Preprint Preload insufficiency as common denominator of exertional dyspnoea in distinct post-COVID phenotypes, 2025, Oruqaj et al.

SNT Gatchaman

SNT Gatchaman

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Preload insufficiency as common denominator of exertional dyspnoea in distinct post-COVID phenotypes
G Oruqaj; K Lo; K Krüger; P Bauer; L Laufer; K Milger; C Tabeling; I Pink; Z Rako; N Kremer; S Yildiz; J Behr; M Hecker; M Kaya; S Kuhnert; HH Krämer-Best; U Matt; S Herold; S Oberwinkler; J Wilhelm; M Witzenrath; T Welte; N Weissmann; HA Ghofrani; F Grimminger; W Seeger; K Tello; N Sommer

INTRODUCTION
The underlying causes of exertional dyspnoea and exercise limitation in post-COVID syndrome remain uncertain. We performed deep-phenotyping of post-COVID patients to evaluate limitations of ventilation, gas exchange and cardiopulmonary circulation in a multicentre, cross-sectional study.

METHODS
The dyspnoea index and aerobic exercise performance (peakVO2) were determined by questionnaires and cardiopulmonary exercise testing, respectively, in a cohort of 86 post-COVID patients and 12 controls. Lung function, gas exchange and ventilation-perfusion mismatch were evaluated. Cardiac parameters were measured by echocardiography and, in a subgroup, systemic vascular characteristics by pulse wave analysis.

RESULTS
Post-COVID patients showed low ventilation at peak exercise [VE(peak)], ventilatory inefficiency, low right heart dimensions and low basal oxygen uptake. In a multivariate regression analysis, ventilatory parameters -high breathing frequency at peak exercise (β=0.15, p=0.004) and low forced expiratory volume in 1 s (β=-0.33, p=0.007) -and right atrial end-systolic area index (RA ESAi; β=-0.34, p<0.001) were independent predictors of dyspnoea, while low VE(peak) (β=0.46, p<0.001) and low aerobic capacity (β=0.51, p<0.001) independently predicted low peakVO2. Low RA ESAi was associated with a low diffusion coefficient (r=0.36), low end-tidal pCO2 (r=0.39) and high heart rate (r=-0.31). Subgroup analysis of patients showed specific associations between dyspnoea and diastolic and bronchial function, low blood pressure, hyperventilation or oxygen uptake.

CONCLUSION
Preload insufficiency associated with gas exchange disturbances contributes to the sensation of dyspnoea in post-COVID patients, as well as ventilatory limitations, while peakVO2 was predominantly associated with aerobic capacity. Three phenotypes were defined, indicating the need for tailored interventions.

Link | PDF (Preprint: MedRxiv) [Open Access]
 
It's reduced filling pressures (and here they're measuring right atrial area in 2D echocardiography as substitute for RA volume).

We hypothesised that the association of reduced heart volumes may indicate right heart preload insufficiency. We analysed right heart catheter (RHC) data from eight post-COVID patients in whom RHC was performed for clinical reasons. In these patients, no evidence of PH was observed, either at rest or during exercise (Supplementary Table S5). However, the limited rise in RA pressure during exercise may suggest preload insufficiency, as previously defined (26, 27). Indeed, we observed a negative RAP/CO-slope (Fig. 2c iii), in contrast to the positive RAP/CO slopes found in healthy individuals [28, 29].
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[27] is Systrom's Unexplained Exertional Dyspnea Caused by Low Ventricular Filling Pressures: Results from Clinical Invasive Cardiopulmonary Exercise Testing (2016, Pulmonary Circulation) where their discussion says —

In this retrospective analysis of iCPET data, we have identified a group of patients with exercise intolerance as a consequence of impaired Qt augmentation associated with low biventricular filling pressures. This contrasts with the more common hemodynamic profiles of patients with cardiac limits related to heart failure or pulmonary vascular disease, which are characterized by exercise-induced elevations of PCWP or mPAP, respectively. These low filling pressures were associated with blunted SV augmentation, suggesting inadequate preload as an etiology for low Qt. When such patients were challenged with intravenous saline, the majority demonstrated improvements in Qtmax on subsequent testing, supporting the hypothesis that inadequate ventricular filling accounts for the pathologic exercise response.
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In the recent Charité conference Systrom said of this initial 2016 paper: "We had an invasive cardiopulmonary exercise test of about 800 patients. We ruled out everything heart and lung related. And there was a subset of patients left over with exertional intolerance sick enough to come to our lab, get a catheter in their neck, and they didn't have heart or lung disease and we asked 'ok what's going on with them?' And the answer was, largely, preload insufficiency. This is what we saw. What differentiated this group of undifferentiated exercise intolerance was filling pressures too low in the upright position, especially at maximum exercise: not as much of a signal at rest. Here's the right atrial pressure, a surrogate for the left atrial pressure [pulmonary capillary wedge pressure] and you can see what differentiates these patients without heart or lung disease from normals. We did a crude regressions against time-honored VO2max and the lower the filling pressures were on both sides of the heart, the worse the VO2max and the mechanism for it was largely, we thought at the time, cardiac output. So we called this 'preload insufficiency'. We learned the hard way after the fact that most of these patients met IOM criteria for ME/CFS. So that's how the lung doctor got into this business back in the day."
 
Because it's a circuit, not a length of pipe with a start and an end? And "afterload" affects "preload"? Perhaps someone's written a Theory of Special Relativity for the cardiovascular system.

I think preload is used to indicate the degree of muscle cell stretch when teaching about Frank-Starling, but in practice we measure chamber volumes (with imaging) and pressures (with catheters) when we can't actually measure the muscle cell stretch itself.

Will be fascinating to see if and why reduced blood volume is the explanation for OI. It sure felt that way with my disease onset, noting significant diuresis and hands and feet that felt 'empty'. But then there's the renin paradox (why's it remain low with hypovolaemia?). Maybe it's a screwup with brain renin and that there subfornical organ.

How Is the Brain Renin–Angiotensin System Regulated? (2017, Hypertension)

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity (2012, American Journal of Physiology-Heart and Circulatory Physiology)

Maybe it's lymphocytes.

A primitive type of renin-expressing lymphocyte protects the organism against infections (2021, Nature Scientific Reports)

Elusive and Heterogenous Nature of Renin Cells (2024, Hypertension) —

Furthermore, renin-producing cells (RPCs) share an ancestry relationship with erythropoietin-synthesizing kidney pericytes and may contribute to the control of oxygen delivery to tissues. Outside the kidney, a primitive type of renin expressing B-1 lymphocytes adds another line of defense linking the immune and endocrine systems in the preservation of homeostasis.
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When I drink a 600 ml cup of broth, salty) the veins on my hands bulge. Normally they are just visible.
Makes a bood draw a lot easier, but what would be the effect on the results of a blood test when I dilute what is in my veins.

I asked around internationally. Only one researcher, not in Europe, answered.
It's from a private email, but sharing a formula for someone in the field of biology won't be a problem, I think.

Quote:
"If you wanted to measure the total amount of glucose in a person's blood, you would need to measure the glucose per ml of blood and then multiply by the total volume of blood.
If you then wanted to know how much glucose was available in the blood at any given time for every kg of a person's body weight you would have to divide the total glucose in the individual's blood by the individual's body weight. In biolology we virtually need to make our measurements relative to something else and this is indeed normally done. We call it "normalization".

Not taking blood volume into account when measuring substances in the blood, could that lead to not finding things in the blood?
And what about measuring differences when researching medications?
 
SNT Gatchaman said:
Because it's a circuit, not a length of pipe with a start and an end? And "afterload" affects "preload"? Perhaps someone's written a Theory of Special Relativity for the cardiovascular system.

I think preload is used to indicate the degree of muscle cell stretch when teaching about Frank-Starling, but in practice we measure chamber volumes (with imaging) and pressures (with catheters) when we can't actually measure the muscle cell stretch itself.

Will be fascinating to see if and why reduced blood volume is the explanation for OI. It sure felt that way with my disease onset, noting significant diuresis and hands and feet that felt 'empty'. But then there's the renin paradox (why's it remain low with hypovolaemia?). Maybe it's a screwup with brain renin and that there subfornical organ.

How Is the Brain Renin–Angiotensin System Regulated? (2017, Hypertension)

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity (2012, American Journal of Physiology-Heart and Circulatory Physiology)

Maybe it's lymphocytes.

A primitive type of renin-expressing lymphocyte protects the organism against infections (2021, Nature Scientific Reports)

Elusive and Heterogenous Nature of Renin Cells (2024, Hypertension) —
Click to expand...

Maybe the answer for hypovolemia is insufficient total blood vessel capacity, ie not enough blood vessels with enough capacity to carry the expected volume.
 
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