Unraveling the Gordian knot of coronary pressure-flow autoregulation

Abstract

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today. The purpose of this review is to highlight current knowledge regarding the complex interrelationship between the pathways and mechanisms proposed to dictate the degree of coronary pressure-flow autoregulation. Our group recently likened the intertwined nature of the essential determinants of coronary flow control to the symbolically unsolvable "Gordian knot". To further efforts to unravel the autoregulatory "knot", we consider recent challenges to the local metabolic and myogenic hypotheses and the complicated dynamic structural and functional heterogeneity unique to the heart and coronary circulation. Additional consideration is given to interrogation of putative mediators, role of K⁺ and Ca²⁺ channels, and recent insights from computational modeling studies. Improved understanding of how specific vasoactive mediators, pathways, and underlying disease states influence coronary pressure-flow relations stands to significantly reduce morbidity and mortality for what remains the leading cause of death worldwide.

Keywords: Coronary blood flow; Heterogeneity; Local metabolic control; Myogenic response.

Fig. 1.

Representative effects of coronary perfusion pressure on A. Coronary blood flow; B. Coronary resistance; C. Myocardial oxygen consumption; D. Coronary venous PO₂ in cases of strong (data from [8]) vs. poor (data from [9]) autoregulation.

Fig. 2.

Schematic diagram of proposed parallel metabolic and myogenic pathways of coronary control. A. Coronary autoregulation adjusts to the level of myocardial oxygen consumption (MVO₂) (data from [5]); B. Coronary resistance is coupled with underlying changes in coronary venous PO₂ (data from [8, 23, 24, 112]); C. Coronary pressure-flow relationship in the absence and presence of Ca²⁺ channel blockade (data from [8]); D. Coronary arteriolar responses to intraluminal pressure at different levels of underlying tone (data from [33]).

Fig. 3.

Relationship between A. coronary blood flow and B. myocardial oxygen delivery vs. coronary perfusion pressure under control (data from [9]), hypoxemic (data from [25]), hemodilution (data from [9]), and dobutamine infusion (data from [25]) conditions in swine. Relationship between C. coronary blood flow and C. myocardial oxygen delivery vs. coronary perfusion pressure under control (data from [8]), inhibition of K_V channels with 4-aminopyridine (4AP) (data from [8]), and obese (data from [42]) conditions. Relationship between E. coronary resistance and coronary venous PO₂ at coronary perfusion pressures ranging from 60 to 120 mmHg (data from [8, 9, 25, 42, 47]). Relationship between F. autoregulatory gain (pressure range 60 to 120 mmHg) and coronary venous PO₂ at perfusion pressure of 100 mmHg (data from [8, 9, 25, 42, 47]).

Fig. 4.

A. Schematic representation of 1: Myocardial circulation model and 2: Representative vessel model from Gharahi et al. [101] (reprinted with permission from Wiley). B. Representative relationship between experimentally measured vs. model predicted coronary blood flow vs. coronary perfusion pressure. C. Predicted activation signals for myogenic and metabolic control plotted relative to coronary perfusion pressure in epicardium, midwall, and endocardium.