In this cross-sectional study, we tried to identify the factors associated with the 6MWD in a large and fully characterized population of SSc patients. Our results can be summarized as follows: aside from demographic parameters, we observed significant and independent associations of the 6MWD with ΔHR and resting HR, with PAH and history of arterial thrombosis, and with CRP levels; we found no independent association of the 6MWD with ILD or musculoskeletal involvement; and in a sensitivity analysis, the HAQ-DI score was also independently associated with the 6MWD.
Although literature data are conflicting, the results of our univariate analyses mostly confirm findings from previous works, which observed associations of the 6MWD with age, BMI and cardiopulmonary parameters (especially PFT and TTE), but no major influence of musculoskeletal involvement [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. Multivariate analyses from previous studies have also established age , gender , HAQ scores  and CRP  as independent factors associated with the 6MWD. Independent associations with dyspnea , initial and final SpO2 , initial Borg score  and DLCO [21, 28] were also reported, but since our goal was to identify associations with specific organ involvements rather than their mediators, we chose not to include these variables in our multivariate model.
Association of the 6MWD with ΔHR
Association between the 6MWD and ΔHR has never been studied previously in SSc. Interestingly, similar findings were made in IPF  and PAH  patients, where the variation in HR was found to be an important factor associated with the 6MWD as well as a valuable prognostic marker.
Interpretation of this result in the context of the 6MWT is challenging. On the one hand, the lower increase in HR observed in some SSc patients could simply indicate lower exercise intensity due to limited functional capacities or a lack of motivation . On the other hand, it could also reflect an actual impairment of the chronotropic response to exercise. Chronotropic incompetence, defined as the inability to increase HR above 80% of its predicted peak value during a maximal exercise test, is a major cause of exercise intolerance in various cardiopulmonary diseases [40, 41]. It is a common finding in patients with heart diseases (sick sinus syndrome, atrial fibrillation, ischemic heart disease, chronic heart failure), neurological disorders (through autonomic dysfunction) or specific medication intakes (such as β-blockers and nondihydropyridine calcium-channel blockers) [40, 41].
Since the 6MWT is a submaximal exercise test, the diagnosis of chronotropic incompetence cannot be made here with certainty; and since detailed patient comorbidities are not available, the causes for the impaired chronotropic response in our population cannot be investigated fully. However, it is interesting to note that negative chronotropic drug intake was not independently associated with the 6MWD in our patients, making the hypothesis of a medication-induced chronotropic incompetence unlikely. Conversely, SSc is frequently associated with autonomic dysfunction  (especially in terms of HR regulation ) and with a specific myocardial disease , both of which could induce chronotropic incompetence.
Overall, this result suggests that an impaired chronotropic response could be an important factor associated with exercise intolerance in SSc. Interestingly, Someya et al.  showed in a previous work that the HR at the end of the 6MWT was higher in SSc patients than in controls to try and compensate for a decreased stroke volume. Thus, it seems reasonable to assume this compensation mechanism would be impaired in SSc patients with chronotropic incompetence, resulting in lower exercise capacities. In any case, this finding warrants further investigations, using maximal incremental exercise tests.
Association of the 6MWD with resting HR
Interestingly, we found that both ΔHR and resting HR are independently associated with the 6MWD. This result suggests that, during SSc, exercise capacities are conditioned not only by the patient’s ability to increase his or her HR during exercise, but also by his or her baseline HR value.
Only two studies have so far tested the association of the 6MWD with resting HR in SSc and they yielded discrepant results [19, 29]. Our observation is supported by similar findings in patients with nonidiopathic PAH and chronic heart failure [39, 45].
Here again, interpretation of this result in the context of our study is difficult. Heart rate is tightly regulated by the autonomous system in order to adapt cardiac output to situations of stress or exercise . Thus, the reduction of physical performance in SSc patients with increased resting HR could be suggestive of advanced autonomic dysfunction (loss of balance between sympathetic and vagal basal tones) and/or severe myocardial disease (compensating mechanism for a decreased resting stroke volume), as implied by our previous result. Alternatively, this could also indicate global deconditioning or performance anxiety.
Either way, further studies are needed to better appreciate the pathophysiological implications of this result.
Association of the 6MWD with PAH but not with ILD
Our multivariate analysis also revealed a significant and independent association of the 6MWD with PAH, but not with ILD. Interestingly, all previous studies that tested the relation between the 6MWD and PH consistently found a shorter walked distance in PH patients [21, 30] or an association with echocardiographic markers of PH [16, 19, 24, 29] (with only one exception ). Conversely, data regarding the influence of ILD on the 6MWD are more conflicting, with some studies observing shorter 6MWD in SSc-ILD patients [16, 30] and others reporting no significant difference [20, 21]. However, accurate comparison with previous works is challenging because of heterogeneity in design and population (notably in PH diagnosis, ILD definition and severity).
It is interesting to note that our result is in line with several data pleading for a predominant importance of pulmonary hemodynamic alterations over lung parenchymal involvement. In patients with IPF and PH, the 6MWD is significantly associated with hemodynamic parameters measured during right heart catheterization (RHC), but not with lung volumes assessed by spirometry . In SSc-ILD patients, gas transfer alteration has a stronger prognostic value than lung volume reduction [47, 48].
However, if this result confirms that PAH contributes to impaired exercise capacities during SSc, we also observed in a previous work that the 6MWD correlated poorly with RHC parameters in SSc-PAH patients . Taken together, these results suggest an impact of confounding extracardiopulmonary factors on the walked distance.
Association of the 6MWD with HAQ-DI score
Another interesting finding of our study is the strong association observed between the 6MWD and the HAQ-DI score.
Several teams have already reported similar results, both in univariate and multivariate regressions [21, 23]. Remarkably, in a previous work, Chow et al.  showed that the HAQ-DI score was not associated with parameters of cardiopulmonary severity in SSc patients with PAH. This implies that the patient perception of disability and functional limitation may not be entirely explained by the actual severity of the disease. Moreover, the 6MWD has been shown to be associated with scales of depression, anxiety and quality of life in several cardiorespiratory diseases [45, 51].
Overall, these results suggest that if the 6MWD is influenced to some extent by the objective severity of organ involvements, it is also greatly conditioned by the patient’s subjective impression of disability and quality of life impairment.
Association of the 6MWD with CRP
An independent association between CRP levels and the 6WWD was observed in our population. A similar result was also found in previous work by Schoindre et al.  both in univariate and multivariate regressions, but not by Deuschle et al. . Interestingly, CRP levels are associated with the EScSG-AI score, Medgser severity score and HAQ-DI score and with poorer prognosis in SSc patients . In line with our prior results, this observation could suggest that the 6MWD also captures the overall disease activity and severity.
No major influence of the musculoskeletal involvement on the 6MWD
Contrary to a common idea , it is interesting to note that musculoskeletal involvement is not independently associated with the 6MWD in our population. However, we did not consider which sites were involved in patients with joint or muscle symptoms. Therefore, we could not test the association between the 6MWD and lower limb involvement, which could contribute to explain this negative result. The effect of joint and muscle symptoms has been suggested previously in univariate analyses [21, 25, 26] but has never been tested in multivariate regression. Interestingly, quadricipital strength and joint involvement have been found to correlate both with the 6MWD and with the HAQ-DI score in SSc patients [25, 26, 53], which suggests that this score may also account for the musculoskeletal-induced disability impacting on the 6MWD.
Our study draws strength from a large sample size and an important number of variables collected.
Our study also has some limitations. We did not perform incremental exercise testing to correlate the 6MWD with objective physiological parameters collected during effort. Similarly, we did not study autonomic dysfunction to help explain the results observed with HR variation and ΔHR.
In our multivariate regression, we chose to include only parameters relating to organ involvement (e.g., PAH and ILD) and exclude variables mediating them (e.g., NYHA class, PFT results and TTE data). Indeed, we believed that inserting the latter in our model could mask interesting associations of the 6MWD with organ involvement.