Sex differences in right ventricular adaptation to pressure overload in a rat model

Cheng, Tik-Chee; Tabima, Diana M.; Caggiano, Laura R; Frump, Andrea L.; Hacker, Timothy A.; Eickhoff, Jens; Lahm, Tim; Chesler, Naomi C.

doi:10.1152/japplphysiol.00175.2021

Cited by 7 publications

(4 citation statements)

References 56 publications

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“…However, a few studies over the past five years have raised the possibility that modulators other than sex hormones may also underlie the sexual dimorphism of RV remodeling. In a rat PAB model, ovary-intact and ovariectomized females had similar amounts of collagen content in the RV, 29 indicating that regulation of cardiac collagen content does not depend upon estrogen. Additionally, some sex chromosome-specific genes are associated with pathologic cardiac remodeling but not sex-hormone signaling.…”

Section: Discussionmentioning

confidence: 86%

“…In these studies, ovariectomized adult female rodents developed worse disease progression, with more severe fibrosis and increased mortality, than those with intact ovaries. 28 Other studies of female rodents with and without ovariectomy have shown an estrogen-dependent anti-fibrotic signaling pathway in the pressure overloaded ventricle, 4, 6, 29, 30 though mechanistic details remain to be elucidated. Aside from sex hormone regulation of fibrosis, sex differences in cardiac fibroblasts (CFs) have also been reported.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

Russo,

Dun,

Mehta

et al. 2024

Preprint

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Background: Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or etiology. In both, RVD arises from the chronic RV pressure overload, and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of HF and PAH patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV remodeling are incompletely understood. We sought to elucidate the cardiac pathophysiology underlying the sex-specific RV remodeling phenotypes, RV failure (RVF) versus compensated RVD. Methods: We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses. Results: M-PAB developed severe RVD with RVF, increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and activation and recruitment of macrophages. Despite the same severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. Conclusions: ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in male PAB mice. Adaptive RV remodeling of female PAB mice lacked these histopathologic changes. Our findings suggest that these two pathophysiologic processes likely contribute to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

Russo,

Dun,

Mehta

et al. 2024

Preprint

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“…Establishing a representative control cohort using sampling methodologies [ 45 ] probably would provide more robust comparisons between normotensive and PH model parameters. Lastly, it is well established that PH disproportionately affects women, with sex differences being a significant area of attention in the PH community [ 60 ]. Combining a larger, more diverse patient cohort in the parameter inference performed here may elucidate sex-dependent differences in right atrium, right ventricle and pulmonary artery, parameters.…”

Section: Discussionmentioning

confidence: 99%

Parameter inference in a computational model of haemodynamics in pulmonary hypertension

Colunga

Colebank

Olufsen

2023

J. R. Soc. Interface.

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Pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg, is characterized by increased pulmonary vascular resistance and decreased pulmonary arterial compliance. There are few measurable biomarkers of PH progression, but a conclusive diagnosis of the disease requires invasive right heart catheterization (RHC). Patient-specific cardiovascular systems-level computational models provide a potential non-invasive tool for determining additional indicators of disease severity. Using computational modelling, this study quantifies physiological parameters indicative of disease severity in nine PH patients. The model includes all four heart chambers, the pulmonary and systemic circulations. We consider two sets of calibration data: static (systolic and diastolic values) RHC data and a combination of static and continuous, time-series waveform data. We determine a subset of identifiable parameters for model calibration using sensitivity analyses and multi-start inference and perform posterior uncertainty quantification. Results show that additional waveform data enables accurate calibration of the right atrial reservoir and pump function across the PH cohort. Model outcomes, including stroke work and pulmonary resistance-compliance relations, reflect typical right heart dynamics in PH phenotypes. Lastly, we show that estimated parameters agree with previous, non-modelling studies, supporting this type of analysis in translational PH research.

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“…Additionally, studies have shown distinct differences in myocardial response to pressure overload, a common precursor of heart failure, in female and male animals [14][15][16] . Rat studies have shown that females typically exhibit diastolic dysfunction characterized by decreased compliance of the heart muscle, for which no mechanistic therapies have been established, and males more often develop systolic dysfunction with decreased ejection fraction and increased fibrosis, for which therapies have been established 17 . Heart failure itself also shows a sex-dependent divergence; HF with preserved ejection fraction, coupled with increased ventricular stiffness, is more common in women, whereas men are more afflicted by HF with reduced ejection fraction, leading to ventricular dilation 6 .…”

Section: Introductionmentioning

confidence: 99%

Healthy human induced pluripotent stem cell-derived cardiomyocytes exhibit sex dimorphism even without the addition of hormones

Givens,

Andebrhan,

Schmuck

et al. 2024

Preprint

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a valuable cell type for studying human cardiac health and diseasein vitro. However, it is not known whether hiPSC-CM display sex dimorphism and therefore whether sex should be incorporated as a biological variable inin vitrostudies that include this cell type. To date, the vast majority of studies that utilize hiPSC-CM do not include both male and female sex nor stratify results based on sex because it is challenging to amass such a cohort of cells. Here we generated three female and three male hiPSC-lines from adult left ventricular cardiac fibroblasts as a resource for studying sex differences inin vitrocardiac models. We used this resource to generate hiPSC-CM and maintained them in basal media without exogenous hormones. Functional assessment of CM showed enhanced calcium handling in female-derived hiPSC-CM relative to male. Bulk RNA sequencing revealed over 300 differentially expressed genes (DEG) between male and female hiPSC-CM. Some of the DEG are X and Y-linked genes and many are implicated in cardiac health and disease including potassium channels which could account for net differences in calcium handling shown here. Gene ontology analysis of DEG showed distinct differences in pathways related to cardiac pathology including cell-cell adhesion, metabolic processes, and response to ischemic stress. These findings highlight the importance of considering sex as a variable when conducting studies to evaluate aspects of human cardiac health and disease related to cardiomyocyte function.

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Sex differences in right ventricular adaptation to pressure overload in a rat model

Cited by 7 publications

References 56 publications

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

Parameter inference in a computational model of haemodynamics in pulmonary hypertension

Healthy human induced pluripotent stem cell-derived cardiomyocytes exhibit sex dimorphism even without the addition of hormones

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