Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease

Kessler, Elise L.; Rivaud, Mathilde R.; Vos, Marc A.; Veen, Toon A.B. van

doi:10.1186/s13293-019-0223-0

Cited by 81 publications

(60 citation statements)

References 89 publications

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“…To examine collective associations of up-and down-regulated signaling pathways, a network model describing interaction among the differentially expressed genes was reconstructed ( Figure 4F). The network has shown that metformin treatment inhibits increased inflammation and apoptosis by lowering the Tgf-β/BMP signaling pathway Metformin has also been shown to promote cell proliferation and anti-apoptosis by increasing the Jak/Stat and AMPK-PGC1α signaling pathways ( Figure 4F,G) [19]. Taken together, these data suggest promising positive effects of metformin on myocardial I/R injury, consistent with previous findings [20,21].…”

Section: Metformin Treatment Results In Changes Of Multiple Cellular supporting

confidence: 89%

Metformin Alleviates Left Ventricular Diastolic Dysfunction in a Rat Myocardial Ischemia Reperfusion Injury Model

Kang

Chae

et al. 2020

IJMS

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An increased incidence of myocardial infarction (MI) has recently emerged as the cause of cardiovascular morbidity and mortality worldwide. In this study, cardiac function was investigated in a rat myocardial ischemia/reperfusion (I/R) model using echocardiography. Metformin administration significantly increased ejection fraction and fractional shortening values on Days 3 and 7 when MI occurred, indicating that metformin improved left ventricular systolic function. In the Sham + MET and MI + MET groups, the E’ value was significantly different up to Day 3 but not at Day 7. This may mean that left ventricular diastolic function was effectively restored to some extent by Day 7 when metformin was administered. These results suggest that diastolic dysfunction, assessed by echocardiography, does not recover in the early phase of ischemic reperfusion injury in the rat myocardial I/R model. However, administering metformin resulted in recovery in the early phase of ischemic reperfusion injury in this model. Further gene expression profiling of left ventricle tissues revealed that the metformin-treated group had notably attenuated immune and inflammatory profiles. To sum up, a rat myocardial I/R injury model and ultrasound-based assessment of left ventricular systolic and diastolic function can be used in translational research and for the development of new heart failure-related drugs, in addition to evaluating the potential of metformin to improve left ventricular (LV) diastolic function.

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Section: Metformin Treatment Results In Changes Of Multiple Cellular supporting

confidence: 89%

Metformin Alleviates Left Ventricular Diastolic Dysfunction in a Rat Myocardial Ischemia Reperfusion Injury Model

Kang

Chae

et al. 2020

IJMS

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“…Sex differences in human disease are usually attributed to sex specific life experiences, and sex hormones that influence the function of susceptible genes throughout the genome. [1][2][3][4][5] Such factors do account for some dissimilarities. However, a major cause of sex-determined expression of disease has to do with differences in how males and females transcribe their gene-rich human X chromosomes, which is often underappreciated as a cause of sex differences in disease.…”

Section: Introductionmentioning

confidence: 99%

X-linked diseases: susceptible females

Migeon

2020

Genetics in Medicine

139

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The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.

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“…There is increasing attention to potential sex differences in cardiovascular biology and disease in studies of animal models and human patients (17,23,31,38). In the current study, we evaluated the effects of cardiac IR injury on female and male pigs prior to sexual maturity (39).…”

Section: Discussionmentioning

confidence: 99%

“…These data provide initial evidence that prepubertal female and male pigs may respond differently to cardiac surgery, with prepubertal female pigs being predisposed to a greater detrimental response. In many studies of cardiac injury response in mice and humans, males are predominantly studied due to their greater fibrotic response to cardiac injury (16,17,27). In adult females of reproductive age, estrogen signaling is antifibrotic and cardioprotective after cardiac injury (14,15,33), but may be less effective prior to puberty or after menopause.…”

Section: Discussionmentioning

confidence: 99%

Scar Formation and Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1-Month-Old Swine

Agnew

Velayutham

Ortiz

et al. 2019

Preprint

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Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation. Less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs, to assess regenerative repair in young large mammals. Female and male P30 pigs were subjected to cardiac ischemia (1 hour) by occlusion of the left anterior descending artery followed by reperfusion, or to sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 hours post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated cardiomyocyte (CM) cell cycling at 2-months-of-age in multinucleated CMs in both sham-operated and IR pigs. Regional scar formation and inflammation in the epicardial region proximal to injury were observed 4 weeks post-IR. Sex differences were found, suggestive of females creating a greater fibrotic response with worse cardiac function, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in P30 swine, at a time when CMs are still cycling. Pigs subjected to IR show myocardial damage with a prolonged decrease in cardiac function, formation of a small, regional scar with increased inflammation. These data demonstrate that P30 pigs do not regenerate myocardium, even in the presence of CM mitotic activity, but form a scar after transient IR injury.NEW & NOTEWORTHYHere, we report for the first time ischemia/reperfusion (IR) cardiac injury in 1-month-old (P30) pigs. This model of IR injury highlights lack of cardiac regeneration, even in the presence of cardiomyocyte (CM) cell cycling in young swine. An effective injury approach is described for use in large mammals to investigate cardiac function, CM cell cycling, extracellular matrix (ECM) remodeling, and gene expression changes, while highlighting the importance of studying both sexes.

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Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease

Cited by 81 publications

References 89 publications

Metformin Alleviates Left Ventricular Diastolic Dysfunction in a Rat Myocardial Ischemia Reperfusion Injury Model

Metformin Alleviates Left Ventricular Diastolic Dysfunction in a Rat Myocardial Ischemia Reperfusion Injury Model

X-linked diseases: susceptible females

Scar Formation and Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1-Month-Old Swine

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