Abstract
Background
Cardiac Resynchronisation Therapy (CRT) has demonstrated short and long-term benefit in heart failure with reduced ejection fraction (HFrEF), including ischaemic (ICM) and non-ischaemic cardiomyopathy. However, there is a paucity of evidence regarding its role in cardiac sarcoidosis (CS).
Methods
Consecutive CS patients with CRT and baseline left ventricle ejection fraction (LVEF)≤40 referred to one specialist hospital in London between November 2008-March 2023 were retrospectively reviewed. The baseline characteristics, short-term echocardiographic, clinical parameters and long-term primary and secondary outcomes were compared against a cohort of ICM patients with CRT and baseline LVEF≤40. Patients with incomplete follow-up were excluded. The primary endpoint was a composite of all-cause mortality, cardiac transplantation or heart failure hospitalisation. Secondary endpoint included ventricular arrhythmic events.
Results
63 CS and 93 ICM patients were analysed. A greater proportion of ICM patients male with older ages overall (both p < 0.01), whereas a larger proportion of CS patients had atrioventricular block and heart failure hospitalisations (both p < 0.01). Both cohorts demonstrated significant serial increase in left ventricular (LV) ejection fraction and reduction in LV end-systolic and end-diastolic volumes (p < 0.01). After a mean follow up of 40.9 (±32.0) months, the primary and secondary endpoint was reached by significantly more CS patients (log-rank p = 0.008 and log-rank p = 0.004). Age (HR: 1.12 (95 %CI 1.06-1.17, p < 0.001) and presence of CS (HR: 8.33 (95 %CI 3.03-22.93, p < 0.001) were independent predictors of the primary endpoint on multivariable analysis.
Conclusion
CS patients with CRT demonstrated reverse remodelling, but had adverse long-term primary and secondary outcomes when compared to ICM patients.
Graphical abstract
Introduction
Sarcoidosis is a multisystemic inflammatory disease characterised by non-caseating granulomatous tissue formation. Its commonest manifestation site is within the lungs, with an estimated 90 % of all cases demonstrating pulmonary involvement. Yet, sarcoidosis can impact numerous extra-pulmonary organ systems – up to 25-30 % of sarcoidosis cases demonstrate cardiac involvement and as such, these patients are diagnosed with cardiac sarcoidosis (CS).
With cardiac involvement, myocardial granulomatous infiltration and subsequent inflammation and fibrosis ensues. In early, ‘silent’ disease, small regions of fibrotic changes to basal portions of the ventricular septum can be appreciable; with unopposed myocardial inflammation, basal to interventricular septal fibrosis may progress with more extensive fibrotic changes involving both left and right ventricles. Symptoms from CS are therefore usually in keeping with the extent and degree of inflammation and fibrosis in the ventricles – the commonest mode of presentation in CS patients are high-grade atrioventricular block, followed by symptomatic heart failure and ventricular tachyarrhythmia events (VAEs).
There are 3 published criteria used to diagnose CS, all of which place emphasis on the presence of either certain multimodality imaging findings, clinical findings (such as presence of atrioventricular block, ventricular arrythmia or left ventricular systolic dysfunction), and finally obtaining a myocardial histological diagnosis consistent with sarcoidosis (the latter criteria is not an essential requirement in the 2016 Japanese Circulation Society guidelines however). Obtaining a myocardial tissue diagnosis in CS can be challenging, especially given the variable diagnostic yield with endomyocardial biopsy. Cardiac magnetic resonance imaging (cMRI) has become a powerful tool in aiding the diagnosis of CS by identifying both presence and pattern of myocardial fibrotic changes using late gadolinium enhancement. Equally, the usage of 18-F fluorodeoxyglucose position electron tomography (FDG PET) can help identify active inflammatory changes within the myocardium attributable to CS. Once diagnosed, the management of CS involves reducing active myocardial inflammation using corticosteroids and or immunosuppressive therapies, treating and preventing ventricular arrythmias and managing heart failure resultant from left ventricular (LV) dysfunction.
The use of implantable cardiac devices is now well established in the treatment of heart failure (HF) secondary to both ischaemic and non-ischaemic cardiomyopathy. The European Society of Cardiology (ESC) provide guidance on the usage of both cardiac resynchronisation therapy (CRT) pacemakers and defibrillators (CRT-P and CRT-D), as well as guidelines on the usage of implantable cardiac defibrillators (ICD). ,
Whilst ESC 2022 guidelines give a number of class IIa recommendations for ICD implantation in CS patients, specific guidelines on the use of CRT do not yet exist in this cohort. , This overall necessitates the adapted usage of current CRT guidance in the CS population; yet, the evidence from which CRT guidelines have been drawn is largely based on ischaemic cardiomyopathy (ICM) and non-ischaemic, dilated cardiomyopathy (DCM) populations.
The extent to which, therefore, CRT provides long-term prognostic benefit in CS when compared to more prevalent HF causes is poorly highlighted in current literature with the exception of small scale studies. ,
To date, there is no study comparing performance of CRT in CS with ICM. The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) trial previously reported no significant difference in long-term outcomes of CRT in ischaemic and non-ischaemic cardiomyopathy. Given CS is often defined as a ‘mimicker’ of other cardiomyopathies, it is important to determine whether CRT has any therapeutic benefit in CS, especially given the inflammatory nature and differences in both pattern and extent of myocardial fibrosis when compared to other causes of HF.
This is the first study to compare the prognostic benefit of CRT in a tertiary cohort of CS patients, with a cohort of ICM patients in the United Kingdom (UK).
Methods
Study population & study design
The device database (‘Pacenet’) of the Royal Brompton Hospital (RBH) in London, UK, was searched from November 2008-March 2023 to identify and select patients with a known diagnosis of ICM, with CRT (either CRT-P or CRT-D) and a baseline left ventricular ejection fraction (LVEF)≤40 % alongside complete follow-up (including serial echocardiograms) to date. This cohort was compared to known CS patients with CRT and baseline LVEF≤40 % that had been referred to the RBH cardiac sarcoidosis service. If a patient had an overlapping or mixed diagnosis of CS and ICM, they were excluded from analysis.
In cases of systemic sarcoid, extra-cardiac sarcoidosis was confirmed according to ATR/ERS/WASOG criteria and a confirmed, probable or presumed CS diagnosis was made by the CS multidisciplinary team (MDT) using established international guidelines. , Patients requiring a CRT upgrade were also included.
Both cohorts were retrospectively followed up till 1st March 2024. Baseline characteristics at time of CRT implantation was compared between the two groups including device complications. A patient was described as a ‘responder’ if there was an increase of 5 % LVEF on serial echocardiography. The short-term outcomes (clinical and echocardiographic) assessed at least 6 months after CRT implantation were change in LVEF, Left Ventricular Internal Diameter systole (LVIDs), Left Ventricular Internal Diameter diastole (LVIDd), Left Ventricular End Systolic Volume index (LVESVi), Left Ventricular End Diastolic Volume index (LVEDVi), Left Atrial Volume index (LAVi), Right Ventricular (RV) basal diameter, mitral regurgitation on a scale of 0-9 (none, trivial, mild, mild to moderate, moderate, moderate to severe, severe, very severe and torrential), Tricuspid Annular Plane Systolic Excursion (TAPSE) and New York Heart Association (NYHA) class. The long-term primary endpoint was a composite of all-cause mortality, cardiac transplantation and acute heart failure admissions. The long-term secondary endpoint included VAEs defined as sustained ventricular tachycardia episodes lasting more than 30 seconds at more than 100 beats/minute leading to haemodynamic compromise, or an aborted sudden cardiac death event (receiving appropriate anti-tachycardia (ATP) pacing or shock from the CRT-D device).
Ethical considerations
Given the retrospective nature of the study, the Royal Brompton and Harefield Research Office waived informed patient consent, nor were patients involved in the design or conduct of this research.
Statistical analysis
Continuous variables are presented as means ± standard deviation and categorical variables as frequencies and percentages. Group comparisons were made using Chi-square and Fisher’s exact test for categorical variables and Student’s t-test for continuous variables. Factors known to affect CRT response (age, gender, QRS duration, left bundle branch block, beta-blockers, ace inhibitor) were included in multivariable analysis. CS was also added to the model to see if any differences in outcome existed. Kaplan-Meier survival curves were created for primary and secondary endpoints for the two cohorts with events and follow-up starting from time of CRT implantation. All statistical tests were 2-tailed, and a P value of <0.05 was considered significant. Data were analysed using a commercially available software (SPSS, IBM, vol.29.0).
Results
Baseline characteristics of cardiac sarcoidosis patients
Baseline characteristics in CS patients are presented in Table 1 . A total of 63 CS patients with CRT devices and a baseline LVEF≤40 % (4 pacemakers, 59 defibrillators) were included. Four (6.3 %) patients had a confirmed CS diagnosis with endomyocardial biopsy, 32 (50.8 %) had a probable CS diagnosis with positive extra-cardiac biopsy and the remaining 27 (42.9 %) had a presumed clinical CS diagnosis. Isolated CS was diagnosed in 13 (20.6 %) patients by the CS MDT team. A total of 23 (36.5 %) CS patients required a CRT-D upgrade (17 had a permanent pacemaker (PPM) and 6 had an ICD previously).
| Cardiac Sarcoidosis (n = 63) | Ischaemic Cardiomyopathy (n = 93) | P value | |
|---|---|---|---|
| Age in mean±SD (years) | 57.5 (±10.7) | 68.6 (±7.8) | <0.001 |
| Male (%) | 46 (73.0) | 87 (93.5) | <0.001 |
| Caucasian (%) | 49 (77.8) | 70 (75.3) | 0.718 |
| Device upgrades (%) | 23 (36.5) | 25 (26.9) | 0.201 |
| Defibrillator (%) | 59 (93.7) | 84 (90.3) | 0.461 |
| Prior VT (%) | 14 (22.2) | 19 (20.4) | 0.788 |
| Prior AVB (%) | 30 (47.6) | 8 (8.60) | <0.001 |
| Prior HF hospitalization (%) | 54 (85.7) | 22 (23.7) | <0.001 |
| SUVmax>2.5 at baseline | 35 (59.3) | NA | NA |
| Biopsy Heart (%) | 4 (6.3) | NA | NA |
| Biopsy Extra-cardiac (%) | 32 (50.8) | NA | NA |
| Diabetes (%) | 16 (25.4) | 31 (33.3) | 0.289 |
| Hypertension (%) | 27 (42.9) | 46 (49.5) | 0.417 |
| Chronic kidney disease (%) | 10 (15.9) | 21 (22.6) | 0.303 |
| Atrial fibrillation (%) | 17 (27.0) | 38 (40.9) | 0.075 |
| Chronic Obstructive Pulmonary Disease (%) | 4 (6.3) | 5 (5.4) | 0.798 |
| Cerebrovascular accident (%) | 6 (9.5) | 7 (7.5) | 0.658 |
| Baseline Echocardiogram | |||
| LVEF mean (±SD) | 29.0 (±8.6) | 28.2 (±7.4) | 0.533 |
| EDVI ml mean (±SD) | 96.1 (±41.5) | 100.4 (±34.8) | 0.585 |
| ESVI ml mean (±SD) | 68.8 (±39.1) | 74.7 (±31.6) | 0.424 |
| Medications at baseline | |||
| ACE inhibitor (%) | 29 (46.0) | 52 (55.9) | 0.225 |
| ARB (%) | 18 (28.6) | 23 (24.7) | 0.593 |
| ARNI (%) | 17 (27.0) | 13 (14.0) | 0.043 |
| Beta blocker (%) | 54 (85.7) | 78 (83.9) | 0.754 |
| MRA (%) | 48 (76.2) | 61 (65.6) | 0.157 |
| Calcium Channel Blocker (%) | 0 (0) | 7 (7.5) | 0.042 |
| Digitalis (%) | 3 (4.8) | 5 (5.4) | 1.000 |
| Diuretics (%) | 22 (34.9) | 52 (55.9) | 0.010 |
| Statin (%) | 9 (14.3) | 78 (83.9) | <0.001 |
| Amiodarone (%) | 11 (17.5) | 19 (20.4) | 0.644 |
| Corticosteroids (%) | 40 (63.5) | 2 (2.2) | <0.001 |
| Methotrexate (%) | 31 (49.2) | 0 (0) | <0.001 |
| Hydroxychloroquine (%) | 14 (22.2) | 0 (0) | <0.001 |
| Anticoagulation (%) | 26 (41.3) | 36 (38.7) | 0.749 |
| Baseline ECG | |||
| LBBB intrinsic (%) | 24 (38.1) | 48 (51.6) | 0.097 |
| RBBB intrinsic (%) | 11 (17.5) | 17 (18.3) | 0.896 |
| Paced LBBB (%) | 21 (33.3) | 13 (14.0) | 0.004 |
| Paced RBBB (%) | 3 (4.8) | 4 (4.3) | 1.000 |
| NVCD (%) | 4 (6.3) | 10 (10.8) | 0.345 |
| QRS duration mean (±SD) | 156.0 (±25.2) | 152.3 (±29.1) | 0.493 |
| Device Complication | |||
| Major (%) | 3 (4.8) | 6 (6.5) | 0.740 |
| Minor (%) | 3 (4.8) | 5 (5.4) | 1.000 |
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