Characteristics of undiagnosed coronary artery disease in sudden cardiac death:autopsy findings and genetics

Abstract Sudden cardiac death (SCD) remains a major health problem worldwide, and a great proportion of victims do not have a previously diagnosed heart disease. Especially in older population, the majority of SCDs are caused by coronary artery disease (CAD); however, the burden of CAD among the young has also been noted. The aim of this thesis was to study the characteristics of SCDs associated with CAD, especially in younger victims and in those with no prior history of heart disease. The study population consisted of 5,869 SCD victims from Northern Finland who underwent medicolegal autopsy between the years 1998–2017. In Study I, CAD was found to be the most common cause of SCD. At autopsies, a prior silent myocardial infarction (SMI) was detected in about 42% of the victims without a clinical history of CAD, and it was associated with myocardial hypertrophy and SCD during physical activity. A prior electrocardiogram was abnormal in 67% of the SCD victims with a previous SMI. In Study II, 10% of the study population were found to be aged under 50 years and the most common cause of SCD among these young SCD victims was CAD. In about 90% of the cases SCD occurred in the absence of previously diagnosed CAD, but at least one known cardiovascular risk factor was present in over half of the victims. Despite the young age, advanced heart disease was a common finding at autopsies. In Study III, the genetic background of cardiac hypertrophy was investigated in SCD victims with single-vessel CAD without a previously diagnosed heart disease. Possible disease-causing variants were detected in 8% of the study victims, while variants of uncertain significance existed in about 40% of the study victims. All detected variants were in myocardial structure protein coding genes. In Study IV, temporal trends in the incidence and characteristics of SCDs were studied in subjects under 40 years of age. The incidence of SCD decreased during the years 1998–2017. Most SCDs in this age group were due to non-ischemic myocardial diseases, and the incidence of CAD-related SCD decreased. The findings of this thesis increase the understanding of CAD-related SCDs, especially among younger population. In addition, Studies I and III provide novel information on the role of SMIs and genetics in the risk of SCD among victims without a previously diagnosed CAD.Tiivistelmä Sydänperäinen äkkikuolema on edelleen merkittävä terveysongelma maailmanlaajuisesti, ja suurella osalla uhreista ei ole aiemmin todettua sydänsairautta. Etenkin iäkkäillä suurin osa äkkikuolemista johtuu sepelvaltimotaudista, mutta sen taakka myös nuoremmilla on tiedostettu. Tämän väitöskirjatutkimuksen tavoitteena oli tutkia sepelvaltimotautiin liittyvien äkkikuolemien tunnuspiirteitä erityisesti nuoremmilla uhreilla sekä niillä, joilla ei ole aiemmin todettua sydänsairautta. Tutkimusjoukkoon kuului 5869 sydänperäisen äkkikuoleman uhria Pohjois-Suomesta, joille tehtiin ruumiinavaus vuosina 1998–2017. Tutkimuksessa I sepelvaltimotaudin todettiin olevan yleisin äkkikuoleman syy. Ruumiinavauksissa aiemmin sairastettu hiljainen sydäninfarkti todettiin 42 %:lla uhreista, joilla ei ollut aiemmin diagnosoitua sepelvaltimotautia, ja se oli yhteydessä sydämen hypertrofiaan sekä äkkikuolemaan fyysisen rasituksen aikana. Ennen kuolemaa nauhoitettu sydänsähkökäyrä oli poikkeava 67 %:lla uhreista, joilla todettiin aiemmin sairastettu hiljainen sydäninfarkti. Tutkimuksessa II havaitsimme, että 10 % tutkimusjoukostamme oli alle 50-vuotiaita ja sepelvaltimotautioli heillä yleisin äkkikuoleman syy. Noin 90 %:ssa tapauksista äkkikuolema esiintyi ilman aiempaa tietoa sepelvaltimotaudista, mutta yli puolella oli ainakin yksi tiedossa oleva sydän- ja verisuonisairauksien riskitekijä. Nuoresta iästä huolimatta pitkälle edennyt sydänsairaus oli yleinen löydös ruumiinavauksissa. Tutkimuksessa III tutkimme sydämen hypertrofian geneettistä taustaa äkkikuoleman uhreilla, joilla oli yhden suonen sepelvaltimotauti ilman aiemmin diagnosoitua sydänsairautta. Löysimme todennäköisesti sydänsairautta aiheuttavia geenimuutoksia 8 %:lla tutkituista uhreista, ja 40 %:lla todettiin merkitykseltään epäselvä geenimuutos. Geenimuutokset todettiin sydänlihasproteiineja koodaavissa geeneissä. Tutkimuksessa IV tutkimme alle 40-vuotiaiden äkkikuolemien ilmaantuvuuden ja tunnuspiirteiden ajallisia kehityssuuntia. Äkkikuolemien ilmaantuvuus väheni vuosina 1998–2017. Suurin osa äkkikuolemista tässä ikäryhmässä johtui ei-iskeemisistä sydänsairauksista, ja sepelvaltimotautiperäisten kuolemien ilmaantuvuus väheni. Tämän väitöstutkimuksen havainnot lisäävät ymmärrystä sepelvaltimoperäisistä äkkikuolemista erityisesti nuoremman väestön keskuudessa. Lisäksi tutkimuksissa I ja II saatiin uutta tietoa hiljaisten sydäninfarktien ja genetiikan roolista äkkikuoleman riskissä uhreilla, joilla ei ole aiemmin diagnosoitua sepelvaltimotautia

Sudden cardiac death after alcohol intake:classification and autopsy findings

Abstract Alcohol is known to have an immediate effect on cardiac rhythm, and previous studies have found that a notable proportion of sudden cardiac deaths (SCD) occur after alcohol intake. The objective of the present study was to investigate the association between the timing of alcohol intake and SCD. Our study population is drawn from the Fingesture study, which includes 5869 consecutive SCD cases from Northern Finland who underwent medicolegal autopsy 1998–2017. Toxicological analysis was performed if there was any suspicion of toxic exposure, or if there was no obvious immediate cause of SCD at autopsy. We found that 1563 (27%) of all SCD victims had alcohol in blood or urine at autopsy (mean age (61 ± 10 years, 88% male). Eighty-six percent of alcohol-related SCD victims had higher urine alcohol concentration than blood alcohol concentration, referring to the late-stage inebriation. These results suggest that the majority of alcohol-related SCDs occur at the late stage of inebriation

Temporal trends in the incidence and characteristics of sudden cardiac death among subjects under 40 years of age in Northern Finland during 1998–2017

Abstract Background: Although the mean age of sudden cardiac death (SCD) victims has increased during recent decades, overall incidence has remained relatively stable. Small but very important proportion of SCDs occur in subjects under 40 years of age and temporal trends in the incidence and characteristics of SCD in this age-group are not well known. Methods: The Fingesture study has prospectively gathered data from 5,869 consecutive autopsy verified SCD victims in Northern Finland during 1998–2017. On the basis of Finnish law, all who die unexpectedly undergo autopsy. Results: Out of total 5,869 SCDs, 160 occurred in subjects under 40 years of age (3%) indicating a total incidence of 2.9/100,000/year. Incidence decreased during the study period: 4.0/100,000/year (n = 50) in 1998–2002, 3.7/100,000/year (n = 45) in 2003–2007, 2.5/100,000/year (n = 36) in 2008–2012, and 1.5/100,000/year (n = 29) in 2013–2017. Coronary artery disease (CAD) was the cause of death in 46 SCD victims (29%). Among nonischemic causes, most common were obesity-related hypertrophic myocardial disease (24%), primary myocardial fibrosis (19%), and hypertensive myocardial disease (6%). The incidence of SCD caused by CAD decreased as follows: 1.5/100,000/year in 1998–2002, 1.2/100,000/year in 2003–2007, 0.6/100,000/year in 2008–2012, and 0.2/100,000/year in 2013–2017. Proportion of male gender (81%) and obesity as a comorbidity (body mass index >30 kg/m², 40%) remained relatively stable during the period (p = 0.58 and p = 0.79, respectively). Conclusions: The incidence of SCD in subjects under 40 years of age has decreased in Northern Finland during 1998–2017. According to autopsy data, most of the deaths are due to nonischemic myocardial diseases and relative proportion of CAD has decreased

Coronary artery disease as the cause of sudden cardiac death among victims < 50 years of age

Abstract Coronary artery disease (CAD) is the most common cause of sudden cardiac death (SCD). Atherosclerosis increases with age, but also many victims of SCD in young and middle-aged population have CAD at autopsy. The purpose of this study was to determine the characteristics and autopsy findings of SCD due to CAD among victims of SCD under the age of 50. Fingesture is a population-based study consisting of consecutive series of victims of autopsy verified SCD in Northern Finland between the years 1998 to 2017 (n = 5,869). Histological examinations were part of all autopsies and a toxicology investigation was performed if needed. Analyses included information accumulated from death certificates, medical records, autopsy data, standardized questionnaire to the closest family members of the victims of SCD and police reports of the conditions of the death. Overall, 10.4% of all SCDs occurred among victims under the age of 50 years (610 victims). Most common underlying cause of SCD among these younger SCD victims was CAD (43.6%). The prevalence of CAD as the cause of SCD became more common in young SCD victims after the age of 35 years. The mean age of ischemic SCD victims was 44±5 years and most were men (89.5%). Most victims (90.2%) had no clinical diagnosis of CAD, however 33.8% had an autopsy evidence of silent myocardial infarction. SCD occurred during physical activity in 24.1%. Three-vessel disease was detected in 44.4% of the study victims. Cardiac hypertrophy (58.3%) and myocardial fibrosis (82.6%) were also common. At least 1 cardiovascular risk factor was present in 64.7% of SCD victims. In conclusion, most SCDs among victims < 50 years of age are due to CAD

Blood alcohol levels in Finnish victims of non-ischaemic sudden cardiac death

Abstract Introduction: Non-ischaemic heart disease (NIHD) is the underlying pathology in∼20% of all sudden cardiac deaths (SCDs). Heavy drinking is known to be associated with SCD due to ischaemic heart disease, but studies on association of recent alcohol consumption and SCD in patients with NIHD are scarce. We evaluated the blood alcohol levels of autopsy verified non-ischaemic SCD victims. Methods: Study population was derived from the Finnish Genetic Study of Arrhythmic Events (Fingesture) (n = 5869, mean age 65 ± 12, 79% males). All deaths occurred in Northern Finland during 1998–2017. All victims underwent a medico-legal autopsy. Subjects of SCD due to ischaemic heart disease were excluded. Results: A total of 1301 (mean age 57 ± 12, 78% males) victims of SCD due to NIHD were included in the study. The blood ethanol level was elevated in 543 (42%) subjects, out of which the blood alcohol level was ≥0.10%in 339 (62%) subjects and ≥0.15%in 252 (46%) subjects. Male SCD victims had alcohol in blood more frequently compared to females (45% versus 31%, p < .001). Conclusion: Elevated blood alcohol level is common in SCD victims due to NIHD, especially in males. Recent alcohol consumption might contribute to the subsequent SCD in many non-ischaemic SCD victims

Sudden Cardiac Death in Women

Despite recent progress in profiling of risk for sudden cardiac death (SCD) and prevention and intervention of cardiac diseases, SCD remains a major cause of death. Among women, the incidence of SCD is significant, but lower than in men, particularly in the premenopausal and early postmenopausal years. Possibly, as a consequence of the difference in population burden, the mechanisms and risk markers of SCD are not as well defined for women. The aim of this study was to determine the autopsy findings and causes of death among women in a large SCD population. Additionally, we sought to classify prior ECG characteristics in male and female subjects with SCD. The Fingesture study has systematically collected clinical and autopsy data from subjects with SCD in Northern Finland between 1998 and 2017. The cohort consists of 5869 subjects with SCD. Previously recorded ECGs were available and analyzed in 1101 subjects (18.8% of total population; and in 25.3% of women). Female subjects with SCD were significantly older than men: 70.1±13.1 years versus 63.5±11.8 years (mean ± standard deviation, P<0.001). The most frequently identified cause of death was ischemic heart disease in both sexes: 71.7% among women versus 75.7% among men, P=0.005. In contrast, women were more likely to have nonischemic cause of SCD than men (28.3% versus 24.3%, P=0.005). The prevalence of primary myocardial fibrosis was higher among women (5.2%, n=64) than in men (2.6%, n=120; P<0.001). Female subjects with SCD were more likely to have normal prior ECG tracings (22.2% versus 15.3% in men, P<0.001). A normal ECG was even more common among nonischemic female subjects with SCD (27.8% versus 16.2% in men, P=0.009). However, ECG markers of left ventricular hypertrophy, with or without repolarization abnormalities, were more common among women (8.2%; 17.9%) than in men (4.9%; 10.6%, P=0.036; P<0.001, respectively). Women were considerably older at the time of SCD and more commonly had nonischemic causes. Women were also more likely to have a prior normal ECG than men, but an increased marker for SCD risk based on ECG criteria for left ventricular hypertrophy with repolarization abnormalities was more commonly observed in women

Plaque histology and myocardial disease in sudden coronary death:the Fingesture study

Abstract Aims: At least 50% of deaths due to coronary artery disease (CAD) are sudden cardiac deaths (SCDs), but the role of acute plaque complications on the incidence of sudden death in CAD is somewhat unclear. The present study aimed to investigate plaque histology and concomitant myocardial disease in sudden coronary death. Methods and results: The study population is derived from the Fingesture study, which has collected data from 5869 consecutive autopsy-verified SCD victims in Northern Finland (population ≈600 000) between 1998 and 2017. In this substudy, histological examination of culprit lesions was performed in 600 SCD victims whose death was due to CAD. Determination of the cause of death was based on the combination of medical records, police reports, and autopsy data. Plaque histology was classified as either (i) plaque rupture or erosion, (ii) intraplaque haemorrhage, or (iii) stable plaque. The mean age of the study subjects was 64.9 ± 11.2 years, and 82% were male. Twenty-four per cent had plaque rupture or plaque erosion, 24% had an intraplaque haemorrhage, and 52% had a stable plaque. Myocardial hypertrophy was present in 78% and myocardial fibrosis in 93% of victims. The presence of myocardial hypertrophy or fibrosis was not associated with specific plaque histology. Conclusions: Less than half of sudden deaths due to CAD had evidence of acute plaque complication, an observation which is contrary to historical perceptions. The prevalence of concomitant myocardial disease was high and independent of associated plaque morphology

Genetic contributions to the expression of acquired causes of cardiac hypertrophy in non-ischemic sudden cardiac death victims

AbstractThe contribution of genetic variants to non-ischemic sudden cardiac death (SCD) due to acquired myocardial diseases is unclear. We studied whether SCD victims with hypertension/obesity related hypertrophic myocardial disease harbor potentially disease associated gene variants. The Fingesture study has collected data from 5869 autopsy-verified SCD victims in Northern Finland. Among SCD victims, 740 (13%) had hypertension and/or obesity as the most likely explanation for myocardial disease with hypertrophy and fibrosis. We performed next generation sequencing using a panel of 174 cardiac genes for 151 such victims with the best quality of DNA. We used 48 patients with hypertension and hypertrophic heart as controls. Likely pathogenic variants were identified in 15 SCD victims (10%) and variants of uncertain significance (VUS) were observed in additional 43 SCD victims (28%). In controls, likely pathogenic variants were present in two subjects (4%; p = 0.21) and VUSs in 12 subjects (25%; p = 0.64). Among SCD victims, presence of potentially disease-related variants was associated with lower mean BMI and heart weight. Potentially disease related gene variants are common in non-ischemic SCD but further studies are required to determine specific contribution of rare genetic variants to the extent of acquired myocardial diseases leading to SCD

Causes and characteristics of unexpected sudden cardiac death in octogenarians/nonagenarians

Abstract Introduction: The risk for sudden cardiac death (SCD) increases with ageing. Methods: We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims in Northern Finland. All the victims underwent medico-legal autopsy as medico-legal autopsy is mandatory in cases of unexpected sudden death in Finland. All the non-cardiac deaths such as pulmonary embolism and cerebral hemorrhage were excluded from the study, as were unnatural deaths such as intoxications. Results: Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those &lt; 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P &lt; .001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged &lt; 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged &lt; 80 years (P = .001). SCD victims 80 years or older were less likely to die during physical activity than those under 80 years old (5.6% vs. 15.9%, P &lt; .001). Dying in sauna was more common among those ≥ 80 years than among those &lt; 80 years (5.5% vs. 2.6%, P &lt; .001). Conclusion: In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged &lt; 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones

Electrocardiographic associations with myocardial fibrosis among sudden cardiac death victims

Abstract Objective: A major challenge in reducing the incidence of sudden cardiac death (SCD) is the identification of patients at risk. Myocardial fibrosis has a substantial association with SCD risk but is difficult to identify among general populations. Our aim was to find electrocardiographic (ECG) markers of myocardial fibrosis among SCD victims. Methods: Study population was acquired from the Fingesture study, which has gathered data from 5869 consecutive autopsied SCD victims in Northern Finland between 1998 and 2017. The degree of fibrosis was determined in histological samples taken from the heart during autopsy and was categorised into four groups: (1) no fibrosis, (2) scattered mild fibrosis, (3) moderate patchy fibrosis and (4) substantial fibrosis. We were able to collect ECGs from 1100 SCD victims. Results: The mean age of the study subjects was 66±13 years and 75% were male. QRS duration in ECG correlated with the degree of fibrosis (p&lt;0.001, β=0.153). Prevalence of fragmented QRS complex, pathological Q waves and T wave inversions correlated with increased degree of fibrosis (p&lt;0.001 in each). Depolarisation abnormalities were observed both in ischaemic and non-ischaemic heart disease. Repolarisation abnormalities reached statistical significance only among ischaemic SCD victims. An abnormal ECG was observed in 75.3% of the subjects in group 1, 73.7% in group 2, 88.5% in group 3 and 91.7% in group 4 patients (p&lt;0.001). Conclusions: Myocardial fibrosis was associated with QRS prolongation, deep Q waves, T wave inversions and QRS fragmentation. The results provide potentially useful non-invasive early recognition of patients with fibrotic cardiomyopathy and risk of SCD