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© American Heart Association, Inc. All rights reserved. Initially, patients with HFrEF were deemed to have died suddenly if their symptoms had not recently worsened, and if another cause for cardiac arrest could not be identified.1 Yet, this approach was difficult to apply in practice. Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. However, the cellular and molecular bases of these defects remain controversial. In the early stages of congestive heart failure, your dog may show no signs at all. Three decades ago, sudden deaths were typically ascribed to an acute coronary occlusion. Normal impulse formation and conduction in cardiac myocytes depend on INa. The congenital long QT syndrome is associated with gain-of-function mutations in SCN5A, the cardiac Na channel,145 and loss of function in one of the genes that underlies the delayed rectifier K current (KCNH2, KCNQ1, KCNE1, KCNE2).146 Both types of mutations presumably produce prolongation of the ventricular action potential147 and exaggerated dispersion of repolarization, much like that in cells and tissues isolated from failing ventricles.8 QT interval shortening has been associated with sudden death,148–151 perhaps attributable to short but spatially heterogenous action potentials in the ventricle leading to ventricular fibrillation. The abnormal physiology of repolarization associated with the long QT syndrome may also predispose to lethal arrhythmias in the setting of ischemic heart disease.28 Common polymorphisms in long QT genes have also been described that predispose drug-induced QT interval prolongation and ventricular arrhythmias.152–154 It is possible that the same or other yet-to-be-discovered polymorphisms predispose to lethal arrhythmias in HF, a syndrome associated with diminished repolarizing reserve. Congestive heart failure is a severe progressive condition that affects the pumping power of heart muscles. According to specialists, there is plenty of work to be done to offer a cure for heart failure. There are likely to be specific genetically determined factors that are associated with a phenotypic response to stressors that includes the development of malignant ventricular arrhythmias. In the later stages of heart failure, doctors may recommend surgery to insert a left ventricular assisted device (LVAD) into the heart. Congestive heart failure (CHF) is a chronic progressive condition that affects the pumping power of your heart muscles. Weakness or lethargy (tiredness) 5. Second, a linkage between ventricular remodelling and acute mechanical failure resulting in sudden death has been supported by studies of sacubitril-valsartan in HFrEF. It is likely the natriuretic peptides are insufficient to prevent phenotypic progression in the failing heart; indeed, elevations in BNP are potent predictors of SCD in HF.118 Angiotensin II inhibits a number of K currents, including the Ca2+-activated K current in vascular smooth muscle cells,119 the transient outward K current (Ito1),116 and delayed rectifier K currents in the heart and smooth muscle.120–125 Other direct effects of angiotensin II on cardiac membrane transport include increasing chloride current112 and decreasing electrogenic Na+-K+ ATPase.126, The function of a number of ion channels and electrogenic transporters are regulated by aldosterone. Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Original received May 25, 2004; resubmission received August 10, 2004; accepted September 2, 2004. Sudden death in patients with HF is a complex phenotypic expression of a systemic disease that most often results from the unfortunate confluence of a number of factors. falling sand grains or snowflakes) is tolerated for long periods because tiny internal mechanisms ‘self-organize’ in a highly interdependent manner to support overall structural integrity.24,25 However, the ability of the self-organizing process to maintain stability is limited. The cellular substrate in regions remote from a scar and in chronically ischemic or hibernating myocardium consist of apoptosis with compensatory cellular hypertrophy.82 Myocytes isolated from both noninfarcted regions83 and hibernating myocardium84 are characterized by prolongation of AP duration and abnormalities of Ca+2 handling. AP prolongation in and of itself is likely to be an adaptive and perhaps an anti-arrhythmic response. Difficulty exercising 4. The ischemic and infarcted myocardium exhibits regional cellular and tissue remodeling, as well as inhomogenities of sympathetic nervous system innervation, that creates a substrate that is exquisitely sensitive to arrhythmia triggers. Greenberg H, Case RB, Moss AJ, Brown MW, Carroll ER, Andrews ML; MADIT-II Investigators. Sudden Cardiac Death and Athletes Sudden cardiac death (SCD) is a sudden, unexpected death caused by a change in heart rhythm (sudden cardiac arrest). Systematic comparisons of the CaT profile and dynamics in cells isolated from different regions of the failing heart are limited. The abrupt loss of structural integrity result from continuation of the same process; it does not require any new trigger, even though the collapse is acute. Interestingly, acute contractile failure may also be the underlying mechanism of sudden death, even if the electrocardiogram manifests ventricular tachycardia or fibrillation. Sudden death from congestive heart failure occurs because the heart is irritable from something else- and that something else is electrolyte imbalances from thiamine, potassium and Magnesium Deficiency. The concept of self-organizing criticality has also recently been used to understand biomedical events, such as protein–protein interactions, cancer, neurodegenerative disease, and genetic and metabolic cascades,26,27 as well as the initiation of cellular and organismal death. Steinberg BA, Al-Khatib SM, Edwards R, Han J, Bardy GH, Bigger JT, Buxton AE, Moss AJ, Lee KL, Steinman R, Dorian P, Hallstrom A, Cappato R, Kadish AH, Kudenchuk PJ, Mark DB, Inoue LY, Sanders GD. Although innumerable studies emphasize the arrhythmogenicity of sympathetic stimulation and the protective effects of parasympathetic stimulation, the actual electrophysiologic (or other) mechanisms by which the autonomic limbs exert their effects are complex and incompletely known. A mechanistic analog for SCD is the “multi-hit” hypothesis of tumorigenesis (Figure). has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. If an event had not been foreseen, physicians believed that a new mechanism had emerged and had triggered the abrupt circulatory collapse. Was the inevitability of death sufficient to negate the diagnosis of an unexpected death? The most common symptoms of heart failure are: breathlessness – this may occur after activity or at rest; it may be worse when you're lying down, and you may wake up at night needing to catch your breath Individuals with congestive heart failure often report dizziness, vertigo, nausea and … SCD is frequently associated with coronary artery disease (CAD),68–72 even in young victims.73 The majority of cases of HF in this country are the result of CAD,74–81 most often chronic CAD in the setting of previous myocardial infarction. Coughing 2. What if a patient had end-stage HFrEF but had stabilized with intensive therapy and then died abruptly? Milton Packer, What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?, European Heart Journal, Volume 41, Issue 18, 7 May 2020, Pages 1757–1763, https://doi.org/10.1093/eurheartj/ehz553. Difficult or rapid breathing 3. It is therefore noteworthy that, when cardiac resynchronization induces significant reverse remodelling, the substrate for acute electrical cascade is reduced (Take home figure)37,38; the risk of sudden death is decreased by ≈50% in patients without an ICD, primarily related to a decrease in lethal ventricular tachyarrhythmias in those who experience a marked decrease in ventricular volumes (Table 1).38,39 In contrast, in patients with severe symptoms and persistently dilated and fibrotic hearts, a significant risk for sudden death remains following cardiac resynchronization, and it is not reduced by an ICD.19,20. Significant alterations in conduction and activation of a number of initially adaptive but ultimately maladaptive signaling cascades contribute to the generation of a highly arrhythmogenic substrate. This current is also an important contributor to the AP plateau. There is likely to be a number of genetic factors that contribute to the complex phenotypic manifestation of SCD in the failing heart. Effect of drug, device and surgical interventions on the risk of sudden death in patients with left ventricular systolic dysfunction. Cardiac arrest is the mode of demise in 30–50% of patients with heart failure and a reduced ejection fraction (HFrEF), and conversely, systolic dysfunction is a major risk factor for sudden cardiac death in the community.1 Despite their clinical importance, the mechanisms that lead to abrupt circulatory collapse have long been misunderstood. The underlying basis of AP prolongation in the failing heart is likely to be multifactorial, with the extent to which reduction in functional expression of K currents versus other mechanisms (alterations in Ca2+ handling or changes in depolarizing currents) contribute to arrhythmia predilection being largely unknown. demise within 1 h of the onset of new cardiac symptoms—was developed to identify the event in the general population with no known heart disease. Recent studies show that substantial number of heart failure patients die from processes other than cardiac disease, in particular malignancies, respiratory problems and septicemias. In some patients with an ICD, the ventricular tachyarrhythmia recurs immediately or persists despite repetitive discharges.21 Acute mechanical failure is responsible for the abrupt cessation of circulatory support; the observed tachyarrhythmia represents an epiphenomenon. The extent to which AP prolongation correlates or is associated with altered dynamics of repolarization remains to be clarified. Some of the contributors may be well-known candidate genes in signaling pathways associated with electrical instability, generation, or progression of the HF phenotype and/or triggers associated with neurohumoral signaling and ischemia. The major causes of death are progression of heart failure and sudden non-arrhythmogenic death unrelated to ICDs – for example, secondary to stroke. The SWORD Investigators, Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure, Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure, Sudden death in implantable cardioverter-defibrillator recipients: clinical context, arrhythmic events and device responses, Mechanisms and immediate outcome of in-hospital cardiac arrest in patients with advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy, Diverse mechanisms of unexpected cardiac arrest in advanced heart failure, Self-organized criticality: an explanation of 1/ƒ noise, Cascading network failure across the Alzheimer's disease spectrum, Analysis of cascading failure in gene networks, Left ventricular geometry predicts ventricular tachyarrhythmia in patients with left ventricular systolic dysfunction: a comprehensive cardiovascular magnetic resonance study, Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure, Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction: a meta-analysis of randomized trials, Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study, Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), Effect on mode of death of heart failure treatment started with bisoprolol followed by Enalapril, compared to the opposite order: results of the randomized CIBIS III trial, Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials, Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment, Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchron-ization therapy, Left ventricular dimensions predict risk of appropriate shocks but not mortality in cardiac resynchronization therapy-defibrillator recipients with left bundle-branch block and non-ischemic cardiomyopathy, Reverse remodeling and the risk of ventricular tachyarrhythmias in the MADIT-CRT, Predictors of mortality from pump failure and sudden cardiac death in patients with systolic heart failure and left ventricular dyssynchrony: results of the CARE-HF trial, Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction, Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients, Declining risk of sudden death in heart failure, Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras, 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). asystole, bradyarrhythmia, or electromechanical dissociation).23,28 Incessant ventricular tachyarrhythmias that persist despite repetitive ICD discharges also reflect cascading mechanical failure.21 Because these rhythms are dissociated from mechanical activity, the lethal consequences of mechanical failure cannot be prevented by an ICD. In human HF, significantly reduced IK1 is observed at negative voltages.15 The molecular basis of IK1 downregulation in human HF is uncertain, but two studies report no change in the steady-state level of Kir2.1 mRNA in failing compared with normal hearts.19,20 Another study reported a differential reduction in IK1 in cells isolated from failing hearts with dilated versus ischemic cardiomyopathy, with the former group exhibiting altered voltage dependence compared with the latter,21 highlighting the importance of disease etiology in the details of electrical remodeling. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Cytokines and other mediators of inflammation have direct effects on ion channels91,92 and Ca2+ homeostasis, perhaps exaggerating the arrhythmogenic risk in the failing electrically remodeled heart. However, if unexpectedness were the determining factor in the identification of sudden deaths, could physicians reliably gauge the degree of unexpectedness? Regional heterogeneity of the electrophysiological properties of the infarcted heart is profound. Heart failure occurs when your heart can’t pump enough blood to meet your body’s demand. Inexcitable barriers and other tissue discontinuities may be created by fibrosis in the failing heart; however, cellular coupling may be impacted by a significant reduction in the density and altered distribution of gap junction channels. If sudden deaths comprise half of the deaths and if ICDs prevent half of sudden deaths, then ICDs should lead to a ≈25% reduction in all-cause mortality.2,9 However, the magnitude of the overall survival benefit is attenuated in those with advancing symptoms or comorbidities, in whom non-tachyarrhythmic events contribute importantly to the total deaths.2,11,12 In contrast, in patients with minimal symptoms or end-organ dysfunction, ICDs decrease all-cause mortality, because of the absence of competing risks for death.2,11–13. Some clues come from consideration of rare diseases associated with a high risk of SCD (rare disease paradigm). Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. ‘Self-organizing criticality’ within the ventricular myocardium relies on complex adaptations to progressive cardiomyocyte stress and stretch, which can come to an abrupt end (‘cascading failure’), thus leading to acute circulatory collapse (i.e. Background—Sudden unexpected death frequently occurs in chronic heart failure.The importance of acute coronary events in triggering sudden death (SD) is unclear. Heart failure serves to enhance the risk by the associated alterations in the myocardial substrate and increasing the frequency/intensity of triggers of malignant arrhythmias. The risk of SCD is highly time-variant, reflecting temporal heterogeneity of both the myocardial substrate and triggers. Angiotensin II delivered to the myocardium or produced locally by any one of a host of peptidases promotes the elaboration of cytokines, growth factors, and the elaboration of fibrosis by myofibroblasts. Congestive Heart Failure (CHF) is not yes or no it is a spectrum of severity. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, Professor Michael A. Gatzoulis speaks about his life, career, and pioneering work with adult congenital heart disease, The growing population of patients with adult congenital heart disease: novel insight into treatment, participation in competitive sport, and care planning, Coronary flow velocity reserve predicts adverse prognosis in women with angina and no obstructive coronary artery disease: results from the iPOWER study, Out-of-Hospital Cardiac Arrest: Handle With Care–, Assessment and pathophysiology of microvascular disease: recent progress and clinical implications, http://creativecommons.org/licenses/by-nc/4.0/, Receive exclusive offers and updates from Oxford Academic, Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study, Anti-cancer drugs associated with sudden death and ventricular arrhythmias: a cardio-oncology pharmacovigilance analysis, The risk of sudden cardiac death or ventricular arrhythmias on Immune checkpoint Inhibitors, Survival analysis in arrhythmogenic/dilated cardiomyopathy caused by pathogenic DSP truncating variants. The consequences of the effects of fibrosis include an enhanced predisposition to macroscopic discontinuities in conduction, unidirectional block, and re-entry. A correlation of clinical and hemodynamic studies in patients with hyperthyroidism with and without congestive heart failure. Once the limit is breeched, the extreme interdependence leads to a ‘cascading failure’, where the tiny fault of one part immediately triggers the failure of other components. From September 16, 1997, to July 18, 2001, we randomly assigned 2521 patients in equal proportions to receive placebo, amiodarone (Cordarone, Wyeth–Ayerst Pharmaceuticals), or a single-chamber ICD programmed to shock-only mode (model 7223, Medtronic). The process of cardiac remodelling in patients with HFrEF represents a self-organizing system of highly vulnerable interdependence. This denervation is associated with an exaggerated response to infused catecholamines or denervation supersensitivity in the form of exaggerated shortening of ventricular effective refractory periods and enhanced inducibility of ventricular fibrillation in the presence of catecholamines.97 Alterations of sympathetic innervation are not limited to the acute and healing phases of myocardial infarction. For example, angiotensin converting-enzyme inhibitors and beta-blockers might prevent a new myocardial infarction that can trigger sudden death.30 Beta-blockers and spironolactone may protect against circadian catecholamine surges and/or electrolyte imbalances that can trigger lethal ventricular tachyarrhythmias.16 These possibilities are difficult to dismiss, since most of the large-scale trials with neurohormonal antagonists were carried out in an era when the background utilization of ICDs was very low, thus making it impossible to distinguish between purely electrical (ICD-preventable) and primarily mechanical (ICD-non-preventable) pathways leading to sudden death. Left-sided heart failure occurs when the heart is unable to pump enough blood throughout the body. Evidence for the importance of mechanoelectrical feedback, Myocardial fibrosis predicts appropriate device therapy in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death, Hormone-electrolyte interactions in the pathogenesis of lethal cardiac arrhythmias in patients with congestive heart failure. We head each section with the supposition that the abnormality reviewed is the cause of SCD in HF. Tel: +1 214 820 7500, Email: Search for other works by this author on: Sudden unexpected death in patients with congestive heart failure: a second frontier, Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial, Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial, Rosuvastatin in older patients with systolic heart failure, Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial, Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease, The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure, Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II), Defibrillator implantation in patients with nonischemic systolic heart failure, Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure, Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials, New York Heart Association class and the survival benefit from primary prevention implantable cardioverter defibrillators: a pooled analysis of 4 randomized controlled trials, Stretch-induced arrhythmias in the isolated canine ventricle. J Clin Invest. All patients were followed until October 31, 2003. However, this approach could not be applied to patients with HFrEF, who had ongoing symptoms and an established cardiovascular disorder. 1-800-AHA-USA-1 1-800-242-8721 Left ventricular reconstruction (LVR) can help treat CHF, reduce the risk of sudden death and improve your quality of life. Did the designation of sudden death imply the development of a new pathophysiologic mechanism? Cardiac dilatation and scarring are ideal substrates for the initiation of ventricular tachyarrhythmias that can lead to circulatory collapse.14,15 Fibrosis probably underlies the genesis of most sustained ventricular tachyarrhythmias, whether or not the patient has coronary artery disease.15 But what are the acute triggers for these fibrosis-related arrhythmias? The details of altered neurohumoral signaling are controversial, but universally accepted are the activation of adrenergic and renin-angiotensin-aldosterone (RAAS) signaling and its role in progression in the HF phenotype. A number of studies in animal models and humans have implicated altered conduction through the myocardium in sudden death. Variable changes in the density of DHP binding sites have been reported.7 Similarly, studies of human Ca channel subunit mRNA in HF exhibit disparate findings.37–39 The complexity of the molecular basis of channel remodeling is highlighted by reports of isoform switching of both α1C39,40 and β subunits41 in the failing heart. sudden death) in the absence of an identifiable triggering event. This pattern of redistribution of Cx43 is prominent in the border zones of experimental myocardial infarction, which is characterized by slow conduction and is an important substrate for re-entrant ventricular arrhythmias.64–66 Alterations in cell size and shape characterize the failing heart.

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