Obesity Cardiomyopathy in Sudden Cardiac Death

Background Obesity cardiomyopathy (OCM) can be associated with sudden cardiac death (SCD) but its pathologic features are not well described. Objectives The objective of this study was to characterize the clinical and pathological features of OCM associated with SCD. Methods This was a retrospective case control autopsy study. OCM was identified by an increased heart weight (>550 g in males; >450 g in females) in individuals with obesity (body mass index [BMI] ≥30 kg/m2) in the absence of other causes. Cases of OCM with SCD were compared to sex and age matched SCD controls with obesity or with normal weight (BMI 18.5-24.9 kg/m2) and morphologically normal hearts. Autopsy measures included: heart weight, atrial dimensions, ventricular wall thickness, and epicardial adipose tissue. Fibrosis was assessed microscopically. Results Of 6,457 SCD cases, 53 cases of OCM were identified and matched to 106 controls with obesity and 106 normal weight controls. The OCM mean age at death of individuals with OCM was 42 ± 12 with a male predominance (n = 34, 64%). Males died younger than females (40 ± 13 vs 45 ± 10, P = 0.036). BMI was increased in OCM cases compared to controls with obesity (42 ± 8 vs 35 ± 5). The average heart weight was 598 ± 93 g in OCM. There were increases in right and left ventricular wall thickness (all P < 0.05) in OCM cases compared to controls. Right ventricular epicardial fat was increased in OCM compared to normal weight controls only. Left ventricular fibrosis was identified in 7 (13%) cases. Conclusions OCM may be a specific pathological entity associated with SCD. It is most commonly seen in young males with increased BMI.

ejection fraction 5 and has been shown to exacerbate cardiomyopathy. 6esity is a recognized cause of cardiac enlargement with left ventricular (LV) hypertrophy, diastolic dysfunction, and atrial enlargement [7][8][9] in both males and females. 10,113][14] At autopsy, cardiomegaly is seen in individuals with obesity, often explained by coexisting hypertension, CAD, or diabetes. 15,16[19] This condition can be associated with SCD.In this study, we aim to characterize the clinical and pathological features of OCM associated with SCD by comparing this population to 2 control groups: SCD subjects with obesity or with normal weight and morphologically normal hearts.A minimum of 10 blocks are taken for microscopic examination with sections including the RA, LA, RVOT, anterior, lateral and posterior right ventricle (RV), septum, anterior, lateral and posterior LV, the atrioventricular valves, and all 3 coronary arteries.

METHODS
The conduction system was also sampled routinely.
More blocks were taken if pathology was identified.
Slides were stained with hematoxylin and eosin to examine for fibrosis.A picrosirius red was used to highlight fibrosis, if required.
Cases were placed into groups based on BMI.
Those with a BMI $30 kg/m 2 were defined as obese and those with a BMI of 18.5 to 24.9 kg/m 2 were defined as normal weight individuals (Figure 1).
Pathological diagnostic criteria used for the classification of unexplained cardiomegaly were increased heart weight above 550 g in males and above 450 g in females in the absence of CAD, hypertension, diabetes, or valvular disease. 20Cases with significant CAD (a lumen of <2 mm 2 ) were excluded.
Hypertrophic cardiomyopathy and infiltrating diseases such as amyloid were excluded on histology.These diagnostic criteria were then applied to individuals with obesity and normal weight group individuals.
Individuals with obesity and cardiomegaly were defined as OCM.Age and sex matched controls with obesity were selected based upon a BMI of >30 kg/m 2 with a morphologically normal heart weighing <550 g in males and 450 g in females. 20Age and sex matched normal weight controls were selected based upon a BMI between 18.5 and 24.9 kg/m 2 and a morphologically normal heart weighing <550 g in males and 450 g in females.Controls were matched at a 2:1 ratio.In instances where there was more than 1 possible control match to the index OCM case, a random number generator was used for selection.

RESULTS
There were 53 cases of otherwise unexplained cardiomegaly from a cohort of 1,202 individuals with obesity, denoted as OCM (Figure 1).There were  2).The heart weight of individuals with OCM were higher than those in the controls with obesity and the normal weight control group.Hearts from controls with obesity showed a modest but significant increase in weight when compared to normal weight individuals (P < 0.001) (Table 2 and Figure 3).The relationship between body weight and heart weight is shown in Figure 4.
The    SCD victims with obesity are more commonly male and males die at a younger age when compared to females which is also noted clinically. 21,22The pathology is characterized by RV hypertrophy and symmetrical LV hypertrophy in the absence of myocyte disarray or infiltrative disease.Fibrosis is seen in a minority of cases.Biventricular hypertrophy in obesity has been previously noted on imaging in prior studies. 23Atrial enlargement was also observed when controls with obesity were compared to normal weight controls suggesting this occurs as a response to obesity and further develops with progression to OCM.The RV hypertrophy seen in OCM may be consequences of increased blood volume and left sided failure or sleep apnea and pulmonary hypertension. 24terior RV epicardial fat was increased in OCM cases compared to both controls with obesity and normal weight controls suggesting this develops along with cardiac enlargement in obesity.This fat may also contribute to the increased weight of the OCM heart.
PRIOR PATHOLOGY STUDIES.Previous postmortem studies examining OCM have been limited by small numbers, 17,25 inclusion of individuals with hypertension, and CAD 18,25,26 or inclusion of hearts weighing <550 g in males and 450 g in females. 17,26Smith and Willis reported on the hearts of 133 individuals with obesity.They found the heart of the individuals with obesity to be heavier than lean individuals, attributed The cause of OCM associated with SCD is not fully understood.Adiposity of the heart 26 along with cardiac steatosis 27 and fatty heart 28 have been used to describe the obese heart.This increased metabolically active epicardial fat found in individuals with obesity and may contribute to the development of cardiomyopathy. 29Only a small proportion of cases had fibrosis on microscopy suggesting that SCD in OCM may be mediated through increased ventricular mass.
Previous studies have strongly associated increased ventricular mass with SCD. 30,31THOLOGICAL IMPLICATIONS.The findings of this study highlight that individuals with obesity who die suddenly have pathological enlargement of the heart in the absence of other causes.The number of cases identified in this study is likely to be an underrepresentation of the incidence of this condition as some cases may be mislabeled as hypertensive heart disease at initial autopsy, despite the absence of a history of hypertension. 15,32INICAL IMPLICATIONS.OCM may represent a specific pathological entity associated with SCD.
Public health initiatives to address obesity may be one potential target to decrease SCD risk.For instance, structural heart abnormalities, which occur in individuals with obesity, have been shown to improve following weight loss and bariatric surgery. 33,34The effect of the intervention on SCD risk has yet to be established therefore prospective assessment is warranted.
STUDY LIMITATIONS.There may be an element of referral bias in the data provided as pathologists may The study was undertaken at the Cardiac Risk in the Young Centre for Cardiovascular Pathology based at St George's University of London and is a national referral center for SCD.SCD was defined as an unexpected death occurring instantaneously or within 1 hour of the development of symptoms or if unwitnessed, occurring within 24 hours of last being seen well.Primary care correspondence, clinical notes, coroner's history, post mortem reports, and family questionnaires were reviewed to obtain circumstances of death and past medical history.Noncardiac causes of death were eliminated by trained autopsy pathologists at the initial autopsy and negative toxicology.Macroscopic measurements of the ventricular muscle wall and epicardial fat thickness along with the cavity diameters were taken at a midventricular level.The right ventricular outflow tract (RVOT) was measured 10 mm below the pulmonary valve.The left atrium (LA) was measured between the ostia of the left and right superior pulmonary veins and from the atrioventricular junction to the superior surface.The right atrium (RA) was measured from the inferior vena cava ostium to the tip of the appendage and between the ostia of the inferior vena cava and the superior vena cava.

STATISTICS.
Categorical and binary data are presented as frequencies (percentages) and continuous data are presented as mean AE SD.Paired samples t-test was used to compare normally distributed continuous variables across 2 matched groups.Wilcoxon matched-pair signed rank test was performed on non-normally distributed or ordinal variables across dependent groups.Given the matching aspect of the data collection, conditional logistic regression was used for associations between cardiomegaly as a binary outcome and various potential explanatory variables measured by odds ratios and their 95% CI.The statistical software package SPSS package 27 (IBM) was utilized to perform these tests.Ethical and research governance approval was granted for this study (10/H0724/38).

FIGURE 1 A
FIGURE 1 A Flow Chart of the Study With Pie Charts Illustrating the Frequency of Unexplained Cardiomegaly in Individuals With Obesity and Healthy Weight Individuals

FIGURE 2 Obesity
FIGURE 2 The Gross and Microscopic Findings in Individuals With Unexplained Cardiomegaly in Obesity, OCM

DISCUSSION
On autopsy of individuals with SCD, cardiomegaly is 5 times more common in individuals with obesity compared to normal weight individuals.Hearts from subjects with obesity are heavier than heart from normal weight controls.In a proportion of individuals with obesity there is a further increase in heart weight with wall thickening of both the RV and LV.A minority of these individuals show fibrosis.This data supports the case for a new specific pathological entity associated with SCD: OCM.We propose a definition of OCM with SCD as follows: cardiomegaly (>550 g in males and >450 g in females) in individuals with a BMI >30 kg/m 2 with no history of hypertension or diabetes and no other cardiac disease such as CAD or valve disease at autopsy.Based on this study, OCM with SCD occurs predominantly in individuals with a BMI of >35 kg/m 2 .

FIGURE 3
FIGURE 3 Boxplot Chart for Heart Parameters choose to refer more complex cases to the Cardiac Risk in the Young Centre for Cardiovascular Pathology.A small proportion may have had undetected hypertension.Furthermore, all decedents died suddenly and thus the relevance of OCM to the general population with obesity is uncertain.We cannot exclude the existence of electrical abnormalities not detected by pathology or genetics as there is no national electrocardiographic screening program in the United Kingdom.

FUTURE WORK.
Genetic analysis of cases and followup of relatives will allow us to further elucidate any underlying genetic susceptibility to OCM or determine whether this is purely an acquired condition.Furthermore, correlation with clinical phenotype in living patients and association with outcomes is required.CONCLUSIONS OCM, defined as cardiomegaly in individuals with obesity without other etiologies of heart disease, may represent a specific pathological entity associated with SCD.In this study, OCM was characterized by RV hypertrophy and symmetrical LV hypertrophy in the absence of myocyte disarray with only a minority showing fibrosis.Its relevance and basis as a marker of risk for SCD now requires assessment in population studies.

FIGURE 4 A 4 ACKNOWLEDGMENTS
FIGURE 4 A Scatterplot of Heart Weight vs Body Weight

TABLE 1
Demographics and Body Size Parameters of the 3 CohortsValues are mean AE SD, n, or ratio unless otherwise indicated.Significant values are given in bold.

TABLE 2
Values are mean AE SD unless otherwise indicated.Significant values are given in bold.OCM ¼ obesity cardiomyopathy; RVOT ¼ right ventricular outflow tract.