|Year : 2012 | Volume
| Issue : 1 | Page : 4-11
Pulmonary arterial hypertension: Advances in pathophysiology and management
Sandeep Chopra1, Dinesh K Badyal2, P Chris Baby1, Davis Cherian1
1 Department of Cardiology, Christian Medical College, Ludhiana, India
2 Department of Pharmacology, Christian Medical College, Ludhiana, India
|Date of Submission||18-Jul-2011|
|Date of Decision||29-Sep-2011|
|Date of Acceptance||18-Oct-2011|
|Date of Web Publication||14-Jan-2012|
Dinesh K Badyal
Department of Pharmacology, Christian Medical College, Ludhiana
Source of Support: None, Conflict of Interest: None
Pulmonary arterial hypertension (PAH) is a heterogeneous, hemodynamic, and pathophysiological state which is commonly found throughout the world, but the disease burden is greater in India and in other developing countries. It is a disease characterized by vascular obstruction and vasoconstriction leading to progressive increase in pulmonary vascular resistance and right ventricular failure. PAH is a progressive disorder carrying a poor prognosis; however, dramatic progress has occurred in our knowledge of its pathogenesis and consequently, its treatment over the last two decades. In this article, we attempt to provide an overview of the etiology, pathophysiology, and current therapeutic modalities in the treatment of PAH. Patients suspected to have PAH should be submitted to a battery of investigations which help in establishing the diagnosis, identifying the etiology, guiding in treatment and informing the prognosis. All patients should be considered for standard therapy with oxygen, anticoagulation, and diuretics for right heart failure. Oral calcium channel blockers should be used in patients with a favorable response to acute vasodilator challenge. Disease targeted therapies include prostacyclines, endothelin receptor blockers, and phosphodiesterase-5 inhibitors. A brief mention of new and potential therapeutic strategies is also included.
Keywords: Management, pathophysiology, pulmonary arterial hypertension
|How to cite this article:|
Chopra S, Badyal DK, Baby P C, Cherian D. Pulmonary arterial hypertension: Advances in pathophysiology and management. Indian J Pharmacol 2012;44:4-11
|How to cite this URL:|
Chopra S, Badyal DK, Baby P C, Cherian D. Pulmonary arterial hypertension: Advances in pathophysiology and management. Indian J Pharmacol [serial online] 2012 [cited 2022 Jul 3];44:4-11. Available from: https://www.ijp-online.com/text.asp?2012/44/1/4/91858
| » Introduction|| |
Pulmonary artery hypertension (PAH) is defined as a mean pulmonary artery pressure (PAPm) ≥ 25 mmHg with a pulmonary capillary wedge pressure ≤ 15 mmHg, measured by cardiac catheterization. , A patient is said to be suffering from idiopathic PAH (IPAH), when there is no identifiable etiology for the rise in pulmonary artery pressure. IPAH was earlier known as primary pulmonary hypertension (PPH). The etiology of secondary PAH includes a wide spectrum of factors like drugs, toxins, portal hypertension, HIV, collagen vascular diseases, and persistent pulmonary hypertension of newborn, etc. The geographic distribution and economic diversity along with significant regional variations in human development and healthcare infrastructure make the estimation of the disease prevalence very difficult.
| » Scenario in India and in the Developing World|| |
India is currently in the grip of an epidemic of cardiovascular disease (CVD) secondary to diabetes, hypertension, and atherosclerosis.  CVD is a leading cause of death and disability and the absolute magnitude of CVD morbidity and mortality is staggering. With most of the public health attention being focused on atherosclerotic cardiovascular disease, the problem of pulmonary hypertension is largely overlooked. The etiology of pulmonary hypertension is diverse and all the identifying causes of PAH are prevalent in the developing world in a much larger magnitude as compared to the western world.
Estimates of disease prevalence are very difficult in the developing world because of geographic, economic, socio cultural, and ethnic diversity along with regional variations in healthcare infrastructure. A lot of patients with PAH are unlikely to reach centers that have the capability of making the diagnosis, especially in patients with IPAH. Disease registries therefore capture only a small proportion of patients with the disease.
No published estimates are available on the expected magnitude of the incidence of IPAH in India; however, overall magnitude is likely to be substantial if the data on incidence (1-4 per million per year) from industrialized countries are to be extrapolated.
The magnitude of PAH as a result of uncorrected congenital heart disease (CHD) is likely to be staggering given the large number of these patients in the developing world.  Population based studies done in school children have reported a CHD prevalence of approximately 4/1000. ,
The disease burden is estimated with extrapolating from the prevalence data.
The other conditions which may have increased prevalence in India include portal hypertension, HIV associated PAH, and PAH associated with respiratory system disorders. Pulmonary venous hypertension is very common in India due to the large prevalence of rheumatic valvular heart disease and contributes to a large majority of patients with severe pulmonary hypertension.  There are no published estimates in India of magnitude of PAH resulting from PAH related to collagen vascular disorders, drugs/toxins, persistent pulmonary hypertension of the new born, and PAH caused by chronic thrombotic or embolic disease.
| » Clinical Features|| |
The earliest presenting symptoms are effort related. Patients come with exertional dyspnea with an insidious onset. When right ventricular failure sets in, patients start having lower extremity edema from venous congestion. Angina is a common symptom, representing more advanced disease. Orthopnea and paroxysmal nocturnal dyspnea (PND) are seen in patients with PAH related to left ventricular diastolic dysfunction.  On examination, the jugular venous pressure is found to be raised with a large 'a' wave. Owing to the high pressure, the pulmonary artery pulsations are palpable. A left parasternal heave is also felt. On auscultation, an ejection click and a flow murmur in the pulmonary area is usually heard. Signs of right ventricular failure like hepatomegaly and ascites may occur late in the course.
| » Pathophysiology|| |
PAH was once regarded mainly as a disease of excess vasoconstriction, but this view was incomplete and new concepts have been developed in the recent years in the pathophysiology of this disease process. There is unchecked increase in the proliferation of smooth muscle cells and dysregulated control of endothelial cells with apoptosis and dysfunction in some areas and profuse proliferation in others. PAH is a disease of the precapillary pulmonary arterial bed, including the medium sized pulmonary arteries and pulmonary arterioles characterized by vascular obliteration. PAH is considered a panvasculopathy. Serum serotonin levels are elevated; hence decreasing the vasodilator/ vasoconstrictor ratio. , Prothrombotic factors including tissue factors are increased.  Widespread endothelial apoptosis result in proliferation of apoptosis- resistant endothelial precursor cells that proliferate and eventually form plexiform lesions.  In the media, pulmonary artery smooth muscle cell (PASMC) apoptosis is suppressed and proliferation is enhanced.  The factors which promote PASMC proliferation include mutation  or downregulation  of bone morphogenetic protein receptor type 2 (BMPR2), mitochondrial metabolic abnormalities, de novo expression of survivin protein,  increased expression of serotonin transporters,  increased expression of platelet derived growth factor receptor,  and tyrosine kinase activation. 
PAH has a genetic component. The bone morphogenetic proteins (BMP) are part of the transforming growth factor superfamily (TGF-β). Most patients with familial PAH have loss of function mutation in BMPR2. , TGF-β receptors control diverse processes involved in vascular remodeling including cell proliferation, apoptosis, cellular differentiation, and collagen and extracellular matrix turnover. A loss of function mutation in the BMPR2 results in an imbalance in the equilibrium between the opposing effects of TGF-β and BMP signaling, which in the smooth muscle cell favors a pro proliferative and anti apoptotic response, but in the case of endothelial cells, has anti proliferative and pro apoptotic effect. This leads to smooth muscle cell proliferation and endothelial hyperplasia. Complex pathophysiological and histological changes are observed in patients with PAH [Figure 1]. Plexiform arteriopathy is the pathological hallmark of advanced PAH. It represents a collection of proliferating endothelial cells, smooth muscle cells, fibroblasts and endothelial progenitor cells. Proximal to these lesions, the pulmonary arterioles are dilated and this is accompanied by distal loss of vasculature. The latter process is possibly because of increased apoptosis of endothelial cells and pericytes.  Hypovasodilatation seen in patients of PAH appears to be the result of loss of endothelial cell integrity for which a defect in the nitric oxide synthase system appears to be responsible. Patients with IPAH have been found to have decreased levels of endothelial derived vasodilator prostacyclin and nitric oxide. Increased levels of endothelin 1 which is a potent vasoconstrictor have been found in such patients.  The dysfunctional pulmonary hypertensive endothelial cell phenotype is characterized by uncontrolled proliferation, increased production of vasoconstrictor mediators such as endothelin, expression of 5-lipooxygenase, and decreased synthesis of prostacyclin.  In patients with IPAH, expression of prostacyclin synthase is reduced in pulmonary arteries, which is one of the phenotypic alterations present in pulmonary endothelial cells in these patients. Reduced expression of endothelial isoform of NO synthase has been demonstrated in the pulmonary vasculature and correlates inversely with the extent and severity of morphological lesions.  Serotoninergic appetite suppressants such as fenfluramines have been associated with increased risk of PAH.  Serotonin acts at membrane receptors resulting in vasoconstriction and also enters pulmonary vascular smooth cells leading to proliferation. Voltage gated potassium channels in pulmonary artery smooth muscle cells appear to be blocked by anorectic agents, thus causing enhanced smooth muscle cell proliferation and vasoconstriction.
|Figure 1: Pathogenesis for development of PAH and sites of drug action. Kv-voltage-gated potassium channels; ACE- angiotensin converting enzyme; PDE-phophodiesterase enzyme |
(Adapted from: Archer SL, Weir KE, and Wilkins MR. the Basic Science of Pulmonary Arterial Hypertension for Clinicians: new concepts and experimental therapies. Circulation. 2010 May 11; 121(18): 2045-2066)
Click here to view
| » Classification|| |
The Venice 2003 classification  is summarized in [Table 1]. This classification helps immensely as a guide to clinical assessment and treatment for these patients. In addition, PAH has been classified functionally in a similar pattern to New York Heart Association functional classification of Heart disease [Table 2].  Modification of the Venice classification was done in 2008 by a consensus of international group of experts at Dana point, California [Table 3]. This has maintained the general philosophy and organisation of the Venice classification, yet incorporates recent information on this subject.  IPAH is a rare disease, though secondary PAH associated with other conditions like connective tissue disorders and congenital heart disease is relatively common.
|Table 3: Updated clinical classification of Pulmonary Hypertension from Dana point, 2008|
Click here to view
| » Diagnostic Workup|| |
Patients of PAH must undergo a complete evaluation to help establish a diagnosis (to rule out secondary causes), to assess the severity, as a guide to treatment modalities and for determining the prognosis. Electrocardiogram (ECG), chest X-rays, echocardiogram, and a complete blood profile including liver, renal and thyroid function tests are recommended. , Biomarkers are useful in assessing severity and a correlation with hemodynamics. Elevated levels of N-terminal pro-brain natriuretic peptide and serum uric acid correlate with adverse right ventricular (RV) function and prognosis. ,, As connective tissue and collagen vascular diseases have a strong association with PAH, immunological tests may be done to rule out the same if the index of suspicion is high. HIV infection should be ruled out in all patients. Spiral CT chest has been successfully used in diagnosing chronic thromboembolic pulmonary arterial hypertension (CTEPH). It helps in visualizing thrombi in the pulmonary vasculature and also shows a mosaic perfusion of the lung parenchyma in CTEPH. Pulmonary angiography helps to confirm and rule out treatable forms of CTEPH in patients whose perfusion scans suggest segmental or lobar defects. MRI can help assess RV mass and volume and the presence of septal delayed contrast enhancement at the RV enhancement points correlates with the severity of PAH.  Right heart catheterization helps in confirming the diagnosis of PAH, exclusion of other causes, assessing the severity of the disease and establishing its prognosis. Acute vasodilatory testing may be done with drugs including adenosine, epoprostenol, and nitric oxide to assess pulmonary vasoreactivity which serves as a guideline while initiating treatment.  The six minute walk test helps in staging the disease, estimating prognosis and is used as an endpoint for calculating the efficacy of therapy. 
| » Management|| |
The diagnostic protocol mentioned should be followed to establish a correct diagnosis and rule out secondary causes. Baseline assessment of the disease should be carefully recorded through various modalities including cardiac catheterization and exercise testing. Vasoreactivity should be tested before initiating therapy with calcium channel blockers and non reactive patients should be offered other therapies. The beneficial effects of drug therapy should be closely monitored over six to eight weeks. Treatments which are not effective should be replaced.
| » General Measures|| |
Patients are advised to avoid heavy physical exertion and exposure to high altitude, while low grade aerobic exercises as tolerated are recommended. Patients should adhere to a sodium restricted diet and should be immunized against influenza and pneumococcus. Pregnancies should be avoided or terminated early as there is a high mortality rate associated with the same. Many PAH patients develop anxiety and depression and require psychosocial support. Elective surgeries carry an increased risk and if unavoidable, these patients should be administered epidural rather than general anesthesia. The following treatment is recommended:
| » Supportive Treatment|| |
This may help patients who experience activity induced hypoxia which in turn contributes to pulmonary vasoconstriction. ,
A few trials have shown improved survival in patients with PAH treated with oral anticoagulation. , Various guidelines recommend anticoagulation with warfarin in patients with IPAH and CTEPH. ,
This drug exerts a favorable effect in patients with RV failure with an approximate 10% increase in the resting cardiac output. ,
These drugs help markedly in symptom relief by taking care of the fluid overload related to right heart failure. ,
Acute Vasoreactivity Test and treatment with Calcium channel blockers
Current recommendations include the use of an oral calcium channel blocker in patients without right heart failure who have had a favorable response to acute vasodilator challenge on cardiac catheterization. , A favorable response is defined as a fall in mean pulmonary artery pressures of ≥ 10 mmHg and ≤ 40 mmHg on acute vasodilator testing with drugs like intravenous epoprostenol, adenosine, or inhaled nitric oxide. High doses of drugs including amlodipine (20 to 30 mg per day), nifedipine (180-240 mg per day), and diltiazem (720-960 per day) have to be used to realize full benefit. Verapamil should be avoided because of its negative inotropic effect. Patients initiated on calcium channel blockers should be closely followed up after three months and alternative PAH therapy should be considered in non responders.
| » Specific Drug Therapies|| |
Prostacyclin is a product of arachidonic acid metabolism and is a potent vasodilator of pulmonary and systemic circulations and also inhibits platelet aggregation. Prostacyclin levels are low in patients with PAH and this leads to a relative rise in thromboxane levels which further is responsible for vasoconstriction and smooth muscle proliferation.  Prostacyclin analogs including epoprostenol, treprostinil, iloprost, and beraprost are currently in use as therapeutic agents in PAH. The route of administration varies for most of them as intravenous, subcutaneous, inhalational, and oral depending on the individual half-life and mode of absorption.
Intravenous epoprostenol was the first prostacyclin analog approved by the US FDA for the treatment of PAH. It has a rapid onset of action and reaches steady state levels in less than fifteen minutes, but has a very short half life of less than six minutes; hence must be delivered by a continuous intravenous infusion via a tunneled catheter.  Patient education is a must for the use of epoprostenol as the sterile preparation of the drug and the infusion pump use must be done by the patient or his/her attendants. The starting dose of the drug is 2 ng/kg/min (started in the hospital) and this is usually up titrated to the chronic therapeutic dose of 25 to 40 ng/kg/min. A high output cardiac failure is a known adverse effect of cardiac overdose.  Side effects include flushing, headache, nausea, diarrhea, jaw discomfort with eating, chronic foot pain, and gastropathy. Local site infections and sepsis related to the catheter site are also known complications of epoprostenol use. Intravenous epoprostenol has been shown to improve symptoms, exercise capacity and prognosis in IPAH and also in PAH associated with scleroderma. 
Treprostinil is a prostacyclin analog with a longer half life (4.5 hours) and is stable at room temperature. It has been approved by the Food and Drug Administration (FDA) for use as a subcutaneous infusion for patients with functional class II, III, and IV PAH. Treprostinil was first studied in a multi-center trial of 470 patients of PAH and showed a significant improvement in exercise capacity and pulmonary hemodynamics at 12 weeks of treatment.  Intravenous treprostinil has also been evaluated, but there has been an increased overall infection rate noted compared to epoprostenol. Side effects of subcutaneous therapy include pain and erythema and at infusion site, headache, diarrhea, rash, and nausea. 
Iloprost is a synthetic prostanoid which can be delivered in an inhalational form through an adaptive aerosol device. It has been approved by the FDA for treatment of functional class III and IV patients with PAH.  It has to be administered six to nine times a day when the patient is awake. It is stable at room temperature and has minimal systemic side effects because of direct pulmonary deliverability. Disadvantages of iloprost include requirement of multiple doses and absence of treatment during sleep.  Common side effects include cough, headache, flushing, and jaw pain. Long term prospective data on iloprost use in PAH has shown only modest survival benefit  and hence its role has been suggested as an adjunctive to epoprostenol. ,
Beraprost is an orally active prostanoid which is not approved by the FDA, but is approved in Japan for the treatment of PAH. It has been shown to improve exercise capacity and symptoms at 12 weeks, but loses its efficacy over a year. 
Endothelin Receptor Blockers
Endothelial cells produce endothelin-1 which is one of the most potent vasoconstrictor ever isolated. ET-1, ET-2, and ET-3 are the members of a family of similar polypeptides, but each one is encoded by different genes. There are two different types of ET receptors which have been cloned, ET A and ET B . ET B receptor activation leads to decreased arterial pressure and natriuresis through effects on adrenal gland, heart (negative inotropy), decreasing sympathetic activity, and systemic vasodilatation. ET A receptor activation leads to increased arterial pressure and sodium retention via increased sympathetic activity, positive inotropy of the heart, increased catecholamine release, and systemic vasoconstriction.  The endothelin system is hyperactive in PAH with increased endothelin levels and up regulation of endothelin receptors in pulmonary vasculature. Various endothelin receptor blockers are available for therapy.
Bosentan is a non-selective endothelin antagonist blocking both ET A and ET B and was the first oral drug which was FDA approved for the treatment of PAH. Multiple trials have demonstrated the efficacy of bosentan in improving pulmonary hemodynamics and functional capacity in patients with PAH. Recent studies have demonstrated improved survival at one and two years post therapy. , Bosentan has also been studied in the pediatric age group and has demonstrated a significant hemodynamic improvement in pulmonary artery pressures. The approved dosage of bosentan is 125 mg twice a day and is the first line medication in patients who have the New York Heart Association (NYHA) class III to IV symptoms. Bosentan use causes a dose dependant increase in hepatic transaminases in 10% patients and dose reduction/interruption is recommended for a ≥ threefold rise.  There have been no reports of permanent liver damage. 
Sitaxsentan is an ET A receptor selective antagonist which is administered as a once daily oral dose. It is not FDA approved, but is currently in use in Europe and Canada. It is not as hepatotoxic as bosentan and a rise in prothrombin time is a frequent side effect because of the inhibition of CYP2C9 P450 enzyme which is involved in the metabolism of warfarin.  Ambrisentan is also a relatively selective ET A blocker which is FDA approved for PAH treatment in patients with functional class II and III symptoms. It is given as a five mg daily oral dose and studies have shown improvements in functional class and quality of life indices. There is little risk of hepatotoxicity. So far, there is no data on survival improvement with Ambrisentan therapy.  As a class, endothelin receptor antagonists are teratogenic and hepatotoxic to different degrees. Patients on these drugs should be regularly monitored with liver function tests and pregnancy tests in women of child bearing potential.
Nitric oxide (NO) is a vasodilator and inhibits smooth muscle cell proliferation. It is produced by nitric oxide synthase, the levels of which are decreased in patients with PAH. The effects of NO are mediated through cGMP which is degraded by phosphodiesterase (PDE) especially PDE-5. Hence, PDE-5 inhibitors have been used in the treatment of PAH as they prolong and increase the vasodilating effects of cGMP. Sildenafil is a highly selective PDE-5 inhibitor which was initially approved for the treatment of erectile dysfunction. It was subsequently found to have pulmonary vasodilatory effects and when administered orally has been shown to be as effective in improving pulmonary hemodynamics as inhaled NO.  Sildenafil has a preferential effect on the pulmonary circulation and has been shown to improve significantly the six minute walk distance and functional capacity in patients with PAH. The recommended dose is 20 mg three times a day and doses upto 80 mg three times a day have been used. However, escalation above the recommended dose has not been proved to be of additional benefit. Side effects include headache, flushing, dyspepsia, and epistaxis, but in general, the drug is well tolerated. 
Tadalafil is a longer acting PDE-5 inhibitor which is currently undergoing clinical trials and remains investigational as a therapeutic agent for patients with PAH. 
Vardenafil is a new PDE-5 inhibitor which has been approved for the treatment of erectile dysfunction, but is not yet approved for the treatment of PAH. It lacks selectivity for the pulmonary circulation even though it has the most rapid onset of action. 
| » Disease targeted therapy of PAH|| |
The ACCP 2007 recommendations  for PAH are based on functional class with other variables like six minute walk distance and right heart failure also being considered. These recommendations have targeted different functional classes with specific drug therapy (from the above mentioned groups of drugs).
Functional Class II: Approved therapies include oral sildenafil, intravenous and subcutaneous treprostinil, and oral ambrisentan. Sildenafil may be the first choice due to ease of oral therapy, better safety profile, and lower cost.
Functional Class III: Approved medications include bosentan/ ambrisentan, sildenafil, intravenous prostanoids like epoprostenol, inhaled iloprost or IV treprostinil. Oral medications are preferred in stable class III patients, while unstable patients should receive intravenous, inhaled, or subcutaneous prostanoids.
Functional Class IV: All available medications are approved for the therapy, but intravenous epoprostenol is the treatment of choice. Intravenous treprostinil is the second choice of therapy.
For patients with functional class I, no specific therapy as mentioned above is indicated; however, these patients may be initiated on general measures and supportive treatment and monitored for disease progression.
| » Combination Therapy|| |
As most of the medication mentioned above target different pathophysiological pathways, combination therapy targeting more than one pathway is likely to be more effective than monotherapy. The goal of combination therapy is to maximize efficacy and minimize toxicity. There may be synergism between two drug groups like prostanoids and PDE-5 inhibitors. The most commonly used combination is the addition of sildenafil to endothelin receptor antagonists, though the co-administration of bosentan and sildenafil can accentuate bosentan induced hepatotoxicity. 
| » Invasive Techniques|| |
Atrial septostomy: Creating an interatrial communication allows right to left shunting decompressing the right ventricle. It has been shown to be of benefit in patients with refractory right heart failure. 
Lung and combined heart lung transplant: These have been used as treatment options for 30 years with long term outcomes being comparable with patients with other primary indications for the same surgery. Hemodynamic studies, post-surgery, have shown improvement in pulmonary hemodynamics with reduction in pulmonary vascular resistance and improvement in right ventricular function. 
Pulmonary thromboendarterectomy may be considered as a treatment option in patients with CTEPH if they have surgically accessible disease. 
Right ventricular assist devices are investigational tools which may help in the control of refractory right heart failure. 
| » Controversies in treatment (use of ACE inhibitors)|| |
Previous publications suggested that inhibitors of the angiotensin converting enzyme (ACE) 1 could alleviate pulmonary hypertension and reduce right heart hypertrophy.  However, therapeutic interventions in animal models with PAH and clinical data do not support this fact. In addition, ACE inhibitors are known to possess anti hypertrophic properties in the myocardium. In patients with severe pre capillary pulmonary hypertension, in which adaptive right ventricular hypertrophy is an essential mechanism to cope with the increased afterload, pharmacological regression of the RVH could thus be potentially detrimental. 
| » Cost considerations|| |
The PAH specific oral therapies in India are expensive, and thus, beyond the reach of common man. The approximate annual cost is Rs. 15,000 for sildenafil and Rs. 48,000 and Rs. 83,000 for bosentan 62.5 mg and 125 mg, respectively.
| » Clinical response to treatment|| |
Adequate clinical response is defined as the achievement of a stable and a satisfactory clinical state, including absence of clinical signs of RV failure, stable WHO functional class I or II without syncope, a six minute walk distance of more than 500 meters, near normal or normal BNP plasma levels, no pericardial effusion, and right atrial pressures < 8mm Hg. ,,
Inadequate clinical response maybe stable and not satisfactory if the limits described above are not fulfilled although the general condition of the patient is stable or unstable and deteriorating if the patient has progression of signs and symptoms of RV failure, worsening functional WHO class, a six minute walk distance < 300 meters, rising BNP plasma levels, evidence of pericardial effusion and right atrial pressures >15 mmHg. ,,
| » Future Therapies|| |
Vasoactive Intestinal Polypeptide (VIP): VIP is a potent systemic and pulmonary vasodilator and its inhaled form has been found to improve hemodynamics in patients with PAH. 
Gene Therapy: As heritable PAH is most commonly associated with heterozygous mutations in the gene in BMPR2, the idea of using BMPR2 replacement gene therapy has raised the possibility of permanent cure of this disease. However, at this stage, no human clinical trial has been completed to show positive results in this therapeutic modality. The major hindrance to widespread acceptance and use of gene therapy is the limitation of vector technology. 
Targeting Pro-proliferative pathways: As PAH is characterized by excessive vasoconstriction and proliferation of vascular smooth muscle cells because of the over activity of several growth factors, these are being considered as potential therapeutic targets. Several case reports have suggested that in end stage pulmonary hypertensive patients, treatment with platelet derived growth factor (PDGF) inhibitor, imatinib could improve the clinical condition. , Serotonin is a mediator of vascular proliferation in pulmonary hypertension. Treatment of mice with overexpression of serotonin transporter with inhibitors of serotonin transporter has been found to limit PAH progression. 
| » Conclusion|| |
PAH is a complex condition which has to be understood as hemodynamic abnormality seen in different disease states. Different investigations are essential to diagnose the underlying etiology and to assess disease severity. Since the treatment varies with the etiology of PAH, it is important to diagnose the underlying etiology accurately. Significant improvements in patient outcomes have been noted with the three commonly used therapies including prostanoids, endothelin receptor blockers, and PDE-5 inhibitors. In our country, however, cost remains a major limiting factor in delivering these novel therapies to the common man.
| » References|| |
|1.||Badesch DB, Abman SH, Ahearn GS, Barst RJ, Simonneau G, Vallerie V, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:35S-62. |
|2.||Badesch DB, Abman SH, Simonneau G, Rubin LJ, Mclaughlin VV. Medical therapy for pulmonary arterial hypertension. Updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917-28. |
|3.||Reddy KS. Cardiovascular disease in non-western countries. N Engl J Med 2004;350:2438-40. |
|4.||Kumar RK, Shrivastava S. Pediatric heart care in India. Heart 2008;94:984-90. |
|5.||Chadha SL, Singh N, Shukla DK. Epidemiological study of congenital heart disease. Indian J Pediatr 2001;68:507-10. |
|6.||Gupta I, Gupta ML, Parihar A, Gupta CD. Epidemiology of congenital and rheumatic heart disease in children. J Indian Med Assoc 1992;90:57-9. |
|7.||Kumar RK, Rammohan R, Narula J, Kaplan EL. Epidemiology of streptococcal pharyngitis, rheumatic fever and rheumatic heart disease. In: Narula J, Virmani R, Reddy KS, Tandon R, editors. Rheumatic fever, Washington, DC; American Registry of Pathology; 1999. p. 41-78. |
|8.||McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:14S-34. |
|9.||Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995;99:249-54. |
|10.||Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70-5. |
|11.||White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, et al. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:583-90. |
|12.||Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. Faseb J 2005;19:1178-80. |
|13.||Landsberg JW, Yuan JX. Calcium and TRP channels in pulmonary vascular smooth muscle cell proliferation. News Physiol Sci 2004;19:44-50. |
|14.||Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 2001;104:790-5. |
|15.||McMurtry MS, Moudgil R, Hashimoto K, Bonnet S, Michelakis ED, Archer SL. Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;292:L872-8. |
|16.||McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115:1479-91. |
|17.||Eddahibi S, Raffestin B, Hamon M, Adnot S. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J Lab Clin Med 2002;139:194-201. |
|18.||Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science 2002;296:1646-7. |
|19.||Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML, Desai AA, Singleton PA, Sammani S, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 2008;33:278-91. |
|20.||Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-44. |
|21.||Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741-5. |
|22.||Michelakis ED, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation 2008;118:1486-95. |
|23.||Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361:1533-44. |
|24.||Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-61. |
|25.||Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609-16. |
|26.||Simmoneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Dominoghetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S. |
|27.||Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S-7S. |
|28.||Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54. |
|29.||Puchalski MD, Lozier JS, Bradley DJ, Minich LL, Tani LY. Electrocardiography in the diagnosis of right ventricular hypertrophy in children. Pediatrics 2006;118:1052-5. |
|30.||Raymond R, Hinderliter A, Willis P, Ralph D, Caldwell EJ, Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-9. |
|31.||Fijalkowska A, Kurzyna M, Torbicki A, Szewczysk G, Florczyk M, Pruszczyk P, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129:1313-21. |
|32.||Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, et al. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 1999;160:487-92. |
|33.||Torbicki A, Kurzyna M, Kuca P, Fijalkowska A, Sikora J, Florczyk M, et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 2003;108:844-8. |
|34.||Sanz J, Dellegrottaglie S, Kariisa M, Sulica R, Poon M, O'Donnell TP, et al. Prevalence and correlates of septal delayed contrast enhancement in patients with pulmonary hypertension. Am J Cardiol 2007;15:731-5. |
|35.||Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R, Arnold A, et al. The 6-minute walk test: A quick measure of functional status in elderly adults. Chest 2003;123:387. |
|36.||Kawut SM, Horn EM, Berekashvili KK, Garofano RP, Goldsmithth RL, Wildsmit AC, et al. New predictors of outcome in idiopathic pulmonary arterial hypertension. Chest 2008;134:139-45. |
|37.||Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81. |
|38.||Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70-5. |
|39.||Badesch DB, McLaughlin VV, Delcroix M, Vizza CD, Olschewski H, Sitbon O, et al. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:56S-61. |
|40.||Barst RJ, McGoon M, McLAughlin V, Tapson V, Oudiz R, Shapiro S, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119-25. |
|41.||Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302. |
|42.||Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analog, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-4. |
|43.||Tapson VF, Gomberg-Maitland M, McLaughlin VV, Benza RL, Widlitz AC, Krichman A, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: A prospective, multicentre, open label, 12-week trial. Chest 2006;129:683-8. |
|44.||Olschewski H, Simonneau G, Galie N, Higenbottam T, Naije R, Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9. |
|45.||Opitz CF, Wensel R, Winkler J, Halank M, Bruch L, Kleber FX, et al. Clinical efficacy and survival with first line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J 2005;26:1895-902. |
|46.||Diedrich D, Yang ZH, Buhler FR, Luscher TF. Impaired endothelium dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway. Am J Physiol 1990;258:H445-51. |
|47.||Mclaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, et al. Survival with first line Bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244-9. |
|48.||Sitbon O, McLaughlin VV, Badesch DB, Barst RJ, Black C, Galiè N, et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax 2005;60:1025-30. |
|49.||Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmokinetics, safety and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmocol Ther 2003;73:372-82. |
|50.||Price LC, Howard LS. Endothelin receptor antagonists for pulmonary arterial hypertension. Rationale and place in therapy. Am J Cardiovasc Drugs 2008;8:171-85. |
|51.||Safdar Z. Effect of transition from sitaxsentan to ambrisentan in pulmonary arterial hypertension. Vasc Health Risk Manag 2011;7:119-24. |
|52.||Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57. |
|53.||Ghofrani AH, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, et al. Differences in Hemodynamic and Oxygenation Responses to Three Different Phosphodiesterase-5 Inhibitors in Patients With Pulmonary Arterial Hypertension. J Am Coll Cardiol 2004;44:1488-96. |
|54.||Benza RI, Rayburn BK, Tallaj JA, Pamboukian SV, Bourge RC. Treprostinil based therapy in the treatment of moderate to severe pulmonary arterial hypertension. Chest 2008;134:139-45. |
|55.||Kothari SS, Yusuf A, Juneja R, Yadav R, Naik N. Graded balloon atrial septostomy in sever pulmonary hypertension. Indian Heart J 2002;54:164-9. |
|56.||Hertz M, Taylor D, Trulock E, Boucek MM, Mohacsi PJ, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: 19 th official report - 2002. J Heart Lung Transplant 2002;21:950. |
|57.||Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011-20. |
|58.||Kindo M, Radovancevic B, Gregoric ID, Conger JL, Kadipasaoglu K, Tamez DA, et al. Biventricular support with a Jarvik 200- ventricular assist device in a calf model of pulmonary hypertension. ASAIO J 2004;50:444-50. |
|59.||Okada K, Bernstein ML, Zhang W, Schuster DP, Botney MD. Angiotensin converting enzyme inhibition delays pulmonary vascular neointimal formation. Am J Respir Crit Care Med 1998;158:939-50. |
|60.||Gladwin MT, Ghofrani AH. Update on Pulmonary Hypertension 2009. Am J Respir Crit Care Med 2010;181:1020-6. |
|61.||Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al. Long term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-8. |
|62.||Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865-70. |
|63.||Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-9. |
|64.||Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339-46. |
|65.||Reynolds PN. Gene therapy for pulmonary hypertension: prospects and challenges. Expert Opin. Biol Ther 2011;11:133-43. |
|66.||Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412-3. |
|67.||Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006;145:152-3. |
|68.||Guilluy C, Eddahibi S, Agard C, Guignabert C, Izikki M, Tu L, et al. Rho A and Rho kinase activation in human pulmonary hypertension: Role of 5-HT signalling. Am J Respir Crit Care Med 2009;179:1151-8. |
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Serum expression of Rho kinase, endothelin-1, and nitric oxide in pediatric patients with congenital heart disease accompanied by pulmonary hypertension
| ||Xing-Zhen Sun, Jian Hu, Xiang-Yang Tian, Ze Hong |
| ||Asian Journal of Surgery. 2021; |
|[Pubmed] | [DOI]|
||Pulmonary hypertension in majority countries: opportunities amidst challenges
| ||Gerald J. Maarman, Jane Shaw, Brian Allwood |
| ||Current Opinion in Pulmonary Medicine. 2020; 26(5): 373 |
|[Pubmed] | [DOI]|
||PHARMACOTHERAPY OF PULMONARY HYPERTENSION DURING PREGNANCY AND POSTPARTUM PERIOD
| ||E A Ushkalova, N K Runihina, I M Novikova |
| ||I.P. Pavlov Russian Medical Biological Herald. 2013; 21(1): 129 |
|[Pubmed] | [DOI]|
||Pulmonary Arterial Hypertension in Pediatric Patients with Hematopoietic Stem Cell Transplant–Associated Thrombotic Microangiopathy
| ||Sonata Jodele,Russel Hirsch,Benjamin Laskin,Stella Davies,David Witte,Ranjit Chima |
| ||Biology of Blood and Marrow Transplantation. 2013; 19(2): 202 |
|[Pubmed] | [DOI]|
||Pulmonary Arterial Hypertension: New Insights Into the Optimal Role of Current and Emerging Prostacyclin Therapies
| ||Aaron B. Waxman,Roham T. Zamanian |
| ||The American Journal of Cardiology. 2013; 111(5): 1A |
|[Pubmed] | [DOI]|