Insights Into the Metabolic Aspects of Aortic Stenosis With the Use of Magnetic Resonance Imaging

Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.

A ortic stenosis (AS) is a common cardiovascular disorder, with an estimated prevalence of approximately 2% among individuals aged 65 to 70 years, increasing to 3% to 9% after the age of 80 years. 1 This presents an increasing societal and economic burden. Current guidelines recommend aortic valve replacement as the definitive treatment for severe AS, but only after the onset of clinical symptoms or when there is impaired left ventricular (LV) systolic function. Therapeutic alternatives to valve replacement are extremely limited, particularly those to aid the myocardium cope better with AS.
There is also no treatment for asymptomatic moderate or severe AS with preserved systolic function, and patients currently wait until valve replacement is warranted, that is, as an end-stage mechanical option.
Understanding the metabolic and physiologic pathways in AS may identify suitable targets for future treatments that could provide alternatives to end-stage valve replacement. Ongoing pressure overload in AS increases myocardial wall stress and leads to an increase in wall thickness and mass, which results in left ventricular hypertrophy (LVH). 2 Pathologic LVH in AS appears to be a typical cardiac phenotypic response to stress, encompassing structural and metabolic remodeling eventually leading to a cardiomyopathy-like process with impaired myocardial metabolism and energetics ( Figure 1).
Identifying early markers of cardiac decompensation would help to identify those most at risk of transition to heart failure (HF).
In this review, we discuss the metabolic alterations that occur in AS and the potential links between abnormal metabolism and progression from compensated ("appropriate physiologic") hypertrophy to HF.
We focus on the role of magnetic resonance (MR) metabolic imaging in detecting these changes (Central Illustration) and introduce the subject of metabolic modulation as a potential therapeutic option in AS.

NORMAL CARDIAC METABOLISM
As a continually working aerobic biological pump, the adult human heart has the highest energy demand for adenosine triphosphate (ATP) per gram weight of any organ: around 6 kg daily, which is 15-20 times its own weight. 3,4 Normal cardiomyocyte metabolism ( Figure 2) comprises 3 key stages. The first stage is substrate utilization, that is, cellular uptake of substrates followed by their breakdown via metabolic pathways, such as beta-oxidation and glycolysis, to generate acetyl coenzyme A (acetyl-CoA) which then enters the tricarboxylic acid or Krebs cycle. In the adult heart, fatty acids (FAs) are the main energy source, accounting for 60% to 90%, and the remaining 10% to 40% comes from glucose, amino acids, pyruvate, lactic acid, ketone bodies, and other sources. 5,6 The second stage is oxidative phosphorylation, that is, the process in which the high-energy phosphate compound, ATP, is formed through phosphorylation of adenosine diphosphate (ADP) in the inner mitochondrial membrane as a result of the transfer of electrons from the reduced NADH/FADH 2 , produced in beta-oxidation, glycolysis, and the Krebs cycle, to O 2 by series of electron carriers. The third component is ATP transfer and utilization, that is, the transport of energy to, and its consumption by, the myofibrils. This is facilitated through an energy-transfer mechanism termed the creatine kinase (CK) energy shuttle. 7 The CK system plays an important role in myocardial energy metabolism by maintaining ADP levels high in the mitochondria (CK mitochondrial isoform), where ATP is generated, and low at sites of ATP utilization (CK muscle isoform), thereby enhancing the efficiency of the energy utilization processes ( Figure 2). 8 The phosphocreatine (PCr)/ATP ratio is one indicator of this energetic state of the myocardium and is reduced in hypertrophied hearts 9 and in HF. 10 However, PCr/ATP ratio does not directly reflect the rate of ATP production through the CK reaction. ATP levels fall only when PCr levels are substantially depleted, because the CK system strongly favors ATP synthesis above PCr synthesis, which may be more important in the progression to HF in patients with LVH. 11 The metabolic flexibility of the heart allows it to consume nearly all types of energy substrates to form ATP, 6 determined by external factors such as the availability of substrates in the blood 12     An overview of the various cardiac magnetic resonance metabolic imaging techniques and their ability to study specific aspects of cardiac metabolism in aortic stenosis. 1 H ¼ proton; 13 C ¼ carbon; 31     The final step of energy transfer is accomplished through oxidative phosphorylation (Ox Phos), supplying >95% of ATP consumed by the heart. The boxes above each metabolic pathway indicate the pathologic and physiologic condition in which the specific substrate becomes a predominant contributor to metabolism.
ATGL ¼ adipose triglyceride lipase; DGAT ¼ diacylglycerol acyltransferase; mCPT1 ¼ muscle form of carnitine-palmitoyl transferase 1; PDH ¼ pyruvate dehydrogenase; TAG ¼ triacylglycerol; TCA ¼ tricarboxylic acid; other abbreviations as in Figure 2. AS and metabolic syndrome. Our group has shown that steatosis is present in severe AS and independently correlates with LV dysfunction as measured by myocardial strain parameters ( Figure 4B). Importantly, following valve replacement, there is both regression of steatosis and improvement in myocardial strain. 28 Thus, the evidence so far supports the hypothesis of substrate switch, lipid overload, and subsequent mitochondrial dysfunction and contractile     overcome, however, with hyperpolarized 13 C imaging, 40 where the MR-active nuclei such as 13 C are mixed with a low concentration of free electrons and the sample is irradiated with microwaves in a high magnetic field (>3.0-T) and at low temperature (w1 K).  Studies have shown that PCr/ATP is a better predictor of long-term survival than New York Heart Association functional class or LV ejection fraction in several cardiac conditions, including dilated cardiomyopathy, 70 hypertrophic cardiomyopathy, 71 HF with preserved ejection fraction, 72 and ischemic heart disease. 73 CK reaction rate and flux also can be probed with the use of 31 P-MRS, which provides a more accurate assessment of cardiac energetic state than PCr/ ATP alone. 61 We 74 and others 75 have demonstrated that both PCr/ATP ratio and CK flux are reduced in symptomatic AS patients, being lowest in those with associated systolic failure, 61 and correlates with LV end-diastolic pressures and end-diastolic wall stress, in line with previous histologic animal and human studies. 59,60 Studies have also shown that impaired energetics in AS are reversible following relief of pressure overload and hypertrophy regression. 76,77 The method and sample spectra comparing the PCr/ATP from a healthy volunteer, and asymptomatic AS patient, and a symptomatic are shown in Figure 5.

OTHER PRESSURE-OVERLOAD LV DISORDERS
These metabolic changes secondary to reduced myocardial FA metabolism are not exclusive to AS; other pressure-overload LV disorders, such as hypertensive heart disease, show a similar maladaptive substrate switch and consequential energy-hungry state. 78,79 As in AS, these phenomena precede the increase in LV mass and are potentially responsible for decreased myocardial efficiency and subsequent heart failure. 80 The basis of these metabolic changes in the pressure-overloaded heart is substantial metabolic reconfiguration, including substrate utilization switch from FAs to glucose, uncoupling of glucose uptake from oxidation with enhanced glycolysis, 15 FAO down-regulation, 16  Overall, decreased FAO clearly contributes to the reappearance of the fetal metabolic pattern in hypertrophied and failing hearts that leads to increased reliance on glycolysis 87 combined with up-regulation of anaplerosis to maintain TCA flux, 17 and it slightly improves myocardial oxygen efficiency, but this metabolic profile is inefficient in utilizing carbon substrates for ATP production during increased energy demand, leading to impaired myocardial energetics and depletion of contractile reserve. 7,18 Accompanying this switch is also an imbalance between FA uptake and FA oxidative metabolism,

FUTURE DIRECTIONS
Because lipid metabolism seems to underpin both the metabolic and the hypertrophic mechanisms seen in

HIGHLIGHTS
Understanding the cellular pathophysiologic processes in AS may help to identify patients likely to decompensate early, and to explore potential therapeutic targets that could delay disease progression.
Altered cardiac substrate utilization and consequent myocardial steatosis and reduced energy efficiency has been implicated in the transition from compensated hypertrophy to heart failure in AS.
Magnetic resonance spectroscopy allows detailed assessment of changes to cardiac substrate and high-energy phosphorous metabolism, improving our understanding of the links between abnormal metabolism and impairment of cardiac function in AS.