Title: Non-invasive Coronary Physiological Reserve to Determine the Physiological Significance of Aortic Stenosis
Funder: Medical Research Council

Abstract: Background: Exertional symptoms in aortic stenosis indicate necessity for valve replacement, but are mimicked by other conditions or masked by inactivity. Late intervention risks irreversible deterioration of cardiac function, whilst early intervention poses surgical risk without benefit. Increased afterload and ventricular remodelling alters microcirculatory physiology to cause myocardial ischaemia and symptoms Determining the microcirculatory impact may guide intervention before irreversible damage occurs. This can be quantified using invasive wave intensity analysis utilising commercially available wires with pressure and Doppler flow sensors. We showed that in patients with severe symptomatic aortic stenosis, the intensity of microcirculatory-originating suction wave that drives coronary perfusion in early diastole, diminishes when the heart rate increases. This index, the coronary physiological reserve, corrects to a normal pattern of increased wave intensity, immediately after percutaneous aortic valve replacement. However, the impact of less severe aortic stenosis on the microcirculatory-originating waves and the coronary physiological reserve is undetermined. Furthermore, the invasive nature of the current technique limits its utility. We have shown that it is feasible to measure coronary physiological reserve non-invasively using a Pulsecor assessment of central pressure and transthoracic coronary Doppler using a Philips iE33 echocardiography machine. During this fellowship, I will develop this technique and validate against its invasive equivalent. I will use both to assess the coronary physiological reserve in differing severities of aortic stenosis to understand the impact of increasing afterload. Hypothesis: 1. Non-invasive coronary wave intensity and coronary physiological reserve are equivalent to their invasive counterparts. 2. Coronary physiological reserve is increased in mild-moderate aortic stenosis, but is decreased in subjects with moderate-severe aortic stenosis. 3. Myocardial blood flow as assessed by quantitative perfusion cardiac MRI is reduced in those with reduced coronary physiological reserve. Study design: I will study coronary physiological reserve using both invasive and non-invasive techniques in 31 patients with aortic stenosis. I will also determine its relationship with myocardial blood flow measured by cardiac MRI. Results: We anticipate that a dome-shaped parabolic relationship exists between increasing aortic stenosis severity and the microcirculatory wave intensity. The ‘tipping point‘ represents the onset of impaired myocardial perfusion; this may indicate necessity for intervention before the onset of symptoms Opportunity: This study will improve our understanding of coronary physiology in aortic stenosis. By using commonly available equipment it will provide a new objective, non-invasive measurement of the physiological significance of aortic stenosis to guide decisions for valvular intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR