Disentangling the Gordian knot of local metabolic control of coronary blood flow

Abstract

Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o₂) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation. For a number of years, coronary venous Po₂ has been generally accepted as a measure of myocardial tissue oxygenation and thus the classically proposed error signal for the generation of vasodilator metabolites in the heart. However, interpretation of changes in coronary venous Po₂ relative to MV̇o₂ are quite nuanced, inherently circular in nature, and subject to confounding influences that remain largely unaccounted for. The purpose of this review is to highlight difficulties in interpreting the complex interrelationship between key coronary outcome variables and the arguments that emerge from prior studies performed during exercise, hemodilution, hypoxemia, and alterations in perfusion pressure. Furthermore, potential paths forward are proposed to help to facilitate further dialogue and study to ultimately unravel what has become the Gordian knot of the coronary circulation.

Keywords: coronary circulation; coronary venous Po2; local metabolic control; myocardial oxygen consumption.

Fig. 1.

Classic relationships between coronary blood flow and myocardial oxygen consumption (A), coronary blood flow and coronary venous Po₂ (B), and coronary venous Po₂ and myocardial oxygen consumption (C) in dogs.

Fig. 2.

Schematic representation of the interrelations between the primary variables proposed to modulate local metabolic control of coronary blood flow.

Fig. 3.

Relationship between coronary blood flow and heart rate [index of myocardial oxygen consumption (MV̇o₂)] across multiple species: mouse (84), rat (41), dog (3), swine (70), horse (77), and human (53).

Fig. 4.

Relationship between coronary blood flow and coronary venous Po₂ (A) and coronary venous Po₂ and myocardial oxygen consumption (B) across multiple species: dog (38, 51, 110), swine (43, 54, 81), and human (53, 55).

Fig. 5.

Relationship between coronary blood flow and coronary venous hemoglobin saturation across multiple species: dog (38, 51), swine (43, 81), and human (36, 55).

Fig. 6.

Relationship between coronary blood flow (A), myocardial oxygen delivery (B), coronary venous Po₂ (C) relative to arterial oxygen content in response to hemodilution (solid line; Refs. 18, 19, 46, 65, 76, 113) and hypoxemia (dashed line; Refs. 37, 45, 56, 74, 82, 114, 115). Arterial oxygen content was used to normalize the level of oxygen deficit in each study.

Fig. 7.

Relationship between coronary blood flow and coronary perfusion pressure (A) and autoregulatory gain (change in coronary flow over 20-mmHg increments at pressures ranging from 120 to 60 mmHg) relative to coronary venous Po₂ (B). Responses are plotted in the absence (solid line) and presence of euvoluemic hemodilution (dashed line) (~50% reduction in hematocrit) plus dobutamine (increase heart rate ~75–100% above baseline levels). Data from Kiel et al. (64).

Fig. 8.

Relationship between coronary blood flow (A) and coronary venous Po₂ (B) vs. myocardial oxygen consumption in conscious instrumented dogs at rest and during graded treadmill exercise. Responses are plotted in the absence and presence of nitric oxide synthesis inhibition with N-nitro-l-arginine. Data replotted from Tune et al. (109).

Fig. 9.

Coronary blood flow (A), myocardial oxygen consumption (B), and coronary venous Po₂ (C) at rest and during exercise in the absence and presence of the K_V channel inhibitor 4-aminopyridine (4-AP) in conscious instrumented swine. Data from Berwick et al. (10). *P < 0.05 vs. control.

Fig. 10.

Coronary blood flow (A) and myocardial oxygen consumption (B) at rest and during exercise (Ex) in the absence and presence of the K_ATP channel inhibitor glibenclamide + the adenosine receptor blocker 8-phenytheophylline (8-PT) ± the nitric oxide synthase inhibitor [N-nitro-l-arginine (LNNA)] in conscious instrumented dogs. Myocardial oxygen consumption (C) and systolic wall thickening (D) vs. coronary blood flow with and without glibenclamide (Glib) + 8-PT and the vasodilator sodium nitroprusside (SNP) under baseline resting conditions [data from Duncker et al. (35) and Ishibashi et al. (61)]. *P < 0.05 vs. control. †P < 0.05 vs. glibenclamide + 8PT.

Fig. 11.

Coronary venous Po₂ vs. myocardial oxygen consumption at rest and during exercise in the absence and presence of the Kv channel blocker 4-aminopyridine [4-AP; data from Berwick et al. (10); A] and the K_ATP channel inhibitor glibenclamide [data from Duncker et al. (35); B].