Rapamycin and risk of cardiovascular disease

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#324

How does one know if they are “prone to clots”? Do a coagulation panel?

Whether this study of transplant patients (high at risk) on chronic mTOR inhibitor translates to healthy, as just don’t know. But all the more to tread very carefully, MITIGATE risk.

Agreed, not only for ameliorating Rapamycin risk but fundamental CAD risk.

This is yet another reason I donate blood every 7 weeks, to improve my blood clotting function and von Willebrand factor vWf. I also take 3g/day DHA/EPA, also a blood thinner. Often, when I do lancet pin pricks, the blood squirts out when I pinch my finger. I also take several natural products which also add with thinning.

Is this why women have las CAD than men up until older age, well past menopause…loss of blood, thinner, less problematic iron/clotting??

Cardiovascular benefits of phlebotomy: relationship to changes in hemorheological variables
https://sci-hub.se/10.1177/0267659113505637

“Blood loss, such as following regular donation, is associated with significant reductions in key hemorheological variables, including whole blood viscosity (WBV), plasma viscosity, hematocrit and fibrinogen. An elevated WBV appears to be both a strong predictor of cardiovascular disease and an important factor in the development of atherosclerosis. In addition to WBV reduction, phlebotomy may reduce an individual’s cardiovascular risk through reductions in excessive iron, oxidative stress and inflammation. Reflecting these findings, blood donation in males has shown significant drops in the incidence of cardiovascular events as well as in procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting”

von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?
https://sci-hub.se/10.1016/s0008-6363(97)00039-4

“The vascular endothelium is involved in the production of many important substances which are involved in cardiovascular pathophysiology. One such substance which is synthesized by, and stored in, endothelial cells is von Willebrand factor vWf . When released, vWf appears to mediate platelet aggregation and adhesion. The close association between vWf and the processes of thrombus formation thrombogenesis or atherogenesis also suggests that high vWf levels may be a useful indirect indicator of atherosclerosis and/or thrombosis”

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#325

I’m going to get a fibrinogen blood level. I’ve never had it checked
I definitely like the idea of donating blood to reduce the coagulation factors as well as blood viscosity. I stopped doing it with Covid bit will start again. Any particular reason for every 7 weeks? Seems frequent.
I bled quite a bit after having a tooth pulled a couple years ago which is oddly reassuring.

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#326

Wonder what the normal or ideal range is for oxLDL? Sounds more specific.

#327

The shortest gap for men! 8 weeks for women. As long as my hematocrit is above minimum, they allow donation.

I watch my CBC and iron markers pretty regularly, and as I’ve previously posted, dumping iron to run just above anemia, renewing albumin is a major longevity hack. Been doing it for 5 years now, I’ve never felt better overall, so it’s not obvious this frequency is detrimental. Although I don’t run marathons, I run 4-5k daily, I don’t see any obvious impact on my oxygenation or fatigue.

I meet a lot of old folks who have been donating for as long as they can remember.

#328

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#329

The more I think about it the more I think that it’s a really smart thing to do. Doesn’t it also reduce cancer risk?

#330

I like this test . I got 96 years . Not bad. Apparently I don’t drink enough or make enough friends every year.

#331

I don’t have much in the literature database on cancer and phlebotomy.

Iron and Cancer

“Epidemiological studies have demonstrated an association between excess iron and increased cancer incidence and risk, while experimental studies have implicated iron in cancer initiation, tumor growth, and metastasis. The roles of iron in proliferation, metabolism, and metastasis underpin the association of iron with tumor growth and progression. Cancer cells exhibit an iron-seeking phenotype achieved through dysregulation of iron metabolic proteins”

Makes sense?

Women live longer.

Red meat = colorectal cancer risk

Low protein = low iron = less cancer/CAD (and AD) = LONGEVITY??

And Rapamycin dysregulates iron liver homeostasis = LONGEVITY IN MICE.

#332

The impact of phlebotomy and hydroxyurea on survival and risk of thrombosis among older patients with polycythemia vera

“Phlebotomy, increasing phlebotomy intensity , and a higher proportion of days covered
(PDC) by HU were all significantly associated with lower mortality. When thrombosis was
the outcome of interest, phlebotomy, and increasing phlebotomy intensity were significantly associated with a lower risk of thrombotic events, so was a higher HU PDC. In this population-based study of older adults with PV reflecting contemporary clinical practice, phlebotomy and HU were associated with improved OS and decreased risk of thrombosis.”

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#333

From what I’ve read it does appear that the cancer reduction from blood donations is indeed related to iron.
There was a concern at one time that the increased hematopoietic cell divisions may lead to lymphoma, but a very large study disproved that notion.

#334

@rivasp12

Reviewing this paper you posted:

mTOR Inhibition and Cardiovascular Diseases Dyslipidemia and Atherosclerosis (2018)

The authors state “Furthermore, the risk of CVD is not higher in renal or liver transplantation patients receiving rapalogs despite significant dyslipidemia triggered by the treatment”

And the two references in support of this statement:

Sirolimus and Cardiovascular Disease Risk in Liver Transplantation

"We reviewed all 1812 liver recipients who underwent transplantation from 1998 to 2010, identifying a cohort using sirolimus as part of the initial immunosuppression (SRL Cohort) and a control group of the remaining patients from this period where SRL was never given (Non-SRL Control).

Conclusions. Sirolimus causes hypertriglyceridemia and hypercholesterolemia, but it does not increase the incidence of MI or other CVDs. Considering the SRL Cohort has more cardiac risk factors and nearly double 10-year predicted CVD risk, the fact that the CVD incidence is similar suggests that sirolimus is in fact cardioprotective."

2nd reference:

Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors

https://sci-hub.se/10.1016/j.transproceed.2011.08.009

" The incidence of coronary artery disease was higher among patients treated with mTOR inhibitors (P .04). CVD, defined as myocardial infarction, percutaneous coronary intervention, stroke, aortic aneurysm, pulmonary thromboembolism, sudden cardiac death appeared in 26 study group compared with four control patients (P .24). The risk of any CVD was not significantly higher
among patients receiving mTOR inhibitors hazard ratio 1.94; 95% confidence interval 0.83– 4.52). In conclusion, no correlation was observed between the duration of mTOR
therapy and CVD"

Yet, some “concerning comments” in the discussion. Not a statistically mediated dismissive study?

“We observed more cardiovascular events among patients treated with mTOR inhibitors, although the incidence was not significantly more common compared with a control group; it was not affected by the duration of therapy. The risk of occurrence of a cardiovascular event was nearly twice as great in those recipients treated with an mTOR inhibitor, but it did not reach significance. We did noticed a higher incidence of coronary artery disease during mTOR inhibitor therapy. mTOR inhibitors have proven effects on hypercholesterolemia and hypertriglyceridemia in renal transplantation. Our study confirmed their detrimental influence”

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#335

Thank you for this insight.

#336

When I first posted this topic I felt that rapamycin was atherosclerosis protective despite the elevations in lipids. Nothing has persuaded me to believe otherwise though there’s some evidence in an article posted by RapAdmin that 6 mg dosing may be ideal for this.
At the time I wasn’t at all aware of the possible pro coagulation effects in a defined cohort of patients, which may well explain the CVD incidents, though not reaching clinical significance.
This, along with some of the replies including your own has absolutely persuaded me to add some supplements, get my fibrinogen checked, and resume regular blood donations.
Don’t get me wrong, I’m not in a panic over this, but I’m not willing to just dismiss it either. Might be foolhardy.

#337

“The risk of occurrence of a cardiovascular event was nearly twice as great in those recipients treated with an mTOR inhibitor, but it did not reach significance”

That’s one heck of a trend, and likely safe to presume that it would easily reach statistical significance with a higher number of patients.

Yes, higher exposure of rapamycin (daily vs weekly) but also higher increases in lipids compared to weekly use.

How exactly can this be used to justify not only ignoring lipid increases from rapamycin but to characterize them as helpful?

#338

But is “this” sufficient to reduce all cause mortality risk??

Is this enough for cancer risk reduction, since we’re all here because wild type mice live longer taking chronic Rapamycin?

Do we know if 6mg week sufficiently depresses mTOR to delay all cause mortality? Mice taking human equivalent of 13mg/day reduced mTOR 30%.

And yes, we’re all learning from each other, hopefully for the betterment of all.

#339

Yes, you’re right. None of that is known.

#340

Only helpful in the sense of assisting in bioavailability as in other hydrophobic drugs like clozapine.

#341

Sorry do you mean helpful re mTOR inhibition?

Why don’t you equate mTOR inhibition to something far more relevant than bioavailability…such as longevity?

We know without debate mTOR slows down cancer proliferation. Mice still die of cancer, just later.

That’s the elephant in the room.

#342

No, I was responding to davin asking how lipids could be helpful with rapamycin. Nothing to do with mTOR.

#343

Ok fair enough, but stats like doubling the risk of CVD events (even if not statistically significant because the study was under-powered for this variable) along with the lipid increases, while at the same time knowing that lipids are at very minimum an important causal factor in CVD, how is this not convincing that treating lipid elevations from rapamycin is a good idea?

Isn’t it conceivable, for instance, that the anti-inflammatory/anti-proliferative effects of rapamycin partially blunt its overall effect on CVD but that residual risk remains due to the lipid elevations? The pro-coagulant effects of rapa are interesting as well. Amla extract as noted previously appears to lower lipids significantly but also has anti-platelet effects, although that may or may not be much help on the venous side of things.