Catheter Ablation of Ventricular Tachycardia in Histologically Confirmed, Clinically Diagnosed, and Suspected Cardiac Sarcoidosis

Abstract

Background: Cardiac sarcoidosis (CS) is a rare, potentially life-threatening condition associated with ventricular tachycardia (VT). Outcomes of catheter ablation for VT in patients with histologically diagnosed sarcoidosis and those with suspected or clinically diagnosed sarcoidosis have not been well studied. This study addressed this knowledge gap.

Methods and Results: We conducted an observational retrospective chart review of patients with CS who underwent VT ablation between 2007 and 2024 at Mayo Clinic Hospital. The cohort was divided into 2 groups: those with histologically diagnosed sarcoidosis and those with clinical or suspected sarcoidosis diagnosed according to Japanese Circulation Society 2016 guidelines. The primary endpoints were VT recurrence, cardiovascular mortality, and heart transplantation. Eighty-eight patients were included in the study: 33 with histologically confirmed CS and 55 with clinical/suspected CS. Systemic sarcoidosis was more common in the group with histologically confirmed CS, whereas mid-myocardial non-ischemic late gadolinium enhancement was more prevalent in the group with clinical/suspected CS. The 1-year composite event-free survival rate was 56.1%. In multivariate analysis, systemic sarcoidosis was independently associated with lower event-free survival rates.

Conclusions: Patients with histologically confirmed CS had worse VT ablation outcomes than those with clinical/suspected CS. This difference may be driven by a higher prevalence of systemic sarcoidosis in the former group. These findings highlight the need for a comprehensive management approach in both groups.

Central Figure

Cardiac sarcoidosis (CS) is a rare manifestation of systemic sarcoidosis, diagnosed in less than 5% of patients with systemic sarcoidosis.¹ However, the true incidence of CS is likely underestimated. Advances in imaging techniques have increased the detection of cardiac involvement 2-fold compared with traditional diagnostic methods.² This shift may explain the significant rise in CS diagnoses in recent years.³ CS carries a poor prognosis, with a 5-year cumulative incidence of adverse outcomes, including death, heart transplantation, or left ventricular assist device implantation, ranging from 4% to 13%.⁴

Among arrhythmias associated with CS, ventricular tachycardia (VT) is the second most common arrhythmia after atrial fibrillation and has the most significant impact on patient mortality.⁵ Despite its serious implications, diagnosing CS remains a formidable challenge, especially when seeking histological confirmation. Endocardial biopsy, the standard for obtaining tissue samples, yields a positive diagnosis in only 20% of patients due to the patchy nature of the disease and its varying stages of inflammation and fibrosis.^6,7

To address diagnostic inconsistencies, guidelines from 3 major organizations have been developed. The guidelines developed by the steering committee of A Case Control Etiologic Study of Sarcoidosis (ACCESS), revised in 2014, advocate for histological confirmation via myocardial biopsy;⁸ the Heart Rhythm Society (HRS) guidelines propose both histological and clinical diagnostic pathways, allowing for extracardiac biopsy evidence of sarcoidosis coupled with cardiac-specific findings such as imaging or electrocardiographic abnormalities;^9,10 and the Japanese Circulation Society (JCS) guidelines take a more inclusive approach, introducing a diagnostic category for cases without histological confirmation. The revised 2016 JCS criteria emphasize advanced imaging markers, including ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) and late gadolinium enhancement (LGE) on cardiac magnetic resonance (MR) imaging, alongside clinical and electrocardiographic indicators.⁷ These guidelines categorize the diagnosis of sarcoidosis (cardiac or extracardiac) into 3 categories, namely: (1) histological sarcoidosis, when a biopsy from any organ demonstrates non-caseating granulomas and other granulomatous diseases are ruled out; (2) clinical sarcoidosis, when at least 2 organs are clinically compromised and at least 2 of the 5 characteristic laboratory results are present; and (3) suspected sarcoidosis, when the diagnosis of sarcoidosis is highly suspected, but the clinical criteria are not met.

Conversely, CS can be diagnosed as:

• isolated CS, which is histological CS (and thus histological sarcoidosis) if there is a positive cardiac biopsy or, if there is no positive cardiac biopsy but the clinical criteria for CS are met, suspected CS (because only one organ is compromised)

• histological systemic sarcoidosis with cardiac involvement, which is either histological CS if there is a positive cardiac biopsy or clinical CS if there is only an extracardiac biopsy

• clinical systemic sarcoidosis with cardiac involvement, which is diagnosed if the criteria for clinical sarcoidosis and the criteria for CS are met, but there is no cardiac or extracardiac biopsy.

No prior studies have explored the impact of varying diagnostic categories on VT ablation outcomes. We hypothesized that a clinical or suspected diagnosis of CS, rather than representing a distinct condition, reflects a different diagnostic pathway compared with histologically diagnosed sarcoidosis. The aim of this study was to address this gap by comparing the characteristics and outcomes of patients undergoing VT ablation, based on whether there is histological confirmation of sarcoidosis via cardiac or extracardiac biopsy, with those of patients without histological confirmation.

Methods

Study Design and Population

This was an observational retrospective study. We included patients who underwent VT ablation for isolated CS or systemic sarcoidosis with cardiac involvement on the basis of suspected, clinical, or histological diagnosis according to the JCS 2016 guidelines. Ischemic heart disease was ruled out in all patients by invasive coronary angiogram, and genetic cardiomyopathies were excluded in those who underwent genetic testing. Patients aged <18 years and those with other inflammatory or infiltrative conditions that could explain their clinical, radiological, and histological findings were excluded. The first VT ablation performed at Mayo Clinic Arizona was considered the index procedure. Patients who underwent an index procedure between December 2007 and September 2024 at the 3 major Mayo Clinic campuses in the US (Phoenix, Arizona; Jacksonville, Florida; and Rochester, Minnesota) were included.

The population was divided into 2 groups. The first group, termed “histological sarcoidosis,” included patients with a histological examination from any organ showing findings consistent with sarcoidosis. The second group, termed “clinical sarcoidosis,” included all patients with suspected or clinically diagnosed sarcoidosis for whom a biopsy was either not performed or yielded non-specific or negative results. Baseline data, procedure characteristics, and outcomes were collected for further analysis.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board (24-009460).

Preprocedural PET and Cardiac MR

Scar or active inflammation was assessed on the basis of LGE on cardiac MR and an increase in ¹⁸F-FDG uptake on PET. Data from cardiac MR imaging performed at any time before the ablation and from PET scans performed within 6 months before the VT ablation were analyzed. For patients with multiple PET scans or cardiac MR images prior to the ablation, data from the most recent study was used. The results of the PET scans conducted more than 6 months prior to the VT ablation were included solely to determine whether JCS major Criterion B was met.

Procedure

Patients underwent the procedure under conscious sedation or general anesthesia. Intracardiac echocardiography was used as an intraprocedural guide. Left ventricle access was granted via a transseptal or retrograde aortic approach. Epicardial access was performed at the operator’s discretion based on radiological findings, electrocardiographic characteristics of the clinical VT, and procedural feasibility, as described previously.¹¹ For epicardial access, most patients underwent a subxiphoid approach, except for 1 patient who had concomitant open surgery for tricuspid valve repair. A 3-dimensional electroanatomical map was created, and activation and/or entrainment mapping were used for patients with inducible and tolerated VT. Otherwise, pace and substrate mapping were performed. All patients underwent radiofrequency ablation, except for 1 who had open surgical access with exclusive cryoablation. Additional ablation strategies, such as cryoablation or alcohol ablation, were used at the operator’s discretion. Postablation testing, including programmed ventricular stimulation and isoproterenol infusion, was performed at the discretion of the operator. The endpoints of the procedure included non-inducibility of clinical VTs and substrate modification, aiming to eliminate the arrhythmogenic substrate and reduce the risk of VT recurrence.

Follow-up and Endpoint Definitions

The primary endpoint was event-free survival from VT recurrence, cardiovascular mortality, or heart transplant. Data from office visits, implantable cardioverter defibrillator (ICD) interrogations, and emergency room visits were reviewed. If none of the long-term outcomes occurred, the period from the procedure to the last office or emergency room visit was considered the follow-up period. For patients who presented any long-term outcomes, the follow-up time was defined as the time from the procedure to event occurrence. Patients who presented with VTs lasting more than 30 s and who required external cardioversion or appropriate ICD shock were considered to have VT recurrence.

For patients with an inducibility test at the end of the procedure, the success of the procedure was defined as follows: complete acute success, defined as the absence of any inducible VT at the end of the procedure; partial acute success, defined as the absence of clinical VT at the end of the procedure; and unsuccessful, defined as the presence of inducible clinical VT at the end of the procedure. Procedure complications were classified as major when they were life-threatening or required any additional invasive intervention (surgical or percutaneous intervention); otherwise, they were categorized as mild. Antiarrhythmic drug (AAD) reduction was defined as a decrease in the number of AADs prescribed before admission compared with after discharge.

Statistical Analysis

Continuous variables are presented as the mean±SD and were compared using Student›s t-tests. Categorical variables are presented as absolute and relative frequencies and were compared using the Chi-squared test or Fisher’s exact test (if the frequency of observation was <5 in the contingency table). Binary outcomes were compared by odds ratios (ORs), and 95% confidence intervals (CIs) are reported. Continuous variables were compared by mean differences (MDs) and 95% CIs. Event-free survival was evaluated through Kaplan-Meier analysis. The time-to-event endpoints were analyzed with log-rank tests. A bivariate Cox regression model was conducted for event-free survival, and variables with P<0.1 were included in the multivariate model to identify independent predictors of long-term event-free survival. Statistical significance was set at P<0.05. Statistical analyses were performed using R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

We included 88 patients who underwent VT ablation between December 2007 and September 2024. Histological confirmation from any organ involved was documented for 33 (37.5%) patients, with 10 of these patients having a positive endocardial biopsy meeting the HRS criteria for confirmed CS; 23 patients had a positive extracardiac biopsy, meeting the HRS criteria for probable CS. Suspected CS and clinically diagnosed CS with no histological confirmation were present in 55 (62.5%) patients. Twenty-seven patients from the group without histological confirmation underwent genetic studies, all of which showed no significant findings. Endomyocardial biopsy was negative in 16 patients and was not attempted in 39 patients. CS diagnosis preceded the ablation procedure in 66 (75%) patients.

Baseline Characteristics

Baseline characteristics are presented in Table 1. The mean age of patients was 56.3±10.2 years, 14 (16%) were female, and the mean left ventricular ejection fraction (LVEF) was 42±12.3%. Patients with a histological diagnosis of sarcoidosis were younger (52.9±8.8 vs. 58.3±10.5 years; P=0.01) and had higher rates of systemic sarcoidosis (88% vs. 11%; P<0.01). Immunomodulators before the procedure, particularly corticosteroids, were more common in patients with than without a histological diagnosis (70% vs. 29%; P<0.01). Atrial fibrillation was present in 41 (47%) patients, atrial flutter was present in 12 (14%), low-grade atrioventricular block was present in 30 (34%), and high-grade atrioventricular block was present in 23 (26%).

Table 1.

Baseline Characteristics in the Entire Study Cohort and for Patients With Clinical and Histologically Diagnosed CS Separately

	Total (n=88)	Clinical CS (n=55)	Histological CS (n=33)	P value
Age (years)	56.3±10.2	58.3±10.5	52.9±8.8	0.01*
Female sex	14 (16)	7 (13)	7 (21)	0.29
Systemic sarcoidosis	35 (40)	6 (11)	29 (88)	<0.01*
JCS Criterion B	41 (47)	28 (51)	13 (39)	0.29
CHF	77 (88)	45 (82)	32 (97)	0.047*
Diabetes	18 (20)	10 (18)	8 (24)	0.50
CKD	24 (27)	14 (25)	10 (30)	0.62
Hypertension	44 (50)	28 (51)	16 (48)	0.83
BMI (kg/m2)	31.3±7	31.6±7.1	30.7±6.8	0.58
Current smoker	3 (3)	2 (4)	1 (3)	1
History of SCD	18 (20)	10 (18)	8 (24)	0.50
Immunomodulator	39 (44)	16 (29)	23 (70)	<0.01*
Corticosteroids	26 (30)	9 (16)	17 (52)	<0.01*
Mycophenolate	11 (12)	4 (7)	7 (21)	0.09
Methotrexate	9 (10)	7 (13)	2 (6)	0.47
Leflunomide	4 (5)	1 (2)	3 (9)	0.15
Biologics	4 (5)	1 (2)	3 (9)	0.15
β-blockers	73 (83)	45 (82)	28 (85)	0.71
AADs	71 (81)	43 (78)	28 (85)	0.44
Sotalol	14 (16)	10 (18)	4 (12)	0.56
Mexiletine	17 (19)	8 (15)	9 (27)	0.14
Amiodarone	52 (59)	30 (55)	22 (67)	0.26
High-grade AV block	23 (26)	14 (25)	9 (27)	0.85
Low-grade AV block	30 (34)	19 (35)	11 (33)	0.91
Atrial fibrillation	41 (47)	27 (49)	14 (42)	0.54
Atrial flutter	12 (14)	9 (16)	3 (9)	0.52
Previous VT ablation	21 (24)	14 (25)	7 (21)	0.65
VT storm at admission	21 (24)	12 (22)	9 (27)	0.56
LVEF (%)	42.8±12.3	43.8±12.8	41±11.4	0.30
Normal LVEF	30 (34)	20 (36)	10 (30)	0.56
Mildly reduced LVEF	19 (22)	11 (20)	8 (24)	0.64
Reduced LVEF	39 (44)	24 (44)	15 (45)	0.87
LVDDdA (mm)	58.4±7.4	59±6.8	57.4±8.2	0.37
LVPWdB (mm)	9.8±1.8	9.8±1.9	9.8±1.7	0.98
IVSdB (mm)	10.1±2.5	9.9±2.3	10.4±2.8	0.48
Reduced RVEF	26 (30)	13 (24)	13 (39)	0.12

Unless indicated otherwise, data are given as the mean±SD or n (%). Continuous variables were compared using Welch’s 2-sample t-test; categorical variables were compared using the χ² test or Fisher’s exact test. *Statistically significant P value. ^ACalculated for 90 patients with available data (57 in the clinical cardiac sarcoidosis [CS] group, 33 in the histological CS group). ^BCalculated for 80 patients with available data (49 in the clinical CS group, 31 in the histological CS group). AADs, antiarrhythmic drugs; BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; ICD, implantable cardioverter defibrillator; IVSd, interventricular septal thickness in diastole; JCS, Japanese Circulation Society; JCS Criterion B, basal thinning of the ventricular septum or abnormal ventricular wall anatomy; LVDDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVPWd, left ventricular posterior wall thickness in diastole; RVEF, right ventricular ejection fraction; SCD, sudden cardiac death; VT, ventricular tachycardia.

Figure 1 illustrates the distribution of the JCS’s major criteria. No significant differences were documented between patients with clinical/suspected sarcoidosis and those with histological sarcoidosis. All patients met Criterion A, because each presented with sustained VT. Criterion B was met by 47% of patients, and Criterion C was met by 90% of patients. Among the 56 patients who underwent a PET scan, 59% met Criterion D; of the 51 patients who underwent cardiac MR, 98% met Criterion E.

Figure 1.

(A) Delayed enhanced short-axis image through the mid-left ventricle (LV) from a cardiac magnetic resonance image demonstrating extensive mid-myocardial and subepicardial delayed enhancement (arrows). (B) Fused perfusion (Left) and ¹⁸F-fluorodeoxyglucose (FDG; Right) images from a cardiac positron emission tomography-computed tomography scan of the same patient demonstrating a perfusion defect with corresponding increased metabolic activity consistent with active sarcoid-related myocardial inflammation. (C) Distribution of ¹⁸F-FDG uptake in 17-segment models for patients with a histological and clinical diagnosis. There were no significant differences between the 2 groups. (D) Distribution of Japanese Circulation Society (JCS) major criteria. JCS B, basal thinning of the ventricular septum or abnormal ventricular wall anatomy; JCS C, LV contractile dysfunction or focal ventricular wall asynergy; JCS D, ⁶⁷Ga citrate scintigraphy or ¹⁸F-FDG positron emission tomography (PET) reveals abnormally high tracer accumulation in the heart; JCS E, gadolinium-enhanced magnetic resonance imaging (MRI) reveals delayed contrast enhancement of the myocardium. For JCS D, 56 patients who underwent PET scans were included in the analysis. For JCS E, 51 patients who underwent cardiac MRI were included in the analysis. Statistical tests: χ² test or Fisher exact test.

Systemic sarcoidosis was documented in 35 patients. Lung involvement was observed in 28 patients, lymphatic system involvement was observed in 15, liver involvement was observed in 6, skin involvement was observed in 4, ophthalmic involvement was observed in 2, gastric involvement was observed in 2, skeletal involvement was observed in 2, renal involvement was observed in 1, and brain involvement was observed in 1.

PET Scan and Cardiac MR Findings

The PET and cardiac MR findings are summarized in Table 2. Recent cardiac PET scan data (<6 months before ablation) were available for 49 patients. On average, PET scans were performed 47.7±44.2 days before ablation. Increased ¹⁸F-FDG uptake was documented in 15 (31%) patients, with no significant difference between the 2 groups (28% for clinical vs. 35% for histological; P=0.58). Septal inflammation was present in 5 (10%) patients, and multifocal areas of inflammation were present in 8 (16%) patients.

Table 2.

PET and Cardiac MR Imaging Findings

	Total	Clinical CS	Histological CS	OR (95% CI)	P value
Previous PET scan	n=49	n=29	n=20
18F-FDG uptake	15 (31)	8 (28)	7 (35)	1.4 (0.3–5.7)	0.58
Septal 18F-FDG	5 (10)	2 (7)	3 (15)	2.3 (0.2–30.7)	0.39
Multifocal 18F-FDG	8 (16)	5 (17)	3 (15)	0.8 (0.1–5.1)	1
Previous cardiac MR	n=51	n=37	n=14
LGE present	50 (98)	36 (97)	14 (100)	NA	NA
Septal LGE	33 (65)	24 (65)	9 (64)	1 (0.2–4.5)	1
Right ventricle LGE	12 (24)	8 (22)	4 (29)	1.4 (0.3–7)	0.71
Left ventricle LGE	49 (96)	35 (95)	13 (100)	NA	NA
Multifocal LGE	38 (75)	27 (73)	11 (79)	1.4 (0.3–9.1)	0.68
Mid-myocardial LGE	24 (47)	23 (62)	1 (7)	0.1 (0–0.4)	<0.01*
Transmural LGE	23 (45)	15 (41)	8 (57)	1.9 (0.5–8.3)	0.29
Subepicardial LGE	19 (37)	11 (30)	8 (57)	3.1 (0.7–13.7)	0.07

Unless indicated otherwise, data are given as n (%). Statistical tests: χ² test or Fisher’s exact test. *Statistically significant P value. CI, confidence interval; CS, cardiac sarcoidosis; FDG, fluorodeoxyglucose; LGE, late gadolinium enhancement; MR, magnetic resonance; NA, not applicable; OR, odds ratio; PET, positron emission tomography.

LGE was present in 50 of 51 (98%) patients for whom cardiac MR data were available. On average, cardiac MR scans were performed 238±407 days before ablation. Septal involvement was reported in 65% of patients, right ventricular involvement excluding the septal area was reported in 24%, and left ventricular involvement excluding the septal area was reported in 96%. Multifocal areas of LGE were found in 75% of patients, mid-myocardial LGE was found in 47% of patients, transmural LGE was found in 45%, and subepicardial LGE was found in 37%. The distributions among the analyzed groups were comparable, except for the mid-myocardial areas of LGE, which were more common in the clinical/suspected than histological group (62% vs. 7%; P<0.01). T₂-weighted imaging was limited due to the presence of cardiac devices in most patients. Of the 20 patients for whom T₂ data were available, 5 demonstrated abnormal signal intensity suggestive of active myocardial edema and inflammation.

Procedure Characteristics

The mean procedure time was 362±115 min, and the mean number of ablation deliveries was 39.8±27, with a mean ablation time of 136±104 min. A mean of 2.5±2 VTs were induced, with a mean of 1.1±0.8 clinical VTs induced. Of 60 patients with available data, a clinical VT with a right bundle branch block morphology was documented in 43 (72%), whereas left bundle branch block was present in 23 (38%) patients. Epicardial access and mapping were performed in 24 (27%) patients, and 22 (25%) patients received an epicardial ablation (Table 3).

Table 3.

Ablation Characteristics

Variable	Total (n=88)	Clinical CS (n=55)	Histological CS (n=33)	OR or MD (95% CI)	P value
Procedure timeA (min)	361.6±114.8	363.8±107.5	358.3±127	5.5 (−49.8, 60.7)	0.84
Ablation timeB (min)	135.9±103.6	122.3±87.5	160.4±125.8	−38.1 (−95.6, 19.2)	0.19
No. ablation deliveriesB	39.76±26.6	37.34±24.95	43.85±29.32	−6.5 (−20.34, 7.33)	0.35
Fluoroscopy timeC (min)	41.17±29.14	42.68±30.65	38.76±26.86	3.92 (−8.83, 16.68)	0.54
Induced VTsD	2.46±2.13	2.36±2.04	2.64±2.33	−0.28 (−1.33, 0.76)	0.59
Induced clinical VTsE	1.1±0.75	1.03±0.72	1.2±0.8	−0.17 (−0.52, 0.2)	0.37
Clinical VT CLF (ms)	361.9±94.5	340.4±97	391.02±83.1	−50.62 (−97.33, −3.98)	0.03*
Clinical VT RBBBG	43 (71.6)	28 (73.7)	15 (0.68)	0.8 (0.2, 2.4)	0.87
Clinical VT LBBBG	23 (38.3)	13 (34.2)	10 (45.4)	1.6 (0.5, 4.7)	0.56
Epicardial mapping	24 (27.2)	13 (23.6)	11 (33.3)	1.6 (0.6, 4.2)	0.45
Ent./act. mapping	31 (35.23)	17 (30.9)	14 (42.42)	1.6 (0.7, 4.0)	0.39
Cryoablation	2 (2.2)	2 (3.7)	0	NA	NA
Alcohol ablation	3 (3.4)	3 (5.4)	0	NA	NA
Epicardial ablation	22 (25)	12 (21.82)	10 (30.3)	1.6 (0.6, 4.0)	0.53

Unless indicated otherwise, data are given as the mean±SD or n (%). Continuous variables were compared using Welch’s 2-sample t-test; categorical variables were compared using the χ² test. *Statistically significant P value. ^AData available for 79 patients; ^Bdata available for 70 patients; ^Cdata available for 83 patients; ^Ddata available for 82 patients; ^Edata available for 81 patients; ^Fdata available for 62 patients; ^Gdata available for 60 patients. CL, cycle length; Ent./act. mapping, entrainment and/or activation mapping; LBBB, left bundle branch block; RBBB, right bundle branch block; VT, ventricular tachycardia. Other abbreviations as in Table 2.

Acute Outcomes

The acute outcomes are presented in Table 4. A post-procedure induction test was performed in 62 (70%) patients, of whom 37 (60%) achieved acute complete success and 22 (35%) achieved acute partial success. Logistic regression was conducted to assess potential predictors of acute success in patients who underwent post-procedure induction testing. After adjustment, none of the baseline or procedural characteristics was significantly associated with complete acute success. A reduction in AADs after discharge was documented in 20 (23%) patients. Eight patients experienced recurrence before discharge, and no in-hospital mortalities were recorded. However, 1 patient underwent heart transplantation before discharge.

Table 4.

Acute and Long-Term Outcomes

	Total (n=88)	Clinical CS (n=55)	Histological CS (n=33)	OR (95% CI)	P value
Post-procedure induction test	62 (70)	41 (75)	21 (64)	0.6 (0.2–1.7)	0.28
Acute complete successA	37 (60)	24 (59)	13 (62)	1.1 (0.3–4)	0.80
Acute partial successA	22 (35)	16 (39)	6 (29)	0.6 (0.2–2.2)	0.42
Unsuccessful ablationA	3 (5)	1 (2)	2 (10)	4.1 (0.2–254)	0.26
AADs reductionB	20 (23)	13 (24)	7 (22)	0.9 (0.3–2.8)	0.85
In-hospital recurrence	8 (9)	6 (11)	2 (6)	0.5 (0–3.2)	0.70
VT recurrenceB	54 (62)	30 (55)	24 (75)	2.5 (0.9–7.5)	0.06
Repeat VT ablation	37 (42)	24 (44)	13 (39)	0.8 (0.3–2.2)	0.70
Heart transplant	12 (14)	4 (7)	8 (24)	4.0 (1–20)	0.05
Cardiovascular mortality	6 (7)	3 (5)	3 (9)	1.7 (0.2–13.7)	0.67
ICD shocks reductionC	45 (83)	24 (83)	21 (84)	1.1 (0.2–6.3)	1

Unless indicated otherwise, data are given as n (%). Statistical tests: χ² test or Fisher’s exact test . ^ACalculated for 62 patients with a post-procedure induction test. ^BCalculated for 87 patients; 1 patient who underwent a heart transplant before discharge was excluded. ^CCalculated for 54 patients with at least 1 shock before the procedure and available data. AADs, antiarrhythmic drugs; CI, confidence interval; CS, cardiac sarcoidosis; ICD, implantable cardioverter defibrillator; OR, odds ratio; VT, ventricular tachycardia.

Two (2%) patients presented major complications, including hemoperitoneum with hemorrhagic shock and cardiac tamponade. Minor complications were reported in 8 patients. The distribution of complications is summarized in Table 5.

Table 5.

Distribution of Complications (n=88 Patients)

	No. patients
Minor complication	8
Complete atrioventricular block	2
Vascular access associated	2
Phrenic nerve injury	1
Pericardial effusion	3
Major complication	2
Hemoperitoneum with hemorrhagic shock	1
Cardiac tamponade	1

Post-procedure ICD programming had a median therapy threshold cycle length of 360 ms (interquartile range 340–403 ms) and a median detection of 20 beats (interquartile range 16–29 beats). In 99% of patients with enabled therapies, antitachycardia pacing therapy preceded ICD shock. The distribution of these parameters was equivalent between the 2 groups (P=0.09 and 0.17, respectively).

Long-Term Outcomes and Survival Analysis

During a mean follow-up of 4.18±3.98 years, 6 (7%) patients died because of a cardiovascular cause. Heart transplantation was performed in 12 (14%) patients, and it tended to be more common in patients with a histological diagnosis (24% vs. 7%; P=0.05), although the difference was not statistically significant. Repeated VT ablation was required for 37 (42%) patients, and 54 (62%) patients experienced at least 1 VT recurrence.

Of the 54 patients who experienced a VT recurrence, 27 underwent a PET scan within ±90 days of the event. Active inflammation was documented in 14 (51.9%) of these patients.

Survival analysis with Kaplan-Meier curves is shown in Figure 2. The overall 1- and 2-year event-free survival rates were 56.1% (95% CI 46.1–68.3%) and 38% (95% CI 28–51.6%), respectively. Patients with a histological diagnosis presented lower composite event-free survival rates than patients with clinical/suspected CS (HR 2.13; 95% CI 1.24–3.64; log-rank P=0.005). In addition, patients with systemic sarcoidosis experienced worse outcomes during follow-up than those with isolated CS (HR 2.48; 95% CI 1.44–4.28; log-rank P=0.001).

Figure 2.

Survival analysis. (A) Kaplan-Meier curve comparing patients with clinical and histologically diagnosed sarcoidosis. (B) Kaplan-Meier curves for patients with isolated cardiac sarcoidosis and systemic sarcoidosis. (C) Overall Kaplan-Meier curve. CI, confidence interval; HR, hazard ratio.

Multivariate Cox regression analysis revealed that systemic sarcoidosis was the only independent variable associated with lower event-free survival (HR 4.65; 95% CI 1.0–21.1; P=0.046). Multifocal LGE on CMR was associated with higher event-free survival (HR 0.38; 95% CI 0.15–0.93; P=0.035; Supplementary Tables 1,2). The ICD shock rate per 100 days was significantly lower after the procedure (1.29±1.99 vs. 0.32±0.99 pre- vs. postablation, respectively; MD 0.97 ICD shocks per 100 days [95% CI 0.47–1.46]; P<0.01). ICD shock reduction was achieved in 45 (83%) of 54 patients whose data were available and who experienced at least 1 shock before ablation. This reduction was consistent in both the clinical/suspected and histological diagnosis groups (83% vs. 84%, respectively; odds ratio 1.1; 95% CI 0.2–6.3; P=1; Figure 3). Notably, variations in device programming, particularly therapy cycle length and interval thresholds, did not affect event-free survival rates.

Figure 3.

Reduction in the frequency of implantable cardioverter defibrillator (ICD) shocks after ventricular tachycardia (VT) ablation. Statistical test: unpaired t-test. The reduction in ICD shock rate was analyzed for 54 patients with at least 1 shock before the procedure and available data. Pre- and postablation mean ICD shock rate data were available for 77 patients. CI, confidence interval; MD, mean difference; OR, odds ratio.

Discussion

Main Findings

This study highlights several important findings. In our population, systemic sarcoidosis was more common in patients with histological confirmation than in those with clinically diagnosed or suspected sarcoidosis. Regarding imaging characterization between the analyzed groups, mid-myocardial LGE was more prevalent in patients with clinically diagnosed or suspected sarcoidosis. The composite event-free survival was lower in patients with histologically confirmed sarcoidosis, as well as in those with systemic sarcoidosis. Multivariate analyses showed that systemic sarcoidosis was independently associated with worse outcomes, whereas histological confirmation did not independently affect event-free survival. Catheter ablation for VT demonstrated an acceptable complication rate, leading to a significant reduction in ICD shocks, although VT recurrence remained high and was associated with both scar and active inflammation.

The histological confirmation of CS is notoriously difficult due to the disease’s patchy distribution and the challenges in obtaining biopsy samples from affected organs. Only 10–20% of suspected cases achieve histological confirmation from myocardial tissue,^6,7 aligning with the 11.4% rate observed in the present study. These findings emphasize the importance of including patients without histological confirmation in clinical research, because this group has been underrepresented in prior studies.

Impact of Diagnostic Criteria on Outcomes

The inclusion criteria defined by previous studies reporting VT ablation outcomes are heterogeneous, including the HRS, JCS, and ACCESS guideline definitions of CS.^12–19 The present study offers new insights into the role of diagnostic criteria on VT ablation outcomes.

Kusano et al.²⁰ compared outcomes between patients with a histological and clinical diagnosis of CS according to the JCS 2016 guidelines and reported that all-cause mortality and adverse event rates were higher in the histological CS group. When Kusano et al. compared patients with histologically confirmed CS, probable CS (extracardiac biopsy confirming sarcoidosis), and patients with undefined CS (the absence of histological confirmation in any organ), no differences were found for all-cause mortality and a lower rate of event-free survival was reported for patients with histologically confirmed CS.²⁰ The findings of the present study suggest that cardiac or extracardiac histological confirmation of sarcoidosis is associated with lower event-free survival after VT ablation. However, this effect may be driven by the higher prevalence of systemic sarcoidosis in the group with histologically confirmed sarcoidosis.

Isolated CS has been proposed to be an initial manifestation of sarcoidosis (which may affect other organs later), a type of sarcoidosis affecting only the heart, or an imprecise diagnosis associated with modest involvement of other organs without clinical, radiological, or histological findings.²¹ The standardized use of whole-body imaging techniques, such as PET scans, may help uncover potential systemic involvement that may otherwise be challenging to detect.²² The prognostic impact of isolated CS vs. systemic involvement remains ambiguous.^23,24

PET Scans and Cardiac MR Imaging

The prevalence of mid-myocardial LGE was notably higher in clinically diagnosed patients than in those with biopsy-proven sarcoidosis. Studies have shown that the prevalence of mid-myocardial/subepicardial involvement in CS is greater in patients who present with ventricular arrhythmias and sudden cardiac death.^25,26 Obtaining biopsies from these regions remains challenging, which reduces the diagnostic yield of endocardial biopsy and complicates histological confirmation.²⁷ However, despite its uneven distribution, mid-myocardial LGE did not have a significant effect on event-free survival in the Cox regression model after adjustment.

Importantly, in a significant proportion of patients with recurrence after ablation, active inflammation was identified by PET. Therefore, in patients presenting with recurrence, it would be appropriate to extend the evaluation to exclude reactivation of inflammation. The limited availability of cardiac MR imaging and PET scan data highlights the absence of standardized diagnostic criteria for sarcoidosis, particularly in patients from the early years of the inclusion period. This may affect not only the diagnostic pathway but also ablation planning, because information from cardiac MR and PET scans regarding the distribution of fibrosis or inflammation can guide the identification of target areas for ablation.

Clinical Impact of VT Ablation

VT ablation is generally reserved for patients with VT refractory to medical therapy. In the present cohort, most patients had reduced LVEF, indicating the coexistence of electrical and contractile dysfunction. Although VT recurrence and repeat ablation rates were high, we found a 7% cardiovascular mortality rate, suggesting an acceptable survival rate in this high-risk population. Moreover, the procedure led to a reduction in AAD use in 23% of patients and a substantial reduction in ICD shocks in 83% of the patients with at least 1 shock before the procedure, underscoring ablation as an effective alternative for patients with VT refractory to medical therapy. These results highlight the role of VT ablation as a complementary pillar to guideline-directed medical therapy, which has been shown to improve outcomes in patients with systolic heart failure.²⁸

Future Directions

The role of emerging technologies such as pulsed field ablation for ventricular arrhythmias in patients with CS remains undefined. However, previously reported cases suggest the feasibility of this approach, particularly given the suboptimal success rates associated with radiofrequency ablation.^29,30

The development of predictive tools, including previously reported parameters such as electrocardiographic patterns (e.g., prolonged T-peak to T-end interval) and biomarkers such as troponin, which have been associated with worse outcomes, may help identify appropriate candidates for this procedure.^31,32

Study Limitations

This study has several limitations. As a retrospective analysis, it is subject to selection bias and incomplete data. The rarity of CS limited the sample size, potentially affecting statistical power and the ability to identify independent predictors of success. The long recruitment period also introduces variability due to evolving technologies and guidelines, such as the relatively recent adoption of epicardial ablation. Finally, the morphologies of VT recurrences were not analyzed or correlated with the initially targeted ablation VT due to the limited availability of electrograms. Larger prospective studies are needed to validate these findings.

Conclusions

This study demonstrates that patients with histologically confirmed CS had worse VT ablation outcomes than those with clinical/suspected CS. This difference may be driven by a higher prevalence of systemic sarcoidosis in the group with histologically confirmed CS. Although VT recurrence remains a challenge, the procedure significantly reduces ICD shocks, offering a valuable therapeutic option for patients with refractory VT. Active inflammation identified by PET was observed in a significant proportion of patients with recurrence after ablation, highlighting the importance of ongoing inflammatory activity in arrhythmia recurrence. These findings contribute to the growing body of evidence supporting VT ablation in managing this complex condition.

Acknowledgments

This publication was supported and/or funded (in part or fully) by Mayo Clinic Arizona Cardiovascular Clinical Research Center (MCA CV CRC). We are thankful for their generous support. Contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the MCA CV CRC.

Sources of Funding

This research received no specific grant from public, commercial, or not-for-profit funding agencies.

Disclosures

The authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Mayo Clinic Institutional Review Board (24-009460).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-25-0285

References

• 1.   Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H, Bresnitz EA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164: 1885–1889.
• 2.   Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009; 120: 1969–1977.
• 3.   Kandolin R, Lehtonen J, Airaksinen J, Vihinen T, Miettinen H, Ylitalo K, et al. Cardiac sarcoidosis: Epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 2015; 131: 624–632.
• 4.   Pöyhönen P, Lehtonen J, Velikanova D, Simonen P, Uusitalo V, Mälkönen H, et al. 30-year trends in the incidence, characteristics, and outcome of cardiac sarcoidosis in a nationwide cohort. JACC Adv 2024; 3: 101102.
• 5.   Desai R, Kakumani K, Fong HK, Shah B, Zahid D, Zalavadia D, et al. The burden of cardiac arrhythmias in sarcoidosis: A population-based inpatient analysis. Ann Transl Med 2018; 6: 330–330.
• 6.   Uemura A, Morimoto S, Hiramitsu S, Kato Y, Ito T, Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: Evaluation of endomyocardial biopsies. Am Heart J 1999; 138: 299–302.
• 7.   Terasaki F, Azuma A, Anzai T, Ishizaka N, Ishida Y, Isobe M, et al. JCS 2016 guideline on diagnosis and treatment of cardiac sarcoidosis: Digest version. Circ J 2019; 83: 2329–2388.
• 8.   Judson M, Baughman R, Teirstein A, Terrin M, Yeayer H Jr. Defining organ involvement in sarcoidosis: The ACCESS proposed instrument. ACCESS Research group. A Case Control Etiologic Study of Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 75–86.
• 9.   Birnie DH, Sauer WH, Bogun F, Cooper JM, Culver DA, Duvernoy CS, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014; 11: 1304–1323.
• 10.   The Japan Society of Sarcoidosis and Other Granulomatous Disorders, the Diffuse Pulmonary Study Group of the Health and Labor Sciences Research Grant-supported Rare/Intractable Disease Project, et al. Committee for revision of the diagnostic standard for sarcoidosis. Diagnostic standard and guideline for sarcoidosis – 2006. Jpn J Sarcoidosis Granulomatous Disord 2007; 27: 89–102 [in Japanese].
• 11.   Vemulapalli HS, Rodriguez-Riascos JF, Muthu P, Prajapati P, Raman A, Iyengar S, et al. Epicardial access for ventricular tachycardia and premature ventricular complexes ablation: An institutional experience. Heart Rhythm O2 2025; 6: 204–213.
• 12.   Siontis KC, Santangeli P, Muser D, Marchlinski FE, Zeppenfeld K, Hoogendoorn JC, et al. Outcomes associated with catheter ablation of ventricular tachycardia in patients with cardiac sarcoidosis. JAMA Cardiol 2022; 7: 175.
• 13.   Kaur D, Roukoz H, Shah M, Yalagudri S, Pandurangi U, Chennapragada S, et al. Impact of the inflammation on the outcomes of catheter ablation of drug-refractory ventricular tachycardia in cardiac sarcoidosis. J Cardiovasc Electrophysiol 2020; 31: 612–620.
• 14.   Muser D, Santangeli P, Pathak RK, Castro SA, Liang JJ, Magnani S, et al. Long-term outcomes of catheter ablation of ventricular tachycardia in patients with cardiac sarcoidosis. Circ Arrhythm Electrophysiol 2016; 9: e004333.
• 15.   Kumar S, Barbhaiya C, Nagashima K, Choi EK, Epstein LM, John RM, et al. Ventricular tachycardia in cardiac sarcoidosis: Characterization of ventricular substrate and outcomes of catheter ablation. Circ Arrhythm Electrophysiol 2015; 8: 87–93.
• 16.   Bandyopadhyay D, Sahoo D, Zein J, Brunken R, Tchou P, Culver D. Outcome of cardiac sarcoidosis after radiofrequency ablation and placement of AICD: A propesity matched analysis. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 70–79.
• 17.   Tokuda M, Tedrow UB, Kojodjojo P, Inada K, Koplan BA, Michaud GF, et al. Catheter ablation of ventricular tachycardia in nonischemic heart disease. Circ Arrhythm Electrophysiol 2012; 5: 992–1000.
• 18.   Jefic D, Joel B, Good E, Morady F, Rosman H, Knight B, et al. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: Report from a multicenter registry. Heart Rhythm 2009; 6: 189–195.
• 19.   Koplan BA, Soejima K, Baughman K, Epstein LM, Stevenson WG. Refractory ventricular tachycardia secondary to cardiac sarcoid: Electrophysiologic characteristics, mapping, and ablation. Heart Rhythm 2006; 3: 924–929.
• 20.   Kusano K, Ishibashi K, Noda T, Nakajima K, Nakasuka K, Terasaki S, et al. Prognosis and outcomes of clinically diagnosed cardiac sarcoidosis without positive endomyocardial biopsy findings. JACC Asia 2021; 1: 385–395.
• 21.   Isobe M, Tezuka D. Isolated cardiac sarcoidosis: Clinical characteristics, diagnosis and treatment. Int J Cardiol 2015; 182: 132–140.
• 22.   De Bortoli A, Birnie DH. Diagnosis and treatment of cardiac sarcoidosis. Circ J 2023; 87: 471–480.
• 23.   Mactaggart S, Ahmed R. Comparison of prognosis in isolated versus systemic manifestations of cardiac sarcoidosis. Curr Probl Cardiol 2024; 49: 102671.
• 24.   Yoshida S, Nakata T, Naya M, Momose M, Taniguchi Y, Fukushima Y, et al. Prognostic implications of sarcoidosis granulomas: Insights from the multicenter registry, the Japanese Cardiac Sarcoidosis Prognostic Study. Circ Rep 2023; 5: 252–259.
• 25.   Devesa A, Robson PM, Cangut B, Vazirani R, Vergani V, LaRocca G, et al. Specific locations of myocardial inflammation and fibrosis are associated with higher risk of events in cardiac sarcoidosis. Heart Rhythm 2025; 22: 1606–1614.
• 26.   Tavora F, Cresswell N, Li L, Ripple M, Solomon C, Burke A. Comparison of necropsy findings in patients with sarcoidosis dying suddenly from cardiac sarcoidosis versus dying suddenly from other causes. Am J Cardiol 2009; 104: 571–577.
• 27.   Ramirez R, Trivieri M, Fayad ZA, Ahmadi A, Narula J, Argulian E. Advanced imaging in cardiac sarcoidosis. J Nucl Med 2019; 60: 892–898.
• 28.   Sykora D, Bratcher M, Churchill R, Kim BM, Elwazir M, Young K, et al. Medical therapy and clinical outcomes in cardiac sarcoidosis patients with systolic heart failure. Circ J 2024; 89: 41–52.
• 29.   Muthu P, Prajapati P, Vemulapalli H, Rodriguez-Riascos JF, Raman A, Srivathsan K. Ablation of premature ventricular complexes originating from papillary muscle using pulsed field energy: The first in USA experience. Heart Rhythm 2024, doi:10.1016/j.hrthm.2024.10.067.
• 30.   Prajapati P, Muthu P, Vemulapalli HS, Rodriguez-Riascos JF, Raman A, Srivathsan K. Rescuing failed radiofrequency ablation: Pulsed field ablation in ventricular tachycardia. HeartRhythm Case Rep 2025; 11: 223–228.
• 31.   Takaya Y, Nakagawa K, Miyoshi T, Nishii N, Morita H, Nakamura K, et al. Impact of high-sensitivity cardiac troponin T on clinical outcomes in patients with cardiac sarcoidosis. Circ J 2025; 89: 442–449.
• 32.   Kataoka S, Yagishita D, Yazaki K, Kanai M, Hasegawa S, Shoda M, et al. Prolonged T-peak to T-end interval predicts implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis. Circ J 2023; 87: 1058–1067.