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Dilated cardiomyopathy is a primary disease of the heart muscle, which affects relatively young patients with a low comorbidity profile. It is characterized by structural and/or functional abnormalities leading to systolic dysfunction of the left ventricle or of both ventricles, often associated with dilatation, in the absence of an ischaemic, valvular, or pressure overload cause sufficient to explain the phenotype. Although the prognosis of the disease has greatly improved over the last few decades, prognostic stratification remains a fundamental objective, especially about the prediction of potentially life-threatening arrhythmic events. An accurate diagnostic work-up and an appropriate aetiopathogenetic characterization affect the patients’ outcome and represent the essential basis of an adequate prognostic stratification. It is necessary to adopt a multiparametric approach, especially when the aim is the prediction of arrhythmic risk; it includes an integration of medical history and physical examination with cardiac imaging and genetic testing, in order to obtain a personalized diagnosis and therapeutic strategies. Furthermore, the evaluation should be repeated at every clinical check-up, considering the dynamic trend of the pathology and the arrhythmic risk changes over time. This article aims to illustrate how, starting from an exhaustive aetiological and clinical–instrumental characterization, including all diagnostic methods available at present time, it is possible to obtain a tailored diagnostic evaluation and stratification of the arrhythmic risk as accurate as possible.

Genotype positive–phenotype negative (GEN+PHEN−) individuals harbour a pathogenic or likely pathogenic variant without exhibiting a phenotypic manifestation of the disease. In the last few years, the widespread use of genetic testing in probands and relatives has increasingly led to the identification of these individuals, with emerging dilemmas regarding their clinical management. A genetic variant may exhibit a variable expressivity even in the same family and spontaneous conversion to overt phenotype is largely unpredictable. Little is known about the possible influence of environmental factors, such intense or moderate exercise with open questions regarding their possible role in promoting or worsening the phenotypic expression. Current guidelines for sports participation in this setting acknowledge the weak burden of evidence and the many uncertainties. The recommendations to engage in intensive exercise and competitive sports are usually contingent on annual clinical surveillance, except for pathogenic variants in specific genes, such as lamin A/C or plakophilin-2. In certain conditions, such as arrhythmogenic cardiomyopathy, guidelines do not differentiate between GEN+PHEN− individuals and patients with overt disease and recommend avoiding participation in high-intensity recreational exercise and competitive sports. It should be emphasized that international guidelines, traditionally restrictive in terms of sports participation and focused on disqualification, embraced recently a more liberal attitude promoting a shared decision-making approach in the absence of clinical markers of increased risk. In this review, we will discuss the current state of knowledge on GEN+PHEN− individuals and the dilemmas surrounding the impact of exercise and prognosis, focusing on cardiomyopathies and channelopathies, which are the predominant causes of sudden cardiac death in the young and in young athletes.

Background Physical activity may increase the risk of cardiotoxicity (myocardial ischemia, major arrhythmias) of 5-Fluorouracil, but this risk has never been investigated for its prodrug capecitabine. Patients and Methods One hundred and ninety-two consecutive patients undergoing capecitabine chemotherapy from December 1, 2010 through July 31, 2016 were prospectively evaluated. The baseline evaluation included electrocardiography (ECG) and echocardiography (2DE); a follow-up evaluation, including ECG and exercise stress testing (2DE in case of ECG abnormalities), was done after ≥10 days of treatment. Cardiotoxicity was suspected from ischemic ECG changes, new kinetic abnormalities at 2DE, Lown classification ≥2 ventricular arrhythmia, symptomatic arrhythmias, or positive stress test, and confirmed by a negative stress test after capecitabine washout. Results Cardiotoxicity was diagnosed in 32 patients (16.7%): six at rest and 26 during exercise. All 32 patients had ECG abnormalities: ST-segment changes (24 patients), negative T-waves (2) and/or arrhythmias: ventricular arrhythmias (14 cases), supraventricular tachycardia (2), complete heart block (1). Eight patients had typical symptoms, 6 had atypical symptoms, 1 had syncope, 17 (53%) were asymptomatic. Cardiotoxicity was more common in patients with atypical symptoms during daily life (OR = 15.7) and in those on a therapeutic schedule of 5 days/week (OR = 9.44). Conclusion Capecitabine cardiotoxicity is frequent, and often elicited by physical effort. Oncologists, cardiologists, and general practitioners should be aware of this risk. Active cardiotoxicity surveillance with ECG (and echocardiogram and/or stress testing in suspected cases) during therapy is recommended. Clinical Trials registration number CRO-2010-17.

BackgroundCardiac involvement in amyloid light-chain (AL) amyloidosis usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is an uncommon scenario characterized by a challenging diagnostic and therapeutic workup.Case summaryA 57-year-old asymptomatic man was presented for an incidental finding of myocardial necrosis at the electrocardiogram (ECG) performed for newly diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinaesia with normal LV systolic function with ‘apical sparing’ pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischaemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic workup was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow, and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed, and the patients was timely started on chemotherapy.DiscussionThe diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flowchart has to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.

Background Practice guidelines recommend Sodium-glucose co-transporter-2 inhibitors (SGLT2-i) for patients with heart failure with reduced ejection fraction (HFrEF). This study aimed to describe our population of patients with indications for Dapagliflozin, to compare it with the DAPA-HF trial population and assess the possible prognostic evolution. Methods We retrospectively analysed clinical data of the first 100 HFrEF patients treated with Dapagliflozin at our heart failure clinic (Centro Cardiologico Monzino) from September 2021. Results Table 1 shows patient characteristics in our study (n = 100) and in the DAPA-HF trial (n = 2373). Our patients had a mean age of 69±11 years, mean left ventricular ejection fraction of 31,1±8,0%, New York Heart Association class II (78%), class III (21%) and class IV (1%). 64% of our patients performed cardiopulmonary exercise test (CPET), with mean peak VO2/kg of 14,3±4,5 ml/min/kg and mean VE/VCO2 slope of 39,1±10,5. In our study, compared to the DAPA-HF trial population, there were fewer diabetic patients (14,1% vs 41,8%, p < 0,001), a larger number of patients with implanted cardioverter defibrillator (ICD) (59,6% vs 26,2%, p < 0,001) and cardiac resynchronization therapy (CRT) (22,2% vs 8,0%, p < 0,001). Furthermore, our population had a higher percentage of patients already on optimised therapy with Sacubitril/Valsartan (86,9% vs 10,5%, p < 0,001) and mineralocorticoid receptor antagonists (82,8% vs 71,5%, p < 0,001), along with beta-blockers (97,9% vs 96%, p = 0,434). Conclusions Our patients were slightly older and frailer than those in the pivotal DAPA-HF trial and probably at a more advanced stage of the disease as suggested by the higher prevalence of ICD/CRT and Sacubitril/Valsartan. Based on these results, it may be that the expected prognostic benefit of adding Dapagliflozin to their therapy, in terms of absolute risk, will be lower than in the DAPA-HF trial. Future studies and a longer follow-up are needed to compare death and hospitalisation rates.

Background Immune checkpoint inhibitors (ICI) have revolutionized the clinical management of a broad spectrum of solid and hematopoietic malignancies over the past decade. ICI are associated with several Immune-related Adverse Events, among which myocarditis and atrioventricular blocks are uncommon but potentially fatal toxicities. Material and Methods We describe two patients undergoing treatment with PD-1 checkpoint inhibitors for metastatic cancers who developed myositis and myocarditis complicated by complete atrioventricular block (CAVB). The first patient had a history of metastatic sarcomatoid urothelial carcinoma treated with Pembrolizumab. After two cycles, he developed eyelid ptosis and was hospitalized for syncopal episodes due to CAVB associated with ICI myocarditis. The second patient had a history of metastatic melanoma and was hospitalized for myocarditis and myositis after the second infusion of Nivolumab. Results In the first case, high-dose corticosteroid therapy was promptly initiated, with subsequent rapid recovery of sinus rhythm and rapid resolution of symptoms. The second patient, despite high-dose corticosteroid therapy, developed CAVB requiring implantation of a definitive PM. After initiation of mycophenolate mofetil and intravenous immunoglobulin therapy, gradual recovery was observed. Both patients had normal left ventricular function with no wall motion abnormalities. However, speckle tracking echocardiography revealed a normal global longitudinal left ventricular strain (GLS) of -19.8% in patient 1 and a depressed GLS of -14.7% in patient 2, consistent with the different evolution of the two myocarditis. Conclusions We recommend a high degree of caution and awareness to all physicians when treating immunotherapy patients. Myocarditis is a relatively rare but potentially fatal event due to its early onset, non-specific clinical presentation and fulminant progression. GLS may be useful in detecting myocardial damage in these patients. Discontinuation of ICI, cardiac pacing, treatment with high-dose corticosteroids and immunosuppressive agents may improve the outcome.

Background Cardiac involvement in light-chain amyloidosis (AL) usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is un uncommon scenario characterised by a challenging diagnostic and therapeutic work-up. Case Summary A 57-year-old asymptomatic man presented for an incidental finding of myocardial necrosis at the ECG performed for newly-diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinesia with normal LV systolic function with ‘apical sparing’ pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic work-up was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed and the patients was timely started on chemotherapy. Discussion The diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flow-chart have to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.

A 55-years old sporty man, without any cardiovascular risk factors nor previously known cardiological history, presented for a cardiological evaluation due to extra-systolic palpitations and dyspnea. The ECG documented a new onset of right bundle branch block, left anterior fascicular block and first degree of atrio-ventricular block. Echocardiography revealed severe left ventricular (LV) systolic dysfunction (LV ejection fraction -EF- 34%), showing also right ventricular (RV) dilatation and disfunction. A 24-hour Holter monitoring did not show any significant arrhythmias and maximal stress test did not reveal any ECG changes nor arrhythmias. Cardiac magnetic resonance (CMR) confirmed the presence of severe biventricular dysfunction; multiple areas of edema and late gadolinium enhancement (LGE) were observed, with ischemic and nonischemic pattern and extensive involvement of the RV and the interventricular septum. In the suspicion of cardiac sarcoidosis a 18-fluorodeoxyglucose positron emission tomography (PET) was performed, confirming the presence of an inflammatory cardiomyopathy in an active phase. A subsequent endomyocardial biopsy was performed, which demonstrated the presence of non-caseating granulomas, signs of inflammation and fibrosis, consistent with the diagnosis of cardiac sarcoidosis. No signs of extra-cardiac involvement were present. The patient started anti-inflammatory therapy with Prednisone and Metotrexate, along with anti-neurohormonal therapy. However, due to a significant increase in ventricular arrhythmic burden, an implantable cardioverter defibrillator was placed during early follow-up, and Amiodarone therapy was started. After 5 months of medical therapy, PET scan showed a marked reduction of cardiac inflammation and echocardiography showed a significant LVEF improvement (from 34% to 43%). After slow tapering of steroid therapy Prednisone was stopped, whereas Metotrexate, Amiodarone and anti-neurohormonal therapy were maintained. Follow-up is still ongoing without clinical events. Sarcoidosis is a systemic inflammatory disease characterized by the presence of non-caseating granulomas in multiple organs. Cardiac involvement is associated with higher incidence of heart failure, ventricular arrhythmias and all-cause mortality. Isolated cardiac involvement is rare but associated with worse prognosis. Multimodality imaging is of paramount importance for the diagnosis and monitoring therapy.

Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of variant ATTR-CM (ATTRv-CM) among elderly patients. Methods Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2012 and June 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. Results The study population consisted of 2164 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). ATTRv-CM was diagnosed in 20% (n=431) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) other pathogenic TTR variants. During a median (range) follow up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p Conclusions Up to 20% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.

A 27-year-old woman, without previous cardiological history, was admitted at our emergency department in the clinical context of an acute pericarditis. Echocardiography documented mild pericardial effusion (8 mm) without any sign of hemodynamic impact. The patient was then admitted at our Cardiology Unit. During the hospitalization a complete transthoracic echocardiogram showed a normal biventricular morphology and function, normal valvular function and found an anechoic structure on the postero-lateral left atrial wall (1.75×1.5 cm). To better characterize this accidental finding, a transesophageal echocardiography was performed unmasking a dilated coronary sinus with anomalous course. A subsequent cardiac computed tomography was performed showing anomalous systemic venous return with the persistency of the left superior vena cava draining into the coronary sinus. No other congenital anomalies were found. PLSVC is present in approximatively 0.5% of individuals in the general population and is the most frequent congenital malformation of the thoracic venous return. In about 90% coexists with the right superior vena cava and co-occur in almost 40% of patients with other congenital heart abnormalities such as atrial septal defect, aortic coarctation, bicuspid aortic valve, tetralogy of Fallot, transposition of the great vessels, anomalous connections of the pulmonary veins, dextroversion and cor triatatum. Patients usually are asymptomatic. Nevertheless, this congenital malformation may cause chest discomfort, cardiac arrhythmias, thromboembolic events, decreased exercise tolerance and syncope. Moreover, the correct identification of this condition has important clinical implications. In fact, it is a relative contraindication to the administration of retrograde cardioplegia during cardiac surgery. Furthermore, the placement of central venous-access line, pulmonary artery catheterization or the implantation of pacemaker/resynchronization leads could be difficult or can result in incorrect positioning. In these cases, it is recommended to access to the right heart through the right subclavian vein instead the left one. Legend: *: Anomalous course of coronary sinus; LA: Left Atrium; LV: Left Ventricle; Ao: Aorta; RA: Right Atrium; R-SVC: Right superior vena cava; L-SVC: Left superior vena cava; LSPV: Left superior pulmonary vein.

A 63 years old man, with multiple cardiovascular risk factor, presented at the emergency department with a transient ischemic attack during an hypertensive crisis. Electrocardiogram revealed a sinus rhythm and no sign of ischemia. No critical stenosis were detected at ultrasonography of the supra-aortic trunks. Brain CT showed an arachnoid cyst in right posterior cerebellar site. Transthoracic echocardiographic showed normal wall motion with a left ventricular ejection fraction of 66%. The transesophageal echocardiography, performed for searching possible emboligenic heart disease, revealed a fistulous aneurysmal formation arising from the left main coronary artery. Angio-CT confirmed a CAF between distal left main coronary artery and right atrium, with a retro-aortic serpiginous course and an ectasic vascular structure (above 8.35 mm), this pathological vessel also had an aneurismatic formation of maximum diameter of 1 cm. CT scan detected also a 50% soft eccentric plaque in mid circumflex coronary artery and a less than 50% soft eccentric plaque in the right coronary artery. An elective hospitalization was performed in order to better assess the CAF. Coronary angiography revealed no significant coronary atherosclerotic disease and confirmed the CAF with its convoluted course. No left to right shunt was found either in cardiac magnetic resonance (Qp/Qs close to 1) or in right heart catheterization. Maximal stress test with cycloergometer was negative for clinical and electrocardiographic inducible ischemia (120W). CAF is a rare vascular abnormality, occurring in only 0.002% of the general population. The majority of CAFs have a congenital origin, but occasionally they may be acquired after cardiac surgery or repeated myocardial biopsies in cardiac transplantation. The CAFs may increase in size over time, although this does not occur invariably, and complications include: myocardial ischemia (due to myocardial ‘steal’), thrombosis and embolism, heart failure, atrial fibrillation, rupture, endocarditis/endarteritis, arrhythmias and also spontaneous rupture of the CAF causing hemopericardium. Current treatment options for CAF include surgery or transcatheter closure. Considered the age of the patient, the absence of clinical symptoms and the absence of left to right shunt, a conservative strategy was chosen. The patient had strict follow up, with clinical and echocardiographic assessment every 6 months, and with annually CT scan and stress test. During these 9 years of follow up the CAF remained stable, and the patients clinically asymptomatic.

Background Familial patterns of inheritance and genetic mutations have been identified as pathogenic in nearly 40-50% of previously defined “idiopathic” Dilated Cardiomyopathy (DCM). Genetic testing in the proband allows cascade genetic screening in relatives, in order to promote an early diagnosis even in a pre-clinical stage of the disease, as recommended by international guidelines. This study aims to describe the clinical characteristics of screened relatives of Dilated Cardiomyopathy (DCM) patients, at baseline and during follow-up. Methods Screened relatives of patients affected by DCM were enrolled retrospectively and followed from January 2000 to August 2021. At baseline, the family screening included a clinical evaluation, ECG and echocardiogram. If likely pathogenetic (LP) or pathogenetic (P) variant was identified in the proband Genetic testing was offered and performed on relatives according to available consensus documents from the age of 10-12 years. The onset of disease was defined as left ventricular (LV) dilation and/or LV systolic dysfunction. The following information was obtained during the follow-up: all-cause death, cardiovascular death, sudden cardiac death (SCD), hospitalization for heart failure (HF), heart transplantation, ventricular assist device (VAD) implantation, ICD or CRT-D implantation and major ventricular arrhythmias (MVA). Results We enrolled 203 relatives from 32 families with DCM. The median follow-up was 94 months. At baseline, symptomatic relatives for dyspnea (NYHA II-III class) were 29 (14%), versus 174 (86%) of asymptomatic (NYHA I). All these subjects showed initial signs of DCM and experienced more frequently adverse outcomes, such as hospitalization for HF (p Among asymptomatic relatives, patients with initial signs of disease were 46 (26%), 20 (43%) with LV dilation and dysfunction, 18 (39%) with LV dysfunction and 7 (15%) with LV dilatation. During follow-up, 5 of them (11%) died and 2 (4%) experienced SCD (one carrier of FLNC variant). Globally, affected relatives at baseline carried a LP/P variant in more than half of the cases (57%), the remaining part being relative of proband with no or negative genetic testing. Non-affected relatives were 128 (74%) at baseline. 15 relatives (12%) developed initial signs of DCM (5 with LV dilation, 5 with LV dysfunction, 5 with LV dilation and dysfunction) during follow-up. Of those, 13 patients (87%) carried a LP/P variant. The genes mostly involved were TTN (9 cases,69%), followed by DSP and FLNC. Conclusions Familial screening allows an early diagnosis of DCM-affected patients. Asymptomatic relatives at the baseline showed a better outcome compared with symptomatic ones. However, SCD events were only detected in the asymptomatic group. Moreover, subjects who develop the disease during follow-up were carriers of a LP/P variant. Seriate follow-up is mandatory in relatives independently by symptoms at the baseline: genetic testing supports a focused clinical screening of high-risk relatives.

Background The combined prognostic role of cardiac magnetic resonance (CMR) and genotype in cardiomyopathies has not been fully investigated. The aim of this study was to identify specific genotype-CMR phenotype correlations in a well-characterized cohort of patients with a spectrum of left-sided cardiomyopathies spanning from arrhythmogenic (ACM) to dilated cardiomyopathy (DCM), and analyze patients’ outcome. Methods and Results One-hundred and seventy-four patients with DCM (127) and left sided ACM (47), who underwent a comprehensive evaluation including genetic testing and CMR imaging, were enrolled in this study. The phenotype was classified as DCM or ACM according to current consensus criteria. The primary outcome was a composite of sudden cardiac death/life-threatening ventricular arrhythmias (SCD/MVA). DCM patients showed more frequently pathogenic or likely pathogenic (P/LP) variants of non-arrhythmic genes (34% vs. 7%, p < 0.001), whereas ACM patients reported more frequently P/LP variants of arrhythmic genes (47% vs. 8%, p < 0.001) and non-ischemic free-wall LGE (30% vs. 10%, p = 0.002). After a median follow-up of 92 months (interquartile range 46 - 168), 39 patients (22%) reached the combined endpoint. Carrying a P/LP variant of arrhythmic genes (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.1 - 4.4, p = 0.024) along with presence of LGE (HR 4.5, 95% CI 1.99 - 11.5, p < 0.001) were independently associated with the study endpoint. Conclusion In cohort of well-characterized left sided cardiomyopathies patients spanning from ACM to DCM, a P/LP variant of arrhythmic genes along with presence of LGE were independent predictors of SCD/MVA.

A healthy 55-year-old competitive sportsman, with familial history of early sudden cardiac death, came to our attention following the finding of asymptomatic exercise-induced myocardial ischemia (ST depression in V3- V6). Computed tomography (CT) coronary angiogram excluded atherosclerotic disease but showed a dominant right coronary artery (RCA) originating from left Valsalva sinus and with an interarterial course between the ascending aorta and the pulmonary artery. Both the trunk of the pulmonary artery and the right ventricle were reported as mildly dilated Transthoracic echocardiography showed a normal left ventricle (LV), while confirmed right ventricle (RV) dilatation, moderate tricuspid regurgitation (TR) and interatrial septal aneurysm. Stress echocardiography excluded inducible ischemia, but highlighted exercise-induced pulmonary hypertension (PH) (PAPs 25 → 70 mmHg), while a transesophageal echo confirmed a left-to-right shunt due to a 8-mm Patent Foramen Ovale (PFO). Rheumatological, thromboembolic and parenchymal lung diseases were excluded as possible causes of exercise-induced PH; a rest right heart catheterization (RHC) showed a Qp/Qs ratio at the upper limits of normal range without PH. Nuclear stress testing identified trivial asymptomatic septal ischemia. The patients started medium dose of beta-blockers and early follow-up was planned. This clinical case raises some questions: why is RV dilated? What role does PFO play? What is the cause of the inducible ischemia? What is the pathogenesis of exercise-induced PH? Pulmonary Arterial Hypertension, in early stages, often manifests only under exertion, but it is usually characterized by exercise dyspnea and low oxygen saturation. Moreover, intracardiac shunts may be involved in developing PH. In this specific case, pulmonary trunk may be expanded by pressure overload, causing the compression of aberrant RCA and consequent ischemic abnormalities. RV dilatation might be explained by exercise-induced PH itself, but it was not severe and has to be demonstrated by exercise right heart catheterization. The main questions are: which is the primary etiology of right chamber enlargement and myocardial ischemia? Which is the most appropriate therapeutic approach (i.e. conservative vs interventional)?

Background The association between chronic neuropathic pain in childhood, left ventricular hypertrophy(LVH), early ischemic stroke and unexplained renal failure is suggestive of FD. However, because of the heterogeneity of the genetic substrate, different and more subtle phenotypic manifestations are possible as well as single organ involvement. Diagnostic criteria require an initial measurement of both alpha-galactosidase A (α-Gal-A) activity levels in leukocytes and globotriaosylsphingosine (LysoGb3, a glycosphingolipid derivative) concentration. Genetic testing is needed to confirm the diagnosis if α-Gal-A is decreased or absent and Lyso-Gb3 is increased. Case report A 35-year-old man was referred to our outpatient cardiology clinic at the beginning of summer 2022. He had a family history of sudden death, he had no cardiovascular risk factors and a history of severe acral pain during childhood. On medical background, he had undergone renal transplantation after two years of hemodialysis therapy due to nephroangiosclerosis and tubulointerstitial nephritis, identified in renal biopsy. On physical examination were visible neither angiokeratomas nor ocular manifestations. ECG showed LV hypertrophy and a transthoracic ECO confirmed LV concentric hypertrophy, a preserved LV ejection fraction and the presence of unexplained subtle LV systolic dysfunction due to an abnormal LV global longitudinal strain. Laboratory tests revealed normal serum creatinine and elevated NT-ProBNP levels. Unfortunately, a CMR examination was not performed because of the patient's claustrophobia. Genetic and enzymatic analyses were performed on the high suspicion of a cardiac storage disorder. The enzymatic activity of α-Gal-A and lyso-Gb3 concentration was within normal values, whereas genetic analysis detected a missense mutation (c.376A>G) in exon 3 causing an amino acid substitution (p.S126G). The suspicion of FD was confirmed. Discussion This is an interesting case with a diagnosis of FD that is controversial for several reasons. The c.376A>G is a rare mutation, found mainly in female patients with normal α-Gal-A and LysoGb3 levels ​​and associated with isolated renal failure. In addition, this variant is typically responsible for the late onset of the disease, occurring after 40 years of age2,8–11. Our patient is young and presents early cardiac and severe nephrological involvement, both typical clinical features of FD. A normal activity of α-Gal-A is consistent with the missense gene mutation: enzyme activity appears to be normal up to at least 90-95% reduction of function. To date, there is little evidence in the scientific literature of similar cases and the clinical presentations associated with this mutation are contradictory. Since 2002, c.376A>G has been known to be a pathogenetic variant of FD12, in 2010 it was associated to late-onset disease13. However, in the International Fabry Disease Genotype-Phenotype Database, it is considered a likely benign variant of FD2. Conclusion In this case report, we emphasize that high clinical suspicion should lead to more diagnostic evaluations, including genetic testing in the daily routine. Additional studies are needed to better understand the role of the c.376 A>G mutation in the FD.

Background For patients with heart failure, prescription of loop diuretics (LD) and higher doses are associated with adverse prognosis. We investigated LD dose trajectories and their associations with outcomes in patients with dilated cardiomyopathy (DCM). Methods Associations between outcomes and both furosemide equivalent dose (FED) at enrolment and change in FED in the subsequent 24 months were evaluated. According to FED trajectory, patients were divided in i) dose↑ (FED increase by ≥50% or newly initiated); ii) dose↓ (FED decrease by ≥50%); iii) stable dose (change in FED by Results Of 1,131 patients enrolled, 738 (65%) were prescribed LD at baseline. Baseline FED was independently associated with outcome (HR per 20mg increase: 1.12 [95% CI 1.04-1.22, p=0.003]. Of the 908 with information on FED within 24 months from enrolment, 31% were never-users; 29% dose↓; 26% stable dose and 14% dose↑. In adjusted models, compared to never-users, stable dose had a higher risk of primary outcome (HR 2.42 [95% CI: 1.19-4.93], p=0.015), while dose↑ had the worst prognosis (HR 2.76 [95% C.I. 1.27-6.03], p=0.011). The results were consistent for the secondary outcome. Compared to patients who remained on LD, discontinuation of LD (143, 24%) was associated with improved outcome (HR 0.43 [95% C.I. 0.28-0.65], p Conclusions In a large cohort of patients with DCM, LD use and increasing FED are powerful markers of adverse outcomes. Patients who never require LD have an excellent prognosis.

Background Myocardial infarction with non-obstructed coronary arteries (MINOCA) is an increasingly recognized condition with challenging management. Prognosis of this patients could be of concern, in particular for those who experienced recurrent acute myocardial infarction (re-AMI). Moreover, there are limited data on characteristics of re-AMI among MINOCA patients. Methods In this retrospective multicentre cohort study involving seven Hub Hospitals across Italy we enrolled consecutive patients 18 years and older discharged with diagnosis of MINOCA according to the IV universal definition of myocardial infarction who experienced hospitalization for re-AMI during follow-up. Results A total of 54 patients were included (mean age 66±13). Compared to MINOCA patients without re-AMI (n=695), on first angiography MINOCA patients with re-AMI showed less frequently angiographically normal coronaries (37 versus 53%, p=0,032) and had higher prevalence of atherosclerosis involving 3 vessels or left main stem (17% versus 8%, p=0,049). Twenty four patients (44%) with re-AMI underwent a new coronary angiography and 25% had normal coronary arteries, 12% had mild luminal irregularities ( Among patients undergoing new angiography, only 4% had LDL cholesterol under 55 mg/dL, atherosclerosis progression was observed in 11 (46%), 38% received revascularization and 33% experienced a new cardiovascular event (death, AMI, heart failure, stroke) at subsequent follow-up. Conclusions In the present study near one out of two patients with re-AMI after MINOCA showed angiographic atherosclerosis progression requiring revascularization in the majority of cases. These patients rarely presented with recommended LDL cholesterol levels and are at risk for further cardiovascular events, indicating a possible underestimation of cardiovascular risk in this population.

Objective We aimed to evaluate in a real world primary percutaneous coronary intervention (pPCI) registry the impact of the evolution of evidence-based treatments on prognosis, comparing different decades of treatment. Methods Consecutive STEMI patients undergoing pPCI at University Hospital of Trieste, Italy, were enrolled in a pPCI registry. Outcomes were evaluated during two successive periods: the first cohort (old treatments cohort) included STEMI patients treated between January 2007 and December 2012, and the second cohort (new treatments cohort), included STEMI patients treated between January 2013 and December 2020. Cox regression models were performed to predict the risk of the study primary endpoint (PE) a composite of all cause death, reinfarction and re-PCI at 5 years. The secondary endpoint was all cause of mortality at 5 years. Moreover, we evaluated the incidence of stent thrombosis at 12 months. Results A total of 2425 STEMI patients, 947 in the old treatments cohort and 1478 in the new treatments cohort were analysed. The mean age of the population was 66 ± 12.5 years, most were males (74.3%), 20.2% were diabetics, and 12% presented in Killip class III-IV. At 5-years of follow-up the new treatments cohort compared to the old treatments cohort presented a lower rate of primary outcome (18.5% vs 23.1%, p=0.006) and mortality (15.5% vs 19.9%, p=0.006). At Cox regression model adjusted for baseline differences between the two cohorts, patients in the new treatments cohort had lower risk of PE (HR 0.717, 95% CI 0.567–0.907, p=0.006) and mortality (HR 0.662, 95% CI 0.509–0.860, p=0.002). When considering both clinical and procedural variables, complete revascularization (HR 0.459, 95% CI 0.265–0.796, p=0.006) and the administration of prasugrel or ticagrelor (HR 0.721, 95% CI 0.524–0.992, p=0.013) were independent predictors of PE as well as of 5 years mortality. The new treatments cohort compared to the old treatments cohort had more frequent use of radial approach (83.1% vs 24.4%, p0.001), however they were not associated with PE. Patients receiving prasugrel or ticagrelor or drug eluting stent (DES) were at lower risk of stent thrombosis at 12 months (HR 0.502, 95% CI 0.280–0.900, p=0.021). Conclusions In a real-word STEMI population the prognosis of patients is improved in the last decades, and this was associated to the use of new antithrombotic treatments and to the implementation of complete revascularization. The application of new evidence-based therapies in clinical practise is fundamental to improve patient prognosis because the benefits demonstrated by clinical trials have translated into a benefit in the real-world population.

Background Vaccination represents a cornerstone of prevention in the COVID-19 pandemic. Rare adverse events including acute pericarditis and myopericarditis have been reported. Material and Methods All consecutive patients referred to our referral center for pericardial diseases following COVID-19 vaccination from 1st April 2021 to 15th April 2022 were included. Acute pericarditis and myopericarditis were diagnosed according to ESC guidelines. Patients with SARS-CoV-2 infection were excluded from the study. Results Twenty-four patients (79% males) aged 39.7 ± 19.8 years were referred to our center with pericarditis after receiving COVID-19 vaccination. 13 (54%) patients were diagnosed with myopericarditis. The mean time between vaccination and symptoms onset was 7.0 ± 4.9 days and the most frequent symptom was pericarditic chest pain (83%). Respectively, 50% and 33% of patients presented after the second and the third dose of the vaccine. Almost all patients were treated with both nonsteroidal anti-inflammatory drugs and colchicine. Five patients (21%) experienced a recurrence of pericarditis. No patient died or developed constrictive pericarditis. Mean follow-up was 8.0 ± 3.2 months. Conclusions COVID-19 vaccine-related pericarditis typically manifest with mild clinical signs, in young males, a few days after the second or third vaccine dose and are commonly characterized by a rapid complete recovery. Despite these rare side effects, the benefits of COVID-19 vaccination clearly outweigh the limited risk of pericarditis and myocarditis, and vaccination is strongly recommended to prevent COVID-19 infection, transmission and related complications.

Background Titin truncating variants (TTNtv) represent the most prevalent genotype underlying dilated cardiomyopathy (DCM). Recent molecular studies provided initial evidence about different pathogenic mechanisms produced by different mutation sites of the truncating variant (A-Band vs non-A-band), possibly related to the presence or absence of truncated titin (TTN) peptides. However, to date, clinical studies on DCM patients carrying TTNtv failed to demonstrate any relevant clinical difference according to the titin band affected. We hypothesized this lack of variation could be partially explained by the selection bias of including only DCM phenotype patients. Thus, we studied the clinical phenotypes and outcomes of our entire population of subjects with pathogenic TTNtv regardless of phenotypic expression at the onset. Methods We retrospectively analyzed a population of pathogenic TTNtv carriers, enrolled in the Trieste Heart Muscle Disease Registry. TTNtv were classified according to their site (Z disk, I band, A band, A-M junction, M band) and further grouped for analysis in A-band and non-A band. Variables were expressed as mean±SD, median and interquartile range, or counts and percentage, as appropriate. Kaplan-Meier curves were estimated for the composite endpoints of (i) heart failure-related death, heart transplant, and destination left ventricular assist device implantation and (ii) first major ventricular arrhythmia (MVA, defined as SCD or life-threatening ventricular arrhythmia) and compared by the log-rank test. Results 154 TTNtv carriers were included in the study, of whom 66% were probands. The most prevalent phenotype was DCM (92%). The mean age of subjects at diagnosis was 43±16 years and 70% were males. There was no difference between groups in the first composite outcome of heart failure-related death, heart transplant, and destination left ventricular assist device implantation. Instead, major ventricular arrhythmias were significantly more frequent in the non-A-band group, in which 47% (n=14) of TTNtv carriers experienced MVA as compared to 19% (n=20) of subjects in the A-band group (p=0.001). Interestingly, we observed a tendency in MVA occurrence at a higher mean left ventricular ejection fraction (LVEF) in the non-A-band group as compared to the A-band group (42±13% vs 35±9%, respectively). Conclusions Among TTNtv carriers referred to a tertiary center, those with a mutation in the non-A band seem characterized by higher arrhythmic risk. This novel finding highlights the importance of considering the site of TTN truncating variants to guide the most appropriate clinical management for each patient.

Background Recent studies have highlighted a direct link between dietary nutrients, microbiota and cardiovascular disease (CVD). In this context, trimethylamine-N-oxide (TMAO), a metabolite derived from the intestinal microbiota, stands out, paving its way as one of the important biomarkers associated with atherosclerosis, increased risk of CVD, recurrent events and adverse outcomes. Methods 81 patients who survived acute myocardial infarction (AMI), (both STEMI 50 / NSTEMI 31) were enrolled in this study together with 10 healthy individuals. Further, we evaluated the relationship between plasma TMAO levels and cardiovascular events during the follow-up. The measurement of plasma levels of TMAO was performed using liquid chromatography-tandem mass spectrometry (LC-MS). Results The median plasma concentration of TMAO were significantly higher in patients with AMI compared with healthy control (1.62 (1.37–2.25) µM. vs 0.55 (0.35–0.74) µM, p < 0.0001). During a median follow-up of 61.74 (59.34–64.24) months, 10 out of 81 patients (12.3%) had a re-infarction. Patients who had another ischemic event had higher TMAO values compared with individuals who did not (2.29 (1.60–6.49) µM vs 1.60 (1.34–2.09) µM, p = 0.026). Further, TMAO values positively correlate with CRP, a pro-inflammatory marker. However, at multivariate Cox regression analysis, plasma TMAO values were not predictive of re-infarction. Conclusions The data of our pilot study show that higher TMAO values are associated with the risk of recurrent ischemic event. A future prospective study, including larger cohort is necessary to analyze this issue.

Background The impact of complete revascularization (CR) on survival and occurrence of heart failure (HF) after ACS is still unsettled. Goal of this study was to evaluate the impact of CR on HF hospitalization and adverse outcomes in patients with ACS and multivessel coronary artery disease undergoing PCI. Methods Consecutive ACS patients with multivessel disease from the CORALYS registry were included. First hospitalization for HF or cardiovascular (CV) death was the primary endpoint. Patients were stratified according to CR. Results Of 14699 patients in the CORALYS registry, 5054 had multivessel disease. 1473 (29.2%) underwent CR, while 3581 (70.8%) did not. Over 5 years follow-up, CR was associated with a reduced incidence of the primary endpoint (adjusted HR 0.66, 95% CI 0.51-0.85), first HF hospitalization (adj HR 0.67, 95% CI 0.49-0.90), CV death (adj HR 0.56, 95% CI 0.38-0.84) and all-cause death (adj HR 0.74, 95% CI 0.56-0.97). The results were consistent in the matched population and in the IPTW analysis. The benefit of CR was consistent across ACS presentations (HR 0.59, 95% CI 0.39-0.89 for STEMI and HR 0.71, 95% CI 0.50-0.99 for NSTE-ACS) and in patients with LVEF>40% (HR 0.52; 95% CI 0.37-0.72), while no significant benefit was observed in patients with LVEF≤40% (HR 0.77; 95% CI 0.37-1.10, p for interaction 0.04). Conclusions In patients with ACS and multivessel disease, CR reduced the risk of first hospitalization for HF and CV death, as well as first HF hospitalization, CV and overall death. When feasible, CR should be performed in all patients with ACS to reduce the incidence of HF and death. Future studies are needed to assess the evidence of CR in patients with depressed LVEF.

A 33yo man, ex-convict, with a history of IV substance abuse, without previous cardiological history, was admitted at our emergency department in the clinical context of an acute pericarditis, intermittent fever in the last 10 days and non-itchy maculo-papular erythema of palms and thorax. EKG documented a diffuse ST-segment elevation, chest X-rays revealed a bilateral pleural effusion and echocardiography documented a normal biventricular morphology and function, normal valvular function, and a circumferential pericardial effusion (14mm). The patient was admitted at our Cardiology Unit after a negative PCR SARS-CoV-2 test. Blood chemistry showed elevated WBC count with an important neutrophilia (24.000/mm3; 90% neutrophils), elevated TnI-HS (236 ng/L; n.v. After 10 days of hospitalization, the patient's clinical status continued to deteriorate. The intermittent fever (max 41°C) was not responsive to any treatment. The evanescent skin rash had spread to the whole body and was concomitant with the fever peaks. The indexes of inflammation were rising (C-reactive protein 400 mg/L) and so were the WBC count (36.000/mm3). The patient lost weight (-8kg), developed hand and feet arthralgia, diffuse myalgia, painful retronucal lymph nodes, pharyngodynia and abdominal pain. An abdominal echography and CT were performed with evidence of mild abdominal effusion and splenomegaly. Hepatic cytolysis indices began to rise (AST 100 U/L; ALT 150 U/L; LDH 385 U/L). At that point, on the basis of Yamaguchi's Criteria, we suspected our patient could be affected by Adult-onset Still's disease (AOSD) with an initial stage of hemophagocytic lymphohistiocytosis (HLH). Prednisone (IV 2 mg/kg/die) was administered for 72h with an incomplete clinical and biochemical response (C-reactive Protein 180 mg/L). Subsequently, Anakinra (SC 100 mg/die) was administered with a complete clinical response in less than 72h. AOSD is very uncommon. The annual incidence is 0.16/100.000 with an equal distribution between sexes. HLH have been observed in 15% of patients, meanwhile myopericarditis is a rare complication. Although rare, it is fair to know and consider AOSD in the complicated and tricky diagnostic process of myopericarditis. A noteworthy point of this case report is the extreme efficacy of Anakinra in contexts of systemic inflammation and myopericarditis. A point still to be clarified concerns the duration of the treatment and the down-titration of Anakinra in these complicated contexts.

Background Out-of-hospital cardiac arrest (OHCA) is the third leading cause of death in industrialized countries. Although most cardiac arrests are witnessed, survival is only 2-10%, since bystanders are often unable to correctly perform cardio-pulmonary resuscitation (CPR). This study aims to assess the theoretical and practical knowledge of CPR and the use of the automatic external defibrillator (AED) in university students. Materials and methods The study involved a total of 1686 students from 21 different faculties of the University of Trieste, 662 students from health faculties and 1024 from non-health faculties. Basic life support and early defibrillation (BLSD) courses have been included in health faculties and made mandatory for students in their final years. Through the platform “EUSurvey” from March to June 2021, they were given an online questionnaire of 25 multiple choice questions to investigate the performance of BLSD. Results In the overall population, only 68.7% knew how to diagnose a cardiac arrest and the 47.5% knew the time frame after which irreversible brain damage occurs. Practical knowledge was analysed by evaluating the correct answers to all four questions on performing CPR (hand position during compressions, frequency of compressions, depth of compressions, and ventilations-compressions ratio). Health faculties students have better theoretical and practical knowledge of CPR than their colleagues in non-health faculties (11,2% vs 4,3%; p value Discussion The knowledge of cardiac arrest needs to be improved in the overall university population. The obligatory inclusion of BLSD courses in healthcare degree courses has led to a significant increase in knowledge on the issue. Given this, we believe it is important to extend these courses to all university students.

Background Many prognostic risk scores have been developed for ambulatory Heart Failure (HF) patients, but none of these has been validated in Dilated Cardiomyopathy (DCM), that is a peculiar model of HF. Aims To evaluate and compare the applicability and performance of major HF risk models in a large real-world population of DCM patients Methods This was a retrospective study including 784 consecutive non ischemic DCM patients, both inpatients and outpatients, enrolled in the Heart Muscle Disease Registry (HMDR) of Trieste between January 2000 and December 2017. The following scores designed to estimate 1- to 3-year all-cause mortality were calculated in each participant: CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality), MAGGIC (Meta-analysis Global Group in Chronic Heart Failure), simplified-SHFM (Seattle Heart Failure Model), 3-CHF (Cardiac and Comorbid Conditions), GISSI-HF (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico-Heart Failure), MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes), Barcelona Bio-HF, Krakow score. Results During the follow-up (5,83 ± 4,9 years) 191 patients (20% of the population) met the primary composite endpoint (158 deaths, 30 heart transplantations and 3 LVAD implants). Due to the high quote of missing parameters, only four of the prognostic models (MAGGIC, CHARM, 3-CHF and simplified-SHFM) could be tested in the final statistical analysis. The observed-to-predicted mortality ratios suggested an overestimation of mortality by all scores. The prognostic accuracy of the scales was suboptimal in DCM patients for MAGGIC (AUC 0.754) and CHARM (AUC 0.720) scores, worse for 3-CHF (AUC 0,677) and simplified-SHFM (AUC 0,667) scores, with the MAGGIC and simplified-SHFM respectively providing the best and worst performance. Conclusions The performance of HF prognostic risk scores is suboptimal for DCM patients. The need for new precise risk models tailored for this disease has to be considered.

A 41-year-old man, without previous cardiological history, presented at the emergency department with hypotension and multi-organ failure. Laboratory testing showed elevated white cell blood count (16780/mcL; normal value 4000-11000/mcL; 90% neutrophils), high-sensibility troponin I (23247 ng/L; normal value After initial hemodynamic stabilization with endovenous inotropes, diuretics, and mechanical circulatory support (intra-aortic balloon pump), coronary angiography was performed showing normal coronary arteries. Since fulminant myocarditis was suspected and magnetic resonance was not feasible due to the patient's instability, an endomyocardial biopsy (EMB) was performed with the evidence of myocardial edema, initial myocardial fibrosis, and the concomitant presence of lymphocytic and eosinophilic endo-myocarditis (despite normal eosinophilic blood count) without evidence of active viral replication. After careful exclusion of latent or active infections, high doses of corticosteroids and azathioprine were initiated, with rapid laboratoristic and clinical response. EKG showed AV block regression and QRS width's normalization, so the pacemaker was removed. LVEF rapidly improved and was completely normalized at discharge after two weeks. In the early follow-up, a cardiac magnetic resonance (CMR) was performed with evidence of persistency of mildly dilated LV, normalization of LV wall thickness and biventricular function, a diffuse increase of T1 relaxation time, increased T2 signal of the anterior and septal walls, and intramural anteroseptal late gadolinium enhancement (LGE). Fulminant myocarditis is a rare presentation of acute myocarditis, with low incidence but high mortality. The inflammation of the myocardium itself leads to acute heart failure, cardiogenic shock, and cardiac arrhythmias, including sinus arrest, AV block, ventricular tachycardia, and ventricular fibrillation during the acute phase. In our case, AV block could be an expression of anteroseptal involvement, documented at CMR. This localization has already been associated with worse clinical presentation and could be a marker of poor prognosis. Diagnosis and treatment of fulminant myocarditis require EMB, to obtain information about the etiology and active viral replication in the heart tissue. In our case, the florid inflammatory state and the absence of viral replication allowed prompt treatment with immunosuppressors, with a quick and full recovery of biventricular function in only two weeks.

Background although cardiopulmonary exercise testing (CPET) is a recognized tool for prognostic stratification in patients with dilated cardiomyopathy (DCM), there are no data about the prognostic value of its repetition during follow-up in this setting. The aim of this study was to test the prognostic value of repeating CPET during follow-up, among a large cohort of DCM patients. Methods in this multicenter, retrospective study, we analyzed DCM patients who consecutively performed at least two CPET during a clinical stable phase of disease. All patients performed CPET and echocardiogram within 10 days. The study end-point was a composite of death from all causes, heart transplantation, implantation of durable left ventricular assist device, life-threatening ventricular arrhythmias or hospitalization for HF. Results 216 DCM patients were enrolled (52±12 years, 78% male, NYHA I-II 82%, LVEF 32±9%, 94% on ACE inhibitors, 95% on beta-blockers); the duration of the disease at the time of first CPET was 68 months. The interval between the two CPETs was 15 (11;23) months. During a median follow-up of 38 months from the second CPET, 108 (47%) patients went through the end-point. Time-dependent ROC curves revealed that to repeat during a follow-up of 12 months both CPET and echocardiogram gives a more accurate prognostic stratification than basal echocardiography + basal CPET. Despite an higher AUC (0.91 vs 0.85) there were no significant different accuracies (95% CI: 83.6 - 98 vs 75.5–96.5; p-value: 0.2) between the repetition of CPET plus echocardiogram vs. the repetition of the echocardiogram alone. Among patients who experienced the study outcome, there was a substantial stability of echocardiographic values (relative variation of LVEF +2.7%, LVEDV +1.3%) but a significant worsening of functional capacity (relative variation of percentage predicted VO2 peak +6%, p-value: 0.002). Conversely, there were a significant improvement in echocardiographic values and CPET values in events-free patients (LVEF relative variation -8.6% p-value: 0.002; ppVO2 peak relative variation -6.8%, p-value: 0.002). Conclusion in a large population of clinically stable DCM patients, the systematic repetition of echocardiography or both CPET and echocardiography showed no significant prognostic impact, in presence of stable or worsened echocardiogram. Nevertheless, when there is a clinical variation of symptoms or a failing in the reverse remodeling process, 1-year repetition of CPET can identify higher risk patients.

Background The purpose of this study is [1] to evaluate the incidence of heart failure with improved ejection fraction (HFimpEF) in patients with reduced ejection fraction (HFrEF, EF Methods N=699 patients, admitted between January 2000 and December 2020, were selected from the Cardiac Surgery database of our facility and analyzed retrospectively. The selection criteria for this study were [1] having EF40% and at least 10% EF points improvement at 1-3 months follow-up. We assessed the incidence of improved Ejection Fraction (impEF) after surgical revascularization at 3-months follow-up, defined as the improvement of Ejection Fraction from a baseline LVEF of ≤40% to a new LVEF >40%, within a measurable improvement of ≥10 points of percentage from baseline EF; predictors of impEF were investigated and the association between impEF and mortality risk was finally explored. Results At 3-months follow-up, 221 patients were evaluated and the 42.5% (n=94) of these showed impEF. BMI, LVESVi and LVEF were predictors of impEF at multivariable analysis. ImpEF was significantly associated with better long-term survival in our cohort. Conclusions In patients with reduced EF undergoing surgical myocardial revascularization, impEF occurs in 42.5% of cases within 3 months and is associated with better overall survival. The predictors of impEF identified in this study might be helpful in the definition of patients at higher probability of impEF before surgery.

Background Pericarditis and pericardial effusion (PE) are rare but potentially life-threatening complications in chronic graft-vs-host disease (cGVHD). Limited data are currently available in this setting, based on small single-center retrospective studies. The purpose of this study is to characterize the clinical presentation, management, and outcomes of pericarditis and PE complicating cGVHD in allogeneic hematopoietic cell transplant recipients. Material and Methods We included all consecutive patients referred to our pericardial diseases referral center from 1st May 2008 to 1st May 2022. All patients had no previous cardiovascular or autoimmune diseases and suffered from severe cGVHD with involvement of at least 2 organs. Pericarditis and PE were diagnosed according to ESC guidelines. Conditioning-related toxicity and infections were carefully excluded. Results Pericarditis was diagnosed in 4 patients (2 males, mean age 48.5 ±9.0 years), of whom 2 developed mild PE. PE without pericarditis was diagnosed in 5 patients (80% male, aged 53.2 ±8.9 years), in 2 patients it was reported as severe, requiring pericardial drainage. The average time after allogeneic hematopoietic stem cell transplantation was 22 months (range, 4 to 58 months). All patients required escalation of the corticosteroid therapy they were chronically taking, and in 4 cases the therapy was boosted with non-steroidal anti-inflammatory drugs. Only one patient developed a recurrence and died of multiorgan failure associated with severe cGVHD (involving eyes, mucous membranes, skin, joints, liver, pleuro-pericardial effusion) refractory to immunosuppressive therapy. Overall survival was 89% and no patient developed constrictive pericarditis. Mean follow-up was 69±55 months. Conclusions Pericarditis and PE related to cGVHD typically occur with mild clinical signs in the context of severe cGVHD, however in our study 22% of patients required pericardial drainage at diagnosis. The mainstay of treatment is high-dose steroids and usually the majority of patients have a favorable outcome.

Background Pulmonary hypertension (PH) is defined as a resting mean pulmonary artery pressure of 20 mmHg or above. The importance of identifying the underlying causes of PH is well known for a correct management and treatment. In particular, any cardiac causes, included shunt, must be investigated. Case Summary A 73-year-old woman presented to the emergency room for asthenia and dyspnea. First line exams as ECG and X-ray were executed resulting normal. Laboratory assessment showed an elevated brain natriuretic peptide at 675 pg/ml and a D-dimer value of 1116 ng/mlFEU (n.v. < 500 ng/mlFEU) so with the suspect of pulmonary thromboembolism a CT-scan with contrast was performed. It was negative for acute thromboembolism, but it revealed an enlarged pulmonary artery (with a diameter of 39 mm), a possible defect of interatrial septum and an anomalous drainage of inferior vena cava (IVC) into the left atrium (LA). A transthoracic echocardiogram confirmed the anomalous drainage of IVC into the LA that appears dilated but was not diagnostic for the interatrial defect. Furthermore, PH was suspected (systolic peak tricuspid regurgitation velocity of 3,5 m/s, RA area of 24 cm2, tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure of 0.26 mm/mmHg). A 6-minute walking distance was 376 m. The patient completed the exams with a transesophageal echocardiography that revealed an inferior-type caval vein defect and an over-developed Eustachian valve which divides the right atrium (RA) and connect the IVC with the LA directing the blood flow towards it through the inter-atrial septal defect. Discussion The Eustachian valve is an embryologic remnant at the junction of the IVC and RA. While it typically does not have any pathologic significance, veno-arterial shunting can rarely occur in patients with prominent eustachian valves and atrial septal defects.

A 39 year old man presented to the emergency department with dyspnoea on exertion, chest pain and fatigue. Few years before, the patient was stabbed in the left chest thus developing Pneumothorax and mild pericardial effusion successfully treated with chest tube drainage and medical therapy. Physical examination revelead giugular vein distension and lower extremity edema. The echocardiographic evaluation showed typical signs of constrictive pericarditis which was confirmed by cardiac catheterization. Furthermore, because of clinical worsening and the absence of ongoing inflammation on PET-TC, the patient was referred to surgery. Pericardiectomy was successfully performed with rapid symptoms relief and clinical benefits. Histologic examination of pericardium showed the presence of thick fibrotic tissue with clusters of squamous epithelial cells with no cellular atypias or malignancy. Therefore, we hypothesize that following the chest stabbing wound, squamous and epitheloid cells have invaded the pericardial space producing a fibrotic reaction responsable of the development of the constriction. Furthermore multimodality imaging has been essential for diagnosis and management.

Aims The prognostic role of bone tracer uptake in transthyretin cardiac amyloidosis (ATTR-CA) is controversial. The study investigated the potential prognostic significance of biventricular (BiV) uptake in ATTR-CA. Methods Consecutive ATTR-CA patients who had cardiac scintigraphy with acquisition of planar and single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre (NAC) and four Italian centres were included. Planar BiV uptake was defined in presence of right ventricle (RV) uptake and graded in combination with SPECT imaging. The primary outcome was all-cause mortality. Results Among 1422 patients with ATTR-CA, BiV uptake was found in 85% of cases on planar scintigraphy and in 100% of cases on SPECT images. During a median follow-up of 39 months, BiV uptake at planar scintigraphy was associated with a higher all-cause mortality compared to isolated LV uptake (40.5% vs 10.7%, p Conclusions Planar RV uptake leading to BiV uptake identified ATTR-CA patients with worse outcome, potentially serving as a novel prognostic marker.

Background MessengerRNA (mRNA) COVID-19 vaccination has been associated with a higher-than-expected occurrence of acute myocarditis. Scarce information is available on mid-term prognosis and changes in cardiac function, volumes, and tissue characterization on cardiac magnetic resonance (CMR). Methods Retrospective, multicenter study including patients with a definite diagnosis of acute myocarditis within 30 days from mRNA COVID-19 vaccination, with a confirmed myocarditis diagnosis based on endomyocardial biopsy (EMB) or autopsy or by the coexistence of positive biomarkers (troponin >99th upper reference limit or elevated creatine kinase myocardial band [CK-MB]) and cardiac MRI findings consistent with AM according to the 2018 updated Lake Louise Criteria. Results 77 patients (median age 25 years [IQR 20-35], 15% female) were included and followed-up for 147 days [IQR 74-215]. Follow-up CMR was available in n=49 patients and showed no changes in biventricular ejection fraction (EF) as compared to CMR at diagnosis (left ventricular EF: 59%[55-65]vs. 60%[57-64], p=0.507, right ventricular EF: 56%[52-62]vs. 57%[52-61], p=0.563, respectively). Late gadolinium enhancement was present in all patients at diagnosis and persisted in only n=39 (79.6%) at follow-up (p=0.001), generally sparing the anterior wall and the septum. N=10 (20.4%) had a persistent edema based on T2-weighted short tau inversion recovery (STIR) sequences, with predominant involvement of inferior or inferior-lateral walls. The proportion of patients with increased T1 and T2 mapping signals significantly decreased at follow-up (n=13 (68%) vs. n=4 (13%),p No differences in morpho-functional CMR parameters based on the type of vaccine administered were found (BNT162b2 Pfizer/BioNTech®, n=36, 73.5%, m-RNA-1273 Moderna®, n=13, 26.5%). Among patients with available follow-up (N=75, 97.4%), no major adverse cardiovascular events nor myocarditis recurrence or death were reported. Conclusions At mid-term follow-up, patients who experienced an acute myocarditis after a mRNA COVID-19 vaccine had preserved biventricular EF. The rate and localization of residual scar or edema on CMR is in line with classic viral myocarditis with a good prognosis. This new piece of information should further reassure patients who experience acute myocarditis after mRNA COVID-19 vaccination.

A 60-year-old man with a previous myocardial infarction was admitted to our ICU for acute pulmonary edema in the context of an acute antero-lateral non-ST elevation myocardial infarction. Echocardiography showed severe left ventricular (LV) dilatation with extensive wall motion abnormalities, large apical aneurysm and severe systolic dysfunction. Coronary angiography showed a triple-vessel disease with proximal occlusion of the left anterior descending artery. During the hospitalization, multiple episodes of drug-resistant monomorphic ventricular tachycardias occurred, requiring repeated DC Shock. After Heart Team discussion, the patient underwent coronary artery bypass grafting, LV restoration according to the procedure described by Guilmet and surgical cryoablation. The Guilmet septoexclusion is indicated when the interventricular septum is more involved than the free wall. After aneurysm incision, cryolesions were applied at the septum and at the transitional zone of the scar and viable tissue. Thus, the anterior free wall was sewn obliquely to the septum. Finally, the edges of the incision, anterior and septal, were sewn together to assure a definitive hemostasis (overcoat technique). After surgery, an implantable cardioverter-defibrillator was implanted in secondary prevention. The postoperative course and subsequent cardiological follow-up were characterized by a gradual clinical improvement with mild increasing in LV function and reduction in ventricular arrhythmias. Nowadays, combined aneurysmectomy and endocardial ablation are rarely performed, but should be considered in patients with LV aneurysm who manifest drug-resistant ventricular arrhythmias. Encircling cryoablation in a remodelled ventricle is safe and effective in reducing ventricular arrhythmias which are a negative prognostic factor.

Background Genetic testing is one essential element in the diagnostic workup of patients with idiopathic dilated cardiomyopathy (DCM), and genotype-phenotype correlations are still poorly understood. We assessed the diagnostic yield of genetic testing in a selected DCM cohort including both familial and nonfamilial cases and evaluated phenotypic differences and the relationship of left ventricular reverse remodeling (LVRR) with the presence of pathogenic (P) or likely pathogenic (LP) variants of disease-associated DCM genes. Methods From 680 outpatients with heart with reduced ejection fraction followed at our Heart Failure Outpatient Clinic we selected subjects with a diagnosis of DCM before 65 years of age and without secondary causes of DCM including ischemic, valvular, hypertensive, or drug-induced heart disease or myocarditis. All patients underwent extensive clinical, laboratory, and imaging evaluation at the time of diagnosis and during regular follow-up visits and were offered genetic investigations with Next Generation Sequencing (NGS) of 42 disease-associated DCM genes. Results Of 680 DCM outpatients, 70 fulfilled the definition of idiopathic DCM and 66 gave consent to undergo genetic investigation (median age at diagnosis 57 years, 68% males). A total of 18 pathogenic/likely pathogenic (P/LP) variants were identified in 16 patients (diagnostic yield 24%), the most common (7, 39% of all variants) involving the TTN gene, followed by lamin A/C (n=3), cytoskeleton Z-disk (n=3), motor sarcomeric (n=2), desmosomal (n=1), and ion channel (n=1) gene variants. At the time of DCM diagnosis, patients with P/LP had a higher left ventricular (LV) ejection fraction (LVEF) compared with subjects (31±11% vs 28±8%, p=0.17). After a median follow-up of 53 (IQR 20-111) months, P/LP-positive patients had lower systolic and diastolic blood pressure and higher plasma natriuretic peptide levels than patients without P/LP variants. Patients without P/LP variants exhibited a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, p=0.0008) and decrease in LVEDDi (-3 vs. -1 mm/m2, p=0.03) compared with subjects carrying P/LP variants (Figure). Conclusions Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer left ventricular reverse remodeling in response to guideline-directed medical therapy.

Transthyretin (TTR) amyloid cardiomyopathy due to mutation on TTR gene (vATTR) has extremely different features according to the type of mutation, ranging from a mild to an extensive cardiac involvement. Data about electrocardiographic findings (ECG) in vATTR are limited and not informative of genotype correlation. Aim of this study is to analyze ECG characteristics and their correlation to clinical and echocardiographic aspects in patients with vATTR cardiomyopathy, focusing on different TTR mutations. This is a multicentric, retrospective, observational study performed in six Italian referral centres for cardiac amyloidosis. We divided patients in two groups, according to the previously described phenotypic manifestations of the TTR mutation. Of 64 patients with vATTR cardiomyopathy, 23 (36%) had prevalent cardiac (PC) TTR mutations and 41 (64%) patients had a prevalent neurological (PN) TTR mutations. Patients with PC mutations were more frequently males and older, with advanced NAC staging. At baseline ECG, atrial fibrillation was more common in patients with PC, while pacemaker induced rhythm in those with PN mutations. Prevalence of atrioventricular and intraventricular blocks, pseudonecrosis pattern and low voltages were not significantly different in both groups. PQ and QRS durations were longer and voltage to mass ratio was lower in PC mutations. Different TTR mutations tend to have distinctive ECG features. The standard ECG in vATTR is extremely heterogeneous and the specific mutations are associated with distinct instrumental and clinical features. The differences between PN and PC vATTR are only partially explained by the different degree of cardiac infiltration.

Background Neutrophil–lymphocyte ratio (NLR) is an easily obtained inflammatory biomarker. Recently it has emerged as baseline NLR is independently associated with incident cardiovascular (CV) events and all-cause mortality. However, its role in acute myocarditis (AM) has not been evaluated. Purpose The aim of the present study was to investigate the prognostic value of NLR in patients with AM. Methods All consecutive patients with a diagnosis of AM admitted to two tertiary referral cardiac centres (King's College Hospital, London, UK and Azienda Sanitaria Universitaria Giuliano-Isontina, Trieste, Italy) between October 2006 and June 2020 were included in the study. Diagnosis was confirmed by either cardiac magnetic resonance or endomyocardial biopsy. The outcome measure was all-cause mortality. Patients were divided into two groups according to NLR value defined in previous studies (i.e, 2.5). Results A total of 260 patients with AM were included in the study. Baseline characteristics were comparable in both groups. Approximately two thirds of patients were males (n=175, 67%) with a mean age of 45±16 years. Main clinical presentation was predominantly infarct-like (n=189, 73%), followed by heart failure (HF) (n=46, 18%) and arrhythmic (n=25, 10%). Patients admitted with a HF presentation were more prevalent in the group with elevated NLR, while no difference was found in the other clinical presentations. For all patients, ECG features were comparable between groups. However, patients with elevated NLR presented with slightly lower LVEF (54±11% vs 49±13% respectively, p=0.001). Higher NLR was associated with worse prognosis (Figure 1, p=0.02). Conclusions The NLR is a promising and accessible inflammatory biomarker. In patients with AM, elevated NLR is associated with worse prognosis. Further research is advocated to confirm these data in larger populations.

Aims There is still uncertainty on the management of patients with pheochromocytoma-induced CS (PICS), as only a few clinical cases have been reported. The aim of this study is to investigate the clinical presentation, management, and outcome of patients with PICS. Methods We collected retrospectively 18 patients without previously known pheochromocytoma with histologically proven PICS admitted to 8 European hospitals. Results Among the 18 patients with a mean age of 50 years, 50% were men. The main clinical features at presentation were pulmonary congestion (83%) and cyclic fluctuation of hypertension crises and hypotension (72%). On echocardiography, mean left ventricular ejection fraction (LVEF) was 25% with an atypical-Takotsubo pattern (basal/midventricular) in 50%. Laboratory exams showed increased inflammatory markers, in particular, the mean white blood count was 21.9*109/L. Inotropes/vasopressors were started in all patients and a temporary mechanical circulatory support (t-MCS) was required in 11 (61.1%) patients. All patients underwent surgical removal of the pheochromocytoma but 4 (22.2%) on t-MCS. Echocardiogram (16/17 patients) revealed a mean LVEF of 55% at discharge. Only one patient required heart transplantation (5.5%), and all patients were alive at a median follow-up of 679 days. Conclusions In patients with PICS, characteristically, an atypical Takotsubo pattern was observed in almost half of the cases. Although the use of exogenous catecholamine can be perceived as deleterious, we showed a fairly good mid-term prognosis with rapid improvement of LVEF in most, even if adrenalectomy often occurred on t-MCS.

Background Risk scores are important tools for the prognostic stratification of pulmonary arterial hypertension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown. Methods Patients with PAH enrolled from 2001 to 2021 were divided in ≥ 65 years old vs Results Among 383 patients, 152 (40%) were ≥ 65 years old. Older patients had more comorbidities, with the exception of obesity and diabetes (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in Conclusions Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients. Comorbidities increased the accuracy of risk scores only in younger patients.

Background Arrhythmogenic dilated cardiomyopathy (AR-DCM) combines phenotypical aspects of dilated cardiomyopathy (DCM) and risk of sudden cardiac death (SCD), typical of the arrhythmogenic form (ACM). However, AR-DCM is often ambiguously defined leaving clinicians uncertain on how to identify these high-risk patients. The aims of the study were to re-define AR-DCM based on outcome related arrhythmic markers and to test the usefulness of the novel AR-DCM definition in identifying arrhythmogenic genotypes (i.e., LMNA, FLNC, RBM20, and desmosomal genes). Materials and methods Consecutive DCM patients with genetic evaluation and Holter ECG monitoring or telemetry in two referral institution were analyzed. The arrhythmic markers tested to define AR-DCM were: SCD or major ventricular arrhythmias (MVA), unexplained syncope, rapid nonsustained ventricular tachycardia (nsTV), ≥1000 premature ventricular contractions/24 hours, or ≥50 ventricular couplets/24 hours. Patients were labeled as Early AR-DCM if criteria were met within 12 months from enrolment. The primary endpoint was a composite of SCD/MVA; the secondary endpoint was a composite of all-cause mortality/heart transplant/LVAD implantation (D/HTx/LVAD). Results Among the 743 DCM patients included, 290 had disease-related variants (39%), 94 (30%) of these carried arrhythmogenic genotype. Early AR-DCM was identified in 429 (58%) patients. During a median follow-up of 7.0 [2.2-13.8] years, among arrhythmic markers the occurrence of syncope and/or nsVT within 12 months from enrolment were the only arrhythmic markers independently associated with SCD/MVA (Figure), while the occurrence of early MVA and/or nsTV emerged as the strongest long-term predictors of D/ HTx/LVAD. Family history of MVA was also independently associated with primary and secondary endpoints, and together with MVA, nsTV or unexplained syncope increased the agreement between AR-DCM and arrhythmogenic genotypes in 1 out 2 patients. Conclusions A combination of early (i.e., within 1 year from diagnosis) MVA or nsVT or unexplained syncope might be proposed as a clinically useful new definition of AR-DCM, especially if associated to family history of MVA. This definition in fact allows clinicians to anticipates worse long-term arrhythmic and global outcomes, and to accurately identify malignant arrhythmogenic genotypes.

Background Inflammatory heart disease is a heterogeneous process with variegate clinical manifestations. The acute phase is characterized by a sudden injury involving cardiomyocytes, cardiac conduction system and/or pericardium, with different pathophysiological implications. Case Summary A 26-year-old previously healthy woman presented for worsening fatigue and bradycardia. The ECG at admission showed total heart block with infra-Hisian escape rhythm, heart rate was 36 bpm. She reported no history of tick bite or recent inflammatory event; body temperature was 36,8 °C. Laboratory assessment showed persistently raised troponin (28943 -> 32632 ng/l), C-reactive protein was 0,70 mg/l, white blood cells 4,86×10^3/µl, procalcitonin 0,03 µg/l, interleukin-6 was 60,5 pg/ml (n.v. Discussion In heart inflammatory diseases with bradyarrhythmic onset, atrioventricular conduction may be restored with targeted therapy. Multimodality assessment is crucial in the diagnostic and therapeutic work-up of these cases.

Purpose We described the incidence and ECG factors associated with de novo atrial fibrillation (AF) in patients diagnosed with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) to drive tailored arrhythmia screening. Background Data on the incidence rate and factors associated with de novo AF in patients with ATTRwt CA is limited. Methods Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >1-year follow up (FU) were enrolled in the study and were divided into three groups according to presence of AF: (1)patients with ‘known AF’; (2)patients in ‘sinus rhythm’ and (3)patients developing ‘de novo AF’ during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. Results Overall, 266 patients were followed for a median of 469 days: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. Age and gender were similarly distributed. At multivariable analysis, PR (Hazard Ratio[HR]: 1.008 95% C.I. 1.001-1.016), QRS (HR: 1.022 95% C.I. 1.002-1.043) and left atrial dilatation>50mm (HR: 3.429 95% C.I. 1.565-7.329) were associated with de novo AF at FU. Patients presenting with at least two risk factors (PR>200ms, QRS>120ms or LAD>50mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646). Conclusions Incidence of de novo AF in patients with ATTRwt is 20.7%/year. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Background Cardiac tamponade complicates 18,7% of patients with type A aortic dissection and is associated with dramatically worse outcome and a nearly doubling of in-hospital mortality. Immediate surgical repair with intra-operative pericardial drainage is the treatment of choice. Nevertheless, the management of unstable patients who cannot undergo cardiac surgery in short time is controversial. Case report Here we present a case report of an 82-year woman with type A aortic dissection complicated by cardiac tamponade. The patient alerted the emergency system because of a sudden epigastric pain. On her arrival to the hospital, her systolic blood pressure was 50 mmHg; despite intravenous fluids and inotropic support, she remained hypotensive. Transthoracic echocardiography revealed an intimal flap involving ascending aorta and aortic arch, and a hemodynamically significant pericardial effusion. Immediate surgical repair was not possible due to the lack of available operating rooms. To stabilize the patient, percutaneous pericardiocentesis from apical approach was attempted, unsuccessfully. A second attempt of percutaneous pericardiocentesis was made from substernal approach, with removal of just 150 cc of pericardial fluid and insertion of a pigtail drainage catheter. Thanks to this procedure systolic blood pressure raised up to 100 mmHg and the patient was stabilized. A CT Angiography scan was performed, showing an aortic dissection extending from the aortic valvular plane to the origin of the right iliac artery. The patient maintained hemodynamical stability until surgical intervention, which started four hours later her arrival. The patient underwent substitution of ascending aorta, aortic hemiarch, non-coronary sinus and aortic valve. There were no complications related to the pericardial drainage and in 34th post-operative day she was discharged in good condition. Conclusion Percutaneous pericardiocentesis should be considered in unstable patients with type A dissection complicated by cardiac tamponade who cannot await surgical treatment, providing that very small amount of pericardial fluid is removed, in order to maintain systolic blood pressure around 90 mmHg.

Background Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF (AHF) is lacking. Objectives We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for AHF. Methods We enrolled 1176 consecutive patients with a primary diagnosis of AHF and with available non-invasive estimation of TR and pulmonary arterial systolic pressure (PASP). Results Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (i.e., PASP>40mmHg), right ventricular dysfunction (RVD) and mitral regurgitation (MR) was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (PASP, left ventricle ejection fraction – LVEF, RVD and MR; HR=1.623, p=0.004) and the association with outcome was maintained when clinical variables were added to the multivariable model (HR=1.515, p=0.035). The association between moderate-severe TR and outcome was consistent in patients with vs without PH, with vs without RVD, and with vs without LVEF Conclusions In patients hospitalized for AHF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. However, the combination of moderate-severe TR and PH conferred a further incremental mortality risk.

A 66yo man, without previous cardiological history, 3-month history of asthenia and left leg claudication, presence of tibial painless nodular lesions, was admitted at our emergency department in the clinical context of an acute aortic syndrome with chest and interscapular pain, fluctuating systemic BP (215/90 ←→ 90/60 mmHg) ​​and 60 mmHg pressure gradient between the arms. EKG documented diffuse negative T waves. Echocardiography revealed normal biventricular morphology and function and normal valve system. TC angiography documented a dilated aortic root (46mm), diffuse thickening of the aortic walls from the valvular plane (8mm), with involvement of the coronary and epiaortic arteries (50% stenosis of left subclavian artery), extended up to the aortic bifurcation to affect the common iliac arteries. Blood chemistry showed high C-reactive protein levels (29 mg/L; n.v.

A 71-year-old man, former smoker, without other cardiovascular risk factors nor previously known cardiological history, was admitted to our emergency department for nonproductive cough and right-sided chest pain, worsened by inspiration. ECG documented reduced peripheral QRS voltages. Echocardiography was performed, revealing the presence of an inhomogeneous, hyperechoic neoformation involving the lateral wall of the right ventricle (RV), dislocating the right coronary artery, protruding into the cavity towards the intraventricular septum and reaching the sub-valvular apparatus of the tricuspid valve, without any hemodynamic interference. Pericardial effusion was also documented (maximum 20 mm around the atrioventricular groove), without signs of cardiac tamponade. For better mass characterization, a computed tomography (CT) scan and a cardiac magnetic resonance (CMR) were performed, confirming the presence of a solid neoformation involving the RV and pericardial effusion, also showing right pleural effusion. Furthermore, right hilar and subcarinal lymphadenomegaly with compression of the bronchi was observed. A positron emission tomography (PET) scan showed areas of increased 18-fluorodeoxyglucose (18FDG) uptake in supra- and infra diaphragmatic lymph nodes, adrenal glands, bones, and lungs. Due to the clinical suspicion of a lymphoproliferative neoplasm, corticosteroid therapy was started. Before a diagnostic lymph node biopsy could be performed, the patient had a syncopal episode due to cardiac tamponade, requiring pericardiocentesis. During hospitalization, continuous heart monitoring revealed intermittent third-degree atrioventricular block, so a permanent pacemaker was implanted. Finally, an excisional lymph node biopsy was obtained, and a diagnosis of diffuse large B-cell lymphoma was established. Treatment with Prednisone, Cyclophosphamide, Vincristine, nonpegylated liposomal Doxorubicin, and Rituximab (R-COMP) was promptly started. Seven months later, after five cycles of chemotherapy, complete remission was documented by PET scan, and the cardiac mass was no longer evident at echocardiography. Metastatic involvement of the heart is a relatively frequent event in oncologic patients, with an estimated prevalence of 8% at autopsy. Lymphoproliferive neoplasms have a not negligible rate of heart mestastatization (9,4%). Neoplastic invasion secondary to lymphoma tends to infiltrate the myocardium, typically causing arrhythmias and conduction disturbances. Diagnostic evaluation relies upon echocardiography, CT and CMR. PET/TC is of paramount importance to assess the malignant nature of the mass, to stage the disease and to evaluate the response to chemotherapy. Metastatic cardiac involvement typically occurs as a late manifestation of disseminated lymphoma and the prognosis is usually poor; however, survival is increasing thanks to new chemo-immunotherapy strategies.

Case summary A 60-year-old man, normal-weighted, former smoker with a known non obstructive hypertrophic cardiomyopathy (HCM), severe mitral and tricuspid regurgitation and permanent atrial fibrillation was hospitalized for decompensated heart failure (recent worsening of exertional dyspnoea and appearance of lower limbs oedema). At the admission the ECG documented a permanent AF with normal average heart rate (66 rpm). Blood tests showed only a mildly elevation of BNP (497 pg/ml). Before the valvular repair surgery patient completed the diagnostic work-up with spirometry and cardiopulmonary exercise testing (CPET). The spirometry showed a mixed disorder predominantly obstructive (FEV1 1.8 L/min, 51% of predicted value), consistent with COPD. Also DLCO was moderately reduced. CPET documented a severe reduction in functional capacity (VO2 peak/Kg 9.2 ml/Kg/min, 32% of predicted value, Watt at peak 61), clear signs of cardiac and pulmonary vascular limitation (VO2 Work Slope 7.1, VE/VCO2 Slope 45). Interestingly, during the entire duration of the effort there were an exercise oscillatory ventilation (EOV). Instead, cardiopulmonary registration at rest showed an advanced oscillatory breathing disorder with regular long phases of apnea (average duration of 40 sec). Apnea phases were diurnal and were associated with desaturation at pulsossimetry (SpO2 93-92%). This rest breathing disorder consisted with the definition of Cheyne-Stokes respiration. Of note, the patient had no previous history of OSAS or central sleeping disorder. Discussion Cheyne-Stokes respiration (CSR) is historically considered as a central sleeping disorder, particularly common in patients with heart failure with reduced ejection fraction (HFrEF) with a wide prevalence range between 16% up to 50%. It is also well known its negative prognostic value as it highly impairs quality of life and increases cardiac mortality. Recently, in HFrEF patients emerged that CSR could be also diurnal and sometimes associated to EOV. The peculiarity of this clinical case lies firstly in the fact that we clearly documented a possible overlap through EOV and CSR, respectively seen as exerctional and rest advanced breathing disorders. Secondly, CSR was previously reported predominantly in case of LVEF < 40%, but this patient had a non obstructive HCM without systolic disfunction (LVEF was 63%). This suggest that CSR and EOV could have the same pathophysiology pathway, with a continuum through each other, regardless the model of HF (reduced vs preserved ejection fraction). Keywords: Cardiopulmonary Exercise Testing, Exercise Oscillatory Ventilation, Cheyne-Stokes Breathing, Heart Failure, Hypertrophic Cardiomyopathy.

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Prognostic stratification of cardiomyopathies represents a cornerstone for the appropriate management of patients and is focused mainly on arrhythmic events and heart failure. Cardiopulmonary exercise testing provides additional prognostic information, particularly in the setting of heart failure. Cardiopulmonary exercise testing data, integrated in scores such as the Metabolism Exercise Cardiac Kidney Index score have been shown to improve the risk stratification of these patients. Cardiopulmonary exercise testing has been analysed as a potential supplier of prognostic parameters in the context of hypertrophic cardiomyopathy, for which it has been shown that a reduced oxygen consumption peak, an increased ventilation/carbon dioxide production slope and chronotropic incompetence correlate with a worse prognosis. To a lesser extent, in dilated cardiomyopathy, it has been shown that the percentage of oxygen consumption peak, not the pure value, and the ventilation/carbon dioxide production slope are associated with a greater cardiovascular risk. Few data are available about other cardiomyopathies (arrhythmogenic and restrictive). Cardiomyopathy patients should be early and routinely referred to heart failure advanced centres in order to perform a comprehensive risk stratification which should include a cardiopulmonary exercise test, with variables and cut-offs shown to improve their risk stratification.