Clinical research Coronary heart disease

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1 European Heart Journal (2006) 27, doi: /eurheartj/ehi796 Clinical research Coronary heart disease Compensatory enlargement of human coronary arteries during progression of atherosclerosis is unrelated to atheroma burden: serial intravascular ultrasound observations from the REVERSAL trial Ilke Sipahi 1, E. Murat Tuzcu 1 *, Paul Schoenhagen 1,2, Stephen J. Nicholls 1, Volkan Ozduran 1, Samir Kapadia 1, and Steven E. Nissen 1 1 Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195, USA and 2 Department of Diagnostic Radiology, The Cleveland Clinic Foundation, Cleveland, OH, USA Received 8 October 2005; revised 17 December 2005; accepted 26 January 2006; online publish-ahead-of-print 8 March 2006 KEYWORDS Coronary artery disease; Remodelling; Intravascular ultrasound; Imaging Aims On the basis of the evidence from autopsy studies, it is accepted that compensatory enlargement (remodelling) of coronary arteries during progression of atherosclerosis diminishes once atheroma burden (cross-sectional area stenosis) reaches 40%. Our aim was to evaluate whether atheroma burden is a limiting factor for coronary arterial remodelling using in vivo serial intravascular ultrasound (IVUS). Methods and results From the cohort of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, we identified 210 focal coronary lesions at baseline IVUS. Of these, 128 lesions that had an increase in atheroma area at the 18-month follow-up IVUS were included in the analysis. Lesions were matched at baseline and follow-up. The increase in external elastic membrane (EEM) area for each mm 2 increase in atheroma area was not significantly different in lesions with,40 and 40% atheroma burden at baseline (1.62 vs mm 2, P ¼ 0.30). There were no correlations between atheroma burden at baseline and change in EEM (r ¼ 0.02, P ¼ 0.86) or change in lumen (r ¼ 0.04, P ¼ 0.64) areas. Conclusion Assessment of coronary arterial remodelling by serial IVUS revealed that compensatory remodelling is not limited by atheroma burden. Atheroma burden is not a determinant of arterial enlargement during the progression of atherosclerosis. Introduction In a seminal article published in 1987, Glagov et al. 1 demonstrated that coronary arteries enlarge in response to the development of atherosclerotic plaques. This phenomenon is commonly referred to as arterial remodelling. According to the analyses of Glagov et al., 1 the compensatory remodelling process maintained luminal dimensions during early atherosclerosis. Importantly, these investigators reported that the capacity for compensatory enlargement diminished as plaques reached a cross-sectional area stenosis (atheroma burden) of 40% and plaque growth beyond this point resulted in a reduction of luminal area. This initial histological autopsy study and subsequent histological 2 and intravascular ultrasound (IVUS) 3 5 studies of arterial remodelling were based on the examination of lesions with varying disease severity using a cross-sectional study design, in which data were obtained only at a single time point. However, using this approach, the temporal * Corresponding author. Tel: þ ; fax: þ address: tuzcue@ccf.org sequence of plaque growth, remodelling, and luminal compromise could only be inferred. Serial in vivo IVUS studies are more difficult to perform, but allow direct assessment of the plaque progression and remodelling response We sought to examine the validity of Glagov s observation that coronary arteries lose their capacity for remodelling with increasing atheroma burden by using serial IVUS. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial 11,12 examined coronary disease progression during moderate or intensive lipid-lowering therapy. This trial represented an ideal setting for examining the serial remodelling response, because coronary atheroma, lumen, and vessel dimensions were evaluated by IVUS over time. Methods Study population The REVERSAL trial enrolled patients aged years who required coronary angiography for a clinical indication and demonstrated at least one obstruction with angiographic luminal diameter & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Atheroma burden and compensatory enlargement of coronaries 1665 narrowing of 20%. 11,12 The target vessel for the IVUS interrogation (a single coronary artery per patient) must not have undergone percutaneous intervention, nor have an angiographic luminal narrowing of.50%. We screened the baseline IVUS tapes of the 502 patients who completed the REVERSAL trial to identify those who had a focal atherosclerotic lesion. Diffusely diseased arteries were excluded because of the relative difficulty in serial matching of the lesion sites in such arteries. The lesions were further screened for the absence of extensive calcification precluding accurate measurement of external elastic membrane (EEM) area. A single lesion was selected from each patient (the most proximal one in the case of multiple acceptable lesions). A total of 210 lesions met the inclusion criteria. Because we intended to examine Glagov s conclusion that remodelling prevents lumen loss until an atheroma burden of 40% and plaque growth beyond this point results in luminal compromise, we included the 128 lesions that showed plaque growth (i.e. an increase in atheroma area at follow-up) in the current analysis. The REVERSAL trial complied with the Declaration of Helsinki. The Institutional Review Board of the Cleveland Clinic Foundation approved research using this database. Intravascular ultrasound The acquisition and measurement methodology of coronary IVUS images used in atherosclerosis progression regression trials have been described in detail previously. 11,13 Briefly, after administration of mg of intracoronary nitroglycerin, a 30 MHz, 2.6 F (0.87 mm) IVUS catheter (Ultracross, Boston Scientific Scimed Inc., Maple Grove, MN, USA) was advanced into the target vessel for IVUS interrogation and the transducer was positioned distal to a side branch (distal fiduciary site). A motorized pullback system withdrew the transducer at a speed of 0.5 mm/s. During the pullbacks, images were obtained at 30 frames/s and were recorded on s-vhs videotape for off-line analysis. After digitization of the videotapes, measurements of EEM area (a measure of arterial area) and lumen area were performed in accordance with the standards of the European Society of Cardiology 14 and American College of Cardiology. 8 Measurements were performed at every 60th frame (i.e. every 1 mm), starting at a distal fiduciary site and ending at a proximal fiduciary site. Atheroma area was calculated as EEM area minus lumen area. For this study, the frame with the largest amount of atheroma relative to the arterial size on inspection of the lesion was identified as the lesion site. For the lesion sites, atheroma burden was then calculated as: Atheroma burden ¼ Atheroma area 100% EEM area As the presence of an atherosclerosis free arc of artery has been suggested to be critical for compensatory remodelling to occur, 1 we also evaluated atheroma eccentricity at the lesion sites, which was calculated as: 8 Atheroma eccentricity index Maximum atheroma thickness Minimum atheroma thickness ¼ Maximum atheroma thickness Follow-up IVUS was performed after an 18-month treatment regimen with randomized double-blind atorvastatin 80 mg/day or pravastatin 40 mg/day. The IVUS interrogation was repeated under identical conditions at follow-up. Distances from the proximal and distal fiduciary sites, as well as plaque characteristics (e.g. calcifications and plaque shape) and perivascular structures, were used to match the lesion site at baseline and follow-up. The IVUS measurements were repeated at the lesion site at follow-up. Assessment of arterial remodelling To reproduce Glagov s finding that luminal compromise begins once an atheroma burden of 40% is reached, we correlated atheroma burden and lumen area using only the baseline data. 1 Subsequently, we evaluated the relationship between atheroma burden at the beginning of the study, and the actual change in lumen area over time (i.e. serial approach). We evaluated the relationship between atheroma burden and EEM area using the same methods. The primary outcome measure of this study was the homogeneity of regression slopes correlating the change in atheroma area with the change in EEM area in lesions with,40 and 40% atheroma burden at baseline. A difference in the regression slopes would demonstrate that for each mm 2 change in atheroma area, the change in EEM area would be different for lesions with,40 and 40% atheroma burden. This would signify a differential remodelling response in the two groups of lesions. In addition, this outcome measure was evaluated after controlling for on-treatment (follow-up) LDL cholesterol and log-transformed C-reactive protein levels, in an effort to limit the possible effects of statins. The same outcome measure was also evaluated using different cut-off values for atheroma burden. For further analysis, serial remodelling response was evaluated by change in EEM area/change in atheroma area, which was calculated as: 8 EEM area at follow up EEM area at baseline Atheroma area at follow up Atheroma area at baseline A ratio of.1 was considered as expansive (over-compensatory), as incomplete, and,0 as constrictive remodelling, and the categories of the remodelling response were compared according to baseline atheroma burden. The relationship between the atheroma burden and the serial remodelling response was also evaluated by correlating baseline atheroma burden with change in EEM area/ change in atheroma area as continuous variables. Data analysis Analyses were performed with SPSS 11.5 for Windows (SPSS Inc., Chicago, IL, USA). Quantitative data are expressed as mean + SD and categorical data as n (%), unless stated otherwise. Comparison of baseline and follow-up data was performed with the paired t-test, except for the non-normally distributed C-reactive protein, for which Wilcoxon s signed rank test was used. Whether the category of remodelling differed in lesions with,40 and 40% atheroma burden was examined with Fisher s exact test. Relationships were assessed by linear regression analysis, and the homogeneity of regression slopes was tested by analysis of covariance. Spearman s rank correlation was used in the case non-normally distributed data (change in EEM area/change in atheroma area). The outcome measure of homogeneity of regression slopes correlating the change in atheroma area with the change in EEM area in lesions with,40 and 40% atheroma burden was re-evaluated with follow-up LDL cholesterol and log-transformed C-reactive protein levels entered into the model as covariates. Adjustments using these two parameters were performed in an effort to control for the possible effects of statins on remodelling. Two-sided P-values of less than 0.05 were considered significant. The alpha level was not adjusted for multiple testing. Results Characteristics of the study population The clinical characteristics of the study population are presented in Table 1. Total cholesterol, LDL cholesterol, and triglycerides were lower, and HDL cholesterol was higher at follow-up when compared with baseline.

3 1666 I. Sipahi et al. Table 1 Characteristic Clinical characteristics of the study population Age (years) Male 89 (70%) Body mass index (kg/m 2 ) Smoking history Never 46 (36%) Past 45 (35%) Current 37 (29%) Hypertension 85 (66%) Diabetes 21 (16%) Baseline lipid profile and C-reactive protein Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol, (mg/dl) Triglycerides (mg/dl) C-reactive protein, (mg/l) 2.5 ( ) (median, interquartile range) Follow-up lipid profile and C-reactive protein Total cholesterol (mg/dl) * LDL cholesterol (mg/dl) * HDL cholesterol (mg/dl) ** Triglycerides (mg/dl) * C-reactive protein (mg/l) 2.0 ( ) (median, interquartile range) Previous statin use 37 (29%) Treatment allocation Atorvastatin 80 mg/day 59 (46%) Pravastatin 40 mg/day 69 (54%) *P, compared with baseline. **P ¼ compared with baseline. IVUS data at baseline and follow-up Of the 128 lesions analysed, 11(9%) were in the left main, 35 (27%) in left anterior descending, 46 (36%) in the left circumflex, and 36 (28%) in the right coronary artery. Range for atheroma burden was 28 77% at baseline. Twenty-eight lesions had,40% and 100 lesions had 40% atheroma burden. By definition, atheroma area was greater at follow-up (Table 2). This was associated with increased EEM and lumen areas at follow-up (P, for both). Atheroma burden and remodelling There was an inverse relation between lumen area and atheroma burden when only the baseline data were used (r ¼ 20.57, P, ) (Figure 1). The correlation was evident when the analysis was limited to lesions with 40% atheroma burden at baseline (r ¼ 20.51, P, 0.001). However, there was no statistically significant correlation when this analysis was limited to lesions with,40% atheroma burden (r ¼ 20.24, P ¼ 0.22) (P ¼ 0.51 for the heterogeneity of slopes for atheroma burden values,40 and 40%). However, very different results were observed with the serial approach. There was no relationship between the actual change in lumen area at follow-up and the atheroma burden (r ¼ 0.04, P ¼ 0.64), regardless of whether arteries had,40 or 40% atheroma burden Table 2 Intravascular ultrasound measurements at baseline and follow-up Measurement Baseline Follow-up P-value Atheroma area (mm 2 ) ,0.001 EEM area (mm 2 ) ,0.001 Lumen area (mm 2 ) ,0.001 Atheroma burden (%) ,0.001 Maximum atheroma thickness (mm) Minimum atheroma thickness (mm) Atheroma eccentricity index (P ¼ 0.98 for the heterogeneity of slopes for atheroma burden values,40 and 40%). Similarly, when only the baseline data were used, there was a trend for an inverse relationship between crosssectional area stenosis (atheroma burden) and EEM area (r ¼ 20.17, P ¼ 0.06). However, there was no relationship between atheroma burden and change in EEM area over time (r ¼ 0.02, P ¼ 0.86). There were significant correlations between changes in atheroma and EEM areas in lesions with both,40 (r ¼ 0.68, P, 0.001) and 40% (r ¼ 0.73, P, 0.001) atheroma burden (Figure 2). As the primary outcome measure, the increase in EEM area for each mm 2 increase in atheroma area (i.e. slope of the regression line) was not significantly different in lesions with,40 and 40% atheroma burden at baseline (1.62 vs mm 2, P ¼ 0.30). After controlling for on-treatment LDL cholesterol and C-reactive protein levels, the increase in EEM area for each mm 2 increase in atheroma area was also not different in the two groups (1.56 vs mm 2, P ¼ 0.38). Similarly, the slopes of the regression lines were not significantly different in lesions with baseline atheroma burden,50 and 50% (1.33 vs mm 2, P ¼ 0.99) and,60 and 60% (1.32 vs mm 2, P ¼ 0.77). There was no relationship between baseline atheroma burden and change in EEM area/change in atheroma area when both parameters entered into the regression analysis as continuous variables (r ¼ 0.04, P ¼ 0.64). The category of the remodelling response was also not significantly different according to baseline atheroma burden (P ¼ 0.44) (Figure 3). Representative serial IVUS images of lesions with,40 and 40% atheroma burden are shown in Figure 4. Eccentricity and remodelling There was no correlation between atheroma eccentricity index at baseline and change in EEM area/change in atheroma area (r ¼ 0.04, P ¼ 0.70). There was no correlation between minimum atheroma thickness at baseline and change in EEM area/change in atheroma area as well (r ¼ 20.06, P ¼ 0.54). Coronary risk factors (age, male gender, current smoking, hypertension, diabetes and on-treatment total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and log-transformed C-reactive protein levels) were not determinants of change in EEM area/ change in atheroma area either (P for all).

4 Atheroma burden and compensatory enlargement of coronaries 1667 Figure 1 (A) shows the correlation between atheroma burden and lumen area when only the baseline data are used. There is no significant correlation in lesions with,40% atheroma burden (dashed line). There is a significant negative correlation in lesions with.40% atheroma burden (straight line). (B) examines the relationship between atheroma burden and change in lumen area. (C) shows the correlation between atheroma burden and EEM area using the baseline data only. (D) examines the same relationship serially. Figure 2 Changes in atheroma and EEM areas are closely correlated in lesions with either,40 (A) or40% (B) atheroma burden at baseline. Slopes of the two regression lines are not significantly different (1.62 vs. 1.28, P ¼ 0.30). Discussion Our serial IVUS observations demonstrate that the extent of coronary arterial enlargement in response to progression of atherosclerosis is not related to per cent cross-sectional stenosis (atheroma burden). The increase in EEM area for each mm 2 increase in atheroma area is not significantly different in lesions with,40 and 40% atheroma burden and is independent of the eccentricity of the lesion at baseline. Arterial remodelling is the mechanism by which the luminal size is preserved despite the development of an atherosclerotic plaque. This phenomenon was first systematically described in a histopathological study by Glagov et al. 1 Using 136 left main coronary arteries obtained at autopsy, these investigators demonstrated a positive correlation between internal elastic membrane area (a measure of arterial area) and plaque area, which showed that arteries enlarge as atherosclerosis progresses. In addition, there was a negative correlation between atheroma burden and lumen area in lesions with 40% atheroma burden. Importantly, this correlation was not observed in lesions with,40% atheroma burden. Therefore, it was

5 1668 I. Sipahi et al. concluded that the compensatory enlargement sharply declines after coronary lesions occupy 40% of the arterial area. This conclusion has been widely accepted. 3,4,15 18 However, there are theoretical limitations with this approach. Because atheroma burden is calculated as (internal elastic membrane area 2 lumen area)/internal elastic membrane area, 1 the relationship between lumen area and atheroma burden can be described as the relationship Figure 3 Frequencies of the different categories of remodelling are not different, according to baseline atheroma burden (P ¼ 0.44). between a and (b 2 a)/b. Therefore, mathematically, as a decreases, (b 2 a)/b will increase. This can explain the smaller lumen areas with larger atheroma burden. In fact, results from other histopathological studies do not completely support the conclusion that compensation fails when stenosis reaches 40%. In one study, there was an increase in lumen area with increasing plaque area, suggesting that more severely diseased arteries had greater over-compensation. 19 Interestingly, in the same study, there was an inverse relationship between lumen area and atheroma burden, which paralleled the results of Glagov et al. 1 This discrepancy demonstrates the contradictory interpretations conveyed by studying the relationship between lumen area and plaque area, rather than lumen area vs. a function of lumen area (i.e. atheroma burden). The limitation of studying arterial remodelling by correlation analysis of mathematically related variables has also been reported in an IVUS study. 20 Because of the limitations of the assessing arterial remodelling at a single time point, the American College of Cardiology/ European Society of Cardiology clinical expert consensus document on IVUS has stated that evidence of remodelling would be best directly derived from measurements obtained at different time points (i.e. serial assessment). 8 We found important differences when we analysed remodelling using the two approaches. The comparison of single time point assessment that uses only the baseline data with Figure 4 (A) and(b) show the IVUS images of a lesion with,40% atheroma burden at baseline (36%). At follow-up, atheroma area is increased. However, owing to concomitant expansion of the EEM area, the lumen is not compromised. (C) and (D) show the images of a lesion with 40% atheroma burden at baseline (51%). Again, along with an increase in atheroma area, there is an increase in EEM area and the lumen is not compromised at follow-up.

6 Atheroma burden and compensatory enlargement of coronaries 1669 serial assessment that uses both baseline and follow-up data provides insights into the reasons for the discrepancy. The former approach is the method introduced by Glagov and coworkers. Using this method, we could reproduce the findings of these investigators, demonstrating compensatory remodelling in lesions with,40% atheroma burden, but a lack of compensation once atheroma burden reaches 40%. However, the results were very different when remodelling was assessed over the 18-month follow-up period. This serial approach revealed that lesions with 40% atheroma burden have the same remodelling behaviour as lesions with,40% atheroma burden. This serial approach explores the relationship between lumen area and atheroma burden by adding a third independent variable (i.e. lumen area at follow-up) to the relationship. The addition of this variable to the correlation analysis weakens the possibility of an inevitable correlation between mathematically related variables. Because of this additional variable in the serial assessment, the time-dependent phenomena of remodelling and luminal compromise during plaque progression could be explored, demonstrating that atheroma burden is not a determinant of compensatory remodelling of coronary arteries. Glagov et al. 1 also proposed that earlier (i.e. less stenotic) lesions are usually more eccentric, and the presence of a larger arc of disease-free arterial wall in these lesions accounts for their greater capacity for compensatory remodelling. We found no relationship between atheroma eccentricity index and the serial remodelling response, which does not support this hypothesis. We found no relationship between minimum atheroma thickness (another measure of disease-free arterial wall) and remodelling either. Limitations Serial IVUS studies are limited by difficulties in matching single cross-sections at different time points because of the diffuse nature of atherosclerosis. Therefore, in contemporary serial IVUS trials studying progression and/or regression of atherosclerosis, volumetric assessment of disease burden is preferred over two-dimensional measurements. 11,13 However, to be able to reproduce the results of Glagov et al., 1 we choose the two-dimensional approach of these investigators. Although every effort was made to match the lesion sites at baseline and follow-up, matching may have been imperfect in some cases. The included lesions were identified in patients undergoing either a moderate or an aggressive lipid-lowering regimen. Therefore, our results describe observations in lesions with progression of disease, despite lipid-lowering therapy. As treatment with statins may alter the remodelling response, 9,21 we did a secondary analysis of the outcome measure using LDL cholesterol and C-reactive protein levels as covariates. Even though these two variables did not influence the lack of relationship between atheroma burden and remodelling, there is still a possibility that our findings may not be applicable to lesions of patients not undergoing statin treatment. Similarly, these findings may not be applicable to diffuse or overtly calcified lesions, which were not included in this study. Conclusions Assessment of arterial remodelling using serial in vivo IVUS reveals that atheroma burden (per cent cross-sectional area stenosis) is not a determinant of the extent of coronary arterial enlargement during disease progression. We demonstrate that serial assessment of atherosclerotic disease provides novel insights into the relationship between the plaque progression and the remodelling response. Acknowledgements We thank Timothy Crowe, William A. Magyar, Deborah Hansen, Tammy Churchill, Benlan Wong, and Aaron Loyd at The Cleveland Clinic Foundation Intravascular Ultrasound Core Laboratory for their technical support. The REVERSAL trial was funded by Pfizer. This substudy is partially funded by the National Institutes of Health, National Center for Research Resources, General Clinical Research Center Grant MO1 RR P.S. was supported by a postdoctoral fellowship grant of the Ohio Affiliate of the American Heart Association. A Ralph Reader Overseas Research Fellowship from the National Heart Foundation of Australia supports S.J.N. Conflict of interest: I.S. received an educational grant from Pfizer. E.M.T. has received research support and lecture honoraria from Pfizer. S.J.N. received lecture honoraria from Pfizer. S.E.N. has received research support from and is an unpaid consultant to Pfizer. References 1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. 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Am J Cardiol 1997; 79: Hamasaki S, Higano ST, Suwaidi JA, Nishimura RA, Miyauchi K, Holmes DR Jr, Lerman A. Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries. Arterioscler Thromb Vasc Biol 2000;20: Clinical vignette doi: /eurheartj/ehi766 Online publish-ahead-of-print 7 February 2006 Atrial pathology in cardiac amyloidosis: evidence from ECG and cardiovascular magnetic resonance C. Paul Leeson 1 *, Saul G. Myerson 2, Genevieve B. Walls 1, Stefan Neubauer 2, and Oliver J. Ormerod 1 1 Department of Cardiology, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK and 2 University of Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, UK * Corresponding author. Tel: þ ; fax: þ address: paul.leeson@cardiov.ox.ac.uk A 59-year-old man presented with chest pain and singlevessel coronary disease on angiography. Left ventricular function was normal with mild hypertrophy. He was treated for coronary disease but represented 18 months later with biventricular heart failure. There had been a striking ECG evolution: ST-segment change; reduced QRS amplitude; increased P-wave width and amplitude; and progressive increase in PR interval ( ms) (Panel A). Echocardiography now demonstrated a grossly hypertrophied, sparkling, left ventricle (Panel B) and Doppler evidence of restrictive cardiomyopathy. Cardiac magnetic resonance imaging (Panel C) revealed widespread, diffuse enhancement with contrast on inversion recovery sequences, including both atria, in keeping with an infiltrative cardiomyopathy such as amyloid. Left ventricular function was poor (ejection fraction 23%), with severe hypertrophy (septal thickness 19 mm; mass index 134 g/m 2 ) and small left ventricular volumes (EDV 69 ml, ESV 51 ml). Urine electrophoresis revealed lambda light chain proteinuria and bone marrow biopsy a plasma cell dyscrasia. Progressive reduction in QRS amplitude with progressive increase in left ventricular thickness is classical for cardiac amyloid. P-wave morphology demonstrated additional significant atrial involvement. Restrictive cardiomyopathy leads to bi-atrial enlargement and increased P-wave amplitude and width. Furthermore, atrial amyloid deposition delays atrial conduction and thereby increases the PR interval and broadens the P-wave. Both atrial pathologies were clearly demonstrated by cardiovascular magnetic resonance imaging, with bi-atrial enlargement and marked wall enhancement consistent with atrial amyloid deposition. Cardiovascular magnetic resonance imaging is a powerful tool to aid diagnosis and assess severity in infiltrative cardiomyopathies. Panel A. Repeat electrocardiograms in the same patient over 18 months. There has been a marked increase in P-wave width and amplitude, lengthening of the PR interval, and a reduction in amplitude of the QRS voltage. Panel B. Echocardiogram showing gross increase in size of left ventricle with sparkling appearance suggestive of amyloid. Panel C. Cardiovascular magnetic resonance image showing extensive enhancement (white) of the ventricular myocardium, and also of both atria, with gadolinium contrast using a late inversion-recovery technique.