© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Spotlight on sudden cardiac death
aArrhythmia Research Group, DHVD, National Heart, Lung & Blood Institute, 2 Rockledge Ctr., MSC-7940, 6701 Rockledge Dr., Bethesda, MD 20892, USA
bMolecular Cardiology, Fondazione Salvatore Maugeri, Via Ferrata 8, 27100 Pavia, Italy
cDivision of Cardiology, University of Miami School of Medicine, Miami, FL, USA
* Corresponding author. Tel.: +1-301-435-0507; fax: +1-301-480-1454
Received 26 February 2001; accepted 27 February 2001
Sudden cardiac death (SCD) is a very common mechanism for cardiac mortality in all developed nations, yet means to identify individuals at increased risk for this condition and effective strategies for its prevention remain elusive. For many years the focus of SCD research has concentrated on averting those conditions that are its primary antecedents, such as athero-thrombotic coronary artery disease, hypertension and heart failure. Recently however, major advances have occurred in understanding those more immediate cellular and molecular influences that contribute to the overall prevalence of SCD and the mechanisms responsible for its initiation in both apparently healthy individuals and those with established cardiac diseases. This "Spotlight" issue of the Journal has been designed to highlight many of these new discoveries and the remarkable progress and challenges that characterize this field today.
A number of factors have contributed to the difficulties that characterize the historically slow pace of progress in SCD research. Rather than being associated with specific, identifiable symptoms, the pathophysiology of SCD, in most cases, is diffuse in presentation, unpredictable in time, and its major cause, initiation of lethal ventricular arrhythmias, appears highly varied in different individuals. As suggested by the most commonly used definition of SCD, "...any near instantaneous, electrically-based, cessation of cardiac output in individuals with otherwise uncompromised circulatory function," the forms of cardiac disease from which it arises are broad, and include a full spectrum of conditions from structural malformations, to progressive acquired pathologies, as well as terminal manifestations of otherwise silent genetic susceptibilities that may express at any life stage. Recent discoveries concerning several of these latter conditions (e.g. the Long QT Syndromes) have, however, over the past five years, catapulted SCD research to the forefront of investigations on the molecular causes of cardiovascular disease; and continuing population and laboratory discoveries on the heritable origins of mechanisms of SCD have finally begun to provide the clues essential to developing more effective strategies for their prevention.
The papers selected for this issue convey some of the excitement occurring in a variety of aspects of SCD research. They reflect the significant advances achieved in understanding its epidemiology, in identifying new physiological, behavioral and environmental risk factors for its occurrence, mechanisms of lethal arrhythmogenesis involved, and the relative effectiveness of different approaches to therapy. We believe the Journal's decision to highlight these achievements, here and now, reflects well on the many important recent contributions to this area and should help stimulate new work and ideas needed in stimulating the translation of scientific advances into medical practice.
The series of invited review articles begins with four papers that provide a broad overview of the occurrence of SCD in different populations, highlighting what has been learned about the risks that influence its onset, as well as providing new information on advances in drug and device therapy and strategies that hold promise for prediction. Myerburg and Spooner [1] consider the issue that most unexpected SCD's actually occur in relatively low-risk, low incidence populations, making determination of potential victims difficult given the success of contemporary risk stratification. They provide suggestions concerning new directions in molecular and genetic risk factor profiling and, like the paper of Priori et al. that follows in the section on genetic mechanisms, discuss the potential that advances in this latter area hold for detecting functional and structural susceptibilities inaccessible with other clinical modalities. The second paper by Albert and Ruskin [2] continues with a comprehensive review of the impact of traditional population and newly recognized risks, highlighting the role of transient, initiating factors, such as physical exertion and stress, as well as other under-recognized events in the arrhythmic process. Drs. Bardy, Siscovick and co-workers [3] follow with additional epidemiological observations and consideration of the implications of advances in device and prevention strategies aimed at reducing SCD prevalence in the community. They provide insight on the recent surge in dissemination of automated external defibrillators and directions for future efforts to integrate this important "rescue" technology into settings where SC D most frequently occurs. The paper by Lombardi et al. [4] concludes this section with an analysis of heart-rate variability and its ability to identify changes in autonomic neural function indicative of enhanced cardiac electrical instability.
The paper by Drs. Prioiri, Napolitano and Grillo [5] then advances the appealing, yet provocative concept that undetected sub-clinical genetic abnormalities may contribute significantly to the occurrence of lethal arrhythmias in a much larger number of SCD victims than previously suspected. They extend their group's genetic discoveries on potential genetic modifiers and issues of penetrance in rare inherited arrhythmias, suggesting similar anomalies contribute to cases of "idiopathic ventricular fibrillation." This theme of relating previously unsuspected genetic contributions to more common elevations in SCD risk is continued in the following review by Dr. Roden [6]. His contribution provides perspective on now well established findings that genetic variation, not just in ion channel genes, but also in genes coding for proteins involved in the metabolism and action of drugs, and environmental agents can be significant determinants in the initiation of lethal arrhythmias in some individuals. This view on the pharmacogenetics and pharmacogenomics of compounds that induce torsade de pointes and related arrhythmias, and the molecular basis of these events, provides a blueprint for understanding the cardiac effects of many types of common pharmaceuticals, a focus generating governmental and regulatory interest as well.
There follows a series of four papers dealing with those electrophysiological mechanisms that lead acutely to sudden death initiation. The first, from Drs. Gronefeld and Hohnloser [7], sets the stage by illuminating actual cardiac electrophysiological recordings in high risk patients implanted with advanced electrical defibrillating devices (ICDs). The work provides a surprisingly clear view of events as they occur "real-time" in patients. Their experience with onset of SCD events in high-risk, diseased hearts has important implications regarding future developments of the ICD as a diagnostic, as well as a therapeutic tool, and also has relevance to SCD events in less severe forms of disease. Drs. Jalife and Samie [8] next examine the unifying theory that ventricular tachycardias and fibrillation originate as a single mechanism, with rotating waves of excitation organizing into electrical "rotors" and spiral wave forms of activation which, depending on interactions within myocardial tissue, result in reentrant and degenerative conduction and SCD onset. Their contribution thus provides new views on both mechanisms of reentry and the transition between different terminal arrhythmic states. The second paper, by Drs. Chen and Karguezian [9], presents a related view of these same mechanisms, placing boundaries on critical parameters through computerized analysis of initiating events in the dog ventricle. At the next lower level of mechanistic discrimination, Drs. Saffitz, Lerner and Beardslee [10] provide a review of the possible role of diminished inter-cellular electrical communications and cellular uncoupling in the generation of ventricular arrhythmias in acute ischemia. Their discoveries, concerning alterations in gap junctions and changes in connexin gene expression in experimental animals, exemplifies powerful new functional genomic approaches being used to dissect and model newly revealed gene variants associated with human disease.
The final three reviews provide extensive discussion of structural and mechanical factors in the generation of the potentially arrhythmogenic cardiac substrate in disease remodeled hearts, the setting for most common forms of SCD. Drs. Lab and Babuty [11] explore the role of cellular mechanisms in mechano-electrical transduction pathways in the myocardium and the ways altered coupling at this level may contribute to arrhythmogenesis. Continuing, Drs Kohl-Nesbitt and co-workers [12] summarize their ideas on commotio cordis and how critically timed, sharp chest compression can initiate accidental SCDs that occur during vigorous sports activities (e.g. baseball) or vehicular trauma. The final review by Drs. Thiene, Corrado [13] and colleagues completes this view by providing analysis of the spectrum of pathological changes apparent on careful examination of cardiac tissues on autopsy of SCD victims. Their examination, extending to the molecular-histological level, helps identify structural anomalies that predispose to sudden death in a variety of inherited and acquired conditions.
The series of original research contributions which follows the reviews reveals the diversity and richness of approaches being applied in SCD research today. Like the papers that precede them, they range broadly in investigative scope, from predictive studies on theoretical mathematical and genetically engineered models of ion channel dysfunction, to exploration of various dog, rabbit and pig models of disease. They conclude with several contributions that explore both functional and structural defects that lead to increased SCD incidence in man.
Drs. Clancy and Rudy [14] begin with a study of the complex effects of alterations in the Ikr channel, Herg, in their "virtual" action potential computer model. The calculations presented suggest how kinetic changes in channel behavior can lead to arrhythmia-generating early after-depolarizations. The following pair of papers from Drs. Escande, Delombe and co-workers [15,16], deal with mice engineered to express a dominant-negative mutation in the Iks channel associated with the KCNQ1 gene that encodes the KvLQT1 channel in man. In the first, they suggest evidence that such mutations may affect not just myocardial repolarization, but may also be capable of inducing deficiencies in sinus node automaticity and ventricular activation pathways. In the second, they cleverly exploit this mouse model as a screening tool for detecting drugs that block Irr. Dr. Rosen and co-workers [17] next consider manifestations of channel behavior that result in the fascinating phenomena of "cardiac memory" in the paced dog ventricle, suggesting how such interactions can alter the balance between pro- and anti-arrhythmic actions of channel directed anti-arrhythmic drugs. Dr. Hondeghem et al. [18] continue on this theme with an interesting paper on pro- and anti-arrhythmic drug actions, and their association with changes in action potential duration in an electrophysiological study on isolated rabbit hearts. The contributions from the labs of Drs. Vos, Wellens et al. [19] and by Dr. deGroot and co-workers [20] conclude this section with studies that address arrhythmogenic mechanisms in an intact dog model of complete AV block, and the perfused, ischemic pig heart, respectively. In the former, a retrospective examination of SCDs in a large series of chronically blocked animals suggests that torsade de pointes tachyarrhythmias are likely to underlie SCD in this preparation and that changes in action potential duration can help identify susceptibility to this mechanism in the presence of major defects in conduction. The studies presented on the highly relevant pig model suggest that partial uncoupling between cells in mid-myocardium and sub-epicardial tissue layers may underlie second, acute phase arrhythmias that occur in this model during ischemia.
The final series of five papers deal with use of molecular, electrical and histological markers to identify increased predisposition to SCDs in man, while the last proposes an exciting new theory on the neural origins of lethal arrhythmias following myocardial infarction. Dr. Jouven and colleagues lead off with evidence that resting heart rate is an independent risk predictor for SCD in their long term longitudinal study of male Parisian civil servants [21]. The paper by Dr. Parchure et al. [22] focuses attention on use of altered QT dispersion as an indicator of cardiac arrest in patients with Printzmetal's angina, while the very extensive study of patients identified with acquired Long QT syndrome by Dr. Chevalier et al. [23] suggests QT dispersion may also be one of several markers helpful in characterizing individuals predisposed to this condition. Interestingly, they report molecular screening of more than a dozen such individuals revealed only one with mutations in an inherited Long QT associated ion channel gene. The paper by Dr. Corrado et al. [24] offers more of their careful histological work, continuing on the theme established in their review paper [13]. Here, they detail structural autopsy findings on a series of 273 SCDs in young people in the Veneto area. As recently observed in a retrospective series of autopsies done on unselected SCDs in adults and young people near Minneapolis, these investigators find in this likely "healthier" population, that structural defects with potentially adverse implications for tissue conduction irregularities are present in almost 90 percent of these cases. The concluding contribution by Dr. Chen et al. [25] proposes that myocardial infarction and ischemia result in cardiac nerve injuries that result in enhanced sympathetic nerve sprouting, increased electrical heterogeneity and propensity for SCD initiation. This interesting idea provides different perspective on earlier observations of the antiarrhythmic effects of beta-adrenergic blockers and deserves greater exploration.
The progress summarized in this issue suggests that indeed understanding of the electrogenic and conductive abnormalities that contribute to the origins of SCD has advanced considerably. Given these achievements, and important studies ongoing in many outstanding labs and clinics across the world, we remain encouraged and optimistic that much more effective prevention and diagnostic strategies for the devastating outcome of sudden, potentially fatal arrhythmic events remain not too far from present scientific horizons.
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- Myerburg J.R., Spooner P.M. Directions in sudden death prevention. Opportunities for new clinical and basic research. Cardiovasc Res (2001) 50:177–185.
[Abstract/Free Full Text] - Albert C.M., Ruskin J.N. Risk stratifiers for SCD in the community: primary prevention of SCD. Cardiovasc Res (2001) 50:186–196.
[Free Full Text] - Sotoodehnia N., Zivin A., Bardy G.H., Siscovick D. Reducing mortality from sudden cardiac death in the community: lessons from epidemiology and clinical applications research. Cardiovasc Res (2001) 50:197–209.
[Abstract/Free Full Text] - Lombardi F., Mäkikallio T.H., Myerburg R.J., Huikuri H.V. Sudden cardiac death: role of heart rate variability to identify patients at risk. Cardiovasc Res (2001) 50:210–217.
[Free Full Text] - Priori S.G., Napolitano C., Grillo M. Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res (2001) 50:218–223.
[Abstract/Free Full Text] - Roden D.M. Pharmacogenetics and drug induced arrhythmias. Cardiovasc Res (2001) 50:224–231.
[Abstract/Free Full Text] - Grönefeld G., Hohnloser S.H. What do inplantable cardioverter/defribrillators teach us about the mechanisms of sudden cardiac death? Cardiovasc Res (2001) 50:232–241.
[Abstract/Free Full Text] - Samie F., Jalife J. Mechanisms underlying ventricular tachycardia and its transition to ventricular fibrillation in the structurally normal heart. Cardiovasc Res (2001) 50:242–250.
[Abstract/Free Full Text] - Karagueuzian H.S., Chen P.-S. Cellular mechanism of reentry induced by a strong electrical stimulus. Implications for fibrillation and defibrillation. Cardiovasc Res (2001) 50:251–262.
[Abstract/Free Full Text] - Lerner D.L., Beardslee M.A., Saffitz J.E. The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia. Cardiovasc Res (2001) 50:263–269.
[Free Full Text] - Babuty D., Lab M.J. Mechanoelectric contributions to sudden cardiac death. Cardiovasc Res (2001) 50:270–279.
[Free Full Text] - Kohl P., Nesbitt A., Cooper P., Lei M. Sudden cardiac death by commotio cordis: role of mechano-electro feedback. Cardiovasc Res (2001) 50:280–289.
[Abstract/Free Full Text] - Basso C., Calabrese F., Corrado D., Thiene G. Postmortem diagnosis in sudden cardiac death victims: Macroscopic, microscopic and molucular findings. Cardiovasc Res (2001) 50:290–300.
[Free Full Text] - Clancy C., Rudy Y. Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cardiovasc Res (2001) 50:301–313.
[Abstract/Free Full Text] - Decolombe S., Lande G., Charpentier F., Roon M., van den Hoff M., Escande D. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterization. Cardiovasc Res (2001) 50:314–327.
[Abstract/Free Full Text] - Lande G., Decolombe S., Charpentier F., Bammert A., Moorman A.F., Escande D. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmalogical profile. Cardiovasc Res (2001) 50:328–334.
[Abstract/Free Full Text] - Plotnikov A.N., Shvilkin A., de Groot J.R., Xiong W., Rosenshtraukh L.V., Rosen M.R. Interactions between antiarrythmic drugs and cardiac memory. Cardiovasc Res (2001) 50:335–344.
[Abstract/Free Full Text] - Hondeghem L., Dujardin K., De Clerck F. Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia. Cardiovasc Res (2001) 50:345–353.
[Abstract/Free Full Text] - van Opstal J.M., Verduyn S.C., Leunissen J.D.M., de Groot S.H.M., Wellens H.J., Vos M.A. Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block. Cardiovasc Res (2001) 50:354–361.
[Abstract/Free Full Text] - de Groot J.R., Wilms-Schopman F.J.G., Opthof T., Remme C.A., Coronel R. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res (2001) 50:362–372.
[Abstract/Free Full Text] - Jouven X., Zureik M., Guérot C., Ducimetière P. Resting heart rate as a predictive risk factor for sudden death in middle-aged men. Cardiovasc Res (2001) 50:373–378.
[Abstract/Free Full Text] - Parchure N., Batchvarov V., Malik M., Camm A.J., Kaski J.-C. Increased QT dispersion in patients with Prinzmetal's variant angina and cardiac arrest. Cardiovasc Res (2001) 50:379–385.
[Abstract/Free Full Text] - Chevalier P., Rodriguez C., Bontemps L., Miquel M., Cura C., Touboul P., et al. Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res (2001) 50:386–398.
[Abstract/Free Full Text] - Corrado D., Basso C., Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res (2001) 50:399–408.
[Abstract/Free Full Text] - Chen P.-S., Chen L.S., Cao Ji.-M., Sharifi B.G., Karagueuzian H.S., Fishbein M.C. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res (2001) 50:409–416.
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