On the threshold!
We are on the threshold of a major paradigm shift in the treatment and prevention of CVD and EPA is taking center stage.
This is something many of us will probably never see again in our lifetime and those who have boarded the train years ago on this Board will hopefully be able to share this amazing ride with loved ones and friends for years to come.
Thanks Dancing for sharing about the sad passing of a key researcher in the EPA space, sadly before R-It Trial reaching completion and the dramatic presentation st AHA.
That there are members on this Board with diverse backgrounds goes without stating. However, among the many there are some very unique members who have over time almost become like members of a large family. Just to name a few :
BB, JL, Vbru, North, FFS, Sam, SK, AVII, Kiwi, STS, HDG, CardioMD, TTE, Chas, Marzan, AnonFish, KevGee, Dancing in the dark, ZIP, RetinaMD, Bfost, etc etc etc.( apologies for not listing others ).
Like in any big family one has to sit back and see the big picture and not be distracted by nuances of idiosyncrasies of personality.
That JL can let off steam is probably an understatement! That JL is bright and knows a great deal about O3s and EPA and inflammation goes without saying! In this context JL has brought a great deal of value to the Board!
That JL tends to connect dots in his thesis is also evident and can be irritating to many and such irritation is justified as one needs evidence to support such hypotheses - eg SI, IR, FAS etc.
However, this is no way erases all the immense value that JL has and continues to bring to the Board.
We have all lived and learnt over the decades about proposed hypotheses and their demise with subsequent outcomes trials.
Several decades ago it was hypothesized that the reason why postmenopausal women have an increase in CV events compared to women prior to menopause was due to the “cv protective effect of estrogen” in premenopausal women. For years HRT was promoted as providing CV benefit in women following menopause in addition to other benefits. Then the HERS and WHI Trials were published and researchers had to humbly acknowledge that HRT INCREASED CVE and Pulmonary embolism and Breast Cancer in postmenopausal women. The “CV benefit “ hypothesis of HRT was put to rest.
Similarly, years ago , Cardiologists had hypothesized that Homocysteine was an important marker of CV risk ( based on genetic studies). Armed with this hypothesis, cardiologists and PCPs started to measure Homocysteine levels in at risk subjects and found that Vitamin B12, Vitamin B6, and Folic Acid would decrease these “elevated “ Homocysteine levels by 20-30%. Prescription grade mixtures of these Vitamins became readily available ( Folbee, Metanx, etc ) and often were added to other meds for cardiac patients almost as routinely as adding Aspirin. Then the Outcomes trials surfaced where cardiac patients received these mixtures and despite a 28% decrease ( which was expected) CVE tended to increase! NorVit ( Norwegian Vitamin Trial ) and HOPE 2. In fact the title of the presentation at the European Cardiology meeting was : “ Is Homocysteine dead “. Another hypothesis put to rest.
I recall attending an Endocrine Conference years ago in New Orleans where we enjoyed a presentation on how Cyclosporine in vitro inhibited a family of Interleukins. One of the hypothesis at the time was that estrogen deficiency mediated it’s effects on bone turnover and resultant postmenopausal osteoporosis was via various Interleukins . We promptly returned to Philadelphia and administered Cyclosporine to surgically induced menopause ( oophorectomy ) in rats with the hypothesis that the bone turnover would be favorably influenced histologically. I can still remember receiving a call late on a Saturday night from the Histomorphometrist at UPenn asking me what the hell we were giving to rats as the bone volume had so dramatically decreased. We called the manufacturer of Cyclosporine and advised them to send us a new batch and repeated the study with a dose response design . Not only was our hypothesis turned upside down but this opened a new chapter and Chief of Endocrinology whom I worked with became an authority on Immuno- suppressive induced bone disease.
Mother Nature is far too smart and hypotheses are just that. As one tests these hypotheses over the years one naturally develops a humility to the wonders of Mother Nature.
On the subject of humility, it is important imo to keep an eye on the big picture.
CardioMD is a relatively new member to the Board and I do find his contributions of value. He comes across with great integrity and sincerity with a spontaneous expression of care and compassion for his patients and a strong focus on the science and respect for KOLs in the CV space. At the same time he speaks his mind and doesn’t hold back - I personally respect him greatly for that. All these great positive traits of CardioMD were not in the least diminished when I recall him expressing that Endocrinologists deal with “hormones “ and not CV research or lipids ( I am quoting on recall and although the verbiage here may not be precise that was the theme of that statement ) . Well, I have as an Endocrinologists worked with Evan Stein MD, Ph D. in Cincinnati in his Lipid Research Laboratory and Evan is an earlier pioneer in CV research ( LRC-CPPT etc ). I subsequently returned to Philadelphia and directed the Cholesterol Treatment center and published in the Diabetic, Endocrine and Lipid Space. Many of the Endocrinologists I interacted with were engaged in Lipid Research. A close friend of mine ( Endocrinologist ) worked at UT Southwestern under Scott Grundy ( Chief of Diabetes and Metabolism and Nutrition- the key figure in the ATP, NCEP and AHA/ACC Guidelines ). He also worked with Brown and Goldstein Nobel Laureates on LDL , the former being a hepatologist and the latter being a molecular geneticist. The list of Endocrinologist engaged in Lipid Research over the years goes on and on including Ed Bierman, John Brunzell , Alan Chait and more recently Eliot Brinton a co-author with Bhatt on the R-It paper.
Despite, the above, one chose not to engage in a personality contest with CardioMD as one finds so much value in one CardioMD brings to the Board that such statements can easily be overlooked.
What is transpiring and in motion is far bigger and way more important than minor in my mind irrelevancies.
The big picture:
Preston Mason has probably done the key research in the EPA space to elucidate how EPA is mediating it’s effects on a biochemistry, physical chemistry and measures of oxidation and inflammation. For example he has published that the unique chemical structure of EPA with 20 carbin length and 5 double bonds provides important clues to it’s unique effects. He tested different C lengths and different double bonds and the effects are significantly less. EPA with this structure is able to be positioned between Lipid membranes and infer antioxidant and membrane stabilization with decrease in cholesterol domains and cholesterol crystals which imparts plaque stabilization- further bring explored clinically by Mat Budoff in the Elaborate Trial. Furthermore, the antioxidant effects of EPA result in decrease in oxidized LDL, demonstrated in the Anchor Study, and awaiting further analysis from R-It.
DHA, on the other hand, with a 22 C length and 6 double bonds is unable , due its chemical structure, to be positioned between the Lipid membranes and thus has less antioxidant effects compared to EPA ( published by Preston Mason ).
It therefore appears likely, that Preston Mason’s research, with regard to EPA will likely be clinically validated with subsequent analyses from R-It and it is likely that the correlation with EPA and to a lesser extent oxidized LDL-C and other inflammatory markers. The key driver will probably be the incremental increase from low baseline circulating EPA levels and CV events and TG will occupy a minor role ( if any ) in this correlation but will serve more as an identifier ( target ) of at risk population and not and not a target to modify per se. With such data, it is likely that MOA via antioxidant, anti-inflammatory, plaque stabilization properties may surface. SI and IR will not appear in that discussion as such measures were not the target in either Preston Mason’s elegant research, nor in Jelis and more recently R-It. Does that mean JLs hypothesis is wrong? Absolutely not. It is a hypothesis, and being so needs further testing to be validated or invalidated.
It reminds me of JLs great Taoist story about Chan : it may be good or it may be bad. The key to this story ( IMO) is not knowing - and discovery is born out of exploration from the state of not knowing!
Final note:
We are on threshold of history in the making! The last time this occurred was with the LDL-C hypothesis and the granting of the Nobel Prize to Brown and Goldstein.
Perhaps we are approaching the dawn of another Nobel Prize with groundbreaking research on EPA during which Preston Mason, Bhatt and others may be key players in this history making occasion. I believe that we on this Board should celebrate this occasion as it unfolds and forget our personality idiosyncrasies and keep our eyes on the ball ( amazing unfolding of EPA facts ) - this is an amazing journey and the funny graphics of FFS, the clever humor of TTE, our own unyielding Hulk BB, super precise HDG, always dependable Rx Sam, Statistical AVII, super smart JL, great CardioMD, SK, North..etc etc .... this is a historic journey.... let us enjoy the ride and for a moment forget the trivia!!
Peace and thank you to All !!!
