Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Abstract

Post-exertional malaise (PEM) is the hallmark clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM involves a constellation of substantially disabling signs and symptoms that occur in response to physical, mental, emotional, and spiritual over-exertion. Because PEM occurs in response to over-exertion, physiological measurements obtained during standardized exertional paradigms hold promise to contribute greatly to our understanding of the cardiovascular, pulmonary, and metabolic states underlying PEM. In turn, information from standardized exertional paradigms can inform patho-etiologic studies and analeptic management strategies in people with ME/CFS. Several studies have been published that describe physiologic responses to exercise in people with ME/CFS, using maximal cardiopulmonary testing (CPET) as a standardized physiologic stressor. In both non-disabled people and people with a wide range of health conditions, the relationship between exercise heart rate (HR) and exercise workload during maximal CPET are repeatable and demonstrate a positive linear relationship. However, smaller or reduced increases in heart rate during CPET are consistently observed in ME/CFS. This blunted rise in heart rate is called chronotropic intolerance (CI). CI reflects an inability to appropriately increase cardiac output because of smaller than expected increases in heart rate. The purposes of this review are to (1) define CI and discuss its applications to clinical populations; (2) summarize existing data regarding heart rate responses to exercise obtained during maximal CPET in people with ME/CFS that have been published in the peer-reviewed literature through systematic review and meta-analysis; and (3) discuss how trends related to CI in ME/CFS observed in the literature should influence future patho-etiological research designs and clinical practice.

Keywords: chronic fatigue syndrome; chronotropic incompetence (CI); exercise; exercise test; heart rate; myalgic encephalomyelitis (ME).

Figure 1

Flow diagram describing the systematic review.

Figure 2

Standardized mean differences (d) for heart rate at peak exertion during maximal cardiopulmonary exercise testing, comparing patients with ME/CFS (n = 1,053) and matched control subjects (n = 569). Boxes represent point estimates, and whiskers are 95% confidence intervals. Patients with ME/CFS had lower peak heart rates than matched control subjects (large effect size).

Figure 3

Standardized mean differences (d) for exercise heart rate at ventilatory anaerobic threshold (VAT), comparing patients with ME/CFS (n = 778) and matched control subjects (n = 378). Boxes represent point estimates, and whiskers are 95% confidence intervals. Patients with ME/CFS had lower heart rates at VAT than matched control subjects (moderate effect size).

Figure 4

Heart rate responses to exercise in non-ME/CFS (solid line) and ME/CFS (dashed line). Arrow sizes represent the direction and magnitude of the influence of the dominant controllers of heart rate in shaded region.