Pulmonary Hypertension and Exercise Intolerance in Patients with Heart Failure Javed Butler, MD, Don B

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Pulmonary Hypertension and Exercise Intolerance in Patients With Heart Failure Javed Butler, MD, Don B. Chomsky, MD, John R. Wilson, MD, FACC Nashville, Tennessee

OBJECTIVES This study was undertaken to investigate the relationship between pulmonary hypertension and exercise performance in patients with heart failure. BACKGROUND The exercise capacity of patients with heart failure is frequently reduced. Pulmonary hypertension may contribute to this exercise intolerance by impairing blood flow through the pulmonary circulation. METHOD Three hundred twenty patients with heart failure underwent upright treadmill exercise testing with hemodynamic monitoring. The incidence of pulmonary hypertension and the relationship between pulmonary vascular resistance (PVR) and exercise cardiac output and minute oxygen consumption (VO2) were examined. RESULTS Pulmonary vascular resistance was normal (Ͻ1.5 Wood Units; Group 1) in 28% of the patients, mildly elevated (1.5 to 2.49 Wood Units; Group 2) in 36%, moderately elevated (2.5 to 3.49 Wood Units; Group 3) in 17% and severely elevated (Ͼ3.5 Wood Units; Group 4) in 19%. Increasing PVR was associated with significantly lower peak exercise VO2 (Group 1: 13.9 Ϯ 3.7; 2:13.7 Ϯ 3.4; 3: 11.8 Ϯ 2.4; 4: 11.5 Ϯ 2.6 L/min, p Ͻ 0.01 Groups 3 and 4 vs. 1) and lower peak exercise cardiac output (Group 1: 10.0 Ϯ 2.8, 2:9.0 Ϯ 3.0; 3: 7.4 Ϯ 2.1; 4: 6.3 Ϯ 2.0 L/min, p Ͻ 0.05, Groups 2, 3 and 4 vs. 1). The pulmonary wedge pressure decreased during exercise, consistent with impaired left ventricular filling, in 36% of patients with severe pulmonary hypertension (Group 4) versus only 13% of patients with normal PVR (p Ͻ 0.01). CONCLUSIONS Pulmonary vascular resistance is frequently increased in heart failure and is associated with a reduced cardiac output response to exercise, suggesting that pulmonary hypertension impairs exercise performance in heart failure. (J Am Coll Cardiol 1999;34:1802–6) © 1999 by the American College of Cardiology

Exercise intolerance is a serious and almost universal prob- nary hypertension may be an important contributor to lem in patients with chronic heart failure (1,2). In the past, exercise intolerance in heart failure. this problem has been attributed primarily to left ventricular This study was undertaken to investigate the relationship dysfunction, impaired skeletal muscle arteriolar vasodilation between pulmonary hypertension and exercise performance and changes in skeletal muscle characteristics, possibly due in heart failure. Speciﬁcally, we sought to deﬁne the to muscle deconditioning (1–4). Relatively little attention incidence of pulmonary hypertension in ambulatory patients has been focused on the pulmonary circulation and right with heart failure. Second, we examined the relationship ventricle, aside from reports of a correlation between right between pulmonary vascular resistance (PVR), peak exercise ventricular function, pulmonary artery pressures and maxi- minute oxygen consumption (VO2) and the cardiac output mal exercise performance (5). response to exercise. Pulmonary hypertension is a well-established complica- tion of chronic heart failure (6,7). During exercise, excessive METHODS pulmonary vascular resistance theoretically could impair the delivery of blood to the left ventricle and thereby attenuate Patient population. The study population consisted of all the cardiac output response to exercise. Therefore, pulmo- ambulatory patients with heart failure who underwent right heart catheterization with exercise studies between Decem- ber 1993 and March 1997. During that time period, right heart catheterization with exercise was used routinely to From the Division of Cardiology, Vanderbilt University Medical Center, Nashville, investigate exercise performance in patients referred to the Tennessee. Supported in part by RO-1 HL53059 from the National Institutes of Vanderbilt Heart Failure and Heart Transplantation Pro- Health and by a Grant-in-Aid from the National American Heart Association. Manuscript received October 14, 1998; revised manuscript received June 15, 1999, grams. Patients were excluded if their ejection fraction was accepted August 6, 1999. more than 40%, if they were dependent on inotropic or JACC Vol. 34, No. 6, 1999 Butler et al. 1803 November 15, 1999:1802–6 Pulmonary Hypertension in Heart Failure

tion was measured with a Instrumentation Laboratories 282

Abbreviations and Acronyms Co-oximeter precalibrated with human blood. Blood O2 ANOVA ϭ analysis of variance content was calculated as the product of hemoglobin, 1.34 O ϭ oxygen 2 ml O2/g hemoglobin and percent O2 saturation. Oxygen PVR ϭ pulmonary vascular resistance ϭ extraction was calculated as the ratio of the arteriovenous O2 VO2 minute oxygen consumption difference and arterial O2 content. Derived variables. The following hemodynamic variables were calculated using standard formulas: mean arterial mechanical support, if they were limited by angina during pressure, arteriovenous O2 difference and systemic vascular exercise, or if they exhibited arterial oxygen desaturation resistance. Mean arterial pressure was calculated as diastolic ϩ during exercise. A total of 320 patients were studied. pressure one-third of the pulse pressure. Total pulmonary Average age of these patients was 52 Ϯ 10 years (range: 21 resistance was calculated as the mean pulmonary artery to 75 years). Seventy-four percent of the patients were men. pressure divided by the cardiac output. Pulmonary vascular There were approximately equal proportions of patients resistance was calculated as (mean pulmonary artery with ischemic and dilated cardiomyopathy. Left ventricular pressure-pulmonary wedge pressure)/cardiac output. Ther- ejection fraction was 23% Ϯ 9% (range: 8% to 40%). modilution cardiac output values were obtained with the Ϯ patient in the resting supine position whereas Fick cardiac Overall, mean peak VO2 was 13.0 3.4 ml/min/kg. All patients had exertional dyspnea, fatigue or both and were output values were calculated during upright exercise. classified according to New York Heart Association classi- Statistical analysis. Initially descriptive analyses were per- fication between class II to IV. formed on all the patients. The patients were then divided Protocol. On the day of the study, patients arrived in the into four groups. Group 1 consisted of patients with normal Ͻ morning at Vanderbilt University Heart Failure and Heart resting PVR ( 1.5 Wood Units). Group 2 had PVR Transplantation Program’s catheterization procedure labo- between 1.5 and 2.49 Wood Units, Group 3 had pulmonary ratory having fasted overnight. A 7F Swan Ganz thermodi- vascular resistance between 2.5 and 3.49 Wood Units and Ͼ lution catheter was inserted percutaneously through an Group 4 had 3.5 Wood Units. These groups were internal jugular vein (brachial vein if internal jugular can- compared for various clinical, hemodynamic and ventilatory nulation unsuccessful) and positioned in the pulmonary parameters. Categorical variables were compared using chi- artery. square test and continuous variables using analysis of vari- Ͻ Supine central hemodynamic measurements were ob- ance (ANOVA). A two-tailed p value of 0.05 was used for tained that included pulmonary artery pressure, right atrial statistical significance. When continuous variables were pressure and pulmonary capillary wedge pressure. Blood found to be significantly different using ANOVA and a p Ͻ pressure was measured by a sphygmomanometer. Supine value 0.05, post hoc analyzes were performed with un- cardiac output was also determined by thermodilution, in paired t testing using Bonferonni correction to detect triplicate. Blood samples were drawn from the pulmonary differences between individual classes. Continuous variables are presented as mean Ϯ SD and categorical variables as artery for measurement of hemoglobin oxygen (O2) saturation. percentages. SPSS for Windows Release 7 (SPSS Inc., Patients then stood up on the treadmill and were con- Chicago, Illinois) was used for statistical calculations. nected to a Medgraphics Cardio O2 Metabolic Cart. The RESULTS patient’s left index finger was attached to a pulse oximeter to continuously monitor arterial hemoglobin O2 saturation. Supine resting and peak exercise hemodynamic responses The patient then began exercising on the treadmill, using for the entire population are summarized in Tables 1 and 2. a modified Naughton protocol. Each exercise stage lasted Resting pulmonary artery pressure averaged 28 Ϯ 3 min. Speed and grade for each stage was as follows: 1 11 mm Hg, pulmonary wedge pressure 18 Ϯ 9mmHg, (1 mph, 0), 2 (2 mph, 0), 3 (2 mph, 3.5), 4 (2 mph, 7), 5 total pulmonary resistance 7.06 Ϯ 4.28 Wood Units and (2 mph, 10.5), 6 (2 mph, 14), 7 (2 mph, 17.5), 8 (2 mph, PVR 2.45 Ϯ 1.57 Wood Units. With exercise, patients Ϯ 21), 9 (2.5 mph, 21), 10 (3 mph, 21). All patients continued achieved peak VO2 levels of 13.0 3.4 ml/min/kg. At peak exercising until symptoms of dyspnea or fatigue, or both, exercise, PVR was unchanged from resting levels (2.41 Ϯ forced them to stop. Central hemodynamic measurements 1.52 Wood Units). and respiratory gas exchange analysis were recorded contin- Pulmonary vascular resistance. Resting PVR was normal uously throughout exercise. Blood sampling from the pul- (Ͻ1.5 Wood Units; Group 1) in 28% of the patients, mildly monary artery was performed during the last 45 s of each elevated (1.5–2.49 Wood Units; Group 2) in 36%, moder- stage. ately elevated (2.5–3.49 Wood Units; Group 3) in 17%, and Measured variables. Arterial hemoglobin concentration severely elevated (Ͼ3.5 Wood Units; Group 4) in 19%. was measured by Coulter Counter; hemoglobin O2 satura- There were no significant differences in these group in their 1804 Butler et al. JACC Vol. 34, No. 6, 1999 Pulmonary Hypertension in Heart Failure November 15, 1999:1802–6

Table 1. Demographic and Clinical Characteristics PVR (WU) PVR (WU) PVR (WU) PVR (WU) Overall <1.5 1.5–2.49 2.5–3.49 >3.5 p Age (yr) 52 ϩ 10 49 Ϯ 12 53 Ϯ 09 52 Ϯ 10 53 Ϯ 11 NS LVEF (%) 23 Ϯ 924Ϯ 07 23 Ϯ 08 24 Ϯ 13 21 Ϯ 7NS NYHA % 2 3436313335 3 4445414443NS 4 2219282322 IHD (%) 51 49 55 50 52 NS DCM (%) 49 51 45 50 48 DCM ϭ dilated cardiomyopathy; IHD ϭ ischemic heart disease; LVEF ϭ left ventricular ejection fraction; NS ϭ nonsignificant; NYHA ϭ New York Heart Association Classification; PVR ϭ pulmonary vascular resistance; WU ϭ Wood Units. age, etiology of heart failure and baseline ejection fractions 1 decreased their pulmonary wedge pressure with exercise as (Table 1). compared with 22%, 29% and 36% in Groups 2, 3 and 4, Increasing PVR was associated with significantly lower respectively (p ϭ 0.005). When compared with patients resting cardiac output (Group 1: 5.2 Ϯ 1.3; 2: 4.6 Ϯ 1.0; 3: who increased their pulmonary wedge pressure with exer- 4.2 Ϯ 1.2; 4: 3.3 Ϯ 0.7 L/min, p Ͻ 0.01 Groups 2, 3 and cise, patients who exhibited a decrease in pulmonary wedge Ϯ 4 vs. Group 1), lower peak exercise VO2 (Group 1: 13.9 pressure during exercise had significantly higher resting 3.7; 2: 13.7 Ϯ 3.4, 3: 11.8 Ϯ 2.4; 4: 11.5 Ϯ 2.6 ml/min/kg, PVR (3.65 Ϯ 2.14 vs. 2.25 Ϯ 1.36 Wood Units) and higher p Ͻ 0.01 Groups 3 and 4 vs. Group 1), and lower peak right atrial pressures at peak exercise (13 Ϯ 7 vs. 9 Ϯ exercise cardiac output (Group 1: 10.0 Ϯ 2.8; 2: 9.0 Ϯ 3.0; 7 mm Hg) (both p Ͻ 0.0001). 3: 7.4 Ϯ 2.1; 4: 6.3 Ϯ 2.0 L/min, p Ͻ 0.05 Groups 2, 3 and 4 vs. Group 1) (Table 3; Fig. 1). However, pulmonary DISCUSSION hypertension was observed in patients with preserved exer- Ͻ cise capacity as well as in patients with severe exercise Pulmonary vascular resistance in normal individuals is 1.5 intolerance. For example, 18% of the patients in this study Wood Units (8). During exercise, pulmonary pressures Ͼ had peak exercise VO2 levels 16 ml/min/kg. In these increase as a function of increased blood flow. Cardiac patients, 41% had PVR of 1.5–2.49 Wood Units, 5% had output, however, increases out of proportion to pulmonary pulmonary resistances of 2.5–3.49 Wood Units and 7% had pressures, resulting in a drop in PVR. pulmonary resistance Ͼ3.5 Wood Units. In patients with longstanding heart failure and high Pulmonary vascular resistance decreased significantly pulmonary wedge pressures, several histologic changes occur with exercise in patients with severe pulmonary hyperten- that lead to initially reversible and then irreversible pulmo- sion (Group 4) but increased significantly in patients with nary hypertension. These changes include medial hypertro- normal PVR (Group 1) (Fig. 2). phy, intimal and adventitial fibrosis and focal hemosiderosis Pulmonary wedge pressures decreased during exercise in (6). Theoretically, these changes can impair flow through 28% of the entire population (mean decrease ϭ 5 Ϯ the lungs and contribute to exercise intolerance in heart 3 mm Hg), possibly reflecting impaired delivery of blood to failure. the left ventricle. Thirteen percent of the patients in Group To investigate the impact of PVR on exercise performance in heart failure, we examined hemodynamic parameters at rest and during exercise in a large group of patients Table 2. Resting and Peak Exercise Hemodynamics referred to the Vanderbilt Heart Failure and Transplant Baseline Peak Exercise Programs. The patients in general had relatively severe -mean ؉ SD) (mean ؉ SD) exercise intolerance, as evidenced by an average peak exer) cise VO of 13.4 ml/min/kg. However, 16% of the patients MBP (mm Hg) 86 Ϯ 11 95 Ϯ 16 2 had peak VO levels Ͼ16 ml/min/kg, consistent with RAP (mm Hg) 8 Ϯ 59Ϯ 6 2 PA (mm Hg) 28 Ϯ 11 40 Ϯ 13 Functional Class II exercise limitation. Ϯ Ϯ PCWP (mm Hg) 18 09 23 10 Incidence of pulmonary hypertension. Seventy-two per- Cardiac output (L/min) 4.5 Ϯ 1.3 8.5 Ϯ 3.0 Ϯ Ϯ cent of the patients studied had pulmonary hypertension TPR (wood units) 7.06 4.28 5.54 3.06 (Ͼ1.5 Wood Units), including 19% with severe pulmonary PVR (wood units) 2.45 Ϯ 1.57 2.41 Ϯ 1.52 hypertension (PVR Ͼ3.5 Wood Units). This frequency of VO (ml/min/kg) 13.0 Ϯ 3.4 2 pulmonary hypertension is similar to that observed by MBP ϭ mean blood pressure; PA ϭ pulmonary artery; PCWP ϭ pulmonary capillary wedge pressure; PVR ϭ pulmonary vascular resistance; RAP ϭ right atrial pressure; Costard-Jackle et al. (9) in 288 patients evaluated at ϭ ϭ TPE total pulmonary resistance; VO2 peak oxygen consumption. Stanford University Medical Center for heart transplanta- JACC Vol. 34, No. 6, 1999 Butler et al. 1805 November 15, 1999:1802–6 Pulmonary Hypertension in Heart Failure

Table 3. Comparison Between Patients With Normal and Increased PVR PVR (WU) PVR (WU) PVR (WU) PVR (WU) Pby Variable <1.5 1.5–2.49 2.5–3.49 >3.5 ANOVA Rest MBP (mm Hg) 87 Ϯ 11 87 Ϯ 11 86 Ϯ 10 82 Ϯ 11** Ͻ 0.001 Peak exer MBP (mm Hg) 99 Ϯ 16 97 Ϯ 16 93 Ϯ 15 88 Ϯ 16** Ͻ 0.001 Rest RAP (mm Hg) 6 Ϯ 57Ϯ 48Ϯ 510Ϯ 5** Ͻ 0.001 Peak exer RAP (mm Hg) 8 Ϯ 68Ϯ 612Ϯ 7** 12 Ϯ 6** Ͻ 0.001 Rest MPAP (mm Hg) 20 Ϯ 824Ϯ 9* 33 Ϯ 9** 41 Ϯ 8** Ͻ 0.001 Peak exer MPAP (mm Hg) 34 Ϯ 11 38 Ϯ 12 44 Ϯ 11** 51 Ϯ 10** Ͻ 0.001 Rest PCWP (mm Hg) 14 Ϯ 815Ϯ 921Ϯ 9** 25 Ϯ 6** Ͻ 0.001 Peak exer PCWP (mm Hg) 21 Ϯ 11 21 Ϯ 11 24 Ϯ 10 27 Ϯ 8** 0.004 Rest CO (L/min) 5.2 Ϯ 1.3 4.6 Ϯ 1.0** 4.2 Ϯ 1.2** 3.3 Ϯ 0.7** Ͻ 0.001 Peak exer CO (L/min) 10.0 Ϯ 2.8 9.0 Ϯ 3.0* 7.4 Ϯ 2.1** 6.3 Ϯ 2.0** Ͻ 0.001 Change in CO (L/min) 4.8 Ϯ 2.4 4.4 Ϯ 2.5 3.2 Ϯ 1.7** 3.0 Ϯ 1.7** Ͻ 0.001 Ϯ Ϯ Ϯ Ϯ Ͻ VO2 (ml/min/kg) 13.9 3.7 13.7 3.4 11.8 2.4** 11.5 2.6** 0.001 *p Ͻ 0.05 vs. PVR Ͻ 1.5; **p Ͻ 0.01 vs. PVR Ͻ 1.5. ANOVA ϭ analysis of variance; CO ϭ cardiac output; exer ϭ exercise; MBP ϭ mean blood pressure; MPAP ϭ mean pulmonary artery pressure; PCWP ϭ pulmonary ϭ ϭ capillary wedge pressure; RAP right atrial pressure; VO2 peak oxygen consumption. tion. These investigators noted that approximately 79% of cardiac output. One might expect that an increase in cardiac their patients had pulmonary hypertension, with close to output and pulmonary flow during exercise would produce 35% having PVR Ͼ3.5 Wood Units. pulmonary vasodilation, due to recruitment and distention This high incidence of pulmonary hypertension may of the pulmonary vascular bed. Instead, we observed a reflect a referral bias because patients with mild heart failure decrease in resistance in patients with high resting pulmo- are rarely referred to specialty heart failure and heart nary vascular resistance but an increase in patients with transplantation programs. Nevertheless, these findings in- normal resistance. dicate that pulmonary hypertension is an extremely com- A similar response was noted by Janicki et al. (10). These mon problem in patients with moderate to severe heart investigators observed that pulmonary resistance increased failure. We also noted that some patients with relatively by 0.22 Wood Units in patients with initial PVR Ͻ1.5 mild exercise symptoms had pulmonary hypertension. For Wood Units whereas pulmonary resistance decreased by 1.2 example, 58 of the patients in our study had a peak exercise Wood Unit in patients with initial PVR Ͼ3.5 Wood Units. Ͼ VO2 16 ml/min/kg, a level of exercise ability usually The reason for this response is unclear, although the degree associated with only mild exertional symptoms. In these of change in either direction is small and unlikely to be patients, 41% had PVRs of 1.5 to 2.49 Wood Units, 5% had physiologically important. pulmonary resistances of 2.5 to 3.49 Wood Units and 7% had pulmonary resistance Ͼ3.5 Wood Units. Therefore, the Effect of pulmonary hypertension on exercise perfor- absence of major exertional symptoms does not exclude the mance. Does the presence of pulmonary hypertension im- possibility of severe pulmonary hypertension. pair exercise performance? In this study, pulmonary hypertension was associated with a reduced peak exercise VO2 Effect of exercise on pulmonary resistance. During exer- and reduced cardiac output response to exercise, with the cise, PVR changed relatively little, despite an increase in degree of exercise abnormalities paralleling the degree of

Figure 1. Resting and peak exercise cardiac output in the patient population (n ϭ 320). Figure 2. Effect of exercise on pulmonary vascular resistance. 1806 Butler et al. JACC Vol. 34, No. 6, 1999 Pulmonary Hypertension in Heart Failure November 15, 1999:1802–6 pulmonary hypertension. These findings are consistent with Reprint requests and correspondence: Dr. John R. Wilson, an adverse effect of pulmonary hypertension on exercise Division of Cardiology, 315 MRB II, Vanderbilt University performance. In addition, we frequently observed a decrease Medical Center, Nashville, Tennessee 37232. E-mail: in the pulmonary wedge pressure during exercise in patients [email protected]. with moderate to severe pulmonary hypertension, suggesting impaired delivery of blood to the left ventricle. This pattern was observed in 36% of patients with severe pulmo- REFERENCES nary hypertension but only in 13% of patients with normal 1. Wilson JR, Mancini DM. Factors contributing to the exercise limita- PVR. Patients who exhibited a decrease in pulmonary tion of heart failure. J Am Coll Cardiol 1993;22:93A–8A. wedge pressure during exercise also had higher right atrial 2. Drexler H, Coats AJS. Explaining fatigue in congestive heart failure. pressures at peak exercise than other patients, consistent Annu Rev Med 1996;47:241–56. 3. Sullivan MJ, Hawthorne MH. Exercise intolerance in patients with with right ventricular failure. chronic heart failure. Prog Cardiovasc Dis 1995;38:1–22. It should be reiterated, however, that the presence of 4. Clark AL, Poole-Wilson PA, Coats AJS. Exercise limitation in pulmonary hypertension was not invariably associated with chronic heart failure: central role of the periphery. J Am Coll Cardiol 1996;28:1092–102. major exercise intolerance, since over 50% of the patients 5. Baker BJ, Wilen MM, Boyd CM, et al. Relation of right ventricular Ͼ with peak exercise VO2 16 ml/min/kg had pulmonary ejection fraction to exercise capacity in chronic left ventricular failure. hypertension. Other factors, such as right ventricular func- Am J Cardiol 1984;54:596–99. 6. Mancini DM. Pulmonary factors limiting exercise capacity in patients tion, likely modulate the impact of pulmonary hypertension with heart failure. Prog Cardiovas Dis 1995;38:347–70. on cardiac output responses to exercise. 7. Winkel E, Kao W, Costanzo MR. Pulmonary hypertension and In summary, these observations suggest that pulmonary cardiac transplantation. Handbook of Cardiac Transplantation. Hen- ley and Belfus, 1996. hypertension is a very common problem in patients with 8. Baim DS, Grossman W. Cardiac catheterization, angiography and heart failure. These findings also provide suggestive evi- intervention. Williams and Wilkins, 1996. dence that pulmonary hypertension contributes to exercise 9. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of intolerance in heart failure by impairing the cardiac output potential reversibility of pulmonary hypertension with nitroprusside is response to exercise. However, it should be emphasized that useful in defining a high risk group. J Am Coll Cardiol 1992;19:48– the presence of a relationship does not establish causality. 54. 10. Janicki JS, Weber KT, Likoff MJ, Fishman AP. The pressure-flow Additional studies are needed to determine the impact of response of the pulmonary circulation in patients with heart failure and reducing PVR on exercise performance in heart failure. pulmonary vascular disease. Circulation 1985;72:1270–8.