For those interested in the Saturday Morning Lp(a) Class, the course is now linked to my bio and is open access. Big thanks to @TheBhupiThakur for organizing the twittorials. It is ~500 tweets in 24 classes. Syllabus enclosed. I wish to all the joy of learning.

Not all apoB-containing particles tell the same story. 🔹 Non–Lp(a) apoB → greater coronary plaque burden 🔹 Greater relative Lp(a) contribution → more vulnerable plaque features New in #EJPC: Balance between apoB and Lp(a) may add another layer to cardiovascular risk assessment and personalized prevention. ow.ly/uL2650ZWCIC @EJPCEiC @AboyansV @SilCastelletti @PTBuketAkinci @PeroneFrancesco @SMosteoru @TimKambic

The story of Lp(a) and TGs is now expanding, and this paper goes nicely with the prior one that just came out in JACC BTS. More to come with our new methods to directly measure Lp(a)-TG.

We did check, we did not see any significant correlations with apoB48.

Its likely a particle size issue as apoC-III and ANGPTL inhibitors do not affect Lp(a) levels. Chylomicrons and large VLDL are large for apo(a) to dock on them. That being said, epidemiologically, there is a mild inverse association of Triglycerides and Lp(a) (r~0.15).

This is likely not a triglyceride issue per se, but a particle size issue. Chylomicrons (Balance) are too large for apo(a) to attach to them, thus Lp(a) particles can't form easily. In contrast with VLDL (ESSENCE) the Lp(a) values seems c/w other studies. FCS is very rare, so although insightful, this does not affect advice for testing.

Here is a new paper for the lipid nerds from the Balance and ESSENCE trials: Lp(a) is genetically determined—but can change due to metabolic factors. In genetically confirmed FCS, Lp(a) is markedly suppressed, especially in those with small apo(a) isoforms genetically programmed for high Lp(a). Why? Likely the absence of normal LPL-mediated lipolysis/remodeling in a chylomicron-dominant state, altering the apoB-100 particles available for Lp(a) assembly. And the OxPL story (@OxPL_apoB) is striking: OxPL-apo(a) falls disproportionately, with a ~70% lower OxPL-apo(a)/OxPL-apoB ratio—evidence that OxPL partitioning shifts away from Lp(a). jlr.org/article/S0022-2275(2…

Now that OxPL is having a larger interest, here is more food for thought: why is human Lp(a) the only one that accumulates E06-detectable OxPL? And why does plasminogen of all species tested to date bind OxPL? Back to the future from our 2013 paper summarizing over 10 years of work, as we were thinking of a potential therapy for Lp(a). @swissCTO ncbi.nlm.nih.gov/pubmed/2382…

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Well, its funny that you ask, what do you think of this J-curve? We published this in 2006 and suggested Lp(a) acts as a scavenger of OxPL- and perhaps it had a beneficial effect at low levels. ncbi.nlm.nih.gov/pubmed/1754…

Lp(a) carries biologically active oxidized phospholipids (OxPL). New research links its OxPL cargo to platelet hyperactivation through CD36, connecting Lp(a) biology to thrombosis and highlighting the importance of what the particle carries. Lp(a) may be more involved in platelet function that previously appreciated, see our review on this also. ncbi.nlm.nih.gov/pubmed/3793… doi.org/10.1161/CIRCRESAHA.1…

We have a new paper today that links Lp(a) with triglycerides in patients with moderate hypertriglyceridemia (TG 150-500). Using our new methods we developed @UCSDCardiology Lp(a) becomes TG- and cholesterol-enriched. ApoC-III inhibition reduced Lp(a)-TG and Lp(a)-C by ~60–70% without lowering Lp(a) particle number, revealing pharmacologically modifiable Lp(a) heterogeneity. We now need to see how Lp(a)-C and Lp(a)-TG correlate with CV outcomes. sciencedirect.com/science/ar…

You did not measure OxPL in your Lp(a) prep, thus cant claim your findings are due to OxPL. Oxidizing with glucose oxidase and MPO likely creates a large number of species that could explain your results. t would be good to tease those out in future studies.

Statins raise Lp(a), and because it carries OxPL, the OxPL-apoB rises (note the OxPL-apoB is not a measure of "total OxPL"). Statins lower the # of LDL particles substantially, more ta increase in Lp(a)/OxPL, thus the net benefit is present. In SPARCL it was baseline OxPL, not the change that was highly predictive of new stroke. Appreciate the nice questions.

Yes, this can't be studied in patients, but in experimental models, it suggests OxPL exit tissue before there is physical regression when switching from high fat to low fat diet. See our 2007 paper. ncbi.nlm.nih.gov/pubmed/1708…

Here is our @JACCJournals paper on Lp(a) vs OxPL in same model in pre-existing mild-mod aortic stenosis. Each are independent predictors of progression, but in same model, @OxPL_apoB is a significant predictor but Lp(a) is not. This type of work over for 2 decades allowed us to understand not all Lp(a) particles are similar @EricTopol @hsbhatia ncbi.nlm.nih.gov/pubmed/3954…

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.

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.

Surprising (and very interesting) that apoC3i olezarsen appeared to reduce triglycerides more in those with versus without baseline fibrate therapy - both in severe and moderate hypertriglyceridemia. I thought it would have been the opposite. authors.elsevier.com/c/1niLb…

In this #JACC interview, Associate Editor Dr. @jasonwasfy sits down with Dr. Steven E. Nissen to discuss new findings on lipoprotein(a), oxidized phospholipids, and the Phase 2 lepodisiran program. 📄: bit.ly/3UiDsQ1 #ESCCongress #cvLipids piped.video/qAXs7Lu5KcQ?si=6JLb…

OxPL are the rage now, its nice to see this finally reach critical mass. BTW, these lepodisiran data were measured in our lab @UCSDCardiology. We first published in 2015 the reduction in @OxPL_apoB and OxPL-apo(a) with the precursor to pelacarsen in Lancet. ncbi.nlm.nih.gov/pubmed/2621…