Background Gadolinium-enhanced cardiovascular magnetic resonance is an emerging tool for the diagnosis of cardiac sarcoidosis (CS); however, the correlations between extent of late gadolinium enhancement (LGE) and efficacy of steroid therapy and adverse outcomes in patients with CS remain unclear.
Objective We aimed to clarify the prognostic impact of extent of LGE in patients with CS.
Methods Before the start of steroid therapy, 43 consecutive LGE-positive patients with CS were divided into two groups based on the extent of LGE by a median value: small-extent LGE (LGE mass <20% of LV mass; n=21) and large-extent LGE (LGE mass ≥20% of LV mass; n=22). We examined the correlations between extent of LGE and outcomes after steroid therapy.
Results Among the 6 patients who died from heart disorders, 11 patients who were hospitalised because of heart failure and 6 patients who suffered life-threatening arrhythmia during the follow-up period, large-extent LGE predicted higher incidences of cardiac mortality and hospitalisation for heart failure. Multivariate Cox regression analysis showed that large-extent LGE was independently associated with combined adverse outcomes including cardiac death, hospitalisation for heart failure, and life-threatening arrhythmias. In the small-extent LGE group, LV end-diastolic volume index significantly decreased and LVEF significantly increased after steroid therapy, whereas in the large-extent LGE group, neither LV volume nor LVEF changed substantially.
Conclusions Large-extent LGE correlates with absence of LV functional improvement and high incidence of adverse outcomes in patients with CS after steroid therapy.
- Myocardial Disease
Statistics from Altmetric.com
Sarcoidosis is a multisystem granulomatous disorder of unknown cause with symptomatic myocardial involvement in up to 7% of affected patients.1–3 Although it is generally associated with a low mortality rate, concomitant cardiac involvement worsen its prognosis.4 ,5 Therefore, detection of myocardial involvement is critical for management of patients with sarcoidosis. In patients with sarcoidosis, gadolinium-enhanced cardiovascular magnetic resonance (CMR) is a useful diagnostic tool to qualitatively detect myocardial involvement.6–8 In most patients with cardiac sarcoidosis (CS), late gadolinium enhancement (LGE) is typically localised in the basal and lateral segments of the LV wall or epicardium, which does not fit any specific coronary perfusion area.9 LGE in CMR has been reported to reflect myocardial fibrosis and granulomatous inflammation in patients with CS.7 It has also been reported that the presence of myocardial LGE can predict adverse events in patients with systemic sarcoidosis.7 ,10 However, the prognostic impact of the extent of LGE has not been fully investigated. In this study, we examined the correlations between the extent of LGE and adverse outcomes, as well as the efficacy of steroid therapy in patients with CS.
Medical records were screened to identify patients diagnosed with CS in our institution from May 2000 to May 2012. CS was diagnosed according to the guidelines of the Specific Diffuse Pulmonary Disease Research Group, Sarcoidosis Division (Japanese Ministry of Health and Welfare).11 In brief, CS was diagnosed on the basis of histological findings or clinical findings. Histological diagnosis of CS was confirmed when histological analysis of endomyocardial biopsy specimens demonstrated epithelioid granuloma without caseating granulomas. Clinical diagnosis of CS was confirmed by the presence of an electrocardiographic (ECG) abnormality suggesting myocardial injury, and at least one of the following items: abnormal wall motion, regional wall thinning, or dilatation of the LV; perfusion defect on thallium-201 myocardial scintigraphy or abnormal accumulation by gallium-67-citrate scintigraphy or technetium-99m-pyrophosphatemyocardial scintigraphy; abnormal intracardiac pressure, low cardiac output, or depressed LVEF; and interstitial fibrosis or cellular infiltration over moderate grade even if the findings were non-specific. All patients underwent coronary angiography, and no significant coronary artery stenosis was noted. All baseline characteristics, including CMR data, were collected within 1 month before steroid therapy initiation. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease Study equation,12 with coefficients modified for Japanese patients,13 as follows: estimated glomerular filtration rate (mL/min/1.73 m2) = 194×serum creatinine−1.094 × age−0.287×(0.739 if female).
As per the standard protocol,14 CS patients administered a starting dose of 60 mg prednisolone on alternate days for 1 month, and this dose was tapered gradually to the final maintenance dose of 10 mg on alternate days. All study patients received the final maintenance dose of prednisolone after 6 months. No patients enrolled in this study were receiving immunosuppressant therapy. This study was approved by the ethics committee of National Cerebral and Cardiovascular Center, and patients gave informed consent.
All patients underwent echocardiographic examinations with commercially available ultrasonography systems before and 6 months after initiation of steroid therapy. LV volumes and LVEF were measured by the modified Simpson's method, according to the guidelines of the American Society of Echocardiography.15
CMR imaging was performed using a 1.5-T MR system (Magnetom Sonata, Siemens, Erlangen, Germany) with a standardised clinical protocol. All CMR images were electrocardiographically gated and obtained during repeated breath-holds. Cine images were acquired with a steady-state free precession (SSFP) with the following parameters: repetition time, 3.2 ms; echo time, 1.6 ms; flip angle, 55°; matrix, 190×190; field of view, 340 mm; section thickness, 6 mm; section interval, 10 mm; sensitivity encoding factor, 2. After localisation of the heart, cine images of 9–12 contiguous short-axis sections encompassing the entire LV and 2-, 3-, and 4-chamber long-axis sections were collected. Then, gadopentetate meglumine (0.15 mmol/kg; Magnevist; Schering AG, Berlin, Germany) was administered at a rate of 3–4 mL/s using a power injector. LGE images were acquired 10 min after the injection of gadopentetate meglumine, with an inversion-recovery SSFP pulse sequence with inversion time of 300 ms.16 ,17 The parameters used in SSFP for LGE were repetition time, 3.5 ms; echo time, 1.7 ms; flip angle, 60°; matrix, 256×129; field of view, 340 mm; section thickness, 8 mm; section interval, 10 mm; sensitivity encoding factor, 1. Among the 9–12 short-axis slices, we excluded both ends of the apex and the base because the scans of these sections did not include the LV muscle or the bevelled myocardium, which caused incorrect signal intensities. Then, seven adjacent slices in the middle of the remaining slices were obtained by using localiser of LV long-axis.17
CMR data analyses
Cine images were analysed using ARGUS (Siemens, Germany) to calculate LV volumes, mass and function. LGE images were analysed using Ziostation 2 (Ziosoft, Tokyo, Japan). Regions of LGE in seven slices of short-axis LGE imaging were automatically defined as those exhibiting signal intensity above a predetermined threshold. We used a threshold of 5 SDs above the signal intensity of non-damaged myocardium, because LGE quantification with the threshold of 5SD demonstrated the best agreement with visual assessment and best reproducibility among different techniques with different thresholds, as previously reported.18 ,19 The LGE mass was calculated using the LGE area obtained from the seven LGE imaging slices. The extent of LGE was expressed as a percentage of LV mass according to the following equation:
The patients were divided into two groups using the median value for the extent of LGE: small-extent LGE group (LGE <20%) and large-extent LGE group (LGE ≥20%). The methods used for assessing LGE and representative images for both groups are shown in figure 1.
The primary composite outcome was defined as cardiac death, hospitalisation for heart failure, and life-threatening arrhythmia. Life-threatening arrhythmia was defined as documented or appropriate implantable cardioverter defibrillator treatment for termination of ventricular fibrillation or sustained ventricular tachycardia and successful cardiopulmonary resuscitation for cardiac arrest. Follow-up information was obtained by retrospective chart review. The composite end-point included only the first event for each patient. If a patient was admitted to our hospital due to heart failure and then died of heart failure, it counted as one event. Additionally, we did not count hospital admissions due to non-cardiac causes as events of hospital admission. No patients were lost to follow-up.
All data are expressed as means±SD. Statistical analyses were performed using JMP10 (SAS Institute, Cary, North Carolina, USA). A p value less than 0.05 was considered statistically significant. Continuous variables were compared using paired or unpaired Student t test, as appropriate. Categorical variables of the two groups were compared using the χ2 test. Long-term survival was estimated by Kaplan–Meier analysis, and differences in survival were assessed using the log-rank test. Univariate and multivariate Cox proportional hazards regression models were constructed to investigate the predictors of baseline data for combined adverse outcomes. Echocardiographic measurements were used for analysis of pretherapy and post-therapy LV volumes and LVEF. Pearson's correlation coefficient analysis was used to assess the correlation between extent of LGE and LVEF changes. Multivariate linear regression analysis was also performed with adjustment for LVEF. Receiver-operating characteristic (ROC) curve was used to examine the performance characteristic of %LGE mass. Area under the curve (AUC), and 95% confidence of ROC curve, were calculated to provide a measure of the accuracy of %LGE mass to predict combined adverse outcomes. Variables with a p value <0.05 in the univariate models were included in the multivariate analysis.
Overall, 71 patients were diagnosed with CS. Of these, 21 were excluded because they did not undergo CMR. Among the 50 CS patients who underwent CMR, seven patients, including two patients without LGE, were excluded because they did not receive steroid therapy. Eventually, 43 patients met the inclusion criteria for this study (15 men and 28 women; mean age, 59±10 years; age range, 29–73 years). The mean follow-up duration was 39±19 months (range, 8–73 months). Twenty-two patients were assigned to the large-extent LGE group, and 21 patients were assigned to the small-extent LGE group, using the median value for the extent of LGE.
Patient baseline characteristics are summarised in table 1. Demographic factors, New York Heart Association (NYHA) functional class, and organ involvement did not differ between the two groups. The B-type natriuretic peptide (BNP) level in the small-extent LGE group was significantly lower than that in the large-extent LGE group. No significant differences in systemic inflammatory markers, indicating the activity of systemic sarcoidosis, were observed between the two groups. Before initiation of steroid therapy, there was also no difference between the two groups in type of medication or implanted device, including permanent pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronisation therapy.
Echocardiographic data and CMR analysis
Echocardiographic and CMR data before steroid therapy are also shown in table 1. CMR was performed 13±7 days before the initiation of steroid therapy. Lower LVEF and higher LV end-diastolic and end-systolic volume indices were observed in the large-extent LGE group before steroid therapy. Although the difference between the two groups was not statistically significant, there was a trend toward larger LV mass in the large-extent LGE group.
Extent of LGE as a predictor of adverse events
During the follow-up period, six patients died of heart disorders, including five patients with heart failure and one patient with refractory ventricular arrhythmia. There were no non-cardiac deaths in this study. Additionally, 11 patients were hospitalised for heart failure, and six suffered life-threatening arrhythmia. Among these six life-threatening arrhythmias, five patients suffered sustained ventricular tachycardia, and one patient suffered ventricular fibrillation. Four of the five ventricular tachycardia cases were identified by the implantable cardioverter defibrillator electrogram; three cases were terminated by appropriate shock, and one case by antitachycardia pacing. Furthermore, one ventricular tachycardia case, with symptoms of palpitation and decreased blood pressure, was identified by ECG and terminated by cardioversion. Implantable cardioverter defibrillator was implanted in him after the event.
There were no cardiac deaths in the small-extent LGE group during the follow-up period. The survival rate in the large-extent LGE group was lower than that in the small-extent LGE group: 95% after 1 year, 77% after 3 years, and 72% after 5 years. A log-rank test revealed a significant difference in combined adverse outcomes (log-rank: χ2=8.10, p=0.004), cardiac mortality (log-rank: χ2=6.36, p=0.012), and hospitalisation for heart failure (log-rank: χ2=8.60, p=0.003) (figure 2) between the small-extent and large-extent LGE groups. On the other hand, extent of LGE did not appear to be associated with future occurrences of life-threatening arrhythmias (log-rank: χ2=0.87, p=0.352). The univariate Cox proportional hazards model showed that the extent of LGE expressed as %LGE mass, NYHA functional class, BNP and LVEF were associated with combined adverse outcomes (table 2). Additionally, multivariate analysis revealed that extent of LGE was an independent predictor of combined adverse outcomes (adjusted HR=1.10, 95% CI 1.01 to 1.21, p=0.021). In the present patient population, ROC curve analysis indicated that %LGE mass had the modest ability to predict combined adverse outcomes (AUC=0.77, 95% CI 0.60 to 0.89). A cutoff level of %LGE ≥21.9% best predicted combined adverse outcomes, with a sensitivity of 81.3% and a specificity of 70.3%. The test's positive and negative predictive values were 61.9% and 86.3%, respectively.
Association of extent of LGE with improvement in LV function after steroid therapy
Changes in LV end-diastolic volume index and LVEF from baseline to 6 months after steroid therapy are presented in figure 3. In the small-extent LGE group, LV end-diastolic volume index significantly decreased (92±27 and 85±20 mL/m2 before and after steroid therapy, respectively; p=0.005) and LVEF significantly increased (45±11 and 50±10% before and after steroid therapy, respectively; p<0.001) at 6 months after steroid therapy. However, in the large-extent LGE group, neither LV volumes nor LVEF changed substantially (LV end-diastolic volume index: 130±38 and 131±40 mL/m2 before and after steroid therapy, respectively; p=0.731, LVEF: 36±6 and 35±8% before and after steroid therapy, respectively; p=0.213). Furthermore, regression analysis revealed a significant negative correlation between extent of LGE and changes in LVEF (r2=0.38, p<0.001) (figure 4A). We observed an association between extent of LGE and changes in LVEF even after adjustment for LVEF before steroid therapy (r2=0.43, p<0.001). On the other hand, a significant association was not found between changes in LVEF and pretherapy LVEF (p=0.145) (figure 4B).
LGE imaging by CMR has revolutionised the diagnosis of cardiomyopathies. Furthermore, in patients with sarcoidosis, this technique is also highly useful for the detection of myocardial involvement. Since the extent of LGE can now be quantified by commercially available software, we attempted to clarify the prognostic impact of quantitative evaluation of LGE in CS patients in the present study. We obtained evidence that the extent of LGE before steroid therapy was inversely correlated with improvement in LVEF at 6 months after steroid therapy, and that a larger extent of LGE predicted a higher incidence of cardiac events, even after adjustment for LVEF.
Prediction of adverse outcomes
It has been reported that survival of CS patients with preserved LVEF is better than that of patients with low LVEF.14 ,20 Recently, the prognostic capability of LGE imaging for predicting outcomes has been assessed. It has been shown that the presence of LGE predicts adverse outcomes in patients with dilated cardiomyopathy21 ,22 and in patients with hypertrophic cardiomyopathy.23–25
In patients with systemic sarcoidosis, Greulich et al and Patel et al reported that the presence of myocardial LGE can predict adverse cardiac outcomes.7 ,10 However, in their study patients, systemic sarcoidosis was diagnosed on the basis of involvement of organs other than the heart; therefore, many patients without myocardial involvement were included. In patients with CS, granulomatous inflammation and myocardial fibrosis tend to develop during the early stages of the disease. Since LGE reflects myocardial fibrosis and granulomatous inflammation,7 most CS patients may have a certain extent of LGE when they were diagnosed with CS.6 Indeed, our study demonstrated that, among the 50 patients who were diagnosed with CS according to the guideline11 and underwent CMR in our hospital, 96 percent of the patients did have LGE, and that their baseline characteristics revealed relatively advanced myocardial impairment compared with those reported in previous studies.7 ,10 We therefore hypothesised that quantitative evaluation of LGE would be useful for the prediction of cardiac events in CS patients. The results of the present study demonstrated that CS patients with a large extent of LGE had a high incidence of adverse outcomes, including cardiac death and hospitalisation for heart failure.
In this study, approximately 25% of the CS patients required hospitalisation for heart failure during the follow-up period. Furthermore, 45% of these patients died of refractory heart failure. The extent of LGE indicates the severity of myocardial fibrosis, which is linked to the severity of LV dysfunction.26 ,27 Therefore, the presence of large-extent LGE could predict refractory heart failure in CS patients. On the other hand, life-threatening arrhythmias occurred in 14% of these patients with CS. The frequency of life-threatening arrhythmias was higher in the large-extent LGE group, although the difference was not significant. Even localised lesions in the myocardium could be origins of re-entry arrhythmias, regardless of the extent of LGE, that is, myocardial fibrosis. In fact, in this study population, two patients with small-extent LGE who had a localised lesion in the LV septum or apex showed symptomatic ventricular tachyarrhythmias. This may imply that even small amounts of LGE can precipitate arrhythmias, whereas heart failure tends to occur when LGE is more extensive.
Prediction of improvement in LV function
Although little is known about the overall beneficial or adverse effects of steroid therapy in patients with CS, it has been reported that such patients with mildly to moderately reduced LVEF (30–54%) showed improvement in LV function after steroid therapy to a greater extent than that in patients with CS with severely reduced LVEF,19 suggesting that adequate improvement in myocardial function cannot be expected in patients with severe myocardial impairment. In patients with dilated or ischaemic cardiomyopathy, a smaller extent of LGE, indicating a low degree of myocardial impairment, has been reported to be an indicator of recovery of LV systolic function.28 ,29 In the present study, extent of LGE predicted improvement in LVEF in patients with CS after steroid therapy, being consistent with previous reports.
Autopsy findings in patients with CS in a previous study showed that LGE represents fibrosis and granulomatous inflammation in the myocardium.7 Considering our results showing that patients with large-extent LGE before steroid therapy had no improvement in LVEF, LGE appears to reflect the degree of irreversible myocardial damage rather than granulomatous inflammation. In fact, in this study, some patients with severely reduced LVEF and mild LGE showed a good response to steroid therapy, suggesting that extent of LGE is a useful indicator of the expected improvement in LVEF, independent of LVEF before steroid therapy.
Several limitations to this study should be acknowledged. This was a single-centre retrospective observational study, and only patients who underwent CMR imaging before steroid therapy were enrolled. The results of the present study are limited by the small sample size and number of events. Some patients with CS who required a mechanical device, such as a pacemaker or implantable cardioverter-defibrillator for urgent conduction blocks or ventricular tachyarrhythmia at the initial visit, could not undergo CMR. There is a possibility that patients prone to arrhythmia events have therefore been excluded.
We conclude that the presence of large-extent LGE in patients with CS is linked to the absence of LV functional improvement and a high incidence of adverse outcomes after steroid therapy. We suggest that CMR imaging is useful for establishing the diagnosis of CS and also for predicting adverse events and the efficacy of steroid therapy.
What is known on this subject?
Late gadolinium enhancement (LGE) on cardiac MRI is an emerging tool for the diagnosis of cardiac sarcoidosis (CS).
What might this study add?
We suggest that cardiac MRI is useful for establishing the diagnosis of CS and also for predicting adverse events and the efficacy of steroid therapy.
How might this impact on clinical practice?
The prognostic impact of LGE in patients with CS after steroid therapy has not been well investigated. We demonstrated that large-extent LGE in patients with CS is linked to the absence of LV functional improvement and a high incidence of adverse outcomes after steroid therapy.
Contributors The contribution of each author is as follows; conception and design or analysis or analysis and interpretation of data, TI, TH YM and NY. Drafting of the manuscript or revising it critically for important content, TI, TH, NY, AF, HT, MA, HK, HO, SK and WS. Final approval of the manuscript submitted, TA and MK.
Funding This work was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare-Japan (H23-Nanchi-Ippan-22 to MK), grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology-Japan (21390251 to MK), grants from the Japan Heart Foundation (MK), and grants from the Japan Cardiovascular Research Foundation (MK).
Competing interests None.
Patient consent Obtained.
Ethics approval The ethics committee of National Cerebral and Cardiovascular Center.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.