Cardiac Function
1 Exercise Testing Abnormalities
Cardiopulmonary exercise testing (CPET) provides objective measurement of integrated cardiovascular, pulmonary, and metabolic function during physical exertion. CPET findings in ME/CFS represent some of the most reproducible objective abnormalities documented in the illness.
1.1 Cardiopulmonary Exercise Testing (CPET) Methodology
CPET involves graded exercise (typically on a cycle ergometer or treadmill) with continuous measurement of oxygen consumption (VO2, the volume of oxygen extracted from inspired air per unit time), carbon dioxide production (VCO2, the volume of CO2 expired), and their ratio expressed as the respiratory exchange ratio (RER = VCO2/VO2), which indicates fuel substrate utilization. Simultaneously, the system records minute ventilation (VE, total air volume breathed per minute), heart rate via continuous electrocardiographic monitoring, periodic blood pressure measurements, and work rate (power output in watts or treadmill speed and grade).
Testing continues until volitional exhaustion or limiting symptoms. Criteria for maximal effort include an RER exceeding 1.10, achievement of age-predicted maximal heart rate, or a plateau in VO2 despite increasing work rate.
1.2 Key NIH Deep Phenotyping CPET Findings
The Walitt et al. study documented several critical cardiopulmonary abnormalities in PI-ME/CFS patients ((Walitt et al. 2024)):
Reduced Peak Oxygen Consumption (VO2peak) Peak VO2 represents maximal aerobic capacity and integrates cardiac output, oxygen delivery, and peripheral oxygen extraction. PI-ME/CFS patients demonstrated significantly reduced VO2peak compared to matched healthy controls (Walitt et al. 2024). This reduction indicates impaired aerobic capacity beyond what deconditioning alone would predict; ME/CFS patients showed greater deficits than sedentary controls matched for activity level, with reductions typically ranging from 15–30% below predicted values (Keller et al. 2024) (Lim et al. 2020). More severely affected patients show greater reductions. The finding correlates with functional limitation and disability, providing objective confirmation of patient-reported exercise intolerance.
Chronotropic Incompetence Chronotropic incompetence refers to an inadequate heart rate response to exercise ((Walitt et al. 2024)):
- ME/CFS patients fail to achieve age-predicted maximal heart rate
- Heart rate rise is blunted relative to work rate increases
- Chronotropic index (proportion of heart rate reserve used) is reduced
Chronotropic incompetence limits cardiac output augmentation during exercise, as cardiac output = heart rate \(\\times\) stroke volume. Without adequate heart rate increase, oxygen delivery to exercising muscles is compromised.
Deconditioning as an alternative explanation. It must be acknowledged that some portion of the cardiovascular findings — reduced peak VO₂, chronotropic incompetence, reduced blood volume, and orthostatic intolerance — can be explained by physical deconditioning rather than primary disease pathology. Prolonged inactivity reduces cardiac stroke volume, blunts heart rate variability, and decreases plasma volume, all of which overlap with the ME/CFS cardiovascular phenotype. However, deconditioning does not explain: (a) the selective pattern of orthostatic abnormalities (disproportionate CBF decline relative to systemic hemodynamics), (b) the GPCR autoantibody evidence linking specific receptor dysfunction to exercise and orthostatic impairment, (c) the failure of Day 2 CPET recovery that persists after controlling for fitness level, and (d) the lack of correlation between disease duration and cardiac volume reductions (Julia L. Newton et al. 2016). Deconditioning is a contributing factor in many patients — worsening baseline function through inactivity — but it is insufficient as a primary explanation for the full cardiovascular phenotype.
Mechanisms of Chronotropic Incompetence Several mechanisms have been proposed; their relative contributions in ME/CFS remain under investigation:
- Parasympathetic excess: Sustained vagal tone preventing heart rate acceleration—supported by HRV findings showing altered autonomic balance (J. L. Newton et al. 2007)
- Sympathetic dysfunction: Impaired catecholamine release or receptor sensitivity
- Sinoatrial node dysfunction: Intrinsic pacemaker abnormality (hypothesized but not directly demonstrated in ME/CFS)
- G-protein-coupled receptor (GPCR) autoantibodies: A growing body of evidence implicates autoantibodies targeting G-protein-coupled receptors in ME/CFS cardiovascular dysfunction. Loebel et al. first documented elevated autoantibodies against beta-adrenergic (\(\beta_1\), \(\beta_2\)) and muscarinic cholinergic (M3, M4) receptors in ME/CFS patients (Loebel et al. 2016), findings subsequently validated in Swedish cohorts including cerebrospinal fluid samples (Bynke et al. 2020). Azcue et al. (2026) provide the most detailed autonomic–autoantibody correlation data to date: \(\beta_2\)-adrenergic AAb titers correlated significantly with sympathovagal imbalance in ME/CFS (\(r=0.45\), \(p=0.001\), \(n=59\)) as measured by HRV frequency-domain parameters, providing the strongest quantitative link yet between GPCR autoantibodies and cardiac autonomic dysfunction in ME/CFS (Azcue et al. 2026).
The cardiovascular effects of these autoantibodies are multifaceted. Beta-adrenergic receptor autoantibodies may exert either agonistic effects (causing inappropriate receptor activation) or antagonistic effects (blocking normal catecholamine signaling), depending on the specific antibody epitope and receptor subtype. Muscarinic receptor autoantibodies similarly can enhance or impair parasympathetic signaling to the heart and vasculature. This bidirectional potential explains why the same class of autoantibodies might produce different phenotypes across patients.
Levels of vasoregulative GPCR autoantibodies correlate with symptom severity, autonomic dysfunction, and disability in ME/CFS (Freitag et al. 2021). The correlation with autonomic measures supports a direct pathophysiological role rather than an epiphenomenon of chronic illness. Beta-2 adrenergic receptor autoantibodies appear particularly relevant to cardiovascular symptoms, with immunoadsorption targeting these antibodies showing preliminary efficacy in post-COVID ME/CFS (Stein et al. 2025). BC007, a DNA aptamer that neutralizes GPCR autoantibodies, has shown promise in case reports for improving fatigue and microcirculatory function (Hohberger et al. 2021). Three complementary approaches to the autoantibody hypothesis—immunoadsorption, BC007, and daratumumab—are in active clinical trials (Appendix Ongoing and Planned ME/CFS Research Studies, Section Autoimmunity and Immunomodulation).
- Central nervous system dysfunction: Impaired autonomic outflow from brainstem centers
- Gut-mediated vagal impairment (Wirth-Scheibenbogen 2025): Recent work by Wirth and Scheibenbogen (Wirth and Scheibenbogen 2025) provides mechanistic support for gut-mediated vagal dysfunction in ME/CFS. Butyrate enhances enterochromaffin cell serotonin production (W. Barton et al. 2025), and enterochromaffin serotonin activates vagal afferents via 5-HT3 receptors (J. R. Barton et al. 2023) (Kaelberer et al. 2018). Since ME/CFS patients show butyrate deficiency and gut dysbiosis (Hsu et al. 2025), reduced enterochromaffin serotonin could impair vagal afferent signaling, potentially weakening efferent vagal tone to the heart. This pathway may contribute to the chronotropic incompetence and reduced heart rate variability observed in ME/CFS patients. While no direct evidence yet links this pathway to cardiac chronotropy in ME/CFS, it offers a testable hypothesis for the gut-cardiac connection. See Section Replication Status: Not Yet Replicated of Chapter Gastrointestinal and Microbiome Dysfunction for the full evidence chain and Section Enterochromaffin-Vagal Serotonin Pathway in ME/CFS of Chapter Neurological and Neurocognitive Dysfunction for the neurophysiological implications.
The finding of chronotropic incompetence, combined with reduced HRV and abnormal baroreflex sensitivity (J. L. Newton et al. 2007), indicates autonomic dysfunction affecting cardiac pacing.
Current evidence establishes that autonomic dysfunction affects cardiac pacing in ME/CFS but does not determine whether the primary site of dysfunction is central (brainstem outflow), peripheral (sinoatrial node, nerve fibers), autoimmune (GPCR autoantibodies), or gut-mediated (enterochromaffin-vagal pathway). These mechanisms are not mutually exclusive, and their relative contributions likely vary across patients. Resolving this requires intervention studies targeting each mechanism independently.
1.3 Two-Day CPET Protocol
A particularly informative methodology involves repeat CPET on consecutive days:
Rationale Single CPET testing may not capture the distinctive post-exertional deterioration characteristic of ME/CFS. Two-day protocols assess recovery capacity and reproducibility of maximal effort.
Findings in ME/CFS
- Day 1: Reduced but measurable aerobic capacity
- Day 2: Further significant reductions in VO2peak, anaerobic threshold, and work capacity
- Healthy controls: Reproduce or slightly improve Day 1 performance
- Magnitude: ME/CFS patients show 10–25% decline on Day 2 (Keller et al. 2024) (Lim et al. 2020)
This failure to reproduce exercise capacity distinguishes ME/CFS from other fatiguing conditions and reflects the pathognomonic post-exertional malaise. A systematic review of two-day CPET studies confirmed significant reductions in work capacity and oxygen consumption on Day 2, supporting this protocol as an objective marker of PEM (Lim et al. 2020).
Mechanisms of Day 2 Decline
- Delayed recovery of metabolic substrates
- Persistent inflammatory activation
- Autonomic dysfunction exacerbation
- Mitochondrial damage from oxidative stress
- Central nervous system effects (increased perceived exertion)
1.4 Anaerobic Threshold
The anaerobic threshold (AT, also called ventilatory threshold or lactate threshold) represents the exercise intensity at which anaerobic metabolism begins to supplement aerobic energy production:
- Reduced AT in ME/CFS: Occurs at lower work rates and VO2 levels
- Early lactate accumulation: Muscles rely on anaerobic glycolysis sooner
- Implications: Limited sustainable activity before symptom exacerbation
- Mechanism: Reflects impaired oxygen delivery, mitochondrial dysfunction, or both
The reduced AT has practical implications: patients exceed their aerobic capacity during activities that healthy individuals perform entirely aerobically, leading to metabolic stress and symptom generation.
1.5 Ventilatory Efficiency
Ventilatory efficiency describes how effectively ventilation eliminates CO2, typically expressed as the VE/VCO2 slope:
- Increased VE/VCO2 slope: More ventilation required per unit CO2 eliminated
- Causes: Ventilation-perfusion mismatch, increased dead space, hyperventilation
- Consequences: Dyspnea at lower work rates, earlier exercise termination
- ME/CFS findings: Variable; some patients show ventilatory inefficiency
2 Cardiac Output and Stroke Volume
Cardiac output (CO) determines oxygen delivery capacity and is the product of heart rate and stroke volume.
2.1 Preload Failure Hypothesis
Multiple lines of evidence support inadequate cardiac preload (ventricular filling) as a contributor to ME/CFS cardiovascular dysfunction:
- Reduced end-diastolic volume: Less blood fills the ventricles during diastole
- Decreased stroke volume: By Frank-Starling mechanism, reduced preload produces smaller stroke volume
- Compensatory tachycardia at rest: Heart rate increases to maintain resting cardiac output; however, during exercise, chronotropic incompetence prevents further adequate heart rate augmentation, creating a ceiling effect
- Exercise limitation: The combination of low stroke volume and inadequate heart rate response severely limits cardiac output augmentation during exertion
Evidence for Preload Failure
- Echocardiographic studies showing reduced left ventricular end-diastolic volume (Julia L. Newton et al. 2016)
- Correlation with blood volume measurements (Julia L. Newton et al. 2016)
- Invasive cardiopulmonary exercise testing (iCPET): Joseph et al. conducted a randomized, placebo-controlled trial (n=45) using invasive hemodynamic monitoring during exercise in ME/CFS patients (Joseph et al. 2022). Pyridostigmine increased right atrial pressure (+1.0 vs. \(-\) 0.6 mmHg; \(P < 0.05\)), while peak VO2 improved after pyridostigmine but declined after placebo (+13.3 vs. \(-\) 40.2 mL/min; \(P < 0.05\); treatment effect 53.6 mL/min). The worsening hemodynamics after placebo (i.e., from exercise alone) provides direct invasive evidence that exercise itself exacerbates neurovascular dysregulation in ME/CFS—an objective physiological correlate of post-exertional malaise
Supine Hemodynamic Abnormalities While cardiovascular dysfunction in ME/CFS is most apparent during orthostatic stress, some patients demonstrate abnormalities even at rest in the supine position. Newton et al. documented reduced cardiac volumes on cardiac MRI that correlated with blood volume deficits rather than deconditioning, with end-diastolic volume, end-systolic volume, and end-diastolic wall mass all significantly reduced (Julia L. Newton et al. 2016). Critically, these reductions showed no correlation with disease duration, arguing against deconditioning as the primary mechanism.
Reduced resting cardiac output in the supine position has been reported in some ME/CFS cohorts, with the magnitude of reduction correlating with symptom severity (Julia L. Newton et al. 2016). This finding suggests that the cardiovascular impairment is not solely a failure of orthostatic compensation but reflects a baseline deficit in cardiac filling and output. Patients with more severe supine abnormalities tend to show greater decompensation during orthostatic challenge, as they have less hemodynamic reserve to mobilize when gravitational stress is applied.
2.2 Reduced Blood Volume
Blood volume deficits are well-documented in ME/CFS ((Streeten and Bell 1998), (Julia L. Newton et al. 2016), (Raj et al. 2005)):
- Plasma volume: Reduced by 10–20% in most studies (Streeten and Bell 1998)
- Red cell mass: Variable findings; may be proportionally reduced or relatively preserved
- Total blood volume: Typically 10–15% below normal (Julia L. Newton et al. 2016)
- Correlation with symptoms: Lower blood volume correlates with worse orthostatic intolerance and fatigue (Julia L. Newton et al. 2016)
Mechanisms of Hypovolemia
- RAAS dysfunction: Impaired aldosterone response to hypovolemia
- Natriuretic peptide elevation: Promoting sodium and water excretion
- Reduced erythropoietin: Leading to mild anemia in some patients
- Capillary leak: Increased vascular permeability shifting fluid to interstitium
- Inadequate fluid intake: Secondary to nausea or other symptoms
2.3 Venous Pooling
Excessive venous pooling in dependent body parts reduces venous return:
- Lower extremity pooling: Blood accumulates in leg veins during standing
- Splanchnic pooling: Blood redistributes to abdominal vasculature
- Impaired venoconstriction: Venous tone fails to increase appropriately
- Consequences: Reduced cardiac preload, orthostatic symptoms
2.4 Anatomical Venous Compression: May Thurner Syndrome as a Potential Contributor
Certainty: 0.25. May Thurner syndrome (MTS)—anatomical compression of the left common iliac vein between the right common iliac artery and lumbar vertebra—may contribute to venous return impairment in a subset of ME/CFS patients through direct mechanical obstruction. No peer-reviewed literature directly links MTS to ME/CFS; the connection is inferred from shared pathophysiology.
Epidemiological overlap. MTS has an anatomical prevalence of 22–24% in cadaver studies, with female predominance (2–3:1) and a mean diagnostic delay of 4.2 years from symptom onset (Neglén and Raju 2008) (Ferreira et al. 2023). These figures loosely parallel ME/CFS demographics (female predominance, long diagnostic delays), raising the possibility of undiagnosed MTS in ME/CFS cohorts. However, no study has systematically screened ME/CFS patients for iliac vein compression.
Mechanistic pathways.
- Impaired venous return during upright posture. Hartung et al. (2019) used transcranial Doppler to demonstrate a 36% reduction in internal jugular vein flow velocity from supine to upright posture in MTS patients, versus 24% in controls (Hartung et al. 2019). The upright flow velocity correlated with orthostatic symptoms (r = 0.62). If this mechanism operates in ME/CFS patients with undiagnosed MTS, venous compression could compound the pre-existing preload failure, blood volume deficits, and orthostatic intolerance discussed above.
- Autonomic dysfunction from venous compression. Anderson et al. (2021) documented reduced heart rate variability (SDNN), impaired Valsalva response, and elevated plasma norepinephrine in MTS patients versus controls (Anderson et al. 2021). The COMPASS-31 autonomic symptom score in MTS (34.2) overlaps with ME/CFS ranges, and 45% of MTS patients developed orthostatic hypotension on tilt-table testing.
- Venous stasis and systemic inflammation. Chronic iliac vein compression produces venous hypertension, endothelial activation, and localized inflammation—mechanisms overlapping with the endothelial dysfunction documented in ME/CFS (Section Vascular Dysfunction).
Treatment response as circumstantial evidence. Fatigue improved in 32–68% of MTS patients after iliac vein stenting, with SF-36 vitality domain gains of 19 points (far exceeding the minimal clinically important difference of 3–5 points) (Wolpert et al. 2020) (O’Sullivan et al. 2018) (Ferreira et al. 2023). While this venous fatigue is distinct from ME/CFS, the magnitude of improvement suggests venous drainage can be a reversible contributor to fatigue in at least some patients. However, MTS stenting literature may be affected by publication bias (positive series preferentially published), and stenting carries neurovascular risks not discussed in the fatigue outcome literature (stent thrombosis, distal embolisation).
Critical counter-argument. If MTS contributes to ME/CFS, why don’t the 22–24% of the general population with anatomical MTS have ME/CFS rates anywhere near that proportion? The answer must be that MTS is neither necessary nor sufficient—it acts as a co-factor, compounding pre-existing ME/CFS pathology (blood volume deficits, autonomic dysfunction, cerebral hypoperfusion) rather than causing it de novo. Whether this co-factor effect is large enough to detect in a cohort study remains entirely untested.
Falsifiable predictions:
- Iliac vein compression severity on CT venography or MRV should correlate with orthostatic symptom severity in ME/CFS patients
- ME/CFS patients with confirmed MTS who undergo iliac vein stenting should show improvement in orthostatic intolerance and fatigue beyond that expected from non-specific procedural effects
- Internal jugular vein flow velocity during upright posture (measured by TCD) should be lower in ME/CFS patients with than without MTS
Critical gap. No study has screened an ME/CFS cohort for May Thurner syndrome. The 22–24% anatomical prevalence means MTS could potentially affect a substantial subset, but this remains entirely untested. Not yet replicated in any ME/CFS context.
3 Cardiac Biomarkers
3.1 Troponin
Cardiac troponins (cTnI, cTnT) are released from damaged cardiomyocytes:
- Baseline levels: Generally normal in ME/CFS
- Post-exercise: Whether mild elevations occur after exertion in ME/CFS is not yet established in the literature
- Clinical significance: Cardiac biomarkers are not currently validated as ME/CFS diagnostic markers
3.2 BNP and NT-proBNP
B-type natriuretic peptide (BNP) and its N-terminal fragment are released in response to cardiac wall stress:
- Findings in ME/CFS: Variable; some studies report mild elevations (Tomas et al. 2017)
- Mechanism: May reflect right heart strain from pulmonary issues or left ventricular stress
- Correlation: Elevated BNP correlates with reduced cardiac volumes in ME/CFS (Tomas et al. 2017)
- Clinical utility: Not established as ME/CFS biomarker
3.3 Cardiac Structure and Function
Echocardiographic studies report variable findings, with evidence for subclinical dysfunction in some patients ((Julia L. Newton et al. 2016)):
- Reduced cardiac volumes: Smaller left ventricular end-diastolic volume correlating with plasma volume deficits (Julia L. Newton et al. 2016)
- Diastolic dysfunction: Some studies report impaired ventricular relaxation
- Reduced contractile reserve: Limited ability to augment function during stress echocardiography (preliminary data)
- Strain imaging: Speckle tracking echocardiography may detect subtle abnormalities not apparent on conventional imaging (requires further study)
These findings suggest that cardiac abnormalities in ME/CFS are primarily functional consequences of hypovolemia and autonomic dysfunction rather than primary myocardial disease.
The NCX1 reversal cascade documented in skeletal muscle by Wirth et al. (Wirth and Scheibenbogen 2022) (Wirth and Scheibenbogen 2024) — capillary hypoperfusion → anaerobic metabolism → intracellular Na+ overload → NCX1 reverse-mode → intracellular Ca2+ overload → mitochondrial damage — applies equally to cardiac muscle, where NCX1 is the dominant calcium extrusion mechanism. In cardiomyocytes, Ca2+ overload specifically impairs diastolic relaxation (lusitropy), producing the elevated E/e’ ratio pattern of diastolic dysfunction.
Proposed mechanism connecting ionic cascade to reduced cardiac output: The reduced resting cardiac output documented in ME/CFS (Julia L. Newton et al. 2016), typically attributed to hypovolemia and preload failure, may also reflect a component of chronic low-grade diastolic dysfunction from ongoing cardiac NCX1 reversal at subthreshold intensity (not generating overt PEM-equivalent events but continuously impairing myocardial relaxation). Impaired diastolic relaxation reduces preload by shortening the period available for ventricular filling, compounding the hypovolemia-driven preload failure.
Falsifiable predictions:
- Echocardiography in ME/CFS patients should show elevated E/e’ ratio (diastolic dysfunction marker) correlating with disease severity and with post-exercise muscle sodium accumulation on 23Na-MRI
- Cardiac 23Na-MRI (feasible on 3T scanners) should demonstrate elevated myocardial sodium in ME/CFS patients at rest compared to healthy controls
- MDC002 (targeting Na+/K+-ATPase and NCLX) should improve E/e’ ratio alongside the primary muscle PEM endpoint
(Certainty: 0.35. Skeletal muscle NCX reversal is evidence-supported; extension to cardiac muscle is mechanistically sound but not yet measured. The diastolic dysfunction correlation with disease severity is not yet established. Not yet replicated in ME/CFS.)
Neutrophil extracellular traps accumulate in cardiac tissue during myocarditis, where the midkine–LRP1 axis drives NET-mediated fibrosis and ventricular dysfunction (Weckbach et al. 2019). This mechanism may underlie the subclinical post-viral cardiomyopathy reported in some ME/CFS and Long COVID patients, and suggests that cardiac NET burden—not just circulating NET markers—merits investigation in this population.