Journal of
Clinical Medicine
Review
Coronary Physiology: Modern Concepts for the Guidance of
Percutaneous Coronary Interventions and Medical Therapy
Monica Verdoia * and Andrea Rognoni
Citation: Verdoia, M.; Rognoni, A.
Coronary Physiology: Modern
Concepts for the Guidance of
Percutaneous Coronary Interventions
and Medical Therapy. J. Clin. Med.
2023, 12, 2274. https://doi.org/
10.3390/jcm12062274
Academic Editor: Gjin Ndrepepa
Received: 7 February 2023
Revised: 8 March 2023
Accepted: 10 March 2023
Published: 15 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Clin. Med. 2023, 12, 2274. https://doi.org/10.3390/jcm12062274
Nuovo Ospedale Degli Infermi, Azienda Sanitaria Locale Biella, 13900 Biella, Italy
* Correspondence: monica.verdoia@aslbi.piemonte.it
Abstract: Recent evidence on ischemia, rather than coronary artery disease (CAD), representing
a major determinant of outcomes, has led to a progressive shift in the management of patients
with ischemic heart disease. According to most recent guidelines, myocardial revascularization
strategies based on anatomical findings should be progressively abandoned in favor of functional
criteria for the guidance of PCI. Thus, emerging importance has been assigned to the assessment of
coronary physiology in order to determine the ischemic significance of coronary stenoses. However,
despite several indexes and tools that have been developed so far, the existence of technical and
clinical conditions potentially biasing the functional evaluation of the coronary tree still cause
debates regarding the strategy of choice. The present review provides an overview of the available
methods and the most recent acquirements for the invasive assessment of ischemia, focusing on the
most widely available indexes, fractional flow reserve (FFR) and instant-wave free ratio (iFR), in
addition to emerging examples, as new approaches to coronary flow reserve (CFR) and microvascular
resistance, aiming at promoting the knowledge and application of those “full physiology” principles,
which are generally advocated to allow a tailored treatment and the achievement of the largest
prognostic benefits.
Keywords: coronary flow; coronary reserve; percutaneous coronary intervention
1. Background
The improvements in percutaneous coronary intervention (PCI) techniques and the
availability of newer generations of drug-eluting stents (DES) have led to an escalation in
the number and complexity of procedures [1–3]. Nevertheless, impaired outcome has been
observed in certain subsets of patients experiencing higher rates of target lesion failure
and recurrent ischemic events [4,5], as well as bleeding complications in consequence of
the antithrombotic agents. Therefore, a new approach of limiting PCI procedures and
stent implantation only when clearly required has become the most common practice
among interventionalists. In fact, optimal medical therapy has been shown to be superior
to an interventional strategy in particular conditions, thus pointing to the need for non-
anatomical criteria to be considered for the guidance of PCI procedures.
Indeed, angiographic criteria for the quantification of the severity of a lesion have
been proven unsatisfactory for the correct stratification of its risk of instabilization and
functional impact [6,7]. In fact, other parameters, in addition to the conventional minimal
lumen diameter and the percentage of stenosis at angiography, have been shown to play a
relevant prognostic role. Lesion length, plaque morphology, amount of served myocardium
and distal vascular bed, in addition to the complex regulation of vasomotricity, represent
factors that should certainly be taken into account, although requiring further diagnostic
investigation after angiography, by the use of intracoronary imaging or functional tests [8,9].
The invasive assessment of the ischemic potential of coronary lesions has gained
ground due to accumulating of clinical evidence, currently being recommended as a class
https://www.mdpi.com/journal/jcm
J. Clin. Med. 2023, 12, 2274 2 of 12

Ia strategy for the management of intermediate coronary lesions, according to European

guidelines, and as a class IIa strategy, according to the U.S. regulations [10,11].
Several indexes of coronary physiology have been proposed, whose features are
shown in Table 1, although these are affected by technical and clinical factors; therefore,
these indexes may provide potentially incomplete or misleading results. Moreover, acute
patients and particular coronary anatomies, such as tandem lesions, as well as diffuse
and microvascular disease, still represent particularly challenging settings, in which the
assessment of coronary physiology is still poorly validated.

Table 1. Technical features, advantages, and pitfalls of the different indexes for the assessment of
coronary physiology.

FFR iFR CFR IMR

Cut-off ≤0.80 ≤0.90 ≤2.0 >25 U
Timing of acquisition Averaged (5 cycles) Single beat Averaged (3 cycles) Averaged (3 cycles)
Adenosine, Adenosine, Adenosine,
Stressing agent -
papaverine, other papaverine, other papaverine, other
Epicardial stenosis + + + -
Microcirculation assessment - + + +
Validation in ACS - + - -
Tandem lesions - + + +
Side branch correction - + + +
Co-registration - + - -
Low-flow condition sensitivity + - - -
Wire drift sensitivity + - + -
ACS = acute coronary syndrome; FFR = fractional flow reserve; iFR = instant wave-free flow reserve;
CFR = coronary flow reserve; IMR = index of microvascular resistance; U = units.

2. Traditional Indexes: Fractional Flow Reserve

Fractional flow reserve (FFR) was introduced around 20 years ago in order to provide
a faster and easier estimation of the hemodynamic impact of a stenosis on the coronary
reserve, based on the assumption that coronary pressure is proportional to coronary flow,
when coronary resistance is minimal and constant [12].
In fact, the FFR is the ratio between mean coronary pressure distal to a coronary
stenosis and mean aortic pressure at the level of the guiding catheter measured during
maximal pharmacological vasodilation, when resistance is considered to be null.
Two randomized clinical trials have demonstrated the safety and effectiveness of
conditioning coronary revascularization, according to the results of FFR.
The DEFER study [13] randomized patients with stable angina and intermediate
stenosis, but FFR > 0.75, to deferral or performance of PCI. The authors concluded that
patients with FFR > 0.75 were stable and safe, and that stenting did not decrease the risk of
cardiac events for CAD without significant ischemia.
The FAME study [14] compared FFR-guided PCI with angio-guided PCI in patients
with multivessel CAD, showing a significant reduction of MACE at 1 year with FFR. In this
study, PCI was indicated for FFR values < 0.80, and around 30% of patients presented with
acute coronary syndrome (ACS), although no dedicated sub-analysis was performed.
Similar advantages were confirmed in the subsequent FAME2 trial [15], where FFR-
guided PCI was compared with optimal medical therapy (OMT), which was interrupted
for excess benefit with PCI, mainly driven by a reduction in recurrent revascularization
(HR 0.13; 95% CI 0.06–0.30, p < 0.001).
Indeed, only 1047 patients were randomized to FFR within the three trials; however,
subsequent studies and a recent Japanese multicenter registry confirmed the safety of
relying on FFR, leading to a reclassification and “downgrading” of the functional impact of
a stenosis in around 40% of the cases [16].
 Similar advantages were confirmed in the subsequent FAME2 trial [15], where
guided PCI was compared with optimal medical therapy (OMT), which was interru
for excess benefit with PCI, mainly driven by a reduction in recurrent revasculariza
(HR 0.13; 95% CI 0.06–0.30, p < 0.001).
Indeed, only 1047 patients were randomized to FFR within the three trials; how
J. Clin. Med. 2023, 12, 2274 subsequent studies and a recent Japanese multicenter registry confirmed 3 of 12 the safe
relying on FFR, leading to a reclassification and “downgrading” of the functional im
of a stenosis in around 40% of the cases [16].
However, discrepancy between FFR and coronary flow reserve has been docume
However, discrepancy between FFR and coronary flow reserve has been documented
in around 30% of the patients [17], mainly due to technical and clinical fac
in around 30% of the patients [17], mainly due to technical and clinical factors, conditioning
conditioning the hemodynamic status and therefore, the assessment of FFR.
the hemodynamic status and therefore, the assessment of FFR.
In fact, the invasively validated measurement of FFR, derived from an experime
In fact, the invasively validated measurement of FFR, derived from an experimental
animal model, was corrected for right atrial pressure, whose omission, in the clini
animal model, was corrected for right atrial pressure, whose omission, in the clinically
used “crude” FFR, could lead to falsely higher values and thus, to an underestimatio
used “crude” FFR, could lead to falsely higher values and thus, to an underestimation of
the significance of a lesion, especially in subjects with elevated diastolic pressures,
the significance of a lesion, especially in subjects with elevated diastolic pressures, thus
accounting for the elevation of the cut-off to 0.80 [18].
accounting for the elevation of the cut-off to 0.80 [18].
In effect, even if constant coronary resistance could be achieved, the relation
In effect, even if constant coronary resistance could be achieved, the relationship
between pressure and flow in the coronary circulation is not linear, but incremental,
between pressure and flow in the coronary circulation is not linear, but incremental, with
a variable slope and a baseline intercept which should correspond to coronary w
a variable slope pressure
and a baseline intercept
([19], Figure 1). which should correspond to coronary wedge
pressure ([19], Figure 1).

Maximum hyperemia

Microvascular resistance
Coronary flow

Myocardial demand
Pzf

Pv Coronary pressure
Figure 1. Relationship between coronary blood flow and pressure during different hemodynamic
Figure 1. Relationship between coronary blood flow and pressure during different hemodyn
conditions (Pv = venous pressure;
conditions Pzf = baseline
(Pv = venous pressure;pressure corresponding
Pzf = baseline pressure to zero-flow condition),
corresponding to zero-flow condi
adapted from van adapted
de Hoef from
et al. van
[19].de Hoef et al. [19].

Moreover, the complete

Moreover,abolition of coronary
the complete abolitionresistance,
of coronaryi.e.,resistance,
the achievement of
i.e., the achievemen
maximal hyperemia, represents a debated issue. Among hyperemic agents,
maximal hyperemia, represents a debated issue. Among hyperemic agents, for y for years,
adenosine has represented
adenosine has therepresented
pharmacological strategy of choice,
the pharmacological strategyalthough
of choice,weighted
although weighte
by a longer duration of the
a longer exam, of
duration complications, patients’ intolerance,
the exam, complications, patients’ especially
intolerance, with
especially
intravenous infusion of adenosine,
intravenous infusionasofwell as inadequate
adenosine, as well response, being
as inadequate more common
response, being more com
with low-dose adenosine boli and
with low-dose amongboli
adenosine certain
and subsets of patients
among certain [20].of patients [20].
subsets
In fact, previousInstudies suggested
fact, previous an age-related
studies suggesteddecrease in absolute
an age-related coronary
decrease va-
in absolute coro
sodilator reserve,vasodilator
mediated by a lowermediated
reserve, response byto endothelium-derived
a lower response to relaxing factors in
endothelium-derived rela
a dysfunctional endothelium, but also byendothelium,
factors in a dysfunctional a lesser effectbut
of also
adenosine on vascular
by a lesser smooth on vasc
effect of adenosine
muscle due to desensitization. In fact, experimental models have shown a greater lo-
cal release of adenosine in the coronary microcirculation of older animals, which could
potentially impair the effectiveness of an exogenous administration [21].
Nevertheless, alternative pharmacological agents for the achievement of hyperemia,
such as papaverine, have not been validated in large scale studies [22].

3. Non-Hyperemic Indexes: Instant-Wave Free Ratio (iFR)

The stability of coronary flow across a wide range of coronary stenoses under baseline
resting conditions provides an ideal setting for the assessment of coronary lesions through
pressure-derived indexes.
J. Clin. Med. 2023, 12, 2274 4 of 12

The identification of a wave-free period during the diastolic period of the cardiac cycle
(from 25% of the initiation of the diastole to 5 ms before its ending), where coronary flow is
maximal and myocardial contraction is absent, represents a condition of resting “maximal”
coronary flow that can be assimilated to the hyperemic condition, although not requiring
pharmacological vasodilatation [23].
The instant wave-free flow reserve (iFR) is, therefore, defined as the ratio between
the mean instant pressure distal to coronary stenosis and the mean pressure at the aortic
root during such periods, as identified on the electrocardiogram. The ADVISE (Adenosine
Vasodilator Independent Stenosis Evaluation) and ADVISE Registry studies were the first to
assess the diagnostic accuracy of iFR against FFR as the ischemic reference standard [24,25].
It emerged that iFR had a good correlation with FFR (r = 0.9, p < 0.001) and showed excellent
diagnostic efficiency, with fewer repeated measurement differences.
The JUSTIFY-CFR study showed that iFR had a better correlation with coronary flow
reserve than did FFR [26]. Moreover, van de Hoef et al. compared iFR and FFR, with refer-
ence to myocardial perfusion scintigraphy. They found that iFR and FFR were discordant
in around 20% of the cases, but FFR did not always produce highly accurate results, and
thus, was not necessarily a better discriminator of coronary ischemia than iFR [27].
The subsequent large-scale trials DEFINE-FLAIR [28] and iFR SWEDEHEART [29]
randomized over 4500 patients to show the noninferiority of iFR to FFR. The two studies
and the subsequent pooled analysis confirmed the safety of deferring myocardial revascu-
larization according to coronary physiology in patients with intermediate-severity coronary
lesions, and the noninferiority of an iFR- versus a FFR-guided strategy, additionally point-
ing at the potential advantages of the non-hyperemic index in terms of procedure duration,
patients’ tolerance, and complications [23,30].
Theferore, iFR has been equated to FFR in most recent 2019 ESC guidelines on myocar-
dial revascularization [31].
Indeed, iFR has been suggested to be more sensitive to hemodynamic variations in
blood pressure and heart rate, conditioning the duration of diastolic period, than FFR.
Moreover, patients in atrial fibrillation could present another limitation of the diagnostic
accuracy of iFR, due to the instant estimation of the value and the larger variability of the
diastolic period, which could be instead balanced by an averaged measure as FFR.
In a previous study, Verdoia et al. demonstrated that pre-procedural beta-blockers
were associated with higher absolute values and a lower rate of positive iFR, as compared
to FFR [32]. Nevertheless, contrasting results were demonstrated by the same authors in
elderly patients, where FFR levels tended to be higher and potentially underestimative,
whereas iFR was less affected by age [33].
Other potential advantages of iFR are linked to technical factors that can potentially
overcome the limitations of FFR. In fact, FFR is more sensitive to catheter dumping or wire-
drift, the latter often being dependent on the entrapment of small air bubbles in the cavity
of the pressure sensor or electrical and thermal instability, which can occur more frequently
in longer registrations as in the FFR [34,35]; FFR has been demonstrated to be largely
inadequate in the presence of proximal stenosis, reduced myocardial viability, or modest
distal territory, or in the case of elevated diastolic pressure and microvascular disfunction,
conditions that occur quite frequently in patients with advanced age, hypertension, diabetes,
renal failure, or ACS, representing the majority of current cath-lab population [36].
Similar limitations have been observed in low-flow conditions, such as aortic stenosis
or left ventricular dysfunction, inducing peripheral vasoconstriction and an increase in
microvascular resistances in order to maintain the perfusion, causing an increase in the
distal pressure (Pd) and a reduction of proximal pressure (Pa), thus resulting in potentially
overestimated FFR values.
In addition, the avoidance of pharmacological hyperemia with iFR has shown more
promising results in terms of safety, and mainly among patients with acute coronary
syndrome. In the COMPARE-ACUTE trial, which assessed FFR guided revascularization
versus conventional strategy in acute STEMI patients with multivessel disease, serious
J. Clin. Med. 2023, 12, 2274 5 of 12

adverse events occurred in 0.2% of the study population, including dissections and abrupt
vessel occlusion, with negative prognostic consequences [37].
Indeed, only around 15% of the patients had ACS at presentation in the main iFR trials;
however, iFR results led to similar outcomes, regardless of clinical presentation [38], and
similar results were also confirmed in large scale registries [39].
Moreover, iFR could be less conditioned by the impairment of microvascular circulation,
which often occurs in patients with ACS, and especially in STEMI settings, where peripheral
resistances progressively reduce within days, allowing for a proportional increase in flow [40].
Another scenario in which iFR has been suggested to overcome FFR is represented by
complex tandem lesions and diffuse disease. In fact, the presence of a proximal stenosis could
result in a decreased coronary pressure, leading to an underestimation of the distal stenosis,
and inversely, the distal obstruction could raise the Pd, resulting in lower FFR values.
The instantaneity of the iFR, allowing a point-by-point measurement alongside a coronary
vessel, without time restrictions linked to the duration of hyperemia, provides the possibility
of separately interrogating different parts of a diseased vessel, with the pullback of the wire,
not being additionally conditioned by pressure interactions for lesions in series [41].
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 6 of 13
Moreover, motorized iFR pullback recording, combined with real-time computer
tracking of the pressure-wire movement, provides a complete physiological map of any
coronary vessel, whereby the graphical representation of the point estimations of the iFR
can be integrated with a co-registered angiogram, providing a fusion of functional and
anatomical information [42], as show in Figure 2.

Figure 2.2.Co-registration of pullback

Co-registration instantinstant
of pullback wave-free flow reserve
wave-free flow(iFR) and coronary
reserve (iFR) andangiography.
coronary
(A) (left image)
angiography. (A)displays a pattern
(left image) of afocal
displays disease:
pattern two
of focal pressure
disease: twodrops aredrops
pressure evident
arein the iFR
evident in
the iFR registration
registration graph (white
graph (white arrows)arrows) corresponding
corresponding to twotofocal
two stenoses
focal stenoses
on theonmid
the mid
and and distal
distal left
left anterior
anterior descending
descending artery
artery (black
(black arrows).
arrows). (B) (right
(B) (right image)
image) showsshows a pattern
a pattern of diffuse
of diffuse disease:
disease: no
no significant pressure drop is evident in the iFR
significant pressure drop is evident in the iFR graph. graph.

The development of such technology allows for instant calculation of the predicted
post-PCI iFR values, thus potentially allowing for the minimizing of interventional
approaches to only significant lesions, especially in diffuse multivessel disease.
Moreover, the implementation of iFR with co-registration could even overcome the
J. Clin. Med. 2023, 12, 2274 6 of 12

The development of such technology allows for instant calculation of the predicted
post-PCI iFR values, thus potentially allowing for the minimizing of interventional ap-
proaches to only significant lesions, especially in diffuse multivessel disease.
Moreover, the implementation of iFR with co-registration could even overcome the
potential advantages of quantitative flow ratio (QFR), a computational model based on
blood flow velocity and calculated on three-dimensional coronary tree images, which are
acquired with coronary CT or angiography [43,44]. QFR allows for attributing a physiolog-
ical significance to pure anatomical findings, although representing only a mathematical
estimation, thus far less precise than a direct measurement, as in iFR.

4. From Stenosis to Ischemia: New Concepts of Coronary Physiology

Pressure indexes have been used for the assessment of coronary stenoses for an
extended period of, based on the demonstration of a direct association between coronary
pressure and flow.
However, the relationship between coronary pressure and flow is not linear, but incre-
mental, with a variable slope (Figure 1) and a non-zero intercept, being largely conditioned
by the variations in coronary resistances, which are increased in stenosed as compared to
healthy coronary arteries [19].
Thus, coronary pressure evaluation only provides a crude and largely imprecise esti-
mation of the impairment of coronary flow, resulting in the underestimation of the disease,
especially in conditions of generalized low flow and in particular, in the absence of angio-
graphically apparent epicardial stenoses. Thus, low coronary flow may be observed, despite
a normal FFR value, whereas an abnormal FFR value can coexist with preserved coronary
flow, leaving myocardial function unaffected down to FFR values of around 0.4 [45].
Microvascular coronary circulation plays a key role in such processes, representing the
principal site of regulation of coronary resistances. In fact, in healthy coronary vessels, the
epicardial arteries only account for up to 10% of coronary resistance, while the development
of atherosclerotic lesions can significantly increase such levels of resistance, counterbal-
anced by a progressive adaptative reduction in the resistance of arterioles, which undergo
autoregulatory vasodilation. Reaching a complete exhaustion of the reserve vasodilatory
capacity can lead to myocardial ischemia. Indeed, as pointed out in recent studies, the
presence of ischemia exhibits a greater prognostic weight, independently from the existence
of epicardial stenoses.
Despite the dominant role of coronary microcirculation in myocardial perfusion, it
has been largely neglected by currently available methods for the assessment of coronary
physiology, mainly due to the technical complexity of its evaluation.
However, several factors can lead to an impairment of coronary microcirculation, even in
the absence of atherosclerotic obstructions, such as left ventricular hypertrophy, hypertension,
diabetes, and aging itself, conditions that are becoming more and more common, especially
with the progressive increase in elderly patients admitted to the cath lab.
Thus, increasing attention has been focused on the evaluation of microvascular func-
tional status in clinical settings.
In addition to non-invasive provocative tests that cannot be performed during angiog-
raphy, but must be either obtained in advance or re-accessed during invasive procedures,
flow assessment can be performed during coronary angiography by thermodilution or
the Doppler technique, both of which provide a measure of coronary flow velocity. The
thermodilution-derived CFR has been validated in animal and human models and has
been compared in an animal model to a reference standard of absolute flow, appearing to
correlate more closely to the standard than does Doppler-derived CFR [46].
Flow velocity in the coronary circulation is only moderately reduced at every bifur-
cation, due to the reduction of the diameter of vessels in the arterial bed downstream, in
consequence of the increase in total cross-sectional area, which is directly related to the
amount of perfused myocardial mass [47].
J. Clin. Med. 2023, 12, 2274 7 of 12

Coronary flow reserve (CFR), the ratio of coronary flow velocity during maximal
vasodilation to coronary flow velocity during resting conditions, is a widely studied and
well-validated flow-based physiological parameter which has recently been successfully
applied to coronary invasive assessment modalities, with the development of a wire-based
thermodilution technique [48,49].
The pressure sensor can also act as a thermistor. With commercially available software,
the shaft of the wire acts as a proximal thermistor. Room temperature saline can be injected
into the coronary artery, and this system will calculate the transit time, which is inversely
proportional to coronary flow. Measurements after 3 mL of saline injection per time
are repeated, both at rest and after the induction of hyperemia, which can be achieved
with several agents (papaverine, nitroprusside, or adenosine), although the latter, with
J. Clin. Med. 2023, 12, x FOR PEER REVIEW
intravenous infusion, currently represents the most applied agent [50]. 8 of 13
Both requiring the achievement of hyperemia, CFR and FFR are nevertheless extremely
different, interrogating different domains of the coronary tree, the latter being more focused
on epicardial between
discordance vessels, while the former
FFR and CFR inon microvasculature.
30–40% of vessels withIn fact, large-scalestenoses.
intermediate application
As
of CFR, in addition to pressure-indexes, has led to the evidence of discordance
recently well shown by van de Hoef et al. [19] and depicted in Figure 3, abnormal between
FFR and CFR
fractional flowin reserve
30–40% andof vessels withCFR
a normal intermediate stenoses.
should indicate As recently
epicardial well shown
disease, by
while not
van de Hoef et al. [19] and depicted in Figure 3, abnormal fractional
flow-limiting, whereas normal FFR and a CFR < 2.0 should represent a predominant flow reserve and a
normal CFR should indicate
microvascular involvement. epicardial disease, while not flow-limiting, whereas normal
FFR and a CFR < 2.0 should represent a predominant microvascular involvement.

Non significant No evidence of

epicardial ischemia
Coronary Flow Reserve

disease =
>2

= X
Follow-up

Significant Microvascular
epicardial disfunction
<2

stenosis (Confirm IMR >

= 25 U)
PCI =
OMT

<0.80 >0.80
Fractional Flow Reserve
Figure3.3.Diagnostic
Figure Diagnosticand and clinical
clinical implications
implications of a physiology”
of a “full “full physiology”
approachapproach
based onbased on the
the relation-
relationship
ship betweenbetween
fractionalfractional flowand
flow reserve reserve and coronary
coronary flow reserve.
flow velocity velocity reserve.

Nevertheless, aa variability
Nevertheless, variability in
in the
the normality
normality ofof CFR
CFR has
has been
been reported,
reported, with
with aarange
range
between
betweenapproximately
approximately2.52.5and
and6;6;therefore,
therefore,aavalue
value>2.0
>2.0 can
can be
be abnormal
abnormal for
for aa particular
particular
patient
patient inina specific vessel.
a specific For For
vessel. example, Demir
example, et al. et
Demir recently documented
al. recently an overes-
documented an
timation of thermodilution-derived CFR as compared to Doppler-derived
overestimation of thermodilution-derived CFR as compared to Doppler-derived CFR, with a
CFR,
poor
withdiagnostic accuracyaccuracy
a poor diagnostic of the common thresholdthreshold
of the common of <2.0 and a weak
of <2.0 andcorrelation between
a weak correlation
hyperemic microvascular
between hyperemic resistance and
microvascular the index
resistance andofthe
microvascular resistance [51]
index of microvascular resistance
[51] Furthermore, few randomized trials have so far addressed the prognostic impact
of CFR.
Furthermore, few randomized trials have so far addressed the prognostic impact of
CFR.
The DEFINE-FLOW trial [52] randomized 430 patients with a positive FFR to
undergo or postpone PCI according to CFR values (< or ≥2.0). The trial reported an
increase in myocardial revascularization and infarction when deferring PCI in
J. Clin. Med. 2023, 12, 2274 8 of 12

The DEFINE-FLOW trial [52] randomized 430 patients with a positive FFR to undergo
or postpone PCI according to CFR values (< or ≥2.0). The trial reported an increase in
myocardial revascularization and infarction when deferring PCI in hemodynamically sig-
nificant lesions with preserved CFR. However, according to the investigators, the unblinded
design may have also driven the performance of interventions in the deferred arm.
On the contrary, opposite positive results have emerged when applying CFR to patients
with angina symptoms and/or signs of ischemia, but no obstructive coronary artery disease
(INOCA). In fact, rather than PCI guidance, the evaluation of microvascular physiology, in
association with traditional pressure indexes, in patients with ischemic heart disease (IHD)
is currently becoming the major field of application for CFR.

5. Coronary Physiology in Patients with INOCA

Among patients presenting with evidence of acute or chronic ischemia, the absence
of epicardial coronary stenoses is currently becoming more frequent, being observed
in up to 50% of the patients undergoing coronary angiography, even with a positive
noninvasive test [53].
Coronary microvascular disfunction has been claimed for such findings, although still rep-
resenting a challenging condition, whose identification and management is largely undefined.
However, several studies and a recent large-scale meta-analysis [54] have well defined
the negative prognostic role of myocardial ischemia, even in the absence of macroscopic
coronary artery disease. In Kelshiker et al. [54], abnormal coronary flow reserve (CFR)
was associated with a higher incidence of all-cause mortality (HR: 3.78, 95% confidence
interval (CI): 2.39–5.97) and a higher incidence of MACE (HR 3.42, 95% CI: 2.92–3.99), with
a proportional increase in mortality of 16% per a 0.1 CFR unit reduction. These data were
also confirmed for mortality (HR: 5.44, 95% CI: 3.78–7.83) and MACE (HR: 3.56, 95% CI:
2.14–5.90) among patients with isolated coronary microvascular dysfunction.
Thus, novel indexes, specifically addressing the identification of impairments of
microvasculature, have been progressively developed.
The index of microvascular resistance (IMR) is a parameter specifically addressing
microvasculature, which can be derived from thermodilution-derived mean transit time
during CFR measurement. An IMR greater than 25 units is considered abnormal and
diagnostic for microvascular angina [55].
In the CorMicA Trial, among 391 patients with angina, a stratified medical therapy
driven by coronary function testing resulted in an improvement in quality of life, although
not in conditioning long-term outcomes [56].
In effect, the relevant benefits of optimizing medical therapy, independent of coronary
revascularization, have recently emerged in several randomized trials [57,58].
Nevertheless, the pharmacological agents preferred in patients with INOCA are still
poorly defined in the absence of dedicated randomized trials.
In the retrospective analysis of a large cohort of patients with acute coronary syndrome
and no evidence of coronary epicardial disease, Ciliberti et al. [59] documented that the
use of beta-blockers was significantly associated with a less frequent occurrence of adverse
outcomes at long-term follow-up among patients with MINOCA, whereas ASA displayed
a potentially harmful impact on prognosis.
Similar conclusion was reached by Lindahl et al. in a subanalysis of 9138 patients with
MINOCA enrolled in the SWEDEHEART registry (the Swedish Web-System for Enhance-
ment and Development of Evidence-Based Care in Heart Disease Evaluated According to
Recommended Therapy). After a mean follow-up of 4.1 years, there was a significantly
lower event rate associated with the use of statins, ACE inhibitors/ARBs, and a trend for a
lower event rate with the use of β-blockers (hazard ratio, 0.86 [95% CI, 0.74–1.01]), while
dual antiplatelet treatment was not associated with a lower event rate. [60]
The results of the MINOCA-BAT trial (NCT03686696), randomizing 3500 MINOCA
patients to β-blocker and ACEi or ARB versus placebo, will shed additional light on the
topic, and are expected in 2025 [61].
J. Clin. Med. 2023, 12, 2274 9 of 12

In patients with suspected vasospastic angina, calcium-channel blockers and nitrates

should be preferred as second-line treatments; nicorandil and cilostazol can also be consid-
ered as potential options [62].
On the contrary, in patients with suspect plaque erosion or calcific nodules, poten-
tially triggering the formation of thrombus, the use of antithrombotic agents should be
encouraged, based on the results of the EROSION (Effective Anti-Thrombotic Therapy
Without Stenting: Intravascular Optical Coherence Tomography-Based Management in
Plaque Erosion) study [63].
Thus, the identification of the underlying mechanism and the tailoring of pharmaco-
logical therapy appears to be vital for the appropriate management of these patients.
Therefore, a “full” physiology approach, including a complete assessment of epicardial
and microvascular circulation, should be advocated in order to relieve symptoms and
prevent ischemia, thus improving the outcomes of these patients. Nevertheless, further
studies are certainly warranted to define the most appropriate indexes and the prognostic
implications of a physiology-based strategy.

Author Contributions: Conceptualization, M.V. and A.R.; methodology, M.V.; validation, M.V. and
A.R.; data curation, M.V.; writing—original draft preparation, M.V.; writing—review and editing,
A.R.; visualization, M.V.; supervision, A.R. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki.
Conflicts of Interest: The authors declare no conflict of interest.

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