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Aortic stenosis with impaired ventricular function manifests impaired cardiac metabolism: implications for prognosis and surgical intervention
  1. H Ashrafian1,
  2. NJ Howell2,
  3. J Ormerod2,
  4. F Hammer2,
  5. N Drury2,
  6. V Steeples1,
  7. C Lygate1,
  8. MP Frenneaux2,
  9. D Pagano2,
  10. H Watkins1
  1. 1Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK
  2. 2Department of Cardiovascular Medicine, Birmingham University, Birmingham, UK

Abstract

Introduction It is increasingly recognised that energy deficiency contributes to the pathogenesis of left ventricular hypertrophy (LVH) and heart failure (HF). To delineate the metabolic mechanisms contributing to the transition from LVH to HF and to relate these to the operative risk of aortic valve replacement (AVR) in aortic stenosis (AS), the cardiac metabolic transciptome was studied at progressive stages in a murine model of AS and in patients with advanced AS with indices of HF.

Methods The expression pattern of master metabolic transcription factors (eg, PGC-1α and PPARα) and their downstream metabolic pathways were assessed in mice having undergone transverse aortic constriction at progressive stages of acute left ventricular pressure overload, compensated LVH and LVH plus HF, corresponding to the phases of AS. This pattern of metabolic changes was compared with patients undergoing AVR surgery for advanced AS with haemodynamic features of HF. Mass spectrometry was used to assess high-energy phosphate species and other metabolites in the myocardium.

Results Although acute pressure overload was not accompanied by any significant changes in the metabolic transcriptome, compensated LVH and the transition to HF were accompanied by consistent downregulation of master transcriptional regulators controlling mitochondrial biogenesis/fatty acid metabolism (eg, PGC1α, PPARα and ERRα) and their downstream pathways (eg, CPT-1; fig 1). A corresponding pattern of energetic compromise (including reduced ATP/ADP) was observed in advanced AS with HF (fig 2).

Abstract 124 Figure 1.

Metabolic transcriptome of the transition from left ventricular hypertension (LVH) to heart failure (HF) in a murine aortic banding model of progressive HF. Progressive left ventricular assessment as assessed by echocardiography was associated with progressive reductions in the expression levels of mRNA coding for key metabolic modulators (n  =  5 in each group, *p<0.05, **p<0.01).

Abstract 124 Figure 2.

Metabolic transcriptome of human left ventricular hypertension (LVH) resulting from advanced aortic stenosis. In accord with the murine data, manifest advanced LVH in aortic stenosis patients was associated with progressive reductions in the expression levels of mRNA coding for key metabolic modulators (n  =  5 in each group, *p<0.05, **p<0.01, ***p<0.001).

Conclusions Our findings suggest that the downregulation of cardiac metabolism resulting from the observed progressive downregulation of the cardiac metabolic transcriptome during the transition from LVH to HF may contribute to the pathogenesis of ventricular dysfunction and predispose patients to adverse surgical outcomes. A combination of timely surgery coupled with interventions that augment myocardial metabolism and energetics may ameliorate both the prognosis of AS with HF and the prognosis of surgery.

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