Cardiac remodelling in the era of aggressive medical therapy: does it still exist?

Cardiac remodelling in the era of aggressive medical therapy: does it still exist?

International Journal of Cardiology 83 (2002) 217–225 www.elsevier.com / locate / ijcard Cardiac remodelling in the era of aggressive medical therapy...

324KB Sizes 0 Downloads 5 Views

International Journal of Cardiology 83 (2002) 217–225 www.elsevier.com / locate / ijcard

Cardiac remodelling in the era of aggressive medical therapy: does it still exist? a, b a b b Nicholas G. Bellenger *, Jonathan M.A. Swinburn , Kim Rajappan , Avijit Lahiri , Roxy Senior , Dudley J. Pennell a a

Cardiovascular MR Unit, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK b Cardiac Research Department, Northwick Park Hospital, Harrow, UK Received 28 July 2001; received in revised form 19 December 2001; accepted 23 January 2002

Abstract Aim: To delineate the natural history of left ventricular remodelling following large anterior myocardial infarction (MI), in the era of aggressive medical therapy. Methods: Seventeen selected patients underwent cardiovascular magnetic resonance (CMR) at 2 weeks and 1, 3, 6 and 12 months post infarction. Results: There was a significant increase in left ventricular (LV) end-diastolic volume index (EDVI) and LV ESVI from 2 weeks to 1 month (P,0.05) but no significant change thereafter. The LV ejection fraction (EF) decreased from 2 weeks to 1 month (P,0.05) and then increased over the year (P50.02). Throughout the study period the sphericity index increased. There was a significant and progressive decrease in LV mass index over the year, which was associated with a decrease in wall thickness at both the infarct and non-infarct sites. Independent predictors of an early increase in LVESVI were increasing age, increasing CK-MB and not receiving treatment with a statin. Conclusion: This study delineates the natural history of left ventricular remodelling in the modern medical era in those patients who have suffered a large anterior MI. Classical remodelling occurred up to 1 month, but thereafter was attenuated. These findings would suggest that remodelling is not as prevalent in the modern era, and that combined medical management with thrombolysis, ACEi, beta-blockers and statins may strongly influence the development of this remodelling.  2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Remodelling; Myocardial infarction; Cardiovascular magnetic resonance

1. Introduction Following myocardial infarction (MI), the heart undergoes a process of architectural remodelling that has profound effects on both cardiac function and prognosis [1–4]. This has been demonstrated in both animal [5–8] and human studies using echocardiography [9,10], computed tomography [11] and *Corresponding author. 2 St. Edmunds, 86 Christchurch Road, Winchester, Hampshire SO23 9TE, UK. Tel.: 144-20-7351-8810; fax: 144-20-7351-8816. E-mail addresses: [email protected] (N.G. Bellenger), [email protected] (N.G. Bellenger).

radionuclide ventriculography (RNV) [12]. In recent years however, there have been major advances in both the immediate and long term therapy of patients who have suffered MI, many of which may affect the remodelling process. In particular, the use of angiotensin converting enzyme inhibitors (ACEi), but also beta-blockers, aspirin and thrombolysis [13–17]. There have been few studies of this remodelling process in the modern therapeutic era, which may be partly attributed to the limitations of the techniques available. Echocardiography is well established, rapid and safe but suffers from relatively poor inter-study reproducibility [18,19] and requires large patient

0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00034-7

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

218

numbers in studies. Nuclear cardiology offers higher reproducibility but the radiation exposure limits the repeated temporal study of individuals, and it does not provide a measure of ventricular geometry or mass. Fast acquisition cardiovascular magnetic resonance (CMR) provides an accurate measure of volume, function and mass that is free of ionizing radiation, and the high reproducibility permits the use of a small number of patients to reach statistical significance [20–25]. We used CMR to delineate the natural history of left ventricular remodelling in a group of patients most likely to undergo adverse remodelling, namely those who have suffered large anterior myocardial infarction. We hypothesized that combined aggressive medical therapy may limit infarction related remodelling.

2. Methods

2.1. Patients We studied 17 consecutive patients who presented to Northwick Park Hospital with their first anterior MI and who satisfied the inclusion criteria (Table 1). Only those patients who had a large anterior MI as

judged by clinical history of classical pain and autonomic features for .1 h, electrocardiography with .2 mm ST elevation in .2 adjacent anterior leads, plasma creatine kinase (CK) levels at least two times the upper limit of normal (male .175, female .150) with an MB fraction of .5% were included. Furthermore regional wall motion abnormalities had to be present in .2 adjacent anterior segments by echocardiography and the total wall motion score by CMR had to be .20 to ensure only those patients with large anterior infarcts were included (mean5 2964 using a 16 segment model and a score of 1—normal, 2—hypokinetic, 3—akinetic, 4— dyskinetic). The average age was 59611years and 12 were men. All patients received aspirin at the time of admission, 12 patients received thrombolysis, but five did not due to the presence of contra-indications. The mean peak CK was 250161957. All patients had significant regional wall motion abnormality on echo before entry into the study. The patients medications between day 5 and 1 year included aspirin in 100%, angiotensin converting enzyme inhibitors (ACEi) in 94%, statins in 88%, beta-blockers in 65%, and diuretics in 35%. No patients were receiving calcium channel blockers and only one received nitrates

Table 1 Clinical variables for the patients studied Patient No.

Gender

Age

Ethnidity

Smoker

Chol

Fx

Diabetes

Rx

Peak CK

ACE

Beta-blocker

Statics

Nitrates

1 2 3 4 5

F M M M M

62 60 46 51 64

Caucasian Caucasian Asian Caucasian Asian

Y Ex N Y Y

8.3 4.9 6.9 6.2 –

N N Y Y N

N Y N N Y

b-PA None t-PA t-PA t-PA

3985 2328 3417 2310 1941

Aten Cerv Aten Aten Aten

Atorv 10 Simv 20 Atorv 15 Atorv 20 Simv 20

N N Imdur 30 N N

6 7 8 9 10 11 12 13 14 15 16 17

M M M M F F M F M M F M

58 58 47 67 82 44 52 41 65 75 61 73

Caucasian Caucasian Asian Asian Caucasian Caucasian Caucasian Caucasian Caucasian Asian Caucasian Caucasian

N N Ex N Ex N Es Y N N Y Y

7.3 4.2 3.8 5 10.7 7.8 5.5 8.3 5.5 4.9 5.8 7.9

N Y N Y N Y Y Y N N Y Y

N Y Y N N N N Y N N N N

None None t-PA t-PA Strep None t-PA Strep t-PA Strep t-PA None

1421 138 a 2597 984 2982 994 3254 415 725 1318 5912 7509

Opt 50 Ram 5 Poem 4 Ram 5 Ram 53/12 Then Los 50 Opt 50 Opt 50 Ram 10 Opt 50 Poem 4 N Ram 10 Lisin 10 Opt 50 Opt 50 Opt 50 Opt 50

Simv 10

N N N N N N N N N N N N

253/1 12.5 50 25 50

Carv 12.5 Carved 25 Car 12.5 Aten 50 N Aten 100 Carv 25 Atem 50 Aten 25 N N Aten 25

Prev 40 N Ateol 20 Sim 20 Ator 20 Ator 20 Sim 20 Sim 10 Sim 20 Sim 20

Chol—cholesterol level, Fx—family history, Rx—treatment, strep—streptokinase, CK—creatine kinase, ACE—angiotensin converting enzyme inhibitor. Opt5optimal 50 (30 capt tds or 50 losartan od) 25 (25 captopal td or 25 lostan od etc.). The dose stated for each medication is the maximum tolerated. The time to reach maximum dose was up to 3 weeks post MI. a Delayed presentation.

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

(Table 1). Only one patient (patient 3) was hypertensive prior to their MI. All other cardiovascular risk factors are shown in Table 1. All patients underwent CMR at Royal Brompton Hospital at 260.5 weeks post infarction, as well as 160.1, 360.3, 660.9, and 11.362.6 months. One patient died at home prior to the 6 month scan and one patient could not attend their year scan. The study was approved by the ethics committee of both centers and written consent was obtained.

2.2. CMR Subjects were imaged with a Picker Edge 1.5 T scanner (Picker, Cleveland, OH), using the body coil and electrocardiogram (ECG) triggering, as previously described [23]. In brief, the cardiac short axis was determined from three scout images of the left ventricle (LV), the transverse, vertical long axis and breath-hold diastolic horizontal long axis. The basal short axis slice was positioned just forward of the atrio-ventricular ring, and all subsequent breath-hold cines were acquired in 1 cm steps towards the apex. A breath-hold segmented gradient echo fast lowangle shot (FLASH) sequence was used for each of the contiguous short axis slices. Parameters were as follows: Echo time (TE) 3.8 ms, repeat time (TR)5 RR interval, slice thickness 10 mm, field of view 35335 cm, read matrix 256, phase matrix 128, frames 16, flip angle 358, phase encode group 6–10. An average of ten short axis segments was needed to encompass the entire left ventricle. The average scanning time was 18 min. Image Analysis was performed on a personal computer using in-house developed software (CMRtools Royal Brompton and Harefield NHS trust). End-diastolic and end-systolic images were chosen as the maximal and minimal cross-sectional areas in each cine. Short axis end-diastolic epicardial and endocardial borders were traced manually for each slice. From the area within the contours and the slice thickness, the epicardial and endocardial volumes were calculated, the difference representing myocardial volume. Mass was derived from this volume multiplied by the specific density of myocardium (1.05 g / cm 3 ) [26]. End-systolic endocardial borders were also traced; the difference between end-diastolic and end-systolic representing the left

219

ventricular stroke volume. Ejection fraction (%) was calculated as LV stroke volume / LV end-diastolic volume. Papillary muscles were included in the mass and excluded from the volume. Care was taken not to include atrial slices at end-systole secondary to apical movement of the base of the heart during LV contraction. Further information on the geometric changes with time was provided by calculating the sphericity index from the ratio of the left ventricular long axis dimension (apex to mitral valve in the horizontal long axis) and the short axis diameter at the level of the tips of the papillary muscles [31]. Left ventricular wall thickness was measured from the short axis slices in the infarcted and non-infarcted regions (most remote from the infarcted region to avoid any influence from adjacent infarcted myocardium). All analysis was performed with investigators blinded to the patient details and previous results, and the scans were presented in random order. The reproducibility of this technique in our center has been previously published and the interstudy percentage variability was 2.5% for EDV, 3.1% for ESV, 4.8% for EF and 3% for mass [23,24].

2.3. Statistical analysis Clinical variables were compared between each time interval using analysis of variance with post-hoc testing and the results were expressed as mean6standard deviation (S.D.) with a P value of ,0.05 considered statistically significant. These variables included heart rate, blood pressure, LV enddiastolic volume index (EDVI), LV end-systolic volume index (ESVI), LV ejection fraction (EF), and LV mass index (MI). Multivariate logistic regression analysis was performed to assess the relationship between continuous independent variables (heart rate, blood pressure, age, cholesterol, hours of pain, peak CK and CK-MB) and changes in LV EDVI, ESVI, EF and LVMI over the different time intervals. Analysis of variance was also performed to assess the relationship between nominal independent variables (sex, ethnicity, risk factors and individual medications) and these continuous independent variables. Adjustments were included to correct for the effect of multiple comparisons. The statistical software program StatView version 4.53 (Abacus Concepts Inc., Berkeley, California, USA) was used. From previous-

220

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

ly published reproducibility figures [23,24], the minimum detectable difference in EDV, ESV, EF and mass by CMR using 17 subjects is 8.4 ml, 7.4 ml, 2.8% and 7.3 g, respectively.

3. Results

3.1. Clinical variables The patient’s average heart rate between the four time intervals tended to decrease but this was only significant between 2 weeks and 6 months (P,0.05), with mean heart rates of 68616 at baseline, 66618 at 1 month, 65612 at 3 months, 63611 at 6 months, and 6369 at 1 year. There was no significant difference in systolic / diastolic blood pressure between scans, with 119624 / 76611 mmHg at 2 weeks, 125630 / 79611 at 1 month, 126630 / 7960 at 3 months, 120625 / 75613 at 6 months, and 118625 / 75613 at 1 year.

3.2. Left ventricular volumes and function There was a significant increase in LVEDVI from 2 weeks to 1 month (101626 to 106626 ml / m 2 , P, 0.05) but no significant difference thereafter (103624 ml / m 2 at 3 months, 102626 ml / m 2 at 6 months, 102628 ml / m 2 at 1 year). Similarly there was a significant increase in LVESI from 2 weeks to 1 month (62627 to 69630 ml / m 2 , P50.007) but no significant difference thereafter (63626 ml / m 2 at 3 months, 62629 ml / m 2 at 6 months, and 61631 ml / m 2 at 1 year). Although not significant, both LVEDVI and LVESVI showed a trend towards a reduction in size after 1 month (Fig. 1). There was a significant decrease in LVEF from 2 weeks to 1 month (40613% to 37614%, P,0.05) followed by a significant increase from 1 month to 3 months (37614% to 41613%, P50.005), and 1 month to 1 year (37614% to 43615%, P50.02). There was no significant difference between 3 months and 6 months (42614% at 6 months) (Fig. 1).

Fig. 1. Changes in LV end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF) and mass index (LVMI) between 2 weeks, 1, 3, 6 and 12 months.

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

3.3. Left ventricular mass index Throughout the study period there was a significant decrease in LV mass index, with a mean mass of 83617 g / m 2 at 2 weeks, 79616 g / m 2 at 1 month (P50.007 vs. 2 weeks), 73618 g / m 2 at 3 months (P50.006 vs. 1 month), 67618 g / m 2 at 6 months (P50.007 vs. 3 months), and 61611 g / m 2 at 1 year (P50.0001 vs. 2 weeks) (Fig. 1).

3.4. Infarct and non-infarct wall thickness There was a significant decrease in both the infarcted and non-infarcted wall thickness from 2 weeks to 6 months. The mean wall thickness in the infarct site decreased from 9.162.7 mm at 2 weeks to 8.163.3 mm at 1 month (P,0.01), 6.863.0 mm at 3 months (P,0.01 vs. 1 month), 6.063.3 mm at 6 months (P,0.05 vs. 3 months), and 5.062.9 mm at 1 year (P,0.001 vs. 6 months). The mean wall thickness in the non-infarct site decreased from 12.963.3 mm at 2 weeks to 11.862.6 at 1 month (P,0.01), 11.262.6 at 3 months (P,0.05 vs. 1 month), and 10.762.7 mm at 6 months (P,0.01 vs. 3 months), and 10.962.5 mm at 1 year (ns vs. 6 months).

221

were significantly associated with the increase in LVEDVI and LVESVI nor the decrease in LVEF and LVMI over this time period. These variables included heart rate, blood pressure, age, admission cholesterol and hours of pain. Of the nominal variables (sex, ethnicity, treatment with ACE-inhibitors, beta-blockers, calcium antagonists, nitrates, diuretics, a past history of smoking, hypertension, diabetes, hyperlipidemia, family history) there were only two statistically significant associations. Gender was associated with a decrease in mass between 2 weeks and 1 month (male mean difference526.566.5 g / m 2 , female50.0562.5 g / m 2 , P,0.05). Treatment with a statin was significantly associated with a reduced ESVI over 6 months (on statin mean difference5 5.268.3 g / m 2 , off statin51861.4 g / m 2 , P,0.05) Only two patients did not receive statins, patient 7 and 9 (Table 1). Their admission cholesterol was 4.2 and 5.0 mmol / l and their peak CK was 138 and 984, respectively. There were no other statistically significant associations for any of the other time interval comparisons, except total CK and the reduction in LVMI over the year (P50.002).

4. Discussion

3.5. Sphericity index The sphericity index progressively increased throughout the study from 1.4760.19 at 2 weeks to 1.5560.22 at 1 month (P,0.05), 1.6060.16 at 3 months (P,0.001 vs. 2 weeks), 1.6460.22 at 6 months (P,0.001 vs. 2 weeks), and 1.760.2 at 1 year (P,0.001 vs. 6 months). This would imply a favourable alteration of geometry throughout the study with the ventricle adopting a less spherical shape.

3.6. Predictors of remodelling Multiple regression analysis for the change in LV EDVI, ESVI, EF and mass index between 2 weeks and 1 month post MI demonstrated that the only significant predictors were increasing age for DLVESVI (P,0.05) and DLVEF (P,0.01) and increasing levels of CK-MB for DLVESVI (P,0.05) and DLVEF (P,0.05). Total CK predicted DLVEF (P,0.01) and DLVMI (P,0.05). No other variables

This study delineates the natural history of left ventricular remodelling in the era of aggressive medical therapy in those patients who have suffered a large anterior MI. By using CMR, which has previously been shown to permit the use of a small number of patients to reach statistical significance [24], and by studying those patients most likely to remodel, this study confirms and extends previous reports on the remodelling process. In these patients, classical remodelling occurred between 2 weeks and 1 month, whereby there is an increase in LVEDVI and ESVI and a decrease in EF and LVMI, but after this the process was markedly attenuated. Classical expansion and volume increase did not occur after 1 month and there was some improvement in left ventricular geometry and EF. LVMI continued to decrease over the year due to both infarct resorption and prevention of compensatory hypertrophy in the remote myocardium. These findings would suggest that remodelling is not as prevalent in the modern era, and that combined

222

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

medical management with thrombolysis, ACEi, betablockers and statins may strongly influence the development of this remodelling.

There have, however, been few serial studies of individuals on modern combination therapy following large anterior MI.

4.1. Previous studies of remodelling post acute MI

4.3. Previous studies using CMR

Early studies confirmed the classical description of post infarction left ventricular remodelling whereby early expansion from cellular necrosis and slippage is followed by a more progressive and insidious dilatation with alteration of left ventricular geometry and the adoption of a more spherical shape. Compensatory hypertrophy of the non-infarcted area leads to an increase in total left ventricular mass [1–3,27]. For example, Jeremy et al. [28] used radionuclide angiography in their study of 50 patients following their first MI, and found a 42% increase in LVEDV over 6 months with those with anterior MI showing progressive dilatation at each scan. Other studies with CT have shown progressive LV dilatation and reduction in mass [11]. Echocardiography has been widely used to study this process, from early studies by Picard et al. [29] who demonstrated infarct expansion over 3 months, to the large SAVE database that revealed a 27% increase in LV cavity area at 1 year. More recently Gaudron et al. [12] studied 70 patients following their first MI and found almost 26% may develop early left ventricular dilatation with 20% suffering progressive dilatation thereafter. These, and many other studies, however, were performed in patients generally not treated with modern aggressive therapy that includes a combination of early thrombolysis with the addition of ACEi, beta-blockade and aggressive cholesterol lowering.

There have been few studies of remodelling post MI using CMR. Most have focused on animal models and of those studies performed in humans the majority have used traditional GRE cine imaging which suffers from long acquisition times. Very few have attempted to use the modern fast acquisition breathhold imaging and fewer still relate to patients treated with the full range of modern medical therapies now available. Early work using CMR examined the effect of MI in animals at one time point. In terms of dynamic remodelling, however, Kramer et al. [8] used an ovine model to performed coronary ligation and induce an anteroapical infarct. They found a significant increase in these volumes and mass measured by CMR over 6 months. The infarct wall thickness fell with no change in wall thickness in the non-infarcted regions. In man, Konermann et al. [32] examined the remodelling process using traditional cine CMR and long acquisition times. They demonstrated an increase in LV EDVI, LV ESVI and mass over 26 weeks, with the greatest increase in volume occurring in those with anterior infarction. Kramer et al. applied their experience from ovine work to man in the study of 26 patients following anterior MI from a single vessel left anterior descending artery occlusion [8]. Over 8 weeks the EDVI increased but the ESVI did not. The mass index reduced over this time. They demonstrated an improved ejection fraction over this time period due to improved regional function in both infarcted and non-infarcted regions. The growing remit of pharmaceutical interventions has fuelled the demand for reproducible measures of cardiac remodelling. As such CMR has been used to assess the response of animal models of MI to agents such as angiotensin converting enzyme inhibitors (ACEi), beta-blockers and angiotensin II antagonists [33–35]. Johnson et al. is one of the few authors to use CMR to obtain a comprehensive evaluation of the left ventricle in patients. They examined 35 patients with EF.40% and demonstrate a fall in LV mass index between 1 week and 3 month post MI by an

4.2. Recent studies Recent studies have focused on the potential of a number of agents for inhibiting or reversing this remodelling process through such mechanisms as the resolution of stunning [10,15] or inhibition of neuroendocrine stimulation [3,8]. ACEi have been shown to limit the increase in EDV over time [10,15,13,16], and the benefit of beta-blockade in patients with chronic stable heart failure would suggest that these agents may have similar effects [30]. Certainly Carvedilol has already been shown to attenuate remodelling following myocardial infarction [31].

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

ACEi [16]. There was, however, no difference in volume between treatment group and control. In a similar study but with patients with EF ,40% they found the LV EDV and mass increased with some improvement in EF [36]. Overall there is little consensus as to the process of cardiac remodelling following MI in the current era of modern medical therapy and few studies have attempted to utilise the accuracy and reproducibility of CMR.

4.4. Predictors of remodelling Many studies have demonstrated that anterior MIs are more likely to undergo remodelling, and for that reason this study focused on individuals with anterior MI [12,29]. Early work in rats [37] as well as later human studies [12] have shown an association between the size of the MI and the degree of remodelling that occurs. This is reflected in our study by the significant predictive power of the CK-MB on the decrease in ESVI between 2 weeks and 1 month. This may explain why other studies have shown early changes in ESVI post MI to be a powerful predictor of future morbidity and events [4]. In patients receiving modern therapy, however, the CK-MB did not predict any later progressive remodelling. Age was an additional predictor of early remodelling and may reflect the poor prognostic value that age has on survival post MI. Nevertheless, age did not preclude later inhibition of the remodelling process. The only other significant predictor was treatment with statins. Although only two patients did not receive a statin due to having an admission cholesterol of ,5 mmol / l, these two patients (patient 7 and 9 in Table 1) had a significantly greater increase in ESVI between 2 weeks and 1 month. Such small numbers precludes any definitive comment but interestingly, these patients did not have particularly large MIs when compared to the group and although one did not receive thrombolysis, four patients in the statin group did not either.

223

as they have previously been shown to produce the greatest remodelling. However this precludes the extrapolation of these findings to patients with inferior MIs or patients with previous infarction. CMR has previously been shown to permit the use of a small number of patients to reach statistical significance [24], however, the small numbers do not allow examination of the effect of individual medications or doses of those medications. All patients received modern therapy on clinical grounds and no attempt to randomize to different medications or different combinations was made. No placebo control group was included in the study as this would be ethically unacceptable. A further limitation was the lack of consistent, systematic angiography data to control for the effect of infarct related artery flow and re-occlusion, both of which may effect remodelling. Furthermore, none of the patients in this study received primary angioplasty. Nevertheless, it is reasonable to assume that such interventions are likely to reduce the degree of remodelling still further and may simply increase the significance of this study. The viability of the infarct zone may affect the degree of remodelling. Viability was not measured in this study and the lack of remodelling may reflect the presence of viable myocardium in all our subjects. Nevertheless, all patients suffered large anterior MIs and are a representative group of such patients receiving modern medical therapy. This study was not powered for, nor did it attempt to explore the complex pathophysiology or tease out specific reasons for reverse remodelling, but offers an accurate observational description of the architectural and functional changes in the left ventricle following MI in the current era. Such an important observation may well be the stimulus for further research into the reasons for such reverse remodelling. Larger studies should be conducted to confirm these initial findings and explore the degree to which the presence of viable myocardium, myocardial stunning, hibernating myocardium and specific therapeutic interventions influence the remodelling process.

4.5. Limitations The aim of this study was to follow the serial changes in patients with large anterior MIs on aggressive medical therapy. This group was chosen

5. Conclusion This study delineates the natural history of left

224

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225

ventricular remodelling in the era of aggressive medical therapy in those patients who have suffered a large anterior MI. Classical remodelling with infarct expansion and a decrease in EF and LVMI occurred up to 1 month. Thereafter, however, remodelling no longer occurred, with no difference in EDVI or ESVI and some improvement in EF and left ventricular geometry by 6 months. LV mass index, however, continued to decline progressively, both due to infarct resorption and prevention of compensatory hypertrophy in the remote myocardium. These findings would suggest that remodelling is not as prevalent in the modern era, and that combined medical management with thrombolysis, ACEi, beta-blockers and statins may strongly influence the development of this remodelling. Larger studies, with a more heterogeneous population, would delineate the minority of patients that may still be at risk of remodelling.

References [1] Pfeffer MA, Braunwald E. Ventricular remodelling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81:1161–72. [2] McKay RG, Pfeffer MA, Pasternak RC et al. Left ventricular remodelling following myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693–702. [3] Mitchell GF, Lamas GA, Vughan DE, Pfeffer MA. Left ventricular remodelling in the year after first anterior myocardial infarction. J Am Coll Cardiol 1992;19:1136–44. [4] White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44–51. [5] Eaton LW, Bulkley BH. Expansion of acute myocardial infarction: its relationship to the infarct morphology in a canine model. Circ Res 1981;49:80–90. [6] Weisman HF, Bush DE, Mannisi JA, Bulkley BH. Global cardiac remodelling after acute myocardial infarction: a study in the rat model. J Am Coll Cardiol 1985;5:1355–62. [7] Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted ventricle of the rat. Circ Res 1985;57:84– 95. [8] Kramer CM, Lima JAC, Reichek N et al. Regional function within noninfarcted myocardium during left ventricular remodelling. Circulation 1993;88:1279–88. [9] Eaton LW, Weiss JL, Bulkey BH, Garrison JB, Weisfelt MD. Regional cardiac dilatation after myocardial infarction; recognition by two dimensional echocardiography. New Engl J Med 1979;300:57–62. [10] St John Sutton M, Pfeffer MA, Plappert T et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994;89:68–75.

[11] Rumberger JA, Behrenbeck T, Reen JR, Reed JE, Gersh BJ. Nonparallel changes in global left ventricular chamber volume and muscle mass during the first year after transmural myocardial infarction in humans. J Am Coll Cardiol 1993;21:673–82. [12] Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular dysfunction and remodelling after myocardial infarction. Potential mechanisms and early predictors. Circulation 1993;87:755–63. [13] Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Effect of enalapril on ventricular remodelling and function during healing after anterior myocardial infarction in the dog. Circulation 1995;91:802–12. [14] Pfeffer MA, Lamas GA, Vughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl J Med 1988;319:80–6. [15] Kramer CM, Ferrari VA, Rogers WJ, Teobald TM, Nance ML, Axel L, Reichek N. Angiotensin-converting enzyme inhibition limits dysfunction in adjacent regions during left ventricular remodelling. J Am Coll Cardiol 1996;27:211–7. [16] Johnson DB, Foster RE, Barilla F et al. Angiotensin-converting enzyme inhibitor therapy affects left ventricular mass in patients with ejection fraction .40% after acute myocardial infarction. J Am Coll Cardiol 1997;29:49–54. [17] Bottini PB, Carr AA, Prisant M, Flickinger FW, Allison JD, Gottdiener JS. Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens 1995;8:221–8. [18] Kronik G, Slany J, Mosslacher H. Comparative value of eight M-mode echocardiographic formulas for determining left ventricular stroke volume. Circulation 1979;60:1308–16. [19] Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: Echocardiographic–angiographic correlations in the presence or absence of asynergy. Am J Cardiol 1976;37:7–11. [20] Atkinson DJ, Edelman RR. Cineangiography of the heart in a single breath hold with segmented turbo-FLASH sequence. Radiology 1991;178:357–60. [21] Bogaert JG, Bosmans HT, Rademakers FE, Bellon EP, Herregods MC, Verschakelen JA, Van der Werf F, Marchal GJ. Left ventricular quantification with breath hold MR imaging: comparison with echocardiography. MAGMA 1995;3:5–12. [22] Sakuma H, Fujita N, Foo TKF. Evaluation of left ventricular volume and mass with breath hold cine MR imaging. Radiology 1993;188:377–80. [23] Bellenger NG, Francis JM, Davies LC, Coats AJS, Pennell DJ. Establishment and performance of a magnetic resonance cardiac function clinic. J Cardiovasc Magn Reson 2000;2:15–22. [24] Bellenger NG, Davies LC, Francis JM, Pennell DJ. Reduction in sample size for studies of remodelling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271–9. [25] Bellenger NG, Burgess M, Ray SG, Coats A, Lahiri A, Cleland JGF, Pennell DJ. on behalf of the CHRISTMAS steering committee and investigators. Comparison of left ventricular ejection fraction and volumes in heart failure by two-dimensional echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: are they interchangeable? Eur Heart J 2000;21:1387–96. [26] Katz J, Milliken MC, Stray-Gundersen J, Buji LM, Parkley RW, Mitchell JH, Peshock RM. Estimation of human myocardial mass with MR imaging. Radiology 1998;169:495–8. [27] Touchstone DA, Beller GA, Nygaard TW, Tedesco C, Kaul S. Effects of successful intravenous perfusion therapy on regional myocardial function and geometry in humans: a tomographic assessment using two-dimensional echocardiography. J Am Coll Cardiol 1989;13:1506–13.

N.G. Bellenger et al. / International Journal of Cardiology 83 (2002) 217 – 225 [28] Jeremy RW, Allman KC, Bautovitch G, Harris PJ. Patterns of left ventricular dilatation during the six months after myocardial infarction. J Am Coll Cardiol 1989;13:304–10. [29] Picard MH, Wilkins GT, Ray PA, Weyman AE. Natural history of left ventricular size and function after acute myocardial infarction. Circulation 1990;82:484–94. [30] Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. New Engl J Med 1996;334:1349–55. [31] Senior R, Basu S, Kinsey C, Schaeffer S, Lahiri A. Carvedilol prevents remodelling in patients with left ventricular dysfunction after acute myocardial infarction. Am Heart J 1999;137:646–52. [32] Konermann M, Sanner BM, Horstmann E et al. Changes of the left ventricle after myocardial infarction—estimation with cine MRI during the first six months. Clin Cardiol 1997;29:201. [33] Saeed M, Wendland MF, Seelos K et al. Effect of cilazepril on regiona left ventricular wall thickness and chamber dimension following acute myocardial infarction: in vivo assessment using MRI. Am Heart J 1992;123:1472.

225

[34] Kramer CM, Ferrari VA, Rogers WJ, Theobald TM, Nance ML, Axel L, Reichek N. Angiotensin-converting enzyme inhibition limits dysfunction in adjacent non-infarcted regions during left ventricular remodeling. J Am Coll Cardiol 1996;27:211–7. [35] Kramer CM, Nicol PD, Rogers WJ et al. B-blockade improves adjacent regional sympathetic innervation during post-infarction remodelling. Am J Physiol 1999;277:H1429. [36] Foster RE, Johnson DB, Barilla F et al. Changes in left ventricular mass and volume in patients receiving angiotensin-converting enzyme enzyme inhibitor therapy for left ventricular dysfunction after Q-wave MI. Am Heart J 1998;136:269, (Abstract). [37] Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure–volume relations in rats with healed myocardial infarction. Circ Res 1981;49:618–26.