Advanced Cardiovascular & Lipid Testing

The Cholesterol Myth That Won’t Die

Here is a number that has terrorized a generation: 200. Total cholesterol above 200 mg/dL and you get a lecture, a prescription, and a lifetime of statin therapy. Below 200 and you get a pat on the back. This approach to cardiovascular risk assessment is roughly as sophisticated as predicting the weather by looking out the window.

Total cholesterol is a nearly useless predictor of heart attack risk. Half of all heart attacks occur in people with “normal” cholesterol. The Women’s Health Initiative found that women with LDL below 130 had the same cardiovascular event rate as those above 160. The Framingham Heart Study showed that total cholesterol above 200 had a predictive value of only about 50% — no better than a coin flip.

The reason is simple: standard lipid panels measure the amount of cholesterol inside lipoproteins. They do not measure the number, size, density, or oxidation status of those lipoproteins. And it is the lipoproteins — the vehicles — that cause atherosclerosis, not the cholesterol cargo they carry.

Standard Lipid Panel: What It Tells You (and What It Hides)

Total Cholesterol

Nearly useless in isolation. Cholesterol is a vital molecule — every cell membrane requires it, every steroid hormone is built from it, vitamin D synthesis depends on it, bile acids that digest fat are made from it, and myelin sheaths that insulate neurons are composed of it. A total cholesterol below 150 is associated with increased risk of hemorrhagic stroke, depression, cancer mortality, and hormonal dysfunction. The body does not make a molecule it does not need.

LDL-C (Calculated LDL Cholesterol)

Standard “optimal” <100 mg/dL — but this number is calculated, not measured.

LDL-C is estimated using the Friedewald equation: LDL-C = Total Cholesterol - HDL-C - (Triglycerides/5). This equation fails when triglycerides exceed 400 mg/dL, and it systematically underestimates LDL-C at low LDL levels and high triglyceride levels — precisely the pattern seen in insulin-resistant patients who are at highest cardiovascular risk. The newer Martin-Hopkins equation is more accurate but still an estimate.

The deeper problem: LDL-C tells you the mass of cholesterol carried in LDL particles but not how many particles are carrying it. This is the concordance/discordance problem that makes LDL-C dangerously misleading.

HDL-C

Optimal: >55 mg/dL (women), >45 mg/dL (men)

Higher HDL is generally protective — HDL performs reverse cholesterol transport, removing cholesterol from arterial walls and returning it to the liver. But HDL quantity is not the whole story. Dysfunctional HDL (oxidized by myeloperoxidase) can be pro-inflammatory despite a high number. HDL functionality testing is emerging but not yet widely available.

Triglycerides

Optimal: <100 mg/dL (standard <150)

Triglycerides are the metabolic canary. Fasting triglycerides above 100 mg/dL reflect insulin resistance, excessive carbohydrate intake, or impaired fatty acid metabolism. Above 150 is diagnostic of metabolic syndrome (combined with other criteria). Above 500 requires urgent treatment to prevent pancreatitis.

Triglycerides are the most diet-responsive lipid marker. A whole-food, lower-carbohydrate diet can drop triglycerides 30-50% in weeks. Omega-3 fatty acids at pharmacological doses (4g/day EPA+DHA) reduce triglycerides by 25-45%.

Advanced Lipid Testing: What Actually Predicts Heart Attacks

LDL Particle Number (LDL-P)

Optimal: <1000 nmol/L

Measured by NMR LipoProfile (LabCorp) or ion mobility (Quest). LDL-P is the single best lipoprotein predictor of cardiovascular events, superior to LDL-C, total cholesterol, and even ApoB in some analyses (MESA study, Framingham Offspring).

The concordance/discordance concept: Imagine two patients, both with LDL-C of 130 mg/dL. Patient A has 1,100 large buoyant LDL particles, each carrying a generous cholesterol load. Patient B has 1,800 small dense LDL particles, each carrying a smaller cholesterol load — the total cholesterol content is identical, but the particle number is 64% higher. Patient B has dramatically higher cardiovascular risk despite identical LDL-C.

When LDL-C and LDL-P are discordant (LDL-C “normal” but LDL-P elevated), cardiovascular risk tracks with LDL-P, not LDL-C. Discordance is most common in insulin resistance, metabolic syndrome, diabetes, and familial combined hyperlipidemia.

Small Dense LDL (sdLDL)

Pattern A (large buoyant): Less atherogenic — these particles are too large to easily penetrate the arterial endothelium and are more resistant to oxidation. Pattern B (small dense): Highly atherogenic — these particles penetrate the endothelial wall more easily, bind more readily to arterial proteoglycans, are retained longer in the subintimal space, and are more susceptible to oxidation.

The driver of Pattern B: insulin resistance and high triglycerides. When triglycerides are elevated, CETP (cholesterol ester transfer protein) shuffles triglycerides into LDL particles and cholesterol out. Hepatic lipase then hydrolyzes the triglyceride-enriched LDL, shrinking it into small dense particles. This is why the triglyceride/HDL ratio is such a powerful surrogate marker for LDL particle size.

Lipoprotein(a) — Lp(a)

Risk threshold: >30 mg/dL or >75 nmol/L = 2-3x cardiovascular risk (Note: mg/dL and nmol/L are NOT interconvertible with a simple factor because Lp(a) particle size varies)

Lp(a) is the genetic wildcard of cardiovascular risk. It is an LDL particle with an extra protein — apolipoprotein(a) — covalently bonded to ApoB. Lp(a) is prothrombotic (it resembles plasminogen and competes for plasminogen receptors, impairing fibrinolysis), pro-inflammatory, and carries oxidized phospholipids that promote atherosclerosis.

Lp(a) levels are 90% genetically determined (by the LPA gene on chromosome 6). Diet, exercise, and statin therapy have minimal impact. You only need to test it once in a lifetime — it does not change.

Interventions for elevated Lp(a): Niacin (1-2g/day extended-release) reduces Lp(a) by 20-30% — the only widely available intervention. PCSK9 inhibitors (evolocumab, alirocumab) reduce Lp(a) by approximately 20-25%. Antisense oligonucleotides targeting hepatic Lp(a) production (pelacarsen, olpasiran) are in Phase 3 trials showing 80-90% reductions — potentially game-changing for high-Lp(a) patients.

Apolipoprotein B (ApoB)

Optimal: <80 mg/dL (some cardiologists target <60 mg/dL for highest-risk patients)

Every atherogenic lipoprotein — LDL, VLDL, IDL, Lp(a) — carries exactly one ApoB molecule. Therefore, ApoB directly reflects the total number of atherogenic particles in circulation. Many lipidologists now consider ApoB the single best lipid marker because it captures the atherogenic burden in one number, it is directly measured (not calculated), it does not require fasting (unlike triglycerides), and it captures the risk from all atherogenic particles, not just LDL.

The European Atherosclerosis Society and Canadian Cardiovascular Society have both recommended ApoB as a primary treatment target. If you could order only one advanced lipid marker, make it ApoB.

Oxidized LDL (oxLDL)

Native LDL is not atherogenic. It becomes atherogenic when it is oxidized — modified by reactive oxygen species, myeloperoxidase, lipoxygenase, or glycation (in diabetes). Oxidized LDL is recognized by scavenger receptors on macrophages, which engulf it without limit (unlike the regulated LDL receptor), becoming foam cells — the hallmark of early atherosclerotic plaque.

OxLDL is a marker of the oxidative damage that initiates and perpetuates plaque formation. Elevated oxLDL reflects systemic oxidative stress, inflammation, poor antioxidant status, smoking, diabetes, and metabolic syndrome.

Triglyceride/HDL Ratio

Optimal: <1.0 Concerning: 2.0-3.0 Highly atherogenic: >3.5

This ratio is the poor man’s insulin resistance test and LDL particle size predictor. A TG/HDL ratio above 2.0 strongly predicts predominance of small dense LDL (Pattern B), insulin resistance, and cardiovascular risk. It is calculated from the standard lipid panel — no advanced testing needed. A TG/HDL ratio of 1.0 or below almost always indicates large buoyant LDL, insulin sensitivity, and favorable metabolic status.

Inflammatory and Vascular Markers

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

Optimal: <0.5 mg/L (standard cardiovascular risk cutoff <1.0 mg/L low risk, 1-3 moderate, >3 high)

CRP is an acute phase protein produced by the liver in response to IL-6. It is a marker of systemic inflammation and an independent predictor of cardiovascular events — even after adjusting for all traditional risk factors (Ridker, JUPITER trial).

The JUPITER trial demonstrated that statin benefit correlates more strongly with CRP reduction than with LDL reduction. Patients who achieved CRP <2.0 AND LDL <70 had the best outcomes. This supports the inflammatory hypothesis of atherosclerosis: it is the fire (inflammation), not just the fuel (cholesterol), that causes the damage.

An optimal CRP below 0.5 mg/L reflects minimal systemic inflammation. A CRP above 3 mg/L demands investigation beyond cardiovascular risk — infection, autoimmune disease, obesity (adipose tissue is a major IL-6 source), periodontitis, or occult malignancy.

Homocysteine

Optimal: <8 umol/L (standard “normal” <15)

Homocysteine is a sulfur-containing amino acid generated during methionine metabolism. Elevated homocysteine directly damages vascular endothelium, promotes oxidative stress, impairs nitric oxide production, enhances thrombosis, and accelerates atherosclerosis.

The metabolism of homocysteine requires B12 (methylcobalamin), folate (methyltetrahydrofolate), B6 (pyridoxal-5-phosphate), and betaine (trimethylglycine). Deficiency of any of these nutrients elevates homocysteine. MTHFR polymorphisms (C677T, A1298C) impair folate metabolism and are common drivers of elevated homocysteine.

A homocysteine of 12 is called “normal.” It is not optimal. Evidence suggests that every 5 umol/L increase in homocysteine raises cardiovascular risk by 20% (Boushey et al., 1995, JAMA). Target <8 with activated B vitamins: methylfolate (800-2000 mcg), methylcobalamin (1000-2000 mcg), P5P (25-50 mg), and betaine/TMG (500-1500 mg).

Fibrinogen

Optimal: <350 mg/dL

Fibrinogen is a clotting protein and acute phase reactant. Elevated fibrinogen increases blood viscosity and clotting tendency — contributing to both arterial (heart attack, stroke) and venous (DVT, PE) thrombosis. It is an independent cardiovascular risk factor. Elevated by: inflammation, smoking, obesity, oral contraceptives, pregnancy. Reduced by: omega-3 fatty acids, nattokinase, exercise, and moderate alcohol intake.

Lp-PLA2 (PLAC Test)

Optimal: <200 ng/mL

Lipoprotein-associated phospholipase A2 is an enzyme carried on LDL particles that is specific to vascular inflammation. Unlike CRP (which reflects systemic inflammation from any source), Lp-PLA2 is specific to inflamed arterial plaque. It is a marker of plaque instability and vulnerability to rupture. Elevated Lp-PLA2 identifies patients at risk for acute coronary events even with “normal” cholesterol and CRP.

Myeloperoxidase (MPO)

Optimal: <420 pmol/L

MPO is released by activated neutrophils within atherosclerotic plaque. It oxidizes LDL (creating oxLDL), damages HDL (rendering it dysfunctional), and destabilizes the fibrous cap of plaque. Elevated MPO is a marker of vulnerable plaque and near-term coronary event risk. It is most useful in the emergency department for risk stratification of chest pain, but elevated levels in outpatient testing should prompt aggressive risk reduction.

TMAO (Trimethylamine N-Oxide)

Optimal: <6.2 umol/L

TMAO is a metabolite produced when gut bacteria metabolize carnitine (red meat), choline (eggs, liver), and phosphatidylcholine. The gut microbiome converts these substrates to trimethylamine (TMA), which the liver then oxidizes to TMAO via FMO3 (flavin monooxygenase 3).

TMAO promotes atherosclerosis by enhancing macrophage foam cell formation, promoting platelet hyperreactivity, and impairing reverse cholesterol transport. The Cleveland Clinic studies (Hazen laboratory) have established TMAO as an independent predictor of major cardiovascular events.

The clinical nuance: TMAO levels depend more on gut microbiome composition than on dietary intake. Vegetarians who consume carnitine produce far less TMAO than omnivores because their gut bacteria lack the enzymes to convert carnitine to TMA. This is a microbiome problem, not purely a dietary problem.

Cardiovascular Imaging

Coronary Artery Calcium (CAC) Score

The CAC score, measured by non-contrast CT, quantifies calcified plaque in the coronary arteries.

• CAC 0: Very low risk. 10-year event rate <1%. This is the most powerful negative predictor in cardiovascular medicine — a CAC of 0 virtually rules out significant coronary artery disease.
• CAC 1-99: Mild calcification. Risk depends on age and sex.
• CAC 100-399: Moderate to significant calcification. Aggressive risk factor modification warranted.
• CAC >400: Extensive calcification. High 10-year event rate. Statin therapy + comprehensive intervention.

The CAC score is most valuable for reclassifying risk in “intermediate risk” patients — those with borderline labs or conflicting risk factors. A 55-year-old man with mildly elevated LDL-C but a CAC of 0 can likely defer statin therapy. The same man with a CAC of 300 needs aggressive treatment regardless of lipid levels.

CIMT (Carotid Intima-Media Thickness)

Ultrasound measurement of the carotid artery wall thickness. Increased CIMT (>0.9 mm) reflects subclinical atherosclerosis. It is non-invasive, radiation-free, and repeatable — useful for tracking progression or regression of arterial disease over time.

The Optimization Protocol

Cardiovascular disease is not a cholesterol disease. It is an inflammatory, metabolic, oxidative disease that happens to involve cholesterol-carrying lipoproteins. The protocol addresses all drivers:

Diet: Mediterranean pattern — extra virgin olive oil (polyphenols reduce oxLDL), fatty fish (EPA/DHA), nuts, vegetables, legumes, moderate wine (optional). Reduce refined carbohydrates and seed oils (high in omega-6, promote inflammation).

Omega-3 fatty acids: EPA+DHA 2-4g/day. The REDUCE-IT trial showed 4g/day of icosapent ethyl (pure EPA) reduced cardiovascular events by 25% beyond statin therapy. Triglyceride-lowering, anti-inflammatory, anti-arrhythmic, and membrane-stabilizing.

Address insulin resistance FIRST: This is the root cause in the majority of dyslipidemia patients. Insulin resistance drives high triglycerides, low HDL, small dense LDL, and Pattern B — the entire atherogenic triad. Weight loss (especially visceral fat), resistance training, time-restricted eating, and carbohydrate moderation are first-line interventions.

Natural lipid interventions: Berberine (500 mg 2-3x/day — activates AMPK, comparable to metformin for glucose, reduces LDL 20-30%), red yeast rice (contains naturally occurring monacolin K — identical to lovastatin — 2.4-4.8 mg monacolin K per day, ensure citrinin-free), plant sterols/stanols (2g/day reduce LDL 10-15%), citrus bergamot (1000 mg/day — reduces LDL and supports HDL function).

For elevated Lp(a): Niacin extended-release 1-2g/day (start 500 mg, titrate slowly, take with aspirin to reduce flushing). Niacin is the only widely available agent that meaningfully reduces Lp(a).

For elevated homocysteine: Methylfolate 800-2000 mcg + methylcobalamin 1000-2000 mcg + P5P 25-50 mg daily. Recheck in 3 months.

Exercise: 150-300 minutes/week moderate intensity. Resistance training 2-3x/week. Exercise raises HDL, reduces triglycerides, improves insulin sensitivity, reduces inflammation, and improves endothelial function — addressing virtually every pathway of cardiovascular risk simultaneously.

The standard lipid panel is a blunt instrument from a simpler time. Advanced testing — ApoB, LDL-P, Lp(a), oxLDL, hs-CRP, homocysteine, and CAC scoring — provides the resolution needed to identify true risk, target intervention, and monitor response. The goal is not a number on a lab report. The goal is arterial health.