Cardiac autonomic impairment and chronotropic incompetence in fibromyalgia

Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain and discomfort. In general, FM is accompanied by other symptoms such as fatigue, sleep disorders, reduced muscular strength and endurance, parasthesis, irritable bowel and joint stiffness [1]. Over the last two decades, the understanding regarding FM physiopathology has substantially advanced, with a growing body of evidence suggesting that autonomic nervous system dysfunction (also called dysautonomia) plays a role in this disease [2‐4].

In this regard, Furlan et al. [5] showed that women with FM have exacerbated sympathetic activity at rest. Furthermore, FM women undertaking a tilt test displayed an inability to increase sympathetic discharge and decrease vagal activity. Accordingly, dysautonomia has also been noticed in response to standing and cold exposure [6], both well-known autonomic function stressors.

Importantly, autonomic nervous system dysfunction has been associated with higher cardiovascular risk in several populations [7, 8]. In this regard, heart rate (HR) response to a graded exercise test has been largely used for assessing risks and prognoses in patients with overt or subclinical cardiovascular diseases [9, 10]. For example, an attenuated HR response to exercise (that is, chronotropic incompetence (CI))-which results from the combination of parasympathetic withdrawn and sympathetic activation-has been considered a strong and independent predictor of mortality and coronary heart disease, even when controlled for age, physical fitness, standard cardiovascular risk factors and ST-segment changes with exercise [9, 10]. Kingsley et al. [11] evaluated for the first time autonomic modulation in women with FM after an acute bout of resistance exercise. The authors contended that patients had greater parasympathetic and lower sympathetic modulation than healthy controls. However, the authors did not evaluate autonomic control during exercise, precluding a more definitive conclusion about their findings [11]. In this respect, Van Denderen et al. 1992 observed attenuated (nor)epinephrine concentrations during a graded exercise until exhaustion in FM patients versus healthy controls, suggesting a disturbance in autonomic control.

Thus, we aimed to gather knowledge on the cardiac autonomic modulation in FM patients in response to exercise and to investigate whether this population suffers from CI.

All subjects achieved RER > 1.05 and volitional exhaustion. Significant differences were found in VO₂ max (FM: 22 ± 1 vs. CTRL: 32 ± 2 mL/kg/min, P < 0.01), peak HR (FM: 148 ± 5 vs. CTRL: 177 ± 3 bpm, P < 0.001), HR at RCP (FM: 133 ± 4 vs. CTRL: 177 ± 5 bpm, P < 0.001).

Chronotropic reserve was significantly lower for the patients with FM when compared with CTRL (72.5 ± 5 vs. 106.1 ± 6, respectively; P < 0.001) (Figure 1). Eight of the 14 patients with FM (57.1%) presented CI whereas none of the healthy subjects presented it. deltaHRR1 (FM: 24.5 ± 3 vs. CTRL: 32.6 ± 2 bpm; P = 0.059) and deltaHRR2 (FM: 34.3 ± 4 vs. CTRL: 50.8 ± 3; P = 0.002) were also lower in FM versus CTRL (Figure 2, panels A and B, respectively).

This study indicates that patients with FM present abnormal HR response during and after exercise. In addition, we have identified that 57.1% of the patients presented CI, which is a powerful predictor of all-cause and cardiac death [7, 8].

CI has been recognized as a predictor of outcome in several cohorts that have included tens of thousands of patients [10, 16]. For instance, Sandvik et al. [10] observed that the HR increase during exercise was negatively associated with survival and that a reduction in the HR increase was a strong predictor of mortality from cardiovascular disease in a cohort of apparently healthy men. We observed a similar abnormal chronotropic response, suggesting that FM patients may also have a higher risk of mortality when compared with their healthy matched controls.

The mechanisms underlying CI during exercise still remain elusive. However, the most likely explanation for abnormal HR response involves abnormalities in autonomic nervous system modulation [17]. Several studies using power spectrum analysis of HR variability with different stressors (for example, tilt table test and 24 h electrocardiogram registration) have showed increased sympathetic and decreased parasympathetic tones in FM patients [2‐4]. Interestingly, this autonomic dysfunction appears to be characterized by sustained sympathetic hyperactivity at rest, and hyporeactivity to stress [1]. In this context, the blunted HR response during exercise seen in FM patients may be related to the desensitization of cardiac β1 receptors through a heightened sympathetic activity similar to heart failure [17]. Longitudinal studies are necessary to test the predictive power of CI as a non-invasive marker of risk in patients with FM.

In addition to the sympathetic hypoactivity observed during maximal exercise, cardiac autonomic impairment was noted following exercise, as suggested by a delayed deltaHRR recovery, which is initially affected by parasympathetic reactivation followed by sympathetic withdrawal. Altogether, these findings suggest that dysautonomia may play a role in FM. However, additional studies using more direct measurements of autonomic nervous system (for example, microneurography) may provide further insights on dysautonomia in FM.

Importantly, autonomic dysfunction has been associated with a variety of symptoms in FM, including sleep disorders, chronic pain, allodynia, anxiety, pseudo-Raynaud's phenomenon, sicca syndrome and intestinal irritability [18]. Thus, strategies aimed to attenuate dysautonomia may be considered therapeutically promising in FM. In this regard, Figueroa et al. [2] showed that a 16-week resistance training program led to improvements in resting vagal modulation and pain perception in women with FM. Additionally, the same group demonstrated that aerobic exercise training may improve post-exercise autonomic modulation in obese and type 2 diabetic patients [19]. Long-term studies should explore the therapeutic role of different types of exercise training (for example, low- or high-intensity, resistance, endurance or combined exercise programs) in modulating autonomic nervous system (for example, delayed HR recovery) in FM. Whether or not exercise-induced autonomic modulation may ameliorate CI in FM patients is also unclear.

Even though we have excluded all subjects taking drugs which affect chronotropic response to exercise (for example, beta-blockers), it is important to note that our patients were under a variety of medications (for example, antidepressant drugs), which may somehow affect the autonomic system [20]. Nonetheless, we extensively reviewed the literature and found no evidence of an influence of such drugs on chronotropic reserve or HR recovery. Accordingly, post-hoc sub-group analyses revealed that patients not taking antidepressants also had delayed HR recovery when compared with paired controls (deltaHRR1 = -13 bpm; P = 0.02 and deltaHRR1 = -20 bpm; P = 0.002). Moreover, five of nine patients (55.5%) not using antidepressant drugs presented CI. This prevalence was similar to that observed in subjects altogether (57.1%), suggesting that these drugs played a minor (if any) role in the current findings. Further studies assessing patients free of medication may be needed to fully clarify this issue.

Considering that both RER and HR during exercise are dependent on the volitional effort of the person exercising, one may speculate that a submaximal effort may explain the low HR responses in 57% of the FM patients tested. However, all of the patients reported volitional exhaustion at the end of the test. This, along with the fact that a RER greater than 1.05 was achieved in all tests, allows us to believe that CI may actually have accounted for low HR responses seen in this study.

Patients with FM presented an abnormal HR response to exercise, suggesting cardiac autonomic impairment and higher risk of cardiac events and mortality.