Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism.

Loreta Casquel De Tomasi,Stephen C Kolwicz,Antonio Carlos Cicogna,Carlos Roberto Padovani,Son Nguyen,Katashi Okoshi,Dijon Henrique Salomé Campos,Paula Grippa Sant’Ana,Gilson Masahiro Murata,Sudhiranjan Gupta

doi:10.1371/journal.pone.0193553

Abstract

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.

Highlights

Based on epidemiological evidence demonstrating reduced cardiovascular risk and mortality with consumption of diets high in unsaturated fatty acids [1,2], dietary intervention strategies remain an attractive therapeutic option to combat the metabolic and cardiac remodeling processes that occur in the hypertrophied heart
The Aortic stenosis (AS) group presented with decreased E/A ratios, in addition to, significantly increased left atrium (LA) diameter and LA to aorta ratio (LA/Ao), indicative of diastolic dysfunction (Table 1)
The major finding of the present study is that rat hearts subjected to supra-valvar aortic stenosis (SVAS) developed significant hypertrophy, diastolic dysfunction, and are prone to depletion of the unsaturated fatty acids, oleate and linoleate, within the endogenous cardiac lipid pools, potentially identifying this as an additional feature of abnormal lipid metabolism in pathological hypertrophy

Summary

Introduction

Based on epidemiological evidence demonstrating reduced cardiovascular risk and mortality with consumption of diets high in unsaturated fatty acids [1,2], dietary intervention strategies remain an attractive therapeutic option to combat the metabolic and cardiac remodeling processes that occur in the hypertrophied heart. Previous studies using various high fat diets in animal models have yielded mixed results These studies have suggested that lipid metabolic pathways may be improved [3,4,5,6] following high fat diet administration but pathological remodeling remains unaffected [4,5] or attenuated [6,7,8]. We hypothesized that administration of a diet high in unsaturated fatty acids would have a beneficial effect on cardiac dysfunction, pathological remodeling, and lipid metabolism in the pressure-overloaded heart

Methods

Results

Conclusion