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14 October 2016
Remnant cholesterol and decreased myocardial function in type 2 diabetes

Study indicates that increasing levels of remnant cholesterol and triglycerides have detrimental effects on left ventricular function in individuals with type 2 diabetes patients with or without statin therapy.

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.
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate whether remnant cholesterol and its marker, triglyceride levels, are associated with cardiac function in type 2 diabetes patients.
Study design: Cohort echocardiographic study
Study population: 924 patients with type 2 diabetes recruited by two centres were included; mean age was 65 years, 65% were male and median diabetes duration was 11 years. 79% of patients were receiving a statin (median low-density lipoprotein cholesterol [LDL-C] was 1.8 mmol/L in these patients versus 2.0 mmol/L in patients not on a statin). Triglycerides were similar in each group (median 1.7 mmol/L).  
Key outcomes: - Measures of cardiac structure, systolic and diastolic function, assessed by comprehensive echocardiography including 2D-speckle tracking echocardiography.
- Lipid measurements: Plasma triglycerides and remnant cholesterol, calculated as total-cholesterol – high-density lipoprotein cholesterol – LDL-C
Methods: Due to their skewed distribution, data for triglyceride and remnant cholesterol levels were logarithmically transformed before analysis. The effect of increasing levels of triglycerides and remnant cholesterol on measures of cardiac structure, systolic and diastolic function was evaluated using multivariable linear regression analysis, including age, sex, haemoglobin A1c, body mass index, systolic blood pressure and albuminuria as covariates.
Main results:

- Triglycerides and remnant cholesterol were not associated with left ventricular ejection fraction.
- However, both variables were associated with subtle measures of systolic function, including global longitudinal systolic strain, and longitudinal displacement. Increasing levels of both lipid parameters were associated with a decrease in left ventricular function. Similar effects were observed in patients receiving statin therapy without established heart disease (Figure, for remnant cholesterol).

Figure. Association of remnant cholesterol levels with global longitudinal strain and longitudinal displacement in patients with type 2 diabetes.

Authors’ conclusion: In patients with type 2 diabetes, a subtle decrease in left ventricular function is present with increasing levels of remnant cholesterol and triglyceride levels indicating an effect of these on cardiac function that is not detectable by conventional echocardiography.

COMMENT

This report shows that increasing levels of remnant cholesterol and triglycerides (which are makers of remnant cholesterol) are associated with subtle changes in left ventricular systolic function in type 2 diabetes patients, the majority of whom were on statin therapy and had well controlled LDL-C level. These findings, which are strengthened by the size and well- characterized nature of the study cohort, suggest an effect of these lipoproteins on cardiac function that is not detectable by conventional echocardiography.
Fatty acids (derived from triglycerides) act as energy providing substrates in the heart, with the balance between lipid uptake and oxidation preventing accumulation of excess lipid. In individuals with diabetes, this balance is distorted, leading to ventricular dysfunction independent of underlying coronary artery disease.1 Obesity-mediated alterations in myocardial lipid metabolism, including accumulation of various lipid intermediates such as triacylglycerol, are linked to the development and progression of myocardial dysfunction. Animal studies have previously shown associations between cholesterol levels and diastolic and systolic function.2,3 The current study shows that remnant cholesterol influenced sensitive measures of longitudinal myocardial function (i.e. global longitudinal strain and longitudinal displacement),4 thus lending support to the proposal that subclinical atherosclerosis may explain, at least partly, the decreased myocardial function seen in type 2 diabetes patients with this dyslipidaemia. Alternatively, others have suggested that myocardial steatosis may be the link between diastolic dysfunction and coronary microvascular dysfunction in women.5

Evidence from this study that increasing levels of remnant cholesterol and triglyceride levels had a detrimental effect on cardiac function that is not detectable by conventional echocardiography, provides additional support for the role of remnant cholesterol (for which triglycerides are a marker) as a contributor to lipid-related residual cardiovascular risk in statin-treated type 2 diabetes patients. These results reinforce the importance of therapeutic targeting of remnant cholesterol to both improve cardiac function and reduce lipid-related residual cardiovascular risk in these high risk patients.

References 1. Schulze PC, Drosatos K, Goldberg IJ. Lipid use and misuse by the heart. Circ Res 2016;118:1736-51.
2. Huang Y, Walker KE, Hanley F et al. Cardiac systolic and diastolic dysfunction after a cholesterol-rich diet. Circulation 2004;109:97–102.
3. 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.
4. 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.
5. 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.
Key words triglycerides; remnant cholesterol; myocardial function; echocardiography; residual cardiovascular risk; type 2 diabetes