800px-RCA_atherosclerosis

The passage below is from “Metabolic Regulation: A Human Perspective”, by Keith N. Frayn. I sometimes read things with a “PH filter” (and sometimes with a more global filter depending on context), and this particular passage was read with my “PH filter”… It got me thinking about the relationship of elevated non-esterified fatty acid concentrations in the plasma, adipose tissue, atherosclerosis, and if there is any connection between those and pulmonary hypertension. For some perspective, fatty acid metabolism is dysregulated in PH patients, with decreased fatty acid oxidation in myocardium and potentially increased lipid accumulation in myocardium and other tissues, increasing risk of lipotoxicity. Patients also typically have hyperglycemia and insulin resistance, as well as dyslipidemia, and are also known to have elevated levels of plasma acyl-carnitines (the form of fatty acid needed to enter the mitochondria for beta-oxidation to produce ATP). Furthermore, there is a global metabolic dysregulation involving not only the myocardium, but the pulmonary vasculature, immune cells, bone marrow progenitor cells, and even skeletal muscle. [I have a lot of theories about this, especially about how nutrition comes into play (for instance, could low-carb diets be beneficial if this is the case?), but I will leave those for another time.]

“Prolonged exposure of the blood vessels to high concentrations of cholesterol and triacylglycerol can lead to the buildup of fatty deposits, atheroma, in arterial walls – the process known as atherosclerosis.
Excessive release of non-esterified fatty acids can also have adverse effects. This can occur in stressful situations. Excessive fatty acid concentrations have adverse effects on the heart and may predispose it to irregular patterns of contraction and, in severe cases, to ventricular fibrillation, an uncoordinated fluttering in which the pumping of blood effectively ceases. This is a possible link between an acutely stressful situation and a heart attack. In addition, elevated non-esterified fatty acid concentrations lead to increased hepatic secretion of triacylglycerol in the very-low-density lipoproteins, thus exacerbating any tendency to atherosclerosis. Elevated non-esterified fatty acid concentrations acting over a long time impair the sensitivity of tissues to insulin and may impair insulin secretion from the pancreatic beta-cell. Some prospective studies, in which participants are followed over several years, have shown that elevated plasma non-esterified fatty acids are associated with an increased risk of subsequently developing type 2 diabetes mellitus, and also of dying suddenly from a heart attack (the latter is probably related to the adverse effects on heart rhythm mentioned above).
One dramatic (although unusual) example of excessive lipid concentrations is fat embolus. If excess fat, usually in the form of triacylglycerol, is liberated into the plasma, then droplets of fat will circulate and may block blood vessels. This can occur after injury, when long bones such as the femur are fractured. Loosely connected fat cells are present in bone marrow and, if the bone fractures, the cells, their triacylglycerol contents, and some intact cells can be liberated in an entirely uncontrolled manner into the bloodstream. Globules of this fat may block blood vessels, particularly in the lung, leading to the difficulties with breathing.
These features of excessive concentrations of lipid fuels in the circulation highlight the need to regulate their entry to and removal from the bloodstream. White adipose tissue plays an essential role in these processes.”

Fatty acids are very important fuels for the heart (of which 60-90% of its preferred fuel is fatty acids) and for the body during starvation. They are hydrophobic (“water-fearing”) and need transport mechanisms (e.g. chylomicrons and lipoprotein particles) to travel through the body’s blood circulatory system. Non-esterified fatty acid transport is a highly regulated process. If the transport mechanisms “fail” somehow, or there is a dysregulation in this process, this could result in elevated plasma levels of non-esterified fatty acids which could be dangerous (as mentioned in the above passage). You don’t want fatty acids in plasma. You want them packaged and released at the site of the tissue where they are needed in a controlled way.

It is important to note that atherosclerosis is the result of an immune response: by definition you need a macrophage deposited in an arterial wall to initiate the process of athersclerosis. Thus, the increased risk of elevated non-esterified lipids, triacylglycerols, or cholesterol, resulting in atherosclerosis is only one part of the equation; the other part is that you need elevated inflammation (circulating immune cells, cytokines, and inflammatory markers, etc.). Due to the fact that macrophages and inflammation are involved, there is a large consensus in the scientific community that cardiovascular disease is an autoimmune phenomenon. It is also important to note that macrophages (dysregulation and/or overactivation), and elevated immune responses, are implicated in PH. Since autoimmunity is also implicated in PH, and in PH there is a dysregulation of fatty acid metabolism, perhaps PH is an “atherosclerosis of the lungs”? Atherosclerosis results in a narrowed vascular lumen. In PH, the pulmonary arterial vascular lumens are significantly narrowed, but this is due to hyperplasia and hypertrophy. But perhaps this hyperplasia and hypertrophic response is stimulated by an atheroma developed somewhere in the lungs? Or fat deposits are caught somehow in the lung, as mentioned in the last sentence of the 3rd paragraph in the above passage, but not as a result of a bone fracture, but by some other means?

If this were true, then this makes sense why PH patients are not at increased risk for coronary atherosclerosis: the atherosclerosis has “already occurred” in lungs first before hitting heart and coronary circulation. It also makes sense why PH targets the lungs specifically. Perhaps PH patients are more genetically susceptible to embolism in the lungs? If I recall correctly, I believe this has been confirmed in the literature.

What about adipose tissue? It is technically now considered an endocrine organ, even though it is dispersed throughout the body. Adiponectin, an adipose tissue hormone, is implicated in PH. Also, a few quick searches on Google have yielded some hits regarding adipose tissue around the heart. Is adipose tissue accumulating in heart or pulmonary organs? Is there such a thing as heart or pulmonary adipose tissue?

One last note: while I don’t think we fully understand all of the details up fatty acid uptake and metabolism, perhaps there is something worth investigating regarding CD36 (the fatty acid transport protein, bringing in fatty acids from the circulation into cells) involvement in pulmonary vasculature as well as the increased expression of lipoprotein lipase? It is important to remember, however, that if CD36 is involved, according to M. Talati, “not all increases in CD36 expression are pathological; for example, exercise-induced cardiac hypertrophy does not lead to cardiac failure.”

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