Notes on sudden cardiac death

Notes on Sudden Cardiac Death
Definitions • Unexpected natural death from a cardiac cause within a short time period (generally demise from cardiovascular collapse <= 1 hour from onset of symptoms according to Framingham Heart Study) in a person without any prior condition that would appear fatal (Zipes and Wellens 1998; 98:2334-2351) (Leor et al NEJM 1996; 334:413-419) (Marks and Greene Cardiac Arrhythmias 1995) Other researchers use WHO definition of sudden death as death occurring within 24 hours of the onset of acute symptoms (Myers and Dewar Br Heart J 1975 37:1133-1143) Prodromal symptoms often non-specific, and chest pain (ischaemia), palpitations (tachyarrhythmia) or dyspnoea (cardiac failure) are suggestive only. (Zipes and Wellens 1998; 98:2334-2351)

Epidemiology • Sudden cardiac death accounts for 300-400,000 deaths per year in US, and is most common and often the first presentation of CHD responsible for >50% of the mortality from cardiovascular disease in US (Zipes and Wellens 1998; 98:2334-2351) or between 200,000 and 600,000 p.a. in US (Marks and Greene Cardiac Arrhythmias 1995) (Hirsch and Adams Spitz and Fisher) 80-90% of sudden cardiac death patients have significant CAD (Chugh et al Circulation 2000 102(6):649-654) Sudden cardiac death in those with structurally normal heart – 20% of sudden cardiac deaths (Brugada et al 2004 Circulation 109:30-35) 50% (Chugh et al Circulation 2000 102(6):649-654) 80% have CHD – smaller amount of nonatherosclerotic coronary artery causes e.g. arteritis, embolism, dissection and malformations such as anomalous left coronary artery origin (Zipes and Wellens 1998; 98:23342351) In Paris study, 72% of sudden cardiac death victims had no cardiac history. 83% occurred at home (and at rest), 30% of those were sleeping. Sudden cardiac death usually occurred on a background of severe coronary disease with multivessels stenosed, but rarely thrombosed (15%) (Fornes et al Journal of Forensic Sciences 1993 38(5))

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Notes on sudden cardiac death Davies and Popple (Histopathology 1979 3:255-277) stated that 33% have recent occlusive thrombus, whilst 66% have stenosis only. Occlusive thrombus present in 30% cases of sudden cardiac death, mural thrombus in 43% and plaque fissuring in 8%. Davies 1992 Circulation 85: (Supl 1) 19-24). New thrombotic event underlies 50-70% of sudden deaths caused by IHD. (Davies Heart 2000 83:361-366) Occlusive thrombus recognised by hospital pathologists in 23% of cases, recent MI in 20% and old MI scar in 56%. Occlusive thrombus more common in those with prodromal chest pain. 25% of non-fatal infarctions are silent and medically unattended. (Norris Heart 2000 83:726-730) 50-75% of sudden death cases have thrombus (remainder have >75% cross sectional area luminal narrowing) (Kolodgie Heart 2004 90: 1385-1391) New coronary plaque rupture independent of old MI is major cause of sudden death in those with old MI (recent thrombus/ plaque rupture in 55%, arrhythmia in 24%, pump failure in 14%) (Takada et al Legal Medicine 2003 5:S292-294) 4.1% in 16-64 age-group are unexplained (Sudden Arryhthmic Death Syndrome) (Behr et al 2003 Lancet 362:1457-59) Incidence of sudden cardiac death in England in healthy people 16-64 years is 11 per 100,000 (3500 deaths) per year (Behr et al 2003 Lancet 362:1457-59) Most people who die of SADS are young males who die while inactive or in sleep (Behr et al 2003 Lancet 362:1457-59) Ventricular fibrillation is the main mechanism of sudden cardiac death – vast majority have structural heart disease, those who do not have ‘idiopathic VF’. (Gaita F et al Circulation 2003; 108:965-970) 80% occur at home and 40% are unwitnessed (Maastricht study) (Zipes and Wellens 1998; 98:2334-2351) First-degree relatives of those suffering sudden cardiac death identified 7 families with familial cardiac disease, with probable Long QT syndrome predominating. (Behr et al 2003 Lancet 362:1457-59) Familial history of sudden cardiac death is associated with major (resuscitated cardiac arrest, syncope) and minor (palpitations, dizziness, atrial fibrillation) arrhythmic events and inducible VF at programmed stimulation (Gaita F et al Circulation 2003; 108:965-970) Myocardial fibrosis provides a predisposition to electrical instability, re-entry circuits and fatal arrhythmias. (Lecomte D et al Journal of Forensic Sciences 2003; 38(3)? Page)

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Notes on sudden cardiac death • Sudden death due to primary VF without evidence of structural heart disease occurs in approximately 5% of cases. (Zipes and Wellens 1998; 98:2334-2351) 33% of people present with CAD present with sudden cardiac death (Chi and Kloner stress and MI) in sudden cardiac death 95% of hearts have an abnormality, although in 30% this abnormality is non-specific e.g.. Interstitial fibrosis (Chugh et al Circulation 2000 102(6):649654) acute MI was the underlying mechanism of sudden cardiac arrest (out-of-hospital) in 24/47 patients; ischaemic event or primary arrhythmia due to old MI in 19/47 (de VreedeSwagemakers JJM et al Heart 1998 79:356-361) new thrombotic event underlies 50-70% of sudden deaths caused by Ischaemic Heart Disease (Davies Heart 2000 83:361-366)

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Risk Factors • Generally identify risk of structural heart disease underlying sudden cardiac death rather than the proximate precipitator of the event. 80% of those who suffer sudden cardiac death have CHD (Zipes and Wellens 1998; 98:2334-2351) Incidence of sudden cardiac death increases with age, sex variation M>F (3-4 times higher), white=black (because incidence of heart disease increases with age) Among people with CHD, the proportion of sudden deaths decreases with age. Peaks of incidence birth-6 months (SIDS) and 45-75 due to CHD Physical activity controversial. Vigorous activity – can trigger sudden death and MI (increased platelet adhesiveness) but decreased in moderate activity. Regular exercise in dogs increases vagal activity and reduces ischaemia induced VF and death. Vigorous activity in untrained people may have adverse effects – relative risk in men with low levels of habitual activity = 56 (95% CI 23-131) whilst in those with high levels of habitual activity = 5 (95% CI 2-14) Myocardial Infarction Onset Study 5 fold increase of risk of MI on heavy exertion and 2 fold increase in Triggers and Mechanisms of Myocardial Infarction Study (TRIMM) (Willich et al Circulation 1993 87(5):1442-1450). Maastricht Sudden Death study – 67% of sudden deaths were inactive at time of event. Sexual activity doubles risk of MI (Chi and Kloner stress and MI) Anatomy – acute changes in plaque morphology (thrombus, plaque disruption or both >50% of sudden cardiac deaths). Plaque erosion is common. Rupture >older women. ?role of

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Notes on sudden cardiac death apoptosis in genesis of arrhythmias or conduction disturbances? Hypertension LVH Impaired left ventricular function (particularly in men) – in severe heart failure, non-sustained VT may be independent marker of increased mortality due to sudden cardiac death. Also major independent predictor of sudden death in ischaemic and non-ischemic cardiomyopathies. 50% of those who die due to heart failure do so suddenly. Intraventricular conduction block Elevated serum cholesterol – predisposition to vulnerable plaque rupture? Glucose intolerance Decreased vital capacity Smoking –Framingham study 2.5 times risk of sudden death in smokers of >20 per day (increased platelet adhesiveness, catecholamine release?) Relative weight Heart rate Emotional stress/arousal –fear, anger, tension, sadness, police questioning or arrest, altercations (verbal or physical) (Lecomte et al 1996 79:1-10) o role of emotional stress in coronary heart disease suggested by John Hunter ‘my life is at the mercy of any scoundrel who chooses to put me in a passion’. (Lecomte et al For Sci Int 79:1-10) o stressful cardiac sudden death occurs primarily in those with severe heart disease (40/43 cases) with no premonitory symptoms, and occurred instantaneously. 75% of cases occurred during the stress or within minutes afterwards. (Lecomte et al For Sci Int 79:1-10) o Reich et al (JAMA 1981 246(3):233-235) studied people who had VF and identified preceding acute psychological disturbances in the preceding 24 hours in 21% – predominant affect was anger. Others included acute depression, fear, anticipatory excitement and grief. o Sporting events – increased mortality from CHD on day of Netherlands v France 1996 European Football Championship (penalty shoot out); increased admissions for acute MI day of England v Argentina 1998 World Cup (penalty shoot out); reduction in mortality from MI in men following France winning 1998 World Cup (Chi and Kloner stress and MI) o Disasters – Los Angeles /Northridge earthquake 1994 – sharp increase in sudden cardiac deaths on day of earthquake (from a daily average of 4 in preceding

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Notes on sudden cardiac death week to 24 on day of earthquake – relative risk 2.4 (95% CI 1.9-3.0). Most deaths occurred in those with CAD and the team estimate that 41% of sudden deaths in persons with atherosclerotic cardiovascular disease that occur under ordinary circumstances are related to a triggering mechanism. In 2/3rds symptoms developed or the victim died immediately or within the first hour after the earthquake. Unusual physical exertion contributed in only 3 cases. Hospital admissions for acute MI increased by 35% in California in week after earthquake, and those with implantable cardioconvertors experienced an increase in VT /VF in 2 weeks following quake. (Leor et al NEJM 1996; 334:413-419) 1981 Athens earthquake – increase in deaths due to atherosclerosis (Trichopoulos et al Lancet 1983 26:441443); Massachusetts Blizzards 1974-78 increase of 22% deaths due to atherosclerosis. (Glass and Zack Lancet 1979 1:485-487) o War – initial days of 1991 Gulf War – missile strike in Israel, sharp increase in sudden cardiac deaths (Meisel et al Lancet 1991 338:660) o Life events – on impact of collapse and death of close person, during period of acute grief (within 16 days), threat or loss of close person, during mourning or anniversary, loss of status or self esteem, personal danger or threat of injury, real or symbolic, after danger is over, reunion, triumph, happy ending (peak ages affected men 45-55, women 70-75). Common denominators = overwhelming excitement, loss of control over situation/ self, giving up/ hopelessness/ helplessness (Engel Folklore or folk wisdom?) Cardiac Arrhythmia Pilot Study (CAPS) – depression, type B behaviour and low pulse-rate reactivity to challenge all significant predictors of cardiac arrest. Recurrent Coronary Prevention Project – type A behaviour significant predictor of sudden cardiac death (in post- MI follow up). (Willich et al Circulation 1993 87(5):1442-1450)-

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Notes on sudden cardiac death o Day of week – stress of returning to work – increased MI incidence on Mondays (Chi and Kloner stress and MI) Time of day – circadian rhythm (Chi and Kloner stress and MI) (Willich et al Circulation 1993 87(5):1442-1450)- more sudden deaths (three-fold increase), strokes and MIs, episodes of transient myocardial ischaemia, ventricular and supraventricular arrhythmias in morning on wakening/ hours immediately after arising from bed ? sympathetic discharge in response to venous pooling which triggers increased heart rate, systemic arterial blood pressure and increased blood coagulability (viscosity and platelet aggregation), decreased fibrinolytic activity? (Leor et al NEJM 1996; 334:413-419) sudden deaths associated with the evening (6-10pm) (Myers and Dewar Br Heart J 1975 37:1133-1143) (Willich et al Circulation 1993 87(5):1442-1450) Relationship with food –association of sudden death with the hour after a meal (Myers and Dewar Br Heart J 1975 37:1133-1143) Type of water - Davies and Popple (Histopathology 1979 3:255-277) reported an excess of sudden cardiac deaths in areas with soft water post MI – whole set of predictive factors (MADIT trial population (Multicentre Automatic Defibrillator Implantation Trial) – spontaneous non-sustained VT, inducible VT not suppressed by iv procainamide and an ejection fraction of <35% Alcohol – heavy drinking (>6 drinks daily) can induce cardiac arrhythmias and VT and have a 2 fold increase in risk compared to other drinking categories combined, particularly in older drinkers (50-59). This association was clearer in those with no evidence of prexisting ischaemic heart disease. Heavy drinking raises blood pressure. Heavy drinking is associated with an increase in incidence of sudden death as well as the suddenness of death. (Wannamethee and Sharper Br Heart J 1992 68:443-8) Arrhythmias described in heavy drinkers after binges include isolated ectopic beats, AF, paroxysmal atrial tachycardia, junctional tachycardia and VT. Mechanism unknown. Conduction defects known in overt alcoholic cardiomyopathy. (Ettinger et al Am Heart J 1978 95(5): 555562) alcohol increases blood pressure. (Hirsch and Adams) Sudden death also recorded in alcoholic fatty liver (Sheppard and Davies). ECG abnormalities – AV block or intraventricular conduction defects and QT prolongation in survivors of out-of hospital cardiac arrest and non-sustained VT. Autonomic state – sinus node activity taken as surrogate for autonomic activity within ventricles - baroreflex sensitivity,

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Notes on sudden cardiac death reflecting a vagal response to acute blood pressure elevation is reduced in patients at risk of sudden death. Heart rate variability reflects tonic vagal action and baroreflex activity reflects reflex vagal activity. Chaos theory – apparently irregularly irregular events, such as ventricular ectopy, are non-randomly distributed in time, and their clustering can be quantified by fractal geometric analysis, which could help identify at risk patients. Myocardial infarction produces regional cardiac sympathetic and parasympathetic dysfunction in infracted area and in regions apical to infarct (disruption of fibres crossing area of infarction). Denervated regions are more sensitive to catecholamines, resulting in differential conduction/ refractoriness, predisposing to arrhythmias. (Similar situation also seen in heart failure and ventricular dilatation). I.e. Creates electrical heterogeneity, favouring development of VF. Vagal stimulation is profibrillatory to atria, but may mitigate ventricular arrhythmias. Increase in basal tone or acute stimulation of the CNS by drugs or electrical stimuli lowers the threshold for cardiac electric instability and may evoke a variety of arrhythmias, including VF (Willich et al Circulation 1993 87(5):1442-1450) Deaths from vagal inhibition have been described by Simpson (1949 Lancet 558-560) – afferent stimulation from sensory nerves of the skin, pharynx, glottis, pleura, peritoneum covering viscera and extending into the spermatic cord, of the cervix, of the urethra, and of the peritoneum via spinal cord lateral tracts to the vagal nucleus to exert their effect via efferent fibres. Particularly important in any pressure to the neck or during medical procedures without adequate sedation/ anaesthesia. Blow to larynx or upper abdomen, kick to scrotum, pressure on carotid sinus, cannulation of cervix etc implicated in sudden death due to vagal reflex (Hirsch and Adams). Carotid sinus pressure – usually used to elucidate underlying mechanism and prompt treatment of various supraventricular tachycardias and their differentiation from ventricular arrhythmias. Case reports of VT arising as a result of coronary sinus pressure, mechanism unknown. Ventricle appears to be influenced by vagal stimulation, and increased vagal tone as part of the carotid sinus reflex produces a negative inotropic effect on the left ventricle. ? do those who experience problems have an unusually rich ventricular cholinergic

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Notes on sudden cardiac death innervation? After release of CSP there is a reflex sympathetic stimulation, and catecholamines released come from myocardial stores rather than those of sympathetic nerve endings, allowing possible asymmetric distribution of catecholamines contributing to genesis of ventricular ectopics and arrhythmias. Also, CSP induces AV block, and decreased heart rate, associated with increased asynchrony of recovery of excitability of ventricular muscle. (Cohen Am Heart Journal 1972 84(5):681-686) One group has reported the apparent association of sudden death in adults with a common mitochondrial DNA deletion (mtDNA4977 deletion), with cardiac muscle being particularly affected (Polisecki et al J Forensic Sci 2004 49(6):1-4) Transient Risk Factors (Zipes and Wellens 1998; 98:23342351) – structural cardiac abnormalities provide substrate upon which transient risk factors operate. o Myocardial ischaemia – assumed that in CHD transient ischaemia, perhaps caused by coronary artery spasm or platelet thrombi precipitate lethal arrhythmia (because 20% only of cardiac arrest survivors develop transmural infarction). Perhaps it is combination of ischaemia, hypertrophy, CCF and cardiac dilatation as well as regional autonomic dysfunction? May be caused/ exacerbated in certain circumstances by anti-arrhythmic drugs e.g.. Flecanide in CAST ( Cardiac Arrhythmia Suppression Trial) o Reperfusion o Haemodynamic dysfunction o Abnormalities in electrolytes (hypokalaemia and hypomagnesaemia) o Changes in Ph or P02 o Influence of central and peripheral neurophysiological actions o Transient effects of drugs, toxins or alcohol Degree of coronary cardiac death artery atherosclerosis and sudden

Coronary blood flow begins to reduce with stenosis >50% and decreases rapidly when it exceeds 70%. Calculation of % diameter stenosis doesn’t take into account other factors influencing physiological impact of the stenosis e.g. lesion length or geometry. PM studies using perfusion-fixed material (at or near diastolic pressure levels) have shown stenotic

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Notes on sudden cardiac death lumen to be usually circular, even in advanced lesions. The problem with determining % stenosis is that adjacent areas are used as a reference, but these are not usually free of disease, and the effect of arterial remodelling (to conserve lumen diameter) will result in underestimation. (Stary et al Circulation 1995 92: 1355-1374) The heart receives 1/20th of the cardiac output under basal conditions. This increases 3-4 fold with exercise, to accommodate the increase in oxygen demand. Increase in blood flow is needed by myocardium due to the near complete oxygen extraction under basal conditions. Coronary artery disease of epicardial vessels incorporates a new pathological resistance to coronary blood flow; o Stenosis of <50% is unlikely to be of haemodynamic significance o Stenoses >50% - there is a complex and curvilinear relation to reduction in maximum coronary flow o Longer lesions produce greater haemodynamic changes (studies now use PET to measure coronary flow) (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) Prinzmetal’s variant angina – mild coronary stenoses displaying vasoconstrictive responses, sufficient to occlude artery, causing ST elevation, which can resolve by the administration of nitrates. The reason for the sensitivity of the arteries is unknown. (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) Microvascular angina – instability of microvascular tone on exercise (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) 33% of sudden cardiac deaths are caused by acute total coronary occlusion by thrombus (Willich et al Circulation 1993 87(5):1442-1450) others say very many fewer thrombi will be found but that sudden cardiac death occurs on a background of severe coronary artery disease (Myers and Dewar Br Heart J 1975 37:1133-1143) episodes of symptomatic or asymptomatic myocardial ischaemia with underlying chronic coronary artery disease are associated with increased risk of sudden arrhythmia (Willich et al Circulation 1993 87(5):1442-1450) 40-86% of those surviving cardiac arrest have >75% stenosis recent occlusive thrombus found in 15-64% of sudden cardiac death minimum degree of disease reasonably associated with sudden death is one area of 85% stenosis (pinpoint) Davies and Popple (Histopathology 1979 3:255-277). They go on to say that 75% is the least degree of stenosis reasonable to cause death, when taken in conjunction with circumstances of

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Notes on sudden cardiac death death. In a later article Davies (Histopathology 1999 34:9398) states that 75% is ‘pinpoint’. For practical reasons, Davies and Popple (Histopathology 1979 3:255-277) state that ‘it is reasonable to assume that under 65 yrs-of-age heavy calcification is likely to be associated with enough stenosis to cause death – over 65 the correlation of calcification with stenosis is far less good. no specific pattern of coronary artery lesions favour sudden death (Zipes and Wellens 1998; 98:2334-2351) although Myers and Dewar (Br Heart J 1975 37:1133-1143) found sudden death to be associated with recent occlusion of the right coronary artery and with posterior infarction than of the left anterior descending and anterior infarction. acute ischaemia can be provoked by spasm (e.g. at the site of an eccentric coronary plaque in which a segment of normal media is retained (Davies Histopathology 1999 34:93-98)), platelet thrombi, dissection, plaque rupture or other vasoactive event platelet activation and aggregation followed by thrombus formation on fissured plaque can have direct effect on electrophysiological properties of the heart and provoke arrhythmias chronic ischaemia and collateral formation mitigates extent of ischaemia produced by sudden coronary occlusion thrombosis of the right coronary artery is clinically associated with transient AV block beginning some 24 hours after onset of pain and lasting 3-4 days before sinus rhythm returns. Davies and Popple (Histopathology 1979 3:255-277). Some called right coronary artery as artery of sudden death, others called left coronary artery that due to occlusion of this causes infarction of over 60% of the left ventricle, and is often rapidly fatal from cardiogenic shock. Davies and Popple (Histopathology 1979 3:255-277). Visual aid for assessment of coronary artery stenosis (Champ and Coghill J Clin Path 1989 42(8):887-8) – a narrowing of 75% reduces coronary blood flow at times of stress and exertion and narrowing of 90% means that coronary blood flow is severely reduced at rest. One could do planimetry of multiple cross sections of vessels that have been fixed, decalcified and stained for elastin, and give a good estimation of luminal area narrowing. Vessels that have been perfused and fixed at physiological pressures before dissection give the

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Notes on sudden cardiac death most meaningful results. But we use the more simple subjective measure of slicing and estimation. Estimate pictures given for concentric round, eccentric round and slit shaped lumena. Major cause of acute coronary thrombosis is plaque rupture (Kolodgie Heart 2004 90: 1385-1391)

Role of Ischaemia • pH drops to <6, interstitial potassium levels increase to >15 mmol/L, intracellular calcium levels rise and neurohumoral changes contribute to electrophysiological changes – slowed conduction, reduced excitability and prolonged refractoriness, cell-to-cell uncoupling and the generation of spontaneous electrical activity the accumulation of free fatty acids and their metabolites, the formation of lysophosphoglycerides and impaired myocardial glycolysis may all contribute to electrical instability leading to cardiac arrhythmias. Development of VF? Re-entry is dominant mechanism, but also regional changes in automaticity and triggered activity due to after-depolarisations Reperfusion may be arrhythmogenic Global myocardial dysfunction in severely diseased hearts is more likely to lead to bradycardia, asystole or EMD/ PEA Electrical heterogeneity is key to development of VF – all hearts demonstrate some degree of heterogeneity e.g. conduction velocities and refractoriness etc between different cell types (ventricular muscle versus Purkinje fibres) – therefore must be extreme heterogeneity e.g. if one region becomes ischaemic etc Myocardial necrosis caused by either proximal coronary artery occlusion or intramyocardial platelet aggregation and microemboli can create a substrate for VF (Willich et al Circulation 1993 87(5):1442-1450) Scarred myocardium is associated with electrical instability (Willich et al Circulation 1993 87(5):1442-1450) (Lecomte et al For Sci Int 1996 79:1-10) Ischaemia is the common basis of arrhythmias in sudden death. The ischaemia is produced by fixed atheromatous obstructions compounded by transient risk factors e.g. transient elevations in blood pressure, which increase afterload, increase oxygen demand; or sympathomimetic irritation of the heart e.g. by caffeine, cocaine and epinephrine; coronary artery spasm at site of fixed but eroded obstruction; platelet embolisation from an ulcerated plaque leading to localised myocardial ischaemia and irritability;

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Notes on sudden cardiac death transient thrombosis at the site of a fixed but eroded obstruction. (Hirsch and Adams) Only a small amount of cardiac arrest survivors go on to develop signs of an infarct, just electrical instability (Hirsch and Adams) 4/5ths of patients with CAD do not have evidence of Q wave infarcts after cardiac arrest, although 38% have elevated cardiac enzymes consistent with myocardial damage. 19% of patients with CAD have a new Q-wave MI associated with the episode of VF. (Marks and Greene Cardiac Arrhythmias 1995) Cause of death in those with coronary stenosis but no recent occlusion can be regarded as pathophysiological due to enhanced ventricular electrical instability. Examination of the conduction system often unrewarding. Davies and Popple (Histopathology 1979 3:255-277). Old scarring from previous infarcts is present in 16-55% of sudden ischaemic deaths Davies and Popple (Histopathology 1979 3:255-277).

Atherosclerotic plaque factors • Picture of histological lesion types based on American Heart Association Committee on Vascular lesions. (Fayed and Fuster Circ Res 2001; 89: 305-316) Erosion of proteoglycan-rich and smooth muscle cell rich plaques lacking a superficial lipid core or plaque rupture is a frequent finding in sudden death due to coronary thrombosis (44%). Occurs more often in younger individuals, women, with less luminal stenosis, less calcification and less often have foci of macrophages and T cells in comparison with plaque ruptures. (Farb et al Circulation 1996 93:1354-1363) Plaque rupture in 60-75% of patients with acute coronary syndromes. ACS (unstable angina, acute MI and sudden death) precipitated by luminal thrombi o Rupture – lesion with necrotic core, overlying thin disrupted fibrous cap infiltrated by macrophages and T lymphocytes. The luminal thrombus forms due to physical contact between platelets and thrombogenic necrotic core. o Erosions – luminal thrombus superimposed on proteoglycan rich plaque containing mostly smooth muscle cells with few inflammatory cells (25-40% of all coronary thrombi). Most lack necrotic core, but when present, there is no direct communication with luminal thrombus as overlying fibrous cap is intact and thick. o Calcified nodule – least common (2-7%) of lesions that cause coronary thrombi. Contain calcified plates with

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Notes on sudden cardiac death bony nodules that penetrate lumen, which contains disrupted endothelium. (Kolodgie Heart 2004 90: 13851391) Plaque progression beyond 40-50% cross sectional luminal stenosis occurs secondary to repeated ruptures, which are clinically silent. The % of healed plaque ruptures mirrors % stenosis. (Kolodgie Heart 2004 90: 1385-1391) Thin cap fibroatheromas cause less severe narrowing, but sudden death is the 1st presentation of their coronary disease. They are primarily located in the proximal coronary arteries especially the LAD. Risk factors for TCFAs – increased total cholesterol, increased total cholesterol/ HDL-C ratio, women >50 yrs, patients with increased CRP levels. (Kolodgie Heart 2004 90: 1385-1391) The vulnerable atherosclerotic plaque – often no severe stenosis, large lipid pool (core >50% of overall plaque volume), inflammatory cell accumulation (high density of macrophages, T lymphocytes), thin fibrous cap (in which collagen structure is disorganised), smooth muscle cell loss (‘low density’), collagen loss, overexpression of metalloproteinases, tissue factors and PAI-1. (Tissue factor +ve expressed by macrophages in atheroma, and potently initiates blood coagulation cascade. PAI-1 also macrophage expressed – inhibits fibrinolysis). (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) (Davies Heart 2000 83: 361366) Atherosclerotic plaque (Davies Heart 2000 83: 361-366) o Core of lipid (extracellular mass of lipid containing cholesterol and its esters) surrounded by capsule of CT and macrophages, many of which are lipid laden ‘foam cells’. These macrophages are circulating monocyte derived, which have crossed the arterial lumen and are highly activated, producing procoagulant tissue factor and inflammatory cell mediators e.g. TNF alpha, interleukins and metalloproteinases. The connective tissue capsule surrounding the inflammatory mass is predominantly collagen, synthesised by smooth muscle cells. The portion of the capsule separating the core from the arterial lumen is the plaque cap. o Plaque progression – endothelium over and between plaques shows enhanced replication, implying endothelial cell immaturity and abnormal physiological function. Focal denudation allows exposure of underlying CT matrix and platelet adhesion, contributing to plaque smooth muscle cell growth by release of platelet derived growth factor.

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Notes on sudden cardiac death • Mechanisms of thrombosis (Davies Heart 2000 83: 361-366) o Extension of denuded area with thrombus adherence (endothelial erosion). Linked to proximity of macrophages which cause endothelial cell death by apoptosis and by production of proteases which cut loose the endothelial cells from their adhesion to the vessel wall. Occurs in 50% of major thrombi in women. o Plaque disruption/ fissuring/ rupture – plaque cap tears, exposing lipid core to arterial blood. The core is highly thrombogenic, containing tissue factor, collagen fragments and crystalline surfaces to accelerate coagulation. Thrombus forms in the plaque and expands and distorts to extend into the lumen. The CT matrix in the cap is constantly being replaced and maintained by the smooth muscle cells. Collagen synthesis is reduced by inflammation by inhibiting the SMCs and causing death by apoptosis. Macrophages also produce wide range of MMPs capable of degrading all components of the CT matrix (they are activated by plasmin). MMPs are upregulated by inflammatory cytokines e.g. TNF alpha and the plaque is disrupted (‘auto destruct phenomenon associated with enhanced inflammatory activation’). Occurs in >85% of major coronary thrombi in white men with increased LDL and reduced HDL. Sequence of thrombotic events (Davies Heart 2000 83: 361366) o Platelet thrombus in core, protrudes into lumen and fibrin component increases. Covering with activated platelets, which are swept downstream in clumps into distal intra-myocardial arteries as microemboli. Thrombus may occlude artery leading to final stage in which there is a loose network of fibrin containing large numbers of entrapped RBCs. This can propagate distally after the onset of myocardial infarction. The final stage thrombus has structure making it susceptible to natural/ therapeutic lysis, but this will expose the deeper/ earlier thrombus, which is more resistant to lysis. Symptoms in relation to coronary thrombi (Davies Heart 2000 83: 361-366) o Thrombi which project into the lumen but do not occlude (mural thrombi) are the basis of unstable angina. The balance between prothrombotic and antithrombotic factors ensures that the thrombus neither progresses to occlude, or resolves to heal. Plaque disruption associated with intraplaque thrombus are associated with onset/ exacerbation of stable angina by sudden increase in plaque volume.

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Notes on sudden cardiac death o Mechanisms of myocardial ischaemia attacks – changes in thrombus size for short periods of time; intense local vasoconstriction/ spasm (many disrupted plaques are eccentric, with retention of arc of normal vessel wall in which constriction can reduce blood flow); platelet deposition is known potent stimulus for local smooth muscle constriction; embolisation of platelet aggregates into myocardial vascular bed both block smaller arteries and cause vasoconstriction within the myocardium (platelet thrombi associated with microscopic foci of myocyte necrosis). Significant proportion of thrombotic occlusions causing infarction don’t develop at sites where there was pre-existing high grade stenosis or even a plaque identified at all (Davies Heart 2000 83: 361-366) 68% of occlusions leading to acute infarction were judged to have caused <50% stenoses previously; 14% developed on high grade stenoses of >70% diameter. (Davies Heart 2000 83: 361-366) artery responds to plaque growth by increasing its cross sectional area while maintaining normal lumen dimensions (remodelling) (Davies Heart 2000 83: 361-366) 24% of lesions occluding >80% diameter will progress to chronic total occlusion by 5 years (Davies Heart 2000 83: 361-366) transmural regional acute MI is caused by occlusion which develops after a short time (few hours) and persists for at least 6-8 hours (Davies Heart 2000 83: 361-366) non transmural (non Q wave) regional infarcts have areas of necrosis of different ages, i.e. following repetitive episodes of short lived occlusion, platelet embolisation or both. (Davies Heart 2000 83: 361-366) Further factor in limiting spread of necrosis and preserving subendocardial zone is the existence of prior collateral flow in the affected area (Davies Heart 2000 83: 361-366) Dyslipidaemia increases risk of ACS – hypercholesterolaemia promotes accumulation of oxidatively modified LDL (oxLDL) in arterial wall, promoting endothelial cell dysfunction and leucocyte invasion. OxLDL and its components are highly proinflammatory and pro-atherogenic. Oxidative stress induces activation of vascular cells e.g. that promote monocyte recruitment and proliferate into macrophages. Expression of VCAM 1 (vascular cell adhesion molecule) and chemokines e.g. MCP-1 (monocyte chemoattractant protein 1) giving rise to the leucocyte invasion of the intima. Dyslipidaemia therefore induces oxidative stress, leading to vascular inflammation and initiation, progression and complications of

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Notes on sudden cardiac death atherosclerosis. (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) o LDL cholesterol leads to increased oxidised LDL accumulation, reactive oxygen species production, endothelial cell activation/ dysfunction, macrophage accumulation/ proliferation and smooth muscle cell activation/ apoptosis (Aikaw and Libby. Cardiovascular Pathology 2004 13: 125-138) Atherosclerosis pathogenesis (Kumar et al Robbins 2005) – ‘response to injury hypothesis’ (chronic inflammatory response of the arterial wall initiated by injury to the endothelium. Lesion progression is sustained by the interaction between modified lipoproteins, macrophages, T lymphocytes and the normal constituents of the arterial wall. o Chronic endothelial injury (due to hypercholesterolaemia, haemodynamic disturbances that accompany normal circulatory function (giving rise to tendency for plaques to develop at ostia of vessels, branch points and along the posterior wall of the abdominal aorta, where there are disturbed patterns of flow – areas of disturbed turbulent flow and low sheer stress are prone to atherosclerosis while those with smooth laminar flow seem to be protected), inflammatory cytokines, cigarette smoke and ?infectious agents) – with resultant endothelial cell dysfunction, yielding increased permeability, leucocyte adhesion and thrombotic potential o Accumulation of lipoproteins, mainly LDL with its high cholesterol content in the vessel wall o Modification of lesional lipoproteins by oxidation o Adhesion of blood monocytes (and other leucocytes) to the endothelium, followed by their migration into the intima and their transformation into macrophages and foam cells o Adhesion of platelets o Release of factors from activated platelets (platelet derived growth factor), macrophages or vascular cells that cause migration of smooth muscle cells from the media into the intima o Proliferation of smooth muscle cells in the intima, and elaboration of extracellular matrix, leading to the accumulation of collagen and proteoglycans o Enhanced accumulation of lipids both within cells (macrophages and smooth muscle cells) and extracellularly

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Notes on sudden cardiac death Cardiomyopathies • second largest patient group experiencing sudden cardiac death Hypertrophic cardiomyopathy – prevalence 2 in 1000 young adults, incidence of sudden cardiac death 2-4% per year in adults and 4-6% per year in children and adolescents. Risk of sudden death – sustained tachycardia, family history of sudden cardiac death, diverse genotype, recurrent syncope, multiple episodes of non-sustained VT, massive LVH. Mechanisms? Arrhythmias, abrupt haemodynamic deterioration, and/or ischaemia Idiopathic dilated cardiomyopathy – 10% of sudden cardiac deaths in adults. Mortality 10-50% annually. Risk of sudden death – non-sustained VT, bundle branch re-entry causing VT and syncope. Triggers in heart failure – myocardial stretch, neuroendocrine factors, electrolyte disturbances, proarrhythmic effects of anti-arrhythmics and excessive stimulation of sympathetic and rennin-angiotensin systems. Arrhythmogenic Right Ventricular Dysplasia – young individuals and adults – gene defect on chromosomes 1 and 4 q23-q24. 30% familial (AD). Exercise can precipitate VT with annual incidence of 2% sudden death. Fatty and fibro fatty forms. 50% have involvement of left ventricle and septum. Predilection sites for fatty degeneration reflect ECG abnormalities, and slowed intraventricular conduction (prolonged QRS interval).

Left Ventricular Hypertrophy • Strong independent risk factor for cardiovascular deaths, and particularly sudden death in those with history of hypertension. Sheppard and Davies. Possible mechanism? Altered intramyocardial blood flow, particularly subendocardial zone (wall stress at highest), seen as increased subendocardial fibrosis. Metabolic demand outstrips oxygen supply. Sheppard and Davies. Hypertensive hearts have prolonged QT interval Other triggers – myocardial ischaemia, interstitial fibrosis and electrolyte disturbances generating tachyarrhythmias A heavy heart is usually an electrically unstable heart (Hirsch and Adams) – associated with ectopic beats, VT and sudden death. Aetiology unknown. Concentric hypertrophy –

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Notes on sudden cardiac death increased afterload and? Increased sympathetic tone, activation of rennin-angiotensin system or both – in arterial hypertension. (or less often, aortic valvular stenosis, thyrotoxicosis and isometric exercise). Eccentric hypertrophy (LVH with ventricular dilatation) – increased afterload and increased preload (volume of blood drained from central veins and pumped into ventricles by atria). Seen in obesity (blood volume increases end diastolic pressure of left ventricle). LVH with dilatation can also reflect decompensation of atherosclerosis, valvular insufficiency, myocarditis or other cardiomyopathies. (Hirsch and Adams) Hearts over 550g in total weight will have LV enlargement of a degree to be reasonably associated with death. Davies and Popple (Histopathology 1979 3:255-277). The risk is greatest with pressure overload on the left ventricle as in aortic stenosis or systemic hypertension. Gross right ventricular hypertrophy is also associated with sudden death since it virtually always reflects significant pulmonary hypertension. Davies and Popple (Histopathology 1979 3:255-277). Structural changes in hypertension – increased pressure exerts an increased load on thin walled chambers or tubes by increasing wall tension (by Laplace’s law). The rise in tension results in increased wall tensile stress. Normalisation of this stress can be achieved by either increasing wall thickness or by decreasing chamber/ lumen diameter, or both. Patterns of LV wall remodelling depends on; age, genetic influences, haemodynamics, 24 hour blood pressure profile, arterial stiffness, plasma volume, myocardial performance, neurohormonal status. (Mayet and Hughes Heart 2003 89: 1104-1109) Hypertensive changes are either hypertrophy (increased LV mass) or remodelling (normal LV mass but abnormal relative wall thickness). Hypertrophy also involves interstitial fibrosis. (Mayet and Hughes Heart 2003 89: 1104-1109) LVH predicts poor prognosis (3 fold increase risk independent of blood pressure level). Possibly due to heterogenous electrical conduction due to myocardial interstitial fibrosis, or impaired coronary perfusion. (Mayet and Hughes Heart 2003 89: 1104-1109) Consequences of hypertrophy/ remodelling – impaired relaxation and coronary reserve, leading to ischaemia even in absence of coronary artery disease. Impaired relaxation results in longer LV filling time, more blood in atria and increase force of atrial contraction. Diastolic function is impaired, and as it progresses, LV compliance reduces (increased fibrosis), and heart becomes stiffer. Pressure in all

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Notes on sudden cardiac death chambers increases, and LV end diastolic volume decreases, with a resultant reduction in Stroke volume and leads to low output symptoms, e.g. fatigue. (Mayet and Hughes Heart 2003 89: 1104-1109) As LV filling pressure become very high, pulmonary congestion can occur. (Mayet and Hughes Heart 2003 89: 1104-1109) Arterial remodelling and stiffness also occurs. (Mayet and Hughes Heart 2003 89: 1104-1109)

Valvular Disease • • • • Risk of sudden death in aymptomatic aortic valve disease is low Valve replacement? Risk of sudden death due to arrhythmias, prosthetic valve dysfunction, co-existing CAD 20% of post-op deaths and incidence of 2-4% over 7 year follow up mitral valve prolapse? – may be coincidental finding as so common. If have MR and LV dysfunction or myxomatous degeneration of valve – more risk of complications e.g. infective endocarditis, cerebro-embolic events and sudden cardiac death.

Congenital heart disease • • • Increased risk in tetralogy of Fallot, transposition of great arteries, aortic stenosis, pulmonary vascular obstruction. Late complication of surgery for complex repairs In tetralogy of Fallot QRS prolongation relates to right ventricular size and is a predictor for sudden cardiac death

Drugs • Direct capability of provoking ventricular tachyarrhythmias e.g. Class 1A anti-arrhythmics (procainamide, quinidine), class 1C (flecanide) Non anti-arrhythmic drugs e.g. Antihistamines Polydrug interactions e.g.. Phosphodiesterase inhibitors and positive inotropic agents Hypokalaemia e.g.. Potassium-wasting diuretics

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Notes on sudden cardiac death

(Source: Zipes and Wellens 1998 p.2344)

Primary electrophysiological abnormalities/ inherited ion channelopathies • Ion channel proteins are responsible for the currents that generate the cardiac action potential, and alterations of their function are known to be associated with a variety of phenotypes – the final outcome being similar, an alteration in ion channel activity and the development of an arrhythmogenic substrate.. (Brugada et al 2004 Circulation 109:30-35) NB. SCN5A mutations all cause deaths occurring in sleep including SUNDS, SIDS, Brugada, LQTS and conduction system disease, and therefore could be the same - 20 -

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Notes on sudden cardiac death disease with variable penetrance (Vatta M et al 2002 Human Molecular Genetics 11(3):337-345)

o However, Long QT syndrome and other channelopathies have variable penetrance (Behr et al 2003 Lancet 362:1457-59) o 68% of patients with Long QT syndrome have an identifiable disease-causing mutation (Behr et al 2003 Lancet 362:1457-59) o QT interval represents ventricular repolarisation – prolonged QT interval associated with increased risk of life threatening ventricular arrhythmias. The QT interval is related to the effective refractory period of the myocardium, and changes to this period leave the myocardium vulnerable to fibrillation both at atrial and ventricular levels. (Gaita F et al Circulation 2003; 108:965-970) o Structural normality is normally identified by fairly gross means, such as ECG and catheterisation. However, PET scans, genetic testing and MRI is beginning to identify structural abnormalities and/ or genetic defects in previously described ‘idiopathic ventricular arrhythmias’. (Zipes and Wellens 1998; 98:2334-2351)

Long QT syndrome – characterised by prolonged period of recovery from depolarisation and a tendency to syncope and sudden death mediated by VT. Prolongation of QT interval first associated with congenital deafness in the AR Jervell and Lang-Nielson syndrome and without deafness in the AD Romano-Ward syndrome. (Hirsch and Adams)cardiac electrophysiological dysfunction without structural disease – gain of function in SCN5A (gene encoding for α subunit of cardiac sodium channel (late INa)) is associated with LQT3 form, other forms of long QT linked to loss of function of IKs and IKr (prolongation of cardiac action potential and lengthened QT interval which can lead to early after depolarisations) (Brugada et al 2004 Circulation 109:30-35) (Zipes and Wellens 1998; 98:2334-2351) o Other genes implicated in long QT – KCNQ1, KCNH2, KCNE1, KCNE2, SCN5A (Behr et al 2003 Lancet 362:1457-59) o DNA mapping studies confirmed the genetic substrate encoding defective ion channel proteins, but only 6070% of patients have a genetic defect confirmed at screening (Gaita F et al Circulation 2003; 108:965-970)

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Notes on sudden cardiac death o AD mode of inheritance (Gaita F et al Circulation 2003; 108:965-970) o A specific kind of VT called Torsade de Pointes occurs in LQTS (Zipes and Wellens 1998; 98:2334-2351) o Seven genetic loci identified, 6 described (all ionchannel encoding genes). 5 encode potassium channel proteins (LQT1, LQT2, LQT5, LQT6 and LQT7 encoding KVLQT1, mink, HERG, MiRP1 and Kir2.1 respectively), whereas LQT3 encodes cardiac sodium channel gene SCN5A (Vatta M et al 2002 Human Molecular Genetics 11(3):337-345) o LQT1/ LQT2 – incidence of cardiac events is higher than LQT3, but lethality of events is higher in LQT3 (Zipes and Wellens 1998; 98:2334-2351) o LQT1 related to exercise trigger, whilst LQT3 related to sleep/ rest trigger (Zipes and Wellens 1998; 98:23342351) o It has been proposed that long QT syndrome is due to deficient adrenergic innervation by the stellate ganglion and upper thoracic sympathetic ganglia on the right side. Ablation of the right stellate ganglion reduces the fibrillation threshold of the ventricles, whereas ablation of the left side renders the heart more resistant to fibrillation. The sympathetic current from the right side is primarily chronotropic whereas the innervation from the left is inotropic. An imbalance between signals from each side, caused by some defect (?in brain, cord, sympathetic nerves or ganglia) results in sympathetic imbalance (Hirsch and Adams)

(Source: Zipes and Wellens 1998 p.2341)

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Notes on sudden cardiac death

Short QT syndrome o Genetically heterogenous disorder – characterised by marked abbreviation of QT interval (<300 ms) and high incidence of atrial and ventricular arrhythmias and sudden death in young patients? Gain of function mutation of KCNE2 (IKr) (shortens action potential and QT interval) (Brugada et al 2004 Circulation 109:30-35) o Clinical manifestations wide – range from palpitations and dizziness to sudden death. AD mode of inheritance. (Gaita F et al Circulation 2003; 108:965-970) o QT interval is shortened by increases in heart rate, hyperthermia, increased calcium or potassium plasma levels, acidosis or alterations of autonomic tone (Gaita F et al Circulation 2003; 108:965-970) o Lone AF in young individuals might be related to short QT syndrome (Gaita F et al Circulation 2003; 108:965970) Brugada syndrome – First described in 1992. Specific ECG pattern of right bundle-branch block, ST segment elevation in leads V1-V3 associated with sudden death in those with no demonstrable structural heart disease (Brugada et al 1998 Circulation 97:457-460). Due to decrease in function of cardiac sodium channel – SCN5A gene on chromosome 3 but with different biophysical properties to mutant channel in LQT3 (Brugada et al 2004 Circulation 109:30-35), 10-20% of patients have an identifiable disease-causing mutation (Behr et al 2003 Lancet 362:1457-59). AD mode of inheritance (Vatta M et al 2002 Human Molecular Genetics 11(3):337345) Catecholaminergic polymorphic ventricular tachycardia – effort/ stress induced ventricular arrhythmia in young children which can degenerate into cardiac arrest and cause sudden death. The ECG pattern resembles arrhythmias associated with calcium overload and delayed after depolarisations observed during digitalis toxicity. (Priori S et al 2001 Circulation 103:196-200). 2 genetic variants – 1 AD caused by mutations in gene encoding the cardiac ryanodine receptor (RyR2) and 1 recessive form caused by mutations in human cardiac calsequestrin (CASQ2), both of which are calcium binding proteins located in the sarcoplasmic reticulum and are involved in the excitation coupling complex. (Mutation reduces calcium storage capacity and release functions of SR and destabilises calcium transport predisposing to adrenergic

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Notes on sudden cardiac death mediated arrhythmias) (Viatchenko-Karpinski et al 2004 Circulation Research 94:471-477) Sudden unexpected nocturnal death syndrome – disorder found in southeast Asia – abnormal ECG with STsegment elevation in leads V1-V3 and sudden death due to VF – identical to Brugada syndrome. Called lai-tai (sleep death, Laos), pokkuri (sudden and unexpected death, Japan), bangungut (to rise and moan in sleep, Philippines). (Zipes and Wellens 1998; 98:2334-2351). Genetic studies confirm that the disease is phenotypically, genetically and functionally the same disorder (SCN5A mutation) (Vatta M et al 2002 Human Molecular Genetics 11(3):337-345) recent study shows that the responsible arrhythmias occur during night terrors which occur in non-REM sleep from which the victim cannot be aroused. There is a sudden surge of catecholamines, and precipitous rises in blood pressure. Progressive conduction system disease (Lev-Lenegre syndrome) – decrease in function of cardiac sodium channel – SCN5A mutation (Brugada et al 2004 Circulation 109:30-35) (Vatta M et al 2002 Human Molecular Genetics 11(3):337345) Familial atrial fibrillation – increase in IKs current caused by mutation in α subunit KCNQ1 Wolff-Parkinson-White syndrome – risk of sudden death <1 per 1000 patient years of follow up. Usually have symptomatic arrhythmias before event, 10% first presentation is sudden death. AF is rapidly conducted to ventricles over accessory pathway to produce rapid ventricular rates, which degenerate into VF. (Zipes and Wellens 1998; 98:2334-2351) (Marks and Greene Cardiac Arrhythmias 1995) Congenital complete AV block Idiopathic ventricular tachycardias with monomorphic and polymorphic contours – sporadic and familial forms. Paroxysmal and frequently precipitated by stress/ emotion

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Mechanisms in sudden cardiac death • • • • • Sudden cardiac death is an electrical accident as only a small proportion of people at risk develop sudden death Many other individuals have the anatomical substrates and functional substrates conducive to developing VT or VF Transient events perturb the balance The interplay between all factors is crucial VF is self electrocution/ turning the switch off (Hirsch and Adams)

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Notes on sudden cardiac death • Combination of triggering event and susceptible myocardium has evolved as a biological model for the initiation of lethal arrhythmia (Chugh et al Circulation 2000 102(6):649-654) Arterioscerotic heart disease usually kills by pump failure or sudden arrhythmia. (Hirsch and Adams) Pump failure is more likely in dilated heart, infarcts, global subendocardial fibrosis. When congestive failure is severe, all organs are underperfused, including the heart. The left ventricle suffers global hypoxia, and can lead to ectopics and bradycardia. Electrical or sudden deaths are due to electrical instability, increased by hypertension and LVH. The fundamental difference between living and dead organisms is functional (electrochemical intercellular communication) rather than structural, the pathologist who focuses exclusively on anatomic causes of death is doomed to fail. (Hirsch and Adams) Thrombus seen by naked eye in a coronary artery provides good evidence of acute myocardial ischaemia even if the artery is not completely occluded, as distal emboli of small clumps of platelets from the thrombus cause microscopic foci of myocardial necrosis and therefore a substrate for re-entry tachycardias. (Davies Histopathology 1999 34:93-98) Sudden cardiac deaths are mediated by acute derangements of physiologic function. (Hirsch and Adams) The functional derangement is sometimes obvious, e.g. cardiac rupture, but usually electrical. It is thus inferred from the presence of chronic cardiac disease. Destabilisation of the heart and production of arrhythmias occurs as product of predisposing anatomical substrate and acute transient risk factors such as altered autonomic tone, coronary artery spasm and increased platelet adhesiveness. (Hirsch and Adams) Where functional disturbances are severe enough, death can occur without the anatomical substrate. Lown demonstrates that psychological stress can lower the fibrillation threshold by means of increased sympathetic tone, and that stimulation of the hypothalamus can induce cardiac arrhythmias. The orderly propagation of the contractile wavefront depends on the continuous overriding of the potential ectopic pacemakers and on the absence of re-entry pathways, either within the ventricles or between atria and ventricles. (Hirsch and Adams) When an ectopic ventricular focus takes over and drives the rest of the myocardium in an orderly fashion, premature ventricular contractions or sustained VT are produced. In the presence of re-entry pathways, the ectopic signal can generate an uncoordinated wavefront and VF ensues. Because

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Notes on sudden cardiac death no net forward pumping of blood is produced, VF and certain forms of VT are lethal. (Hirsch and Adams) Ventricular ectopy = ventricular irritability – increased by hypertrophy, ischaemia, sympathetic discharge, ethanol intoxication, hyperthyroidism, drugs including MAO inhibitors, TCAs, caffeine, theophylline and other sympathomimetic drugs, agents found in diet pills and nasal decongestants. (Hirsch and Adams) Myocardial depression on the other hand leads to delayed AV conduction and block, potentially leading to cardiac standstill and death. E.g. parasympathetic discharge, myoedema, hypothermia, hyperkalaemia (Hirsch and Adams) The electrochemical discharge from the CNS to the heart and blood vessels can be strong enough or imbalanced enough to produce standstill, VF or emptying of the heart by virtue of vascular redistribution. (Hirsch and Adams). The exact areas of the brain of vasomotor centres are unknown, but critical areas are region of 3rd ventricle, midbrain, medulla oblongata. (Hirsch and Adams) Sympathetic discharge flows down interomediolateral columns of the spinal cord, leaving the cord in the thoracic and lumbar regions by way of the chains of sympathetic ganglia running adjacent to the vertebral column. From the upper thoracic ganglia and from the stellate ganglion in particular, efferent branches pass into the mediastinum and along the base of the heart to innervate the myocardium and cardiac blood vessels. Parasympathetic discharges originating in the vasomotor centres exit the brain by way of the vagus nerves, which descend into the mediastinum and innervate the heart. Mechanical trauma along these pathways can induce profound electrical disturbances in the heart. Transverse fractures of the floor of the skull running near the base of the 3rd ventricle, fractures of the posterior fossa, dislocations of the neck, forceful facial impacts that cause hyperextension of the head with pontomedullary lacerations and gunshot wounds to the spine or brain can all give rise to instantaneous death (central cardiac concussion) (Hirsch and Adams) Spontaneous subarachnoid haemorrhages can cause instantaneous death due to tamponade of blood in cisterns at base of 3rd ventricle and along the medulla. In respiratory arrest, the first response to hypoxia is tachycardia, then bradycardia until a slow pacemaker takes over. When cellular metabolism is so disturbed that electromechanical dissociation takes place, there is no flow/ output.

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Notes on sudden cardiac death

Interaction of various anatomic/ functional and transient factors that modulate potential arrhythmogenic mechanisms capable of causing sudden cardiac death. (Source: Zipes and Wellens 1998)

Willich et al (Circulation 1993 87(5):1442-1450) model of ‘triggering of sudden cardiac death’ – external trigger causes increase in sympathetic nervous activity, this activity may act on coronary arteries, myocardial tissue or the conduction system, or a combination. The effect on the artery occurs when haemodynamic forces cause a vulnerable plaque to rupture. Transformation of stable to vulnerable plaque? Could be accumulation of lipid pool covered by thin fibrous cap, increased collagenase activity. Exposed collagen can lead directly to occlusive thrombus formation and fatal MI. Gradual growth of thrombus may lead to reduced blood flow, micro emboli and myocardial ischaemia or small areas of myocardial necrosis (both of which have been shown to be associated with reduced threshold for VF. Damage of myocardial tissue or conduction system by necrosis, fibrosis, hypertrophy or other changes may increase risk of acute electric instability. The diversity of findings suggests that many potential triggers may interact, synergistically or alone, with structural and functional abnormalities to produce a common clinical endpoint – sudden cardiac death. Mechanisms? Increased sympathetic discharge and circulating catecholamines. Raise heart rate and BP, and thus oxygen demand. Alpha sympathetic receptors stimulated, increasing coronary tone reducing relative oxygen supply. Increased

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Notes on sudden cardiac death ventricular inotropy and changes in coronary tone may alter shear stress of blood against vulnerable atherosclerotic plaque, contributing to fracture. Raised catecholamines triggering arrhythmias directly, and increasing platelet aggregation. (Leor et al NEJM 1996; 334:413-419) (Chi and Kloner stress and MI) (Reich et al JAMA 1981 246(3):233235) Excitation causing sinus tachycardia/ ventricular irritability; rapid shifts between sympathetic/ parasympathetic effects e.g. uncertainty causing shift between ‘fight-flight’ and ‘conservation-withdrawal’ systems. Combination of neurogenic adrenergic and cholinergic activity in conjunction with local myocardial factors leading to escape rhythms. Vagal stimulation causing slow heart rate and facilitation of reentrant ectopic activity and thus VF. QT prolongation, premature beats and VF have all been experimentally demonstrated by cortical and sub cortical CNS stimulation therefore higher neural mediating control systems exist (psych-neuro-cardiovascular circuit). (Engel Folklore or folk wisdom?) (Reich et al JAMA 1981 246(3):233-235) Mechanism defined for both out-of-hospital and in-hospital settings – 3 common rhythm disturbances – VF, asystole and EMD. Relative proportions depend on patient population. 33%-50% have VF as initial rhythm recorded. (Marks and Greene Cardiac Arrhythmias 1995) Ambulatory monitoring shows 85% of sudden cardiac deaths due to VT rapidly degenerating into VF. After prolonged VF the voltage of the signal decreases to fine VF and then to ‘flat line’ or asystole. (Marks and Greene Cardiac Arrhythmias 1995) Davies and Popple (Histopathology 1979 3:255-277) point out that in those with a macroscopic normal heart, and where ECGs were found, no conduction system abnormality was found anatomically in those with long QT, inverted T waves, episodic supraventricular tachycardias, multifocal ventricular and atrial ectopics. Probability of sudden death being due to IHD when no other cause can be found on macroscopic examination in hearts with coronary atherosclerosis (Davies Histopathology 1999 34:93-98);

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Notes on sudden cardiac death Pathology
Pericardial tamponade Rupture of acute infarct Coronary thrombus Acute MI/ coronary thrombus Coronary thrombosis alone Healed previous infarct scar thrombus No thrombus – no scars X3 vessels with >75% stenosis X2 vessels with >75% stenosis X1 vessel with >75% stenosis Stenosis <75% alone

Approximate probability death being due to IHD
100%

of

90% – no 70%

Less than 50%

Modified in Sheppard and Davies (Practical Cardiovascular pathology) – high probability for acute infarct with coronary thrombosis and atherosclerosis, through medium probability for high grade stenosis (>75% diameter) with old infarction and/or LVH to low probability for high grade stenoses but normal myocardium and very low probability for <50% stenosis, no scars or LVH.

Homicide by heart attack Davis criteria (J For Sci; 1978;23(2):384-7) 1. The criminal act should be of such severity and have such sufficient elements of intent to kill or maim, either in fact or in statute, so as to lead logically to a charge of homicide in the event that physical injury had ensued. 2. The victim should have realised that the threat to personal safety was implicit. A logical corollary would be a feared threatening act against a loved one or friend. 3. The circumstances should be of such a nature as to be commonly accepted as highly emotional. 4. The collapse and death must occur during the emotional response period, even if the criminal act had already ceased. 5. The demonstration of an organic cardiac disease process of a type commonly associated with a predisposition to lethal cardiac arrhythmia is desirable.

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Notes on sudden cardiac death Modified Davis criteria (Turner et al 2004 49(3):1-5); 1. The action of the perpetrator towards the victim should be of such severity and have sufficient elements of intent to frighten, injure or kill, either in fact or in statute, so as to lead logically to a charge of homicide in the event that the death resulted from physical injury. 2. The victim should have realised that the threat to personal safety was implicit. A logical corollary would be a feared threatening act against a loved one or friend. 3. The circumstances should be of such a nature as to be commonly accepted as highly emotional. 4. The collapse (and subsequent death, in most cases) must occur within the emotional response period, even if the criminal act had already ceased. In certain circumstances, death may be delayed, typically via medical intervention. 5. Autopsy should demonstrate an organic cardiac disease process of a type commonly associated with a predisposition to lethal cardiac arrhythmia. In the absence of a grossly or microscopically identifiable organic cardiac disease, the case may involve a functional cardiac disorder (such as a conduction system disorder) that has no anatomic correlation. • Modified criteria take into account cases where injury has occurred (unlike Davis) and incorporates NAME guidelines. National Association of Medical Examiners NAME ‘Guide for Manner of Death Classification’ – deaths resulting from fear or fright that is caused by verbal assault, threats of physical harm, or via acts of aggression intended to instil fear may be classified as homicide, as long as there is a close temporal relationship between the incident and the death. Recovery after initial collapse, then death following decompensation would not be homicide (Turner et al 2004 49(3):1-5); If coronary arteries poor, defence could reasonably claim that death could have occurred at any time (Knight and Saukko 2004) Standard of proof must be attained Easier to claim that emotional stress associated with traumatic event caused increased demands upon a weakened heart and caused it to fail (Knight and Saukko 2004) May sometimes have morphological evidence of the effects of catecholamines on the myocardium in form of

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Notes on sudden cardiac death contraction bands in myofibrils, especially subepicardial layers (Knight and Saukko 2004) Average jury is likely to think it too much of a coincidence that a man drops dead on the spot, even if the extent of coronary artery disease is of long standing (but he has not suffered any symptoms) (Knight and Saukko 2004) Strict test is ‘would he have died when he did die if the assault had not taken place?’ – may only be answerable when considering all the circumstances (with a common sense view of coincidence in terms of immediacy in time and apply the ‘beyond reasonable doubt’ test) (Knight and Saukko 2004) The fact that a person is in a poor state of health and might die from minimum trauma is no defence – ‘an assailant must take his victims as he finds them’ (Knight and Saukko 2004) The prevalence of CAD is so widespread that a close association in time must be shown before any causal connection can be accepted. (Knight and Saukko 2004)

Commotio cordis/ cardiac concussion • • • First described in 1930s Registry in US – 140 cases in 5 years (mean age 14 years, male), 5-10 cases p.a. no data for UK. sudden death in young athletes with trivial non-penetrating impacts to anterior chest, leaving no visible trauma, and in which resuscitation attempts unsuccessful despite early cardioversion (survival now approx 15% due to rapid defibrillation) no pathological changes seen, and no cardiac enzyme rise ?troponins? syncopal events now also recognised due to chest wall impact mechanism – animal research using ECG/ cardiac cycle gated impact studies show impact directly over precordium at >30mph gives rise to increasing risk of VF (30% at 30 mph, 70% at 40 mph) with impact occurring at vulnerable part of cycle (30ms prior to T wave peak). Thump in cycle at other times gives rise to ST elevation and transient heart block. Multifactorial – altered myocardial substrate with premature ventricular depolarisation as the trigger. Change in substrate? Not vagal inhibition, could be rise in left ventricular pressure, activating stretch activated channels (potassium and others), or effect of K/ATP channel (which are responsible for ST elevation and contribute to risk of VF in ischaemia) as blocker (glibeclamide) reduces ST elevation and incidence of VF

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Notes on sudden cardiac death following induced chest blows. Clinical colloraly – R on T phenomenon (VF caused by premature ventricular contractions falling on vulnerable portion of T wave, in ischaemic conditions (acute MI/ coronary ischaemia) but not non-ischaemic conditions such as continuous ventricular pacing). (Link 2003 Progress in Biophysics and Molecular Biology 82:175-186) (Koehler et al Am J For Med and Path 25(3):205-208) (Maron BJ et al JAMA 2002 287(9):11421146) (Link et al NEJM 338(25):1805-1811) Cardiac concussion involves absorbtion of mechanical energy from blunt impact as harmonic oscillations which are dampened out and converted to heat. A small part of the imparted kinetic energy may be converted to electrical impulses. (Hirsch and Adams) Resuscitation Council – precordial thump can convert pulseless VT to perfusing rhythm - termination of VF less common. Can also convert bradycardic rhythms or VT with pulse to pulseless VT or VF, accelerated VT or complete heart block – therefore only recommended for pulseless person whose rhythm is monitored

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Notes on sudden cardiac death

References
Aikawa M, Libby P. The vulnerable atherosclerotic plaque. Pathogenesis and therapeutic approach. Cardiovascular pathology. 2004; 13: 125-138 Australian Resuscitation Council. Precordial thump – policy statement No. 11.2.2 July 1999 Behr E, Wood DA, Wright M et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. The Lancet 362: 1457-59 Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-Segment elevation in leads V1 through V3. A marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998; 97:457-460 Brugada R, Hong K, Dumaine R et al. Sudden death associated with Short-QT syndrome linked to mutations in HERG. Circulation 2004; 109:30-35 Cohen MV. Ventricular fibrillation precipitated by carotid sinus pressure: case report and review of the literature. American Heart Journal 1972; 84(5):681-686 Chi JS, Kloner RA. Stress and myocardial infarction. Heart. 2003; 89: 475-476 Chugh SS, Kelly KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation. 2000 102(6):649-654 Crossman DC. The pathophysiology of myocardial ischaemia. Heart. 2004; 90: 576-580 Davies MJ, Popple A. Sudden unexpected cardiac death – a practical approach to the forensic problem. Histopathology. 1979; 3:255-277 Davies MJ. Anatomic features in victims of sudden coronary death. Circulation. 1992; 85 (Supplement 1); 19-24 Davies MJ. The pathophysiology of acute coronary syndromes. Heart. 2000; 83:361-366 Davis JH. Can sudden cardiac death be murder? Journal of Forensic Sciences 1978; 23(2):384-7 De Vreede-Swagemakers JJM, Gorgels APM, Dubois-Arbouw WI et al. Circumstances and causes of out-of-hospital cardiac arrest in sudden death survivors. Heart 1998; 79:356-361 Ettinger PO, Wu CF, De La Cruz Jr C, Weisse AB et al. Arrhythmias and the ‘Holiday Heart’: alcohol-associated cardiac rhythm disorders. American Heart Journal 1978 95(5): 555-562 Engel GL. Sudden and rapid death during psychological stress -Folklore or folk wisdom?. Annals of Internal Medicine. 1971; 74: 771-782 Farb et al Circulation 1996 93:1354-1363 Fayed ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circulation Research. 2001; 89:305-316

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Notes on sudden cardiac death

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Notes on sudden cardiac death

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