Substrate For Sudden Cardiac Death Research Articles

Imaging for the assessment of the arrhythmogenic potential of mitral valve prolapse.

Mitral valve prolapse (MVP) is the most common valve disease in the western world and recently emerged as a possible substrate for sudden cardiac death (SCD). It is estimated an annual risk of sudden cardiac death of 0.2 to 1.9% mostly caused by complex ventricular arrhythmias (VA). Several mechanisms have been recognized as potentially responsible for arrhythmia onset in MVP, resulting from the combination of morpho-functional abnormality of the mitral valve, structural substrates (regional myocardial hypertrophy, fibrosis, Purkinje fibers activity, inflammation), and mechanical stretch. Echocardiography plays a central role in MVP diagnosis and assessment of severity of regurgitation. Several abnormalities detectable by echocardiography can be prognostic for the occurrence of VA, from morphological alteration including leaflet redundancy and thickness, mitral annular dilatation, and mitral annulus disjunction (MAD), to motion abnormalities detectable with "Pickelhaube" sign. Additionally, speckle-tracking echocardiography may identify MVP patients at higher risk for VA by detection of increased mechanical dispersion. On the other hand, cardiac magnetic resonance (CMR) has the capability to provide a comprehensive risk stratification combining the identification of morphological and motion alteration with the detection of myocardial replacement and interstitial fibrosis, making CMR an ideal method for arrhythmia risk stratification in patients with MVP. Finally, recent studies have suggested a potential role in risk stratification of new techniques such as hybrid PET-MR and late contrast enhancement CT. The purpose of this review is to provide an overview of the mitral valve prolapse syndrome with a focus on the role of imaging in arrhythmic risk stratification. CLINICAL RELEVANCE STATEMENT: Mitral valve prolapse is the most frequent valve condition potentially associated with arrhythmias. Imaging has a central role in the identification of anatomical, functional, mechanical, and structural alterations potentially associated with a higher risk of developing complex ventricular arrhythmia and sudden cardiac death. KEY POINTS: • Mitral valve prolapse is a common valve disease potentially associated with complex ventricular arrhythmia and sudden cardiac death. • The mechanism of arrhythmogenesis in mitral valve prolapse is complex and multifactorial, due to the interplay among multiple conditions including valve morphological alteration, mechanical stretch, myocardial structure remodeling with fibrosis, and inflammation. • Cardiac imaging, especially echocardiography and cardiac magnetic resonance, is crucial in the identification of several features associated with the potential risk of serious cardiac events. In particular, cardiac magnetic resonance has the advantage of being able to detect myocardial fibrosis which is currently the strongest prognosticator.

SCN5A variants as genetic arrhythmias triggers for familial bileaflet mitral valve prolapse

Mitral valve prolapse (MVP) is a common valvulopathy with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. The association of MVP with ventricular arrhythmias as a substrate of SCD has been documented in patients with MVP. Genetic variations in DCHS1, DZIP1, FLNA and PLD1 genes have been associated with MVP. The index case, a 42-year-old woman, was diagnosed with a bileaflet myxomatous MVP after a resuscitated SCD at the age of 27 years. MVP was the only abnormality found to explain the occurrence of life-threatening ventricular arrhythmia. Structural cardiac diseases and Brugada syndrome were excluded. Family screening revealed one symptomatic daughter with a history of two syncopes at 11 years old during physical effort. Her echocardiography showed a bileaflet MVP and a mildly dilated left ventricle. The MVP is complicated by moderate mitral regurgitation (MR). The oldest sister, 23 years old is currently asymptomatic. Her echocardiography revealed a prodromal MVP with a mild holosystolic MR. The father had normal echocardiography. The aim of this study was to identify the likely causative genetic etiology of the familial MVP and particularly the arrhythmias substrate linked to this phenotype. Whole exome sequencing (WES) was performed for the family. WES data were analyzed with a primary focus on genes related to MVP but also on genes implicated in valvular and aortic defects. Using family-based exome sequencing, no variants were found in known MVP genes. However, we identified two missense variants in the SCN5A gene. A rare variant SCN5A: p.Ala572Asp and the functional modifying SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as a potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease

BackgroundLate gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). ObjectivesThe authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). MethodsPatients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. ResultsOf 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell’s C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell’s C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. ConclusionsComprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Characterization of the electrophysiological substrate in patients with Barlow's disease.

Myxomatous mitral valve prolapse (MVP) and mitral-annular disjunction (Barlow disease) are at-risk for ventricular arrhythmias (VA). Fibrosis involving the papillary muscles and/or the infero-basal left ventricular (LV) wall was reported at autopsy in sudden cardiac death (SCD) patients with MVP. We investigated the electrophysiological substrate subtending VA in MVP patients with Barlow disease phenotype. Twenty-three patients with VA were enrolled, including five with syncope and four with a history of SCD. Unipolar (Uni < 8.3 mV) and bipolar (Bi < 1.5 mV) low-voltage areas were analyzed with electro-anatomical mapping (EAM), and VA inducibility was evaluated with programmed ventricular stimulation (PES). Electrophysiological parameters were correlated with VA patterns, electrocardiogram (ECG) inferior negative T wave (nTW), and late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance. Premature ventricular complex (PVC) burden was 12 061.9 ± 12 994.6/24 h with a papillary-muscle type (PM-PVC) in 18 patients (68%). Twelve-lead ECG showed nTW in 12 patients (43.5%). A large Uni less than 8.3 mV area (62.4 ± 45.5 cm2 ) was detected in the basal infero-lateral LV region in 12 (73%) patients, and in the papillary muscles (2.2 ± 2.9 cm2 ) in 5 (30%) of 15 patients undergoing EAM. A concomitant Bi less than 1.5 mV area (5.0 ± 1.0 cm2 ) was identified in two patients. A history of SCD, and the presence of nTW, and LGE were associated with a greater Uni less than 8.3 mV extension: (32.8 ± 3.1 cm2 vs. 9.2 ± 8.7 cm2 ), nTW (20.1 ± 11.0 vs. 4.1 ± 3.8 cm2 ), and LGE (19.2 ± 11.7 cm2 vs. 1.0 ± 2.0 cm2 , p = .013), respectively. All patients with PM-PVC had a Uni less than 8.3 mV area. Sustained VA (ventricular tachycardia 2 and VF 2) were induced by PES only in four patients (one with resuscitated SCD). Low unipolar low voltage areas can be identified with EAM in the basal inferolateral LV region and in the papillary muscles as a potential electrophysiological substrate for VA and SCD in patients with MVP and Barlow disease phenotype.

In-depth phenotypic characterisation of myocardial fibrosis by cardiovascular magnetic resonance predicts sudden cardiac death in coronary heart disease: a long-term prospective outcome study

Abstract Background Prospective studies harnessing late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) afford the potential to non-invasively characterise the phenotypic substrate for sudden cardiac death (SCD) and simultaneously interrogate its mechanistic drivers. Purpose To assess the utility of infarct characterisation by CMR, including scar microstructure analysis, to predict SCD in prospectively investigated patients with coronary heart disease (CHD). Methods Patients with stable CHD were prospectively recruited into a registry between August 2009 and January 2016. The primary outcome for this study was SCD or aborted SCD. Patients with a secondary prevention implantable cardioverter defibrillator (ICD) indication were excluded. All patients had CMR with LGE imaging. Infarct quantification (core scar and peri-infarct zone [PIZ]) was performed by an independent level 3 CMR reader. Outcome events were adjudicated by a panel of cardiologists blinded to the CMR data. To investigate fibrosis microstructure, bespoke computational image processing algorithms were applied to the LGE images in order to extract specific morphological and texture related features. Results Of 437 patients (mean age 64, mean left ventricular ejection fraction [LVEF] 47%, 91% with LGE) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. Patients with higher PIZ mass had an increased risk of the primary outcome (10-year risk 0.7%, 24.0% and 37.8% for patients with PIZ mass &amp;lt;5.66g, 5.66–12.28g and ≥12.29g respectively, P&amp;lt;0.001; figure 1a). On univariable analysis, an increase in PIZ mass and core infarct mass was associated with an increased risk of the primary outcome (per gram: HR 1.12, 95% CI 1.09–1.15, P&amp;lt;0.001 and HR 1.05, 95% CI 1.04–1.06, P&amp;lt;0.001 respectively). PIZ mass and core infarct mass remained independently associated with the primary outcome after adjustment for baseline predictors (per gram: HR 1.10, 95% CI 1.06–1.14, P&amp;lt;0.001 and HR 1.04, 95% CI 1.02–1.06, P&amp;lt;0.001 respectively) and together provided incremental value compared to conventional variables in predicting the endpoint (Harrell's C-statistic 0.76 to 0.82, figure 1b-c). Bespoke analysis of imaging data identified several shape-based scar metrics that associated with the primary outcome (figure 2). These included core infarct transmurality, radiality and interface length (the latter defining the core scar-PIZ boundary length), and the number of PIZ islets. Conclusions In this large prospective study of patients with stable CHD, both PIZ mass and core infarct mass independently predicted long-term SCD risk after adjusting for conventional predictors including LVEF. Reassuringly, minimal or absent LGE portended a comparatively low risk of SCD. Analysis of the scar microstructure identified several shape-based features that associated with SCD. These results highlight a potential avenue towards a more personalised approach to ICD implantation decisions. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Lung and Heart Institute, Imperial College London

Simulated heterogeneity in purkinje-ventricular electrophysiology following acute myocardial infarction remodelling

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences Background Coronary heart disease is a common substrate for sudden cardiac death. Several clinical and experimental studies on ischemic heart diseases have highlighted the involvement of the His-Purkinje system in the initiation and maintenance of ventricular arrhythmias. Biophysically-detailed mathematical models and computational multiscale simulations can help in gather insights of the cellular and tissue mechanisms underlying the trigger and maintenance of arrhythmias. Purpose The goal of this study is to evaluate the effects of ionic remodelling on human Purkinje and ventricular cells in the acute stage post myocardial infarction. Methods Two recently published computational models were used to represent the electrophysiology of cardiac Purkinje and ventricular cells, including transmural heterogeneity (endo, mid, epi myocytes). Cardiac ionic remodelling was observed at the border zone of the infarcted region, mostly in canine and porcine models. For both ventricular and Purkinje models, remodelling was implemented as a variation of the number of function channels, i.e., of the current conductance for Na+, Ca2+ and K+ currents. Simulations were performed for both models at different pacing frequencies (cycle length from 400 to 1000 ms) to assess a set of action potential (AP) biomarkers and AP rate-dependence at fast pacing. Early afterdepolarisation (EADs) were induced at slow pacing under hERG block. Results Figure 1 reports the results for the ventricular (A) and Purkinje (B) electrophysiology for the healthy (blue) and post-infarction (red) tissues at 1 Hz (left), at different frequencies (middle) and under 85% hERG block at 0.25 Hz (right). At 1 Hz, ionic remodelling reduced the AP depolarisation rate, abolished the AP notch and led to AP prolongation for both models. Purkinje AP showed also elevated resting membrane potentials and increased diastolic depolarisation. The mid-cardiomyocyte and Purkinje models showed a small increase in the APD- rate dependence slope. Ionic remodelling did not affect significantly the EAD dynamics in the ventricular model, apart from further delaying the AP repolarisation. In the Purkinje model, ionic remodelling led to automaticity and changed the EAD dynamics, which disappeared from the paced AP but occurred after the spontaneous AP. Conclusion In this study we investigated the effects of ionic current remodelling in ventricular and Purkinje cells following acute myocardial infarction. Results showed that remodelling at the border zone increased the heterogeneity between Purkinje and ventricular cells. A further step into the investigation of pro-arrhythmic mechanisms induced by myocardial infarction will be to perform multiscale simulations at whole organ level in 3D anatomical models of human ventricles, including the His-Purkinje system. Abstract Figure 1

Risk stratification of sudden cardiac death in heart failure patients: is left ventricular ejection fraction alone sufficient?

According to current clinical guidelines, the risk of sudden cardiac death (SCD) in patients with heart failure is specified by left ventricular (LV) ejection fraction (EF). We believe that risk stratification and choice of patient management tactics should be based on modern diagnostic techniques aimed at identifying the anatomical and electrophysiological substrate of SCD. Therefore, LVEF alone is not enough to solve such problems. This review presents an analysis of current research on the novel predictors of SCD. The most promising areas include the identification of electrocardiological markers of fatal ventricular arrhythmias, modern ultrasound and magnetic resonance imaging techniques. The importance of electrophysiological tests in the verification of SCD risk is discussed. Based on the literature analysis, we can conclude that only a combination of different factors can significantly increase the diagnostic value of prognostic model and improve the primary prevention of SCD.

Second opinion system for sudden cardiac death cases in forensic practice.

Sudden cardiac death (SCD) represents a considerable percentage of cardiovascular deaths worldwide. The most frequent pathological substrate of SCD is atherosclerotic coronary artery disease (CAD). The other, less common, pathologies which can cause SCD include cardiomyopathies, congenital diseases (including abnormal anatomy), and arrhythmias such as channelopathies, many of which are genetically determined. Autopsies of SCD victims are generally performed by forensic pathologists. In some cases, a third person responsibility could be invoked. While CAD diagnosis at post-mortem examination is not a major challenge for the forensic pathologist, the other rarer diseases may be. In such instances, referral of the hearts to specialized centers with recognized expertise is recommended, and this is particularly important in cases of SCDs of young people. Moreover, in order to avoid the frequent overdiagnosis of a pathological heart, an expert opinion should be sought for even in the presence of a morphologically normal heart. In cases where retention of the heart is not feasible, it is essential to provide an extensive photographic documentation, with the indication of the sampling sites for histological examination. However, some practical aspects, as the criteria for case selection in routine forensic practice are missing. In this paper, we present the recommendations for heart retention for a second expert opinion and the alternative of documentation and sampling for cases where retention is not possible.

Dynamic predictive accuracy of electrocardiographic biomarkers of sudden cardiac death within a survival framework: the Atherosclerosis Risk in Communities (ARIC) study

BackgroundThe risk of sudden cardiac death (SCD) is known to be dynamic. However, the accuracy of a dynamic SCD prediction is unknown. We aimed to measure the dynamic predictive accuracy of ECG biomarkers of SCD and competing non-sudden cardiac death (non-SCD).MethodsAtherosclerosis Risk In Community study participants with analyzable ECGs in sinus rhythm were included (n = 15,716; 55% female, 73% white, age 54.2 ± 5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity and traditional ECG metrics (heart rate, QRS, QTc) were measured. Adjudicated SCD was the primary outcome; non-SCD was the competing outcome. Time-dependent area under the receiver operating characteristic curve (ROC(t) AUC) analysis was performed to assess the prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years using a survival analysis framework. Reclassification improvement as compared to clinical risk factors (age, sex, race, diabetes, hypertension, coronary heart disease, stroke) was measured.ResultsOver a median 24.4 y follow-up, there were 577 SCDs (incidence 1.76 (95%CI 1.63–1.91)/1000 person-years), and 829 non-SCDs [2.55 (95%CI 2.37–2.71)]. No ECG biomarkers predicted SCD within 3 months after ECG recording. Within 6 months, spatial ventricular gradient (SVG) elevation predicted SCD (AUC 0.706; 95%CI 0.526–0.886), but not a non-SCD (AUC 0.527; 95%CI 0.303–0.75). SVG elevation more accurately predicted SCD if the ECG was recorded 6 months before SCD (AUC 0.706; 95%CI 0.526–0.886) than 2 years before SCD (AUC 0.608; 95%CI 0.515–0.701). Within the first 3 months after ECG recording, only SVG azimuth improved reclassification of the risk beyond clinical risk factors: 18% of SCD events were reclassified from low or intermediate risk to a high-risk category. QRS-T angle was the strongest long-term predictor of SCD (AUC 0.710; 95%CI 0.668–0.753 for ECG recorded within 10 years before SCD).ConclusionShort-term and long-term predictive accuracy of ECG biomarkers of SCD differed, reflecting differences in transient vs. persistent SCD substrates. The dynamic predictive accuracy of ECG biomarkers should be considered for competing SCD risk scores. The distinction between markers predicting short-term and long-term events may represent the difference between markers heralding SCD (triggers or transient substrates) versus markers identifying persistent substrate.

Usefulness of Single Nucleotide Polymorphisms as Predictors of Sudden Cardiac Death

The pathophysiology of sudden cardiac death (SCD) remains incompletely understood. Genetic mutations can create a favorable substrate for SCD. Our aim is to evaluate the evidence of single nucleotide polymorphisms (SNPs) as predictors of SCD. We searched the Medline database (2000 to 2017) and selected all case-control or cohort studies that reported associations between SNPs and SCD. Our search terms included "polymorphisms" and "sudden death." We collected the study design, population ethnic background, gene testing strategy, the association between the SNP and SCD, and the cardiovascular comorbidities of the population. Our search yielded 723 studies, of which we included 24 based upon our inclusion criteria. The studies had a total population of 78,165 participants, with a median age of 62.5 years (IQR 56 to 66) and 35% (IQR 13 to 32) were female. Almost all studies were conducted in white patients of European descent and the most commonly used genetic strategy was candidate gene panels. Fifteen of the studies had a case-control design that included SCD patients without known heart disease as the comparison group and the other 9 studies included patients with heart failure and coronary artery disease. The studies evaluated 53 SNPs and the most common genetic loci were SCN5A, RyR2, CASQ2, NOSA1P, and AGTR. SNPs with the 3 strongest statistically significant ORs >1 were: rs6684209 of CASQ2 (odds ratio [OR] 19), rs3814843 of CALM1 (OR 5.5), and rs35594137 of GJA5 (OR 3.6). In Conclusion, many SNPs are associated with SCD, with the strongest associations seen in SNPs of genes related to intracellular calcium handling. These findings were generated primarily using a candidate gene strategy in white patients with European descent.

Global Electrical Heterogeneity: Mechanisms and Clinical Significance.

This review summarizes recent findings and discusses a clinical significance of a vectorcardiographic (VCG) Global electrical heterogeneity (GEH). GEH concept is based on the concept of the spatial ventricular gradient (SVG), which is a global measure of the dispersion of total recovery time. We quantify GEH by measuring five features of the SVG vector (SVG magnitude, direction (azimuth and elevation), a scalar value, and spatial QRS-T angle) on orthogonal XYZ ECG. In analysis of more than 20,000 adults we showed that GEH is independently associated with sudden cardiac death (SCD) after adjustment for demographics, cardiovascular disease (time-updated incident non-fatal cardiovascular events [coronary heart disease, heart failure, stroke, atrial fibrillation, use of beta-blockers], and known risk factors [cholesterol, triglycerides, physical activity index, smoking, diabetes, obesity, hypertension, anti-hypertensive medications, creatinine, alcohol intake, left ventricular ejection fraction, and time-updated ECG metrics (heart rate, QTc, QRS duration, ECG-left ventricular hypertrophy, bundle branch block or interventricular conduction delay)]. This finding suggests that GEH represents an independent electrophysiological substrate of SCD.

Abstract 16980: Defining the Arrhythmia Burden in Adults With Repaired Coarctation of the Aorta

Introduction: Ventricular and atrial arrhythmias have been shown to correlate with the risk of sudden cardiac death (SCD) in adult congenital heart disease (ACHD). Patients with repaired coarctation of the aorta (CoA) remain one of the highest risk ACHD populations for late SCD. However, the etiology of SCD is poorly understood in this population. Hypothesis: We hypothesize that adults with repaired CoA have an increased prevalence of atrial and ventricular arrhythmia. Methods: We identified 165 adults with repaired CoA (39±11years old, 45% women) and retrospectively analyzed all cardiac rhythm testing (2008-2018). The prevalence of atrial fibrillation (AF), atrial flutter (AFL), supraventricular tachycardia (SVT) and non-sustained ventricular tachycardia (NSVT) were analyzed and compared to prevalence in the general (non-repaired CoA) population. Results: Ventricular and atrial arrhythmia were found to be more common in adults with repaired CoA. The odds of NSVT occurring were 2.4 (95% CI: 1.5-3.8). Atrial arrhythmia risk varied by type with the odds of atrial arrhythmia in the CoA group ranging from 4.4 to 129 times the risk of the general population (See Figure). Conclusions: In this relatively young cohort of adults with repaired CoA, the incidence of ventricular and atrial arrhythmia was significantly higher than the general population. This data indicates that further study of arrhythmogenic substrate for SCD in repaired CoA is important.

Anorexia nervosa and heart disease: a systematic review.

Anorexia nervosa (AN) is an eating disorder that most frequently afflicts females in adolescence. In these subjects, cardiovascular complications are the main cause of morbidity and mortality. Aim of this review is to analyze the hemodynamic, pro-arrhythmic and structural changes occurring during all phases of this illness, including re-feeding. A systematic literature search was performed on studies in the MEDLINE database, from its inception until September 2017, with PUBMED interface focusing on AN and cardiovascular disease. This review demonstrated that the most common cardiac abnormalities in AN are bradycardia and QT interval prolongation, which may occasionally degenerate into ventricular arrhythmias such as Torsades des Pointes or ventricular fibrillation. As these arrhythmias may be the substrate of sudden cardiac death (SCD), they require cardiac monitoring in hospital. In addition, reduced cardiac mass, with smaller volumes and decreased cardiac output, may be found. Furthermore, mitral prolapse and a mild pericardial effusion may occur, the latter due to protein deficiency and low levels of thyroid hormone. In anorectic patients, some cases of hypercholesterolemia may be present; however, conclusive evidence that AN is an atherogenic condition is still lacking, although a few cases of myocardial infarction have been reported. Finally, refeeding syndrome (RFS), which occurs during the first days of refeeding, may engender a critically increased risk of acute, life-threatening cardiac complications.

Cardiac magnetic resonance imaging and primary prevention implantable cardioverter defibrillator therapy: current recommendations and future directions.

: Implantable cardioverter defibrillators (ICDs) have proven to be the most effective preventive therapy of sudden cardiac death (SCD). Based on current guidelines, the indication for prophylactic ICD therapy is primarily based on a left ventricular ejection fraction (LVEF) less than 35%. However, patients with low LVEF may never have an arrhythmic event while patients with normal to moderately reduced LVEF, who are traditionally felt to be at lower risk, can experience SCD. Therefore, LVEF alone is not an ideal risk stratification parameter to determine ICD therapy. The arrhythmic risk depends mainly on myocardial histopathologic features and electrical properties, which are largely not reflected by left ventricular systolic performance. In addition, several studies demonstrated that the presence of myocardial fibrosis represents a substrate for malignant ventricular arrhythmias and SCD. Cardiac MRI with late gadolinium enhancement is a refined technique able to accurately identify and quantify ventricular myocardial fibrosis and numerous studies demonstrated its ability to better stratify arrhythmic risk compared with LVEF. Recently, the combination of conventional clinical risk factors and biomarkers, namely N-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein, with cardiac MRI (CMR) findings is proving to more effectively predict arrhythmic risk. Moreover, the application of strain technique to CMR and new tissue characterization indices such as T1 mapping represents an attractive possibility to predict the occurrence of tachyarrhythmia. The aim of this review is to provide state-of-the-art evidence and future perspectives on the use of CMR for primary prevention ICD therapy.

Sudden Cardiac Death Substrate Imaged by Magnetic Resonance Imaging: From Investigational Tool to Clinical Applications.

Sudden cardiac death (SCD) is a devastating event afflicting 350 000 Americans annually despite the availability of life-saving preventive therapy, the implantable cardioverter defibrillator. SCD prevention strategies are hampered by over-reliance on global left ventricular ejection fraction <35% as the most important criterion to determine implantable cardioverter defibrillator candidacy. Annually in the United States alone, this results in ≈130 000 implantable cardioverter defibrillator placements at a cost of >$3 billion but only a 5% incidence per year of appropriate firings. This approach further fails to identify individuals who experience the majority, as many as 80%, of SCD events, which occur in the setting of more preserved left ventricular ejection fraction. Better risk stratification is needed to improve care and should be guided by direct pathophysiologic markers of arrhythmic substrate, such as specific left ventricular structural abnormalities. There is an increasing body of literature to support the prognostic value of cardiac magnetic resonance imaging with late gadolinium enhancement in phenotyping the left ventricular to identify those at highest risk for SCD. Cardiac magnetic resonance has unparalleled tissue characterization ability and provides exquisite detail about myocardial structure and composition, abnormalities of which form the direct, pathophysiologic substrate for SCD. Here, we review the evolution and the current state of cardiac magnetic resonance for imaging the arrhythmic substrate, both as a research tool and for clinical applications.

Role of pharmacotherapy in cardiac ion channelopathies.

In the last decade, there have been considerable advances in the understanding of the pathophysiology of malignant ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD). Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10%-15% of SCD occurs in the presence of structurally normal heart, and the majority of these patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modifications of the function of the channel resulting in an electrophysiological substrate of VT and SCD. Collectively, these disorders are referred to as cardiac ion channelopathies. The four major syndromes in this group are: the long QT syndrome (LQTS), the Brugada syndrome (BrS), the short QT syndrome (SQTS), and the catecholaminergic polymorphic ventricular tachycardia (CPVT). Each of these syndromes includes multiple subtypes with different and sometimes complex cardiac ion channel genetic abnormalities. Many are associated with other somatic and neurological abnormalities besides the risk of VT and SCD. The current management of cardiac ion channelopathies can be summarized as follows: (1) in symptomatic patients, the implantable cardioverter defibrillator (ICD) is the only viable option; (2) in asymptomatic patients, risk stratification is necessary, followed by either the ICD, pharmacotherapy, or a combination of both. A genotype-specific approach to pharmacotherapy requires a thorough understanding of the molecular-cellular basis of arrhythmogenesis in cardiac ion channelopathies as well as the specific drug profile.

The value of cardiac magnetic resonance and distribution of late gadolinium enhancement for risk stratification of sudden cardiac death in patients with hypertrophic cardiomyopathy

BackgroundThe presence of late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM) is associated with worse clinical outcome and the extent of LGE predicts the increased risk of sudden cardiac death (SCD). Limited data exist regarding the distribution of LGE. We attempted to verify whether the presence of LGE outside the interventricular insertion points carries additional risk for patients with HCM. MethodsIn this prospective study, 328 patients with HCM, who underwent cardiac magnetic resonance (CMR) were enrolled. Five major risk factors for SCD were assessed in all patients. The median follow-up was 37 months. ResultsLGE was detected in 226 (68.9%) patients. In 70 (21.3%) patients it was present only at the interventricular insertion points – LGE (+) group, while in 156 (47.6%) it was noted in other locations – LGE (++) group. Primary endpoint defined as SCD or appropriate implantable cardioverter-defibrillator intervention occurred in 14 (4.3%) patients, one in LGE (+) and 13 in LGE (++). In multivariable analysis including five traditional risk factors and left ventricular ejection fraction <50%, only the presence of LGE outside the insertion points was a significant predictor of SCD/aborted SCD (HR 10.01, 95% CI 1.21–83.86, p=0.033). The performance of the multivariable sudden cardiac death risk model was improved by the addition of LGE (++) to the traditional risk factors (likelihood ratio p=0.005). The Kaplan–Meier curves showed better event-free survival in the LGE (−) and LGE (+) patient groups compared to the LGE (++) group. ConclusionsIn HCM patients, presence of LGE outside interventricular insertion points is associated with increased risk of sudden cardiac death or its equivalent as well as overall mortality. Cardiac fibrosis as a substrate for SCD in HCM may be identified on CMR and serve as an imaging biomarker of increased risk.

83 The Effects of Training and Detraining on T Wave Inversion in a Cohort of Athletes

<h3>Purpose</h3> T wave inversion (TWI) is the electrical hallmark of cardiac conditions such as hypertrophic cardiomyopathy (HCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC), which may be the substrate for sudden cardiac death in the young athlete. Such repolarization anomalies can feature on the ECG of an apparently healthy athlete and pose major diagnostic dilemmas in sports cardiology, as regular, prolonged high intensity, physical activity is associated with such repolarization changes. Athletes themselves are reluctant to detrain during the season, which makes interpreting any reversible effects of exercise on the ECG more difficult. This study aimed to investigate the effect of detraining on TWI in athletes. <h3>Methods</h3> Between 2013–2014, 36 professional footballers demonstrated TWI at mid-season ECG screenings (trained period). They were followed up during the “off-season” after a period of detraining (6–8 weeks). TWI was defined as −0.1 mV or greater 2 or more contiguous leads, in the anterior leads-V2-V3/4; inferior-II, III, aVF; or lateral-beyond V4 +/- aVL. Comparisons were drawn by 2 independent cardiologists, between trained and detrained ECG repolarization patterns. Every individual was subsequently investigated for an underlying cardiomyopathy. <h3>Results</h3> Athletes were male and aged 24.5+/-2.7 years. 27 (75%) were Afro-Caribbean and 25% Caucasian (p = 0.0141). TWI was most commonly observed in the anterior leads (n = 20, 55%), followed by inferior (n = 10, 28%) and lateral (n = 6, 17%). No Caucasian player had TWI in the lateral leads. After detraining, 16 players demonstrated resolution of anterior TWI (80%, p = 0.0293), 8 in inferior leads (80%, p = 0.2353) and 4 in the lateral leads (67%, p = 0.638) (Figure 1). All players with abnormal TWI according to consensus guidelines were comprehensively evaluated with no cardiomyopathy identified. <h3>Conclusion/implications</h3> Convincing athletes to detrain in order to interpret repolarisation anomalies is particularly difficult, due to enthusiasm for continued participation and reluctance to stop exercising. In our cohort of athletes who did detrain during the ‘off-season’, we observed resolution of TWI in the majority of athletes (both Afro-Caribbean and Caucasian) after a relatively brief period of detraining which may be deemed a physiological phenomenon. This was statistically significant in the anterior leads. However, TWI in the inferior and/or lateral leads should always raise the suspicion of an underlying cardiomyopathy, especially if persistent after detraining.

102 Myocardial Fibrosis in Stroke Survivors

Background Myocardial fibrosis (MF) is a substrate for sudden cardiac death. Cardiac death is the commonest cause of death in stroke survivors. We recently showed that MF in stroke survivors can be treated by spironolactone and amiloride in a randomised placebo-controlled cross-over study. Purpose To determine the prevalence of severe MF in stroke survivors, as evidenced by Procollagen carboxyl-terminal telopeptide (PICP) >127 µg/L (which is 78% specific and 75% sensitive at diagnosing severe fibrosis, as identified by histological assessment of myocardial biopsy). We also tested the hypothesis that PICP is associated with reversible cardiac pathologies in stroke survivors. Methods 186 stroke survivors were studied. Patients who were known to have liver or lung fibrosis or recent surgery (within last 6 months), or atrial fibrillation were excluded at recruitment because these conditions can affect PICP levels. The concentration of PICP was measured by radioimmunoassay using a kit from Orion Diagnostics, Finland (assay coefficient of variation; = 1.48%). Dipyridamole myocardial perfusion imaging was performed. Ejection fraction was determined using gated SPECT. Left ventricular mass index (LVMI) was determined by echocardiography. Results 186 stroke survivors (111 male, 75 female) were studied. Severe MF is prevalent amongst stroke survivors. 36% (67 out of 186) had PICP >127 µg/L. Stroke survivors with severe fibrosis were older [68 (8) vs 65 (10), p = 0.049], but had similar blood pressure (144/79 mmHg in severe fibrosis patients, vs 144/80 mmHg), history of angina or myocardial infarction and degree of inducible ischaemia (0, interquartile range (IQR) = 0–3, vs 0 (IQR 0–4), p = 0.79) when compared with those with lower PICP levels (Table 1). There was a very weak correlation between PICP and LVMI [r = 0.2, p = 0.011]. No correlation was found between PICP and ejection fraction or BNP levels at rest or QT dispersion (Table 2). Interestingly, stroke survivors taking ACE-inhibitors had less severe MF (Mantel-Haenszel OR = 0.3, 95% CI = 0.15–0.74; Fisher’s exact 2-sided p = 0.007). Conclusions Severe MF is common in stroke survivors. Whilst a statistically significant association was found between MF and LVMI, the correlation is very weak.

Myocardial fibrosis in stroke survivors

Stroke survivors are most likely to die of cardiac death, yet few undergo comprehensive cardiac assessment to look for reversible causes. Myocardial fibrosis (MF) is not only the hallmark of cardiomyopathy, but also a substrate for sudden cardiac death, ventricular tachyarrhythmia and heart failure. Procollagen carboxyl-terminal telopeptide (PICP) was found to be a marker of MF. The relationship between PICP and cardiac abnormalities in stroke survivors is unknown. We recently showed that MF in stroke survivors can be treated by spironolactone and amiloride in a randomised placebo-controlled cross-over study with reduction in PICP levels and QTc [1].