The New Science of Heart Health: Biomarkers That Predict Cardiac Events Years Before Symptoms

Beyond Basic Blood Work: A Systems Approach to Cardiac Risk Assessment

Lately, there's been a spirited debate among health experts on social media about the "best" test for assessing cardiac risk. These conversations miss a fundamental truth: the human body is not a collection of isolated biomarkers, but a complex adaptive system. Relying on a single lab value, no matter how insightful, is inherently reductionistic. To truly understand cardiovascular health, we need to look beyond individual tests and explore how multiple systems, metabolic, inflammatory, hormonal, and more, interconnect and influence heart health. Let's look at integrative approaches that provide a more complete picture of your cardiac health.

Why Traditional Heart Risk Assessment Falls Short

The conventional approach to heart disease risk often relies too heavily on isolated biomarkers like Total cholesterol or LDL cholesterol. This misses the complex interplay of physiological, psychological, social, and environmental factors that contribute to cardiovascular health.

Take stress, which is not a simple biochemical reaction or a psychological state, but a complex, systemic phenomenon. Similarly, heart disease risk must be understood through multiple lenses to create truly effective prevention strategies.

Advanced Lipid Markers: Moving Beyond Basic Cholesterol

ApoB: The Rising Star in Cardiovascular Risk Assessment

Apolipoprotein B (ApoB), Apolipoprotein A1(ApoA1), and the ApoA1 to ApoB ratio are increasingly recognized as a superior biomarkers for assessing cardiovascular risk compared to traditional cholesterol measures like LDL-C. Leading lipidologists and researchers have been arguing that ApoB is a more accurate measure of atherogenic lipoproteins than LDL-C, non-HDL-C, or even LDL particle count (LDL-P).

Others, such as Dr. Peter Attia, have also shifted their clinical practice to rely more on ApoB, citing its ability to capture all atherogenic particles, not just LDL.

Why does this matter? Because ApoB measures ALL potentially harmful cholesterol-carrying particles, not just LDL. Each atherogenic particle contains exactly one ApoB molecule, making it a precise count of your total atherogenic burden.

LDL-P: Particle Number Over Concentration

LDL particle number (LDL-P) is promoted as a key or even superior marker for cardiovascular risk by several groups and experts, particularly in cases where traditional cholesterol measures (like LDL-C) may be misleading.

Many lipid experts highlight that LDL-P may be a stronger predictor of cardiovascular events than LDL-C, especially in cases of discordance (where LDL-C and LDL-P do not match). The Framingham Offspring Study and the Multi-Ethnic Study of Atherosclerosis (MESA) both found that high LDL-P predicted more cardiovascular events, even when LDL-C was low.

Why this matters: You can have "normal" LDL cholesterol but a high number of small, dense LDL particles that are more likely to penetrate arterial walls and cause plaque. This is especially common in people with:

• Insulin resistance

• Metabolic syndrome

• Type 2 diabetes

• Obesity

• High triglycerides with low HDL

Lipoprotein(a): The Hidden Cardiovascular Risk Factor

Lipoprotein(a), or Lp(a), is a specialized form of LDL that's largely determined by genetics and is increasingly recognized as an independent risk factor for cardiovascular disease. What makes Lp(a) particularly concerning:

• Elevated levels increase risk of heart attack, stroke, and aortic valve stenosis

• It's not measured in standard lipid panels and often goes undetected

• Levels are primarily determined by genetics and remain relatively stable throughout life

• Up to 20% of the population has elevated levels, many without knowing it

• Standard cholesterol-lowering medications like statins have minimal effect on Lp(a)

Testing and Intervention: Lp(a) should be measured at least once in everyone's lifetime, particularly those with:

• Family history of premature cardiovascular disease

• Personal history of cardiovascular disease without traditional risk factors

• Recurrent cardiovascular events despite optimal lipid-lowering therapy

• Familial hypercholesterolemia

While treatment options specifically targeting Lp(a) are still emerging, knowing your level can influence overall risk management strategies and the aggressiveness of treatment for other risk factors. I have experienced good lowering of Lp(a) using higher doses of omega-3 supplements.

Ceramides: Emerging Lipid Biomarkers

Ceramides are bioactive lipids that have recently emerged as important predictors of cardiovascular events and mortality. These lipid molecules are involved in inflammation-related signaling and play a crucial role in cellular function.

What makes ceramides valuable as biomarkers:

• Ceramide ratios (particularly Cer(d18:1/18:0)/Cer(d18:1/24:0)) may predict cardiovascular events independently of traditional risk factors

• They appear to improve risk prediction beyond LDL-C and have been implemented for clinical use at major medical centers

• Elevated ceramides have been associated with a 3-5 fold increase in cardiovascular events in multiple studies

• The relationship between ceramides and cardiovascular outcomes appears to be linear, unlike the U-shaped relationship sometimes seen with LDL-C

• They may help identify residual cardiovascular risk in patients with well-controlled traditional risk factors

Testing for ceramides may be particularly valuable in patients with complex lipid profiles, discordances between traditional risk markers, or those with metabolic disorders where standard risk assessment may underestimate actual risk.

Advanced Imaging: Seeing What Blood Tests Can't Show

CCTA with AI Enhancement: The Future of Risk Assessment

CLEERLY is an FDA-cleared, AI-driven platform that analyzes coronary computed tomography angiography (CCTA) images, to identify, quantify, and characterize coronary artery plaque, stenosis, and ischemia. CCTA is sometimes referred to as calcium score. Its goal is to provide a comprehensive, non-invasive assessment of coronary artery disease (CAD) to help predict heart attack risk and guide personalized treatment strategies.

CaRi-Heart is another AI-enabled cardiac analysis platform, developed by Caristo Diagnostics, that uses CCTA imaging to assess coronary inflammation, a key driver of atherosclerosis and plaque vulnerability. The CaRi-Heart analysis provides a "CaRi-Heart Risk Score" based on perivascular fat attenuation index (FAI), which reflects coronary inflammation and predicts future cardiac events.

These advanced imaging technologies go beyond simply measuring plaque buildup to assess:

• Plaque composition (calcified vs. soft, vulnerable plaque)

• Inflammatory activity around the arteries – this is a strong early predictor of the start of plaque formation and when increased around existing plaques, is a predictor of impending rupture

• Early signs of disease before symptoms appear

I have been using the CLEERLY scan in my practice for the past two years and getting great clinical insights. I am excited to begin using the CaRi-Heart now that it is approved in the US because inflammation is a huge risk factor, and if you want to read the summary of the ORFAN Study, you can find it HERE, it was quite convincing for me that this is the high priority test.

Inflammation and Oxidative Stress Markers

Since inflammation plays a central role in heart disease, these markers can give valuable insights:

• High-sensitivity C-reactive protein (hsCRP): A marker of systemic inflammation

• Myeloperoxidase (MPO): Indicates oxidative stress in blood vessels

• Lipoprotein-associated phospholipase A2 (Lp-PLA2): Reflects inflammation specifically in blood vessels

• Oxidized LDL: Measures the actual oxidized particles that trigger plaque formation

Nutritional and Metabolic Markers

• Homocysteine: Elevated levels suggest B-vitamin deficiencies and increased heart risk

• HbA1c and fasting insulin: Measures glucose control and insulin resistance

• Omega-3 Index: Assesses levels of heart-protective omega-3 fatty acids

• CoQ10 levels: Important for heart muscle function, often depleted by statin medications

Nitric Oxide Pathway Markers

ADMA: Endothelial Function and Cardiovascular Risk

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase that has emerged as an important marker of cardiovascular risk. By inhibiting the production of nitric oxide (NO), ADMA can impair endothelial function, leading to vasoconstriction and potentially contributing to atherosclerosis.

Key points about ADMA:

• Elevated levels have been associated with increased risk of cardiovascular events and mortality

• It's been linked to conditions including hypertension, hypercholesterolemia, diabetes, chronic kidney disease, and heart failure

• In prospective studies, ADMA has predicted cardiovascular events independently of traditional risk factors

• It provides insight into endothelial dysfunction, which often precedes overt cardiovascular disease

• May help explain the "L-arginine paradox" in cardiovascular disease

Homoarginine: A Protective Cardiovascular Marker

Unlike many biomarkers where elevated levels indicate increased risk, homoarginine (hArg) shows an inverse relationship with cardiovascular events – lower levels predict higher risk. This endogenous, non-proteinogenic amino acid differs from arginine by an additional methylene group and may impact nitric oxide synthesis.

Important aspects of homoarginine:

• Low homoarginine levels have been associated with increased risk of cardiovascular events and mortality in multiple studies

• The relationship is particularly strong in patients with impaired kidney function

• Low levels correlate with heart failure and left ventricular dysfunction

• May serve as a marker of previously unrecognized pathophysiological processes

• Potential supplementation with homoarginine is being explored as a therapeutic approach

Muscle and Metabolic Markers

3-Methylhistidine: A Marker of Muscle Metabolism and Cardiovascular Risk

3-Methylhistidine (3-MH) is a byproduct of muscle protein breakdown that has shown intriguing relationships with cardiovascular health. While traditionally used to assess skeletal muscle turnover, recent research suggests it may have important implications for cardiovascular risk assessment.

Key findings about 3-MH:

• Low serum 3-MH levels have been associated with increased cardiovascular event risk in certain populations, particularly hemodialysis patients

• It appears to be a marker of better lean tissue mass and nutritional status when elevated

• Low 3-MH has been linked to arterial stiffness, a key factor in cardiovascular disease

• The exact mechanism linking 3-MH to cardiovascular outcomes is still being investigated

• May provide insights into the connection between muscle metabolism and cardiovascular health

Succinate: Metabolic Signaling and Cardiovascular Function

Succinate is a metabolic intermediate in the Krebs cycle that has emerged as an important signaling molecule in cardiovascular health and disease. Under normal conditions, succinate levels are tightly regulated, but during stress conditions like ischemia, levels can rise dramatically.

Important aspects of succinate in cardiovascular health:

• Elevated plasma succinate has been associated with hypertension and metabolic disorders

• During myocardial ischemia, succinate accumulation contributes to reperfusion injury

• It serves as a signal for inflammation and may contribute to atherosclerosis

• May provide a link between metabolic dysfunction and cardiovascular disease

• Emerging as a potential therapeutic target for cardiovascular protection

The Physical Domain: Beyond Blood Tests

VO₂ Max: The Ultimate Fitness Biomarker

VO₂ max is the maximum amount of oxygen your body can utilize during intense exercise and is one of the most powerful predictors of cardiovascular health and longevity. Here's why VO₂ max is important:

• Powerful predictor: Research shows VO₂ max is a stronger predictor of mortality than traditional risk factors like smoking, hypertension, or diabetes

• Early warning system: Decline in VO₂ max can precede other signs of cardiovascular disease

• Personalized exercise prescription: Knowing your VO₂ max allows for targeted exercise programming to improve cardiorespiratory fitness

• Objective measure: Provides a quantifiable baseline and goal for fitness improvement

• Holistic biomarker: Reflects the integrated function of multiple physiological systems; cardiovascular, respiratory, muscular, and metabolic

Testing methods:

• Gold standard: Cardiopulmonary exercise test (CPET) in a clinical setting with respiratory gas analysis

• Field tests: Submaximal exercise tests like the Cooper 12-minute run or Rockport walking test

• Wearable technology: Fitness watches (Garmin) and rings (Oūra, Ultrhuman) now provide estimated VO₂ max values

One of my favorite devices is the Calibre, a simple and accurate home device that can measure your VO₂ max in as little as six minutes. For under $500 you can use this device to watch your number on a regular basis. We use this in our clinic to test VO₂ max as well as resting metabolic rate (RMR) and we can link our dashboard to our clients device and monitor changes over time.

Even modest improvements in VO₂ max (10-15%) can significantly reduce cardiovascular risk, making this an actionable metric for both assessment and intervention.

Other valuable physical assessments include:

• Heart Rate Variability (HRV): Measures autonomic nervous system balance and resilience

• Endothelial function testing: Assesses the health of your arterial lining

• Sleep quality assessment: Poor sleep is linked to increased cardiovascular risk

The Psychological and Social Domains

We are wired for connection. Social bonds serve as one of the most powerful regulators of stress physiology, buffering against the effects of adversity. Conversely, social isolation, relationship conflict, and community breakdown can amplify stress reactivity.

Psychosocial factors that significantly impact heart health include:

• Chronic stress levels

• Social connection vs. isolation

• Sense of purpose and meaning

• Depression and anxiety screening

Environmental Domain

Environmental factors represent a significant, yet often overlooked, driver of cardiovascular disease, with research that shows exposure to outdoor and indoor air pollution, temperature extremes, second-hand smoke, and heavy metal overload collectively contribute to more than 18% of all cardiovascular-related deaths across Europe.

Action Steps for Holistic Heart Health

• Request comprehensive testing: Beyond basic lipids, ask for ApoB, LDL-P, Lp(a), and inflammatory markers

• Consider advanced imaging: Especially if you have family history or other risk factors, even with "normal" lipids

• Assess your cardiorespiratory fitness: VO₂ max testing provides valuable insight into overall cardiovascular health

• Monitor stress physiology: HRV monitoring and cortisol testing can reveal how stress impacts your cardiovascular system

• Evaluate sleep quality: Poor sleep significantly increases heart risk through multiple pathways

• Build social connections: Strong relationships buffer physiological stress and improve heart outcomes

• Find purpose and meaning: The spiritual domain impacts physical health through multiple mechanisms

Remember that heart disease begins in your 20’s, many years before the first symptoms. A truly holistic approach detects imbalances early, when lifestyle interventions can make the most difference, and considers all dimensions of health; physical, psychological, social, environmental, and spiritual.

By understanding your cardiovascular health through these multiple lenses, you can develop a personalized prevention strategy that addresses the root causes of heart disease, not just the symptoms.