Pulmonary Hypertension


Article Author:
Sean Oldroyd


Article Editor:
Abhishek Bhardwaj


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
5/6/2019 12:24:52 AM

Introduction

Pulmonary hypertension encompasses a heterogeneous group of disorders with the common feature of elevated pulmonary vascular resistance. Patients often present with nonspecific symptoms of worsening weakness and dyspnea on exertion. Pulmonary hypertension is a progressive disease with treatment focused on management of symptoms and treatment of underlying diseases.[1]

Etiology

Pulmonary hypertension (PH) arises from many etiologies. In 1998, the World Health Organization (WHO) organized PH into 5 classifications according to the cause, and these classifications were updated in 2013 (figure 1). Group 1 can be thought of as primary pulmonary hypertension, or pulmonary arterial hypertension (PAH). Among this group, idiopathic PAH is the most common condition, with other causes such as toxin-induced, connective tissue disorders, and other related conditions being less prevalent. Group 2 involves PH due to left heart disease, which is the most common cause of PH. Group 3 PH is due to lung diseases such as chronic obstructive pulmonary disease and interstitial lung disease. Chronic pulmonary thromboembolism causes group 4 PH, and group 5 PH is due to unclear or multifactorial causes, as noted in the figure.[1][2][3][4]

Epidemiology

PAH is a rare disease. The estimated prevalence is between 15 and 50 cases per million individuals. Among those with PAH, idiopathic PAH is the most common and is more common in women than men. Pulmonary hypertension due to other diseases, such as chronic heart or lung diseases, reflects epidemiology similar to the associated disease.[5][6]

Pathophysiology

PAH is most-commonly idiopathic and is characterized by increased vascular resistance and blood vessel narrowing within the pulmonary vasculature. Restricted flow through pulmonary arteries, as found in PAH, is thought to have molecular and genetic causes which lead to hypertrophy of smooth muscle, endothelial cells, and adventitia. In response to the increased resistance, the right ventricle will increase filling and stroke volume, which further increases pulmonary arterial pressure. Over time, right ventricular hypertrophy develops. In the other groups of PH, increased pulmonary vascular resistance is similarly due to restricted flow, but it is typically secondary to another process such as left heart disease, chronic lung disease or chronic pulmonary thromboembolism.[1]

Histopathology

In idiopathic PAH, arterial walls show medial hypertrophy, with the proliferation of endothelial cells, smooth muscle cells, fibroblasts, and myofibroblasts, as well as the transition of endothelial cells in the pulmonary arteries to smooth muscle-like mesenchymal cells. Additionally, there may be an inflammatory component of PAH, as affected vessels display increased macrophages and lymphocytes.

History and Physical

The presenting symptoms of PH will reflect the underlying cause of hypertension, but PH patients will typically complain of dyspnea, fatigue, angina, and they may present after a syncopal episode. Group one PH patients will often complain about steadily worsening dyspnea on exertion.[1] Similarly, the physical exam may be nonspecific, but symptoms typically reflect the degree of right ventricular (RV) dysfunction. As RV function decreases, blood pressure may be normal to low, and jugular venous pulsations may be noted. Murmurs may be auscultated and reflect the underlying cause. Right-sided murmurs, such as tricuspid regurgitation, may develop as right heart strain and dilation increased. An aortic or mitral stenosis murmur points to left heart disease as a contributing factor in the patient’s PH. The remainder of the exam may reflect signs of right heart failure, such as hepatomegaly, peripheral edema, and ascites. 

Evaluation

Biomarkers that are commonly evaluated in the context of heart diseases, such as brain natriuretic peptide (BNP) and troponin, are commonly measured in patients suspected of having PH, but there is no clearly-established role for these tests in the diagnosis of PH. The 6-minute walk test is useful to establish a baseline of functional performance as well as to monitor the progression of the disease. A chest radiograph may be useful to evaluate for signs of cardiomegaly, increased right ventricular size, or pulmonary vascular congestion which may be seen in left heart disease. [1] [7]

Electrocardiogram (ECG) may show signs of left heart disease such as left ventricular hypertrophy in group two PH. Right axis deviation as well as upright R waves in V1-V2 with deeper S waves in V5-V6 may represent right ventricular hypertrophy or right heart strain and can be seen in PAH. Similar to chronic lung diseases such as chronic obstructive pulmonary disease, frequent premature atrial contractions, and multifocal atrial tachycardia may be present on ECG.[1] 

The noninvasive screening test of choice is a transthoracic echocardiogram. Pulmonary artery systolic pressure greater than 40 mm Hg or mean pulmonary artery pressure (PAP) of 25 mm Hg should indicate further evaluation for pulmonary hypertension. Other noninvasive measures may be used as indirect markers of PH, such as the Tei myocardial performance index, which measures the efficiency of the RV, and the tricuspid annular plane systolic excursion (TAPSE), which will decrease as the RV dilates and function declines.[1]

Right heart catheterization allows for measurement of mean PAP as well as pulmonary capillary wedge pressure (PCWP). Mean PAP greater than 25 mm Hg with associated PCWP less than 15 mm Hg is diagnostic of PAH, while elevated mean PAP and PCWP greater than 15 mm Hg is typical in patients with PH due to left heart disease. Vasoreactivity testing may be done during right heart catheterization, in which nitric oxide or another vasodilator is administered during the procedure. A reduction of 10 mmHg or more in mean PAP without a reduction in cardiac output is considered a positive vasoreactivity test.[1] [7]

Treatment / Management

Treatment of pulmonary hypertension secondary to other diseases (groups 2 to 4) should focus on treatment of the underlying disease, and there is no established role for the medications indicated for PAH in these patients.[1]  Group one PH treatment can be considered a stepwise progression, and typically requires referral to a center equipped to diagnosis, treat, and monitor PAH. Calcium channel blockers such as nifedipine, diltiazem, and amlodipine are useful in patients with a positive vasoreactivity test. For patients with a negative vasoreactivity test or who have an inadequate response to calcium channel blockers. Treatment is focused on decreasing pulmonary vascular resistance and PAP but is not curative.[8][9][10][11]

Endothelin receptor antagonists such as ambrisentan, bosentan, and macitentan bind to endothelin and inhibit vasoconstriction that is typically caused by endothelin. These can be given orally and are recommended for mild and moderate disease, NYHA class II and III. Phosphodiesterase 5 (PDE-5) inhibitors (tadalafil, sildenafil, vardenafil) inhibit enzymatic processes and result in increased cyclic guanosine monophosphate, causing pulmonary and systemic vasodilation. Prostaglandin analogs replete the decreased prostaglandin that is decreased in pulmonary hypertension. These activate the prostacyclin receptor which will ultimately lead to pulmonary vasodilation. Epoprostenol is given as a continuous intravenous infusion, and treprostinil may be given intravenously, subcutaneously, orally, and via inhalation. [12][13]

Patients with PH due to chronic thromboembolism should be referred for evaluation for endovascular thrombectomy. The final treatment option for patients who fail aggressive medical treatment is heart-lung transplantation.[1] [14]

Differential Diagnosis

Diagnosis of PH is commonly delayed as the presenting symptoms overlap other disease processes. Other conditions to be considered in the differential diagnosis include, but are not limited to, congestive heart failure, coronary artery disease, pulmonary fibrosis, chronic obstructive pulmonary disease, valvular heart disease, hypothyroidism, and pulmonary embolism.[1]

Enhancing Healthcare Team Outcomes

Pulmonary hypertension has many causes and without treatment, it carries high morbidity and mortality. The condition is best managed by a multidisciplinary team that includes a pulmonologist, cardiologist, thoracic surgeon, radiologist, pathologist, specialty nurses and an internist. The key is to treat the primary condition causing pulmonary hypertension. The majority of causes of secondary pulmonary hypertension are cardiac and lung disorders with a minor contribution from other vasculitic syndromes. Without treatment, premature death is common. Those who are treated do have a longer life expectany but lack of medication compliance/treatment can lead to a poor quality of life.[15][16][17] (Level V)


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    Contributed by Sean Oldroyd
Attributed To: Contributed by Sean Oldroyd

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Pulmonary Hypertension - Questions

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A 33-year-old female is admitted to the hospital with a possible diagnosis of pulmonary hypertension. She says she has not felt well for the past 12 months and is getting worse. She complains of progressive dyspnea, fatigue, substernal chest pain, and episodic spells of fainting. Of the following features on auscultation, which is least consistent with a diagnosis of pulmonary hypertension?



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In a 44-year-old with idiopathic pulmonary arterial hypertension, one would expect to find which of the following?



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What is an initial goal for the management of pulmonary hypertension?



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Which of the following will be elevated in a patient with pulmonary hypertension?



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Bosentan is a drug that is approved for use in pulmonary arterial hypertension. What is the mechanism of action of this drug?



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Which of the following groups with pulmonary arterial hypertension (PAH) has a contraindication to calcium channel blocker (CCB) therapy?



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What test is the gold standard for diagnosing pulmonary hypertension?



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What clinical finding is characteristic of pulmonary hypertension?



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Primary pulmonary hypertension characteristically occurs in which of the following populations?



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A patient with pulmonary hypertension requires a cardiac transplant. He undergoes an exhaustive work-up and his pulmonary resistance is 8 Wood's units. What is the next step in his management?



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A 46-year-old female is recently diagnosed with sarcoidosis by her pulmonologist and has scheduled a follow up with her primary care provider. At the visit, she has no symptoms and is concerned about long-term effects of her condition on her cardiovascular health. After reading the pulmonologist's note, it is clear to you that the resistance in the patient's pulmonary vasculature will be markedly increased due to her disease. What cardiovascular structure would be expected to have the greatest increase in pressure due to her sarcoidosis?



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Which of the following is correctly associated with pulmonary hypertension? Select all that apply.



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A 37-year old female with chronic progressive shortness of breath and dyspnea undergoes a right heart catheterization. A calcium channel blocker is administered intravenously to assess for reactivity of the pulmonary vessels. After the calcium channel blocker was given, the patient had a decrease in mean arterial pressure of 5 mmHg with the mean pulmonary arterial pressure decreasing to 40 mmHg. Her cardiac output dropped by 10%. What is the best next step in management?



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Pulmonary Hypertension - References

References

ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association., McLaughlin VV,Archer SL,Badesch DB,Barst RJ,Farber HW,Lindner JR,Mathier MA,McGoon MD,Park MH,Rosenson RS,Rubin LJ,Tapson VF,Varga J,, Journal of the American College of Cardiology, 2009 Apr 28     [PubMed]
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