Title: Repurposing Medications for Treatment of Pulmonary Arterial Hypertension: What's Old Is New Again
Abstract: HomeJournal of the American Heart AssociationVol. 8, No. 1Repurposing Medications for Treatment of Pulmonary Arterial Hypertension: What's Old Is New Again Open AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessResearch ArticlePDF/EPUBRepurposing Medications for Treatment of Pulmonary Arterial Hypertension: What's Old Is New Again Kurt W. Prins, MD, PhD, Thenappan Thenappan, MD, E. Kenneth Weir, MD, Rajat Kalra, MBChB, Marc Pritzker, MD and Stephen L. Archer, MD Kurt W. PrinsKurt W. Prins Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN , Thenappan ThenappanThenappan Thenappan Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN , E. Kenneth WeirE. Kenneth Weir Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN , Rajat KalraRajat Kalra Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN , Marc PritzkerMarc Pritzker Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN and Stephen L. ArcherStephen L. Archer Department of Medicine, Queen's University, Kingston, ON Originally published28 Dec 2018https://doi.org/10.1161/JAHA.118.011343Journal of the American Heart Association. 2019;8:e011343IntroductionPulmonary arterial hypertension (PAH) is a rare but lethal disorder caused by several pathological changes in the pulmonary vasculature. There is endothelial cell dysfunction characterized by exaggerated secretion of vasoconstrictive, pro‐proliferative substances, such as endothelin, and impaired release of vasodilatory, antiproliferative molecules, such as nitric oxide and prostacyclin.1 This imbalance contributes to increases in pulmonary artery (PA) smooth muscle cell (PASMC) tone and proliferation.1 Moreover, endothelial cells exhibit metabolic reprogramming with a switch to anaerobic glycolysis.4 In PASMCs, there is evidence of hypercontractility,5 proliferation and apoptosis resistance due to genetically6 and epigenetically8 controlled mechanisms, calcium mishandling,9 metabolic reprogramming,5 and abnormal mitochondrial dynamics.13 Mitochondrial metabolic reprogramming, creating a Warburg metabolic phenotype that promotes proliferation, is also observed in pulmonary vascular fibroblasts.15 Extracellular matrix (ECM) remodeling promotes PAH by increasing vessel stiffness and thereby altering signaling pathways and inducing metabolic derangements through mechanotransduction.3 Finally, there is evidence of a significant inflammatory response with T cell, B cell, and dendritic cell infiltration into the pulmonary vasculature20 and elevated levels of circulating inflammatory cytokines.20 These molecular, cellular, and histological changes manifest as reduced pulmonary arterial compliance24 and elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressures25 that, in aggregate, augment the workload of the right ventricle.26 As PAH progresses, the heightened demands on the right ventricle lead to right ventricular hypertrophy (RVH), fibrosis, and metabolic derangements that often culminate in RV failure.27 RV dysfunction is the strongest predictor of mortality in PAH28 and is the major reason that the median survival with PAH is only 5 to 7 years, both in registries30 and in population‐based studies.33Although there have been significant gains in the understanding of the pathophysiology of PAH in recent years, advances in PAH therapeutics have not kept pace, and many promising basic science discoveries have not been tested in patients. Approved PAH medications are predominately pulmonary vasodilators that modulate the endothelin, nitric oxide, and prostacyclin pathways.34 These therapies primarily address the vasoconstrictive phenotype of PAH, which is the predominant feature in only 5% to 10% of patients35 or those patients deemed vasoresponders.36 Although current medications provide benefits to nearly all PAH patients even if they are not vasoresponders, they were approved because they significantly increase exercise capacity (6‐minute walk distance [6MWD]), improve quality of life, and/or reduce morbidity37; however, only epoprostenol confers a clear survival benefit.46 Consequently, there is an urgent need to develop novel, effective therapies that target additional molecular pathways that drive the pathogenesis of PAH in order to supplement our current treatment options with the hopes of accelerating progress toward a cure.The strategy of expanding the PAH pharmacopeia by repurposing medications that are used as therapy for other medical conditions is attractive because it may accelerate the development of new therapies and reduce the costs associated with new drug discovery for this orphan disease. In PAH, this consideration is important because, worldwide, many PAH patients do not even have access to currently approved therapies,47 so discovery of an inexpensive treatment option would very likely have a significant global impact. Available drugs have established safety profiles, so the considerable time and money required to exclude common toxicities and to demonstrate tolerability and safety can be reduced. Nevertheless, even for available agents, the need to confirm dosing and to establish the disease‐specific adverse effect profiles cannot be circumvented. Experience suggests that PAH patients may be either more or less sensitive to many drugs. For example, PAH patients require higher doses of calcium channel blockers than do patients with angina pectoris due to coronary artery disease.48 Conversely, PAH patients cannot tolerate the equivalent dose of the tyrosine kinase inhibitor sorafenib49 that cancer patients do. Nonetheless, repurposing has been effectively implemented in PAH. Sildenafil, a phophodisesterase type 5 inhibitor used for erectile dysfunction,50 was first tested in an acute treatment protocol in 13 pulmonary hypertension patients and provided a favorable hemodynamic response. Sildenafil administration led to a decrease in mean pulmonary arterial pressure (mPAP) and PVR and an increase in cardiac index.51 Then, a small placebo‐controlled crossover trial conducted in 22 PAH patients showed that sildenafil (dose: 25–100 mg, 3 times/day) increases exercise capacity and cardiac index, calculated using echocardiography, and improves quality of life.52 These findings provided biological plausibility for the SUPER (Sildenafil Use in Pulmonary Arterial Hypertension) trial, which documented significant increases in 6MWD and reductions in mPAP and PVR after 12 weeks of sildenafil treatment.40 These findings ultimately led to US Food and Drug Administration approval of sildenafil for PAH.Preclinical research has identified many molecular pathways that contribute to pathological pulmonary vascular remodeling and RV dysfunction in PAH that have yet to be exploited therapeutically. mutations in BMPR2 (bone morphogenic protein receptor 2), for example, are associated with hereditable PAH,6 and the BMPR2 pathway is downregulated in diverse rodent models of PAH53; however, no current therapy targets BMPR2. Multiple mechanisms contribute to impaired BMPR2 signaling including inflammation‐mediated dysregulation,55 estrogen‐induced suppression,57 autophagosomal degradation,58 and impaired membrane trafficking of the protein.59 When these mechanisms are targeted in preclinical studies, BMPR2 signaling is partially restored and reductions in pulmonary vascular disease severity are observed.60 Moreover, the cancer‐like,61 autoimmune/inflammatory,20 and Warburg metabolic phenotypes4 that promote vascular obstruction and fibrosis caused by increased proliferation and impaired apoptosis of PASMCs,12 endothelial cells,4 and fibroblasts15 can also be inhibited to halt or even reverse pulmonary hypertension in animal studies, and yet none of these pathways are exploited by approved PAH‐targeted therapies. Another untapped target in PAH is the right ventricle, where ischemia and fibrosis, relating to impaired angiogenesis and a Warburg metabolic phenotype, contribute to RV dysfunction.65 Importantly, the metabolic changes and the related RV dysfunction can be partially reversed via pharmacological intervention.65 Moreover, in the RV cardiomyocyte, microtubule remodeling causes mistrafficking and dysregulation of JPH2 (junctophilin 2) and subsequent pathological t‐tubule remodeling. This pathway can be rectified with colchicine, suggesting a novel therapeutic target to improve RV function.67 These are just a few of the numerous molecular pathways in both the pulmonary vasculature and the right ventricle that could be targeted to expand the PAH pharmacopeia to improve outcomes for PAH patients.In this review, we discuss and evaluate the rigor of the preclinical data that support the notion that 22 medications could potentially be used to target molecular mechanisms involved in the pathogenesis of pulmonary vascular remodeling and RV dysfunction in PAH. We highlight currently available drugs that have clinical safety profiles with preclinical evidence of physiological changes at the whole‐animal level. We also discuss the available data from completed and ongoing exploratory clinical trials that are attempting to translate the information gleaned from animal models into therapy for PAH patients. Hopefully, this strategy will more rapidly fill the pipeline of drugs for PAH by identifying new agents that can potentially ameliorate or even cure this orphan disease. Repurposing medications may realize benefits for patients by accelerating the flow of ideas from the bench to the bedside.Aldosterone AntagonistsAldosterone is a steroid hormone that binds mineralocorticoid receptors, which are present in multiple tissues, including the heart and pulmonary vasculature. Aldosterone alters gene regulation and promotes a wide array of physiological effects including sodium and water retention, cardiac fibrosis, and activation of the sympathetic nervous system.68 The broad distribution of mineralocorticoid receptors and diverse physiological effects underlies the use of aldosterone antagonists for several clinical indications, including left‐sided systolic heart failure,70 systemic hypertension,72 and refractory ascites in cirrhotic patients.73 Aldosterone antagonists are generally well tolerated. The most important adverse effect is hyperkalemia, which is more frequently observed in patients also treated with an angiotensin‐converting enzyme inhibitor74 or in patients with chronic kidney disease.75 Finally, gynecomastia occurs in 6.9% to 10% of patients and can be painful and esthetically problematic in men.68 However, eplerenone, a newer aldosterone antagonist, does not cause gynecomastia and is effective in treating left heart failure.71Contributing to the biological plausibility of targeting aldosterone in PAH, serum aldosterone levels are elevated in PAH patients and correlate with hemodynamic measures of pulmonary vascular disease. In a study that compared 5 controls with 20 PAH patients, serum levels of aldosterone were significantly higher in PAH patients (control versus PAH: 1200±424 versus 5959±2818 pg/mL, P<0.02).76 Moreover, serum aldosterone levels were positively correlated with PVR (r=0.72, P<0.02) and transpulmonary gradient (r=0.69, P<0.02) and inversely correlated with cardiac output (r=−0.79, P<0.005).76 Likewise, plasma and lung aldosterone levels are elevated in the monocrotaline rat (MCT rat) model of PAH.77In PAH, increased serum aldosterone levels dampen activation of nitric oxide synthase in endothelial cells,77 promote adverse ECM remodeling in response to hypoxia in endothelial cells,78 and stimulate PASMC proliferation.79 Finally, aldosterone increases expression of the transcription factor Nedd9 (neural precursor cell expressed developmentally downregulated 9) via inhibition of proteolytic degradation in endothelial cells. Nedd9 then transcriptionally activates COL3A1 (collagen type III alpha 1 chain)80 to further promote ECM remodeling.The preclinical data supporting the use of aldosterone antagonists to counteract mineralocorticoid pathway activation to combat pulmonary vascular disease are robust. Aldosterone negatively regulates endothelin B receptor–mediated nitric oxide production in pulmonary endothelial cells. Aldosterone increases production of reactive oxygen species, which oxidize endothelin receptor B at cysteine 405, an amino acid that lies in the endothelin nitric oxide synthase activating region of the receptor. The oxidation of endothelin receptor B reduces nitric oxide production77 (Figure 1). Treatment of rats with monocrotaline‐PAH with the aldosterone antagonist spironolactone (25 mg/kg per day) beginning at the time of monocrotaline injection increases nitric oxide levels in lung extracts and blunts development of adverse pulmonary vascular remodeling.77 In a reversal study, spironolactone (25 mg/kg per day) given 14 days after monocrotaline injection significantly reduced PA systolic pressure and PVR index.77 Eplerenone also slows the development of pulmonary vascular disease. Eplerenone (0.6 mg/g chow), initiated concurrently with exposure to hypoxia (O2 tension 76 mm Hg for 21 days) in the Sugen‐5416 (SU‐5416) hypoxia rat model, reduces PA systolic pressure.77Download figureDownload PowerPointFigure 1 Spironolactone, allopurinol, DHEA, and rosiglitazone combat oxidative stress. DHEA indicates dehydroepiandrosterone; eNOS, endothelial nitric oxide synthase; ET, Endothelin‐b receptor; Nox4, NADPH oxidase 4.Another pathological mechanism by which excess aldosterone promotes pulmonary vascular disease is ECM remodeling. In human PA endothelial cells, hypoxia enhances c‐Fos/c‐Jun binding to the proximal AP1 (activator protein 1) site of the promoter region of StAR (steroidogenic acute regulatory protein) and increases StAR expression.78 StAR promotes aldosterone synthesis, which in turn induces transcription of CTGF (connective tissue growth factor), collagen III, and MMP2 (matrix metalloprotease 2) and MMP9.78 In a series of in vivo experiments distinct from those described in the previous paragraph, treatment of SU‐5416 hypoxia rats with eplerenone (0.6 mg/g chow for 21 days) starting at the time of SU‐5416 injection reduces CTGF and collagen III levels in the pulmonary vasculature and lessens the severity of experimental PAH.78 In a reversal study, spironolactone (25 mg/kg per day) given 14 days after SU‐5416 for 7 days at hypoxia and continued for 16 to 17 days in normoxia reduces RVH, mPAP, and right atrial pressure.78Aldosterone also promotes PASMC proliferation. Aldosterone increases the abundance of phosphorylated p70S6K (70‐kDa ribosomal S6 kinase), the active form of the major downstream effector kinase of mTORC1 (mammalian target of rapamycin complex 1), through a mechanism dependent on both Akt79 and the mTORC1 subunit Raptor79 in cultured PASMCs. The activation of mTORC1 promotes proliferation and apoptosis resistance of cultured PASMCs (Figure 2).79 When administered in a preventative manner, spironolactone reduces phosphorylated p70S6K expression in the pulmonary vasculature in MCT rats.79 Furthermore, combining spironolactone and a small interfering RNA targeting Raptor prevents pulmonary vascular remodeling in MCT rats.79 In a regression protocol, spironolactone plus small interfering RNA to Raptor reverses pulmonary hypertension in SU‐5416 hypoxia rats.79 Using a scoring system modified from Provencher et al,81 the scientific rigor score is 4 (Table 1) for the preclinical data supporting the use of aldosterone in PAH.Download figureDownload PowerPointFigure 2 Multiple pathways can be inhibited to alter the proliferation/apoptosis balance of pulmonary artery smooth muscle cells. Bcl‐2 indicates B cell lymphoma 2; BRD‐4, bromodomain‐containing protein 4; FOXO1, forkhead box protein O1; MAPK, mitogen‐activated protein kinases; mTORC, mammalian target of rapamycin complex; NFATC2, nuclear factor of activated T cells 2; P, phosphorylation; Parp‐1, poly(ADP‐ribose) polymerase 1; PDGF, platelet derived growth factor; PPAR‐γ, peroxisome proliferator‐activator‐γ; STAT3, signal transducer and activator of transcription 3; TNF‐α, tumor necrosis factor‐α.Table 1 Numerical Score of Preclinical Rigor of Potentially Repurposed MedicationsDrugNumber of PAH Models UsedRegression EvaluatedaHuman Tissue/Cells EvaluatedaRandomization SpecifiedaPower CalculationaMultiple Publications Demonstrating EfficacyaMale and Female SexaLong‐Term Safety EvaluationaTotal ScoreAldosterone antagonist211001005Allopurinol100001002Anakinrab200000002Anastrozole411000107Apabetalone111100004β‐Adrenergic blockers210001004Chloroquine110000002Colchicine110001003DHEA311001005Dichloroacetate5111011111Metformin411001108Nab‐rapamycin210101106Olaparib211100005Paclitaxel211000004Ranolazine210001004Rituximabb110000002Rosiglitazone/pioglitazone411001108Tacrolimus311000005Tocilizumab211000004Trimetazidine110000002TNF‐α inhibitor211111007Verteporfin101000002DHEA indicates dehydroepiandrosterone; PAH, pulmonary arterial hypertension; TNF‐α, tumor necrosis factor α.a1 = yes, 0 = no.bIndicates a molecule with similar mechanism of action was used in preclinical studies.The impact of spironolactone in PAH is currently being investigated in 2 ongoing clinical trials. The CAPS‐PAH (Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study) is a single‐center, double‐blind, placebo‐controlled, crossover study that will investigate whether addition of spironolactone to ambrisentan alters exercise capacity in 30 PAH patients (ClinicalTrials.gov identifier NCT02253394). PAH patients on ambrisentan for >90 days who are New York Heart Association (NYHA) functional class II or III will be randomized to 50 mg of spironolactone daily or placebo for 90 days and then will undergo testing. After a 21‐day washout period, patients will cross over to the other arm for another 90 days of treatment, followed by a repeat assessment. The primary end points are change in 6MWD and maximal oxygen consumption. Secondary outcomes will include estimated cardiac output and RV function using echocardiography, biomarkers of RV failure (NT‐pro‐BNP [N‐terminal probrain natriuretic protein], IL6 [interleukin 6], troponin, and collagen III), and quality of life.Concurrently, a multicenter, double‐blind, randomized, placebo‐controlled trial will also examine whether treatment with spironolactone alters outcomes in 70 PAH patients (ClinicalTrials.gov identifier NCT01712620). Patients in NYHA functional classes I to III who are either on stable PAH‐specific vasodilator therapy for 4 weeks or treatment‐naïve before enrollment will be randomized to placebo or spironolactone (25 mg daily for 7 weeks and, if tolerated, increased to 50 mg daily during week 8). The study will last for 24 weeks with the primary end points being change in 6MWD and clinical worsening. Secondary end points will include change in placebo‐corrected maximal oxygen consumption, RV function (quantified by cardiac magnetic resonance imaging [MRI]), and markers of inflammation. Finally, discontinuation rates due to adverse effects including hyperkalemia and gynecomastia will be recorded.In summary aldosterone antagonists could combat endothelial dysfunction, prevent ECM remodeling, and slow PASMC proliferation in PAH. The 2 ongoing clinical trials will determine whether aldosterone antagonists are tolerable and effective in PAH.AllopurinolOxidative stress, including an increase in reactive oxygen species formation, is implicated in the pathogenesis of pulmonary vascular remodeling.82 Xanthine oxidase catalyzes the transformation of hypoxanthine to xanthine and then to uric acid with the associated production of 4 superoxide anions.83 Thus, xanthine oxidase is potentially a major regulator of cellular oxidative stress (Figure 1).84 A pathological role for xanthine oxidase in PAH is suggested in several human studies. In a study of 99 PAH patients, the natural logarithmic transformation of serum uric acid is positively correlated with right atrial pressure (r=0.64, P<0.001).85 Higher serum levels of uric acid are associated with lower 6MWD and higher mortality in a study of 29 PAH patients.86 Furthermore, xanthine oxidase activity is elevated in the serum of PAH patients compared with control participants (5201±2836 [n=31] versus 2424±1419 [n=6] arbitrary units, P=0.026).87 In lung extracts of PAH patients, expression of the oxidative stress markers 8‐hydroxyguanosine and nitrotyrosine are increased.88 Mass spectrometry reveals elevated levels of 5‐hydroxyeicosatetraenoic acid, the oxidized product of 5‐oxo‐eicosatetraenoic acid, in lungs of PAH patients who had not been treated with prostacyclin.88 Moreover, expression of the antioxidant enzyme SOD2 (superoxide dismutase), which catalyzes breakdown of superoxide anion to the less toxic H2O2,89 is reduced in PAH lungs.88 SOD2 downregulation (in PAH patients and experimental PAH) was independently confirmed and shown to result from an epigenetic mechanism mediated by DNMT1 (DNA methyltransferase 1) and DNMT3b. Methylation of the promoter of the SOD2 gene reduces SOD2 protein levels and decreases H2O2, which activates HIF‐1α (hypoxia‐inducible factor 1α), creating a state of pseudohypoxia (normal oxygen tension but activation of hypoxic signaling pathways).8 Interestingly, this pathological process can be reversed by the DNMT inhibitor decitabine, which is used to treat patients with myelodysplastic disorders.90Allopurinol, a xanthine oxidase inhibitor, is used to prevent gout91 and nephrolithiasis caused by hyperuricosuria.92 Allopurinol is well tolerated for extended periods under these conditions. However, renal dysfunction increases the risk of side effects including gastrointestinal discomfort, lung toxicity, epidermolysis syndrome, and hypersensitivity syndrome.93 Two preclinical studies have examined the utility of allopurinol in pulmonary vascular disease.Rats exposed to hypoxia (10% oxygen for 7 or 21 days) have elevated levels of PCOOH (phosphatidylcholine hydroperoxide), a marker of oxidative stress that reflects increased xanthine oxidase activity.94 Treating hypoxic rats with allopurinol (50 mg/kg every 12 hours starting the day before hypoxia exposure) decreases PCOOH levels and blunts adverse pulmonary vascular remodeling and reduces RVH.94 Likewise, neonatal rats exposed to hypoxia (13% O2 from birth for 14 days) have increased serum and lung xanthine oxidase activity,95 and allopurinol (50 mg/kg per day starting the first day of hypoxia) normalizes xanthine oxidase activity and reduces RVH and adverse pulmonary vascular remodeling.95No clinical trials are currently investigating the use of allopurinol in PAH. The ease of administration and favorable side‐effect profile suggests that a trial of allopurinol in PAH is feasible. However, human doses would need to be much lower than those used in rodent studies (Table 2),96 and the rigor of the preclinical studies is low, with a score of 2 (Table 1).Table 2 Summary of Preclinical Results of Potentially Repurposed Drugs for PAHDrugMechanism of ActionDownstream ConsequenceIn Vivo EffectsAnimal Model UsedAnimal Model DoseEquivalent Human DoseaMaximal Daily Dose in Clinical PracticeAldosterone antagonistInhibition of aldosterone signaling1. Increased nitric oxide levels in the PV2. Reduced ECM remodeling in the PV3. Inhibition of mTORC1 signaling leading to reduced PASMC proliferation1.Blunted PV remodeling2. Reduced RVHMCTSU‐5416 hypoxiaSpironolactone (25 mg/kg/d)Eplerenone (0.6 mg/g chow)Spironolactone: 4.0 mg/kg/dEplerenone: 0.1 mg/g foodSpironolactone: 200 mgEplerenone: 100 mgAllopurinolXanthine oxidase inhibitor1. Reduced PCOOH levels2. Normalization of xanthine oxidase activity3. Reduction in overall oxidative stress1.Blunted PV remodeling2. Reduced RVHHypoxic adult and neonatal rats50 mg/kg/d50 mg/kg every 12 h8.1 mg/kg/d8.1 mg/kg every 12 h300 mgAnakinraBlock inflammatory cytokine IL11. Reduced IL1 mRNA in lungs2. Reduced macrophage infiltration into pulmonary vasculature1. Blunted PV remodeling in MCT rats2. Reduced RVH in MCT ratsMCTHypoxiaAnakinra not used in preclinical studyAnakinra not used in preclinical study100 mgAnastrozoleInhibitor of estrogen signaling1. Increased BMPR2 signaling2. Increased expression of PPAR‐γ3. Increased expression of CD364. Increased insulin sensitivity5. Reduction in PASMC proliferation1. Blunted PV remodeling2. Reduced RVHHypoxic ratsHypoxic miceSU‐5416 hypoxiaBMPR2 R899X mice0.03–3 mg/kg/d0.005–0.5 mg/kg/d1 mgApabetalonebBRD‐4 inhibitor1. Reduced levels of oncogenic proteins NFATC2, Bcl‐2, and survivin2. Increased expression of p213. Reduction in PASMC proliferation1. Blunted PV remodeling2. Reduced RVHSU‐5416 hypoxiaApabetalone not used in preclinical studyApabetalone not used in preclinical study300 mgβ‐Adrenergic blockersCounteract excessive sympathetic nervous system activation in right ventricle and pulmonary vasculature1. Normalization of β‐adrenergic signaling in the right ventricle2. Increased SERCA2a mRNA levels1. Blunted PV remodeling2. Decreased RV fibrosis3. Improved RV function4. Augmented exercise capacity5. Improved survivalMCT,SU‐5416 hypoxiaArotinolol (0.25 mg/kg/d)Bisoprolol (10 mg/kg/d)Carvedilol (15 mg/kg/d)Arotinolol (0.04 mg/kg/d)Bisoprolol (1.6 mg/kg/d)Carvedilol (2.4 mg/kg/d)Arotinolol: NA,Bisoprolol: 10 mgCarvedilol: 100 mgChloroquineInhibitor of lysosomal degradation1. Increased BMPR2 signaling via reduction in lysosomal degradation2. Reduction in PASMC proliferation1. Blunted PV remodeling2. Reduced RVHMCT50 mg/kg/d8.1 mg/kg/d2.3 mg/kgColchicineAnti‐inflammatory and normalization of JPH2 levels via microtubule depolymerization1. Reduction in PASMC proliferation2. Restoration of structure and function of T‐tubules in RV cardiomyocytes1. Reduced PV remodeling2. Reduced RVH3. Improved RV function4. Enhanced exercise capacityMCT1.0 mg/kg/d for 5 d0.5 mg/kg 3 times/wk0.16 mg/kg for 5 d0.08 mg/kg 3 times/wk2.4 mgDHEAInhibits STAT3 which reduces NFATC2 and survivn and increases BMPR21. Reduction in PASMC proliferation2. Increased PASMC apoptosis3. Increased BMPR2 signaling1. Reduced PV remodeling2. Reduced RVH3. Improved RV function4. Enhanced exercise capacityMCT,SU‐5416 hypoxia10 mg/kg/d30 mg/kg every other day1% in food1.6 mg/kg/d4.8 mg/kg every other day0.16% in food100 mgDichloroacetateCounteract Warburg metabolic effect via PDK inhibition1. Improved glucose oxidation2. Reduced PASMC proliferation3. Increased PASMC apoptosis4. Increased potassium channel levels5. Depolarization of mitochondria1. Reduced PV remodeling2. Improved RV function3. Enhanced RV contractility4. Reduced RVH5. Increased exercise capacity6. Improved survivalHypoxic ratsMCTSU‐5416FHRPAB rats70–80 mg/kg/d0.75 g/L drinking water11.3–12.9 mg/kg/d0.12 g/L of drinking water25 mg/kgMetforminInhibitor of MAPK activation, inhibitor of aromatase transcription, augments AMP activation1. Reduced PASMC proliferation2. Reduced PASMC contractility3. Reduced RV lipid deposition1. Reduced PV remodeling2. Reduced RVHHypoxic ratsMCTSU‐5416 hypoxiaBMPR2 R899X100 mg/kg/d25 g/kg of high‐fat chow16.1 mg/kg /d4.0 g/kg chow2550 mgNab‐rapamycinInhibitor of mTORC1 and mTORC21. Reduced PASMC proliferation2. Increased PASMC apoptosis1. Reduced PV remodeling (dose dependent)2. Reduced RVH (dose dependent)MCTHypoxic miceNab‐rapamycin not used in preclinical studyNab‐rapamycin not used in preclinical study100 mg/m2OlaparibInhibitor of PARP11. Reduced PASMC proliferation2. Increased PASMC apoptosis1. Reduced PV remodeling2. Reduced RVHMCTSU‐54166 mg/kg/d0.97 mg/kg/d800 mgPaclitaxelFOXO1 Activator1. Reduced PASMC proliferation2. Increased BMPR2 signaling3. Increased PASMC apoptosis1. Reduced PV remodeling2. Reduced RVH3. Improved RV functionSU‐5416 HypoxiaMCT5–7 mg/kg/wk1 mg/kg/wk aerosolized0.8–1.1 mg/kg/wk0.16 mg/kg/wk aerosolized225 mg/m2 every 3 to 4 wksRanolazineReduction of FAO and enhancement of glucose oxidation (by activating Randle cycle)1. Reduced Glut1 and HK1 mRNA levels2. Increased RV glucose oxidation3. Increased ATP production4. Decreased FAO1. Reduced RVH2. Improved RV function3. Decreased RV fibrosis4. Reduced risk of arrhythmias5. Increased exercise capacityPAB ratsMCT20 mg/d0.25–0.5% in chow3.2 mg/d0.04–0.08% in chow2000 mgRituximabbAnti‐inflammatory via blocking of CD201. Reduced IL6, HIF‐1α, and VEGF2. Decreased PASMC proliferation1. Reduced PV remodeling2. Reduced RVHOvalbumin immunization plus SU‐5416 ratsRituximab not used in preclinical studyRituximab not used inpreclinical study1000 mg every 2 wkRosiglitazone/pioglitazonePPAR‐γ activators1. Increased adiponectin levels2. Reduced NOX4 levels3. Reduced PASMC proliferation4. Improved mitochondrial organization5. Induced FAO genes6. Improved FAO efficacy in cardiomyocytes1. Reduced PV remodeling2. Reduced RVH3. Improved RV functionApoE knockout miceHypoxic ratsHypoxic miceSU‐5416 ratsRosiglitazone (8–10 mg/kg/d)Pioglitazone (20 mg/kg/d)Rosiglitazone (1.3–1.6 mg/kg/d)Pioglitazone (3.2 mg/kg/d)Rosiglitazone: 8 mgPioglitazone: 45 mgTacrolimusCalcineurin inhibitor1. Sequestered FK‐binding protein 2 from BMPR1 receptors2. Increased BMPR2 signaling3. Improved endothelial function4. Reduced PASMC proliferation1. Reduced PV remodeling2. Reduced RVHBMRP2 endothelial knockout miceMCTSU‐5416 hypoxia0.05 mg/kg/d0.008 mg/kg/d0.6 mg/kgTocilizumabbInhibit inflammatory cytokine IL61. Reduced STAT3 activation2. Induced PASMC apoptosis1. Reduced PV remodeling2. Reduced RVHMCTSU‐5416 hypoxiaTocilizumab not used in preclinical studyTocilizumab not used in preclinical study800 mg every 4 wkTrimetazidineReduce FAO and enhance glucose oxidation (by activating Randle cycle)1. Reduced Glut1 and HK1 m