[Preprint] The Mechanism of Effort Intolerance in Patients with Peripheral Arterial Disease: a Combined Stress Echocardiography and [CPET], 2023

The Mechanism of Effort Intolerance in Patients with Peripheral Arterial Disease: a Combined Stress Echocardiography and Cardiopulmonary Exercise Test
Eihab Ghantous, Aviel Shetrit, Yonatan Erez, Ryan S. Zamanzadeh, David Zahler, Yoav Granot, Erez Levi, Michal Laufer Perl, Shmuel Banai, Yan Topilsky, Ofer Havakuk

Background: Data to delineate exercise intolerance in patients with peripheral arterial disease (PAD) are scarce. We used a combined stress echocardiography and cardiopulmonary exercise test (CPET) to explore effort intolerance in PAD.

Methods: Twenty-eight patients who had both PAD and coronary artery disease (CAD) were compared with sex and age-matched 31 CAD patients and 15 normal controls using a symptom-limited ramp bicycle CPET on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation: (VO2)/(echocardiography-calculated cardiac output) at each activity level.

Results: Along stages of exercise (unloaded; anaerobic threshold; peak), in PAD+CADF patients compared with CAD or controls: diastolic function worsened (E/e' 13.2± 3.1 vs 9.3± 2.4 vs 9.6± 4; 16.6± 4.3 vs 10.4± 2.5 vs 9.1± 3.8; 15.8± 4 vs 11.9± 2.9 vs 9.1± 4.1), and oxygen consumption (6.1± 1.4 vs 5.8± 1.9 vs 6.5± 2.5; 14.2± 1.8 vs 17.1± 2.9 vs 18.1± 3.3; 14.9± 2 vs 19.3± 2.5 vs 22± 3.6 ml/kg/min) and oxygen pulse (6.5± 1.9 vs 6.5± 2 vs 6.6± 2.3; 8.2± 1.8 vs 10± 2.4 vs 8.1± 2.3; 8.1± 2.2 vs 11.1± 2 vs 11.7± 2.6ml/beat) were reduced. Notably, oxygen pulse was blunted due to an insufficient increase in both stroke volume (89±11 vs 92± 11 vs 92± 13; 95± 10 vs 104± 9 vs 103± 11; 86± 10 vs 97± 10 vs 98± 11ml) and oxygen extraction (0.06± 0.03 vs 0.07± 0.03 vs 0.07± 0.03; 0.09± 0.03 vs 0.12± 0.03 vs 0.12± 0.03; 0.09± 0.03 vs 0.13± 0.03 vs 0.13± 0.03l/l). Chronotropic incompetence was more prevalent in PAD patients and persisted after correction for beta-blockers use (62% vs 42% and 11% respectively). Reduced ventilatory efficiency (peak VE/VCO2 36.8± 4.9 vs 31.5± 4 vs 30.5± 5l/l) and reduced mechanical efficiency (slope of oxygen consumption/work rate 8.96± 0.42 vs 10.37± 0.41 vs 10.8± 0.49l/W) were found.

Conclusion: Exercise limitation is affected by diastolic dysfunction, chronotropic incompetence and peripheral factors in PAD patients.

Clinical Perspectives: Peripheral arterial disease (PAD) is characterized by exercise intolerance. Yet, the mechanism behind this limitation is not well characterized. We show here that effort limitation in PAD is caused by a combination of central and peripheral cardiovascular factors including diastolic dysfunction, chronotropic incompetence and insufficient peripheral muscle oxygen extraction. These data may assist targeting future therapeutic measures.

Link

 

Selected quotes from discussion, my summary and emphasis bolding —

 

So what is the best radiographic test for diastolic filling during exercise?

And is anyone researching that radiological test on ME/CFS?

Perhaps they said it in the discussion bit but too much to read and scroll through and guess you would know.

 

I guess you could do either invasive CPET with intravascular catheters or simply transthoracic echocardiograhy. I'll have to look back at the Systrom papers. The latter sounds much more achievable. I can't think of a radiological equivalent like cardiac MRI, but I'd have to check whether nuclear medicine imaging could be used. Broadly speaking you want something you can deploy while the person is exercising, which limits the field. I think much of this has been done in the early days of ME (eg Paul Cheney) and like many of those findings, subsequently ignored or hand-waved away by team BPS as "deconditioning".

 

I was interested to see that here was an example of a common condition, where there is an established model of how we think it works, that has been standard thinking for many decades. You have atherosclerosis (eg from smoking), causing arterial stenosis and resulting inflow limitation to (typically) lower limbs and that is associated with reduced exercise capacity. When bad enough patients claudicate (get significant pain in leg muscles from ischaemia) and walkable distance drops - say 200m on the flat or 20m when much worse. Everyone's happy that that's the explanation for exercise limitation. Yes they don't get PEM, they can stop and symptoms recover, ready for another round of steps and pain.

However, it is recognised that there are some features that don't quite add up. These patients can increase exercise capacity and that improves their symptoms (presumably to a limit), but at the same time there's no change in the underlying macrostructural abnormality, eg something like 80% diameter loss in the common femoral artery would still be there - the atherosclerotic plaque doesn't really go away with exercise. As they say in the preprint, objective data like the ankle-brachial index doesn't change. Is something else underlying the exercise limitation that's masked, that can get corrected or at least improved with training?

So there's something else going on as well. Atherosclerosis is a systemic metabolic process, relating to chronic inflammation and endothelial dysfunction. It isn't just eating lots of fat and simply getting cholesterol plaques. Often people tend to be isolated brain, heart or limb in terms of which bits of the vasculature they get into trouble with too, though the vasculopath can be more of a full house. I wonder if it's a more locally extreme result of the endothelial dysfunction that could be present in ME/LC. These researchers are showing that there is more going on - that patients with atherosclerosis affecting large and medium sized arteries also probably have more widespread endothelial dysfunction that is affecting their microvasculature. Ie it's not just about the plaques you can easily see in aortas, coronaries, carotids etc, there's a more global vascular disturbance that also relates to the smallest vessels.

These researchers are suggesting all this would be occult because unless you assess these patients exercising you don't see it. They would generally be assessed resting, after all they've got a fixed structural vascular abnormality that shows nicely lying quietly on your back in an MRI scanner.

There seems to be lots of new ideas overturning what we thought we knew. Eg endothelial cells were thought to rely on glycolysis not ox-phos, despite being bathed in immediately adjacent oxygenated blood. Now it would seem that's wrong for normally functioning, quiescent ECs going about their routine job of controlling vessel diameter. They need mitochondrial ATP for NO signalling to their neighbouring vascular smooth muscle cells. Damaged mitochondria means endothelial dysfunction.

It may be that this sort of endothelial dysfunction is the cause of diastolic dysfunction in us (poor vascular control, reduced filling pressures, small hearts, low input failure). Maybe that underlies POTS/orthostatic intolerance. Similar to these patients showing abnormalities during exercise, we show abnormalities just standing up (if you care to look). Maybe even, part of "autonomic dysfunction" and symptoms often attributed to anxiety is an imbalance brought about by a crude compensation of increased sympathetic inputs, at least as far as the cardiovascular system goes. We might have a vastly more profound and global degree of metabolic dysfunction than these patients, so our endothelial dysfunction could be really quite bad, but spread through the body, affecting especially the microcirculation that makes up the majority of our vessels, and not usually resulting in haemodynamically significant large artery stenoses, because it's a different process driving it.

PEM I think would be essentially unrelated. I.e as above, people with PAD can stop and recover and repeat ad infinitum and not deteriorate. PEM probably is immune/metabolic, although there may be an element of shear stress and increased vascular and endothelial (and maybe even red cell) damage, but I'd imagine this would be a lesser contribution.

It's a bit late so I hope these thoughts don't jump around too much. There's much to read, but I'm pretty sure the vessels are going to be front and centre to explain much, but certainly not all, symptomatology, even if it's an immunometabolic cause at the top.

(I don't think ECGs would be much help, but exercise echocardiography could show quite a bit. Also Flow Mediated Dilation in the arm itself. I need to re-watch Paul Cheney's video I linked above with some of this in mind).

 

I did message her a couple of weeks ago on this question, but it looks like she hasn't recently checked in, so will follow-up with email.

I was thinking that for peripheral vascular disease, some improvements could be made in endothelial dysfunction (generally, microcirculation) following exercise - which in this case would be graded as a very reasonable approach. This probably wouldn't be helping established larger flow-limiting lesions, though may help prevent progression, complications such as plaque rupture, or new ones from forming. I guess part of the investigations would need to determine how exercise positively affects the degree of inflammation.

Cardiologists recommend exercise for POTS, which they find promotes recovery. Judging by this approach there is probably a group that is essentially isolated POTS, without the PEM etc of ME. Maybe they don't have the same type and/or degree of major metabolic impairment. Maybe the mechanism is different (eg auto-antibodies per Scheibenbogen).

This question of overlapping symptoms or subtypes in the cardiovascular domain relates to an idea I try to keep in the back of my mind. BPS and LP proponents are adamant that some proportion of people recover using their methods. The particular methods and conceptual framework may be irrelevant of course (and they ignore the failures) but it may be that they're seeing a group who have spontaneously recovered from a significant portion of, say, upstream immunometabolic derangement, but are left with delayed downstream vascular dysfunction, which maintains a lot of the symptoms. That residual might respond to exercise and perhaps that's what PG experienced.

If that were true, then clinical assays stemming from things like Maureen Hanson's urine metabolomics could be key. If you could identify the subset of already adequately partly recovered patients, such that the indicators of PEM are below some now established threshold, then they might safely build exercise to accelerate recovery. Endothelial cells are quite long-lived, turning over every 3-6 years as I recall. Perhaps exercise encourages autophagy/mitophagy or frank apoptosis and so helps turn over the struggling ECs and reduce overall endothelial dysfunction. My cardiologist had said that if it recovers, POTS usually takes 2-5 years, which to my mind might fit with this sort of timeframe.

 

See also thread An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries (2020) which discusses endothelial dysfunction in cardiac disease. Note the overlap symptoms seen in some of these patients, including fatigue and disturbed sleep.