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Precision Medicine in Cardiology: The Role of Genomics and AI to optimize Coronary Artery Disease Treatment and Prevention
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Precision Medicine in Cardiology: The Role of Genomics and AI to optimize Coronary Artery Disease Treatment and Prevention

- Dr. Peter Kozlowski, MD

The World Health Organization (WHO) estimates that over 75% of premature cardiovascular disease (CVD) (1) is preventable… A shocking study (2) published on June 4th, 2024 said (2); “At least 6 in 10 U.S. adults (61%), more than 184 million people, are expected to have some type of CVD within the next 30 years, reflecting a disease prevalence that will have a $1.8 trillion price tag in direct and indirect costs.” Are we doing enough for our patients?

 

Coronary artery disease is frequently referred to as a “silent killer” as it can damage the heart and blood vessels, increasing the risk of heart attack, stroke, or other cardiovascular events without causing noticeable symptoms until serious complications arise. My role as a primary care physician was to provide regular medical check-ups and screenings to identify coronary artery disease at early stages to prevent cardiovascular complications. Per the American Academy of Family Practice (AAFP) U.S. Preventive Services Task Force (USPSTF) (3), they recommend screening men 35 years and women 45 years and older and older for lipid disorders. By screening, they mean a serum Lipid Panel, as they state there is good evidence (4) that high levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL) cholesterol are important risk factors for CVD. And they also recommend prescribing a statin for the primary prevention of CVD for adults aged 40 to 75 years who have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year risk of a cardiovascular event of 10% or greater. Pretty simple, but I did not come out of Family Practice Residency with a lot of tools in my tool belt.

Thanks to my mentors and training from the Institute of Functional Medicine I was taught to use advanced coronary markers;

 

 

There are more, but these are the ones that I have relied on the most throughout my career. I have seen many patients who have had a cholesterol, LDL, and HDL that would not qualify for treatment based on AAFP guidelines, but who have advanced markers out of balance that I treat. I have also seen many patients who have elevated cholesterol, LDL, and low HDL who have been told to take statins but have refused them. I have always started with advanced markers in these patients and if their advanced markers are elevated, we initiate treatment, both nutraceutical and pharmaceutical if needed. And if they are not, we plan for monitoring, while always discussing lifestyle interventions.  

 

Despite those robust evidence of the importance of these markers they are not considered mainstream and most patients who come to me have not had them done. By using the advanced markers, I believed I was doing enough, but as medicine and technology are evolving, so must we as practitioners. Besides from learning from other practitioners I think one of the greatest gifts of my career has been to learn from my patients. Due to the persistence of one of my patients. I completely evolved the way I work with cardiovascular preventative care. Let's s take a look;

 

Case Study: The Patient Who Evolved My Approach to CVD 

 

 

Primary Care Physician Workup 

 

Yearly Visit to Mayo Clinic for Executive Health Program 

 

 

Advanced Cardiac Workup 

 

 

Despite this incredibly comprehensive workup, he was not convinced and came to me asking if there was more testing that could be done. So, we ordered advanced cardiac markers and here are his results:

 

 

Based on these numbers, despite his fear, I initially agreed with the Mayo Clinic and his PCP that CV disease/cholesterol was not something he needed to worry about at this time. I reassured him we would continue to monitor his bloodwork every 6 to 12 months and intervene if needed. We discussed that he was making every lifestyle intervention he could: diet, exercise, tracking blood sugar, managing stress, etc. But not convinced he asked if there was anything else we could test.

 

Genomics 

 

I spent most of my career advising patients against genomics testing as my introduction to genomics was the MTHFR gene and the general concept that methylation SNP’s (Single Nucleotide Polymorphism’s) were the answer to everything. It didn’t make sense to me that one pathway could be the answer to all health ills. I had also seen patients who ordered popular ancestry tests and then run them through programs that would assess mostly genes related to detox. It was information overload without actionable concise steps. My general opinion on this was, why don’t we test your body for toxins? Because if you don’t have a buildup of toxins, does it really matter what your genes are?  Basically, phenotype over genotype. The world of genomics has dramatically changed since my first exposure and now I do genomic testing with all my patients if possible. There is more research, more pathways to look at, a better understanding of how genes interact with each other, and better research in how to support our patients based on their genomics. My patient understanding the risks and benefits wanted to look at his genomics, for this article we will solely focus on what we found related to his cardiac risk…

 

Cardiac Pathway (11)

 

Coagulation Pathway (12)

 

Homocysteine & Methylation Pathway (13)

 

 

 

This patient has 2 variants of IL1RL1, which is a receptor that interacts with IL33 to stop inflammation and scarring in the heart. Individuals with this variant have a form of the receptor that is essentially "floating" in the blood, rather than in the heart muscle so it is less able to stop inflammation, it is called sST2.

 

This patient had zero copies of IL33 C helps to make a molecule called interleukin 33, which can help stop cardiac inflammation when bound to the correct form of its receptor.  

 

IL1RL1 when combined with lack of benefit of IL33 conveys an almost 5 times risk (OR= 4.98) of both CAD and CHF. The reason is that this combo creates a floating or soluble form of the anti-inflammatory compound referred to in the literature as sST2.

 

He also had one variant of F5T which codes for Factor V “Leiden,” individuals with this SNP have decreased ability to stop the "coagulation cascade" once it starts. This leads to more clotting and a higher risk of blood clots in the legs as lungs. There are conflicting studies as to whether Factor V Leiden contributes to or accelerates coronary artery disease. I have listed one study which supports acceleration of coronary artery disease. I believe in this patient it did contribute to his early plaque. I find it interesting that I have had several young patients with the IL1RL1 combined with the lack of benefit of IL33, but without F5T, who did not have coronary artery disease at a young age.  

 

Lastly the patient had 5 SNPs within his methylation pathway, I do not routinely screen homocysteine but seeing his genomic report led me to checking his levels and starting supplementation support for the methylation pathway. Elevated homocysteine (14) has been found as a risk factor for coronary artery disease in numerous studies.  

 

Despite his extensive cardiovascular testing coming back without major concerns, based on his genomic profile my patient asked if there was any other testing we could do to assess his coronary artery disease phenotype.  

 

To assess his phenotype, I ordered coronary computed tomographic angiography (CCTA), the CCTA data is then run through a set of of artificial intelligence-based algorithms, to basically give us a map of the plaque in his coronary vessels. Very different than a Coronary Calcium score, as the CCTA with the AI algorithms allow us to see both calcified plaque and the non-calcified and low-density non-calcified plaques, which are the more dangerous plaques.   The SCOT HEART trial (15) showed, “the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization.” Please see his image below.  

 

 

A close-up of an ultrasound Description automatically generated

 

 

Stage 1 (43.2 mm3 Total Plaque: 0.7 mm3 Low-Density - Non-Calcified, 42.5 mm3 Non-Calcified, 0 mm3 Calcified. 30% stenosis of the left anterior descending artery (LAD).  

 

Phenotypically he had the most dangerous plaque in the most dangerous place, the LAD is frequently referred to as the “widow maker.” Remember his grandfather and great grandfather?  

 

We were now in agreement that he required aggressive treatment.  

 

When reviewing treatment options I came across a study (16) which showed a cardiovascular relative risk reduction of 31% using Colchicine. In June 2023 (17), the U.S. Food and Drug Administration approved the use of low-dose colchicine to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease. Colchicine is a gout drug… but colchicine is believed to be cardioprotective because it blocks inflammation… Remember his SNP’s?

 

“This patient has 2 variants of IL1RL1, which is a receptor that interacts with IL33 to stop inflammation and scarring in the heart. Individuals with this variant have a form of the receptor that is essentially "floating" in the blood, rather than in the heart muscle so it is less able to stop inflammation.

 

This patient had zero copies of IL33 C helps to make a molecule called interleukin 33, which can help stop cardiac inflammation when bound to the correct form of its receptor.”

 

He has a reduced ability genetically to turn off cardiac inflammation… colchicine turns off cardiac inflammation… Truly personalized medicine. There are current studies in trial to test whether colchicine lowers sST2 (18).  

 

To further optimize his care, we went back to his genomics and created a personalized treatment plan;

 

Lower IL1RL1-mediated Inflammation:

 

•Colchicine 0.6mg PO QOD – sST2 (IL1RL1 and IL1B)

•Sulforaphane 0.1-0.5mg/kg QD (19)

•Berberine 500mg QD (20)

•Resolvins/SPMs (21)

•EGCG 500mg QD (22)

•Curcumin 1g QD (23)

•Quercetin 1g QD (24)

 

Anticoagulants (F5 T 1 variant)

 

 

•Nattokinase 100mg BID – F5 and has cardiac outcomes (25)

•Pycnogenol 100mg BID – F5 (26)

 

The goal is to remain on this regimen for 12 months, while monitoring liver and kidney function due to the colchicine, and then repeat CCTA. 4 months after initiating care the patient went back to the Mayo Clinic for another executive workup and had already seen an improvement in cardiovascular markers. No changes were made, but the consideration to add/change to a statin is in consideration pending results after 12 months.  

 

Discussion  

 

I believe this is the future of medicine happening today, the ability to use genomics and AI to truly personalize cardiovascular prevention. We were able to use genomics to stratify risk, use AI for diagnosis, and use genomics again to truly personalize care.  

 

This was the first case in my career where I believe genomics outweighed lifestyle and environment, this is a young male living extreme healthy lifestyle who ended up with coronary disease at a young age despite his best efforts.  

 

We could have started with the CCTA before the genomics however the patient was concerned over the radiation with CCTA, so it was his genomics that made him decide the risk of undiagnosed coronary artery disease outweighed the risk of radiation from CCTA.  

 

Working with genomics has been the most difficult tool I have added to my tool belt, there is a lot of information, it doesn't always match up, it can create extra stress, we do not express all of our genes, but when used properly I believe it is the most important testing I have added for my patients. It can help aid in prevention but also help guide treatment if disease has onset.  

 

We have so many tools available to us to support our patients and I believe that we as Functional Medicine practitioners need to continue be part of the solution to move healthcare forward.

 

 

Dr. Peter Kozlowski, MD, is a renowned functional medicine practitioner and speaker specializing in personalized approaches to chronic disease. He is the author of Unfunc Your Gut, where he emphasizes the connection between gut health and overall wellness, and Get the Func Out, where he explores the connection between the alarming rise of hormonal imbalances due to environmental toxins, along with offering detox strategies. Dr. Kozlowski is highly regarded for his personalized patient care and commitment to promoting optimal health and well-being.

 

 

 

 

 

 

 

 

 

 

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