The Vasoreactive Patient: Diagnosis, Treatment, and Follow-up

Charles D. Burger, MD
Associate Professor of Medicine Chair, Pulmonary and Critical Care Medicine Mayo Clinic Jacksonville, Florida

Srinivas Murali, MD
Professor of Medicine Drexel University College of Medicine Director, Division of Cardiovascular Medicine Allegheny General Hospital Pittsburgh, Pennsylvania

Introduction

The consensus recommendation from the American College of Chest Physicians1 is that all patients with pulmonary arterial hypertension undergo acute vasoreactivity testing as part of their workup. It is uncommon, however, to identify patients truly meeting current definitions of an acute response. The following case illustrates the issues surrounding the less common finding of a patient who demonstrates acute vasoreactivity.

Case Description

A 48-year-old woman presented to the pulmonary hypertension clinic with gradual and progressive dyspnea on exertion, intermittent palpitations, and chronic mild lower extremity edema of insidious onset over many months. There was no history of paroxysmal nocturnal dyspnea, chest pain, pleuritic pain, or hemoptysis. Her WHO functional class was III.

She had a past medical history of:

• Raynaud’s phenomenon since age 13
• CREST syndrome at age 35 on the basis of Raynaud’s phenomenon, gastroesophageal reflux, telangiectasias, positive antinuclear antibody test results, and anticentromere antibodies
• Pulmonary hypertension risk factors included collagen vascular disease; there was no history of anorexigen, cocaine. or amphetamine use, thromboembolic disease, hematologic disorder, HIV infection, left heart disease or congenital heart disease, parenchymal lung disease, liver disease, or sleep-disordered breathing
• Benign thyroid cyst with normal thyroid function testing

The patient’s current medications included aspirin 81 mg daily and omeprazole 40 mg daily.

Her family history was positive for hypertension, hyperlipidemia, and coronary artery disease. Her father possibly had giant cell arteritis. There was no pulmonary hypertension.

Her social history included no workplace or environmental exposures and no significant alcohol use. She was a lifelong nonsmoker.

Physical examination revealed that the patient was well developed and well nourished, with a BMI of 21.8 (height 156 cm; weight 53 kg). Vital signs included a blood pressure of 134/90 mmHg, a heart rate of 72 beats per minute and regular, and a respiratory rate of 15 breaths per minute. Examination of the skin revealed scattered telangiectasias with sclerodactyly and acrocyanosis consistent with known Raynaud’s phenomenon. Evaluation of the neck revealed normal jugular venous pressure without carotid bruits. Auscultation of the chest revealed clear lung fields. The heart rate and rhythm were normal with an increased second heart sound and a grade II/VI systolic murmur best heard at the lower left sternal border. Extremity examination revealed trace edema without clubbing.

Prior evaluation had revealed the following:

• Mild cardiomegaly on chest x-ray
• Normal serum chemistries, CBC, TSH, and hepatic profile; serologies with increased antinuclear antibodies as previously mentioned
• Computed tomography: no evidence of parenchymal lung disease, mediastinal adenopathy, or aberrant pulmonary arteries or veins
• Electrocardiography: sinus rhythm, left posterior fascicular block
• Echocardiography: right ventricular enlargement; normal left ventricular size and function
• Cardiopulmonary exercise testing: reduced O₂ pulse (60% predicted)
• Left heart cardiac catheterization: 70% occlusion of right coronary artery, coronaries otherwise normal; mixed venous oxygen saturations approximately 70%; no step-up in oxygen saturation
• Right heart catheterization:
  
  • Right atrial pressure 3 mmHg
  • Right ventricular pressure 83/3 mmHg - Pulmonary artery pressure 76/18 with a mean of 44 mmHg
  • Pulmonary artery occlusion pressure (wedge) 9 mmHg
  • Pulmonary vascular resistance 600 dyne sec cm-5
  • Cardiac output 4.8 L/min; cardiac index 3.1 L/min/m²

Figure 1. Chest radiogram demonstrating an enlarged pulmonary artery.Initial impressions included:

• Likely pulmonary arterial hypertension associated with CREST (APAH):
  • WHO functional class III
  • Clinically progressive
• Coronary artery disease: single vessel disease limited to the right coronary artery

At this point additional testing to document exercise capacity and pulmonary function and to exclude chronic thromboembolism, unexpected parenchymal lung disease, or obstructive sleep apnea/hypoventilation syndrome was undertaken with the following results:

• Chest x-ray (Figure 1)
• Six-minute walk test: the patient was able to walk 532 meters on room air, while maintaining normal oxygen saturations between 97% and 99%; evaluation of dyspnea during the test using the Borg Scale revealed a score of 1/10
• Overnight oximetry: normal
• Pulmonary function testing: normal FVC and FEV1 with a minimally depressed DLCO of 74% predicted
• Lung ventilation/perfusion scanning: no perfusion defects
• Echocardiography (Figure 2): right ventricular enlargement with decreased function; normal left ventricular size and function; right ventricular systolic pressure estimate of 51 mmHg; mild to moderate tricuspid regurgitation

Figure 2. Echocardiogram demonstrating right ventricular enlargement and a suggestion of bowing of the interventricular septum toward the left.

Clinical Course

Repeat right heart catheterization redemonstrated previous pulmonary pressures. The patient underwent acute vasodilator testing using epoprostenol revealing a substantial decrease in pulmonary pressures and pulmonary vascular resistance as shown in Table 1. At this point additional testing with nifedipine recapitulated the response obtained during the administration of short-acting epoprostenol without hypotension or adverse events. Interestingly, a trial of an acute dose of sildenafil 25 mg was given with similar hemodynamic effect. The patient was discharged with nifedipine XL 90 mg BID with long-term follow-up. A summary of longterm follow-up shows favorable functional class and exercise capacity improvements as evidenced by attainment of normal functional class and 6-minute walk distance. This was accompanied by regression of initial right ventricular abnormalities on echocardiography (Table 2).

Discussion

As stated in the introduction to this case, ACCP guidelines for the evaluation of patients with PAH include the assessment of acute vasoreactivity. This procedure serves two important roles: to identify patients who may be calcium channel antagonist responders, and to assess overall prognosis. Short-acting vasodilators have largely replaced the direct use of a calcium channel antagonist for assessing vasoreactivity as growing experience in the 1990s suggested that a minority of patients could actually receive long-term benefit from calcium channel antagonists and that acute administration could sometimes result in patient deterioration or death. Acute vasoreactivity is observed in fewer than 20% of patients with idiopathic PAH and in an even smaller number of patients with APAH at initial presentation.

In addition to identifying patients with idiopathic PAH who may be candidates for long-term calcium channel antagonist therapy, favorable hemodynamic responses observed during the administration of short-acting vasodilators can predict long-term response even if calcium channel blockers were not used in the management of the patient.2

Acute vasoreactivity testing is typically performed with a short-acting agent such as inhaled nitric oxide, intravenous epoprostenol, or adenosine, although recent data suggest that inhaled iloprost may also be helpful in this regard.3,4, 5, 6

In general, baseline hemodynamic measurements are obtained prior to testing. A short-acting agent is administered and/or titrated to maximal effect or to dose-limiting side effects and the hemodynamics are repeated.

The consensus definition of acute vasoreactivity from the European Society of Cardiology (ESC) has largely replaced the previous definition of acute vasoreactivity of a greater than 20% decrease in mean PAP or PVR following the administration of short-acting vasodilators. The current ESC definition of positive acute vasodilator response is a fall in PAP mean by at least 10 mmHg; a fall to an absolute PAP mean less than 40 mmHg; and unchanged or increased CO.

Figure 3. Kaplan-Meier survival curves demonstrating excellent long-term survival of patients with sustained response to calcium channel blocker (CCB) therapy. The overall number of patients achieving this survival was low (less than 6% of all idiopathic PAH patients in this series). Adapted from Sitbon O, et al.(Sitbon O, Jais X, Ioos V, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105-3111.)The finding of acute vasoreactivity does not guarantee the efficacy of calcium channel blocker treatment in patients with PAH. At least one study suggests that only approximately 50% of the small subset of adult patients with documented vasoreactivity were able to be treated over the long term with calcium channel blockers.7 For this reason, documented acute response during hemodynamic testing or monitoring is important before considering long-term treatment with these agents. Contraindications for calcium channel antagonist use in PAH include documented sensitivity to these agents and significant right heart dysfunction or failure. Agents with a significant negative inotropic effect, such as verapamil, should be avoided.

Figure 4. Kaplan-Meier survival curves demonstrating excellent long-term survival of patients with sustained response to calcium channel blockers. Contained for reference are survival curves of idiopathic PAH patients within the NIH registry (-). Adapted from Rich S, et al. (Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81.)Long-term follow-up is critical in patients initially treated with calcium channel blockers. Continued sustained response as evidenced by the attainment of functional class I or II is the current suggested goal indicating adequacy of response according to ACCP guidelines.1 Continued robust clinical follow-up and documentation are important as the initial effects of therapy can wane, creating the need for alternate treatment regimens.

Nonetheless, patients with idiopathic PAH with documented acute vasoreactivity and excellent sustained longterm functional class and hemodynamics have superior survival rates compared with nonresponders even under treatment with other agents8 ,9 (Figures 3 and 4).

This patient in particular shares a number of these favorable characteristics, at least with the current follow-up. She demonstrates initial vasoreactivity that is recapitulated with calcium channel antagonist therapy with subsequent improvement to WHO functional class I (Table 2). Although repeat hemodynamics were not obtained, regression of right ventricular changes on echocardiography suggests that sustained improvements in the initial hemodynamics are likely present. It is important to note that this patient carries a diagnosis of APAH and CREST syndrome. As mentioned, vasoreactivity is infrequently reported in this subset of patients10 and thus data regarding long-term outcome in vasoreactive APAH patients are lacking. The dramatic response to therapy in this patient, however, appears favorable and at least initially parallels responses that when seen in idiopathic PAH patients are associated with good outcome. Thus, acute vasoreactivity testing must be done using a short-acting vasodilator in all suspected idiopathic PAH patients. Whether it is necessary in all PAH patients is still not settled.

Key Words—Vasoreactive, CREST syndrome, coronary artery disease, calcium channel antagonist, acute vasoreactivity testing.

Address for reprint requests and other correspondence: Charles D. Burger, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: burger.charles@mayo.edu.

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