Cardiac autonomic neuropathy in fibromyalgia: Revisited

Abstract

BACKGROUND:

Fibromyalgia (FM) is associated with widespread autonomic dysfunction where sympathetic predominance explains associated complaints such as widespread pain, sleep disorders and anxiety. Recent studies indicate a possible neurovascular autonomic interaction in the pathogenesis of FM.

OBJECTIVE:

Our study paradigm included a modified Ewing’s battery of autonomic function tests to find the cardiac autonomic neuropathy (CAN) in FM patients. The battery comprises some tests such as the Valsalva maneuver, which are effort-dependent, so we also aimed to identify a potential simplified test out of the whole battery as an index marker of CAN in FM patients.

METHODS:

Forty-two female patients with FM were included in this study and were administered sympathetic and parasympathetic reactivity tests to explore the presence of CAN. We compared the results from each sympathetic and parasympathetic reactivity test against CAN.

RESULTS:

Delta heart rate in the deep breathing test was significantly different in patients with and without CAN. Delta heart rate also exhibited best diagnostic performance (AUC $=$ 0.769, 95% CI: 0.619–0.920, $p<$ 0.001), with 88% sensitivity, 64% specificity, and 89% negative predictive value (NPV). The 30: 15 ratio during the lying to standing test also emerged as a suitable index; however it did not show any difference between CAN and non-CAN patients.

CONCLUSION:

The delta heart rate has the best diagnostic accuracy, primarily in CAN’s exclusion by its very high sensitivity and NPV.

Keywords

Fibromyalgia autonomic nervous system pain central sensitization cardiac autonomic neuropathy

1. Introduction

Fibromyalgia (FM) is a chronic debilitating pain disorder considered either as centralized pain syndrome or a state of generalized sympathetic dysfunction. Studies favoring central sensitization are based on the concept of a higher gain setting of pain processing mechanisms. On the contrary, theories supporting peripheral sympathetic overactivity in patients with FM could provide a basis for underlying stiffness and post-exertional pain [1]. Autonomic dysfunction may underlie multiple comorbidities and coexisting signs and symptoms like sleep disorders, anxiety, Raynaud’s-like phenomenon, Sicca symptoms, intestinal irritability, dry eyes, dry mouth and widespread pain in FM patients [2]. Fatigue, fever, and myalgia in patients with FM can be attributed to dysregulation of circulatory levels of proinflammatory cytokines [3]. A low heart rate variability (HRV) in rheumatoid arthritis is associated with increased serum inflammatory cytokine levels and patient-reported pain [4]. Recent evidence views FM as stress-related dysautonomia with neuropathic pain features. The presence of stimulus-independent pain along with allodynia and paresthesias in FM patients point towards a sympathetically mediated neuropathic pain [5]. Dorsal root ganglia are considered a potential autonomic-nociceptive short-circuit site where the sprouting of sympathetic fibers follows after peripheral nerve injury and involves adenosine triphosphate (ATP), along with norepinephrine release from sympathetic nerve endings [6]. The FM patients have a neurovascular disease inclusive of cardiovascular and nociceptive neural modulation [7]. Some studies corroborate our findings and have shown a blunted response to an orthostatic challenge in patients with FM, thus providing support for a cardiovascular alteration in FM [1]. A neurovascular coupling encompassing causal link between the cardiovascular (endothelial dysfunction), orthostatic intolerance, and central pain processing deficit has been proposed in FM patients. An ineffective tuning of spatial and temporal summation of pain by central inhibitory mechanisms, like diffuse noxious inhibitory control [DNIC], which in turn are modulated by vagal activity, may underlie FMS pathogenesis [8].

The cardiovascular autonomic reflex is intact in FM patients, and the possibility of a vascular end-organ dysfunction cannot be ruled out, as stated in our previous study [9]. We proposed a model linking probable autonomic dysfunction with physical deconditioning arising due to the lack of physical activity caused by chronic debilitating pain in patients with FM [10].

Cardiac autonomic neuropathy (CAN) is associated with life-threatening clinical entities such as silent myocardial ischemia, coronary artery disease, and stroke, resulting in increased mortality. The gold standard for the diagnosis of CAN is Ewing’s battery, which includes five standardized tests. However, in our laboratory, we use a modified Ewing’s battery because the traditional Ewing’s battery does not include the cold pressor test (Table 1) [11]. These effort-dependent tests require the patient’s compliance and may not be beneficial in detecting CAN in FM patients [10]. With this background in mind, we analyzed FM patients’ data who were administered a battery of autonomic tests to estimate the status of CAN. We also tried to find a simplified test out of the modified Ewing’s battery for screening FM patients for possible CAN.

An extensive biochemical investigation was performed in each patient to rule out any comorbidity. The results of a complete blood count, Westergren erythrocytic sedimentation rate, muscle enzymes, rheumatoid factor, thyroid function tests, and serum electrolytes were normal in the patients. Patients with a history of hypertension, diabetes mellitus, coronary artery disease, hypovolemia, adrenal insufficiency, cardiomyopathies, congenital cardiac disease, malignancy, and autoimmune diseases were excluded from the study. Patients with a history of smoking, alcoholism, and drug intake (anticholinergics and antidepressants for at least four weeks before the study) were also not included. Furthermore, pregnant women or women who took oral contraceptive pills or followed hormonal replacement therapy, were also not included.

2. Methods

The study was conducted at the Autonomic Function Laboratory, Department of Physiology, AIIMS, New Delhi, India, after ethical approval was granted by the ethics committee of the institute. The data were collected from 42 patients with FM, recruited from the Rheumatology Clinic for a study aimed at comparing autonomic function in FM patients vs healthy normal controls [10]. Informed consent was obtained from all FM patients prior to the study.

All patients were requested to refrain from analgesics and intense physical activity on the day of the examination. Patients were asked to fast for 12 h before the procedure and asked to avoid taking antidepressants, neuroleptics, caffeine, nicotine, or antihistamines. The tests were carried out in a quiet environment with steady temperature levels between 22–24 ${}^{\circ}$ C.

Assessment of autonomic function was done by a standard battery of non-invasive tests of autonomic function based on modified Ewing criteria. The modified battery incorporates two additional indices/parameters to the original Ewing battery tests [11]. The expiratory/inspiratory heart rate ratio (E/I) was added to parasympathetic reactivity parameters, and the diastolic blood pressure response to the cold pressor test was added to sympathetic reactivity parameters.

Table 1
The modified Ewing battery for the autonomic function test

	Indices/parameters	Normal (0)	Borderline (1)	Abnormal (2)
Parasympathetic	Valsalva ratio	$\geqslant$ 1.21	1.11–1.2	$\leqslant$ 1.1
reactivity tests	Delta heart rate (deep breathing test)	$\geqslant$ 15 beats/minute	11–14	$\leqslant$ 10
	E/I ratio (deep breathing test)	$\geqslant$ 1.2	1–1.1	$\leqslant$ 1
	30: 15 ratio (lying to standing test)	$\geqslant$ 1.04	1.01–1.03	$\leqslant$ 1.0
Sympathetic	Diastolic blood pressure response to handgrip test (mmHg)	$\geqslant$ 15	11–14	$<$ 10
reactivity tests	Systolic blood pressure response to standing (mm Hg)	$<$ 10	11–29	$\geqslant$ 30
	Diastolic blood pressure response to cold pressor test (mmHg)	$<$ 5	5–9	$\geqslant$ 10

In short, tests of parasympathetic cardio-vagal regulation included heart rate analysis in the standing position (the 30: 15 ratio), heart rate variation with deep breathing (delta heart rate and E/I ratio), and the alsalva ratio (VR). Tests of sympathetic adrenergic vascular regulation included blood pressure (BP) analysis in the standing position, sustained handgrip, and cold pressor test. Heart rate variation was assessed by electrocardiogram recordings of beat-to-beat (R-R intervals) between two consecutive electrocardiogram R waves. The diagnostic indices/parameters obtained from the modified battery of autonomic function tests are as follows:

Delta heart rate: The subject sits quietly and then breathes deeply and evenly at 6 breaths/min. The maximum and minimum heart rates during each breathing cycle are measured, and the mean of the differences during three successive breathing cycles are taken to give the maximum-minimum heart rate.

ii.

The expiration/inspiration (E/I) ratio is calculated as the mean of the longest R-R interval during expiration divided by the mean of the shortest R-R interval during inspiration, while the patient lay quietly and breathed deeply with an ECG that recorded heart rate variation over six breathing cycles.

iii.

For the heart rate response to the Valsalva manoeuver, the ratio of the longest R-R interval to the shortest R-R interval is checked during forced exhalation into the mouthpiece of a manometer against 40 mmHg for 15 seconds.

iv.

The ratio of postural change (30: 15 ratio) is the ratio of the longest RR interval around the 15 ${}^{\text{th}}$ beat after standing to the shortest R-R interval around the 30 ${}^{\text{th}}$ beat after standing.

During the three subsequent blood pressure tests, blood pressure response to standing from a lying position, cold pressor test (10 ${}^{\circ}$ C for one minute), and a sustained handgrip (50 % of maximal contraction for one minute) is recorded.

Each test was scored as either normal (0), borderline (1), or abnormal (2), as shown in Table 1. On the basis of those scores and values, all FM patients were categorized into two groups: those with CAN and those without CAN. The presence of CAN in our study was defined as those patients with $\geqslant$ 2 abnormal tests.

2.1 Statistical analysis

The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS), version 19.0 (IBM, Armonk, NY, USA). Independent Student’s $t$ -test was carried out to evaluate the differences between FM patients with and without CAN. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to quantify the diagnostic performance of tests. Sensitivity, specificity, positive and negative predictive values were calculated using Easy ROC software [12]. The Cohen’s kappa was used to assess agreement. All tests were two-tailed, and significance was defined at the 5% level ( $p<$ 0.05).

3. Results

An analysis of the results revealed that that out of 42 patients with FM, 25 patients had CAN, and 17 patients did not have CAN. The autonomic score of patients with CAN was 5.52 $\pm$ 1.66, and those without CAN was 2.18 $\pm$ 0.81 ( $p=$ 0.000; CI (lower-upper): 2.18–4.13).

All patients had confirmed primary FM with a mean duration of illness (with CAN 5.76 $\pm$ 2.78 vs without CAN 5.1 $\pm$ 3.39 years). The mean number of tender points among the patients with CAN was 15.68 $\pm$ 1.82 and 15.29 $\pm$ 1.93 for those without CAN. The mean age of patients in both categories (CAN: 40.44 $\pm$ 6.4 vs without CAN 38.06 $\pm$ 6.4 years) was statistically similar. The FM patients with CAN had a similar systolic blood pressure (116.56 $\pm$ 13.55 vs 117.06.62 $\pm$ 12.23 mmHg; $p>$ 0.05), diastolic blood pressure (76.80 $\pm$ 9.99 vs 80.71 $\pm$ 10.02 mmHg; $p>$ 0.05), resting heart rate (80.96 $\pm$ 11.79 vs 83.76 $\pm$ 12.92; $p>$ 0.05), and respiratory rate (20.08 $\pm$ 1.64 vs 20.35 $\pm$ 3.48; $p>$ 0.05) as compared to patients without CAN.

Patients with FM in our study were divided into two categories: those with ( $n=$ 25) and without CAN ( $n=$ 17) and analyzed for the difference in response to a battery of the autonomic function test (Table 2). The value of the delta heart rate ( $p=$ 0.03) was significantly lower among patients with CAN, while the E/I ratio did not differ significantly between the two groups ( $p=$ 0.08). Values of VR and 30: 15 ratio were comparable among the two groups.

Table 2
Diagnostic indices/parameters in FM patients with and without CAN

Serial number	Autonomic function test	Parameters	CAN ( $n=$ 25)		Non-CAN ( $n=$ 17)		$P$ value
1	Deep breathing test (DBT)	Delta heart rate ( $\Delta$ HR)	15.60	$\pm$ 8.49	24.76	$\pm$ 9.9	0.03
2		Expiration:Inspiration ratio (E/I)	1.3	$\pm$ 0.14	1.34	$\pm$ 0.13	0.08
3	Valsalva maneuver (VM)	Valsalva ratio (VR)	1.84	$\pm$ 0.54	1.88	$\pm$ 0.44	0.84
4	Lying to standing test (LST)	HR response to LST (30: 15 ratio)	1.18	$\pm$ 0.29	1.31	$\pm$ 0.17	0.12
5		Fall in SBP (mm Hg)	11	$\pm$ 7.07	7.09	$\pm$ 4.93	0.12
6	Handgrip test (HGT)	Rise in DBP (mm Hg)	7.92	$\pm$ 5.15	12.12	$\pm$ 9.12	0.06
7	Cold pressor test (CPT)	Rise in DBP (mm Hg)	12.48	$\pm$ 8.97	16.59	$\pm$ 8.33	0.14

Table 3

Performance of diagnostic indices/parameters in FM patients

Diagnostic index	AUC (95% CI)	$p$	Cut- off	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Overall agreement (%)	Kappa ( $p$ value)
Delta heart rate	0.769 (0.619–920)	0.00	18	88 (64–99)	64 (43–82)	63 (41–94)	89 (65–95)	64	0.34	(0.007)
E:I	0.682 (0.522–0.843)	0.03	1.2	94 (71–99)	32 (15–54)	49 (26–98)	89 (55–95)	48	0.085	(0.320)
VR	0.546 (0.341–0.751)	0.66	1.7	69 (39–91)	50 (27–73)	47 (25–80)	71 (41–87)	45	0.07	(0.23)
30: 15 ratio in LST	0.710 (0.540–0.879)	0.02	1.11	100 (78–100)	38 (18–62)	54 (29–98)	100 (66–100)	83	0.28	(0.01)
Fall in SBP in LST	0.361 (0.153–0.569)	0.19	8	64 (31–89)	44 (22–69)	41 (19–76)	67 (32–86)	60	0.183	(0.23)
Rise in DBP in HGT	0.652 (0.479–0.824)	0.09	12	41 (18–67)	88 (69–98)	70 (41–87)	69 (42–92)	64	0.19	(0.15)
Rise in SBP in CPT	0.696 (0.527–0.866)	0.02	12	82 (57–96)	68 (46–85)	64 (42–91)	85 (61–94)	50	$-$ 0.182	(0.083)

Legend: AUC – area under the curve, CAN – cardiovascular autonomic neuropathy, CI – confidence interval, DBP – diastolic blood pressure, E/I – expiration/inspiration index, NPV – negative predictive value, PPV – positive predictive value, SBP – systolic blood pressure, VR – Valsalva ratio.

Figure 1.

Receiver operating characteristic (ROC) curve for delta heart rate parameter in the deep breathing test. ROC was performed for delta heart rate values obtained from the deep breathing test. The area under the curve (AUC) is 0.769, 95% CI: 0.619–0.919, $p<$ 0.001.

Patients with CAN exhibited a greater reduction in systolic blood pressure during LST and a smaller rise in diastolic blood pressure while performing HGT and CPT than those who did not have CAN but failed to get a level of significance.

In the FM patients with CAN, the parameters obtained during the deep breathing test viz. delta heart rate and E/I ratio yield no significant correlation ( $r=$ 0.35, $p=$ 0.09). However, there is a positive correlation in FM patients without CAN ( $p=$ 0.53, $p=$ 0.03) between the delta heart rate and E/I ratio. Similarly, there is no correlation between the delta heart rate during deep breathing and resting heart rate among the two groups (with CAN, $p=$ 0.853; without CAN, $p=$ 0.904).

Table 3 shows the AUC for the parameters mentioned above. The delta heart rate showed the best diagnostic performance (Fig. 1) (AUC $=$ 0.769, 95% CI: 0.619–0.919, $p<$ 0.001). The following three other indices/parameters had AUC values approaching levels of acceptable discrimination (between 0.7–0.8), which indicates a high diagnostic performance:

•

HR response (30: 15) to LST (AUC $=$ 0.710, 95% CI: 0.540–0.879, $p=$ 0.02)

•

Rise in diastolic blood pressure while in CPT (AUC $=$ 0.696, 95% CI: 0.527–0.866, $p=$ 0.02)

•

E/I ratio (AUC $=$ 0.682, 95% CI: 0.522–0.866, $p=$ 0.03)

Inferior, non-significant results were obtained for VR ( $p=$ 0.66), SBP fall in LST ( $p=$ 0.19) and the rise in diastolic blood pressure in HGT ( $p=$ 0.09).

Figure 2.

A unified hypothesis for pathophysiology of fibromyalgia.

The overall agreement of the classification of patients according to the three indices/parameters (delta heart rate, 30: 15 ratio, DBT rise in HGT) with the gold standard of CAN diagnosis (based on the modified Ewing battery score) was over 64% (64–83%). The Cohen’s kappa coefficient indicated fair agreement for the delta heart rate (kappa $=$ 0.34, $p=$ 0.007) and for 30: 15 ratio in the lying standing test with kappa values 0.28 ( $p=$ 0.01). None to slight agreement results were obtained for other indices/parameters. The overall agreement of the classification of patients according to both deep breathing test parameters (delta HR and E/I ratio) into normal (without CAN) and abnormal category (with CAN) stands at 79% and is fair with Cohen’s kappa value $=$ 0.364, $p=$ 0.007)

4. Discussion

The presence of CAN increases the risk of intraoperative and perioperative hemodynamic instability, development of orthostatic hypotension, and silent myocardial infarction. Early diagnosis of CAN can aid in the prognosis, proper management, and rehabilitation of FM patients [13].

Various CAN-based studies that examined the modified Ewing’s batteries of autonomic function tests have utilized tests in various combinations ranging from just one test to five tests to diagnose CAN [11]. A set of three tests viz. R-R variation, Valsalva maneuver, and postural blood pressure change have been recommended for longitudinal testing of the cardiovascular autonomic system [14]. Cardiovascular autonomic responses are quantified by changes in the heart rate and blood pressure in response to some of the physiological stimuli. During the progression of autonomic neuropathy in diabetes mellitus, the pattern of CAN worsening follows a characteristic sequence, with first the HR-based and then the BP-based tests becoming abnormal [15]. Ewing et al. [16] showed a coexisting parallel autonomic and peripheral neuropathy in long-term diabetes. Reduced delta heart rate value is regarded as pathognomic of cardiac vagal neuropathy. In some patients, delta heart rate values decline over two to three years as peripheral neuropathy progresses [17, 18].

We reported a higher sympathetic vascular tone in patients with FM than healthy controls in a previous study. The sympathetic reflex arc is intact, leaving the likelihood of vascular end organs’ defects, which are continuously subjected to persistently high blood pressure [10].

In our study, only the delta heart rate value is different among the FM patients (CAN vs non-CAN). The mean value of the delta heart rate in FM patients with CAN actually falls within the normal established range but is significantly lower than those of patients without CAN. Our findings suggest that the delta HR is the most useful index for CAN diagnosis because it yields high sensitivity and a moderately high specificity in FM patients. Our study demonstrated the best AUC for the delta HR and exhibits a fair agreement with the autonomic function test score. The delta heart rate shows the best diagnostic accuracy in our study, primarily in excluding CAN, by its very high sensitivity and negative predictive value (NPV). The 30: 15 ratio during the lying to standing test also shows a similar performance (AUC: 0.710, 95% CI: 0.540–0.879), sensitivity: 99%s specificity: 38%, and a fair agreement with the gold standard. However, it does not reveal any significant difference with respect to the presence or absence of CAN in FM patients. Our results indicate a plausible parasympathetic insufficiency among FM patients presenting with CAN.

Resting heart rate may also reflect vagal damage, but this is a clearly less sensitive indicator of parasympathetic dysfunction than the delta heart rate [19, 20]. We report that delta-HR values in our study do not correlate with resting heart rate. This indicates that irrespective of the resting heart rate, delta-HR values can be used to distinguish normal from abnormal autonomic function. Another parameter derived from the deep breathing test, the E: I ratio, correlates almost precisely with the more widely used delta HR in normal FM patients but not those with FM in our study [21].

A vagal nerve stimulation study in FM patients suggest tuning down of central sensitization mechanisms [22]. Vagal nerve stimulation can also reduce inflammation and decrease TNF release [23]. Diminished vagal anti-inflammatory signals can allow cytokine overproduction in animals [24]. An imbalance between the ANS and the hypothalamic-pituitary-adrenal axis is implicated in FM and related disorders such as chronic fatigue syndrome and irritable bowel disease. The nucleus tractus solitarius (NTS) acts as an integrating center that receives primary afferents from the vagus nerve and the spinal pathways involved in the pain processing. It also serves as an integrating center for the autonomic and sensory system. A disruption of subdiaphragmatic vagal afferents may cause long-lasting sensory abnormalities by altering descending antinociceptive mechanism [25]. Moreover, upregulation of the sympathoadrenal axis may cause widespread sensitization of primary afferent nociceptors [26].

4.1 Limitations

This study is not without limitations. A small number of patients were recruited for the present study because of time constraints. Moreover, we did not distinguish between mild, moderate, and severe CAN. However, the goal was to simplify and identify a simple screening tool for the examination procedure for CAN diagnosis in FM patients. Further studies are necessary to explore the overexpression of cytokines and their correlation with vagal function to find effective management of the symptoms and rehabilitation of FM patients.

5. Conclusion

We conclude that sympathetic overactivity in FM versus healthy controls reported in the literature may have underpinnings for under-normal vagal activity in FM patients. We also propose a modified model that can be viewed as a unified mechanism of autonomic dysfunction in FM’s pathophysiology (Fig. 2) [10].

Attempts to simplify the diagnosis of CAN in FM patients should be made. A deep breathing test could be used as a simplified test to differentiate patients into the CAN and non-CAN category. Effort-dependent such as the Valsalva manoeuvre and handgrip test should be modified for chronic pain patients.

Footnotes

Conflict of interest

None to report.

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Cardiac autonomic neuropathy in fibromyalgia: Revisited

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Methods

Table 1 The modified Ewing battery for the autonomic function test

3. Results

Table 2 Diagnostic indices/parameters in FM patients with and without CAN

4.1 Limitations

5. Conclusion

Footnotes

Conflict of interest

References

Table 1
The modified Ewing battery for the autonomic function test

Table 2
Diagnostic indices/parameters in FM patients with and without CAN