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OBESITY

Obesity and • Higher prevalence of Cardiac Disease in obese individuals MARY N SHEPPARD ST GEORGE’S MEDICAL • There are several ways in which SCHOOL, LONDON obesity directly affects the [email protected] cardiovascular system 7/5/2018 OBESITY 2018 1 7/5/2018 OBESITY 2018 3

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OBESITY AND DISEASE

• Obesity affects 20% of the population aged under 35 in the UK. • In our cohort of young unexpected SCDs, 20% of individuals were obese. • SADS was the most common post-mortem finding in young obese individuals, • High burden of unexplained LVH and CAD

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OBESITY AND SCD

♥ Body weight affects heart weight ♥ Obesity and electrical instability and prolonged QT interval has been described previously, ♥ The QT prolongation is one of the mechanisms underlying fatal in obese individuals with a structurally normal heart ♥ Unexplained LVH was more frequently observed in obese young ♥ CAD is more prevalent in obese young people. ♥ SCD in young obese individuals occurs frequently without antecedent symptoms or a significant past medical history

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Sudden Cardiac Death

500,000 deaths in UK 50,000 SCD in the UK

CORONARY ARTERY DISEASE 81%

Bowker, Sheppard,Wood, Davies et al JRSM 2003 BHF study CRY DEPT. CARDIOVASCULAR 7/5/2018 OBESITY 2018 15 PATHOLOGY, LONDON 2018

Blocked vessel and old damage

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HYPERTROPHY OF THE LEFT > 15mm 25-30mm

Heart weight 500 gms in males 400gms In Females

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INCREASED THICKNESS OF VENTRICLE WALL Fibrosis in Left Ventricle

>15 mm HYPERTENSIVE HEART DISEASE

Post LV wall EVG

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CORONARY ARTERY Post Surgery DISEASE ♥ After coronary artery bypass surgery also there are more adverse outcomes in obese patients. ♥ Obesity is an independent predictor of coronary They have increased incidence of artery disease, as observed in the Framingham postoperative thromboembolism, infections of heart study,Manitoba study, and Harvard public the sternum, and saphenous vein harvest sites. health nurses study There is also a higher incidence of atrial ♥ Autopsy among 15 to 34 year olds who died from arrhythmias. accidental causes show plaques and ulceration in Pulmonary complications in the severely obese the and abdominal , which ♥ (BMI >35) and when complicated by diabetes, correlate with the amount of abdominal fat and renal dysfunction or age BMI (PDAY study) 7/5/2018 OBESITY 2018 21 7/5/2018 OBESITY 2018 23

ATHEROMA HYPERTENSION • Men, hypertension is 15% in those with BMI ♥ Obesity accelerates atherosclerosis decades <25 and 42% if BMI is >30; before clinical manifestations appear and this remained significant even after • Women are 15% and 38%, respectively adjustment of other risk factors like high • Factors like low-grade inflammation mediated cholesterol, hypertension, smoking, and through adipokines, hyperinsulinemia, and increased HbA1c. insulin resistance, over-activity of the ♥ The density of macrophages per mm2 of sympathetic nervous system and a disordered plaques also correlate with visceral obesity sleep pattern increase the systemic vascular resistance in obese patients 7/5/2018 OBESITY 2018 22 7/5/2018 OBESITY 2018 24

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ADIPOSE TISSUE PULMONARY ♥ Adipose tissue has a resting blood flow of 2 HYPERTENSION to 3 mL/100 g/min, but can increase up to 10- • Increased pulmonary vascular resistance is fold; this occurs usually after food intake. combination of intrinsic pulmonary disease, sleep With increasing obesity the perfusion per unit apnea/hypoventilation, recurrent pulmonary ♥ thromboembolism, or left ventricular dysfunction, mass decreases. It falls from 2.36 mL/min to all of which are more common in obese 1.53 mL/min when the percentage of fat individuals increases from 20% to 36% of the body • Nocturnal dysrhythmias, right and left heart weight failure, , stroke, and ♥ Increase in cardiac output is not directly mortality are more common in those with proportional to the total fat. obstructive7/5/2018 sleep apneaOBESITY 2018 25 7/5/2018 OBESITY 2018 27

Obesity increases adverse cardiac CARDIAC HYPERTROPHY events in many ways ±Indirectly mediated through risk factors • Increased cardiac output in obese patients is associated with metabolic syndrome like to meet the metabolic demand of the dyslipidemia, hypertension, and glucose adipose tissue and is achieved with increase intolerance in stroke volume. ±Pro-inflammatory and prothrombotic state • The left ventricular chamber dilates to causing endothelial damage and vascular accommodate the increased venous return hypertrophy and, in turn, develops an eccentric type of ±Sleep disorders associated with obesity hypertrophy to keep the wall stress normal

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Genetic? Autopsy Series of Maternal Cardiopulmonary Deaths from 1994 to 2009 in Two Tertiary Centres in the United Kingdom

Keiko Ogo MD Sofia V de Noronha MSc PhD Prof Sebastian Lucas FRCPath (Expert of maternal autopsy) Mary N Sheppard MD FRCPath (Specialist of cardiac pathology)

• Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust Hospital • CRY Centre for Cardiac Pathology, Imperial College London • Department of Histopathology, St Thomas’ Hospital 7/5/2018 OBESITY 2018 30

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Result Result Study design - Retrospective s Body mass index (BMI) s Data available in 49/84 cases (58% of the cohort) Retrieval of maternal deaths due to cardiopulmonary causes from combined archives of autopsies and consultation cases (1994 − 2009)

Royal Brompton Hospital / CRY St Thomas’ Hospital Underweight (< 18.5) Morbidly obese (≥ 40) (n = 50) (n = 34) Normal (≥ 18.5, < 25) 14% 2% 43% 35% 84 cases 29% 20% Obese (≥ 30, < 40)

61 20 3 Overweight (≥ 25, < 30) Deaths beyond 1 year Maternal deaths Late maternal deaths (Cases of peripartum ) ! 63% of the cases with known BMI were obese (43%) or overweight (20%) *Septic shock and eclampsia fits were excluded.

Result Result Demographics - maternal age at death s Diagnoses s Cardiovascular disease Pulmonary vascular disease Thrombotic disease Mean: 30 ± 7 years 25 Range: 15 − 49 20 15 Median: 31 32% 10

≥ 5 35 Number of cases

0 MorphologicallyCardiomyopathy normal Coronaryheart arteryCHD pathologyAortic dissectionValvular heartOther disease cardiacPH Pulmonary embolicTTP diseaseOther thrombosis

The leading causes 1. Sudden death with a morphologically normal heart 2. Cardiomyopathy 3. PH 4. Pulmonary embolic disease (PTE + AFE)

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Emerging entities in maternal death EFFECT ON HEART SD with • Role of channelopathy (e.g. Long QT syndrome) morphologically (genetic inheritable disease) in maternal death normal heart • Importance of family screening* • Cardiomyopathy of obese individuals = SADS (adipositas cordis) is caused by a direct effect of obesity on the heart. • ? Acquired LVH • Obesity, hypertension, diabetes etc • The increase in the fat content of the heart is • ? Genetic – role of family screening because of a metaplastic phenomenon

• Known links to ischaemic heart disease and pulmonary • thrombo-embolism in maternal death Obesity • But we also highlight the association of obesity to non- ischaemic heart disease such as normal heart and LVH

* Behr ER et al. Sudden arrhythmic death syndrome: familial evaluation identifies 7/5/2018 OBESITY 2018 39 inheritable heart disease in the majority of families. Eur Heart J. 2008

OBESITY CM OBESITY CM

• Obesity is becoming a worldwide phenomenon. ♥ The existence of a cardiomyopathy of obesity is Myocardial changes associated with the obese state supported by a range of evidence are increasingly recognized, independent of ♥ Epidemiologic study findings, which have shown hypertension, obstructive sleep apnoea and an association between obesity and ♥ Clinical studies that have confirmed the association of adiposity with left ventricular dysfunction, independent of hypertension, coronary artery disease and other heart disease

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Important mechanisms in development of obesity cardiomyopathy • Metabolic disturbances (insulin resistance, increased free fatty acid levels • Increased levels of adipokines • Activation of the renin–angiotensin–aldosterone and sympathetic nervous systems • Myocardial remodelLing • Small-vessel disease (both microangiopathy and endothelial dysfunction).

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Beware the FATYY heart

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Posterior fat Obese Normal Heart

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Immobile fatty heart

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Fat on the epicardial surface

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Well defined border between Photo 2 Ill-defined border epicardial fat and myocardium

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Anterior Photo 1 Adult heart showing the variable amount of epicardial Lateral fat normally seen in different parts of the right ventricle wall. In this case epicardial

Posterior fat is thickest in the lateral wall; less fat is present anteriorly; there is no fat on the posterior wall.

Heart of a 2 year old child showing no epicardial fat in either the left or right ventricles. 7/5/2018 OBESITY 2018 58 7/5/2018 OBESITY 2018 60

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OBESITY CARDIOMYOPATHY

Heart weight >500 in males >400 in females Thickness >15mm

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FATTTY INFILTRATION

RIGHT VENTRICLE

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Normal coronary arteries

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Fatty hypertrophy of Right Ventricle

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(a) (b)

(c) A s no epicardial fat and minimal intramyocardial fat. There is a greater amount of fatty infiltration of the myocardium in micrographs (b) and (c) but in both cases the fat is still confined to the outer half 7/5/2018 OBESITY 2018 85 7/5/2018 OBESITYof the2018 right ventricle wall. 87

Hearts from three different patients showing extensive full- thickness fatty infiltration of the right ventricle wall. The ventricle in each case is still of normal thickness and there is no significant fibrosis 7/5/2018 OBESITY 2018 86 7/5/2018 OBESITY 2 88

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DISTRIBUTION OF FAT IN THE RIGHT VENTRICLE OF NORMAL

D.Tansey, Z.Aly, M.N. Sheppard Histopathology 2006

FAT IN THE HEART Background:

IS IT A GOOD OR BAD THING ! Fat is normally present on the epicardial surface of the right ventricle and around the coronary blood vessels, the amount varying with a person’s age and nutritional status.

Unlike ARVC simple fatty infiltration is not arrhythmogenic and is not a recognised cause of sudden death. We were first to highlight this obvious fact.

Our study was undertaken to show the amount of fat and its distribution in the right ventricle of ‘normal’ hearts.

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Anterior Wall Lateral Wall

no. patients no. patients 30 14 What harm is fat in the heart ? 25 12

20 10

15 8

6 10 4 5 2

0 0 0mm 2mm 4mm 6mm 8mm 10mm 12mm 0mm 2mm 4mm 6mm 8mm 10mm 12mm

thickness of epicadial fat thickness of epicardial fat

Graph 1.

Posterior Wall

no. patients Thickness of Epicardial Fat in Anterior, Lateral 80 and Posterior Right Ventricle Wall 70 60

50 Epicardial fat thickness ranged from 0 to 14mm and 40 was greatest in the lateral wall. The least amount of 30 epicardial fat was present posteriorly. 20

10

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Epicardial Fat Thickness and Patient Age

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8 Right 6 Membranous septum Membranous 4 septum 2 0 Dividing bundle 12mm 10mm Bundle 8mm left over 40years Av 6mm thickness of epicardial fat Hiss 20-39years in lateral right ventricle wall right 0-19years 4mm node 2mm 0mm Graph 2. Relationship of Thickness of Epicardial Fat in Lateral Right Ventricle Wall to Age Interventricular Females generally had more epicardial fat than Interventricular septum males. Th e amount of epicardial fat also tended to septum increase with age. In fants had little or no epicardial fat; the greastest amount of fa t was seen in patients 7/5/2018 over 40 years of age. OBESITY 2018 93 OBESITY7/5/2018 2018 95

FAT INFILTRATION Conduction system fat

• Sinus node, , right bundle branch, and the myocardium near the atrioventricular ring, are replaced by fat cells. • These can occasionally cause conduction defects like sinoatrial block, , and, rarely, . Irregular bands of adipose tissue may separate and cause pressure-induced atrophy of the

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Adipose Cells HEART FAILURE ♥ Several factors primarily caused by obesity, • These adipose cells may also secrete locally like increased blood volume, elevated cardiac active molecules like adipokines, which output, left , and left indirectly cause injury to adjacent ventricular diastolic dysfunction, in addition to myocardial cells. adipositas cordis, play a role in causing heart failure. • Accumulation of triglycerides in nonfat cells like myocytes can also directly cause ♥ This is in addition to indirect effects mediated cell dysfunction because of lipotoxicity through other frequently coexisting conditions like diabetes, hypertension, and coronary artery disease. 7/5/2018 OBESITY 2018 97 7/5/2018 OBESITY 2018 99

Obesity Cardiomyopathy

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ARRHYTHMIAS

♥ There is an increase in the incidence of sudden cardiac death and arrhythmias in obesity. ♥ Fatal arrhythmias may be the most frequent cause of death among obese patients. According to the Framingham data, sudden cardiac death was 40 times higher in obese men and women

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ARRHYTHMIAS

♥ Changes occur in the autonomic system with weight gain. A 10% increase in body weight causes a decrease in parasympathetic tone and increase in heart rate. ♥ Heart rate decreases with weight reduction. There is a significant improvement in heart rate variability with 10% weight loss. ♥ Both increased resting heart rate and decreased heart rate variability are predictors of mortality,

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Fig 9: Fat admixed with degenerative myocardial cells with nuclear irregularity, intracytoplasmic vauoles and myofibrillar loss. Note also the scattered lymphocytes in the interstitium

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Fig 8: fibrofatty replacement in the right ventricle with isolated degenerate clusters of myocardial cells . Note extensive fat in outer myocardium and residual myocytes in subendocardium and within trabeculae. Elastic Van Gieson

a b

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5400 REFERRALS IN TOTAL

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Referring pathologist's opinion given

31% (772)

69% Yes (1723) No

MNS opinion (n=766)

31% Misdiagnosis # ARVC 72 Agree LVH 31 69% HCM 29 Disagree Normal 9 Other 94

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Arrhythmogenic cardiomyopathy Sudden death in athletes:

CRY DEPT. CARDIOVASCULAR PATHOLOGY, LONDON 2017

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LARGE MASSES

• Large accumulation of subepicardial fat can mimic (pseudopericardial effusion). • Lipomatous hypertrophy caused by fat deposition in the can cause it to be up to more than 20 mm thick and can even suggest a tumor

CRY DEPT. CARDIOVASCULAR 7/5/2018 OBESITY 2018 123 PATHOLOGY, LONDON 2017

FAT IN THE HEART • ARVC should be kept distinct from fatty infiltration of the right ventricle • A certain amount of intramyocardial fat is present • The characteristic echocardiographic in the right ventricular antero-lateral and apical appearance of LHIS involves an interatrial regions even in the normal heart and that the septal thickness >2 cm usually represented epicardial fat increases with increasing body weight. by an hourglass appearance denoted by fat mass superior as well as inferior, sparing • Fibro-fatty ARVC must besides fatty replacement of the right ventricular myocardium, show the in between. degenerative changes of the myocytes and interstitial fibrosis, with or without extensive replacement-type fibrosis. • Adopt7/5/2018 strict diagnosticOBESITY criteria 2018 122 7/5/2018 OBESITY 2018 124

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Lipomatous Hypertrophy • Lipomatous hypertrophy of the interatrial septum is indistinguishable from lipoma except that the former occurs in the atrial septum with a typical distribution (generally sparing the fossa ovalis). • In the absence of symptoms of atrial arrhythmias, or rare vena caval obstruction, they do not require resection. • With advanced imaging techniques, LHIS is picked up incidentally in the course of work-up for other conditions. 7/5/2018 OBESITY 2018 125 7/5/2018 OBESITY 2018 127

Intraatrial lipomatous Lipomatous hypertrophy hypertrophy • Lipomatous hypertrophy of the interatrial septum (LHIS) is an exaggerated growth of normal fat existing within the septum and is not a true tumor. The septal hypertrophy may be as much as 2 cm in thickness and is seen primarily in older patients and in those who are obese. • It has been suggested that this disorder is associated with the presence of coronary artery disease in proportion to the degree of atrial septal thickness. 7/5/2018 OBESITY 2018 126 7/5/2018 OBESITY 2018 128

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Intraatrial location

• The walls of the left and right atria fold inward toward each other, forming a fat-filled depression between them called Waterston's groove. • Fat contained in this region is not a true interatrial septal density, but in reality is fat that overlies the epicardial surface of the heart.

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Intraatrial lipoma • Exact etiology of LHIS remains unclear • Embryonal mesenchymal cells within the primitive atria that can develop into adipocytes with an appropriate stimulus, particularly obesity and advanced age • The resultant effect is adipocyte hyperplasia and fat accumulation occurring in the epicardium, that is an extracardiac deposition fat, rather than within the interatrial septum as recently illustrated by Silbiger 7/5/2018 OBESITY 2018 130 7/5/2018 OBESITY 2018 132

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Intracardiac lipoma

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Benign Malignant

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