Gender differences in molecular remodeling in pressure overload hypertrophy

Weinberg, Ellen O.; Thienelt, C. D.; Katz, Sidney; Bartúnek, Jozef; Tajima, Masahiro; Rohrbach, Susanne; Douglas, Pamela S.; Lorell, Beverly H.

doi:10.1016/s0735-1097(99)00165-5

Cited by 218 publications

(137 citation statements)

References 42 publications

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“…The remodeling process accelerated the progression to heart failure, characterized by significant chamber dilation and a decrease in the ratio of wall thickness to chamber diameter (h/r) by 6 months of age. However, the progression to failure was delayed in females (37), indicating that, despite a similar degree of LV hypertrophy between males and females, there were significant gender differences in the LV-adaptive response to pathological hypertrophy and depressed function, similar to recent studies in the TNF-␣ overexpression model and in a rat model of pressure overload hypertrophy (38). The etiology of these differences is unclear but may be related to: (a) a reduced adaptive hypertrophic reserve in males (39); (b) the lower mitochondria respiratory and lysosomal enzyme activity in females (40); (c) a higher percentage of the V1 myosin isozyme, which is up-regulated by estrogen in females (41); and (d) the intrinsic gender-specific differences in cardiac muscle physiology and biochemistry (42).…”

Section: Discussionsupporting

confidence: 72%

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Haghighi

Schmidt

Hoit

et al. 2001

Journal of Biological Chemistry

115

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To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca 2؉ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val 49 3 Gly mutant (2-fold), which is a superinhibitor of SR Ca 2؉ -ATPase affinity for Ca 2؉, were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC 50 level of SR Ca 2؉ uptake for Ca 2؉ (0.67 ؎ 0.09 M) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca 2؉ signal decay time (165%) than overexpression (2-fold) of wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed function and impaired ␤-adrenergic responses in mutant hearts. The depressed contractile parameters were associated with left ventricular remodeling, recapitulation of fetal gene expression, and hypertrophy, which progressed to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results suggest a causal relationship between defective SR Ca 2؉ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations.Cardiac hypertrophy and failure are highly complex disorders that arise as a result of a combination of mechanical, hemodynamic, hormonal, and pathological stimuli (1). In response to these effectors, the heart undergoes an adaptive response of compensatory hypertrophy (2) followed by decompensated heart failure that is characterized by defects in Ca 2ϩ handling during excitation-contraction coupling. Studies of end-stage-failing hearts have shown that the disturbed calcium homeostasis is associated with alterations in the expression levels or the activity of key Ca 2ϩ -handling proteins, leading to abnormal excitation contraction coupling and diastolic as well as systolic dysfunction (3, 4). Specifically, alterations in SR 1 Ca 2ϩ -ATPase (SERCA2a) activity, the major Ca 2ϩ transport protein in SR, have been implicated as important determinants in the deteriorated function of the failing heart (5-7). The activity of SERCA2a is regulated by phospholamban (PLB), a 52-amino acid, muscle-specific SR phosphoprotein (8 -10). Dephosphorylated PLB inhibits the Ca 2ϩ affinity of SERCA2a, whereas the phosphorylated form of PLB dissociates from SERCA2a leading to increases in Ca 2ϩ uptake rates and accelerated ventricular relaxation (11-13).The role of PLB in the regulation of basal contractility has been elucidated through the development of genetically engineered mouse models. Phospholamban ablation resulted in significant increases in cardiac contractile parameters, whereas overexpressing PLB was associated with depressed cardiac function (14, 15). Actually, an inverse relationship betwe...

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Section: Discussionsupporting

confidence: 72%

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Haghighi

Schmidt

Hoit

et al. 2001

Journal of Biological Chemistry

115

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“…5 For patients undergoing CABG, congestive heart failure has been shown to account for the excess mortality in women, 2 and congestive heart failure is an independent predictor of mortality in both women and men in BARI and other revascularization studies. 5,6 Compelling evidence implicates a higher incidence of hypertensive heart disease, a steeper pressure-volume relationship, and more diastolic dysfunction 12 in women in comparison with men and is supported by reports of sex differences in molecular remodeling in pressure overload hypertrophy 13 and in cardiac adaptation to isolated systolic hypertension. 14 It has been postulated that the hypertrophied left ventricle is less able to withstand transient periods of ischemia and volume shifts and comparatively higher contrast loads (corrected for smaller size in women) associated with revascularization.…”

Section: In-hospital Mortalitymentioning

confidence: 97%

Coronary Revascularization in Women in 2003

Jacobs

2003

Circulation

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During the past 3 decades, numerous and remarkably consistent studies have reported sex differences in the epidemiology, prevention, diagnosis, and clinical manifestations of coronary artery disease, 1 and, especially noteworthy, in the sex differences in patients undergoing coronary revascularization, where a disturbingly higher mortality rate has been noted in women. 2,3 In fact, multiple paradoxes have been observed. Differences between women and men in the extent of epicardial coronary artery disease in relation to risk factors and the degree of stable and unstable angina, in the relationship between congestive heart failure and left ventricular systolic function, and recently, in the higher in-hospital mortality after revascularization in younger but not older women in comparison to men have been noted. 4 It has been suggested that improvements in procedural technology and technique, particularly the increasing performance of off-pump procedures and use of heparin bonded circuits, and the widespread use of stents and adjunctive pharmacotherapy in patients undergoing both coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) would improve outcomes in women. Therefore, it is timely to review the current status and issues concerning coronary revascularization in women. Clinical, Angiographic, and Procedural CharacteristicsVirtually all single-center and large-scale multicenter registries have reported that in comparison to men, women undergoing CABG or PCI have more comorbid disease, are older, are smaller in size, and have a higher prevalence of hypertension, diabetes mellitus, hypercholesterolemia, peripheral vascular disease, and unstable angina, as well as more severe (Canadian Cardiovascular Society class III-IV) angina. Despite a lower prevalence of previous myocardial infarction and left ventricular dysfunction than men, they have more congestive heart failure. [2][3][4][5][6] Yet, the extent of epicardial coronary artery disease, as measured by angiography, is similar (or less) in women in comparison to men, a finding that refutes the hypothesis that women are referred for coronary angiography less often or later in the course of their disease than men. Although the reasons for this sex difference in the degree of symptoms and risk factors in relation to the extent of angiographic disease are unclear, microvascular dysfunction, abnormal vasomotor tone, and endothelial dysfunction in women are often implicated. Despite smaller vessel size in women, coronary lesion morphology and distribution is similar to that in men, except that women tend to have more ostial lesions. 5 For patients undergoing CABG, the increased incidence of incomplete revascularization in women is no longer apparent, although women receive fewer internal mammary artery conduits than men, 2,5 a difference unexplained by unstable symptoms or the prevalence of diabetes. In patients undergoing contemporary PCI, stent usage is similar in women and men after adjusting for vessel size. 6 In comparison with...

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“…Alternatively, an intrinsic di erence between the male and female rat heart may exist, and thus selectively in¯uence the pattern of cardiac remodelling. In fact, a recent study by Weinberg et al (1999) demonstrated signi®cant gender di erences in cardiac remodelling and ventricular function, despite a similar degree of left ventricular hypertrophy and systolic wall stress.…”

Section: British Journal Of Pharmacology Vol 136 (5)mentioning

confidence: 97%

Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

Mercier

Pham-Dang

Clement

et al. 2002

British J Pharmacology

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1 The in¯uence of menopause on ventricular function and remodelling remains unde®ned. The following study examined the e ect of ovariectomy on ventricular contractility, cardiac hypertrophy and extracellular matrix protein expression. 2 Elevated circulating levels of the vasoconstrictor endothelin-1 have been reported in postmenopausal women. Moreover, endothelin-1 has been shown to in¯uence blood pressure, ventricular function and cardiac remodelling. In this regard, the potential pathophysiological role of endothelin-1 in the ovariectomized rat was assessed via the administration of the selective endothelin A receptor (ET A ) antagonist BMS-182874.3 In 3 and 6 week ovariectomized female Sprague ± Dawley rats, uterus atrophy was associated with a signi®cant increase in mean arterial pressure, and left ventricular systolic pressure, as compared to sham. By contrast, right ventricular contractile indices were normal in the ovariectomized rat. Despite increased systolic load, left ventricular hypertrophy was not evident, prepro-atrial natriuretic peptide (prepro-ANP) mRNA levels and collagen protein content were similar to sham. 4 The treatment of ovariectomized rats with BMS-182874 (60 mg kg 71 per day) did not reverse uterus atrophy. However, BMS-182874 normalized mean arterial pressure, and left ventricular systolic pressure in the ovariectomized rat. 5 Thus, despite elevated blood pressure, ovariectomized rats were not associated with either cardiac hypertrophy or ®brosis. Lastly, endothelin-1, acting via the stimulation of the ET A receptor represents an integral mechanism implicated in the increase of mean arterial pressure following ovariectomy.

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Gender differences in molecular remodeling in pressure overload hypertrophy

Cited by 218 publications

References 42 publications

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Coronary Revascularization in Women in 2003

Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

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Gender differences in molecular remodeling in pressure overload hypertrophy

Cited by 218 publications

References 42 publications

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Coronary Revascularization in Women in 2003

Elevated mean arterial pressure in the ovariectomized rat was normalized by ETA receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

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Product

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Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis