Potential Benefits of Advanced Cholesterol Testing, PART TWO

By Paul E. Lemanski, MD, MS, FACP

Editor’s Note: This is the 113th in a series on optimal diet and lifestyle to help prevent and treat disease. Any planned change in diet, exercise or treatment should be discussed with and approved by your personal physician before implementation. The help of a registered dietitian in the implementation of dietary changes is strongly recommended.

Medicines are a mainstay of American life and the healthcare system not only because they are perceived to work by the individuals taking them, but also because their benefit may be shown by the objective assessment of scientific study. Clinical research trials have shown that some of the medicines of Western science may reduce the risk of Type 2 diabetes, heart attacks, strokes, cardiovascular death and even some cancers.

In the first 112 installments of the Non-Medicated Life, a healthy diet and lifestyle has been shown to accomplish naturally for the majority of individuals most of the benefits of medications in the prevention of the chronic medical conditions mentioned above. In order to maximize the benefit of lifestyle changes, it is best to first establish a baseline of laboratory tests of so called “surrogate markers” of risk. Markers such as fasting blood sugar, Hemoglobin (Hgb) A1C, total cholesterol, HDL (the good cholesterol) and LDL (the bad cholesterol) and Triglycerides (blood fats) are routinely followed serially to determining increasing or decreasing risk. 

After a discussion with your primary care physician or cardiologist, additional cholesterol-based testing may be helpful. “Advanced” cholesterol testing such as High Sensitivity C-Reactive Protein (HS-CRP), Apolipoprotein B (Apo B), Trimethylamine-N Oxide (TMAO), and Nuclear Magnetic Resonance LipoProfile (NMR LipoProfile) may offer additional identification of risk – and when measured serially (at a series of time points) may help direct and refine lifestyle choices. 

In this two-part article, Part One addressed the first two advanced tests (HS-CRP and Apo B) in the November 2023 issue: adksports.com. Part Two will now address the remaining advanced tests (TMAO and NMR LipoProfile). Please note: another important advanced test Lipoprotein A or Lp(a) that does not respond to lifestyle changes was addressed in its own article and will not be discussed here – see Non-Medicated Life: An Important New Test Beyond Routine Cholesterol Testing in the January 2023 issue: adksports.com.

Trimethylamine-N Oxide (TMAO) is a test developed at the Cleveland Clinic to help explain why some individuals with “normal” cholesterol levels still develop heart disease. TMA (Trimethylamine) is produced by gut bacteria (gut microbiome) acting upon lecithin, choline, and carnitine from dietary sources. TMA is then absorbed from the gut and travels to the liver where it is oxidized to TMAO. TMAO is then released back into the circulation where it may damage the endothelial cells that line arteries. This damage then allows LDL, or the “bad” cholesterol, to penetrate the arterial wall and form a cholesterol plaque – the necessary first step in atherosclerosis.

The potential dietary sources of lecithin, choline and carnitine are red meat, eggs, dairy products and fish. Eating sufficient amounts of any or all of these may result in the selection and overgrowth of gut bacteria that can metabolize TMA. Experiments done with broad spectrum antibiotics that suppress such bacteria show a suppression in TMAO. In experiments in which both regular meat eaters and vegans were given a steak dinner, the regular meat eaters subsequent TMAO blood level was elevated, but the vegans did not show an increase in TMAO. Only by increasing the frequency of meat consumption in vegans was an increase in TMAO recorded. It appears that by increasing the frequency of meat consumption it is actually possible to alter the gut microbiome population to favor bacteria that can metabolize TMA.

TMAO may help answer the question: how much meat may I eat (and still be healthy from a cardiovascular perspective)? Because TMAO levels are also, in part, determined by your genetics, measurement may provide individualized feedback on the safe frequency and amount of consumption of red meat, fish and dairy products. Of course, the saturated fat content of red meat consumed is also important, as saturated fat will increase the concentration of LDL in the blood. Thus, substituting filet mignon (lower saturated fat) for porterhouse (higher saturated fat), as well as decreasing portion size and frequency of consumption, may lower cardiovascular risk as shown quantitatively by measuring both TMAO and LDL cholesterol.

Nuclear Magnetic Resonance LipoProfile (NMR LipoProfile) is a specialized blood test in which blood samples are subjected to NMR analysis in a manner similar to MRI of solid tissues. The NMR LipoProfile allows a delineation of the size distribution of LDL and HDL particles in the blood and a quantitation of particle number. You will recall that LDL and HDL in the blood exists as spherical particles. These particles are heterogenous in size, meaning that there are small, medium, and large sized LDL and HDL particles. This becomes potentially an important consideration because different size particles appear to be associated with different levels of risk. For example, so called small, dense LDL particles (smaller in size than average LDL, and denser in that they contain relatively more protein) are more likely to form plaques than so called large, fluffy LDL particles (larger in size than average LDL, and fluffy in that they contain more of a fat called triglyceride).

The distribution of these particles in a normal individual follows a bell curve, with few small LDL on one end, few large LDL on the other end, and medium size particles in between representing the majority. The area under this particle distribution bell curve is what is typically reported as your LDL number in milligrams per deciliter (mg/dL). By changing the shape of this bell curve, to have the “hump” of the curve toward one side or the other, may change the number of high-risk particles or low-risk particles, without changing the total area under the curve. Thus, the benefit of the NMR LipoProfile may be knowing the LDL subclass distribution and not only the total LDL in mg/dL.

Moreover, lifestyle changes may alter the particle distribution markedly. For example, exercise and weight loss result in predominately more large, fluffy LDL particles and fewer small, dense LDL particles, even if the LDL in mg/dL does not change appreciably. Patients are often upset that instituting an exercise program did not lower their LDL appreciably in mg/dL. The NMR LipoProfile may help to quantitate the benefit and provide valuable feedback that encourages continuation of beneficial lifestyle changes.

In summary, the determination of global cardiovascular risk is helped with the measurement of “surrogate markers” of risk, most commonly the standard cholesterol profile, assessed over time, to identify increasing or decreasing risk. Diet and lifestyle, as well as medications may appreciably change risk. After a discussion with your primary care physician or cardiologist, additional testing may be helpful. Beyond routine cholesterol testing, advanced tests may offer a way to further refine risk. Moreover, such advanced testing – such as HS-CRP, Apo B, TMAO, and NMR LipoProfile – when measured over time, may provide additional quantitative feedback on how you may further lower risk and help direct and refine lifestyle choices.

Paul E. Lemanski, MD, MS, FACP (plemanski3@gmail.com) is a board-certified internist practicing internal medicine and lifestyle medicine in Albany. Paul has a master’s degree in human nutrition, he’s an assistant clinical professor of medicine at Albany Medical College, and a fellow of the American College of Physicians.