@stockrock Thank you for a great post.
You mentioned the potential for label extension into late-stage but I wondered what your thoughts are on potential label extension (or would this come under off label?) for end-stage HF without (ahead of) LVAD implantation?
MSB’s ann 2024:
“Every year in the United States over 100,000 patients progress to end-stage HFrE”
According to the Cleveland clinic, ischemic cases make up approximately 60% of cardiomyopathy. I don’t know the percentage of that number who would have inflammation but this paper says the highly prevalent nature of inflammation in HF is striking. Authors cite findings from various studies in both reduced and preserved EF. In the RELAX trial 57% had elevated CRP:
https://www.sciencedirect.com/science/article/pii/S0735109720302576
(My personal experience of a chronic condition is that it wasn’t stable but would cycle through acute phases)
LVADs
By my estimates, every year in the US, approx 35 000 people with ischemic heart failure, reduced EF and inflammation progress to end-stage. They have symptoms even when at rest, which means they have difficulty performing basic functions, such as getting dressed and walking across a room.
Cardiologists would likely have a good idea of where a patient is heading and I’d think LVADs would be discussed. If Revescor gets AA, then LVAD + MPCs would be discussed as a future option.
In recent years, there’s been a lot of negative publicity about medical devices: spinal cord stimulators; the FDA letter from 2009 circulated recently on X by Brook Jackson; LVAD devices.
The following article advises the FDA recalled the HeartMate 3 Left Ventricular Assist System (Class 1 - a correction but not removal from market):
https://www.fda.gov/medical-devices/medical-device-recalls/abbott-recalls-heartmate-3-left-ventricular-assist-system-lvas-implant-kit-risk-blood-leakage-or-air
This recall occurred after 2 FDA whistleblowers flagged safety concerns over Heartmate 3 in December 2023:
https://cardiovascularbusiness.com/topics/clinical/heart-failure/former-fda-employees-share-concerns-about-heart-device-safety-data
Implanting an LVAD is a very invasive operation and the devices can cause AEs that can in themselves be life-threatening, ones our cells might not be able to mitigate. In our LVAD RCT, for example, there was no difference in the incidence of infection between treatment and placebo group. Surely it’s best clinical practice to try to prevent an invasive operation in such poorly patients?
There’s also the crucial issue of informed consent: If Revescor got approval for LVADs and I had end-stage HF, I’d be asking my cardiologist if I could have the cells asap, ahead of the LVAD. It’s not as if they can tell me that hadn’t been done before. Could that be an option?
Can you Break the Vicious Cycle at any Stage?
Obviously, early intervention is best before fibrosis sets in; however, even at a late stage, it may be possible to break the vicious cycle, especially if gut permeability is a driver of systemic inflammation:
In the past 5 years there’s been an explosion of interest in the gut-heart axis. Here’s just one review:
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.125.325516
@LeftYahoo Thank you for reading my post and the information you provided in this post 79610313 It’s much appreciated, especially your industry insights. You’re right to be a stickler. I recall I myself wrote some time ago that inflammation in itself was unlikely to be the cause because trials that targeted it (ie. with anti TNF) in CHF had failed.
I think endothelial dysfunction is the root of HF but I guess it’s fair to say we don’t know the cause? As Dr Perin said, we don’t fully understand the complex interplay between the innate and adaptive immune systems but while endotoxins may not be the direct cause of ED, macrophage-associated inflammation seems to play a role in progression and aberrant repair such as fibrosis post MI.
Macrophage-rich atherosclerotic plaques are a feature of late stage HF:
https://academic.oup.com/cardiovascres/article/118/13/2768/6373890
https://pmc.ncbi.nlm.nih.gov/articles/PMC10155014/
If the plaques rupture, that could cause strokes and heart attacks. My question to experts: Could the cells’ ability to polarise from M1 to M2 make the lesions (such as described in Prasad’s paper) less likely to rupture, even at a late stage?
Endotoxins and Endotoxemia
Endotoxins (LPS) are implicated in progression of HF and a worse outcome, not just in the early stage. The study below was in class 2 patients. Authors found LPS responsiveness in patients with chronic HF is an independent predictor of death:
https://pubmed.ncbi.nlm.nih.gov/26264758/
This study looked at gut barrier dysfunction and endotoxemia in HF:
https://www.sciencedirect.com/science/article/abs/pii/S0002870323001461
Authors say that while a cause-effect between gut dysbiosis and HF has not been established, endotoxemia is a frequent feature of severe and/or decompensated HF. They cite studies finding patients with HF display increased systemic levels of LPS which correlate to disease severity, “suggesting a potential interplay between endotoxemia and myocardial damage.”
There may not be an abundance of evidence for endotoxins as the culprit in ED because you don’t tend to find what you’re not looking for. I don’t even know if LPS levels are routinely checked for in CHF?
That may be because the dogma of cholesterol being the root cause still prevails:
The sugar industry paid 3 Harvard professors to demonise saturated fat. Aconspiracy fact:
https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-industry-shifted-blame-to-fat.html
The Seven Countries Study didn’t support the lipid hypothesis. Quite the reverse. I only read his mass market paperback but you’ll find more detail in Wolfgang Lutz’s scholarly workDismantling a Myth, which should be in medical libraries. (This is why I never thought CSL’s heart trial would succeed.)
The diet British cardiologist Aseem Malhotra is popularising (His stance on statins was vindicated in a court case last year.) IMO is based on Lutz’s. If cardiologists worked with their patients to gradually and safely reduce carbs, that would improve kidney function. Lutz is most famous IMO for his work on IBD but he treated a range of diseases and said it was possible to reverse diabetes (which would reduce the market for SGLT2 inhibitors).
Is the Cardiac Benefit of SGLT2is Overstated?
Revascor is positioned for reduced EF, so I’ll focus on DAPA HF and Empire Reduced trials in dapagliflozin and empagliflozin respectively.
Participants were excluded who hadn’t tolerated SGLT2 inhibitors.These drugs have known serious adverse effects such as urinary and genital infections and ketoacidosis (unclear data on the incidence of this very serious AE). These have been flagged by the FDA and reported in detail by patients online. (One FDA reviewer of dapagliflozin was unwilling to rule out a potential increase in risk for bladder cancer.)
The reports of significant efficacy in the composite outcome in the trials could have been driven by the less serious outcome of decompensated HF, as stated in the NEJM correspondence. The reduction in cardiac death was not significant in either trial. Further, Vertis trial in Ertugliflozin didn’t show any benefit in preventing MACE.
Importantly, there’s more to HF than the heart itself but these drugs are unlikely to be able to improve ED because their effect on preventing strokes is unclear.
IMO their cardiac benefits have been grossly overstated:
After five years of SGLT2is as SoC in HF you’d expect to see some impact on the appalling CHF statistics. While it’s hard to find recent numbers on LVAD implantation (2023, 2024), this paper reports a steady increase in heart transplants with 4,446 new adult candidates in 2022:
https://pubmed.ncbi.nlm.nih.gov/38431362/
(Re. Lefty’s point about the potential interaction with our cells, a significant number of late and end-stage patients wouldn’t be taking them because of intolerance to them or else they’ve stopped working, so i don’t see how that could be an issue.)
Patients with HF are on a lot of different drugs. If we were heading in the right direction Malhotra wouldn’t be on the war path. I just don’t see how any tablet can have an impact on endothelial dysfunction (tho Merck and Bayer claim this for Vericiguat). In contrast, there’s so much research by independent groups on MSCs’ ability to improve blood flow and circulation: angiogenesis; restoration of mucosal integrity by maintaining tight junctions; polarisation of macrophages from M1 to M2, to name a few. Further, rather than being a mindless pump, the heart is able to direct different types of blood to different organs, which calls for cells that are able to communicate intelligently with an intelligent organ.
If we can learn from the ARDS trial, my take after reading the Bowdish paper was that if the cells had been appropriately delivered (according to inflammatory biomarkers, as in the EAP and first part of the trial), there likely wouldn’t have been an overall neutral effect. That, and patients should have received them ahead of invasive vents.
Our cells shouldn’t be a medicine of last resort. It also goes against the zeitgeist. The cells are a gift from a human to a fellow human. At the very least, they should save them from the machines.
ALL IMO. I welcome corrections.
(20min delay)