Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart

Yamamoto, Keiji; Masuyama, Tohru; Sakata, Yasushi; Nishikawa, Nagahiro; Mano, Toshiaki; Yoshida, Junichi; Miwa, Takeshi; Sugawara, Motoaki; Yamaguchi, Yoshiaki; Ookawara, Tomomi; Suzuki, Keiichiro; Hori, Masatsugu

doi:10.1016/s0008-6363(02)00341-3

Cited by 210 publications

(145 citation statements)

References 25 publications

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“…Standard histological analysis with trichrome staining (results not shown) revealed cellular hypertrophy and interstitial fibrosis as reported in prior studies. 26,27 Body weight showed less of an increase with age in the HS group compared with the LS group from 8 to 16 weeks but reached values similar to the controls at 20 weeks. The lung/body weight increased significantly in the HS group at weeks 16 and 20, suggestive of pulmonary edema, which correlated with the increase in EDP and development of edema, both consistent with a transition to a heart failure state.…”

Section: Hemodynamicsmentioning

confidence: 79%

Development of Heart Failure in Chronic Hypertensive Dahl Rats

et al. 2006

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Abstract-The impact of hypertension on left ventricular (LV) structure, pump function, and heart failure in Dahl salt-sensitive rats is poorly characterized but hypothesized to yield insights into the pathophysiology of heart failure with normal or preserved ejection fraction. Eighty Dahl salt-sensitive rats were fed either a high-salt (HS) or low-salt (LS, controls) diet starting at age 7 weeks. Ventricular properties were measured by echocardiography, hemodynamics and end-systolic and end-diastolic pressure-volume relationships (ESPVR and EDPVR, respectively). Compared with LS controls, HS rats developed severe hypertension and LV hypertrophy. At week 12, HS rats developed passive diastolic dysfunction (leftward/upward shifted EDPVR, increased chamber stiffness) with reductions in end-diastolic volume. However, the ESPVR also shifted upward (enhanced end-systolic function) so that overall pump function was enhanced compared with LS, and there was no change in end-diastolic pressure (EDP). At 16 and 20 weeks, HS hearts enlarged so that end-diastolic volumes and EDPVRs became similar to the respective age-matched LS controls. Concomitantly, the ESPVRs and overall pump function curves also moved toward controls, and ejection fraction declined. Despite normal or enhanced overall pump function at these times, EDP and wet lung weight increased, indicative of development of heart failure. In the Dahl salt-sensitive rat, which pathophysiologically retains salt and water, the development of heart failure (increased EDP and wet lung weight) is dissociated from changes in passive diastolic and active systolic properties. These observations suggest that a volume overload sate plays an important pathophysiological role in development of heart failure despite preserved overall ventricular pump function in this model of chronic hypertension. Key Words: remodeling Ⅲ heart failure Ⅲ diastole Ⅲ hypertrophy Ⅲ renal disease H eart failure commonly occurs in patients with a normal or preserved ejection fraction (HFPEF). 1-3 It was advocated previously that HFPEF is primarily because of diastolic dysfunction and, thus, termed "diastolic heart failure" (DHF). 4,5 However, data from our recent clinical and animal studies suggest that HFPEF can occur without diastolic dysfunction. 6 -10 We found that HFPEF in the setting of idiopathic hypertrophic cardiomyopathy and infiltrative cardiac diseases is indeed because of diastolic dysfunction, defined by a reduced chamber capacitance in the absence of systolic dysfunction. 10 However, in the setting of long standing hypertension, HFPEF may not always be because of diastolic dysfunction. 10 We proposed other, extracardiac factors leading to a volume-overloaded state as the underlying pathology, such as might occur with salt and water handling impairments encountered in the setting of renal dysfunction.Two potential limitations of prior studies contribute to the controversy. First, barring a few notable exceptions, 7,11-13 studies of HFPEF have evaluated diastolic properties without any ser...

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Section: Hemodynamicsmentioning

confidence: 79%

Development of Heart Failure in Chronic Hypertensive Dahl Rats

et al. 2006

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“…Consistent with their impaired cardiac function, diabetic rats developed myocardial fibrosis, the marked fibrotic regions (as observed by immunohistochemical staining), as well as deposition of collagen fibers in the interstitial spaces among cardiomyocytes (as observed by TEM), our observations are similar to those described in other reports [29,30] . Increased myocardial fibrosis is a major factor responsible for myocardial stiffness and eventual systolic [31,32] . Our most significant finding is that treatment with fasudil attenuated interstitial myocardial fibrosis in diabetic rats and improved cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Zhou

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

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“…The quantity of hydroxyproline was multiplied by the conversion factor 7.46 to calculate total collagen (24). To determine soluble collagen content, myocardium was extracted and digested with cyanogen bromide (CNBr) according to the modified procedure of Yamamoto et al (25). The quantity of non-cross-linked (soluble) and cross-linked (insoluble) collagen in the myocardium was determined from the product of the percentage of collagen soluble to CNBr digestion, the total myocardial collagen concentration and the difference between the total collagen concentration and soluble collagen concentration, respectively.…”

Section: Myocardial Cell Cross-sectional Area and Collagen Volume Framentioning

confidence: 99%

Prenatal nicotine exposure induces gender-associated left ventricular-arterial uncoupling in adult offspring

Wang

Ouyang

Huang

et al. 2012

Molecular Medicine Reports

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Abstract. Alterations in vascular or myocardial structure and function have been demonstrated in offspring subjected to prenatal nicotine exposure (PNE), however, limited data are available on how these changes interact. The present study assessed the hypothesis that prenatal nicotine exposure induced gender-specific alterations of left ventricular-arterial coupling indices in adult offspring. Female Sprague-Dawley rats were exposed to either nicotine (8 mg/kg/day) or saline via subcutaneous osmotic mini-pumps throughout gestation. Male and female offspring, aged 12 months, underwent non-invasive echocardiography and invasive left ventricular cannulation. Left ventricular-arterial coupling was analysed as the ratio of effective arterial elastance (Ea) to ventricular end-systolic elastance (Ees). The left ventricular myocardium and aorta were stained with hematoxylin and eosin and the myocardial cell cross-sectional area was calculated. Simultaneously, the ratio of medium thickness to internal diameter in the aorta and mesenteric artery was determined. The fibrosis component of left ventricle myocardium was analyzed by Sirius-red staining and further confirmed by hydroxyproline determination. The elastic properties of the aortic wall were analyzed by van Gieson staining. PNE caused significant increases in pulse pressure (56.36±7.41 vs. 50.16±4.94 mmHg; P<0.05) and left ventricular meridional wall stress (78.25±9.12 vs. 69.64±7.58 kdyne/cm 2 ; P<0.05) in male offspring compared with the control. Conversely, no similar effect was observed in female offspring. An elevated augmentation index was noted in male and female pups. Additionally, Ea/Ees was reduced in PNE males compared with control males, due to a disproportionate increase in Ees vs. Ea whereas in females, Ea/Ees did not differ significantly due to tandem increase in Ea and Ees. In addition, collagen cross-linking was markedly higher in male offspring, whereas it was unaltered in females compared with their respective controls. Fragmentation of the elastic network in the aorta and the increased ratio of medial thickness to internal diameter in the mesenteric artery were more evident in male offspring when compared with female offspring. PNE caused combined ventricular-arterial stiffening in male and female offspring, with lower Ea/Ees in males, while Ea/Ees was preserved in females. Enhanced collagen cross-linking in the myocardium, underdeveloped elastic fibers in the aorta and remodeled resistance vessels were associated with pathological ventricular arterial mismatching. The results of the present study indicated that male offspring were more susceptible to the development of ventricular and arterial dysfunction in response to PNE compared with female offspring.

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Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart

Abstract: Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.

Cited by 210 publications

References 25 publications

Development of Heart Failure in Chronic Hypertensive Dahl Rats

Development of Heart Failure in Chronic Hypertensive Dahl Rats

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Prenatal nicotine exposure induces gender-associated left ventricular-arterial uncoupling in adult offspring

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