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Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol
1588
Letters to the Editor
Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol Keisuke Kida a,⁎, Kihei Yoneyama a, Yasuyuki Kobayashi b, Makoto Takano a, Yoshihiro J. Akashi a, Fumihiko Miyake a a b
Department of Cardiology, St. Marianna University School of Medicine, Japan Department of Radiology, St. Marianna University School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 10 November 2012 Accepted 18 January 2013 Available online 14 February 2013 Keywords: Beta blocker Ejection fraction Echocardiography Myocardial fibrosis
Several studies have demonstrated the improvement of left ventricular ejection fraction (LVEF) in heart failure patients after the long-term treatment with beta blockers [1], although, not all patients have similar results. To date, it has not been fully investigated that patients with systolic heart failure respond uniformly to this therapy. Myocardial fibrosis triggers impaired cardiac systolic function and has an association with adverse cardiovascular events [2,3]. Nowadays, late gadolinium enhancement (LGE) on cardiac magnetic resonance images (CMR) is widely used to assess myocardial tissue viability [4,5]. This study was designed to investigate whether myocardial fibrosis determined by LGE on CMR would be useful to assess left ventricular reverse remodeling (LVRR) in patients with nonischemic cardiomyopathy (NICM) treated with beta blockers. This study was conducted on 77 patients with congestive heart failure who had a first-time admission to the St. Marianna University School of Medicine Hospital. All patients underwent conventional coronary angiography to exclude coronary artery disease. Finally, 31 patients were diagnosed with NICM and enrolled in the present study. One month after the initial admission, all patients underwent CMR. Steady-state free-precession images were acquired using a 1.5 T MR Imager (Achieva, Philips, Germany). Gadolinium-based contrast agent (0.15 mmol/kg, Magnevist®, Schering AG, Germany) was intravenously administered, and then contrast-enhanced images were acquired after 10 to 15 min. All patients were divided into two groups, the positive LGE group or the negative LGE group. All echocardiographic measurements were obtained using a commercially available sector scanner (Aplio®, Toshiba, Tokyo, Japan). LVEF was calculated according to the modified Simpson's method. In addition, all patients underwent echocardiography at baseline (before discharge, 1 month after admission) and followup (6 months after baseline). LVRR was defined as the combined presence at follow-up of 1) an increase in LVEF of at least 10 points and 2) a decrease in indexed left ventricular end-diastolic diameter (LVDd) of at least 10% or an indexed LVDd ≤ 33 mm/m2 [6]. All patients were divided into the two groups, the LVRR group or the non LVRR group. All values are expressed as means ± standard deviation, and categorical variables are presented as a percentage. Differences in clinical characteristics and echocardiographic parameters were analyzed by the Student's t test for continuous values and by the chi-square for categorical values between the positive and negative LGE groups. A ⁎ Corresponding author at: Department of Cardiology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae, Kawasaki, Kanagawa, 216-8511, Japan. Tel.: +81 44 977 8111; fax: +81 44 9767093. E-mail address: [email protected] (K. Kida).
paired t test was used to compare baseline and follow-up measurements. Delta values were calculated as follows: the value at follow-up minus the value at baseline. The level of statistical significance was established at p b 0.05. This study was performed in accordance with the ethical principles set forth in the Declaration of Helsinki. The St. Marianna University School of Medicine Institutional Committee on Human Research approved the study protocol. Informed content was obtained from all participants before enrollment. Of the study patients, 20 patients (65%) had positive LGE and 11 patients (35%) had negative LGE (Table 1). LVRR was found in 18 patients out of the 31 patients (58%) at follow-up. During the study period, the dosages of carvedilol significantly increased in each group (LVRR, 6.9 ± 3.3 to 15.1 ± 5.7 mg/day, p b 0.0001; non LVRR, 7.3 ± 3.1 to 14.2 ±6.1 mg/day, p = 0.0002). However, no differences in the dosage of carvedilol (p = 0.63) were found between the two groups. The absence of LGE predicted LVRR with the sensitivity, specificity, positive predictive value, and negative predictive value of 55.6%, 92.3%, 90.9%, and 60.0%, respectively. No significant differences in LVDd (positive LGE, 64.1 ±9.5; negative LGE, 60.2 ± 8.6 mm, p = 0.27) or left ventricular end-systolic dimension (LVDs) at baseline (positive LGE, 56.0 ± 10.9; negative LGE, 51.8 ± 9.4 mm, p = 0.30) were found between the two groups (Fig. 1). These parameters at follow-up significantly decreased in the both groups (LVDd: positive LGE, p = 0.0004; negative LGE, p = 0.001; LVDs: positive LGE, p b 0.0001; negative LGE, p b 0.0001) and significantly differed between the two groups LVDd: positive LGE, 59.7 ± 9.5; negative LGE, 50.7±7.6 mm, p = 0.01; LVDs: positive LGE, 48.1 ±11.5; negative LGE, 35.4 ± 6.8 mm, p = 0.002). No significant differences in LVEF at baseline were found between the positive (29.6 ±7.9%) and negative (26.0 ± 7.2%, p = 0.23) LGE groups. LVEF at follow-up significantly increased in the both groups (p= 0.0002 and p b 0.0001), however, LVEF at follow-up (positive LGE, 38.9 ± 9.9%; negative LGE, 53.7 ± 6.0%, p b 0.0001) and the improvement in LVEF (positive LGE, 9.3 ± 9.1%; negative LGE, 27.7 ± 9.5%, p b 0.0001) significantly differed between the two groups. Our study result indicated that the improvement in LVEF and LVRR significantly differed between the positive and negative LGE patients.
Table 1 Baseline characteristics of the study population (n = 31). Gender F/M (n) Age (year) BMI (kg/m2) Hypertension (%) Hyperlipidemia (%) Diabetes mellitus (%) NYHA (I/II/III) LGE (%) Medications (%) at discharge Beta blocker ACEI or ARB Aldosterone antagonist Diuretic Calcium antagonist
8/23 54 ± 13 25 ± 4 18 (58) 11 (35) 2 (6) 6/22/3 20 (65) 31 (100) 31 (100) 27 (87) 25 (81) 3 (10)
Values are mean ± SD or number (%). BMI, body mass index; NYHA; New York Heart Association, LGE, late gadolinium enhancement; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers.
Letters to the Editor
LVEF (%)
* *
baseline
follow-up
LVDd (mm)
* *
1589
outcomes in patients with NICM [2,3,7,8]. Bello et al. [9] demonstrated that the improvement in LV function could be predicted by gadolinium CMR in heart failure patients with ischemic and NICM who were receiving beta blockers. In their study, all patients with ICM had LGE. In the present study, all patients with NICM were treated with carvedilol and 65% patients had LGE on CMR. Park et al. [5] conducted a study in patients with NICM and found significant differences in follow-up LVDs, LVDd and LVEF between positive and negative LGE patients. They concluded that the absence of LGE was associated with the excellent sensitivity and negative predictive values in predicting functional recovery of NICM. In their study, most of the study patients (80%) received beta blockers, although, the remaining patients were not treated with beta blockers. In addition, 20% patients had atrial fibrillation. In the present study, we excluded patients with atrial fibrillation and followed up for 6 months for the assessment of cardiac function, which is different from the study of Park et al. who followed up for approximately 8 months. In conclusion, the absence of LGE on CMR predicted improved LVEF and LVRR in patients with NICM receiving carvedilol. We thank Dr. Kengo Suzuki and Dr. Kei Mizukoshi, the echocardiography staff and Dr. Yukihisa Ogawa, the CMR staff in the department of Radiology in the St. Marianna University School of Medicine Hospital for their technical assistance. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References
baseline
follow-up
LVDs (mm)
* *
baseline
follow-up
Fig. 1. Comparisons in echocardiographic characteristics at baseline and follow-up in the positive and negative late gadolinium enhancement groups.◯, negative LGE; ●, positive LGE.* Significant difference between baseline values and those at follow-up.¶ Significant difference at follow-up between the positive and negative LGE groups.LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension.
The parts of the myocardium without myocardial fibrosis contributed to the improvement of LVEF and LVRR. The presence of LGE on CMR is thus considered as a significant predictor for clinical adverse
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.01.043
[1] Hori M, Sasayama S, Kitabatake A, et al. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial. Am Heart J 2004;147(2):324–30. [2] Wu KC, Weiss RG, Thiemann DR, et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51(25):2414–21. [3] Cho JR, Park S, Choi BW, et al. Delayed enhancement magnetic resonance imaging is a significant prognostic factor in patients with non-ischemic cardiomyopathy. Circ J 2010;74(3):476–83. [4] Schalla S, Bekkers SC, Dennert R, et al. Replacement and reactive myocardial fibrosis in idiopathic dilated cardiomyopathy: comparison of magnetic resonance imaging with right ventricular biopsy. Eur J Heart Fail 2010;12(3):227–31. [5] Park S, Choi BW, Rim SJ, et al. Delayed hyperenhancement magnetic resonance imaging is useful in predicting functional recovery of nonischemic left ventricular systolic dysfunction. J Card Fail 2006;12(2):93–9. [6] Barbati G, Merlo M, Marocco P, et al. Relative survival in dilated cardiomyopathy: a stratification study of long-term outcome to evaluate life insurance cover. J Insur Med 2009;41(2):117–26. [7] Lehrke S, Lossnitzer D, Schob M, et al. Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy. Heart 2011;97(9):727–32. [8] Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 2006;48(10):1977–85. [9] Bello D, Shah DJ, Farah GM, et al. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation 2003;108(16):1945–53.
Letters to the Editor
Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol Keisuke Kida a,⁎, Kihei Yoneyama a, Yasuyuki Kobayashi b, Makoto Takano a, Yoshihiro J. Akashi a, Fumihiko Miyake a a b
Department of Cardiology, St. Marianna University School of Medicine, Japan Department of Radiology, St. Marianna University School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 10 November 2012 Accepted 18 January 2013 Available online 14 February 2013 Keywords: Beta blocker Ejection fraction Echocardiography Myocardial fibrosis
Several studies have demonstrated the improvement of left ventricular ejection fraction (LVEF) in heart failure patients after the long-term treatment with beta blockers [1], although, not all patients have similar results. To date, it has not been fully investigated that patients with systolic heart failure respond uniformly to this therapy. Myocardial fibrosis triggers impaired cardiac systolic function and has an association with adverse cardiovascular events [2,3]. Nowadays, late gadolinium enhancement (LGE) on cardiac magnetic resonance images (CMR) is widely used to assess myocardial tissue viability [4,5]. This study was designed to investigate whether myocardial fibrosis determined by LGE on CMR would be useful to assess left ventricular reverse remodeling (LVRR) in patients with nonischemic cardiomyopathy (NICM) treated with beta blockers. This study was conducted on 77 patients with congestive heart failure who had a first-time admission to the St. Marianna University School of Medicine Hospital. All patients underwent conventional coronary angiography to exclude coronary artery disease. Finally, 31 patients were diagnosed with NICM and enrolled in the present study. One month after the initial admission, all patients underwent CMR. Steady-state free-precession images were acquired using a 1.5 T MR Imager (Achieva, Philips, Germany). Gadolinium-based contrast agent (0.15 mmol/kg, Magnevist®, Schering AG, Germany) was intravenously administered, and then contrast-enhanced images were acquired after 10 to 15 min. All patients were divided into two groups, the positive LGE group or the negative LGE group. All echocardiographic measurements were obtained using a commercially available sector scanner (Aplio®, Toshiba, Tokyo, Japan). LVEF was calculated according to the modified Simpson's method. In addition, all patients underwent echocardiography at baseline (before discharge, 1 month after admission) and followup (6 months after baseline). LVRR was defined as the combined presence at follow-up of 1) an increase in LVEF of at least 10 points and 2) a decrease in indexed left ventricular end-diastolic diameter (LVDd) of at least 10% or an indexed LVDd ≤ 33 mm/m2 [6]. All patients were divided into the two groups, the LVRR group or the non LVRR group. All values are expressed as means ± standard deviation, and categorical variables are presented as a percentage. Differences in clinical characteristics and echocardiographic parameters were analyzed by the Student's t test for continuous values and by the chi-square for categorical values between the positive and negative LGE groups. A ⁎ Corresponding author at: Department of Cardiology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae, Kawasaki, Kanagawa, 216-8511, Japan. Tel.: +81 44 977 8111; fax: +81 44 9767093. E-mail address: [email protected] (K. Kida).
paired t test was used to compare baseline and follow-up measurements. Delta values were calculated as follows: the value at follow-up minus the value at baseline. The level of statistical significance was established at p b 0.05. This study was performed in accordance with the ethical principles set forth in the Declaration of Helsinki. The St. Marianna University School of Medicine Institutional Committee on Human Research approved the study protocol. Informed content was obtained from all participants before enrollment. Of the study patients, 20 patients (65%) had positive LGE and 11 patients (35%) had negative LGE (Table 1). LVRR was found in 18 patients out of the 31 patients (58%) at follow-up. During the study period, the dosages of carvedilol significantly increased in each group (LVRR, 6.9 ± 3.3 to 15.1 ± 5.7 mg/day, p b 0.0001; non LVRR, 7.3 ± 3.1 to 14.2 ±6.1 mg/day, p = 0.0002). However, no differences in the dosage of carvedilol (p = 0.63) were found between the two groups. The absence of LGE predicted LVRR with the sensitivity, specificity, positive predictive value, and negative predictive value of 55.6%, 92.3%, 90.9%, and 60.0%, respectively. No significant differences in LVDd (positive LGE, 64.1 ±9.5; negative LGE, 60.2 ± 8.6 mm, p = 0.27) or left ventricular end-systolic dimension (LVDs) at baseline (positive LGE, 56.0 ± 10.9; negative LGE, 51.8 ± 9.4 mm, p = 0.30) were found between the two groups (Fig. 1). These parameters at follow-up significantly decreased in the both groups (LVDd: positive LGE, p = 0.0004; negative LGE, p = 0.001; LVDs: positive LGE, p b 0.0001; negative LGE, p b 0.0001) and significantly differed between the two groups LVDd: positive LGE, 59.7 ± 9.5; negative LGE, 50.7±7.6 mm, p = 0.01; LVDs: positive LGE, 48.1 ±11.5; negative LGE, 35.4 ± 6.8 mm, p = 0.002). No significant differences in LVEF at baseline were found between the positive (29.6 ±7.9%) and negative (26.0 ± 7.2%, p = 0.23) LGE groups. LVEF at follow-up significantly increased in the both groups (p= 0.0002 and p b 0.0001), however, LVEF at follow-up (positive LGE, 38.9 ± 9.9%; negative LGE, 53.7 ± 6.0%, p b 0.0001) and the improvement in LVEF (positive LGE, 9.3 ± 9.1%; negative LGE, 27.7 ± 9.5%, p b 0.0001) significantly differed between the two groups. Our study result indicated that the improvement in LVEF and LVRR significantly differed between the positive and negative LGE patients.
Table 1 Baseline characteristics of the study population (n = 31). Gender F/M (n) Age (year) BMI (kg/m2) Hypertension (%) Hyperlipidemia (%) Diabetes mellitus (%) NYHA (I/II/III) LGE (%) Medications (%) at discharge Beta blocker ACEI or ARB Aldosterone antagonist Diuretic Calcium antagonist
8/23 54 ± 13 25 ± 4 18 (58) 11 (35) 2 (6) 6/22/3 20 (65) 31 (100) 31 (100) 27 (87) 25 (81) 3 (10)
Values are mean ± SD or number (%). BMI, body mass index; NYHA; New York Heart Association, LGE, late gadolinium enhancement; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers.
Letters to the Editor
LVEF (%)
* *
baseline
follow-up
LVDd (mm)
* *
1589
outcomes in patients with NICM [2,3,7,8]. Bello et al. [9] demonstrated that the improvement in LV function could be predicted by gadolinium CMR in heart failure patients with ischemic and NICM who were receiving beta blockers. In their study, all patients with ICM had LGE. In the present study, all patients with NICM were treated with carvedilol and 65% patients had LGE on CMR. Park et al. [5] conducted a study in patients with NICM and found significant differences in follow-up LVDs, LVDd and LVEF between positive and negative LGE patients. They concluded that the absence of LGE was associated with the excellent sensitivity and negative predictive values in predicting functional recovery of NICM. In their study, most of the study patients (80%) received beta blockers, although, the remaining patients were not treated with beta blockers. In addition, 20% patients had atrial fibrillation. In the present study, we excluded patients with atrial fibrillation and followed up for 6 months for the assessment of cardiac function, which is different from the study of Park et al. who followed up for approximately 8 months. In conclusion, the absence of LGE on CMR predicted improved LVEF and LVRR in patients with NICM receiving carvedilol. We thank Dr. Kengo Suzuki and Dr. Kei Mizukoshi, the echocardiography staff and Dr. Yukihisa Ogawa, the CMR staff in the department of Radiology in the St. Marianna University School of Medicine Hospital for their technical assistance. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References
baseline
follow-up
LVDs (mm)
* *
baseline
follow-up
Fig. 1. Comparisons in echocardiographic characteristics at baseline and follow-up in the positive and negative late gadolinium enhancement groups.◯, negative LGE; ●, positive LGE.* Significant difference between baseline values and those at follow-up.¶ Significant difference at follow-up between the positive and negative LGE groups.LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension.
The parts of the myocardium without myocardial fibrosis contributed to the improvement of LVEF and LVRR. The presence of LGE on CMR is thus considered as a significant predictor for clinical adverse
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.01.043
[1] Hori M, Sasayama S, Kitabatake A, et al. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial. Am Heart J 2004;147(2):324–30. [2] Wu KC, Weiss RG, Thiemann DR, et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51(25):2414–21. [3] Cho JR, Park S, Choi BW, et al. Delayed enhancement magnetic resonance imaging is a significant prognostic factor in patients with non-ischemic cardiomyopathy. Circ J 2010;74(3):476–83. [4] Schalla S, Bekkers SC, Dennert R, et al. Replacement and reactive myocardial fibrosis in idiopathic dilated cardiomyopathy: comparison of magnetic resonance imaging with right ventricular biopsy. Eur J Heart Fail 2010;12(3):227–31. [5] Park S, Choi BW, Rim SJ, et al. Delayed hyperenhancement magnetic resonance imaging is useful in predicting functional recovery of nonischemic left ventricular systolic dysfunction. J Card Fail 2006;12(2):93–9. [6] Barbati G, Merlo M, Marocco P, et al. Relative survival in dilated cardiomyopathy: a stratification study of long-term outcome to evaluate life insurance cover. J Insur Med 2009;41(2):117–26. [7] Lehrke S, Lossnitzer D, Schob M, et al. Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy. Heart 2011;97(9):727–32. [8] Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 2006;48(10):1977–85. [9] Bello D, Shah DJ, Farah GM, et al. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation 2003;108(16):1945–53.