Pulmonary arterial hypertension develops when small arteries inside the lungs become unusually stiff, leading to dangerously high blood pressure and eventual heart failure. The stiffening and remodeling of pulmonary arteries also causes excessive cell growth and proliferation of pulmonary arterial vascular smooth muscle cells. This manifestation irrevocably damages the lungs and impairs breathing.
Patients experience shortness of breath, dizziness, and chest pressure. Despite a combination of medications and oxygen therapy, which ameliorate symptoms, the condition inevitably worsens and quality of life declines.
“Pulmonary arterial hypertension is partially driven by the proliferation of pulmonary arterial vascular smooth muscle cells induced by stiffening of pulmonary arteries,” reports Dr. Yuanjun Shen, lead author of a new study in the journal Science Signaling.
Shen, of the Lung Center in the division of pulmonary, critical care and sleep medicine at the University of California, Davis, has been exploring the potential benefits of an experimental drug called SRT2104, which appears to reverse the cause of the disease. The investigational medication has been studied as a potential treatment for a diverse range of other medical conditions, such as type 2 diabetes, psoriasis, and dyslipidemia.
SRT2104 was developed as a selective small molecule involved in the regulation of energy homeostasis and the modulation of various metabolic pathways. The UC Davis team turned to animal models to determine whether SRT2104 might offer treatment benefits by reversing the invariable downhill course of the disease.
The team noted an unusually low abundance of TSC2 proteins in the disease itself, especially in pulmonary arterial vascular smooth muscle cells, which proliferate wildly in the disease. In the examination of lung tissue from 16 patients with pulmonary arterial hypertension, Shen and colleagues noted the hallmarks of the disease: low TSC2 proteins and high levels of pulmonary arterial vascular smooth muscle cells. They further found activated cell growth pathways, which boosted the proliferation of pulmonary arterial vascular smooth muscle cells.
This proliferation, in turn, led to further stiffening, feeding into a vicious cycle—a feedback loop—that worsened harmful vessel remodeling. By comparison, samples from healthy controls showed an abundance of TSC2 proteins and no proliferation of pulmonary arterial vascular smooth muscle cells.
Examining the animal models, Shen and colleagues found that mice whose smooth muscle was even partially deficient in TSC2 proteins developed stiffer pulmonary arteries and pulmonary hypertension. Yet, when the experimental drug was administered to each of two groups of animal models, SRT2104 restored TSC2 protein abundance, reversed pulmonary arterial remodeling and mitigated pulmonary hypertension in both rodent models. The team concluded that apparent cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation because the vicious cycle and low TSC2 protein levels do not exist in treated mice—or healthy people.
Pulmonary arterial hypertension is considered a rare disease in the United States because fewer than 200,000 people are diagnosed with it annually. Despite the rare disease designation the disorder is marked by escalating medical costs and is responsible for disproportionately high losses of productivity and personal income.
The research, which examined the investigational drug SRT2104, involved a far-flung team of collaborators. In addition to investigators at UC Davis, many team members were in Pennsylvania at the University of Pittsburgh’s Heart, Lung, Blood and Vascular Medicine Institute as well as the University of Pennsylvania’s Perelman School of Medicine. Other investigators were at Brigham and Women’s Hospital in Boston and Ohio State University in Columbus.
Current Treatment
PAH represents an imbalance between vasoconstrictors and proliferative mediators (e.g., endothelin-1) and vasodilators (e.g., nitric oxide, prostacyclin).[42] Three key therapeutic approaches target either the nitric oxide, endothelin-1, or prostacyclin pathways (Table 7). The emergence of targeted therapies for PAH has raised the 1-year survival rates to 91% and the 5-year survival rates to 61% for newly diagnosed patients.[43][44]
The 4 US FDA-approved treatment classes for PAH include phosphodiesterase type 5 inhibitors (PDE5Is), oral endothelin-receptor antagonists (ERAs), prostacyclin pathway agents (PPAs), and soluble guanylate cyclase (sGC) stimulants.
Table 7: PAH-Specific FDA-Approved Therapies [45]
| Class | Agent | Administrative Route |
| PPAs | Epoprostenol | Continuous IV infusion via a central venous catheter |
| Treprostinil | Continuous IV infusion via a central venous catheter or continuous SC infusion; inhaled; oral | |
| Iloprost | Inhaled | |
| Selexipag | Oral; IV formulation is available for temporary use when unable to take oral therapy | |
| ERAs | Bosentan | Oral |
| Ambrisentan | Oral | |
| Macitentan | Oral | |
| sGC stimulants | Riociguat | Oral |
| PDE5Is | Sildenafil | Oral; IV |
| Tadalafil | Oral |
From: Strategies For Individualizing Pulmonary Hypertension Treatment to Ensure Optimal Patient Outcomes
IV—intravenous
SC—subcutaneous
According to the treatment algorithm proposed by the 6th World Symposium on Pulmonary Hypertension, select patients with PAH should undergo acute vasoreactivity testing (AVT) to identify the small subset of PAH patients (10% to 20%) who may respond to CCB therapy.[3] This includes patients with IPAH, HPAH, and drug/toxin-induced PAH (i.e., individuals who are most likely to be vasoreactive).[3]
Patients with associated forms of PAH are rarely vasoreactive, and, as such, vasoreactive testing is not indicated.[3][46] This includes patients with PAH due to connective tissue disease, congenital heart disease, HIV, portal hypertension, and schistosomiasis.[3][46] For patients with PAH who are vasoreactive, the American College of Chest Physicians (ACCP) and the 6th World Symposium on Pulmonary Hypertension both recommend an initial trial of therapy with an oral CCB.[3][45]
Improved survival was reported in an observational study of 64 patients with IPAH, which reported that the 5-year survival was greater among patients who received CCB therapy (primarily nifedipine) compared with a control group of patients (comprised non-vasoreactive IPAH patients and historical controls).[47]
Another observational study of 557 patients with IPAH found that only 13% had a positive vasoreactivity test, and 54% of the vasoreactive patients with IPAH who received CCB therapy maintained functional improvement after one year.[48] Responders were more vasoreactive (i.e., had a greater decrease of mPAP during the vasoreactivity test) and had less severe disease at baseline.[48]
The daily doses of these drugs that have shown efficacy in IPAH are relatively high: 120–240 mg for nifedipine, 240 to 720 mg for diltiazem, and up to 20 mg for amlodipine.[26][45] Due to its potential negative inotropic effects, verapamil should be avoided.[45]
Many of the adverse events (AEs) associated with CCBs are because of the potent systemic vasodilatory properties of CCBs (e.g., hypotension, peripheral edema).[49][50][49] Paradoxically, while pulmonary vasodilation from CCB therapy may reduce hypoxic vasoconstriction, loss of hypoxic vasoconstriction can worsen ventilation-perfusion mismatch and hypoxemia.[51][52] CCBs may also be associated with deterioration of right ventricular function due to the negative inotropic effect of CCBs.[53]
Individuals who respond to CCB therapy should be reassessed after 3 to 6 months of treatment.[3] A poor response to therapy necessitates evaluation for non-CCB PAH-specific treatments.[3][45]
For patients with PAH who are typically non-vasoreactive (e.g., connective tissue disease-PAH) and have not undergone vasoreactive testing, and for patients who are non-vasoreactive or are vasoreactive and have failed CCB therapy, PAH-specific therapy is indicated.[3] The ACCP guidelines use the WHO FC to select suitable agents, while the 6th World Symposium on Pulmonary Hypertension utilizes the allocation of PAH-specific therapy based upon high risk and low or intermediate-risk categories.[45][3]
PAH-specific therapy consistently improves hemodynamic measures, WHO FC, and the 6MWD.[54][55] A meta-analysis of 21 randomized trials (3140 patients) found that therapy with a prostanoid, an ERA, or a PDE5I improved mortality compared with no therapy (1.5% vs. 3.8%; risk reduction [RR], 0.57; 95% confidence interval [CI], 0.35-0.92).[55]
For treatment-naïve PAH patients with WHO FC I symptoms, the ACCP guidelines suggest monitoring closely for disease progression to a functional level that warrants therapy (e.g., WHO FC II).[45]
For patients with WHO FC II or III or who have low or intermediate risk PAH, both the ACCP guidelines and 6th World Symposium on Pulmonary Hypertension recommend dual combination therapy with an ERA (e.g., ambrisentan) and PDE5I (e.g., tadalafil) for most patients.[3][45]
Tadalafil plus ambrisentan—A randomized trial (AMBITION) of 500 drug-naïve patients with group 1 PAH (mostly idiopathic and connective tissue disease-related) with class II or III symptoms compared the combination of 10 mg of ambrisentan and 40 mg of tadalafil with either agent alone.[56] The combined regimen, administered on average for 18 months, resulted in a 50% reduction in the clinical failure rate (18% versus 31%) and improved exercise capacity (49 versus 24 meters).[56] The reduction in clinical failure rate was primarily driven by decreased hospitalizations for progressive PAH (which portends a poor prognosis) rather than by improved survival or WHO FC.[56] AEs (e.g., edema, headache, nasal congestion, anemia, syncope) were reported more frequently in those receiving combination therapy (45% vs. 30%), but rates of hypotension were similar.[56]
Other combination oral regimens of dual therapy consisting of an ERA and a PDE5I are feasible options in patients not suited to the ambrisentan/tadalafil combination (e.g., contraindications to the drug or AEs).
Macitentan plus sildenafil—The SERAPHIN trial compared the oral ERA, macitentan, with placebo in 250 patients with moderate-to-severe PAH; 85% of patients had IPAH or connective tissue disease-associated PAH, and the majority were FC II or III. Approximately 60% of patients were already on a PDE5I (i.e., combined therapy), mostly sildenafil, and 40% were treatment-naïve (i.e., single-agent therapy with macitentan). Over a 2-year period, fewer patients treated with macitentan (3 mg or 10 mg daily) progressed or died on therapy (38% and 31%, respectively, vs. 46%). Exercise capacity and WHO FC also improved with macitentan treatment. This benefit was observed independent of whether patients were on combination or single-agent oral therapy for PAH.[57][58]
Bosentan plus tadalafil—The PHIRST trial randomly assigned 405 patients with mostly FC II and III PAH, half of whom were on bosentan, to receive tadalafil (2.5, 10, 20, or 40 mg) or placebo once daily for 16 weeks. Tadalafil (40 mg) significantly increased the 6MWD and the time to clinical worsening while also decreasing the incidence of clinical worsening and improving health-related quality of life (QoL).[59]
Bosentan plus sildenafil—In a prospective study, the addition of sildenafil to bosentan in PAH patients who had developed clinical deterioration improved symptoms, exercise capacity, and WHO FC.[60] Improvement was more frequent and of greater magnitude in patients with IPAH than individuals with scleroderma-associated PAH.[60] In another study of patients failing monotherapy with either bosentan or sildenafil, the addition of either agent also resulted in improved FC and survival in those with IPAH compared with those with connective tissue-associated PAH.[61]
According to the 6th World Symposium on Pulmonary Hypertension, single-agent oral therapy may be appropriate for patients with low- or intermediate-risk diseases who have a low-risk profile and for patients who have been stable on monotherapy for a prolonged period (e.g., 5 to 10 years).[3]
Other possible indications include patients >75 years old with multiple risk factors for heart failure, individuals suspected to have pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, patients with contraindications to combination therapy (e.g., severe liver disease), individuals with portopulmonary hypertension and HIV (i.e., patients who were not included in the combination trials), or patients who decline combination therapy.[3]
Per the ACCP guidelines, options for these patients include ERAs (i.e., ambrisentan, bosentan, macitentan), PDE5Is (i.e., sildenafil, tadalafil), and sGC stimulators (i.e., riociguat).[45]
The choice of therapy may depend on several factors, including patient preferences, cost, route of administration, toxicity profile, comorbidities (e.g., liver failure, kidney failure), and potential drug interactions with other agents.[3] For patients with WHO FC III (not WHO FC II) symptoms who have rapid progression or other markers of poor clinical diagnosis (e.g., echocardiographic evidence of severe right ventricular dilatation), the ACCP guidelines advise consideration of initial treatment with a parenteral prostanoid (i.e., IV epoprostenol or treprostinil, SC treprostinil).[45]
ERAs as a group—In a meta-analysis of 16 randomized trials that compared ERAs with placebo in individuals with FC II/III, patients receiving ERAs had improved exercise capacity (mean increase of 25 m), FC (odds ratio [OR], 1.41; 95% CI, 1.16-1.70), and symptoms, and reduced odds of FC deterioration (OR, 0.43; 95% CI, 0.26-0.72). There was low certainty of the evidence of a possible reduction in mortality from ERA use (OR 0.78, 95% CI, 0.58-1.07).[62]
Ambrisentan—Randomized placebo-controlled trials (e.g., ARIES-1, ARIES-2) of patients with moderate-to-severe IPAH and connective tissue disease-related PAH (mostly WHO FC II and III) consistently reported that ambrisentan, administered for up to 2 years, delayed disease progression and clinical worsening. Moreover, ambrisentan was associated with improved exercise tolerance, WHO FC, pulmonary vascular hemodynamics, and QoL.[63][64][65]
Bosentan—Bosentan has been shown in individuals with group 1 PAH to delay clinical worsening and improve pulmonary vascular hemodynamics and exercise capacity.[66][67][68][69] The mortality of bosentan-treated IPAH patients appears favorable compared with historical controls.[68][70]
Macitentan—In the aforementioned SERAPHIN trial that compared macitentan with placebo in 250 patients with moderate-to-severe PAH (mostly WHO FC II and III), the benefits that were observed in the patients taking combined therapy (e.g., slower disease progression and lower mortality, improved exercise tolerance) were also seen in a subgroup of patients who were on single-agent therapy with macitentan.[57][58]
The main AEs of ERAs are hepatotoxicity and peripheral edema.[57][63][64][65][67][71][72] Additionally, ERAs are also potent teratogens, requiring meticulous, double-method contraception if used by women with childbearing potential. Macitentan may also be complicated by nasopharyngitis and anemia.[57]
Ambrisentan is contraindicated in patients with concurrent idiopathic pulmonary fibrosis (IPF); one randomized study reported that this agent was associated with an increased risk of IPF disease progression and hospitalizations.[73]
PDE5Is as a group—A meta-analysis of 36 studies (2999 patients) reported that patients with group 1 PAH treated with PDE5Is were more likely to improve their WHO FC (OR, 8.59; 95% CI, 3.95-18.72) and less likely to die (OR, 0.088; 95% CI, 0.07-0.68).[74]
Sildenafil—Sildenafil improves pulmonary hemodynamics and exercise capacity in individuals with group 1 PAH.[75][76][77][78] The SUPER-1 trial randomly assigned 277 patients with group 1 PAH to receive sildenafil or placebo three times daily for 12 weeks.[75] The sildenafil group demonstrated significant improvement in hemodynamics and 6MWD, which persisted during one year of follow-up.[75]
A follow-up, open-label 3-year extension trial (SUPER-2) reported persistent improvement in the 6MWD and WHO FC in 46% and 29% of patients, respectively.[79] The estimated 3-year survival rate was 79%.[79]
Tadalafil—In the PHIRST-1 and -2 trials that included 405 PAH patients, half of whom were treatment naïve, tadalafil increased the 6MWD and the time to clinical worsening when compared with placebo.[59]
Common AEs of PDE5Is include headache, gastrointestinal (GI) upset, flushing, and muscle pain.
Riociguat—Data have shown that riociguat improves outcomes for individuals with group 1 PAH. In trials of WHO FC II and III PAH patients (PATENT-1 and -2), half of whom were treatment-naïve, riociguat improved exercise tolerance, PVR, symptoms, WHO FC, and time to clinical worsening for up to 2 years of treatment. Riociguat had a favorable safety profile and was well tolerated, with syncope as the most frequently reported AE (4% vs. 1%).[80][81]
Parenteral prostanoids as a group—Several parenteral prostanoids are available with the strongest evidence of efficacy in favor of IV epoprostenol. In a meta-analysis of 17 trials (765 patients with PAH), patients on prostacyclin agonists were more than twice as likely to have improved WHO FC, 6MWD, and pulmonary hemodynamics compared with a control group of PAH patients (placebo, any other treatment, or usual care). Mortality improved in individuals receiving IV agents (OR, 0.29; 95% CI, 0.12-0.69).[82]
Epoprostenol—In patients with PAH, IV epoprostenol consistently improves hemodynamic parameters and functional capacity.[82][83][84] The efficacy of IV epoprostenol was demonstrated in a trial that randomly assigned 81 patients with WHO FC III or IV IPAH (three-quarters and one-quarter, respectively) to receive IV epoprostenol as single-agent therapy or standard therapy (typically oral therapy) for 12 weeks.[85] Intravenous (IV) epoprostenol improved QoL, mPAP, PVR, and exercise capacity. A total of 8 patients died during the study, all of whom were in the standard therapy group.[85]
AEs that may be associated with epoprostenol include jaw pain, diarrhea, and flushing. Central venous catheter infection may also occur and contribute to the morbidity and mortality of continuous epoprostenol therapy.[82][86]
Treprostinil—IV and SC treprostinil improve hemodynamic parameters, symptoms, exercise capacity, and possibly survival in patients with group 1 PAH.[87][88][89] The AEs of treprostinil are similar to those of epoprostenol. The ACCP guidelines advise considering the addition of a parenteral or inhaled prostanoid for PAH patients with WHO FC III who have evidence of progression of their disease and/or markers of poor clinical prognosis despite treatment with 1 or 2 classes of oral therapies.[45] Several combinations involving parenteral or inhaled prostacyclin analogs have been shown to be beneficial in individuals with PAH.
Sildenafil plus epoprostenol—A trial randomly assigned 267 patients with group 1 PAH receiving epoprostenol to have sildenafil or placebo added for 16 weeks. Most patients were WHO FC III at the beginning of the study. Compared with the placebo, the combination regimen was associated with improved hemodynamic parameters, exercise capacity, QoL, and time to clinical worsening.[90]
Bosentan plus epoprostenol—A study (BREATHE-2 trial) randomly assigned 22 individuals with group 1 PAH receiving epoprostenol to have either bosentan or placebo added for 16 weeks. The dual therapy was associated with improved hemodynamic parameters, exercise capacity, and WHO FC compared with baseline.[91]
Inhaled treprostinil plus either bosentan or sildenafil—In one trial (TRIUMPH), 235 patients with group 1 PAH who were deteriorating despite bosentan or sildenafil therapy were randomly assigned to receive the addition of either inhaled treprostinil or placebo for 12 weeks. The treprostinil group had a significant improvement in their 6MWD and QoL.[92]
Sildenafil plus inhaled iloprost—Studies have demonstrated that in patients with group 1 PAH have reported that the addition of sildenafil to inhaled iloprost resulted in an improvement in exercise capacity, WHO FC, and hemodynamics.[93]
Bosentan plus inhaled iloprost—A study showed that the combination of bosentan with inhaled iloprost resulted in a marked increase in exercise capacity.[94] For high-risk PAH patients, the 6th World Symposium on Pulmonary Hypertension recommends initial combination therapy that includes IV PPAs, with IV epoprostenol receiving the strongest recommendation.[3] In contrast, for WHO FC IV PAH patients who are willing and able to manage parenteral prostanoids, the ACCP suggests monotherapy with either IV epoprostenol, IV treprostinil, or SC treprostinil.[45]
Emerging Treatments
Several therapies are currently undergoing investigation in clinical trials for the treatment of PAH.
Mutations in bone morphogenetic protein (BMP) receptor type 2 (BMPR2) play a known role in the pathogenesis of PAH.[95] BMP is a member of the transforming growth factor (TGF)-beta family of proteins.[96] Sotatercept acts as a ligand trap for members of the TGF-beta superfamily and restores the balance between the growth-promoting activin pathway and the growth-inhibiting BMP pathway.[97]
A total of 2 doses of sotatercept (0.3 or 0.7 mg/kg subcutaneously every three weeks) were compared with placebo in a 24-week multicenter trial of 106 patients with PAH receiving standard therapy.[98] Sotatercept reduced the PVR by 145.8 and 239 dyne/sec/cm for the 0.3 and 0.7 mg/kg dosing strategies, respectively. Exercise tolerance was also improved as measured by an increase in the 6MWD (29.4. [0.3 mg/kg] and 21.4 m [0.7 mg/kg]), and levels of BNP were also reduced. The most common AEs were headache, diarrhea, and peripheral edema. Of note, sotatercept resulted in thrombocytopenia and an increased hemoglobin level, and one patient in the sotatercept 0.7-mg group died from cardiac arrest.[98]
Selonsertib is a first-in-class small-molecule (apoptosis signal-regulating kinase 1 [ASK1]) inhibitor developed to treat diseases with a high burden of oxidative stress, including PAH.[99] The randomized, double-blind, placebo-controlled phase 2 ARROW trial included 151 study participants.[100] All were aged 18 to 75 years and had a diagnosis of PAH. From December 2014 to November 2015, patients were stratified by PAH etiology and background therapy, and underwent random assignment to selonsertib 2 mg, selonsertib 6 mg, selonsertib 18 mg, or placebo administered once daily via tablet. The primary outcome was a change in PVR from baseline to 24 weeks, as measured by RHC. Mean change in PVR was 6 dynes/cm in the placebo group, 35 dynes/cm in the selonsertib 2-mg group (P = .21), 28 dynes/cm in the selonsertib 6-mg group (P = .27) and –21 dynes/cm in the selonsertib 18-mg group (P = .60).[100] Additionally, the investigators reported no improvement in secondary outcomes such as exercise capacity, symptom burden, or worsening clinical events.
Ralinepag is a selective non-prostanoid prostacyclin receptor agonist formulated as an oral, extended-release tablet taken once daily.[101] In a phase 2 randomized placebo-controlled trial, ralinepag significantly reduced PVR compared with placebo (−29.8%; P = .03) in 61 patients receiving mono- (41%) or dual- (59%) background therapy.[102] Ralinepag was initiated at a dose of 10 μg twice daily and titrated as tolerated over nine weeks to a maximum total daily dosage of 600 μg (300 μg twice daily). Reported AEs included headache, nausea, diarrhea, jaw pain, and flushing. This agent is currently undergoing investigation in ongoing clinical trials. (NCT03626688; NCT04084678)
reference link : https://www.ncbi.nlm.nih.gov/books/NBK580558/
More information: Yuanjun Shen et al, Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension, Science Signaling (2022). DOI: 10.1126/scisignal.abn2743
