Functional Medicine Cardiovascular Risk Reduction Protocol

Beyond the Cholesterol Myth

For fifty years, cardiovascular medicine has been dominated by one narrative: cholesterol causes heart disease, so lower cholesterol with statins. This story is incomplete to the point of being misleading.

Half of all heart attacks occur in people with “normal” LDL cholesterol. Meanwhile, some populations with very high cholesterol (like the Tsimane of Bolivia) have the lowest rates of heart disease ever recorded. Something does not add up.

Functional medicine does not dismiss cholesterol — it contextualizes it. The real drivers of atherosclerotic cardiovascular disease (ASCVD) are:

1. Inflammation — the match that lights the fire in the arterial wall
2. Oxidative stress — LDL becomes dangerous only when oxidized
3. Insulin resistance — the metabolic engine that produces atherogenic particles
4. Endothelial dysfunction — the damaged soil where plaques take root

Standard lipid panels measure the wrong things. Advanced testing reveals who is actually at risk.

Advanced Lipid Testing

NMR LipoProfile / Cardio IQ

Standard LDL cholesterol (LDL-C) is a calculated value that tells you nothing about the number or size of LDL particles. Two people with an LDL-C of 130 can have vastly different cardiovascular risk:

• Person A: 800 large, buoyant LDL particles (Pattern A) — low risk
• Person B: 1800 small, dense LDL particles (Pattern B) — high risk

Small dense LDL particles are atherogenic because they:

• Penetrate the arterial endothelium more easily
• Are more susceptible to oxidation
• Have a longer half-life in the bloodstream (the liver’s LDL receptors recognize them poorly)
• Bind to arterial proteoglycans, getting trapped in the vessel wall

LDL particle number (LDL-P): The best predictor of cardiovascular events in the lipid panel. Optimal <1000 nmol/L. High risk >1600 nmol/L.

Apolipoprotein B (ApoB)

Each atherogenic lipoprotein particle (LDL, VLDL, IDL, Lp(a)) carries exactly one ApoB molecule on its surface. Therefore, ApoB is a direct count of all atherogenic particles — one measurement that captures the entire atherogenic burden.

• Optimal: <80 mg/dL (some experts say <60 mg/dL for high-risk patients)
• Desirable: <90 mg/dL
• High risk: >120 mg/dL

ApoB is increasingly considered the single best lipid marker for cardiovascular risk. It is discordant with LDL-C in approximately 30% of patients — meaning LDL-C gives a false sense of security or unnecessary alarm in nearly a third of cases.

Lipoprotein(a) — Lp(a)

The most important cardiovascular risk factor that most doctors never test. Lp(a) is a genetically determined lipoprotein particle consisting of an LDL particle with an additional protein, apolipoprotein(a), attached. It is:

• Atherogenic — promotes plaque formation like LDL
• Thrombogenic — structurally similar to plasminogen, competing for binding sites and inhibiting fibrinolysis (clot dissolution)
• Inflammatory — carries oxidized phospholipids that activate endothelial inflammation

20-25% of the population has elevated Lp(a). It is the #1 inherited cardiovascular risk factor. Levels are >90% genetically determined and do not change significantly with diet or exercise.

• Desirable: <30 mg/dL (or <75 nmol/L)
• Moderate risk: 30-50 mg/dL
• High risk: >50 mg/dL (or >125 nmol/L)

No drug effectively lowers Lp(a). Niacin (vitamin B3) at high doses (2000-3000mg/day, flush form) can reduce Lp(a) by 20-30% — the only intervention with consistent evidence. PCSK9 inhibitors lower it modestly (20-25%). New antisense oligonucleotides (pelacarsen, olpasiran) targeting Lp(a) are in phase 3 trials but not yet available.

If Lp(a) is elevated, aggressive management of all other modifiable risk factors is essential: keep ApoB low, hs-CRP low, blood pressure optimal, insulin resistance resolved.

Oxidized LDL (oxLDL)

Native LDL is not inherently dangerous. It becomes atherogenic when oxidized. OxLDL is recognized by scavenger receptors on macrophages, triggering foam cell formation — the initiating event of plaque development. Reducing oxidized LDL through antioxidant support, anti-inflammatory diet, and reducing oxidative stress (smoking cessation, blood sugar control, toxin reduction) is a direct intervention against plaque formation.

Triglyceride/HDL Ratio

A simple, powerful surrogate marker available on any standard lipid panel:

• Optimal: <1.0
• Acceptable: 1.0-2.0
• Insulin resistant + predominance of small dense LDL: >2.0
• Metabolic syndrome likely: >3.5

This ratio reflects insulin resistance-driven dyslipidemia: high triglycerides (from hepatic de novo lipogenesis driven by insulin and fructose) + low HDL (accelerated catabolism in insulin resistance) + small dense LDL (triglyceride-enriched LDL remodeled by hepatic lipase).

Inflammatory Markers

High-Sensitivity C-Reactive Protein (hs-CRP)

CRP is produced by the liver in response to IL-6. It reflects systemic inflammation from any source — gut, adipose tissue, infections, autoimmunity, periodontitis.

• Optimal: <1.0 mg/L
• Moderate risk: 1.0-3.0 mg/L
• High risk: >3.0 mg/L
• Very high / acute inflammation: >10 mg/L (look for active infection or injury)

The JUPITER trial demonstrated that even patients with low LDL but high hs-CRP benefit from statin therapy — proving that inflammation, not just cholesterol, drives events.

Homocysteine

An amino acid metabolite that is directly toxic to endothelial cells, promotes oxidative stress, and increases thrombotic risk. Elevated homocysteine is often a sign of impaired methylation — the MTHFR connection.

• Optimal: <7 micromol/L
• Acceptable: 7-10 micromol/L
• Concerning: 10-15 micromol/L
• High risk: >15 micromol/L

Causes of elevated homocysteine: MTHFR polymorphisms (C677T, A1298C — present in 40-60% of the population), B12 deficiency, folate deficiency, B6 deficiency, hypothyroidism, renal insufficiency, medications (methotrexate, metformin, PPIs, anticonvulsants).

Fibrinogen

An acute-phase reactant and clotting factor. Elevated fibrinogen increases blood viscosity and thrombotic risk. Optimal: 200-300 mg/dL. Elevated by inflammation, smoking, oral contraceptives, obesity.

Lp-PLA2 (Lipoprotein-associated Phospholipase A2)

Also called the PLAC test. Lp-PLA2 is an enzyme produced by macrophages within arterial plaques. It is a specific marker of vascular inflammation — arterial wall inflammation, not systemic. Elevated Lp-PLA2 indicates active atherosclerotic plaque inflammation and is an independent predictor of heart attack and ischemic stroke. Optimal: <200 ng/mL.

MPO (Myeloperoxidase)

An enzyme released by neutrophils within vulnerable (unstable) plaques. Elevated MPO suggests the presence of thin-capped, rupture-prone plaques — the plaques most likely to cause acute events. It is a marker of vulnerable plaque rather than plaque burden.

Endothelial Function and Nitric Oxide

The endothelium — the single-cell-thick lining of blood vessels — is an active organ that produces nitric oxide (NO), the master vasodilator. NO relaxes smooth muscle, inhibits platelet aggregation, prevents leukocyte adhesion, and suppresses smooth muscle proliferation. Endothelial dysfunction (reduced NO production) is the earliest measurable event in atherosclerosis — it precedes plaque formation by years.

Supporting nitric oxide production:

• L-citrulline: 3-6g/day. Converts to L-arginine in the kidneys, then to NO via eNOS. More effective than supplementing L-arginine directly (L-arginine undergoes significant first-pass metabolism).
• L-arginine: 3-6g/day. The direct substrate for eNOS. Use in combination with citrulline.
• Beetroot juice/powder: Rich in dietary nitrate, which is converted to nitrite by oral bacteria and then to NO in the stomach and tissues. 500ml beet juice or 6-12g beet root powder daily. Shown to lower blood pressure by 4-10 mmHg.
• Dark chocolate (>70% cacao): Flavanols stimulate eNOS. 30-40g/day.
• Arugula and leafy greens: Among the highest dietary nitrate sources.
• Exercise: The most potent stimulus for eNOS upregulation. Shear stress from blood flow activates eNOS. Regular exercise literally teaches your blood vessels to produce more NO.

Do NOT use antiseptic mouthwash daily — it kills the oral bacteria (Veillonella, Rothia) that convert dietary nitrate to nitrite, reducing the nitrate-NO pathway by 50%.

The Statin Conversation

Statins are the most prescribed drug class in history. Functional medicine takes a nuanced position:

When statins are most appropriate:

• High ApoB (>120) + elevated Lp(a) + elevated hs-CRP + family history of premature ASCVD
• Known ASCVD (secondary prevention — post-heart attack, post-stent)
• Familial hypercholesterolemia (genetic LDL receptor mutations)
• High coronary artery calcium (CAC) score with concordant risk factors

Statin side effects requiring management:

• CoQ10 depletion — statins block HMG-CoA reductase, which is upstream of both cholesterol AND CoQ10 synthesis. Always supplement CoQ10 200-400mg/day (ubiquinol form) with any statin. Failure to do so contributes to myalgia, fatigue, and potentially cardiomyopathy (ironic — the drug prescribed for the heart depletes a nutrient the heart needs most).
• Muscle pain (myalgia) — affects 10-20% of patients (higher than clinical trial data suggests, due to the nocebo-controlled design issue). CoQ10 supplementation and vitamin D optimization often resolve it.
• Insulin resistance — statins increase the risk of new-onset type 2 diabetes by 9-12%. Monitor fasting insulin and HbA1c.
• Cognitive effects — brain fog, memory issues reported by some patients. The brain requires cholesterol for synaptic function and myelin maintenance.

Natural Lipid Support

Red Yeast Rice

Contains monacolin K, which is chemically identical to lovastatin. Dose: 1200mg twice daily (providing approximately 10mg monacolin K — equivalent to lovastatin 20mg). Produces LDL reduction of 15-25%. Must supplement with CoQ10 (same HMG-CoA reductase inhibition as pharmaceutical statins). Quality varies dramatically between brands — some contain citrinin (a nephrotoxic mycotoxin). Use third-party tested products.

Bergamot Extract

From the bergamot orange (Citrus bergamia) of Calabria, Italy. Contains unique flavanone glycosides (brutieridin and melitidin) that inhibit HMG-CoA reductase through a different mechanism than statins. Dose: 500-1000mg/day of standardized extract (minimum 25% flavonoids). Studies show reductions in total cholesterol (20-30%), LDL (20-25%), triglycerides (20-30%), and increases in HDL (15-20%). Also improves arterial stiffness and blood sugar. Can be combined with low-dose statins.

Plant Sterols and Stanols

Structurally similar to cholesterol, plant sterols compete for intestinal absorption, reducing cholesterol uptake by 30-50%. Dose: 2g/day with meals. Reduces LDL by 5-15%. Found in fortified foods or supplements. FDA-approved health claim.

Omega-3 Fatty Acids (EPA Focus)

For triglyceride reduction, EPA is the key omega-3. Dose: 2-4g EPA/day. The REDUCE-IT trial (icosapent ethyl, a prescription EPA) showed 25% reduction in cardiovascular events with 4g EPA daily. The mechanism goes beyond triglyceride reduction — EPA stabilizes cell membranes, reduces inflammation, and improves endothelial function.

Niacin (Vitamin B3)

The only intervention that significantly lowers Lp(a) (20-30% reduction). Also raises HDL (15-35%), lowers triglycerides (20-50%), shifts LDL from small dense to large buoyant, and lowers LDL-P. Dose: 1000-2000mg/day of immediate-release (flush) niacin. Start at 100mg with dinner and increase by 100mg weekly. The flush (warmth, redness, tingling) is mediated by prostaglandin D2 and is harmless — it diminishes with consistent use. Take with food. Aspirin 81mg 30 minutes before can reduce flush. Avoid sustained-release niacin — hepatotoxic. Monitor liver enzymes and uric acid.

Berberine

Upregulates LDL receptor expression (increasing LDL clearance), activates AMPK, reduces PCSK9 expression. Dose: 500mg 2-3 times daily with meals. Lowers LDL by 15-20%, triglycerides by 20-30%. Do not combine with statins without monitoring (additive effects).

Fiber

Soluble fiber binds bile acids in the intestine, forcing the liver to pull cholesterol from the blood to make more bile. Psyllium husk: 5-10g/day (reduces LDL by 5-10%). Oat beta-glucan: 3g/day. Ground flaxseed: 30g/day (also provides ALA omega-3 and lignans).

Homocysteine Protocol

When homocysteine is elevated, the methylation cycle needs support:

• Methylfolate (5-MTHF): 1-5mg/day (dose depends on MTHFR status and homocysteine level)
• Methylcobalamin (B12): 1000-5000mcg/day sublingual
• P5P (active B6): 50-100mg/day
• TMG (trimethylglycine / betaine): 500-3000mg/day — provides methyl groups through the BHMT pathway (alternative to MTHFR-dependent pathway)
• Riboflavin (B2): 25-50mg/day — FAD is a cofactor for MTHFR itself; riboflavin supplementation alone can lower homocysteine in those with the MTHFR C677T variant

Target: bring homocysteine below 7 micromol/L. Recheck every 3 months until stable.

Blood Pressure Optimization

Hypertension is a downstream consequence of insulin resistance, endothelial dysfunction, sympathetic overdrive, magnesium and potassium deficiency, and stress. Before (or alongside) medications:

• Magnesium: 400-800mg/day (glycinate, taurate, or citrate). Magnesium relaxes vascular smooth muscle, improves endothelial function, and is a natural calcium channel blocker. Meta-analyses show 5-8 mmHg systolic reduction.
• Potassium: 3500-4700mg/day from food (avocado, sweet potato, spinach, salmon, white beans). Potassium opposes sodium’s effect on blood pressure. Most Americans get 2500mg/day — far below the recommended intake.
• CoQ10: 100-300mg/day. Shown to reduce systolic BP by 11-17 mmHg in meta-analyses.
• Aged garlic extract: 600-1200mg/day (Kyolic). Stimulates NO production, reduces arterial stiffness. Meta-analysis: 8-10 mmHg systolic reduction.
• Hibiscus tea: 2-3 cups daily. ACE inhibitory activity. Clinical trials show 7-13 mmHg systolic reduction.
• Beetroot: See nitric oxide section above. 4-10 mmHg reduction.
• Stress reduction: chronic stress activates the sympathetic nervous system, elevating BP. Meditation, deep breathing, and biofeedback have 5-10 mmHg effects.
• DASH diet principles: high in vegetables, fruits, legumes, nuts, whole grains, lean protein. Low in sodium (<2300mg, ideally <1500mg), processed foods, and added sugars. Proven 11-14 mmHg systolic reduction.

Imaging and Screening

CIMT (Carotid Intima-Media Thickness)

Ultrasound measurement of the inner two layers of the carotid artery wall. Thickening reflects early atherosclerosis. Non-invasive, no radiation, repeatable. Useful for tracking progression or regression of disease over time. Limitation: measures wall thickness, not plaque composition.

CAC Score (Coronary Artery Calcium)

A CT scan that quantifies calcified plaque in the coronary arteries. Scored in Agatston units:

• 0 — no calcified plaque detected. Very low 10-year risk (<1%). Consider de-escalating statin therapy.
• 1-99 — mild plaque. Moderate risk. Aggressive lifestyle intervention.
• 100-399 — moderate plaque. High risk. Lifestyle + consider pharmacotherapy.
• ≥400 — extensive plaque. Very high risk. Aggressive treatment warranted.

CAC is the strongest reclassifier of cardiovascular risk. A 55-year-old with CAC of 0 has a different prognosis than a 55-year-old with CAC of 350, even if their LDL-C is identical. CAC changes the conversation.

Exercise: The Master Cardioprotective Agent

Zone 2 Cardio

Sustained aerobic exercise at a pace where you can maintain a conversation but prefer not to. Heart rate approximately 60-70% of max. This builds mitochondrial density, improves fat oxidation, increases capillary density, and strengthens the heart. 150-180 minutes per week is the sweet spot. Walking, cycling, swimming, rowing.

Resistance Training

Builds muscle mass (an independent predictor of cardiovascular survival), improves insulin sensitivity, raises HDL, and reduces arterial stiffness. 2-4 sessions per week.

VO2max

VO2max (maximal oxygen uptake) is the strongest predictor of all-cause mortality — stronger than smoking, diabetes, or hypertension. Moving from the bottom 25th percentile to even the 25th-50th percentile reduces mortality risk by 50%. Every increase in cardiorespiratory fitness pays dividends. This is not about elite performance — it is about not being in the bottom quartile.

The Metabolic Connection

The most common lipid pattern in the developed world — high triglycerides, low HDL, high small dense LDL — is not a cholesterol disorder. It is an insulin disorder.

When insulin resistance drives hepatic de novo lipogenesis, the liver overproduces VLDL (triglyceride-rich) particles. These VLDL particles exchange triglycerides for cholesterol esters with LDL and HDL via CETP (cholesteryl ester transfer protein). The triglyceride-enriched LDL is then remodeled by hepatic lipase into small dense LDL. The triglyceride-enriched HDL is cleared faster, reducing HDL levels.

Result: high TG, low HDL, high sdLDL, high LDL-P — the “atherogenic dyslipidemia” phenotype. All from insulin resistance.

The treatment is not a statin. The treatment is fixing insulin resistance: reduce refined carbohydrates, exercise (especially resistance training), improve sleep, manage stress, optimize magnesium and chromium, consider berberine or metformin.

Fix the metabolism. The lipids follow. The arteries heal. The risk drops. This is cardiovascular medicine from the root.