B P5 C36 Coronary Blood Flow and Myocardial Ischemia Flashcards
Myocardial oxygen extraction is near-maximal at rest, averaging _________ of arterial oxygen content.
70% to 80%
Because of the high resting oxygen extraction, increases in myocardial oxygen consumption are primarily met by proportional increases in coronary flow and oxygen delivery
_____________________= product of hemoglobin concentration and arterial oxygen saturation plus a small amount of oxygen dissolved in plasma that is directly related to arterial oxygen tension (Pao2 )
Arterial oxygen content (Cao2 )
In addition to coronary flow, oxygen delivery is directly determined by arterial oxygen content (Cao2 )
Coronary venous oxygen tension (PvO2) can only decrease from 25 mm Hg to approximately ___ mm Hg
15 mm Hg
For any given flow level, anemia results in _____reductions in oxygen delivery, whereas hypoxia, resulting from the nonlinear oxygen dissociation curve, results in relatively small reductions in oxygen content until PaO2 falls to the steep portion of the oxygen dissociation curve (below 50 mm Hg)
Anemia: proportional
Hypoxia: small
Identify the major determinants of myocardial oxygen consumption
Heart rate
Systolic pressure (or myocardial wall stress)
Left ventricular (LV) contractility
**There are five main determinants of ventricular mechanical performance: preload (or Frank-Starling mechanism), afterload, contractility, lusitropy (diastolic function), and HR.
A twofold increase in any of these individual determinants of oxygen consumption requires an approximately 50% increase in coronary flow.
Resting coronary blood flow under normal hemodynamic conditions averages _____ mL/min/g and can increase fourfold to fivefold during vasodilation
0.7 to 1.0 mL/min/g
Identify the phenomenon in coronary blood flow
Regional coronary blood flow remains constant as coronary artery pressure is reduced below aortic pressure over a wide range when the determinants of myocardial oxygen consumption are kept constant
Coronary Autoregulation
When pressure falls to the lower limit of autoregulation,coronary resistance arteries are maximally vasodilated to intrinsic stimuli, and flow becomes pressuredependent, resulting in the onset of subendocardial ischemia
The ability to increase flow above resting values in response to pharmacologic vasodilation is termed ________________________
Coronary flow reserve
Factors that decreases Maximum perfusion and coronary flow reserve
Decreased maximum flow
↑ LV mass
↓ Microvascular function
↑ HR
↑ Preload
Coronary reserve also is diminished by anything that increases resting flow.
Factors that increases resting flow__
↑ HR
↑ SBP
↑ Contractility
↓ Hb
Coronary reserve also is diminished by anything that increases resting flow.
Factors that increases resting flow__
↑ HR
↑ SBP
↑ Contractility
↓ Hb
Coronary reserve also is diminished by anything that increases resting flow
Factors that increases resting flow
↑ HR
↑ SBP
↑ Contractility
↓ Hb
Although initial studies suggested that the lower pressure limit of autoregulation is _____ mm Hg, it was later shown that coronary flow can be autoregulated to mean coronary pressures as low as _____ mm Hg (diastolic pressures of 30 mm Hg) in conscious dogs in the basal state
70 mm Hg
40 mm Hg
Subendocardial flow occurs primarily in diastole and begins to decrease below a mean coronary pressure of ___ mm Hg.
In contrast, subepicardial flow occurs throughout the cardiac cycle and is maintained until coronary pressure falls below ___ mm Hg
40 mm Hg
25 mm Hg
With the development of hemodynamically significant epicardial artery narrowing (>____% diameter reduction), the fixed conduit artery resistance begins to contribute an increasing component to total coronary resistance and, when severely narrowed (>_____%), may reduce resting flow.
> 50%
90%
The resistance to coronary blood flow can be divided into three major components
R1 - no measurable pressure drop in the epicardial arteries, indicating negligible conduit resistance
R2 - dynamic and arises primarily from microcirculatory resistance arteries and arterioles
R3 - extravascular compressive resistance (R3 ), varies with time throughout the cardiac cycle and is related to cardiac contraction and systolic pressure development within the left ventricle
With the development of hemodynamically significant epicardial artery (R1) narrowing (>_____% diameter reduction), the fixed conduit artery resistance begins to contribute an increasing component to total coronary resistance and, when severely narrowed (>____%), may reduce resting flow.
> 50%
> 90%
The second component of coronary resistance (R2) is dynamic and arises primarily from _____.
Microcirculatory resistance arteries and arterioles
Even in the maximally vasodilated heart, capillary resistance accounts for no more than 20% of the microvascular resistance. Thus a twofold increase in capillary density would increase maximal myocardial perfusion by only approximately 10%.
The third component, _____ (R3), varies with time throughout the cardiac cycle and is related to cardiac contraction and systolic pressure development within the left ventricle
Extravascular compressive resistance
__________________ do not contribute significantly to coronary vascular resistance, yet arterial diameter is modulated by a wide variety of paracrine factors
Epicardial conduit arteries
State the effects of the ffg substances both “normal response” and in patients with “atherosclerosis” in the conduit (C) and resistance vessels (R)
Acetylcholine
Thrombin
Serotonin
ADP
Thromboxane 2
Cholinergic stimulation
Sympathetic stimulation
Normal response/response in CAD
Acetylcholine
Conduit: dilate/constrict
Resistance: dilate/less dilation
Thrombin
C/R: dilate/constrict
Serotonin
C: constrict/constrict
R: dilate/constrict
ADP
C/R: dilate/less dilate
TX2
C/R: constrict/constrict
Cholinergic
Same with ACH
Sympathetic
Alpha: constrict/constrict
Beta 1 and 2: dilate/less dilate on C, dilate on R
Nitric oxide is produced in endothelial cells by the enzymatic conversion of L-arginine to. _____ via type III or endothelial nitric oxide synthase (eNOS
Citrulline
NO-mediated vasodilation is impaired in many disease states and in patients with one or more risk factors for coronary artery disease (CAD). This occurs via inactivation of NO by _____ generated in response to oxidative stress. Such inactivation is the hallmark of impaired NO- mediated vasodilation in atherosclerosis, hypertension, and diabetes.
Superoxide anion
The endothelins—ET-1, ET-2, and ET-3—are peptide endothelium- dependent constricting factors. _____ is a potent constrictor derived from the enzymatic cleavage of a larger precursor molecule (pre- pro–endothelin) via endothelin-converting enzyme. In contrast with the rapid vascular smooth muscle relaxation and recovery
ET-1
During sympathetic activation, coronary tone is modulated by norepinephrine released from myocardial sympathetic nerves, as well as by circulating norepinephrine and epinephrine.
In conduit arteries, sympathetic stimulation leads to alpha1 constriction as well as beta-mediated vasodilation. The net effect is to _____ epicardial coronary arteries. This dilation is potentiated by concomitant flow-mediated vasodilation from metabolic vasodilation of coronary resistance vessels.
When NO-mediated vasodilation is impaired, _____ predominates and can dynamically increase stenosis severity in asymmetric lesions where the stenosis is compliant.
Dilate
Alpha1 constriction
The effects of sympathetic activation on myocardial perfusion and coronary resistance vessel tone are complex and depend on the net actions of _____.
(1) Beta1-mediated increases in myocardial oxygen consumption (resulting from increases in the determinants of myocardial oxygen consumption)
(2) Direct beta2-mediated coronary vasodilation
(3) Alpha1-mediated coronary constriction
Under normal conditions, exercise-induced _____ “feed-forward” dilation predominates, resulting in a higher flow relative to the level of myocardial oxygen consumption.
This neural control mechanism produces transient vasodilation before the buildup of local metabolites during exercise and prevents the development of subendocardial ischemia during abrupt changes in demand
Beta2-adrenergic
After nonselective beta blockade, sympathetic activation unmasks _____-mediated coronary artery constriction.
Although flow is mildly decreased, oxygen delivery is maintained by increased oxygen extraction and a reduction in coronary venous PO2 at similar levels of cardiac workload
Alpha1
_____ results in transient functional occlusion of a coronary artery that is reversible with nitrate vasodilation. It most frequently occurs in the setting of a coronary stenosis, leading to dynamic stenosis behavior that can dissociate the effects on perfusion from anatomic stenosis severity
Coronary spasm
In CAD, endothelial disruption probably plays a role in focal vasospasm; the normal vasodilation from autacoids and sympathetic stimulation is converted into a vasoconstrictor response because of the lack of competing _____. Nevertheless, although impaired endothelium-dependent vasodilation is a permissive factor for vasospasm, it is not causal, and a trigger is required (e.g.,thrombus formation, sympathetic activation).
Endothelium-dependent vasodilation
Nitroglycerin dilates epicardial conduit arteries and small coronary resistance arteries but does not increase coronary blood flow in the ___________ heart
Normal
Transient arteriolar vasodilation is overcome by autoregulatory escape, which returns coronary resistance to control levels
It can produce vasodilation of larger coronary resistance arteries that improves the distribution of perfusion to the subendocardium when flow-mediated NO-dependent vasodilation is impaired. It also can improve subendocardial perfusion by reducing LV end-diastolic pressure through systemic venodilation in HF.
All calcium channel blockers induce vascular smooth muscle relaxation and are, to various degrees, pharmacologic coronary vasodilators.
In ______________ the vasodilator response is similar to that of nitroglycerin
Epicardial arteries
Calcium channel blockers also submaximally vasodilate coronary resistance vessels can sometimes precipitate subendocardial ischemia in the presence of a critical stenosis.
This arises from a transmural redistribution of blood flow, which is called ______________, as well as the tachycardia and hypotension
Coronary steal
_________________ dilates coroary arteries through activation of A2 receptors on vascular smooth muscle and is _____________ of the endothelium
Adenosine
Independent
_________________ dilates coroary arteries through activation of A2 receptors on vascular smooth muscle and is _____________ of the endothelium (restricted to vessels smaller than 100um)
Larger upstream resistance arteries dilate through a _________________ mechanism from the increase in shear stress
Adenosine
Independent
NO-dependent
______________ produces vasodilation by inhibiting the myocyte reuptake of adenosine
Dipyridamole
Reversed by aminophylline
______________ is a short-acting coronary vasodilator that was the first agent used for intracoronary vasodilation. It causes vascular smooth muscle relaxation by inhibiting phosphodiesterase and increasing (cAMP).
After bolus injection, it has a rapid onset of action, but the vasodilation is somewhat more prolonged than after adenosine. Its actions are independent of the endothelium.
Papaverine
Structure of the coronary microcirculaiton and their regulators
Epicardial arteries
Small arteries
Arterioles
Epicardial arteries - conduit artery function, regulated by shear stress, and contribute minimal pressure drop (<5%)
Small arteries - response to local shear stress and luminal pressure changes (myogenic response)
Arterioles - changes in local tissue m olism and directly control perfusion of the low-resistance coronary capillary bed
Structure of the coronary microcirculaiton and their regulators
Epicardial arteries
Small arteries
Arterioles
Epicardial arteries - conduit artery function, regulated by shear stress, and contribute minimal pressure drop (<5%)
Small arteries - response to local shear stress and luminal pressure changes (myogenic response)
Arterioles - changes in local tissue m olism and directly control perfusion of the low-resistance coronary capillary bed
________________ refers to the ability of vascular smooth muscle to oppose changes in coronary arterial diameter
Myogenic response
Vessels relax when distending pressure is decreased and constrict when distending pressure is elevated
Effect of the following in coronary resistance
Adenosine
Hypoxemia
Anemia
Hypercapnia
Acidosis
All vasodilate
In terms of coronary flow reserve, arterial pressure supplying the RCA substantially exceeds ________________, minimizing the compressive determinants of coronary reserve.
RV oxygen consumption is ___________ than LV consumption, and coronary venous oxygen saturations are h_____ than in the left coronary circulation.
RV pressure
Lower
Higher
Effect of CAD in the epicardial coronary artery disease
Dominant epicardial resistance in CAD
The angiographically visible epicardial coronary arteries are normally able to accommodate large increases in coronary flow without producing any significant pressure drop and thus serve a conduit function to the coronary resistance vasculature.
This changes dramatically in CAD, in which the epicardial artery resistance becomes dominant.This fixed component of resistance increases with stenosis severity and limits maximal myocardial perfusion.
The most important determinant of stenosis resistance for any given level of flow is the ____________________________
Minimum lesional crosssectional area within the stenosis
Resistance is inversely proportional to the square of the crosssectional area,
Difference of outward vs inward remodelling
Inward remodelling reduces minimal lesion ares along the length of the vessel
Diffuse abluminal outward remodeling with thickening of the arterial wall is common in coronary atherosclerosis but does not alter the pressure-flow characteristics of the stenosis for a given intraluminal geometry.
By contrast, diffuse inward remodeling effectively reduces minimal lesion areaalong the length of the vessel and can lead to underestimation of stenosis severity using relative diameter or area measurements (see Chapter 21) and at the same time can contribute to a significant longitudinal pressure drop that also reduces maximum perfusion.1
Stenosis pressure drop and resistance increase exponentially as minimum lesional cross-sectional area ______________
This reflects that the pressure drop becomes ___________________ and varies with the square of the flow or flow velocity. As a result, the instantaneous stenosis resistance progressively increases during vasodilation.
Decreases
Flow dependent
As illustrated in Fig. 36.11A, there is no significant pressure drop across a stenosis (ΔP) or stenosis-related alteration in maximal myocardial perfusion until stenosis severity exceeds a 50% diameter reduction (cross-sectional area reduction of 75%). As stenosis severity exceeds 50%, the pressure flow relation becomes curvilinear (Fig. 36.11B) and increases in stenosis resistance are accompanied by concomitant increases in ΔP across the stenosis that reduce distal coronary pressure.
There is no significant pressure drop across a stenosis (AP) or stenosis-related alteration in maximal myocardial perfusion until stenosis severity exceeds a ____% diameter reduction (cross-sectional area reduction of 75%).
50% (CSA reduction of 75%)
A critical stenosis, one in which subendocardial flow reserve is completely exhausted at rest, usually develops when stenosis severity exceeds ________
Under these circumstances, pharmacologic vasodilation of subepicardial resistance vessels results in a reduction in distal coronary pressure that actually redistributes flow away from the subendocardium, leading to a _______________ phenomenon
90%
Transmural steal
It is expressed as the ratio of maximally vasodilated flow to the corresponding resting flow value in a specific region of the heart and quantifies the ability of flow to increase above the resting value
Absolute Flow Reserve
Absolute flow reserve is not only altered by factors that affect maximal coronary flow (e.g., stenosis severity, impaired microcirculatory control, arterial pressure, heart rate) but also by the corresponding resting flow value. As noted previously, resting flow can vary with hemoglobin content, baseline hemodynamics, and the resting oxygen extraction. Reductions in absolute flow reserve, therefore, can arise from inappropriate elevations in resting coronary flow as well as from reductions in maximal perfusion.
In this approach, relative differences in regional perfusion (per gram of tisssue) are assessed during maximal pharmacologic vasodilation or exercise stress and expressed as a fraction of flow to normal regions of the heart.
Relative coronary flow reserve
This approach compares relative perfusion states under the same hemodynamic conditions and is fairly insensitive to variations in mean arterial pressure, heart rate, and preload.
______________ is an indirect index determined by measuring the driving pressure for microcirculatory flow distal to the stenosis (distal coronary pressure minus coronary venous pressure) relative to the coronary driving pressure available in the absence of a stenosis (mean aortic pressure minus coronary venous pressure)
Fractional Flow Reserve
simplified clinical FFR index of mean distal coronary pressure/mean aortic pressure (Pd/Pao).
___________reflects the ratio of distal coronary pressure to aortic pressure averaged throughout mid-diastole (i.e., the “wave-free period”).
Instantaneous wave-Free Ratio (iFR)
Resting pressure gradient does not develop until stenosis severity reaches a level that significantly affects maximal perfusion during vasodilation
During mid-diastole, distal coronary resistance is free of the compressive effects of systole and phasic coronary flow and the stenosis diastolic pressure gradient are maximal
iFR will overestimate the functional significance of a stenosis versus FFR in circumstances in which resting flow is abnormally elevated
________________ defined as starting 25% into cardiac diastole and ending 5 ms before the end of diastole
Wafe Free Period
The increase in LV mass in the absence of vascular proliferation reduces the maximum perfusion per gram of myocardium. The net effect of LV hypertrophy is that coronary flow reserve at any given coronary arterial pressure is ___________ in a manner that is inversely related to the change in LV mass.
Reduced
CMVD
As with hypertrophy, flow per gram of myocardium will be normal at rest and reduced during pharmacologic vasodilation.
In contrast to hypertrophy, absolute flow remains ______________ at rest in microvascular disease, and the absolute vasodilated flow is reduced.
Normal
Microvascular dysfunction in the presence of normal coronary arteries (0% stenosis) attenuates coronary flow reserve.
Conversely, for any given stenosis, the FFR measured in the presence of microvascular disease will be _______________ than when vasodilator responses are normal.
Higher
Describe the CFR and FFR values for
Normal
Flow limiting stenosis
Non flow limiting stenosis
Diffuse/small vessel disease
Normal - normal CFR ans FFR
Flow limiting stenosis - abnormal CFR and FFR
Non flow limiitng stenosis - normal CFR, abnormal FFR
Diffuse/small vessel disease - abnormal CFR, normal FFR
Microvascular d function in the presence of normal coronary arteries (0% stenosis) attenuates coronary flow reserve. Conversely, for any given stenosis, the FFR measured in the presence of microvascular disease will be higher than when vasodilator responses are normal. Thus, when maximum vasodilation is not achieved, FFR will underestimate the physiologic severity of the stenosis.
Resting distal coronary pressure consistently falls as stenosis severity exceeds ____% diameter reduction, and the resultant interarterial pressure gradient increases endothelial shear stress in pre- existing collaterals smaller than 200 μm in diameter.
70%
Proliferation of coronary collaterals occurs in response to repetitive stress-induced ischemia and the development of transient interarterial pressure gradients between the source and recipient vessel through a process termed ____________________
Arteriogenesis
Collateral perfusion also can originate from de novo vessel growth, or ____________________, which refers to the sprouting of smaller, capillary-like structures from preexisting blood vessels
Angiogensis
Although many interventions have been demonstrated to cause favorable angiogenesis of capillaries and improve myocardial function, few interventions have increased arteriogenesis in mature collaterals, and randomized human clinical trials have been disappointing. Part of this limitation may arise from the fact that no intervention has resulted in _____, the sine qua non of functional collateral formation.
Measurable increases in maximum vasodilated myocardial perfusion or coronary flow reserve indices
The control of blood flow to collateral-dependent myocardium is governed by a series resistance arising from interarterial collateral anastomoses, largely epicardial, as well as the native downstream microcirculation.
___________________ is therefore the major determinant of perfusion, and coronary pressure distal to a chronic occlusion is already near the lower autoregulatory pressure limit.
Collateral resistance
Irreversible myocardial injury begins after ________________ of coronary occlusion in the absence of significant collaterals
20 minutes
Total coronary artery occlusions shorter than ___ minutes do not cause irreversible injury but can cause myocardial stunning and also precondition the heart and protect it against recurrent ischemic injury.
20 mins
Irreversible injury begins _____ minutes and progresses as a wavefront from endocardium to epicardium.
After _____ minutes, the inner third of the left ventricle (LV) wall is irreversibly injured.
After 20 mins
After 60 mins
After _____ hours, only a subepicardial rim of tissue remains, with the transmural extent of infarction completed between 3 and 6 hours after occlusion.
After 3 hours
The most important factor delaying the progression of irreversible injury is the magnitude of _____, which is directed primarily to the outer layers of the heart.
Collateral flow
Reperfusion after prolonged ischemia is accompanied by the development of _____ within the infarct area
No-reflow
Repetitive reversible ischemia or angina occurring before an occlusion can reduce irreversible injury through __________________
Preconditioning
The _________________________ is the most important determinant of the actual time course of irreversible injury in patients with chronic CAD.
Magnitude of residual coronary flow through collaterals or through a subtotal coronary occlusion
The relation between infarct size and the area at risk of ischemia during a total occlusion is inversely related to collateral flow
Brief reversible ischemia preceding a prolonged coronary occlusion reduced infarct size, a phenomenon termed ____________________
Acute preconditioning
Preconditioning also develops on a chronic basis (__________________) and, once induced, persists for up to 4 days. It reduces MI size and also protects the heart from ischemia-induced stunning.
Delayed preconditioning
____________________ ability to engage cardiac protection by producing intermittent ischemia or administering pharmacologic agonists at reperfusion.
It has the greatest clinical potential to affect irreversible injury because it can be induced after myocardial ischemia is established rather than requiring pretreatment
Myocardial postconditioning
A number of experimental studies have demonstrated that ischemia in an extremity remote from the infarct can reduce infarct size. _____ is particularly attractive because it can be easily implemented using a blood pressure cuff and has been shown to experimentally reduce infarct size when administered before and after the onset of ischemia as well as at the time of reperfusion.
Remote conditioning
____________ transient coronary occlusion resulting from coronary vasospasm or transient thrombosis in a critically stenosed coronary artery, producing transmural ischemia
Supply induced ischemia
__________________ inability to increase flow in response to increases in myocardial oxygen consumption in which ischemia predominantly affects the subendocardium
Demand induced ischemia
Coronary occlusion results in an immediate fall in coronary venous oxygen saturation, with a reduction in ATP production. This causes a decline in regional contraction within several beats, reaching dyskinesis within _____ minute.
1 minute
As regional contraction ceases, concomitant changes include a reduction in global LV contractility (dP/dt), a progressive rise in LV end-diastolic pressure, and a fall in systolic pressure.The magnitude of the systemic hemodynamic changes varies with the severity of ischemia and the amount of the left ventricle subjected to ischemia. Significant electrocardiographic ST-segment changes develop within ____ minutes as efflux of potassium into the extracellular space reaches a critical level
2 minutes
_____ are variable and usually are the last event in the evolution of ischemia
Symptoms of chest pain
On restoring perfusion, the sequence is reversed, with resolution of chest pain occurring before hemodynamic changes resolve, but regional contraction can remain depressed, reflecting the development of _____.
Stunned myocardium
Physiologic changes after coronary occlusion
Coronary occlusion results in an immediate fall in __________________, with a reduction in ATP production.
This causes a decline in _________________ within several beats, reaching dyskinesis within 1 minute.
As regional contraction ceases, concomitant changes include a reduction in _____________________, a progressive rise in LV end-diastolic pressure, and a _______ in systolic pressure.
Significant electrocardiographic __________________ develop within 2 minutes as efflux of potassium into the extracellular space reaches a critical level.
Symptoms of ______________ are variable and usually are the last event
- Coronary venous oxygen saturation
- Regional contraction
- Global LV contractility (dP/dt)
- Fall
- ST-segment changes
- Chest pain
Upon restoring perfusion, the sequence is reversed, with r lution of chest pain occurring before hemodynamic changes resolve, but regional contraction can remain depressed, reflecting the development of stunned myocardium
When coronary pressure distal to a stenosis falls below the lower limit of autoregulation, __________________ is exhausted, resulting in the onset of subendocardial ischemia
Flow reserve
In steady-state ischemia, the close matching between perfusion and contraction leads to a reduced regional oxygen consumption and energy utilization, a phenomenon termed ____________________. This reestablishes a balance between supply and demand,
Short-term hibernation
Chronic contractile dysfunction and regional cellular mechanisms that downregulate contractile and metabolic function of the heart so as to protect it from irreversible injury
Hibernating myocardium
Myocardial function normalizes rapidly after single episodes of ischemia lasting less than _____ minutes.
<2 minutes
Myocardial function remains depressed for up to 6 hours after resolution of ischemia following a 15-minute occlusion in the absence of tissue necrosis, a phenomenon called ______________
Myocardial stunning
Prolonged sublethal ischemia, as seen in short-term hibernation, leads to stunning on restoration of perfusion that may take up to _____ week to resolve in the absence of necrosis
1 week
_____ is also responsible for postoperative pump dysfunction after cardiopulmonary bypass.
Stunned myocardium
_______________ any myocardial region in which contractile function improves after coronary revascularization
Viable dysfunctional myocardium
When resting flow relative to a remote region is normal in dysfunctional myocardium distal to a stenosis, the region is _________________.
In contrast, when relative resting flow is reduced in the absence of symptoms or signs of ischemia ____________________
Chronically stunned
Hibernating myocardium
The progression from chronically stunned myocardium (with normal resting flow) to hibernating myocardium (with reduced resting flow) is related to the functional significance of the chronic stenosis supplying the LAD region and is probably a reflection of its propensity to produce repetitive supply- or demand-induced ischemia.This progression can be seen as soon as ___ week after placement of a critical stenosis that exhausts coronary flow reserve
1 week
