Browsing by Subject "Pulmonary Hypertension"

Now showing 1 - 5 of 5
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    Association of premature menopause with incident pulmonary hypertension: A cohort study
    (PLOS, 2021-03-10) Honigberg, Michael C.; Patel, Aniruddh P.; Lahm, Tim; Wood, Malissa J.; Ho, Jennifer E.; Kohli, Puja; Natarajan, Pradeep; Medicine, School of Medicine
    Background: Several forms of pulmonary hypertension (PH) disproportionately affect women. Animal and human studies suggest that estradiol exerts mixed effects on the pulmonary vasculature. Whether premature menopause represents a risk factor for PH is unknown. Methods and findings: In this cohort study, women in the UK Biobank aged 40-69 years who were postmenopausal and had complete data available on reproductive history were included. Premature menopause, defined as menopause occurring before age 40 years. Postmenopausal women without premature menopause served as the reference group. The primary outcome was incident PH, ascertained by appearance of a qualifying ICD code in the participant's UK Biobank study record. Of 136,715 postmenopausal women included, 5,201 (3.8%) had premature menopause. Participants were followed up for a median of 11.1 (interquartile range 10.5-11.8) years. The primary outcome occurred in 38 women (0.73%) with premature menopause and 409 (0.31%) without. After adjustment for age, race, ever-smoking, body-mass index, systolic blood pressure, antihypertensive medication use, non-high-density lipoprotein cholesterol, cholesterol-lowering medication use, C-reactive protein, prevalent type 2 diabetes, obstructive sleep apnea, heart failure, mitral regurgitation, aortic stenosis, venous thromboembolism, forced vital capacity (FVC), the forced expiratory volume in 1 second-to-FVC ratio, use of menopausal hormone therapy, and hysterectomy status, premature menopause was independently associated with PH (hazard ratio 2.13, 95% CI 1.31-3.23, P<0.001). In analyses of alternate menopausal age thresholds, risk of PH appeared to increase progressively with younger age at menopause (Ptrend <0.001), with 4.8-fold risk in women with menopause before age 30 years (95% CI 1.82-12.74, P = 0.002). Use of menopausal hormone therapy did not modify the association of premature menopause with PH. Conclusions: Premature menopause may represent an independent risk factor for PH in women. Further investigation of the role of sex hormones in PH is needed in animal and human studies to elucidate pathobiology and identify novel therapeutic targets.
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    Beet-ing Muscle Dysfunction and Exercise Intolerance in Pulmonary Hypertension
    (2019-10) Long, Gary Marshall; Coggan, Andrew R.; Brown, Mary Beth; Lahm, Tim; Avin, Keith; Arnold, Brent
    Background: Pulmonary Hypertension (PH) is a devastating disease characterized by pulmonary arterial remodeling, right ventricular dysfunction and ultimately right heart failure. Increased emphasis has been given to skeletal muscle dysfunction in PH, and to its implication in the severe exercise intolerance that is a hallmark of the condition. In this dissertation, skeletal muscle blood flow was measured via the microsphere technique at rest and during exercise (Aim 1), with an acute dose of dietary nitrate via beetroot juice (BRJ) gavage used to determine if supplementation could improve muscle blood flow and alter energetics (Aim 2). VO2max, voluntary running and grip strength tests were used to determine the effect of disease on performance, and to test for an ergogenic effect of BRJ vs. placebo (PL) in healthy and PH rats (Aim 3). Methods: A prospective, randomized, counterbalanced, placebo-controlled trial was used to examine the aforementioned aims across four groups; PH rats (induced with monocrotaline, MCT, 60mg/kg, s.q., 4 weeks) supplemented with BRJ (MCT BRJ, n=9); PH rats supplemented with placebo (MCT PL, n=9); healthy control rats (vehicle, s.q.) supplemented with BRJ (CON BRJ, n=8); healthy control rats supplemented with placebo (CON PL, n=9). Results: Monocrotaline induced a severe PH phenotype evidenced by increased RV wall thickness, RV hypertrophy, RVSP and reduced cardiac output and stroke volume compared to controls (p=<0.001). MCT rats demonstrated lower muscle blood flow at rest, and more prominently during exercise compared to controls (p=0.007-0.047), regardless of supplementation. MCT rats displayed a greater reliance on anaerobic metabolism, demonstrated by increased blood lactate accumulation (p=<0.001), and this was significantly related to reduced blood flow during exercise (r=-0.5879, p=0.001). BRJ supplementation resulted in increased plasma nitrate and nitrite compared to PL (p=<0.001), but at the skeletal muscle level, only nitrate was increased after BRJ. BRJ did not have a significant effect on blood flow, with no improvement during exercise shown vs. PL. Similarly, BRJ did not significantly improve exercise function in MCT or CON rats. Conclusion: MCT rats demonstrated a reduction in muscle blood flow, with BRJ supplementation not resulting in improved flow or exercise performance.
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    The effect of hypoxia on ER-β expression in the lung and cultured pulmonary artery endothelial cells
    (2014-03-12) Selej, Mona M.A.; Lahm, Tim; Petrache, Irina; Schweitzer, Kelly S.
    17-β estradiol (E2) exerts protective effects in hypoxia-induced pulmonary hypertension (HPH) via endothelial cell estrogen receptor (ER)-dependent mechanisms. However, the effects of hypoxia on ER expression in the pulmonary-right ventricle (RV) axis remain unknown. Based on previous data suggesting a role of ER-β in mediating E2 protection, we hypothesized that hypoxia selectively up-regulates ER-β in the lung and pulmonary endothelial cells. In our Male Sprague-Dawley rat model, chronic hypoxia exposure (10% FiO2) resulted in a robust HPH phenotype associated with significant increases in ER- β but not ER-α protein in the lung via western blotting. More importantly, this hypoxia-induced ER-β increase was not replicated in the RV, left ventricle (LV) or in the liver. Hence, hypoxia-induced ER-β up-regulation appears to be lung-specific. Ex vivo, hypoxia exposure time-dependently up-regulated ER-β but not ER-α in cultured primary rat pulmonary artery endothelial cells (RPAECs) exposed to hypoxia (1% O2) for 4, 24 or 72h. Furthermore, the hypoxia induced ER-β protein abundance, while not accompanied by increases in its own transcript, was associated with ER-β nuclear translocation, suggesting increase in activity as well as post-transcriptional up-regulation of ER-β. Indeed, the requirement for ER-β activation was indicated in hypoxic ER-βKO mice where administration of E2 failed to inhibit hypoxia-induced pro-proliferative ERK1/2 signaling. Interestingly, HIF-1α accumulation was noted in lung tissue of hypoxic ER-βKO mice; consistent with previously reported negative feedback of ER-β on HIF-1α protein and transcriptional activation. In RAPECs, HIF-1 stabilization and overexpression did not replicate the effects of ER- β up-regulation seen in gas hypoxia; suggestive that HIF-1α is not sufficient for ER-β up- regulation. Similarly, HIF-1 inhibition with chetomin did not result in ER-β down-regulation. HIF-1α knockdown in RPAECs in hypoxic conditions is currently being investigated. Hypoxia increases ER- β, but not ER-α in the lung and lung vascular cells. Interpreted in context of beneficial effects of E2 on hypoxic PA and RV remodeling, our data suggest a protective role for ER-β in HPH. The mechanisms by which hypoxia increases ER-β appears to be post-transcriptional and HIF-1α independent. Elucidating hypoxia-related ER-β signaling pathways in PAECs may reveal novel therapeutic targets in HPH.
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    Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure
    (Wiley, 2020-01-01) Hester, James; Ventetuolo, Corey; Lahm, Tim; Medicine, School of Medicine
    Pulmonary hypertension (PH) encompasses a syndrome of diseases that are characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling and that frequently lead to right ventricular (RV) failure and death. Several types of PH exhibit sexually dimorphic features in disease penetrance, presentation, and progression. Most sexually dimorphic features in PH have been described in pulmonary arterial hypertension (PAH), a devastating and progressive pulmonary vasculopathy with a 3-year survival rate <60%. While patient registries show that women are more susceptible to development of PAH, female PAH patients display better RV function and increased survival compared to their male counterparts, a phenomenon referred to as the “estrogen paradox” or “estrogen puzzle” of PAH. Recent advances in the field have demonstrated that multiple sex hormones, receptors, and metabolites play a role in the estrogen puzzle and that the effects of hormone signaling may be time and compartment specific. While the underlying physiological mechanisms are complex, unraveling the estrogen puzzle may reveal novel therapeutic strategies to treat and reverse the effects of PAH/PH. In this article, we (i) review PH classification and pathophysiology; (ii) discuss sex/gender differences observed in patients and animal models; (iii) review sex hormone synthesis and metabolism; (iv) review in detail the scientific literature of sex hormone signaling in PAH/PH, particularly estrogen-, testosterone-, progesterone-, and dehydroepiandrosterone (DHEA)-mediated effects in the pulmonary vasculature and RV; (v) discuss hormone-independent variables contributing to sexually dimorphic disease presentation; and (vi) identify knowledge gaps and pathways forward.
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    Studying the Effect of TBX4 Loss-of-Function on Postnatal Lung Development and How it Predisposes to Pulmonary Hypertension
    (2024-07) Maldonado Velez, Gabriel; Aldred, Micheala A.; Machado, Roberto F.; Tepper, Robert S.; Wek, Ronald C.; White, Kenneth E.
    The term pulmonary hypertension (PH) describes a heterogeneous group of pulmonary and cardiovascular disorders and is estimated to affect 1% of the global population. The World Symposium on Pulmonary Hypertension divides patients into a five-tier classification system based on etiology and clinical findings with the aim of improving the clinical approach to patients. Group 1 PH, also known as pulmonary arterial hypertension, is a rare form of the disease with a prevalence of 15-50 cases per one million individuals. Deleterious variants within the bone morphogenetic protein receptor type 2 (BMPR2) gene are found in approximately 70-80% of the cases. However, at least twelve additional genes are known to have a definitive gene-disease relationship with PAH, including T-box 4 (TBX4). Genetic predisposition may also contribute to group 3 PH, also known as PH due to chronic lung disease or hypoxia. Heterozygous pathogenic variants within TBX4 have been reported in cases from both PH groups. Therefore, the diagnosis and classification of PH in patients with TBX4 mutations may be more challenging due to its contributions to the pathogenesis of both groups. For a decade, deleterious variants or large mutations involving TBX4 have been reported throughout the literature, but more progress has yet to be made toward understanding the mechanisms underlying the pathogenesis of PH in those patients. Therefore, in this project, using mouse genetics, we sought to disrupt Tbx4 expression and investigate if there is consistency with the diseases observed in humans. We found that Tbx4 mutant lungs have increasing alveolar simplification as confirmed by mean linear intercept (MLI) at P14 (25%), P36 (31.7%), and P180 (49.5%). The lungs also have reduced vascularization as indicated by a 39.4% reduction in the number of vWF-positive vessels. Consistent with PH, mutant mice have higher RVSP (19.4%), vascular remodeling, and mild right ventricular hypertrophy (RVH). RNA sequence analyses revealed enrichment of pathways (canonical WNT, VEGF, and BMP signaling) and genes (Lgr5, Tnc, Wnt3a, Areg, Gdf2, and Bmper) relevant to lung alveologenesis, angiogenesis, and PH. This study contributes significant knowledge that clinicians can use to diagnose, classify, and treat patients with TBX4 mutations.