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Aims: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement., Methods and Results: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%., Conclusions: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment., Methods and Results: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m 2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m 2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines., Conclusions: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival., Methods and Results: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival., Conclusions: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: To evaluate short-term changes in tricuspid regurgitation (TR) after transcatheter edge-to-edge mitral valve repair (M-TEER) in secondary mitral regurgitation (SMR), their predictors and impact on mortality., Methods and Results: This is a retrospective analysis of SMR patients undergoing successful M-TEER (post-procedural mitral regurgitation ≤2+) at 13 European centres. Among 503 patients evaluated 79 (interquartile range [IQR] 40-152) days after M-TEER, 173 (35%) showed ≥1 degree of TR improvement, 97 (19%) had worsening of TR, and 233 (46%) remained unchanged. Smaller baseline left atrial diameter and residual mitral regurgitation 0/1+ were independent predictors of TR ≤2+ after M-TEER. There was a significant association between TR changes and New York Heart Association class and pulmonary artery systolic pressure decrease at echocardiographic re-assessment. At a median follow-up of 590 (IQR 209-1103) days from short-term echocardiographic re-assessment, all-cause mortality was lower in patients with improved compared to those with unchanged/worsened TR (29.6% vs. 42.3% at 3 years; log-rank p = 0.034). Baseline TR severity was not associated with mortality, whereas TR 0/1+ and 2+ at short-term follow-up was associated with lower all-cause mortality compared to TR 3/4+ (30.6% and 35.6% vs. 55.6% at 3 years; p < 0.001). A TR ≤2+ after M-TEER was independently associated with a 42% decreased risk of mortality (p = 0.011)., Conclusion: More than one third of patients with SMR undergoing successful M-TEER experienced an improvement in TR. Pre-procedural TR was not associated with outcome, but a TR ≤2+ at short-term follow-up was independently associated with long-term mortality. Optimal M-TEER result and a small left atrium were associated with a higher likelihood of TR ≤2+ after M-TEER., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions., Methods and Results: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%., Conclusion: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy., (© 2022 European Society of Cardiology.)

Aims: In patients with heart failure and reduced ejection fraction (HFrEF) and secondary mitral regurgitation (SMR), impaired right ventricular function (RVF) may negatively influence the prognosis. Percutaneous mitral valve repair (pMVR) can promote the recovery of RVF. We sought to characterize the response of the right ventricle to pMVR in HFrEF with SMR and to assess the association between improved RVF after pMVR and outcomes., Methods and Results: Overall, 221 patients with HFrEF and SMR ≥3+ successfully treated with pMVR in four tertiary care centres for heart failure were included. Improved RVF was defined as Δ right ventricular fractional area change (ΔRVFAC) ≥5% at early follow-up (median time 4 months). The primary endpoint was a composite of death/heart transplantation (D/HT). Mean age was 69 ± 11 years, mean left ventricular ejection fraction was 31 ± 8% and mean RVFAC was 34 ± 9%. ΔRVFAC ≥5% occurred in 88 patients (40%) and was independent of the measures of left ventricular reverse remodelling. During a median follow-up of 29 months (interquartile range 12-46), 81 patients (37%) reached the primary endpoint. After adjustment for other significant covariates, ΔRVFAC ≥5% was significantly associated with lower risk of D/HT (hazard ratio 0.52, 95% confidence interval 0.29-0.94, P = 0.030). In the secondary outcome analysis exploring the risk of heart failure hospitalizations, ΔRVFAC ≥5% confirmed the prognostic association with the endpoint., Conclusions: In patients with HFrEF and SMR, about 40% of patients improved RVF after pMVR. RVF improvement was associated with better long-term survival free from HT and lower risk of heart failure hospitalization., (© 2021 European Society of Cardiology.)

Aims: Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM., Methods and Results: We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]. Median follow-up was at least 2.5 years in each group. TTN subjects presented with DCM at higher age than LMNA subjects (probands 47.9 vs. 40.4 years, P = 0.004; relatives 59.8 vs. 47.0 years, P = 0.01), less often developed LVEF <35% [probands hazard ratio (HR) 0.38, P = 0.002], had higher age of death (probands 70.4 vs. 59.4 years, P < 0.001; relatives 74.1 vs. 58.4 years, P = 0.008), and had better composite outcome (malignant ventricular arrhythmia, heart transplantation, or death; probands HR 0.09, P < 0.001; relatives HR 0.21, P = 0.02) than LMNA subjects and iDCM subjects (HR 0.36, P = 0.07). An LVEF increase of at least 10% occurred in 46.9% of TTN subjects after initiation of standard heart failure treatment, while this only occurred in 6.5% of LMNA subjects (P < 0.001) and 18.5% of iDCM subjects (P = 0.02). This was confirmed in families with co-segregation, in which the 10% point LVEF increase occurred in 55.6% of subjects (P = 0.003 vs. LMNA, P = 0.079 vs. iDCM)., Conclusions: This study shows that tTTN-associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation-induced DCM or iDCM., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: Although acute heart failure (AHF) is a potential complication of acute aortic syndromes (AAS), its clinical details and management implications have been scarcely evaluated. This study aimed to assess prevalence, pathophysiological mechanisms, impact on treatment, and in-hospital mortality of AHF in AAS., Methods and Results: Data were collected from a prospective AAS registry (398 patients diagnosed between 2000 and 2013). Patients with AHF were identified by the presence of dyspnoea as the presentation symptom or radiological signs of pulmonary congestion or cardiogenic shock, including patients with cardiac tamponade (CT). AHF frequency was 28% (Stanford type A 32% vs. type B 20%, P = 0.01). Four mechanisms leading to AHF were identified, alone or in combination: CT (26%), aortic regurgitation (25%), myocardial ischaemia (17%), and hypertensive crisis (10%). In type A patients, aortic regurgitation and CT were the most frequent mechanisms, whereas myocardial ischaemia and hypertensive crisis were the most frequent in type B patients. Although no difference was noted for diagnostic times, AHF at presentation led to a longer surgical delay in type A AAS. In-hospital mortality was higher in patients with AHF compared with those without (34% vs. 17%, P < 0.001). After multivariable analysis, AHF was associated with increased risk of in-hospital death (adjusted odds ratio 1.97, 95% confidence interval 1.14-3.36, P = 0.014)., Conclusion: AHF occurs in more than a quarter of patients with AAS of both type A and type B, is due to a variety of pathophysiological mechanisms, and is associated with increased surgical delay and in-hospital mortality., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: Atrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2 DS2 -VASc score, and outcome with vitamin K antagonists (VKAs)., Methods and Results: A retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre-selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2 DS2 -VASc score of 0, of whom 9.8% developed TE during follow-up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C-index of 0.75 [95% confidence interval (CI) 0.70-0.80] and the D-statistic was 1.30 (95% CI 1.05-1.56). VKA treatment was associated with a 54.8% (95% CI 31-97%, P = 0.037) relative risk reduction in HCM patients with AF., Conclusions: The study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2 DS2 -VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: There is experimental evidence that transplanting skeletal myoblasts (SM) into the post-infarction myocardial scar improves regional and global left ventricular (LV) function., Aims: To evaluate short- and long-term regional and global LV functional effects of percutaneously transplanted SM in patients with ischaemic heart failure., Methods and Results: Ten patients (mean age 60+/-10 years, 8 males) with dilated ischaemic cardiomyopathy underwent percutaneous injection of autologous myoblasts. Regional and global LV function was evaluated by 2-dimensional echocardiography and tissue Doppler imaging (TDI) at rest and during low-dose dobutamine infusion to assess contractile reserve. After a baseline examination, sequential follow-ups were performed at 1, 3, and 6 months and 1 year. NYHA functional class decreased from 2.7+/-0.5 to 1.9+/-0.5 (p<0.01) at one year. LV function and volumes at rest remained unchanged while contractile reserve significantly improved during follow-up. At low-dose dobutamine infusion, the peak systolic velocity in the regions of myoblasts injection significantly increased at TDI examination (from 7.7+/-2.1 to 8.6+/-1.8 cm/s, p=0.02); LV ejection fraction improved (from 40+/-9% to 46+/-8%, p<0.0001) and end-systolic volumes decreased (from 56+/-28 to 50+/-25 ml/m(2), p=0.001) at 1 year., Conclusion: In patients with ischaemic heart failure, percutaneous injection of autologous myoblasts may improve regional and global LV systolic function during dobutamine infusion, at 1-year follow-up.

Background: Diabetes mellitus in patients with coronary artery disease is associated with poor outcome. In this study, the relation between myocardial viability, diabetes, coronary revascularisation and outcome was evaluated., Methods: 129 patients (31 diabetic, 98 non-diabetic) with ischaemic cardiomyopathy underwent dobutamine stress echocardiography to assess myocardial viability. Patients with >or=4 viable segments were defined as viable and patients with <4 viable segments as nonviable. Left ventricular ejection fraction (LVEF) was assessed before and 9-12 months post-revascularisation. At the same time-points, LV volumes were measured to evaluate LV remodelling. Finally, cardiac events were noted during 5-year follow-up., Results: The extent of viable myocardium was comparable between diabetic and non-diabetic patients. After revascularisation, LVEF increased >or=5% in 44% of diabetic and in 40% of non-diabetic patients. LVEF only improved in patients with viable myocardium. Ongoing LV remodelling occurred in 36% and 35% of diabetic and non-diabetic patients respectively, and was related to non-viability, whereas viability protected against ongoing LV remodelling, both in diabetic and non-diabetic patients. Viability was the only predictor of survival after revascularisation., Conclusions: Diabetic, viable patients with ischaemic LV dysfunction exhibit improvement in LVEF post-revascularisation with prevention of ongoing LV remodelling, similar to non-diabetic patients. Myocardial viability was also the only predictor of long-term outcome.

Background: Little is known about the morphological and functional evolution of ventricular abnormalities in Loeffler endocarditis., Methods and Results: We describe 5 patients, including 3 with long-term echocardiographic follow-up, in whom apical obliteration due to fibro-thrombotic thickening of the endocardium showed favorable patterns of evolution. In one patient there was almost complete resolution of the obliterative process with consequently increased effective ventricular volume. In two patients formation of a flow-passage in the fibrocalcific apical 'floor' between the main medioventricular cavity and the apical chamber, leading to a 'double-chambered' left ventricle was observed., Conclusions: Medical therapy and appropriate anticoagulation, can induce favorable long-term ventricular remodeling in Loeffler endocarditis.

Background: QT dispersion is prolonged in numerous cardiac diseases, representing a general repolarization abnormality., Aim: To evaluate the influence of viable myocardium on QT dispersion in patients with severely depressed left ventricular (LV) function due to coronary artery disease., Methods and Results: 103 patients with ischemic cardiomyopathy (LV ejection fraction [EF]: 25+/-6%) were studied. Patients underwent 12-lead electrocardiography to assess QT dispersion, and two-dimensional echocardiography to identify segmental dysfunction. Dobutamine stress echocardiography (DSE) was then performed to detect residual viability. Resting echo demonstrated 1260 dysfunctional segments; of these, 476 (38%) were viable. Substantial viability (> or =4 viable segments on DSE) was found in 62 (60%) patients. QT dispersion was lower in these patients, than in patients without viability (55+/-17 ms vs. 65+/-22 ms, P=0.012). Viable segments negatively correlated to QT dispersion (r=-0.333, P=0.001). In contrast, there was no correlation between LVEF and QT dispersion (r=-0.001, P=NS)., Conclusions: There is a negative correlation between QT dispersion and the number of viable segments assessed by DSE. Patients with severely depressed LV function and a low QT dispersion probably have a substantial amount of viable tissue. Conversely, when QT dispersion is high, the likelihood of substantial viability is reduced.