Coronary Blood Flow and Coronary Autoregulation

1. Anatomy of the Coronary Circulation

Heart and coronary circulation - anterior view (left) and posteroinferior view from diaphragm (right). AV = atrioventricular; SA = sinoatrial.

• Epicardial arteries - large conduit vessels on the surface, function primarily as low-resistance conduits with little direct control over flow; they are the principal sites of atherosclerosis
• Intramuscular arteries - penetrate from epicardium toward endocardium
• Subendocardial arterial plexus - a rich interconnected network just beneath the endocardium, compensates for systolic compression

Epicardial coronary arteries and the subendocardial arterial plexus - note how penetrating branches supply myocardium from outside in.

2. Normal Coronary Blood Flow - Resting Values

3. Phasic Nature of Coronary Blood Flow

Phasic coronary blood flow. Top: Aortic pressure. Middle: Left coronary flow - note near-zero to briefly negative flow during early systole, then massive peak in diastole. Bottom: Right coronary flow - more parallels aortic pressure throughout cycle.

Left Coronary Artery

• Flow actually reverses transiently in early systole (isovolumetric contraction phase) because LV contraction compresses intramuscular vessels before the aortic valve opens and aortic pressure can rise
• During mid-to-late systole, flow resumes but at sub-maximal levels as aortic pressure drives flow against rising intramyocardial pressure
• Diastole is the critical phase: with relaxed ventricle no longer compressing vessels and aortic pressure still relatively high, flow spikes to peak values
• ~80% of total left coronary flow occurs during diastole - Barash's Clinical Anesthesia, p. 863; Miller's Anesthesia

Right Coronary Artery

• Flow profile more closely parallels aortic pressure throughout the cycle
• Systole contributes a substantially greater proportion than in the left
• No systolic reversal occurs
• Reason: RV wall tension is far lower (pulmonary resistance << systemic resistance), so RV contraction does not occlude intramural vessels

Clinical consequence - Tachycardia

4. Epicardial vs. Subendocardial Blood Flow

• Intramyocardial pressure is greatest near the endocardium and least near the epicardium during systole
• Net subendocardial perfusion is preserved normally because the subendocardial plexus has lower intrinsic vascular resistance, achieving relatively greater diastolic flow to compensate
• When diastolic aortic pressure is pathologically low (e.g., aortic regurgitation) OR coronary resistance is high (e.g., stenosis, elevated LVEDP), subendocardial blood flow falls disproportionately below epicardial flow
• The coronary perfusion pressure for the LV = Aortic diastolic pressure - LVEDP. Elevated LVEDP directly impedes subendocardial perfusion

5. Determinants of Coronary Blood Flow

5.1 Perfusion Pressure

• LV coronary perfusion pressure = Aortic diastolic pressure - LVEDP
• RV coronary perfusion pressure = Aortic diastolic pressure - RV end-diastolic pressure
• Flow is directly related to aortic diastolic pressure and the duration of diastole

5.2 Coronary Vascular Resistance

1. Metabolic/local vasodilator factors (most dominant - see Section 6)
2. Autonomic nervous system (see Section 7)
3. Myogenic response (component of autoregulation - Section 8)
4. Endothelial factors (NO, endothelin, prostacyclin)
5. Extravascular compression (as above - systolic)
6. Circulating hormones (angiotensin II, vasopressin, serotonin)

6. Metabolic Control of Coronary Blood Flow (Primary Regulator)

Vasodilator Mediators Released with Increased Metabolism or Hypoxia:

7. Autonomic (Nervous) Control of Coronary Blood Flow

7.1 Sympathetic Stimulation

• α₁-adrenoceptors predominate in large and intermediate epicardial vessels → vasoconstriction (but these vessels contribute little to resistance)
• α₂-adrenoceptors predominate in coronary arterioles (resistance vessels) → vasoconstriction when activated
• Intracoronary α₁-agonist (phenylephrine) → minimal effect on flow because epicardial vessels do not determine resistance
• Intracoronary α₂-agonist → decreases coronary blood flow through arteriolar constriction
• β₁-adrenoceptors are also present in arterioles; activation → coronary vasodilation

• Sympathetic stimulation → ↑HR, ↑contractility → ↑MVO2 → metabolic vasodilation
• This overwhelms the direct α-mediated vasoconstriction under normal circumstances
• Net result: sympathetic stimulation → overall increase in coronary blood flow

7.2 Parasympathetic (Vagal) Stimulation

• Vagal release of acetylcholine activates endothelial M₃ (muscarinic) receptors → NO release → vasodilation (endothelium-intact coronary arteries)
• HOWEVER: In vessels with endothelial dysfunction (atherosclerosis), M₃ activation → vasoconstriction (smooth muscle direct effect)
• Vagal fibers to the ventricular coronary system are sparse; most fibers are near the SA node
• Net indirect effect: vagal stimulation → ↓HR, ↓contractility → ↓MVO2 → metabolic decrease in coronary blood flow
• Vagal influence on coronary resistance is limited - much greater effect on heart rate than coronary resistance

8. Coronary Autoregulation

Definition

Autoregulatory Range

• Below ~60 mmHg: maximal vasodilation is already present and vasodilator reserve is exhausted - flow becomes pressure-dependent (passive)
• Above ~140-150 mmHg: vessels are distended to a degree that overcomes the ability of VSMCs to constrict - flow becomes pressure-dependent (breakthrough)

Mechanisms of Autoregulation

A. Myogenic Response (Bayliss Mechanism)

• Intrinsic property of vascular smooth muscle
• Increased intraluminal pressure → vascular wall stretch → VSMC depolarization → activation of mechanosensitive channels → Ca²⁺ influx → VSMC contraction → vasoconstriction → normalized flow
• Decreased pressure → VSMC relaxation → vasodilation → normalized flow
• This is a pressure-sensing, flow-maintaining reflex intrinsic to the VSMC

B. Metabolic (Adenosine/O₂) Mechanism

• If perfusion pressure decreases → flow transiently decreases → O₂ delivery falls → tissue PO₂ falls → adenosine released → arteriolar dilation → flow restored
• If pressure increases → flow increases → washout of vasodilator metabolites + mild hyperoxia → mild vasoconstriction → flow returned toward baseline
• Fluctuations in adenosine and PO₂ contribute to coronary autoregulation beyond the pure myogenic response - Boron & Boulpaep, p. 824

C. Endothelial Mechanisms

• Flow-mediated shear stress → NO release → vasodilation
• Endothelin-1 → vasoconstriction (longer-term modulation)

What Happens When Autoregulation Fails?

• Arterioles are maximally dilated
• Further pressure reduction causes proportional flow reduction
• Subendocardium suffers first (as detailed in Section 4)
• Coronary stenosis shifts the autoregulatory curve: distal pressure is chronically reduced, metabolic vasodilation is already partly invoked to maintain resting flow - this consumes vasodilator reserve

9. Coronary Flow Reserve (CFR) and Fractional Flow Reserve (FFR)

Coronary Flow Reserve (CFR)

• Defined as: maximal hyperemic flow / resting flow
• Normal CFR ≥ 2.5-3.0 (i.e., flow can increase 2.5-3 fold above resting)
• Measured using Doppler wire or pressure-wire thermodilution technique
• CFR < 2.0 = abnormal (indicates microvascular dysfunction or epicardial stenosis)
• Evaluates both epicardial conduit stenosis AND microvascular reserve

Fractional Flow Reserve (FFR)

• Defined as: Pd / Pa at maximal hyperemia (distal pressure/proximal pressure)
• Derived from: At maximal vasodilation (adenosine-induced), resistance is minimal and fixed, so FFR = Pd/Pa
• FFR < 0.80 = hemodynamically significant stenosis that would benefit from intervention
• Specifically assesses the epicardial stenosis contribution to ischemia
• Measured with coronary pressure-sensor guidewire at maximal adenosine-induced hyperemia

Instantaneous Wave-Free Ratio (iFR)

• Measures gradient across stenosis during late diastole (wave-free period - minimal microvascular resistance fluctuations)
• Does not require adenosine (useful in asthma, adenosine-intolerant patients)
• iFR < 0.89 = hemodynamically significant ischemia
• Shown non-inferior to FFR in outcome trials (DEFINE-FLAIR, iFR-SWEDEHEART)

Index of Microcirculatory Resistance (IMR)

• Calculated as: mean transit time × distal pressure (thermodilution-based)
• IMR < 25 = normal microcirculation
• Important predictor of outcomes independent of epicardial stenosis - Harrison's 22nd ed., p. 2635

10. Coronary Steal

• In the ischemic zone distal to a stenosis: metabolic vasodilation has already maximally dilated arterioles (vasodilator reserve exhausted)
• Vasodilator drugs can only dilate vessels in non-ischemic parallel vascular beds
• This increases flow through non-ischemic beds → decreases pressure at the upstream branch point
• Result: reduced pressure distal to the stenosis → reduced flow to the already-ischemic zone → coronary steal

11. Collateral Circulation

• When a coronary artery is abruptly occluded → ischemia → infarction
• When narrowing is gradual → collateral vessels develop from existing branches via:
  • Mechanical stress changes in vessel walls supplying the ischemic zone
  • Angiogenic molecules (VEGF, FGF, HIF-1α) released from ischemic tissue
  • Endothelial/smooth muscle cell proliferation and vascular remodeling
• Collaterals can ameliorate or prevent infarction in chronic subtotal occlusions
• Ipsilateral collaterals (same vessel) vs. contralateral collaterals (opposite vessel supplying via retrograde flow)
• Angiographic assessment is important for CTO PCI planning - Boron & Boulpaep, p. 825; Fuster & Hurst, p. 124

12. Summary - Integrated Control Hierarchy

Oxygen Demand Signal
        ↓
Metabolic Vasodilation (PRIMARY)
   - Adenosine (principal mediator)
   - K⁺, CO₂, H⁺, low PO₂, NO, PGI₂
        ↓
Myogenic Autoregulation (PRESSURE SENSOR)
   - Maintains constant flow 60-140 mmHg
   - VSMC stretch → constriction; reduced stretch → dilation
        ↓
Sympathetic Modulation (SECONDARY - usually overridden by metabolic)
   - Direct: α₁/α₂ constriction (epicardial/arteriolar)
   - Indirect: ↑MVO₂ → metabolic vasodilation (dominant)
   - β₁ arteriolar dilation
        ↓
Parasympathetic (MINOR - endothelium-dependent)
   - M₃ → NO → vasodilation (intact endothelium)
   - M₃ → vasoconstriction (dysfunctional endothelium)
        ↓
CORONARY FLOW proportional to MVO₂

13. Key Clinical Correlates (DM Cardiology)

• Guyton and Hall Textbook of Medical Physiology, pp. 267-270
• Boron & Boulpaep Medical Physiology, pp. 823-825
• Barash, Cullen & Stoelting's Clinical Anesthesia (9th ed.), pp. 863-864
• Miller's Anesthesia (10th ed.), pp. 7585-7586
• Katzung's Basic and Clinical Pharmacology (16th ed.), pp. 303-304
• Fuster & Hurst's The Heart (15th ed.), pp. 124-125
• Harrison's Principles of Internal Medicine (22nd ed.), p. 2635
• Braunwald's Heart Disease (relevant sections on myocardial ischemia and coronary physiology)