Cardiology Pulmonary Hypertension Case File

Pulmonary Hypertension Case File

Eugene C. Toy, Md, Michael d . Faulx, Md

Case 29

A 37-year-old woman presents to her primary care physician with a 9-month history of swelling in her legs. She admits to cutting down on her weekly exercise routine as she “feels extremely tired with exercise.” Her medical history is significant for limited systemic sclerosis (SSc) diagnosed 8 years ago. On exam, vital signs are within normal limits. Heart auscultation reveals a loud P2, and a systolic murmur at the left sternal border that increases with inspiration. Jugular venous pressure is elevated at 8 cm H2O. The lungs are clear to auscultation. Examination of the lower extremities reveals 2+ pitting edema that extends to the midleg. Chest x-ray shows mildly dilated pulmonary arteries but is otherwise normal.

• What is the most likely diagnosis?
• What is the best next diagnostic step?
• What is the best next therapeutic step?

Answer to Case 

Pulmonary Hypertension

Summary: A 37-year-old woman with a history of limited systemic sclerosis (SSc) is now presenting with signs and symptoms consistent with right-heart failure.

• Most likely diagnosis: Pulmonary arterial hypertension (PAH).
• Next diagnostic step: Echocardiogram.
• Next therapeutic step: Pulmonary vasodilators in addition to diuretics.

ANALYSIS

Objectives

1. Understand the classification of pulmonary hypertension (PH).
2. Recognize the integral role of right-heart catheterization in the diagnosis of PH.
3. Interpret hemodynamic values based on heart catheterization.
4. Recognize the relatively poor prognosis of this disease despite various therapeutic options.

Considerations

This is a young woman who is presenting with signs and symptoms of right-heart failure. Her presenting symptom is lower limb edema. The differential diagnosis of bilateral lower limb edema commonly includes venous insufficiency, nephrotic syndrome, cirrhosis, and heart failure. Her exertional symptoms and diminished functional capacity, in addition to the jugular venous distension, make heart failure more likely. A common cause of right-heart failure seen in clinical practice is actually left-heart failure. Given the clear lung exam and lack of pulmonary edema on chest x-ray, PAH is the likely cause of the right-heart failure. Moreover, left-heart failure is usually caused by ischemic and structural diseases of the heart, entities that are rare in this age group.

Approach To:

Pulmonary Hypertension

DEFINITIONS

Pulmonary Capillary Wedge Pressure (PCWP): Value obtained during right-heart catheterization that reflects left atrial pressure and therefore filling pressures on the left side of the heart. Normal values range from 5 to 12 mmHg (<15 mmHg).

Pulmonary Hypertension (Ph ): Mean pulmonary artery pressure (mPAP) > 25 mmHg.

Pulmonary Venoushy Pertension: Left-heart disease (left atrial hypertension) as the cause of PH.

Transpulmonary Gradient (tpg ): PCWP – mPAP. Normal value < 12 mmHg.

CLINICAL APPROACH

Causes and Classification

The diagnosis oh Ph is made on a hemodynamic basis with mpa P> 25mmh g. The current classification scheme utilizes differences in clinical features and treatment of the various groups (Table 29-1). An important diagnostic goal is to distinguish PAH from PH due to left-heart disease. The latter is referred to as pulmonary venous hypertension and has a distinctly different prognosis and therapeutic approach. It should be noted that chronic thromboembolic pulmonary hypertension (CTEPH), a complication of pulmonary hypertension that occurs in approximately 4% of patients with acute pulmonary emboli, is classified as a separate group because of its potential surgical curability.

The normal physiologic response to hypoxia is vasodilation. A notable exception is the pulmonary circulation, in which hypoxia causes vasoconstriction in an attempt to redistribute blood to better-ventilated areas. This partly explains the pathophysiology of PH in lung disease (type 3 PH). It should also be noted that in all types of PH, as the right ventricle progressively fails, hypoxia ensues, leading to a vicious cycle.

Clinical Presentation

Patients with PH usually present with insidious symptoms at a more advanced stage of the disease. Symptoms include shortness of breath and fatigue with exertion, as

Abbreviations: CTD, connective tissue disease; PH, pulmonary hypertension; SSc,systemic sclerosis.

well as reduced exercise tolerance. Chest pain may occur even in the presence of normal coronaries due to right ventricular wall strain. With progression of disease and worsening of right-heart failure, patients develop peripheral edema and even syncope.

signs of Ph and resultant right-heart failure include elevated jugular venous pressure, parasternal heave (indicating right ventricular hypertrophy), a loud pulmonary compollelit of the second heart sound, a tricuspid regurgitation murmur that is heard best at the left parasternal border and worsens with inspiration, ascites, and lower extremity edema. Other signs are specific to the underlying etiology. Murmurs indicate valvular disease that is associated with pulmonary venous hypertension (eg, murmurs of aortic stenosis and mitral regurgitation). Lung exam may reveal fine crackles in interstitial lung disease, coarse crackles in left heart failure, or prolonged expiratory phase and reduced breath sounds in obstructive lung disease. Stigmata of liver disease, including spider angiomata, may be detected. Connective tissue diseases manifest with various skin and joint changes, such as skin thickening that occurs in SSc.

Diagnosis

The echocardiogram is usually the first test to objectively identify elevated pulmonary

pressures by estimating the pulmonary artery systolic pressure (PASP). Pa sP > 40 mmh g gives a close approximation of mPa P> 25 mmh g. An echocardiogram will also assess for the various causes of pulmonary venous hypertension, including left-sided valvular abnormalities and systolic and diastolic dysfunction. However, the diagnosis of PH and an accurate assessment of left- and right-sided filling pressures can be made only by pulmonary artery (right-heart) catheterization. This modality will directly measure mPAP. Furthermore, it allows assessment of filling pressures on the left side of the heart by measuring the PCWP, which will help to differentiate between PAH and pulmonary venous hypertension. Cardiac output and pulmonary vascular resistance can also be calculated.

Hemodynamics (Figure 29-1)

Elevated mPa P, normal Pc wP: This excludes left-heart disease as a cause of PH. The diagnosis is PAH. 

Elevated mPa P, elevated Pc w P, normal t Pg: The normal TPG indicates that the elevated mPAP can be entirely explained by the PCWP, that is, left-heart failure resulting in PH and right-heart failure. This entity is referred to as pulmonary venous hypertension.

Elevated mPa P, elevated Pc w P, elevated t Pg: In this scenario the elevated TPG indicates that the mPAP is elevated out of proportion to the PCWP. It can be explained by one of two scenarios: (1) pulmonary venous hypertension combined with PAH, or (2) isolated pulmonary venous hypertension in which remodeling of the pulmonary vasculature has occurred as a protective mechanism against pulmonary edema. This results in a fixed PH that persists regardless of volume status. If PAH is confirmed by heart catheterization, the next step is to determine pulmonary vasodilator reactivity. An acute pulmonary vasodilator

Figure 29-1. Hemodynamic interpretation measured in mmHg in pulmonary hypertension (mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient).

(eg, inhaled nitric oxide) is administered and mPAP is monitored. A favorable response has therapeutic and prognostic implications that will be discussed further.

The remaining diagnostic workup will help in diagnosing the type of PH. Routine laboratory tests include liver function tests to assess for cirrhosis, antinuclear antibody (aNa) as a screening test for connective tissue disease, and an hiv test. Chest x-ray reveals dilated pulmonary arteries. In pulmonary venous hypertension, evidence of pulmonary edema may be seen. The fibrosis seen in advanced stages of interstitial lung disease can also be identified. A ventilation-perfusion (V/Q) scan is the preferred initial diagnostic modality for CTEPH. It is important

to note that in CTEPH the initial inciting pulmonary embolus may not have been clinically apparent. Therefore, this disease should be ruled out irrespective of a history of thromboembolism. Pulmonary function tests can document obstructive or restrictive lung disease, and polysomnography can evaluate for obstructive sleep apnea. Finally, electrocardiogram abnormalities include right-axis deviation, right atrial enlargement, and right ventricular hypertrophy (Figure 29-2).

Treatment and Outcomes

Treatment of Ph involves general suppostive measutes, pulmonary vasodilators, and treating the underlying cause. Patients with symptomatic volume overload should be treated with diuretics, mainly loop diuretics such as furosemide. Hypoxia may cause PH and is also a result of PH. Therefore oxygen supplementation is warranted both for symptomatic relief, as well as to interrupt the vicious cycle that hypoxia triggers, including further pulmonary vasoconstriction and right ventricular ischemia. The indication for anticoagulation with warfarin has been established mainly in the idiopathic form of PAH.

Figure 29-2. Electrocardiogram of a patient with pulmonary hypertension. Note the right-axis deviation

(mean QRS axis between +90° and +180° with a negative QRS deflection in lead I and a positive deflection in lead aVF), right atrial enlargement (P wave in lead II > 2.5 mm in height), and right ventricular enlargement (prominent R wave in lead V1).

An understanding of the pathophysiology of PAH at a molecular level is the basis for the therapeutic indications of pulmonary vasodilators (Figure 29-3). Prostacyclin and nitric oxide promote vasodilation and inhibit platelet activation and cellular proliferation. Their effects are mediated through cAMP and cGMP, respectively, molecules that are inhibited by phosphodiesterase. On the contrary, agonists of endothelin receptor A produce vasoconstriction. Use of pulmonary vasodilators is indicated mainly for PAH. They have shown favorable effects on symptoms, functional capacity, hemodynamics, and in the case of epoprostenol, mortality. They are generally not indicated for other types of PH, and pulmonary vasodilators may actually worsen pulmonary venous hypertension.

Figure 29-3. The pathways involved in the pathophysiology of pulmonary arterial hypertension, and the various drugs that target these pathways (cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; ECE, endothelin-converting enzyme; ET, endothelin; NO, nitric oxide; NOS, NO synthase; PDE, phosphodiesterase; PGI2-, (prostaglandin I2). (Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2013-2014. All Rights Reserved.)

Patients who demonstrate vasoreactivity at the time of heart catheterization show good outcomes with calcium channel blockers, and in this population it should be used as first-line therapy. Commonly used agents include high-dose amlodipine and nifedipine. Epoprostenol, a synthetic prostacyclin, has demonstrated morbidity and mortality benefits. The main drawback is the administration by a continuous intravenous infusion; catheter-related infections are an important side effect. Other members of this class include iloprost, an inhaled agent, and treprostinil, an agent that can be given via inhalation, subcutaneous infusion, or intravenous infusion. The endothelin receptor antagonists include the oral agents, bosentan and ambrisentan. Finally, the phosphodiesterase-5 inhibitors, sildenafil and tadalafil, may be used as oral agents.

Patients who are refractory to medical therapy, especially intravenous prostacyclin, and those with poor prognostic factors may be offered lung transplantation or heart-lung transplantation. Right ventricular failure, even when severe, may be reversible with lung transplantation alone, which provides a reduction in right ventricular afterload. However, it is difficult to predict the extent to which right ventricular function will recover, and thus the decision as to whether to proceed with additional heart transplantation is center-dependent. One specific indication for heart-lung transplantation is PAH resulting from complex congenital heart disease. CTEPH is potentially curable with surgical intervention in the form of pulmonary thromboendarterectomy if deemed feasible by a pulmonary angiogram. Close outpatient follow-up for patients with PAH is essential. The 6-minute walk test has been established as a good indicator of disease progression and treatment response, and involves measuring the distance walked as well as oxygen desaturation.

A registry of patients with idiopathic PAH in the pretreatment era demonstrated poor prognosis, with survival rates at 1, 3, and 5 years of 68%, 48%, and 34%, respectively. PAH associated with SSc may portend an even worse prognosis. With the advent of numerous therapeutic modalities, the disease course may be altered. However, response to treatment varies among the different types of PAH. PAH due to connective tissue disease has a less favorable response. Patients who demonstrate response to acute pulmonary vasodilator testing have a very favorable outcome, with one study demonstrating survival rates of almost 95% at 5 years. These patients however, are a minority. In nonresponders, only epoprostenol has shown survival benefits.

CASE CORRELATION

• See also Case 23 (dyspnea) and Case 26 (adult congenital heart disease).

COMPREHENSION QUESTIONS

29.1 A 27-year-old woman with no prior medical history presents with progressive shortness of breath on exertion. Echocardiogram reveals a pulmonary artery systolic pressure of 50 mmHg with normal systolic and diastolic function and no left-sided valvular abnormalities. The remaining workup is negative. What is the best next step?

A. Amlodipine

B. Epoprostenol

C. Right-heart catheterization

D. Evaluation for lung transplantation

29.2 A 33-year-old woman recently diagnosed with heritable PAH presents to discuss treatment options. She demonstrated positive pulmonary vasoreactivity at the time of her initial heart catheterization. What will you recommend as the first-line agent?

A. Epoprostenol

B. Nifedipine

C. Sildenafil

D. Bosentan

29.3 An 84-year-old man undergoes a right-heart catheterization. Values obtained include mPAP of 38 mmHg and PCWP of 30 mmHg. His medical history is significant for severe aortic stenosis and diabetes mellitus. What is the likely cause of his PH?

A. Heritable PAH

B. Idiopathic PAH

C. PH due to obstructive lung disease

D. PH due to left heart disease

ANSWERS

29.1 C . PH can be diagnosed only with a right-heart catheterization. Moreover, it is important to perform a pulmonary vasoreactivity test at the time of diagnosis.

29.2 B. The first-line agent for patients that demonstrate pulmonary vasoreactivity is a calcium channel blocker.

29.3 D . The elevated mPAP indicates PH. The elevated PCWP and normal calculated TPG indicate that left-heart disease (specifically severe aortic stenosis) is explaining the PH.

CLINICAL PEARLS

• When assessing symptoms such as shortness of breath, it is important to ask direct questions to determine any change in functional capacity. In many cardiovascular diseases, patients will slowly decrease the intensity/ frequency of their exercise, which may mask exertional symptoms.
• As a general rule, right-sided murmurs intensify with inspiration whereas left-sided murmurs intensify with expiration (RILE). Inspiration decreases intrathoracic pressure, increasing the venous return to the right side of the heart, thus worsening the murmur.
• It is important to distinguish PAH from pulmonary venous hypertension with a heart catheterization. Therapy differs between the two groups.
• It is important to recognize CTEPH, as it is possibly curable with surgical intervention.

References

Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301. 

McLaughlin VV, McGoon MD. (2006). Pulmonary arterial hypertension. Circulation. 2006;114(13): 1417–1431. 

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(2):76–81.

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