physiology of coronary circulation

1. CORONARY
CIRCULATION
Dept of cardiology
Dr. Kapil.R

2. MYOCARDIAL OXYGEN EXTRACTION
HEPATIC 45-55%
RENAL <15%

3. MYOCARDIAL OXYGEN CONSUMPTION
Mv02
Oxygen
delivery
Hemoglobin
concentration
oxygen saturation
Pa02(dissolved
oxygen)
Coronary
blood flow
Exercise&Pv02
25mm->15mm

4. DETERMINANTS OF MV02
2fold increase increase  50 % inc. in CBF
LV
CONTRACT
ILITY
SYSTOLIC
PRESSURE
HEART
RATE

5. CORONARY FLOW
RESERVE
Ability to increase
flow above resting
values in response
to pharmacologic
vasodilatation is
termed coronary
flow reserve

6. PHASIC VARIATIONS IN CORONARY BLOOD FLOW
Phasic coronary arterial inflow and venous outflow at rest and during adenosine
vasodilation. Arterial inflow primarily occurs during diastole. During systole (dotted vertical
lines), arterial inflow declines as venous outflow peaks, reflecting the compression of
microcirculatory vessels during systole. After adenosine administration, the phasic variations in
venous outflow are more pronounced

7. Coronary
flow
reserve
Maximal
vasodilatation
LV hypertrophy
Microvascular
disease
Heart rate(diastolic
filling)
preload
Resting flow
(T-2/ VIRGO 3A)
Heart rate
Systolic BP
Anemia&hypoxia
Contractility

8. AUTOREGULATION

9. TRANSMURAL VARIATION OF AUTOREGULATION
•High resting flow
•Diastolic flow
Systolic &diastolic
flow

10. R1 - epicardial conduit
resistance(insignificant)
R2 -metabolic and
autoregulatory
arterioles and small
arteries
R3 - time-varying
compressive resistance
endocardial>epicardial
NORMAL HEART
R2 > R3 >R 1
PROXIMAL STENOSIS OR
PHARMACOLOGICAL
VASODILATION
R1 > R3 > R2.

11. Epicardial arteries (>400 μm)
conduit artery function
shear stress
pressure drop (<5%)
Small arteries (100 to 400 μm)
local shear stress luminal pressure
changes (myogenic response)
Arterioles (<100 μm)
changes in local tissue metabolism
Capillaries <20% of microvascular
resistance( 2 fold 10%)

13. PHYSIOLOGIC ASSESSMENT OF CORONARY ARTERY STENOSES
Vasodilatation in
distal coronary bed
Subendocardial steal

14. CNTD..

16. LIMITATIONS
EPICARDIAL STENOSIS+
MICROCIRCULATION
AFR-1. Maximal Flow
2. Resting Flow
Maximal Flow
1. Stenosis Severity
2. Microcirculation
3. Bp& Hr
Resting Flow –
1. Oxygen Extraction
2. Hb SATURATION

17. RFR&FFR- STENOSIS WITH NORMAL VESSEL
ASSUMES MAX. VASODILATATION RESISTANCE VESSELS
NEGATES MICROCIRCULATION

18. EFFECT OF MICROCIRCULATION ON FFR & AFR

19. PATHOLOGIC STATES - MICROCIRCULATORY RESERVE
LV HYPERTROPHY
•Normal Maximal
Absolute Flow Per
Minute At Rest And Vd
•Reduced Absolute
Flow Per Min/ Gram Of
Tissue
MICROVASCULAR
DYSFUNCTION
• Mass Remains Normal
• Absolute Flow/
Min=absolute
Flow/Min/Gram
• Degree Of Vasodilatation
Reduced /Min And
/Min/Gram Of Tissue
HYPERCHOLESTERO
LEMIA
• Reduced Flow
Induced
Vasodilatation
• Impaired NO
• Shift Of NO-
EDHF(H2O2)
Compensatory
Response

22. CORONARY FLOW RESERVE
• CFR, the ratio of maximal to basal arterial flow epicardial
coronary artery and the supplied vascular bed—to achieve maximal
blood flow in response to hyperemic stimulation
• a higher CFR  epicardial and microvascular bed resistances are
low (i.e., normally low resistance;
• a lower CFR (<2.0) does not indicate which component is affected, a
fact that limits the clinical applicability of this measurement for
lesion assessment

24. • During maximal hyperemia (induced pharmacologically), coronary
resistance is at the lowest level and remains constant, so that flow
is directly related to the measured pressure.
• The total myocardial blood flow (Qn) in an area served by a
coronary artery with a stenosis is the sum of the flow through the
stenosis (Qs) and the collateral flow (Qc).
• Fractional flow reserve is then simply defined as the ratio of the
measured flow (Qs) to the maximal flow that should be present
without any stenosis (Qn)

25. • FFR independent of sex or CAD risk factors, SHT /T2DM and
has less variability with common doses of adenosine.
• De Bruyne - FFR is independent of hemodynamic conditions.
• Changes in heart rate affected by pacing, changes in
contractility affected by dobutamine infusion, and changes in
blood pressure affected by nitroprusside infusion did not alter
FFR

26. • Pressure a surrogate measure of flow
• V = IR
• Resistance stable by maximal vasodilatation

28. COMMON PHARMACOLOGICAL AENTS

29. ADENOSINE
• Short half-life, with a return to basal flow
within 30 to 60 seconds after cessation of
infusion.
• IV adenosine - 10% drop in MAP /chest
burning.
• IC adenosine –> dominant art. -(AV) block at
high enough doses  transient decline in
MAP.

30. • Validation studies – central vein / peripheral vein  delay in
hyperemia
• Jeremias and colleagues examined differences in FFR between IC
adenosine (15 to 20 μg in the RCA or 18 to 24 μg in the LCA) and IV
adenosine (140 μg/kg/min) in 52 patients with 60 lesions and found
a strong linear relationship between IC and IV adenosine
(regression coefficient [r] = 0.978, P < .001). The mean
measurement difference for FFR was 0.004 (standard deviation [SD]
± 0.03). A small random scatter in both directions of FFR was noted
in 8.3% of stenoses, where the IC adenosine FFR value was 0.05
greater than the IV adenosine FFR value, suggesting a suboptimal IC
hyperemic response for which a repeated, higher IC adenosine dose
may be helpful

32. CLINICAL VALIDATION OF INTRACORONARY PRESSURE MEASUREMENTS
Pijls’ group studied 60 patients accepted for single-vessel
percutaneous transluminal coronary angioplasty (PTCA) who
had a positive (abnormal or ischemic) exercise test in the
preceding 24 hours.
FFR was measured before and 15 minutes after PTCA, and the
exercise test was repeated after 1 week.
If the second exercise test had reverted to normal after PTCA,
FFR values were associated with inducible ischemia.
All except two FFR measurements greater than 0.74 were not
associated with ischemia, and all FFR measurements of 0.74 or
less were related to inducible ischemia

33. PIJL’s & collegues
• compared FFR with a combined ischemic standard of common noninvasive testing
modalities in 45 patients with moderate coronary stenoses and chest pain
syndromes. When the FFR was less than 0.75 (21 patients), reversible myocardial
ischemia was demonstrated unequivocally on at least one noninvasive test (bicycle
exercise testing, thallium scintigraphy, stress echocardiography with dobutamine),
and all these positive test results were reversed after PTCA or coronary artery
bypass grafting (CABG).
• In 21 of 24 patients with an FFR greater than 0.75, all of the tests showed no
demonstration of ischemia, and no revascularization procedure was performed.
Importantly, no revascularization was required after 14 months of follow-up.
• The sensitivity of FFR in the identification of reversible ischemia was 88%, the
specificity was 100%, the positive predictive value (PPV) was 100%, the negative
predictive value (NPV) was 88%, and the accuracy was 93%.

34. • As per ACC)/AHA/SCAI guidelines, use of FFR is a
class III indication when the clinical scenario,
angiogram, and ischemic test are concordant.
Otherwise, the FFR serves to alleviate uncertainty
when the clinical and testing data are at odds
with one another. If the operator—for whatever
reason—elects to use FFR, this decision should be
based on FFR’s ability to precisely define the
ischemic potential of a stenosis in question

35. FFR & ANGIOGRAPHY
• Toth - > 4000 intermediate lesions in which a slight yet statistically
significant correlation was found between %DS as measured by QCA and
FFR, with an r value of 0.38 (P < .001). A 50% or greater diameter stenosis
had mediocre overall sensitivity (61%), specificity (67%), and diagnostic
accuracy (64%) for predicting an FFR of less than 0.80.
• > DS 70% or greater- highly specific (98%) but poorly sensitive (13%), with
a net decrease in the overall diagnostic accuracy for detecting functionally
significant lesions.
• Optimal diagnostic threshold of stenosis diameter was markedly lower in
coronary segments that supply a larger myocardial area -FFR depends to
some extent on the downstream mass.
• In particular, left main stenoses were often underestimated by the
classical 50% diameter cutoff compared with FFR

37. CLINICAL DECISION MAKING IN THE “GRAY ZONE” FFR OF 0.75 TO 0.80
• Agarwal et al. - 238 patients( gray zone FFR) ,
revascularization reduced MACE than medical Rx.
• IRIS-FFR - multicenter registry, the risk of MACE
was not significantly different between deferred
and revascularized lesions for FFR 0.76 or greater
(including the gray zone).
• In these situations, the decision to revascularize
should be based on the clinical context

38. FFR / IVUS / OCT
• Several IVUS studies have compared FFR with IVUS measurements
(e.g., MLA). Takagi and colleagues - MLA <4 mm2 FFR < 0.75,
although several patients had a nonischemic FFR.
• The reason for this variance is that resistance to flow is based on
various anatomic factors (entrance angle, length, MLA,
eccentricity), of which MLA is only one.

39. • (1) entrance angle; (2) diseased segment length; (3) stenosis length; (4–6)
shape factors of lumen area (minimum lumen diameter, minimum lumen
area, eccentricity of stenosis); and (7) area of reference vessel
• Total pressure loss across a stenosis 1.Frictional losses along the
leading edge of the stenosis 2. inertial losses stemming from the sudden
expansion, which causes flow separation and eddies (exit losses).
Frictional losses are linearly related to flow by Poiseuille’s law, and inertial
losses (exit losses) increase with the square of the flow (Bernoulli’s law).
The total change in pressure gradient (ΔP) is the sum of the two: the loss
coefficients, f1 and f2, are functions of stenosis geometry and rheologic
properties of blood (viscosity and density)

40. • FFR represents the net myocardial blood flow across the stenosis
supplying the specific myocardial bed. For example, a 70% stenosis
in a vessel subtending a small diagonal or a previously infarcted
mid–anterior descending territory will have less physiologic impact
compared with an identical lesion in a mid-anterior descending
territory subtending a normal anterior wall region because of the
significantly higher flow requirements.
• Thus it is not uncommon to encounter a visual-functional
mismatch, wherein the angiography or IVUS measurements do not
correspond with the FFR and the clinician’s impression of lesion
significance; in addition, the use of IVUS to determine lesion
significance has not been shown to have a strong correlation with
FFR or perfusion imaging

41. • Fractional Flow Reserve and Intravascular Ultrasound Relationship
Study (FIRST) demonstrated that using IVUS-MLA to guide
intervention in intermediate lesions by calculation of the MLA was
limited in accuracy (64% sensitivity and specificity) and highly
variable based on reference vessel characteristics.
• Previous work has varied greatly when defining an MLA that
denotes functional significance, and currently the routine use of
IVUS in place of FFR is not recommended.

42. DEFER & FAME trials
• DEFER study- at 5 years, the risk of death or MI was no different
between the deferred and treated (performed) groups (3.3% vs.
7.9%). Furthermore, the end point was much more frequently
encountered in the group with the significant FFR and subsequent
revascularization (15.7%), suggesting that lesions with an FFR of
greater than 0.75 had a very good 5-year prognosis that was not
improved with PCI.

43. • Specifically, in the group with deferred revascularization, three cardiac
deaths and no MIs were reported over the course of the 5-year follow-up,
and in the group that received PCI (despite an FFR > 0.75), two cardiac
deaths and six MIs were reported during the same period.
• the FAME trial(multivessel lesions ) there were 513 lesions with an FFR
greater than 0.80 (i.e., deferred PCI) in 509 patients. In a 2-year follow-up,
nine late MIs were reported, of which eight were related to either a stent
in another lesion or a new lesion, and thus a 0.2% rate of late MI was
reported in FFR-negative lesions that did not receive a stent. Furthermore,
of those same 513 lesions in 509 patients, 53 repeat revascularizations
were reported. However, 37 of those involved restenosis in a stent or a
new lesion. This left only 10 lesions that had clearly progressed over the 2
years needing revascularization—a rate of 2%.

44. • These data strongly support the hypothesis that lesions in patients with
stable CAD whose FFR is not physiologically significant (i.e., >0.80) have
an exceptionally good prognosis without PCI, and the recommendation is
that these lesions receive treatment with optimal medical therapy alone

45. FAME -2 trial
• FAME 2 trial- enrolled 1220 patients with angiographic disease in one, two, or
three vessels that was suitable for PCI. After performing FFR, all patients with
lesions that had an FFR less than 0.80 were randomized to either receive PCI or
medical therapy. A composite of death from any cause, nonfatal MI, or
unplanned hospitalization leading to urgent revascularization during a 2-year
follow-up was the primary end point .
• 764 lesions with an angiographic stenosis of greater than 50% that had a
corresponding FFR less than 0.80 (mean of 0.68 ± 0.15). Within this cohort were
3 deaths (0.7%), 14 MIs (3.2%), and 49 urgent revascularization (11.1%) end
points. In the corresponding group that received revascularization for these FFR-
significant lesions, only 1 death occurred (0.2%), 15 MIs were reported (3.4%),
and 7 patients needed urgent revascularization (1.6%)

47. • data strongly suggest that lesions with abnormal FFR values do not
have the good long-term prognosis that those with normal FFR
values have and that PCI of these lesions significantly improves
patient outcomes.

48. • Routine use of FFR, even in those considered angiographically unambiguous,
frequently leads to changes in the number and location of lesions that are
functionally significant, and therefore it directs the clinician to what the
appropriate treatment should be.
• In an analysis of the FAME trial, lesions with 50% to 70% diameter narrowing
were hemodynamically significant based on FFR in only 35% of cases.
• In lesions with 71% to 90% narrowing, for which most operators would perform
PCI, 20% were not hemodynamically significant by FFR.
• In two recently published studies of patients undergoing diagnostic angiography
with routine FFR, clinicians were led to change their initial angiography-guided
management decisions of medical therapy, PCI, or CABG in 26%(van belle) and
43%(curzon) of patients after taking the FFR data into consideration

49. • Reclassification of the revascularization strategy according to the revascularization
strategy a priori. Despite minor overall changes, a change in strategy has been
observed in 43% of all patients

50. IMPLICATIONS FOR FFR IN PATIENTS WITH MULTIVESSEL CAD & CABG
• Botman & c. - 525 lesions in 153 patients referred for bypass surgery on clinical
grounds. FFR was performed on all lesions to be grafted, and the surgeon was
blinded to the results. Repeat angiogram was performed 1 year after CABG, and at
this early time, 21.4% of grafts on functionally insignificant lesions (FFR > 0.75)
were occluded, compared with 8.9% of grafts on vessels with an FFR less than 0.75.
• Although the highest percentage of occluded 50% stenosis, a high percentage of
graft failure was still seen in the group with 50% to 70% stenosis.
• Thus FFR-guided bypass is a reasonable strategy to predict bypass graft patency
and has superiority over the strategy of grafting all vessels with lesions with 50% or
more stenosis

51. INCORPORATING FFR in SYNTAX score –FAME
• When the SYNTAX score was applied to those patients in the FAME trial, 497
patients were divided into tertiles based on their angiographic SYNTAX score
(34% in the low-risk SYNTAX score group, 34% in the intermediate-risk SYNTAX
score group, and 32% in the high-risk SYNTAX score group). When the functional
data were then added to the SYNTAX score, lesions that had an FFR greater than
0.80 were no longer considered.
• This allowed a significant reclassification of patients to the same risk tertiles,
with 59% -low risk SYNTAC group , 21% - intermediate-risk group, and only 20%
in the highest-risk group .
• Together, these studies strongly support the utilization of routine measurement
of FFR in patients with multivessel disease to provide optimal outcomes, best
revascularization strategies, and best decision making.

53. • FFR-guided bypass was compared with angiography-guided bypass surgery in a
retrospective review of 627 patients with stable CAD referred for CABG with at least
one angiographically intermediate stenosis.
• In 31% of patients, FFR had been performed to determine whether an intermediate
stenosis should be grafted or not.
• In this group, the incidence of three-vessel disease was downgraded after FFR from
94% to 86%, and use of FFR was associated with a smaller number of anastomoses
and rates of on-pump surgery.
• At 3 years, no difference in adverse events was found compared with those patients
who underwent angiography-guided CABG, and the rate of angina was lower in the
FFR group (31% vs. 47%, P < .001), possibly owing to a higher ratio of arterial-venous
anastomosis

56. LMCA
• Hamilos &c. examined 5-year outcomes in 213 patients with an
angiographically equivocal LMCA stenosis in whom revascularization
decisions were guided by FFR.
• When FFR was 0.80 or greater, patients were treated medically or
another stenosis was treated by coronary angioplasty (nonsurgical group;
n = 138).
• When FFR was less than 0.80, CABG surgery was performed (surgical
group; n = 75). The 5-year survival and event-free survival rates were
similar, with 90% (74% in the nonsurgical [FFR ≥0.80]) group—and 85%
(82% in the surgical [FFR <0.80] group [P = .48).
• It is worth noting that only 23% of patients with LMCA narrowing >50%
had hemodynamically significant FFR (i.e., <0.80).

57. SURVIVAL RATE & MACE

58. SERIAL (MULTIPLE) LESIONS IN A SINGLE VESSEL
• If multiple stenoses are present in the same vessel, the hyperemic flow
and pressure gradient through the first stenosis will be attenuated by the
presence of the second one and vice versa.
• Each stenosis will mask the true effect of its serial counterpart by
limiting the achievable maximum hyperemia .
• If the distance between the two lesions is greater than six times the
vessel diameter, the stenoses generally behave independently and the
overall pressure gradient is the sum of the individual pressure losses at
any given flow rate

59. • When addressing two stenoses in series, equations have been derived to
mathematically predict the FFR (FFRpred) of each stenosis separately (i.e., as if the
other one were removed), using arterial pressure (Pa), pressure between the two
stenoses (Pm), distal coronary pressure (Pd), and coronary occlusive pressure (Pw).
• FFRapp, the ratio of the pressure just distal to that just proximal to each stenosis,
and FFRtrue, the ratio of the pressures distal and proximal to each stenosis but after
removal of the other one, have been compared in instrumented dogs and in
humans.
• FFRtrue was more overestimated by FFRapp than by FFRpred.
• It was clearly demonstrated that the interaction between two stenoses is such that
the FFR of each lesion cannot be calculated by the equation for isolated stenoses
applied to each separately; however, the FFR for each lesion can be predicted by
more complete equations that take into account Pa, Pm, Pd, and Pw. Although
calculation of the exact FFR for each lesion separately is possible, it remains largely
academic.

60. • In clinical practice, the use of the pressure
pullback recording is particularly well suited to
identify the various regions of a vessel with large
pressure gradients that may benefit from
treatment.
• The one stenosis with the largest gradient can be
treated first, after which the FFR can be
remeasured for the remaining stenoses to
determine the need for further treatment

61. • Multiple LAD lesions (1–4) were seen on angiography in a patient with a positive
stress test for anterior ischemia. Fractional flow reserve (FFR) assessment of the
LAD beyond all the lesions show a physiologically significant gradient in the vessel
(FFR = 0.73).
• Pullback recording during continuous hyperemia demonstrates the relative
changes in FFR at lesions 1 to 4. The largest change in the pressure gradient is seen
to occur at lesion 3 only.
• RAO v. LAD following stenting of lesion 3 with a final FFR across all lesions of 0.88.

62. DIFFUSE CORONARY DISEASE
• The perfusion pressure gradually diminishes along diffusely diseased
atherosclerotic coronary artery
• FFR is reduced but is unassociated with a focal stenotic pressure loss.
• Therefore in the diffusely diseased vessel, mechanical therapy directed at a
presumed “culprit” stenosis to reverse such abnormal physiology would be
ineffective in restoring normal coronar perfusion.
• A continuous-pressure pullback from a distal location to a proximal location will
identify any specific area of focal angiographic narrowing and will confirm the
presence of diffuse atherosclerosis.
• Diffuse atherosclerosis, as opposed to a focal narrowing, is characterized by a
continuous and gradual pressure recovery without localized abrupt increase in
pressure related to an isolated region

63. • pressure pullback recording at maximum hyperemia provides the
necessary information to decide whether and where stent
implantation may be useful.
• The location of a focal pressure drop superimposed on the diffuse
disease can be identified as an appropriate location for treatment.
• In some cases the gradual decline of pressure along the vessel
occurs over a very long segment, such that interventional treatment
is not possible Medical treatment (or CABG) can then be elected.

64. • FFR- 0.67, which reflects ischemia-producing lesions. However, the
gradual decrease in gradient from pressure distal to the stenosis
(Pd) to arterial pressure (Pa) is reflective of severe, diffuse
narrowing in the major portion of the vessel. This gradual change in
the pressure curve shows that an extremely long segment is
responsible for the ischemia and is most likely not best treated with
multiple stents

65. FFR in STEMI

66. NONHYPEREMIC PRESSURE RATIO INDICES OF CORONARY
STENOSIS SIGNIFICANCE
• Sen & c. found a period of diastole in which
equilibration or balance is reached between
pressure waves from the aorta and distal
microcirculatory reflection; hence it is wave free.
This wave-free period (WFP) occurs 75% of the
way through diastole to just before systole and is
a period during which the resistance is fixed

67. PRE-RQUISITES FOR MEASURING PRESSURE GRDS.
• Wave free period resistance stable  ratio of proxinal
/distal pressures prop.  CBF
• Pressure grd.  flow velocity
• To asses severity of stenosis 1. velocity constant 2. high
velocity
• Varying velocity varying grds.

68. • resistance low&most stable- wave-free period.
• Coronary pressure and flow are linearly related
• Velocity  high & stable during wfp.

69. • iFR measures the ratio of distal coronary to aortic pressure during a period in
diastole where microvascular resistance is naturally at its most stable. By only
measuring pressure within this specific portion of the cardiac cycle, iFR facilitates
the pressure-only assessment of the haemodynamic impact of a coronary
stenosis without the need for pharmacological vasodilatation

70. • iFR requires proprietary software, thus limiting real-time
application to a specific pressure system and sensor wire (Philips
Volcano, Verrata).
• The original iFR software required electrocardiographic (ECG)
gating and was susceptible to poor ECG signals, whereas Pd/Pa is
displayed continuously in real time and has fewer unacceptable
artifacts.
• Both iFR and Pd/Pa are susceptible to transient hyperemia of
contrast media, nitroglycerin, or saline flush and thus require
some time before measurement to ensure a resting state

71. ADVISE & RESOLVE study
• ADVSIE  iFR & FFR 80% correspondence
• RESOLVE - In 1974 lesions, the optimal iFR to predict an FFR less
than 0.8 was 0.92 with an accuracy of 80%. For the resting Pd/Pa
ratio, the cutpoint was 0.92 with an overall accuracy of 92% with no
significant differences between iFR and Pd/Pa.
• Both measures have 90% accuracy to predict positive or negative
FFR in 65% and 48% of lesions, respectively.
• These data suggest that resting indices of lesion severity
demonstrated an overall accuracy with FFR of approximately 80%,
which can be improved to 90% in a subset of lesions

72. DEFINE FLAIR & iFR SWEDE HEART
• The DEFINE-FLAIR74 (n = 2492) and the iFR-SWEDEHEART73
(n = 2109) trials tested whether iFR-guided PCI was
noninferior to FFR-guided coronary revascularization. The
two trials had nearly identical trial designs and used the
same primary composite end point of all-cause mortality,
nonfatal MI, and unplanned revascularization
• Although both trials had the limitations of studying low-risk
populations and large noninferiority margins, the results
have led many to adopt iFR in practice

73. • Safety of using iFR instead of FFR in patients at
increased risk (i.e., more severe ischemic lesions
with low FFR) CAD is debatable because the
average FFR in the two iFR studies was much higher
than in FAME trials (FFR 0.83 vs. 0.71).
• Although IFR and FFR are concordant 80% of the
time, discordance occurs in approximately 20% of
patients and raises a clinical decision-making
dilemma

83. Thank You...