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Nick Norwitz

@nicknorwitz

May 24

Lp(a) Explained: Genetics, Risk, and What You
Can Actually Do ❤️‍🔥🫀
🔗 all references and more info at the end

1/9) By now, you’ve probably heard the term Lp(a). But to get everyone up to speed, Lp(a) is a major causal risk factor for atherosclerosis. On a per particle basis, it’s thought to be ~6X as atherogenic as LDL particles.

Now, two more things to know about Lp(a):

i) Its levels are largely (~90%) genetically determined
ii) There aren’t many medications or lifestyle treatments to modify Lp(a)

So, what do you do if you’re genetically cursed, like me?

Well, if you read the full letter (🔗 at the end), I promise on my own heart that you'll understand of Lp(a): what it is, why it matters, and what you can do to reduce your risk... and why I'm not panicking, despite my 165 nmol/l.

#hearthealth #lpa #ApoB #LDL #inflammation #IL6 #niacin #cardiovascularhealth #ApoE4 #HRT #oxidation #seedoils #metabolichealth #medicaleducation #meded #atherosclerosis #siRNA #

2/9) The letter will progress in 7 chapters, the first three of which I'll review in this thread:
1. Defining Lp(a)
2. Guidelines on Measuring Lp(a) & Risk Thresholds
3. Medications in Development to Lower Lp(a) 🧪
4. How to Reduce Cardiovascular Risk if you have high Lp(a) 🫀
5. How Statins Increase Lp(a) and What is Means 💊
6. Oxidized Phospholipids: The Cargo of Lp(a)
7. Nuance Notes for the Nerds 🤓: Lp(a) as an acute phase reactant, Menopause, HRT, and ApoE4

3/9) Defining Lp(a)

To understand Lp(a) you first need to understand a better-known lipoprotein particle, the "LDL particle." LDL particles are spheres that carry fat and cholesterol around the bloodstream.

A core feature of both LDL and Lp(a) is an ApoB lipoprotein that gives the particles function. In fact, the broader class of particles floating in the bloodstream that includes both LDL and Lp(a) is called ApoB-associated lipoprotein particles.

That makes sense, right?

🚨Now, here’s the critical difference between LDL and Lp(a): Lp(a) has a “tail.” 🐕

That tail is an additional protein called apolipoprotein(a) -- apo(a) in the graphic -- which is coded in your DNA by the LPA gene.

The apolipoprotein(a) “tail” attaches to the ApoB with a bond (called a “disulfide bridge” for the need-to-know nerds).

So, to quickly review: LDL and Lp(a) are both particles containing ApoB. But Lp(a) has the addition of an apolipoprotein(a) attached to the ApoB.

Terms:
👉ApoB (or ApoB100) - Major lipoprotein defining a class that includes LDL particles and Lp(a) particles
👉apolipoprotein (a) - the "tail" on Lp(a). It attaches on ApoB
👉LPA - the gene that codes for apolipoprotein (a)

Next question: What does the apolipoprotein(a) tail do?

Read 9 tweets

Nick Norwitz

@nicknorwitz

May 17

"The Science Isn't Settled" - Please read this thread to the end if you've been following the KETO-CTA "drama" ... there's a BIG surprise... 🧵💣

1/6) One thing that's become obvious to me in the past month is that social media is shaped by Selective Attention.

This thought occurred to me this morning as I was composing a reply to the first comment on this morning's #StayCurious Metabolism Newsletter about CAC Scores.

I'll copy that in (2/7) below for easier reading (pictured on the bottom left).

For what it's worth my colleagues and I cc @realDaveFeldman @AdrianSotoMota @khurramn1 et al. are not dogmatic with respect to #statins, keto, etc. nor do we ever discourage anyone #LMHR or otherwise, from thinking critically and responsibly about their own INDIVIDUAL health journey.

You'll note quite clearly that I said in the reply (and/or I've said before) that were I to be over 40 y/o (see letter for why I said 40) with a positive CAC I'd take lipid lowering medications even in the light of the KETO-CTA data where ApoB did not predict progression (rationale, below). That's not news. Now, I wouldn't do it blindly. I have my thoughtful concerns. But I would do it.

One point @PeterAttiaMD has made with which I more-or-less agree (although we certainly don't see eye-to-eye on this topic), is that the buffet of pharmaceutical options for lipid management has grown, providing more choices for patients to fit their preferences and concerns.

2/6) Here's the copy & pasted reply to the first comment. I'd highlight that this is not an outlier reply, but routine. While we are very careful not to give medical advice via social media, we do spend a tremendous amount of time trying to support people (esp #LMHR) 'caught between a rock and a hard place.'

Often, this is in private DMs, or even phone calls. The irony is I've probably spent more time indirectly helping #LMHR individuals lowering LDL/ApoB than almost all of our detractors and - I'll just call a duck a duck - trolls. This is not because I ever push the "you should" do X. But - I think - because I walk people thought the thought processes that would go through my own head.

The Copy & Pasted Reply from this AM (open to critique):

If I were in your shoes, here a few questions I'd ask myself:

1) Did keto change my LDL/ApoB? For most, this is not the case. But, in your case, certainly seems your LDL is higher on keto than vegan.

2) If 'yes' keto did increase your LDL/ApoB what is the relative contribution of fiber vs SAT/UNSAT ratio vs lipid energy model/ #LMHR physiology? You can play with these variables within a ketogenic diet, e.g. swapping butter as a cooking fat for sesame oil or avocado oil, or adding soluble fiber in the form of low-carb whole foods.

3) Do I know if your/my CAC increased on keto, or was 128 at baseline when I started keto?

4) Even if it did, e.g. if you're LMHR, do the data suggest LDL/ApoB lowering would improve risk? I'd say the data aren't clear. In our analyses (KETO-CTA), while NCPV metric specifically increased more in those with positive baseline CAC-- and with a high degree of inter-metric variability (e.g. median TPS score change was 0 -- in both those with positive and negative CAC, ApoB did not predict plaque progression. We will definitely have more to say on this over the summer and I'm sorry academic moves at the pace of a narcoleptic turtle.

5) That said, I'd also ask myself about the additional possible benefits of a given medication, e.g. anti-inflammatory effects of statins, potential effect on MPO (see other letter), etc.

6) On balance, if it were me in your shoes, I would apply the precautionary principle where possible (emphasis on "where possible," as idk if you're using a ketogenic diet therpauetically). That means, if I were >40 and had a positive CAC and was able to add carbs (e.g. going from <20g/d to 150g/d of 'healthy carbs') and/or carb cycle (see prior letter) and/or start pharmacotherapy with careful monitoring of biomarkers of personal interest (e.g. desmosterol levels were I to take a statin) that's what I would do.

3/6) I will caveat that reply, and any of my two cents on lipids and cardiovascular health, with the obvious fact that I am a 29-year-old PhD (MD PhD in 12 days! Sorry, had to drop that in there), and NOT a board certified cardiologist, nor do I have decades of experience treating patients with lipid disorders, like some of my associates from whom I have the pleasure of learning (cc @Lipoprotein @drjohnm - conversion with the latter releasing on @chadinabhan podcast soon).

While I'm certainly "enthusiastic" - @VivaLongevity accurately called me a "good promoter" on his podcast with @realDaveFeldman I hope I've been clear about what I am, and what I am not:

✅I am:
I am curious and relatively sharp, if I do say so myself. (I think I have the receipts to back that.) I also try my best to be honest and transparent (more on that in a moment).

❌I am not:
I am not a cardiologist, nor have I ever pretended to be. I'm not even a listened clinician. So I'm never giving you personal medical advice.

🤔Area of Growth and Reflection:
Another thing I am is impatient. As my mentors and friends can tell you, I sometimes "jump the gun." This had gotten me in trouble my whole life. Only now, with a more public presence (and sorry to those who don't like me, that's only going to become more pronounced with time) the stakes are raised. My actions don't just impact me, and you can choose to believe me or not, but I do spend a lot of time reflecting on how I could do better as a communicator moving forward. I've learned a lot over the past two months alone.

Read 6 tweets

Nick Norwitz

@nicknorwitz

May 17

The Power of CAC = 0: When Does LDL Matter?
(🔗to full letter at the end)
1/7) One landmark study published in the journal Circulation in 2023 followed 23,132 middle-aged people (median age 57) from the Western Denmark Heart Registry for a median follow-up of 4.3 years.

Over this time, 552 had cardiovascular events. And the researchers sought to answer the question: What predicted who would have a cardiovascular event?
But there’s more…

They broke those 23,132 participants into those who had a positive Coronary Artery Calcium (CAC) scan and those who had a CAC of 0.

🫀Among those with CAC > 0, LDL-C did predict who would have a cardiovascular event.
🫀Among those with CAC = 0, there was no association between LDL-C and cardiovascular disease events.

2/7) Here are data from Figure 1.

If CAC > 0: As LDL-C rises, the adjusted Hazard Ratio (aHR) increases. aHR is a ratio of how likely an event is to occur in one group compared to another over time.

Here, we are comparing people across LDL-C spectrum. Among those with CAC > 0, higher LDL-C has an aHR > 1 meaning higher risk of heart events and cardiovascular disease in those with higher versus those with lower LDL-C.
* “adjusted” for age, sex, smoking status and diabetes.

If CAC = 0: What you can clearly see is a flat red line at 1. This suggests higher LDL-C does not associate with higher risk of heart events and cardiovascular disease in those with CAC = 0. It provides some warranty.

What’s more, even when they took those with very high LDL-C > 193 mg/dl vs LDL-C <116 mg/dl, when CAC = 0 there was no observed benefit of having lower cholesterol (aHR = 0.95).

Ref, PMID: 36621817

3/7) The researchers also replicated these findings in an entirely separate cohort, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Notably, in this study, the median age = 62 years and median follow-up = 16.6 years.

Despite the older age and longer timeframe, the results remained the same: higher LDL-C was not associated with heart attacks or cardiovascular disease when CAC = 0.

Zooming out and summarizing: Among those with CAC = 0 in the initial population of >23,000 middle-aged adults, there was no significant association between LDL-C and heart attacks or atherosclerotic cardiovascular disease. These results were replicated in another cohort with a 16.6-year follow-up period.

Read 7 tweets

Nick Norwitz

@nicknorwitz

May 16

1/4) Today’s Video (just released) is a Microbiome Masterclass! (link at the end)
I’ll review

1️. Why your microbiome is CRUCIAL to your health

2️. How to tell if your microbiome is OUT OF BALANCE, scientifically this is called “microbiome dysbiosis,” although the answer might not be what you expect.

3️. What all those gut health BUZZWORDS actually mean—like prebiotics, probiotics, postbiotics, fermented foods, and more

4️. How to TAKE CARE OF your microbiome—including surprising ways your mind can directly influence your gut.

5️. Where THE FUTURE of microbiome science is headed…

2/4) As a teaser, in this thread, let me give you a peek from part 4, subsection 6 (How to TAKE CARE OF your microbiome: Your Mental Health Changes Your Gut Health)

While we all intuitively know our gut feeling can impact our mood, our guts and brains have a bidirectional relationship.

What I’m really trying to say is that your mind and brain can talk to your gut and influence gut and microbiome health. Let me give you 2 examples:

A recent study showed that the brain can alter levels of a molecule, indole-3-acetate (IAA), that can effectively poison stem cells in the lining of the intestines, contributing to poor gut health and gastrointestinal symptoms.

👉 Specifically, psychological stress, via activation of the fight-or-flight branch of the nervous system, causes changes in microbiome function…
👉 This increases levels of the indole-3-acetate molecule in the gut
👉 IAA harms the energy producing mitochondria in intestinal stem cells, leading to stem cell failure and contributing to poor gut health.

3/4) Another recent study found that Stress changes activity in the central amygdala which signal via the Vagus nerve from the brain to glands in the intestines called Brunner’s Glands.

Brunner’s glands secrete mucin to feed gut bacteria. And stress, via this brain-to-gut axis, inhibits Bruner’s glands starving specific gut bacteria, altering the microbiome, leading to bloating and other unfortunate symptoms.

But what does this mean practically?

Relaxation techniques, light breathing exercises, yoga, mediation, sex, and “user-specific relaxation techniques” can be a gut health hacks!

Read 4 tweets

Nick Norwitz

@nicknorwitz

May 13

Is eating keto all the time really optimal? Or should you Carb Cycle? 🥯🔄🥯

1/4) Let’s discuss “Cyclic Metabolic Switching” (CMS) Theory

The CMS posits that extended fasting (or carbohydrate restriction) sufficient to trigger the metabolic state of ketosis leads to the activation of adaptive cellular stress response pathways.

During this time, cell growth pathways—including those stimulated by the hormone insulin, and a key metabolic regulator called mTOR—are inhibited. Then, during refeeding, pathways that promote cell growth (like those downstream of insulin and mTOR) are activated

🔄This creates cycles of activation between stress response pathways and growth and development pathways.

2/4) Analogy: It’s the metabolic equivalent of a good weightlifting program: you stress your muscles to trigger adaptation. Then, you need to rest and recover—and it’s during that rest (when you eat and sleep that growth occurs.

But if you spend too much time in either phase—too much exercise with too little recovery, or too much eating and sleeping with not enough stress—your health will suffer.

🌊In general, and as a high-level truth, biology and physiology operate in ebbs and flows

3/4) That said, if you want candid my opinion: I don’t think Carb Cycling is necessary.

There aren’t conclusive data, but I strongly believe you can “hack” the Cyclic Metabolic Switch

Remember, refeeding refers to giving your body a “growth” stimulus. While the “growth” pathways are complex, one could argue that insulin is the most relevant hormone for signaling growth. And you don’t need carbs to spike insulin. Protein also spikes insulin. In fact, some proteins, like whey protein, can spike insulin quite a lot.

But don’t expect to see the same jump in blood sugar. Protein doesn’t have sugar, and protein also increases other counterbalancing hormones, like glucagon.

Still, you get a “growth” signal and insulin spike from protein. Having large enough protein can spike insulin and signal growth pathways. This is why I don’t this you need to carb cycle to activate Cyclic Metabolic Switching.

Read 4 tweets

Nick Norwitz

@nicknorwitz

May 8

1/11) Since our KETO-CTA paper was published on April 7, 2025 there has been an undeniable and conspicuous spiral of events, leading to a strong diverse set of opinions on the data.

It’s also been noted that since around April 18th, my co-authors and I have been quiet regarding criticisms rendered. I’ll speak for myself when I say this wasn’t personal my preferred approach.

However, it was the strong preference of JACC Advances that we work through the preferred academic channels – namely, by responding to Letters to the Editors passed to us from the journal. Now that we’ve done so (links at the end), I’m pleased to break my silence and speak more freely.

2/11) First and foremost, I encourage everyone to listen to this recent hour-long conversation between Dave Feldman and Chris MacAskill about the controversy.

Truthfully, I think it was among the most honest, humble, and sincere conversations my ears have ever had the pleasure of capturing.

Please start there if you’ve been following the controversy and want a grounding perspective.
youtu.be/cM0KaSp5IIE?si…

3/11) The April 7th Paper was Fully Peer-Reviewed. But it Wasn’t Perfect

Now, here are some points I’d like to make to begin to reanimate productive discussion and resolve confusions.

First, let’s get this straight, the April 7th published paper was fully peer-reviewed and approved by all the authors. That’s not in question and was previously clarified in a joint statement.

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