Regulation of coronary blood flow in health and ischemic heart disease

Abstract

The major factors determining myocardial perfusion and oxygen delivery have been elucidated over the past several decades, and this knowledge has been incorporated into the management of patients with ischemic heart disease (IHD). The basic understanding of the fluid mechanical behavior of coronary stenoses has also been translated to the cardiac catheterization laboratory where measurements of coronary pressure distal to a stenosis and coronary flow are routinely obtained. However, the role of perturbations in coronary microvascular structure and function, due to myocardial hypertrophy or coronary microvascular dysfunction, in IHD is becoming increasingly recognized. Future studies should therefore be aimed at further improving our understanding of the integrated coronary microvascular mechanisms that control coronary blood flow, and of the underlying causes and mechanisms of coronary microvascular dysfunction. This knowledge will be essential to further improve the treatment of patients with IHD.

Keywords: Coronary artery disease; Coronary blood flow; Hypertrophy; Ischemic heart disease; Microvascular dysfunction.

Fig. 1

Autoregulatory relation under basal conditions and following metabolic stress (e.g., tachycardia). The normal heart maintains CBF constant (left panel) as regional coronary pressure is varied over a wide range when the global determinants of oxygen consumption are kept constant (red lines). Below the lower autoregulatory pressure limit (approximately 40 mm Hg), subendocardial vessels are maximally vasodilated and myocardial ischemia develops. During vasodilation (blue lines), flow increases four to five times above resting values at a normal arterial pressure. Coronary flow ceases at a pressure higher than right atrial pressure (P_RA), called zero flow pressure (P_{f = 0}), which is the effective back pressure to flow in the absence of coronary collaterals. Following stress (right panel), tachycardia increases the compressive determinants of coronary resistance by decreasing the time available for diastolic perfusion and thus, reduces maximum vasodilated flow. Increases in myocardial oxygen demand or reductions in arterial oxygen content (e.g. from anemia or hypoxemia) increase resting flow. These changes reduce coronary flow reserve, the ratio between dilated and resting coronary flow, and cause ischemia to develop at higher coronary pressures. Abbreviations: LV, left ventricular; HR, heart rate; SBP, systolic blood pressure; Hb, hemoglobin. Reprinted from Canty and Duncker with permission.

Fig. 2

Transmural variations in coronary autoregulation and myocardial metabolism. Increased vulnerability of the subendocardium (ENDO; red) versus subepicardium (EPI; gold) to ischemia reflects the fact that autoregulation is exhausted at a higher coronary pressure (40 versus 25 mm Hg). This is the result of increased resting flow and oxygen consumption in the subendocardium and an increased sensitivity to systolic compressive effects because subendocardial flow only occurs during diastole. Subendocardial vessels become maximally vasodilated before those in the subepicardium as coronary artery pressure is reduced. These transmural differences can be increased further during tachycardia or during conditions with elevated preload, which reduce maximum subendocardial perfusion. Modified from Canty and Duncker with permission.

Fig. 3

Schematic drawing of an arteriole (top) and of endothelium, vascular smooth muscle and cardiomyocyte (at the bottom) illustrating mechanisms for control of vasomotor tone and diameter. Neurohumoral, endothelial, and metabolic influences are detailed in the bottom part of the figure. Abbreviations: K_Ca, calcium-activated K⁺ channel; K_ATP, ATP-sensitive K⁺channel; K_V, voltage-gated K⁺ channel; K_IR, inward rectifying K+ channel; Trp, transient receptor potential channels; O₂, oxygen; ATP, adenosine triphosphate; NO, nitric oxide; TXA₂, thromboxane A₂ and receptor; 5HT, 5-hydroxytryptamine and receptor; P2, purinergic type 2 receptor; M, muscarinic receptor; H₁ and H₂, histamine type 1 and 2 receptors; B₂, bradykinin type 2 receptor; ECE, endothelin-converting enzyme; bET-1, big endothelin-1; ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; L-arg, l-arginine; COX-1, cyclooxygenase 1; CYP450, cytochrome P450; ACE, angiotensin-converting enzyme; AI, angiotensin I; AII; angiotensin II; AT₁, angiotensin type 1 receptor; AT₂, angiotensin type 2 receptor; ET_A, endothelin type A receptor; ET_B, endothelin type B receptor; PG, prostaglandins; AA, arachidonic acid; EDHF, endothelium-derived hyperpolarizing factor; O₂⁻, superoxide anion; VGCC, voltage-gated calcium channels; IP, prostacyclin receptor; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; H₂O₂, hydrogen peroxide; α₁, α₁-adrenergic receptor; α₂, α₂-adrenergic receptor; β₂, β₂-adrenergic receptor; ACh, acetylcholine; NE, norepinephrine; NPY, neuropeptide Y; P1, purinergic type 1 receptor; and Y₁, neuropeptide Y receptor. Reproduced from Laughlin et al. with permission.

Fig. 4

A. Fluid mechanics of a stenosis. The pressure drop across a stenosis can be predicted by the Bernoulli equation. It is inversely related to the minimum stenosis cross-sectional area and varies with the square of the flow rate as stenosis severity increases. Abbreviations: ΔP, pressure drop; Q = flow; f₁, viscous coefficient; f₂, separation coefficient; A_s, area of the stenosis; A_n, area of the normal segment; L, stenosis length; μ, viscosity of blood; ρ, density of blood. Interrelation among the epicardial artery stenosis pressure flow relation (B), and the distal coronary pressure-flow relation (C). Red circles and lines depict resting flow and blue circles and lines maximal vasodilation for stenoses of 50, 70, and 90% diameter reduction. As shown in panel B, the stenosis pressure flow relation becomes extremely nonlinear as stenosis severity increases. As a result, there is very little pressure drop across a 50% stenosis, and distal coronary pressure and vasodilated flow remain near normal. However, a 90% stenosis critically impairs flow and, because of the steepness of the pressure flow relation, causes a marked reduction in distal coronary pressure. Modified from Canty and Duncker with permission.

Fig. 5

Effects of hypertrophy on absolute flow (ml/min) and flow per gm of tissue (ml/min/gm). A. With acquired hypertrophy, myocardial mass increases without proliferation of the microcirculatory resistance arteries. Absolute LV flow is shown in panel A. The increase in LV mass causes a proportional increase in absolute flow at rest although the maximum absolute flow per minute during vasodilation remains unchanged. B. When tissue perfusion is assessed using flow per gm of myocardium (as obtained using PET for example), the maximum flow per gram of tissue falls inversely with the increase in LV mass. In contrast, the resting flow per gram of myocardium remains constant since the increase in absolute resting flow is proportional to the increase in LV mass. Regardless of whether absolute flow or flow per gm is measured, the net effect of these opposing actions is to decrease coronary flow reserve at any coronary pressure in LVH. As a result of the reduction in microcirculatory reserve in the absence of a coronary stenosis, the functional significance of a 50% stenosis (triangles) in the hypertrophied heart could approach a more severe stenosis (in the example, 70%, circles) in normal myocardium. This can even result in ischemia with normal coronary arteries during stress. Modified from Canty and Duncker with permission.

Fig. 6

Impaired microcirculatory control with abnormal NO-mediated endothelium-dependent resistance artery dilation. A. Effects of blocking nitric oxide synthase (NOS) with the L-arginine analog LNAME in chronically instrumented dogs. There is an increase in the lower autoregulatory pressure limit, resulting in the onset of ischemia at a coronary pressure of 61 mm Hg versus 45 mm Hg under normal conditions that occurred without a change in heart rate (modified from Smith and Canty). B. Transmural perfusion before and after blocking NO-mediated dilation with LNNA in exercising dogs subjected to a coronary stenosis. Although coronary pressure and hemodynamics were similar, blood flow was lower in each layer of the heart after blocking NOS and was not overcome by metabolic dilator mechanisms during ischemia. Collectively, these experimental data support the notion that abnormalities in endothelium-dependent microvascular vasodilation can amplify the functional effects of a proximal coronary stenosis (modified from Duncker and Bache). Abbreviations: Endo, endocardium; Epi, epicardium; LNAME, N^G-nitro-L-arginine methyl ester; LNNA, N^G-nitro-L-arginine. Reprinted from Canty and Duncker with permission.

Fig. 7

A. There is a wide variation in paired measurements of functional stenosis severity using different indices of flow reserve in the same patient. Simultaneous intracoronary catheter based measurements of absolute flow reserve are compared to fractional flow reserve (FFR). This variability reflects differences in the contribution of the microcirculation and stenosis in individual patients (adapted from Johnson et al.). B. Hypothetical effects of microvascular dysfunction on the stenosis pressure flow relation and measurements of fractional flow reserve. The upper blue dashed line shows the idealized linear relation between absolute flow reserve and FFR when the coronary microcirculation is normal and maximally vasodilated. The lower red dashed line indicates the relation between absolute flow reserve and FFR when there is microvascular dysfunction. Individual stenoses are illustrated by the solid blue lines. The presence of microvascular dysfunction will limit vasodilation. Thus, absolute flow reserve will be reduced and overestimate stenosis severity. In contrast, since distal coronary pressure is higher with submaximal vasodilation, fractional flow reserve, and relative flow reserve will underestimate stenosis severity. It is likely that these interactions contribute to the variability demonstrated in Fig 7A. Modified from Canty and Duncker with permission.