Prevention of Coronary Heart Disease: The Importance of Imaging and Advanced Biomarkers

Although a healthy diet and lifestyle are key factors in reducing atherosclerotic cardiovascular disease (ASCVD) and atrial fibrillation not all cardiovascular disease is related to lifestyle. Some individuals, no matter how dedicated to the prevention of their ancestor’s fate, cannot escape what the skeptical cardiologist has termed “the cardiovascular cards you are dealt.“

The story of my friend’s wife, “Lisa”, which I described in a 2014 post exemplifies this. At the age of 58, she had undergone a coronary artery calcium scan suggested by me. The calcium score was alarmingly high. Most women her age have no build-up of calcified plaque in their coronary arteries: a zero CAC score is expected.

We can enter Lisa’s numbers into the online MESA calculator to see how she compares to other white 59 year old women. The calculator tells us that 72% of her peers have a zero calcium score and a score of 208  is higher than 95% of her peers. Although the 95th percentile is a good place to be for SAT scores it is not for atherosclerosis. This means substantial amount of fatty and calcififed atherosclerotic plaque has built up in the arteries and puts the individual at significantly greater risk for heart attack and stroke. A calcium score of 100-300 confers a 7.7 times increased risk compared to an individual with similar risk factors with a zero calcium score.

The only clue that Lisa might be at risk for advanced premature ASCVD was that her mom at the age of 62 had suffered a heart attack and had a stent placed in one of her coronary arteries.

The occurrence of significant premature ASCVD in a parent or sibling substantially increases the chances that a patient will have premature ASCVD and the earlier it occurred in the parent or sibling the higher the risk.
Some of this excess risk is transmitted by measurable risk factors such as hypertension and hyperlipidemia and some through lifestyle factors but the majority of it is through genetic factors that haven’t been fully identified.

How much of an individual’s risk for heart attack  is determined by genetics versus lifestyle?

When I’m seeing a patient for the first time, I take a detailed family history. I want to know if the patient’s parents or siblings (first degree relatives) had any heart disease or died unexpectedly at an early age. A history of heart attack, coronary stents or bypass surgery, especially if onset was prior to age 65 years in these first degree relatives increases the risk of such events in my patient.

I am particularly interested in sudden unexpected death in the family.

Some of this increased family risk arises from shared lifestyle factors like cigarette smoking but a substantial amount is inherited.

A large Swedish study found that adopted men and women with at least one biological parent with coronary heart disease (CHD) were 1.5 times more likely to have CHD than adoptees without. In contrast, men and women with one adoptive parent with CHD were not at increased risk.

Since 2007 an intense project to identify genetic factors responsible for CAD has been underway at multiple academic centers and common genetic variants at >150 loci have now been found which associated with higher risk of CAD. They account for around 35% of the heritability of cardiovascular disease. A subset of these loci harbor genes that modify CAD risk based on their associations with traditional cardiovascular risk factors (such as low-density lipoprotein cholesterol and blood pressure), but the mechanism of association with CAD is unknown for most genes.

In 2014 only 50 genetic variants had been identified and I quoted Dr. Robert Roberts:

” All of these risk variants are extremely common with more than half occurring in >50% of the general population. They increased only minimally the relative risk for coronary artery disease. The most striking finding is that 35 of the 50 risk variants act independently of known risk factors, indicating there are several pathways yet to be appreciated, contributing to the pathogenesis of coronary atherosclerosis and myocardial infarction. All of the genetic variants seem to act through atherosclerosis, except for the ABO blood groups, which show that A and B are associated with increased risk for myocardial infarction, mediated by a prolonged von Willebrand plasma half life leading to thrombosis”

Polygenetic risk scores slightly improve CHD risk estimation over standard risk factors but they are not useful yet in clinical practice.

In 2019 I wrote about Eric Topol’s My Gene Rank app which took my 23 and Me genetic data and gave me a very high-risk score. Fortunately, I knew this to be inaccurate as I had undergone CAC and coronary CT angiogram testing which demonstrated that my coronaries had less atherosclerosis than the average man my age.

Topol stated that he had never ordered a calcium scan because “there are so many patients who have been disabled by the results of their calcium score even though they have no symptoms.” Ironically, he was taking a statin drug because of his own high MyGeneRank score (which presumably disabled him.)

Identifying High Risk Individuals Early to Prevent Heart Disease

Our job as preventive cardiologists is to identify those at high risk for ASCVD and lead them to lifestyle choices and medicine that dramatically lowers that risk.  We educate them that the large build-up of subclinical atherosclerosis we identified does not have to result in sudden death, crippling heart attacks, or strokes. We reassure them that with the right tools we can help them live a long, productive, healthy and happy life.

The standard approach to estimating ASCVD risk fails in about 25% of individuals as it does not accurately convey the high risk of the patient with family history and it overestimates risk in many elderly individuals who have an excellent family history.
It is in these patients that testing for the actual presence of atherosclerosis, either by vascular screening or coronary calcium is helpful.

The 2018 ACC/AHA guidelines recognize other “risk-enhancing factors.”

Interestingly the guidelines include ABI (which I do not find helpful) but not carotid vascular screening which has frequently guided me to earlier therapy in youngish individuals with abnormal biomarkers or strong family history.
Vascular screening in young subjects may detect subclinical atherosclerosis as measured by thickening of the carotid wall (IMT) or early carotid plaque prior to the formation of calcium in the coronary arteries. Advanced IMT precedes the formation of soft plaque in arteries and only later is calcium deposited in the plaque.
It’s never too early to start thinking about your risk of cardiovascular disease. If heart disease runs in your family or you have any of the “risk-enhancing” factors listed above, consider a CAC, nontraditional lipid/biomarkers, or vascular screening to better determine where you stand and what you can do about it.

Clearly, family history of premature ASCVD is important but the devil is in the details. What relatives count? What was the event in the family member? If it was sudden death was an autopsy done? What lifestyle risk factors played a role?

These confounding variables make it essential that patients potentially at risk due to strong family history be assessed with both atherosclerotic imaging and advanced lipid biomarkers.

Nontraditional Lipid biomarkers?

Simultaneous with assessing these patients for subclinical atherosclerosis with imaging techniques I check three key biomarkers

1. Lipoprotein (a) (a highly atherogenic, inherited marker that is not measured in standard lipid panels)
2. Apolipoprotein B (apoB, now recognized as our single best measure of atherogenic dyslipidemia)
3. High-sensitivity CRP (the most studied and useful measure of inflammation)

An apoB particle is the basic unit of injury to the arterial wall. The more apoB particles within the lumen of the artery, the greater the trapping of apoB particles within the arterial wall, the greater the injury to the arterial wall. The more apoB particles are reduced by therapy, the less the injury to the arterial wall, the greater the opportunity for healing. Moreover, nowadays apoB can be measured accurately and inexpensively.^67–69 Thus, apoB integrates the information from the conventional lipid panel and, therefore, unifies, amplifies, and simplifies our understanding of the role of the apoB lipoprotein particles in atherogenesis.

Reducing The Excess Risk of Premature CAD

For many individuals there are clear-cut lifestyle changes that can be implemented once advanced CAD is identified: cigarette smoking cessation, weight loss through combinations of diet and exercise with resulting control of diabetes, However, many patients like Lisa, are non-smokers, living a good lifestyle by exercising regularly, eating an excellent diet with plenty of fresh fruit, vegetables, fish and healthy oils and without obesity or diabetes. There is no evidence that modifying lifestyle in this group is going to slow down an already advanced progression of atherosclerosis.

Patients like Lisa have inherited predisposition to CAD, it is not due to their lifestyle.
Lisa’s cardiologist  suggested she get a copy of Dr. Esselstyn’s book “Prevent and Reverse Heart Disease”. This book, based on the author’s experience in treating 18 patients with advanced CAD espouses an ultra low fat diet. Esselstyn declares that “you may not eat anything with a face or a mother (meat/poultry/fish)” and bans full-fat dairy products and all oil (“not even a drop”)
Such “plant-based diets” (often a codeword for vegan or vegetarianism) lack good scientific studies supporting efficacy (see my posts here and here) and are extremely hard to maintain long term. There is nothing to suggest that Lisa’s long-term risk of heart attack and stroke would be modified by following such a Spartan dietary regimen.

Her cardiologist did recommend two things proven to be beneficial in patients with documented advanced CAD: statins and aspirin.

Taking a statin drug will arrest the atherosclerotic process and substantially reduce lifetime risk of heart attack and stroke as I’ve discussed here and here.
An aspirin is now indicated since significant atherosclerosis has now been documented to be present as I’ve discussed here.

Looking at Lisa Seven Years Later

In the world of preventive cardiology we measure success by the major cardiovascular events that didn’t happen. This might seem boring or unrewarding and probably explains why so many bright and dynamic cardiologists gravitate toward invasive and interventional subspecialties which produce immediate and dramatic results in patients.

I checked in with Lisa recently. She has done very well, cardiac-wise. She was started on rosuvastatin and an aspirin. Her lipids substantially improved. She developed myalgias on a higher dosage rosuvastatin and now takes 10 mg alternating with 5 mg plus 10 mg ezetimibe to reach goal levels of atherogenic dyslipidemic particles without any side effects.

Unlike her mother, she did not suffer a heart attack or require a stent in her early sixties and likely never will.

Unfortunately, I see far too many patients these days who suffered their heart attacks, stents or coronary bypass surgeries in their 40s or 50s like one of their parents because their premature build-up of atherosclerotic plaque and high risk was not identified early on. I also hear from patients regularly that a close member has dropped dead suddenly or suffered a heart attack.

Seeing patients for the first time after their ASCVD event or hearing of friends, relatives, colleagues who have dropped dead suddenly saddens me immensely. A great opportunity to prevent misery and death was missed.

Included in my discussions with my patients with premature ASCVD, therefore, is a strong recommendation to encourage their brothers, sisters, and children to undergo a thoughtful assessment for ASCVD risk.

Also, although I’m reluctant to pry into the health and family history of casual acquaintances, I’ve started trying to make sure nearly everyone I speak with is aware of the need to be proactive about identifying their risk of ASCVD and taking appropriate measures.

We can blame a lot of heart disease on lifestyle: poor diets and lack of exercise are huge factors leading to obesity, diabetes, hypertension and hyperlipidemia, but in many patients I see who develop heart disease at an early age, lifestyle is not the issue, it is the genetic cards that they have been dealt.
Until we develop reliable genetic methods for identifying all those at high risk it makes sense to utilize methods such as vascular screening or coronary calcium to look for atherosclerosis in individuals with a family history of premature CAD.
Once advanced atherosclerosis is identified, we have extremely safe and effective medications that can help  individuals like Lisa deal with the cardiovascular cards they have been dealt.

Unexpectedly Yours,

-ACP