Joshua Samsoondar

Hao Yin Verified account @HaoYin20 · Jun 12

Loeys-Dietz syndrome 3
#Aortopathy

Microfibril Denudation Marks Early Aortic Vulnerability in SMAD3 Variant Carriers: A Multigenerational Study

@atvbahajournals 2026
ahajournals.org/doi/10.1161/AT…

Thanks to our excellent surgeon collaborators led by Dr. Michael Chu @MichaelMwachu 🙏👍, we collected 7 LDS3 ascending aortas & assembled a large family with 57 SMAD3 variant carriers😎

Using molecular pathology & RNAseq, we identified a SMAD3-dependent transcriptional program for microfibrils.

Microfibrils are the structural sheath for elastic lamina & the adhesive anchors b/w aortic smooth muscle cells and elastin fibers.

LDS3 aortas lose microfibrils even at elastin-intact zones, creating a physical SMC-elastin separation, which is filled by glycosaminoglycans

Does this mechanically soft GAG matrix contribute to the weakening of SMC mechanosensing and ultimately LDS vulnerability to #AorticDissection?🤓

More studies from Pickering lab
@LHSCCanada @WesternU @SchulichMedDent
are on the way!😆

Thanks for all your interest! This is likely the last regular X post before completing another paper revision👋

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Anish Koka, MD Verified account @anish_koka · Oct 6, 2025

The problem with the value proposition for coronary CTA is that in reality the use case is mostly limited to low risk (young) people presenting with chest pain to the ER. That use case shrank with the advent of high sensitivity troponins.

Everything else is essentially made up.

Finding epicardial coronary disease in asymptomatic individuals should have died with COURAGE (2007) which showed no benefit to stenting asymptomatic individuals.

More nails in the coffin: ORBITA 1 & 2 are trials of patients with severe disease AND angina that can be interpreted to show stents may be of benefit in improving symptom burden (controversial) but in reference to the question about life saving coronary CTa it should be an important signal because of the question that isn’t even being asked : do stents in the setting of stable angina and severe disease save lives ?

If finding epicardial disease was SO parachute like lifesaving — why wouldn’t that signal show up in the very contemporary orbita 1 / 2 ? Not a single stent manufacturer will fund a large enough RCT in the setting of stable CAD bc the probability of benefit is so low.

The remaining glimmer of hope for stents for stable coronary disease came from FFR - a technique that ostensibly tells you in the Cath lab if a particular coronary lesion is causing a blood flow mismatch at the muscle level (ischemia).

When they took people with multi vessel disease and randomized people to FFR guided PCI or PCI just based on how visually narrow the lesion is … there was no difference. Stenting of epicardial disease again fails to show benefit!

But maybe FFR guided stenting makes sense?

Well there are significant problems with that because there is essentially one group that has generated the data to suggest benefit to FFR guided therapy in the FAME1 and FAME2 trials.

In other hands (FUTURE trial) an FFR guided approach increased mortality, and in ORBITA, the FFR substudy showed no interaction between FFR and angina.

Even more damning ISCHEMIA a large trial testing whether blood flow mismatch seen by nuclear perfusion studies could predict who to stent — was also negative! Basically if you have a large amount of ischemia maybe there’s benefit, but even moderate ischemia may not be that worth intervening on. (Category of feels good, but doesn’t benefit patients)

FFR should have died a quiet death, but it was resurrected by something called CT-FFR which purports to give you the same information as invasive FFR which normally required a catheter in a coronary vessel and administration of a vasodilator. Apparently something something AI / math supported analysis of IV contrast as it flows through the coronary vessel can approximate the invasive FFR measurement.

Except it is pretty poor at predicting invasive FFR in the range of numbers that really matter.

So to summarize — we have a probably garbage indicator (FFR) and a test (CT-FFR) that doesn’t even approximate the garbage indicator.

So what exactly are we doing here by recommending coronary CTA +/- CTFFR to asymptomatic people??

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John Mandrola, MD Verified account @drjohnm · Oct 6, 2025

If every CT scanner in the US broke down for a year, heart disease deaths would not change.

The prevalence of soft thinking amongst doctors is shocking

aafp.org/pubs/afp/issue…

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