinositol 3-kinase and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were increased, in the heart of sedentary rats, and all of these effects were prevented by exercise. Thus, exercise training had a beneficial effect on cardiac remodeling and attenuated heart failure in hypertensive rats, with these effects likely being attributable to the attenuation of left ventricular concentricity and restoration of coronary angiogenesis through activation of phosphatidylinositol 3-kinase(p110alpha)-Akt-mammalian target of rapamycin signaling.

Dobutamine stress testing as a diagnostic tool for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy.

OBJECTIVES: We performed dobutamine stress testing for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy (DCM). BACKGROUND: Catecholamine sensitivity is reduced in failing hearts as a result of myocardial abnormalities in the beta-adrenergic receptor signaling pathway. However, little is known about adrenergic myocardial contractile reserve in asymptomatic or mildly symptomatic patients with DCM. METHODS: The maximal first derivative of left ventricular pressure (LV dP/dt(max)) was determined during infusion of dobutamine (10 microg kg(-1) min(-1)) in 46 asymptomatic or mildly symptomatic (New York Heart Association functional class I or II) patients with DCM. The expression of messenger ribonucleic acid (mRNA) for contractile regulatory proteins in endomyocardial biopsy specimens was quantified by reverse transcription and real-time polymerase chain reaction analysis. Plasma norepinephrine levels were measured in all patients and [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy performed. RESULTS: Patients were classified into 3 groups based on the percentage increase in LV dP/dt(max) induced by dobutamine (DeltaLV dP/dt(max)) and on LV ejection fraction (LVEF) at baseline: group I (n = 18): DeltaLV dP/dt(max) >100% and LVEF >25%; group IIa (n = 17): DeltaLV dP/dt(max) 25%; and group IIb (n = 11): DeltaLV dP/dt(max)

Altered autonomic control in conscious transgenic rabbits with overexpressed cardiac Gsalpha.

Both enhanced sympathetic drive and altered autonomic control are involved in the pathogenesis of heart failure. The goal of the present study was to determine the extent to which chronically enhanced sympathetic drive, in the absence of heart failure, alters reflex autonomic control in conscious, transgenic (TG) rabbits with overexpressed cardiac Gsalpha. Nine TG rabbits and seven wild-type (WT) littermates were instrumented with a left ventricular (LV) pressure micromanometer and arterial catheters and studied in the conscious state. Compared with WT rabbits, LV function was enhanced in TG rabbits, as reflected by increased levels of LV dP/dt (5,600 +/- 413 vs. 3,933 +/- 161 mmHg/s). Baseline heart rate was also higher (P < 0.05) in conscious TG (247 +/- 10 beats/min) than in WT (207 +/- 10 beats/min) rabbits and was higher in TG after muscarinic blockade (281 +/- 9 vs. 259 +/- 8 beats/min) or combined beta-adrenergic receptor and muscarinic blockade (251 +/- 6 vs. 225 +/- 9 beats/min). Bradycardia was blunted (P < 0.05), whether induced by intravenous phenylephrine (arterial baroreflex), by cigarette smoke inhalation (nasopharyngeal reflex), or by veratrine administration (Bezold-Jarisch reflex). With veratrine administration, the bradycardia was enhanced in TG for any given decrease in arterial pressure. Thus the chronically enhanced sympathetic drive in TG rabbits with overexpressed cardiac Gsalpha resulted in enhanced LV function and heart rate and impaired reflex autonomic control. The impaired reflex control was generalized, not only affecting the high-pressure arterial baroreflex but also the low-pressure Bezold-Jarisch reflex and the nasopharyngeal reflex.

Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.

Differential myolysis of myocardium and skeletal muscle in hamsters with dilated cardiomyopathy: beneficial protective effect of diltiazem.

BACKGROUND: Although dilated cardiomyopathic hamsters (TO-2) with mutation of the delta-sarcoglycan gene exhibit histological features of muscular dystrophy, it remains to be elucidated whether both myocardium and skeletal muscle are injured in a similar manner. METHODS AND RESULTS: The progression of myolysis in both myocardium and skeletal muscle were assessed biochemically and pathologically in TO-2 and F1B control hamsters. Left ventricular (LV) function was assessed by echocardiography and cardiac catheterization. Both the plasma concentration of cardiac troponin T and the plasma activity of alpha-hydroxybutyrate dehydrogenase (HBD) peaked at 8 weeks of age, and thereafter reduced greatly in TO-2 hamsters. Activity of creatine kinase (CK) in TO-2 hamsters was significantly greater than in controls throughout the observation period. Pathological findings of both nuclear chain and central nuclei in skeletal muscles were observed in TO-2 hamsters throughout the observation period, suggesting regeneration. LV dysfunction was first evident at 8 weeks of age and deteriorated thereafter in TO-2 hamsters. Treatment of TO-2 hamsters with diltiazem from 5 to 8 weeks of age could avert the LV functional deterioration and the increment in alpha-HBD activity, but CK activity was unchanged. CONCLUSIONS: Despite myolysis in skeletal muscle occurring consistently throughout the observation period, cardiac myolysis occurred predominantly in the early phase. These initial cardiac events might involve coronary spasm and/or calcium overload in the myocardium.

Overexpressed cardiac Gsalpha in rabbits.

We overexpressed cardiac Gsalpha in rabbits using the beta-myosin heavy chain promoter. Gsalpha protein levels in the heart were increased 3-fold by Western blotting in both juvenile (3-4 months), adult (8-10 months), and older (11-16 months) rabbits, compared with wild type (WT) littermates. In transgenic (TG) rabbits, baseline levels of heart rate were elevated, P<0.05 (268+/-17 vs. 209+/-15 beats/min), as well as left ventricular (LV) contractility (LV dP/dt 5475+/-482 vs. 3740+/-246 mm Hg/s). These values and LV ejection fraction remained significantly elevated in older TG rabbits (11-16 months). However, maximal levels of LV dP/dt and heart rate with a high dose of isoproterenol (0.4 microg/kg/min) were similar in adult TG and WT rabbits. In isolated myocytes from the LV of adult rabbits, baseline percent contraction was increased, P<0.05, in TG (11.2+/-0.5%) compared to WT (9.3+/-0.5%), while maximal responses to isoproterenol (100 nM) were similar in adult TG (16.2+/-0.5%) and WT myocytes (15.6+/-0.4%). Although TG mice with overexpressed cardiac Gsalpha develop cardiomyopathy at 8-12 months of age, even at 16 months of age, there was no evidence of cardiomyopathy either in terms of LV function or histology in TG rabbits. In addition, Gialpha was elevated in the LV of adult (8-10 months old) TG rabbits compared to WT, but not in juvenile (3-5 months old) TG rabbits. Although both TG mice and rabbits with overexpressed cardiac Gsalpha exhibited enhanced heart rate and contractility, the TG rabbit does not develop cardiomyopathy, potentially due to a compensatory increase in Gialpha.