If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Cardiac syndrome X (CSX) patients have impaired coronary flow velocity reserve (CFVR).
•
Left ventricular global longitudinal strain (LVGLS) values are reduced at rest and during exercise in CSX patients.
•
CFVR and LVGLS are more profoundly impaired in CSX subgroup with slow coronary flow (SCF).
•
Presence of SCF in CSX patients also reflects worse clinical presentation.
•
Findings might contribute to further risk stratification of this population.
Abstract
Background
Microvascular dysfunction (MVD) is associated with adverse prognosis and may account for abnormal stress tests and angina symptoms in women with cardiac syndrome X (CSX). The aim of our study was to assess MVD by coronary flow velocity reserve (CFVR) and left ventricular (LV) contractile function by LV global longitudinal strain (LVGLS) in CSX patients with respect to presence of slow coronary flow (SCF). It was of additional importance to evaluate clinical status of CSX patients using Seattle Angina Questionnaire.
Methods and results
Study population included 70 women with CSX (mean age 61 ± 7 years) and 34 age-matched controls. CSX group was stratified into two subgroups depending on SCF presence: CSX-Thrombolysis In Myocardial Infarction (TIMI) 3- normal flow subgroup (n = 38) and CSX-TIMI 2- SCF subgroup (n = 32) as defined by coronary angiography. LVGLS measurements and CFVR of left anterior descending (LAD) and posterior descending (PD) artery were performed. CFVR-LAD and PD were markedly impaired in CSX group compared to controls (2.34 ± 0.25 vs 3.05 ± 0.21, p < 0.001; 2.32 ± 0.24 vs 3.01 ± 0.13, p < 0.001), and furthermore decreased in CSX-TIMI 2 patients. Resting, peak, and ΔLVGLS were all significantly impaired in CSX group compared to controls (for all p < 0.001), and furthermore reduced in CSX-TIMI 2 subgroup. Strongest correlation was found between peak LVGLS and CFVR LAD (r = −0.784, p < 0.001) and PD (r = −0.772, p < 0.001). CSX-TIMI 2 subgroup had more frequent angina symptoms and more impaired quality of life.
Conclusions
MVD in CSX patients is demonstrated by reduction in CFVR and LVGLS values. SCF implies more profound impairment of microvascular and LV systolic function along with worse clinical presentation.
Patients with chest pain and normal coronary arteries represent a nonhomogeneous population. Cardiac syndrome X (CSX) is defined by angina-like chest pain, ST segment depression during exercise, and normal coronary arteries found mostly in post-menopausal women [
]. Although our understanding of this clinical entity remains incomplete, CSX is pathophysiologically linked to microvascular dysfunction (MVD) which is the result of anatomic and functional abnormalities of coronary microcirculation [
]. Another phenomenon, slow coronary flow (SCF), is characterized by delayed opacification of coronary arteries in the absence of an obstructive coronary disease [
]. Both CSX and SCF share the primary abnormality of microvascular function as the most important underlying mechanism, and clinically fall under the framework of microvascular angina [
Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the women’s ischemia syndrome evaluation study and the St James Women take Heart Project.
]. It also accounts for angina symptoms and abnormal stress tests (electrocardiographically positive, while negative by wall motion criteria) in this population [
In everyday clinical practice, MVD can be reliably assessed by coronary flow velocity reserve (CFVR) acquired with transthoracic Doppler echocardiography (TDE) which has been proven to be an efficacious, versatile, and reproducible non-invasive method [
N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.
Time-dependent changes of plasma adiponectin concentration in relation to coronary microcirculatory function in patients with acute myocardial infarction treated by primary percutaneous coronary intervention.
N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.
Time-dependent changes of plasma adiponectin concentration in relation to coronary microcirculatory function in patients with acute myocardial infarction treated by primary percutaneous coronary intervention.
On the other hand, potential subtle impairments of left ventricular (LV) contractility caused by MVD in CSX are more difficult to assess by conventional echocardiography compared to evident wall motion abnormalities present in patients with obstructive coronary artery disease (CAD) [
]. LV longitudinal function is particularly susceptible to the effects of myocardial ischemia and as such is considered an early marker of subclinical systolic dysfunction [
Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.
]. Furthermore, LVGLS exercise parameters as additional measures of myocardial deformation capacity should give greater insight into the LV systolic function [
Evaluation of CSX patients in regard to the presence of SCF and potential subtle changes in myocardial systolic function have not been investigated to date. We have hypothesized that patients with CSX and SCF will have greater impairment of CFVR and LV longitudinal function as assessed by TDE CFVR and LVGLS, respectively. Therefore, the aim of our study was to assess MVD by TDE CFVR, and LV contractile function by LVGLS in CSX patients with respect to presence of SCF. It was of additional importance to evaluate clinical status of CSX patients using the Seattle Angina Questionnaire (SAQ).
Methods
Study population
The initial study population included 124 patients. Seven patients had to be excluded from further analysis because of the poor acoustic window preventing reliable calculation of LVGLS at rest (2 patients) and during exercise (5 patients), while CFVR measurement was inadequate in 11 patients. One patient was excluded because of atrial fibrillation, while another one had left bundle branch block. Thus, the final study population consisted of 104 patients, 70 postmenopausal women with CSX (mean age 61 ± 7 years) and 34 age-matched controls (mean age 59 ± 7 years). All the women were recruited at the Cardiology Clinic, Clinical Center of Serbia, Belgrade.
CSX diagnosis was based upon a history of angina like chest pain, stress echocardiography (SE) tests positive by electrocardiographic while negative by wall motion criteria, and angiographically normal coronary arteries (<20% coronary stenosis) [
]. The decision to perform coronary angiography in the face of a negative SE test was taken on the basis of clinical status. The control group included healthy, asymptomatic women with low pretest probability (<5%) for CAD [
The exclusion criteria for this study were: presence of epicardial stenosis and severe coronary tortuosity, myocardial bridging, cardiomyopathies, significant LV hypertrophy, moderate to severe valvular disease, previous myocardial infarction and revascularization procedures, hypo- or hyperthyroidism, second-degree atrio-ventricular block, ejection fraction <55%, permanent atrial fibrillation, bundle branch block, and chronic obstructive pulmonary disease.
The study was approved by the institutional ethical committee and written informed consent was obtained from all participants involved.
Study protocol
Echocardiographic examination, SE test, LVGLS, and CFVR measurements were performed in all 104 women. Left heart catheterization was performed for the whole CSX group, while none of the controls had undergone coronary angiography because of ethical reasons.
Coronary angiography and thrombolysis in myocardial infarction flow
Coronary angiographies were performed by radial approach in multiple views according to standard technique. Coronary flow was assessed by two experienced interventional cardiologists (B.B., D.O.) based on Thrombolysis In Myocardial Infarction (TIMI) flow grade classification which reflects the speed and completeness of contrast progression into the coronary tree. TIMI-2 flow was defined as delayed contrast progression requiring 3 or more heart beats to opacify the distal part of the vessel [
Thrombolysis in myocardial infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.
Standard transthoracic echocardiographic and SE studies were performed using commercially available GE Healthcare Vivid E9 cardiovascular ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway) equipped with a 1.3–4.0 Mhz transducer (GE Vivid M5S probe, GE Healthcare). All conventional echocardiographic views, two-dimensional, M-mode, and Doppler measurements were obtained according to recent guidelines [
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
]. LV and atrial volumes, as well as the ejection fraction were assessed using the modified Simpson’s biplane method. Left atrial volume was indexed for body surface area (LAVI) [
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
]. Pulsed-wave Doppler with the sample volume placed at the mitral leaflet tips was used for early (E) and late (A) diastolic peak velocity measurements. Deceleration time and E/A ratio were calculated as well. Tissue Doppler imaging was used in order to obtain early (e’) and late (a’) diastolic peak mitral annular velocities, as well as isovolumetric relaxation time (IVRT). Ratio of early transmitral flow velocity to early diastolic mitral annular velocity (E/e’) has been calculated as an indirect estimate of LV filling pressure [
N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.
CFVR was performed using the Acuson Sequoia C 256 (Siemens Medical Solutions, Mountain View, CA, USA) with 4-MHz transducer, within two weeks after the coronary angiography. With the patient positioned in the left lateral decubitus, coronary flow was searched for in the mid/distal portion of the left anterior descending (LAD) coronary artery with the transducer placed at the cardiac apex or 1 intercostal space higher in order to obtain modified, three-chamber view. Evaluation of posterior descending (PD) coronary artery flow was done in the apical two-chamber view. Probe position was adjusted to align the ultrasound beam as parallel as possible to the direction of the flow. Color Doppler imaging was performed by decreasing the Nyquist limit to 16−24 cm/s. With a sample volume 3–5 mm wide and positioned on the LAD or PD color flow signal in diastole, pulsed Doppler tracings of peak flow velocities were recorded. After acquiring Doppler tracings in baseline conditions, under continuous electrocardiographic and echocardiographic monitoring, adenosine 140 µg/kg/min was administrated over 2 min and peak diastolic coronary flow velocities were obtained during maximal hyperemia. Three optimal flow profiles at rest and during hyperemia were obtained, and results were averaged. CFVR was calculated as the ratio of hyperemic to baseline diastolic flow velocities, and was considered preserved if it was >2 [
N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.
Prognostic value of preserved coronary flow velocity reserve by noninvasive transthoracic Doppler echocardiography in patients with angiographically intermediate left main stenosis.
]. CFVR measurements were read by two experts independently, who were blinded to other patients’ data. Theophylline and caffeine-containing products were withheld for at least 12 h before the tests. We have recently reported interobserver agreement for CFVR evaluation of 96% [
Prognostic value of preserved coronary flow velocity reserve by noninvasive transthoracic Doppler echocardiography in patients with angiographically intermediate left main stenosis.
], while feasibility to obtain adequate CFVR for LAD was 97.4% and for PD was 90.4%.
Stress echocardiography
All patients underwent maximal symptom limited SE test under Bruce treadmill protocol. Electrocardiogram (ECG) and blood pressure were continuously monitored. ECG tracing was considered positive for myocardial ischemia in the presence of horizontal or down-sloping ST‐segment depression ≥1.0 mm recorded 80 msec after the J‐point for 3 consecutive beats [
]. In order to evaluate LV wall motion abnormalities, standard apical views were acquired at rest and imminently after peak exercise.
Global longitudinal strain by 2D speckle tracking method
Two-dimensional images of LV apical views at rest and peak exercise were acquired at 60–90 frames/second, and stored for off-line analysis. LVGLS was measured using the commercial software for speckle tracking analysis (GE Echo PAC v.112, GE Healthcare). Before the tracking, opening and closing characteristics of the aortic valve were defined by the event timing function. LV endocardial border was traced in all three apical views, and automatically generated region of interest was manually adjusted until tracking was considered optimal. Subsequently, deformation parameters were generated for all accepted LV segments. LVGLS was calculated and expressed as an average of all analyzed segmental strain values. Strain values were reported in absolute numbers. Calculation of LVGLS was software generated for a 17-segment model. According to recent recommendations, segments with unacceptably poor tracking quality were excluded from further analysis [
Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.
]. LV contractile reserve parameters were calculated as an absolute increase in LVGLS (ΔLVGLS) and in LVEF (ΔLVEF) from rest to peak exercise.
We have assessed reproducibility of LVGLS measurements by randomly selecting 20 examinations. While unaware of the primary LVGLS analysis results, two investigators (I.J. and A.D.D.) reviewed the acquisitions initially selected to evaluate intra- and inter-observer variability which were calculated by using intraclass correlation coefficients. Results of the analysis were as follows: intra-observer intraclass correlation coefficient of LVGLS at rest and peak exercise was 0.95 [95% confidence interval (CI) 0.86–0.98] and 0.93 (95% CI 0.84–0.97); both p < 0.001 respectively, while inter-observer intraclass correlation coefficient of LVGLS at rest and peak exercise was 0.92 (95% CI 0.80–0.97) and 0.91 (95% CI 0.78–0.97); both p < 0.001, respectively.
Seattle Angina Questionnaire
Symptom burden in the CSX group was evaluated by using SAQ, which is a self-administered, 19-item questionnaire that assesses five dimensions of functional status - physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life [
All data were entered into the database and then processed in the statistical program SPSS 21 (SPSS, Chicago, IL, USA). All numeric data were expressed as mean ± standard deviation (SD), and attributed as frequencies or percentages. Differences in continuous variables were assessed with Student’s t-test. Categorical data were expressed as percentages and compared using the chi-square test or Fisher exact test, as appropriate. Statistical correlation between echocardiographic variables was examined with Pearson’s linear correlation coefficient. Intra-observer and inter-observer reproducibility of LVGLS were assessed using the intraclass correlation coefficient. Statistical significance was defined as p < 0.05.
Results
Baseline clinical characteristics of patients with CSX and the control group are presented in Table 1. As previously noted, out of 104 women enrolled in this study, 70 women represented the CSX group, while 34 women represented age- and body surface area (BSA)-matched controls. The CSX group was further divided into two subgroups depending on the presence of SCF: group with normal flow was named CSX-TIMI 3 (n = 38), while the group with SCF was named CSX-TIMI 2 (n = 32). There were no significant differences regarding the presence of cardiovascular risk factors, nor the baseline hemodynamic parameters among the study groups. Concerning the medical treatment, use of trimetazidine was far more frequent in the CSX group, which is in line with angina symptoms being present in this group opposite to controls.
Table 1Clinical characteristics of patients and controls.
Variables
Controls
CSX
p-value
CSX
p-value
(n = 34)
(n = 70)
CSX vs. Controls
TIMI 2 (n = 32)
TIMI 3 (n = 38)
TIMI 2 vs. TIMI 3
Age – years
59 ± 7
61 ± 7
0.282
60 ± 6
62 ± 7
0.237
BSA – m2
1.79 ± 0.18
1.80 ± 0.14
0.796
1.81 ± 0.15
1.78 ± 0.13
0.269
Current smoker - no. (%)
14 (41)
29 (41)
0.980
14 (44)
15 (39)
0.717
Hypertension – no. (%)
26 (76)
62 (88)
0.109
29 (91)
33 (87)
0.620
Diabetes mellitus – no. (%)
3 (9)
9 (13)
0.546
6 (19)
3 (8)
0.283
Hypercholesterolemia – no. (%)
21 (62)
54 (77)
0.101
27 (84)
27 (71)
0.186
Family history of CAD – no. (%)
20 (59)
39 (58)
0.764
16 (50)
23 (60)
0.377
Medical therapy – no. (%)
Beta blockers
17 (50)
55 (79)
0.003
27 (84)
28 (74)
0.278
ACE inhibitor
16 (47)
39 (56)
0.407
16 (50)
23 (60)
0.377
Angiotensin receptor blocker
2 (6)
6 (8)
0.629
5 (16)
1 (3)
0.086
Calcium-channel blocker
10 (29)
25 (36)
0.523
10 (31)
15 (39)
0.474
Statin
16 (47)
45 (64)
0.094
22 (69)
23 (60)
0.474
Long-acting nitrates
0 (0)
5 (7)
0.170
2 (6)
3 (8)
0.790
Diuretic
9 (26)
39 (56)
0.005
18 (56)
21 (55)
0.934
Trimetazidine
0 (0)
33 (47)
<0.001
15 (47)
18 (47)
0.967
Diastolic blood pressure – mmHg
77 ± 6
77 ± 7
0.914
77 ± 8
77 ± 7
0.906
Systolic blood pressure – mmHg
124 ± 9
123 ± 13
0.499
122 ± 15
123 ± 10
0.923
Baseline heart rate – beats/min
68 ± 7
67 ± 8
0.796
68 ± 8
67 ± 8
0.672
Plus–minus values are means ± SD.
BSA, body surface area; CAD, coronary artery disease; CSX, cardiac syndrome X; ACE, angiotensin-converting enzyme; TIMI, Thrombolysis In Myocardial Infarction.
Resting echocardiographic parameters of CSX and the control group are summarized in Table 2. LV mass indexed to BSA was normal for both groups, without signs of LV hypertrophy. LAVI was larger in CSX group compared to controls. There were no significant differences in echocardiographic parameters between the two CSX subgroups. All the women included in the study had normal LVEFs, without a difference between CSX and controls.
Table 2Echocardiographic, CFVR, and LVGLS values for CSX group and controls.
Variables
Controls
CSX
p-value
CSX
p-value
(n = 34)
(n = 70)
CSX vs. Controls
TIMI 2 (n = 32)
TIMI 3 (n = 38)
TIMI 2 vs. TIMI 3
LV end-diastolic dimension- mm
46 ± 5
48 ± 5
0.316
48 ± 6
47 ± 3
0.454
LV end-systolic dimension - mm
29 ± 3
30 ± 4
0.130
30 ± 5
29 ± 3
0.281
Cardiac index - L/min/m2
2.7 ± 0.7
2.7 ± 0.6
0.690
2.7 ± 0.7
2.6 ± 0.5
0.493
Left atrial dimension - mm
34 ± 3
36 ± 4
0.005
36 ± 5
36 ± 3
0.469
Left atrial volume/BSA - ml/m2
24 ± 6
28 ± 7
0.016
28 ± 6
27 ± 8
0.636
LAVI > 34 ml/m2 – no. (%)
4 (12)
12 (17)
0.476
5 (16)
7 (18)
0.600
LV mass/BSA - gr/m2
71 ± 16
77 ± 17
0.065
81 ± 20
74 ± 13
0.123
E wave - m/s
0.69 ± 0.1
0.57 ± 0.1
<0.001
0.57 ± 0.13
0.57 ± 0.14
0.972
A wave - m/s
0.70 ± 0.2
0.66 ± 0.2
0.332
0.66 ± 0.20
0.66 ± 0.13
0.924
E/A
1.0 ± 0.3
0.90 ± 0.3
0.022
0.93 ± 0.33
0.88 ± 0.27
0.503
E deceleration time - msec
186 ± 27
218 ± 40
<0.001
225 ± 38
212 ± 42
0.165
Mitral lateral annular e’ - m/s
0.106 ± 0.026
0.084 ± 0.021
<0.001
0.084 ± 0.023
0.085 ± 0.020
0.867
Mitral lateral annular a’ - m/s
0.107 ± 0.023
0.115 ± 0.098
0.644
0.127 ± 0.144
0.105 ± 0.023
0.371
Mitral lateral annular IVRT - msec
71 ± 12
84 ± 16
<0.001
85 ± 16
84 ± 16
0.880
E/e’ lateral
6.80 ± 1.51
6.96 ± 2.04
0.694
7.14 ± 2.45
6.80 ± 1.63
0.479
Mitral septal annular e’ - m/s
0.084 ± 0.020
0.064 ± 0.014
<0.001
0.063 ± 0.013
0.064 ± 0.015
0.634
Mitral septal annular a’ - m/s
0.099 ± 0.019
0.105 ± 0.098
0.730
0.117 ± 0.144
0.095 ± 0.018
0.344
Mitral septal annular IVRT - msec
68 ± 11
85 ± 17
<0.001
85 ± 15
85 ± 18
0.500
E/e’septal
8.5 ± 2.0
9.1 ± 2.2
0.191
9.2 ± 2.4
9.0 ± 2.1
0.679
E/e’ mean value
7.7 ± 1.7
8.0 ± 2.0
0.341
8.2 ± 2.3
7.9 ± 1.7
0.524
Baseline diastolic flow velocity (m/sec)- LAD
0.25 ± 0.04
0.29 ± 0.06
<0.001
0.30 ± 0.08
0.28 ± 0.04
0.077
Hyperemic diastolic flow velocity (m/sec)-LAD
0.76 ± 0.14
0.68 ± 0.13
0.003
0.65 ± 0.16
0.70 ± 0.11
0.125
CFVR LAD
3.05 ± 0.21
2.34 ± 0.25
<0.001
2.14 ± 0.19
2.50 ± 0.17
<0.001
Baseline diastolic flow velocity (m/sec) – PD
0.25 ± 0.03
0.29 ± 0.04
<0.001
0.30 ± 0.05
0.28 ± 0.03
0.038
Hyperemic diastolic flow velocity (m/sec) – PD
0.75 ± 0.10
0.66 ± 0.09
<0.001
0.64 ± 0.11
0.68 ± 0.08
0.068
CFVR PD
3.01 ± 0.13
2.32 ± 0.24
<0.001
2.13 ± 0.19
2.46 ± 0.16
<0.001
LVEF at rest- %
68.5 ± 4.2
66.8 ± 5.4
0.129
66 ± 5.7
67.5 ± 5.2
0.244
LVEF at peak exercise- %
71.7 ± 2.9
69.4 ± 3.4
0.068
69.2 ± 3.9
69.6 ± 3.2
0.815
Δ LVEF
2.93 ± 1.2
2.86 ± 1.3
0.875
2.8 ± 1.6
2.9 ± 1.2
0.957
LVGLS at rest - %
−23.2 ± 1.2
−19.6 ± 2.2
<0.001
−18.0 ± 1.7
−20.8 ± 1.7
<0.001
Peak LVGLS - %
−28.4 ± 1.3
−23.3 ± 2.8
<0.001
−20.9 ± 1.8
−25.3 ± 1.9
<0.001
Δ LVGLS
5.2 ± 0.8
3.8 ± 1.4
<0.001
2.9 ± 1.1
4.5 ± 1.2
<0.001
Angina during exercise - no. (%)
0 (0)
27 (39)
<0.001
22 (69)
5 (13)
<0.001
Plus–minus values are means ± SD.
CSX, cardiac syndrome X; TIMI, Thrombolysis In Myocardial Infarction; LVEF, left ventricular ejection fraction; BSA, body surface area; LAVI, left atrial volume index; IVRT, isovolumetric relaxation time; CFVR, coronary flow velocity reserve; LAD, left anterior descending artery; PD, posterior descending coronary artery; LVGLS, left ventricular global longitudinal strain.
In the CSX group E wave velocities and E/A ratio were decreased while deceleration time was longer. Furthermore, both lateral and septal mitral annular e’ velocities were significantly reduced, while IVRTs were longer in the CSX group compared to controls. Difference in mean E/e’ ratio did not reach the level of statistical significance between the groups.
CFVR and LVGLS parameters at rest and peak exercise
Peak diastolic flow velocities obtained at baseline and maximal hyperemia are summarized in Table 2. Baseline velocities both for LAD and PD were significantly higher in the CSX group. CFVR LAD (2.34 ± 0.25 vs 3.05 ± 0.21, p < 0.001) and PD (2.32 ± 0.24 vs 3.01 ± 0.13, p < 0.001) were markedly impaired in the CSX group compared to controls. Further subgroup analysis showed that CFVR LAD (2.14 ± 0.19 vs 2.50 ± 0.17, p < 0.001) and PD (2.13 ± 0.19 vs 2.46 ± 0.16, p < 0.001) were significantly more decreased in CSX-TIMI 2 compared to CSX-TIMI 3 patients.
LVGLS values at rest and peak exercise are presented in Table 2. The present study showed that even resting LVGLS values were significantly impaired in the CSX group compared to controls (−19.6 ± 2.2 vs −23.2 ± 1.2, p < 0.001). Further subgroup analysis revealed that LVGLS values were markedly lower in CSX-TIMI 2 compared to CSX-TIMI 3 patients (−18.0±1.7 vs −20.8 ± 1.7, p < 0.001). At peak exercise, LVGLS increased significantly more in controls compared to CSX group (−28.4 ± 1.3 vs −23.3 ± 2.8, p < 0.001), and in subgroup analysis peak LVGLS was higher in CSX-TIMI 3 patients (−25.3 ± 1.9 vs −20.9 ± 1.8, p < 0.001).
Regarding LV contractile reserve, LVEF did not considerably change at peak exercise, nor was ΔLVEF significantly different between analyzed groups and subgroups. Conversely, ΔLVGLS was significantly lower in CSX group compared to controls (3.8 ± 1.4 vs 5.2 ± 0.8, p < 0.001), and it was further more impaired in CSX-TIMI 2 compared to CSX-TIMI 3 patients (2.9 ± 1.1 vs 4.5 ± 1.2, p < 0.001). Also, CSX-TIMI 2 subgroup had more frequent angina symptoms during SE test (p < 0.001).
For the whole study population significant correlations were found (Fig. 1, Fig. 2) between resting LVGLS and CFVR LAD and PD respectively (r = −0.719, p < 0.001, r = −0.706, p < 0.001), peak values of LVGLS and CFVR LAD (r = −0.784, p < 0.001) and PD (r = −0.772, p < 0.001), as well as ΔLVGLS and CFVR LAD and PD (r = 0.589, p < 0.001, r = 0.585, p < 0.001).
Fig. 1Correlation between coronary flow velocity reserve (CFVR) of left anterior descending artery (LAD) and A) resting values of left ventricular global longitudinal strain (LVGLS), B) peak LVGLS, C) Δ LVGLS.
Fig. 2Correlation between coronary flow velocity reserve (CFVR) of posterior descending artery (PD) and A) resting values of left ventricular global longitudinal strain (LVGLS), B) peak LVGLS, C) Δ LVGLS.
By using SAQ, we analyzed functional status of women within the CSX group (Fig. 3). CSX-TIMI 2 subgroup had more frequent angina symptoms and more impaired quality of life compared to CSX-TIMI 3 patients. Degree of physical limitation, angina stability, and treatment satisfaction were similar between the subgroups.
Fig. 3Seattle Angina Questionnaire. Higher scores represent better function of each variable in Seattle Angina Questionnaire.
This study has comprehensively evaluated the impairment of microvascular and LV contractile function assessed by CFVR and LVGLS in CSX patients with regard to the presence of SCF. We report the following main findings: (1) CFVR both for LAD and PD, as well as resting, peak, and ΔLVGLS values are reduced in women with CSX in comparison to controls; 2) impairment of LVGLS and CFVR is more pronounced in CSX-TIMI 2 subgroup; 3) significant correlations were found between LVGLS and CFVR; 4) CSX-TIMI 2 subgroup had more frequent angina symptoms and more impaired quality of life.
This is the first study to our knowledge that has stratified women with CSX according to the presence of SCF, revealing that microvascular function was more profoundly impaired in CSX-TIMI 2 subgroup. Also, one of the unique features of our research was the evaluation of CFVR both for LAD and PD demonstrating very similar changes in different coronary territories, thus implicating homogenous distribution of MVD in this population [
There are numerous mechanisms involved in the pathogenesis and clinical manifestation of CSX, with the most dominant being MVD which accounts for the impairment of myocardial perfusion in these patients [
]. The fact that women with CSX have impaired quality of life, adverse prognosis coupled with lack of diagnostic and treatment strategies, places MVD as a research priority area [
Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the women’s ischemia syndrome evaluation study and the St James Women take Heart Project.
Evaluation of microvascular impairment in CSX patients was previously done by Galiuto et al. who found markedly lower TDE CFVR LAD values in CSX group in comparison to controls [
]. Sicari et al. reported that in patients with near-normal coronary arteries and negative SE tests, CFVR adds incremental value to prognostic stratification [
Our results showed that CFVR for both arteries was impaired in CSX patients, particularly more in the CSX-TIMI 2 subgroup. Another interesting feature was the finding of significantly higher baseline flow velocities both for LAD and PD in CSX group. With the underlying mechanism not entirely elucidated, histopathological features presenting with thickening of the vessel walls and lumen area reduction found in these patients [
]. Our findings are overall suggestive of myocardial flow deregulation which is in agreement with several earlier publications dealing with this matter [
]. Rinkevich et al. have reported significantly higher resting flow velocities and increased baseline MBF in women with CSX assessed by myocardial contrast echocardiography [
]. Our results have also demonstrated a decrease in hyperemic flow velocities in the CSX group further contributing to CFVR reduction. This finding corresponds to increased coronary microvascular resistance which was also demonstrated in CSX patients [
], but none of them have focused on differences in both microvascular function and LV deformation parameters in CSX patients with reference to coronary flow. Also, this is the first study to our knowledge that has demonstrated impaired resting LVGLS values in women with CSX, notably more in the CSX-TIMI 2 subgroup. A study dealing with similar matter did not find a difference in resting LVGLS between CSX and the control group, being performed on a smaller number of patients who were not further stratified depending on the presence of SCF [
]. Michelsen et al. stratified women with MVD on the basis of CFVR impairment, also not demonstrating a difference in LVGLS between the groups in baseline conditions [
]. Far more heterogeneous study group, as well as the lack of an age- and sex-matched control group were methodological differences noticed between this and our study.
Concerning the LV contractile reserve assessment, ΔLVEF had increased in controls and CSX patients, but without significant difference between the groups, hence confirming the fact that this method was not able to distinguish delicate impairments in LV systolic function present in the CSX group. Thus, SE assessment of myocardial deformation capacity in women with CSX should provide greater insight into the LV systolic function [
The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
]. Peak LVGLS was markedly reduced in the CSX group, especially more in the subgroup with SCF. Moreover, ΔLVGLS an already adopted parameter for valvular disease and cardiomyopathy assessment [
The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
], may also harbor additional clinical and prognostic information in patients with CSX. Accordingly, our findings of significantly lower ΔLVGLS in the CSX group implicate a reduction of longitudinal fiber contribution to LV systolic function [
]. In subgroup analysis, SCF presence was related to even more pronounced LV contractile reserve impairment.
Association between ΔLVGLS and CFVR LAD was demonstrated in a recent publication from the iPOWER cohort, which also discovered that women with MVD had significantly lower LVGLS at hyperemia as well as an impaired ΔLVGLS [
]. We have also found significant correlations between CFVR (both for LAD and PD) and rest-, peak-, and Δ LVGLS values implicating an association between microvascular and LV systolic function.
All of these findings strongly support the notion that in women with CSX, MVD plays a role in subtle LV systolic function impairment. Presence of SCF in this population is associated with even greater CFVR reduction and therefore further worsening of global LV systolic function.
Considering LV diastolic indices, we have found that women from the CSX group had delayed relaxation pattern, with normal LV filling pressures. Impaired diastolic properties observed in the CSX group represent the earliest abnormalities in the ‘‘natural course’’ of diastolic function impairment [
Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
More pronounced deterioration of microvascular function found in CSX-TIMI 2 subgroup is also reflected in clinical symptoms since these women had more impaired quality of life and a higher angina frequency according to SAQ.
Study limitations
This study reflects a single-center experience, with a sample size that exceeds previously reported data.
We also acknowledge that the cross-sectional design of our study limits its ability to establish causality between CFVR and LVGLS, although it has been previously shown that coronary microvascular dysfunction is able to compromise myocardial perfusion and thus result in subtle deterioration of LV systolic function [
We did not exclude subjects with traditional cardiovascular risk factors which can also influence vascular function and lead to MVD. However, women with CSX were strictly matched to a control group which gives strength to our findings.
We have only assessed the integrity of endothelium-independent mechanisms of MVD. The main limitation of CFVR measurement is that it does not measure the absolute volumetric flow, yet only the flow velocity. Thus the validity of this method lies in the assumption that epicardial vessel diameter remains constant in the basal state and during hyperemia. Under these conditions, flow velocity changes reflect flow volume changes of the resistance vessels, which represent “the bottleneck” to hyperemic flow [
Assessment of an absolute blood velocity can be underestimated by large incident angle between the Doppler beam and blood flow. However, CFVR calculation being the ratio of hyperemic to baseline velocities obtained at the same position, permits flow pattern assessment without the need for absolute values. Also, we kept an angle of ultrasound beam as parallel as possible to the direction of coronary flow. Evaluation of CFVR both for LAD and PD was more technically challenging, but clinically important in order to demonstrate a similar pattern of MVD distribution in different myocardial territories. Only few previous studies had CFVR sampled both for LAD and PD, but none of them in the setting of CSX. Still, in our study feasibility for CFVR was excellent for both arteries.
Image quality dependency, limitation characteristic for STE is amplified during SE. In some patients, we observed a significant decline in image quality imminently after peak exercise because of lung interference. Also, heart rate increase further reduces strain accuracy. Therefore technical proficiency remains very important in image processing.
Conclusion
Our results strongly support the notion that women with CSX have marked MVD which is related to subtle LV systolic function impairment both in resting conditions and during exercise. Presence of SCF in this population is associated with even greater CFVR reduction and therefore further worsening of global LV systolic function. These data could be used for further risk stratification of this specific population.
Acknowledgments
This study was partially supported by the grants of the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant numbers III41022 and ON175020).
Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the women’s ischemia syndrome evaluation study and the St James Women take Heart Project.
N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.
Time-dependent changes of plasma adiponectin concentration in relation to coronary microcirculatory function in patients with acute myocardial infarction treated by primary percutaneous coronary intervention.
Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.
Thrombolysis in myocardial infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Prognostic value of preserved coronary flow velocity reserve by noninvasive transthoracic Doppler echocardiography in patients with angiographically intermediate left main stenosis.
The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
30061-7&id=gr1.jpg){kind=link}
30061-7&id=gr2.jpg){kind=link}
30061-7&id=gr3.jpg){kind=link}