Two Different Hemodynamic Responses in ME/CFS Patients with Postural Orthostatic Tachycardia Syndrome During Head-Up Tilt Testing

Abstract:

Introduction: While the diagnosis of postural orthostatic tachycardia syndrome (POTS) is based on heart rate (HR) and blood pressure (BP) criteria, the pathophysiology of POTS is not fully understood as multiple pathophysiological mechanisms have been recognized. Also, cardiac function, being dependent on preload, afterload, contractility, and HR, has not been properly studied. Preload and contractility changes can be inferred from stroke volume index (SVI) changes during a tilt test. Afterload plays a minor role in POTS as a normal BP response is a prerequisite for POTS. Therefore, we analyzed the HR-SVI relation during a tilt test in myalgic encephalomyelitis (ME/CFS) patients with POTS and compared the data with ME/CFS patients with a normal HR-BP response and with that of healthy controls (HC).

Material and Methods: In ME/CFS patients with either POTS (n = 233) or a normal HR-BP response (n = 507) and healthy controls (n = 48), we measured SVI (by suprasternal echo), HR, and BP during the tilt.

Results: In all ME/CFS patients, the decrease in SVI was larger compared to HC. In patients with a normal HR-BP response and in POTS patients with a HR increase between 30-39 bpm, there was an inverse relationship between the HR increase and SVI decrease during the tilt, compatible with increased venous pooling. In POTS patients with a HR increase ≥40 bpm, this inverse relation was lost, and SVI changes were significantly less compared to POTS patients with a HR increase between 30-39 bpm, suggestive of a hyperadrenergic response.

Conclusions: In ME/CFS patients with POTS, two different hemodynamic profiles can be observed: in patients with a limited HR increase, mainly increased venous pooling is observed, while in patients with a large (≥ 40 bpm) HR increase the data are suggestive of a hyperadrenergic response. These two different profiles may have different therapeutic implications.

Source: van Campen CLMC, Rowe PC, Visser FC. Two Different Hemodynamic Responses in ME/CFS Patients with Postural Orthostatic Tachycardia Syndrome During Head-Up Tilt Testing. J Clin Med. 2024 Dec 18;13(24):7726. doi: 10.3390/jcm13247726. PMID: 39768649. https://www.mdpi.com/2077-0383/13/24/7726 (Full text)

The Cardiac Output-Cerebral Blood Flow Relationship Is Abnormal in Most Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with a Normal Heart Rate and Blood Pressure Response During a Tilt Test

Abstract:

Introduction: Orthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HCs), the regulation of CBF is complex and cardiac output (CO) is an important determinant of CBF: a review showed that a 30% reduction in CO results in a 10% reduction in CBF. In previous and separate ME/CFS studies, we showed that CO and CBF decreased to a similar extent during tilt testing.

The aim of the study: to test the relationship between CBF and CO, which seems to be abnormal in ME/CFS patients and is different from that in HCs.

Methods: In this retrospective study we analyzed this relationship in a large group of patients. To compare the patient data with those of HCs, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed. A total of 534 ME/CFS patients and 49 HCs underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO2. To measure CBF, extracranial Doppler flow velocity and vessel diameters were obtained using a GE echo system. The same device was used to measure suprasternal aortic flow velocities. End-tidal PCO2 was recorded using a Nonin Lifesense device.

Results: In 46 (9%) patients, CO and CBF changes were in the normal range for HCs, and in 488 (91%) an abnormal CO and CBF reduction was found. In patients with abnormal CO and CBF reductions, the slope of the regression line of CO versus CBF reduction was almost 1. The multiple regression analysis of the latter group showed that the CO reduction for the most part predicted the CBF reduction, with a limited role for the PETCO2 reduction.

Conclusions: Two different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range for HCs and those with an abnormal CO and CBF reduction during the tilt (91% of patients). In the latter group of patients, an almost 1:1 relationship between the CO and CBF reduction suggests the absence of compensatory vasodilation in the cerebral vasculature. This might indicate endothelial dysfunction in most ME/CFS patients and may have clinical and therapeutic implications.

Source: van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. The Cardiac Output-Cerebral Blood Flow Relationship Is Abnormal in Most Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with a Normal Heart Rate and Blood Pressure Response During a Tilt Test. Healthcare (Basel). 2024 Dec 20;12(24):2566. doi: 10.3390/healthcare12242566. PMID: 39765993. https://www.mdpi.com/2227-9032/12/24/2566 (Full text)

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing.
Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published.
Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001).
Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.
Source: van Campen CMC, Rowe PC, Visser FC. Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Medicina. 2023; 59(12):2153. https://doi.org/10.3390/medicina59122153 https://www.mdpi.com/1648-9144/59/12/2153 (Full text)
Source:

Influence of end-tidal CO2 on cerebral blood flow during orthostatic stress in controls and adults with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Brain perfusion is sensitive to changes in CO2 levels (CO2 reactivity). Previously, we showed a pathological cerebral blood flow (CBF) reduction in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during orthostatic stress. Limited data are available on the relation between CO2 and CBF changes in ME/CFS patients. Therefore, we studied this relation between ME/CFS patients and healthy controls (HC) during tilt testing.

In this retrospective study, supine and end-tilt CBF, as measured by extracranial Doppler flow, were compared with PET CO2 data in female patients either with a normal heart rate and blood pressure (HR/BP) response or with postural orthostatic tachycardia syndrome (POTS), and in HC. Five hundred thirty-five female ME/CFS patients and 34 HC were included.

Both in supine position and at end-tilt, there was a significant relation between CBF and PET CO2 in patients (p < 0.0001), without differences between patients with a normal HR/BP response and with POTS. The relations between the %CBF change and the PET CO2 reduction were both significant in patients and HC (p < 0.0001 and p = 0.0012, respectively).

In a multiple regression analysis, the patient/HC status and PET CO2 predicted CBF. The contribution of the PET CO2 to CBF changes was limited, with low adjusted R2 values. In female ME/CFS patients, CO2 reactivity, as measured during orthostatic stress testing, is similar to that of HC and is independent of the type of hemodynamic abnormality. However, the influence of CO2 changes on CBF changes is modest in female ME/CFS patients.

Source: van Campen CLMC, Rowe PC, Verheugt FWA, Visser FC. Influence of end-tidal CO2 on cerebral blood flow during orthostatic stress in controls and adults with myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2023 Sep;11(17):e15639. doi: 10.14814/phy2.15639. PMID: 37688420; PMCID: PMC10492011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492011/ (Full text)

Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients

Abstract:

Introduction: During a standard 70-degree head-up tilt test, 90% of adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develop an abnormal reduction in cerebral blood flow (CBF). A 70-degree test might not be tolerated by young ME/CFS patients because of the high incidence of syncopal spells. This study examined whether a test at 20 degrees would be sufficient to provoke important reductions in CBF in young ME/CFS patients.

Methods: We analyzed 83 studies of adolescent ME/CFS patients. We assessed CBF using extracranial Doppler measurements of the internal carotid and vertebral arteries supine and during the tilt. We studied 42 adolescents during a 20 degree and 41 during a 70 degree test.

Results: At 20 degrees, no patients developed postural orthostatic tachycardia (POTS), compared to 32% at 70 degrees (p = 0.0002). The CBF reduction during the 20 degree tilt of -27(6)% was slightly less than during the reduction during a 70 degree test [-31(7)%; p = 0.003]. Seventeen adolescents had CBF measurements at both 20 and 70 degrees. The CBF reduction in these patients with both a 20 and 70 degrees test was significantly larger at 70 degrees than at 20 degrees (p < 0.0001).

Conclusions: A 20 degree tilt in young ME/CFS patients resulted in a CBF reduction comparable to that in adult patients during a 70 degree test. The lower tilt angle provoked less POTS, emphasizing the importance of using the 70 degree angle for that diagnosis. Further study is needed to explore whether CBF measurements during tilt provide an improved standard for classifying orthostatic intolerance.

Source: van Campen CLMC, Rowe PC, Visser FC. Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Front Pediatr. 2023 May 12;11:1169447. doi: 10.3389/fped.2023.1169447. PMID: 37252045; PMCID: PMC10213432. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213432/ (Full text)

Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Highlights:

  • Adults with ME/CFS experience a 3-fold greater reduction in cerebral blood flow during end-tilt tilt compared to healthy controls, confirming orthostatic intolerance.
  • During tilt testing we found that in 134/362 (37%) patients with ME/CFS without POTS or hypotension, the heart rate increase was below the lower limit of the 95% prediction interval of the heart rate increase of controls, indicative of orthostatic chronotropic incompetence.
  • These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing, confirming another abnormality in the circulatory response to upright posture in ME/CFS.

Abstract:

Background: Orthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence.

This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients.

Methods: From a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test.

To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC.

Results: We compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m2; p<0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p<0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position.

During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients.

Conclusion: These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients.

Source: C. (Linda) M.C. van Campen, Freek W.A. Verheugt, Peter C. Rowe, Frans C. Visser. Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). IBRO Neuroscience Reports [In Press, Journal Pre-proof]  Available online 2 May 2023 https://www.sciencedirect.com/science/article/pii/S2667242123000374 (Full text)

Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration

Abstract:

Background: Postural orthostatic tachycardia syndrome (POTS) has been described early after the onset of the COVID-19 infection, but also orthostatic hypotension (OH). In the present study, we hypothesized that orthostatic intolerance decreases over time.
Methods: In 29 long-haul COVID-19 (LHC) patients, a tilt test was performed, including measurements of cerebral blood flow (CBF) by extracranial Doppler. The time interval between the onset of infection and the tilt test varied between 3 and 28 months.
Results: In the first 12 months after the infection, 71% of the LHC patients showed POTS and after 24 months none of them. In the first 12 months, 29% of patients had a normal heart rate and blood pressure response (normHRBP) and after 24 months 75% (distribution of POTS, OH, and a normHRBP over time: p < 0.0001). Linear regression showed that, over time, there was a decrease in the abnormal CBF during the tilt (p = 0.024) but remained abnormal.
Conclusion: In LHC patients, hemodynamic abnormalities of a tilt test change over time. Patients studied early after the onset of the disease mainly exhibit POTS, but patients studied later in the time course mainly show a normHRBP or OH. In addition, the abnormal CBF reduction improves over time, but CBF remains abnormal.
Source: Campen CMCv, Visser FC. Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration. Healthcare. 2022; 10(10):2105. https://doi.org/10.3390/healthcare10102105 https://www.mdpi.com/2227-9032/10/10/2105/htm (Full text)

Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease.
Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients.
Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test.
Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.
Source: van Campen CMC, Visser FC. Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Healthcare. 2022; 10(10):2058. https://doi.org/10.3390/healthcare10102058 (Full text)

Validity of 2-Day Cardiopulmonary Exercise Testing in Male Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: Among the main characteristics of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of ME/CFS symptoms. The gold standard for measuring the severity of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients. A consecutive day CPET protocol has shown a difference on day 2 in ME/CFS patients in contrast to sedentary controls. Because of the low number of male ME/CFS patients in the published literature, and because of a possible gender difference in the clinical phenotype, the aim of this study was to examine whether the response to a 2-day CPET protocol in a larger sample of male ME/CFS patients was similar to that observed in females.

Methods: From 77 male patients, 25 male ME/CFS patients fulfilled the criteria of a 2-day CPET protocol for analysis. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were made at maximal (peak) and ventilatory threshold (VT) intensities. Data were analysed using a paired t-test.

Results: Baseline characteristics of the group were as follows. Mean age was 44 (12) years, mean BMI was 27.1 (4.4) kg/m2. Median disease duration was 10 years (IQR 7 – 13). Heart rate, systolic and diastolic blood pressure at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between <0.005 and <0.0001). All patients experienced a deterioration of performance on CPET2 as measured by the predicted and actual VO2 and workload at peak exercise and ventilatory threshold.

Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a consecutive day CPET. These results are similar to published results in female ME/CFS populations.

Source:

 

The higher resting heart rate in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy controls: relation with stroke volumes

Abstract:

Introduction: In patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a higher-than-normal resting heart rate has been reported in a number of studies. As heart rate is linked to stroke volume, the present study explored the relationship between the supine heart rate and stroke volume index in healthy controls and in ME/CFS patients. Moreover, as patients with a postural orthostatic tachycardia syndrome (POTS) during tilt testing, have a higher supine heart rate than patients with a normal heart rate and blood pressure response during tilting, these two patient groups were also compared.

Methods and results: From a database of individuals who had undergone tilt-testing, including supine Doppler measurements for stroke volume index calculation, we selected ME/CFS patients and healthy controls without evidence of hypotension or syncope. 474 ME/CFS patients were analyzed, 314 with a normal heart rate and blood pressure response and 160 with POTS during tilt-testing, and 56 healthy controls. Resting stroke volume indices were similar between the 3 groups. All 3 groups had an inverse relation between the resting stroke volume index and resting heart rate (all p<0.0001). The slope of the relation was not significantly different between the 3 groups. Using the upper limit of the 95% prediction interval for the heart rate of healthy controls, 46 (15%) of patients with a normal heart rate and blood pressure response had a resting heart rate above the upper limit, 248 (85%) a heart rate between the upper and lower limit. In 47 (29%) patients developing POTS the resting heart rate was above the upper limit, and in 113 (71%) patients within the upper limit and lower limit. This distribution was significantly different between the two patient groups (p=0.0001).

Conclusion: Patients and healthy controls showed a significant and inverse relation between the SVI and heart rate at rest. Already at rest heart rate in patients developing POTS during tilt-testing were higher compared to the patients with a normal heart rate and blood pressure response per unit of SVI, but the heart rate of the majority of all patients fell within the limits of normal of healthy controls. The difference of patients with heart rate above the upper limit versus between the upper limit and lower limit deserves further investigation and may have therapeutic implications.

Source: VAN CAMPEN, C (Linda) M.C.; VISSER, Frans C.. The higher resting heart rate in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy controls: relation with stroke volumes.. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: https://esmed.org/MRA/mra/article/view/2891. Date accessed: 17 july 2022. doi: https://doi.org/10.18103/mra.v10i6.2891.