FRACTIONAL FLOW RESERVE

DR VISHWANATH HESARURSENIOR RESIDENT

DEPT OF CARDIOLOGYJNMC, BELGAUM.

CORONARY BLOOD FLOW AND MYOCARDIAL ISCHEMIA

UNIQUE FEATURES OF CORONARY BLOOD FLOW

• Phasic flow

• Transmural flow

• Extravascular compression

• Oxygen Extraction

Phasic flow

• Coronary perfusion – intermittent rather than continuous

Determinants of Myocardial Oxygen Consumption

• In contrast to most other vascular beds, myocardial oxygen extraction is near-maximal at rest, averaging 60% to 80% of arterial oxygen content. So it might increase to maximum 90 % after heavy exercise.

• Thus because of high resting tissue extraction of oxygen, increase in the myocardial oxygen consumption ( MVo2)are primarly met by a proportional increase in coronary blood flow.

• The major determinants of MVo2 are heart rate, systolic pressure (or myocardial wall stress), and left ventricular (LV) contractility.

• A twofold increase in any of these individual determinants of MVo2 requires an approx 50% increase in coronary blood flow.

• Coronary blood flow at rest is Approx 250ml/min.• Myocardium will regulate its own blood flow between perfusion

pressure of 40 to 140 mmhg, beyond this is pressure dependent.

Autoregulation• 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.

• When pressure falls to the lower limit of autoregulation, coronary resistance arteries are maximally vasodilated to intrinsic stimuli, and flow becomes pressure-dependent, 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.

• Transmural variations in the lower autoregulatory pressure limit, which result in increased vulnerability of the subendocardium to ischemia.

• Subendocardial flow occurs primarily in diastole and begins to decrease below a mean coronary pressure of 40 mm Hg.

• By contrast, subepicardial flow occurs throughout the cardiac cycle and is maintained until coronary pressure falls below 25 mm Hg.

• This difference arises from – Increased oxygen consumption in the subendocardium.– Higher resting flow rates– Increased sensitivity to systolic compressive affects ie

subendocardial flow occurs only in diastole.

• The transmural difference in the lower autoregulatory pressure limit results in vulnerability of the subendocardium to ischemia in the presence of a coronary stenosis.

Determinants of Coronary Vascular Resistance

• The resistance to coronary blood flow can be divided into three major components

• R1 ( Epicardial arteries )- Under normal circumstances, there is no measurable pressure drop in the epicardial arteries, indicating negligible conduit resistance.

• R2 ( Microcirculatory resistance arteries & arteriole (20 to 400 μm in diameter)- distributed throughout the myocardium & respond to physical forces (intraluminal pressure and shear stress), as well as the metabolic needs of the tissue.

• R3 (Extravascular compressive resistance)- During systole, cardiac contraction raises the extravascular pressure to values equal to LV pressure at the subendocardium. This declines to values near pleural pressure at the subepicardium.

• The increased effective back pressure during systole produces a time varying reduction in the driving force for the coronary flow that impedes the coronary flow to subendocardium.

• In heart failure compressive effects from elevated ventricular diastolic pressures also impede perfusion via passive compression by increasing extra vascular tissue pressure during diastole.

Physiological assesment of coronary artery stenosis

• The physiologic assessment of stenosis severity is a critical component of the management of patients with obstructive epicardial CAD.

• Stenosis in the epicardial artery result in reduced perfusion pressure , arterioles downstream dilate to maintain normal resting flow .

• As stenosis progress, arteriolar dilatation becomes chronic, decreasing potential to augment flow and thus reduce coronary flow reserve.

• As CFR approaches to 1, any further decrease in perfusion pressure or increase in MV02 result in ischemia.

• The total pressure drop across a stenosis is governed by three hydrodynamic factors —viscous losses, separation losses, and turbulence.

The Coronary Pressure–Flow Relationships

• Myocardial ischemia results from an imbalance between myocardial oxygen supply and demand.

• Coronary blood flow provides the needed oxygen supply for any given myocardial oxygen demand and normally increases automatically from a resting level to a maximum level in response to increases in myocardial oxygen demand from exercise and neurohumoral or pharmacological hyperemic stimuli.

• This increase from baseline to maximal flow has been termed coronary flow reserve (CFR).

• Blood flow has 3 major resistance components: the epicardialvessel (R1), the small arteries and arterioles (R2), and the intramyocardial capillary system (R3).

• When coronary reserve is normal, these 3 resistances are assumed to be functioning normally.

• In patients without atherosclerosis, the large epicardial vessel resistance (R1) is trivial.

• Arteries with diameters 400 um have only minimal resistance.

• Adjustment of coronary resistance occurs principally at the R2 resistance (vessels 400 um in diameter) and is due to the integrated action of several control mechanisms.

• Across a normal epicardial artery, supplying normal myocardium, coronary blood flow can increase 3-fold in adults.

• Autoregulation automatically maintains the basal flow at a constant level in response to changing pressure and oxygen demand.

• Atherosclerotic narrowings produce epicardialvessel resistance and, after a critical reduction in vessel lumen area, can abolish not only coronary reserve but also autoregulation, thus reducing resting coronary blood flow.

• Coupled with reduced flow is the loss of pressure distal to a stenosis.

• The resistance to flow through a stenosiscaused by viscous friction, flow separation, turbulence, and eddies at the site of the stenosis results in energy loss.

• Energy loss produces pressure loss distal to the stenosis and thus a pressure gradient across the narrowed segment (Figure 1).

• The pressure loss or gradient increases with increasing coronary flow along a quadratic pressure drop–flow relationship of the specific coronary stenosis

• In vessels without a stenosis, the pressure–flow curve of maximal vasodilation is linear in the physiological pressure range .

• However, when a stenosis is present, the maximal flow at any given arterial pressure is lower.

• In this setting, the coronary pressure–flow line at maximum vasodilation is no longer straight but curvilinear because stenosis resistance is flow dependent.

• The clinical significance of these observations is that 2 nearly identical angiographic stenoses (eg, 60% diameter narrowing) can have a dramatically different clinical impact for the patient.

• One stenosis would limit flow for increasing demand and would produce angina, whereas the other would be angiographically apparent but would remain clinically unimportant

Coronary Pressure and Fractional Flow Reserve

• Myocardial perfusion pressure, normally the diastolic coronary pressure, equals aortic pressure minus the left ventricular diastolic pressure or central venous pressure.

• Across normal coronary arteries, aortic pressure is transmitted completely, without appreciable pressure loss even to the most distal regions.

• As noted earlier, the distal coronary pressure in arteries with an atherosclerotic narrowing is decreased in relationship to the degree of stenosis resistance.

• Pijls et al related the distal coronary pressure to the ischemic potential of a stenosis by calculating a value called the fractional flow reserve (FFR).

• By taking the ratio of the coronary pressure measured distal to the stenosis to aortic pressure as the normal perfusion pressure (distal coronary pressure/aortic pressure) and obtaining these measurements when the microvascular resistance was minimal and assumed to be constant (that is, at maximal hyperemia), the percentage of normal coronary flow, or a fraction of normal flow (ie, FFR), can be calculated.

• The FFR measures the maximum achievable myocardial blood flow in the presence of a coronary artery stenosis as a percentage of the maximum blood flow in the hypothetical case of a completely normal artery

• FFR model assumes that under maximum arterial vasodilation, the resistance of the myocardium is minimal and constant across different myocardial vascular beds, and thus blood flow to the myocardium is proportional to the driving pressure (myocardial perfusion pressure).

• FFR can be derived separately for the myocardium, for the epicardial coronary artery, and for the collateral supply.

• Calculations of myocardial, coronary, and collateral FFR from pressure measurements taken during maximal arterial vasodilation (ie, hyperemia) are as follows:

• The FFR is simplified to Pd/Pa given the assumption that Pv is negligible relative to Pa.

• An FFR value of 0.6 means that the maximum myocardial flow across the stenosis is only 60% of what it should be without the stenosis.

• An FFR of 0.9 after percutaneous coronary intervention (PCI) means that the maximum flow to the myocardium is 90% that of a completely normal vessel.

• FFR has a normal value of 1.0 for every patient and every coronary artery.

• An FFR 0.75 is associated with inducible ischemia (specificity, 100%), whereas a value 0.80 indicates absence of inducible ischemia in the majority of patients (sensitivity, 90%).

Fractional Flow Reserve

• Based on the principle that the distal coronary pressure measured during vasodilation is directly proportional to maximum vasodilated perfusion.

• FFR is defined as the ratio of maximum blood flow in a stenotic artery to maximum blood flow in the same artery if there were no stenosis.

• FFR is simply calculated as a ratio of mean pressure distal to a stenosis (Pd) to the mean pressure proximal stenosis, that is the mean pressure in the aorta (Pa), during maximal hyperaemia.

LIMITATIONS OF CORONARY ANGIOGRAPHY

– Interpretation is highly subjective – CAG provides a 2–dimentional view of a 3-dimensional

lumen.– Severity of a stenotic lesion is reported in comparison to a

normal reference segment . This is particularly fallacious in case of diffuse disease.

– CAG is a lumenography & does not provide information regarding vessel wall & extent of positive or negative remodeling.

– An ecentric stenosis has varying appearance of severity in different views. The length, size and severity of a lesion & its relationship with the vessel wall can affect the coronary flow.

– Several artifacts contribute to the disparity in interpretation like vessel foreshortening, overlapping vessels, calcification & contrast streaming.

TECHNIQUE

Catheter • Diagnostic catheters can not be used to measure FFR -

pressure measurements can be inaccurate & the wire manipulation is met with friction due to smaller internal diameters compared to guide catheters.

• The main advantage of using guide catheters is that PCI is immediately possible if required.

• Guide catheter with Side holes should not be used– It can create a false gradient between the side holes & the tip

of the guide catheter creating a false Positive FFR.– Pharmacological vasodilatory agents may be flushed into the

aorta instead of the coronary artery.

Pressure Wire

• Two pressure wires are available namely PressureWire ( st Jude medical, MN, USA) & Volcano WaveWire ( Volcano Inc, CA,USA)

• Both have the pressure sensor (solid-state (electronic) sensor) located at the junction of the radiopaque & radiolucent part of the wire, 30 mm from the tip.

• The wires are 0.014-inch (0.33-mm) floppy-tipped guide wire

36

PressureWire®

The distal pressure in the coronary artery is measured by a tiny sensor located 3 cm from the tip of an 0.014” guidewire, called PressureWire®.

0.014”

3 cm

Pressure Monitoring Guide Wire

Maximal Hyperaemia

• Epicardial & resistance arteries have to be vasodilated.

• Epicardial vessels are dilated using a bolus of 100-200 mcg of intracoronary nitroglycerine at least 30 seconds before the first measurement.

• Hyperaemia is induced in the resistance vessels using adenosine ( IC or IV ) or papaverine ( IC )

IV vs IC PHARMACOLOGIC HYPEREMIC AGENTS

Maximum Hyperemia

Horizontal Pd/Pa line:

Steady State and likely

Maximum Hyperemia

Anticoagulation• Standard protocols for anticoagulation should

be followed.• Heparin is administered according to body

weight to maintain an ACT of at least 250.

• Display• The pressure wire is connected to an interface

( Analyzer Express, St Jude medical inc. or combomap, volcano Inc.) which shows the mean Aortic pressure (Pa) & the mean pressure at the tip of the guide wire (Pd) simultaneously & provides a FFR value immediately.

42

RadiAnalyzer®

PressureWire® is attached to RadiAnalyzer®, an interface which makes the FFR calculations automatically during the procedure. It displays both aortic and distal pressure wave forms.

Cathlabrecording

system

PressureWire

AO transducer

IBP

inp

ut

FFR

Precautions

• Guiding catheter should not have side holes• Introducer needle should be removed before

equalising or taking measurements.• Equalise the pressure measured by the

pressure wire & guiding catheter.• Height of the transducer should be adjusted to

the patients heart level.• Appropriate dose & route of pharmacological

agents to achieve maximal hyperaemia is essential to obtain accurate results

• Use central vein for IV adenosine.

Pressure Measurement

Step 1: Zero the Pressure System to the Atmosphere

Step 2: Insert the Pressure Sensor Guide Wire Into the Guide and Equalize the 2 Pressures

Step 3: Advance the Pressure Wire Sensor Distal to the Region of Interest

Step 4: Induce Maximal Hyperemia

Step 5: Wire Pullback to Check for Signal Drift

0

100

50

Pa = Guiding Catheter

Pd = Pressure Wire

Pressure Monitoring Guide Wire

UNIQUE FEATURES OF FFR

• Normal value of 1 irrespective of the patient , artery or vascular bed. It is independent of gender & other factors like DM & HTN

• Well defined cut-off values : – FFR values ≤ 0.75 is invariably associated with inducible ischemia

(sensitivity 88%, specificity 100%, positive predictive value 100% & overall accuracy 93%)

– FFR ≥0.80 is usually not associated with inducible ischemia.– The gray zone of 0.75 to 0.80 spans over a small range of FFR values.

• Systemic haemodynamics like heart rate , blood pressure & LV contractility do not affect the value of FFR since the value of Pd & Pa are taken simultaneously.

• Reproducibility : FFR is reproducible since the microvasculature has the capacity to vasodilate the same extent repeatedly.

• Contribution of collateral vessels is taken in to account. The pressure distal to the stenosis is influenced by antegrade flow & retrograde flow & is therefore influenced by a stenotic vessel supplied by collateral & a stenotic vessel giving collaterals to a more severely stenosed vessel.

• Spatial resolution – During maximal hyperaemia, pulling back the pressure

wire can provide an instantaneous measure of the signifance of a particular segment of the coronary artery with a spatial resolution of a few millimeters.

– It therefore provides a per segment analysis of the coronary artery.

– This is especially useful in case of sequential stenosis to determine the stenosis with the maximum haemodynamic significance.

• Relation between FFR & viable myocardium : – If a stenotic vessel supplies a larger viable myocardial mass, there

will be larger hyperaemic flow during maximal vasodilationresulting in a greater gradient between Pd & Pa & thus , a lower value of FFR.

– Therefore , the haemodynamic significance of a lesion is dependent on its perfusion territory.

APPLICATIONS OF FFR IN SPECIFIC SUBSETS

Intermediate lesions

• Intermediate lesions with a FFR of ≥ 0.80 can be safely defered.

• The DEFER study has shown that patients with single vessel stenosis and FFR >0.75 who did not undergo PCI had excellent outcomes.

• The risk of cardiac death or MI related to the stenosis was < 1% per year and was not reduced with PCI.

• In contrast, patients with single-vessel stenosis and FFR <0.75 are 5× more likely to experience cardiac death or MI within 5 years, despite undergoing revascularization.

• Deferral of revascularization for single-vessel stenoses according to the FFR value is safe regardless of the stenosis location.

• Muller et al showed that medical treatment of patients with proximal left anterior descending stenoses and FFR >0.80 had excellent 5-year outcomes.

• Even for patients with small coronary arteries (diameter <2.8 mm), FFR can safely determine stenoses that necessitate revascularization.

• Physiologic and Anatomical Evaluation Prior to and After Stent Implantation in Small Coronary Vessels (PHANTOM) trial,

– 60 patients with small coronary arteries underwent FFR.

– 56 of the 60 patients had undergone IVUS.

– Patients were stratified according to FFR (<0.75 and >0.75).

– The group with FFR <0.75 underwent revascularization.

– At 1 year, there was no occurrence of MI or death in either group.

– In patients with FFR <0.75, 24% underwent a repeat PCI, but only 2.6% of patients with FFR >0.75 underwent revascularization.

– Overall, there was no correlation between FFR and IVUS.

Multivessel Coronary Artery Disease

• FFR has a major impact on the revascularisation strategy in multivessel disease .

• In patients who have triple vessel disease , FFR may demonstrate haemodynamically significant stenosis of only two vessels.

• Conversely , a patient with apparently one or two vessel disease may have a haemodynamic significant lesion in LM artery or in all three vessels.

• This can affect the decision of PCI versus surgical revascularisation & also the number of stents used during PCI.

• The FAME study showed a reduced rate of mortality & MI after 2 yrs in the subset with FFR guided PCI, in patients with multivesseldisease.

Ref. NEJM Vol 360, No 3, pp 213-224. Slides courtesy Nico H J Pijls.

FAME study: Study Population

The FAME study was designed to reflect daily practicein performing PCI in patients with multivessel disease

Inclusion criteria:• ALL patients with multivessel disease• At least 2 stenoses ≥ 50% in 2 or 3 major epicardialcoronary artery disease, amenable for stenting

Exclusion criteria:• Left main disease or previous bypass surgery• ST-elevation MI with CK > 1000 U/l within last 5 days• extremely tortuous or calcified coronary arteries

Note: patients with previous PCI were not excluded

• CONCLUSIONS:Routine measurement of FFR in patients with multivessel disease (MVD) who are undergoing PCI with drug-eluting stents (DES) significantly improves outcomes at 1 year by reducing MACE (composite rate of death, nonfatal myocardial infarction, and repeat revascularization)

FAME II: Fractional Flow Reserve-Guided Percutaneous Coronary Intervention plus Optimal Medical Treatment versus Optimal

Medical Treatment Alone in Patients with Stable Coronary Artery Disease

73%50% randomly

assigned to FU27%

Registry

When all FFR > 0.80

(n=332)

MT

Randomized Trial

At least 1 stenosiswith FFR ≤ 0.80 (n=888)

Randomization 1:1

PCI + MT MT

Follow-up after 1, 6 months, 1, 2, 3, 4, and 5 years

De Bruyne B, et al. N Engl J Med. 2012 Sep13;367(11):991-1001.

FAME 2 Study Flow Chart

Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI

N = 1220

FFR in all target lesions

Cu

mu

lati

vein

cid

ence

(%)

FAME 2: Primary OutcomesDeath, MI, Urgent Revascularization

30

25

20

15

10

5

0

441447166

414414156

370388145

322351133

283308117

253277106

22024393

19221274

16217564

12715552

10011741

709225

375313

MTPCI+MTRegistry

No. at risk

0 1 2 3 4 5 6 7 8 9 10 11 12Months after randomization

PCI+MT vs. MT:PCI+MT vs. Registry:MT vs. Registry:

HR 0.32 (0.19-0.53); p<0.001HR 1.29 (0.49-3.39); p=0.61HR 4.32 (1.75-10.7); p<0.001

De Bruyne B,et al. N Engl J Med. 2012 Sep 13;367(11):991-1001.

FAME 2: Primary Outcomes

Primary Endpoint

Death

Myocardial Infarction

Urgent Revascularization

Free from Angina (1 month)

FFR-Guided PCI(n=447)

4.3%

0.2%

3.4%

1.6%

89%

MT(n=441)

12.7%

0.7%

3.2%

11.1%

71%

P-Value

<0.001

0.31

0.89

<0.001

<0.001

De Bruyne B,et al. N Engl J Med. 2012 Sep 13;367(11):991-1001.

FAME 2 TRIAL

• Conclusion• In patients with stable coronary artery disease and

at least one stenosis with an FFR≤0.80, OMT alone was associated with a more than fourfold larger hazard of major adverse cardiac events than FFR-guided PCI with drug-eluting stents plus OMT.

• In contrast, in patients with hemodynamically non-significant stenoses (FFR>0.80), OMT alone was associated with a favourable clinical outcome.

Left-Main Coronary Artery Disease

• Left main coronary artery poses certain challenges which make the interpretation of CAG & severity of stenosis difficult.

– Greater inter-observer variability– Under-estimation of functional significance since it supplies

a large myocardial territory– Diffuse atherosclerosis in a short LMCA results in absence of

a reference segment to judge the significance of a lesion– Spilling of contrast medium in to the aorta– Overlapping the catheter with the LMCA– Non – invasive testing may lead to false negative results since

reduced tracer uptake in all vascular territories leading to balanced ischemia.

– FFR has been found to be safe in guiding LMCA revascularisation in several studies & is associated with improved outcomes.

Tandem Lesions

• Tandem lesions are defined as 2 separate lesions with >50% stenosis each in the same coronary artery, separated by an angiographically normal segment.

• If the FFR is<0.75, Hirota et al suggested performing PCI for the stenosis that showed marked narrowing first and then repeating the FFR measurement.

• If the FFR remains <0.75, the other stenosis was revascularized as well; in contrast, if the FFR value of the first lesion increased after PCI to >0.75, then the second lesion was treated only medically

Treat lesion 2,

Final FFR

J Am Coll Cardiol Intv.

2012;5(10):1013-1018.

Considerations for Serial lesions

Pre FFR (1+2) with

pullback

Lesion 1 large dP,

Stent

Recheck FFR

• Lesion with largest pressure drop was

stented first (116 total stents, 70 proximal,

46 distal)

• Strategy not clearly stated but seems like

goal was to achieve post stent FFR > 0.80

• Revascularization deferred in 61% lesions

• ≥2 stents deployed in only 18% vessels

N=298 Lesions, at least 20 mm apart, either chronic CAD or no

Kim et al. J Am Coll Cardiol Intv 2012;5:1013-8

FFR Guided PCI of Serial Lesions

N=131 Patients with multiple 40-70% stenoses, 2 centers

Bifurcation lesions

• Bifurcation lesions are particularly difficult to evaluate by angiography.

• After stenting the main vessel, the side branch appears pinched which is grossly overestimated by angiography

• Koo et al showed that kissing balloon dilatation of the ostial side branch lesions with FFR < 0.75 only , resulted to a FFR > 0.75 in 95% patients after 6 months.

• If the FFR of an apparently pinched side branch is >0.75, it can safely be left alone.

FFR in Bifurcation DiseaseN = 110 patients with FFR guided bifurcation PCI with DES

compared with 110 matched angiographic guided bifurcation

PCI

Koo et al., European Heart Journal 2008 29(6):726-732

FFR in Bifurcation DiseaseN = 26 patients with FFR guided side branch PCI with DES with

baseline and follow up FFR

Koo et al., European Heart Journal 2008 29(6):726-732

Post stenting• Nico H.J. Pijls at al showed that FFR

measured after stenting should be >0.90 & is an independent predictor of 6 month mortality.

• The registry was performed in 750 patients in 15 hospitals in 8 countries (5 centers in the United States, 5 centers in Europe, and 5 centers in Asia).

Coronary Pressure Measurement After Stenting PredictsAdverse Events at Follow-UpA Multicenter Registry, (Circulation. 2002;105:2950-2954.)

CABG conduit patency

• 20-25 % of grafts done to physiologically nonsignificant lesions ( FFR > 0.80) were found to be occluded at 1 yr.

• This occurs because blood flow favors a path of lower resistance through the native vessel with a nonsignificant obstruction as compared to a vein graft.

• Thus FFR can provide information about future graft patency & allows an appropriate selection of the vessel which should not be grafted

Graft intervention

• FFR can be used to determine the physiological significance of a lesion in a graft vessel.

• The same cut off af ≤ 0.75 has been used in a small study comparing FFR to stress myocardial perfusion imaging with an acceptable specificity & negative predicitivevalue.

PITFALLS OF FFR

Hemodynamic Artifacts

• Damped pressure waveforms.

• Guide obstruction

• Contrast media

• Very small guide (<5F)

• Pressure signal drift

• Side holes and ostial

‘pseudostenosis’

Technical• loose connections• Improper zero• Calibration offset

Anatomic• Extreme tortuosity• Inability to wire vessel• Spasm

MechanicalWire/artery impact

PharmacologicInadequate hyperemia

Effect of Wire Introducer

Guiding catheter related

• Small ostium, too large guiding catheter

• Solve by dislodging guiding and using iv adenosine

guiding in ostium

guiding out ostium

Impact of Catheter Size on Hyperemic Flow

De Bruyne, et al. Cathet Cardiovasc Diagn 1994;33:145-152.

Pd

Pc

FFR and Guidings with Side-Holes

Pa

Pressure recorded by guiding

PaPc =

When wedging of the catheter, withdraw guiding from ostium

For flow or pressure measurements:NO SIDE-HOLES

Side Holes

Sensor proximal to side holes

Guiding Catheter With Sides Holes

Notch

Notch

No notch

Drift Drift True Gradient

Notch

CONCLUSION• FFR strongly supports the concept of 'Functionally Complete

Revascularisation', that is stenting of the physiologically significant ischemic stenosis & medical management of the non-ischemic stenosis .

• In spite of the strong evidence favoring its use, FFR is still not used widely .

• The application of FFR along with angiography combines two gold standard investigations to provide an all in one anatomical & physiological assessment of CAD.

• Its application in various subsets of coronary artery anatomies make FFR an essential tool in the cath lab ,in decision making & improving outcomes of patients undergoing PCI.

Coronary Flow and Flow Reserve

• As stenosis severity increases, maximal coronary flow becomes attenuated and CFR decreases.

• CFR is a combined measure of the capacity of the major resistance components (the epicardial coronary artery and supplied vascular bed) to achieve maximal blood flow in response to hyperemic stimulation.

• A normal CFR implies that both the epicardial and minimally achievable microvascular bed resistances are low and normal.

• However, when abnormal, CFR does not indicate which component is affected, thus limiting the clinical applicability of this measurement.

• Although early studies in animals and patients suggested an absolute CFR of 3.5 to 5 in adult patients with chest pain syndromes and CAD risk factors undergoing cardiac catheterization with angiographically normal vessels, the normal CFR was 2.70 to 6 which suggests a degree of patient variability and microvascular disease.

• In patients with essential hypertension and normal coronary arteries or in patients with aortic stenosisand normal coronary arteries, CFR may be reduced, in part because of myocardial hypertrophy and an abnormal microvasculature.

• CFR can be altered by changes in either basal or hyperemic flow, which are influenced by hemodynamics, loading conditions, and contractility.

• For example, tachycardia increases basal flow and decreases hyperemic flow, thus reducing CFR 10% for each 15-beat increase in heart rate.

• Because CFR is a summed response of both the epicardial and microvascular flow, clinicians are reluctant to use CFR as the sole indicator of lesion significance except when it is normal.

• To increase confidence in CFR as a measure of lesion severity, the determination of relative CFR (rCFR) has been proposed by Gould et al,3 who defined rCFR as the ratio of maximal flow in a coronary artery with stenosis (QS) to maximal flow in a normal coronary artery without a stenosis (QN).

• It was shown that rCFR was independent of the aortic pressure and rate–pressure product and was well suited to assess the physiological significance of coronary stenoses when an adjacent nondiseased coronary artery was available

• For invasive catheterization laboratory flow studies, rCFR was defined as the ratio of CFRtarget to CFRnormal reference vessel:

• The normal range for rCFR is 0.8 to 1.0.

• Because of the variability of CFR and limitations in patients with multivessel CAD, rCFR is not commonly used.

• Likewise, rCFR relies on the assumption that the microvascularcirculatory response is uniformly distributed among the myocardial beds; thus, rCFR is of no value in patients with myocardial infarction (MI) or left ventricular regional dysfunction or in patients in whom the microcirculatory responses may be heterogeneous (eg, those with myocardial fibrosis or asymmetric hypertrophy).

• In clinical terms, CFR is best used to assess the microcirculation in the absence of epicardial artery narrowings.

• CFR is not used to assess stenosis significance because of the influence of hemodynamics and the unknown impact of the microcirculation.

Rentrop Grade of Collateral Filling

• Rentrop et al. proposed the system below to grade collateral filling of recipient arteries:

• Rentrop Grade 0No visible filling of any collateral channels.

• Rentrop Grade 1Collateral filling of branches of the infarct related artery.

• Rentrop Grade 2Partial collateral filling of the epicardial segment of the infarct related artery .

• Rentrop Grade 3Complete collateral filling of the infarct related artery.

Laminar flow• Laminar flow is the normal condition for blood flow throughout most

of the circulatory system. • It is characterized by concentric layers of blood moving in parallel

down the length of a blood vessel.• The highest velocity (Vmax) is found in the center of the vessel. • The lowest velocity (V=0) is found along the vessel wall. • The flow profile is parabolic once laminar flow is fully developed. This

occurs in long, straight blood vessels, under steady flow conditions.• One practical implication of parabolic, laminar flow is that when flow

velocity is measured using a Doppler flowmeter, the velocity value represents the average velocity of a cross-section of the vessel, not the maximal velocity found in the center of the flow stream.

• The orderly movement of adjacent layers of blood flow through a vessel helps to reduce energy losses in the flowing blood by minimizing viscous interactions between the adjacent layers of blood and the wall of the blood vessel.

• Disruption of laminar flow leads to turbulence and increased energy losses.

Turbulent Flow

• Generally in the body, blood flow is laminar. However, under conditions of high flow, particularly in the ascending aorta, laminar flow can be disrupted and become turbulent.

• When this occurs, blood does not flow linearly and smoothly in adjacent layers, but instead the flow can be described as being chaotic.

• Turbulent flow also occurs in large arteries at branch points, in diseased and narrowed (stenotic) arteries (see figure below), and across stenotic heart valves.

• Turbulence increases the energy required to drive blood flow because turbulence increases the loss of energy in the form of friction, which generates heat.

• When plotting a pressure-flow relationship (see figure to right), turbulence increases the perfusion pressurerequired to drive a given flow.

• Alternatively, at a given perfusion pressure, turbulence leads to a decrease in flow.

Viscosity of Blood

• Viscosity is an intrinsic property of fluid related to the internal friction of adjacent fluid layers sliding past one another

• This internal friction contributes to the resistance to flow. • The interactions between fluid layers depend on the chemical nature of the

fluid, and whether it is homogeneous or heterogeneous in composition. • For example, water is a homogeneous fluid and its viscosity is determined by

molecular interactions between water molecules.• Water behaves as a Newtonian fluid and therefore under non-turbulent

conditions, its viscosity is independent of flow velocity (i.e., does not change with changes in velocity).

• Although plasma is mostly water, it also contains other molecules such as electrolytes, proteins (especially albumin and fibrinogen), and other macromolecules.

• Because of various molecular interactions between these many different components of plasma, it is not surprising that plasma has a higher viscosity than water.

• In fact, plasma at 37°C is about 1.8-times more viscous than water at the same temperature; therefore, the relative viscosity of plasma (compared to water) is about 1.8.

• The addition of formed elements to the plasma (red cells, white cells, and platelets) further increases the viscosity.

• Of these formed elements, red cells have the greatest effect on viscosity under normal conditions.

• As shown in the figure to the right in which whole blood viscosity is determined in vitro using a viscometer, an increase in red cell hematocritleads to an increase in relative viscosity.

• Note that the increase is non-linear, so that doubling hematocrit more than doubles the relative viscosity.

• Therefore, blood viscosity strongly depends on hematocrit. • At a normal hematocrit of 40-45%, the relative viscosity of blood is 4-5. • Patients with a condition called polycythemia, which is a abnormal elevation

in red cell hematocrit, have much higher blood viscosities. • This increases the resistance to blood flow and therefore increases the work of

the heart and can impair organ perfusion. • Some patients with anemia have low hematocrits, and therefore reduced

blood viscosities.

• A second important factor that influences blood viscosity is temperature.

• Just like molasses, when blood gets cold, it get "thicker" and flows more slowly.

• Therefore, there is an inverse relationship between temperature and viscosity.

• Viscosity increases about 2% for each degree centigrade decrease in temperature.

• Normally, blood temperature does not change much in the body. However, if a person's hand is exposed to a cold environment and the fingers become cold, the blood temperature in the fingers will fall and viscosity increase, which together with sympathetic-mediated vasoconstriction will decrease blood flow in the cooled region.

• When whole body hypothermia is induced in critical care or surgical situations, this will also lead to an increase in blood viscosity and therefore affect systemic hemodynamics and organ blood flow.

• Unlike water, blood is non-Newtonian, meaning that viscosity is not independent of flow at all flow velocities. In fact, during conditions such as circulatory shock where microcirculatory flow in tissues is reduced because of decreased arterial pressure, low flow states can lead to several-fold increases in viscosity. Low flow states permit increased molecular interactions to occur between red cells and between plasma proteins and red cells. This can cause red cells to stick together and form chains of several cells (rouleau formation) within the microcirculation, which increases the blood viscosity.

• If clotting mechanisms are stimulated in the blood, platelet aggregation and interactions with plasma proteins occur. This leads to entrapment of red cells and clot formation, which dramatically increase blood viscosity.

• There is a microcirculatory phenomenon called the Fahraeus-Lindqvist effect that leads to a reduction in hematocrit in small arterioles (less than 200 microns in diameter) and capillaries relative to the hematocrit of large feed arteries. This decrease in hematocrit in these flow vessels reduces the relative blood viscosity in the small vessels, which helps to offset the increase in viscosity that can occur because of reduced velocity in these same vessels. The net effect of these changes is that blood flow in the microcirculation has a lower viscosity than what is predicted by in vitro blood viscometer measurements. In vivo measurements of blood viscosity were made in dog hindlimbs in 1933 by Whittaker and Winton (J. Physiol. 78:339, 1933). At a given arterial blood hematocrit, the relative viscosity of blood is much lower than predicted from in vitro experiments (compare figure at right with previous figure that used a viscometer).