The Cholesterol Paradox, Part 3 – LDL in Heart Disease & Pulmonary Hypertension

LDL Cholesterol

There is more to LDL than meets the eye… While it is true that LDL is an established marker of cardiovascular disease risk, we need to be clear just how and why exactly this is so.

First things first. LDL is a means for delivering cholesterol to tissues that need it (and all cells need cholesterol to survive). Cholesterol (and thus LDL) is necessary for life: it is involved in hormone synthesis (including sex hormones), cell wall synthesis and maintenance, and the synthesis of vitamin D and bile acids. Additionally, it is involved in the process of repairing cellular injury. Now to tackle a few myths…

Myth #1 – LDL is the cause of Heart Disease

While LDL is involved in the atherosclerosis process, it isn’t the driving force, the immune system is… Atherosclerosis is the result of an immune response, by definition you need a macrophage deposited in an arterial wall to initiate the process of atherosclerosis. Thus, elevated non-esterified lipids, triacylglycerols, or cholesterol, resulting in increased risk of atherosclerosis is only one part of the equation; the other part is that you need elevated inflammation (macrophage immune cells, cytokines, etc.).1

Now while LDL is necessary, it is true you don’t want too high of an amount. More specifically, you don’t want a large number of small LDL particles. What does that mean and how does that relate to standard cholesterol testing? Firstly, a standard lipid panel done by your doctor does not provide the information necessary for accurate atherosclerosis risk assessment. To really understand your risk, you really need to know the LDL particle size and number. Small LDL particles, and increased numbers of those particles, are the real risk factors for atherosclerosis and heart disease. Testing can be done by labs like Quest Diagnostics which use NMR to analyze the LDL particle size and particle count for you.2,3,4 

Myth #2 – Very low levels of LDL are beneficial

While you don’t want too much LDL (in the form of high numbers of small LDL particles), you also don’t want too little. Recently, Kopeć et al. found low levels of LDL in PAH patients and that low circulating cholesterol is a marker of increased mortality in PAH and may accelerate disease progression: “While high LDL-C levels are associated with worse prognosis in the general population, there are some populations with chronic diseases including diabetes, heart failure, chronic kidney disease, and rheumatoid arthritis where low LDL-C levels have been linked to increased mortality. In PAH, low LDL-C levels might accelerate disease progression by several mechanisms including exacerbation of inflammation and direct effects on the arterial wall. In fact, we have recently shown that low LDL-C levels are associated with increased stiffness of pulmonary arteries. Conversely, as observed in other diseases, chronic inflammation, hepatic congestion, and low nutritional status, might be associated with reduced LDL-C levels in individuals with PAH.”5

They go on to say that the “traditional interpretation of hypercholesterolemia as a risk factor for increased mortality may not apply in PAH population. Instead, our finding of the deleterious signal of low LDL-C levels in PAH corresponds with the concept of cholesterol paradox and reverse epidemiology whereby lower levels of traditional risk factors are associated with worse prognosis. The evidence of a survival advantage associated with higher cholesterol levels has been provided for several populations with debilitating disorders such as heart failure, rheumatoid arthritis, acute myocardial infarction and in the elderly.”

They also mention that PAH treatment (vasodilator therapy, etc.) improves LDL-C.

Question: Is a low-fat diet or a high-fat diet good for PH?

My personal theory is that a high-fat, low carbohydrate diet may be very beneficial for PH, but this is a tough question and warrants serious investigation. For example, it is known that PH patients have a dysregulated fatty acid metabolism.6 Normally, the heart’s metabolism derives ~70-80% of its energy from fatty acid oxidation, but in PH this changes and glycolysis is the favored metabolic pathway. Whether this change is pathological or due to physiological adaptation is not certain. For example, it is known that a switch to aerobic glycolysis in tissues that normally rely on glucose and fatty acid oxidation is usually a pathological switch (cancer cells switch their metabolism to aerobic glycolysis).7 But perhaps glycolysis (which is a rapid but inefficient mechanism of obtaining energy) is needed by the right ventricle in PAH so it can quickly adapt to increased pulmonary vascular resistance?

Whether the PAH patient has a dysregulated fat metabolism as a result of insulin resistance and/or metabolic syndrome (which is known to be present in a majority of PAH patients), or as a result of underlying genetics or the PAH disease itself (e.g. a result of the BMPR2 mutation, or from the phenotype of proliferative PASMCs, and/or the chronic inflammation that occurs along with PAH), is also unknown. If dysregulated fat metabolism was a result of insulin resistance or metabolic syndrome than in theory dietary interventions could significantly improve the body’s metabolism and hopefully PAH (low-carb diets like The Paleo Diet and Ketogenic Diet have been shown to improve insulin resistance, improve inflammation, and improve cardiac function for a variety of individuals, more on this later…).8,9,10

Regardless of the underlying mechanism of dysregulated fat metabolism, this does not necessarily imply that individuals with or without PAH should decrease their dietary fat intake to absolute zero. Again, I personally suspect that specifically high-fat low-carb diets can improve PH, but I also admit that if dysregulated fat metabolism is a driver of PH (which it isn’t proven that it is), then high-fat diets may not be so beneficial.

However, additional observations by Kopeć et al. provide support in favor of my theory of high-fat, low-carb diets research potentially improving PAH: “In rabbits, it has been demonstrated that hypercholesterolemia can increase pulmonary artery relaxation in response to methacholine. Another experimental study in rats with monocrotaline induced PAH showed that high-fat diet and hypercholesterolemia was associated with better prognosis as compared with standard diet.” 



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