General Discussion

...in Korea.

Many of the other arteriosclerosis lipoprotein A related studies actually include inclisiran either as a co-administration agent or as a standalone; some with statins, for which I have developed either a tolerance or, as I suspect, a degree of hypersensitivity. I am experiencing the muscular issues..

In my career in drug development, I've come to understand that getting to a phase 3 trial is not an indication that a drug is safe and effective; if it were, there would be no reason to do a phase 3 trial. I have been around phase 3 trials that completed without the drug being approved, a famous case in which I was peripherally involved being omapatrilat, a dual ACE/NEP inhibitor, which failed in phase 3 owing to an incidence of angioedema in a subset of patients. (I tend to think that with modern molecular biology screening, it would have been possible for the drug to have been approved; it addressed a refractory population, generally African American who do not respond well to traditional blood pressure medicines.)

In any case, I don't think my case requires waiting for an additional treatment option in clinical trials. In the worst case, I will need a TAVR, which I've already begun investigating on an admittedly superficial level at this point. I only recommend the use of experimental treatments to friends and colleagues who ask for my comments in situations in which no viable approved treatment options exist, such as certain cancers.

There is an online calculator for TAVR risk which I've used. The risk of a fatal failure is reported for my age, GFR (which is required for some reason) is about 1.5%. It's not preferable to zero risk, but isn't all that bad either.

In a sense, PCSK9 inhibitors are a case of shutting the barn door after the horses escape to use the well worn cliche. It is possible that inclisiran will slow progression of the disease somewhat, but will not reverse it, at least from my preliminary understanding as I look into the matter in the literature.

It is interesting that of my six maternal aunts, three of them, as well as my mother, were reported to have rheumatic fever related valve disease. One of my aunts was the tenth person ever to have an artificial heart valve replacement - obviously open heart, not TAVR. She lived for about 15 years after the procedure if memory serves me well. Whether the etiology of their syndromes was in fact related to rheumatic fever or represented a genetic case is interesting to consider. During their lives diagnostic tools of the type we have today simply did not exist. None of my three maternal uncles had valve disease. Only three of my affected aunts died from heart disease, the one who was the tenth case, and two of her sisters, although one was in her mid 80's, a long well lived life, and the other who passed suddenly in her 60s despite life long heart issues. My mother did not live long enough to develop full blown heart disease; she died of a brain tumor at 51.

No one in my paternal family exhibited heart disease, although it appears that my paternal uncle and father had a genetic anomality known as Barrett's esophagus, which I have apparently inherited. I've outlived both of them. This syndrome triggers cancer upon exposure to nitrosamines, to which both my father and uncle were exposed owing to their really bad cigarette addictions. I may have been exposed to nitrosamines from an unexpected complication related to making the synthesis of valsartan "greener," recycling DMF. I get routinely checked: So far, so good.

The molecular biology of lipoprotein A strikes me as interesting, and may involve an allosteric interaction if I'm reading my preliminary papers from the literature correctly, and I'm looking into it both out of curiosity and personal interest. Thank you for stimulating that interest.

Thanks as well for your comments and suggestions. Right now I'm happy with my medical care which strikes me as sufficiently reasonable. It's a bit unnerving to recognize this syndrome, to be sure, but I've been increasingly aware of my mortality as time goes on, and frankly, regard mortality in a positive light, as it makes life precious in a sense. Facing a risk gives me an excuse to say some things I have wanted to say to my sons and to my wife without being overly morbid.

I have lived a life better than I deserved I think. I can't argue with it.