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R3i EDITORIAL

14 October 2016

Remnants linked with diabetic myocardial dysfunction

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Cholesterol-rich remnants are the products of the degradation of very low-density lipoproteins (secreted from the liver) and chylomicrons (secreted from the intestine). Plasma level of remnant cholesterol, a measure of remnant lipoproteins, is highly correlated with circulating levels of triglycerides, a key component of atherogenic dyslipidaemia that is a driver of cardiovascular risk .
Indeed, bearing in mind that the cholesterol content of these remnant lipoproteins is about five times that of low-density lipoprotein cholesterol (LDL-C), perhaps it is not surprising that accumulating evidence from observational, genetic and mechanistic studies shows that elevated levels of remnant cholesterol are causal for atherosclerotic vascular disease.1

Added to this, this month’s Focus article2 suggests that cholesterol-rich remnants may have detrimental effects on ventricular function in individuals with type 2 diabetes, specifically influencing sensitive measures of longitudinal myocardial function that are not detected on routine echocardiography. In a large, well characterized cohort study, Jørgensen and colleagues evaluated a number of different parameters of cardiac structure, systolic and diastolic function, as assessed by comprehensive echocardiography including 2D-speckle tracking echocardiography, which is sensitive to subtle changes in cardiac function. Calculated remnant cholesterol was defined as total-cholesterol – high-density lipoprotein-cholesterol – LDL-C. The authors showed that a doubling in remnant cholesterol was associated with significant changes in global longitudinal strain (by 0.33%, p=0.02) and longitudinal displacement (?0.25 mm, p= 0.01). Importantly, these associations were also present in type 2 diabetes subjects with well controlled LDL-C levels on statin therapy, thus adding further support for a role for cholesterol-rich remnants as contributors to lipid-related residual cardiovascular risk.

What of the mechanism(s) underlining the effect of remnant cholesterol on ventricular function? It may be that the accumulation of these cholesterol-rich lipoproteins may cause myocardial dysfunction (cardiac lipotoxicity), as proposed recently.3 In support, there is evidence from animal studies that higher cholesterol levels influence diastolic and systolic function.4,5 This suggests that elevated levels of remnant cholesterol are not only associated with subclinical atherosclerosis but also result in subtle detrimental changes in ventricular function in type 2 diabetes, possibly via microvascular effects.6 All possibilities may be implicated in the development of diabetic dysfunction typically seen in these individuals.

Given the accumulating evidence to support remnant cholesterol as a contributor to residual cardiovascular risk,1,7 how can this parameter be best targeted? In previous discussions on the R3i website, the potential of selective peroxisome proliferator-activated receptor (SPPARM) ?-agonism has been highlighted. In a recent phase II study, the novel SPPARM? pemafibrate (K-877) was shown to reduce plasma triglycerides by up to 43% and remnant cholesterol by up to 50%.8 Additionally, as discussed in this month’s Landmark study, post hoc analyses from the ANCHOR study, in statin-treated patients with residual hypertriglyceridaemia (?2.26 and <5.65 mmol/L), the addition of icosapent ethyl (eicosapentaenoic acid ethyl ester) reduced remnant cholesterol by about 30%.9

Whether the reduction in remnant cholesterol with these treatments translates to reduction in lipid-related residual cardiovascular risk awaits the results of ongoing cardiovascular outcomes studies. So, in the not too distant future, will clinicians have within their therapeutic armamentarium possibilities for targeting residual cardiovascular risk? We shall have to wait and see……………….

References

1. Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther 2014;141:358-67.
2. Jørgensen PG, Jensen MT, Sørensen TB et al. Cholesterol remnants and triglycerides are associated with decreased myocardial function in patients with type 2 diabetes. Cardiovasc Diabetol 2016;15:137.
3. Schulze PC, Drosatos K, Goldberg IJ. Lipid use and misuse by the heart. Circ Res 2016;118:1736-51.
4. Liu L, Mu Y, Han W, Wang C. Association of hypercholesterolemia and cardiac function evaluated by speckle tracking echocardiography in a rabbit model. Lipids Health Dis 2014;13:128.
5. Mochizuki Y, Tanaka H, Matsumoto K et al. Clinical features of subclinical left ventricular systolic dysfunction in patients with diabetes mellitus. Cardiovasc Diabetol. 2015;14:37.
6. Wei J, Nelson MD, Szczepaniak EW et al. Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women. Am J Physiol Heart Circ Physiol 2016;310:H14–9.
7. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol;13:26
8. Ishibashi S, Yamashita S, Arai H et al. Effects of K-877, a novel selective PPAR? modulator (SPPARM?), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
9. Ballantyne CM, Bays HE, Philip S et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): Effects on remnant-like particle cholesterol from the MARINE and ANCHOR. Atherosclerosis 2016;253:81-7.