Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans

Abstract

Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[(¹⁸F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT⁺) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT⁻). Measured by [¹¹C]acetate with PET, IGT⁺ subjects have a significant increase in myocardial oxidative index. IGT⁺ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT⁺ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT⁺ versus IGT⁻. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism.

FIG. 1.

Plasma glucose (A), insulin (B), NEFA (C), TG (D), and chylomicron-TG (E) excursion after standard liquid meal intake at time 0. P values are two-way ANOVA comparisons between groups in a model that also included time and time × group interaction. •, IGT+; ○, IGT−.

FIG. 2.

¹⁸F activity in plasma (A), chylomicron fraction (B), plasma TG (C), and plasma NEFA (D) after oral administration of 14(R,S)-¹⁸FTHA. Data were analyzed using two-way ANOVA with group, time, and time × group interaction as independent variables in the model. None of the group comparisons were significant. ID, ingested dose. •, IGT+; ○, IGT−.

FIG. 3.

Anterioposterior whole-body PET acquisition performed 6 h after oral administration of 14(R,S)-¹⁸FTHA from an IGT⁻ (A) and IGT⁺ subject (B). SUV from whole-body PET in the heart (C), liver (D), skeletal muscle (E), thigh subcutaneous (SC) adipose tissue (F), anterior SC abdominal adipose tissue (G), and perirenal adipose tissue (H). P values are from Mann–Whitney test. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 4.

Fractional 14(R,S)-¹⁸FTHA uptake rate in the heart (A) and liver (C) and net chylomicron–fatty acid uptake rate in the heart (B) and liver (D) between times 90 and 120 min after oral administration of the tracer. Radioactivity in aorta (closed circles), left ventricle (open circles), and liver (closed squares) during dynamic PET acquisition is shown from a representative participant (E). P values are from Mann–Whitney test.

FIG. 5.

Spearman correlation between myocardial 14(R,S)-¹⁸FTHA SUV and left ventricular ejection fraction (A), stroke volume (B), time-to-peak left ventricular filling rate (C), and myocardial oxidative index (D). Spearman correlation between perirenal (visceral) (E) and anterior subcutaneous (SC) abdominal (F) adipose tissues and waist circumference.