David Systrom, researcher, Brigham and Women's Hospital, USA

The problem is recognised as very disabling. In right heart failure or biventricular failure from lung disease or alcoholism if too much diuretic is given then not enough fluid is getting back to the heart for it to pump on. The person usually can barely lift an arm, let alone go to the toilet.

But I am a bit sceptical about calling this 'preload'. This is a catchy term developed in the 1960s together with 'afterload'. Neither are actually loads. Preload mostly seems to mean a low central venous pressure and I think it would be better to call it that, because if it is more than that, and it is likely to be more complicated, then it should be specified. I may be biased but the cardiologists who threw 'preload' into their conversations when I was a young physician tended to be showmen rather than clinical scientists.

 

That's really interesting. Thanks for sharing.

 

What symptoms would suggest preload failure?

Can I have it while still being able to do walks of up to 1 hour with only minor PEM? That's a lot less than other people of my age, but more than many patients.

I can also swim for a few minutes but cannot seem to increase my endurance even when doing it regularly. It feels like there is some physiological limitation that doesn't get better with training.

I get chest pain, palpitations and sensation of painfully overstimulated heart when doing too much activities or spend too much time upright. This lasts for hours, days, weeks. Sounds like sympathetic overdrive to me.
The immediate response to excessively intense exertion is becoming extremely tired and sleepy and lying down (despite the presumed sympathetic overdrive).

I can get a feeling of shortness of breath while doing activities, and dizziness after walking upstairs. Holding my breath almost immediately becomes unpleasant and hard to bear. There's clearly something wrong with my breathing and breath holding tolerance.

My heart rate is no longer consistent with POTS but is a little too high at rest.

I tire more rapidly and profoundly from exercise even compared to people who are much older than me. But the most noticable limitation is probably in the total amount of activity over the course of the day.

Hot weather makes the aforementioned things worse and especially causes initial orthostatic hypotension.

Would testing positive for preload failure lead to some useful treatments? I know Systrom tested pyridostigmine which had some positive effect but not in the longer term. Are there any other, established treatments?

 

I’ve now watched Systrom’s presentation in its entirety. I find it hard to reconcile some things. He strikes me as a serious person who doesn’t give off that used car salesman vibe that 99% of “CFS specialists” do. Yet, his statements don’t map onto the data shown on slides. He says preload failure is ubiquitous in this pt population. His word. If that’s so, hasn’t he solved the age old mystery of no biomarker for ME/CFS? This is supposed to be unambiguous evidence of organic pathology not seen in deconditioning studies. Who has attempted to replicate this? I mean, CPET is a mainstream medical test, not some new unproven technology like the nanoneedle.

Secondly, the Mestinon thing. I find it difficult to believe that a mainstream drug that’s been around forever has not been noticed before to be a successful treatment for autonomic dysfunction such as Pots. The results of the study on women don’t look clinically significant to me. Yet he continues to use this in the clinic. Also, why slice and dice your data and start talking about only women halfway through the talk? Could it be because none of the hypothesised associations are sig in the overall sample including men? One of the questions in the Q&A asked about men and the response was vague and unsatisfactory.

 

My understanding is that invasive CPET is a highly specialized test that is offered only in few clinics. Presumably very few people even know about its use in ME/CFS and LC although this is difficult to estimate because with LC things are evolving rapidly.

I heard from several other patients that had it done outside of Systrom's clinic and the findings were apparently replicated. In some cases it was the first time the doctors had ever done it on a person with ME and were surprised by the results.

That said, if a test has a very high rate of being positive that could also mean it's unreliable. I'm mentioning this because there is a theoretical possibility, not because I have a bad impression. Systrom comes across as a serious down-to-earth researcher.

 

The point is that this is mainstream technology accepted in mainstream medicine, not some highly speculative fringe science paper. If what he says is true, and remember he first published these results many years ago when we were still on the previous forum (the initial paper on unexplained dyspnea), it’s surprising that people are still being sectioned under the mental health act and generally ridiculed.

 

He says preload failure is ubiquitous in this pt population. His word. If that’s so, hasn’t he solved the age old mystery of no biomarker for ME/CFS?

Secondly, the Mestinon thing. I find it difficult to believe that a mainstream drug that’s been around forever has not been noticed before to be a successful treatment for autonomic dysfunction such as Pots.

Great points. However preload failure happens also in heart failure, mitral regurgitation and mitral stenosis, and it would not be enough on its own to signal ME/CFS, however, perhaps sensitive tests on the heart could be included in diagnostics? We don't yet know, presumably, what percentage of the ME pt population have preload failure.

Also, the approach to prescribing for ME/CFS hasn't really been 'try it and see what happens', at least in the UK. Unless it's in the NICE Guidelines it's not usually tried. And isn't it likely it will be of help to a specific subset of patients, as with other treatments. We are still only just able to discriminate between different groups in a lab (is it Montreal? And the genetics data anticipated might shed some light perhaps. I'm in a fog of hopefully now fading PEM here today), and I don't think that work has been replicated elsewhere yet? I'm asking my GP today to let me try mestinon to see if it helps as muscle weakness has been a big feature of my ME, disproportionate to other ME symptoms when I've been mild, and I have both orthostatic intolerance and a consistently good response to TVNS suggesting some vagus nerve involvement. Perhaps it will help.

 

100% especially as this appears to be accepted medical procedure and not fringe. And understood to be debilitating.

 

This is interesting; however, is this preload failure not a consequence of 'something'. It might be helpful to identify patients objectively from healthy folks, but this has to be downstream of? Infection? Immune issues? Autoimmunity? I doubt this will be unique to post viral conditions.... I hope it is the start of a new understanding and move forward.

 

There was also this case report of a woman with ME/CFS who was cured by an intervention to treat narrowing of the transverse sinuses. These are veins at the back of the head.

https://pubmed.ncbi.nlm.nih.gov/26623235/

 

Is this the sort of thing that could be tested for easily? Has it been ruled out for most pwME?

 

(50 min interview with Systrom)

Emerge Australia Imagine Podcast Series, 1/18/24: “Dr David Systrom”

“the silver lining..,at least with respect to research interests and funding, from the long COVID pandemic really has been additional money and interest in the direction of ME/CFS”

“I am excited globally about the very notion that you mentioned earlier that long COVID has spawned interest respect research treatments into ME/CFS. So that globally excites me..And so the fact that all of this has begun to come around not only for long COVID, but for ME is super exciting.”

“we all know that ME/CFS was given short shift for a long, long time and continues to be to a degree by the medical establishment. And yes, then along came long COVID and really got people's attention, both because of the incredibly high incidence and then prevalence, but then the similarities, as you mentioned in your introduction to ME/CFS.”

“first part was the discovery, initially with ME and then with long COVID, that there is evidence, we think, of neurovascular dysregulation during acute exercise. And we've come at that from a couple of major lines of evidence.”

“So pretty universally in both ME/CFS and long COVID, we will observe what we call preload failure. And these are exceedingly low pressures feeding the right heart. And in the upright position, many of our patients know gravity is the enemy.”

“What we're seeing is a tendency of blood to pull in the legs and the abdomen & failure of the autonomic nervous system to squeeze down the big veins, push physically blood back up northward to the right heart..see that w/these low filling pressures, again, called preload failure...we found something similar on the arterial side. And at the end of the day, I think it's mostly about lax blood vessels. They're abnormally dilated. And on the arterial side, what that means is an individual perfuses or sends blood flow inappropriately to organ systems that do not need it.

So our best guess is that blood is going to places like the gut and the kidney and even the skin, in large volume when it should be directed by the autonomic nervous system, toward the exercising muscle. And that fails to happen. And what we see is evidence of impaired oxygen extraction by the muscle. So the blood is going to where it's not needed. And what suffers is the oxygen delivery, the appropriate oxygen delivery to the muscle where the mitochondria can take it up and use it. So we see evidence of impaired oxygen extraction coming back at the tip of this pulmonary artery catheter at maximum exercise.”

“we've also increasingly recognized over recent time that these same nerve fibres normally play a major role in blood vessel tone. So what we found in that Philip Joseph paper was that nearly half of the patients that we did skin biopsies on and this invasive exercise test had evidence of the small fibre neuropathy by a skin biopsy. So that's how we come to the conclusion that this is quote, neurovascular dysregulation. The exercise test shows us abnormally dilated veins and arteries and abnormal blood flow. And the skin biopsy, which we marry in a sense to the exercise test, tells us that there is a very high prevalence of small fibre neuropathy.”

“Last little bit, this is unpublished. More recently, we've done dual skin biopsies with Peter Novak, who is a world renowned neurologist at Brigham Faulkner. Peter's Autonomic Function Lab does the initial superficial skin biopsy above the ankle.

That's the so-called epidermal biopsy, but additionally does one a little deeper up in the thigh. And what we can get then is sweat glands and their innervation by these small fibre nerves. And what we found is nearly two-thirds of patients with both ME and long COVID have evidence of small fibre neuropathy when we do the deeper biopsy and we get the sweat glands.”

"So we think we've begun to build a case for neurovascular dysregulation in both diseases as a cause for symptoms"