0.79 (CI95%:0.65-0.92), respectively.

CONCLUSION: As response parameters to cardiopulmonary exercise testing, HR slope and work ΔV´O2/ΔW have shown to be useful in discriminating between CFS and MM.

Keywords: Chronic fatigue syndrome, mitochondrial myopathy, cardiopulmonary exercise testing. Received May23, 2016; Accepted May 28, 2016; Published June 02, 2016. Copyright: © 2016 Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Editor: Antonio J. Carcas Sansuán

Cite as: Estébanez M., García F., Arpa FJ., Martínez P., Gómez JF., Borobia AM, Moreno-Arrones BR, Barbado FJ. Discriminative value of cardiopulmonary progressive exercise test in mitochondrial myopathy and chronic fatigue syndrome. IBJ Plus 2016 1(1):e0002. Funding: The author(s) declared that no grants were involved in supporting this work.

Competing Interests: Miriam Estébanez Muñoz is the executive editor of IBJ Infectious Diseases. Alberto M. Borobia Pérez is the

executive editor of IBJ Clinical Pharmacology.

1. Introduction

Chronic fatigue syndrome (CFS) and mitochondrial

myopathy (MM) can present as exercise intolerance in

adults with a normal creatine phosphokinase (CK) and

electromyography. CSF is an illness of unknown cause,

characterized by disabling fatigue lasting more than 6

months, and prominently features subjective

impairments in concentration, short-term memory and

sleep as well as musculoskeletal pain, in absence of a

recognizable medical and psychiatric disorder (1). MM

is one of the most common muscle diseases (2).

Primary mitochondrial respiratory chain disease is a

heterogeneous group of disorders characterized by

impaired energy metabolism due to presumed

genetically-based oxidative phosphorylation

dysfunction. Some patients present with symptoms that

are strongly suggestive of a mitochondrial cytopathy,

but many have nonspecific symptoms that overlap with

other diagnosis as CFS. It is probably that true cases of

MM had been diagnosed as CFS. So, it is necessary to

be in mind these disorders before the final diagnosis of

CFS. However, the study of the oxidative

phosphorylation requires an extensive laboratory

testing, including a muscle biopsy (3). It would be

interesting in the clinical practice to have a non

invasive and easy-to-conduct test, to discriminate

between both pathologies.

The exercise tolerance test has been studied as a

diagnostic tool to compare CFS patients with controls

(4-7), as well as to compare MM patients with controls (8-14). Most studies on the physical work capacity of

CFS have assessed the aerobic capacity by ensuring

maximal oxygen consumption (V’O2 max) and/or

heart rate response during exercise (15-19). A typical

finding in these studies is a low or near normal

V’O2max (18,19) and lower than anticipated maximal

heart rate (17,19-22). Thus, the picture emerging from

previous findings is that CFS patients have an aerobic

capacity lower than expected when compared with age

matched healthy subjects and an elevated subjective

perception of exercise intensity (19). Recent evidence

suggests that cardiovascular dysregulation may play an

important role in the etiology of this syndrome (17, 23

25).

The few published reports of pulmonary function

and exercise performance in patients with

mitochondrial disease have found abnormal cardiac

and ventilatory responses, low maximal oxygen uptake,

high respiratory exchange ratio at maximal exercise,

and elevated blood lactate levels during exercise that

recovers slowly following completion of exercise

(26,27). The low oxygen cost of exercise (oxygen

uptake/Watt) reported in MM patients (27) has been

interpreted as an increase in exercise efficiency.

Nevertheless, since it has been described in other

entities (28), the patients with MM might develop an oxygen deficit during the exercise that is repaid as an

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Table 3.Exercise response in the three study groups*

∗ Data are presented as average ± standard deviation or percentage. Abbreviations: HR=heart rate, V´O2=oxygen uptake, W=work rate, VE=minute ventilation, BR=breathing reserve, f=respiratory rate, VT=tidal volume, VD/VT=death space volume/tidal volume ratio, HRR=heart rate reserve, HR slope=cardiovascular response slope, V´O2/HR=oxygen pulse, ∆V´O2/W=oxygen cost, AT=anaerobic threshold.

Average comparison by ANOVA and post-hoc Bonferroni correction: † p<0.001 vs. control group, ‡ p<0.01 vs. control group, § p<0.05 vs. control group, ¶ p<0.001 vs. MM group, # p<0.01 vs. MM group.

The area under the ROC curve of the HR slope to (95%CI: 62.4-93.2%), positive predictive value 70.6%

discriminate CFS was 0.718 [CI 95%: 0.56-0.87] (95%CI: 44.1-88.6%), negative predictive value 76.7%

(Figure 1). The cutoff point to achieve a better (95%CI: 57.3-89.4%), likelihood-ratio positive 3.5

sensitivity-specificity relationship was 8.65 1/ml/kg. In (95%CI: 1.5-8.4) and accuracy 74.5% (95%CI: 59.4

the patients with exercise intolerance, a HR slope > 85.6%).

8.65 1/ml/Kg allowed to identify CFS with a sensitivity

Figure 1. HR slope ROC curve to discriminate chronic fatigue syndrome

(CFS) and work ∆V´O2/W ROC curve to discriminate mitochondrial

myopathy (MM).

The area under the ROC curve of the work 74.2% (95%CI: 55.1-87.5%), negative predictive value

ΔV´O2/ΔW to discriminate MM was 0.79 [CI 95%: 61.1% (95%CI: 36.1-81.7%), likelihood-ratio positive

0.65-0.92] (Figure 1). A work oxygen cost 1.8 (95%CI: 1.04-3.20) and accuracy 69.4% (95%CI:

(ΔV’O2/ΔW) > 12.8 ml/min/w identify a MM with a 54.4-81.3%).

sensitivity of 76.7 (95%CI: 57.3-89.4%), specificity

57.9% (95%CI: 34.0-78.9%), positive predictive value Figure 2 represents the probability of being a

patient with CFS as a function of the HR slope value along the entire curve starting at very low values. A cut

obtained in the cardio-pulmonary exercise test. point at 12.36 1/ml/kg results in a 21% sensitivity in

Increases in this value produce an increase in the the ROC curve. Below this value, all patients with MM

probability of having CFS, and patients are distributed in our sample can be found.

Figure 2. Probability of having mitochondrial myopathy as a function of

Figure 3 represents the probability of being a probability of suffering this disease with values above

patient with CFS as a function of the work ΔV´O2/ΔW 17 ml/min/watt. On the other hand, values less than

value obtained in the exercise tolerance test. Unlike in 10.4 ml/min/watt (100% of sensitivity in the ROC

the previous figure, patients with CFS are not curve) would have a low probability of belonging to

distributed along the entire curve, and have a low the MM group.

Figure 3. Probability of having mitochondrial myopathy as a function of

4. Discussion

There were two major findings of this study. First, As reported in previous studies (4-14), peak V’O2

patients with MM and CSF presented less exercise is diminished in both groups of patients in compared

capacity (peak V´O2 and peak W) compared to with controls. In patients with MM, oxygen

controls. Secondly, there were important differences in consumption is limited by structural and functional damage in mitochondrial oxidative phosphorylation, in

addition to the negative role played by lack of physical

conditioning (8-14). In patients with CFS, it has been

hypothesized that physical deconditioning plays a role

in fatigue maintenance, since it is possible that the

tendency towards hypovolemia, by reduction of

venomotor tone and the depletion of salt, collaborates

with the reduction in oxygen consumption to affect

cardiac output (6). However, in our study, there was no

significant difference between control subjects and

both groups of patients in oxygen pulse (table 3), so the

results found cannot be explained by differences in

physical condition. What is the exercise limiting factor

in CSF? We observed that the peak HR of the MM and

CFS groups is significantly lower than that of controls,

without differences in basal HR between them. The HR

slope or slope with which heart rate increases is, on the

other hand, significantly superior in the CFS group

with respect to the two remaining comparative groups.

De BP et al. (5) also reported significantly lower peak

HR in CFS patients in compare with control subjects.

These authors hypothesized that a lower peak HR as a

consequence of a slow acceleration in response to

exercise. In according to our results, this conclusion

may be incorrect because of they did not measured the

HR slope. We suggested that an excessive

tachycardization in response to exercise provokes early

fatigue and it is the exercise limiting factor in CSF.

The study of pacemaker regulation by the systemic

nervous system has been the protagonist in the

literature dedicated to CFS, supported by the theory

that acute or persistent viral infection (post-viral CFS) favors a chronotropic hyper-response to exercise (34

36). On the other hand, a disproportionate cardiac

response to exercise has been documented in healthy

individuals with physical deconditioning (37). In our

study, with comparable degrees of physical

conditioning (peak V´O2/HR) in both groups of

patients, significant differences were only found in the

HR slope with respect to controls in the CFS group.

Therefore we can conclude that some unknown factor

exists, present in CFS, that interferes with the control

of heart rate, and that could favor the maintenance of

fatigue. Along these lines Boneva et al (38) find that

compared to controls, patients with CFS present an

increased HR and a reduction in the variability of HR

that persists during sleep, which is associated with a

higher basal level of norepinephrine and a lower basal

level of aldosterone. These findings support the theory

that alterations in cardiovascular regulation, secondary

to an autonomic cardiovascular deregulation in favor of

the sympathetic system, play an important role in the

physiopathology of this disease.

What is most relevant for clinical practice, and the

objective of our study, is to find non-invasive and

easily reproducible parameters that permit the

differentiation of patients with CFS and MM, since patients with CFS may simulate the presentation of

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