Cardiopulmonary exercise testing suggests a beneficial response to pulmonary endarterectomy in a patient with chronic thromboembolic obstruction and normal preoperative pulmonary hemodynamics

Abstract Abstract

Pulmonary endarterectomy offers a symptomatic and survival benefit in patients with chronic thromboembolic pulmonary hypertension through sustained improvement in right ventricular function. However, its role in patients with symptom limitation, chronic thrombotic obstruction, and a normal pulmonary hemodynamic profile is less clear. Cardiopulmonary exercise testing (CPET) stresses the cardiopulmonary system and has a characteristic response in pulmonary hypertension. CPET may therefore reveal abnormalities in patients with chronic thrombotic obstruction where hemodynamic investigations conducted at rest are reassuring. Using incremental CPET, we demonstrated improvements in right ventricular performance and ventilatory efficiency following pulmonary endarterecomy in a patient with preoperative exercise limitation and normal pulmonary hemodynamics. Careful evaluation of exercise responses may extend the potential benefit offered by pulmonary endarterectomy in patients with chronic thromboembolic obstruction irrespective of their resting hemodynamic profile.

Case Description

A 61-year-old gentleman with a history of systemic hypertension treated with amlodipine was referred to our Pulmonary Vascular Disease Unit for investigation of suspected chronic thromboembolic pulmonary hypertension. He had a history of acute pulmonary embolism 11 months previously and had been treated with a vitamin K antagonist. During this period, he was troubled by persistent exertional breathlessness and chest discomfort, causing limitation on walking up two flights of stairs. Premorbidly, he kept active, able to run several miles without undue limitation.

Sequential computed tomography pulmonary angiography examinations performed in his local hospital suggested chronic thromboembolic obstruction with bilateral lower lobe segmental obstruction and stenoses. This was confirmed on magnetic resonance (MR) pulmonary angiogram at our institution (Fig. 1A). Echocardiography demonstrated preserved right ventricular (RV) systolic function with RV dimensions at the upper limit of normality. Trace tricuspid regurgitation was seen with an estimated systolic pulmonary artery pressure of 26 mmHg + right atrial pressure. Left atrial size and left ventricular systolic and diastolic function were normal.

Figure 1.

Maximum-intensity-projection image of a magnetic resonance pulmonary angiogram conducted preoperatively (A) and postoperatively (B). Images show normal-caliber main pulmonary artery with no tricuspid regurgitation. Compared to preoperatively, there has been marked improvement in left lower lobe changes (arrow), although a mild segmental attenuation remains in the anterior and lateral segments. There is mild segmental attenuation in the apical segment of the right upper lobe. The remaining lobes are well perfused.

Laboratory testing measured serum pro brain natriuretic peptide as less than 30 pg/mL, and cardiac MR showed RV end diastolic volume index of 108 mL/m² and RV ejection fraction of 50%. In view of the mild RV dilatation and normal premorbid functional capacity, right heart catheterization (RHC) was undertaken, which showed normal resting pulmonary hemodynamics (Table 1, “Preoperative”). Cardiopulmonary exercise testing (CPET) using an incremental protocol revealed a low peak oxygen consumption (), normal anaerobic threshold, attenuated O₂ pulse evolution, and mildly elevated ventilation for a given volume of carbon dioxide output (V_e/ slope; Table 2, “Preoperative”). Arterial blood gas analysis obtained at peak exercise showed a mildly elevated alveolar-arterial (Aa) oxygen gradient and increased alveolar dead space fraction (V_d/V_t).

Table 1.

Right heart catheterization hemodynamics obtained pre- and postoperatively

Hemodynamic parameters	Preoperative	Postoperative
HR, beats/min	62	60
RAP, mmHg	6	5
mPAP, mmHg	15	15
CO, L/min	4.6	4.6
PCWP, mmHg	6	7
PVR, dyn/s/cm5	157	139
Ca, mL/mmHg	4.12	4.51
RC product, s	0.48	0.47

^NoteA minor increase in pulmonary arterial compliance is noted despite similar resting cardiac outputs and mean pulmonary artery pressures. Ca: pulmonary artery compliance; CO: cardiac output; HR: heart rate; mPAP: mean pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RC: product resistance compliance time constant product.

Table 2.

Pre- and postoperative cardiopulmonary exercise testing parameters

Peak exercise parameter	Preoperative	Postoperative
Work, W	157 (79)	178 (88)
, mL/kg/min	25.0 (90)	28.7 (107)
OUES	2,010	2,218
Anaerobic threshold, %	53	55
RER	1.13	1.19
HR, beats/min	157 (99)	155 (98)
O2 pulse, mL/beat	12.5 (90)	14.1 (101)
Ve, L/min	64 (59)	80 (77)
(HR/ slope)	56.6	51.3
(Ve/ slope)	31.1	32.9
Aa gradient, kPa	3.6	3.2
Vd/Vt, %	39	39
Serum lactate, mmol/L	9.1	9.3

^NoteImprovement is seen in exercise capacity and O₂ pulse at peak exercise. Ventilatory efficiency, which is effort independent, is unchanged. Parameters in parentheses assessed from the onset of work. Aa: alveolar-arterial; HR: heart rate; OUES: oxygen uptake efficiency slope; RER: respiratory exchange ratio; V_d/V_t: alveolar dead space fraction; V_e: ventilation; : volume of carbon dioxide output; : peak oxygen consumption.

In view of the patient’s exercise limitation, surgically accessible proximal distribution of thrombotic obstruction, and mild RV dilatation, the patient was offered pulmonary endarterectomy, with the intention of achieving significant symptomatic benefit. Surgery was performed 7 months following referral and showed Type II thromboembolic disease bilaterally. Good surgical clearance was achieved with histological findings of organizing thrombus, recanalized neointima, and hemosiderin, typical of thromboembolic disease (Fig. 2). There was no evidence of vasculitis as a cause for in situ thrombosis.

Figure 2.

A, Web from a 5-mm artery showing a thin rim of tunica media (black edge) and central fibroelastic tissue (neointima, stained red; scanning magnification, elastic Van Gieson [EVG] stain). B, Closer examination of the neointima shows structured walls on perforating vessels (50×, EVG stain). C, Elsewhere, thrombus is incorporated into the arterial wall, seen as fibrin (asterisk) in the neointima (200×, hematoxylin and eosin stain). D, Also seen in the neointima, refractile brown granules of hemosiderin (arrows), some within macrophages, which are a breakdown product of hemoglobin (400×, EVG stain).

Six months following surgery, the patient returned for reassessment and reported remarkable improvement in exercise tolerance. No exercise training program had been undertaken postoperatively, and the patient’s weight was unchanged. Repeat RHC showed similar resting right heart hemodynamics although pulmonary artery compliance had marginally increased. The resistance compliance time constant product remained unchanged (Table 1, “Postoperative”). CPET was undertaken and results compared to preoperative levels (Table 2; Fig. 3). This showed an improved exercise capacity (Fig. 3C) and peak O₂ pulse, unchanged V_e/ slope, at anaerobic threshold, and reduced heart rate/ slope. Postoperatively, end-tidal CO₂ was higher at anaerobic threshold, and a higher peak RER was observed. The exercise breathing pattern was similar to the preoperative CPET with no change in peak exercise V_d/V_t. Repeat cardiac MR imaging showed marginal reduction in end diastolic volume index (96 mL/m²) with similar ejection fraction (52%). MR angiography documented improved perfusion to the lower lobe lung segments with residual minor segmental vessel attenuation (Fig. 1B).

Figure 3.

Nine-panel display of cardiopulmonary exercise test parameters. Triangles: preoperative values; circles: postoperative values.

Discussion

The pre- and postoperative CPET results support a recovery of physiological deficit on exercise following pulmonary endarterectomy that may be mediated by improved RV performance and ventilatory efficiency. This occurred despite similar resting hemodynamic profiles pre- and postoperatively and underscores the value of an exercise assessment method in a patient with predominantly exercise-related symptoms. Postoperatively, we observed an increase in peak O₂ pulse with a lower chronotropic response to exercise. This may signify greater myocardial reserve and improved exercise RV stroke volume augmentation following surgery. Increased pulmonary artery compliance may mediate this effect on account of reduced RV afterload. This highlights potential subclinical impairment in preoperative RV function in our patient that is overlooked by routine hemodynamic assessments conducted at rest.

Both the preoperative CPET and the postoperative CPET were characterized by mild hyperventilation with increased effort, suggested in the postoperative CPET by the higher RER. Improved ventilatory efficiency at anaerobic threshold was suggested by higher end-tidal CO₂ following surgery, although V_e/ slope and peak exercise V_d/V_t were unchanged. This may explain our patient’s recovery of exercise tolerance during everyday activities, although our findings contrast with improvement in resting V_d/V_t shown after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension (CTEPH).¹ CTEPH is characterized by a 2-compartment model of proximal pulmonary artery obstruction along with secondary small vessel remodeling thought to arise from chronic overperfusion to unobstructed lung units.² Our patient had evidence of mild RV dilatation and may represent a clinically relevant earlier stage in the development of CTEPH. Subtle coexistent small vessel hypertensive changes and impaired RV adaptation on exercise may therefore contribute to mild exercise ventilatory inefficiency.

Exertional dyspnoea in the setting of chronic pulmonary vascular obstruction and normal pulmonary hemodynamics at rest may be multifactorial in origin, necessitating careful patient evaluation. Prioritization of patients for pulmonary endarterectomy relies largely on the subjective evaluation of the surgeon and the prediction of significant hemodynamic benefit that justifies the risk of the procedure, which, in our center, carries a mortality risk of less than 5%.³ On CPET, our patient showed indirect evidence of improved stroke volume augmentation with improvement in ventilatory efficiency at thresholds relevant to everyday activities. This may in part be mediated by greater pulmonary arterial compliance, increased RV adaptation, and reduced ventilation/perfusion (V/Q) mismatch, all consistent with findings following pulmonary endarterectomy undertaken for CTEPH. Exercise hemodynamic assessment may have helped further evaluate the mechanism of improvement. However, supine exercise catheterization, as is the practice in our institution, cannot be compared with upright CPET cycle ergometry due to differences in V/Q distribution and venous return. This report highlights the value of CPET as an indirect marker of cardiopulmonary function and suggests a genuine physiological benefit from pulmonary endarterectomy in a patient with normal pulmonary hemodynamics at rest. Insight into possible mechanisms of improved exercise tolerance in this rare but important patient group warrants wider evaluation.

Source of Support: Nil.

Conflict of Interest: None declared.