Fulvestrant for the Treatment of Pulmonary Arterial Hypertension

Kawut, Steven M.; Pinder, Diane; Al‐Naamani, Nadine; McCormick, Amber; Palevsky, Harold I.; Fritz, J.S.; Smith, K. Akaya; Mazurek, Jeremy A.; Doyle, Margaret F.; MacLean, Margaret R.; DeMichele, Angela; Mankoff, David A.

doi:10.1513/annalsats.201904-328rl

Cited by 25 publications

(28 citation statements)

References 15 publications

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“…However, due to the low number of participants, no final conclusions on the effects of fulvestrant on PAH can be drawn. Nevertheless, it was generally well tolerated (Kawut et al, 2019).…”

Section: Novel Treatment Options Targeting Specific Pathways In Pahmentioning

confidence: 99%

Current and future treatments of pulmonary arterial hypertension

Sommer

Ghofrani

Pak

et al. 2020

British J Pharmacology

124

111

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Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life-limiting illness with no prospect of cure.PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH.Abbreviations: 6MWD, 6-min walk distance; ALK1, activin receptor-like kinase 1; ANP, atrial natriuretic peptide; ASK1, apoptosis signal-regulating kinase 1, MAP3K5; Bcl-2, B-cell lymphoma 2; BMP, bone morphogenetic protein; BMPR2, bone morphogenetic protein receptor 2; BNP, brain natriuretic peptide; BRD4, bromodomain-containing protein 4; CO, cardiac output; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; DCA, dichloroacetate; DHEA, dehydroepiandrosterone; DMT, DNA methyltransferase; E2, oestradiol; ERAs, endothelin receptor antagonists; FDA, U.S. Food and Drug Administration; FHIT, fragile histidine triad; FKBP12, FK506-binding protein; FOX, forkhead box protein; HDACs, histone deacetylases; HIF, hypoxia-inducible factor; HMGB1, high mobility group box-1; IPAH, idiopathic pulmonary arterial hypertension; KCNK3, potassium channel subfamily K member 3 gene; mPAP, mean pulmonary arterial pressure; mTOR, mechanistic target of rapamycin; NAD+, nicotinamide adenine dinucleotide; NFAT, nuclear factor of activated T-cells; Nrf2, nuclear factor erythroid 2-related factor 2; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; PA, pulmonary artery; PAEC, pulmonary arterial endothelial cells; PAH, pulmonary arterial hypertension; PASMCs, pulmonary arterial smooth muscle cells; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RCT, randomised controlled trial; ROCK, Rho-associated protein kinase; RTK, receptor TK; RUNX2, runt-related transcription factor 2; RV, right ventricle; SIRT, Sirtuin; SMURF-1, Smad ubiquitin regulatory factor 1; STAT, signal transducer and activator of transcription; TGFβR, TGFβ receptor; TPH1, tryptophan hydroxylase 1; UCP2, uncoupling protein 2; VCAM1, vascular cell adhesion molecule 1; VE/VCO2, minute ventilation/carbon dioxide production; VIP, vasoactive intestinal peptide; VO2max, maximal oxygen uptake.

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“…However, due to the low number of participants, no final conclusions on the effects of fulvestrant on PAH can be drawn. Nevertheless, it was generally well tolerated (Kawut et al, 2019).…”

Section: Novel Treatment Options Targeting Specific Pathways In Pahmentioning

confidence: 99%

Current and future treatments of pulmonary arterial hypertension

Sommer

Ghofrani

Pak

et al. 2020

British J Pharmacology

124

111

View full text Add to dashboard Cite

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“…Another trial targeted estrogen signaling by investigating the utility of fulvestrant, a selective ER-α antagonist (given 500 mg intramuscularly on days 0, 14, 28, and 56; NCT02911844), in five patients. Fulvestrant did not change RV function as quantified by TAPSE (25 [18–27.5] vs. 19.5 [14.5–28.5] mm; p = 0.47; data presented as median [IQR] comparing follow-up vs. baseline measurements), RV index of myocardial performance (0.52 [0.37–0.82] vs. 0.29 [0.26–0.66]; p = 0.47), or stroke volume (62.2 [48–79.9] vs. 56 [36–73.5] mL; p = 0.07) after ~9 weeks follow-up (Kawut et al, 2019 ). Moreover, fulvestrant did not alter pulmonary vascular disease severity as assessed by RV systolic pressure (87 [40–89] vs. 86 [35–100] mmHg; p = 1.0) (Kawut et al, 2019 ).…”

Section: Targeting Sex Hormones: Previous and Ongoing Clinical Trialsmentioning

confidence: 99%

“…Fulvestrant did not change RV function as quantified by TAPSE (25 [18–27.5] vs. 19.5 [14.5–28.5] mm; p = 0.47; data presented as median [IQR] comparing follow-up vs. baseline measurements), RV index of myocardial performance (0.52 [0.37–0.82] vs. 0.29 [0.26–0.66]; p = 0.47), or stroke volume (62.2 [48–79.9] vs. 56 [36–73.5] mL; p = 0.07) after ~9 weeks follow-up (Kawut et al, 2019 ). Moreover, fulvestrant did not alter pulmonary vascular disease severity as assessed by RV systolic pressure (87 [40–89] vs. 86 [35–100] mmHg; p = 1.0) (Kawut et al, 2019 ). Thus far, these two trials have not demonstrated adverse RV effects of modulating estrogen signaling, but larger studies are needed to clarify the role of estrogen signaling in RV remodeling in PAH.…”

Section: Targeting Sex Hormones: Previous and Ongoing Clinical Trialsmentioning

confidence: 99%

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside

2021

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There are inherent distinctions in right ventricular (RV) performance based on sex as females have better RV function than males. These differences are magnified and have very important prognostic implications in two RV-centric diseases, pulmonary hypertension (PH), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In both PH and ARVC/D, RV dysfunction results in poor patient outcomes. However, there are no currently approved therapies specifically targeting the failing RV, an important unmet need for these two life-threatening disorders. In this review, we highlight human data demonstrating divergent RV phenotypes in healthy, PH, and ARVC/D patients based on sex. Furthermore, we discuss the links between estrogen (the female predominant sex hormone), testosterone (the male predominant sex hormone), and dehydroepiandrosterone (a precursor hormone for multiple sex hormones in males and females) and RV function in both disorders. To provide potential mechanistic insights into sex differences in RV function, we review data that investigate how sex hormones combat or contribute to pathophysiological changes in the RV. Finally, we highlight the ongoing clinical trials in pulmonary arterial hypertension targeting estrogen and dehydroepiandrosterone signaling. Hopefully, a greater understanding of the factors that promote superior RV function in females will lead to novel therapeutic approaches to combat RV dysfunction in PH and ARVC/D.

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“…The pro-inflammatory E2 metabolite 16-hydroxyestrone (16-OHE 1 ) as compared to the 2compounds (2-methoxyestrone [2-ME] and 2-methoxyestradiol) has been linked to cancer angioinvasion and PAH (18)(19)(20). A pilot study of the E2 receptor modulator fulvestrant reduced circulating hematopoietic progenitors and 16-hydoxyestradiol in post-menopausal women (21).…”

Section: Abstract Word Count: 250mentioning

confidence: 99%

Insights from the Menstrual Cycle in Pulmonary Arterial Hypertension

et al. 2021

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declared that no conflict of interest exists. M.W. has served as a consultant for United Therapeutics and Ximedica. C.E.V. has served as a past consultant for Acceleron Pharma, as a site PI for a clinical trial funded by Eiger Biopharmaceuticals. She has received a research grant to her institution from the CHEST Foundation Research Grant in Pulmonary Arterial Hypertension (supported by Actelion) and a research grant to her institution from United Therapeutics.

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Fulvestrant for the Treatment of Pulmonary Arterial Hypertension

Cited by 25 publications

References 15 publications

Current and future treatments of pulmonary arterial hypertension

Current and future treatments of pulmonary arterial hypertension

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside

Insights from the Menstrual Cycle in Pulmonary Arterial Hypertension

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