This case classically depicts a number of features of diabetic cardiovascular disease. The patient had Type I, insulin-dependent diabetes mellitus (IDDM, juvenile onset) for more than 20 years, with hypertension, and complications affecting multiple organ systems. Primarily, she had diffuse vascular disease affecting a wide range of different caliber blood vessels, from the smallest to the largest. This is a crucial feature of longstanding diabetes for 10 or more years, whether it is insulin dependent or not (types I and II, respectively), and particularly when it is associated with systemic hypertension. Even the autonomic and peripheral diabetic neuropathy, which has been associated with metabolic derangements that affect neural transmission, may have an ischemic component mediated by microvascular damage to nerve fibers.
The classification of blood vessel calibers by size as macrovascular, small, and microvascular is an arbitrary one, and varies between investigators. Nevertheless, it is useful because pathological injury is generally limited to one class of vessel (e.g. atherosclerosis affects the macrovasculature), and tissue damage may depend on the size of the vessel affected in the process. In general, macrovascular blood vessels are the major elastic capacitance vessels including the aorta and the iliac arteries (these have a media composed of multiple lamellae or layers of elastic tissue and smooth muscle cells), and the muscular arteries including the aortic branch vessels (e.g. coronary, carotid, femoral, popliteal, renal, celiac, superior mesenteric, etc.). The muscular arteries have an intima separated from the media by an internal elastic lamella, and the media is composed of smooth muscle tissue. The macrovasculature is primarily affected by atherosclerosis. Microvascular vessels are the small arteries below 100-200 )jm (micrometers or microns), although some investigators would consider vessels beginning at 50-100 |im and smaller. The microvasculature includes vessels identified as arterioles, capillaries, and venules. These vessels are affected by smooth muscle hypertrophy, and increased connective tissue deposition (fibrillar and non-fibrillar collagen).
In diabetes mellitus, it is common to find increased basement membrane material surrounding capillaries, and intercalated around smooth muscle cells in the media of small vessels. In addition, the microvasculature may have endothelial cell dysfunction, and hyper-reactivity (e.g. spasm) of the endothelial and smooth muscle cells, which may lead to tissue damage. The small vessels are arteries with calibers ranging between 50-100 jim and 1000 |im. These are muscular vessels, easily identified by microscopic tissue examination, that are generally affected by "sclerosis" not atherosclerosis. This means that they are 'stiffer' or hardened (literal definition of sclerosis) due to the deposition of connective tissue and smooth muscle hyperplasia. The end-result is an increase in resistance to blood flow, and with severe proliferative changes, there is decreased luminal caliber, thereby causing chronic obstruction and tissue ischemia. Essentially, diabetic vascular injury is ubiquitous and diffuse, eventually affecting all blood vessels, leading to extensive tissue and multiorgan damage.
The patient in this case had macrovascular disease with significant atherosclerosis of coronary arteries, the aorta and its branches. It was the disease of the superior mesenteric artery that precipitated the ischemic bowel disease, requiring surgical intervention. Histologically, there was an atherosclerotic plaque with remote and recent hemorrhage, which can trigger vascular instability or dynamic changes in the vessel, leading to acute luminal occlusion (thrombosis) and subsequent ischemia. There were also changes of sclerosis, with features of Monckeberg's medial sclerosis and calcification. This is a degenerative change that involves the internal elastic lamella with spread of calcium and scar tissue into the media. Monckeberg's medial sclerosis is a common finding in diabetic patients, particularly in the lower extremities where it may lead to vascular insufficiency and gangrene.
She had evidence of small vessel disease, with thickened small arteries in the heart, and in the kidneys. The latter are associated with arterionephrosclerosis secondary to hypertension, which leads to chronic cortical ischemia, scarring, and renal dysfunction. Although her renal dysfunction was also related to microvascular disease, it is not uncommon in diabetic patients to develop ischemia due to vascular pathology affecting all sizes of vessels (e.g. renal artery, small arteries, arterioles, and capillaries). In the heart, small artery disease may lead to focal areas of ischemia with subsequent scarring, which may contribute to the hypertensive and diabetic cardiomyopathy (see below). The ulceration and dry gangrene on her extremities may also have been secondary to disease of small arteries in the muscle and skin.
There was also evidence of microvascular disease in different organs. She had retinopathy leading to blindness. This is often secondary to rupture of capillary microaneurysms with retinal and vitreous hemorrhage and proliferation of new vessels and scar tissue obliterating the retina (e.g. proliferative retinopathy). Ischemic damage may also result from hypertensive sclerosis and narrowing of arterioles. In the kidney, in addition to hypertensive arterionephrosclerosis, she had nodular diabetic glomerulosclerosis or Kimmelstiel-Wilson disease. The latter causes marked nodular thickening and ultimate obliteration of glomerular capillary loops. Only recently has it been shown to be secondary to damage to the glomerular capillaries leading to microaneurysms with ultimate thrombosis and reorganization. These microaneurysms, which occur due to localized injury to the capillary endothelial cells with outpouching of the lumen, are similar to those found in the eye and in the heart.
The patient had a clinical history of congestive heart failure, and her heart was hypertrophied (500 g, normal up to 350 g), with microscopic changes of interstitial and replacement fibrosis. The left and right ventricles were hypertrophied. These findings were characteristic of hypertensive and diabetic cardiomyopathy, with thick-walled chambers and microscopic scarring. Pathophysiologically, the chamber dimensions are small (e.g. decreased end-diastolic volume), and generally the contractility of the ventricle is normal or super-normal. The congestive heart failure symptoms result from diastolic dysfunction. The ventricles are stiff with poor compliance; they pump adequately but fill poorly. As seen in the present case, the description of the ventricular chamber sizes, and the dilation of both atria are typical of a heart with diastolic dysfunction (the atria dilate because of the poor compliance of the ventricles).
The pathogenesis of hypertensive and diabetic cardiomyopathy is complex and multiple factors contribute to its development. Though the diabetic heart is often affected by significant coronary artery atherosclerosis, large vessel ischemia may not be sufficient to account for the disease. In this patient, there was no evidence of large areas of scarring secondary to coronary artery disease. However, small vessel sclerosis certainly contributes to microscopic areas of scarring. These hearts have significant microvascular disease, with microaneurysms present in arterioles and capillaries (Figure 11). In addition, the microvasculature is hyper-reactive (e.g. spasm) and leads to multiple areas of reperfusion damage in the myocardium, with eventual replacement by scar tissue (Figures 12 and 13). Finally, the effects of hypertension also lead to hypertrophy of myocardial cells. The combination of scar tissue and hypertrophy contributes the major component of the diastolic dysfunction, although metabolic cellular considerations (e.g. poor relaxation of cells due to abnormal calcium flux) also play a role.
Despite the fact that the immediate cause of death in this patient could be directly attributed to the mesenteric artery thrombosis, and bowel ischemia, there was significant evidence for systemic disease affecting multiple organs. This is a very typical scenario in diabetic patients, because the disease affects vessels of all calibers, leading to tissue damage throughout the body.
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