European Heart Journal – Cardiovascular Imaging (2014) 15, 769–775 doi:10.1093/ehjci/jet285
Radial artery intima-media thickness predicts major cardiovascular events in patients with suspected coronary artery disease 1 Department of Clinical Physiology, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden; 2Department of Cardiology, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden; 3Department of Molecular and Clinical Medicine/Clinical Physiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-41345 Gothenburg, Sweden; and 4 Translational Sciences, CVGI Innovative Medicine Unit, AstraZeneca R&D, S-43183 Mo¨lndal, Sweden
Received 22 August 2013; accepted after revision 16 December 2013; online publish-ahead-of-print 26 January 2014
Aims
In the present study, we investigated the prognostic value of radial artery intima-media thickness (rIMT) in patients with suspected coronary artery disease (CAD). Carotid artery intima-media thickness is a well-known surrogate marker of atherosclerosis. Recently, using very high-resolution ultrasound, we showed rIMT can be imaged with great precision and is related to various cardiovascular risk factors. ..................................................................................................................................................................................... Methods and We recruited a total of 416 patients (62 + 9 years, 44% male) with suspected CAD, referred to myocardial perfusion results scintigraphy (MPS). Among these patients, 133 underwent coronary angiography on clinical indication. Two-dimensional images of carotid and radial arteries were acquired bilaterally (using 8 and 55 MHz ultrasound, respectively). All patients were followed regarding major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, stroke, and coronary revascularization. A group of 20 healthy subjects (aged 61 + 3, 50% male) were recruited for reference. During 3 years of follow-up, 77 MACE occurred. Patients with MACE exhibited significantly thicker rIMT vs. those without (0.35 + 0.06 vs. 0.32 + 0.07 mm, P , 0.001). Increased rIMT was associated with an increased occurrence of significant coronary artery narrowing, diagnosed by coronary angiography (P ¼ 0.028). Patients with rIMT values above the median had a nearly three-fold increased risk for MACE (hazard ratio 2.8, 95% confidence interval 1.6– 4.8). In multivariate analysis, rIMT (P ¼ 0.011) remained a significant predictor of MACE, along with type II diabetes (P ¼ 0.012), body mass index (P ¼ 0.024), and MPS-verified ischaemia (P , 0.001). ..................................................................................................................................................................................... Conclusion Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
atherosclerosis † cardiovascular disease † intima-media thickness † radial artery † ultrasound
Introduction Atherosclerosis is a slow-progressing systemic vascular disease that begins with intimal thickening. When hampered haemodynamic and proinflammatory conditions are combined with metabolic disturbances, complex lesions may form, leading to the final clinical manifestations.1,2 Although various imaging biomarkers of atherosclerosis are available, improved techniques are needed to complement the existing ones. Intravascular ultrasound, coronary angiography, and computed tomography are invasive or associated
with radiation. Non-invasively measured carotid artery intima-media thickness (cIMT) is able to predict future cardiovascular (CV) events,3 – 5 and has been widely used in clinical trials as a responseto-treatment marker for different CV treatments.6,7 However, changes in cIMT are small and large patient populations are required. Thus, more sensitive surrogate markers of atherosclerosis are needed. Since atherosclerosis is a systemic disease, therefore, we believe that the same disease process affects other arteries. The radial artery is a muscular artery, comparable to the coronary arteries in its histopathology and size.8 There is also a close relationship
* Corresponding author. Tel: +46 704185580; Fax: +46 31 821198, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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Charlotte Eklund 1,3*, Elmir Omerovic2, Inger Haraldsson 2, Peter Friberg 3, and Li-Ming Gan 3,4
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between the endothelial function of this peripheral vascular bed and the coronary arteries.9 Based on these similarities, we hypothesized that rIMT may be a useful surrogate marker of atherosclerosis in the coronary artery. With very high-resolution ultrasound it is possible to image the radial artery vascular wall at a resolution as low as 20 mm. This technique has previously been used to image the abdominal aorta, coronary artery morphology, and progression of atherosclerotic lesions in mice.10 – 12 The method is non-invasive, easy to perform, and has good accuracy in human studies.13 We showed recently that rIMT, in a fashion similar to cIMT, was associated with a number of traditional CV risk factors in a patient population suspected to have coronary artery disease (CAD).14 In the present study, we aimed to evaluate the potential value of rIMT as a prognostic marker for CV events in a patient population with suspected CAD. To assess the relevance of radial artery IMT as a surrogate marker of coronary atherosclerosis in this patient population, we compared with the results of coronary angiography in a subset of the patients. A group of age-matched healthy volunteers were recruited to evaluate the range of rIMT.
signals were simultaneously recorded. Digital cine loops in B-mode were digitally stored for further analysis. The procedures, including IMT and plaque definitions, were performed according to the recommendations outlined in the ‘Mannheim Carotid IMT consensus update (2004 – 11)’.15 The total sum of the plaque area in the left and right carotid bulbs was used in the analysis.
Methods
Radionuclide myocardial perfusion scintigraphy
Study population
MPS with radionuclide technetium (99mTc) sestamibi using single-photon emission computed tomography (SPECT) was performed according to the standard clinical protocol as a part of the routine examination, before the patients were included in the study. Images were acquired with two different dual-head SPECT cameras (Infinia or Hawkeye, General Electric, USA), each equipped with a low-energy, high-resolution collimator. Two-day rest/stress protocols were used. An experienced physician interpreted the clinical ischaemic score. The ischaemia area was scored as small, medium, or large (extent of left ventricular perfusion defect: ,10, 10– 19, or .19%, scored as 1 – 3, respectively). Severity was scored as low, medium, or high (1 – 3, respectively). The clinical ischaemia score was calculated as the product of the ischaemia severity and area scores. MPS-verified ischaemia was defined as a clinical ischaemia score .1.
High-resolution ultrasound of the radial artery The imaging procedure has been described previously.14 Briefly, a 55-MHz linear transducer (RMV708, Vevo 770, Visualsonics, Toronto, Canada) was used to scan the vessel walls of the left and right radial artery. Cine-loops in B-mode were stored digitally, and mean IMT in the far wall was measured offline. An average value between the left and right radial artery was used for analysis. IMT measurements were performed in peak systole (defined as the frame in cardiac systole at which the artery had its largest diameter in a cine loop), as in an earlier standardized protocol.13 All offline measurements were performed by a single reader who was blinded to patients’ clinical characteristics.
Variability of rIMT The reproducibility of offline IMT measurements in the radial artery has been assessed in our previous study, in which the coefficients of variation for intra-observer and inter-observer variability of rIMT measurements were 5 and 6%, respectively.14
Ultrasound of the carotid artery Images of the left and right carotid arteries were acquired with an eight linear transducer (Siemens, Acuson Sequoia 512, Mountainview). ECG
To compare the extent of coronary atherosclerosis and its relevance to radial artery IMT, we evaluated coronary angiography results from study patients who had a clinical indication for this procedure (n ¼ 133). The angiographic procedure was performed according to the standard clinical protocol at the Department of Cardiology at our hospital. The results of the diagnostic angiograms were obtained through hospital records and classified into two categories: normal findings or significant CAD (pathological). A pathological angiogram was defined by the presence of one or more lesions in one or more coronary arteries with .50% narrowing. An angiogram was classified as pathological if there was severe and diffuse lumen narrowing, even in the absence of focal lesions. In those patients (n ¼ 5) where the radial artery was used as the puncture site, the data for the punctured artery were excluded.
Follow-up All patients were followed with regard to CV events over a 3-year period after their study visit. Follow-up was accomplished by telephone interviews and confirmed through hospital records. The following CV events were recorded: non-fatal MI; non-fatal stroke; coronary revascularization, both acute and scheduled (percutaneous coronary intervention or coronary artery bypass graft surgery); and death and cause of death (determined using hospital records only). MACE included MI, stroke, cardiovascular death, and coronary revascularization.
Healthy subjects To evaluate the range of rIMT in age-matched healthy subjects, we recruited 20 healthy volunteers (10 males and 10 females) with a mean age 61 + 3 years (range 55 – 68 years). All healthy subjects had normal lipid levels [high-density lipoprotein (HDL], cholesterol, low-density lipoprotein (LDL), and triglycerides], no diabetes or hypertension, did not take lipid lowering or antihypertensive medication, no family history of MI, and no previous known CAD. All subjects were nonsmokers or had not smoked within the last 10 years. Further, to exclude CAD, all subjects underwent a standard exercise ECG test with normal ECG, heart rate, and blood pressure reactions. Radial artery IMT was then measured as described previously.
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This was a prospective study with a 3-year follow-up period to detect CV events. A total of 416 patients referred for clinical radionuclide myocardial perfusion scintigraphy (MPS) for evaluation of chest pain due to suspected CAD were consecutively recruited at the time of their MPS at the department of Clinical Physiology at Sahlgrenska University Hospital in Gothenburg between February 2006 and April 2008. Five patients were excluded due to death of non CV causes (four patient by cancer and one by accident). Of the 411 remaining patients, 230 were female and 181 were male; the mean age was 62 + 9 years (range 56 – 68 years). The study patients were examined according to the study protocol within four weeks after the MPS. Patients and investigators were blinded to the MPS test results. Written informed consent was obtained from all patients. The local ethics committee at the Sahlgrenska Academy in Gothenburg approved the study.
Coronary angiography substudy
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Laboratory analyses Blood samples were acquired from all patients. All biochemical analyses were performed using commercially available kits, according to the manufacturer’s protocols. Triglycerides and cholesterol in serum were measured using reagent systems from Roche (Triglycerides/GB kit No: 12146029216, Cholesterol kit No: 2016630, Roche Diagnostics GMBH, Mannheim, Germany). The HDL in plasma was measured using an enzymatic colorimetric method (Direct HDL-Cholesterol, RANDOX Cat No. CH2652). The assay was performed on a Cobas Mira Analyzer (Hoffman-La Roche & Co., Basel, Switzerland). The LDL was calculated with Friedewald’s equation (only in patients with triglycerides ,4 mmol/L): ‘LDL ¼ total cholesterol 2 HDL – (0.45 × triglycerides)’.
The data are expressed as mean value and standard deviation (SD) for continuous variables, and frequency and percentage for categorical variables. Different groups were compared with Student’s t-test for continuous variables and the x 2 test for categorical variables. The Shapiro – Wilk test was used to assess normal distribution. The Wilcoxon rank-sum test was used for variables with non-normal distribution. Multivariate logistic regression was used to test rIMT as a predictor for the presence of significant CAD. The Kaplan– Meier survival plot was used to analyse cumulative CV events during the follow-up period. Categorization of rIMT values by median and tertiles was based on the distribution of rIMT values at baseline. The log-rank test was used to explore the difference in time-to-event rates between the two groups, while the log-rank test for trends was used for tertiles. To evaluate the association between rIMT and CV events, adjusted hazard ratios (HR) were estimated using Cox proportional-hazards regression models with rIMT as a continuous variable. The following variables were included in the model: rIMT, cIMT, age, sex, smoking habits, diabetes, hyperlipidaemia, hypertension, and inducible ischaemia on MPS. The proportionality of hazards was assessed graphically with log– log plots, as well as by the formal post-estimation test based on Schoenfeld residuals. We assessed possible multicollinearity between the variables in the model by calculating the variance inflation factor. A backward stepwise model was used and variables with P-values ,0.05 and .0.1 were entered and removed from the model, respectively. HR and 95% confidence intervals (CI) were each estimated in univariate and multivariate models with rIMT as both categorical and continuous variables. All analyses were performed using Stata software (version 12, StataCorp, College Station, TX, USA) and IBM SPSS software version 20.0 (IBM Corporation, Armonk, NY, USA). P-values ,0.05 (2-tailed) were considered statistically significant.
Results Patient characteristics Inducible myocardial ischaemia by MPS was present in 18% of the study population (75 patients). At the time of the study visit, 23% of the cohort had a history of CAD. The mean rIMT in the study population (n ¼ 411) was 0.32 + 0.07 mm. Characteristics of the participants, grouped according to the occurrence of MACE, are shown in Table 1. Patients with events (n ¼ 66) exhibited significantly thicker rIMT compared with event-free subjects (0.349 + 0.06 vs. 0.315 + 0.07 mm, P,0.001), and the significance remained after controlling for age (P ¼ 0.004). The groups did not differ significantly with respect to family history, current smoking, body mass index (BMI), systolic blood pressure, LDL, total cholesterol, or triglycerides. A sub-group of patients (n ¼ 72) in the study
Angiographic findings and rIMT Among the 416 patients included in the study, 133 (51 females and 82 males; mean age 63 + 9 years) underwent one or more coronary angiography examinations on clinical indications. The angiogram closest to the study date, and before revascularization, was chosen for analysis. The clinical indications were as follows: 69 with stable angina pectoris, 29 with unstable angina pectoris, 7 with ST elevation myocardial infarction (MI), 18 with atypical chest pain, 2 with heart failure/cardiomyopathy, 2 with silent myocardial ischaemia, 2 with cardiac arrest, and 4 with valvular heart disease. Patients who underwent coronary angiography (n ¼ 133) were more likely to have previously diagnosed CAD (46%) than the rest of the cohort (13%; P , 0.001). The mean rIMT was 0.34 + 0.06 mm. Most of these patients were on lipid lowering treatment (51% of the patients with normal findings, 64% of the patients with single vessel disease, and 75% of the patients with multivessel disease). An angiogram with significant CAD was observed in 94 (71%) of the patients (37 with single vessel disease and 57 patients with multivessel disease). Among these patients, 62% had MACE during the 3-year follow-up period. Patients with pathological angiograms showed significantly thicker rIMT compared with patients with normal findings (rIMT 0.35 + 0.06 vs. 0.32 + 0.06 mm, P ¼ 0.028). The statistically significant correlation between rIMT and pathological findings remained after controlling for previously diagnosed MI and lipid lowering treatment (P ¼ 0.034, r ¼ 0.19). There was no difference in the mean rIMT between patients with single vessel and multivessel disease.
Radial artery IMT in healthy subjects There was no significant difference in age between the study population and the healthy volunteers (mean 62 + 9 years in study population vs. 61 + 3 years in healthy subjects, P ¼ 0.407). The mean rIMT in healthy subjects (n ¼ 20) was 0.28 + 0.03 mm. Thus, there was a significantly thicker rIMT in the study population compared to healthy subjects (0.32 + 0.07 vs. 0.28 + 0.03 mm, P , 0.001). Patients with MACE (n ¼ 66) showed an even greater thickening of rIMT compared with the healthy subjects (0.35 + 0.06 vs. 0.28 + 0.03 mm, respectively, P , 0.001). Patients with MACE were somewhat older than the healthy subjects (65 + 8 vs. 61 + 3 years), but the statistically significant difference in rIMT remained after adjusting for age (P , 0.001).
Follow-up During an average follow-up period of 3 years (range 2.73–3.04 years), 77 CV events occurred and 66 patients (16%) experienced at least one event. In patients with multiple events, the time to first event was used in the survival analysis. First-time MACE was 7 nonfatal MI, 4 non-fatal strokes, 2 CV deaths, and 53 coronary revascularization (due to significant CAD on coronary angiogram).
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Statistical analysis
cohort had better CV health than the rest since they took no medication (no history of MI or coronary revascularization, no diabetes mellitus type II, and no diagnosed hypertension) and had no MPS-verified ischaemia. The mean rIMT in this sub-group was 0.297 + 0.05 mm.
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Table 1 Characteristics of patients with suspected CAD, divided into groups according to the occurrence of MACE during a 3-year follow-up period (n 5 411) Patients with no events (n 5 345)
Patients with events (n 5 66)
P
............................................................................................................................................................................... Clinical characteristics Age, years
61 + 9
65 + 8
0.001
Male sex, % (n)
40 (137)
67 (44)
, 0.001
Body mass index, kg/m2 Systolic blood pressure, mmHg
26.2 + 4.0 144 + 23
26.0 + 3.5 147 + 23
85 + 11
84 + 12
55 + 7
52 + 9
Diastolic blood pressure, mmHg
0.393 ,0.02
rIMT, mm
0.315 + 0.07
0.349 + 0.06
,0.001*
cIMT, mm Plaque burden
0.620 + 0.20
0.684 + 0.14
,0.02
11.3 + 11.2
18.7 + 13.9
,0.001
12 (42)
50 (33)
,0.001
Carotid plaque area, mm2 MPS-verified ischaemia, % (n) Clinical history History of MI or coronary revascularization, % (n)
19 (67)
42 (28)
,0.001
Diabetes mellitus type II, % (n) Current smoking, % (n)
10 (33) 12 (42)
21 (14) 12 (8)
,0.02 0.976
Hypertension, % (n)
41 (143)
59 (39)
,0.01
Family history of MIa, % (n) Hyperlipidemia, % (n)
38 (132) 44 (151)
45 (30) 61 (40)
0.243 ,0.01
42 (146) 37 (129)
65 (43) 61 (40)
,0.001 ,0.001
Medication at baseline b-blockers, % (n) Statin treatment, % (n) ACE inhibitors, % (n)
20 (70)
32 (21)
,0.05
Aspirin, % (n) No medication at time of MPS, % (n)
45 (155) 23 (79)
70 (46) 8 (5)
,0.001 ,0.01
3.24 + 1.08 1.51 + 0.37
3.07 + 1.12 1.35 + 0.30
0.255 0.001
Total cholesterol, mmol/L
5.36 + 1.29
5.10 + 1.35
0.144
Triglycerides, mmol/L
1.37 + 0.82
1.52 + 0.82
0.185
Lipids LDL, mmol/L HDL, mmol/L
Data presented are the mean value + SD or percentage (number) of patients. MACE, major adverse cardiovascular events; LVEF, left ventricular ejection fraction; IMT, intima-media thickness; MPS, myocardial perfusion scintigraphy; MI, myocardial infarction; ACE, angiotensin converting enzyme; LDL, low-density lipoprotein; HDL, high-density lipoprotein. a Defined as the occurrence of MI in father/brother before 55 years of age, or in mother/sister before 65 years of age. *P ¼ 0.004 after adjusting for age.
Prognostic value of rIMT During the 3-year follow-up period, patients with rIMT above the median value (≥0.318 mm) suffered from more MACE than patients with rIMT below the median (23.1 vs. 8.9%, P , 0.001). The presence of above-median rIMT was associated with a nearly three-fold greater risk for MACE (HR 2.8, 95% CI 1.6 –4.8, P , 0.001; Figure 1). Tertiles of rIMT were also significantly associated with MACE (P ¼ 0.002, log rank test for trend). The highest risk of developing MACE was observed in patients with rIMT values in the highest tertile (HR ¼ 3.2, 95% CI 1.6 –6.4, top tertile vs. the rest; Figure 2). The lowest event rate was observed in patients with rIMT values in the lowest tertile (rIMT , 0.288 mm). In comparison, the lowest tertile featured 11 events, the middle tertile featured 23 events
(rIMT ¼ 0.288 –0.345 mm) and the highest tertile featured 32 events (rIMT . 0.345 mm). The multivariate Cox regression model shows that rIMT, diabetes mellitus type II, BMI, and MPS-verified ischaemia are significant predictors of MACE; while, age, sex, smoking, hypertension, hyperlipidemia, and cIMT are not (Table 2). Using the same multivariate model as above with rIMT . median and cIMT . median as covariates instead of continuous variables, the results indicated that rIMT . median (P ¼ 0.006, HR 2.2, 95% CI 1.3 –4.0) is a significant predictor for MACE, along with diabetes mellitus type II (P ¼ 0.019), BMI (P ¼ 0.019), MPS-verified ischaemia (P , 0.001), and cIMT . median (P ¼ 0.030, HR 1.9, 95% CI 1.1 –3.5), independent of age, sex, smoking, hypertension, and hyperlipidemia. Interestingly, in patients without MPS-verified ischaemia (n ¼ 334) rIMT values
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LVEF, % Vascular wall thickness
0.965 0.501
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Figure 2 Radial artery IMT magnitude-dependent MACE prediction. This Kaplan– Meier survival graph depicts cumulative cardiovascular events during the 3-year follow-up period in patients grouped according to rIMT tertiles (P ¼ 0.002, log rank test for trend). above the median remained an additive predictor for future MACE (P ¼ 0.016, HR 2.5).
Discussion To the best of our knowledge, no previous study has evaluated the relationship between major adverse cardiovascular events (MACE) and rIMT assessed by this novel technique. The most important findings of this study can be summarized as follows. First, increased rIMT is associated with a higher likelihood of significant coronary artery narrowing on diagnostic angiography.
Study limitations This study demonstrated the prognostic value of rIMT in a patient population with suspected CAD; yet, the applicability of the
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Figure 1 Radial artery IMT and MACE during 3-year follow-up. Kaplan – Meier survival graph showing cumulative cardiovascular events during a follow-up period of 3 years, grouped according to rIMT values above or below the median (HR 2.8, 95% CI 1.6 – 4.8, P , 0.001, log rank test). The number of patients and cardiovascular events are shown.
Secondly, increased rIMT is associated with a greater risk of developing future CV events. We demonstrated previously in the same patient cohort that rIMT and cIMT similarly correlate with numerous traditional CV risk factors.14 Additionally, with consideration to findings of this study, both rIMT and cIMT appear to have prognostic value for medium-term CV events. IMT is probably a more representative marker for systemic atherosclerosis burden than bifurcation plaques, which are likely to be influenced by local haemodynamic conditions and appear at later stages in the atherosclerotic process.1 The radial artery has been evaluated as a graft in bypass surgery, owing to its similarity in size to the coronary arteries.16,17 Both the radial and coronary arteries are muscular arteries, with a similar histological structure.8 Intimal hyperplasia and atheromatous plaques are commonly observed in both coronary and radial arteries; however, internal thoracic arteries (which are elastic arteries) were observed in the same patients, with no evidence of plaque formation.8,18 The similar structures of radial and coronary arteries, as well as their proneness to develop atherosclerosis, may signify that rIMT can indeed be a relevant peripheral surrogate marker for coronary artery atherosclerosis. Radial and carotid arteries are known to have distinct characteristics. As muscular arteries (such as the radial artery) age, the media becomes rich in smooth muscle cells, with more calcification. The media of elastic arteries, such as the common carotid artery, is rich in elastic laminae and ageing results in the loss of one or several elastic laminae during a variable time frame, without any calcification.8,19,20 There is also strong evidence supporting that haemodynamic force, such as shear stress, is a great determinant of the atherosclerotic process.1 The mean wall shear stress is reportedly substantially higher in the common carotid artery (1.2 Pa) than in the brachial (0.5 Pa) or coronary arteries (0.7 Pa).21 – 23 In vitro, shear stress levels of 1.0–1.5 Pa have been shown to induce atheroprotective endothelial gene expression, while a shear stress level of 0.4 Pa stimulates an atherogenic phenotype.24 Wall shear stress decreases with age in the common carotid artery, but not in the brachial artery, where shear stress is observed independent of age. This difference may be due to the different ageing processes in these vessels.25,26 Although cIMT and rIMT appear to have similar prognostic values in this population, it is conceivable that, due to the morphological and haemodynamic differences between these two vessels, their relevance for CAD may vary depending on the patient population studied. In our study, patients with a cIMT . median had a two-fold risk for the occurrence of MACE in a multivariate model. This finding is in agreement with previous studies.5,10,27 However, when adding both cIMT and rIMT as continuous variables into the same multivariate model, only rIMT remained as a predictor. Despite the prevalent use of cIMT as a response-to-treatment marker, trials usually required a large number of patients over a considerable treatment period.6 Very highfrequency ultrasound has substantially improved image resolution; therefore, when applied to a vessel segment relevant to the coronary arteries, rIMT may potentially be used as a marker to follow the effects of future anti-atherosclerotic treatments.
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Table 2 Cox proportional hazard analysis of predictors of cardiovascular events in terms of MACE during a 3-year follow-up period in patients with suspected CAD Univariate model
................................................. HR (95% CI)
P
Multivariate modela
.................................................
HR (95% CI)
P
............................................................................................................................................................................... Age
1.0 (1.0–1.1)
0.001
1.0 (1.0– 1.1)
0.159
Gender Current smoking
2.8 (1.7–4.6) 1.0 (0.5–2.0)
,0.001 0.934
1.5 (0.9– 2.8) 1.0 (0.4– 2.1)
0.188 0.906
2.0 (1.2–3.2)
0.007
1.3 (0.8– 2.3)
0.311
Hyperlipidemia
1.8 (1.1–2.9)
0.026
1.0 (0.5– 1.7)
0.926
Carotid artery IMT MPS-verified ischaemia
2.4 (1.1–5.2) 5.9 (3.69.7)
0.021 ,0.001
1.3 (0.4– 4.1) 6.1 (3.6– 10.3)
Radial artery IMT
1.9 (1.4–2.7)
,0.001
1.6 (1.1– 2.4)
0.010
Diabetes mellitus type II Body mass index
2.4 (1.3–4.2) 1.0 (0.9–1.1)
0.005 0.942
2.3 (1.2– 4.4) 0.9 (0.8– 1.0)
0.012 0.023
0.693 ,0.001
CAD, coronary artery disease; HR, hazard ratio; CI, confidence interval; MPS, myocardial perfusion scintigraphy; IMT, intima-media thickness. a Multivariate model generated with the following variables: age, gender, smoking, hypertension, hyperlipidemia, body mass index, diabetes mellitus type II, MPS-verified ischaemia, carotid IMT, and radial IMT.
method in terms of patient risk stratification in general population needs to be further evaluated. Also, for accurate measurement of rIMT, an ultra-high resolution device is mandatory. Thus, the availability of this technique may be a limitation for widespread use at current stage. Although most of the elective percutaneous coronary intervention was indicated by objectively verified ischaemia, one cannot exclude the potential subjective component in the clinical decisionmaking. Due to the limited number of hard events including CV death, MI and stroke (n ¼ 15), we chose composite CV events as the primary endpoint. However, when analysing hard events per se, rIMT still remains as a prognostic marker [patients in upper vs. lower median rIMT had 5.8 vs. 1.5% hard events (P , 0.05, HR 4.0, 95% CI 1.1 –14.0)].
Conclusion Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD. Increased rIMT is associated with both a higher occurrence of significant coronary artery narrowing on diagnostic angiography, and a greater risk of developing future medium-term CV events. Highresolution rIMT needs to be further evaluated, especially regarding its potential as a new vascular surrogate marker for atherosclerosis in intervention studies.
Acknowledgements We are grateful to Maria Afzelius-Gjorloff and Sinsia Gao at Sahlgrenska University Hospital for valuable assistance. Conflicts of interest: none declared.
Funding This study received financial support from the Sahlgrenska University Hospital research fund (ALF/LUA).
References 1. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009;6:16 –26. 2. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111:3481 –8. 3. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CHet al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262 –9. 4. Simon A, Megnien JL, Chironi G. The value of carotid intima-media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol 2010;30:182 –5. 5. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459 –67. 6. Crouse JR III, Raichlen JS, Riley WA, Evans GW, Palmer MK, O’Leary DHet al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297: 1344 – 53. 7. Bots ML. Carotid intima-media thickness as a surrogate marker for cardiovascular disease in intervention studies. Curr Med Res Opin 2006;22:2181 –90. 8. Barry MM, Foulon P, Touati G, Ledoux B, Sevestre H, Carmi Det al. Comparative histological and biometric study of the coronary, radial and left internal thoracic arteries. Surg Radiol Anat 2003;25:284 – 9. 9. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange Det al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26:1235 –41. 10. Barisione C, Charnigo R, Howatt DA, Moorleghen JJ, Rateri DL, Daugherty A. Rapid dilation of the abdominal aorta during infusion of angiotensin II detected by noninvasive high-frequency ultrasonography. J Vasc Surg 2006;44:372–6. 11. Wikstrom J, Gronros J, Bergstrom G, Gan LM. Functional and morphologic imaging of coronary atherosclerosis in living mice using high-resolution color Doppler echocardiography and ultrasound biomicroscopy. J Am Coll Cardiol 2005;46: 720 – 7. 12. Gan LM, Gronros J, Hagg U, Wikstrom J, Theodoropoulos C, Friberg Pet al. Noninvasive real-time imaging of atherosclerosis in mice using ultrasound biomicroscopy. Atherosclerosis 2007;190:313 –20. 13. Osika W, Dangardt F, Gronros J, Lundstam U, Myredal A, Johansson Met al. Increasing peripheral artery intima thickness from childhood to seniority. Arterioscler Thromb Vasc Biol 2007;27:671–6. 14. Eklund C, Friberg P, Gan LM. High-resolution radial artery intima-media thickness and cardiovascular risk factors in patients with suspected coronary artery disease—comparison with common carotid artery intima-media thickness. Atherosclerosis 2012;221:118 –23. 15. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein Net al. Mannheim carotid intima-media thickness and plaque consensus (2004 –2006 –2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk
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21. Dammers R, Stifft F, Tordoir JH, Hameleers JM, Hoeks AP, Kitslaar PJ. Shear stress depends on vascular territory: comparison between common carotid and brachial artery. J Appl Physiol 2003;94:485 –9. 22. Reneman RS, Hoeks AP. Wall shear stress as measured in vivo: consequences for the design of the arterial system. Med Biol Eng Comput 2008;46:499 –507. 23. Doriot PA, Dorsaz PA, Dorsaz L, De Benedetti E, Chatelain P, Delafontaine P. In-vivo measurements of wall shear stress in human coronary arteries. Coron Artery Dis 2000; 11:495–502. 24. Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282:2035 –42. 25. Samijo SK, Willigers JM, Barkhuysen R, Kitslaar PJ, Reneman RS, Brands PJ et al. Wall shear stress in the human common carotid artery as function of age and gender. Cardiovasc Res 1998;39:515 –22. 26. Dammers R, Tordoir JH, Hameleers JM, Kitslaar PJ, Hoeks AP. Brachial artery shear stress is independent of gender or age and does not modify vessel wall mechanical properties. Ultrasound Med Biol 2002;28:1015 –22. 27. Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2006;37:87–92.
IMAGE FOCUS
doi:10.1093/ehjci/jet283 Online publish-ahead-of-print 23 January 2014
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Multimodality imaging of mid-ventricular obstruction in left ventricular noncompaction Roberto Spoladore1*, Umberto Gianni1, Alberto Castella1, Francesco De Cobelli2,3, and Paolo G. Camici1,3 1 Referral Centre for Primary Cardiomyopathies, Cardio-thoracic and Vascular Department, San Raffaele University Hospital, Milan, Italy; 2Department of Radiology, San Raffaele University Hospital, Milan, Italy; and 3San Raffaele Vita-Salute University, Milan, Italy
* Corresponding author. Tel: +39 0226437608; Fax: +39 0226436218, Email: [email protected]
Noncompaction cardiomyopathy (NCM) is a myocardial disorder, which is thought to occur due to the failure of left ventricle (LV) compaction during embryogenesis, leading to distinct morphological characteristics in the ventricular chamber. The exact prevalence of NCM is still unknown. Several limitations for this assessment are the different diagnostic criteria, the heterogeneous populations, and the retrospective design of most studies. The reported prevalence of NCM in patients referred to echocardiography laboratories ranges between 0.014 and 1.26%. We report of a 42-year-old woman that underwent transthoracic echocardiography for the recent onset of a transient ischemic attack. Echo images revealed a rare case of apical left ventricular noncompaction (LVNC) (Panel A, Supplementary data online, Video S1) with mid-ventricular obstruction (white arrows). A mid-ventricular diastolic gradient of 20 mmHg was present after Valsalva maneuver at pulsed-wave Doppler analysis (Panel B). A diastolic gradient was also present during ventricular ectopic beats (Panel C) with mild increase in the systolic gradient (Panel D). Cardiac magnetic resonance (CMR) two-chamber views (Panel E: diastole; Panel F: systole) confirmed apical LVNC (Supplementary data online, Video S2). Late-gadolinium analysis (Panels G and H) showed a large area of apical myocardial fibrosis compatible with LV aneurysm. Usually, LVNC leads to systolic heart failure and sudden cardiac death. The presence of mid-ventricular obstruction with apical aneurysm is a rare condition with important prognostic and therapeutic implications in LVNC. Multimodality cardiac imaging with CMR integration could better identify patients with large extension of myocardial fibrosis, an important marker for systolic dysfunction progression and ventricular arrhythmias. Moreover, CMR could be more sensitive than echocardiography alone in detecting apical thrombi. Supplementary data are available at European Heart Journal – Cardiovascular Imaging online. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 2012;34:290 –6. Khot UN, Friedman DT, Pettersson G, Smedira NG, Li J, Ellis SG. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with left internal mammary arteries and saphenous vein grafts. Circulation 2004;109:2086 – 91. Kobayashi J. Radial artery as a graft for coronary artery bypass grafting. Circ J 2009;73: 1178– 83. Ruengsakulrach P, Sinclair R, Komeda M, Raman J, Gordon I, Buxton B. Comparative histopathology of radial artery versus internal thoracic artery and risk factors for development of intimal hyperplasia and atherosclerosis. Circulation 1999;100 (19 Suppl):II139 –44. van der Heijden-Spek JJ, Staessen JA, Fagard RH, Hoeks AP, Boudier HA, van Bortel LM. Effect of age on brachial artery wall properties differs from the aorta and is gender dependent: a population study. Hypertension 2000;35:637–42. Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler Thromb 1993;13:90– 7.
Radial artery intima-media thickness predicts major cardiovascular events in patients with suspected coronary artery disease 1 Department of Clinical Physiology, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden; 2Department of Cardiology, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden; 3Department of Molecular and Clinical Medicine/Clinical Physiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-41345 Gothenburg, Sweden; and 4 Translational Sciences, CVGI Innovative Medicine Unit, AstraZeneca R&D, S-43183 Mo¨lndal, Sweden
Received 22 August 2013; accepted after revision 16 December 2013; online publish-ahead-of-print 26 January 2014
Aims
In the present study, we investigated the prognostic value of radial artery intima-media thickness (rIMT) in patients with suspected coronary artery disease (CAD). Carotid artery intima-media thickness is a well-known surrogate marker of atherosclerosis. Recently, using very high-resolution ultrasound, we showed rIMT can be imaged with great precision and is related to various cardiovascular risk factors. ..................................................................................................................................................................................... Methods and We recruited a total of 416 patients (62 + 9 years, 44% male) with suspected CAD, referred to myocardial perfusion results scintigraphy (MPS). Among these patients, 133 underwent coronary angiography on clinical indication. Two-dimensional images of carotid and radial arteries were acquired bilaterally (using 8 and 55 MHz ultrasound, respectively). All patients were followed regarding major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, stroke, and coronary revascularization. A group of 20 healthy subjects (aged 61 + 3, 50% male) were recruited for reference. During 3 years of follow-up, 77 MACE occurred. Patients with MACE exhibited significantly thicker rIMT vs. those without (0.35 + 0.06 vs. 0.32 + 0.07 mm, P , 0.001). Increased rIMT was associated with an increased occurrence of significant coronary artery narrowing, diagnosed by coronary angiography (P ¼ 0.028). Patients with rIMT values above the median had a nearly three-fold increased risk for MACE (hazard ratio 2.8, 95% confidence interval 1.6– 4.8). In multivariate analysis, rIMT (P ¼ 0.011) remained a significant predictor of MACE, along with type II diabetes (P ¼ 0.012), body mass index (P ¼ 0.024), and MPS-verified ischaemia (P , 0.001). ..................................................................................................................................................................................... Conclusion Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
atherosclerosis † cardiovascular disease † intima-media thickness † radial artery † ultrasound
Introduction Atherosclerosis is a slow-progressing systemic vascular disease that begins with intimal thickening. When hampered haemodynamic and proinflammatory conditions are combined with metabolic disturbances, complex lesions may form, leading to the final clinical manifestations.1,2 Although various imaging biomarkers of atherosclerosis are available, improved techniques are needed to complement the existing ones. Intravascular ultrasound, coronary angiography, and computed tomography are invasive or associated
with radiation. Non-invasively measured carotid artery intima-media thickness (cIMT) is able to predict future cardiovascular (CV) events,3 – 5 and has been widely used in clinical trials as a responseto-treatment marker for different CV treatments.6,7 However, changes in cIMT are small and large patient populations are required. Thus, more sensitive surrogate markers of atherosclerosis are needed. Since atherosclerosis is a systemic disease, therefore, we believe that the same disease process affects other arteries. The radial artery is a muscular artery, comparable to the coronary arteries in its histopathology and size.8 There is also a close relationship
* Corresponding author. Tel: +46 704185580; Fax: +46 31 821198, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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Charlotte Eklund 1,3*, Elmir Omerovic2, Inger Haraldsson 2, Peter Friberg 3, and Li-Ming Gan 3,4
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between the endothelial function of this peripheral vascular bed and the coronary arteries.9 Based on these similarities, we hypothesized that rIMT may be a useful surrogate marker of atherosclerosis in the coronary artery. With very high-resolution ultrasound it is possible to image the radial artery vascular wall at a resolution as low as 20 mm. This technique has previously been used to image the abdominal aorta, coronary artery morphology, and progression of atherosclerotic lesions in mice.10 – 12 The method is non-invasive, easy to perform, and has good accuracy in human studies.13 We showed recently that rIMT, in a fashion similar to cIMT, was associated with a number of traditional CV risk factors in a patient population suspected to have coronary artery disease (CAD).14 In the present study, we aimed to evaluate the potential value of rIMT as a prognostic marker for CV events in a patient population with suspected CAD. To assess the relevance of radial artery IMT as a surrogate marker of coronary atherosclerosis in this patient population, we compared with the results of coronary angiography in a subset of the patients. A group of age-matched healthy volunteers were recruited to evaluate the range of rIMT.
signals were simultaneously recorded. Digital cine loops in B-mode were digitally stored for further analysis. The procedures, including IMT and plaque definitions, were performed according to the recommendations outlined in the ‘Mannheim Carotid IMT consensus update (2004 – 11)’.15 The total sum of the plaque area in the left and right carotid bulbs was used in the analysis.
Methods
Radionuclide myocardial perfusion scintigraphy
Study population
MPS with radionuclide technetium (99mTc) sestamibi using single-photon emission computed tomography (SPECT) was performed according to the standard clinical protocol as a part of the routine examination, before the patients were included in the study. Images were acquired with two different dual-head SPECT cameras (Infinia or Hawkeye, General Electric, USA), each equipped with a low-energy, high-resolution collimator. Two-day rest/stress protocols were used. An experienced physician interpreted the clinical ischaemic score. The ischaemia area was scored as small, medium, or large (extent of left ventricular perfusion defect: ,10, 10– 19, or .19%, scored as 1 – 3, respectively). Severity was scored as low, medium, or high (1 – 3, respectively). The clinical ischaemia score was calculated as the product of the ischaemia severity and area scores. MPS-verified ischaemia was defined as a clinical ischaemia score .1.
High-resolution ultrasound of the radial artery The imaging procedure has been described previously.14 Briefly, a 55-MHz linear transducer (RMV708, Vevo 770, Visualsonics, Toronto, Canada) was used to scan the vessel walls of the left and right radial artery. Cine-loops in B-mode were stored digitally, and mean IMT in the far wall was measured offline. An average value between the left and right radial artery was used for analysis. IMT measurements were performed in peak systole (defined as the frame in cardiac systole at which the artery had its largest diameter in a cine loop), as in an earlier standardized protocol.13 All offline measurements were performed by a single reader who was blinded to patients’ clinical characteristics.
Variability of rIMT The reproducibility of offline IMT measurements in the radial artery has been assessed in our previous study, in which the coefficients of variation for intra-observer and inter-observer variability of rIMT measurements were 5 and 6%, respectively.14
Ultrasound of the carotid artery Images of the left and right carotid arteries were acquired with an eight linear transducer (Siemens, Acuson Sequoia 512, Mountainview). ECG
To compare the extent of coronary atherosclerosis and its relevance to radial artery IMT, we evaluated coronary angiography results from study patients who had a clinical indication for this procedure (n ¼ 133). The angiographic procedure was performed according to the standard clinical protocol at the Department of Cardiology at our hospital. The results of the diagnostic angiograms were obtained through hospital records and classified into two categories: normal findings or significant CAD (pathological). A pathological angiogram was defined by the presence of one or more lesions in one or more coronary arteries with .50% narrowing. An angiogram was classified as pathological if there was severe and diffuse lumen narrowing, even in the absence of focal lesions. In those patients (n ¼ 5) where the radial artery was used as the puncture site, the data for the punctured artery were excluded.
Follow-up All patients were followed with regard to CV events over a 3-year period after their study visit. Follow-up was accomplished by telephone interviews and confirmed through hospital records. The following CV events were recorded: non-fatal MI; non-fatal stroke; coronary revascularization, both acute and scheduled (percutaneous coronary intervention or coronary artery bypass graft surgery); and death and cause of death (determined using hospital records only). MACE included MI, stroke, cardiovascular death, and coronary revascularization.
Healthy subjects To evaluate the range of rIMT in age-matched healthy subjects, we recruited 20 healthy volunteers (10 males and 10 females) with a mean age 61 + 3 years (range 55 – 68 years). All healthy subjects had normal lipid levels [high-density lipoprotein (HDL], cholesterol, low-density lipoprotein (LDL), and triglycerides], no diabetes or hypertension, did not take lipid lowering or antihypertensive medication, no family history of MI, and no previous known CAD. All subjects were nonsmokers or had not smoked within the last 10 years. Further, to exclude CAD, all subjects underwent a standard exercise ECG test with normal ECG, heart rate, and blood pressure reactions. Radial artery IMT was then measured as described previously.
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This was a prospective study with a 3-year follow-up period to detect CV events. A total of 416 patients referred for clinical radionuclide myocardial perfusion scintigraphy (MPS) for evaluation of chest pain due to suspected CAD were consecutively recruited at the time of their MPS at the department of Clinical Physiology at Sahlgrenska University Hospital in Gothenburg between February 2006 and April 2008. Five patients were excluded due to death of non CV causes (four patient by cancer and one by accident). Of the 411 remaining patients, 230 were female and 181 were male; the mean age was 62 + 9 years (range 56 – 68 years). The study patients were examined according to the study protocol within four weeks after the MPS. Patients and investigators were blinded to the MPS test results. Written informed consent was obtained from all patients. The local ethics committee at the Sahlgrenska Academy in Gothenburg approved the study.
Coronary angiography substudy
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Laboratory analyses Blood samples were acquired from all patients. All biochemical analyses were performed using commercially available kits, according to the manufacturer’s protocols. Triglycerides and cholesterol in serum were measured using reagent systems from Roche (Triglycerides/GB kit No: 12146029216, Cholesterol kit No: 2016630, Roche Diagnostics GMBH, Mannheim, Germany). The HDL in plasma was measured using an enzymatic colorimetric method (Direct HDL-Cholesterol, RANDOX Cat No. CH2652). The assay was performed on a Cobas Mira Analyzer (Hoffman-La Roche & Co., Basel, Switzerland). The LDL was calculated with Friedewald’s equation (only in patients with triglycerides ,4 mmol/L): ‘LDL ¼ total cholesterol 2 HDL – (0.45 × triglycerides)’.
The data are expressed as mean value and standard deviation (SD) for continuous variables, and frequency and percentage for categorical variables. Different groups were compared with Student’s t-test for continuous variables and the x 2 test for categorical variables. The Shapiro – Wilk test was used to assess normal distribution. The Wilcoxon rank-sum test was used for variables with non-normal distribution. Multivariate logistic regression was used to test rIMT as a predictor for the presence of significant CAD. The Kaplan– Meier survival plot was used to analyse cumulative CV events during the follow-up period. Categorization of rIMT values by median and tertiles was based on the distribution of rIMT values at baseline. The log-rank test was used to explore the difference in time-to-event rates between the two groups, while the log-rank test for trends was used for tertiles. To evaluate the association between rIMT and CV events, adjusted hazard ratios (HR) were estimated using Cox proportional-hazards regression models with rIMT as a continuous variable. The following variables were included in the model: rIMT, cIMT, age, sex, smoking habits, diabetes, hyperlipidaemia, hypertension, and inducible ischaemia on MPS. The proportionality of hazards was assessed graphically with log– log plots, as well as by the formal post-estimation test based on Schoenfeld residuals. We assessed possible multicollinearity between the variables in the model by calculating the variance inflation factor. A backward stepwise model was used and variables with P-values ,0.05 and .0.1 were entered and removed from the model, respectively. HR and 95% confidence intervals (CI) were each estimated in univariate and multivariate models with rIMT as both categorical and continuous variables. All analyses were performed using Stata software (version 12, StataCorp, College Station, TX, USA) and IBM SPSS software version 20.0 (IBM Corporation, Armonk, NY, USA). P-values ,0.05 (2-tailed) were considered statistically significant.
Results Patient characteristics Inducible myocardial ischaemia by MPS was present in 18% of the study population (75 patients). At the time of the study visit, 23% of the cohort had a history of CAD. The mean rIMT in the study population (n ¼ 411) was 0.32 + 0.07 mm. Characteristics of the participants, grouped according to the occurrence of MACE, are shown in Table 1. Patients with events (n ¼ 66) exhibited significantly thicker rIMT compared with event-free subjects (0.349 + 0.06 vs. 0.315 + 0.07 mm, P,0.001), and the significance remained after controlling for age (P ¼ 0.004). The groups did not differ significantly with respect to family history, current smoking, body mass index (BMI), systolic blood pressure, LDL, total cholesterol, or triglycerides. A sub-group of patients (n ¼ 72) in the study
Angiographic findings and rIMT Among the 416 patients included in the study, 133 (51 females and 82 males; mean age 63 + 9 years) underwent one or more coronary angiography examinations on clinical indications. The angiogram closest to the study date, and before revascularization, was chosen for analysis. The clinical indications were as follows: 69 with stable angina pectoris, 29 with unstable angina pectoris, 7 with ST elevation myocardial infarction (MI), 18 with atypical chest pain, 2 with heart failure/cardiomyopathy, 2 with silent myocardial ischaemia, 2 with cardiac arrest, and 4 with valvular heart disease. Patients who underwent coronary angiography (n ¼ 133) were more likely to have previously diagnosed CAD (46%) than the rest of the cohort (13%; P , 0.001). The mean rIMT was 0.34 + 0.06 mm. Most of these patients were on lipid lowering treatment (51% of the patients with normal findings, 64% of the patients with single vessel disease, and 75% of the patients with multivessel disease). An angiogram with significant CAD was observed in 94 (71%) of the patients (37 with single vessel disease and 57 patients with multivessel disease). Among these patients, 62% had MACE during the 3-year follow-up period. Patients with pathological angiograms showed significantly thicker rIMT compared with patients with normal findings (rIMT 0.35 + 0.06 vs. 0.32 + 0.06 mm, P ¼ 0.028). The statistically significant correlation between rIMT and pathological findings remained after controlling for previously diagnosed MI and lipid lowering treatment (P ¼ 0.034, r ¼ 0.19). There was no difference in the mean rIMT between patients with single vessel and multivessel disease.
Radial artery IMT in healthy subjects There was no significant difference in age between the study population and the healthy volunteers (mean 62 + 9 years in study population vs. 61 + 3 years in healthy subjects, P ¼ 0.407). The mean rIMT in healthy subjects (n ¼ 20) was 0.28 + 0.03 mm. Thus, there was a significantly thicker rIMT in the study population compared to healthy subjects (0.32 + 0.07 vs. 0.28 + 0.03 mm, P , 0.001). Patients with MACE (n ¼ 66) showed an even greater thickening of rIMT compared with the healthy subjects (0.35 + 0.06 vs. 0.28 + 0.03 mm, respectively, P , 0.001). Patients with MACE were somewhat older than the healthy subjects (65 + 8 vs. 61 + 3 years), but the statistically significant difference in rIMT remained after adjusting for age (P , 0.001).
Follow-up During an average follow-up period of 3 years (range 2.73–3.04 years), 77 CV events occurred and 66 patients (16%) experienced at least one event. In patients with multiple events, the time to first event was used in the survival analysis. First-time MACE was 7 nonfatal MI, 4 non-fatal strokes, 2 CV deaths, and 53 coronary revascularization (due to significant CAD on coronary angiogram).
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Statistical analysis
cohort had better CV health than the rest since they took no medication (no history of MI or coronary revascularization, no diabetes mellitus type II, and no diagnosed hypertension) and had no MPS-verified ischaemia. The mean rIMT in this sub-group was 0.297 + 0.05 mm.
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Table 1 Characteristics of patients with suspected CAD, divided into groups according to the occurrence of MACE during a 3-year follow-up period (n 5 411) Patients with no events (n 5 345)
Patients with events (n 5 66)
P
............................................................................................................................................................................... Clinical characteristics Age, years
61 + 9
65 + 8
0.001
Male sex, % (n)
40 (137)
67 (44)
, 0.001
Body mass index, kg/m2 Systolic blood pressure, mmHg
26.2 + 4.0 144 + 23
26.0 + 3.5 147 + 23
85 + 11
84 + 12
55 + 7
52 + 9
Diastolic blood pressure, mmHg
0.393 ,0.02
rIMT, mm
0.315 + 0.07
0.349 + 0.06
,0.001*
cIMT, mm Plaque burden
0.620 + 0.20
0.684 + 0.14
,0.02
11.3 + 11.2
18.7 + 13.9
,0.001
12 (42)
50 (33)
,0.001
Carotid plaque area, mm2 MPS-verified ischaemia, % (n) Clinical history History of MI or coronary revascularization, % (n)
19 (67)
42 (28)
,0.001
Diabetes mellitus type II, % (n) Current smoking, % (n)
10 (33) 12 (42)
21 (14) 12 (8)
,0.02 0.976
Hypertension, % (n)
41 (143)
59 (39)
,0.01
Family history of MIa, % (n) Hyperlipidemia, % (n)
38 (132) 44 (151)
45 (30) 61 (40)
0.243 ,0.01
42 (146) 37 (129)
65 (43) 61 (40)
,0.001 ,0.001
Medication at baseline b-blockers, % (n) Statin treatment, % (n) ACE inhibitors, % (n)
20 (70)
32 (21)
,0.05
Aspirin, % (n) No medication at time of MPS, % (n)
45 (155) 23 (79)
70 (46) 8 (5)
,0.001 ,0.01
3.24 + 1.08 1.51 + 0.37
3.07 + 1.12 1.35 + 0.30
0.255 0.001
Total cholesterol, mmol/L
5.36 + 1.29
5.10 + 1.35
0.144
Triglycerides, mmol/L
1.37 + 0.82
1.52 + 0.82
0.185
Lipids LDL, mmol/L HDL, mmol/L
Data presented are the mean value + SD or percentage (number) of patients. MACE, major adverse cardiovascular events; LVEF, left ventricular ejection fraction; IMT, intima-media thickness; MPS, myocardial perfusion scintigraphy; MI, myocardial infarction; ACE, angiotensin converting enzyme; LDL, low-density lipoprotein; HDL, high-density lipoprotein. a Defined as the occurrence of MI in father/brother before 55 years of age, or in mother/sister before 65 years of age. *P ¼ 0.004 after adjusting for age.
Prognostic value of rIMT During the 3-year follow-up period, patients with rIMT above the median value (≥0.318 mm) suffered from more MACE than patients with rIMT below the median (23.1 vs. 8.9%, P , 0.001). The presence of above-median rIMT was associated with a nearly three-fold greater risk for MACE (HR 2.8, 95% CI 1.6 –4.8, P , 0.001; Figure 1). Tertiles of rIMT were also significantly associated with MACE (P ¼ 0.002, log rank test for trend). The highest risk of developing MACE was observed in patients with rIMT values in the highest tertile (HR ¼ 3.2, 95% CI 1.6 –6.4, top tertile vs. the rest; Figure 2). The lowest event rate was observed in patients with rIMT values in the lowest tertile (rIMT , 0.288 mm). In comparison, the lowest tertile featured 11 events, the middle tertile featured 23 events
(rIMT ¼ 0.288 –0.345 mm) and the highest tertile featured 32 events (rIMT . 0.345 mm). The multivariate Cox regression model shows that rIMT, diabetes mellitus type II, BMI, and MPS-verified ischaemia are significant predictors of MACE; while, age, sex, smoking, hypertension, hyperlipidemia, and cIMT are not (Table 2). Using the same multivariate model as above with rIMT . median and cIMT . median as covariates instead of continuous variables, the results indicated that rIMT . median (P ¼ 0.006, HR 2.2, 95% CI 1.3 –4.0) is a significant predictor for MACE, along with diabetes mellitus type II (P ¼ 0.019), BMI (P ¼ 0.019), MPS-verified ischaemia (P , 0.001), and cIMT . median (P ¼ 0.030, HR 1.9, 95% CI 1.1 –3.5), independent of age, sex, smoking, hypertension, and hyperlipidemia. Interestingly, in patients without MPS-verified ischaemia (n ¼ 334) rIMT values
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LVEF, % Vascular wall thickness
0.965 0.501
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Prognostic value of radial artery IMT
Figure 2 Radial artery IMT magnitude-dependent MACE prediction. This Kaplan– Meier survival graph depicts cumulative cardiovascular events during the 3-year follow-up period in patients grouped according to rIMT tertiles (P ¼ 0.002, log rank test for trend). above the median remained an additive predictor for future MACE (P ¼ 0.016, HR 2.5).
Discussion To the best of our knowledge, no previous study has evaluated the relationship between major adverse cardiovascular events (MACE) and rIMT assessed by this novel technique. The most important findings of this study can be summarized as follows. First, increased rIMT is associated with a higher likelihood of significant coronary artery narrowing on diagnostic angiography.
Study limitations This study demonstrated the prognostic value of rIMT in a patient population with suspected CAD; yet, the applicability of the
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Figure 1 Radial artery IMT and MACE during 3-year follow-up. Kaplan – Meier survival graph showing cumulative cardiovascular events during a follow-up period of 3 years, grouped according to rIMT values above or below the median (HR 2.8, 95% CI 1.6 – 4.8, P , 0.001, log rank test). The number of patients and cardiovascular events are shown.
Secondly, increased rIMT is associated with a greater risk of developing future CV events. We demonstrated previously in the same patient cohort that rIMT and cIMT similarly correlate with numerous traditional CV risk factors.14 Additionally, with consideration to findings of this study, both rIMT and cIMT appear to have prognostic value for medium-term CV events. IMT is probably a more representative marker for systemic atherosclerosis burden than bifurcation plaques, which are likely to be influenced by local haemodynamic conditions and appear at later stages in the atherosclerotic process.1 The radial artery has been evaluated as a graft in bypass surgery, owing to its similarity in size to the coronary arteries.16,17 Both the radial and coronary arteries are muscular arteries, with a similar histological structure.8 Intimal hyperplasia and atheromatous plaques are commonly observed in both coronary and radial arteries; however, internal thoracic arteries (which are elastic arteries) were observed in the same patients, with no evidence of plaque formation.8,18 The similar structures of radial and coronary arteries, as well as their proneness to develop atherosclerosis, may signify that rIMT can indeed be a relevant peripheral surrogate marker for coronary artery atherosclerosis. Radial and carotid arteries are known to have distinct characteristics. As muscular arteries (such as the radial artery) age, the media becomes rich in smooth muscle cells, with more calcification. The media of elastic arteries, such as the common carotid artery, is rich in elastic laminae and ageing results in the loss of one or several elastic laminae during a variable time frame, without any calcification.8,19,20 There is also strong evidence supporting that haemodynamic force, such as shear stress, is a great determinant of the atherosclerotic process.1 The mean wall shear stress is reportedly substantially higher in the common carotid artery (1.2 Pa) than in the brachial (0.5 Pa) or coronary arteries (0.7 Pa).21 – 23 In vitro, shear stress levels of 1.0–1.5 Pa have been shown to induce atheroprotective endothelial gene expression, while a shear stress level of 0.4 Pa stimulates an atherogenic phenotype.24 Wall shear stress decreases with age in the common carotid artery, but not in the brachial artery, where shear stress is observed independent of age. This difference may be due to the different ageing processes in these vessels.25,26 Although cIMT and rIMT appear to have similar prognostic values in this population, it is conceivable that, due to the morphological and haemodynamic differences between these two vessels, their relevance for CAD may vary depending on the patient population studied. In our study, patients with a cIMT . median had a two-fold risk for the occurrence of MACE in a multivariate model. This finding is in agreement with previous studies.5,10,27 However, when adding both cIMT and rIMT as continuous variables into the same multivariate model, only rIMT remained as a predictor. Despite the prevalent use of cIMT as a response-to-treatment marker, trials usually required a large number of patients over a considerable treatment period.6 Very highfrequency ultrasound has substantially improved image resolution; therefore, when applied to a vessel segment relevant to the coronary arteries, rIMT may potentially be used as a marker to follow the effects of future anti-atherosclerotic treatments.
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C. Eklund et al.
Table 2 Cox proportional hazard analysis of predictors of cardiovascular events in terms of MACE during a 3-year follow-up period in patients with suspected CAD Univariate model
................................................. HR (95% CI)
P
Multivariate modela
.................................................
HR (95% CI)
P
............................................................................................................................................................................... Age
1.0 (1.0–1.1)
0.001
1.0 (1.0– 1.1)
0.159
Gender Current smoking
2.8 (1.7–4.6) 1.0 (0.5–2.0)
,0.001 0.934
1.5 (0.9– 2.8) 1.0 (0.4– 2.1)
0.188 0.906
2.0 (1.2–3.2)
0.007
1.3 (0.8– 2.3)
0.311
Hyperlipidemia
1.8 (1.1–2.9)
0.026
1.0 (0.5– 1.7)
0.926
Carotid artery IMT MPS-verified ischaemia
2.4 (1.1–5.2) 5.9 (3.69.7)
0.021 ,0.001
1.3 (0.4– 4.1) 6.1 (3.6– 10.3)
Radial artery IMT
1.9 (1.4–2.7)
,0.001
1.6 (1.1– 2.4)
0.010
Diabetes mellitus type II Body mass index
2.4 (1.3–4.2) 1.0 (0.9–1.1)
0.005 0.942
2.3 (1.2– 4.4) 0.9 (0.8– 1.0)
0.012 0.023
0.693 ,0.001
CAD, coronary artery disease; HR, hazard ratio; CI, confidence interval; MPS, myocardial perfusion scintigraphy; IMT, intima-media thickness. a Multivariate model generated with the following variables: age, gender, smoking, hypertension, hyperlipidemia, body mass index, diabetes mellitus type II, MPS-verified ischaemia, carotid IMT, and radial IMT.
method in terms of patient risk stratification in general population needs to be further evaluated. Also, for accurate measurement of rIMT, an ultra-high resolution device is mandatory. Thus, the availability of this technique may be a limitation for widespread use at current stage. Although most of the elective percutaneous coronary intervention was indicated by objectively verified ischaemia, one cannot exclude the potential subjective component in the clinical decisionmaking. Due to the limited number of hard events including CV death, MI and stroke (n ¼ 15), we chose composite CV events as the primary endpoint. However, when analysing hard events per se, rIMT still remains as a prognostic marker [patients in upper vs. lower median rIMT had 5.8 vs. 1.5% hard events (P , 0.05, HR 4.0, 95% CI 1.1 –14.0)].
Conclusion Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD. Increased rIMT is associated with both a higher occurrence of significant coronary artery narrowing on diagnostic angiography, and a greater risk of developing future medium-term CV events. Highresolution rIMT needs to be further evaluated, especially regarding its potential as a new vascular surrogate marker for atherosclerosis in intervention studies.
Acknowledgements We are grateful to Maria Afzelius-Gjorloff and Sinsia Gao at Sahlgrenska University Hospital for valuable assistance. Conflicts of interest: none declared.
Funding This study received financial support from the Sahlgrenska University Hospital research fund (ALF/LUA).
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IMAGE FOCUS
doi:10.1093/ehjci/jet283 Online publish-ahead-of-print 23 January 2014
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Multimodality imaging of mid-ventricular obstruction in left ventricular noncompaction Roberto Spoladore1*, Umberto Gianni1, Alberto Castella1, Francesco De Cobelli2,3, and Paolo G. Camici1,3 1 Referral Centre for Primary Cardiomyopathies, Cardio-thoracic and Vascular Department, San Raffaele University Hospital, Milan, Italy; 2Department of Radiology, San Raffaele University Hospital, Milan, Italy; and 3San Raffaele Vita-Salute University, Milan, Italy
* Corresponding author. Tel: +39 0226437608; Fax: +39 0226436218, Email: [email protected]
Noncompaction cardiomyopathy (NCM) is a myocardial disorder, which is thought to occur due to the failure of left ventricle (LV) compaction during embryogenesis, leading to distinct morphological characteristics in the ventricular chamber. The exact prevalence of NCM is still unknown. Several limitations for this assessment are the different diagnostic criteria, the heterogeneous populations, and the retrospective design of most studies. The reported prevalence of NCM in patients referred to echocardiography laboratories ranges between 0.014 and 1.26%. We report of a 42-year-old woman that underwent transthoracic echocardiography for the recent onset of a transient ischemic attack. Echo images revealed a rare case of apical left ventricular noncompaction (LVNC) (Panel A, Supplementary data online, Video S1) with mid-ventricular obstruction (white arrows). A mid-ventricular diastolic gradient of 20 mmHg was present after Valsalva maneuver at pulsed-wave Doppler analysis (Panel B). A diastolic gradient was also present during ventricular ectopic beats (Panel C) with mild increase in the systolic gradient (Panel D). Cardiac magnetic resonance (CMR) two-chamber views (Panel E: diastole; Panel F: systole) confirmed apical LVNC (Supplementary data online, Video S2). Late-gadolinium analysis (Panels G and H) showed a large area of apical myocardial fibrosis compatible with LV aneurysm. Usually, LVNC leads to systolic heart failure and sudden cardiac death. The presence of mid-ventricular obstruction with apical aneurysm is a rare condition with important prognostic and therapeutic implications in LVNC. Multimodality cardiac imaging with CMR integration could better identify patients with large extension of myocardial fibrosis, an important marker for systolic dysfunction progression and ventricular arrhythmias. Moreover, CMR could be more sensitive than echocardiography alone in detecting apical thrombi. Supplementary data are available at European Heart Journal – Cardiovascular Imaging online. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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