Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator.

BACKGROUND: Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown. METHODS: We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up. RESULTS: Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (χ2=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; χ2=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; χ2=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation. CONCLUSIONS: Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.

Long-term outcome of intraventricular conduction delays in the general population.

BACKGROUND: Previous population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD). METHODS: We studied long-term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12-lead ECG. For left bundle branch block (LBBB) and non-specific IVCD (NSIVCD), two different definitions were used. RESULTS: During 16.5 years' follow-up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04-2.31, p = .032) and 1.27 (95% confidence interval 0.80-2.02, p = .308) for the Strauss' definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R-R' pattern was not associated with any adverse outcome. CONCLUSIONS: In a population study with long-term follow-up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.

Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries.

AIMS: The present study was done to assess the role of sudden cardiac death (SCD) among the presenting manifestations of and fatalities from cardiac sarcoidosis (CS). METHODS AND RESULTS: We analysed altogether 351 cases of CS presenting from year 1998 through 2015 in Finland. There were 262 patients with a clinical diagnosis and treatment of CS, 27 patients with an initial lifetime diagnosis of giant cell myocarditis that was later converted to CS, and 62 cases detected at autopsy and identified by screening >820 000 death certificates from the national cause-of-death registry. The total case series comprised 253 females and 98 males aged on average 52 years at presentation. High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%), unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%). Severe coronary artery disease was found at autopsy concomitant with CS in four of the 38 cases presenting with fatal SCD. Of all deaths recorded till the end of 2015, 64% (n = 54/84) were unexpected SCDs from CS that had either been silent during life or defied all attempts at diagnosis. The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85% (80-90%) at 5 years and 76% (68-84%) at 10 years. CONCLUSION: Together fatal and aborted SCD constitute 14% of the presenting manifestations of CS. Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart.

Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study.

BACKGROUND: This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. METHODS AND RESULTS: We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×10(5) adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×10(5). Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan-Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%. CONCLUSIONS: The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome.

Prevalence and long-term prognostic implications of prolonged QRS duration in left ventricular hypertrophy: a population-based observational cohort study.

OBJECTIVES: ECG left ventricular hypertrophy (ECG-LVH) has been associated with left ventricular dysfunction and adverse prognosis, but little is known about the prevalence and prognostic significance of different levels of QRS duration in the presence of ECG-LVH in a general population. DESIGN: Population-based observational prospective cohort study. PARTICIPANTS: Nationally representative random cluster of Finnish adult population. METHODS: We assessed the prevalence and long-term (median 15.9 years) prognostic significance of QRS duration in ECG-LVH, and compared the risk to individuals without ECG-LVH in a predominantly middle-aged random sample of 6033 Finnish subjects aged over 30 years (mean age 52.2, SD 14.6 years), who participated in a health examination including a 12-lead ECG. MAIN OUTCOME MEASURES: Cardiovascular and all-cause mortality, incidence of heart failure (HF). RESULTS: ECG-LVH was present in 1337 (22.2%) subjects; 403 of these (30.1%) had QRS duration ≥100 ms and 100 (7.5%) had ≥110 ms. The increased risk of mortality in ECG-LVH became evident after a QRS threshold of ≥100 ms. After controlling for known clinical risk factors, QRS 100-109 ms was associated with increased cardiovascular (HR 1.38, 95% CI 1.01 to 1.88, p=0.045) and QRS≥110 ms with cardiovascular (1.74, 95% CI 1.07 to 2.82, p=0.025) and all-cause mortality (1.52, 95% CI 1.02 to 2.25, p=0.039) in ECG-LVH. The risk of new-onset HF was two-fold in subjects with QRS 100-109 ms and threefold in subjects with QRS ≥110 ms, even after adjustment for incident myocardial infarction within the follow-up. When the prognosis was compared with subjects without ECG-LVH, subjects with ECG-LVH but QRS duration <100 ms displayed similar mortality rates with or without ECG-LVH but higher rates of incident HF. CONCLUSIONS: In ECG-LVH, the risk of excess mortality and new-onset HF markedly increases with longer QRS duration, but even QRS duration within normal limits in ECG-LVH carried a risk of HF compared with the risk in individuals without ECG-LVH.

Manifestations and Outcome of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis by 25-Year Nationwide Cohorts.

Background Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) share many histopathologic and clinical features. Whether they are parts of a one-disease continuum has been discussed. Methods and Results We compared medical record data of 351 CS and 28 GCM cases diagnosed in Finland since the late 1980s and followed until February 2018 for a composite end point of cardiac death, aborted sudden death, and heart transplantation. Heart failure was the presenting manifestation in 50% versus 15% (P<0.001), and high-grade atrioventricular block in 21% versus 43% (P=0.044), of GCM and CS, respectively. At presentation, left ventricular ejection fraction was ≤50% in 81% of cases of GCM versus in 48% of CS (P=0.004). The median (interquartile range) of plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) was 5273 (2782-11309) ng/L on admission in GCM versus 859 (290-1950) ng/L in CS (P<0.001), and cardiac troponin T exceeded 50 ng/L in 17 of 19 cases of GCM versus in 48 of 239 cases of CS (P<0.001). The 5-year estimate of event-free survival was 77% (95% CI, 72%-82%) in CS versus 27% (95% CI, 10%-45%) in GCM (P<0.001). By Cox regression analysis, GCM predicted cardiac events with a hazard ratio of 5.16 (95% CI, 2.82-9.45), which, however, decreased to 1.58 (95% CI, 0.71-3.52) after inclusion of markers of myocardial injury and dysfunction in the model. Conclusions GCM differs from CS in presenting with more extensive myocardial injury and having worse long-term outcome. Yet the key determinant of prognosis appears to be the extent of myocardial injury rather than the histopathologic diagnosis.

Relation of intraventricular conduction delay to risk of new-onset heart failure and structural heart disease in the general population.

BACKGROUND: Intraventricular conduction delays (IVCDs) are hallmarks of heart failure (HF) and structural heart disease (SHD) but their prognostic value for HF and SHD is unclear. METHODS: Relation of eight IVCDs and the incidence of first-time HF or SHD was studied in a nationally representative random sample of 6080 Finnish subjects aged ≥ 30 years (mean age 52.1, SD 14.5 years) who participated in the health examination including 12-lead ECG. RESULTS: During 16.5 years' follow up, half of the subjects with left bundle branch block (LBBB) and one third of the subjects with non-specific IVCD developed HF. After controlling for known clinical risk factors the hazard ratio (HR) for new-onset HF for LBBB was 3.29 (95% confidence interval 1.93-5.63, P < 0.001) and 3.53 for non-specific IVCD (1.65-7.55, P = 0.001). In corresponding analysis, LBBB predicted SHD with HR 2.60 (1.21-5.62, P = 0.015). Excluding subjects with history of heart disease, including coronary heart disease, did not have impact on results. Right bundle branch block and other IVCDs displayed no relation to endpoints. CONCLUSION: LBBB and non-specific IVCD were associated with more than three-fold risk of new-onset HF. Furthermore, LBBB was associated with novel SHD. Their presence should alert clinician even in subjects free from any known heart disease.

Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.

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.

F-18-fluorodeoxyglucose positron emission tomography-guided sampling of mediastinal lymph nodes in the diagnosis of cardiac sarcoidosis.

Histologic proof of granulomatous inflammation is prerequisite for the diagnosis of cardiac sarcoidosis (CS). Because of the limited sensitivity of endomyocardial biopsy (EMB), confirmation of sarcoidosis often has to be acquired from extracardiac biopsies. We set out to review our experience of F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG PET) in guiding extracardiac tissue biopsies in suspected CS. We included in this work 68 consecutive patients with proved CS who had undergone cardiac F-18-FDG PET with (n = 57) or without whole-body imaging as part of initial diagnostic evaluation. Their hospital charts, imaging studies, and diagnostic biopsies were reviewed in retrospect. Whole-body PET images showed extracardiac foci of abnormally high F-18-FDG uptake in 39 of 57 patients, of whom 38 had involvement of mediastinal lymph nodes (MLN). Parallel F-18-FDG uptake was found in other lymph nodes (n = 10), lungs (n = 9), liver (n = 3), spleen (n = 2), and thyroid gland (n = 1). Adding the mediastinal findings at cardiac PET without whole-body imaging, abnormal F-18-FDG uptake in MLN was found in totally 43 of the 68 patients with CS (63%). Histology of systemic sarcoidosis was known at presentation of cardiac symptoms in 8 patients. Of the 60 patients with missing histology, 24 patients underwent mediastinoscopy for sampling of PET-positive MLN, most often (n = 20) after nondiagnostic EMB; microscopy revealed diagnostic noncaseating granulomatous inflammation in 24 of the 24 cases (sensitivity 100%). In the remaining 36 patients, sarcoidosis histology was confirmed by EMB (n = 30), by biopsy of lungs (n = 2) or peripheral lymph nodes (n = 2), or at autopsy (n = 1) or post-transplantation (n = 1). In conclusion, MLN accumulate F-18-FDG at PET in most patients with CS and provide a highly productive source for diagnostic biopsies either primarily or subsequent to nondiagnostic EMB.

Usefulness of Cardiac Troponins as Markers of Early Treatment Response in Cardiac Sarcoidosis.

Evaluation and treatment of cardiac sarcoidosis (CS) suffer from lack of sensitive and easily repeatable markers of disease activity. We studied measurements of high-sensitivity cardiac troponin T or troponin I (hs-cTnT/I) taken at presentation and during treatment in 62 patients with new-onset CS (48 women, mean age 49 years). Hs-cTnT was measured in 50 patients and was elevated (>13 ng/L) at presentation in 26 of them (52%). Hs-cTnI was measured in the remaining 12 patients and was elevated (>0.04 ng/mL) in 7 of them (58%). Left ventricular ejection fraction averaged 43 ± 14% in association with elevated hs-cTnT/I (n = 33) versus 53 ± 10% with normal hs-cTnT/I (n = 29; p = 0.001). Hs-cTnT/I was remeasured after 4 weeks of steroid therapy in 38 patients and was normalized in 16 of the 24 (67%) with an elevated pretreatment concentration and remained normal in the rest of the 14 patients (p <0.001). During follow-up (median, 17 months), cardiac death (n = 2), aborted sudden death (n = 5), sustained ventricular tachycardia (n = 8), or new complete atrioventricular block (n = 1) was recorded in 11 of 33 patients with elevated hs-cTnT/I versus in 5 of 29 with normal hs-cTnT/I (log-rank p = 0.068). Two-year event-free Kaplan-Meier cardiac survival estimate (95% confidence interval) was 67% (48% to 81%) with elevated hs-cTnT/I versus 93% (76% to 99%) with normal hs-cTnT/I. In CS, circulating hs-cTnT/I may help clinicians evaluate disease activity and treatment response. Their prognostic value remains tentative pending more follow-up data.

Prognostic implications of intraventricular conduction delays in a general population: the Health 2000 Survey.

AIMS: We examined the prognostic impact of eight different intraventricular conduction delays (IVCD) in the standard electrocardiogram (ECG) in a community cohort. METHODS AND RESULTS: Data were collected from 6299 Finnish individuals. During a mean 8.2 years (interquartile range 8.1 to 8.3) of follow-up 640 subjects died (10.2%); 277 (4.4%) were cardiovascular deaths. For both sexes, all-cause and cardiovascular mortality was higher in subjects with IVCD than in those without. In Cox regression analysis after adjustment for age and gender, the hazard ratio for cardiovascular mortality for non-specific IVCD was 4.25 (95% confidence interval [CI] 1.95-9.26, P < 0.0001) and for left bundle branch block (LBBB) 2.11 (95% CI 1.31-3.41, P = 0.002). Right bundle branch block (RBBB) was not related to additional mortality, while incomplete RBBB (IRBBB) presented a hazard ratio of 2.24 (95% CI 1.064-4.77, P = 0.036). CONCLUSIONS: In the general population, non-specific IVCD, LBBB, and IRBBB were associated with increased relative risk for all-cause and cardiovascular mortality. RBBB did not have an impact on cardiovascular mortality either in subjects with or without previous heart disease.

Prevalence of ventricular conduction blocks in the resting electrocardiogram in a general population: the Health 2000 Survey.

AIMS: The prevalence of eight different ventricular conduction blocks and their association with risk factors and major cardiovascular diseases were studied in a major Finnish population study. METHODS: Data, including 12-lead electrocardiograms, were collected from 6315 subjects. The prevalence of left bundle branch block (LBBB), right bundle branch block (RBBB), non-specific ventricular block, incomplete LBBB, incomplete RBBB, R-R'-pattern, left anterior hemiblock (LAHB), and left posterior hemiblock (LPHB) was calculated for both genders in three age groups. Their association with risk factors and cardiovascular diseases was studied. RESULTS: R-R'-pattern was the most common ventricular conduction block in all age groups (3.9%, p<0.001 for comparison between groups), but it showed no association with cardiovascular diseases. Males had more RBBB (1.5% vs. 0.7%, p<0.001), incomplete LBBB (1.8 vs. 0.4, p<0.001) and non-specific ventricular block (1.1% vs. 0.1%, p<0.001). With increasing age (<45 years vs. >55 years) LBBB, RBBB and LAHB (0 vs. 2.2%, 0.3 vs. 2.2%, 0.2 vs. 1.9% respectively, p-values<0.001) became more prevalent. LBBB, RBBB and non-specific ventricular conduction block were associated with coronary heart disease (angina pectoris in 28.3, 20.3 and 22.9%, respectively) and heart failure (25.0, 10.1 and 11.4%, respectively). LBBB and RBBB were also associated with peripheral vascular disease (8.8%). CONCLUSIONS: Ventricular conduction blocks differ in prevalence between sexes and age groups. They also show disparate association with cardiovascular diseases. These differences need to be taken into consideration in everyday clinical practice.