- Email: [email protected]
Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
ORIGINAL ARTICLE
Original Article
Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy Alex J.A. McLellan, MBBS a,b , Scott C. McKenzie, FRACP a,c and Andrew J. Taylor, PhD, FRACP a,∗ a
The Alfred Hospital, Melbourne, Victoria, Australia St Vincent’s Hospital, Melbourne, Victoria, Australia The Prince Charles Hospital, Brisbane, Queensland, Australia b
c
Background: In acute onset cardiomyopathy, acute myocarditis is an important cause, as it is associated with a greater likelihood of recovery of cardiac function and its presence may direct specific therapies. Myocarditis can be detected by cardiac magnetic resonance imaging (CMR); however its diagnostic utility and relation to prognosis in acute onset cardiomyopathy are unknown. Methods: We performed CMR on 61 patients with acute onset cardiomyopathy and a left ventricular ejection fraction (LVEF) <55%. CMR included assessment of myocardial function, relative myocardial oedema, myocardial inflammation (using global relative enhancement [GRE] of the myocardium 4 minutes post Gad-DTPA contrast) and necrosis or fibrosis (with late gadolinium enhancement [LGE]). Patients were followed up at six months to evaluate LVEF, morbidity and mortality. Results: There was a greater improvement in LVEF at follow up in those with myocardial inflammation identified by elevated GRE compared to those without (mean increase 19.2 ± 2.5% vs. 6.7 ± 1.7%, p < 0.001). However, the presence of myocardial oedema or LGE alone was not associated with a greater recovery of LVEF (p = NS for both). Myocardial inflammation in patients with a baseline LVEF < 35% was also associated with a greater recovery of LVEF (mean increase 21.5 ± 2.9% vs. 9.1 ± 3.0%, p < 0.01). Conclusion: Myocardial inflammation identified by an elevated GRE predicts recovery of LV function in patients with acute onset cardiomyopathy. (Heart, Lung and Circulation (2012);21:30–35) © 2011 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Myocarditis; Cardiomyopathy; Cardiac magnetic resonance imaging; Prognosis; Ejection fraction; Global relative enhancement
Introduction
I
n patients presenting with acute onset cardiomyopathy, acute myocarditis is an important diagnostic consideration. Whilst still controversial, immunosuppression may play a role in the management of some specific forms Received 28 June 2011; received in revised form 24 August 2011; accepted 10 September 2011; available online 3 November 2011 Abbreviations: LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiogram; MRI, magnetic resonance imaging; CMR, cardiac magnetic resonance imaging; GRE, global relative enhancement; STIR, short T1 inversion recovery; LGE, late gadolinium enhancement; IDCM, idiopathic dilated cardiomyopathy; NYHA, New York Heart Association; AICD, automatic implantable cardioverter defibrillator; GCBPS, gated cardiac blood pool scan. ∗ Corresponding author at: The Alfred Hospital, Commercial Rd, Prahran, 3181, Australia. Tel.: +61 3 9076 2000. E-mail address: [email protected] (A.J. Taylor).
of myocarditis such as giant cell myocarditis [1], and it is generally believed that recovery of cardiac function is more likely in cases of acute onset cardiomyopathy due to myocarditis compared with idiopathic dilated cardiomyopathy (IDCM). Whilst the exact incidence of myocarditis is unknown, endomyocardial biopsy (EMB) is positive in 10% of patients with acute onset heart failure [2] and 10% of patients with myocarditis will progress to chronic dilated cardiomyopathy [3]. However, there is no true gold standard test for myocarditis because EMB itself is an insensitive test; post mortem EMB of patients who died from myocarditis is positive in only 25% of single samples from the right ventricle [4]. Noting a 1–6% risk of complication of EMB, the American College of Cardiology suggests limiting the use of EMB to specific scenarios where it would alter management or offer a meaningful prognosis [5]. Recently cardiac magnetic resonance imaging (CMR) has been advocated in the diagnostic algorithm for
© 2011 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 doi:10.1016/j.hlc.2011.09.005
myocarditis [6]. A number of CMR sequences have demonstrated utility in the diagnosis of myocarditis. An elevation in global relative enhancement (GRE) of the myocardium compared to skeletal muscle within 4 minutes of administration of gadolinium-DTPA contrast is suggestive of myocardial inflammation [7] and a cutoff value of GRE > 4.0 differentiated acute myocarditis from healthy controls. Likewise, the presence of myocardial oedema on T2 weighted imaging, as well as the presence of acute necrosis identified by late gadolinium enhancement (LGE) has been demonstrated in myocarditis. Recently, the combination of any two of oedema, inflammation (elevated GRE) and necrosis (LGE) has been advocated for the diagnosis of acute myocarditis [8]. Despite numerous studies evaluating the diagnostic performance of CMR in suspected myocarditis [9,10], none has examined the relationship between inflammatory changes demonstrated by CMR and future recovery of cardiac function in patients with acute onset cardiomyopathy. Furthermore, most studies assessing the diagnostic accuracy of CMR in patients with suspected myocarditis have utilised a group of healthy volunteers as controls, which does not adequately reflect the clinical scenario of a patient presenting with acute onset cardiomyopathy. This scenario is an ongoing challenge for clinicians, as patients with myocarditis within this patient group may follow a different clinical course and require specific therapies compared to those with idiopathic dilated cardiomyopathy (IDCM) who can also present with a similarly acute onset. As a significant proportion of patients with IDCM have regional scarring identified by LGE, the presence of LGE in patients with acute onset cardiomyopathy might not be as reliable in the diagnosis of acute myocarditis. In this retrospective analysis, we evaluated the ability of multisequential CMR in acute onset cardiomyopathy in predicting future recovery of left ventricular (LV) systolic function.
Methods We performed a retrospective analysis of all patients with acute onset cardiomyopathy who underwent CMR at the Alfred Hospital, Melbourne Australia between 22/03/2005 and 1/1/2010. Patients were considered to have acute onset cardiomyopathy if they were previously well, and had a recent (within three months) development of symptoms consistent with heart failure as well as reduced LV systolic function, defined as an LV ejection fraction less than 55% on CMR imaging. We excluded patients who had likely secondary causes of cardiomyopathy such as ischaemic or valvular heart disease, who did not have multisequential CMR performed or if no follow up imaging test was performed. This analysis was performed with the approval of the Alfred Hospital Ethics Committee.
Clinical and Demographic Data On initial CMR, baseline clinical information was prospectively collected regarding height, weight, NYHA class and medications. Six months following the initial CMR examination patients were reassessed for these variables, as well
31
as hospital admissions, cardiac biopsy, device implantation (AICD) and surgical procedures.
CMR Examination The baseline CMR scan was performed on a 1.5-T scanner (Signa Excite, General Electric Healthcare, Milwaukee, USA) using a dedicated cardiac coil and electrocardiographic gating. A bright blood steady state free precession (SSFP) fast imaging employing steady state acquisition (FIESTA) sequence for cine imaging in three apical standard views (four chamber, three chamber, and two chamber) and three short axis planes (apical, mid, and basal) was acquired. LVEF was calculated using biplane analysis of cine images as previously described [11], which correlates strongly with volumetric analysis. Myocardial oedema was identified by increased relative signal intensity on a short inversion time inversion recovery (STIR) sequence. This sequence consisted of a black-blood, T2 -weighted triple inversion recovery sequence (repetition time 2 × R-to-R interval; echo time 65 ms; inversion time 140 ms). Three standard short axis slices identical to those described above were acquired. Relative myocardial STIR intensity was calculated on a slice by slice basis by dividing the signal intensity of myocardium by that of skeletal muscle, and then all three slices were averaged to obtain the final value. A relative STIR > 2.2 was utilised to signify the presence of myocardial oedema. GRE was evaluated with an axial T1 -weighted freebreathing spin echo sequence (repetition time 1R-to-R interval, echo time 20 ms, echo train length determined by R-to-R interval) applied for 4 minutes following a bolus gadolinium-DTPA (0.1 mmol/kg BW Magnevist® , Schering, Germany). Four axial slices through the heart were acquired, and calculation of GRE of the myocardium compared to skeletal muscle was performed as previously described [7]. To reduce error, GRE was calculated in all four axial slices and then averaged to obtain the final relative enhancement value. A GRE > 4.0 was utilised for the presence of myocardial inflammation. Inversion recovery gradient echo sequences 10 minutes after intravenous administration of contrast agent (0.2 mmol/kg gadolinium-DTPA) to demonstrate late gadolinium enhancement (LGE) were performed in the identical long axis and short axis planes to as described above. Imaging parameters for LGE sequences were TR = 6.7, TE = 3.2 ms, inversion times were individually adjusted between 175 and 225 ms to null signal intensity of normal myocardium.
Follow-up Assessment of Cardiac Function Follow up imaging was performed at approximately six months to assess follow up LVEF and change in ejection fraction from baseline. Follow up LVEF by CMR was preferentially included in analysis over nuclear gated cardiac blood pool scan (GCBPS) or transthoracic echocardiography (TTE) due to the higher diagnostic accuracy of volumetric analysis by CMR [12], and the higher interstudy reproducibility of CMR compared to TTE [13].
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
McLellan et al. Heart, Lung and Circulation Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy (2012);21:30–35
Table 1. Baseline Clinical and Imaging Data (Myocardial Inflammation defined as GRE > 4.0). Baseline demographics Age Male sex (%) Height (cm) Weight (kg) BMI NYHA Heart rate (bpm) Baseline CMR GRE Relative STIR Late enhancement (%) Ejection fraction (%) LVEDV index (mL) Baseline medications ACEI (%) B blocker (%) Aldactone (%) Digoxin (%)
Myocardial Inflammation N = 25
No Myocardial Inflammation N = 36
p-Value
44 ± 3.0 16 (64) 168 ± 2.1 74 ± 3.6 19.8 ± 0.5 2.1 ± 0.2 91 ± 4.6
46 ± 2.4 27 (75) 177 ± 1.8 84 ± 3.2 19.5 ± 0.3 1.7 ± 0.2 75 ± 3.5
0.50 0.52 0.002 0.05 0.60 0.10 0.01
8.0 ± 1.0 1.8 ± 0.1 15 (60) 27.5 ± 2.8 144 ± 9.1
2.6 ± 0.1 2.0 ± 0.1 15 (40) 36.9 ± 2.0 127 ± 6.0
0.00002 0.06 0.251 0.009 0.12
18 (72) 15 (60) 17 (68) 4 (16)
26 (72) 19 (53) 28 (78) 7 (19)
0.786 0.767 0.577 0.996
Where no CMR was performed, GCBPS was used due to its high reproducibility and high inter-observer variability [14], and its greater diagnostic accuracy than TTE [12,15].
lower (27.5 ± 2.8% vs. 36.9 ± 2.0%, p = 0.009) and left ventricular end-diastolic volume (LVEDV) index trended to be higher in the group with myocardial inflammation.
Statistics
Relationship of CMR Findings to Recovery of Cardiac Function
All data are presented as mean ± one standard error. Comparisons of group means were performed using paired or non-paired t-tests for normally distributed data, as appropriate. Where data were not normally distributed group mean comparisons were performed with the Wilcoxon rank sum test. Comparisons of proportions were made using Chi-squared analysis or Fisher’s Exact Test, as appropriate. For all comparisons a p-value < 0.05 was considered significant, and all calculations were performed using a computerised statistical package (Sigmastat version 3.5).
Results Sixty one patients were identified who were clinically suspected to have myocarditis and a low ejection fraction.
Baseline Demographics and CMR Findings Defining significant myocardial inflammation as GRE > 4.0, there were 25 patients with myocardial inflammation and 36 without. The two groups were similarly matched for age, gender, body mass index (BMI) and medications at baseline and follow up (Table 1). Patients with myocardial inflammation tended to be more clinically unstable on baseline scan, with significantly higher heart rate and a trend towards poorer NYHA class. A similar baseline LVEF was shown in patients having both CMR and TTE (baseline LVEF by MRI 33.1 ± 1.7%, by TTE 36.1 ± 2.4%; p = NS). Baseline CMR as expected showed a large difference in GRE between the groups as this was the pre-specified condition of stratification. There were non-significant trends to lower STIR and increased LGE in the myocardial inflammation group. Baseline ejection fraction was significantly
Follow up imaging was performed at a mean of 236 ± 25 days. Imaging modality at follow up was most commonly TTE; however, 26% of patients had follow-up CMR and 10% of patients had follow up GCBPS. There was a non significant trend to improved final LVEF (45.9 ± 2.6% vs. 43.6 ± 2.2%, p = 0.51) and a significantly higher improvement in LVEF from baseline in the group with myocardial inflammation compared to those without (19.2 ± 2.5% vs. 6.7 ± 1.7%, p = 0.0002) (Fig. 1). When analysing those patients with a baseline ejection fraction less than 35% (as a threshold for primary prophylaxis with an automated implantable cardioverter defibrillator [AICD]); those with myocardial inflammation had a trend to lower baseline LVEF (19.8 ± 1.7% vs. 24.7 ± 2.1%, p = 0.07) and higher final LVEF (40.1 ± 3.0% vs. 33.8 ± 3.4%, p = 0.18) with a significantly greater change in LVEF (21.5 ± 2.9% vs. 9.1 ± 3.0%, p = 0.006) (see Fig. 2).
50
P < 0.01
40
P 0.5 44
45
Ejection Fraction
ORIGINAL ARTICLE
32
P < 0.001
46
37
35 30
N = 36; FU 265 days
28
No inflammation Inflammation
25 19
20
N = 25; FU 194 days
15 10
7
5 0 Baseline LVEF
Follow up LVEF
Delta LVEF
Figure 1. Comparison of baseline and follow up LVEF in patients with or without myocardial inflammation, defined by a GRE > 4.0.
33
Table 2. Follow up Clinical and Imaging Data (Myocardial Inflammation defined as GRE > 4.0). Clinical data Deaths (%) Hospital admissions (%) Biopsy (n) Biopsy positive for myocarditis (n) NYHA class Change in NYHA class Combined clinical outcome (%)
45
P = 0.07
P = 0.2
No Myocardial Inflammation N = 36
p-Value
1 (4) 7 (28) 7 2 1.0 ± 0.2 1.1 ± 0.2 8
1 (3) 14 (39) 1 0 1.1 ± 0.2 0.6 ± 0.2 15
1.0 0.544 0.006 0.164 0.49 <0.05 0.619
P < 0.01
40
40 34
35
Ejection Fraction
Myocardial Inflammation N = 25
30 25 20
N = 14
25 22
20
No Inflammation Inflammation N = 16
15 9
10 5 0
Baseline EF
Follow up EF
Delta EF
Figure 2. Comparison of baseline and follow up LVEF in patients with a baseline LVEF < 35%, comparing those with and without myocardial inflammation, defined by a GRE > 4.0.
The presence of myocardial oedema, or LGE on baseline CMR scan, was not associated with a greater recovery of LVEF (Table 3). However, when using a combination of any two of oedema (STIR > 2.2), inflammation (GRE > 4) or necrosis (presence of LGE) to stratify patients; there was a lower baseline LVEF, greater improvement in LVEF but similar final LVEF in those with 2 of 3 CMR criteria present (Table 3).
Impact of Myocardial Inflammation on Morbidity and Mortality At six months there was one death in those with myocardial inflammation and one death in those without, with the death in the former group being a HIV related mortality and the death in the latter group related to haemaTable 3. Ejection Fraction by Alternative CMR Definition of Myocardial Inflammation. STIR Baseline LVEF Final LVEF Change in LVEF Late enhancement Baseline LVEF Final LVEF Change in LVEF Combined criteriaa Baseline LVEF Final LVEF Change in LVEF a
Abnormal
Normal
>2.2 31.5 ± 3.4 45.7 ± 2.4 14.2 ± 2.9 Present 28.8 ± 2.5 40.6 ± 2.5 12.4 ± 2.5 ≥2 of 3: 26.6 ± 3.1 44.1 ± 3.0 18.4 ± 2.8
<2.2 32.4 ± 2.0 42.4 ± 2.1 10.5 ± 2.0 Absent 37.8 ± 2.3 48.1 ± 2.3 10.3 ± 2.2 <2 of 3 36.3 ± 1.9 44.6 ± 2.2 8.3 ± 1.9
p-Value 0.98 0.17 0.28 0.01 0.03 0.5 0.01 0.88 0.01
Combined criteria: combination of any two of oedema (STIR > 2.2), inflammation (GRE > 4) or necrosis (presence of LGE).
tological malignancy. There was a trend to increased hospitalisation in the group with no myocardial inflammation (see Table 2). Whilst there was no difference in follow up NYHA class; there was a significantly greater improvement in NYHA from baseline in those with myocardial inflammation compared to those without (1.1 ± 0.2 vs. 0.6 ± 0.2, p = 0.048; Table 2). There was no difference in a combined outcome of hospitalisation, death or deterioration in NYHA class between the two groups (see Table 2). A prophylactic AICD was implanted in 28% of those with myocardial inflammation and 25% of those without. Only one patient had sustained VT requiring device therapy, this patient had no myocardial inflammation on baseline CMR scan.
Discussion The main finding of this study is that myocardial inflammation detected on CMR portends recovery of LV function in patients with acute onset cardiomyopathy. When using a cutoff for GRE of >4 our data suggest those with myocardial inflammation, whilst more decompensated at baseline improve to a greater degree at follow up with a trend to better final LV systolic function. This has important clinical considerations, as those patients with acute onset cardiomyopathy and myocardial inflammation on CMR may have a more favourable prognosis, in addition to being potential candidates for immunosuppressive therapy. Previously Mahrholdt et al. [10] showed an improvement in LVEF in patients with myocarditis defined by the presence of LGE on CMR, however there was no group of patients without baseline LGE to act as a control group for purposes of evaluating the impact of LGE on recovery of cardiac function. Abdel-Aty et al. [8] suggested that three MRI sequences (STIR, early relative enhancement and delayed enhancement) could identify myocarditis with high sensitivity and specificity. However our results showed the strongest prediction of recovery in LVEF when GRE alone was used to signify myocardial inflammation. As the presence of LGE can signify either scarring or acute necrosis, this sequence may not be as reliable when used in a group of patients with acute onset cardiomyopathy as a substantial proportion of these patients have an acute presentation of idiopathic dilated cardiomyopathy (IDCM) [2], and in such patients the presence of LGE is not uncommon [16].
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
ORIGINAL ARTICLE
34
McLellan et al. Heart, Lung and Circulation Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy (2012);21:30–35
With regards to STIR our study showed the patients with myocardial inflammation (as defined by those with raised GRE) had a non significantly lower STIR than those without inflammation (see Table 1). This may be because STIR requires a greater inflammatory insult to cause extracellular oedema; either our patients had less severe inflammation (which is unlikely based on their compromised systolic function) or perhaps that the oedema occurred at an earlier stage and had resolved. The other explanation for our findings may be the lower specificity of STIR for detecting myocarditis compared with GRE; Friedrich et al. [17] reported in a pooled analysis of four papers a lower specificity of STIR (71%) compared with GRE (83%) in the detection of myocarditis. Larger prospective studies are indicated to further validate the prognostic utility of STIR, GRE and late enhancement as inferred in our retrospective analysis. A previous study followed 181 patients with suspected myocarditis for predictors of prognosis [18]. The only multivariate predictors of prognosis were baseline NYHA class, immunohistological signs of inflammation and lack of B-blocker therapy. In that study, ejection fraction was not a significant predictor of prognosis, however the baseline LVEF of 38% was significantly higher than the baseline LVEF of those in our study with myocardial inflammation. Our results suggest ejection fraction will significantly improve in those with myocarditis, including in those with a baseline ejection fraction less than 35%. No patient died in this cohort from a cardiac cause despite severely impaired baseline EF in both groups, this is surprising when compared to the 7% annual mortality in the DEFINITE trial [19] and the 19% mortality at one year in the COMPANION study [20]. The higher mortality in the DEFINITE trial may be explained by ventricular ectopy or non sustained ventricular tachycardia being inclusion criteria, and also the lower LVEF (21%) compared to our study. Another explanation of the low mortality rate may be that as our institution is a heart failure referral centre, more of our patients may have had fulminant myocarditis, which has a better long term prognosis than acute myocarditis [21]. Defibrillators were implanted in 28% of patients with myocarditis and 25% without myocarditis; only one patient received device therapy. The rate of sustained VT or VF was lower than expected; the SCD-HeFT defibrillator arm showed a 5% annual rate of appropriate shocks for VT or VF [22]. These results suggest early implantation of primary prophylaxis defibrillator is unwarranted in the myocarditis population and is in keeping with the ACC guideline for heart failure which recommends AICD implant should follow documentation of sustained reduction in LVEF despite appropriate dose of ACE-I and B-blocker [23] and AICD should not be implanted during the acute phase of myocarditis [24]. Accordingly the SCDHeFT trial did not show survival advantage until after two years of follow up [22]. The main limitation of this study is that it is a retrospective analysis with attendant bias. Of the 75 patients who met inclusion and exclusion criteria, 13 were excluded for lack of follow up imaging, as this was the primary
outcome measure in this study. Whilst CMR is the gold standard for assessment of ventricular function, only 26% of our group had follow up CMR to assess LVEF. In 1/4 of the population, CMR could not be performed at follow up due to the interval implantation of AICD. The majority of patients were followed up with TTE; although this may be a confounder when comparing to baseline CMR LVEF, previous studies have shown a good correlation of TTE, GCBPS and CMR LVEF [25,26]. To validate our findings a prospective study utilising CMR at baseline and follow up would be indicated. Another potential for bias is the more decompensated nature of those with myocardial inflammation, therefore the improvement seen may reflect regression to the mean. However, analysis of those with baseline LVEF < 35% did not show a significant difference in baseline EF between the two groups, whilst still showing a greater improvement in EF and a strong trend to better final LVEF in those with myocardial inflammation.
Conclusion The management of patients with acute onset cardiomyopathy remains challenging, as differentiating those with an acute presentation of a chronic problem, such as IDCM, from those with acute myocarditis carries important prognostic and therapeutic implications. The use of CMR to evaluate myocardial inflammation can assist those treating this often severely ill group of patients.
Financial Support No sources of funding to be noted.
Disclaimers No conflicts of interest to be noted. No relationships with industry to be noted. This study complies with the Declaration of Helsinki, and was approved by the ethics committee at the Alfred Hospital.
Acknowledgement Acknowledge Ms. Susanna Pally for data collection of the MRI database at the Alfred Hospital.
References [1] Cooper Jr LT, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis: natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997;336:1860–6. [2] Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333(5). [3] Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death. Circulation 1999;99:1091–100. [4] Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol 1989;14:915–20. [5] Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, et al. The role of endomyocardial biopsy in the
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. Pennell DJ, Sechtem U, Higgins C, Manning W, Pohost G, Rademakers F, et al. Clinical indications for cardiovascular magnetic resonance (CMR): consensus panel report. Eur Heart J 2004;25:1940–65. Friedrich MG, Strohm O, Schulz-Menger J, Marciniak H, Luft FC, Dietz R. Contrast media – enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 1998;97:1802–9. Abdel-Aty H, Boyé P, Zagrosek A, Wassmuth R, Kumar A, Messroghli D, et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis comparison of different approaches. J Am Coll Cardiol 2005;45:1815–22. Laissy JP, Messin B, Varenne O, Iung B, Karila-Cohen D, Schouman-Claeys E, et al. MRI of acute myocarditis* a comprehensive approach based on various imaging sequences. Chest 2002;122:1638–48. Mahrholdt H, Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H, et al. Cardiovascular magnetic resonance assessment of human myocarditis a comparison to histology and molecular pathology. Circulation 2004;109:1250–8. Pfluger H, Maeder M, LaGerche A, Taylor A. One- and two-dimensional estimation of right and left ventricular size and function – comparison with cardiac magnetic resonance imaging volumetric analysis. Heart Lung Circ 2010;19:541–8. Bellenger NG, Burgess M, Ray SG, Lahiri A, Coats AJ, Cleland JG, et al. 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. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right ventricular volumes, function and mass with cardiovascular magnetic resonance. Am Heart J 2004;147:218–23. Nichols K, Adatepe MH, Isaacs GH, Powell OM, Pittman DE, Gay TC, et al. A new scintigraphic method for determining left ventricular volumes. Circulation 1984;70(October (4)):672–80. Gopal A, Shen Z, Sapin P, Keller AM, Schnellbaecher MJ, Leibowitz DW, et al. Assessment of cardiac function by three-dimensional echocardiography compared with conventional noninvasive methods. Circulation 1995;92(August 15 (4)):842–53. McCrohon JA, Moon JCC, Prasad SK, McKenna WJ, Lorenz CH, Coats AJS, et al. Differentiation of heart failure related
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
35
to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 2003;108(July):54–9. Friedrich M, Sechtem U, Schulz-Menger J. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009;53(17). Kindermann I, Kindermann M, Kandolf R, Kandolf R, Klingel K, Bültmann B, et al. Predictors of outcome in patients with suspected myocarditis. Circulation 2008;118: 639–48. Kadish A, Dyer A, Daubert JP, Quigg R, Estes M, Anderson KP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8. Bristow M, Saxon L, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: 2140–50. McCarthy III RE, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000;342:690–5. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter defibrillator for congestive heart failure. N Engl J Med 2005;352: 225–37. Hunt S, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53: e1–90. Zipes D, Camm A, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Am Coll Cardiol 2006;48(September 5 (5)):e247–346. Demir H, Tan Y, Kozdag G, Isgoren S, Anik Y, Ural D, et al. Comparison of gated SPECT, echocardiography and cardiac magnetic resonance imaging for the assessment of left ventricular ejection fraction and volumes. Ann Saudi Med 2007;27(November–December (6)):415–20. Mistry N, Halvorsen S, Hoffmann P, Müller C, Bøhmer E, Kjeldsen SE, et al. Assessment of left ventricular function with magnetic resonance imaging vs. echocardiography, contrast echocardiography, and single-photon emission computed tomography in patients with recent ST-elevation myocardial infarction. Eur J Echocardiogr 2010;(June 5).
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
Original Article
Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy Alex J.A. McLellan, MBBS a,b , Scott C. McKenzie, FRACP a,c and Andrew J. Taylor, PhD, FRACP a,∗ a
The Alfred Hospital, Melbourne, Victoria, Australia St Vincent’s Hospital, Melbourne, Victoria, Australia The Prince Charles Hospital, Brisbane, Queensland, Australia b
c
Background: In acute onset cardiomyopathy, acute myocarditis is an important cause, as it is associated with a greater likelihood of recovery of cardiac function and its presence may direct specific therapies. Myocarditis can be detected by cardiac magnetic resonance imaging (CMR); however its diagnostic utility and relation to prognosis in acute onset cardiomyopathy are unknown. Methods: We performed CMR on 61 patients with acute onset cardiomyopathy and a left ventricular ejection fraction (LVEF) <55%. CMR included assessment of myocardial function, relative myocardial oedema, myocardial inflammation (using global relative enhancement [GRE] of the myocardium 4 minutes post Gad-DTPA contrast) and necrosis or fibrosis (with late gadolinium enhancement [LGE]). Patients were followed up at six months to evaluate LVEF, morbidity and mortality. Results: There was a greater improvement in LVEF at follow up in those with myocardial inflammation identified by elevated GRE compared to those without (mean increase 19.2 ± 2.5% vs. 6.7 ± 1.7%, p < 0.001). However, the presence of myocardial oedema or LGE alone was not associated with a greater recovery of LVEF (p = NS for both). Myocardial inflammation in patients with a baseline LVEF < 35% was also associated with a greater recovery of LVEF (mean increase 21.5 ± 2.9% vs. 9.1 ± 3.0%, p < 0.01). Conclusion: Myocardial inflammation identified by an elevated GRE predicts recovery of LV function in patients with acute onset cardiomyopathy. (Heart, Lung and Circulation (2012);21:30–35) © 2011 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Myocarditis; Cardiomyopathy; Cardiac magnetic resonance imaging; Prognosis; Ejection fraction; Global relative enhancement
Introduction
I
n patients presenting with acute onset cardiomyopathy, acute myocarditis is an important diagnostic consideration. Whilst still controversial, immunosuppression may play a role in the management of some specific forms Received 28 June 2011; received in revised form 24 August 2011; accepted 10 September 2011; available online 3 November 2011 Abbreviations: LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiogram; MRI, magnetic resonance imaging; CMR, cardiac magnetic resonance imaging; GRE, global relative enhancement; STIR, short T1 inversion recovery; LGE, late gadolinium enhancement; IDCM, idiopathic dilated cardiomyopathy; NYHA, New York Heart Association; AICD, automatic implantable cardioverter defibrillator; GCBPS, gated cardiac blood pool scan. ∗ Corresponding author at: The Alfred Hospital, Commercial Rd, Prahran, 3181, Australia. Tel.: +61 3 9076 2000. E-mail address: [email protected] (A.J. Taylor).
of myocarditis such as giant cell myocarditis [1], and it is generally believed that recovery of cardiac function is more likely in cases of acute onset cardiomyopathy due to myocarditis compared with idiopathic dilated cardiomyopathy (IDCM). Whilst the exact incidence of myocarditis is unknown, endomyocardial biopsy (EMB) is positive in 10% of patients with acute onset heart failure [2] and 10% of patients with myocarditis will progress to chronic dilated cardiomyopathy [3]. However, there is no true gold standard test for myocarditis because EMB itself is an insensitive test; post mortem EMB of patients who died from myocarditis is positive in only 25% of single samples from the right ventricle [4]. Noting a 1–6% risk of complication of EMB, the American College of Cardiology suggests limiting the use of EMB to specific scenarios where it would alter management or offer a meaningful prognosis [5]. Recently cardiac magnetic resonance imaging (CMR) has been advocated in the diagnostic algorithm for
© 2011 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 doi:10.1016/j.hlc.2011.09.005
myocarditis [6]. A number of CMR sequences have demonstrated utility in the diagnosis of myocarditis. An elevation in global relative enhancement (GRE) of the myocardium compared to skeletal muscle within 4 minutes of administration of gadolinium-DTPA contrast is suggestive of myocardial inflammation [7] and a cutoff value of GRE > 4.0 differentiated acute myocarditis from healthy controls. Likewise, the presence of myocardial oedema on T2 weighted imaging, as well as the presence of acute necrosis identified by late gadolinium enhancement (LGE) has been demonstrated in myocarditis. Recently, the combination of any two of oedema, inflammation (elevated GRE) and necrosis (LGE) has been advocated for the diagnosis of acute myocarditis [8]. Despite numerous studies evaluating the diagnostic performance of CMR in suspected myocarditis [9,10], none has examined the relationship between inflammatory changes demonstrated by CMR and future recovery of cardiac function in patients with acute onset cardiomyopathy. Furthermore, most studies assessing the diagnostic accuracy of CMR in patients with suspected myocarditis have utilised a group of healthy volunteers as controls, which does not adequately reflect the clinical scenario of a patient presenting with acute onset cardiomyopathy. This scenario is an ongoing challenge for clinicians, as patients with myocarditis within this patient group may follow a different clinical course and require specific therapies compared to those with idiopathic dilated cardiomyopathy (IDCM) who can also present with a similarly acute onset. As a significant proportion of patients with IDCM have regional scarring identified by LGE, the presence of LGE in patients with acute onset cardiomyopathy might not be as reliable in the diagnosis of acute myocarditis. In this retrospective analysis, we evaluated the ability of multisequential CMR in acute onset cardiomyopathy in predicting future recovery of left ventricular (LV) systolic function.
Methods We performed a retrospective analysis of all patients with acute onset cardiomyopathy who underwent CMR at the Alfred Hospital, Melbourne Australia between 22/03/2005 and 1/1/2010. Patients were considered to have acute onset cardiomyopathy if they were previously well, and had a recent (within three months) development of symptoms consistent with heart failure as well as reduced LV systolic function, defined as an LV ejection fraction less than 55% on CMR imaging. We excluded patients who had likely secondary causes of cardiomyopathy such as ischaemic or valvular heart disease, who did not have multisequential CMR performed or if no follow up imaging test was performed. This analysis was performed with the approval of the Alfred Hospital Ethics Committee.
Clinical and Demographic Data On initial CMR, baseline clinical information was prospectively collected regarding height, weight, NYHA class and medications. Six months following the initial CMR examination patients were reassessed for these variables, as well
31
as hospital admissions, cardiac biopsy, device implantation (AICD) and surgical procedures.
CMR Examination The baseline CMR scan was performed on a 1.5-T scanner (Signa Excite, General Electric Healthcare, Milwaukee, USA) using a dedicated cardiac coil and electrocardiographic gating. A bright blood steady state free precession (SSFP) fast imaging employing steady state acquisition (FIESTA) sequence for cine imaging in three apical standard views (four chamber, three chamber, and two chamber) and three short axis planes (apical, mid, and basal) was acquired. LVEF was calculated using biplane analysis of cine images as previously described [11], which correlates strongly with volumetric analysis. Myocardial oedema was identified by increased relative signal intensity on a short inversion time inversion recovery (STIR) sequence. This sequence consisted of a black-blood, T2 -weighted triple inversion recovery sequence (repetition time 2 × R-to-R interval; echo time 65 ms; inversion time 140 ms). Three standard short axis slices identical to those described above were acquired. Relative myocardial STIR intensity was calculated on a slice by slice basis by dividing the signal intensity of myocardium by that of skeletal muscle, and then all three slices were averaged to obtain the final value. A relative STIR > 2.2 was utilised to signify the presence of myocardial oedema. GRE was evaluated with an axial T1 -weighted freebreathing spin echo sequence (repetition time 1R-to-R interval, echo time 20 ms, echo train length determined by R-to-R interval) applied for 4 minutes following a bolus gadolinium-DTPA (0.1 mmol/kg BW Magnevist® , Schering, Germany). Four axial slices through the heart were acquired, and calculation of GRE of the myocardium compared to skeletal muscle was performed as previously described [7]. To reduce error, GRE was calculated in all four axial slices and then averaged to obtain the final relative enhancement value. A GRE > 4.0 was utilised for the presence of myocardial inflammation. Inversion recovery gradient echo sequences 10 minutes after intravenous administration of contrast agent (0.2 mmol/kg gadolinium-DTPA) to demonstrate late gadolinium enhancement (LGE) were performed in the identical long axis and short axis planes to as described above. Imaging parameters for LGE sequences were TR = 6.7, TE = 3.2 ms, inversion times were individually adjusted between 175 and 225 ms to null signal intensity of normal myocardium.
Follow-up Assessment of Cardiac Function Follow up imaging was performed at approximately six months to assess follow up LVEF and change in ejection fraction from baseline. Follow up LVEF by CMR was preferentially included in analysis over nuclear gated cardiac blood pool scan (GCBPS) or transthoracic echocardiography (TTE) due to the higher diagnostic accuracy of volumetric analysis by CMR [12], and the higher interstudy reproducibility of CMR compared to TTE [13].
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
McLellan et al. Heart, Lung and Circulation Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy (2012);21:30–35
Table 1. Baseline Clinical and Imaging Data (Myocardial Inflammation defined as GRE > 4.0). Baseline demographics Age Male sex (%) Height (cm) Weight (kg) BMI NYHA Heart rate (bpm) Baseline CMR GRE Relative STIR Late enhancement (%) Ejection fraction (%) LVEDV index (mL) Baseline medications ACEI (%) B blocker (%) Aldactone (%) Digoxin (%)
Myocardial Inflammation N = 25
No Myocardial Inflammation N = 36
p-Value
44 ± 3.0 16 (64) 168 ± 2.1 74 ± 3.6 19.8 ± 0.5 2.1 ± 0.2 91 ± 4.6
46 ± 2.4 27 (75) 177 ± 1.8 84 ± 3.2 19.5 ± 0.3 1.7 ± 0.2 75 ± 3.5
0.50 0.52 0.002 0.05 0.60 0.10 0.01
8.0 ± 1.0 1.8 ± 0.1 15 (60) 27.5 ± 2.8 144 ± 9.1
2.6 ± 0.1 2.0 ± 0.1 15 (40) 36.9 ± 2.0 127 ± 6.0
0.00002 0.06 0.251 0.009 0.12
18 (72) 15 (60) 17 (68) 4 (16)
26 (72) 19 (53) 28 (78) 7 (19)
0.786 0.767 0.577 0.996
Where no CMR was performed, GCBPS was used due to its high reproducibility and high inter-observer variability [14], and its greater diagnostic accuracy than TTE [12,15].
lower (27.5 ± 2.8% vs. 36.9 ± 2.0%, p = 0.009) and left ventricular end-diastolic volume (LVEDV) index trended to be higher in the group with myocardial inflammation.
Statistics
Relationship of CMR Findings to Recovery of Cardiac Function
All data are presented as mean ± one standard error. Comparisons of group means were performed using paired or non-paired t-tests for normally distributed data, as appropriate. Where data were not normally distributed group mean comparisons were performed with the Wilcoxon rank sum test. Comparisons of proportions were made using Chi-squared analysis or Fisher’s Exact Test, as appropriate. For all comparisons a p-value < 0.05 was considered significant, and all calculations were performed using a computerised statistical package (Sigmastat version 3.5).
Results Sixty one patients were identified who were clinically suspected to have myocarditis and a low ejection fraction.
Baseline Demographics and CMR Findings Defining significant myocardial inflammation as GRE > 4.0, there were 25 patients with myocardial inflammation and 36 without. The two groups were similarly matched for age, gender, body mass index (BMI) and medications at baseline and follow up (Table 1). Patients with myocardial inflammation tended to be more clinically unstable on baseline scan, with significantly higher heart rate and a trend towards poorer NYHA class. A similar baseline LVEF was shown in patients having both CMR and TTE (baseline LVEF by MRI 33.1 ± 1.7%, by TTE 36.1 ± 2.4%; p = NS). Baseline CMR as expected showed a large difference in GRE between the groups as this was the pre-specified condition of stratification. There were non-significant trends to lower STIR and increased LGE in the myocardial inflammation group. Baseline ejection fraction was significantly
Follow up imaging was performed at a mean of 236 ± 25 days. Imaging modality at follow up was most commonly TTE; however, 26% of patients had follow-up CMR and 10% of patients had follow up GCBPS. There was a non significant trend to improved final LVEF (45.9 ± 2.6% vs. 43.6 ± 2.2%, p = 0.51) and a significantly higher improvement in LVEF from baseline in the group with myocardial inflammation compared to those without (19.2 ± 2.5% vs. 6.7 ± 1.7%, p = 0.0002) (Fig. 1). When analysing those patients with a baseline ejection fraction less than 35% (as a threshold for primary prophylaxis with an automated implantable cardioverter defibrillator [AICD]); those with myocardial inflammation had a trend to lower baseline LVEF (19.8 ± 1.7% vs. 24.7 ± 2.1%, p = 0.07) and higher final LVEF (40.1 ± 3.0% vs. 33.8 ± 3.4%, p = 0.18) with a significantly greater change in LVEF (21.5 ± 2.9% vs. 9.1 ± 3.0%, p = 0.006) (see Fig. 2).
50
P < 0.01
40
P 0.5 44
45
Ejection Fraction
ORIGINAL ARTICLE
32
P < 0.001
46
37
35 30
N = 36; FU 265 days
28
No inflammation Inflammation
25 19
20
N = 25; FU 194 days
15 10
7
5 0 Baseline LVEF
Follow up LVEF
Delta LVEF
Figure 1. Comparison of baseline and follow up LVEF in patients with or without myocardial inflammation, defined by a GRE > 4.0.
33
Table 2. Follow up Clinical and Imaging Data (Myocardial Inflammation defined as GRE > 4.0). Clinical data Deaths (%) Hospital admissions (%) Biopsy (n) Biopsy positive for myocarditis (n) NYHA class Change in NYHA class Combined clinical outcome (%)
45
P = 0.07
P = 0.2
No Myocardial Inflammation N = 36
p-Value
1 (4) 7 (28) 7 2 1.0 ± 0.2 1.1 ± 0.2 8
1 (3) 14 (39) 1 0 1.1 ± 0.2 0.6 ± 0.2 15
1.0 0.544 0.006 0.164 0.49 <0.05 0.619
P < 0.01
40
40 34
35
Ejection Fraction
Myocardial Inflammation N = 25
30 25 20
N = 14
25 22
20
No Inflammation Inflammation N = 16
15 9
10 5 0
Baseline EF
Follow up EF
Delta EF
Figure 2. Comparison of baseline and follow up LVEF in patients with a baseline LVEF < 35%, comparing those with and without myocardial inflammation, defined by a GRE > 4.0.
The presence of myocardial oedema, or LGE on baseline CMR scan, was not associated with a greater recovery of LVEF (Table 3). However, when using a combination of any two of oedema (STIR > 2.2), inflammation (GRE > 4) or necrosis (presence of LGE) to stratify patients; there was a lower baseline LVEF, greater improvement in LVEF but similar final LVEF in those with 2 of 3 CMR criteria present (Table 3).
Impact of Myocardial Inflammation on Morbidity and Mortality At six months there was one death in those with myocardial inflammation and one death in those without, with the death in the former group being a HIV related mortality and the death in the latter group related to haemaTable 3. Ejection Fraction by Alternative CMR Definition of Myocardial Inflammation. STIR Baseline LVEF Final LVEF Change in LVEF Late enhancement Baseline LVEF Final LVEF Change in LVEF Combined criteriaa Baseline LVEF Final LVEF Change in LVEF a
Abnormal
Normal
>2.2 31.5 ± 3.4 45.7 ± 2.4 14.2 ± 2.9 Present 28.8 ± 2.5 40.6 ± 2.5 12.4 ± 2.5 ≥2 of 3: 26.6 ± 3.1 44.1 ± 3.0 18.4 ± 2.8
<2.2 32.4 ± 2.0 42.4 ± 2.1 10.5 ± 2.0 Absent 37.8 ± 2.3 48.1 ± 2.3 10.3 ± 2.2 <2 of 3 36.3 ± 1.9 44.6 ± 2.2 8.3 ± 1.9
p-Value 0.98 0.17 0.28 0.01 0.03 0.5 0.01 0.88 0.01
Combined criteria: combination of any two of oedema (STIR > 2.2), inflammation (GRE > 4) or necrosis (presence of LGE).
tological malignancy. There was a trend to increased hospitalisation in the group with no myocardial inflammation (see Table 2). Whilst there was no difference in follow up NYHA class; there was a significantly greater improvement in NYHA from baseline in those with myocardial inflammation compared to those without (1.1 ± 0.2 vs. 0.6 ± 0.2, p = 0.048; Table 2). There was no difference in a combined outcome of hospitalisation, death or deterioration in NYHA class between the two groups (see Table 2). A prophylactic AICD was implanted in 28% of those with myocardial inflammation and 25% of those without. Only one patient had sustained VT requiring device therapy, this patient had no myocardial inflammation on baseline CMR scan.
Discussion The main finding of this study is that myocardial inflammation detected on CMR portends recovery of LV function in patients with acute onset cardiomyopathy. When using a cutoff for GRE of >4 our data suggest those with myocardial inflammation, whilst more decompensated at baseline improve to a greater degree at follow up with a trend to better final LV systolic function. This has important clinical considerations, as those patients with acute onset cardiomyopathy and myocardial inflammation on CMR may have a more favourable prognosis, in addition to being potential candidates for immunosuppressive therapy. Previously Mahrholdt et al. [10] showed an improvement in LVEF in patients with myocarditis defined by the presence of LGE on CMR, however there was no group of patients without baseline LGE to act as a control group for purposes of evaluating the impact of LGE on recovery of cardiac function. Abdel-Aty et al. [8] suggested that three MRI sequences (STIR, early relative enhancement and delayed enhancement) could identify myocarditis with high sensitivity and specificity. However our results showed the strongest prediction of recovery in LVEF when GRE alone was used to signify myocardial inflammation. As the presence of LGE can signify either scarring or acute necrosis, this sequence may not be as reliable when used in a group of patients with acute onset cardiomyopathy as a substantial proportion of these patients have an acute presentation of idiopathic dilated cardiomyopathy (IDCM) [2], and in such patients the presence of LGE is not uncommon [16].
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy
ORIGINAL ARTICLE
34
McLellan et al. Heart, Lung and Circulation Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy (2012);21:30–35
With regards to STIR our study showed the patients with myocardial inflammation (as defined by those with raised GRE) had a non significantly lower STIR than those without inflammation (see Table 1). This may be because STIR requires a greater inflammatory insult to cause extracellular oedema; either our patients had less severe inflammation (which is unlikely based on their compromised systolic function) or perhaps that the oedema occurred at an earlier stage and had resolved. The other explanation for our findings may be the lower specificity of STIR for detecting myocarditis compared with GRE; Friedrich et al. [17] reported in a pooled analysis of four papers a lower specificity of STIR (71%) compared with GRE (83%) in the detection of myocarditis. Larger prospective studies are indicated to further validate the prognostic utility of STIR, GRE and late enhancement as inferred in our retrospective analysis. A previous study followed 181 patients with suspected myocarditis for predictors of prognosis [18]. The only multivariate predictors of prognosis were baseline NYHA class, immunohistological signs of inflammation and lack of B-blocker therapy. In that study, ejection fraction was not a significant predictor of prognosis, however the baseline LVEF of 38% was significantly higher than the baseline LVEF of those in our study with myocardial inflammation. Our results suggest ejection fraction will significantly improve in those with myocarditis, including in those with a baseline ejection fraction less than 35%. No patient died in this cohort from a cardiac cause despite severely impaired baseline EF in both groups, this is surprising when compared to the 7% annual mortality in the DEFINITE trial [19] and the 19% mortality at one year in the COMPANION study [20]. The higher mortality in the DEFINITE trial may be explained by ventricular ectopy or non sustained ventricular tachycardia being inclusion criteria, and also the lower LVEF (21%) compared to our study. Another explanation of the low mortality rate may be that as our institution is a heart failure referral centre, more of our patients may have had fulminant myocarditis, which has a better long term prognosis than acute myocarditis [21]. Defibrillators were implanted in 28% of patients with myocarditis and 25% without myocarditis; only one patient received device therapy. The rate of sustained VT or VF was lower than expected; the SCD-HeFT defibrillator arm showed a 5% annual rate of appropriate shocks for VT or VF [22]. These results suggest early implantation of primary prophylaxis defibrillator is unwarranted in the myocarditis population and is in keeping with the ACC guideline for heart failure which recommends AICD implant should follow documentation of sustained reduction in LVEF despite appropriate dose of ACE-I and B-blocker [23] and AICD should not be implanted during the acute phase of myocarditis [24]. Accordingly the SCDHeFT trial did not show survival advantage until after two years of follow up [22]. The main limitation of this study is that it is a retrospective analysis with attendant bias. Of the 75 patients who met inclusion and exclusion criteria, 13 were excluded for lack of follow up imaging, as this was the primary
outcome measure in this study. Whilst CMR is the gold standard for assessment of ventricular function, only 26% of our group had follow up CMR to assess LVEF. In 1/4 of the population, CMR could not be performed at follow up due to the interval implantation of AICD. The majority of patients were followed up with TTE; although this may be a confounder when comparing to baseline CMR LVEF, previous studies have shown a good correlation of TTE, GCBPS and CMR LVEF [25,26]. To validate our findings a prospective study utilising CMR at baseline and follow up would be indicated. Another potential for bias is the more decompensated nature of those with myocardial inflammation, therefore the improvement seen may reflect regression to the mean. However, analysis of those with baseline LVEF < 35% did not show a significant difference in baseline EF between the two groups, whilst still showing a greater improvement in EF and a strong trend to better final LVEF in those with myocardial inflammation.
Conclusion The management of patients with acute onset cardiomyopathy remains challenging, as differentiating those with an acute presentation of a chronic problem, such as IDCM, from those with acute myocarditis carries important prognostic and therapeutic implications. The use of CMR to evaluate myocardial inflammation can assist those treating this often severely ill group of patients.
Financial Support No sources of funding to be noted.
Disclaimers No conflicts of interest to be noted. No relationships with industry to be noted. This study complies with the Declaration of Helsinki, and was approved by the ethics committee at the Alfred Hospital.
Acknowledgement Acknowledge Ms. Susanna Pally for data collection of the MRI database at the Alfred Hospital.
References [1] Cooper Jr LT, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis: natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997;336:1860–6. [2] Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333(5). [3] Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death. Circulation 1999;99:1091–100. [4] Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol 1989;14:915–20. [5] Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, et al. The role of endomyocardial biopsy in the
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. Pennell DJ, Sechtem U, Higgins C, Manning W, Pohost G, Rademakers F, et al. Clinical indications for cardiovascular magnetic resonance (CMR): consensus panel report. Eur Heart J 2004;25:1940–65. Friedrich MG, Strohm O, Schulz-Menger J, Marciniak H, Luft FC, Dietz R. Contrast media – enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 1998;97:1802–9. Abdel-Aty H, Boyé P, Zagrosek A, Wassmuth R, Kumar A, Messroghli D, et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis comparison of different approaches. J Am Coll Cardiol 2005;45:1815–22. Laissy JP, Messin B, Varenne O, Iung B, Karila-Cohen D, Schouman-Claeys E, et al. MRI of acute myocarditis* a comprehensive approach based on various imaging sequences. Chest 2002;122:1638–48. Mahrholdt H, Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H, et al. Cardiovascular magnetic resonance assessment of human myocarditis a comparison to histology and molecular pathology. Circulation 2004;109:1250–8. Pfluger H, Maeder M, LaGerche A, Taylor A. One- and two-dimensional estimation of right and left ventricular size and function – comparison with cardiac magnetic resonance imaging volumetric analysis. Heart Lung Circ 2010;19:541–8. Bellenger NG, Burgess M, Ray SG, Lahiri A, Coats AJ, Cleland JG, et al. 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. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right ventricular volumes, function and mass with cardiovascular magnetic resonance. Am Heart J 2004;147:218–23. Nichols K, Adatepe MH, Isaacs GH, Powell OM, Pittman DE, Gay TC, et al. A new scintigraphic method for determining left ventricular volumes. Circulation 1984;70(October (4)):672–80. Gopal A, Shen Z, Sapin P, Keller AM, Schnellbaecher MJ, Leibowitz DW, et al. Assessment of cardiac function by three-dimensional echocardiography compared with conventional noninvasive methods. Circulation 1995;92(August 15 (4)):842–53. McCrohon JA, Moon JCC, Prasad SK, McKenna WJ, Lorenz CH, Coats AJS, et al. Differentiation of heart failure related
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
35
to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 2003;108(July):54–9. Friedrich M, Sechtem U, Schulz-Menger J. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009;53(17). Kindermann I, Kindermann M, Kandolf R, Kandolf R, Klingel K, Bültmann B, et al. Predictors of outcome in patients with suspected myocarditis. Circulation 2008;118: 639–48. Kadish A, Dyer A, Daubert JP, Quigg R, Estes M, Anderson KP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8. Bristow M, Saxon L, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: 2140–50. McCarthy III RE, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000;342:690–5. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter defibrillator for congestive heart failure. N Engl J Med 2005;352: 225–37. Hunt S, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53: e1–90. Zipes D, Camm A, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Am Coll Cardiol 2006;48(September 5 (5)):e247–346. Demir H, Tan Y, Kozdag G, Isgoren S, Anik Y, Ural D, et al. Comparison of gated SPECT, echocardiography and cardiac magnetic resonance imaging for the assessment of left ventricular ejection fraction and volumes. Ann Saudi Med 2007;27(November–December (6)):415–20. Mistry N, Halvorsen S, Hoffmann P, Müller C, Bøhmer E, Kjeldsen SE, et al. Assessment of left ventricular function with magnetic resonance imaging vs. echocardiography, contrast echocardiography, and single-photon emission computed tomography in patients with recent ST-elevation myocardial infarction. Eur J Echocardiogr 2010;(June 5).
ORIGINAL ARTICLE
Heart, Lung and Circulation McLellan et al. (2012);21:30–35 Cardiac Magnetic Resonance Imaging Predicts Recovery of Left Ventricular Function in Acute Onset Cardiomyopathy