PLMI Blog

Atherosclerotic cardiovascular disease (ASCVD) remains a leading global cause of morbidity and mortality, with prevalence projected to rise nearly 90% by 2050 (1–2). Conventional medicine often intervenes when symptoms are overt or a diagnosis is confirmed—addressing hypertension, dyslipidemia, or other risk factors once they surface—overlooking upstream biological stressors that drive vascular dysfunction years before symptoms appear.

Early detection and prevention require understanding the interplay between inherited traits, environmental exposures, and emerging biomarkers.

Advanced biomarkers, including hs-CRP, oxidized lipids, myeloperoxidase (MPO), lipoprotein(a), fasting insulin, uric acid, and homocysteine, provide an earlier, more comprehensive view of cardiometabolic stress. When interpreted through a functional medicine lens, they identify root drivers, quantify disease trajectory, and inform personalized prevention strategies.

Evolutionary Roots of Cardiometabolic Risk

Human biology evolved under conditions of intermittent food scarcity, frequent infection, high physical activity, and restorative rest within strong social networks. Traits that once promoted survival—efficient fat storage, robust inflammatory responses, and thrifty glucose metabolism—now fuel obesity, insulin resistance, and atherosclerotic cardiovascular disease (ASCVD) in modern environments marked by sedentary behavior, chronic stress, and surplus ultra-processed foods. This evolutionary perspective explains why early biomarker assessment is essential: it reveals how adaptive mechanisms have become vulnerabilities in today’s mismatched lifestyle context.

Key evolutionary insights clarify why early biomarker assessment is valuable:

• Thrifty genotype: Genes promoting energy storage conferred survival advantages during periods of famine but now predispose one to diabetes, dyslipidemia, and ASCVD in environments of caloric abundance (3).
• Mismatch theory: Rapid environmental changes create an imbalance between inherited traits and modern lifestyles, turning previously adaptive mechanisms into drivers of noncommunicable disease (4–6).
• Antagonistic pleiotropy: The APOE ε4 allele enhances immune defense and metabolic resilience in early life, supporting survival under infectious and nutrient-scarce conditions. However, this same variant accelerates lipid dysregulation, neuroinflammation, and vascular injury with age, increasing risk for ASCVD and Alzheimer’s disease (7–9).
• Neu5Gc & inflammation: Humans lost the CMAH enzyme during evolution, preventing endogenous Neu5Gc synthesis. Neu5Gc—a sugar found in red meat—can be incorporated into vascular tissues, triggering chronic inflammation and immune activation. Grass-fed meat has a healthier fatty acid profile but still contains Neu5Gc, which digestive enzymes only partially degrade. Moderating red meat intake while emphasizing anti-inflammatory, fiber- and omega-3–rich diets helps reduce vascular and metabolic risk.

By integrating advanced biomarkers, functional medicine detects early metabolic and vascular stress, enabling personalized interventions that align modern lifestyle with our biology to optimize long-term cardiovascular health.

Modern Environmental Impacts

These evolutionary vulnerabilities are exacerbated by contemporary environmental and lifestyle stressors:

Circadian rhythm disruption: Artificial light exposure, irregular schedules, and insufficient sleep disturb metabolic, hormonal, vascular, and gut microbiome rhythms. Aligning daily patterns with natural light cycles—rising with the sun, obtaining morning sunlight, incorporating regular movement, and maintaining consistent sleep—supports homeostasis, hormonal balance, and cardiovascular regulation.

Reduced exposure to nature: Limited time outdoors diminishes physiological recovery, immune regulation, and stress resilience. Immersion in natural environments has been shown to lower inflammation, reduce cortisol, and promote immune balance—factors that are directly relevant to cardiovascular and metabolic health.

Chronic stress & sedentary behaviors: Persistent sympathetic activation from chronic psychological stress, prolonged screen time, and sedentary lifestyles drives systemic inflammation, metabolic dysregulation, and vascular dysfunction. Coupled with frequent consumption of ultra-processed foods, these factors accelerate the development of ASCVD. These connections further underscore the value in stress resolution techniques (somatic modalities), consuming whole, nutrient-dense foods, and remaining mindful of our relationship with stress—grounding into what is in our control.

Collectively, ancestral biology and modern exposures create upstream metabolic and vascular stress that often precedes disease by years. Advanced biomarkers provide early detection, allowing clinicians to intervene at the underlying root systems level rather than waiting for more overt symptoms to emerge.

Integrating Biomarkers into Prevention

ASCVD is not random but a predictable outcome of ancestral biology interacting with a mismatched modern environment. Advanced laboratory markers make these hidden processes visible, offering actionable insights for precision prevention. By detecting metabolic and vascular stress early, clinicians can tailor interventions—ranging from lifestyle optimization and circadian alignment to metabolic support and targeted nutrition—to correct root imbalances and protect long-term cardiovascular health.

ADVANCED LABORATORY MARKERS IN FOCUS

Lipids – Traditional lipid panels remain foundational, but non-traditional lipid indices—ratios and calculated markers that capture interactions among LDL, HDL, and triglycerides—provide greater risk resolution. Gaggini et al. (2022) found that these indices better reflect lipid-driven inflammation and enable earlier identification of high-risk hyperlipidemic patients (12). Notably, elevated remnant cholesterol and abnormal LDL particle size correlate strongly with early atherosclerotic changes, even when total LDL levels appear normal.

High-Sensitivity C-Reactive Protein (hs-CRP) – High-sensitivity C-reactive protein (hs-CRP) is a well-validated marker of systemic inflammation linked to atherosclerotic cardiovascular disease (ASCVD) (13–14). Elevated hs-CRP predicts first and recurrent cardiovascular events, independent of LDL-cholesterol. Clinical trials show its preventive value: rosuvastatin lowered major events in individuals with high hs-CRP despite normal LDL, and canakinumab reduced recurrent events by targeting interleukin-1β–driven inflammation (15–16).

As a non-specific marker influenced by infection, obesity, and autoimmune conditions, hs-CRP should be interpreted in context. Guidelines classify it as a risk-enhancer, useful for refining cardiovascular risk—especially in intermediate-risk patients—though routine population screening is not recommended. Interpreted alongside other risk factors, hs-CRP helps guide early preventive strategies.

Oxidized Lipids – Oxidized LDL (oxLDL) directly drives endothelial injury, foam cell formation, and plaque progression. A 2023 meta-analysis by Hong et al. found that oxLDL was significantly elevated in patients with chronic inflammatory diseases who developed ASCVD. This supports its role as an early marker of oxidative vascular damage, detecting stress before structural atherosclerosis becomes evident (17).

Myeloperoxidase (MPO) – Myeloperoxidase (MPO), released primarily from activated neutrophils and monocytes, catalyzes the formation of reactive oxidants that drive LDL oxidation and endothelial dysfunction. Elevated circulating MPO levels have been consistently associated with plaque instability, acute coronary syndromes, and increased cardiovascular mortality. Experimental studies demonstrate that MPO inhibition reduces atherosclerosis progression in animal models, suggesting MPO functions not only as a biomarker but also as a potential therapeutic target. Clinically, MPO measurement may help identify patients with rupture-prone plaques and heightened near-term cardiovascular risk, providing an opportunity for earlier preventive intervention (18).

Lipoprotein(a)  – Lp(a) is primarily genetically determined and tends to remain relatively stable, making it a persistent cardiovascular risk factor. Elevated Lp(a) promotes atherosclerosis through both pro-inflammatory and pro-thrombotic pathways. Research underscores its clinical significance: Della Corte (2023) highlighted its strong independent association with coronary and valvular disease, while Parcha (2025) advocates for routine early testing in preventive care. Although largely inherited, lifestyle, epigenetic, and metabolic factors may modulate its impact.

Early identification allows clinicians to implement targeted interventions, optimize modifiable risk factors, and provide personalized counseling about inherited cardiovascular risk (19–20).

Fasting Insulin – Fasting insulin often rises years before overt diabetes, making it a valuable marker of early insulin resistance and cardiometabolic stress. Di Pino & DeFronzo (2019) demonstrated that hyperinsulinemia contributes to unexplained cardiovascular risk in type 2 diabetes—even when LDL, blood pressure, and clotting risk are managed. This highlights its role in detecting upstream dysfunction, where early lifestyle interventions can reverse risk before structural vascular damage occurs (21).

Uric Acid – Traditionally linked to gout, uric acid is now recognized as a vascular stress marker. NHANES cohort data revealed a U-shaped association: both low and high serum uric acid levels increased ASCVD and mortality risk (22). Elevated uric acid promotes endothelial dysfunction, oxidative stress, and insulin resistance—processes detectable well before clinical ASCVD events. Identifying abnormal uric acid levels can prompt early dietary and metabolic interventions.

Homocysteine – Homocysteine (tHcy) exerts direct toxicity on endothelial cells, promoting vascular injury. In a 2024 Multi-Ethnic Study of Atherosclerosis (MESA) study, elevated homocysteine independently predicted ASCVD events, and when combined with hs-CRP and Lp(a), doubled the risk for CHD and nearly tripled stroke risk (23). A previous 2023 study published in The Journal of European Review for Medical and Pharmacological Sciences found that elevated homocysteine is especially high in younger and overweight patients, underscoring its value in early detection among at-risk populations. Homocysteine testing can reveal nutrient deficiencies (B12, folate, B6) or genetic polymorphisms that may exacerbate cardiovascular risk (24).

Clinical Integration

ASCVD risk is best assessed through a multi-marker and comprehensive framework rather than isolated values:

• Reclassifying risk: In intermediate-risk individuals, hs-CRP and Lp(a) uncover hidden cardiovascular danger.
• Compounded risk detection: Concurrent elevations of homocysteine, hs-CRP, and Lp(a) identify patients at substantially higher risk (20).
• Detecting upstream injury: Oxidized LDL (oxLDL) and myeloperoxidase (MPO) reveal oxidative and inflammatory damage before structural changes are visible on imaging.
• Spotting early metabolic dysfunction: Fasting insulin and uric acid track metabolic imbalances that drive ASCVD.
• Tailoring by genetics: APOE genotype and inherited Lp(a) levels refine personalized prevention strategies.

This comprehensive approach enables clinicians to intervene earlier, address root causes, and individualize treatment with targeted nutrition, lifestyle, and metabolic support.

Utilizing Evolutionary Insights & Functional Lab Markers

Effectively addressing modern ASCVD requires uniting evolutionary insight with advanced biomarker detection. Our genomes were shaped for survival in environments of scarcity, infection, and high physical demand. Traits that once conferred resilience are now vulnerabilities in today’s sedentary, circadian-misaligned, stress-laden environment.

Advanced laboratory markers reveal these evolutionary mismatches long before clinical disease appears. By understanding how inherited traits interact with modern exposures, clinicians can adopt a holistic and personalized evolutionarily informed approach that empowers patients and optimizes long-term cardiovascular health.

Lifestyle Integration & Preventive Monitoring

Integrating stress resolution techniques, nutrient-dense whole foods, restorative sleep, daily movement, sunlight, and nature exposure attenuates modern contributors to ASCVD when paired with upstream biomarker assessment. Evidence suggests these strategies reduce systemic inflammation, improve endothelial function, restore metabolic balance, and lower cortisol and oxidative stress (25-30). With biomarker monitoring, clinicians can track physiologic improvements, with patients remaining actively engaged in improving their health.

Upstream Assessment of Biomarkers for Optimal Health

Applying functional medicine principles with advanced biomarker assessment creates a framework for proactive, personalized strategies—aligned with circadian and metabolic rhythms—that address root causes of vascular dysfunction and move care beyond reactivity to prevention.

Join Jeffrey Bland, PhD, Erik Lundquist, MD, and Chris Magryta, MD on October 14th, 5–7 PM for this upcoming webinar, Unraveling the Upstream Drivers of ASCVD: A Functional and Evolutionary Lens on Cardiometabolic Risk. This two-hour session explores how evolutionary biology and functional medicine illuminate hidden drivers of atherosclerosis and hyperlipidemia, with practical guidance on advanced biomarkers for early detection and prevention.

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