Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block
Circulation: Arrhythmia and Electrophysiology
Abstract
Background:
Symptomatic high-grade atrioventricular block (AVB) is the most common and often the only presenting manifestation (lone AVB) of cardiac sarcoidosis. Implantation of an intracardiac cardioverter defibrillator instead of a pacemaker is recommended, but the true risk of fatal arrhythmia, one incident to lone AVB in particular, remains poorly known.
Methods:
We used Myocardial Inflammatory Diseases in Finland Study Group Registry to analyze the presentations, left ventricular (LV) function, pacemaker therapy, and ventricular arrhythmias in cardiac sarcoidosis. From year 1988 to 2015, altogether 325 cases of cardiac sarcoidosis were diagnosed in Finland. Of them, 143 patients (112 women, mean age 52 years) presented with Mobitz II second degree or third degree AVB in the absence of other explanatory cardiac disease.
Results:
Concomitant with AVB at presentation, 20 patients had either ventricular tachycardia or severe LV dysfunction with ejection fraction <35% and 29 patients had nonsevere LV dysfunction (ejection fraction, 35%–50%) while 90 patients presented with AVB alone. During a median of 2.8 years’ follow-up, 23 sudden cardiac deaths (fatal or aborted) and 19 ventricular tachycardias were recorded as arrhythmic end point events. Their composite 5-year incidence (95% confidence interval) was 56% (36%–88%) in the AVB subgroup with ventricular tachycardia or severe LV dysfunction versus 24% (12%–49%) in the subgroup with nonsevere LV dysfunction and 24% (15%–38%) with lone AVB (P=0.019). The 5-year incidence of sudden cardiac death was 34% (16%–71%), 14% (6%–35%), and 9% (4%–22%) in the respective subgroups (P=0.060).
Conclusions:
The risk of sudden cardiac death is significant in cardiac sarcoidosis presenting with high-grade AVB with or without ventricular tachycardia or LV dysfunction. The consensus recommendation to implant an intracardiac cardioverter defibrillator whenever permanent pacing is needed seems well-founded.
Graphical Abstract
Introduction
See Editorial by Birnie et al
WHAT IS KNOWN?
•
One-fourth of unexplained atrioventricular blocks (AVBs) in adults aged <55 years are caused by cardiac sarcoidosis.
•
AVB requiring permanent pacemaker is the most common initial manifestation of cardiac sarcoidosis.
WHAT THE STUDY ADDS?
•
AVB because of cardiac sarcoidosis is not a benign condition even if it presents as the only manifestation of cardiac involvement.
•
In patients with AVB and ejection fraction >50%, the rate of sudden cardiac death is 9% in 5 years.
•
In patients with AVB and ejection fraction 35% to 50%, the rate of sudden cardiac death is 14% in 5 years.
•
In cardiac sarcoidosis, all patients who require permanent pacing should be considered for implantation of an intracardiac cardioverter defibrillator.
Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating granulomas and subsequent tissue scarring.1 In the heart, its effects depend on the location and extent of granulomas and vary from silent myocardial involvement to symptomatic atrioventricular block (AVB), ventricular tachyarrhythmias, heart failure, or an unexpected sudden cardiac death (SCD).2–5 The diagnosis of cardiac sarcoidosis (CS) can be challenging, and isolated cardiac involvement in particular may escape detection until autopsy or transplantation.6,7 Although CS seems to have better prognosis today than historically,4 it remains a potentially fatal disease with by far most deaths being arrhythmic in origin rather than due to heart failure.4,5
The current therapy of CS combines steroid-based immunosuppression with medical and surgical interventions targeted at ventricular arrhythmias and heart failure.7 The critical question in the treatment of life-threatening arrhythmias is whether a permanent intracardiac cardioverter defibrillator (ICD) should be implanted. The decision to implant is straightforward if the patient has sustained ventricular tachyarrhythmias, history of prior cardiac arrest, or heart failure with left ventricular (LV) ejection fraction (EF) that remains poor (<35%) despite proper therapy.8,9 However, the most common form of presentation of CS is symptomatic high-grade AVB that not infrequently appears in the presence of normal EF and no arrhythmias, that is, as the lone clinical sign of CS.4,10 Should all these patients also receive an ICD instead of a pacemaker? The answer of recent guidelines is predominantly affirmative with class IIa recommendation (can be useful) for an ICD in CS patients needing permanent pacing.8,9 However, no treatment trials exist, and although small follow-up studies have shown that patients with CS and AVB are not safe from serious arrhythmias,10–12 the long-term risk of an arrhythmic SCD remains poorly quantified. Importantly, there exist no data specific to the prognosis of patients with AVB as the lone first manifestation of CS. We, therefore, screened both our nationwide clinical CS registry and the official cause-of-death registry of Finland to identify a comprehensive series of CS patients presenting with AVB with or without other cardiac manifestations and to study their outcome. Here, we report long-term follow-up data on their survival and incidence of life-threatening arrhythmias, including SCD.
Methods
The data cannot be made available to other researchers for purposes of reproducing the results due restrictions by the patient consent. Individual level data cannot be shared openly.
MIDFIN Registry
The MIDFIN (Myocardial Inflammatory Diseases in Finland) Study Group is a cardiology research network of the Finnish university and central hospitals that focuses on treatment and research of CS and giant cell myocarditis. Cases of CS diagnosed in the cardiology services of the network’s hospitals from the year 1988 onwards have been entered into the MIDFIN registry with data on patients’ demographics, results of diagnostic imaging and laboratory studies, initial and later clinical manifestations, details of treatment with drugs and devices, and occurrence of adverse cardiac events. The methods of case identification and data collection, as well as the criteria for inclusion in the registry, were detailed in our 2015 paper in Circulation.4 In brief, the diagnosis of CS requires clinical manifestations of a myocardial involvement associated with histology of sarcoidosis in myocardial biopsy or, alternatively, clinical manifestations and findings compatible with CS in 18-F-fluorodeoxyglucose positron emission tomography (PET), cardiac magnetic resonance imaging (MRI), or echocardiography associated with extracardiac histology of sarcoidosis. The presence of epithelioid cell granulomas together with isolated giant cells and absence of considerable myocardial necrosis or marked tissue eosinophilia were required for the histological diagnosis of sarcoidosis. These criteria are in conformity with the diagnostic criteria in the 2014 expert consensus statement of the Heart Rhythm Society.8
Present Study Population
At the end of 2015, the MIDFIN registry involved altogether 263 patients diagnosed with CS during life. In addition, 62 cases of CS that had been diagnosed only at autopsy were included in the present study. They were identified from the cause-of-death registry maintained by the national authority (Statistics Finland) by screening the certificates of the 820.605 natural deaths registered from 1998 to 2015. Each autopsy diagnosis was confirmed by reanalyzing the histological samples. The decedents’ premortem medical records were examined for CS manifestations, diagnostic studies, later disease course, and adverse events. In this nationwide population of 325 patients, 144 had presented with Mobitz II second degree or third degree AVB prompting implantation of a permanent pacing device during the first admission. Main presenting manifestation in the remaining 181 patients were ventricular tachycardia [VT] in 42, heart failure in 48, sudden cardiac arrest/SCD in 45, frequent ventricular premature complexes in 19, syndrome mimicking myocardial infarction or exertional angina in 12, atrial arrhythmia in 4, and nonspecific symptoms in 10 patients. One patient presented with AVB with no indication for permanent pacemaker and was therefore not included in the present study. Studies to exclude other potential causes of AVB at the time of CS diagnosis were at the discretion of the treating cardiologist and relied mainly on routine clinical and laboratory assessment and echocardiography. Coronary angiography was done in 79 patients and revealed a significant 3-vessel disease in 1 patient who was excluded from our analysis. The remaining 143 patients constitute the present study population (Figure 1). In 76 of them, the histological diagnosis of sarcoidosis was based on direct myocardial microscopy (endomyocardial biopsy, n=61; explanted heart, n=3; autopsy, n=12). In the rest, histological confirmation was obtained from samples of mediastinal (n=50) or other (n=6) lymph nodes or from biopsies of skin (n=4), lung (n=5), liver (n=1), and central nervous system (n=1).
Definition and Assessment of Adverse Cardiac Events
For the present work, occurrence of death, cardiac transplantation, and life-threatening ventricular tachyarrhythmias were recorded till the end of March 2016. Life-threatening tachyarrhythmias were defined as (1) SCD; (2) aborted SCD, that is, ventricular fibrillation defibrillated either internally by an ICD or externally during resuscitation; and (3) any VT causing syncope or requiring for conversion either ICD therapy or external cardioversion/defibrillation or rescue treatment with an antiarrhythmic drug (amiodarone infusion). These data were collected by review of medical records, 12-lead ECG recordings, ICD reports, rhythm strips, and Holter recordings. The mortality data were double-checked from the official Finnish Population Register in April 2017. The causes of death were determined by medical records and findings at autopsy. The ethics board for Helsinki University Hospital approved the study protocol, and each involved center also granted approval to conduct this study. All patients in the MIDFIN registry, aside from the ones diagnosed postmortem, have given written informed consent for inclusion.
Statistical Analyses
Patient characteristics are presented as mean±SD or median with min-max or interquartile range for continuous variables and as frequencies for categorical variables. Group comparisons of baseline characteristics were made using ANOVA and Kruskal-Wallis test for normally distributed and skewed data, respectively, and with χ2 test for categorical variables. Follow-up times were calculated from the date of pacemaker (or ICD) implantation during the first admission. Transplant-free survival probabilities were estimated using the Kaplan-Meier method. SCD (fatal or aborted) and the composite of SCD or VT were taken as arrhythmic end points with transplantation and death because of heart failure considered competing events.13 Cause-specific cumulative incidence analysis was used to plot the incidence-time curves for the end point arrhythmias, and the Gray test was used to analyze group differences. Furthermore, for the composite of SCD and VT, events per exposure time (100 patient years) and their Poisson 95% confidence interval were also determined. To analyze the association of end point arrhythmias with the patient characteristics, the Fine and Gray model was used to calculate subdistribution hazard ratios and their 95% confidence intervals (CI).13 The influence of immunosuppression on the arrhythmic events was assessed using Cox regression analysis with the initiation of corticosteroid therapy as time-dependent covariate. Pearson correlation coefficient was used to assess the relationship of the log delay in CS diagnosis to the year of AVB presentation. P<0.05 was considered statistically significant. Xlstat Biomed (Addinsoft, Paris, France) and R software (R Development Core Team) were used in calculating cumulative incidence, whereas IBM SPSS Statistics (version 22.0 for Windows and Mac; Armonk, NY: IBM Corp) was used in all other analyses.
Results
Patient Characteristics
The study population consisted of 112 women and 31 men with an average age of 52 years (range, 18–71 years). Seventeen patients had known extra-CS (12 with pulmonary involvement) on admission for symptomatic high-grade AVB. Preexisting hypertension and diabetes mellitus were recorded in 38 and 14 patients, respectively, while none had renal insufficiency or chronic obstructive pulmonary disease. Sixty-three patients (44%) received the diagnosis of CS at or within 3 months of admission for AVB. In the remaining 80 patients, the underlying CS was detected only after a median delay of 23 months (range, 4–133 months) after presentation. The studies exposing CS later were prompted by appearance of impaired LVEF (<50%) in 33 patients by new ventricular arrhythmias in 7 patients and solely by increased awareness and knowledge of CS in 27 patients. Finally, 11 late diagnoses were made at autopsy after SCD, and 2 cases were found at the study of the native heart after transplantation. Of 143 patients, 100 had systemic sarcoidosis based on clinical, histological, or fluorodeoxyglucose-PET findings. The majority of all cases were diagnosed only after 2010, that is, during the last 5 years of the 28-year period covered by the MIDFIN registry (Figure 2).
In addition to high-grade AVB, 20 patients had VT (n=15) or severe LV dysfunction (EF <35%; n=10) at presentation and another 29 patients had concomitant nonsevere LV dysfunction (EF, 35%–50%) without arrhythmias while the remaining patients presented with AVB alone (n=90) or had not EF recorded at presentation (n=4; see Figure 1). As Figure 2 shows, the proportion of the last subgroup increased conspicuously over time being 24 of 49 (49%) among patients diagnosed from 1988 to 2010 versus 66 of 89 (74%) in patients diagnosed from 2011 to 2015 (P=0.006). Table 1 compares selected patient characteristics across the 3 presentation subgroups and shows, among other things, that the diagnosis of the underlying CS was most delayed and least often based on myocardial histology in patients presenting with lone AVB. The diagnostic delay was related to the year of presentation, however, and shortened markedly over the period covered by our work (Figure 3).
| All Patients | AVB+VT or EF<35% | AVB+EF 35%–50% | Lone AVB | PValue | |
|---|---|---|---|---|---|
| n=143 | n=20 | n=29 | n=90 | ||
| Age, y | 52±10 | 53±8 | 53±11 | 50±11 | 0.271 |
| Sex, n of females | 112 (78%) | 15 (75%) | 22 (76%) | 72 (80%) | 0.826 |
| Earlier history of extracardiac sarcoidosis, n | 17 (12%) | 0 | 5 (17%) | 12 (13%) | 0.168 |
| NT-proBNP, ng/L (n=52) | 661 (253–1581) | 1301 (471–2741) | 889 (630–1639) | 338 (118–1056) | 0.014 |
| Troponin-T, ng/L (n=67) | 21 (11–36) | 30 (19–48) | 23 (10–40) | 20 (10–36) | 0.342 |
| Myocardial LGE on MRI (62 studies), n | 50/62 (81%) | 7/8 (88%) | 15/16 (94%) | 28/38 (74%) | 0.204 |
| 18F-FDG PET suggesting myocardial inflammation, n | |||||
| At presentation (62 studies) | 56/62 (90%) | 6/7 (86%) | 10/11 (91%) | 40/44 (91%) | 0.909 |
| Before diagnosis (109 studies) | 96/109 (88%) | 11/13 (85%) | 16/19 (84%) | 69/77 (90%) | 0.744 |
| Diagnosis at presentation, n | 63/143 (45%) | 14/20 (70%) | 14/29 (48%) | 35/90 (39%) | 0.038 |
| Implantation of an ICD at presentation, n | 35 (24%) | 15 (75%) | 8 (28%) | 12 (13%) | 0.000 |
| Delay from presentation to diagnosis, mo | 5 (0–26) | 1 (0–10) | 4 (0–27) | 8 (1–28) | 0.026 |
| Diagnosis from myocardial histology, n | 76 (53%) | 17 (85%) | 17 (59%) | 38 (42%) | 0.002 |
The data are given as number of patients and as mean±SD (age) or median with interquartile range (NT-proBNP, troponin-T, and delay from presentation). P values are from comparisons across the 3 subgroups. Four patients were left out from the analysis because of missing information of the initial EF.
AVB indicates atrioventricular block; CS, cardiac sarcoidosis; EF, ejection fraction; 18F-FDG PET, 18 F-fluorodeoxyglucose positron emission tomography; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and VT, ventricular tachycardia.
Treatment
For treatment of symptomatic high-grade AVB, 107 patients received a permanent pacemaker and 35 patients received an ICD during initial admission (1 patient refused pacemaker implantation). The pacemaker was upgraded to an ICD during later follow-up in 19 patients. The upgrade was prompted by occurrence of life-threatening VT in 4 patients, by severe impairment of LVEF (<35%) in 8 patients, and merely by the establishment of CS diagnosis in 7 patients.
Altogether, 128 patients received corticosteroids starting after confirmation of CS diagnosis. In addition, 2 patients received steroids for high suspicion of CS that was proven histologically after transplantation. The median initial daily dose of prednisone was 40 mg (range, 10–80 mg) and the median duration of treatment, 22 months (range, 1–247 months). In addition to or as a substitution of prednisone, azathioprine, mycophenolate, and methotrexate were given to 55, 11, and 4 patients, respectively. Besides immunosuppression, the drug therapy included β-adrenergic blockers and angiotensin-converting enzyme inhibitors in 112 and 88 patients, respectively, and use of antiarrhythmic drugs (most commonly amiodarone or sotalol) in 46 patients. Four patients underwent VT ablation.
Transplant-Free Survival
Of the 143 patients, 16 died (all of cardiac cause) and 9 underwent transplantation a median of 52 months after presentation and pacemaker/ICD implantation (range, 1–191 months). Of the 16 deaths, 14 were SCD and 2 because of terminal heart failure. The Kaplan-Meier estimate was 99% (95% CI, 95%–100%) for 1-year transplant-free survival and 86% (95% CI, 79%–91%) for 5-year survival. From among the 90 patients presenting with lone AVB, 4 patients died and 6 underwent transplantation. Their 1- and 5-year transplant-free survival estimates were 100% (95% CI, 95%–100%) and 93% (95% CI, 86%–97%), respectively.
Arrhythmic Events
Altogether, 23 of 143 patients experienced either fatal (n=13) or aborted (n=10) SCD as the first event during a median follow-up of 4.1 years (range, 0.1–14.0 years). Six of 10 patients with aborted SCD had an ICD device at the time of the event. Figure 4 illustrates the cumulative incidence of SCD in the 3 presentation subgroups. The curves deviate with a trend to highest SCD incidence in patients presenting with VT and LVEF <35% in addition to AVB (P=0.060).
The composite end point of SCD or VT was recorded in 42 patients. These arrhythmias broke down into 13 fatal SCDs, 8 aborted SCDs, and 21 VTs as first events. Figure 5 demonstrates their incidence-time curves and shows a difference across the subgroups (P=0.019) parallel to the one seen for SCD. The subgroups’ 1- and 5-year incidence estimates of SCD and of SCD or VT are given in Table 2. The rates of the composite of SCD and VT calculated per 100 patient years were 15 (95% CI, 7–27) for the subgroup with VT and LVEF <35% at presentation, 6 (95% CI, 2–11) for the subgroup with LVEF 35% to 50%, and 5 (95% CI, 3–7) for patients presenting with lone AVB.
| Part of Study Population | Incidence (95% CI) of SCD | Incidence (95% CI) of SCD or VT | ||
|---|---|---|---|---|
| 1 Year, % | 5 Years, % | 1 Year, % | 5 Years, % | |
| All patients (n=143) | 4 (2–9) | 17 (11–27) | 9 (6–16) | 31 (23–42) |
| AVB+VT and EF <35% (n=20) | 10 (3–37) | 34 (16–71) | 20 (8–48) | 56 (36–88) |
| AVB+EF 35%–50% (n=29) | 10 (4–30) | 14 (6–35) | 10 (4–30) | 24 (12–49) |
| Lone AVB (n=90) | 1 (0–8) | 9 (4–22) | 7 (3–15) | 24 (15–38) |
Four of 143 patients were left out from comparisons across the subgroups because of missing information of EF at presentation. AVB indicates atrioventricular block; CI, confidence interval; CS, cardiac sarcoidosis; EF, ejection fraction; SCD, sudden cardiac death; and VT, ventricular tachycardia.
To identify possible predictors (other than the presentation subgroup) of arrhythmic events in the 143 patients, the characteristics at presentation (see Table 1) were subjected to assessment of subdistribution hazard ratios by the Fine and Gray model. The results of the analyses, detailed in Table 3, showed that the hazard of either arrhythmic end point increased with age and was higher in women and in patients who had VT at presentation. LVEF predicted the occurrence of SCD or VT as first event but not SCD alone. Of the 42 patients who met the composite end point, 28 had normal or mildly impaired LVEF and no VT at presentation. LVEF decreased at least by 10% before the arrhythmic event in 12 (43%) of the 28 patients. Data on key laboratory measurements (N-terminal pro-B-type natriuretic peptide, troponin-T) and cardiac imaging studies (MRI, PET) were available for analyses in less than half of the study population (see Table 1). None of N-terminal pro-B-type natriuretic peptide >median, troponin-T >median, MRI showing myocardial late gadolinium enhancement (LGE) or PET suggestive of active inflammation were predictive of the end point events.
| Characteristic at Presentation | Sudden Cardiac Death | Sudden Cardiac Death or VT | ||||
|---|---|---|---|---|---|---|
| e/n | SHR (95% CI) | P Value | e/n | SHR (95% CI) | P Value | |
| Age per 1 y | 23/143 | 1.08 (1.03–1.13) | 0.001 | 42/143 | 1.04 (1.01–1.07) | 0.017 |
| Sex, female | 23/143 | 3.92 (2.71–5.98) | <0.001 | 42/143 | 1.88 (1.39–2.53) | <0.001 |
| VT | 23/143 | 4.17 (2.74–6.29) | <0.001 | 42/143 | 2.39 (1.82–3.14) | <0.001 |
| LVEF, per 10% decrease | 20/139 | 1.43 (0.98–2.07) | 0.060 | 39/139 | 1.39 (1.03–1.86) | 0.029 |
CI indicates confidence interval; e/n, the number end point events per number of patients; LVEF, left ventricular ejection fraction; SHR, subdistribution hazard ratio by the Fine and Gray model; and VT, ventricular tachycardia.
To look for influence of immunosuppression on the hazard of arrhythmic events, Cox regression analysis was made with the presentation subgroup as a stratifying factor and start of steroids as time-dependent covariate. The hazard ratios for institution of steroid therapy were not statistically significant.
Discussion
The key message of our study is that high-grade AVB caused by CS is not a benign condition, not even when presenting as the only manifestation of cardiac involvement. This was shown by the 5-year risk of SCD in our middle-aged patients that was 34% if AVB presented together with VT or severe LV dysfunction and still significant from 9% to 14% when AVB was the only sign of CS or presented with nonsevere LV dysfunction. Additional important observations were the high frequency of lone AVB as the initial clinical manifestation of CS and the often remarkably long delays in its diagnosis. Despite having fully normal LV function at presentation, patients with lone AVB also bore the risk of progressive myocardial injury and heart failure as the majority of transplantations (6 of 9) were done in these patients.
Impaired cardiac conduction has long been recognized as one of the main manifestations of sarcoid heart disease.2,3,5,7,14 A more novel observation is that CS often presents as an ostensibly idiopathic AVB in young and middle-aged individuals.10,11 In a recent study from one of our centers,10 14 of 72 patients aged <55 years (20%) presenting with initially unexplainable Mobitz II second degree or third degree AVB had histologically confirmed CS and another 4 patients had giant cell myocarditis. A prospective study from Canada found CS in 11 of 32 patients (34%) aged <60 years presenting with seemingly unexplainable AVB.11 Both works showed that patients presenting with AVB could later experience serious arrhythmias and heart failure, but the size of the risk could not be specified because of the small study groups.10,11 In 2015, Takaya et al12 reported on the outcome of high-grade AVB in a retrospective study of 22 Japanese CS patients aged on average 60 years. During a median follow-up of 45 months, as many as 11 patients (50%) experienced a life-threatening ventricular arrhythmia (ventricular fibrillation or VT), and 1 additional patient was hospitalized for new heart failure.12 Our observations, based on a younger and several times larger CS population, add to the Japanese data by showing that the risk of serious arrhythmias is related to the other cardiac manifestations accompanying AVB at presentation. The majority of our patients (119 of 143; 83%) presented with either lone AVB or AVB associated with nonsevere LV dysfunction and had a markedly lower incidence of ventricular fibrillation or VT (24% at 5 years) than reported by Takaya et al.12
In the current era of heart failure therapy, including mechanical support and transplant surgery, deaths due to terminal heart failure have become rare in CS, the great majority of fatalities being arrhythmic in origin. In our earlier report of 110 CS patients followed for a median of 79 months, only 1 patient died of heart failure while 11 underwent transplantation and as many as 20 patients experienced a fatal or aborted SCD.4 Prevention of an arrhythmic death, therefore, assumes a major role in the current therapy of CS. It relies on the use of ICDs because there exist no data to show that either immunosuppression or antiarrhythmic drugs could control and prevent life-threatening ventricular arrhythmias.7,8,15 Unfortunately, the risk of SCD in an individual with CS defies an easy and reliable prediction. VT at presentation of CS clearly presages a poorer outcome,16,17 and the predictive value of LV systolic dysfunction has also been shown in several studies18–22 though not universally.12,17,23 In our study population, LVEF did predict the composite of SCD or VT statistically significantly but not SCD alone. Kron et al20 reported recently that most CS patients experiencing ventricular fibrillation or VT during follow-up had LVEF at presentation in the range from normal to nonsevere impairment (>35%). Several cardiac MRI studies, reviewed in depth lately by Coleman et al24 and Slart et al,25 have demonstrated that presence of LGE suggestive of scarred myocardium predicts serious ventricular arrhythmias. Some works have even shown that the extent of LGE may outperform LVEF as a prognostic factor.17,26 Follow-up studies after cardiac PET in turn have demonstrated that focal fluorodeoxyglucose uptake, suggesting active inflammation, combined with myocardial perfusion defect, suggesting scar formation, indicates an increased risk of life-threatening arrhythmias as does the mere fluorodeoxyglucose uptake in the right ventricular wall.25,27 Finally, invasive electrophysiological testing may help predict the risk of fatal arrhythmias in selected patients with CS28 although less convincing observations also exist.18
The 2014 HRS (Heart Rythm Society) expert consensus report8 on arrhythmias in CS gave a class IIa recommendation for an ICD in patients with CS and an indication for implantation of a permanent pacemaker. An identical recommendation, with acknowledgment of the low level of evidence (class C, limited data), is written in the newly published 2017 American College of Cardiology/American Heart Association/HRS guideline for treatment of ventricular arrhythmias and prevention of SCD.9 Altogether, 5 studies of CS patients with an ICD have reported on the incidence of arrhythmias and device therapies during follow-up.18–22 The rate of appropriate therapies ranged from an annual average of 9%20 to a cumulative rate as high as 52% in 2 years.22 The rate of inappropriate therapies was also high, however, varying between 11%22 and 30%,21 as was the frequency of other complications (lead problems, infections), exceeding 15% in 2 reports.18,20 The frequency of device-related adverse events even prompted an editorial questioning whether ICD is a savior or sinner in CS.29 In our work, the 5-year incidence of SCD was 34% in CS patients presenting with AVB and VT or severe LV dysfunction and 9% to 14% in those free of serious arrhythmias and having either normal LV function or at worst mild-to-modest dysfunction at presentation. These figures are high and clearly support ICD as the intracardiac device for all CS patients presenting with high-grade AVB. For comparison, recent guidelines in hypertrophic cardiomyopathy state that implantation of an ICD should be considered for primary prevention if the estimated 5-year risk of SCD is ≥6%.30
The frequency of lone AVB as the initial manifestation of CS deserves clinical emphasis. This form of presentation was seen in as many as two-thirds of our study population and represents one-third of all patients in our nationwide CS registry. Our experience (see Figure 3) shows that CS presenting with lone AVB can resist diagnosis for months or even several years, in the worst case until death or transplantation. To avoid long diagnostic delays, cardiac MRI or PET should be used with low threshold to seek signs of inflammatory cardiomyopathy in young and middle-aged patients with unexplainable high-grade AVB. Although the sensitivity of imaging is not well-known, MRI findings predict future events.6–8,10,11 The utility of this approach was recently demonstrated in a study from India where, in addition to sarcoidosis, also tuberculosis can be the cause of PET-positive myocardial inflammation and high-grade AVB.31 As likely as not, increasing availability of MRI and PET combined with growing awareness of CS among clinicians also best explains the increase over time in the total number of annual diagnoses in our study, as well as the proportional growth of the lone AVB subgroup and the shortened delays in its diagnosis (Figures 2 and 3).
Our work has strengths and limitations. Its strengths include the relatively large size (for a study of CS) and the nationwide representativeness of our study population. The present study population is, however, exclusively northern European, and thus, the results may not apply to different racial groups. Furthermore, all diagnoses were histologically confirmed, and the proportion of diagnoses based on myocardial histology was exceptionally high (76 of 143). Most of the limitations are attributable to the mainly retrospective study design and to the ≈30-year period covered by our work. Thus, certain key laboratory measurements and imaging studies (MRI and PET) were available for less than half of the patients at presentation. Furthermore, we were unable to quantify the MRI and PET studies made in different hospitals and could therefore not properly analyze the value of MRI and PET as predictors of outcome. The data on LGE in the present study are also incomplete (62 of 143) and must not be seen as attesting against the known predictive value of LGE.17,24–26 In assessing the predictive value of LV function, we used only LVEF recorded at AVB presentation. It is possible that a trend in LVEF would have been a better predictor of long-term events. Data on the complications of pacemakers and ICDs would have been valuable but are not included in the MIDFIN database and could not be reported here. Finally, the number of end point events, of SCD in particular (23 in 143 patients), was relatively small for statistical outcome analyses. The estimates of SCD incidence have, therefore, wide 95% CIs (see Table 2) and need to be interpreted accordingly.
In conclusion, patients presenting with AVB due to CS are at risk of life-threatening ventricular arrhythmias and SCD in addition to being susceptible to progressive myocardial injury and heart failure. The risk of SCD is 34% in 5 years if AVB is accompanied by VT or poor LVEF (<35%) at presentation and 9% to 14% if AVB is initially accompanied by no arrhythmias and no or mild-to-moderate LV dysfunction only. Lone AVB is a common first sign of CS and can look deceitfully benign though still having the potential for fatal arrhythmia or progressive myocardial injury. Our observations further highlight the need to look for CS as the cause of an otherwise unexplainable high-grade AVB and support the recommendation to consider implantation of an ICD in CS patients with an AVB requiring permanent pacing.
Acknowledgments
We thank our colleagues and staff in all participating hospitals for help with this study.
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© 2018 American Heart Association, Inc.
History
Received: 20 December 2017
Accepted: 28 June 2018
Published in print: August 2018
Published online: 17 August 2018
Keywords
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None.
Sources of Funding
The study was supported by a Finnish government grant for medical research and the Finnish Foundation for Cardiovascular Research.
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