**10. Calcium Channel Blocker therapy (CCB)**

These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. The use of CCBs should be limited to patients without overt evidence of right-sided heart failure. In patients with IPAH (or any other form of PAH), a cardiac index of less than 2 L/min/m2 or a right atrial pressure above 15 mm Hg is a contraindication to CCB therapy, as these agents may worsen right ventricular failure in such cases.

#### **10.1. Specific vasodilator therapy**

These drugs in general work by dilating the pulmonary arteries and, therefore, by reducing the pressure in these blood vessels and some help prevent the excessive overgrowth of tissue in the blood vessels (that decrease remodeling of the vessels). Common side effects include cough, flushing, and headache. Inhaled therapies may be useful as an adjunct to oral therapy.

There are three major classes of drugs used to treat pulmonary arterial hypertension:

#### **10.2. Prostacyclins**

travelers with PH, who will be traveling on long flights or those with a history of oxygen use, should be considered for supplemental in-flight oxygen.[32]. A flight simulation test

**•** Digoxin is reserved for patients with refractory right ventricular failure and for rate control

**•** No specific diet is recommended; however, a low-sodium and low-fluid diet is recom‐ mended in patients with significant volume overload due to right ventricular failure.

**•** Exercise training is well tolerated and improves quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload.[38] Patients with pulmonary hypertension and heart failure should perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight

**•** Vaccination against influenza and pneumococcal pneumonia and avoidance of pregnancy.

Diagnostic catheterization followed by pharmacological testing of vasodilator therapy response is required to test the pulmonary vasoreactivity in patients with IPAH before prescribing a vasodilator. The most commonly used drugs are: iv prostacyclin, iv adenosine, inhaled nitric oxide and inhaled iloprost. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents. A complete right heart catheterization and an invasive monitoring of the systemic pressures are mandatory. The increased pulmonary vascular resistance results from extensive vascular changes and vasoconstriction. Therefore, in pulmonary hypertension true pulmonary vasodilation is only present if, in addition to a decreased pulmonary vascular resistance, reductions in the transpulmonary gradient and the

A positive test or 'responder to vasodilator' is defined as a drop in mPAP of ≥ 10 mmHg to an absolute level < 40 mmHg. A positive test is observed in 10-15% of patients with IPAH. However half of these patients will have a long-term response to calcium channel blockers

Only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, epoprostenol, nitric oxide) derive any long-term benefit from CCBs. Such patients constitute less than 15% of patients with IPAH and probably

Patients who do not have an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy compared with those who have an initial response. These non-responders are those who have no significant change of the mean

**9. Pulmonary vascular reactivity testing and vasodilator therapy**

before the flight can help determine oxygen needs at altitude.[24],[35]

**•** Diuretics are indicated for right ventricular volume overload

in atrial flutter or fibrillation. [24],[35],[37]

mean pulmonary artery pressure are achieved.

less than 3% of patients with other forms of PAH. [24], [35], [39]

(CCB). [39]

lifting) are contraindicated.

10 Pulmonary Hypertension

Prostacyclin dilates systemic and pulmonary arterial vascular beds. These short acting drugs include epoprostenol [41] (Flolan), treprostinil (Remodulin), iloprost [42] (Ventavis), Trepros‐ tinil (Tyvaso). Parenteral vasodilators are used for patients whose IPAH fails to respond to calcium channel blockers or who cannot tolerate these agents and who have New York Heart Association (NYHA) type III or IV right-sided heart failure.

Long-term treatment with intravenous PGI2 improves exercise capacity, hemodynamics, and survival in most patients with PPH in NYHA functional class III or IV. Despite these favorable outcomes, continuous intravenous infusion of PGI2 is not ideal due to its cost and side effects such as flushing, headache, jaw pain, diarrhea and incidence of catheter-related infections. Survival of patients with PPH treated with epoprostenol depends on the severity at baseline, as well as the three-month response to therapy. Lung transplantation should be considered in a subset of patients who remain in NYHA functional class III or IV or in those who cannot achieve a significant hemodynamic improvement after three months of epoprostenol therapy, or both. [40]

### **10.3. Phosphodiesterase type 5 Inhibitors (PDE5i)**

PDE5 inhibitors such as sildenafil [43] (Revatio, Viagra) is an orally active pulmonary vaso‐ dilators. (The dosing is much different when these drugs are used for erectile dysfunction). These drugs promote selective smooth muscle relaxation in lung vasculature by inhibiting PDE5 thereby stabilizing cyclic guanosine monophosphate (cGMP, the second messenger of nitric oxide), allowing a more sustained effect of endogenous nitric oxide, an indirect but effective and practical way of using the NO-cGMP pathway. Sildenafil improves exercise capacity, World Health Organization (WHO) functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. The main side effects of Sildenafil include headache, flushing, dyspepsia, nasal congestion, and epistasis Nitrates should be avoided in patients taking PDE5 inhibitors because the additive effects of the drugs may cause severe systemic hypotension. [44]

**10.5. Combination therapy**

such as lung transplantation.

*10.6.1. Atrial septostomy*

*10.6.2. Lung transplantation*

*10.6.3. Pulmonary thromboendarterectomy*

**10.6. Surgery**

[35],[37]

Patients with PAH may experience clinical and hemodynamic deterioration despite treatment with a single agent. This circumstance requires the addition on a second agent to slow disease progression and aid in clinical improvement.[35],[37] Different combinations have been tried, however current guidelines do not favor a particular combination over others. Several studies are on-going to compare the efficacy of single agent versus combination therapy. Failure of combination therapy requires consideration for parenteral therapy and surgical intervention

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13

Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating in the setting of severe disease with recurrent syncope or right heart failure (or both) despite maximal medical therapy. The procedure can also be used as a bridge to lung transplantation. The rationale for its use is that the controlled creation of an atrial septal defect would allow right-to-left shunting, leading to increased systemic output and systemic oxygen transport despite the accompanying fall in systemic arterial oxygen saturation. The shunt at the atrial level would also allow decompression of the right atrium and right ventricle, alleviating signs and symptoms of right heart failure. Balloon atrial septostomy is a high-risk procedure and should be performed only in experienced centers to reduce the procedural risks.

Lung transplantation has been used in treatment for pulmonary hypertension since the 1980s, even before current medical therapies were available. It is indicated in PAH patients with advanced disease that is refractory to available medical therapy. A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this depends on the transplant institution. The 3- and 5- year survival rates after lung and heart-lung transplantation are approximately 55% and 45%, respectively. [35],[37]

Pulmonary thromboendarterectomy provides a potential surgical cure and should be consid‐ ered in all patients with chronic thromboembolic PAH (CTEPH) affecting central pulmonary arteries. Pulmonary angiography is required to confirm surgical accessibility of chronic thromboemboli. The procedure requires cardiopulmonary bypass and involves dissecting well-organized thromboembolic material as well as part of the intimal layer of the pulmonary arterial bed. Patients with suspected CTEPH should be referred to centers experienced in the procedure for consideration of this procedure. In patients with operable CTEPH, pulmonary

#### **10.4. Endothelin Receptor Antagonists (ERAs)**

Endothelin-1 is a 21–amino acid peptide that plays a key role in the pathobiology of PAH,[45], [46] exerting vasoconstrictor and mitogenic effects by binding to 2 distinct receptor isoforms in the pulmonary vascular smooth muscle cells, endothelin A and B receptors.[47] Endothelin B receptors also are present in endothelial cells, and their activation leads to release of vasodilators and antiproliferative substances such as nitric oxide and prostacyclin that may counterbalance the deleterious effects of endothelin-1.[47]

Bosentan is effective in patients with FC III / IV [48] but more recently bosentan was demon‐ strated to increase the 6 MWD from baseline in FC II patients as well [49]. Sitaxentan, a selective endothelin (ET)-A receptor antagonist, has negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan with reduced hepatotox‐ icity. [50] Dosing is once daily, as opposed to twice daily for bosentan.

Ambrisentan is a nonsulfonamide, propanoic acid– based, A-selective endothelin receptor antagonist with a bioavailability and half-life that allow once-daily dosing. In the ARIES study [51], Ambrisentan showed improvements in 6-minute walk distance in patients with WHO functional class II and III symptoms. It is well tolerated and is associated with a low risk of aminotransferase abnormalities. The most frequent side effects of ambrisentan are fluid retention (ranging from swelling of the extremities to heart failure), nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain and constipation.

ACCP guidelines recommend using the patient's New York Heart Association (NYHA) functional class to guide the choice of vasodilator therapy.[52] Grade A recommendations for vasodilator therapy by functional class from the ACCP are as follows:


#### **10.5. Combination therapy**

Patients with PAH may experience clinical and hemodynamic deterioration despite treatment with a single agent. This circumstance requires the addition on a second agent to slow disease progression and aid in clinical improvement.[35],[37] Different combinations have been tried, however current guidelines do not favor a particular combination over others. Several studies are on-going to compare the efficacy of single agent versus combination therapy. Failure of combination therapy requires consideration for parenteral therapy and surgical intervention such as lung transplantation.

#### **10.6. Surgery**

**10.3. Phosphodiesterase type 5 Inhibitors (PDE5i)**

**10.4. Endothelin Receptor Antagonists (ERAs)**

counterbalance the deleterious effects of endothelin-1.[47]

icity. [50] Dosing is once daily, as opposed to twice daily for bosentan.

flushing, palpitations, nasopharyngitis, abdominal pain and constipation.

vasodilator therapy by functional class from the ACCP are as follows:

**•** Functional class II - Sildenafil

**•** Functional class IV - Intravenous epoprostenol.

or inhaled iloprost

systemic hypotension. [44]

12 Pulmonary Hypertension

PDE5 inhibitors such as sildenafil [43] (Revatio, Viagra) is an orally active pulmonary vaso‐ dilators. (The dosing is much different when these drugs are used for erectile dysfunction). These drugs promote selective smooth muscle relaxation in lung vasculature by inhibiting PDE5 thereby stabilizing cyclic guanosine monophosphate (cGMP, the second messenger of nitric oxide), allowing a more sustained effect of endogenous nitric oxide, an indirect but effective and practical way of using the NO-cGMP pathway. Sildenafil improves exercise capacity, World Health Organization (WHO) functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. The main side effects of Sildenafil include headache, flushing, dyspepsia, nasal congestion, and epistasis Nitrates should be avoided in patients taking PDE5 inhibitors because the additive effects of the drugs may cause severe

Endothelin-1 is a 21–amino acid peptide that plays a key role in the pathobiology of PAH,[45], [46] exerting vasoconstrictor and mitogenic effects by binding to 2 distinct receptor isoforms in the pulmonary vascular smooth muscle cells, endothelin A and B receptors.[47] Endothelin B receptors also are present in endothelial cells, and their activation leads to release of vasodilators and antiproliferative substances such as nitric oxide and prostacyclin that may

Bosentan is effective in patients with FC III / IV [48] but more recently bosentan was demon‐ strated to increase the 6 MWD from baseline in FC II patients as well [49]. Sitaxentan, a selective endothelin (ET)-A receptor antagonist, has negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan with reduced hepatotox‐

Ambrisentan is a nonsulfonamide, propanoic acid– based, A-selective endothelin receptor antagonist with a bioavailability and half-life that allow once-daily dosing. In the ARIES study [51], Ambrisentan showed improvements in 6-minute walk distance in patients with WHO functional class II and III symptoms. It is well tolerated and is associated with a low risk of aminotransferase abnormalities. The most frequent side effects of ambrisentan are fluid retention (ranging from swelling of the extremities to heart failure), nasal congestion, sinusitis,

ACCP guidelines recommend using the patient's New York Heart Association (NYHA) functional class to guide the choice of vasodilator therapy.[52] Grade A recommendations for

**•** Functional class III - Endothelin-receptor antagonists (bosentan), sildenafil, IV epoprostenol,

#### *10.6.1. Atrial septostomy*

Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating in the setting of severe disease with recurrent syncope or right heart failure (or both) despite maximal medical therapy. The procedure can also be used as a bridge to lung transplantation. The rationale for its use is that the controlled creation of an atrial septal defect would allow right-to-left shunting, leading to increased systemic output and systemic oxygen transport despite the accompanying fall in systemic arterial oxygen saturation. The shunt at the atrial level would also allow decompression of the right atrium and right ventricle, alleviating signs and symptoms of right heart failure. Balloon atrial septostomy is a high-risk procedure and should be performed only in experienced centers to reduce the procedural risks. [35],[37]

#### *10.6.2. Lung transplantation*

Lung transplantation has been used in treatment for pulmonary hypertension since the 1980s, even before current medical therapies were available. It is indicated in PAH patients with advanced disease that is refractory to available medical therapy. A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this depends on the transplant institution. The 3- and 5- year survival rates after lung and heart-lung transplantation are approximately 55% and 45%, respectively. [35],[37]

#### *10.6.3. Pulmonary thromboendarterectomy*

Pulmonary thromboendarterectomy provides a potential surgical cure and should be consid‐ ered in all patients with chronic thromboembolic PAH (CTEPH) affecting central pulmonary arteries. Pulmonary angiography is required to confirm surgical accessibility of chronic thromboemboli. The procedure requires cardiopulmonary bypass and involves dissecting well-organized thromboembolic material as well as part of the intimal layer of the pulmonary arterial bed. Patients with suspected CTEPH should be referred to centers experienced in the procedure for consideration of this procedure. In patients with operable CTEPH, pulmonary thromboendarterectomy is the treatment of choice because it improves hemodynamics, functional status, and survival. [35],[37]

class IV with signs of right heart failure, enlarged right atria and ventricle with right ventricular dysfunction and cannot walk more than 300 meters on 6 MWD testing are considered high

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15

The one-year survival of patients with newly diagnosed group 1 PAH can be predicted using a risk score derived from the Registry to Evaluate Early and Long-term PAH Disease Man‐ agement (i.e. the REVEAL registry). This risk score was validated by a prospective cohort study of 504 patients with a mean 6-minute walk testing (6 MWD) of 308 m and 61.5 percent classified as WHO functional class III, which found that a risk score of 1 to 7, 8, 9, 10 to 11, and ≥ 12

Severity of PAH – Patients with severe PAH or right heart failure (i.e., cor pulmonale) die sooner without treatment (usually within one year) than patients with mild PAH or no right heart failure. As an example, patients with IPAH and a mean right atrial pressure ≥ 20 mmHg

In conclusion, age, PAH etiology, World Health Organization functional class, pericardial effusion, 6MWT distance, the need for oxygen during the 6MWT, and brain natriuretic peptide are predictors of prognosis in patients PAH receiving specific therapy and might help identify

Since survival in patients who fall into NYHA classes III or IV is poor (9-18 months), patients with severe symptoms and evidence of impaired cardiac function, which is refractory to conventional therapy or epoprostenol infusion should be considered for lung transplantation.

[1] Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hyperten‐

[2] Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmo‐

[3] Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemi‐

correlated with one-year survival of 95, 92, 89, 72, and 66 percent, respectively. [56]

risk group of pattients with pulmonary hypertension. [25], [55]

have a median survival of approximately one month.[10]

**Author details**

**References**

Dr Saleem Sharieff MBBS, FCPS, FRCPC1,2

1 Grand River Hospital, Kitchener, ON, Canada

sion. J Am Coll Cardiol 2004; 43:5S.

nary hypertension. J Am Coll Cardiol 2009; 54:S43-54.

ology and pathogenesis. *Cleve Clin J Med* 2003; 70 Suppl 1:S2-8.

2 McMaster University Hospital, Hamilton, ON, Canada

a group that could benefit from aggressive upfront therapy. [57]
