Coronary Microcirculation in Aortic Stenosis: Pathophysiology, Invasive Assessment, and Future Directions

Abstract

With the increasing prevalence of aortic stenosis (AS) due to a growing elderly population, a proper understanding of its physiology is paramount to guide therapy and define severity. A better understanding of the microvasculature in AS could improve clinical care by predicting left ventricular remodeling or anticipate the interplay between epicardial stenosis and myocardial dysfunction. In this review, we combine five decades of literature regarding microvascular, coronary, and aortic valve physiology with emerging insights from newly developed invasive tools for quantifying microcirculatory function. Furthermore, we describe the coupling between microcirculation and epicardial stenosis, which is currently under investigation in several randomized trials enrolling subjects with concomitant AS and coronary disease. To clarify the physiology explained previously, we present two instructive cases with invasive pressure measurements quantifying coexisting valve and coronary stenoses. Finally, we pose open clinical and research questions whose answers would further expand our knowledge of microvascular dysfunction in AS. These trials were registered with NCT03042104, NCT03094143, and NCT02436655.

Figure 1

Animal aortic banding model that parallels the development of aortic valvular stenosis: at baseline, the systolic demand (shaded) and diastolic supply (not shaded) are well balanced when recording the aortic and left atrial pressures in this animal model of dynamic, supravalvular stenosis. With progressive banding demand rises (shaded area increases), supply falls (due to acute tachycardia in this animal model but also rising left atrial filling pressures marked as filled areas during diastole). Coronary blood flow (CBF, which corresponds to mean coronary blood flow) begins as diastolic dominant (unique to the normal heart) but concludes as systolic dominant (more typical of a peripheral organ bed) (reprinted from Figure 2 of a 1972 publication [12]).

Figure 2

Myocardial resistance in an animal model of aortic stenosis: at about 2 months of age, a 20–25 mmHg peak systolic gradient is created in dogs who were then studied at 10–14 months of age and compared with normal animals. During intravenous adenosine infusion, coronary flow is measured as a function of coronary pressure with progressive coronary constriction. Open circles represent normal dogs, and closed triangles represent those with supravalvular aortic stenosis. The flow versus pressure relationship (left) shifts to the right and rotates clockwise when moving from normal to aortic stenosis. Its slope relates inversely to the amount of left ventricular hypertrophy (middle), indicating a dose-response relationship. Its intercept correlates directly with left ventricular filling pressures (right). In these ways, the decrease in slope corresponds to an increase in myocardial resistance and the change in intercept to a rising zero-flow pressure due to higher LV filling pressures (reprinted from Figures 1–3 of a 1993 publication [19]).

Figure 3

Myocardial flow versus coronary pressure relationships: during hyperemia, a linear relationship exists between absolute myocardial blood flow and coronary pressure (basically equal to aortic pressure in the absence of a stenosis). This so-called myocardial “load line” has both slope (how much extra flow for an increase in driving pressure) and offset (often referred to as the zero-flow or wedge pressure depending on how it is measured). The slope of the myocardial load line corresponds to the myocardial resistance which can be calculated through the formula R = (Pc − Pzf)/Q, where R is the resistance, Pc is the coronary pressure, Pzf is the zero-flow, and Q is the flow. Under resting conditions (horizontal dashed line), the myocardium is capable of autoregulation to maintain a roughly constant flow over a wide range of perfusion pressures reflected by a constant nonhyperemic pressure ratio (NHPR). A fixed coronary stenosis produces both friction (“f ”) and separation (“s”) components to net pressure loss as can be deduced from the well-known coronary stenosis formula ΔP = f ∗ Q + s ∗ Q², where P is the pressure loss in mmHg and Q is the coronary flow in mL/min [67]. Its intersection with the myocardial load line represents the observations of FFR and maximum flow at peak hyperemia. Potential changes in the myocardial load line have been shown before versus after transcatheter aortic valve implantation (TAVI), although the relative magnitude and time course of a left shift (due to a fall in left ventricular filling pressures) and counterclockwise rotation (corresponding to more flow for the same driving pressure) have not yet been quantified (reprinted from the figure of recent 2020 editorial [68]).

Figure 4

Transmural impact of aortic stenosis with coronary disease: reduced flow from aortic stenosis and coronary stenosis does not affect all layers of the myocardium equally. Under baseline conditions, autoregulation (“auto” subscript) maintains a relatively stable flow for most perfusion pressures. Vasodilation (“max” subscript) produces the net hyperemic myocardial load line from Figure 3 that is made up of a lower offset in the subepicardium (Epi) than the subendocardium (Endo), with potentially different slopes as well. Exercise reduces diastolic perfusion time and increases left ventricular pressures, preferentially affecting the subendocardium both through tachycardia and also increased oxygen consumption. The resulting hypoperfusion can produce the classic symptoms of valvular stenosis.

Figure 5

Clinical case of simultaneous aortic and coronary stenosis assessment: as detailed in the text, this 82-year-old man with exertional dyspnea underwent coronary evaluation before transcatheter aortic valve implantation. Three pressures were measured simultaneously: aortic (via the guide catheter), coronary (via a distal pressure wire), and left ventricular (via a pigtail catheter). Intravenous papaverine induced coronary hyperemia with a fractional flow reserve (FFR) of 0.54. Both the severe aortic stenosis (baseline mean gradient 51 mmHg) and the severe in-stent coronary lesion imbalance myocardial demand (systolic pressure time integral, or SPTI) and diastolic coronary supply (diastolic pressure time integral, or DPTI). This figure allows for a visual understanding of the additive effects of the tandem aortic valve and coronary stenosis.

Figure 6

Clinical case of asymptomatic but severe stenosis: as detailed in the text, this 55-year-old asymptomatic man was referred for an incidental heart murmur on routine physical examination. A treadmill exercise test showed good functional capacity with no symptoms or abnormal responses, and echocardiography found normal ejection fraction. However, his bicuspid aortic valve had moderate-to-severe stenosis at baseline, rising to a mean gradient of 90 mmHg during intravenous dobutamine stress. Furthermore, his left anterior descending (LAD) coronary artery had an angiographically moderate-to-severe stenosis and fractional flow reserve (FFR) of 0.64 during intravenous adenosine infusion. When superimposing these curves (the distal coronary pressure tracing has been time-scaled to match the aortic pressure tracing), myocardial oxygen demand (systolic pressure time integral, or SPTI) greatly exceeds diastolic coronary supply (diastolic pressure time integral, or DPTI) due to increased SPTI from aortic stenosis and decreased DPTI due to coronary stenosis. Despite normal left ventricular function and a lack of symptoms, the patient underwent surgical aortic valve replacement (SAVR) and concomitant coronary artery bypass grafting (CABG) for extremely abnormal hemodynamics.