Abstract Background RASopathy syndromes represent the second most common cause of hypertrophic cardiomyopathy (HCM) in children. RASopathy associated HCM (Ras-HCM) has been shown to differ both in cardiac phenotype and long-term outcomes from sarcomeric HCM. However, there is a lack of knowledge from large cohort studies of how the cardiac phenotype of Ras-HCM changes over time. Aim To describe cardiac phenotype changes over time in children with Ras-HCM Methods Retrospective data from 148 patients diagnosed with Ras-HCM aged <18 years with ³2 follow-up visits were included. Clinical and echocardiographic data were collected at baseline assessment, 1, 2, and 5 years of follow up. Separate analyses were performed for patients who survived, versus patients who died or had a heart transplant (censoring events). Results One-hundred-and-two (68.9%) patients with Noonan syndrome, 25 (16.9%) with Noonan-syndrome with multiple lentigines, 10 (6.8%) with Costello syndrome, 9 (6.1%) with cardio-facio-cutaneous syndrome and 2 (1.4%) patients with Noonan-like syndrome with a median age of diagnosis 0.16 years (0.01-0.89) were seen at a median baseline age of 1.41 years (0.37-5.71) and followed up for a median of 12.1 years (4.8-17.4). During follow up, 18 patients (12.2%) died at a median age of 1.8 years (0.5-8.7) and 17 (12.5%) had a left ventricular myectomy, at a median age of 7.0 years (3.1-12.7). At baseline evaluation, patients who died compared to those who survived had a lower median age [0.4 years (0.1-0.8) versus 2.3 years (0.5-7.6), p<0.001], a higher proportion of them had a NYHA class>I (54.5% vs 15.1%, p<0.001), a higher maximal left ventricular wall thickness (MLVWT) z-score [13.4 (7.5) vs 9.6 (6.2), p=0.04], a higher proportion of left ventricular outflow tract obstruction (LVOTO) [64.7% vs 43.8%, p=0.087] and a higher proportion of biventricular hypertrophy [75% vs 49.2%, p=0.045]. For survivors, the MLVWT z-score improved over follow up [+9.6(6.2) at baseline vs. +7.9(5.5) at 5 years, p=0.072], and the proportion of patients with LVOTO (43.8% at baseline vs. 27.9% at 5 years, p=0.019) and biventricular hypertrophy (49.2% at baseline vs. 35.5% at 5 years, p=0.012) decreased over follow up. Conclusion While at baseline evaluation Ras-HCM has a high burden of symptoms, biventricular hypertrophy and LVOTO for patients who die or have a heart transplant, we have demonstrated that for survivors, over follow up, the phenotype becomes milder.Table 1

Abstract Introduction Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions. Purpose We developed and validate a free digital support tool in the form of an App to provide support and to guide the physician in the differential diagnostic process of patients presenting with primary LVH. Methods We studied 712 patients with definitive diagnosis of sarcomeric HCM or one of its genocopies (414 (58%) males, 48±24 years) referred to four tertiary centers in Europe. Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography, echocardiographic and laboratory. Each patient’s characteristics were inserted by two independent and blind investigators on the App of the digital support tool. The possible diagnostic outcome was categorized as follows: (a) most likely diagnosis (age range for the condition, at least 1 extremely specific RFs or >1 specific RF; (b) possible diagnosis (age range, 1 specific RF); (c) less likely diagnosis (outside age range, no RF selected). Results Ris were common in patients presenting with a genotyped HCM (2568 RFs, 3.5 per patient). RF on physical examination was associated with non sarcomeric aetiology (318/319 physical examination RF identified in non-sarcomeric HCM), whereas 68% of RF associated with sarcomeric HCM were derived from accurate ECG and echocardiography analysis. Sarcomeric HCM, TTR-amyloidosis, Danon and PRKAG2 cardiomyopathy relied extensively on ECG and echocardiographic systematic analyisis (68%, 69%, 67% and 69% respectively). In contrast, AFD, Friederich’s ataxia, Noonan syndrome with multiple lentiges (NSML), mitochondrial, Pompe and Noonan cardiomyopathy presented red flags potentially identifiable in the general practioner setting by anamnesis, physical examination and routine laboratory (57%, 59%, 52%, 57%, 57% and 58% respectively) in the vast majority of case. A total of 697/712 (97.8%) were correctly categorized in the most likely and possible diagnosis section. The App proved to be sensible for sarcomeric HCM, FD (0.99 and 0.91, NPV 0.98 and 0.83) and extremely capable in the identification of rare causes of LVH (Danon, Friederich’s ataxia, LEOPARD, Pompe, Noonan and PRKAG2 diseases). By design, specificity was not high, in particular for sarcomeric HCM and FD. Conclusions The present validation of an App based free digital support tool in the form of an App proved to be extremely sensible in providing the support to the screening of different causes of primary LVH in patients presenting with a HCM phenotype. Further external and multicenter validation is warranted.

Abstract Background Individual prognostic assessment and disease evolution pathways in chronic heart failure (HF) are unmet needs. The application of unsupervised learning methodologies could help at: a) identification of HF patient phenotypes; b) identification of the evolution states and progression in each phenotype and c) assessment of risk of adverse event. Methods We retrospectively analyzed the MECKI registry including 7948 HF patients. After preliminary preprocessing, we selected 4876 patients with a minimum 2–year follow–up. We implemented a Topological Data Analysis (TDA), based on 43 variables derived from clinical, biochemical, cardiac ultrasound and exercise evaluations, to identify several patients’ clusters. Thereafter, we used the trajectory analysis to describe the evolution of HF states, which is able to identify bifurcation points, characterized by different follow–up paths, as well as stopping points, i.e. specific end–stages conditions of the disease. Finally, we conducted a survival analysis to generate 5–year time–to–event curves using as study endpoint the composite of cardiovascular death, LVAD or urgent heart transplant. Findings were validated on internal (n=527) and external (n=777) populations. Results Nineteen patient clusters were identified by TDA. Trajectory analysis revealed a path characterized by 3 bifurcation points with 2 different follow–up path each and 4 stopping points. Clusters survival rate varied from 44% to 100% at 2 years and from 20% to 100% at 5 years, respectively. Finally, we compared the event frequency at a 5–year follow–up for each study cohort cluster with those in the validation cohorts (R = 0.94 and R = 0.84, p &lt; 0.001, for internal and external cohort, respectively). Conclusions Each HF phenotype has a specific disease progression and prognosis. The bifurcation points need attention since are followed by different disease routes as the 4 different disease end–stages which are characterized by different prognosis. These findings allow to individualize HF patient evolutions and to tailor assessment.

BackgroundAcute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy.ObjectivesThe aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis.MethodsFor this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.ResultsOf 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children).ConclusionsGenetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

Background: This study aims to evaluate the prevalence and the clinical significance of the right ventricular pulmonary arterial (RV-PA) uncoupling in patients with cardiac amyloidosis (CA). Methods: The study population consisted in 92 consecutive patients with CA (age 71.1 +/- 12.2 years, 71% males; 47% with immunoglobulin light chain (AL), 53% with transthyretin [ATTR]). A pre-specified tricuspid anulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value <0.31 mm/mmHg was used to define RV-PA uncoupling and to dichotomize the study population. Results: Thirty-two patients (35%) showed RV-PA uncoupling at baseline evaluation (15/44 [34%] AL and 17/48 [35%] ATTR). Patients with RV-PA uncoupling, in both AL and ATTR, showed worse NYHA functional class, lower systemic blood pressure, and more pronounced left ventricular and RV systolic dysfunction than those with RV-PA coupling. During a median follow-up of 8 months (IQR 4-13), 26 patients (28%) experienced cardiovascular death. Patients with RV-PA uncoupling showed lower survival at 12 months follow-up than those with RV-PA coupling (42.7% [95%CI 21.7-63.7%] vs. 87.3% [95%CI 78.3-96.3%], p-value<0.001). Multivariate analysis identified high-sensitivity troponin I values (HR 1.01 [95%CI 1.00-1.02] per 1 pg/mL increase; p-value 0.013) and TAPSE/PASP (HR 1.07 [95%CI 1.03-1.11] per 0.01 mm/mmHg decrease; p-value 0.002) as independent predictors of cardiovascular death. Conclusions: RV-PA uncoupling is common among patient with CA, and it is a marker of advanced disease and worse outcome. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA of different etiology and advanced disease.

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Right ventricular (RV) dysfunction in cardiomyopathies is a consequence of chronic overload (i.e. aortic stenosis, AS) or direct involvement of systemic disorders (i.e. cardiac amyloidosis, CA). The Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure (TAPSE/sPAP) ratio has been recently proposed as a surrogate of RV-arterial coupling (RVAC). This study aims to compare RVAC between CA subgroups and between CA and other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 cardiomyopathies with hypertrophy phenotype (LVH group) [25 pts with hypertrophic cardiomyopathy (HCM), 25 hypertensive pts(HypCM), and 25 pts with AS]. Besides routine echocardiographic measurements, we analysed right chambers dimensions and classical and novel parameters of RV function [TAPSE, TAPSE/sPAP, St wave, global (RVGLS) and free-wall (RVFWS) strain]. RESULTS. Compared to AL, the ATTR group showed higher right chambers dimensions, without differences in all RV systolic parameters. Compared to the LVH group, CA patients showed no differences in RV dimensions while RV systolic parameters, including the TAPSE/sPAP ratio, were significantly reduced in the presence of significantly higher LV filling pressures. At ROC curve analysis, TAPSE (AUC 0.877; 95% CI: 0.811-0.943; p < 0,0001) and TAPSE/sPAP ratio (AUC 0.859; 95% CI: 0.783-0.935; p < 0,0001) showed the best ability in discriminating CA among other forms of LVH (cut-off 20.5 mm for TAPSE with sensibility of 80.5% and specificity of 78.8%, respectively; cut-off 0.62 for TAPSE/sPAP ratio with sensibility of 85.4% and specificity 81.8%). At 24 months follow-up, there were 15 deaths in CA (30%) and 4 in LVH group (5%). At Kaplan-Meier estimation, the TAPSE/sPAP ratio showed progressively a significantly reduced survival in the lowest interquartile ranges. Moreover, at multivariate analysis, TAPSE/sPAP was the only independent prognostic factor (β -5,644; 95% IC: 0,000-0,522; p < 0,027). CONCLUSIONS. The RVAC is significantly impaired in CA compared to the LVH group but not between CA subgroups. Its reduction seems attributable to both increase LV filling pressure, due to the restrictive nature of the infiltrative cardiomyopathy, and reduced RV systolic function, due to either indirect RV chronic overload and direct myocardial infiltration. The TAPSE/sPAP ratio is a surrogate of RVAC and proved to be a novel echocardiographic parameter useful in both discriminating CA among genetic and non-genetic forms of LVH, and stratifying the prognosis. Abstract Table 1 Abstract Figure 1

Abstract Aims Anderson–Fabry disease (AFD) is a rare genetic lysosomal storage disorder which often goes unnoticed until the onset of symptoms requires aggressive treatment. Prompt diagnosis remains crucial. Dedicated centres may offer a remarkable opportunity to develop early detection strategies and prompt appropriate multidisciplinary management. To describe the long-term outcomes of patients diagnosed with AFD followed at a national Cardiomyopathy Referral Center according to phenotype (clinical involvement vs. sub-clinical involvement). Methods and results Consecutive patients visited at our Cardiomyopathy Unit from 1989 to 2020 with >1-year follow-up were retrospectively reviewed. Clinical involvement was defined by the presence of one among left ventricular hypertrophy (LVH)>15 mm, presence of conduction blocks or cardiac implantable electronic devices (CIED), atrial fibrillation, kidney disease (glomerular filtration rate <60 ml/min/m2, dialysis or kidney transplant), stroke or transient ischaemic attack (TIA). Disease progression was defined by either de novo CIED implantation, de novo LVH > 15mm or increased IVS, de novo Stroke/TIA, or progression of kidney disease. Overall, 110 were diagnosed with AFD [first via α galactosidase (αGAL) activity and then confirmed via genetic exam], and 86 (78%) with >1-year follow-up were selected. Clinical involvement was present in 60 (70%) patients. Age at diagnosis was similar between patients with clinical and subclinical phenotype (42 ± 17 vs. 39 ± 15, P = 0.277). Patients manifesting clinical involvement compatible with AFD were more frequently men [N = 25 (42%) vs. 4 (15%), P = 0.025] and probands (P = 0.01). Overall, one organ involvement was present in 31 (52%) patients, two organ involvement in 24 (40%) patients, and three organs in 5 (8%). A total of 46 (77%) patients were referred for enzyme replacement therapy (ERT): 52% received agalsidase α, 26% agalsidase β, and 22% migalastat. Among those with a clinical involvement not on ERT, nine (15%) were scheduled for ERT initiation, three (5%) were considered old for ERT, one (1.5%) refused ERT, and one (1.5%) had an allergic reaction to ERT. At 7 (3–12) years follow-up, both study cohorts manifested signs and symptoms of disease progression, although its incidence was higher in patients with clinical involvement [N = 28 (47%, 4.7%/year) vs. N = 4 (15%, 1.5%/year), in clinical vs. subclinical involvement, respectively, P = 0.01]. The main causes for diseases progression were increase in LVH (28%), de novo LVH (13%), progression of kidney disease (7%), and CIED implantation (5%). All patients with disease progression in the subclinical involvement group had been diagnosed with family screening; among these, two were men and one had a late onset phenotype. Three developed LVH > 15mm and one kidney disease. Conclusions Clinical involvement in AFD is frequent irrespective of age at diagnosis, being present in more than 1-in-2 patients at baseline. Prompt referral to dedicated centres is warranted for appropriate care as disease may progress in both patients with and without initial clinical involvement despite optimal medical management.

Abstract Background Only one score for prediction of new-onset atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) has been developed in North America (HCM-AF North America score). Purpose To develop a new score (HCM-AF South Italy score) in an Italian derivation cohort and to test the new score with that from North America, in an Italian validation cohort. Methods A cohort of 228 patients with HCM and without history of AF, followed at referral center 1 for HCM, was used for model development. A cohort of 226 patients without history of AF, followed at referral center 2, was used for external validation. During follow-up (IQR 3–13 years, median 8 years), 59 (26%) patients developed new-onset AF. Data in the development cohort generated the HCM-AF South Italy score, a point score to predict AF probability: left atrial dimension >49 mm (+5 points), age at clinical evaluation <55 years (+2 points), the use of angiotensin-converting enzyme (ACE) or inhibitor or angiotensin receptor blocker (ARB) at initial evaluation (+2 points), low left ventricular (LV) ejection fraction (<50%) (+2 points), LV outflow tract obstruction (LVOTO) >25 mmHg (+2 points), NYHA class >1 (+1 point). Results Patients from the validation cohort were older, had lower prevalence of HCM family history, lower systolic and diastolic blood pressure, taken fewer drugs like beta-blockers, ACE or ARB, calcium-channel blockers, and antiarrhythmic drugs and had lower LVOTO than patients from the derivation cohort, (overall p<0.05). During follow-up (IQR 1–10 years, median 5 years), 25 (11%) patients developed AF. ROC curve analysis demonstrated that HCM-AF South Italy score was superior to HCM-AF North America score (Figure). A HCM- AF South Italy score >4 identified patients at risk of AF with a sensitivity of 48%, specificity of 76%, PPV of 20% and NPV of 92%. Conclusion Although derived and tested in little and quite different populations, the performance of the HCM-AF South Italy score was superior to that of the score developed in North America. Funding Acknowledgement Type of funding sources: None.

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Cardiac amyloidosis (CA) is an infiltrative disorder characterized by left ventricular (LV) thickening with early systolic and diastolic dysfunction. Due to it poor prognosis, and the beneficial impact of novel treatments when started in early stages of disease, its forward detection is crucial. Aim of this study is comparing the diagnostic accuracy of classical and novel echocardiographic parameters in detecting CA among other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 pts with CA (26 AL and 24 wtATTR) and 75 phenocopies (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive (HypCM) pts, and 25 pts with non-severe aortic stenosis (AS)]. Standard and novel LV morpho-functional echo parameters [LV ejection fraction (LVEF), myocardial contraction fraction (MCF), global longitudinal strain (GLS), relative regional strain ratio (RRSR), ejection fraction on strain ratio (EFSR)], and novel Myocardial Work (MW) parameters [Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE)] were analyzed. RESULTS. LV standard, novel and MW-derived systolic parameters were more impaired in CA compared to LVH group. At ROC curve analysis, GCW showed the best performance in discriminating CA from other forms of LVH (AUC 0.886; 95% CI: 0.819-0.954; P < 0.0001), with a cut-off value < 1473 mmHg% showing 90% of sensitivity and 82% of specificity). At linear regression analysis, GCW correlated with many echocardiographic parameters (IVSD, PWD, RWT ratio, LVMi, MCF, LVESV, LVEF, EFSR and RRSR). At multivariate analysis, PWD (P < 0,029) and RWT ratio (p < 0,014) were the only parameters associated with GCW. At 24 months follow-up, there were 15 deaths in CA and 4 in LVH group. At Kaplan-Meier analysis the overall survival free of cardiovascular death was reduced in the lowest GCW interquartile ranges (log-rank χ2 21.5; p < 0.0001). At Cox hazard ratio analysis, GCW was the only prognostic parameter associated with cardiovascular mortality (β 1.006; 95% CI: 1.003-1.009; P < 0.0001). CONCLUSIONS. Despite CA and LVH patients shows a similar phenotype, the systolic function differs greatly. In the present study, the GCW showed the best ability in detecting CA among other forms of LVH. Its reduction in CA seems reflect the infiltrative burden and its consequences on myocardial deformation properties, while its reduction in LVH group has been attributed elsewhere to fibrotic derangement. GCW showed to be a promising novel diagnostic and prognostic factor in this setting. Abstract Figure 1 Abstract Table 1

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder. Since 2016, pharmacological chaperone Migalastat has been approved for treatment of FD patients with amenable mutations to stabilize defective forms of the enzyme α-galactosidase A. A small but significant reduction in left ventricular (LV) mass after 18 months of Migalastat treatment has been previously reported by echocardiography. However, an integrated assessment of the effect of Migalastat on cardiac involvement, combining LV morphology and tissue composition by CMR with exercise capacity by cardiopulmonary test, is lacking. To determine the effects of 18 month treatment with Migalastat on LV mass, native T1 value and functional capacity in naïve patients with genetically confirmed FD cardiomyopathy. Sixteen treatment naïve FD patients (4 females, mean age 46.4±16.2) with amenable mutations and signs of cardiac involvement underwent CMR with T1 mapping and cardio-pulmonary testing before and after 18 months of migalastat therapy as a part of MAIORA Study. Cardiac involvement was defined as presence of reduced native T1 values at CMR (a surrogate of myocardial glycosphingolipid storage) and/or LV hypertrophy (LVH). Nine patients (56%, 2 females, mean age 56.4±12.7 years) had LVH at baseline. Migalastat treatment was well tolerated in all patients, with no serious adverse event. No change in LV mass was detected at 18 months compared to baseline (95.2 (66.0–184.0) vs 103.0 (71.0–182.0) g/m2; p=0.5516). The same result was found after stratifying patients according to presence/absence of Late Gadolinium Enhancement (LGE) (LGE+ n=8, 2 females, mean age 56.2±13.1 years). There was a trend towards an increased native septal T1 value (870.0 (848–882) vs 860.0 (833.0–875.0) ms at baseline; p 0.056) with unchanged extracellular volume (ECV) (0.26 (0.23–0.028) vs 0.26 (0.22–0.29) at baseline; p 0.276) in the overall cohort. An improvement in functional capacity with a trend towards an increase in percent-predicted peak VO2 (72.0 (61.25–80.75) vs 67.0 (45.2–79.2) at baseline; p 0.056) and a significant increase in VO2 at anaerobic threshold (14.8 (12.6–20.0) vs 13.10 (6.8–18.6) ml/kg/min at baseline; p 0.004) was reported in the total population. In treatment naïve FD patients with amenable mutations and signs of early or overt cardiac involvement, 18-month treatment with Migalastat stabilized LV mass both in patients with and without LGE and was associated with an improvement in exercise tolerance. The trend towards an increase in T1 value associated with unchanged ECV suggests partial clearance of cardiomyocyte glycoshingolipid storage. These real-world data are consistent with a beneficial impact of migalastat on the progression of cardiac involvement in FD. Type of funding sources: Private company. Main funding source(s): Amicus Therapeutics

Abstract Background Cardiac amyloidosis (CA) is an infiltrative disorder characterized by left ventricular (LV) thickening and dysfunction. Due to it poor prognosis its early detection and differential diagnosis among other forms of cardiomyopathies is fundamental. Purpose This study aimed to compare the diagnostic accuracy of LV classical and and novel echocardiographic parameters in differentiating CA from other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. Methods We included 50 patients with CA (26 pts with AL and 24 pts with wild type ATTR form) and 75 patients with LV hypertrophy (LVH) [25 patients with hypertrophic cardiomyopathy (HCM), 25 with hypertensive cardiomyopathy (HypCM), and 25 with aortic stenosis (AS)]. Besides routine echocardiographic measurements, we analysed standard and novel echo parameters implied in LV assessment [LV ejection fraction (LVEF), myocardial contraction fraction (MCF), global longitudinal strain (GLS), relative regional strain ratio (RRSR), ejection fraction on strain ratio (EFSR)], included novel Myocardial Work (MW) parameters [Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE)]. Results Patients in CA group showed a smallest LV cavity size, higher LV mass and, consequently, a more pronounced concentric hypertrophy compared to LVH group. All LV systolic parameters where more impaired in CA than in LVH group. At ROC curve analysis, among all others, GCW showed the best performance in discriminating CA from LVH (AUC 0.886; 95% CI: 0.819–0.954; P<0,0001), with a cut-off value <1473 mmHg% showing good sensitivity and specificity (90% and 82%, respectively). At linear regression analysis GCW correlated with IVSD (P<0,0001), PWD (p<0,0001), RWT ratio (p<0,0001), LVMi (p<0,0001), MCF (P<0,0001), LVESV (p<0,002), LVEF (P<0,0001), EFSR (p<0,0001) and RRSR (p<0,0001). At multivariate analysis, PWD (P<0,029) and RWT ratio (p<0,014) were the only parameters associated. At 24 months follow-up there were 15 deaths in the CA group and 4 in LVH group. At Kaplan-Meier analysis the overall survival free of cardiovascular death was reduced in the lowest GCW interquartile ranges (log-rank χ2 21,5; p<0,0001). At Cox hazard ratio analysis GCW (β 1,233; 95% CI: 1,201–1,246; P<0,0001) was the only prognostic parameter associated with cardiovascular mortality. Discussion Although CA and and LVH have with similar phenotype, they differ greatly in terms of systolic function. The MW, estimated by non-invasive pressure-strain loops, is a novel method for a load-independent LV systolic function assessment. In the present study the GCW showed the best ability in detecting CA in comparison to other parameters usually implied in clinical practice. Conclusion Myocardial performance is significantly reduced in CA compared to other forms of LVH. GCW showed to be a promising novel diagnostic and prognostic factor in this setting. Funding Acknowledgement Type of funding sources: None. Table 1Figure 1

Abstract Background Right ventricular (RV) dysfunction in cardiomyopathies is a consequence of chronic overload (i.e. aortic stenosis) or direct involvement of systemic disorders (i.e. cardiac amyloidosis, CA). The Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure ratio (TAPSE/sPAP) has been recently proposed as a surrogate of RV-arterial coupling (RVAC) in many cardiac disorders. Purpose This study aims to compare RVAC between CA subgroups and between CA and other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. Methods We enrolled 50 patients with CA (26 pts with AL and 24 pts with wild type ATTR form), 75 patients with LV hypertrophy (LVH) [25 patients with HCM, 25 with hypertensive cardiomyopathy (HypCM), and 25 with aortic stenosis]. We analysed right chambers dimensions and classical and novel parameters of RV function [TAPSE, TAPSE/sPAP, St (S' wave at RV TDI), global (RVGLS) and free-wall (RVFWS) strain]. Results The ATTR group showed higher right dimensions than AL, without differences in all RV systolic parameters (see Table 1). Compared to the LVH group, CA patients showed no differences in RV dimensions while RV systolic parameters, included the TAPSE/sPAP ratio, were significantly reduced. At ROC curve analysis TAPSE (AUC 0.877; 95% CI: 0.811–0.943; p<0,0001) and TAPSE/sPAP ratio (AUC 0.859; 95% CI: 0.783–0.935; p<0,0001) showed the best ability in discriminating CA among other forms of LVH (cut-off 20,5 mm for TAPSE with a sensibility of 80,5% and specificity of 78,8%; cut-off 0,62 for TAPSE/sPAP ratio with a sensibility of 85,4% and a specificity 81,8%). At Kaplan-Meier estimation, the TAPSE/sPAP ratio showed a significantly reduced survival in the lowest interquartile ranges. Moreover, at multivariate analysis TAPSE/sPAP was the only independent prognostic factor (β −5,644; 95% IC: 0,000–0,522; p<0,027). Discussion The RVAC is significantly impaired in CA compared to the LVH group but not between CA subgroups. TAPSE/sPAP proved to be a novel echocardiographic parameter useful in discriminating CA among genetic and non-genetic forms of LVH, and that also show prognostic significance. Funding Acknowledgement Type of funding sources: None. Figure 1. K-M for TAPSE/sPAP ratio IQ rangesTable 1

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Left atrial function (LAF) is a determinant of clinical status and outcome in many cardiac disorders, including cardiac amyloidosis (CA). Aim of this study is to explores the LAF in CA and other cardiomyopathies with hypertrophic phenotype, and its consequences on cardiovascular haemodynamics, right ventricular function and survival. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 with hypertrophic phenotype (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive pts (HypCM), and 25 pts with aortic stenosis (AS)]. LAF was analysed using the phasic method [LAEI as reservoir, LAPEF as conduit, LAAEF as active pump and TLAEF as total emptying function; see figure 1] by LA volumes determination. RESULTS. ATTR patients showed higher LA dimensions and impaired reservoir and total LA emptying function (TLAEF) compared to AL without differences LAF. Compared to the LVH group, CA patients showed higher LA dimension with impaired LAF in all phasic parameters, higher LV filling pressures and reduced biventricular function. We further divided CA and LVH patients into four subgroups based on the presence or absence of LA dysfunction (LADys+ for TLAEF values below the median: <50.2%; range 9.3-70.9%]. Among the groups, patients with CA/LADys+ showed worst clinical status, higher pulmonary pressures (sPAP) and lower TAPSE and TAPSE/sPAP ratio values. After a median follow-up of 24 months, 19 patients died from cardiovascular (CV) causes (15 in CA/LADys+ group and 4 in LVH/LADys+). The overall survival free of CV death was 64% in CA/LADys+ and 85% in LVH/LADys+ (4/26) group [log-rank χ2 29.6; p < 0.0001]. A sequential multivariate model was employed to assess whether LAF could predict CV deaths: TLAEF was entered together with established clinical and echocardiographic parameters (NYHA functional class, LAVI, E/Em, sPAP, TAPSE and TAPSE/sPAP ratio). At the final backward analysis, LAVI, TAPSE/sPAP and TLAEF were independent prognosticators of CV death. CONCLUSIONS. LAF is significantly more impaired in CA than LVH group and is associated with worst clinical status, RV dysfunction and higher LV filling and pulmonary pressure. Moreover, LADys is a frequent feature of CA and significantly associated with higher CV mortality. We suggests that LADys in LVH group could results from chronic pressure overload due to LA"s exposure to high LV diastolic pressure (impaired LV compliance). In CA, LADys could also be determined by direct LA infiltration. The pathophysiological result is a progressive LA remodelling with increased LA pressure, consequent backward transmission to the pulmonary venous system and, ultimately, RV dysfunction. TLAEF is parameter of LAF that correlates with increased pulmonary vascular resistance (measured elsewhere with cardiac catheterisation) and RV dysfunction. In CA, it seems promising as marker of the haemodynamic consequences of LADys and CV mortality. Abstract Figure 1 Abstract Figure 2

The usefulness of cardiopulmonary exercise test (CPET) in adult hypertrophic cardiomyopathy (HCM) patients is well-known, whereas its role in pediatric HCM patients has not yet been explored. The present study investigates possible insights from a CPET assessment in a cohort of pediatric HCM outpatients in terms of functional and prognostic assessment. Sixty consecutive pediatric HCM outpatients aged <18 years old were enrolled, each of them undergoing a full clinical assessment including a CPET; a group of 60 healthy subjects served as controls. A unique composite end-point of heart failure (HF) related and sudden cardiac death (SCD) or SCD-equivalent events was also explored. During a median follow-up of 53 months (25th–75th: 13–84 months), a total of 13 HF- and 7 SCD-related first events were collected. Compared to controls, HCM patients showed an impaired functional capacity with most of them showing peak oxygen uptake (pVO2) values of <80% of the predicted, clearly discrepant with functional New York Heart Association class assessment. The composite end-point occurred more frequently in patients with the worst CPETs’ profiles. At the univariate analysis, pVO2% was the variable with the strongest association with adverse events at follow-up (C-index = 0.72, p = 0.025) and a cut-off value equal to 60% was the most accurate in identifying those patients at the highest risk. In a pediatric HCM subset, the CPET assessment allows a true functional capacity estimation and it might be helpful in identifying early those patients at high risk of events.

Myocardial Work (MW) is a novel non-invasive echocardiographic method for myocardial performance assessment. MW is abnormal in patients with many forms of left ventricular hypertrophy [hypertrophic cardiomyopathy (HCM), hypertensive cardiomyopathy (HypCM), aortic stenosis (AS)] while little is known about cardiac amyloidosis (CA). We aimed to evaluate the role of MW in myocardial performance assessment, diagnostic significance and prognostic relevance in CA patients. 25 patients with CA (10 AL pts and 15 ATTRwt pts) and 75 patients with LVH (25 HCM pts, 25 HypCMP pts, 25 pts mild AS pts) were enrolled. Beside routine measurements, deformation parameters [GLS (Global Longitudinal Strain), EFSR (Ejection Fraction on Strain Ratio), RRSR (Relative Regional Strain Ratio)], and MW parameters [MWI (Myocardial Work Index), GCW (Global Constructive Work), GWW (Global Wasted Work), GWE (Global Work Efficiency)] for LV function evaluation were analysed. LV and RV function evaluated with classical and novel parameters were significantly impaired in CA group (see table). Among all these parameters, GCW showed the best performance to discriminate CA from other forms of LVH (AUC 0.90; 95% CI: 0.80–0.99; P<0,0001), with a cut-off value <1141 mmHg% showing good sensitivity and specificity (90% and 82%, respectively). At Kaplan-Meier estimation of cardiovascular mortality there were 9 deaths in the CA group and none in LVH group, showed significantly higher mortality at follow-up (p=0,0001). At multivariate analysis GCW (β=1,006; 95% CI: 1,003–1,009; P<0,0001) was the only prognostic parameter associated with cardiovascular mortality. Myocardial performance was reduced in CA group. GCW was able to discriminate CA from other forms of LVH and showed to be an independent prognostic factor. In our pilot study GCW seems a promising novel diagnostic and prognostic factor in CA. Kaplan-Meier curve Type of funding source: None

The study aims to estimate the neuromyelitis optica (NMO) epidemiology and the costs related to the care pathway. The administrative databases available in the region Campania, which has a population of 5.8 million people, have been interconnected in order to trace the public health services used by NMO patients, who were identified through disease exemption codes in the 2018 cohort. 53 NMO patients were identified, resulting in a 0.09 prevalence per 10,000 inhabitants, and corresponding to 0.327% of rare patients regional population. The female prevalence is double the male one (0.0012% vs. 0.0006%,). The regional average cost per NMO patient is equal to € 10,836.2, that is 4883.4 euro higher than the average regional cost for rare disease patients. Total expenditure amounts to 533,400 euros, equal to 0.005% of public healthcare spending. The highest cost incidence is associated with drugs (60.6% of total expenditure; in particular, the 42.7% for immunosuppressives, the 20.9% for immunostimulatory, the 6.8% for antiviral ones), followed by hospitalizations (32.7%), diagnostics (4.8%), and laboratory tests (1.0%). The analysis confirmed that NMO is an ultra-rare disease. The resulting figure is presumably underestimated due to incomplete diagnoses and to patients not applying for copayment exemption; this represents the main limit of this study. Average annual cost related to NMO amounts to 0.005% of public healthcare spending, and it is 1.8 times higher than the average cost for rare diseases patients.

Right chambers involvement is common in cardiac amyloidosis (CA) but has been ever compared to control groups. Aim of this study is to compare right heart involvement between CA subgroups (AL vs. ATTR amyloidosis) and between CA and other forms of genetic and non-genetic left ventricular hypertrophy. We enrolled 25 patients with CA (10 pts with AL and 15 pts with wild type ATTR amyloidosis) and 75 patients with LVH (25 HCM pts; 25 HypCMP pts; 25 AS pts). Beside routine echocardiographic measurements, we analysed right chambers dimensions and classical and novel parameters for right ventricular (RV) function [TAPSE (Tricuspid Anulus Plane Systolic Excursion), St (S' wave at RV TDI), global and free-wall strain]. ATTR group showed higher right dimensions compared to AL, without differences in RV systolic parameters (see table). CA patients, compared to LVH group, showed no differences in right dimensions. RV systolic parameters were significantly reduced while diastolic Doppler parameters were higher (E/E' 21.7±9.0 vs. 11.2±5.0; p<0.0001). At ROC curve analysis TAPSE showed the best ability in discriminating CA among other forms of LVH (AUC 0.936; 95% CI: 0.879–0.993; p<0.0001), with a sensibility of 94.7% and specificity of 87.3% for a cut-off value of 19.5 mm. At Kaplan-Meier estimation CA patients showed a significantly higher cardiovascular mortality compared to LVH group (9/25 deaths vs. none). At multivariate analysis TAPSE was the only independent prognostic factor (β 1.324; 95% IC: 1.086–1.614; p<0.006). CA group showed a significantly impaired RV systolic function with higher pulmonary pressures compared to LVH group. TAPSE proved to be the only able to discriminate CA among genetic and non-genetic forms of LVH and also to have prognostic significance. Type of funding source: None

Raw data of the paper: Long-term prognostic role of diabetes mellitus and glycemic control in heart failure patients with reduced ejection fraction: Insights from the MECKI Score database. Background. The prognostic role of diabetes mellitus (DM) in heart failure (HF) patients is undefined, since DM is outweighed by several DM-related variables when confounders are considered. We determined the prognostic role of DM, treatment and glycemic control, in a real-life HF population. Methods. 3927 HF patients included in the Metabolic Exercise Cardiac Kidney Index (MECKI) score database were evaluated with median follow-up of 3.66 years (IQR 1.70-6.67). Data analysis considered survival between DM (n=897) vs. non-DM (n=3030) patients, and, in diabetics, between insulin (n=304), oral antidiabetics (n=479), and dietary only (n=88) treatments. The role of glycemic control was evaluated grouping DM patients according to glycated hemoglobin (HbA1c): <7% (n=266), 7.1-8% (n=133), >8% (n=149). All analyses were performed also adjusting for ejection fraction, renal function, hemoglobin, sodium, exercise peak oxygen uptake, and ventilation/carbon dioxide relationship slope. Study primary endpoint was the composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Secondary endpoints were cardiovascular and all causes death. Results. For all endpoints, upon adjustment for confounders, DM status and insulin treatment or dietary regimen were not significantly associated with adverse long-term prognosis compared to non-DM and oral antidiabetic treated patients, respectively. A worse prognosis was observed in HbA1c >8% patients (Log-Rank p<0.001), even after correction for confounding factors. All results were replicated by hazard ratio analysis. Conclusion. In HF patients, DM, insulin treatment and dietary regimen are not adverse outcome predictors. The only condition related to long-term prognosis considering potential confounders is poor glycemic control.