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ABSTRACT: The high prevalence of patients with heart failure (HF) with preserved ejection fraction (HFpEF) has highlighted the pivotal role of diastolic function in the development of HF. Abnormalities of diastolic function induce elevated left ventricular (LV) end-diastolic pressure, which leads to pulmonary edema and the symptoms of HF because the LV, left atrium and the pulmonary veins form 1 chamber while the mitral valve is opening. Thus, LV diastolic dysfunction results in the development of HF, in particular, HFpEF. LV stiffness mainly contributes to the transition to HFpEF, but noninvasive assessment and the therapeutic strategy for LV stiffness have not been fully established. This review will focus on the contribution of LV passive stiffness to the development of HFpEF and on the evaluation and treatment of LV stiffening based on insights gained from a hypertensive HFpEF animal model we have developed.
Circulation Journal 03/2013; · 3.77 Impact Factor
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Yosuke Omori,
Tomohito Ohtani,
Yasushi Sakata, Toshiaki Mano,
Yasuharu Takeda,
Shunsuke Tamaki,
Yasumasa Tsukamoto,
Daisuke Kamimura,
Yoshihiro Aizawa,
Takeshi Miwa,
Issei Komuro,
Tomoyoshi Soga,
Kazuhiro Yamamoto
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ABSTRACT: Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis.
Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients.
L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.
Journal of hypertension 07/2012; 30(9):1834-44. · 4.02 Impact Factor
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Journal of Medical Ultrasonics 04/2012; 37(1):33-35. · 0.33 Impact Factor
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ABSTRACT: We present two cases with ischemic cardiomyopathy and similar functional mitral regurgitation (fMR) at rest, who represented
different outcomes following mitral valve repair. In case 1, fMR was enhanced during exercise echocardiography, and his symptoms
were improved following the repair and coronary artery bypass graft (CABG). In case 2, fMR did not change during exercise,
and the improvement of his symptoms was small following the operation. Exercise echocardiography evidenced variability of
the dynamic changes in fMR in patients with ischemic cardiomyopathy. The variability may be related to the outcome of the
mitral valve repair.
KeywordsEchocardiography-Exercise test-Heart failure-Mitral regurgitation-Mitral valve repair
Journal of Echocardiography 04/2012; 8(3):97-99.
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ABSTRACT: Diabetic retinopathy (DR) is an independent predictor of heart failure (HF) in patients with diabetes mellitus (DM). However, it is unclear how DR is related to the development of HF. We hypothesized that DR is associated with left ventricular (LV) diastolic dysfunction, which is well recognized to subsequently result in HF.
Data were collected in 63 consecutive patients with DM and LV ejection fraction (EF) ≥50%. Patients were excluded if they had HF diagnosed according to the modified Framingham criteria. Doppler echocardiographic indices including peak early-diastolic mitral annular movement velocity (E') were obtained in each patient.We also assessed the diastolic index of echocardiographic color kinesis (CK-DI), which proportionally decreases with LV relaxation abnormality independently of LV filling pressure, as recently published. The DM patients were divided into groups without (DM-N; n = 30) and with (DM-DR; n = 33) DR. Age, gender, LV end-diastolic dimension, EF, E/A ratio of the transmitral flow velocity curves, E', and E/E' were not different between DM-N and DM-DR. However, CK-DI was significantly lower in DM-DR than DM-N.
DR is associated with LV diastolic dysfunction, and this may at least in part explain the increased incidence of HF in DM patients with DR.
Journal of cardiac failure 07/2011; 17(7):556-60. · 3.25 Impact Factor
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Daisuke Kamimura,
Tomohito Ohtani,
Yasushi Sakata, Toshiaki Mano,
Yasuharu Takeda,
Shunsuke Tamaki,
Yosuke Omori,
Yasumasa Tsukamoto,
Kazuharu Furutani,
Yutaka Komiyama,
Masamichi Yoshika,
Hakuo Takahashi,
Toshio Matsuda,
Akemichi Baba,
Satoshi Umemura,
Takeshi Miwa,
Issei Komuro,
Kazuhiro Yamamoto
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ABSTRACT: Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na(+)/K(+)-ATPase and activate the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF.
(i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague-Dawley rats. (iii) Ouabain elevated intracellular Ca(2+) concentration through the entry of extracellular Ca(2+), increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced (3)H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening.
Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.
European Heart Journal 04/2011; 33(11):1408-16. · 10.48 Impact Factor
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Yasuharu Takeda,
Yasushi Sakata, Toshiaki Mano,
Tomohito Ohtani,
Daisuke Kamimura,
Shunsuke Tamaki,
Yosuke Omori,
Yasumasa Tsukamoto,
Yoshihiro Aizawa,
Issei Komuro,
Kazuhiro Yamamoto
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ABSTRACT: The prevalence of heart failure with preserved ejection fraction (HFpEF) has increased in the past two decades, and diabetes mellitus (DM) is frequently associated with HFpEF. Although it has been demonstrated that left ventricular (LV) diastolic and vascular functional abnormalities are generally observed in HFpEF, it remains to be clinically elucidated how an asymptomatic stage progresses to symptomatic HFpEF in DM patients. We aimed to identify risk factors associated with incident HFpEF in DM patients and to evaluate the contribution of LV relaxation and compliance to the development of HFpEF.
The study included 544 consecutive Japanese DM patients with ejection fraction ≥50%. Patients with coronary artery disease or serum creatinine ≥2.0 mg/dL were excluded. Multiple logistic regression analysis revealed that obesity, female gender, anaemia, and impaired LV compliance were independently associated with the prevalence of HFpEF, and that age, LV mass index, an index of LV relaxation, estimated glomerular filtration rate, and history of hypertension were not. There was no difference in haemoglobin A1c or brachial-ankle pulse wave velocity between the DM patients with and without HFpEF.
This study suggests that exacerbation of LV compliance impairment, rather than of relaxation abnormality or vascular stiffening, plays a crucial role in the induction of HFpEF in DM patients regardless of the severity of DM and renal dysfunction. Anaemia and obesity may also contribute to the transition from asymptomatic stage to symptomatic HFpEF even without further progression of LV diastolic dysfunction.
European Journal of Heart Failure 03/2011; 13(6):664-9. · 4.90 Impact Factor
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Yoshihiro Aizawa,
Yasushi Sakata, Toshiaki Mano,
Yasuharu Takeda,
Tomohito Ohtani,
Shunsuke Tamaki,
Yosuke Omori,
Yasumasa Tsukamoto,
Atsushi Hirayama,
Issei Komuro,
Kazuhiro Yamamoto
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ABSTRACT: Systolic abnormality, as well as diastolic dysfunction, is observed in patients with heart failure with preserved ejection fraction (HFPEF). However, the role of these 2 conditions in the transition from asymptomatic diastolic dysfunction to symptomatic heart failure remains unclear. We recently demonstrated that diastolic wall strain (DWS) inversely correlates to the myocardial stiffness constant.
This study consisted of 127 subjects: 52 consecutive HFPEF patients (HFPEF group), 50 asymptomatic hypertensive patients with ejection fraction ≥50% whose age, gender and left ventricular (LV) mass index matched those of the HFPEF group (HT group) and 25 normal volunteers (Normal group). The tissue Doppler-derived peak systolic and early diastolic velocities of the mitral annulus were significantly decreased in groups HFPEF and HT than in group Normal, but were not significantly different between groups HFPEF and HT. DWS was significantly lower in group HFPEF than in group HT.
The transition from asymptomatic diastolic dysfunction stage to HFPEF stage is not attributed to progression of systolic abnormality, and exacerbation of LV distensibility rather than relaxation plays a crucial role in the development of HFPEF.
Circulation Journal 01/2011; 75(3):596-602. · 3.77 Impact Factor
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ABSTRACT: The beneficial effects of beta-blocker therapy on the clinical outcomes of heart failure with reduced ejection fraction (HFREF) are attributed to the improvement in ejection fraction (EF) and left ventricular (LV) reverse remodeling. Previous studies only reported the beta-blocker therapy-induced improvement of diastolic function accompanied by the increase in EF in HFREF patients. This retrospective study aimed to elucidate whether beta-blocker therapy improves diastolic function even without an increase in EF. Out of the consecutive 11,830 echocardiographic reports, HFREF patients without an increase in EF following long-term beta-blocker therapy comprised the study subjects (n=19). During the mean follow-up of 17 months, beta-blocker therapy significantly decreased peak mitral E-wave velocity (70±25-50±18 cm/s, p<0.01) and ratio of peak mitral E- to A-wave velocities (E/A ratio) (1.4±0.8-0.9±0.4, p<0.05), prolonged deceleration time of the mitral E-wave velocity (DcT) (167±54-206±61 ms, p<0.05), and improved New York Heart Association functional class (2.3±0.7-1.8±0.4, p<0.01) without changes in LV volume. Because DcT and E/A ratio are well known to correlate with LV filling pressures in patients with reduced EF, our results indicate a reduction in LV filling pressures without changes in LV volume, suggesting a reduction in LV stiffness. Thus, long-term beta-blocker therapy is likely to improve diastolic function even without a concomitant increase in EF in HFREF patients, which may be also responsible for the beta-blocker-induced improvement of their symptoms of heart failure.
Journal of Cardiology 09/2010; 56(2):176-82. · 1.28 Impact Factor
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Circulation Journal 08/2009; 73(7):1360. · 3.77 Impact Factor
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Circulation Journal 07/2009; 73(6):1170. · 3.77 Impact Factor
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Tomohito Ohtani, Toshiaki Mano,
Shungo Hikoso,
Yasushi Sakata,
Mayu Nishio,
Yasuharu Takeda,
Kinya Otsu,
Takeshi Miwa,
Tohru Masuyama,
Masatsugu Hori,
Kazuhiro Yamamoto
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ABSTRACT: Elevated plasma glucocorticoid level is an independent predictor of increased mortality risk in chronic heart failure, but local biosynthesis and pathophysiological roles of glucocorticoids in the heart remain unclear.
Dahl salt-sensitive rats on high-salt diet and mice with transthoracic aortic banding (TAC) operation (TAC mice), both of which finally represent heart failure, were assessed at compensatory hypertrophic stage. As a model of cardiac-specific activation of steroidogenesis, alpha-myosin heavy chain-steroidogenic acute regulatory protein transgenic mice were used.
In hypertrophied hearts of Dahl salt-sensitive rats and TAC mice, the gene expressions of steroidogenic acute regulatory protein and CYP11A, rate limiting factors of steroid biosynthesis, were significantly upregulated and cardiac corticosterone level was increased compared with age-matched control. Although transgenic mice represented no morphological changes at basal condition, TAC induced greater increases in a ratio of left ventricular weight to body weight (4.8 +/- 0.2 vs.4.3 +/- 0.1 mg/g, P < 0.05) and left ventricular corticosterone level (104.5 +/- 13.3 vs. 69.8 +/- 3.8 pg/mg, P < 0.05) in the transgenic mice than in littermates. In neonatal cardiomyocytes, corticosterone increased atrial natriuretic peptide expression, protein synthesis and cell surface area, and provided the additive hypertrophic effects on phenylephrine-induced hypertrophied myocytes. These effects were prevented by glucocorticoid receptor blockade but not by mineralocorticoid receptor blockade.
In hypertrophied hearts, cardiac steroidogenesis was activated with an increase in cardiac glucocorticoid level. Glucocorticoid had potential of augmenting cardiac hypertrophy via glucocorticoid receptor even under the activation of alpha-adrenoceptor-mediated hypertrophic signaling. Cardiac steroidogenesis system and local glucocorticoid may play important roles in the development of hypertrophy and the progression to heart failure.
Journal of hypertension 04/2009; 27(5):1074-83. · 4.02 Impact Factor
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ABSTRACT: There is an emerging interest in heart failure with preserved ejection fraction (HFPEF) because of its high prevalence in the community and several specific characteristics compared with "classic" heart failure with reduced ejection fraction. HFPEF patients are older and more often female, and lack left ventricular dilatation. A likely principal cause of HFPEF is diastolic dysfunction, particularly ventricular stiffening; however, the clinical phenotype of HFPEF is also modulated by dysfunction of other organs such as kidney, vasculature, etc. Despite its social burden, the diagnostic criteria and therapeutic strategies remain to be established. In particular, the lack of established diagnostic criteria has resulted in conceptual confusions about HFPEF in clinical practice. In this review, what is known and unknown about HFPEF is discussed, and several challenging proposals about its diagnosis and therapy are raised.
Circulation Journal 03/2009; 73(3):404-10. · 3.77 Impact Factor
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ABSTRACT: Left ventricular (LV) wall stiffening plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Based on the linear elastic theory, we hypothesized that the evaluation of epicardial movement during diastole is helpful for the noninvasive assessment of LV wall distensibility.
Based on the linear elastic theory, the epicardial movement index (EMI) was calculated on the echocardiogram as: [see text.] We calculated diastolic wall strain (DWS) as follows to examine whether DWS substitutes for EMI: [see text.] The animal study using hypertensive Dahl salt-sensitive rats, HFpEF model, and normotensive Dahl rats showed the significant and inverse correlation of EMI or DWS with myocardial stiffness constant. Preload alteration did not affect EMI or DWS. In the clinical study, the HFpEF patients had lower EMI and DWS than the normal volunteers and the asymptomatic patients with LV hypertrophy.
The evaluation of epicardial movement may be useful in noninvasively assessing wall distensibility in the absence of LV systolic dysfunction.
Journal of cardiac failure 03/2009; 15(1):68-77. · 3.25 Impact Factor
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ABSTRACT: Noninvasive assessment of left ventricular (LV) diastolic function is not established in patients with preserved ejection fraction. We investigated a relation between diastolic function and diastolic wall dynamics.
In the animal study, data were collected in hypertensive Dahl salt-sensitive rats, a diastolic heart failure (DHF) model (n = 35), and normotensive Dahl rats (n = 26). In the clinical study, echocardiography was conducted in 26 diabetic patients with normal ejection fraction and 10 age-matched controls. The diastolic index of color-encoded images (color kinesis diastolic index [CK-DI]) was calculated as the ratio of LV cavity area expansion during the first 30% of diastolic filling time to that during the whole diastolic filling period. In the DHF model, the E/A ratio of the transmitral flow velocity curves was pseudonormalized with the development of heart failure, but CK-DI was not. CK-DI, not E/A, was significantly and inversely correlated with the time constant of LV relaxation. Angiotensin receptor blocker improved LV relaxation in the DHF model and increased CK-DI, but not E/A. The diabetic patients showed lower CK-DI than the controls, although E/A was not different.
Color-encoded imaging is useful in evaluating LV diastolic function. The prevalence of LV diastolic dysfunction may have been clinically underestimated by the transmitral flow velocity curves.
Journal of cardiac failure 10/2008; 14(7):569-76. · 3.25 Impact Factor
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ABSTRACT: Plasma brain natriuretic peptide (BNP) is widely used as a biomarker of heart failure (HF); however, its concentration is often found to be high even in apparently healthy subjects and little is known about which factors contribute to physiological change in plasma BNP concentration in subjects without HF. We examined the effects of gender, age, and anemia on plasma BNP concentration in apparently healthy subjects. The study population consisted of 1036 healthy subjects who underwent an annual health examination at their company in 2005. There were 874 women, ranging in age from 30 to 63 years (mean, 41 years). Plasma BNP concentration was abnormal (> 18.4 pg/mL) in 292 subjects. The incidence was significantly higher in women than in men (31% versus 14%, P < 0.01). Mean plasma BNP concentration was higher in women than in men. The difference in plasma BNP concentration was associated with the difference in blood hemoglobin and age. Logarithmically transformed BNP concentration correlated inversely with blood hemoglobin (r = -0.30, P < 0.01 for all; r = -0.21, P < 0.01 for women; r = -0.20, P < 0.01 for men). By multiple regression analysis, logarithmically transformed BNP concentration correlated with hemoglobin, age, and gender. In conclusion, anemia is likely a critical determinant that elevates plasma BNP concentration in apparently healthy subjects.
International Heart Journal 10/2008; 49(5):577-86. · 1.16 Impact Factor
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ABSTRACT: Clinical characteristics were compared between hypertensive patients with and without heart failure in the absence of reduced ejection fraction (EF) to gain insights into the effects of renal insufficiency on the prevalence of diastolic heart failure. Study subjects consisted of 691 hypertensive patients with an EF>40%. Patients with serum creatinine >2.5 mg/dL were excluded from the study. The Framingham heart failure criteria were met by 198 patients, and competing risks of the prevalence of heart failure were analyzed. The multiple logistic regression analysis revealed that obesity, female gender, creatinine clearance (CCr), and a ratio of transmitral E velocity to early diastolic mitral annular velocity (E/ E')>15 were independently associated with the prevalence of heart failure with preserved EF. Patients with 60< or =CCr<90 mL/min represented higher E/E' ratio and lower E' velocity than the patients with CCr> or =90 mL/min, although there was no difference in the prevalence of heart failure between the two groups. These indices were not different between the patients with 60< or =CCr<90 mL/min and CCr<60 mL/min, although the prevalence of heart failure was higher in the patients with CCr<60 mL/min. The hemoglobin concentration was significantly decreased and the brachial-ankle pulse wave velocity was significantly elevated in patients with CCr<60 mL/min. Thus, progressive left ventricular diastolic dysfunction and renal insufficiency are competing risks of the prevalence of diastolic heart failure in hypertensive patients. Renal insufficiency may exert its effects through the modulation of extracardiac factors such as anemia and arterial stiffening rather than through the promotion of diastolic dysfunction.
Hypertension Research 10/2008; 31(10):1865-72. · 2.58 Impact Factor
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ABSTRACT: beta-blocker therapy is an established therapeutic strategy for systolic heart failure. However, its benefits in diastolic heart failure (DHF) are controversial.
This study was designed to investigate the effects of bisoprolol on DHF.
Dahl salt-sensitive rats fed on 8% NaCl diet from age 6 weeks, DHF model rats, were divided into three groups at age 13 weeks. One group was treated with bisoprolol 12.5 mg/kg/day (Low dose group, n=18), one group was treated with bisoprolol 250 mg/kg/day (High dose group, n=18), and there was also an untreated group (Untreated group, n=18). The survival rate was best in the High dose group. Left ventricular hypertrophy and the expression of proinflammatory cytokines in the myocardium were significantly attenuated in the High dose group, but not in the Low dose group, and oxidative stress was most suppressed in the High dose group. Measurement with electron spin resonance revealed that bisoprolol had a potent scavenging ability, and bisoprolol attenuated the down-regulation of peroxisome proliferation-activated receptor coactivator-1alpha, an important element in the mitochondrial reactive oxygen species detoxification system.
beta-blocker administration, particularly at high dose, improved the survival rate of the DHF model, at least partly through the attenuation of inflammatory changes and oxidative stress.
European Journal of Heart Failure 06/2008; 10(5):446-53. · 4.90 Impact Factor
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ABSTRACT: Angiotensin II type 1 receptor blocker (ARB) is increasingly prescribed for the treatment of systolic heart failure with a growing body of clinical evidence. The roles of ARB, however, remain to be clarified in the treatment of diastolic heart failure (DHF), particularly at its advanced stage. This experimental study investigated the effects of ARB administered at an advanced stage of hypertensive DHF.
Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks represent overt DHF at age 20 weeks, as noted in previous studies (hypertensive DHF model). The DHF model rats were randomly divided into two groups at age 17 weeks when left ventricular diastolic dysfunction, hypertrophy, fibrosis, macrophage infiltration and reactive oxygen species generation were already augmented; six rats treated for 3 weeks with a subdepressor dose of ARB (olmesartan 0.6 mg/kg per day), and six untreated rats.
The 3-week administration of ARB significantly decreased the left ventricular end-diastolic pressure in association with attenuation of left ventricular hypertrophy, fibrosis and diastolic dysfunction. Macrophage infiltration was attenuated with decreased gene expression of transforming growth factor-beta1 and monocyte chemoattractant protein-1 in the left ventricular myocardium of the ARB-treated rats. The production of reactive oxygen species also decreased with NADPH oxidase activity.
ARB provides beneficial effects in hypertensive DHF independent of its antihypertensive effects even if initiated at an advanced stage. The beneficial effects are at least partly attributed to the attenuation of inflammatory changes and oxidative stress through the suppression of cytokine and chemokine production and of NADPH oxidase activity.
Journal of Hypertension 03/2007; 25(2):455-61. · 4.02 Impact Factor
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Tomohito Ohtani,
Miho Ohta,
Kazuhiro Yamamoto, Toshiaki Mano,
Yasushi Sakata,
Mayu Nishio,
Yasuharu Takeda,
Junichi Yoshida,
Takeshi Miwa,
Mitsuhiro Okamoto,
Tohru Masuyama,
Yasuki Nonaka,
Masatsugu Hori
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ABSTRACT: Cardiac aldosterone levels have not been evaluated in diastolic heart failure (DHF), and its roles in this type of heart failure remain unclear. This study aimed to detect cardiac aldosterone by use of a liquid chromatographic-mass spectrometric method and to assess the effects of mineralocorticoid receptor blockade on hypertensive DHF. Dahl salt-sensitive rats fed 8% NaCl diet from 7 wk (hypertensive DHF model) were divided at 13 wk into three groups: those treated with subdepressor doses of eplerenone (12.5 or 40 mg x kg(-1) x day(-1)) and an untreated group. Dahl salt-sensitive rats fed 0.3% NaCl diet served as controls. Cardiac aldosterone was detected in the DHF rats but not in the control rats, with increased ventricular levels of mineralocorticoid receptor. Cardiac levels of 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone were not different between the control and DHF rats, but the tissue level of corticosterone that has an affinity to mineralocorticoid receptor was 1,000 times as high as that of aldosterone. Aldosterone synthase activity and CYP11B2 mRNA were undetectable in the ventricular tissue of the DHF rats. Administration of eplerenone attenuated ventricular hypertrophy, ventricular fibrosis, myocardial stiffening, and relaxation abnormality, leading to the prevention of overt DHF. In summary, the myocardial aldosterone level increased in the DHF rats. However, its value was extremely low compared with corticosterone, and no evidence for enhancement of intrinsic myocardial aldosterone production was found. The upregulation of mineralocorticoid receptor may play a central role in the pathogenesis of DHF, and blockade of mineralocorticoid receptor is likely an effective therapeutic regimen of DHF.
AJP Regulatory Integrative and Comparative Physiology 03/2007; 292(2):R946-54. · 3.34 Impact Factor
