Investigating cardiac metabolism and the effect of novel metabolic modulation therapy on cardiac physiology and exercise capacity in aortic stenosis: a multi-parametric cardiac magnetic resonance study

Aortic stenosis is a major cause of morbidity and mortality in the western world. Whilst symptomatic patients with severe AS are treated with valve replacement surgery, there remains uncertainty about the best treatment for asymptomatic severe AS. Current guidelines recommend wait and watch strategy and offer surgery on occurrence of symptoms or evidence of systolic dysfunction. The annual rate of sudden cardiac death in asymptomatic severe AS remains close to 1%.
Aortic disease is both a disease of the valve and myocardium. The valve mechanisms and structural LV changes secondary to pressure overload have been extensively studied before, but no medical therapy directed at the valve processes has so far shown beneficial effect on cardiac physiology or disease progression. Changes in cardiac metabolism in pressure overload hypertrophy seem to play an important role in pathophysiology of AS and transition to decompensation. The healthy human heart uses fatty acids as the main energy source ~70% of adenosine triphosphate (ATP) requirements. In AS, there is substrate shift with downregulation of fatty acid oxidation (FAO) and increased reliance on glycolysis, with evidence of myocardial lipid accumulation and impairment of myocardial energetics. Peroxisome proliferator activated receptor-alpha (PPAR-a) plays a central role in FAO signalling and controlling lipid homeostasis in the heart. Downregulation of this transcriptional factor is associated with the metabolic alterations and subsequent lipotoxicity in AS, which ultimately causes reduced ATP production and heart failure. However, it is unclear whether these metabolic changes have a cause or effect relationship with the two main pathological features of AS, left ventricular (LV) pressure loading and LV hypertrophy, and their relationship with myocardial fibrosis (which is commonly seen in AS), is unclear.
Furthermore, it is yet unknown whether modulating cardiac metabolism would have any beneficial effect on disease progression or outcomes in AS.
This thesis set out to establish the relationship between metabolic remodelling and cardiac structure and physiology in AS. It then evaluates the role of novel metabolic modulator therapy in asymptomatic moderate-severe AS.
In Chapter 3 and 4, patients across the spectrum of AS were studied with advanced CMR imaging and phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and cardiopulmonary exercise testing (CPET) respectively. It is demonstrated that metabolic changes, specifically myocardial lipid accumulation (steatosis) and impaired cardiac energetics appear to occur early in the disease process. In addition, whilst impairment in cardiac energetics is related to degree of LV hypertrophy, steatosis appears to be more related to the degree of LV pressure loading from valve obstruction. Furthermore, these patients despite being asymptomatic with normal LVEF have evidence of subclinical LV dysfunction which occurs early in the disease process. Moreover, these patients though able to exercise to volitional exhaustion without developing symptoms have reduced average peak VO2 and VE/VCO2, both of which are predictors of outcome in cardiac disease.
In Chapter 4 and 5, the effect of the PPARa agonist Fenofibrate was evaluated on cardiac metabolism and physiology in a randomised double-blind placebo-controlled study. Fenofibrate reduced myocardial triglyceride content significantly after 6 months’ treatment with evidence of in vivo fatty acid oxidation upregulation. It also caused a modest improvement in cardiac energetics. However, this modulation did not show any measurable improvement in cardiac physiology or exercise capacity.
Together, these data show that myocardial metabolic remodelling plays an important role in pathophysiology and progression of AS. The novel finding from this research is that metabolic changes occur early in the AS disease process and are associated with early subclinical systolic and diastolic dysfunction. This highlights that metabolic remodelling may play a causal role in disease progression. This research has also shown, for the first time, that metabolic alterations in AS are amenable to modulation with a PPARa agonist, with some improvement in cardiac physiology but the benefit of such modulation in advanced disease remains questionable. Whether targeting earlier disease would yield different results remains unanswered.

Keywords: aortic stenosis
magnetic resonance imaging
cardiac metabolism
Advisor: Rider, O
Myerson, S
Neubauer, S