Abnormal Coronary Vascular Response in Patients with [Long COVID] – a Case-Control Study Using Oxygenation-Sensitive [Cardiac MRI], 2025, Weberling+

[SNT Gatchaman]

Abnormal Coronary Vascular Response in Patients with Long COVID Syndrome – a Case-Control Study Using Oxygenation-Sensitive Cardiovascular Magnetic Resonance
Weberling; Hillier; Friedrich; Zahlten; Frey; André; Steen

BACKGROUND
Following the world-wide COVID-19 pandemic, many patients reported ongoing severe cardiovascular symptoms after the acute phase. This multisystemic condition has been named long COVID syndrome. Whilst cardiovascular magnetic resonance (CMR) imaging is the gold standard to diagnose acute myocardial damage, no specific changes have been shown in long COVID patients. However, endothelial dysfunction has been hypothesized to contribute to its pathogenesis. Oxygenation-sensitive CMR during breathing exercise is a simple, non-invasive and accurate test to objectify vascular function, that has not been applied to long COVID patients yet.

METHODS
After receiving approval from the local ethics committee, this prospective observational case-control study enrolled (i) patients reporting symptoms for ≥6 weeks following an acute COVID-19 infection or vaccination, and (ii) healthy volunteers with neither symptoms nor history of cardiovascular disease. Participants completed a questionnaire, point-of-care testing of cardiac biomarkers, a standard non-contrast CMR and an oxygenation-sensitive CMR. Heart rate response and breathing-induced myocardial oxygenation reserve (B-MORE) were assessed during metronome-paced hyperventilation and apnea.

RESULTS
31 patients (17 female; age 39.4 [30.3; 51.6] years) and 27 controls (12 female; age 33.3 [27.3; 46.8]) were included with comparable demographics and cardiovascular risk factors between groups. Laboratory testing and standard CMR did not reveal any pathologies in either of the groups. Indexed left ventricular stroke volume was significantly lower in patients (44.5 ml [41.2; 46.6] vs. 55.9 ml [49.2; 59.2]; p<0.001), whilst ejection fraction and longitudinal strain of both ventricles were comparable (p>0.05 for all). Vasoactive breathing exercises induced a significant increase in heart rate (+35/min [21; 45]) and B-MORE (9.8% [4.3; 17.2]) in controls. In patients however, heart rate increase was blunted (+15/min [7; 26]; p<0.001) and B-MORE was significantly lower (7.3% [3.4; 10.4], p=0.044).

CONCLUSIONS
This pilot study is the first to show a blunted hemodynamic and myocardial oxygenation response to vasoactive breathing maneuvers during Oxygenation-sensitive CMR in long COVID patients. This simple, non-invasive test may be the first to objectify complaints of affected patients and indicates evidence for the crucial role of the endothelium in the pathophysiology of long COVID.

Link | PDF (Journal of Cardiovascular Magnetic Resonance)

 

[SNT Gatchaman]

AI Summary (Gemma3:27b) —

This research investigates the potential role of endothelial dysfunction in the pathophysiology of Long COVID by utilizing oxygen-sensitive cardiac magnetic resonance (OS-CMR) and breathing maneuvers to assess cardiac function. Here's a breakdown of the key findings, methodology, and conclusions:

Key Findings:

• Impaired Hemodynamic & Myocardial Oxygenation: Long COVID patients demonstrated a diminished heart rate increase and reduced myocardial oxygenation response during a hyperventilation and breath-hold challenge compared to healthy controls.
• Endothelial Dysfunction as a Potential Mechanism: The researchers propose that impaired coronary vasoreactivity (ability of blood vessels to dilate and constrict) and direct damage to coronary vessels due to COVID-19 could be underlying causes of these observed deficits.
• Potential Diagnostic Tool: The study suggests that OS-CMR with breathing maneuvers could be a valuable addition to standard CMR assessments for Long COVID patients, potentially identifying subtle cardiac dysfunction not captured by traditional methods.
• No Significant Difference Between Post-Vaccination & Post-Illness Groups: The study found no statistically significant differences in cardiac function between Long COVID patients who had the illness versus those who developed symptoms after vaccination.

Methodology:

• Case-Control Study: Researchers compared a group of Long COVID patients to a healthy control group.
• OS-CMR with Breathing Maneuvers: Participants underwent CMR scans while performing hyperventilation and a prolonged breath-hold. OS-CMR allows for the assessment of myocardial oxygenation.
• B-MORE Calculation: The researchers used the "B-MORE" metric (a measure of myocardial oxygenation change) to quantify the oxygenation response.
• Data Analysis: Statistical analysis was performed to compare the responses between the two groups.

Conclusions:
The study suggests that endothelial dysfunction may play a significant role in the pathophysiology of Long COVID, leading to impaired cardiac function and potentially contributing to the wide range of symptoms experienced by patients. The researchers propose that OS-CMR with breathing maneuvers could be a valuable tool for diagnosing and monitoring cardiac dysfunction in Long COVID patients.

Limitations:

• Small Sample Size: The study was limited by a relatively small number of participants.
• Potential for Bias: While efforts were made to standardize the breathing maneuvers and assess compliance, there's always a potential for bias.
• Lack of Objective Physical Activity Assessment: The study did not include an objective assessment of physical activity levels in participants.
• Assumption of Clinical Comparability: The inclusion of both post-vaccination and post-illness groups assumes they are clinically comparable, which requires further investigation.

Overall, this research provides compelling evidence for the potential role of endothelial dysfunction in Long COVID and highlights the promise of OS-CMR with breathing maneuvers as a novel diagnostic tool.

 

[SNT Gatchaman]

In the assessment of the cardiovascular autonomic and endothelial function, combining oxygenation-sensitive CMR (OS-CMR) with breathing maneuvers is highly reproducible and has been established in patients with coronary artery disease, obstructive sleep apnea, myocardial infarction with non-obstructive coronary arteries (MINOCA), heart failure and in heart transplant recipients. Hyperventilation is a stressor superior to adenosine and substantially increases heart rate specifically in healthy individuals.

OS-CMR makes use of the different relaxation of oxygenated versus deoxygenated hemoglobin measurable through signal alterations in the highly perfused myocardium. In a standardized breathing sequence including hyperventilation followed by a breath-hold, CO2 induces a coronary vasoconstriction followed by a vasodilation. These endothelium-dependent breathing effects induce specific changes of oxygenation in the myocardium, which can be assessed through OS-CMR and which have been standardized as breathinginduced myocardial oxygenation reserve (B-MORE).

The concept is expanded on in the discussion

Hyperventilation is a natural stressor inducing an endothelium-dependent vasoconstriction mediated through low CO2 levels, while the post-hyperventilation breath-hold leads to an increase in CO2 and subsequent vasodilation. Coronary vasodilation in healthy individuals results in a ‘luxury perfusion’ with increased coronary blood flow without an associated increase of demand, which decreases the proportion of deoxygenated hemoglobin in the myocardium. In OS-CMR images this leads to a myocardial signal intensity increase, which can be semi-quantitively expressed with the B-MORE. Hyperventilation however also activates the neuro-humoral axis and increases the rate-pressure product, which increases demand. This triggers a heart rate increase that is reduced in patients with heart disease. Since both B-MORE and heart rate increase are diminished in long COVID patients when compared to controls in our study, a crucial role of the endothelium seems likely.

Spoiler: References for the technique description

Feasibility of cardiovascular magnetic resonance to detect oxygenation deficits in patients with multi-vessel coronary artery disease triggered by breathing maneuvers (2018, Journal of Cardiovascular Magnetic Resonance)

Insights Into Myocardial Oxygenation and Cardiovascular Magnetic Resonance Tissue Biomarkers in Heart Failure With Preserved Ejection Fraction (2022, Circulation: Heart Failure)

The reproducibility of breathing maneuvers as a vasoactive stimulus in the heart: an oxygenation-sensitive resonance imaging study (2023, Journal of Cardiovascular Magnetic Resonance)

Regional Heterogeneity in the Coronary Vascular Response in Women With Chest Pain and Nonobstructive Coronary Artery Disease (2021, Circulation)

The Potential of Oxygenation-Sensitive CMR in Heart Failure (2021, Current Heart Failure Reports)

 

[SNT Gatchaman]

Cohort characteristics —

58 participants (27 controls; 31 patients) were included in this study. Both patients and controls were at a young age and distribution among genders was balanced. The presence of cardiovascular risk factors was scarce with hypertension and a smoking habit being most frequent in both patients and controls. None of the controls and 14 of the patients had known comorbidities. These involved a thyroid disorder (3; 9.1%), asthma (3; 9.1%), celiac disease (2, 6.1%), iron deficiency, polycystic ovary syndrome, testosterone deficiency, prior Lime disease, prior pulmonary embolism, atrial fibrillation, and obstructive sleep apnea (1 each, 3.0%). Only a fraction of both controls and patients were on a vasoactive medication. 5 controls were non-professional endurance athletes, whilst the rest of the controls had ordinary levels of physical activity (<5h / week).

Patient symptoms —

Patients were highly symptomatic at the time of enrolment with angina pectoris, dyspnea and fatigue being the most common complaints. Brain fog, myalgia, anxiety or depression were also common among patients. The prevalence of symptoms was similar between patients who developed long COVID following infection versus vaccination.

Structural cardiac findings —

ventricular ejection fraction were normal in both controls (median LV-EF 61.0%; RV-EF 56.0%) and patients (LV-EF 59.7%; RV-EF 55.4%) and were similar between groups. Equally, left and right global longitudinal strain were normal in both controls (median LV-GLS -19.4%; RV-GLS -24.0%) and patients (-18.5%; -22.7%) and were comparable between groups. Controls had higher volumes (indexed to body surface area) of both the left ventricle (controls 89.7ml; patients 72.9ml) and the right ventricle (96.7ml; 78.3ml) and showed higher indexed stroke volumes of both the left ventricle (55.9ml vs. 44.5ml) and the right ventricle (53.7ml vs. 45.6ml). This difference remained significant even after excluding athletic controls (n=5) from the control group. The maximum wall thickness of the left ventricle was normal

Heart rate response —

the heart rate response was significantly different between patients and controls (p<0.001) with an increase of 35/min [21;45] in controls and 15/min [7;26] in patients, illustrated in Figure 3 and Table 4. After adjustment for age, sex, arterial hypertension and asthma, the heart rate response remained significant (p<0.001), whilst only age (p=0.021) and asthma (p=0.036) revealed a significant correlation with the heart rate response (p>0.05 for the rest).

Breathing-induced myocardial oxygenation reserve (B-MORE) —

The B-MORE was 9.8% in controls [4.3; 17.2] and 7.3% in patients [3.4; 10.4] with a significant difference between the groups (p=0.044). After adjusting for age, sex, arterial hypertension and asthma, B-MORE remained significant (p=0.049), whilst none of the confounders were significantly associated with B-MORE (p>0.05 for all).

 

[SNT Gatchaman]

EDIT: Just to clarify the below is suggesting the possibility of a clinical test. Even though the adverse effects are reported as trivial and very short lived, this is probably not something to try by yourself at home / without medical supervision.

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I wonder if we could do the equivalent of the NASA lean test here? Lie still, just not in an MRI machine, follow the breathing protocol and record (with pulse oxymeter or smart watch) the HR increase?

Here are their results —



It looks like you could possibly use a metronome (app) and "Participants then hyperventilated for 60s (30 breaths per minute, paced by a metronome), controlled through qualitative capnography with visual confirmation of sufficient respiratory excursions" without the capnography check. Then breath-hold for 60 seconds.

From Feasibility of cardiovascular magnetic resonance to detect oxygenation deficits in patients with multi-vessel coronary artery disease triggered by breathing maneuvers (2018, Journal of Cardiovascular Magnetic Resonance) —

 

[Eleanor]

I wonder if we could do the equivalent of the NASA lean test here? Lie still, just not in an MRI machine, follow the breathing protocol and record (with pulse oxymeter or smart watch) the HR increase?

Here are their results —

View attachment 25738

It looks like you could possibly use a metronome (app) and "Participants then hyperventilated for 60s (30 breaths per minute, paced by a metronome), controlled through qualitative capnography with visual confirmation of sufficient respiratory excursions" without the capnography check. Then breath-hold for 60 seconds.

From Feasibility of cardiovascular magnetic resonance to detect oxygenation deficits in patients with multi-vessel coronary artery disease triggered by breathing maneuvers (2018, Journal of Cardiovascular Magnetic Resonance) —

View attachment 25739

I'll try and do this later.

 

[Utsikt]

Does 30 breaths per minute mean 30 inhales and exhales each, or 30 inhales and exhales in total?

 

[SNT Gatchaman]

@Eleanor I don't think this should be tried at home, especially if alone - I meant it might become a clinical test, but without the MRI part. Remember a NASA lean test is done in a doctor's office (without the tilt-table part), but there's someone there to assist if you faint out.

I know the paper reported 55-65% participants having "Tingling sensation, Dizziness, Headache, Dry Mouth, Palpitations. No serious side effects occurred. All side effects ceased within 30s" but "kids don't try this at home" would probably be wisest.

 

[Eleanor]

@Eleanor I don't think this should be tried at home, especially if alone - I meant it might become a clinical test, but without the MRI part. Remember a NASA lean test is done in a doctor's office (without the tilt-table part), but there's someone there to assist if you faint out.

I know the paper reported 55-65% participants having "Tingling sensation, Dizziness, Headache, Dry Mouth, Palpitations. No serious side effects occurred. All side effects ceased within 30s" but "kids don't try this at home" would probably be wisest.

OK! Yes, probably safest.

 

[Dolphin]

Graphical abstract

https://twitter.com/user/status/1911959050448748860