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The 6-Min Walk Distance in Pulmonary Arterial Hypertension

2010; Elsevier BV; Volume: 137; Issue: 6 Linguagem: Inglês

10.1378/chest.10-0351

1931-3543

Robert Naeije,

Heart Failure Treatment and Management

Exercise capacity measured by the distance walked in 6 min (6MWD) has been successfully used as a primary endpoint in most of the randomized controlled trials that have led to the registration of efficacious pharmacologic therapies for pulmonary arterial hypertension (PAH) during the last 2 decades.1McLaughlin VV Archer SL Badesch DB ACCF/AHA et al.ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.Circulation. 2009; 119: 2250-2294Crossref PubMed Scopus (892) Google Scholar As for any biomarker of disease severity, relationships are indirect and, therefore, not necessarily tight. However, a metaanalysis has confirmed that patients with PAH who improve their 6MWD after only a few weeks of any treatment also present with consistent improvements in functional state, hemodynamics, and survival.2Galiè N Manes A Negro L Palazzini M Bacchi-Reggiani ML Branzi A A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.Eur Heart J. 2009; 30: 394-403Crossref PubMed Scopus (545) Google Scholar Accordingly, the 6MWD is integrated in clinical decision making, goal-oriented treatment strategies, and newly designed event-driven trials for the diagnosis of clinical deterioration.3Badesch DB Champion HC Sanchez MA et al.Diagnosis and assessment of pulmonary arterial hypertension.J Am Coll Cardiol. 2009; 54: S55-S66Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar The measurement of a 6MWD is simple, safe, of negligible cost, applicable to daily activities, correlated to peak oxygen uptake (V˙o2), and highly reproducible after a modest < 10% improvement on repeated initial testing.4Fleg JL Piña IL Balady GJ et al.Assessment of functional capacity in clinical and research applications: an advisory from the committee on exercise, rehabilitation, and prevention, council on clinical cardiology, American Heart Association.Circulation. 2000; 102: 1591-1597Crossref PubMed Scopus (239) Google Scholar It has been shown that patients performing the walk test quickly stabilize at a metabolic rate equivalent to the highest achievableV˙o2 with a respiratory exchange ratio equal to or just less than one, which makes the 6MWD a particularly robust measure of purely aerobic exercise capacity.5Deboeck G Niset G Vachiery JL Moraine JJ Naeije R Physiological response to the six-minute walk test in pulmonary arterial hypertension.Eur Respir J. 2005; 26: 667-672Crossref PubMed Scopus (73) Google Scholar It is, therefore, intriguing that many experts persistently sweep negative statements against the use of the 6MWD in the evaluation of PAH, with a variety of arguments ranging from lack of scientific rationale to multifactorial determination of the results.6Roberts K Preston I Hill NS Pulmonary hypertension trials: current end points are flawed, but what are the alternatives?.Chest. 2006; 130: 934-936Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 7Rich S The current treatment of pulmonary arterial hypertension: time to redefine success.Chest. 2006; 130: 1198-1202Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The belief that the 6MWD is flawed in PAH has triggered expert consensus conferences aimed at the determination of improved trial designs, which actually resulted in the integration of the measurement into more composite end points.8Peacock AJ Naeije R Galiè N Rubin L End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?.Eur Respir J. 2009; 34: 231-242Crossref PubMed Scopus (38) Google Scholar There seems to be a hate-love relationship between the 6MWD and the PAH community, much alike the "Je t'aime, moi non plus" song that used to be popularized by Serge Gainsbourg and Brigitte Bardot. This should not be further exacerbated by the report of Degano and colleagues,9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar also from France, published in this issue of CHEST (see page 1297). Randomized controlled trials of new therapies in PAH have traditionally excluded patients with a baseline 6MWD > 450 m, because of a concern that better walking patients would be less severely ill and, accordingly, less sensitive to therapeutic interventions. This cautious strategy has led to the exclusion of a minority of patients with PAH whose clinical characteristics are now necessarily less well known. Degano and colleagues9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar have made use of the extensive database to the French national PAH reference center of the Beclere hospital in Paris to extract data of 49 patients with idiopathic, anorexigen-related, or heritable PAH who walked > 450 m at the time of diagnosis. This subgroup comprised 17% of these patients with PAH, which, as underscored by Degano and colleagues,9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar may be an overestimation because of noninclusion of New York Heart Association class 4 patients, and the a posteriori retrospective nature of their study. Thus, a minority of patients with PAH are particularly performant walkers. As compared with patients matched by diagnosis, hemodynamics, and first-line treatment, they are younger, taller, and thinner, as one might expect. But, more importantly, treatments that improve hemodynamics and functional class are without significant effect on the 6MWD in patients with PAH who initially walk > 450 m in 6 min.9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar This result confirms previously suspected loss of sensitivity of the test along with increased baseline distance. What is, after all, the rationale for exercise testing in PAH? The maximal capacity of an individual to perform aerobic work is defined by aV˙o2max. According to the Fick principle, aV˙o2max, often estimated by a peakV˙o2 in patients (but this is valid if the maximal respiratory exchange ratio is > 1.1), has to be equal to the product of the maximal values of cardiac outputQ˙ and the arteriovenous oxygen content difference, C(a − v)O2. V˙o2=Q˙ ×C( a−v) O2 Because aV˙o2max is typically achieved by exercise that involves approximately half of the total body musculature, it is reasonable to assume that maximal aerobic exercise capacity is essentially determined by maximal cardiac output rather than by peripheral factors. Endurance training increase both maximal cardiac output and oxygen extraction. However, because of progressively increasing affinity of hemoglobin for O2 at decreasing Po2, there is a lower limit of venous O2 content that appears to be similar in healthy athletes and in cardiac patients. This makesV˙o2max essentially dependent on the product of cardiac output and arterial O2 content, which expresses the convectional O2 transport to the exercising muscles. In heart failure, the major determinant ofV˙o2max is maximal cardiac output. In PAH, maximal cardiac output is determined by right ventricular function adaptation to afterload. Patients with PAH also present with an increased physiologic dead space as a cause of wasted ventilation, but most of them maintain a sufficient ventilatory reserve (or maximal voluntary ventilation minus maximal ventilation) at exercise, excluding a component of ventilatory limitation.10Sun XG Hansen JE Oudiz RJ Wasserman K Exercise pathophysiology in patients with primary pulmonary hypertension.Circulation. 2001; 104: 429-435Crossref PubMed Scopus (482) Google Scholar A decrease in arterial O2 content may contribute to decreasedV˙o2max in a proportion of patients with PAH, most of whom present with right-to-left cardiac shunts.10Sun XG Hansen JE Oudiz RJ Wasserman K Exercise pathophysiology in patients with primary pulmonary hypertension.Circulation. 2001; 104: 429-435Crossref PubMed Scopus (482) Google Scholar Recent studies have demonstrated a decreased skeletal muscle strength in PAH,11Meyer FJ Lossnitzer D Kristen AV et al.Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.Eur Respir J. 2005; 25: 125-130Crossref PubMed Scopus (143) Google Scholar, 12Bauer R Dehnert C Schoene P et al.Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension.Respir Med. 2007; 101: 2366-2369Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar but whether this is associated with a decreased oxygen extraction contributing to decreasedV˙o2max is not exactly known.13Naeije R Breathing more with weaker respiratory muscles in pulmonary arterial hypertension.Eur Respir J. 2005; 25: 6-8Crossref PubMed Scopus (36) Google Scholar There has been suggestion that patients with PAH more than patients with heart failure may also present with a decreased maximal O2 extraction added to cardiac output limitation to maximalaerobic exercise capacity,14Tolle J Waxman A Systrom D Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension.Med Sci Sports Exerc. 2008; 40: 3-8Crossref PubMed Scopus (62) Google Scholar but this result could have been accounted for by nonlinear relationships betweenV˙o2 andQ˙.15Wong YY van der Laarse WJ Vonk-Noordegraaf A Reduced systemic oxygen extraction does not prove muscle dysfunction in PAH.Med Sci Sports Exerc. 2008; 40: 1554-1555Crossref PubMed Scopus (6) Google Scholar In summary, the main determinant of decreased aerobic exercise capacity in PAH, as in heart failure, is maximal cardiac output. How does this relate to the 6MWD? A walking (or running, skating, swimming, and so forth) test is simply a translation of muscle mechanical work into a maximal average walking (or running, and so forth) speed. Muscle mechanical work, cardiac output, andV˙o2 are tightly and linearly related. Therefore, aerobic exercise capacity can indeed be estimated in normal subjects by a distance run in 12 min, also called the Cooper test,16Cooper KH A means of assessing maximal oxygen intake. Correlation between field and treadmill testing.JAMA. 1968; 203: 201-204Crossref PubMed Scopus (660) Google Scholar or in patients by a distance walked in 6 min in a hospital corridor, or the 6MWD.17Miyamoto S Nagaya N Satoh T et al.Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing.Am J Respir Crit Care Med. 2000; 161: 487-492Crossref PubMed Scopus (967) Google Scholar In normal subjects as well as in patients, relationships between an average maximal running or walking speed andV˙o2max are significant, but present with interindividual variability due to differences in mechanical efficiency.16Cooper KH A means of assessing maximal oxygen intake. Correlation between field and treadmill testing.JAMA. 1968; 203: 201-204Crossref PubMed Scopus (660) Google Scholar, 17Miyamoto S Nagaya N Satoh T et al.Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing.Am J Respir Crit Care Med. 2000; 161: 487-492Crossref PubMed Scopus (967) Google Scholar Mechanically efficient individuals walk or run or swim faster at a givenV˙o2. However, in any individual patient with PAH, an increased average maximal walking speed is most likely to be accounted for by an increased maximal cardiac output, likely explained by some unloading of the right ventricle. Therefore, the 6MWD can be considered an indirect test of right ventricular function. But then why is the 6MWD losing sensitivity to changes in functional state and hemodynamics at > 450 m? The simple explanation is again in the mechanical efficiency of the walk. The linearity between cardiac output,V˙o2, and maximum average speed is disrupted at some point when subjects should be allowed to switch from walking to running for further linear increase in speed. Running is obviously impossible in hospital corridors, and this accounts for the so-called "ceiling effect."18Frost AE Langleben D Oudiz R et al.The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.Vascul Pharmacol. 2005; 43: 36-39Crossref PubMed Scopus (136) Google Scholar In that situation, as suggested by Degano and colleagues,9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar it may be necessary to apply different exercise testing protocols, with direct measurements ofV˙o2max orQ˙max, and designs allowing for further increase in muscle work without excessive speed, using for example treadmills at increasing slopes.19Shah SJ Thenappan T Rich S Sur J Archer SL Gomberg-Maitland M Value of exercise treadmill testing in the risk stratification of patients with pulmonary hypertension.Circ Heart Fail. 2009; 2: 278-286Crossref PubMed Scopus (30) Google Scholar This is clearly an area still open for research. Degano and colleagues9Degano B Sitbon O Savale L et al.Characterization of pulmonary arterial hypertension patients walking more than 450 m in 6-min at diagnosis.Chest. 2010; 137: 1297-1303Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar are to be commended for calling attention to the need for improved evaluation of less severely ill patients with PAH. It is hoped that their report will overcome the hate-love affair between the 6MWD and the PAH community, and redirect the (cerebral) oxygen uptake of experts toward research for improved pathophysiological understanding of exercise testing in severe pulmonary hypertension.