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The European Society of Cardiology

Impact of cardiopulmonary exercise testing on patient selection for cardiac resynchronisation therapy

Barbara Lamp*, Jürgen Vogt, Henning Schmidt and Dieter Horstkotte

Department of Cardiology, Heart Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany

Received 3 May 2004; accepted 24 May 2004.

* B. Lamp, Department of Cardiology, Heart Center North Rhine-Westphalia, Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany. Tel.: +49-5731-97-1258; fax: +49-5731-97-2194
blamp{at}hdz-nrw.de

Abstract

In patients with systolic heart failure the assessment of peak oxygen consumption during cardiopulmonary exercise (CPX) testing provides an objective measure of functional capacity and important prognostic information. Several studies in pacemaker therapy and in cardiac resynchronization therapy (CRT) have used peak oxygen uptake as an endpoint. This article reviews the impact of CPX testing on patient selection for CRT.

Key Words: Heart failure • Left bundle branch block (LBBB) • Cardiopulmonary exercise testing • Cardiac resynchronisation therapy

List of Abbreviations: HF heart failure • CPX cardiopulmonary exercise • ECG electrocardiogramme • CO cardiac output • VO2 oxygen uptake • VE minute ventilation • VCO2 carbon dioxide output • EF ejection fraction • CO2 carbon dioxide • BNP brain natriuretic peptide • DCM dilated cardiomyopathy • ICM ischaemic cardiomyopathy • CRT cardiac resynchronisation therapy • LVEDD left ventricular enddiastolic diameter • PATH-CHF Pacing Therapies for Congestive Heart Failure (Study) • COMPANION Comparison of Medical Therapy Pacing and Defibrillation in Chronic Heart Failure (Study)

Introduction

Heart failure (HF) is the leading cause of death and hospitalisation in most Western communities.1 Despite modern pharmacological treatment options such as ACE inhibition, beta blockade and aldosterone antagonism, prognosis remains markedly impaired with a one year mortality of approximately 50% in severely symptomatic HF patients.2 Due to limited resources it is increasingly important to use reliable and reproducible parameters for evaluation, risk stratification and treatment control.

Cardiopulmonary exercise (CPX) testing using a ramp protocol with stepwise increase of workload to allow exercise for approximately 10–12 min until exertion has been introduced to assess cardiopulmonary reserve by measuring oxygen uptake, carbon dioxide output and ventilation volumes using breath to breath analyses. CPX in HF is characterized by reduced oxygen consumption, an early plateau of oxygen uptake during maximal exercise and early anaerobic metabolism with increased lactate production and acidosis resulting in rapid ventilation to increase carbon dioxide elimination. In addition the recovery time is prolonged in HF patients. Parameters documented during CPX are heart rate, rhythm, blood pressure, signs of ischemia (ECG), exercise time and workload, recovery time, maximal oxygen consumption, oxygen consumption at anaerobic threshold, tidal volume, ventilation volume per minute, and parameters derived from original data. When appropriate, measurements are corrected for age, gender, and body weight. If performed correctly the test is objective for cardiopulmonary reserve which is less dependent of patient motivation than submaximal test procedures.3,4

Cardiopulmonary exercise test in systolic heart failure

As early as in 1986 Weber correlated functional capacity measured by maximal oxygen uptake during CPX with invasively measured cardiac output (CO) and thus established the "Weber classification"5 (Table 1). Since, CPX testing has become one of the most important objective measures to assess functional status,5,6 prognosis7,8 and treatment effects9,10 in patients with HF.


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  		Table 1 Relation between cardiac output and oxygen consumption at peak exercise (Weber classification5)a

 
In 1992 Van den Broek reported in a cohort of 94 HF patients (dilated cardiomyopathy (DCM) , ischaemic cardiomyopathy (ICM) ) with a mean ejection fraction of 22% that the majority of patients in NYHA class II (43 out of 49, 88%) were in Weber classes A and B.6 In contrast, the majority of NYHA class III patients (33 out of 45, 73%) were in Weber classes C and D. The mean peak VO2 was 20 ml/kg/min for NYHA class II but 13 ml/kg/min in NYHA class III patients (), with an overlap in peak VO2 values between the two groups. Patients with a peak VO2 of 16 ml/kg/min had a 2-year survival of 68% in contrast to 86% for patients with a peak VO216 ml/kg/min. Mancini7 reported a one-year mortality of 10% for transplant candidates with a peak VO2 of 14 ml/kg/min (, DCM 54%, CAD 46%, EF 19%) and suggested peak VO2 of 10 ml/kg/min as a strong indicator for heart transplantation. Aaronson derived similar findings from his cohort of 272 HF patients (mean NYHA class 2.9, DCM , ICM , mean EF 20%).8 Transplant-free survival was 70% after 1, 48% after 3 and 30% after 5 years for patients with a peak VO210 ml/kg/min () or a peak VO2 between 10 and 14 ml/kg/min (). In contrast, patients with a peak VO2 of 14 ml/kg/min had a significantly more favourable prognosis with a survival of 87%, 70% and 60% after 1, 3, and 5 years, respectively. Based on these data peak VO210 ml/kg/min has been implemented in the Aaronson–Mancini score for the assessment of prognosis in severe HF11 and in the AHA/ACC Guidelines for the Treatment of Congestive HF12 as a cutoff point to indicate heart transplantation.

However, some patients do not reach the anaerobic threshold e.g. because of impaired skeletal muscle performance. Under such circumstances other CPX derived parameters have been investigated with regard to their prognostic impact: VE/CO2, VE/CO2 slope, mean response time, recovery time, and various combinations of the above mentioned. In their 1995 study Aaronson et al. demonstrated that the percentage of predicted peak VO2 is a more precise discriminator of prognosis than peak VO2. The proposed cutoff point of 50% has been confirmed by Stelken et al., who showed that in a cohort of 181 HF patients (NYHA II , NYHA III , LVEF 23%) those with an oxygen uptake greater than 50% predicted value had a 94% 2-year survival as compared to only 50% survival in patients with an oxygen uptake of below 50% predicted value.13

In particular VE/VCO2, which is the ratio of ventilatory effort for a given CO2 output, has been shown to be a strong discriminator of impaired oxygen uptake in patients with HF and other severe noncirculatory disease. Comparing patients with chronic liver disease and patients with CHF who had similar peak oxygen uptakes of approximately 14 ml/kg/min, the VE/CO2 ratio, is significantly higher in HF patients (46 versus 36).14

The VE/VCO2 slope (slope of regression relating minute ventilation to carbon dioxide output) has also been proposed as a strong and more exact prognostic indicator in HF patients, since it implies the ventilatory effort as a measure of early CO2 production instead of oxygen uptake.15,16

The combination of CPX derived prognostic markers has recently been shown to discriminate prognosis of HF patients better than VO2max alone: Reduced VO2 plus decreased blood pressure plus impaired mean response time for oxygen uptake (MRT) during exercise indicates an extremely limited prognosis for patients with systolic HF.17

CPX has also been used to control therapeutic results. In 68 HF patients listed for heart transplantation with an initial peak VO214 ml/kg/min, Stevenson et al. demonstrated that patients with a tailored titration of HF medication resulting in an improved of peak VO2 had a better prognosis during follow up than those who failed to improve their peak VO2 during optimisation of HF medication.9

Compared to other prognostic markers in CHF peak VO2 seems more predictive than submaximal exercise tests such as 6-min walking distance.18,19 Combinations of markers as proposed in the Aaronson–Mancini score seem to be most appropriate. Recently the combination of peak VO2 and BNP serum level was found reliable for prognostic information:20 In 250 HF patients with a mean EF of 29% only the combination of peak VO214 ml/kg/min plus BNP137 pg/ml indicated a poor approximately 60% one-year survival. Patients with other constellations (peak VO214 plus BNP137 pg/ml, peak VO214 plus BNP137 pg/ml and peak VO214 plus BNP137 pg/ml) had a one-year survival of approximately 90% and could not be reliably discriminated from each other.

CPX testing in pacemaker therapy

Since the results of CPX testing are widely accepted as objective measures of cardiopulmonary performance and treatment effects in HF patients, CPX has been used to also objectively measure effects of pacemaker therapy. Bonnet evaluated a minute ventilation sensor used for a rate response algorithm by comparing the sensor results with those measured by CPX.21 Rickli used VO2 and VCO2 to demonstrate the superiority of DDD over VVIR and VVI pacing mode.22

Cardiopulmonary exercise testing in cardiac resynchronisation therapy

Cardiac resynchronization therapy (CRT) by bi- or left ventricular pacing has been shown to improve functional status, quality of life, exercise tolerance and to reduce hospitalisation rates in patients with severe idiopathic or ischaemic CHF.23–30 Recently it was demonstrated that the combined endpoint of mortality and hospitalization due to HF was significantly reduced by CRT.31,32 Consequently, CRT has been implemented in the current AHA/ACC/NASPE guidelines for the implantation of permanent pacemakers33 for patients with systolic HF NYHA class>=III, QRS duration130 ms, LVEDD55 mm and EF35%.

However, only in a few studies CPX results were used as primary or secondary endpoints. The first randomized and objective proof of the beneficial effect of CRT came from the PATH-CHF trial.23 This study enrolled HF patients with NYHA class>=III, QRS duration120 ms, LVEDD60 mm and peak VO218 ml/kg/min. Peak VO2 also served as primary endpoint. Patients were randomized after preoperative testing to either best pacing mode or no pacing for one month, had a "wash out" phase of another month and were crossed over to the other treatment arm for the third month. CRT increased peak VO2 by 1.3 ml/kg/min. The effect was reversible by CRT withdrawal for one month and reestablished by starting CRT again.24 These data were reproduced in a second randomized trial, comparing preselected subgroups (QRS duration120–150 ms versus QRS duration150 ms).25 One of the major inclusion criteria as well as primary endpoint was peak VO2. In the entire cohort peak VO2 increase was 1.3 ml/kg/min. However, in the group with QRS150 ms the improvement was 2.3 ml/kg/min, emphasizing that the degree of asynchrony as measured by QRS duration influences the therapeutic success. In a subanalysis of the PATH-CHF II study even a linear correlation (, ) between baseline QRS width and change in peak VO2 after three months of CRT therapy was demonstrated.34 The best balance for sensitivity, specificity and accuracy was demonstrated for a QRS width of 150 ms. This study also demonstrated that in unsuitable patients CRT may result in a significant deterioration of functional capacity. The Contak®-CD trial included 490 patients with ICD indication (NYHA class II–IV and QRS width120 ms) and randomized between ICD only and ICD plus CRT.35 The improvement of peak VO2 in the entire cohort was insignificant (0.8 ml/kg/min). In the subgroup of 176 NYHA class III and IV patients, the improvement was 1.8 ml/kg/min (). These data indicate that apart from baseline QRS duration the degree of functional impairment at baseline accounts for midterm (6–12 months) improvement. This is further supported by observations from the Italian InSync® registry, where patients in lower NYHA classes and longer 6-min walking distances had less functional improvement.36 Taking all published material into account an average peak VO2 improvement of 1.5 ml/kg/min was achieved (Table 2).


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  		Table 2 Major CRT studies – CPX results

 
In highly selected patients with a baseline QRS width150 ms, baseline peak VO218 ml/kg/min and positive acute response of 10% pulse pressure increase during preoperative testing38 it was demonstrated that peak VO2 may increase by up to 2.8 ml/kg/min early after CRT, and that this improvement is constant for at least two years.37 However the individual change in peak VO2 over time remains unpredictable (Fig. 1). In a cohort of 60 patients after CRT, Auricchio demonstrated that the increase in peak VO2 is largest in patients with the worst baseline performance.38



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  		Fig. 1 Individual changes in maximal oxygen uptake after CRT at 1, 3, 6, 9, 12 months (60 patients, EF 22±7%, mean age 62+10 years, 43 male, 39% ischaemic cardiomyopathy, NYHA>=III, QRS duration150 ms, LVEDD65 mm, VO2 max 8 ml/kg/min).

 
Conclusion

CPX testing in patients with systolic HF provides noninvasive objective measures for cardiopulmonary reserve and is thus suitable for evaluation, risk stratification and control of treatment effects. Parameters may be combined for this purpose. Patients with a baseline peak VO214 ml/kg/min regularly benefit from CRT during the first year of treatment. These findings have not yet been implemented in the current Guidelines for the Implantation of Permanent Pacemakers by the ACC/AHA/NASPE,33 while the German "Statement on cardiac resynchronization"39 already recommend a baseline peak VO2 of 14 ml/kg/min as one criterion to indicate CRT.

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