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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

While cholesterol plays vital roles in tissues throughout the body, an excess of the low and very-low density lipoprotein forms (LDL, VLDL) can have devastating consequences.

High levels of high density lipoprotein (HDL), on the other hand, have been linked to better cardiovascular health.

HDL Cholesterol

HDL's reputation as "good cholesterol," involved in moving the waxy substance back to the liver out of the periphery or from dietary intake, started with back in the 1970s that linked low HDL levels to fewer subsequent cases of coronary heart disease over 12 years of follow-up. Other large-scale observational studies have affirmed HDL's protective role.

HDL particles carry away excess cholesterol from atherosclerotic plaques, dubbed reverse cholesterol transport. But HDL also increases endothelial nitric oxide bioavailability, can reduce oxidative stress and inflammation, and decreases expression of endothelial adhesion markers -- all good for cardiovascular health.

"Despite robust relationships in epidemiological studies, however, the observational nature of these findings long meant that the question of whether HDL-c [HDL-cholesterol] played a direct role in the disease process -- or was simply a biomarker of other underlying complications -- remained uncertain," noted a review on HDL in .

Causality has come under question, as genetic studies have turned up little supporting evidence and pharmaceuticals designed to raise HDL levels turned up little to no benefit on cardiovascular outcomes, and even harm in some cases.

There may be a U-shaped relationship between HDL and cardiovascular disease risk. Emerging research suggests that HDL can flip to a "pro-inflammatory noxious equivalent with certain structure and function changes most commonly observed in the presence of systemic inflammation," the review noted, such as from coronary heart disease or type 2 diabetes. The "previously 'protective' response may now paradoxically accelerate vascular damage and increase the risk of mortality via atherosclerotic complications."

Research is looking at a class of HDL-raising agents called cholesteryl ester transfer protein inhibitors, leaning on their ability to also lower LDL cholesterol. But there's also potential to dig deeper into HDL function, the HDL review added.

Early Atherosclerosis

Lower density cholesterol's well-deserved reputation as "bad cholesterol" stems from its role in atherosclerosis. LDL particles transport dietary and endogenous LDL cholesterol through the body, along with VLDL as the main carrier for triglycerides. Both contribute to atherosclerotic cardiovascular disease (ASCVD).

Animal studies, research on genetic forms of hypercholesterolemia, epidemiological studies, and randomized controlled trials have all supported a role of serum cholesterol in atherosclerosis. LDL-c levels of around 100 mg/dL (2.6 mmol/L) or less have been associated with low rates of ASCVD. Cholesterol-lowering drugs used in high-risk patients have proven the causal link between LDL-c lowering and reductions in ASCVD in randomized controlled trials, note the .

In , Peter Libby, MD, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, lays out the process by which the excess cholesterol forms atherosclerosis in arterial vessels.

"On initiation of an atherogenic diet, typically rich in cholesterol and saturated fat, small lipoprotein particles accumulate in the intima," he explained.

Early lesion formation starts when lipoproteins linger and bind to proteoglycan in the intima layer of a vessel. These bound particles "have increased susceptibility to oxidative or other chemical modifications, considered by many to contribute to the pathogenesis of early atherosclerosis," Libby wrote.

Endothelial cells (ECs) are unique for their ability to maintain blood in a liquid state during prolonged contact and generally resist adhesive interactions with leukocyte immune cells. "However, very soon after initiation of hypercholesterolemia, leukocytes adhere to the endothelium and move between EC junctions, or even penetrate through ECs (transcytosis) to enter the intima, where they begin to accumulate lipids and become foam cells," Libby noted.

Once foam cells form, they replicate, and local proliferation dominates in the established atheroma lesion.

At this stage, which is the precursor to complex atheroma, the lesion consists primarily of lipid-engorged macrophages. These so-called fatty streaks have been and can regress somewhat.

Established Atherosclerosis

With inflammation and immune activity, these lesions become complex atheromas. The macrophage foam cells not only hold excess lipid, but also furnish many proinflammatory mediators (including cytokines, chemokines, various eicosanoids, and other lipid mediators), which in turn pump out oxidant species around the atherosclerotic plaque. "This ensemble of inflammatory mediators can promote inflammation in the plaque and thereby contribute to the progression of lesions," Libby wrote.

That inflammation plays a role was affirmed by the CANTOS trial, in which an antibody that neutralizes the proinflammatory cytokine IL-1β cut inflammation and lowered the incidence of cardiovascular events in patients with elevated high-sensitivity C-reactive protein and a previous heart attack.

In addition to this innate immunity, there's mounting evidence for a prominent role of antigen-specific or adaptive immunity in plaque progression, he added. "The activated T cells can then secrete copious quantities of cytokines that modulate atherogenesis."

Arterial smooth muscle cells, "which normally reside quiescent in the middle layer of the artery (the tunica media)" then come into play, entering the intimal layer with bursts of clonal expansion over time, Libby explained in a . Episodes of plaque disruption with thrombosis may expose these cells to potent cell division-inducing factors, including the coagulation factor thrombin. Areas of calcification often develop as well as the plaque evolves.

As these cells accumulate along with an extracellular matrix of interstitial collagen, proteoglycans, and elastin fibers that create the bulk of atherosclerotic plaques, these lesions in the intima initially grow outward to increase the caliber of the entire artery. "Luminal stenosis tends to occur only after the plaque burden exceeds approximately 40% of the cross-sectional area of the artery," he noted.

This staccato atherosclerotic process generally lasts many years and then begins to encroach on the arterial lumen after the plaque burden exceeds the capacity of the artery for positive remodeling. Stenosis of greater than 60% of the vessel diameter can limit blood flow under conditions of increased demand, producing chronic stable angina pectoris or intermittent claudication -- signaling the symptomatic phase.

Read Part 1 of this series: Hypercholesterolemia: A Complex System

Up next: Genetics of Hypercholesterolemia