Targeted therapies in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement. Even though, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.     

Why there is a need to discuss pulmonary hypertension other than pulmonary arterial hypertension?

Pulmonary hypertension(PH) is a condition characterized by the elevation of the mean pulmonary artery pressure above 25 mm Hg and the pulmonary vascular resistance above 3 wood units. Pulmonary arterial hypertension(PAH) is an uncommon conditionwith severe morbidity and mortality, needing early recognition and appropriate and specific treatment. PH is frequently associated with hypoxemia, mainly chronic obstructive pulmonary disease and DPLD and/or left heart diseases(LHD), mainly heart failure with reduced or preserved ejection fraction. Although in the majority of patients with PH the cause is not PAH, a significant number of published studies are still in regard to group Ⅰ PH, leading to a logical assumption that PH due to other causes is not such an important issue. So, is there a reason to discuss PH other than PAH? Chronic lung diseases, mainly chronic obstructive lung disease and DPLD, are associated with a high incidence of PH which is linked to exercise limitations and a worse prognosis. Although pathophysiological studies suggest that specific PAH therapy may benefit such patients, the results presented from small studies in regard to the safety and effectiveness of the specific PAH therapy are discouraging. PH is a common complication of left heart disease and is related to disease severity, especially in patients with reduced ejection fraction. There are two types of PH related to LHD based on diastolic pressure difference(DPD, defined as diastolic pulmonary artery pressure- mean PAWP): Isolated post-capillary PH, defined as PAWP 15 mm Hg and DPD 7 mm Hg, and combined post-capillary PH and pre-capillary PH, defined as PAWP 15 mm Hg and DPD ≥ 7 mm Hg. The potential use of PAH therapies in patients with PH related to left heart disease is based on a logical pathobiological rationale. In patients with heart failure, endothelial dysfunction has been proposed as a cause of PH and hence as a target for treatment, supported by the presence of increased endothelin-1 activity and impaired nitric oxide-dependent vasodilation. Unfortunately, so far, there is no evidence supporting the use of specific PAH therapies in patients with PH related to left heart disease. In conclusion, the presence of PH in patients with conditions other than PAH contributes to the severity of the disease, affecting the outcome and quality of life. The disappointing results regarding the effectiveness of specific PAH therapies in patients withchronic lung diseases and LHD underline the need for seeking new underlying mechanisms and thus novel therapies targeting PH due to left heart disease and/or lung diseases.     

Right heart function and haemodynamics in pulmonary hypertension

The primary challenge in the care of the patient with advanced pulmonary arterial hypertension (PAH) is right ventricular dysfunction with concomitant right heart failure. Right heart function is closely tied to survival in this disease, and there is a growing interest in the study of this unique structure. While echocardiography and cardiac magnetic resonance (CMR) have augmented our ability to image the right ventricle (RV), the primary means of assessing right heart function remains right heart catheterisation. Several of the currently available treatments for PAH have been shown to have effects on the RV, not just the pulmonary vasculature, and, in future, therapies aimed at optimizing right ventricular function may allow better outcomes in this challenging disease. New directions in right ventricular assessment including measurement of pulmonary vascular impedance and more widespread availability of CMR may allow greater knowledge about this little studied, yet highly important, right side of the heart.     

Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4-/- mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH.     

Carbon monoxide reverses established pulmonary hypertension

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by a progressive increase in pulmonary vascular resistance leading to right heart failure. Carbon monoxide (CO) has emerged as a potently protective, homeostatic molecule that prevents the development of vascular disorders when administered prophylactically. The data presented in this paper demonstrate that CO can also act as a therapeutic (i.e., where exposure to CO is initiated after pathology is established). In three rodent models of PAH, a 1 hour/day exposure to CO reverses established PAH and right ventricular hypertrophy, restoring right ventricular and pulmonary arterial pressures, as well as the pulmonary vascular architecture, to near normal. The ability of CO to reverse PAH requires functional endothelial nitric oxide synthase (eNOS/NOS3) and NO generation, as indicated by the inability of CO to reverse chronic hypoxia-induced PAH in eNOS-deficient (nos3-/-) mice versus wild-type mice. The restorative function of CO was associated with a simultaneous increase in apoptosis and decrease in cellular proliferation of vascular smooth muscle cells, which was regulated in part by the endothelial cells in the hypertrophied vessels. In conclusion, these data demonstrate that CO reverses established PAH dependent on NO generation supporting the use of CO clinically to treat pulmonary hypertension.     

Pulmonary Hypertension: Evaluation and Management

Pulmonary hypertension (PH) is a hemodynamic state characterized by elevation in the mean pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and premature death. PH can be the result of a variety of diseases of different etiologies. Pulmonary arterial hypertension (PAH) should be distinctly differentiated from pulmonary venous hypertension (PVH) as a result of left heart disease. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (APAH). In the absence of an identifiable etiology or associated underlying disease, PAH is referred to as idiopathic (IPAH). IPAH, formerly known as primary pulmonary hypertension (PPH), is a rare disease most commonly seen in women of childbearing age. Presenting symptoms and signs are nonspecific and include dyspnea on exertion, fatigue, and a loud pulmonary component of the second heart sound. Transthoracic Doppler echocardiography is an excellent noninvasive test to detect the presence of pulmonary hypertension, although every patient should receive a right heart catheterization to confirm the diagnosis. A detailed work up, including laboratory tests and imaging studies, is also indicated to rule out known causes of pulmonary hypertension. Several targeted treatment options have become available in recent years and include parenteral and inhaled prostanoids, oral endothelin receptor antagonists, and oral phosphodiesterase type-5 inhibitors. As a result of their complex care, patients should be referred to centers with expertise in pulmonary hypertension.     

Diagnosis and management of pulmonary arterial hypertension: Implications for respiratory care

Pulmonary arterial hypertension (PAH) is a pathological condition of the small pulmonary arteries. PAH is characterized histopathologically by vasoconstriction, vascular proliferation, in situ thrombosis, and remodeling of all 3 levels of the vascular walls. These pathologic changes result in progressive increases in the mean pulmonary-artery pressure and pulmonary vascular resistance, which, if untreated, leads to right-ventricular failure and death. PAH can be associated with multiple conditions or risk factors (eg, collagen vascular diseases, liver disease, human immunodeficiency virus, congenital heart disease, or ingestion of certain medications or toxins) or it can be idiopathic. Up to 10% of the idiopathic cases are familial. Regardless of the etiology, the clinical presentation, histopathologic lesions, and response to therapy are all similar. Early in the disease process, the signs and symptoms of PAH are often subtle and nonspecific, making diagnosis challenging. Patients most often present with progressively worsening dyspnea and fatigue. An extensive evaluation is indicated to diagnose PAH, decipher its etiology, and determine long-term treatment goals. Transthoracic echocardiogram is an excellent screening tool to evaluate PAH, but every patient requires a right-side heart catheterization to help stage the disease and guide therapy. Prior to a decade ago, clinicians were only able to offer symptomatic therapy to this challenging group of patients. Earlier diagnosis, rapidly advancing understanding of the pathogenesis, and an increasing number of treatment options have changed the course of PAH, which was once thought to be invariably fatal.     

Update on pulmonary arterial hypertension pharmacotherapy

Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.     

Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.     

Treatments and strategies to optimize the comprehensive management of patients with pulmonary arterial hypertension

The management of pulmonary arterial hypertension (PAH) should aim to provide vasodilation of the pulmonary arteries, treat right ventricular failure, improve functional capacity and quality of life, and improve survival, if possible. Data from right heart catheterization and an estimation of vasoresponsiveness together guide treatment for PAH. The judicious use of calcium channel blockers, prostacyclin analogues, anticoagulation, and endothelin receptor antagonists forms the current basis of therapy. Three drugs-the prostacyclin analogues epoprostenol and treprostinil and the endothelin receptor antagonist bosentan-are currently approved for the primary treatment of PAH and have been clinically shown to improve outcomes. Coumarin derivatives, epoprostenol, and, in selected patients, calcium channel blockers are the only drugs associated with improved survival, and only epoprostenol has been shown to improve survival in a prospective randomized trial. Knowledge of the supportive therapies, indications for surgical intervention, and emerging drug therapies should provide the working armamentarium for clinicians treating this rare but devastating disease.     

肺动脉高压药物靶向治疗的展望

肺动脉高压是一种以肺血管重构为特征,以肺血管阻力病理性增高为主要表现的临床综合征。肺动脉高压患者病情常呈进行性发展,最终导致右心衰竭和死亡。肺动脉高压现有的药物治疗在一定程度上改善了患者的症状,提高了生存率,但不能阻止病情的恶化,肺动脉高压患者的长期预后仍不尽人意。近年来,基于对肺动脉高压病理生理机制的深入认识,肺动脉高压的靶向治疗药物也不断涌现,为肺动脉高压的治疗带来了新的希望。现将肺动脉高压靶向治疗药物的研究进展进行综述。     

Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy

OBJECTIVE: To determine the immediate and long-term effects of adding sildenafil, a phosphodiesterase-5 inhibitor, to the medical regimen of patients with pulmonary arterial hypertension (PAH). PATIENTS AND METHODS: Thirteen patients with PAH received empirical adjunctive sildenafil treatment at the Mayo Clinic in Rochester, Minn, between November 1, 2000, and August 31, 2001. All received a 25-mg dose of sildenafil, increased by 25 mg at 8-hour intervals, if tolerated, up to 100 mg during hemodynamic monitoring for 24 to 48 hours. Long-term effects on right heart hemodynamics were assessed by noninvasive right ventricular systolic pressure, right ventricular index of myocardial performance, and a 6-minute walk test. RESULTS: Sildenafil significantly increased cardiac output (CO) (P = .04) and decreased pulmonary artery systolic pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and mean arterial pressure (P < or = .01) at peak measurements (obtained 1-2 hours after highest dose). At trough measurements (obtained 8 hours after highest dose), sildenafil significantly decreased pulmonary artery systolic pressure, mean pulmonary artery pressure, and mean arterial pressure (P = .01). Ten patients discharged from the hospital were taking the highest-tolerated dose of sildenafil every 8 hours. The right ventricular systolic pressure and right index of myocardial performance showed no significant improvement at follow-up (117 +/- 70 days), although concomitant treatment with epoprostenol could be tapered in 2 patients. Changes in New York Heart Association classes were inconsistent, and improvements in the 6-minute walk test were not significant. CONCLUSION: Sildenafil has an immediate pulmonary vasodilator effect in patients already receiving vasodilators for PAH. Its long-term effects on right heart function and functional status are equivocal. A large, prospective, well-designed study is needed to determine the effects of sildenafil on PAH, both in untreated and concurrently treated patients.     

Extended-release oral treprostinil for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance ultimately resulting in progressive right heart failure. Although new specific treatments have demonstrated improvements in various end points including morbidity/mortality, prognosis remains unfavorable with an on-treatment yearly mortality rate of 10%. Due to complex delivery systems, the use of parenteral prostanoids has been limited to patients with advanced disease. While inhaled prostanoids have had little effect, an oral prostacyclin analog is a desired initial treatment for PAH patients. To that end, UT-15C was synthesized as a sustained-release tablet. FREEDOM-M in treatment-naïve PAH patients resulted in significant improvements of 6-min walk distance supporting the use of oral treprostinil as initial monotherapy in PAH patients with class II or III symptoms. A further study targeting patients on combination treatments is currently exploring a morbidity/mortality end point in a large patient population.     

Pulmonary arterial hypertension: evaluation and management

Pulmonary arterial hypertension (PAH), a rare disease involving the pulmonary vascular circuit, is defined as an elevation in pulmonary arterial pressures and is characterized by symptoms of dyspnea, chest pain, and syncope. If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure. Over the past 5 years, there have been significant advances in this field in regards to understanding the pathogenesis, diagnosis, and classification of PAH. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality. Ongoing research promises to lead to a more comprehensive understanding of the genetics, etiology, and pathogenesis of pulmonary arterial hypertension, which may ultimately translate into more effective therapeutic options.     

Pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease of the small pulmonary arteries characterized by vascular narrowing and increased pulmonary vascular resistance, which eventually leads to right ventricular failure. Vasoconstriction, vascular proliferation, remodeling of the pulmonary vessels, and thrombosis are all contributing factors to the increased vascular resistance seen in this disease. Pulmonary arterial hypertension develops as a sporadic disease (idiopathic), as an inherited disorder (familial), or in association with certain conditions (collagen vascular diseases, portal hypertension, human immunodeficiency virus infection, congenital systemic‐to‐pulmonary shunts, ingestion of drugs or dietary products, or persistent fetal circulation). The pathogenesis of pulmonary arterial hypertension is a complicated, multifactorial process. It seems doubtful that any one factor alone is sufficient to activate the necessary pathways leading to the development of this disease. Rather, clinically apparent pulmonary arterial hypertension most likely develops after a second insult occurs in an individual who is already susceptible owing to genetic factors, environmental exposures, or acquired disorders. Currently, there is no cure for pulmonary arterial hypertension but several novel therapeutic options are now available that can improve symptoms and increase survival.     

Reversal of experimental pulmonary hypertension by PDGF inhibition

Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.     

Pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease of the small pulmonary arteries characterized by vascular narrowing and increased pulmonary vascular resistance, which eventually leads to right ventricular failure. Vasoconstriction, vascular proliferation, remodeling of the pulmonary vessels, and thrombosis are all contributing factors to the increased vascular resistance seen in this disease. Pulmonary arterial hypertension develops as a sporadic disease (idiopathic), as an inherited disorder (familial), or in association with certain conditions (collagen vascular diseases, portal hypertension, human immunodeficiency virus infection, congenital systemic-to-pulmonary shunts, ingestion of drugs or dietary products, or persistent fetal circulation). The pathogenesis of pulmonary arterial hypertension is a complicated, multifactorial process. It seems doubtful that any one factor alone is sufficient to activate the necessary pathways leading to the development of this disease. Rather, clinically apparent pulmonary arterial hypertension most likely develops after a second insult occurs in an individual who is already susceptible owing to genetic factors, environmental exposures, or acquired disorders. Currently, there is no cure for pulmonary arterial hypertension but several novel therapeutic options are now available that can improve symptoms and increase survival.     

Portopulmonary hypertension

Portopulmonary hypertension (PPHT) is a respiratory complication of portal hypertension, defined as an increase in mean pulmonary artery pressure (PAP) of > 25 mmHg with an increase in pulmonary vascular resistance of > 240 dyn.s/cm(-5) and a normal pulmonary capillary wedge pressure ( < 15 mmHg), which often occurs in subjects with liver cirrhosis. Histopathological features of PPHT are endothelial and smooth-muscle cell proliferation and fibrosis leading to luminal obstruction in the resistance arteries. The pathogenesis of PPHT may result from an imbalance between vasoconstrictor and vasodilating factors. The most common pulmonary symptom is exertional dyspnea; fatigue, chest pain and syncope occur more often at an advanced stage. Edema, ascites and prominent jugular veins are signs of both decompensated hepatic cirrhosis and right ventricular failure. Right heart catheterisation is the gold standard for the diagnosis and defines PPHT in mild disease with PAP less than 35 mmHg, moderate disease with PAP between 35 and 45 mmHg, and severe disease with PAP of 45 mmHg or higher. The medical treatment of portopulmonary hypertension is based on the treatment of other forms of pulmonary arterial hypertension, including vasomodulating pharmacologic agents. Liver transplantation is accompanied by high risk of mortality, generally due to acute right ventricular failure and cardiovascular collapse. The prognosis of PPHT is poor with mean survival of 15 months.     

Potts分流术治疗顽固性肺动脉高压:历史与展望

肺动脉高压是继发于先天性心脏病、肺血管病变、肺栓塞或因特发性疾病导致的以肺动脉压力升高为特点的疾病.充分靶向药物降压治疗下仍进展的顽固性肺动脉高压需手术干预,传统的肺移植或心肺联合移植手术面临供体有限、配型困难、免疫排斥等诸多问题.在此背景下,以建立心外体肺分流、缓解致命性右心衰竭为目的的Potts分流术逐渐复兴,但其...