Targeting High Oxygen Consumption to Prevent Cardiac Dysfunction in Patients With Aortic Valve Stenosis

• Editorials
• aortic valve stenosis
• diastole
• hypertrophy
• myocardium
• oxygen consumption

In the aging population, an increasing number of people experience aortic valve stenosis (AS) and develop severe concentric hypertrophy in response to pressure overload of the left ventricle.¹ Although aortic valve replacement (AVR) prevents worsening of cardiac disease, there is currently no treatment that effectively prevents the transition from compensatory hypertrophy to failure of the ventricle in patients with AS. Initially, the hypertrophic response of the ventricle in response to increased pressure is compensatory to preserve wall stress and systolic function. However, chronic overload of the ventricle induces pathological changes that ultimately cause failure of the ventricle. Defining the pathophysiologic mechanisms that underlie the transition from a compensatory to a failing hypertrophied ventricle is key to finding pharmacological treatment options for patients with AS. Imaging studies combining cardiovascular magnetic resonance and ¹¹C-acetate positron-emission tomography to assess myocardial external efficiency (MEE), that is, the ratio between external work and myocardial oxygen consumption (MVO₂), revealed reduced MEE in patients with AS compared with controls.² The hypertrophied ventricle of patients with symptomatic AS is characterized by high MVO₂,^2,3 indicative of high metabolic demand. To match the increased MVO₂, adequate perfusion of the ventricle is crucial. Ongoing concentric hypertrophy of the heart, however, impairs coronary blood flow reserve,⁴ which may underlie angina pectoris in patients with AS and may worsen disease outcome. Coronary perfusion and energy supply to the heart muscle occurs during diastole; coronary inflow (ie, oxygen delivery) is determined by diastolic pressure and duration of diastole.⁵ Concentric hypertrophy will limit coronary flow, in particular, during increased stress (eg, exercise). Ischemic damage of the heart will cause irreversible changes to the heart muscle, including severe mitochondrial damage, collagen formation, and microvascular rarefaction. The increased MVO₂ may represent a stress factor for the pressure-overloaded heart, and detrimental effects may be exacerbated during episodes of exercise. A detrimental effect of exercise has been shown in a mouse model with mild and severe transverse aortic constriction.⁶ In contrast to the beneficial effects of exercise in a mouse model with myocardial infarction,⁷ exercise tended to aggravate pathological cardiac remodeling and dysfunction in AS mice.^6,8 These previous studies indicate that high MVO₂ represents a target to prevent cardiac dysfunction in patients with AS. In patients with symptomatic AS, MEE increased and MVO₂ decreased on AVR in patients with AS.^2,9 Moreover, the AVR-induced increase in MEE was associated with improved exercise capacity assessed during cardiopulmonary exercise testing.² However, AVR did not correct MEE in several patients with AS within a 4-month follow-up,² which may suggest that irreversible damage occurred because of severe cardiac remodeling. As AVR is the final treatment option in patients with severe AS, it would be preferable if medical treatment could be initiated at an earlier stage in patients with asymptomatic AS. One way to reduce stress on the heart is by blocking adrenergic receptor stimulation with a β-blocker, a standard heart failure treatment in patients with reduced ejection fraction. β-blocker use has been associated with better prognosis in patients with AS.¹⁰ In the current issue of Circulation: Cardiovascular Imaging, Hansson et al¹¹ performed a randomized, double-blind, placebo-controlled trial to study whether metoprolol could improve myocardial efficiency in patients with asymptomatic AS. Although treatment with β-blockers may be harmful because of the negative inotropic effect on an already overloaded ventricle, it may represent a therapy to reduce the increased metabolic demand caused by the pressure overload. Forty patients with asymptomatic AS were randomized to metoprolol or placebo treatment for 22 weeks.¹¹ Metoprolol treatment reduced aortic valve gradients, global afterload, and MVO₂, thereby improving myocardial efficiency. Hansson et al¹¹ are the first to illustrate that β-blockade exerts hemodynamic benefit at an early disease stage in patients with AS. Future prospective studies with repeated measurement of myocardial efficiency in patients with AS are warranted to assess the long-term effect of therapy targeted at high MVO₂.

See Article by Hansson et al

An alternative way to tackle high oxygen demand of the heart is by targeting cardiac metabolism.^12–14 In the healthy heart, 95% of the energy demand is met by mitochondrial oxidation of fatty acids and carbohydrates, whereas 5% of ATP is produced via glycolysis. Although fatty acids represent the predominant fuel for the heart, they provide less ATP per oxygen molecule in comparison to carbohydrates.^13,14 Agents that shift mitochondrial oxygenation away from the preferred fatty acids toward carbohydrates would reduce oxygen consumption to produce ATP. Interestingly, hypertrophied hearts shift their metabolism from fatty acids to glucose utilization and glycolytic metabolism, which may represent an attempt to optimize the energetic status of the overloaded heart. A study in human cardiac tissue from patients with AS revealed changes in cardiac substrate transporters and metabolic proteins as underlying causes of the modified metabolic flux in hypertrophied myocardium.¹⁵ Metabolic therapy in symptomatic (advanced) hypertrophic cardiomyopathy patients corrected energy deficiency and improved exercise capacity.¹⁶ Thus, metabolic therapy may also represent a therapy to target high MVO₂ in patients with asymptomatic AS. Treatment is expected to be most effective in patients with asymptomatic AS with increased MVO₂. Patients with asymptomatic AS with increased hemodynamic burden may be identified by analysis of atrial dimensions and diastolic function at rest and during exercise.¹⁷ The key message from cardiovascular imaging studies is that chronically elevated MVO₂ triggers maladaptive remodeling in patients with AS and warrants further investigation to develop preventive treatment strategies at early disease stage.

• © 2017 American Heart Association, Inc.