Coronary Blood Flow

Obtuse Left Marginal Branches of the Circumflex artery

A variable array of branches derived from the circumflex artery and *course toward apex along free wall of the ventricle*.

Posteriolateral Branches of the Circumflex Artery

A variable array of branches from the more *distal portion* of the circumflex artery supply the *diaphragmatic portion of the left ventricle*.

Exhaustion of Vasodilator Reserve in the Coronary Microcirculation (in English!)

A vessel can only dilate so far. Once it is at max dilation, the amount of blood that tissue can get is entirely dependent on BP. So if BP drops, tough luck. In stenosis, heart senses increased BP in vessel and vasodilates which is counterproductive, further reducing pressure and flow after the stenosis. ??????

Cardiac Veins

Accompany the arteries in the sulci and usually lie superficial to them. - Most cardiac veins end in the *coronary sinus*, which lies in the *Posterior AV sulcus*. Coronary sinus empties into the R Atrium just above the tricuspid valve annulus, medial to the orifice of the interior vena cava. - Usually 1-2 *anterior cardiac veins* that pass from the front of the R Ventricle across the anterior AV sulcus to open directly into the R Atrium

Myogenic Component of Autoregulation (of Coronary Blood Flow)

An increase in coronary artery transmural pressure elicits a vasoconstrictor response

Myocardial Metabolism

Anaerobic metabolic capability of mammalian myocardium is very limited and even an arrested heart that is not beating requires O2 to survive. *Cardiac O2 consumption used as a measure of overall myocardial metabolism (and is linked to coronary flow autoregulation)*

Oxygen Extraction

During resting conditions w/ HR ~60bpm, the Coronary Arterial O2 minus Venous O2 Content = very large *~70% of O2 delivered by coronary blood flow is extracted by the myocardium* - This is the largest O2 extraction of all the organs in the body Large oxygen extraction results in a *coronary venous oxygen tension of ~20 mmHg*

Upstream stenosis in series with arteriolar control

Energy losses in a stenosis go up exponentially as a function of flow --> Thus the *pressure just downstream of stenosis falls greatly as flow is increased* Total resistance in a vascular bed is = sum of the resistances in series --> Vasodilation in the *microcirculation compensates for augmented upstream resistance* due to a stenosis

Metabolic Component of Autoregulation (of Coronary Blood Flow)

Level of flow during autoregulation depends on ongoing rate of myocardial O2 metabolism, (flow higher for higher O2 metabolism)

Circumflex Branch of the Coronary Artery

Lies in the atrioventricular (AV) sulcus; defines junction between Left Atrium and Left Ventricle - also defines posterolateral margin of the mitral valve annulus - Obtuse marginal (left marginal) branches - Posteriolateral branches

Tachycardia during exercise abbreviates diastole

Limits the time available for subendocardial perfusion

Equation to Estimate MVO2

MVO2 = (Systolic BP)x(HR)

Aortic Valve Disease

May result in *myocardial ischemia w/o coronary atherosclerosis* *Diastolic Period*: - Aortic pressure abnormally low - LV diastolic pressure abnormally high Thus the (Aortic Pressure minus LV Pressure) *Pressure Gradient during diastole necessary for subendocardial perfusion is compromised* - Unusual for pts w/ isolated aortic insufficiency w/o coronary atherosclerosis to develop angina with exertion - Pts with *Coronary Atherosclerosis Plus Aortic Insufficiency, the aortic regurgitation adds to the problem*

Human Heart Capillary Density

Normal human hearts have a capillary density of 3300/mm2 (skeletal muscle has ~400 capillaries/mm2) - In the heart there's ~1 capillary for each muscle fiber; ratio is maintained in cardiac hypertrophy, but the diffusion distance from capillary to the center of a muscle fiber increases

Collateral Arteries

Normal myocardium contains numerous collateral arteries between major branches of a coronary artery (*homocoronary*) and between R and L coronary arteries (*intercoronary*).

Myocardial Oxygen Metabolism (MVO2)

Normal myocardium is completely dependent on O2 (no anaerobic metabolism) delivered by coronary blood flow - heart myoglobin store only last 3-6 beats before hypoxia and cell death begins to occur Normal O2 extraction by the myocardium is ~70%

Architecture of the coronary circulation

Pic

Double Product

Product of HR and Systolic BP - Useful bedside index of changes in MVO2 - combines 2 important determinants of changes in MVO2: HR and tension development The index is more accurate for estimating changes in an *individual patient* than comparisons among patients because *ventricular radius and mass are not included*.

Clinical Angina Pectoris

Results when myocardial O2 consumption *"demand" exceeds O2 delivery* by coronary blood flow, and the *LV subendocardium becomes hypoxic*. - useful to understand the determinants of myocardial O2 consumption

Stroke Work

SW = (Pressure)x(SV)

Main Coronary Artery

Short trunk (0.5-1.5cm) that divides into the *anterior descending and circumflex branches*.

Diastolic Myocardial Compression

The intramyocardial tissue pressure acts as a 3rd pressure on the compressible coronary vessels creating a so called "waterfall" where flow is proportional to the difference between arterial pressure (P1) and tissue pressure (P3), (*F=P1-P3*) rather than the usual arterial minus venous pressure (P1-P2)

Aortic: Extremely High LV Systolic Pressure

represents very high tension development by the myocardium and thus very high O2 demand

Cardiac Work

is a poor correlate of myocardial O2 Consumption

Too Much vs Too Little Shear Stress

Too much: denudes endothelium from the vascular wall and may result in thrombosis Too low: leads to stasis and thrombosis

Law of LaPlace: Acute changes in Internal radius of the ventricle

*Tension per cardiac fiber* may be calculated with *T = ΔPxr* T = Tension per cardiac fiber r = radius ΔP = Pressure difference from inside to outside of heart

Atherosclerosis

if coronary blood flow is restricted by atherosclerosis, the subendocardium will become ischemic before the subepicardium.

Law of LaPlace: Chronic changes in internal radius of ventricle

*Tension per cross-sectional area* may be calculated with: *T = (ΔPr)/h* T = Tension per cross-sectional area ΔP = Pressure difference from inside to outside of heart h = Wall Thickness *wall thickness increases w/ the increase in ventricular systolic pressure, so the tension per cross-sectional area remains in normal range*

Acetylcholine (ACh)

*ACh acting on muscarinic receptors on endothelial cells --> NO Release* - In normal coronary circulation ACh --> Coronary Vasodilation This *effect is lost or may be reversed to vasoconstriction in atherosclerotic vessels or even in angiographically normal vessels in pts w/ high risk factors for atherosclerosis*!

Aortic Stenosis

*Abnormal systolic pressure difference between the Left Ventricle and the Aorta* - Aortic pressure during diastole tends to be low due to restricted CO 1.) During exercise, heart attempts to increase SV through the stenotic valve --> systolic pressure gradient from left ventricle to aorta increases 2.) Stenotic valve acts as nonlinear resistance where a larger and larger (ventricle) pressure difference is needed to increase flow through the stenosis --> may result in astounding pressure differences across stenotic valve of 100mmHg+ 3.) Aortic pressure low because of the decrease in peripheral resistance due to metabolic vasodilation in exercising skeletal muscle

Dominant Controller of Coronary Blood Flow is...

*Myocardial O2 Consumption (MVO2)* - In normal heart any increase or decrease in myocardial O2 consumption promptly accompanied by corresponding change in coronary blood flow --> this is the mechanism that couples coronary blood flow to myocardial oxygen consumption to produce *local metabolic vasodilation*

Result of the transmural gradient of systolic intramyocardial tissue pressure (Diastolic Myocardial Compression)

*Subendocardium is only perfused during diastole* 1.) *Systole*: Left ventricular contraction responsible for generating both intramyocardial and ventricular cavity pressures 2.) *Diastole*: L-Ventricular cavity pressure is transmitted through the relaxed ventricular muscle diminishing from endocardium to epicardium 3.) *Difference between aortic pressure and L Ventricular cavity pressure during diastole provides pressure gradient for blood flow to the subendocardium* --> this difference integrated over the duration of diastole represents the potential for subendocardial flow during the cardiac cycle (Pic: shaded area)

In autoregulation coronary pressure was decreased 50% from 160mmHg to 80mmHg. How much did flow decrease? a.) ~0% (no change) b.) ~15% c.) ~30% d.) ~50% e.) don't know

*b.) ~15%* (30% also an acceptable answer) 50% would be no autoregulation at all No change = not correct because autoregulation is not perfect

The most important determinate of Myocardial O2 Consumption is: a.) HR b.) Systolic Myocardial Fiber Tension c.) Ventricular Size (Law of LaPlace) d.) Don't Know

*d.) Don't Know* All 3 are important in different ways!!!!

ACh Release of NO in Artherosclerosis

*effect is lost or may be reversed to vasoconstriction in atherosclerotic vessels or even in angiographically normal vessels in pts w/ high risk factors for atherosclerosis*! [Unclear if loss of NO dilation is part of genesis of atherosclerosis or only a marker of the process. One hypothesis is atherosclerosis results in elevated levels of ROS in the vessel wall which are known to inactivate NO.]

Aortic Stenosis and Angina Pectoris

- Aortic pressure low because of the decrease in peripheral resistance due to metabolic vasodilation in exercising skeletal muscle Combo of high myocardial O2 demand, low aortic pressure and abbreviation of diastole w/ tachycardia during exercise may result in subendocardial ischemia and angina pectoris in patients who do not have coronary atherosclerosis.

Right Coronary Artery Branches

- Nodal branch to the sino-atrial node. (This vessel sometimes arises from the circumflex artery.) - Proximal right: gives off a small conus branch which ascends anteriorly over the right ventricular outflow tract - Distally: a number of Right Ventricular branches (also referred to as acute marginal or right marginal branches) - A *transverse branch of the right coronary artery* may continue in the coronary sulcus to the left side of the heart, where it may supply posterior lateral branches to the left ventricle.

Below the Coronary Autoregulatory Range (<60mmHg)

...Coronary circulation is "*maximally dilated*" - May be demonstrated via infusion of a coronary vasodilating agent (Adenosine). - When the coronary circulation is maximally dilated *flow is strongly dependent on pressure --> even a small drop in pressure will decrease flow*

Three Factors that Cause Subendocardial Ishcmeia During Exertion

1.) Nonlinear (exponential) Pressure drop across a Stenosis as a function of flow 2.) Exhaustion of Vasodilator Reserve in the Coronary Microcirculation 3.) Tachycardia during exercise abbreviates diastole

Coronary Blood Flow Summary

1.) Pressure - Autoregulation 2.) Phasic Coronary Flow - Systolic tissue pressure - Transmural flow 3.) Metabolism (the major factor) - Basal - Tension development 4.) Stenosis - Nonlinear series resistor - Loss of autoregulation 5.) Aortic Valve Disease

Threats to Subendocardial Perfusion

Anything that *decreases arterial diastolic pressure difference* (e.g. arterial hypotension, elevated left ventricular diastolic pressure) or *abbreviates diastole* (e.g. tachycardia) is a potential threat to subendocardial perfusion that *must be countered by coronary vasodilation*

HR as a Determinant of Myocardial O2 Consumption per Min

Approximately *linear correlation between HR and MVO2* Heart arrested w/ a high external K+ solution --> MVO2 decreases to ~25% of previous resting value (HR ~60 bpm) = general cost of cardiac "housekeeping" independent of contraction - Cost of electrical activation and associated ion currents estimated as ~ 1% of resting value - Ca2+ pumping necessary for excitation-contraction coupling and relaxation estimated as ~5% of resting value - *~70% of MVO2 is related to cardiac contraction*

Phasic Flow and Transmural Flow

Coronary artery flow is *large during diastole and small during systole*. - occurs despite the fact that aortic BP is greater during left ventricular ejection than when the aortic valve is closed because the *myocardium squeezes down on its own blood flow during systole*

Exhaustion of Vasodilator Reserve in the Coronary Microcirculation

Coronary artery pressure distal to the stenosis falls below the autoregulation range --> Exhaustion of vasodilator reserve in coronary microcirulation --> limits further increase in coronary flow Coronary circulation w/ atherosclerotic stenosis during exercise is caught in the *"Hemodynamic Trap" of further increases in flow --> decreasing pressure distal to the stenosis below the autoregulatory range --> exhausting vasodilator reserve* With vasodilator reserve exhausted, *flow is very pressure dependent* - but any increase in flow across the stenosis further lowers the pressure available to the microcirculation distal to the stenosis. Thus *flow reaches a maximum even if myocardial O2 demand continues to increase --> results in Subendocardial Ischemia and Angina Pectoris*

Pressure-Flow Relation (Autoregulation of Coronary Flow)

Coronary blood flow is dependent on perfusion pressure (difference between arterial and venous pressures) but relationship is *NOT linear bc coronary circulation exhibits strong autoregulation* Autoregulatory pressure range (~60-140mmHg): - Coronary blood flow maintained fairly constant despite changes in arterial perfusion pressure due to *active changes in vascular resistance*

Right Coronary Artery

Descends around the heart in the AV sulcus; defines the junction between Right Atrium and Right Ventricle and outlines the lateral margin of the tricuspid valve - continues in AV sulcus to the diaphragmatic surface of the heart, where its major termination is the *posterior descending artery (posterior interventricular)* which lies in the interventricular sulcus - Posterior IV artery gives off cascade of septal branches that penetrate the muscular IV septum

Left Anterior Descending (Anterior Interventricular) Branch of the Coronary Artery

Descends in the anterior interventricular groove and thereby *defines the anterior margin of the interventricular septum* Gives off a variable number of: - *diagonal branches to the free wall of L ventricle* - *series of septal branches* that *penetrate the interventricular septum*

Hemodynamic Work done by the Left Ventricle

Does not completely correlate with O2 consumption An equal amount of external work done against a high aortic pressure afterload costs more O2 than when afterload is low *Tension development by the ventricle has a high metabolic cost* - Thermodynamically work does cost energy and thus O2, but *work alone is a poor correlate of O2 consumption*

NO in the Coronary Arteries

Downstream arterioles in coronary circulation dilate due to local metabolic vasodilation --> increases flow in upstream epicardial coronary arteries --> increases endothelial shear stress 1.) NO mechanism adjusts upstream conduit vessel diameter so that shear stress on the endothelium is in the physiological range. 2.) NO contributes to the modest epicardial coronary artery dilation that occurs during exercise by the shear mechanism

Thebesian Veins

Drain directly into the ventricular and atrial chambers w/o passing through an epicardial vein There are ~6 arterial shunts 80-200μm in diameter which empty directly into the ventricular chambers known as *arterioluminal vessels* - function of these shunts unknown

Nitric Oxide (NO) (Endothelium Derived Relaxing Factor (EDRF))

Free radical gas released by vascular endothelial cells in response to shear stress due to blood flowing over the endothelial cells --> diffuses from the endothelial cells to adjacent vascular smooth muscle cells --> activates guanylyl cyclase to form *cGMP* from GTP --> cGMP lowers intracellular Ca2+ in smooth muscle and causes relaxation

Aterial-Venous O2 Difference in Coronary System

Higher than anywhere else in the body

Coronary Stenosis

In epicardial coronary artery atherosclerotic stenosis blood flow may become restricted. Flow restriction depends on extent of the stenosis and on the prevailing flow: 1.) *Normal Resting Flow*: ~90% diameter narrowing needed to have a "critical" stenosis that restricts flow 2.) *Increased Coronary Flow* (pharmacological increase, during exercise): ~40% diameter narrowing needed for "critical" stenosis level Reasons for this are the *nonlinear pressure flow characteristics of stenoses* and the *role of autoregulation in the coronary microcirculation* (in stenosis, heart senses increased BP in vessel and vasodilates which is counterproductive, further reducing pressure and flow after the stenosis)

Endocardium/Pericardium Ratio

Inner layers of LV more vulnerable to ischemia than the outer layers for 2 main reasons 1.) *Inner layer flow occurs only during diastole* 2.) *Inner layers are at far end of the coronary arterial* Blood flow is normally *~10% greater in subendocardium than in subepicardium*, at rest and during exercise - However, if coronary blood flow is restricted by *atherosclerosis*, the subendocardium will become ischemic before the subepicardium.

Figure 13

Subendocardium is more vulnerable to ischemia than the subepicardium ???? assortment of pics in one figure ???? - Inner myocardium has a greater tissue pressure - pressure gradient decreased - duration of perfusion is short

Blood Supply to the Heart

Supplied by first 2 branches of the aorta, *Right and Left Coronary Arteries* with their *Ostia w/in the sinuses of Valsalva*. These vessels course over the epicardial surface of the heart like a primitive crown. Branches of the coronary arteries then *penetrate the myocardium from the epicardium to the subendocardium*

Left Coronary Artery

Supplies *anterior portion of the interventricular (IV) septum, anterior wall of the R ventricle and the anterior wall, left margin and a small part of the diaphragmatic surface of the L ventricle* - Both circumflex and right coronary arteries supply diaphragmatic surface of the heart ==> considerable variation in the proportion of blood supply derived from each of these vessels - in few individuals, blood supply of the diaphragmatic surface is "balanced" between the R-Coronary and L-Circumflex vessels In ALL cases, *major blood supply to the L ventricle comes from the L coronary artery*

Aortic Stenosis Syncope

Syncope due to inadequate cerebral perfusion secondary to the low aortic pressure, may occur with exercise in some pts with Aortic Stenosis

Systolic Myocardial Compression

Systolic compression of intramyocardial vessels in the left ventricle is *greatest in the subendocardium* and *generates retrograde flow during systole* --> at onset of *diastole antegrade flow must refill the penetrating vessels before there is flow through the microcirculation in the subendocardium* - During tachycardia when diastole is very brief there may not be adequate time to perfuse the subendocardium! - Inner layer of myocardium is most affected and is usually the first part to be damaged in ischemia

Law of LaPlace [Know This]

Tension developed by fibers in the wall of the LV is not only related to the LV systolic pressure but also to the size of the ventricle: Simplest geometrical model of the LV is a thick walled hollow cylinder, where the equatorial hoop stress tension may be calculated using Law of LaPlace *T = (ΔP)x(r)* T = tensile (hoop) force per cardiac fiber r = radius P = pressure

Blood Supply to the Posterior Portion of the Intraventricular (IV) Septum and the Diaphragmatic Surface of the Left Ventricle

Variable: *Dominant Right Coronary Artery*: in ~90% of human hearts the right coronary artery supplies the posterior descending vessel and a small artery to the AV node *Dominant Left Coronoary Artery*: in ~10% of individuals, circumflex artery supplies the posterior descending vessel

Chronic Increase in LV Systolic Pressure

When there is a chronic increase in LV systolic pressure (e.g. hypertension, or aortic stenosis) the myocardium hypertrophies by adding thick and thin contractile filaments to cardiac cells but NOT by increasing number of cells. - *In hypertrophy, LV wall becomes thicker and thus able to generate a high systolic pressure*

Vasodilator Reserve

difference between the prevailing coronary blood flow and "maximal dilation"

Resting O2 Consumption

~25% for "housekeeping" (cellular repair, protein synthesis etc) ~1% for electrical activation ~5% for Ca pumping (pump Ca OUT for relaxation)