Causes of sudden cardiac arrest and death and the diagnostic yield of sport preparticipation screening in children.

OBJECTIVE: Evidence on the increased risk of sports-related sudden cardiac arrest and death (SCA/D) and the potential benefit of cardiovascular preparticipation screening (PPS) in children is limited. We assessed the burden and circumstances of SCA/D and the diagnostic yield of cardiovascular PPS in children aged 8-15 years. METHODS: Data on the incidence and causes of SCA/D from 2011 to 2020 were obtained from the Veneto region (Italy) sudden death registry, hospital records and local press. During the same period, we assessed the results of annual PPS in 25 251 young competitive athletes aged 8-15 years who underwent 58 185 evaluations (mean 2.3/athlete) in Padua, Italy. RESULTS: Over 10 years, 26 SCA/D occurred in children aged 8-15 years in the Veneto region: 6 in athletes (incidence 0.7/100 000/year, all ≥12 years) versus 20 in non-athletes (0.7/100 000/year, 17/20 ≥12 years). In total, 4/6 athletes versus 1/20 non-athletes survived. The cause of SCA/D remained unexplained in four athletes and in nine non-athletes. No athlete suffered SCA/D from structural diseases potentially identifiable by PPS. The incidence of SCA/D in athletes and non-athletes was 0.2/100 000/year in the 8-11 years group versus 1.3/100 000/year in the 12-15 years group. PPS identified 26 new diagnoses of cardiovascular diseases (CVDs) at risk of SCA/D, more often in children ≥12 years old (0.06%/evaluation) than <12 years old (0.02%/evaluation, p=0.02). Among athletes with a negative PPS, two suffered unexplained SCA/D during follow-up, one during exercise. CONCLUSIONS: In children aged 8-15 years, the incidence of SCA/D and the yield of PPS for identifying at-risk CVD were both substantially higher in those ≥12 years, suggesting that systematic PPS may be more useful beyond this age.

A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Literature-Derived Data.

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

Propofol dose and efficacy of defibrillation testing during implantation of subcutaneous implantable cardioverter-defibrillators: A retrospective, single center cohort study.

INTRODUCTION: Defibrillation testing (DFT) is recommended during subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. Previous studies analyzing the potential interference of propofol with defibrillation threshold are inconsistent. The purpose of this study was to analyze whether propofol affects DFT post S-ICD placement. METHODS: All patients with S-ICD implantation between 01/2017 and 11/2020 at the University Heart Center Freiburg were retrospectively analyzed. Two groups were generated depending on the success of the first shock during DFT. Implantation characteristics and dose of anesthetics were analyzed. RESULTS: In 12 of the included 80 (15%) patients, first shock during DFT failed. The absolute dose of propofol was significantly higher in patients with first shock failure (median 653 mg [IQR 503-855]) compared to patients with first shock termination (376 mg [200-600]; p = 0.027). Doses of opioids and midazolam as well as type of anesthesia did not differ between the groups. A multivariable binary logistic regression analysis confirmed an independent association of first shock termination and propofol dose (per 100 mg: OR 0.73 (95% CI: 0.56-0.95); p = 0.021). CONCLUSION: There is an independent association of propofol dose and first shock failure in routine S-ICD defibrillation testing.

Clinical application of CMR in cardiomyopathies: evolving concepts and techniques : A position paper of myocardial and pericardial diseases and cardiac magnetic resonance working groups of Italian society of cardiology.

Cardiac magnetic resonance (CMR) has become an essential tool for the evaluation of patients affected or at risk of developing cardiomyopathies (CMPs). In fact, CMR not only provides precise data on cardiac volumes, wall thickness, mass and systolic function but it also a non-invasive characterization of myocardial tissue, thus helping the early diagnosis and the precise phenotyping of the different CMPs, which is essential for early and individualized treatment of patients. Furthermore, several CMR characteristics, such as the presence of extensive LGE or abnormal mapping values, are emerging as prognostic markers, therefore helping to define patients' risk. Lastly new experimental CMR techniques are under investigation and might contribute to widen our knowledge in the field of CMPs. In this perspective, CMR appears an essential tool to be systematically applied in the diagnostic and prognostic work-up of CMPs in clinical practice. This review provides a deep overview of clinical applicability of standard and emerging CMR techniques in the management of CMPs.

Cardiac magnetic resonance imaging of arrhythmogenic cardiomyopathy: evolving diagnostic perspectives.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined heart muscle disease characterized by fibro-fatty myocardial replacement, clinically associated with malignant ventricular arrhythmias and sudden cardiac death. Originally described a disease with a prevalent right ventricular (RV) involvement, subsequently two other phenotypes have been recognized, such as the left dominant and the biventricular phenotypes, for which a recent International Expert consensus document provided upgrade diagnostic criteria (the 2020 "Padua Criteria"). In this novel workup for the diagnosis of the entire spectrum of phenotypic variants of ACM, including left ventricular (LV) variants, cardiac magnetic resonance (CMR) has emerged as the cardiac imaging technique of choice, due to its capability of detailed morpho-functional and tissue characterization evaluation of both RV and LV. In this review, the key role of CMR in the diagnosis of ACM is outlined, including the supplemental value for the characterization of the disease variants. An ACM-specific CMR study protocol, as well as strengths and weaknesses of each imaging technique, is also provided. KEY POINTS: • Arrhythmogenic cardiomyopathy includes three different phenotypes: dominant right, biventricular, and dominant left. • In 2020, diagnostic criteria have been updated and cardiac magnetic resonance has emerged as the cardiac imaging technique of choice. • This aim of this review is to provide an update of the current state of art regarding the use of CMR in ACM, with a particular focus on novel diagnostic criteria, CMR protocols, and prognostic significance of CMR findings in ACM.

Ophthalmological involvement in wild-type transthyretin amyloidosis: A multimodal imaging study.

BACKGROUND AND AIMS: Ophthalmological abnormalities have been reported in hereditary transthyretin-related amyloidosis (ATTRv, v for variant) but not in wild-type transthyretin-related amyloidosis (ATTRwt). METHODS: Patients with ATTRwt, ATTRv, and light chain amyloidosis (AL) and healthy subjects (controls) underwent complete eye examination, including optical coherence tomography (OCT), OCT angiography (OCTA), and in vivo corneal confocal microscopy (CCM). RESULTS: Seventeen ATTRwt, nine ATTRv, two ATTRv carriers, and seven AL patients were enrolled. Compared with other groups, ATTRwt patients had 10 letters lower visual acuity and a higher prevalence of glaucoma, cataract, and retinal pigment epithelium alterations. In the whole group of patients, especially in ATTRwt, we observed (1) a reduced corneal nerve fiber length and more tortuous stromal nerves at CCM, (2) a reduced macular volume and peripapillary nerve fiber layer thickness at OCT, and (3) impairment of peripapillary and macular vascularization at OCTA. INTERPRETATION: Ophthalmological abnormalities are common in ATTRwt, significantly impairing visual acuity. Noninvasive imaging modalities allow for the identification of small nerve fibers and small vessel damage, which may represent further warning signs for early diagnosis of ATTRwt.

Peripheral nerve involvement in wild-type transthyretin amyloidosis.

INTRODUCTION AND AIMRPOSE: Neurological involvement other than carpal tunnel syndrome (CTS) has rarely been observed in wild-type transthyretin amyloidosis (ATTRwt). The aim of our study was to investigate peripheral nerve involvement in ATTRwt. METHODS: Patients diagnosed with ATTRwt (negative molecular testing, confirmed cardiac uptake at bone scintigraphy, Perugini score 2 or 3) were considered. Sixteen men (mean age 75 ± 6.2, range 65-86 years) were enrolled. Neurological examination (Neuropathy Impairment Score, NIS), questionnaires on autonomic function and quality of life (QoL), electrodiagnostic studies (EDX), nerve ultrasound, and Sudoscan (electrochemical skin conductance, ESC) were performed. The presence of peripheral neuropathy was defined according to the detection of any abnormal finding at lower limbs other than CTS at EDX studies, regardless of NIS scores. RESULTS: Ten (62.5%) ATTRwt had abnormal NIS scores. At EDX, CTS was observed in 13/16 (81.2%), with 3/16 (18.8%) presenting also axonal peripheral neuropathy. Extensive workup ruled out common causes of neuropathy. Eight (50%) ATTRwt patients had orthostatic hypotension (OH). Abnormal ESC was observed in 9/14 (64%) ATTRwt patients. DISCUSSION: Despite being uncommon, we observed peripheral nervous system involvement in ATTRwt (large and small fiber dysfunction). Being elderly, ATTRwt patients may have age-related conditions acting as confounding factors for the diagnosis of neuropathy that however can be detected with a careful examination and use of specific tests, including those for autonomic dysfunction.

Scarring/arrhythmogenic cardiomyopathy.

The designation of 'arrhythmogenic cardiomyopathy' reflects the evolving concept of a heart muscle disease affecting not only the right ventricle (ARVC) but also the left ventricle (LV), with phenotypic variants characterized by a biventricular (BIV) or predominant LV involvement (ALVC). Herein, we use the term 'scarring/arrhythmogenic cardiomyopathy (S/ACM)' to emphasize that the disease phenotype is distinctively characterized by loss of ventricular myocardium due to myocyte death with subsequent fibrous or fibro-fatty scar tissue replacement. The myocardial scarring predisposes to potentially lethal ventricular arrhythmias and underlies the impairment of systolic ventricular function. S/ACM is an 'umbrella term' which includes a variety of conditions, either genetic or acquired (mostly post-inflammatory), sharing the typical 'scarring' phenotypic features of the disease. Differential diagnoses include 'non-scarring' heart diseases leading to either RV dilatation from left-to-right shunt or LV dilatation/dysfunction from a dilated cardiomyopathy. The development of 2020 upgraded criteria ('Padua criteria') for diagnosis of S/ACM reflected the evolving clinical experience with the expanding spectrum of S/ACM phenotypes and the advances in cardiac magnetic resonance (CMR) imaging. The Padua criteria aimed to improve the diagnosis of S/ACM by incorporation of CMR myocardial tissue characterization findings. Risk stratification of S/ACM patients is mostly based on arrhythmic burden and ventricular dysfunction severity, although other ECG or imaging parameters may have a role. Medical therapy is crucial for treatment of ventricular arrhythmias and heart failure. Implantable cardioverter defibrillator (ICD) is the only proven life-saving treatment, despite its significant morbidity because of device-related complications and inappropriate shocks. Selection of patients who can benefit the most from ICD therapy is one of the most challenging issues in clinical practice.

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.

Cardio-respiratory motion-corrected 3D cardiac water-fat MRI using model-based image reconstruction.

PURPOSE: Myocardial fat infiltrations are associated with a range of cardiomyopathies. The purpose of this study was to perform cardio-respiratory motion-correction for model-based water-fat separation to image fatty infiltrations of the heart in a free-breathing, non-cardiac-triggered high-resolution 3D MRI acquisition. METHODS: Data were acquired in nine patients using a free-breathing, non-cardiac-triggered high-resolution 3D Dixon gradient-echo sequence and radial phase encoding trajectory. Motion correction was combined with a model-based water-fat reconstruction approach. Respiratory and cardiac motion models were estimated using a dual-mode registration algorithm incorporating both motion-resolved water and fat information. Qualitative comparisons of fat structures were made between 2D clinical routine reference scans and reformatted 3D motion-corrected images. To evaluate the effect of motion correction the local sharpness of epicardial fat structures was analyzed for motion-averaged and motion-corrected fat images. RESULTS: The reformatted 3D motion-corrected reconstructions yielded qualitatively comparable fat structures and fat structure sharpness in the heart as the standard 2D breath-hold. Respiratory motion correction improved the local sharpness on average by 32% ± 24% with maximum improvements of 81% and cardiac motion correction increased the sharpness further by another 15% ± 11% with maximum increases of 31%. One patient showed a fat infiltration in the myocardium and cardio-respiratory motion correction was able to improve its visualization in 3D. CONCLUSION: The 3D water-fat separated cardiac images were acquired during free-breathing and in a clinically feasible and predictable scan time. Compared to a motion-averaged reconstruction an increase in sharpness of fat structures by 51% ± 27% using the presented motion correction approach was observed for nine patients.

Global longitudinal strain by CMR improves prognostic stratification in acute myocarditis presenting with normal LVEF.

BACKGROUND: Prognostic stratification of acute myocarditis (AM) presenting with normal left ventricular ejection fraction (LVEF) relies mostly on late gadolinium enhancement (LGE) characterization. Left ventricular peak global longitudinal strain (LV-GLS) measured by feature tracking analysis might improve prognostication of AM presenting with normal LVEF. METHODS: Data of patients undergoing cardiac magnetic resonance (CMR) for clinically suspected AM in seven European Centres (2013-2020) were retrospectively analysed. Patients with AM confirmed by CMR and LVEF ≥50% were included. LGE was visually characterized: localized versus. non-localized, subepicardial versus midwall. LV-GLS was measured by dedicated software. The primary outcome was the first occurrence of an adverse cardiovascular event (ACE) including cardiac death, life-threatening arrhythmias, development of heart failure or of LVEF <50%. RESULTS: Of 389 screened patients, 256 (66%) fulfilled inclusion criteria: median age 36 years, 71% males, median LVEF 60%, median LV-GLS -17.3%. CMR was performed at 4 days from hospitalization. At 27 months, 24 (9%) patients experienced ≥1 ACE (71% developed LVEF <50%). Compared to the others, they had lower median LV-GLS values (-13.9% vs. -17.5%, p = .001). At Kaplan-Meier analysis, impaired LV-GLS (both considered as > -20% or quartiles), non-localized and midwall LGE were associated with ACEs. Patients with LV-GLS ≤-20% did not experience ACEs. LV-GLS remained associated with ACEs after adjustment for non-localized and midwall LGE. CONCLUSION: In AM presenting with LVEF ≥50%, LV-GLS provides independent prognostic value over LGE characterization, improving risk stratification and representing a rationale for further studies of therapy in this cohort.

'Hot phase' clinical presentation in arrhythmogenic cardiomyopathy.

AIMS: The aim of this study is to evaluate the clinical features of patients affected by arrhythmogenic cardiomyopathy (AC), presenting with chest pain and myocardial enzyme release in the setting of normal coronary arteries ('hot phase'). METHODS AND RESULTS: We collected detailed anamnestic, clinical, instrumental, genetic, and histopathological findings as well as follow-up data in a series of AC patients who experienced a hot phase. A total of 23 subjects (12 males, mean age at the first episode 27 ± 16 years) were identified among 560 AC probands and family members (5%). At first episode, 10 patients (43%) already fulfilled AC diagnostic criteria. Twelve-lead electrocardiogram recorded during symptoms showed ST-segment elevation in 11 patients (48%). Endomyocardial biopsy was performed in 11 patients, 8 of them during the acute phase showing histologic evidence of virus-negative myocarditis in 88%. Cardiac magnetic resonance was performed in 21 patients, 12 of them during the acute phase; oedema and/or hyperaemia were detected in 7 (58%) and late gadolinium enhancement in 11 (92%). At the end of follow-up (mean 17 years, range 1-32), 12 additional patients achieved an AC diagnosis. Genetic testing was positive in 77% of cases and pathogenic mutations in desmoplakin gene were the most frequent. No patient complained of sustained ventricular arrhythmias or died suddenly during the 'hot phase'. CONCLUSION: 'Hot phase' represents an uncommon clinical presentation of AC, which often occurs in paediatric patients and carriers of desmoplakin gene mutations. Tissue characterization, family history, and genetic test represent fundamental diagnostic tools for differential diagnosis.

Role of Exercise as a Modulating Factor in Arrhythmogenic Cardiomyopathy.

PURPOSE OF REVIEW: The review addresses the role of exercise in triggering ventricular arrhythmias and promoting disease progression in arrhythmogenic cardiomyopathy (AC) patients and gene-mutation carriers, the differential diagnosis between AC and athlete's heart and current recommendations on exercise activity in AC. RECENT FINDINGS: AC is an inherited heart muscle disease caused by genetically defective cell-to-cell adhesion structures (mainly desmosomes). The pathophysiological hallmark of the disease is progressive myocyte loss and replacement by fibro-fatty tissue, which creates the substrates for ventricular arrhythmias. Animal and human studies demonstrated that intense exercise, but not moderate physical activity, may increase disease penetrance, worsen the phenotype, and favor life-threatening ventricular arrhythmias. It has been proposed that in some individuals prolonged endurance sports activity may in itself cause AC (so-called exercise-induced AC). The studies agree that intense physical activity should be avoided in patients with AC and healthy gene-mutation carriers. However, low-to-moderate intensity exercise does not appear detrimental and these patients should not be entirely deprived from the many health benefits of physical activity.

Negative bone scintigraphy in wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Amyloidosis is a rare systemic disease due to the extracellular tissue deposition of a fibrillar-shaped misfolded protein, called amyloid. Only two types of proteins commonly affect the heart leading to an infiltrative cardiomyopathy: immunoglobulin light chain and transthyretin (TTR) cardiac amyloidosis (CA). Despite the promising role of emerging imaging modalities, such as strain echocardiography, cardiac magnetic resonance and bone scintigraphy, its diagnosis is still often missed or delayed due to their inherent limitations and to a nonspecific clinical scenario with frequent concomitance of cardiac comorbidities. The gold standard for a definite diagnosis still remains endomyocardial biopsy, but in rare cases Congo Red staining could provide false negative results, as in our case, requiring immunoelectron microscopy. CASE PRESENTATION: A middle-aged male adult presented to the emergency department for relapse of heart failure. Echocardiography and cardiac magnetic resonance, along with the history of bilateral carpal tunnel syndrome, were suspicious for TTR-CA. The diagnosis, however, was hampered by concomitant cardiac comorbidities and conflicting results of imaging modalities. In fact bone scintigraphy was negative, as well as Congo Red Staining on myocardial tissue samples obtained by endomyocardial biopsy. Given the high clinical suspicion, immunoelectron microscopy was performed, showing TTR amyloid fibrils deposits, that confirmed the diagnosis. A genetic analysis excluded and hereditary form. The patient was then referred to a specialist center for specific treatment. CONCLUSIONS: This is a rare case of a TTR-CA with a negative Bone Scintigraphy and Congo red staining, which demonstrated that CA is frequently misdiagnosed because of the low specific clinical manifestations and the results of imaging modalities that sometimes could be misleading, with subsequent delayed diagnosis and correct treatment.

Anti-arrhythmic therapy in athletes.

The spectrum of arrhythmias that may be encountered in athletes ranges from isolated ectopic beats to ventricular tachycardia, usually in the context of a structurally normal heart. Anti-arrhythmic therapy in these individuals may be particularly challenging because of the young age, the hypervagotonic state, the desire to maintain a high physical performance, the reluctance to take medications and the need to avoid molecules included in the list of prohibited drugs of the World Anti-Doping Agency. Furthermore, the possible serious adverse effects of anti-arrhythmic drugs should be balanced against the benign nature of arrhythmias in patients with no underlying heart disease. The review summarizes the most common arrhythmias of athletes and the possible therapeutic options, including anti-arrhythmic drugs and non-pharmacological interventions. Eligibility criteria according to current guidelines are also addressed.

The electrocardiographic "triangular QRS-ST-T waveform" pattern in patients with ST-segment elevation myocardial infarction: Incidence, pathophysiology and clinical implications.

BACKGROUND: A specific ECG pattern of presentation of ST-segment elevation acute myocardial infarction (STEMI), characterized by "triangular QRS-ST-T waveform" (TW), has been associated with poor in-hospital prognosis but longitudinal data on its incidence and clinical impact are lacking. We prospectively evaluated the incidence and prognostic meaning of the TW pattern in a cohort of consecutive STEMI patients. METHODS: All STEMI patients who presented within 12h of symptoms onset and showed no complete bundle branch block or paced ventricular rhythm were included. The TW pattern was defined as a unique, giant wave (amplitude≥1mV) resulting from the fusion of the QRS complex, the ST-segment and the T-wave and showing a "triangular" morphology with a positive polarity in the leads exploring the ischemic region. RESULTS: Among 428 consecutive STEMI patients, 367 fulfilled the enrollment criteria. The TW pattern was identified in 5 of 367 patients (1.4%) on the admission ECG. This subset of STEMI patients with TW pattern significantly more often showed a left main coronary artery involvement (2/4, 50% vs 2/322, 0.6%; p<0.001), experienced ventricular fibrillation (5/5, 100% vs 35/362, 9.6% p<0.001), had cardiogenic shock (4/5, 80% vs. 14/362, 3.8%, p<0.001) and died during hospitalization (2/5, 40% vs 15/362, 4.1% p=0.02), compared with those with other ST-segment elevation ECG patterns. CONCLUSIONS: The TW pattern is an uncommon ECG finding, which reflects the presence of a large area of transmural myocardial ischemia and predicts cardiogenic shock accounting for high in-hospital mortality. When present, this ECG pattern should prompt aggressive therapeutic strategies, including mechanical support of circulation.

Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death.

BACKGROUND: Mitral valve prolapse (MVP) may present with ventricular arrhythmias and sudden cardiac death (SCD) even in the absence of hemodynamic impairment. The structural basis of ventricular electric instability remains elusive. METHODS AND RESULTS: The cardiac pathology registry of 650 young adults (≤40 years of age) with SCD was reviewed, and cases with MVP as the only cause of SCD were re-examined. Forty-three patients with MVP (26 females; age range, 19-40 years; median, 32 years) were identified (7% of all SCD, 13% of women). Among 12 cases with available ECG, 10 (83%) had inverted T waves on inferior leads, and all had right bundle-branch block ventricular arrhythmias. A bileaflet involvement was found in 70%. Left ventricular fibrosis was detected at histology at the level of papillary muscles in all patients, and inferobasal wall in 88%. Living patients with MVP with (n=30) and without (control subjects; n=14) complex ventricular arrhythmias underwent a study protocol including contrast-enhanced cardiac magnetic resonance. Patients with either right bundle-branch block type or polymorphic complex ventricular arrhythmias (22 females; age range, 28-43 years; median, 41 years), showed a bileaflet involvement in 70% of cases. Left ventricular late enhancement was identified by contrast-enhanced cardiac magnetic resonance in 93% of patients versus 14% of control subjects (P<0.001), with a regional distribution overlapping the histopathology findings in SCD cases. CONCLUSIONS: MVP is an underestimated cause of arrhythmic SCD, mostly in young adult women. Fibrosis of the papillary muscles and inferobasal left ventricular wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark and correlates with ventricular arrhythmias origin. Contrast-enhanced cardiac magnetic resonance may help to identify in vivo this concealed substrate for risk stratification.