Sex Hormones Are Associated with Right Ventricular Structure and Function

Ventetuolo, Corey E.; Ouyang, Pamela; Bluemke, David A.; Tandri, Harikrishna; Barr, R. Graham; Bagiella, Emilia; Cappola, Anne R.; Bristow, Michael R.; Johnson, Craig W.; Kronmal, Richard A.; Kizer, Jorge R.; Lima, João A.C.; Kawut, Steven M.

doi:10.1164/rccm.201007-1027oc

Cited by 159 publications

(81 citation statements)

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“…Yuan et al [17] have recently demonstrated an endogenous oestrogen deficiency following monocrotaline injury, leading to alterations in oestrogen receptor signalling and metabolism and a pro-proliferative, anti-apoptotic state that is rescued by exogenous oestradiol. These findings have interesting implications when considered in the context of female menopause and waning oestrogen levels, and given that our previous work demonstrated that hormone therapy use is associated with improved RV ejection fraction in healthy post-menopausal females [22]. In PAH, it is unknown whether the hormonal milieu before mid-life increases risk of disease, or perhaps favourably impacts RV adaptation and/or response to PAH therapy.…”

Section: Discussionmentioning

confidence: 88%

“…Higher levels of testosterone may be more detrimental to males compared with females, and testosterone is associated with maladaptive RV hypertrophy and fibrosis in murines and greater RV mass and volumes in an epidemiological cohort [22, 39, 40, 43, 44]. While androgen replacement in testosterone-deficient males has been studied in heart failure, a recently terminated trial of testosterone administration in aged males demonstrated an increased risk of cardiovascular events, highlighting the uncertainties that remain [45–47].…”

Section: Discussionmentioning

confidence: 99%

“…Haemodynamic and morphological parameters of RV function are important predictors of survival in PAH, and females tend to have more favourable RV indices than males [3, 8–10]. In health, males have accelerated cardiomyocyte loss with ageing, lower RV ejection fraction and larger age-related decrements in RV mass as compared with females, although age-related changes in RV function have not been studied in a large-scale manner in PAH [22, 48–50]. …”

Section: Discussionmentioning

confidence: 99%

“…In systemic cardiovascular disease, male and female risk profiles converge following the menopausal transition, and much debate has surrounded hormone therapy and the impact of sex hormones on vascular homeostasis as individuals age [19–21]. We have shown that sex hormones are associated with RV size and function in health, and that females with PAH have greater responses to endothelin receptor antagonists than males with PAH, but the association of sex with haemodynamic burden in well-phenotyped patients is unknown [22, 23]. …”

Section: Introductionmentioning

confidence: 99%

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Sex and haemodynamics in pulmonary arterial hypertension

et al. 2013

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Female sex is a risk factor for pulmonary arterial hypertension (PAH), yet females have better survival than males. We sought to determine if sex was associated with baseline haemodynamics in subjects with PAH, and whether age modified these relationships. We conducted a pooled analysis from 11 randomised trials submitted to the US Food and Drug Administration. The study sample included 1211 subjects with idiopathic PAH, 25% of whom were males, and 489 subjects with connective tissue disease-associated PAH, 13% of whom were males. After multivariable adjustment, right atrial pressure was 1.36 mmHg higher (95% CI 0.44–2.27, p=0.004), cardiac index was −0.14 L·min−1·m−2 lower (95% CI −0.23–0.04, p=0.01) and pulmonary vascular resistance was 1.23 Wood units higher (95% CI 0.18–2.27, p=0.02) in males compared with females. Younger males had 5.43 mmHg (95% CI 2.20–8.66, p=0.001) higher mean pulmonary arterial pressures than younger females, but these relationships were attenuated after age 45 years. In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure. These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex and haemodynamics in pulmonary arterial hypertension

et al. 2013

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“…Close monitoring of RV volumes and function offers the possibility for early therapeutic interventions, but the impact of such a strategy on patient outcomes has yet to be studied. Sex differences and age need to be considered during the interpretation of RV volumes and function, 70,71 and appropriate corrections for these factors may become important in future studies.…”

Section: Cardiac Mri Volumetric Measurementsmentioning

confidence: 99%

Noninvasive Imaging in the Assessment of the Cardiopulmonary Vascular Unit

et al. 2015

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899N oninvasive imaging plays a key role in both the diagnosis and management of patients with pulmonary hypertension (PH). In recent years, there have been 2 major changes in perspective of imaging in PH. The first was the realization that imaging should focus on the evaluation of not only the pulmonary pressures but also the cardiopulmonary unit ( Figure 1). 1,2The second was the emergence of multimodality imaging with a complementary role for echocardiography, magnetic resonance (MRI), computed tomography, and positron emission tomography (PET).2-7 These techniques not only help in the diagnosis of PH but also help identify factors that determine risk and prognosis and gauge therapeutic effects on right ventricular (RV) function in patients with pulmonary arterial hypertension (PAH). Although echocardiography is the mainstay in the assessment of hemodynamic and ventricular function in PH, MRI has emerged as the gold standard for quantifying volumes, function, and flow in the right side of the heart. 2-7 PET is also offering novel insights into perfusion and blood flow, metabolism, neurohormonal activation, and other molecular processes in the right side of the heart but is used mainly for research at this time. Catheterization of the right side of the heart remains the gold standard for defining PH and assessing hemodynamics both at rest and with exercise. Invasive assessment of cardiac output (CO) may, however, have limited accuracy when assumed instead of measured oxygen consumption is used to derive CO (eg, using the Fick method) or when thermodilution is used in the setting of a low-CO state. [8][9][10] This review covers RV imaging studies performed in the field of PH and discusses recent advances in echocardiography and cardiac MRI and PET imaging for detailed assessment of RV function. The review starts with a discussion of important physiological considerations and unmet needs in imaging research of the right side of the heart in PH. Computed tomography angiography, which plays an important role in evaluating chronic thromboembolic PH, is not discussed extensively in this review. Physiological ConsiderationsAlthough PH is a syndrome affecting the pulmonary vasculature, survival of patients with PH is closely related to RV function. 1,[11][12][13][14] The RV initially adapts to the increased afterload by increasing its wall thickness and contractility. These mechanisms are, however, often insufficient, and RV dysfunction eventually occurs. After the recent Fifth World Symposium on Pulmonary Hypertension, a definition of failure of the right side of the heart secondary to PH was adopted: "Right heart failure in the setting of PH can be defined as a complex clinical syndrome due to a suboptimal delivery of blood or elevated systemic venous pressure at rest or exercise as a consequence of elevated RV afterload."2 The proposed definition takes into account both the systolic and diastolic characteristics of function of the right side of the heart, as well as physiological demands such as exercise.In underst...

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Metabolomic Differences in Connective Tissue Disease–Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort

Simpson

Hemnes

Griffiths

et al. 2023

Arthritis & Rheumatology

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ObjectivePatients with connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in CTD‐PAH versus IPAH patients that might underlie these observed clinical differences.MethodsAdult subjects with CTD‐PAH (n=141) and IPAH (n=165) from the PVDOMICS (Pulmonary Vascular Disease Phenomics) Study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad‐based global metabolomic profiling of plasma samples. Subjects were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD‐PAH versus IPAH metabolomic profiles and to measure metabolite‐phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 subjects.ResultsMetabolomic profiles distinguished CTD‐PAH from IPAH, with CTD‐PAH patients demonstrating aberrant lipid metabolism, with lower circulating levels of sex steroid hormones and higher free fatty acids (FA) and FA intermediates in CTD‐PAH. Acylcholines were taken up by the right ventricular‐pulmonary vascular circulation, particularly in CTD‐PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and right ventricular measurements and with transplant‐free survival.ConclusionsCTD‐PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV‐pulmonary vascular FA metabolism may imply reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

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Sex Hormones Are Associated with Right Ventricular Structure and Function

Cited by 159 publications

References 50 publications

Sex and haemodynamics in pulmonary arterial hypertension

Sex and haemodynamics in pulmonary arterial hypertension

Noninvasive Imaging in the Assessment of the Cardiopulmonary Vascular Unit

Metabolomic Differences in Connective Tissue Disease–Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort

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