Background: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton’s kinase (BTK) inhibitor. In this review we aimed to summarize and critically evaluate the association between first and second generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA). Summary: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient’s predisposing risk factors and concomitant cardiac morbidities. More recently both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents. Key Messages: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK-inhibitors.

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Pharmacological therapy (atenolol 50 mg daily, disopyramide 250 mg twice daily), dual-chamber pacemaker implantation.

Introduction Anderson-Fabry disease (FD) is a rare X-linked hereditary disease caused by mutations in the alpha-galactosidase A (GLA) gene, a lysosomal hydrolase that catabolizes lipids. GLA deficency leads to a progressive accumulation of undegraded glycosphingolipids, mainly Globotriaosylceramide (GB3), within lysosomes of cells (epithelial and endothelial cells, neurons, cardiomyocytes and renal cells), leading to cellular dysfunction. The incidence of FD is 1:117.000 but in patients with end stage renal disease (ESRD), incidence is higher, ranging from 0.04% up to 1.16% in male dialysis patients. Classical form of the disease shows renal, cardiac and cerebrovascular involvements usually. Cardiac involvement includes hypertrophic cardiomyopathy, arrhythmias such as complete heart block, valve dysfunction and myocardial infarction. Renal manifestations include proteinuria, progressive loss of renal function with chronic kidney disease (CKD) that leads to ESRD. The diagnosis of FD can be very difficult and often is delayed due to subtle clinical manifestations, but an early diagnosis is crucial to start enzyme replacement therapy (ERT), based on recombinant human GLA, as soon as possible. Clinical Case we describe the case of a 36-years-old male admitted to the Emergency Room of our hospital due to asthenia, nausea, dysphagia, anuria and loss of weight. At physical examination, apical systolic murmur and a bilateral ankle edema. Blood pressure was 195/100 mmHg, heart rate 125 beats per minute, peripheral oxygen saturation 100%. Blood test showed Hemoglobin 8 g/dL, Blood Urea 422 mg/dL, Creatinine 20 mg/dL, Na+ 135 mEq/L, K+ 4 mEq/L, Phosphorus 9 mg/dL. Arterial blood gas analysis showed metabolic and lactic acidosis. The diagnosis of acute kidney injury (AKI) was made, and a dialytic treatment was scheduled. During dialytic session, the patient had a syncope. EKG showed a complete left bundle branch block (LBBB) with advanced atrio-ventricular block (2:1, complete). An echocardiogram highlighted a severe myocardial hypertrophy (septal wall 25 mm) involving also the right ventricle with “ground glass” aspect of the posterolateral, posterior and inferior septum, with minimal pericardial effusion. Heart MRI scan confirmed LV myocardial hypertrophy with circumferential aspect (interventricular septum 26.6 mm), mild decrease in left ventricular ejection fraction (47%) and myocardial hypointensity area in the FSE sequences. Renal ultrasound showed bilateral cortical hyperecogenity, small cortico-medullary border, initial reduction of kidney volume and diffuse perirenal edema. In consideration of the high probability of a storage disease, we performed genetic testing for FD and Gaucher disease, peri-umbilical fat biopsy for Amyloid Disease and a renal biopsy. The genetic test resulted positive for typical mutation of FD and renal biopsy documented ESRD secondary to glycosphingolipid storage disease ceramid type from FD. Conclusion Differential diagnosis of AKI in a young male should include FD, as suggested by the clinical case reported, and nephrologist should screen young patients for α-GLA enzyme deficiency (diagnostic for FD) possibly coupled with renal biopsy in uncertain cases.

Introduction: in medical literature, studies on cardiac metastases are few and discordant and their actual incidence is underestimated. Autoptic examination shows evidence of cardiac metastases in about 9% of all the patients affected by malignant tumor. Each malignant tumor can metastasize to the heart (incidence varying from 2.3% to 18.3%); nevertheless, formation of cardiac metastases is more frequently associated with primitive neoplasms such as pleural mesothelioma (48.4%), melanoma (27.8%), adenocarcinoma as well as lung and kidney carcinomas. Clinical case: patient aged 66, former smoker, no further cardiovascular disease risk factors, no occurrences of heart disease in his past medical history. In 2008 surgical excision of melanoma skin cancer, negative sentinel lymph node. In 2014 cancer relapse, final cycle of chemotherapy treatment completed in July. In October 2014 evidence of liver and adrenal gland metastases. In November 2014 evidence of bone metastases. As the CT scan showed evidence of pleural and pericardial effusion, the patient was requested to undergo cardiac examination and an echocardiogram test in preparation for further chemotherapy treatment. During the medical examination the patient presented with symptoms of marked asthenia, dyspnea under moderate effort (NYHA II), palpitations. BP: 100/60 mmHg. ECG: low voltages, sinus tachycardia, incomplete RBBB, inverted T waves in V1 – V4, III. Home Therapy: Furosemide 25 mg, Cortisone 25 mg, Tramadolo Cloridrato 50 mg, Albumina. The findings of the echocardiogram test showed: enlarged and hyperkinetic left ventricle, abundant circumferential pericardial effusion measuring up to 2,3 cm. Evidence of hyperechogenic areas in the epicardium, myocardium and at the level of mitral valve flaps (figure 1 and 2). In December 2014 hospital admission due to worsening of clinical symptoms, onset of ascites, hyperpotassemia, anemization (Hb 8.6g/dL). During the 72 hours following hospitalisation: STEMI, acute kidney failure, respiratory failure, metabolic acidosis, death. The autoptic examination showed evidence of undifferentiated large cell neoplasm with formation of metastases in the myocardium, mitral valve apparatus and coronary tree. Conclusions echocardiography should always be included in the clinical examinations which patients affected by neoplasm are required to undergo. Serial evaluations allow to identify the occurrence of pericardial effusion and/or heart involvement even in the absence of clinical suspicion. Identifying such anomalies may have important therapeutic implications.

Introduction Primary adipose cardiac tumors are divided into two different entities: lipomatous hypertrophy of the interatrial septum (LHIS) and lipomas. Lipomas are usually benign masses of unknown pathogenesis. Currently few cases are reported in literature, with no differences in gender distribution. Clinical Case A 63–year–old patient presented to our emergency room complaining chest pain and dyspnea on exercise. Her medical history shows severe obesity, hypertention, past surgical removal of several systemic lipomas (uterus lipoma, right ovary lipoma, right thigh and leg lipoma, right forearm and wrist lipoma). A coronary angiography was performed showing the lack of angiographically significant lesions. On suspicion of microvascular angina, she began therapy with Ranolazine and Beta–blockers. Echocardiographic examination showed a lipomatous interatrial septum in the postero–superior tract with a maximum of 22.5mm thickness (image 1). At 12 months, chest CT and MRI scan showed a hyperintense mass on interatrial septum measuring 32x34mm. The formation, mainly protruding in the right atrium, does not obstruct the outlet of the hollow veins, nor the outlet of the pulmonary veins. No hemodynamic compromise and compression were detected. Last follow–up visit our patient presented dyspnea and chest pain, the echocardiogram showed a slight increase of the mass size (see image), with unchanged thicknesses and biventricular pump function. Conclusions In literature there is no evidence of malignant transformation of cardiac lipomas, however well–differentiated cell tumors can coexist with liposarcomas. There are no guidelines for the treatment of cardiac lipomas, radical resection is practiced in the majority of symptomatic patients and should be considered in all patients with cardiac lipoma. Asymptomatic lipomas can excessively grow up and infiltrate into the myocardium, resulting in negative outcomes to a possible subsequent resection. According to the worsening of the clinical course, the patient under consideration was referred for lipoma resection surgery.

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Introduction: Left Ventricular Non Compaction (LVNC) is an unclassified cardiomyopathy characterized by left ventricular hypertrabeculation and deep intertrabecular recesses in communication with the ventricular cavity. LVNC is often associated with other cardiomyopathies or with genetical disorders, and is familial at least in 25% of cases. The diagnosis is based on echocardiographic criteria (Chin et al. 1990; Jenni et al.2001; Stollberger et al. 1987-2002). Hypothesis: The aim of this study was to assess the value of echocardiographic parameters in predicting the occurrence of arrhythmic events in patients with familial LVNC. Methods: we studied 26 subjects, aged 39.9 ± 16.2 years, 11 males and 15 females, at a single institution, representing 7 families with LVNC. None had concomitant hypertension, diabetes mellitus or other significant cardiovascular disorder. Patients were evaluated at 3-month interval either clinically or with 12-Lead ECG, echocardiography and 24-hour Holter monitoring. The average duration of follow up was 36 ± 9 months. Echocardiographic parameters, ejection fraction (EF) and end-diastolic diameter (EDD), were matched with ventricular arrhythmias (VA) to assess their predictive value. The Kaplan-Meier method was used to calculate the probability of ventricular events. Results: Left Ventricular (LV) systolic function was depressed in 10 of 26 patients (38.5%), with a mean EF of 44 ± 3.2% at the first visit. Nine of 26 patients (34.6%) had LV dilatation (EDD ≥ 60 mm): among them only 5 patients (55.5%) had EF < 45%. Six of 26 patients (23.1%) underwent episodes of ventricular tachycardia (VT) during follow up. All 6 patients (100%) had LV dilatation, among them only 3 patients (50%) had depressed EF. By Chi square test and Kaplan Meier analysis, the only echocardiographic predictor of VA was LV dilatation (p < 0.001). Conclusions: In families with isolated LVNC, LV dilatation was the only echocardiographic predictor associated with subsequent development of ventricular arrhythmias. This finding might be helpful to optimally target preventive therapies in patients with familial LVNC.