Effects of sacubitril/valsartan on the functional capacity of real-world patients in Italy: the REAL.IT study on heart failure with reduced ejection fraction.

Background: Heart 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. Methods: A 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). Results: The 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). Conclusions: Sacubitril/valsartan improves the cardiopulmonary capacity of patients with HFrEF in daily clinical practice in Italy.

Pharmacoutilization and adherence to sacubitril/valsartan in real world: the REAL.IT study in HFrEF.

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 in Heart Failure with Reduced Ejection Fraction: Real-World Experience from Italy (the REAL.IT Study).

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.

Cardiac Transplantation in Danon Disease.

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.

Validation of the Italian HeartQoL: a short health-related quality of life questionnaire for patients with ischemic heart disease.

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.

Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants.

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.

Heart transplantation in Danon disease: Long term single centre experience and review of the literature.

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.

Rejection in heart transplantation for cardiac sarcoidosis mimicking idiopathic giant cell myocarditis: long-term follow-up.

: Heart transplantation is a life-saving therapy for some patients admitted for acute myocarditis. However, controversial exists about the major risk of rejection following heart transplantation in specific types of myocarditis. Because of relatively few data on the post heart transplant outcomes, we report the long-term follow-up of a 39-year-old patient with a previous history of ulcerative colitis, which rapidly worsened heart failure until an emergency heart transplant in 2004.The clinical course was complicated by many episodes of rejection; lastly, after the development of severe cardiac allograft vasculopathy, re-heart transplantation was needed. The main findings of this case are: 1) inflammatory aetiology should always be suspected in patients with concomitant autoimmune disease that developing rapidly progressing heart failure; 2) patients with inflammatory myocardial disease undergoing heart transplantation should also undergo strict immunological surveillance; 3) the option of performing the re-heart transplant in a patient with a so complex management in the first one could be uncertain, but in this case the young age and lack of noncardiac comorbidities were effective to favour the survivor after two immunologically so challenging heart transplantation.

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

OBJECTIVES: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.

Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry.

AIMS: To identify differences in clinical epidemiology, in-hospital management and 1-year outcomes among patients hospitalized for acute heart failure (AHF) and enrolled in the European Society of Cardiology Heart Failure Long-Term (ESC-HF-LT) Registry, stratified by clinical profile at admission. METHODS AND RESULTS: The ESC-HF-LT Registry is a prospective, observational study collecting hospitalization and 1-year follow-up data from 6629 AHF patients. Among AHF patients enrolled in the registry, 13.2% presented with pulmonary oedema (PO), 2.9% with cardiogenic shock (CS), 61.1% with decompensated heart failure (DHF), 4.8% with hypertensive heart failure (HT-HF), 3.5% with right heart failure (RHF) and 14.4% with AHF and associated acute coronary syndromes (ACS-HF). The 1-year mortality rate was 28.1% in PO, 54.0% in CS, 27.2% in DHF, 12.8% in HT-HF, 34.0% in RHF and 20.6% in ACS-HF patients. When patients were classified by systolic blood pressure (SBP) at initial presentation, 1-year mortality was 34.8% in patients with SBP <85 mmHg, 29.0% in those with SBP 85-110 mmHg, 21.2% in patients with SBP 110-140 mmHg and 17.4% in those with SBP >140 mmHg. These differences tended to diminish in the months post-discharge, and 1-year mortality for the patients who survived at least 6 months post-discharge did not vary significantly by either clinical profile or SBP classification. CONCLUSION: Rates of adverse outcomes in AHF remain high, and substantial differences have been found when patients were stratified by clinical profile or SBP. However, patients who survived at least 6 months post-discharge represent a more homogeneous group and their 1-year outcome is less influenced by clinical profile or SBP at admission.

Acromegalic Cardiomyopathy With Malignant Arrhythmogenic Pattern Successfully Treated With Mechanical Circulatory Support and Heart Transplantation.

Cardiovascular involvement is common in acromegaly and can lead to development of acromegalic cardiomyopathy, characterized by concentric biventricular hypertrophy with a progressive impairment of diastolic and systolic function. The onset of heart failure and arrhythmias are related to poor prognosis. We report on a case of a 48-year-old man with acromegalic cardiomyopathy caused by pituitary adenoma. Despite the successful trans-sphenoidal resection of the tumour, the patient was rehospitalized for ventricular arrhythmic storms that led to cardiogenic shock, which required mechanical hemodynamic support with intra-aortic balloon pump, venoarterial extracorporeal membrane oxygenation, and urgent heart transplantation.

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy.

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM.

The Italian MacNew heart disease health-related quality of life questionnaire: a validation study.

Patient-centered treatment outcomes such as health-related quality of life are recommended in clinical care and research studies. Health-related quality of life questionnaires need to be validated in the language of the target population. The reliability and validity of the Italian version of the MacNew Questionnaire was determined in patients with angina, myocardial infarction, or ischemic heart failure. Sociodemographic and clinical data were collected on 298 patients [angina, n = 88; MI, n = 106; heart failure, n = 104; mean age, 64.8 (±10.6) years] at three centers in Italy. MacNew mean scores were higher (p < 0.001) in patients with myocardial infarction than in patients with either angina or heart failure with no floor and minimal ceiling effects. The three-factor structure of the original MacNew form was largely confirmed explaining 54.6% of the total variance. The Italian MacNew version demonstrates high internal consistency reliability (Cronbach's α ≥ 0.86), confirms the convergent validity hypotheses with strong correlations on six of eight comparisons (r ≥ 0.86), partially confirms discriminative validity with the SF-36 health transition item, and fully confirms discriminative validity with the Hospital Anxiety and Depression Scale. The Italian version of the MacNew Questionnaire demonstrates satisfactory psychometric properties, and is reliable and valid in Italian-speaking patients with angina, MI, or heart failure. Responsiveness could not be tested due to the cross-sectional design of the parent study, and needs to be investigated in an intervention study.

Infarct-like acute myocarditis: relation between electrocardiographic findings and myocardial damage as assessed by cardiac magnetic resonance imaging.

BACKGROUND: Acute myocarditis (AM) may occasionally have an infarct-like presentation. The aim of the present study was to investigate the relation between electrocardiographic (ECG) findings in this group of patients and myocardial damage assessed by cardiac magnetic resonance imaging (MRI) with the late gadolinium enhancement (LGE) technique. HYPOTHESIS: Myocardial damage may be associated with ECG changes in infarct-like AM. METHODS: Forty-one consecutive patients (36 males; mean age, 36 ± 12 years) with diagnosis of AM according to cardiac MRI Lake Louise criteria and infarct-like presentation were included. The relation between site of ST-segment elevation (STE), sum of STE (sumSTE), time to normalization of STE, and development of negative T wave with the extent of LGE (expressed as % of left ventricular mass [%LV LGE]), was evaluated. RESULTS: Most (80%) patients presented with inferolateral STE; mean sumSTE was 5 ± 3 mm. Normalization of STE occurred within 24 hours in 20 (49%) patients. Development of negative T wave occurred in 28 (68%) patients. Cardiac MRI showed LGE in all patients; mean %LV LGE was 9.6 ± 7.2%. Topographic agreement between site of STE and LGE was 68%. At multivariate analysis, sumSTE (ß = 0.42, P < 0.001), normalization of STE >24 hours (ß = 0.39, P < 0.001), and development of negative T wave (ß = 0.49, P < 0.001) were independently related to %LV LGE. CONCLUSIONS: Analysis of the site of STE underestimates the extent of myocardial injury among patients with infarct-like myocarditis. However, some ECG features (ie, sumSTE, normalization of STE >24 hours, and development of negative T wave) may help to identify patients with larger areas of myocardial damage.

Cardiac magnetic resonance imaging in Danon disease.

Danon disease is a rare X-linked dominant metabolic disorder caused by a primary deficiency in lysosome-associated membrane protein 2. It is characterized by the development of cardiac disease, skeletal myopathy and cognitive disorder. Due to the rarity of Danon disease, physicians may be unfamiliar with the phenotype, confusing it with hypertrophic cardiomyopathy or other causes of left ventricular hypertrophy. The present report demonstrates the clinical value of cardiac magnetic resonance imaging for the diagnostic work-up of Danon disease.

Sudden death associated with danon disease in women.

Danon disease is an X-linked systemic disorder characterized by left ventricular hypertrophy, mental retardation, and skeletal myopathy affecting young men. Electrocardiogram usually displays a Wolff-Parkinson-White preexcitation pattern. Less has been reported about the phenotype in women, although later-onset cardiac symptoms have been described. The aim of this study was to expand the knowledge of the phenotype of Danon disease in women. We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype. Affected family members carried a nucleotide substitution at position 294 in exon 3 (c.294 G → A) that changed a tryptophan residue to a stop codon at position W98X in the lysosome-associated membrane protein 2 (LAMP2) gene. Four women died suddenly (1 aborted) at 37 to 54 years of age. Wolff-Parkinson-White pattern with atrioventricular block was detected in 2 of 6 women. Four had successful pregnancies without symptoms of heart failure. cMRI showed late gadolinium enhancement areas in a clinically healthy woman who was a mutation carrier. Two patients underwent heart transplantation; histology of explanted hearts demonstrated severe interstitial fibrosis, hypertrophic cardiomyocytes with cytoplasmic vacuoles, and myofibrillar disarray. In conclusion, LAMP2 mutation can cause a severe arrhythmogenic phenotype in women that includes a high risk of sudden death. cMRI may be useful in women harboring LAMP2 mutations to permit early detection of cardiac involvement and guide timely considerations of implantable cardioverter-defibrillator therapy. Heart transplantation should be considered at onset of heart failure symptoms owing to rapid progression of the disease.