Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter variant: Fabry disease in Ostrobothnia (FAST) study.

Fabry disease (FD) is an X chromosome-linked, life-threatening lysosomal disease caused by one of more than 1000 currently known variants in the α-galactosidase A (GLA) gene. The follow-up part of the Fabry Disease in Ostrobothnia (FAST) study reports the long-term effect of enzyme replacement therapy (ERT) on a prospectively collected cohort of 12 patients, 4 males and 8 females, mean age 46 years (SD 16), with the classical variant c.679C > T p.Arg227Ter, which is one of the most common FD variants worldwide. In the natural history period of the FAST study, half of the patients in both sexes had at least one major event, of which 80% were of cardiac origin. During 5 years of ERT, four patients had a total of six major clinical events consisting of one silent ischemic stroke, three ventricular tachycardias and two increased left ventricular mass indexes. In addition, four patients developed minor cardiac events, four patients minor renal events, and one patient a minor neurological event. ERTs may delay but not prevent the progression of the disease in most patients with the variant Arg227Ter. This variant might be suitable for investigating the efficacy of second-generation ERTs compared to the currently used ERTs regardless of sex.

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.

Renal denervation in patients who do not respond to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality in advanced heart failure (HF) in about two-thirds of the patients. Approximately one-third of the patients do not respond to CRT. The overactivity of sympathetic nervous system is associated with advanced HF and deteriorates the hemodynamic state. We tested the hypothesis that controlling sympathetic overactivity by renal denervation (RDN) could be beneficial in nonresponders for CRT. In our HeartF-RDN study (ClinalTrials.gov. NCT02638324), RDN could not reverse the progression of HF in subjects with New York Heart Association Classification (NYHA) III-IV stage symptoms.

Pulmonary manifestations and the effectiveness of enzyme replacement therapy in Fabry Disease with the p. Arg227Ter (p.R227*) mutation.

BACKGROUND: Fabry disease (FD) is caused by a defect in α-galactosidase A gene (GLA) which leads to a progressive accumulation of neutral shingolipids, mainly globotriaosylceramide and its metabolites in several organs. Pulmonary manifestations of FD mimic chronic obstructive pulmonary disease and are disproportionate to smoking status. The effect of enzyme replacement therapy (ERT) on pulmonary function is inconclusive. We studied the effect of ERT on pulmonary function in FD with a mutation p. Arg227Ter (p.R227*) which is one of the most common mutations causing classical FD in Finland and worldwide. METHODS: Patients were annually examined by multidisciplinary team. Based on the maximal pulmonary oxygen consumption at the baseline, either cardiopulmonary exercise test or combination of spirometry and 6-minute walking test were performed annually during 5-year follow-up. RESULTS: Four males and eight females met the criteria for ERT and were included in this study. Three of 12 patients had obstruction by GOLD criterion before ERT, and one had a borderline obstruction. In 5 years, five patients were classified as obstructive, although the real change in FEV1/FVC was unchanged in the whole cohort. Only one patient was an active smoker. CONCLUSION: In nonsmokers, pulmonary manifestations in classical FD are mild and might be stabilized by ERT.

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.

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week.

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.

Natural course of Fabry disease with the p. Arg227Ter (p.R227*) mutation in Finland: Fast study.

BACKGROUND: Fabry disease is caused by a deficient or an absent alfa-galactosidase A activity and is an X-linked disorder that results in organ damage and a shortened life span, especially in males. The severity of the disease depends on the type of mutation, gender, skewed X-chromosome inactivation, and other still unknown factors. METHODS: In this article, we describe the natural course of a common classic Fabry disease mutation, p.Arg227Ter or p.R227*, in Finland. RESULTS: Four males and ten females belonged to two extended families. The mean age was 46 years (SD 18.4). Six patients (43%) had cardiac hypertrophy, three patients (21%) had ischemic stroke, and none had severe kidney dysfunction. Three patients had atrial fibrillation; two patients who had atrial fibrillation also had pacemakers. All males over 30 years of age had at least one of the following manifestations: cardiac hypertrophy, stroke, or proteinuria. In females, the severity of Fabry disease varied from classic multiorgan disease to a condition that mimicked the attenuated cardiac variant. No one was totally asymptomatic without any signs of Fabry disease. Cardiac magnetic resonance imaging was performed on nine of 14 patients was the most sensitive for detecting early cardiac manifestations. Five patients (55%) had late gadolinium enhancement-positive segments. CONCLUSION: Cardiac involvement should be effectively detected in females before considering them asymptomatic mutation carriers.

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.

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.

Intravascular Renal Denervation in Renal Dialysis Patients with Uncontrolled Hypertension: A Case Series of Four Patients.

BACKGROUND Hypertension is a common complication of renal dialysis and is inadequately controlled in approximately one-third of patients. Intravascular renal denervation is an option to control sympathetic overdrive and decrease blood pressure. Four renal dialysis patients are presented with uncontrolled hypertension who were treated with intravascular renal denervation. CASE REPORT In a renal dialysis unit, patients were screened for therapy-resistant hypertension, which was defined as an outpatient blood pressure >160/100 mmHg and a blood pressure by interdialytic ambulatory blood pressure monitoring (ABPM) >130/80 mmHg. Four patients were identified with a mean ABPM of 175/95 mmHg. The four patients included a 24-year-old man with neurogenic bladder undergoing hemodialysis; a 55-year-old woman with a history of type 1 diabetes mellitus undergoing peritoneal dialysis; a 56-year-old woman with a history of autosomal dominant polycystic kidney disease (ADPKD) undergoing peritoneal dialysis; and a 72-year-old man with a history of ADPKD undergoing hemodialysis Following intravascular renal denervation, one patient had antihypertensive medicines withdrawn at 12 months, and he remained normotensive up to renal transplantation at 24 months. In two patients, ABPM did not decrease until renal transplantation was performed. The fourth patient was not a candidate for renal transplantation, and he was also a non-responder for intravascular renal denervation. None of the patients experienced hypotension or other adverse events following intravascular renal denervation. CONCLUSIONS A case series of four patients showed that, for some patients who have unresponsive hypertension while on renal dialysis, intravascular renal denervation is a safe procedure.

Renal sympathetic denervation in treating drug-resistant hypertension in a patient on hemodialysis.

A 26-year-old man had an end-stage renal disease because of a neurogenic urinary bladder with a vesicourinary reflux. The first kidney transplant was lost in consequence of chronic allograft nephropathy. Immunosuppressive medication was withdrawn and transplantectomy was performed in November 2010. After transplantectomy, his blood pressure (BP) slowly increased up to 200/100 mmHg. Antihypertensive medication was intensified and a fluid overload was excluded with body composition bioimpedance measurements. Forty-eight-hour ambulatory BP was 180/109 mmHg in the daytime and 178/108 mmHg in the night-time. Bilateral renal denervation (RDN) was performed with a single electrode Symplicity catheter on May 2013. The effect of RDN became evident at the 6 months visit, and all the antihypertensive medicines were withdrawn at 12 months. Fifteen months after RDN, 48-h ambulatory BP was 120/63 mmHg in the daytime and 108/60 mmHg in the night-time. The patient was without antihypertensive medication until retransplantation in May 2015.

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.