Association of Cardiomegaly with Coronary Artery Histopathology and Its Relationship to Atheroma

32 Journal of Atherosclerosis and Thrombosis Vol.18, No.1 Coronary Histopathology in Cardiomegaly 33 Original Article Association of Cardiomegaly with Coronary Artery Histopathology and its Relationship to Atheroma Richard Everett Tracy Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, USA Aims: Hypertrophied hearts at autopsy often display excessive coronary artery atherosclerosis, but the histopathology of coronary arteries in hearts with and without cardiomegaly has rarely been com- pared. Methods: In this study, forensic autopsies provided hearts with unexplained enlargement plus com- parison specimens. Right coronary artery was opened longitudinally and flattened for formalin fixation and H&E-stained paraffin sections were cut perpendicular to the endothelial surface. The mi- croscopically observed presence or absence of a necrotic atheroma in the specimen was recorded. At multiple sites far removed from any form of atherosclerosis, measurements were taken of intimal thickness, numbers of smooth muscle cells (SMC) and their ratio, the thickness per SMC, averaged over the entire nonatheromatous arterial length. When the mean thickness per SMC exceeded a certain cutoff point, the artery was declared likely to contain a necrotic atheroma. Results: The prevalence of specimens with necrotic atheromas increased stepwise with increasing heart weight, equally with fatal or with incidental cardiomegaly, and equally with hypertension- or obesity-related hypertrophy, rejecting further inclusion of appreciable age, race, or gender effects. The prevalence of specimens with thickness per SMC exceeding the cutoff point was almost always nearly identical to the prevalence of observed necrotic atheroma, showing the two variables to be tightly linked to each other with quantitative consistency across group comparisons of every form. Conclusions: In summary, cardiomegaly, irrespective of the specific cause, seems to accelerate the risk of atheromas, and to do so by first altering the arterial architecture, especially by increasing intimal thickness per SMC. J Atheroscler Thromb, 2011; 18:32-41. Key words; Aging, Atherosclerosis, Human, Hypertension, Obesity Abbreviations; SMC: smooth muscle cell, FS: fibroplastic thickness per SMC in intima, CHD: coronary heart disease, YesA: 1 if specimen has an atheroma, NoA: specimen has no atheroma, FI: fibrolastic thickness of intima, SI: SMC numbers in intima, MAP: mean arterial pressure, BMI: body mass index the condition is usually classed among the cardiomy- Introduction opathies. The most common of these are ischemic, hy- When cardiomegaly is encountered at autopsy in pertensive, obesity-related, idiopathic dilated, and hy- the absence of evidence of myocardial lesions, valvular pertrophic cardiomyopathy, as variably defined 1-5). deformities, or other anatomically evident causes, then When the cause of hypertrophy is determined to be hypertension6), obesity7-10), or a combination of the Address for correspondence: Richard E Tracy, Department of two, then the coronary arteries are expected to display Pathology, Louisiana State University Health Sciences Center, 1901 Perdido St 1P5, New Orleans, LA 70112, USA excessive sclerosis. Ischemic cardiomyopathy, clinically E-mail: [email protected] recognized, is said to occur upon finding significant Received: January 28, 2010 coronary stenosis by angiography or noninvasive Accepted for publication: August 19, 2010 methods, whether or not this is confirmed by abnor- 32 Journal of Atherosclerosis and Thrombosis Vol.18, No.1 Coronary Histopathology in Cardiomegaly 33 Original Article mal chamber wall motility2-3). Idiopathic dilated car- said to manifest a “predicted atheroma”, a convention diomyopathy, clinically recognized, manifests dilated adopted to contribute brevity to the exposition and to hypertrophy without anatomic cause, hypertension, or reduce the sizes of some tables. obesity 11-13), and coronary arteries are generally thought to have little atherosclerosis3-13), although Aim contrary evidence has been observed 12-13). Recent studies applying newly introduced technologies for quanti- The presence or absence of observed or predicted fying coronary artery calcifications have reported an atheromas is examined here in relation to heart weight increased extent of such plaques in relation to cardiac in a series of forensic autopsies. The question of cen- hypertrophy2, 6, 14-16); however, these studies in living tral interest is whether cardiomegaly itself might pro- patients were handicapped by the inability to clearly mote observed or predicted atheromas, irrespective of distinguish ischemia from other forms of cardiomyop- the cause of cardiomegaly, a question that has been athy. Whether hypertrophy can itself promote coro- raised by accumulating epidemiological evidence21). nary plaques (rather than result from them) therefore remains a persistent question. Methods Postmortem examination offers some advantages Source of material and some shortcomings for exploring the relationships Specimens of coronary artery were prepared at of cardiomegaly to coronary artery sclerosis. Ischemia autopsy from 462 men and women of black and white from coronary artery stenosis is widely thought to pro- ethnic groups aged 35-98 years in the Orleans Parish duce ventricular hypertrophy only when myocardial Coroner’s Office from 1993-2005, accepting all causes scarring interferes with ventricular function, but not of death except for some selected forms of anatomical- otherwise17); hence, inspection of the myocardium for ly evident heart disease, cerebrovascular disease, and visible lesions should allow for elimination of nearly aortic aneurysms. A basal category using subjects with all instances of ischemic cardiomyopathy. Further- causes of death from violence, or natural causes unre- more, coronary arteries can be examined in gross and lated to hypertension or atherosclerosis, offers an ap- histological detail18-20); however, important clinical in- proximation of a representative sample of the popula- formation is usually unavailable in forensic autopsies. tion22), but this report does not require the use of such In the autopsy series to be reported here only a subset a basal group. This autopsy study, omitting patient of subjects had data on height and weight to use for identifiers, was declared exempt from Internal Review assessing obesity. No information on blood pressure Board review. was available, and evidence of a hypertensive status was extracted from renal histology. Cardiomegaly The aging of coronary arteries is accompanied by The arbitrary cutoff points for defining cardio- progressive alterations of their basic architecture megaly were chosen as heart weight ＞399 grams in throughout sites that are far removed from any form women and ＞449 grams in men. These values corre- of atherosclerosis. The architectural component of late well with the values sometimes applied to echo- particular interest here, revealed in H&E-stained par- cardiographic data as thresholds for diagnosing left affin sections, is thickening of the intima, which oc- ventricular hypertrophy23). These values were abstract- curs with little or no change in the numbers of smooth ed from the autopsy protocols without special han- muscle cells (SMCs)19, 20), so that an increase in the dling, and are expected to include measurement errors amount of interstitial matrix material occurs per of uncertain magnitude. SMC, a quantity abbreviated here as FS, fibroplastic thickness per SMC (excluding atherosclerotic thicken- Cardiac diagnosis ing). Much evidence has accumulated to suggest that Coronary heart disease (CHD) was recognized as the likelihood of finding a necrotic atheroma some- coronary thrombosis, or myocardial lesions (scars or where in the specimen strongly increases with FS in a infarcts) in company with arterial stenosis or occlu- simple mathematical relationship 19, 20). When the sion. All instances of CHD were omitted. Also omit- mean magnitude of FS exceeds a certain defined ted were the few instances of cardiac disorders attrib- amount, the probability of finding an atheroma ex- uted to valvular deformities, right ventricular abnor- ceeds 50%, and the specimen can be declared likely to malities, and chronic renal disease. In 40 cases the contain an atheroma. In this report, any specimen cause of death was determined at autopsy to be left whose mean FS is found to exceed this threshold is ventricular hypertrophy, usually in the form of dilated 34 Tracy Coronary Histopathology in Cardiomegaly 35 cardiomyopathy. These 40 subjects constitute the group of cases referred to as “fatal cardiomegaly” (mean B heart weight, 697 grams). Incidental cardiomegaly in the presence of a clearly apparent cause unrelated to cardiovascular disease occurred in 73 cases, 46 instances of death by violence or poisoning and 27 by assort- ed non-cardiovascular natural diseases (mean heart A weight, 501 grams). This group of 73 subjects was designated “incidental cardiomegaly”. Hypertrophic cardiomyopathy in its original sense of asymmetric septal hypertrophy marked by myocyte disarray4) was not encountered in this series. Processing of specimens The first 9 cm of each right coronary artery was opened longitudinally, dissected from the heart, com- pressed by a sponge to flatten for fixation in 4 % ace- tate-buffered formaldehyde, and cut into 3 to 5 longi- tudinal segments to be embedded in paraffin on edge to allow sectioning perpendicular to the luminal

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