BackgroundHeart failure (HF) significantly affects the morbidity, mortality, and quality of life of patients. New therapeutic strategies aim to improve the functional capacity and quality of life of patients while controlling HF-related risks. Real-world data on both the functional and cardiopulmonary exercise capacities of patients with HF with reduced ejection fraction upon sacubitril/valsartan use are lacking.MethodsA multicenter, retrospective, cohort study, called REAL.IT, was performed based on the data collected from the electronic medical records of nine specialized HF centers in Italy. Cardiopulmonary exercise testing was performed at baseline and after 12 months of sacubitril/valsartan therapy, monitoring carbon dioxide production (VCO2) and oxygen consumption (VO2).ResultsThe functional capacities of 170 patients were evaluated. The most common comorbidities were hypertension and diabetes (i.e., 53.5 and 32.4%, respectively). At follow-up, both the VO2 peak (from 15.1 ± 3.7 ml/kg/min at baseline to 17.6 ± 4.7 ml/kg/min at follow-up, p < 0.0001) and the predicted % VO2 peak (from 55.5 ± 14.1 to 65.5 ± 16.9, p < 0.0001) significantly increased from baseline. The VO2 at the anaerobic threshold (AT-VO2) increased from 11.5 ± 2.6 to 12.5 ± 3.3 ml/kg/min (p = 0.021), and the rate ratio between the oxygen uptake and the change in work (ΔVO2/Δwork slope) improved from 9.1 ± 1.5 to 9.9 ± 1.6 ml/min/W (p < 0.0001).ConclusionsSacubitril/valsartan improves the cardiopulmonary capacity of patients with HFrEF in daily clinical practice in Italy.

AIMS:The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy. METHODS AND RESULTS:An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). CONCLUSIONS:Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials.

BACKGROUND:Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene that is usually lethal without cardiac transplantation. The purpose of this study was to characterize post-transplant outcomes in a large cohort of patients with DD who underwent cardiac transplantation. METHODS:The clinical phenotype and outcome data of patients with DD who underwent cardiac transplantation (n = 38; 19 males and 19 females) were obtained from 8 centers. Study outcomes included graft survival, defined as death or retransplantation, and episodes of acute cellular and antibody-mediated rejection and cardiac allograft vasculopathy at 1 year. RESULTS:Median follow-up time after transplantation for the entire cohort was 4.4 years (IQR: 1.5-12.8 years). The median age at transplant for the cohort was 20.2 years (15.8-27.9 years), with no difference in age between sexes. Median pretransplant left-ventricular ejection fraction for the entire cohort was 30% (range 11%-84%). Males had higher pretransplant aspartate aminotransferase, alanine aminotransferase and creatine phosphokinase levels than females (P < 0.001). There were 2 deaths in the entire cohort and 2 retransplants. There was no difference in actuarial graft survival between males and females (P = 0.8965); the estimated graft survival was 87.1% (95%CI: 63.6%-95.9%) at 5 years. One episode (2.7%) of antibody-mediated rejection, grade 2, and 7 episodes (19%) of acute cellular rejection, grade 2 or 3, were reported in patients who survived to discharge (6 females and 1 male; P = 0.172). CONCLUSIONS:Heart transplantation outcomes are acceptable in DD with high probabilities of 5-year graft survival for males and females suggesting that cardiac transplantation is an effective treatment option for DD patients.

Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP -related arrhythmogenic cardiomyopathies were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area – right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD. Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

The psychometric properties of the core disease-specific 14-item Italian HeartQoL health-related quality of life questionnaire have been evaluated in this study. The Italian version of the HeartQoL, the MacNew questionnaire, and the Hospital Anxiety and Depression Scale were completed by 472 patients (angina, N = 183; myocardial infarction, N = 167; or ischemic heart failure, N = 122) who were recruited in five Italian centers (Florence, Veruno, Turin, Udine, and Naples) between 2015 and 2017. Patients with myocardial infarction reported significantly higher HeartQoL scores than patients with angina or ischemic heart failure. Floor and ceiling effects were always minor on the HeartQoL global scale and physical subscale with moderate ceiling effects on the emotional subscale in the total group and in patients with myocardial infarction. The bifactorial structure of the original HeartQoL questionnaire was confirmed with strong physical, emotional, and global scale H coefficients (> 0.50). The HeartQoL scales demonstrated optimal internal consistency (Cronbach's alpha > 0.84). Convergent and divergent validity were confirmed. Discriminative validity was not confirmed for age, largely confirmed for sex, and fully confirmed for anxiety, depression, and distress. The Italian HeartQoL questionnaire demonstrated adequate key psychometric attributes of internal consistency reliability and validity in Italian-speaking patients with ischemic heart disease.

Danon disease is characterized by hypertrophic cardiomyopathy, skeletal myopathy, and intellectual disability due to deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Although heart transplantation is considered an option for end stage Danon cardiomyopathy, scarce information is available about long term follow up. We report on long term follow up (14.7 years, IQ range 9–21 years) of 4 patients, transplanted for Danon disease cardiomyopathy, showing two LAMP-2 gene variants, the novel c.815T > C and the previously reported c.294G > A. We have also analysed previous published paper on this topic comparing available data from different follow up. Being a skeletal and cardiac muscle disease, with systemic effects, long term results about HTx are indispensable to justify any treatments in this subset of patients.

DEAR EDITOR: Kearns-Sayre syndrome (KSS) is a systemic disease that belongs to a group of neuromuscular disorders known as mitochondrial encephalomyopathies that typically involves the central nervous system, eyes, skeletal muscles, and heart. Acute onset of congestive heart failure (HF) is a possible expression of a rare form of dilated cardiomyopathy (DCM) secondary to KSS. We describe a case of a 16-year-old boy affected by KSS that rapidly progressed to HF needing of orthotopic heart transplantation (HTx). His mitochondrial disease was caused by 4309G>A mutation of the mitochondrially encoded tRNA isoleucine gene encoding for mitochondrial tRNA for isoleucine, diagnosed with mitochondrial DNA (mtDNA) analysis by next-generation sequencing. The definitive diagnosis was confirmed when the patient was 3 years old. At that time, he showed short stature and late development of language capacities; then, he rapidly developed ophthalmoplegia caused by bilateral deficit of extrinsic ocular motility, bilateral ptosis, and blindness due to pigmentary retinopathies. Moreover, he showed moderate myopathy with generalized hypotony. The cardiologic follow-up was negative until 2017, when an initial involvement of the left ventricle (LV) was noted in absence of any symptoms (the LV ejection fraction worst: 62% in 2016 versus 48% in 2017), so a low dosage of angiotensin-converting enzyme inhibitor was suggested. However, in September 2018, he was admitted for acute onset of HF. The transthoracic echocardiogram showed moderate dilation with severe reduction of ejection fraction of both ventricles (Figure 1A). In spite of diuretic and and inotropic treatment, his clinical status dramatically worsened. The right heart catheterization confirmed severe reduction of the cardiac index (1.6 L/min/m), with pulmonary artery pressures in normal range. After a multidisciplinary assessment, including neurologic, endocrinologic, ocular, and renal evaluation, the young patient was referred and received HTx in October 2018. Donor heart was classified as marginal, because of evidence of interventricular septum thickening (12 mm) and an expected ischemic time > 4 hours. For these reasons, the ex vivo normothermic perfusion with Organ Care System (Transmedics) was used, permitting total ischemic time reduction and graft evaluation. Detailed donor data are shown in Table 1. The postoperative course was uneventful, so he was discharged home after 3 weeks. The current immunosuppression therapy includes cyclosporine, mycophenolate, and low dose of corticosteroids. The pathologic findings of the explanted heart are shown in Figure 1B–F. This is a peculiar case of KSS in a young 16-year-old boy with acute presentation of HF due to DCM that underwent HTx successfully. The cardiac involvement in mitochondrial myopathies has hitherto been limited almost exclusively to the conducting tissue; conversely, clinical presentation of DCM in KSS has been described solely in few reports, leading the option of HTx exclusively in selected cases. Considering the scarcity published data on the prevalence of heart involvement in mitochondrial encephalomyopathies, this is the youngest patient that underwent HTx for DCM in KSS with good results in the early and mid-term outcome. As for these rare diseases, the more data about KSS patients are collected, the more we can learn about the phenotypic and genotypic expression of these patients and the better the outcome of KSS patients. Actually, the prognosis quoad vitam of this disease is strongly dependent by the grade of heart involvement; while the quality of life is strictly associated to the morbidity, that depends on severity of peripheral muscle system and ocular involvement. The routinely serial follow-up is crucial in these systemic diseases to be aware of the possible subtle worsening in the clinical history of these patients. Furthermore, the multidisciplinary approach was determinant to have a qualified and complete evaluation of the disease, allowing us to perform HTx, even the lacking data about this rare disease. Finally, the severe involvement of both ventricles ISSN: 0041-1337/19/10312-e393

BACKGROUND:The lack of epidemiological and clinical data is a major obstacle in health service planning for rare diseases. Patient registries are examples of real-world data that may fill the information gap.OBJECTIVE:We describe the Rare Disease Registry of the Friuli Venezia Giulia region of Italy and its potential for research and health planning.METHODS:The Rare Disease Registry data were linked with information on mortality, hospital discharges, ambulatory care, and drug prescriptions contained in administrative databases. All information is anonymous, and data linkage was based on a stochastic key univocal for each patient. Average annual costs owing to hospitalizations, outpatient care, and medications were estimated.RESULTS:Implementation of the Registry started in 2010, and 4250 participants were registered up to 2017. A total of 2696 patients were living in the region as of January 1, 2017. The overall raw prevalence of rare diseases was 22 per 10,000 inhabitants, with higher prevalence in the pediatric population. The most common disease groups were congenital malformations, chromosomal and genetic syndromes, and circulatory and nervous diseases. In 2017, 30 patients died, 648 were hospitalized, and 2355 received some type of ambulatory care. The total annual estimated cost was approximately €6.5 million, with great variability in the average patient cost across diseases.CONCLUSIONS:The possibility of following the detailed real-world care experience of patients with each specific rare disease and assessing the costs related to each step in their care path represents a unique opportunity to identify inefficiencies, optimize care, and reduce waste of resources.

Journal Article PERICARDITIS - MYOCARDITIS - ENDOCARDITIS Get access European Heart Journal Supplements, Volume 21, Issue Supplement_E, May 2019, Pages E36–E39, https://doi.org/10.1093/eurheartj/suz127 Published: 16 May 2019

Journal Article HEART FAILURE 1 Get access European Heart Journal Supplements, Volume 21, Issue Supplement_E, May 2019, Pages E149–E150, https://doi.org/10.1093/eurheartj/suz155 Published: 16 May 2019

Abstract Background Left cardiac sympathetic denervation (LCSD) is an established therapy for refractory ventricular arrhythmias (VAs) in channelopathies. A multicentric American and Indian case series suggested a greater efficacy of bilateral denervation (BCSD) in patients with structural heart disease (SHD). Purpose To describe our single-center experience with BCSD in SHD. Methods Nine patients (78% male, mean 55±18 yrs, mean LVEF 31±14%) with SHD and refractory VAs underwent BCSD. All had a Video-Assisted Thoracoscopic Surgery (VATS), in 2 cases associated with the robotic technique. The underlying cardiomyopathy (CMP) was non-ischemic (NICMP) in most cases (n=5, 55%), ischemic in 2 cases, arrhythmogenic right ventricular (ARVC) in one and related to lamin A/C deficiency in one. All patients had an ICD, 44% (n=4) a CRT-D. NYHA functional class I was present in 4 patients, the rest were in NYHA class II (n=3) or III (n=2). Three patients were candidates to heart transplant/LV assistance device. The arrhythmic burden pre BCSD included in 7 pts (78%) a history of electrical storm (ES); the median number of shocks/patient in the 12 months before BCSD was 5 (IQ range 3–18). Except for 2 patients with previous thyrotoxicosis, the remaining were either on amiodarone (n=6) or on sotalol (n=1) before BCSD. Main BCSD indications were represented by drug refractory fast VT in 7 pts (cycle <250 msec) and by recurrent monomorphic VT episodes (mean cycle 351 msec) after endocardial VT ablation in 2 patients. Results No major complication occurred. One patient (NICMP, NYHA II), has an uneventful follow up (FU) of less than 1 month and was excluded from the efficacy analysis. The median FU in the remaining 8 patients is 10 months (IQ range 6–19), during which the median number of shocks/patients was 0.5 (IQ range 0–3). Overall, 4 patients (50%) had ICD shock recurrences. Two cases (mean LVEF 17.5%, NYHA class III) had an ES during severe hemodynamic instability and subsequently died because of cardiogenic shock respectively 1 and 7 months after BCSD. One case had three, not consecutive ICD shocks 20 months after BCSD in the setting of severe amiodarone-induced thyrotoxicosis. Finally, one patient received a single intra-hospital ICD shock 5 days after BCSD before reintroduction of full-dose beta-blockers. The figure summarizes ICD shocks burden in the 6 months before and after BCSD. Among the 5 patients with NICMP/ARVC (4 in NYHA class I), only 1 had a single ICD shock recurrence. ICD shocks pre versus post BCSD, n=8 Conclusions Our case series, although numerically small, has a good follow-up and is the first reported in Europe. The results are in agreement with the suggested remarkable efficacy of BCSD in patients with good functional capacity and fast VAs. Therefore, cardiac sympathetic denervation should always be considered in patients with SHD and refractory ventricular tachyarrhythmias, especially in case VT ablation is either not indicated or fails.