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Cholesterol Is Not the Villain
Cholesterol is an essential lipid molecule for life: a structural component of all cell membranes, a precursor of steroid hormones (testosterone, cortisol, estrogen), vitamin D and bile acids. The problem is not cholesterol itself, but the excess of oxidized LDL particles in arterial walls. Understanding this distinction is fundamental for correct clinical management.
1. What Is Cholesterol?
Cholesterol is a sterol — a 27-carbon molecule with a four-ring structure — synthesized mainly by the liver (about 75% of total production) and obtained in smaller amounts from the diet (25%). Hepatic biosynthesis occurs via the mevalonate pathway, where the enzyme HMG-CoA reductase (the target of statins) catalyzes the rate-limiting step.
Because it is insoluble in water, cholesterol cannot circulate freely in the blood. To be transported, it must be packaged in protein-lipid particles called lipoproteins. This is where the complexity — and risks — of lipid metabolism lies.
2. Lipoproteins: LDL, HDL, VLDL e Além
Each type of lipoprotein has a distinct composition, function and clinical implication. Reducing everything to "good and bad cholesterol" is a simplification that can obscure important risks.
| Lipoprotein | Main Function | Desirable Value | Risk |
|---|---|---|---|
| LDL-C (Low-Density) | Transports cholesterol from the liver to peripheral tissues | < 130 mg/dL (low risk); < 70 (high risk) | Main causal factor of atherosclerosis |
| HDL-C (High-Density) | Reverse transport: removes cholesterol from tissues to liver | > 40 mg/dL (men); > 50 mg/dL (women) | Low HDL = higher CV risk |
| VLDL (Very Low-Density) | Transports triglycerides from liver to tissues | < 30 mg/dL (estimated) | LDL precursor; associated with high TG |
| Triglycerides (TG) | Energy storage; transported in VLDL and chylomicrons | < 150 mg/dL | Hypertriglyceridemia → pancreatitis, CV risk |
| Lp(a) | LDL variant with additional apolipoprotein(a) | < 30 mg/dL | Independent risk for CAD; genetically determined |
The HDL Paradox
Although HDL is called "good cholesterol," pharmacological attempts to artificially raise HDL (niacin, CETP inhibitors such as dalcetrapib) did not reduce cardiovascular events in clinical trials. This suggests that the functionality of HDL matters more than its absolute concentration.
3. Atherosclerosis: The Silent Disease
Atherosclerosis begins in childhood as fatty streaks in the arterial intima. Decades later, these lesions evolve into stable or unstable atherosclerotic plaques that can rupture and cause acute thrombosis — the final event in heart attack and stroke.
The central process is the oxidation of LDL particles within the arterial wall. Oxidized LDL (oxLDL) recruits circulating monocytes that differentiate into macrophages and phagocytose lipid particles, becoming "foam cells." The accumulation of these cells forms the atheroma.
The vulnerable plaque — lipid-rich, with a thin fibrous cap and necrotic core — can rupture, exposing the subendothelium and triggering the coagulation cascade. Most acute myocardial infarctions occur over plaques that were not "hemodynamically significant" before rupture.
4. Triglycerides: The Forgotten Factor
Elevated triglycerides (hypertriglyceridemia) are associated with higher cardiovascular risk, especially when accompanied by low HDL — a characteristic pattern of metabolic syndrome.
The main cause of elevated TG is not dietary fat, but excess refined carbohydrates and fructose, which stimulate hepatic de novo lipogenesis (fat production from sugars). Alcohol is also a potent inducer of hypertriglyceridemia.
- TG > 500 mg/dL: Risk of acute pancreatitis (emergency)
- TG 200–499 mg/dL: Mixed dyslipidemia; increases CV risk via remnant particles
- TG 150–199 mg/dL: Borderline; address lifestyle
5. Reference Values — AHA/ACC & ESC Guidelines
The American Heart Association and European Society of Cardiology classify lipids in ranges that depend on the patient's overall cardiovascular risk, assessed by scoring systems such as the Pooled Cohort Equations and SCORE2.
| Parameter | Desirable | Borderline | High | Very High |
|---|---|---|---|---|
| Total Cholesterol | < 190 mg/dL | 190–239 | 240–269 | ≥ 270 |
| LDL-C | < 130 mg/dL | 130–159 | 160–189 | ≥ 190 |
| HDL-C (Men) | ≥ 40 mg/dL | — | 35–39 | < 35 |
| HDL-C (Women) | ≥ 50 mg/dL | — | 45–49 | < 45 |
| Triglycerides | < 150 mg/dL | 150–199 | 200–499 | ≥ 500 |
| Non-HDL-C | < 160 mg/dL | 160–189 | 190–219 | ≥ 220 |
Important: the LDL goal is stratified by individual risk. Very high-risk patients (coronary artery disease, diabetics with target organ damage) should have LDL < 55 mg/dL (ESC 2019) or < 70 mg/dL (AHA/ACC). Low-risk patients may tolerate LDL < 130 mg/dL.
6. Diet and Lifestyle: O Que Realmente Funciona
Evidence-Based Dietary Recommendations (AHA/ESC)
- Reduce saturated fat (fatty meats, whole dairy) to < 7% of total calories — each 1% reduction lowers LDL by ~2 mg/dL.
- Eliminate trans fats (hard margarines, ultra-processed products) — they raise LDL and lower HDL simultaneously.
- Increase soluble fiber (oats, beans, flaxseed) — 5–10g/day reduces LDL by 3–5%.
- Phytosterols (2g/day via fortified margarines) — reduce LDL by 8–10%.
- Reduce sugar and alcohol to combat hypertriglyceridemia.
- Omega-3 from fish (EPA+DHA 2–4g/day) reduces TG by 20–30% in severe cases.
Physical Exercise and Lipids
Regular aerobic exercise (150 min/week of moderate intensity) is the most effective method for raising HDL-C (3–9% increase) and reducing triglycerides (10–20%). The effect on LDL is modest with exercise alone, but the combination with diet is synergistic.
7. Pharmacology: Statins, Ezetimibe and PCSK9 Inhibitors
Statins (atorvastatin, rosuvastatin, simvastatin) are the cornerstone of dyslipidemia treatment. They inhibit HMG-CoA reductase, reducing hepatic cholesterol synthesis and upregulating LDL receptors. At high doses, they can reduce LDL by 50–60%.
Ezetimibe blocks intestinal cholesterol absorption via the NPC1L1 protein. It reduces LDL by ~20% and has an additive effect to statins (IMPROVE-IT study: additional 6.4% reduction in cardiovascular events).
PCSK9 inhibitors (evolocumab, alirocumab) are monoclonal antibodies that prevent the degradation of hepatic LDL receptors, expanding the capture of circulating LDL. They reduce LDL by 50–60% additionally to statins. The FOURIER study demonstrated a 15% reduction in major cardiovascular events.
8. Conclusion
The management of dyslipidemia is one of the interventions with the greatest evidence of benefit in cardiovascular prevention. The strategy always starts with the assessment of the patient's global risk, followed by lifestyle modifications and, when necessary, stepped pharmacotherapy. Cholesterol is not an enemy — it is the health of its particles that determines the risk.
References
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