Chase Samsel, MD, FAACAP

Psychiatrist & pediatrician, Chief Medical Officer & Vice President @ Bradley Hospital, Asst Prof @ Brown Med, Lecturer Harvard Med. Views mine. he/him/his

[Chase Samsel, MD, FAACAP @ChaseSamsel]

@gerrylum2 @comma_ai I did not need to exercise that day

[Chase Samsel, MD, FAACAP @ChaseSamsel]

@gerrylum2 @comma_ai Half my time but no prior experience except your videos and online instructions manual you cowrote for comma 3

[Rivian @Rivian]

Somebody called? ☎️👻

Dr. Peter Venkman and the Ecto-R1 are on the case. This year, Ghostbusters takes over Rivian's Halloween mode, with our latest software update starting tomorrow.

Learn more at https://t.co/PUYBG2TYUX

[Atlanta Braves @Braves]

Brb gonna go watch this over and over again

#LetItFly

[Atlanta Braves @Braves]

LET IT FLY, AUSTIN!

#LetItFly

[Awais Aftab @awaisaftab]

“Psychiatric treatment is often enough a frustrating affair, for the patient, for the clinician, for the caregivers, basically for everyone involved…”

On imperfect tools

https://t.co/FT4NWAAiBo

[TheLiftingShrink @psypharmacopeia]

This take is so divorced from reality I don’t even know where to start. I am currently (and have been previously for years!) a military psychiatrist whose patient population is predominately U.S. Marines.

The most common condition I treat is MDD.

They have a sense of purpose. They work out. They don’t need more “tapping into masculine essence.” They need treatment. And yeah that means therapy and sometimes meds.

You won’t find many psychiatrists who appreciate the benefits of lifting weights as much as I do, and it certainly has psychological benefits, but it’s not some panacea for mental illness.

[US Open Tennis @usopen]

The camera panning from the clock at 0:07 to Pierce Brosnan.

Absolute cinema.

[Sam Tsimikas, MD @Lpa_Doc]

My suggestion to everyone speculating is wait for the full results, not just of HORIZON but the other trials. Then send the preponderance of evidence to the jury to decide on the Lp(a) Hypothesis. We really need to know its (patho)physiological role- why does nearly every human have circulating Lp(a)? And why does only human Lp(a) carry OxPL?. We should be grateful so much investment is ongoing to find out what it means to humanity.

[Sam Tsimikas, MD @Lpa_Doc]

Hi all,
The Lp(a) HORIZON trial has released topline data and, quite shockingly, missed its primary endpoint.
In other words, lowering Lp(a) in patients with prior MI, stroke or peripheral arterial disease, who were otherwise very well treated for LDL-C, blood pressure, diabetes and other risk factors, did not reduce the primary cardiovascular endpoint.
We obviously need to see the full data before making firm conclusions, and I don’t want to speculate too much without the details.
But this is a big enough result that it is worth summarizing what we know, what we don’t know, and what this may mean for our patients after 20+ years of trying to test the “Lp(a) hypothesis.”
What we know:
1-There are hundreds if not thousands of genetic, epidemiologic and Mendelian-randomization studies showing that elevated Lp(a) is associated with MI, stroke, peripheral arterial disease and aortic stenosis. That body of evidence is very strong.
2-However, much of those data come from community-based populations, often before the era of intensive LDL-C lowering and modern secondary prevention.
3-There has been much less information about how much residual risk Lp(a) carries in someone who has already had an event and is then treated very aggressively.
4-HORIZON may have had some of the best-treated patients of any recent cardiovascular outcomes trial.
Baseline LDL-C was about 65 mg/dL, a measured LDL-C contains the cholesterol carried on Lp(a), so in reality, 15-20 points lower.
5-In patients with very high Lp(a), if you correct LDL-C for Lp(a)-cholesterol, the actual LDL-C carried by LDL particles may have been closer to 45–50 mg/dL, perhaps even lower in some patients.
6-This raises a very basic question:
Can you still demonstrate a major incremental benefit from lowering another apoB-containing particle when the underlying LDL burden has already been driven this low?

What we don’t know:
1-What was the actual corrected LDL-C in these patients? I think it would be extremely informative to directly measure Lp(a)-C and calculate corrected LDL-C. This may tell us a lot about the biological setting in which pelacarsen was being tested.
2- What was the OxPL status? Our prior work has suggested that much of the pro-inflammatory biology associated with Lp(a) is related to its enrichment in oxidized phospholipids. Did OxPL fall? Did patients with higher OxPL derive more benefit? Was Lp(a) concentration actually identifying the patients with the most pathogenic particles?
3- Did we measure the right component of Lp(a) for trial inclusion? We generally measure molar particle concentration. But is molar concentration itself the main driver of risk, or is it partly a surrogate for what the particle carries? Cholesterol? Triglycerides? Oxidized phospholipids? Other proteins? Could two patients with the same Lp(a) concentration have very different Lp(a)-mediated risk? I think this question deserves much more attention.
3- Were the genetic data telling us exactly what we thought they were telling us? The genetic data are extremely compelling, but genetics reflect lifelong exposure. A clinical trial treats patients late in life, often after decades of arterial injury and after an event has already occurred. Those are not necessarily the same experiment. Could there also be some unrecognized biology linked to the LPA locus that we have not completely accounted for? That possibility should at least be considered.
3- Does very low LDL-C modify the Lp(a) risk relationship? Maybe Lp(a) is particularly important when LDL-C is higher, but its contribution becomes smaller once LDL-C is driven to very low levels. Again, we need the data.
4- Does aspirin or other antiplatelet therapy reduce part of the risk associated with Lp(a)? Lp(a) has potentially important prothrombotic effects. Almost everyone in a trial like HORIZON is receiving contemporary antiplatelet therapy. Could that blunt one component of the risk associated with Lp(a)?
5- Why are these patients still having events? This may be one of the most interesting questions of all. These are patients with LDL-C around 65 mg/dL, and perhaps corrected LDL-C substantially lower, yet cardiovascular events continue to occur. What is driving that residual risk? Inflammation? Thrombosis? Plaque burden that is already too advanced? Other lipoprotein characteristics? Something we are not measuring?
6- Do we need to re-examine some basic assumptions about atherosclerosis? We have spent decades focusing heavily on the quantity of circulating lipoproteins. But perhaps lipoproteins are relatively benign until they undergo biological modification in the artery wall. Oxidation may be one of those key modifications. For some patients, the answer may be to remove more particles from the circulation. For others, perhaps the better approach is to prevent their oxidation or block the downstream biological effects of oxidized lipids. The recent difficulties with anti-inflammatory approaches, including IL-6 inhibition, make these mechanistic questions even more interesting.
7- Was there something specific about pelacarsen, the degree or timing of Lp(a) lowering, advanced disease, trial duration, background therapy or patient selection that mitigated a potential benefit? We simply don’t know yet. That is why the detailed results will be so important.
What does this mean for patients today?
If you have already had an MI, stroke or PAD, the immediate lesson is very clear:
1- Get all of your established risk factors treated aggressively.
2- Get LDL-C/apoB very low.
3- Control blood pressure.
4- Control diabetes.
5- Don’t smoke.
6- Use appropriate antiplatelet and other guideline-directed therapies.
HORIZON shows us what modern secondary prevention should look like.
If you have elevated Lp(a) but have never had an event, the genetic and epidemiologic data still suggest increased lifetime risk.
Until the other 4 outcome trials read out, I would continue to treat every modifiable risk factor aggressively.
We should wait for those trials before drawing broad conclusions about the entire field.
I think the story of Lp(a) therapy is beginning, not ending.
We also need to show tremendous respect and gratitude to the patients who participated in HORIZON and to the investigators and companies that invested enormous resources to actually test the Lp(a) hypothesis, to the ultimate benefit to peole with elevated Lp(a) to best guide how to manage risk.

More to come as we go forward.

[Wassym Bensaid @WassymBensaid]

Rivian OS 2 starts rolling out on R1 today. Rebuilt from the ground up with new design language.

[Chase Samsel, MD, FAACAP @ChaseSamsel]

Excellent foray into this perplexing rise — recognition or new occurrence — of catatonia, and some of exciting new considerations for treatment bucking preconceived notions.

[Joe Pierre, MD @psychunseen]

1/ Some thoughts on CATATONIA...

In 20+ years of inpatient practice in LA, I saw maybe 20 cases and most resolved with brief treatment with lorazepam.

But now that I've been in SF since 2022, I've seen about 80 or more cases... it seems *very* common now!

[Wassym Bensaid @WassymBensaid]

Real-time alerts from Waze are coming to R1 and R2 in-vehicle navigation, starting with speed cameras and police reports in the 2026.31 OTA update. More data and alerts to follow!

[Atlanta Hawks @ATLHawks]

The schedule is (bird) calling 🗣️

[Chase Samsel, MD, FAACAP @ChaseSamsel]

@dieworkwear No love for their third brother, Kevin’s, style?!

[OK Go @okgo]

On this day in 2006, we released the Here It Goes Again music video. This video cost less than $5,000 and was shot in 17 very sweaty takes, but it took us to the Grammys, the VMAs, and to the email inboxes of millions of people (you couldn’t share videos to social media back then).

20 years later, we actually now can share this to social media. Enjoy!

[National Baseball Hall of Fame and Museum ⚾ @baseballhall]

Welcome to baseball immortality, @andruwjones25.

[MLB Network @MLBNetwork]

“Glavine, Maddux and Smoltz told him to play shallow... He played the shallowest center field out of anybody and he took more hits away [than anyone]...”

Mark DeRosa breaks down his former teammate Andruw Jones ahead of his induction into the @baseballhall this weekend.