- Email: [email protected]
Contribution of Age-Related Microvascular Dysfunction to Abnormal Coronary
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 13, NO. 1, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
CORONARY
Contribution of Age-Related Microvascular Dysfunction to Abnormal Coronary Hemodynamics in Patients With Ischemic Heart Disease Tim P. van de Hoef, MD, PHD,a,b,* Mauro Echavarria-Pinto, MD, PHD,b,c,* Martijn Meuwissen, MD, PHD,d Valerie E. Stegehuis, MD,a Javier Escaned, MD, PHD,b,e Jan J. Piek, MD, PHDa
ABSTRACT OBJECTIVES This study sought to investigate the contribution of age-related microcirculatory dysfunction to abnormal coronary hemodynamics in patients with coronary atherosclerosis. BACKGROUND Impairment in myocardial blood supply in patients with coronary atherosclerosis can be accentuated due to age-related changes in microcirculatory function. METHODS Intracoronary pressure and flow were measured with the Doppler technique in 299 vessels (228 patients), and the thermodilution technique in 120 vessels (99 patients). In 172 patients, Doppler measurements were also performed in unobstructed vessels. Associations of coronary hemodynamics with aging were studied in both the stenosed and unobstructed arteries. RESULTS Aging was associated with a progressive increase in minimal microvascular resistance and a progressive decrease in hyperemic flow in both obstructed and nonobstructed coronary arteries. As such, coronary flow reserve decreased with advancing age. Epicardial stenosis severity assessed by resting Pd/Pa, basal stenosis resistance index, and hyperemic stenosis resistance index was equivalent across age groups. By contrast, fractional flow reserve increased with advancing age. Consequently, the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of concomitant focal epicardial and diffuse or microvascular disease (relative risk: 1.6; 95% confidence interval: 1.1 to 2.3; p ¼ 0.017) increased with advancing age, whilst the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of non–flow-limiting stenosis with a healthy microcirculation decreased (relative risk: 0.7; 95% CI: 0.5 to 1.0; p ¼ 0.022). CONCLUSIONS Aging is associated with progressive pan-myocardial impairment of coronary vasodilatory capacity due to an increase in minimal microvascular resistance. Concomitant aging-related impairment in microvascular function impacts the pathophysiology of ischemic heart disease in the individual patient and is not adequately identified by hyperemic coronary pressure measurements alone. (J Am Coll Cardiol Intv 2020;13:20–9) © 2020 by the American College of Cardiology Foundation.
From the aAmsterdam UMC, University of Amsterdam, Heart Center, Department of Interventional Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; bCardiovascular Institute, Hospital Clínico San Carlos, and Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; cHospital General ISSSTE – Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro, México; dDepartment of Cardiology, Amphia Hospital, Breda, the Netherlands; and the eFaculty of Medicine, Complutense University, Madrid, Spain. *Drs. van de Hoef and Echavarria-Pinto contributed equally to this work. This study was funded, in part, by the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 224495 (euHeart project), and by grants from the Dutch Heart Foundation (2006B186 and D96.020).
ISSN 1936-8798/$36.00
https://doi.org/10.1016/j.jcin.2019.08.052
van de Hoef et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 1, 2020 JANUARY 13, 2020:20–9
I
n patients with ischemic heart disease (IHD),
evaluate the origin of age-dependent micro-
ABBREVIATIONS
myocardial
vascular dysfunction, and its impact on
AND ACRONYMS
ischemia
may
originate
from
impairment of myocardial perfusion due to ab-
normalities in both the epicardial and microcircula-
therapeutic
decisions
regarding
coronary AMC = Academic Medical
revascularization.
Centre
tory compartments of the coronary circulation. In the epicardial vessel, the principal mechanism lead-
BSR = baseline stenosis
METHODS
resistance index
ing to impaired myocardial perfusion is a decrease
CFR = coronary flow reserve
in vessel conductance caused by obstructive steno-
DATA SOURCE. We included patients with a
sis. In the coronary microcirculation, impairment of
clinical indication for physiological assess-
myocardial perfusion is a result from abnormal
HSR = hyperemic stenosis
ment of $1 stenosis of intermediate angio-
resistance index
functioning
of
the
21
Age-Related Microvascular Dysfunction in IHD
coronary
resistance
FFR = fractional flow reserve
vessels.
graphic severity (40% to 70% diameter
HUCSC = Hospital Clínico San
This may result from structural remodeling or func-
stenosis) at the Academic Medical Centre
Carlos
tional dysregulation, which, at a difference from
(AMC), Amsterdam, the Netherlands, and
IHD = ischemic heart disease
the epicardial vessel, have a nonatherosclerotic
Hospital Clínico San Carlos (HUCSC), Madrid,
IQR = interquartile range
origin. Although the diagnosis and treatment in
Spain. Exclusion criteria were restricted to
Pa = mean hyperemic aortic
the setting of IHD remains focused on epicardial
culprit vessels of acute coronary syndromes,
pressure
obstructive causes, the pathophysiology underlying
serial stenoses, left main stenosis, significant
myocardial ischemia importantly involves a combi-
valvular pathology, and prior coronary artery
nation of epicardial and microvascular causes of
bypass grafting surgery. The local ethical re-
impaired myocardial perfusion. Concomitant micro-
view boards approved the respective study
vascular disease may importantly affect treatment
protocols, and all subjects gave written
decisions regarding epicardial revascularization (1)
informed consent.
SEE PAGE 30
Pd/Pa = mean hyperemic distal pressure
QCA = quantitative coronary angiography
Tmn = mean transit time
and has been documented to increase susceptibility to myocardial ischemia (2).
PCI = percutaneous coronary intervention
CARDIAC CATHETERIZATION AND HEMODYNAMIC MEASUREMENTS. Cardiac catheterization was per-
formed
according
to
standard
clinical
practice.
One of the factors associated with impairment of
Angiographic images were recorded in a manner
myocardial perfusion at the microvascular level is
suitable for quantitative coronary angiography (QCA)
aging. Understanding the mechanism and magnitude
analysis.
by which aging contributes to microvascular abnor-
equipped guidewires were used to subsequently
malities in patients with IHD is important, among
measure intracoronary pressure and flow. In AMC,
several reasons, because changing demographics
coronary flow was assessed using the Doppler tech-
mean that an increasing number of elderly patients
nique (4), and baseline average peak flow velocity
are being referred for percutaneous coronary inter-
and hyperemic average peak flow velocities average
vention (PCI) (3). Yet our understanding of the influ-
peak flow velocity were labeled baseline and hyper-
ence of aging on the dominant cause of myocardial
emic flow, respectively. In HUCSC, coronary flow was
perfusion impairment, and its impact on therapeutic
assessed with the coronary thermodilution tech-
decisions remains limited. Investigating the specific
nique (5,6). Resting and hyperemic thermodilution
contribution of deranged microvascular function to
curves were obtained in triplicate, and the inverse of
impaired myocardial perfusion is facilitated by recent
the average basal mean transit time and hyperemic
approaches combining invasive pressure and flow
Tmn was labeled baseline and hyperemic flow,
After
diagnostic
angiography,
sensor-
measurements, which allows the selective evaluation
respectively (5,6). In AMC, coronary flow was addi-
of the epicardial coronary artery and coronary
tionally measured in a reference coronary artery,
microvasculature. Accordingly, we studied the asso-
defined as a coronary artery with <30% diameter
ciations of coronary hemodynamics with aging in
stenosis on visual assessment, if available. Hyper-
both stenosed and unobstructed coronary arteries to
emia was induced by either intracoronary bolus
Dr. Echavarria-Pinto was supported by a clinical scholarship from Fundación Interhospitalaria Investigacion Cardiovascular, Madrid, Spain. Drs. van de Hoef, Echavarria-Pinto, and Escaned have served as speakers for St. Jude Medical and Volcano Corporation. Dr. Meuwissen has served as a speaker for Volcano Corporation. Dr. Piek has received consulting and personal fees from Philips/Volcano; and has been an advisory board member for Philips/Volcano. Dr. Stegehuis has reported that she has no relationships relevant to the contents of this paper to disclose. Manuscript received July 17, 2019; revised manuscript received August 23, 2019, accepted August 27, 2019.
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Age-Related Microvascular Dysfunction in IHD
injection (20 to 40 m g) of adenosine at AMC, or intravenous infusion of adenosine (140 m g/kg/min) at HUCSC.
T A B L E 1 Baseline Clinical Characteristics of the
Study Population (N ¼ 327)
Age, yrs
PHYSIOLOGICAL PARAMETERS: DERIVATION AND MEANING. From the invasive coronary pressure and
flow recordings, several physiological parameters were calculated. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to baseline flow, where CFR <2.0 was considered the threshold for myocardial ischemia (7). CFR reflects the vasodilator capacity of the coronary circulation, which is affected by abnormalities in both the epicardial coronary artery and microvasculature.
62 (54–69)
Male
242 (75)
Hypertension
159 (49)
Diabetes
57 (17)
Family history
109 (33)
Dyslipidemia
200 (61)
Smoking
94 (29)
Prior myocardial infarction
133 (41)
Prior percutaneous coronary intervention
97 (30)
Multivessel disease
200 (61)
Values are median (interquartile range) or n (%).
The physiological severity of the stenosis was assessed using pressure-only as well as combined flow
expressed in absolute terms or as a percentage, re-
reserve (FFR) was calculated as the ratio of mean
flects the reserve capacity of the coronary microcir-
hyperemic distal pressure (Pd) to mean hyperemic
culation to vasodilate upon an increase in myocardial
aortic pressure (Pa), where FFR >0.80 was considered
demand.
pressure
and
flow
parameters.
Fractional
normal. The Pd/Pa ratio was also determined during nonhyperemic conditions, and was labeled resting
STATISTICAL ANALYSIS. Normality and homogene-
Pd/Pa. The stenosis resistance index was calculated
ity of the variances were tested using Shapiro-Wilk
as the mean pressure drop across the stenosis (mean
and Levene tests. Categorical variables are pre-
Pa mean Pd) divided by Doppler flow velocity.
sented as counts and percentages. Continuous vari-
Stenosis resistance index was calculated both during
ables are presented as mean SD or median (1st and
resting (baseline stenosis resistance index [BSR])
3rd quartiles [Q1, Q3]). Data were analyzed on a per-
(8–10), and hyperemic conditions (hyperemic stenosis
patient basis for clinical characteristics, and on a
resistance index [HSR]) (11,12). The stenosis resis-
per-vessel basis for the rest of the calculations. For
tance index is a stenosis-specific parameter that re-
descriptive statistics, the study population was
flects the resistance to coronary flow induced by the
stratified into 3 representative age categories, defined
stenosis. This parameter has been validated from
by the quartiles of age. Patients within the first
Doppler measurements only and was therefore
quartile were considered “young,” patients across
calculated from Doppler data only.
quartiles 2 and 3 “intermediate,” and patients within
The functional status of the microvasculature was
the fourth quartile “elderly.” For vessel-to-patient
assessed using calculations of microvascular resis-
analyses,
tance during nonhyperemic conditions, as well as
robust standard errors were used to adjust for clus-
robust
regressions
with
Huber-White
during coronary hyperemia. Microvascular resistance
tering of vessels within patients, where appropriate.
was calculated as mean Pd divided by flow and re-
These results are presented as adjusted mean or
flects the resistance to coronary flow induced by the
adjusted frequency with 95% confidence interval.
microvasculature. In the absence of obstructive cor-
Overall differences between groups were compared
onary artery disease, reference vessel microvascular
with 1-way analysis of variance, Kruskal-Wallis or chi-
resistance was calculated as the ratio between mean
square test, followed by post hoc Student’s t-tests,
aortic pressure and distal flow velocity (during base-
Mann-Whitney
line and hyperemia). Microvascular resistance during
Bonferroni-adjusted significance level. The associa-
nonhyperemic conditions is impacted by the magni-
tion of age with physiological parameters was tested
tude of compensatory vasodilation in the microvas-
with robust linear regression analysis, where appli-
culature
coronary
cable. Linear mixed models were used to identify
autoregulation. Microvascular resistance during hy-
independent predictors of FFR and CFR, using Mal-
peremic conditions is impacted for example by
low’s Cp as criterion for selection of the optimal
microvascular remodeling or extravascular compres-
predictive model, with candidate variables including
sion and is a characteristic of the vasodilator function
clinical characteristics (Table 1), clinical presentation,
of the coronary microvasculature. The difference be-
angiographic stenosis severity, and the interrogated
tween nonhyperemic and hyperemic
vessel (left anterior descending, left circumflex, or
and
is
a
characteristic
of
resistance,
U
or
Fisher
exact
tests,
with
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Age-Related Microvascular Dysfunction in IHD
T A B L E 2 Clinical, Angiographic, and Physiological Characteristics Stratified by Age Categories
Age, yrs <55 (n ¼ 87)
55–69 (n ¼ 166)
$70 (n ¼ 74)
p Value
0.03
Clinical characteristics 69 (80)*
127 (77)
46 (63)†
Hypertension
Male
37 (43)
86 (52)
36 (49)
0.37
Diabetes
13 (15)
35 (21)
9 (12)
0.19 0.04
Family history of cardiovascular disease
35 (40)*
58 (35)
16 (22)†
Dyslipidemia
61 (70)
97 (58)
42 (57)
0.13
34 (39)*‡
47 (28)†
13 (18)†
0.01
Prior myocardial infarction
38 (44)
72 (43)
23 (31)
0.16
Prior PCI
25 (29)
51 (31)
21 (28)
0.91 0.64
Smoking
Multivessel disease Angiographic characteristics
55 (63)
98 (59)
47 (64)
n ¼ 117
n ¼ 207
n ¼ 95
45 (38 to 53)
45 (39 to 52)
54 (45 to 62)
Lesion location LAD
0.58
LCx
21 (15 to 29)
25 (20 to 31)
20 (13 to 29)
RCA
33 (26 to 42)
29 (24 to 36)
26 (19 to 36)
2.9 (2.8 to 3.1)
2.9 (2.8 to 3.0)
3.3 (2.5 to 4.1)
0.53
54 (52 to 56)
53 (52 to 55)
50 (48 to 53)
0.09
0.66
Reference vessel diameter, mm Diameter stenosis, % Pressure measurements Pd/Pa
0.88 (0.86 to 0.91)
0.89 (0.88 to 0.91)
0.89 (0.87 to 0.91)
FFR
0.76 (0.73 to 0.78)*
0.78 (0.76 to 0.80)
0.80 (0.78 to 0.83)†
0.03
Delta Pd/Pa
0.13 (0.11 to 0.14)*
0.12 (0.11 to 0.13)*
0.09 (0.08 to 0.10)†‡
<0.001
85 (75 to 91)*
71 (63 to 77)
57 (44 to 69)†
0.002
CFR, combined
2.4 (2.2 to 2.5)*
2.3 (2.1 to 2.4)*
1.9 (1.8 to 2.1)†,‡
<0.001
CFR, Doppler
2.4 (2.2 to 2.6)*
2.3 (2.2 to 2.4)
2.1 (1.9 to 2.2)†
0.02
CFR, thermodilution
2.2 (1.7 to 2.7)
2.2 (1.9 to 2.4)
1.8 (1.5 to 2.1)
0.13
APV baseline, cm/s
17 (15 to 18)
18 (16 to 19)
18 (15 to 20)
0.72
Intracoronary adenosine Flow measurements
APV hyperemia, cm/s
38 (35 to 42)
39 (36 to 42)
36 (31 to 40)
0.51
Tmn baseline, s
0.74 (0.51 to 0.97)
0.78 (0.67 to 0.89)
0.61 (0.45 to 0.77)
0.25
Tmn hyperemia, s
0.33 (0.27 to 0.40)
0.37 (0.33 to 0.42)
0.34 (0.27 to 0.42)
0.62
BSR, Doppler, mm Hg/cm/s
0.92 (0.62 to 1.21)
0.89 (0.62 to 1.17)
1.02 (0.56 to 1.48)
0.90
HSR, Doppler, mm Hg/cm/s
1.02 (0.72 to 1.31)
1.02 (0.73 to 1.31)
1.14 (0.61 to 1.68)
0.91
0.10 (0.18 to 0.01)
0.12 (0.20 to 0.05)
0.12 (0.26 to 0.01)
0.91
6.10 (5.54 to 6.66)
5.99 (5.54 to 6.44)
6.27 (5.03 to 7.5)
0.89
56 (37 to 75)
63 (54 to 73)
51 (37 to 65)
0.36
2.18 (1.97 to 2.38)
2.27 (2.04 to 2.49)
2.73 (2.23 to 3.23)
0.14
19 (16 to 22)
23 (20 to 26)
23 (18 to 28)
0.17
60 (63 to 57)*
60 (62 to 58)*
52 (56 to 49)†‡
<0.001
Stenosis resistance measurements, Doppler only
Delta SR, Doppler, mm Hg/cm/s Microvascular resistance measurements BMR, Doppler, mm Hg/cm/s BRI, thermodilution, U HMR, Doppler, mm Hg/cm/s IMR, thermodilution, U Change MR, combined, % Reference vessel measurements, Doppler only (n ¼ 172)
n ¼ 54
n ¼ 88
n ¼ 30
CFR, Doppler
3.2 0.6*‡
2.8 0.7†
2.6 0.7†
APV baseline, cm/s
17 (13 to 21)
17 (13 to 22)
16 (13 to 23)
0.72
53 (40 to 68)*
47 (39 to 60)*
39 (34 to 52)†‡
0.005
APV hyperemia, cm/s
<0.001
BMR, Doppler, mm Hg/cm/s
5.75 (4.72 to 7.69)
5.67 (4.5 to 7.47)
5.75 (4.42 to 8.29)
0.92
HMR, Doppler, mm Hg/cm/s
1.89 (1.30 to 2.25)*
1.93 (1.64 to 2.54)*
2.45 (1.95 to 3.08)†‡
0.002
Values are n (%), adjusted mean or adjusted frequency (95% confidence interval), or mean SD. *p < 0.05 vs. elderly. †p < 0.05 vs. young. ‡p < 0.05 vs. intermediate. APV ¼ average peak flow velocity; BMR ¼ basal microvascular resistance index; BRI ¼ basal index of microvascular resistance; BSR ¼ basal stenosis resistance index; CFR ¼ coronary flow reserve; FFR ¼ fractional flow reserve; HMR ¼ hyperemic microvascular resistance index; HSR ¼ hyperemic stenosis resistance index; IMR ¼ hyperemic index of microvascular resistance; LAD ¼ left anterior descending coronary artery; LCx ¼ left circumflex coronary artery; MR ¼ microvascular resistance; PCI ¼ percutaneous coronary intervention; Pd/Pa ¼ resting distal coronary to aortic pressure ratio; RCA ¼ right coronary artery; SR ¼ stenosis resistance index; Tmn ¼ mean transit time.
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Age-Related Microvascular Dysfunction in IHD
F I G U R E 1 Scatterplot of Reference Vessel and Target Vessel CFR Values
According to Age
right coronary artery). These results are presented as beta robust SE, and standardized coefficients to facilitate comparison. For reference vessel analysis, where all patients had presented with stable symptoms, candidate variables included clinical characteristics (Table 2), and the interrogated vessel. Differences were considered significant at p < 0.05 (2-sided). The STATA 13.1 (StataCorp, College Station, Texas) statistical software package was used for all calculations.
RESULTS PATIENT POPULATION. In total, 327 patients with
419 stenosed vessels were investigated: 228 patients (299 vessels) with Doppler-derived flow at AMC (enrolled between 1997 and 2006) (13), and 99 patients (120 vessels) with thermodilution-derived flow at HUCSC (enrolled between 2011 and 2015). ReferBoth in unobstructed reference vessels, and stenosed coronary arteries, aging is
ence vessel measurements were performed in 172 of
associated with a decrease in coronary flow reserve (CFR). Black circles and solid black
228 patients (75%) studied with Doppler-derived flow.
line represent target CFR values and the best-fit linear regression, respectively. Open red
Clinical characteristics of the complete study popu-
triangles and dashed red line represent reference vessel CFR values and the best-fit linear regression, respectively.
lation are shown in Table 1. Overall, coronary stenoses were of intermediate severity, both angiographically (mean diameter stenosis 52.7 11.4%) and physiologically (median FFR 0.81 [interquartile range: 0.72 to 0.88]). Moreover, as shown in Online Figure 1, the distribution of FFR values reflected a clinical population routinely referred for intracoronary physio-
F I G U R E 2 Scatterplot of Reference Vessel Baseline and Hyperemic Flow Velocity
Values According to Age
logical assessment in contemporary clinical practice. CLINICAL AND ANGIOGRAPHIC CHARACTERISTICS ACCORDING TO AGE. Median age of the patient
population was 62 years (Q1, Q3: 54 to 69 years). Accordingly,
patients
were
stratified
in
young (<55 years; n ¼ 87 [27%]), intermediate ($55 and <70 years of age; n ¼ 166 [51%]), and elderly ($70 years of age; n ¼ 74 [23%]). Clinical and angiographic characteristics across these age categories are shown in Table 2. Risk factors for IHD were generally less prevalent in elderly patients, who were significantly less likely to be male, less likely to have a family history of IHD, and less likely to smoke (Table 2). There were no differences in epicardial stenosis location or epicardial stenosis severity by QCA across the age categories. INFLUENCE OF AGE ON CORONARY HEMODYNAMICS IN UNOBSTRUCTED REFERENCE VESSELS. In the 172 anWith increasing age, a dominant decrease in reference vessel hyperemic flow occurs,
giographically normal reference coronary arteries in
whereas resting flow does not change with increasing age. Dark blue circles and solid
patients evaluated with Doppler flow velocity, mean
dark blue line represent reference vessel baseline flow velocity values and the best-fit linear regression, respectively. Open red squares and dashed red line represent
CFR was 2.9 0.7. The distribution of reference
reference vessel hyperemic flow velocity values and the best-fit linear regression,
vessel CFR across age is shown in Figure 1. Reference
respectively.
vessel CFR decreased with advancing age, although the absolute effect was modest (rho ¼ 0.31;
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Age-Related Microvascular Dysfunction in IHD
p < 0.001; R 2 ¼ 0.07; p < 0.001) (Table 2). This progressive impairment of CFR with advancing age
T A B L E 3 Best-Fit Multivariate Linear Regression Model for the Prediction of
Reference Vessel CFR
occurred in the presence of similarly modest agedependent increase
in hyperemic microvascular
resistance (rho ¼ 0.25; p ¼ 0.002; R
2
¼ 0.06;
p ¼ 0.002) and decrease in hyperemic flow velocity (rho ¼ 0.22; p ¼ 0.006; R 2 ¼ 0.05; p ¼ 0.004) (Figure 2). By contrast, no significant changes in resting
microvascular
resistance
(rho
¼
0.01;
p ¼ 0.93; R 2 ¼ 0.00; p ¼ 0.70) or resting flow velocity (rho ¼ 0.013; p ¼ 0.87; R 2 ¼ 0.00; p ¼ 0.98) (Figure 2)
Age, per yr increase History of dyslipidemia Reference vessel, LAD reference LCx RCA
Beta
SE
Standardized Coefficient
p Value
0.016
0.005
0.25
0.001
0.22
0.105
0.16
0.04
0.0035 0.299
0.111 0.191
0.003 0.12
0.98 0.120
Abbreviations as in Table 2.
were documented with advancing age (Table 2). The best multivariable model for the prediction of CFR in reference vessels (R 2 ¼ 0.11; p < 0.001) included age, history of dyslipidemia, and reference vessel location (Table 3). Among these predictors, age was the strongest independent predictor of CFR in reference vessels.
DETERMINANTS OF CFR AND FFR IN STENOSED VESSELS. The best multivariable model for the pre-
diction of CFR in stenosed vessels (R 2 ¼ 0.11; p < 0.001) included age, prior myocardial infarction, multivessel disease, the interrogated vessel, and percent diameter stenosis (Table 4). Among these
INFLUENCE OF AGE ON MICROVASCULAR FUNCTION IN
predictors, age and diameter stenosis were similarly
STENOSED CORONARY ARTERIES. Mean CFR in the
strong independent predictors of CFR.
stenosed coronary arteries was 2.2 0.8. CFR
The best multivariable model for the prediction of
decreased with advancing age, although the absolute
FFR (R 2 ¼ 0.29; p < 0.001) included age, diabetes
effect was modest (rho ¼ 0.17; p < 0.001; R 2 ¼ 0.03;
mellitus, multivessel disease, the interrogated vessel,
p ¼ 0.001) (Figures 1 and 3). This was also expressed in
and percent diameter stenosis (Table 5). Among
the overall percent change in microvascular resis-
these, diameter stenosis was the strongest indepen-
tance, where the decrease in microvascular resistance
dent predictor for FFR. However, also age was inde-
from resting to hyperemic conditions decreased with
pendently associated with FFR.
advancing age (R2 ¼ 0.03; p ¼ 0.002). Hyperemic microvascular resistance showed a significant albeit modest increase with advancing age in those patients
F I G U R E 3 Scatterplot of FFR and CFR Values in Stenosed Vessels According to Age
studied with Doppler flow (hyperemic microvascular resistance R 2 ¼ 0.02; p ¼ 0.03). Trends in microvascular resistance across the age categories were similar between
Doppler-derived
and
thermodilution-
derived flow, but formal statistical significance was not met in the smaller subcohort of thermodilution measurements (Table 2). INFLUENCE OF AGE ON STENOSIS ASSESSMENT.
Diameter stenosis assessed by QCA was similar across the age categories (Table 2). Resting Pd/Pa was equivalent across the age categories, and no association between resting Pd/Pa and age was documented (R 2 ¼ 0.006; p ¼ 0.08). In patients studied with Doppler flow velocity, stenosis resistance index during resting (BSR) and hyperemic conditions (HSR) were similar across age categories (Table 2), and no association with age was documented (BSR R 2 < 0.001; p ¼ 0.59; HSR R 2 < 0.001; p ¼ 0.72). By contrast, FFR was significantly different across the age
categories
(Table
2),
and
increased
with
advancing age (R 2 ¼ 0.03; p < 0.001) (Table 2, Figure 3).
With advancing age, fractional flow reserve (FFR) increases, whereas coronary flow reserve (CFR) decreases. These characteristics occurred while no other index of stenosis severity was associated with age. Closed dots and dashed line represent FFR values and the best-fit linear regression, respectively. Open dots and dashed line represent target vessel CFR and the best-fit linear regression, respectively.
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T A B L E 4 Best-Fit Multivariate Linear Regression Model for the Prediction of CFR in
Stenosed Vessels
disease, and its impact on the physiological assessment of epicardial coronary artery stenosis. Microvascular function becomes increasingly impaired
Beta
Robust SE
Standardized Coefficient
Age, per yr increase
0.015
0.004
0.20
<0.001
Prior myocardial infarction
0.216
0.078
0.13
0.006
0.253
0.080
0.14
0.002
Diameter stenosis
0.014
0.003
0.19
<0.001
Lesion location, LAD reference LCx RCA
0.287 0.097
0.098 0.093
0.14 0.05
0.003 0.301
Multivessel disease
p Value
with aging of the coronary circulation due to an increase in minimal microvascular resistance during hyperemia, leading to an impairment of maximal coronary flow and CFR. This phenomenon occurs similarly in nonobstructed and obstructed coronary arteries, and, due to this phenomenon, the pathophysiological substrate of ischemic heart disease changes substantially with increasing age. Whereas epicardial coronary disease severity was equivalent
Abbreviations as in Table 2.
across age groups at the time of presentation, concomitant microvascular dysfunction was increas-
EFFECT OF AGE ON THE CFR AND FFR RELATIONSHIP.
Age was significantly different across the quadrants of the CFR and FFR relationship (Table 6). Vessels with low FFR and high CFR were more likely observed in younger patients, whereas vessels with high FFR and low CFR were more likely observed in elderly
ingly prevalent with advancing age. These findings are of distinct importance, considering the drastic changes
in
demographics
globally,
where
an
increasing number of elderly patients are referred to the coronary catheterization laboratory with chest pain syndromes.
patients. The Central Illustration shows the distribu-
AGING, CFR, AND FFR. Advancing age was associated
tion of FFR and CFR accordance and discordance
with a decrease in CFR, on the basis of an impairment
across decades. After adjustment for independent
of microvascular vasodilator function leading to a
predictors of FFR and CFR (Tables 4 and 5), there was
pathological
a 1.6-fold increase in risk of an FFR/CFR pattern
resistance. Microvascular resistance in nonhyperemic
reflective of focal stenosis superimposed on diffuse or
conditions did not change with increasing age. This
microvascular disease (high FFR, low CFR) (95%
agrees with previous studies documenting a decrease
confidence interval: 1.1 to 2.3; p ¼ 0.017) with each
in CFR with advancing age in unobstructed coronary
decade increase in age, whereas there was a decrease
arteries (14) and adds that the origin of CFR impair-
in risk of an FFR/CFR pattern reflective of focal non–
ment lies in an increase in minimal microvas-
flow-limiting stenosis with a healthy microcirculation
cular resistance.
increase
in
minimal
microvascular
(low FFR, high CFR) (relative risk: 0.7 per decade in-
The impairment in CFR with advancing age was
crease in age; 95% confidence interval: 0.5 to
associated with a significant, albeit modest, increase
1.0; p ¼ 0.022).
in FFR. This increase in FFR was in contrast with all other parameters of stenosis severity, such as diameter stenosis, resting Pd/Pa, and stenosis resistance
DISCUSSION
index, all of which were not affected by aging. From a
We describe the origin of age-related microvascular dysfunction in the pathophysiology of ischemic heart
clinical perspective, these findings suggest that the detection of stenosis-induced myocardial ischemia with FFR may decrease with aging, whereas the actual hemodynamic stenosis severity is the same
T A B L E 5 Best-Fit Multivariate Linear Regression Model for the Prediction of FFR
Standardized Coefficient
p Value
Beta
Robust SE
Age, per yr increase
0.002
0.001
0.11
0.007
Diabetes
0.033
0.015
0.08
0.029
Multivessel disease
0.034
0.014
0.11
0.018
0.007
0.001
0.50
<0.001
0.046 0.029
0.017 0.015
0.12 0.09
0.006 0.056
Diameter stenosis Lesion location, LAD reference LCx RCA Abbreviations as in Table 2.
across ages, and the overall burden of ischemia as diagnosed with CFR even increases with advancing age. Our findings are suggestive of an increase in ischemia burden with advancing age despite equivalent stenosis severity concur with previous data showing an increase in exercise-related myocardial ischemia on noninvasive stress testing associated with aging despite equivalent extent of angiographic epicardial coronary artery disease (15). CLINICAL IMPLICATIONS. This study is not the first
to report an increase in FFR values with advancing age, which has until now been attributed to a lower
van de Hoef et al.
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Age-Related Microvascular Dysfunction in IHD
T A B L E 6 Accordance and Discordance of FFR and CFR Across Age Categories
Age, yrs <55 (n ¼ 87)
55–69 (n ¼ 166)
$70 (n ¼ 74)
FFR >0.80/CFR $2.0, concordantly normal
33 (26–42)
42 (35–48)
32 (23–42)
0.15
FFR #0.80/CFR $2.0, focal non-flow limiting
28 (20–38)
22 (17–28)
15 (9–23)
0.08
Pressure/Flow Discordance
Overall p Value
FFR >0.80/CFR <2.0, diffuse/microvascular disease
8 (4–14)*
12 (8–17)*
26 (18–36)†‡
<0.001
FFR #0.80/CFR <2.0, concordantly abnormal
31 (23–40)
24 (19–30)
27 (19–38)
0.42
Values are adjusted n or % (95% confidence interval). *p < 0.05 vs. old. †p < 0.05 vs. intermediate. ‡p < 0.05 vs. young. Abbreviations as in Table 2.
prevalence of functionally significant coronary artery
that could actually benefit from stenosis alleviation
disease at older age (16–18). However, our study is the
despite relatively normal FFR values. The upcoming
first to describe the physiological basis of this finding.
multicenter DEFINE-FLOW (Distal Evaluation of
Whereas both nonhyperemic pressure measurements
Functional Performance With Intravascular Sensors
(Pd/Pa),
combined
to Assess the Narrowing Effect – Combined Pressure
pressure-flow indices such as BSR and HSR, docu-
and Doppler FLOW Velocity Measurements) study
ment that the hemodynamic significance of epicardial
may further inform the appropriate management of
stenosis is equivalent across age groups, FFR pro-
patients using combined pressure-flow measure-
gressively underestimates the hemodynamic impact
ments, and provide further insight into the impact of
of the stenosis. This is due to age-related progressive
aging on FFR-CFR results and on patient prognosis.
increase in minimal microvascular resistance leading
By collecting detailed invasive physiology data, this
to a decrease in hyperemic flow, and thus higher FFR
study may further allow more insight into the prog-
values, for the exact same stenosis. Because the
nostic impact of stenosis-specific physiology tools.
as
well
as
stenosis-specific
intrinsic hemodynamic relevance of the stenosis is the same, it seems difficult to argue that elderly patients would benefit less from epicardial revascularization than younger patients with the exact same
C E NT R AL IL L U ST R AT IO N Prevalence of FFR/CFR Accordance and Discordance per Decade Increase in Age
epicardial disease. Because the myocardium thrives
100
on coronary flow, and because flow reserve is a critical determinant of myocardial ischemia (7,19), the
80
age-related microvascular dysfunction may increase the susceptibility for myocardial ischemia due to developing epicardial disease (14). This is supported by previous data documenting an increase in the
Percent
age-related decrease in flow reserve suggests that
60 40
occurrence of myocardial ischemia on noninvasive stress testing with higher minimal microvascular
20
resistance despite equivalent epicardial stenosis severity (2). As such, a normal FFR does not exclude the presence of clinically relevant coronary flow impairment, which is well-documented to be associated with myocardial ischemia (7), and is unequivocally related to impaired prognosis (20,21). Physicians should be aware that, despite the fact that revascularization is currently not supported in these vessels, these anomalies might be a cause of ischemia and
0
<50
50-59
60-69 Age
70-79
≥80
Microvascular / Diffuse Disease (FFR >0.80 / CFR <2.0) Concordantly Normal (FFR >0.80 / CFR ≥2.0) Concordantly Abnormal (FFR ≤0.80 / CFR <2.0) Focal Non-Flow Limiting (FFR ≤0.80 / CFR ≥2.0) van de Hoef, T.P. et al. J Am Coll Cardiol Intv. 2020;13(1):20–9.
thereby justify the clinical presentation, and have important implications for patient prognosis. Further research should focus on the hypothesis
With each decade, the prevalence of a fractional flow reserve (FFR)/coronary flow reserve (CFR) pattern reflective of microvascular and/or diffuse disease increased,
that assessment of physiological stenosis severity
whereas the prevalence of an FFR/CFR pattern reflective of a normal circulation or focal
with stenosis-specific tools, such as indices of steno-
stenosis superimposed on a healthy coronary microcirculation tended to decrease.
sis resistance, might be indicated to identify patients
27
28
van de Hoef et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 1, 2020 JANUARY 13, 2020:20–9
Age-Related Microvascular Dysfunction in IHD
Our current data suggest that nonhyperemic coro-
ACKNOWLEDGMENTS The authors gratefully acknowl-
nary pressure measurements are also unaffected by
edge the nursing staff of the cardiac catheterization
age-related alterations in microvascular vasodilator
laboratories
function and may provide a practical solution to
Amsterdam, the Netherlands, and Hospital Clínico
optimize lesion selection for PCI. Furthermore, the
San Carlos, Madrid, Spain, for their skilled assistance
optimal CFR threshold for identification of clinically
in acquiring the data.
at
the
Academic
Medical
Center,
relevant perfusion impairment, and the impact of PCI on improvement of coronary hemodynamics in the
ADDRESS FOR CORRESPONDENCE: Dr. Tim P. van de
setting of impaired CFR with borderline significant
Hoef, Academic Medical Center, AMC Heartcenter,
epicardial disease remain ill-described and should be
Room B2-213, Meibergdreef 9, 1105 AZ, Amsterdam, the
subject to further evaluation.
Netherlands. E-mail: [email protected].
STUDY LIMITATIONS. Our conclusions refer to pa-
tients with clinical indication for intracoronary interrogation of an epicardial stenosis. Intracoronary
PERSPECTIVES
flow was assessed with both the Doppler and thermodilution technique: the 2 available methods for findings
WHAT IS KNOWN? Concomitant microvascular
were
disease may importantly affect treatment decisions
consistent between technologies, which strengthens
regarding epicardial revascularization and has been
the extrapolation of our findings to the clinical
documented to increase susceptibility to myocardial
setting. Additionally, different administration routes
ischemia. Aging is associated with impaired micro-
and doses of adenosine were used to induce hyper-
vascular function, but our understanding of the in-
emia. Although this limits the internal validity of our
fluence of aging remains limited.
this
purpose.
Nonetheless,
most
findings, it enhances their generalization, because this better reflects real-world use of hyperemic
WHAT IS NEW? Microvascular function becomes
agents. Finally, noninvasive assessment of myocar-
increasingly impaired with aging of the coronary cir-
dial ischemia was not routinely performed in these
culation due to an increase in minimal microvascular
patients, precluding more definitive conclusions
resistance during hyperemia, leading to an impairment
regarding the presence of myocardial ischemia.
of maximal coronary flow and coronary flow reserve. This phenomenon occurs similarly in nonobstructed and obstructed coronary arteries, and, due to this
CONCLUSIONS
phenomenon, the pathophysiological substrate of
Aging is associated with a progressive pan-myocardial increase in minimal microvascular resistance, which leads to an impairment of coronary vasodilatory reserve. In patients with ischemic heart disease, such aging-related impairment in microvascular function importantly contributes to the pathophysiology of ischemic heart disease. This multilevel involvement of the coronary circulation has pertinent diagnostic and
prognostic
consequences
but
cannot
be
adequately identified by hyperemic coronary pres-
ischemic heart disease changes substantially with increasing age. WHAT IS NEXT? Further research should focus on the hypothesis that assessment of physiological stenosis severity with stenosis-specific tools, such as indices of stenosis resistance, might be indicated to identify patients that could actually benefit from stenosis alleviation despite relatively normal FFR values.
sure measurements alone.
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3. Singh M, Rihal CS, Gersh BJ, et al. Twenty-five-year trends in in-hospital and long-term outcome after percutaneous coronary intervention: a singleinstitution experience. Circulation 2007;115:2835–41. 4. Doucette JW, Corl PD, Payne HM, et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation 1992;85:1899–911.
flow reserve: experimental validation. Circulation 2001;104:2003–6. 6. Pijls NH, De Bruyne B, Smith L, et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation 2002;105:2482–6.
5. De Bruyne B, Pijls NH, Smith L, Wievegg M,
7. Johnson NP, Gould KL. Physiological basis for angina and ST-segment change PET-verified thresholds of quantitative stress myocardial perfusion and coronary flow reserve. J Am Coll
Heyndrickx GR. Coronary thermodilution to assess
Cardiol Img 2011;4:990–8.
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8. van de Hoef TP, Meuwissen M, Escaned J, et al. Head-to-head comparison of basal stenosis resistance index, instantaneous wavefree ratio, and fractional flow reserve:
13. van de Hoef TP, Echavarria-Pinto M, van Lavieren MA, et al. Diagnostic and prognostic implications of coronary flow capacity: a comprehensive cross-modality physiological concept in
19. Gould KL, Johnson NP, Bateman TM, et al. Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission to-
diagnostic accuracy for stenosis-specific myocardial ischaemia. EuroIntervention 2015; 11:914–25.
ischemic heart disease. J Am Coll Cardiol Intv 2015;8:1670–80.
mography imaging in revascularization decisionmaking. J Am Coll Cardiol 2013;62:1639–53.
14. Uren NG, Camici PG, Melin JA, et al. Effect of aging on myocardial perfusion reserve. J Nucl Med 1995;36:2032–6.
20. van de Hoef TP, van Lavieren MA, Damman P, et al. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in
9. van de Hoef TP, Nolte F, Damman P, et al. Diagnostic accuracy of combined intracoronary pressure and flow velocity information during baseline conditions: adenosine-free assessment of functional coronary lesion severity. Circ Cardiovasc Interv 2012;5:508–14. 10. van de Hoef TP, Petraco R, van Lavieren MA, et al. Basal stenosis resistance index derived from simultaneous pressure and flow velocity measurements. EuroIntervention 2016;12:e199–207.
15. Kurata C, Uehara A, Sugi T, et al. Exercise myocardial perfusion scintigraphy is useful for evaluating myocardial ischemia even in the elderly. Ann Nucl Med 2000;14:181–6. 16. Fineschi M, Guerrieri G, Orphal D, et al. The impact of gender on fractional flow reserve measurements. EuroIntervention 2013;9:360–6.
coronary stenoses of intermediate severity. Circ Cardiovasc Interv 2014;7:301–11. 21. Lee JM, Choi KH, Hwang D, et al. Prognostic implication of thermodilution coronary flow reserve in patients undergoing fractional flow reserve measurement. J Am Coll Cardiol Intv 2018; 11:1423–33.
17. Park SJ, Kang SJ, Ahn JM, et al. Visual-func11. Meuwissen M, Chamuleau SAJ, Siebes M, et al. The prognostic value of combined intracoronary pressure and blood flow velocity measurements after deferral of percutaneous coronary intervention. Catheter Cardiovasc Interv 2008;71:291–7. 12. Meuwissen M, Siebes M, Chamuleau SA, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 2002;106:441–6.
tional mismatch between coronary angiography and fractional flow reserve. J Am Coll Cardiol Intv 2012;5:1029–36. 18. Lim H-S, Tonino PAL, De Bruyne B, et al. The impact of age on fractional flow reserve-guided percutaneous coronary intervention: a FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial substudy. Int J Cardiol 2014;177:66–70.
KEY WORDS aging, coronary flow reserve, coronary microvascular function, coronary physiology, fractional flow reserve, physiological stenosis severity
A PP END IX For a supplemental figure, please see the online version of this paper.
29
VOL. 13, NO. 1, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
CORONARY
Contribution of Age-Related Microvascular Dysfunction to Abnormal Coronary Hemodynamics in Patients With Ischemic Heart Disease Tim P. van de Hoef, MD, PHD,a,b,* Mauro Echavarria-Pinto, MD, PHD,b,c,* Martijn Meuwissen, MD, PHD,d Valerie E. Stegehuis, MD,a Javier Escaned, MD, PHD,b,e Jan J. Piek, MD, PHDa
ABSTRACT OBJECTIVES This study sought to investigate the contribution of age-related microcirculatory dysfunction to abnormal coronary hemodynamics in patients with coronary atherosclerosis. BACKGROUND Impairment in myocardial blood supply in patients with coronary atherosclerosis can be accentuated due to age-related changes in microcirculatory function. METHODS Intracoronary pressure and flow were measured with the Doppler technique in 299 vessels (228 patients), and the thermodilution technique in 120 vessels (99 patients). In 172 patients, Doppler measurements were also performed in unobstructed vessels. Associations of coronary hemodynamics with aging were studied in both the stenosed and unobstructed arteries. RESULTS Aging was associated with a progressive increase in minimal microvascular resistance and a progressive decrease in hyperemic flow in both obstructed and nonobstructed coronary arteries. As such, coronary flow reserve decreased with advancing age. Epicardial stenosis severity assessed by resting Pd/Pa, basal stenosis resistance index, and hyperemic stenosis resistance index was equivalent across age groups. By contrast, fractional flow reserve increased with advancing age. Consequently, the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of concomitant focal epicardial and diffuse or microvascular disease (relative risk: 1.6; 95% confidence interval: 1.1 to 2.3; p ¼ 0.017) increased with advancing age, whilst the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of non–flow-limiting stenosis with a healthy microcirculation decreased (relative risk: 0.7; 95% CI: 0.5 to 1.0; p ¼ 0.022). CONCLUSIONS Aging is associated with progressive pan-myocardial impairment of coronary vasodilatory capacity due to an increase in minimal microvascular resistance. Concomitant aging-related impairment in microvascular function impacts the pathophysiology of ischemic heart disease in the individual patient and is not adequately identified by hyperemic coronary pressure measurements alone. (J Am Coll Cardiol Intv 2020;13:20–9) © 2020 by the American College of Cardiology Foundation.
From the aAmsterdam UMC, University of Amsterdam, Heart Center, Department of Interventional Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; bCardiovascular Institute, Hospital Clínico San Carlos, and Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; cHospital General ISSSTE – Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro, México; dDepartment of Cardiology, Amphia Hospital, Breda, the Netherlands; and the eFaculty of Medicine, Complutense University, Madrid, Spain. *Drs. van de Hoef and Echavarria-Pinto contributed equally to this work. This study was funded, in part, by the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 224495 (euHeart project), and by grants from the Dutch Heart Foundation (2006B186 and D96.020).
ISSN 1936-8798/$36.00
https://doi.org/10.1016/j.jcin.2019.08.052
van de Hoef et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 1, 2020 JANUARY 13, 2020:20–9
I
n patients with ischemic heart disease (IHD),
evaluate the origin of age-dependent micro-
ABBREVIATIONS
myocardial
vascular dysfunction, and its impact on
AND ACRONYMS
ischemia
may
originate
from
impairment of myocardial perfusion due to ab-
normalities in both the epicardial and microcircula-
therapeutic
decisions
regarding
coronary AMC = Academic Medical
revascularization.
Centre
tory compartments of the coronary circulation. In the epicardial vessel, the principal mechanism lead-
BSR = baseline stenosis
METHODS
resistance index
ing to impaired myocardial perfusion is a decrease
CFR = coronary flow reserve
in vessel conductance caused by obstructive steno-
DATA SOURCE. We included patients with a
sis. In the coronary microcirculation, impairment of
clinical indication for physiological assess-
myocardial perfusion is a result from abnormal
HSR = hyperemic stenosis
ment of $1 stenosis of intermediate angio-
resistance index
functioning
of
the
21
Age-Related Microvascular Dysfunction in IHD
coronary
resistance
FFR = fractional flow reserve
vessels.
graphic severity (40% to 70% diameter
HUCSC = Hospital Clínico San
This may result from structural remodeling or func-
stenosis) at the Academic Medical Centre
Carlos
tional dysregulation, which, at a difference from
(AMC), Amsterdam, the Netherlands, and
IHD = ischemic heart disease
the epicardial vessel, have a nonatherosclerotic
Hospital Clínico San Carlos (HUCSC), Madrid,
IQR = interquartile range
origin. Although the diagnosis and treatment in
Spain. Exclusion criteria were restricted to
Pa = mean hyperemic aortic
the setting of IHD remains focused on epicardial
culprit vessels of acute coronary syndromes,
pressure
obstructive causes, the pathophysiology underlying
serial stenoses, left main stenosis, significant
myocardial ischemia importantly involves a combi-
valvular pathology, and prior coronary artery
nation of epicardial and microvascular causes of
bypass grafting surgery. The local ethical re-
impaired myocardial perfusion. Concomitant micro-
view boards approved the respective study
vascular disease may importantly affect treatment
protocols, and all subjects gave written
decisions regarding epicardial revascularization (1)
informed consent.
SEE PAGE 30
Pd/Pa = mean hyperemic distal pressure
QCA = quantitative coronary angiography
Tmn = mean transit time
and has been documented to increase susceptibility to myocardial ischemia (2).
PCI = percutaneous coronary intervention
CARDIAC CATHETERIZATION AND HEMODYNAMIC MEASUREMENTS. Cardiac catheterization was per-
formed
according
to
standard
clinical
practice.
One of the factors associated with impairment of
Angiographic images were recorded in a manner
myocardial perfusion at the microvascular level is
suitable for quantitative coronary angiography (QCA)
aging. Understanding the mechanism and magnitude
analysis.
by which aging contributes to microvascular abnor-
equipped guidewires were used to subsequently
malities in patients with IHD is important, among
measure intracoronary pressure and flow. In AMC,
several reasons, because changing demographics
coronary flow was assessed using the Doppler tech-
mean that an increasing number of elderly patients
nique (4), and baseline average peak flow velocity
are being referred for percutaneous coronary inter-
and hyperemic average peak flow velocities average
vention (PCI) (3). Yet our understanding of the influ-
peak flow velocity were labeled baseline and hyper-
ence of aging on the dominant cause of myocardial
emic flow, respectively. In HUCSC, coronary flow was
perfusion impairment, and its impact on therapeutic
assessed with the coronary thermodilution tech-
decisions remains limited. Investigating the specific
nique (5,6). Resting and hyperemic thermodilution
contribution of deranged microvascular function to
curves were obtained in triplicate, and the inverse of
impaired myocardial perfusion is facilitated by recent
the average basal mean transit time and hyperemic
approaches combining invasive pressure and flow
Tmn was labeled baseline and hyperemic flow,
After
diagnostic
angiography,
sensor-
measurements, which allows the selective evaluation
respectively (5,6). In AMC, coronary flow was addi-
of the epicardial coronary artery and coronary
tionally measured in a reference coronary artery,
microvasculature. Accordingly, we studied the asso-
defined as a coronary artery with <30% diameter
ciations of coronary hemodynamics with aging in
stenosis on visual assessment, if available. Hyper-
both stenosed and unobstructed coronary arteries to
emia was induced by either intracoronary bolus
Dr. Echavarria-Pinto was supported by a clinical scholarship from Fundación Interhospitalaria Investigacion Cardiovascular, Madrid, Spain. Drs. van de Hoef, Echavarria-Pinto, and Escaned have served as speakers for St. Jude Medical and Volcano Corporation. Dr. Meuwissen has served as a speaker for Volcano Corporation. Dr. Piek has received consulting and personal fees from Philips/Volcano; and has been an advisory board member for Philips/Volcano. Dr. Stegehuis has reported that she has no relationships relevant to the contents of this paper to disclose. Manuscript received July 17, 2019; revised manuscript received August 23, 2019, accepted August 27, 2019.
22
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Age-Related Microvascular Dysfunction in IHD
injection (20 to 40 m g) of adenosine at AMC, or intravenous infusion of adenosine (140 m g/kg/min) at HUCSC.
T A B L E 1 Baseline Clinical Characteristics of the
Study Population (N ¼ 327)
Age, yrs
PHYSIOLOGICAL PARAMETERS: DERIVATION AND MEANING. From the invasive coronary pressure and
flow recordings, several physiological parameters were calculated. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to baseline flow, where CFR <2.0 was considered the threshold for myocardial ischemia (7). CFR reflects the vasodilator capacity of the coronary circulation, which is affected by abnormalities in both the epicardial coronary artery and microvasculature.
62 (54–69)
Male
242 (75)
Hypertension
159 (49)
Diabetes
57 (17)
Family history
109 (33)
Dyslipidemia
200 (61)
Smoking
94 (29)
Prior myocardial infarction
133 (41)
Prior percutaneous coronary intervention
97 (30)
Multivessel disease
200 (61)
Values are median (interquartile range) or n (%).
The physiological severity of the stenosis was assessed using pressure-only as well as combined flow
expressed in absolute terms or as a percentage, re-
reserve (FFR) was calculated as the ratio of mean
flects the reserve capacity of the coronary microcir-
hyperemic distal pressure (Pd) to mean hyperemic
culation to vasodilate upon an increase in myocardial
aortic pressure (Pa), where FFR >0.80 was considered
demand.
pressure
and
flow
parameters.
Fractional
normal. The Pd/Pa ratio was also determined during nonhyperemic conditions, and was labeled resting
STATISTICAL ANALYSIS. Normality and homogene-
Pd/Pa. The stenosis resistance index was calculated
ity of the variances were tested using Shapiro-Wilk
as the mean pressure drop across the stenosis (mean
and Levene tests. Categorical variables are pre-
Pa mean Pd) divided by Doppler flow velocity.
sented as counts and percentages. Continuous vari-
Stenosis resistance index was calculated both during
ables are presented as mean SD or median (1st and
resting (baseline stenosis resistance index [BSR])
3rd quartiles [Q1, Q3]). Data were analyzed on a per-
(8–10), and hyperemic conditions (hyperemic stenosis
patient basis for clinical characteristics, and on a
resistance index [HSR]) (11,12). The stenosis resis-
per-vessel basis for the rest of the calculations. For
tance index is a stenosis-specific parameter that re-
descriptive statistics, the study population was
flects the resistance to coronary flow induced by the
stratified into 3 representative age categories, defined
stenosis. This parameter has been validated from
by the quartiles of age. Patients within the first
Doppler measurements only and was therefore
quartile were considered “young,” patients across
calculated from Doppler data only.
quartiles 2 and 3 “intermediate,” and patients within
The functional status of the microvasculature was
the fourth quartile “elderly.” For vessel-to-patient
assessed using calculations of microvascular resis-
analyses,
tance during nonhyperemic conditions, as well as
robust standard errors were used to adjust for clus-
robust
regressions
with
Huber-White
during coronary hyperemia. Microvascular resistance
tering of vessels within patients, where appropriate.
was calculated as mean Pd divided by flow and re-
These results are presented as adjusted mean or
flects the resistance to coronary flow induced by the
adjusted frequency with 95% confidence interval.
microvasculature. In the absence of obstructive cor-
Overall differences between groups were compared
onary artery disease, reference vessel microvascular
with 1-way analysis of variance, Kruskal-Wallis or chi-
resistance was calculated as the ratio between mean
square test, followed by post hoc Student’s t-tests,
aortic pressure and distal flow velocity (during base-
Mann-Whitney
line and hyperemia). Microvascular resistance during
Bonferroni-adjusted significance level. The associa-
nonhyperemic conditions is impacted by the magni-
tion of age with physiological parameters was tested
tude of compensatory vasodilation in the microvas-
with robust linear regression analysis, where appli-
culature
coronary
cable. Linear mixed models were used to identify
autoregulation. Microvascular resistance during hy-
independent predictors of FFR and CFR, using Mal-
peremic conditions is impacted for example by
low’s Cp as criterion for selection of the optimal
microvascular remodeling or extravascular compres-
predictive model, with candidate variables including
sion and is a characteristic of the vasodilator function
clinical characteristics (Table 1), clinical presentation,
of the coronary microvasculature. The difference be-
angiographic stenosis severity, and the interrogated
tween nonhyperemic and hyperemic
vessel (left anterior descending, left circumflex, or
and
is
a
characteristic
of
resistance,
U
or
Fisher
exact
tests,
with
van de Hoef et al.
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T A B L E 2 Clinical, Angiographic, and Physiological Characteristics Stratified by Age Categories
Age, yrs <55 (n ¼ 87)
55–69 (n ¼ 166)
$70 (n ¼ 74)
p Value
0.03
Clinical characteristics 69 (80)*
127 (77)
46 (63)†
Hypertension
Male
37 (43)
86 (52)
36 (49)
0.37
Diabetes
13 (15)
35 (21)
9 (12)
0.19 0.04
Family history of cardiovascular disease
35 (40)*
58 (35)
16 (22)†
Dyslipidemia
61 (70)
97 (58)
42 (57)
0.13
34 (39)*‡
47 (28)†
13 (18)†
0.01
Prior myocardial infarction
38 (44)
72 (43)
23 (31)
0.16
Prior PCI
25 (29)
51 (31)
21 (28)
0.91 0.64
Smoking
Multivessel disease Angiographic characteristics
55 (63)
98 (59)
47 (64)
n ¼ 117
n ¼ 207
n ¼ 95
45 (38 to 53)
45 (39 to 52)
54 (45 to 62)
Lesion location LAD
0.58
LCx
21 (15 to 29)
25 (20 to 31)
20 (13 to 29)
RCA
33 (26 to 42)
29 (24 to 36)
26 (19 to 36)
2.9 (2.8 to 3.1)
2.9 (2.8 to 3.0)
3.3 (2.5 to 4.1)
0.53
54 (52 to 56)
53 (52 to 55)
50 (48 to 53)
0.09
0.66
Reference vessel diameter, mm Diameter stenosis, % Pressure measurements Pd/Pa
0.88 (0.86 to 0.91)
0.89 (0.88 to 0.91)
0.89 (0.87 to 0.91)
FFR
0.76 (0.73 to 0.78)*
0.78 (0.76 to 0.80)
0.80 (0.78 to 0.83)†
0.03
Delta Pd/Pa
0.13 (0.11 to 0.14)*
0.12 (0.11 to 0.13)*
0.09 (0.08 to 0.10)†‡
<0.001
85 (75 to 91)*
71 (63 to 77)
57 (44 to 69)†
0.002
CFR, combined
2.4 (2.2 to 2.5)*
2.3 (2.1 to 2.4)*
1.9 (1.8 to 2.1)†,‡
<0.001
CFR, Doppler
2.4 (2.2 to 2.6)*
2.3 (2.2 to 2.4)
2.1 (1.9 to 2.2)†
0.02
CFR, thermodilution
2.2 (1.7 to 2.7)
2.2 (1.9 to 2.4)
1.8 (1.5 to 2.1)
0.13
APV baseline, cm/s
17 (15 to 18)
18 (16 to 19)
18 (15 to 20)
0.72
Intracoronary adenosine Flow measurements
APV hyperemia, cm/s
38 (35 to 42)
39 (36 to 42)
36 (31 to 40)
0.51
Tmn baseline, s
0.74 (0.51 to 0.97)
0.78 (0.67 to 0.89)
0.61 (0.45 to 0.77)
0.25
Tmn hyperemia, s
0.33 (0.27 to 0.40)
0.37 (0.33 to 0.42)
0.34 (0.27 to 0.42)
0.62
BSR, Doppler, mm Hg/cm/s
0.92 (0.62 to 1.21)
0.89 (0.62 to 1.17)
1.02 (0.56 to 1.48)
0.90
HSR, Doppler, mm Hg/cm/s
1.02 (0.72 to 1.31)
1.02 (0.73 to 1.31)
1.14 (0.61 to 1.68)
0.91
0.10 (0.18 to 0.01)
0.12 (0.20 to 0.05)
0.12 (0.26 to 0.01)
0.91
6.10 (5.54 to 6.66)
5.99 (5.54 to 6.44)
6.27 (5.03 to 7.5)
0.89
56 (37 to 75)
63 (54 to 73)
51 (37 to 65)
0.36
2.18 (1.97 to 2.38)
2.27 (2.04 to 2.49)
2.73 (2.23 to 3.23)
0.14
19 (16 to 22)
23 (20 to 26)
23 (18 to 28)
0.17
60 (63 to 57)*
60 (62 to 58)*
52 (56 to 49)†‡
<0.001
Stenosis resistance measurements, Doppler only
Delta SR, Doppler, mm Hg/cm/s Microvascular resistance measurements BMR, Doppler, mm Hg/cm/s BRI, thermodilution, U HMR, Doppler, mm Hg/cm/s IMR, thermodilution, U Change MR, combined, % Reference vessel measurements, Doppler only (n ¼ 172)
n ¼ 54
n ¼ 88
n ¼ 30
CFR, Doppler
3.2 0.6*‡
2.8 0.7†
2.6 0.7†
APV baseline, cm/s
17 (13 to 21)
17 (13 to 22)
16 (13 to 23)
0.72
53 (40 to 68)*
47 (39 to 60)*
39 (34 to 52)†‡
0.005
APV hyperemia, cm/s
<0.001
BMR, Doppler, mm Hg/cm/s
5.75 (4.72 to 7.69)
5.67 (4.5 to 7.47)
5.75 (4.42 to 8.29)
0.92
HMR, Doppler, mm Hg/cm/s
1.89 (1.30 to 2.25)*
1.93 (1.64 to 2.54)*
2.45 (1.95 to 3.08)†‡
0.002
Values are n (%), adjusted mean or adjusted frequency (95% confidence interval), or mean SD. *p < 0.05 vs. elderly. †p < 0.05 vs. young. ‡p < 0.05 vs. intermediate. APV ¼ average peak flow velocity; BMR ¼ basal microvascular resistance index; BRI ¼ basal index of microvascular resistance; BSR ¼ basal stenosis resistance index; CFR ¼ coronary flow reserve; FFR ¼ fractional flow reserve; HMR ¼ hyperemic microvascular resistance index; HSR ¼ hyperemic stenosis resistance index; IMR ¼ hyperemic index of microvascular resistance; LAD ¼ left anterior descending coronary artery; LCx ¼ left circumflex coronary artery; MR ¼ microvascular resistance; PCI ¼ percutaneous coronary intervention; Pd/Pa ¼ resting distal coronary to aortic pressure ratio; RCA ¼ right coronary artery; SR ¼ stenosis resistance index; Tmn ¼ mean transit time.
23
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Age-Related Microvascular Dysfunction in IHD
F I G U R E 1 Scatterplot of Reference Vessel and Target Vessel CFR Values
According to Age
right coronary artery). These results are presented as beta robust SE, and standardized coefficients to facilitate comparison. For reference vessel analysis, where all patients had presented with stable symptoms, candidate variables included clinical characteristics (Table 2), and the interrogated vessel. Differences were considered significant at p < 0.05 (2-sided). The STATA 13.1 (StataCorp, College Station, Texas) statistical software package was used for all calculations.
RESULTS PATIENT POPULATION. In total, 327 patients with
419 stenosed vessels were investigated: 228 patients (299 vessels) with Doppler-derived flow at AMC (enrolled between 1997 and 2006) (13), and 99 patients (120 vessels) with thermodilution-derived flow at HUCSC (enrolled between 2011 and 2015). ReferBoth in unobstructed reference vessels, and stenosed coronary arteries, aging is
ence vessel measurements were performed in 172 of
associated with a decrease in coronary flow reserve (CFR). Black circles and solid black
228 patients (75%) studied with Doppler-derived flow.
line represent target CFR values and the best-fit linear regression, respectively. Open red
Clinical characteristics of the complete study popu-
triangles and dashed red line represent reference vessel CFR values and the best-fit linear regression, respectively.
lation are shown in Table 1. Overall, coronary stenoses were of intermediate severity, both angiographically (mean diameter stenosis 52.7 11.4%) and physiologically (median FFR 0.81 [interquartile range: 0.72 to 0.88]). Moreover, as shown in Online Figure 1, the distribution of FFR values reflected a clinical population routinely referred for intracoronary physio-
F I G U R E 2 Scatterplot of Reference Vessel Baseline and Hyperemic Flow Velocity
Values According to Age
logical assessment in contemporary clinical practice. CLINICAL AND ANGIOGRAPHIC CHARACTERISTICS ACCORDING TO AGE. Median age of the patient
population was 62 years (Q1, Q3: 54 to 69 years). Accordingly,
patients
were
stratified
in
young (<55 years; n ¼ 87 [27%]), intermediate ($55 and <70 years of age; n ¼ 166 [51%]), and elderly ($70 years of age; n ¼ 74 [23%]). Clinical and angiographic characteristics across these age categories are shown in Table 2. Risk factors for IHD were generally less prevalent in elderly patients, who were significantly less likely to be male, less likely to have a family history of IHD, and less likely to smoke (Table 2). There were no differences in epicardial stenosis location or epicardial stenosis severity by QCA across the age categories. INFLUENCE OF AGE ON CORONARY HEMODYNAMICS IN UNOBSTRUCTED REFERENCE VESSELS. In the 172 anWith increasing age, a dominant decrease in reference vessel hyperemic flow occurs,
giographically normal reference coronary arteries in
whereas resting flow does not change with increasing age. Dark blue circles and solid
patients evaluated with Doppler flow velocity, mean
dark blue line represent reference vessel baseline flow velocity values and the best-fit linear regression, respectively. Open red squares and dashed red line represent
CFR was 2.9 0.7. The distribution of reference
reference vessel hyperemic flow velocity values and the best-fit linear regression,
vessel CFR across age is shown in Figure 1. Reference
respectively.
vessel CFR decreased with advancing age, although the absolute effect was modest (rho ¼ 0.31;
van de Hoef et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 1, 2020 JANUARY 13, 2020:20–9
25
Age-Related Microvascular Dysfunction in IHD
p < 0.001; R 2 ¼ 0.07; p < 0.001) (Table 2). This progressive impairment of CFR with advancing age
T A B L E 3 Best-Fit Multivariate Linear Regression Model for the Prediction of
Reference Vessel CFR
occurred in the presence of similarly modest agedependent increase
in hyperemic microvascular
resistance (rho ¼ 0.25; p ¼ 0.002; R
2
¼ 0.06;
p ¼ 0.002) and decrease in hyperemic flow velocity (rho ¼ 0.22; p ¼ 0.006; R 2 ¼ 0.05; p ¼ 0.004) (Figure 2). By contrast, no significant changes in resting
microvascular
resistance
(rho
¼
0.01;
p ¼ 0.93; R 2 ¼ 0.00; p ¼ 0.70) or resting flow velocity (rho ¼ 0.013; p ¼ 0.87; R 2 ¼ 0.00; p ¼ 0.98) (Figure 2)
Age, per yr increase History of dyslipidemia Reference vessel, LAD reference LCx RCA
Beta
SE
Standardized Coefficient
p Value
0.016
0.005
0.25
0.001
0.22
0.105
0.16
0.04
0.0035 0.299
0.111 0.191
0.003 0.12
0.98 0.120
Abbreviations as in Table 2.
were documented with advancing age (Table 2). The best multivariable model for the prediction of CFR in reference vessels (R 2 ¼ 0.11; p < 0.001) included age, history of dyslipidemia, and reference vessel location (Table 3). Among these predictors, age was the strongest independent predictor of CFR in reference vessels.
DETERMINANTS OF CFR AND FFR IN STENOSED VESSELS. The best multivariable model for the pre-
diction of CFR in stenosed vessels (R 2 ¼ 0.11; p < 0.001) included age, prior myocardial infarction, multivessel disease, the interrogated vessel, and percent diameter stenosis (Table 4). Among these
INFLUENCE OF AGE ON MICROVASCULAR FUNCTION IN
predictors, age and diameter stenosis were similarly
STENOSED CORONARY ARTERIES. Mean CFR in the
strong independent predictors of CFR.
stenosed coronary arteries was 2.2 0.8. CFR
The best multivariable model for the prediction of
decreased with advancing age, although the absolute
FFR (R 2 ¼ 0.29; p < 0.001) included age, diabetes
effect was modest (rho ¼ 0.17; p < 0.001; R 2 ¼ 0.03;
mellitus, multivessel disease, the interrogated vessel,
p ¼ 0.001) (Figures 1 and 3). This was also expressed in
and percent diameter stenosis (Table 5). Among
the overall percent change in microvascular resis-
these, diameter stenosis was the strongest indepen-
tance, where the decrease in microvascular resistance
dent predictor for FFR. However, also age was inde-
from resting to hyperemic conditions decreased with
pendently associated with FFR.
advancing age (R2 ¼ 0.03; p ¼ 0.002). Hyperemic microvascular resistance showed a significant albeit modest increase with advancing age in those patients
F I G U R E 3 Scatterplot of FFR and CFR Values in Stenosed Vessels According to Age
studied with Doppler flow (hyperemic microvascular resistance R 2 ¼ 0.02; p ¼ 0.03). Trends in microvascular resistance across the age categories were similar between
Doppler-derived
and
thermodilution-
derived flow, but formal statistical significance was not met in the smaller subcohort of thermodilution measurements (Table 2). INFLUENCE OF AGE ON STENOSIS ASSESSMENT.
Diameter stenosis assessed by QCA was similar across the age categories (Table 2). Resting Pd/Pa was equivalent across the age categories, and no association between resting Pd/Pa and age was documented (R 2 ¼ 0.006; p ¼ 0.08). In patients studied with Doppler flow velocity, stenosis resistance index during resting (BSR) and hyperemic conditions (HSR) were similar across age categories (Table 2), and no association with age was documented (BSR R 2 < 0.001; p ¼ 0.59; HSR R 2 < 0.001; p ¼ 0.72). By contrast, FFR was significantly different across the age
categories
(Table
2),
and
increased
with
advancing age (R 2 ¼ 0.03; p < 0.001) (Table 2, Figure 3).
With advancing age, fractional flow reserve (FFR) increases, whereas coronary flow reserve (CFR) decreases. These characteristics occurred while no other index of stenosis severity was associated with age. Closed dots and dashed line represent FFR values and the best-fit linear regression, respectively. Open dots and dashed line represent target vessel CFR and the best-fit linear regression, respectively.
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Age-Related Microvascular Dysfunction in IHD
T A B L E 4 Best-Fit Multivariate Linear Regression Model for the Prediction of CFR in
Stenosed Vessels
disease, and its impact on the physiological assessment of epicardial coronary artery stenosis. Microvascular function becomes increasingly impaired
Beta
Robust SE
Standardized Coefficient
Age, per yr increase
0.015
0.004
0.20
<0.001
Prior myocardial infarction
0.216
0.078
0.13
0.006
0.253
0.080
0.14
0.002
Diameter stenosis
0.014
0.003
0.19
<0.001
Lesion location, LAD reference LCx RCA
0.287 0.097
0.098 0.093
0.14 0.05
0.003 0.301
Multivessel disease
p Value
with aging of the coronary circulation due to an increase in minimal microvascular resistance during hyperemia, leading to an impairment of maximal coronary flow and CFR. This phenomenon occurs similarly in nonobstructed and obstructed coronary arteries, and, due to this phenomenon, the pathophysiological substrate of ischemic heart disease changes substantially with increasing age. Whereas epicardial coronary disease severity was equivalent
Abbreviations as in Table 2.
across age groups at the time of presentation, concomitant microvascular dysfunction was increas-
EFFECT OF AGE ON THE CFR AND FFR RELATIONSHIP.
Age was significantly different across the quadrants of the CFR and FFR relationship (Table 6). Vessels with low FFR and high CFR were more likely observed in younger patients, whereas vessels with high FFR and low CFR were more likely observed in elderly
ingly prevalent with advancing age. These findings are of distinct importance, considering the drastic changes
in
demographics
globally,
where
an
increasing number of elderly patients are referred to the coronary catheterization laboratory with chest pain syndromes.
patients. The Central Illustration shows the distribu-
AGING, CFR, AND FFR. Advancing age was associated
tion of FFR and CFR accordance and discordance
with a decrease in CFR, on the basis of an impairment
across decades. After adjustment for independent
of microvascular vasodilator function leading to a
predictors of FFR and CFR (Tables 4 and 5), there was
pathological
a 1.6-fold increase in risk of an FFR/CFR pattern
resistance. Microvascular resistance in nonhyperemic
reflective of focal stenosis superimposed on diffuse or
conditions did not change with increasing age. This
microvascular disease (high FFR, low CFR) (95%
agrees with previous studies documenting a decrease
confidence interval: 1.1 to 2.3; p ¼ 0.017) with each
in CFR with advancing age in unobstructed coronary
decade increase in age, whereas there was a decrease
arteries (14) and adds that the origin of CFR impair-
in risk of an FFR/CFR pattern reflective of focal non–
ment lies in an increase in minimal microvas-
flow-limiting stenosis with a healthy microcirculation
cular resistance.
increase
in
minimal
microvascular
(low FFR, high CFR) (relative risk: 0.7 per decade in-
The impairment in CFR with advancing age was
crease in age; 95% confidence interval: 0.5 to
associated with a significant, albeit modest, increase
1.0; p ¼ 0.022).
in FFR. This increase in FFR was in contrast with all other parameters of stenosis severity, such as diameter stenosis, resting Pd/Pa, and stenosis resistance
DISCUSSION
index, all of which were not affected by aging. From a
We describe the origin of age-related microvascular dysfunction in the pathophysiology of ischemic heart
clinical perspective, these findings suggest that the detection of stenosis-induced myocardial ischemia with FFR may decrease with aging, whereas the actual hemodynamic stenosis severity is the same
T A B L E 5 Best-Fit Multivariate Linear Regression Model for the Prediction of FFR
Standardized Coefficient
p Value
Beta
Robust SE
Age, per yr increase
0.002
0.001
0.11
0.007
Diabetes
0.033
0.015
0.08
0.029
Multivessel disease
0.034
0.014
0.11
0.018
0.007
0.001
0.50
<0.001
0.046 0.029
0.017 0.015
0.12 0.09
0.006 0.056
Diameter stenosis Lesion location, LAD reference LCx RCA Abbreviations as in Table 2.
across ages, and the overall burden of ischemia as diagnosed with CFR even increases with advancing age. Our findings are suggestive of an increase in ischemia burden with advancing age despite equivalent stenosis severity concur with previous data showing an increase in exercise-related myocardial ischemia on noninvasive stress testing associated with aging despite equivalent extent of angiographic epicardial coronary artery disease (15). CLINICAL IMPLICATIONS. This study is not the first
to report an increase in FFR values with advancing age, which has until now been attributed to a lower
van de Hoef et al.
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Age-Related Microvascular Dysfunction in IHD
T A B L E 6 Accordance and Discordance of FFR and CFR Across Age Categories
Age, yrs <55 (n ¼ 87)
55–69 (n ¼ 166)
$70 (n ¼ 74)
FFR >0.80/CFR $2.0, concordantly normal
33 (26–42)
42 (35–48)
32 (23–42)
0.15
FFR #0.80/CFR $2.0, focal non-flow limiting
28 (20–38)
22 (17–28)
15 (9–23)
0.08
Pressure/Flow Discordance
Overall p Value
FFR >0.80/CFR <2.0, diffuse/microvascular disease
8 (4–14)*
12 (8–17)*
26 (18–36)†‡
<0.001
FFR #0.80/CFR <2.0, concordantly abnormal
31 (23–40)
24 (19–30)
27 (19–38)
0.42
Values are adjusted n or % (95% confidence interval). *p < 0.05 vs. old. †p < 0.05 vs. intermediate. ‡p < 0.05 vs. young. Abbreviations as in Table 2.
prevalence of functionally significant coronary artery
that could actually benefit from stenosis alleviation
disease at older age (16–18). However, our study is the
despite relatively normal FFR values. The upcoming
first to describe the physiological basis of this finding.
multicenter DEFINE-FLOW (Distal Evaluation of
Whereas both nonhyperemic pressure measurements
Functional Performance With Intravascular Sensors
(Pd/Pa),
combined
to Assess the Narrowing Effect – Combined Pressure
pressure-flow indices such as BSR and HSR, docu-
and Doppler FLOW Velocity Measurements) study
ment that the hemodynamic significance of epicardial
may further inform the appropriate management of
stenosis is equivalent across age groups, FFR pro-
patients using combined pressure-flow measure-
gressively underestimates the hemodynamic impact
ments, and provide further insight into the impact of
of the stenosis. This is due to age-related progressive
aging on FFR-CFR results and on patient prognosis.
increase in minimal microvascular resistance leading
By collecting detailed invasive physiology data, this
to a decrease in hyperemic flow, and thus higher FFR
study may further allow more insight into the prog-
values, for the exact same stenosis. Because the
nostic impact of stenosis-specific physiology tools.
as
well
as
stenosis-specific
intrinsic hemodynamic relevance of the stenosis is the same, it seems difficult to argue that elderly patients would benefit less from epicardial revascularization than younger patients with the exact same
C E NT R AL IL L U ST R AT IO N Prevalence of FFR/CFR Accordance and Discordance per Decade Increase in Age
epicardial disease. Because the myocardium thrives
100
on coronary flow, and because flow reserve is a critical determinant of myocardial ischemia (7,19), the
80
age-related microvascular dysfunction may increase the susceptibility for myocardial ischemia due to developing epicardial disease (14). This is supported by previous data documenting an increase in the
Percent
age-related decrease in flow reserve suggests that
60 40
occurrence of myocardial ischemia on noninvasive stress testing with higher minimal microvascular
20
resistance despite equivalent epicardial stenosis severity (2). As such, a normal FFR does not exclude the presence of clinically relevant coronary flow impairment, which is well-documented to be associated with myocardial ischemia (7), and is unequivocally related to impaired prognosis (20,21). Physicians should be aware that, despite the fact that revascularization is currently not supported in these vessels, these anomalies might be a cause of ischemia and
0
<50
50-59
60-69 Age
70-79
≥80
Microvascular / Diffuse Disease (FFR >0.80 / CFR <2.0) Concordantly Normal (FFR >0.80 / CFR ≥2.0) Concordantly Abnormal (FFR ≤0.80 / CFR <2.0) Focal Non-Flow Limiting (FFR ≤0.80 / CFR ≥2.0) van de Hoef, T.P. et al. J Am Coll Cardiol Intv. 2020;13(1):20–9.
thereby justify the clinical presentation, and have important implications for patient prognosis. Further research should focus on the hypothesis
With each decade, the prevalence of a fractional flow reserve (FFR)/coronary flow reserve (CFR) pattern reflective of microvascular and/or diffuse disease increased,
that assessment of physiological stenosis severity
whereas the prevalence of an FFR/CFR pattern reflective of a normal circulation or focal
with stenosis-specific tools, such as indices of steno-
stenosis superimposed on a healthy coronary microcirculation tended to decrease.
sis resistance, might be indicated to identify patients
27
28
van de Hoef et al.
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Age-Related Microvascular Dysfunction in IHD
Our current data suggest that nonhyperemic coro-
ACKNOWLEDGMENTS The authors gratefully acknowl-
nary pressure measurements are also unaffected by
edge the nursing staff of the cardiac catheterization
age-related alterations in microvascular vasodilator
laboratories
function and may provide a practical solution to
Amsterdam, the Netherlands, and Hospital Clínico
optimize lesion selection for PCI. Furthermore, the
San Carlos, Madrid, Spain, for their skilled assistance
optimal CFR threshold for identification of clinically
in acquiring the data.
at
the
Academic
Medical
Center,
relevant perfusion impairment, and the impact of PCI on improvement of coronary hemodynamics in the
ADDRESS FOR CORRESPONDENCE: Dr. Tim P. van de
setting of impaired CFR with borderline significant
Hoef, Academic Medical Center, AMC Heartcenter,
epicardial disease remain ill-described and should be
Room B2-213, Meibergdreef 9, 1105 AZ, Amsterdam, the
subject to further evaluation.
Netherlands. E-mail: [email protected].
STUDY LIMITATIONS. Our conclusions refer to pa-
tients with clinical indication for intracoronary interrogation of an epicardial stenosis. Intracoronary
PERSPECTIVES
flow was assessed with both the Doppler and thermodilution technique: the 2 available methods for findings
WHAT IS KNOWN? Concomitant microvascular
were
disease may importantly affect treatment decisions
consistent between technologies, which strengthens
regarding epicardial revascularization and has been
the extrapolation of our findings to the clinical
documented to increase susceptibility to myocardial
setting. Additionally, different administration routes
ischemia. Aging is associated with impaired micro-
and doses of adenosine were used to induce hyper-
vascular function, but our understanding of the in-
emia. Although this limits the internal validity of our
fluence of aging remains limited.
this
purpose.
Nonetheless,
most
findings, it enhances their generalization, because this better reflects real-world use of hyperemic
WHAT IS NEW? Microvascular function becomes
agents. Finally, noninvasive assessment of myocar-
increasingly impaired with aging of the coronary cir-
dial ischemia was not routinely performed in these
culation due to an increase in minimal microvascular
patients, precluding more definitive conclusions
resistance during hyperemia, leading to an impairment
regarding the presence of myocardial ischemia.
of maximal coronary flow and coronary flow reserve. This phenomenon occurs similarly in nonobstructed and obstructed coronary arteries, and, due to this
CONCLUSIONS
phenomenon, the pathophysiological substrate of
Aging is associated with a progressive pan-myocardial increase in minimal microvascular resistance, which leads to an impairment of coronary vasodilatory reserve. In patients with ischemic heart disease, such aging-related impairment in microvascular function importantly contributes to the pathophysiology of ischemic heart disease. This multilevel involvement of the coronary circulation has pertinent diagnostic and
prognostic
consequences
but
cannot
be
adequately identified by hyperemic coronary pres-
ischemic heart disease changes substantially with increasing age. WHAT IS NEXT? Further research should focus on the hypothesis that assessment of physiological stenosis severity with stenosis-specific tools, such as indices of stenosis resistance, might be indicated to identify patients that could actually benefit from stenosis alleviation despite relatively normal FFR values.
sure measurements alone.
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KEY WORDS aging, coronary flow reserve, coronary microvascular function, coronary physiology, fractional flow reserve, physiological stenosis severity
A PP END IX For a supplemental figure, please see the online version of this paper.
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