Chronic Fatigue Syndrome and Cardiovascular Disease

JACC State-of-the-Art Review

Benjamin H. Natelson, MD; Danielle L. Brunjes, PHD; Donna Mancini, MD


J Am Coll Cardiol. 2021;78(10):1056-1067. 

In This Article

Clinical Identification of ME/CFS

Chronic fatigue syndrome is not diagnosed if accompanied by any medical cause of severe fatigue; thus, its prevalence is low, at about 0.3%, with it occurring in women more often than in men.[1,2] A committee of the Institute of Medicine reviewed the illness;[3] they responded to patient concerns that the illness' name was stigmatizing[4] and recommended changing its name to ME/CFS. Prior to examining the role of cardiovascular disease on ME/CFS, it will be important to describe how the diagnosis is made. To facilitate diagnosis, patients are presented with a visual analog scale while asking them about their symptoms (Figure 1). ME/CFS is defined by medically unexplained fatigue lasting at least 6 months and severe enough to produce a substantial (rated as at least 3 on the visual analogue scale shown in Figure 1) decrease in activity at work, home, social events, or in school. In addition, the patient has to report having significant problems with unrefreshing sleep, symptom worsening following mild physical or emotional demands (called postexertional malaise [PEM]), and either cognitive reports or physiological evidence of orthostatic intolerance (OI) in the form of either orthostatic tachycardia and/or hypocapnia.[5] Because the diagnosis itself implies disability, inability to work is common in these patients.[6] Individuals who report moderate effects on activity and/or on symptom burden carry a less disabling diagnosis—idiopathic chronic fatigue. ME/CFS presents in certain stereotypical ways. First, more than one-third of patients report their illness starting suddenly most often with a flu-like presentation,[7] although there is no convincing evidence of ongoing infection. A major comorbidity is psychiatric diagnosis—most often major depressive disorder and/or generalized anxiety disorder. But, the rates of these disorders occurring[7] do not differ substantially from those occurring during convalescence after myocardial infarction.[8] Importantly, the diagnosis of ME/CFS appears to carry with it an increased risk of early cardiovascular mortality (mean was 59 years of age for ME/CFS vs 78 years of age for the U.S. population).[9] One group of researchers suggested this risk may be a function of reduced levels of omega-3 fatty acids, which they found in most ME/CFS patients.[10]

Figure 1.

ME/CFS Diagnosis Analog Scale
While asking about a patient's symptoms, the visual analog scale shown here is used to facilitate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Because the diagnosis depends on patient self-report across a broad range of symptoms, it is by definition comprised of a heterogeneous patient pool ranging from its being a somatic manifestation of depression to its being a brain disease.[11] This is a classical problem in medicine, which is solved by developing biomarkers that will allow stratification of a subgroup of patients. Until such biomarkers are available, clinical criteria such as sudden vs gradual illness onset can be used to try to reduce heterogeneity. But, because the illness is currently a diagnosis made only when medical causes of severe fatigue have been eliminated, this is a limitation toward understanding pathophysiology and arriving at specific treatments.