The Effects of Biological Sex and Diet on the Development of Heart Failure

Konhilas, John P.; Leinwand, Leslie A.

doi:10.1161/circulationaha.106.672006

Cited by 62 publications

(60 citation statements)

References 188 publications

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“…Experimentally, ovarian hormones, particularly estrogen, have been associated with a plethora of favorable biological and physiological processes, suggesting that ovarian hormones are cardioprotective (27,36,39,54,62). This is supported by evidence in mice showing that the administration of estrogen both before and following MI in males and females reduces infarct size and protects cardiac function post-MI (4,5).…”

Section: Discussionmentioning

confidence: 96%

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats

Pinkham

Whalley

Guild

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Pinkham MI, Whalley GA, Guild SJ, Malpas SC, Barrett CJ. Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats. Am J Physiol Regul Integr Comp Physiol 309: R169-R178, 2015. First published May 20, 2015 doi:10.1152/ajpregu.00026.2015.-There is controversy regarding whether the arterial baroreflex control of renal sympathetic nerve activity (SNA) in heart failure is altered. We investigated the impact of sex and ovarian hormones on changes in the arterial baroreflex control of renal SNA following a chronic myocardial infarction (MI). Renal SNA and arterial pressure were recorded in chloralose-urethane anesthetized male, female, and ovariectomized female (OVX) Wistar rats 6 -7 wk postsham or MI surgery. Animals were grouped according to MI size (sham, small and large MI). Ovary-intact females had a lower mortality rate post-MI (24%) compared with both males (38%) and OVX (50%) (P Ͻ 0.05). Males and OVX with large MI, but not small MI, displayed an impaired ability of the arterial baroreflex to inhibit renal SNA. As a result, the male large MI group (49 Ϯ 6 vs. 84 Ϯ 5% in male sham group) and OVX large MI group (37 Ϯ 3 vs. 75 Ϯ 5% in OVX sham group) displayed significantly reduced arterial baroreflex range of control of normalized renal SNA (P Ͻ 0.05). In ovary-intact females, arterial baroreflex control of normalized renal SNA was unchanged regardless of MI size. In males and OVX there was a significant, positive correlation between left ventricle (LV) ejection fraction and arterial baroreflex range of control of normalized renal SNA, but not absolute renal SNA, that was not evident in ovary-intact females. The current findings demonstrate that the arterial baroreflex control of renal SNA post-MI is preserved in ovary-intact females, and the state of left ventricular dysfunction significantly impacts on the changes in the arterial baroreflex post-MI.

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Section: Discussionmentioning

confidence: 96%

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats

Pinkham

Whalley

Guild

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Sex differences in myocardial function have been described for a number of genetically modified mice and have been attributed both to multiple factors, including estrogens, estrogen receptors and diet. 27 There are very little data about effects of sex in human laminopathies and further evaluation is required. In one series, there was a nonsignificant trend toward an increased prevalence of LMNA mutations in female familial DCM probands.…”

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confidence: 99%

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Chandar¹,

Yeo²,

Leimena³

et al. 2010

Circulation Research

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Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna ؉/؊ ) mice. Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna ؉/؊ mice develop adult-onset DCM with relatively more severe disease in males. Lmna ؉/؊ cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna ؉/؊ mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna ؉/؊ mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna ؉/؊ mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna ؉/؊ mice from 12 to 40 weeks with the ␤-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)Key Words: familial dilated cardiomyopathy Ⅲ lamin A/C Ⅲ mechanical stress Ⅲ exercise Ⅲ carvedilol M utations in the LMNA gene that encodes the nuclear lamina proteins lamin A and lamin C are the most common cause of familial dilated cardiomyopathy (DCM) identified to date, 1 accounting for 5% to 10% familial DCM overall and 30% to 45% families with DCM and conduction system disease (CD). [2][3][4][5] Affected individuals frequently have a rapidly progressive downhill clinical course, requiring pacemaker implantation or heart transplantation, with an increased risk of sudden death. [2][3][4][5] Despite the clinical importance of LMNA mutations, very little is known about mechanisms of disease pathogenesis and strategies to prevent DCM have not been investigated.Because one-third of DCM-causing LMNA mutations are stop codons, splice site variants or insertions/deletions that reduce lamin A/C protein levels, 1,5 Lmna knockout mice are a useful and clinically relevant model to study DCM mechanisms. 6 We have previously reported that homozygous Lmna knockout (Lmna Ϫ/Ϫ ) mice exhibit severe DCM by 4 to 6 weeks. 7 Heterozygous Lmna knockout (Lmna ϩ/Ϫ ) mice show ...

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“…These data from functionally intact myocardium imply a greater mechanical performance of the myocardial myofilaments containing the R403Q mutant ␣-MHC. Interestingly, only male (M) ␣MHC R403Q/ϩ mice develop HCM after 30 wk of age (11,12,24,30,43), a condition that appears to underlie the greater likelihood for M mice to develop heart failure compared with that shown in female (F) mice (17,18,20,24,30,42,45). Men carrying mutant alleles for sarcomeric proteins are likewise more likely than women to develop HCM (8,22,28,49).…”

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confidence: 99%

Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Palmer¹,

Wang²,

Teekakirikul³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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, respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-␣MHC ϩ/ϩ and F-␣MHC ϩ/ϩ , respectively) after ϳ30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-␣MHC R403Q/ϩ and F-␣MHC R403Q/ϩ at younger ages (10 -20 wk) and could account for sex differences in HCM development. The sensitivity of chemically skinned myocardial strips to Ca 2ϩ activation (pCa50) was significantly (P Ͻ 0.05) enhanced in male mice independent of genotype (M-␣MHC Ϫ3 , F-␣MHC ϩ/ϩ 25 Ϯ 3 10 Ϫ3 muscle lengths/s ϫ normalized tension). We did not find a statistically significant sex ϫ mutation interaction for any measure of myofilament performance. Therefore, sarcomeric incorporation of the R403Q myosin similarly enhanced left ventricular myofilament mechanical performance in both male and female mice. The sex-dependent development of HCM due to the R403Q myosin may then be inhibited by female sex hormones, which may additionally underlie the observed sex differences for pCa50 and unloaded shortening velocity. hypertrophic cardiomyopathy; myosin heavy chain; isometric tension; calcium sensitivity; force-velocity HYPERTROPHIC CARDIOMYOPATHY (HCM) in the absence of recognizable hemodynamic risk factors can arise naturally as a consequence of a mutant allele for myosin heavy chain (MHC) (41). Assessing the functional consequences of HCM-associated mutations, such as the R403Q point mutation in cardiac ␣-MHC or ␤-MHC, has played an important role in the identification of modifications in myofilament performance that may lead to the HCM phenotype (9,19,36,51). However, functional data from some models of the R403Q-mutated MHC have been indefinite. For example, myosin isolated from myocardium of HCM patients carrying an allele for the R403Q mutation reportedly reduce (5) or enhance (33) actin filament velocity (V actin ) in the myosin motility assay. Additionally, actin-activated myosin ATPase and V actin of R403Q mutant MHC expressed by baculovirus/insect cell systems are reportedly reduced for rat cardiac ␣-MHC (44) and yet enhanced in chicken gizzard smooth muscle MHC (53).Data from mouse models of the R403Q mutation in ␣-MHC, on the other hand, have provided more consistent findings. Myosin isolated from myocardium of ␣-MHC R403Q/R403Q homozygous mice demonstrate a marked enhancement of actinactivated ATPase, V actin , and stall force of V actin by ␣-actinin (7, 47). Similarly, cardiac myosin isolated from ␣MHC R403Q/ϩ heterozygous mice shows enhanced ATPase (2, 31, 47). Data from ATPase and V actin assays generally correspond to each other and reflect actomyosin cross-bridge kinetics (48), whose enhancement in the R403Q myosin has been corroborated by a shorter cross-bridge time-on measured in the laser trap (47).Left ventricular (LV) function in the ␣MHC R403Q/ϩ heterozygous mouse, which mimics the human genotype leading to HCM, is characterized in part by an earlier and higher peak LV pressure and an elevated free wall fractional shorteni...

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The Effects of Biological Sex and Diet on the Development of Heart Failure

Cited by 62 publications

References 188 publications

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

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