Diagnostic delay in arrhythmogenic cardiomyopathy.

AIMS: Diagnosis of arrhythmogenic cardiomyopathy (ACM) may be challenging, as it comprises diverse phenotypes (right dominant, biventricular, and left dominant), and each may overlap with other clinical entities. The issue of differential diagnosis with conditions mimicking ACM has been previously highlighted; however, a systematic analysis of ACM diagnostic delay, and of its clinical implications, is lacking. METHODS AND RESULTS: Data of all ACM patients from three Italian Cardiomyopathy Referral Centres were reviewed to assess the time from first medical contact to definitive ACM diagnosis; a significant diagnostic delay was defined as a time to ACM diagnosis ≥2 years. Baseline characteristics and clinical course of patients with and without diagnostic delay were compared. Of 174 ACM patients, 31% experienced diagnostic delay, with a median time to diagnosis of 8 years (20% in right-dominant ACM, 33% in left-dominant ACM, and 39% in biventricular). Patients with diagnostic delay, when compared with those without, more frequently exhibited an ACM phenotype with left ventricular (LV) involvement (74 vs. 57%, P = 0.04) and a specific genetic background (none had plakophilin-2 variants). The most common initial (mis)diagnoses were dilated cardiomyopathy (51%), myocarditis (21%), and idiopathic ventricular arrhythmia (9%). At follow-up, all-cause mortality was greater in those with diagnostic delay (P = 0.03). CONCLUSION: Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in specific clinical settings are of key importance for the timely identification of ACM.

Almost one-third of patients with arrhythmogenic cardiomyopathy (ACM) experience a diagnostic delay >2 years. These patients are mostly affected by an ACM phenotype with left ventricular (LV) involvement and present worse mortality compared with those without diagnostic delay.Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up.The most common initial (mis)diagnoses were dilated cardiomyopathy, myocarditis, and idiopathic ventricular arrhythmia. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in these specific clinical settings are of key importance to identify ACM in a timely fashion.

Echocardiographic Markers in the Diagnosis of Cardiac Masses.

BACKGROUND: The echocardiographic parameters required for a comprehensive assessment of cardiac masses (CMs) are still largely unknown. The aim of this study was to identify and integrate the echocardiographic features of CMs that can accurately predict malignancy. METHODS: An observational cohort study was conducted among 286 consecutive patients who underwent standard echocardiographic assessment for suspected CM at Bologna University Hospital between 2004 and 2022. A definitive diagnosis was achieved by histologic examination or, in the case of cardiac thrombi, with radiologic evidence of thrombus resolution after appropriate anticoagulant treatment. Logistic and multivariable regression analysis was performed to confirm the ability of six echocardiographic parameters to discriminate malignant from benign masses. The unweighted count of these parameters was used as a numeric score, ranging from 0 to 6, with a cutoff of ≥3 balancing sensitivity and specificity with respect to the histologic diagnosis of malignancy. Classification tree analysis was used to determine the ability of echocardiographic parameters to discriminate subgroups of patients with differential risk for malignancy. RESULTS: Benign masses were more frequently pedunculated, mobile, and adherent to the interatrial septum (P < .001). Malignant masses showed a greater diameter and exhibited a higher frequency of irregular margins, an inhomogeneous appearance, sessile implantation, polylobate shape, and pericardial effusion (P < .001). Infiltration, moderate to severe pericardial effusion, nonleft localization, sessile implantation, polylobate shape, and inhomogeneity were confirmed to be independent predictors of malignancy in both univariate and multivariable models. The predictive ability of the unweighted score of ≥3 was very high (>0.90) and similar to that of the previously published weighted score. Classification tree analysis generated an algorithm in which infiltration was the best discriminator of malignancy, followed by nonleft localization and sessile implantation. The percentage correctly classified by classification tree analysis as malignant was 87.5%. Agreement between observer readings and CM histology ranged between 85.1% and 91.5%. The presence of at least three echocardiographic parameters was associated with lower survival. CONCLUSIONS: In the approach to CMs, some echocardiographic parameters can serve as markers to accurately predict malignancy, thereby informing the need for second-level investigations and minimizing the diagnostic delay in such a complex clinical scenario.

Sudden cardiac death related to left coronary artery anomalies including hypoplasia and anomalous origin with retro-aortic course.

Congenital anomalies of the coronary arteries are a rare condition with an incidence of 0.3-1.3% in the general population. Clinically, sometimes these anomalies increase the risk of myocardial ischemia, which can present with a wide spectrum of symptoms, from angina to sudden cardiac death (SCD). This case report is about the SCD of an 8-year-old male, in apparent good health, during a football training. Although basic life support maneuvers were performed timely from bystanders and medical staff, the automated external defibrillator (AED) was not used. Autopsy revealed multiple left coronary artery (LCA) anomalies: origin from a separate ostium in the right sinus of Valsalva, slit-like shape of the ostium, acute angle take-off of the LCA from the aorta, retro-aortic course and focal coronary hypoplasia of some branches of the LCA. Microscopic examination revealed diffuse ischemic consequences at a different stage of tissue repair and mild multifocal lymphocytic infiltration. No other significant elements were detected at post-mortem examination. We discuss the forensic evaluation about the cause and the manner of death, considering also the modality of the resuscitation attempts and the claimed malpractice, as often occurs in case of sudden unexpected death in young athletes.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Clinical presentations leading to arrhythmogenic left ventricular cardiomyopathy.

OBJECTIVES: To describe a cohort of patients with arrhythmogenic left ventricular cardiomyopathy (ALVC), focusing on the spectrum of the clinical presentations. METHODS: Patients were retrospectively evaluated between January 2012 and June 2020. Diagnosis was based on (1) ≥3 contiguous segments with subepicardial/midwall late gadolinium enhancement in the left ventricle (LV) at cardiac magnetic resonance plus a likely pathogenic/pathogenic arrhythmogenic cardiomyopathy (AC) associated genetic mutation and/or familial history of AC and/or red flags for ALVC (ie, negative T waves in V4-6/aVL, low voltages in limb leads, right bundle branch block like ventricular tachycardia) or (2) pathology examination of explanted hearts or autoptic cases suffering sudden cardiac death (SCD). Significant right ventricular involvement was an exclusion criterion. RESULTS: Fifty-two patients (63% males, age 45 years (31-53)) composed the study cohort. Twenty-one (41%) had normal echocardiogram, 13 (25%) a hypokinetic non-dilated cardiomyopathy (HNDC) and 17 (33%) a dilated cardiomyopathy (DCM). Of 47 tested patients, 29 (62%) were carriers of a pathogenic/likely pathogenic DNA variant. Clinical contexts leading to diagnosis were SCD in 3 (6%), ventricular arrhythmias in 15 (29%), chest pain in 8 (15%), heart failure in 6 (12%) and familial screening in 20 (38%). Thirty patients (57%) had previously received a diagnosis other than ALVC with a diagnostic delay of 6 years (IQR 1-7). CONCLUSIONS: ALVC is hidden in different clinical scenarios with a phenotypic spectrum ranging from normal LV to HNDC and DCM. Ventricular arrhythmias, chest pain, heart failure and SCD are the main clinical presentations, being familial screening essential for the affected relatives' identification.

[Sudden cardiac death in young people and in adults: primary and contributing causes. The experience of the multidisciplinary network in Emilia-Romagna]. / La morte improvvisa giovanile e in età adulta: cause e concause. L'esperienza della rete multidisciplinare in Emilia-Romagna.

BACKGROUND: The multidisciplinary network of Emilia-Romagna for the study of juvenile sudden cardiac death (SCD) was started in Bologna in June 2018 in order to: (1) define the spectrum of etiologies and mechanisms of SCD in young people; (ii) standardize diagnostic terminology and categories; (iii) identify potentially hereditary genetic heart diseases and define the contribution of post-mortem genetic analysis (so-called molecular autopsy) to the overall diagnostic process; (iv) identify preclinical forms of the pathologies in the first-degree relatives of the deceased subject using both phenotypic and genotypic evaluation and, where possible, undertake therapeutic/prophylactic measures (primary prevention). METHODS: In the first 2 years of activity (01/06/2018-27/08/2020) 50 cases of SCD came to the attention of the Cardiovascular Pathology Unit of the S. Orsola-Malpighi Polyclinic in Bologna, from Centres of Forensic Medicine and Pathological Anatomy in most of the region. RESULTS: Sixty-two percent of cases were sent by forensic pathologists, 36% by clinical pathologists and 2% by the family of the deceased. Medico-legal cases were prompted by autopsies requested by the Judicial Authority in 70% of cases; 55.5% of patients referred by pathologists came from the Cardiovascular Tissue Bank, as part of the regional program for the quality and safety control of organs and tissues from multiorgan-multitissue donors. The average age of the subjects was 35 ± 13.6 years (70% male, range: 1-55 years; median: 38 years). The spectrum of the final diagnoses includes: structurally normal hearts 14%, cardiomyopathies 40%, coronary heart disease 23%, Brugada syndrome 6%, aortic dissection 4%, substance abuse 6%, valvular heart disease 2%, mixed causes 2%. CONCLUSIONS: The network is necessarily centered on post-mortem pathological activities, but it does not end with these. If in 60% of cases the pathological autopsy examination was decisive in identifying the cause of death, in the other cases a detailed final diagnosis was reached only with more complex pathways involving molecular genetics, clinical genetics, and toxicology.

Standard ECG for differential diagnosis between Anderson-Fabry disease and hypertrophic cardiomyopathy.

OBJECTIVES: To evaluate the role of the ECG in the differential diagnosis between Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM). METHODS: In this multicentre retrospective study, 111 AFD patients with left ventricular hypertrophy were compared with 111 patients with HCM, matched for sex, age and maximal wall thickness by propensity score. Independent ECG predictors of AFD were identified by multivariate analysis, and a multiparametric ECG score-based algorithm for differential diagnosis was developed. RESULTS: Short PR interval, prolonged QRS duration, right bundle branch block (RBBB), R in augmented vector left (aVL) ≥1.1 mV and inferior ST depression independently predicted AFD diagnosis. A point-by-point ECG score was then derived with the following diagnostic performances: c-statistic 0.80 (95% CI 0.74 to 0.86) for discrimination, the Hosmel-Lemeshow χ2 6.14 (p=0.189) for calibration, sensitivity 69%, specificity 84%, positive predictive value 82% and negative predictive value 72%. After bootstrap resampling, the mean optimism was 0.025, and the internal validated c-statistic for the score was 0.78. CONCLUSIONS: Standard ECG can help to differentiate AFD from HCM while investigating unexplained left ventricular hypertrophy. Short PR interval, prolonged QRS duration, RBBB, R in aVL ≥1.1 mV and inferior ST depression independently predicted AFD. Their systematic evaluation and the integration in a multiparametric ECG score can support AFD diagnosis.

A Pathogenic Galactosidase A Mutation Coexisting With an MYBPC3 Mutation in a Female Patient With Hypertrophic Cardiomyopathy.

The coexistence of GLA (Pro259Ser, c.775C>T) and MYBPC3 (c.1351+2T>C) mutations was found in a female patient with hypertrophic cardiomyopathy. Histology documented abundant vacuolisation with osmiophilic lamellar bodies and positive Gb3 immunohistochemistry. In the presence of a hypertrophic cardiomyopathy phenotype, the systematic search for unusual findings is mandatory to rule out a phenocopy.

Postmortem diagnosis of left dominant arrhythmogenic cardiomyopathy: the importance of a multidisciplinary network for sudden death victims. "HIC mors gaudet succurere vitae".

An apparently healthy man died suddenly at the age of 49 during physical activity. The heart was referred to our Cardiovascular Pathology Unit for valve tissue banking. Pathology findings led to the diagnosis of arrhythmogenic left ventricular cardiomyopathy. Molecular autopsy was performed and two variants of interest were identified in genes associated with arrhythmogenic cardiomyopathy. The 19-year-old son underwent a cardiac screening comprehensive of electrocardiogram (ECG), echocardiogram, cardiac magnetic resonance and genetic testing, and the diagnosis of arrhythmogenic left ventricular cardiomyopathy was achieved. This case report highlights the need of a systematic evaluation of all sudden death victims with autopsy performed by expert cardiovascular pathologists and implemented by molecular analysis, aiming to identify also rare hereditary diseases and activate proper family screening.

Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset.

OBJECTIVE: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation. METHODS: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated. RESULTS: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p <  0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively). CONCLUSIONS: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy.

Practical implementation of the Endocarditis Team in 'functional' reference centres: the Italian hospital network experience and recommendations of the Italian Society of Echocardiography and Cardiovascular Imaging.

: The 2015 European Society of Cardiology (ESC) guidelines for the management of infective endocarditis recommend the use of a multidisciplinary team in the care of patients with infective endocarditis. A standardized collaborative approach should be implemented in centres with immediate access to different imaging techniques, cardiac surgery and health professionals from several specialties. This position paper has been produced by the Task Force for Management of Infective Endocarditis of Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI) with the aim of providing recommendations for the implementation of the Endocarditis Team within the Italian hospital network. On the basis of the Italian hospital network with many cardiology facilities encompassing a total of 405 intensive cardiac care units (ICCUs) across the country, 224 (3.68 per million inhabitants) of which have on-site 24-h PCI capability, but with relatively few centres equipped with cardiac surgery and nuclear medicine, in the present article, the SIECVI Task Force for Management of Infective Endocarditis develops the idea of a network where 'functional' reference centres act as a link with the periphery and with 'structural' reference centres. A number of minimum characteristics are provided for these 'functional' reference centres. Outcome and cost analysis of implementing an Endocarditis Team with functional referral is expected to be derived from ongoing Italian and European registries.

Contribution of PET imaging to mortality risk stratification in candidates to lead extraction for pacemaker or defibrillator infection: a prospective single center study.

PURPOSE: 18F-FDG PET/CT is an emerging technique for diagnosis of cardiac implantable electronic devices infection (CIEDI). Despite the improvements in transvenous lead extraction (TLE), long-term survival in patients with CIEDI is poor. The aim of the present study was to evaluate whether the extension of CIEDI at 18F-FDG PET/CT can improve prediction of survival after TLE. METHODS: Prospective, monocentric observational study enrolling consecutive candidates to TLE for a diagnosis of CIEDI. 18F-FDG PET/CT was performed in all patients prior TLE. RESULTS: There were 105 consecutive patients with confirmed CIEDI enrolled. An increased 18F-FDG uptake was limited to cardiac implantable electrical device (CIED) pocket in 56 patients, 40 patients had a systemic involvement. We had nine negative PET in patients undergoing prolonged antimicrobial therapy (22.5 ± 14.0 days vs. 8.6 ± 13.0 days; p = 0.005). Implementation of 18F-FDG PET/CT in modified Duke Criteria lead to reclassification of 23.8% of the patients. After a mean follow-up of 25.0 ± 9.0 months, 31 patients died (29.5%). Patients with CIED pocket involvement at 18F-FDG PET/CT presented a better survival independently of presence/absence of systemic involvement (HR 0.493, 95%CI 0.240-0.984; p = 0.048). After integration of 18F-FDG PET/CT data, absence of overt/hidden pocket involvement in CIEDI and a (glomerular filtration rate) GFR < 60 ml/min were the only independent predictors of mortality at long term. CONCLUSIONS: Patient with CIEDI and a Cold Closed Pocket (i.e., a CIED pocket without skin erosion/perforation nor increased capitation at 18F-FDG PET/CT) present worse long-term survival. Patient management can benefit by systematic adoption of pre-TLE 18F-FDG PET/CT through improved identification of CIED related endocarditis (CIEDIE) and hidden involvement of CIED pocket.

Predictors of nonsimultaneous interventricular delay at cardiac resynchronization therapy optimization.

AIM: Cardiac resynchronization is a well tolerated and effective therapy for heart failure, but 30% of patients still do not respond to biventricular pacing. Optimization of device settings, in particular interventricular delay value, represents a plausible target for improving these results, but available literature is discordant. We aimed our study at the identification of the best suitable candidates to interventricular delay optimization. METHODS: A total of 77 consecutive patients with optimized drugs therapy underwent clinical, echocardiographic and electrocardiographic evaluation before and after 6 months from implantation of a biventricular defibrillator in accordance to current guidelines. In each patient, atrioventricular and interventricular delay values were optimized at predischarge with echocardiogram. RESULTS: The only predictor of an optimized interventricular delay value different from simultaneous (i.e. standard shipment setting), at both univariate and multivariate analyses, was a QRS duration greater than 160 ms (odds ratio 22.958; P = 0.003) with a sensitivity of 70.9%. CONCLUSION: Candidates to cardiac resynchronization therapy with a basal QRS greater than 160 ms have a higher chance of requiring echo-guided tailoring of interventricular delay value. A strategy based on these data can potentially improve device programming, reducing by one-third the need for optimization, according to our findings, and at the same time avoid unnecessary time-consuming procedures.

Troponin T elevation in acute aortic syndromes: Frequency and impact on diagnostic delay and misdiagnosis.

AIMS: Despite troponin assay being a part of the diagnostic work up in many conditions with acute chest pain, little is known about its frequency and clinical implications in acute aortic syndromes (AASs). In our study we assessed frequency, impact on diagnostic delay, inappropriate treatments, and prognosis of troponin elevation in AAS. METHODS AND RESULTS: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Cardiac troponin test, using either standard or high sensitivity assay, was performed according to standard protocol used in chest pain units. Troponin T values were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or high sensitivity assay respectively, p = 0.001). Troponin positivity was frequently associated with acute coronary syndromes (ACS)-like electrocardiogram findings, and with a twofold increased risk of long in-hospital diagnostic time (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.05-3.52, p = 0.03). The combination of positive troponin and ACS-like electrocardiogram abnormalities resulted in a significantly increased risk of in-hospital delay/coronary angiography/antithrombotic therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). However, troponin positivity was not associated with in-hospital mortality (OR 1.63, 95% CI 0.86-3.10, p = 0.131). CONCLUSIONS: Troponin positivity was a frequent finding in AAS patients, particularly when a high sensitivity assay was employed. Abnormal troponin values were strongly associated with ACS-like electrocardiogram findings and with in-hospital diagnostic delay but apparently they did not influence in-hospital mortality.

Role of ¹8F-FDG PET/CT in the diagnosis of infective endocarditis in patients with an implanted cardiac device: a prospective study.

PURPOSE: Infective endocarditis (IE) is widely underdiagnosed or diagnosed after a major delay. The diagnosis is currently based on the modified DUKE criteria, where the only validated imaging technique is echocardiography, and remains challenging especially in patients with an implantable cardiac device. The aim of this study was to assess the incremental diagnostic role of (18)F-FDG PET/CT in patients with an implanted cardiac device and suspected IE. METHODS: We prospectively analysed 27 consecutive patients with an implantable device evaluated for suspected device-related IE between January 2011 and June 2013. The diagnostic probability of IE was defined at presentation according to the modified DUKE criteria. PET/CT was performed as soon as possible following the clinical suspicion of IE. Patients then underwent medical or surgical treatment based on the overall clinical evaluation. During follow-up, we considered: lead cultures in patients who underwent extraction, direct inspection and lead cultures in those who underwent surgery, and a clinical/instrumental reevaluation after at least 6 months in patients who received antimicrobial treatment or had an alternative diagnosis and were not treated for IE. After the follow-up period, the diagnosis was systematically reviewed by the multidisciplinary team using the modified DUKE criteria and considering the new findings. RESULTS: Among the ten patients with a positive PET/CT scan, seven received a final diagnosis of "definite IE", one of "possible IE" and two of "IE rejected". Among the 17 patients with a negative PET/CT scan, four were false-negative and received a final diagnosis of definite IE. These patients underwent PET/CT after having started antibiotic therapy (≥48 h) or had a technically suboptimal examination. CONCLUSION: In patients with a cardiac device, PET/CT increases the diagnostic accuracy of the modified Duke criteria for IE, particularly in the subset of patients with possible IE in whom it may help the clinician manage a challenging situation.