Differential Cardiopulmonary Hemodynamic Phenotypes in PASC Related Exercise Intolerance, 2023, Singh et al

[rvallee]

Differential Cardiopulmonary Hemodynamic Phenotypes in PASC Related Exercise Intolerance
https://openres.ersjournals.com/content/early/2023/12/07/23120541.00714-2023

Background
Post-acute sequelae of COVID-19 (PASC) affects a significant portion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom.

Study Objective
This study aimed to characterize the invasive hemodynamic abnormalities of PASC-related exertional intolerance using a larger data set from invasive cardiopulmonary exercise testing (iCPET).

Study Design & Intervention
Fifty-five patients were recruited from the Yale Post-COVID-19-Recovery-Program, with most experiencing mild acute illness. Supine right heart catheterization (RHC) and iCPET were performed on all participants.

Main results
The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO2) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group), On average, the PASC alone group exhibited a “normal” peak exercise capacity, VO2 (89±18% predicted). Approximately 25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise HFpEF and 2 with exercise PH). PASC patient with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO2 with well compensated PH (i.e., peak VO2 and cardiac output >80% respectively) despite aberrant central cardiopulmonary exercise hemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m−2. To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group compromising of obese non-PASC group (n=61) derived from historical iCPET cohort was used. The non-PASC obese patients with preserved peak VO2 (>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14 versus 25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12 versus 86±10%predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO2 was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19).

Conclusions
This study highlights the importance of considering impaired pEO2 in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of current study also highlights the prevalence of a distinct high output failure HFpEF phenotype in PASC with a primary peripheral limitation to exercise.

 

[Mij]

For these patients, the next step is typically a cardiopulmonary exercise test in which the patient rides a stationary bike or runs on a treadmill while sensors track physiological activity up to the point the person feels they have to stop the exercise. However, there are still patients for whom this type of test reveals no cause of exercise intolerance.

The majority of patients just want to know that there’s something real going on. I think that’s a very valid reason to undergo a test.

Yale is one of very few places in the United States where a more advanced version of this evaluation — the invasive cardiopulmonary exercise test, or iCPET — is available. For the test, pressure sensing catheters are inserted into the pulmonary artery, a main blood vessel in the lungs, and at an artery in the wrist. As patients exercise, physicians track various measures to observe how well the heart, lungs, blood vessels, and muscles are functioning.

https://news.yale.edu/2023/12/19/study-helps-explain-post-covid-exercise-intolerance

 

[LarsSG]

More strong evidence that we need to start looking a lot more closely at muscle and microvasculature to figure out why patients aren't able to extract oxygen from their blood. Pretty clear the problem isn't in the heart or lungs.

Also, this is good:

"While deconditioning is commonly suggested to result in impaired pEO2, we did not observe a significant difference in pEO2 amongst PASC patients who underwent supervised out-patient rehabilitation program compared to those who did not undergo rehabilitation. Furthermore, the hallmark of deconditioning is reduced peak CO and bedrest studies demonstrate only a mild impairment of pEO2 24 . In contrast, in the current study PASC patients exhibited a high peak exercise CO along with a normal peak heart rate response."

 

[LarsSG]

Anecdotally, this matches my own experience very well of the early days of ME (once as a teenager, once more recently). One thing that was quite notable to me at the very start in both cases was a distinct inability to output the expected power from my muscles while biking or cross-country skiing. Normal respiration and heart rate, but my muscles clearly were unable to produce the power I was used to. I was used to being limited by my cardiovascular system, meaning I couldn't increase power output without increasing my heart and respiratory rates, but this was something quite different, where the limitation was elsewhere. This was more distinct a day after exertion as well.

This is also different from the experience of exertion at altitude, where there is a similar experience of lack of power output from the muscles, but accompanied by faster breathing and heart rate.

 

[SNT Gatchaman]

More strong evidence that we need to start looking a lot more closely at muscle and microvasculature to figure out why patients aren't able to extract oxygen from their blood. Pretty clear the problem isn't in the heart or lungs.

I've been gathering some papers and will post over the next few days. Some work was done on in this in ME/CFS specifically 20+ years ago, so I think it's probably good for us to have threads for those historical papers too.

 

[SNT Gatchaman]

To date, results of conventional cardiopulmonary exercise testing (CPET) have largely been inconclusive, while broad extrapolation of results from invasive CPET (iCPET) studies involving exercise with pulmonary arterial (PA) and radial arterial catheters in place has been limited by small sample size.

The current study was therefore designed to better characterize the invasive hemodynamic aberrancy of PASC-related exertional intolerance using a larger dataset that includes results of both supine right heart catheterization (RHC) and upright iCPET.

Of the 55 patients referred for evaluation of post-COVID exercise intolerance, 14 had other pathologic factors that could have contributed to symptoms: 8 met criteria for heart failure with preserved ejection fraction (HFpEF) during supine resting RHC and on subsequent iCPET; 2 exhibited exercise pulmonary hypertension (ePH) [...] and 4 exhibited exercise HFpEF

The remaining 41 patients had no evidence of a potential central cardiopulmonary limitation to exercise and were designated as PASC alone. [...] on average, patients were well over a year from their acute infection and the majority (n=31, 76%) had suffered only mild acute illness. Among the PASC alone group, 26 patients (63%) underwent supervised physical rehabilitation prior to their iCPET. There was no significant difference between PASC patients with impaired pEO2 who underwent supervised rehabilitation program

Table 2 compares variables at rest and peak exercise for PASC alone patients and those with HFpEF [...] both groups exhibited a reduced EO2 but a preserved peak VO2 at peak exercise when quantified as the percent of a predicted value [...]. Both groups exhibited a supranormal peak cardiac output (CO) response (119±30% and 132±25% predicted, respectively). The PASC alone group however, attained a supranormal peak CO response despite low cardiac filling pressures (RAP 3±3 and PAWP 8±4 mmHg). This response was not simply driven by heart rate since these patients exhibited appropriate augmentation of their stroke flow. Both groups exhibited appropriate decrease in dead space ventilation (VD/VT) during exercise.

Dead space ventilation, aka physiological dead space is the combination of anatomical (conducting airways) and alveolar (alveoli not adequately perfused by capillaries for gas exchange).

One of the main findings of the current study is the demonstration of persistent exertional dyspnea despite a “normal” peak VO2 response (i.e., ≥80% predicted).

Venous oxygen saturation would be around 70-80% in HCs at rest. It will go down substantially with peak exercise as more oxygen is extracted in muscles.

Functional implication of impaired pEO2 is further supported by the elevated peak exercise mixed venous O2 saturation (MvO2) of 41.9±9.6%. While the current study did not have a healthy comparator group, this level of peak MvO2 is significantly higher than reported for healthy controls (26.5±3.6%). Thus, in PASC patients undergoing conventional non-invasive CPET, the persistent exertional limitation reported in the setting of a “normal” and even improved peak VO2 on non-invasive CPET may in fact reflect an impaired systemic EO2. In the current study, using iCPET, we were able to offer a physiological explanation for the ongoing exertional limitation endured by PASC patients who would otherwise demonstrate a “normal” peak VO2 on conventional non-invasive CPET.

Impaired pEO2 can be attributable to failure of non-exercising vascular beds to vasoconstrict or direct intramuscular blood flow appropriately, or capillary-to-mitochondrial diffusion inadequacy. Recently, using multi-omic proteomic analysis of mixed venous plasma collected during iCPET, our group demonstrated a persistent inflammatory and endotheliopathy proteomic signature among PASC patients with reduced pEO2.

While deconditioning is commonly suggested to result in impaired pEO2, we did not observe a significant difference in pEO2 amongst PASC patients who underwent supervised out-patient rehabilitation program compared to those who did not undergo rehabilitation. Furthermore, the hallmark of deconditioning is reduced peak CO and bedrest studies demonstrate only a mild impairment of pEO2. In contrast, in the current study PASC patients exhibited a high peak exercise CO along with a normal peak heart rate response.

 

[SNT Gatchaman]

See also our other papers tagged oxygen extraction.

 

[EndME]

I've been gathering some papers and will post over the next few days. Some work was done on in this in ME/CFS specifically 20+ years ago, so I think it's probably good for us to have threads for those historical papers too.

Is there a meta-analysis on this somewhere that somehow tries to explain all different results? Personally, I feel like the results aren't consistent enough, possibly due to inconsistent methodology, varying cohorts or it not being quite as useful method as some patients believe, possibly because it only captures downstream effects of muscular or vascular problems in the oxygen extraction.

 

[rvallee]

The majority of patients just want to know that there’s something real going on.

This quote bothered me. It's been said over and over again in the community. The patients know that something is wrong, they want to know WHAT is wrong, because that's how problems become fixable. We all know that unless the problem is understood, there is no way to fix it. This is a huge difference and the framing is just annoying.