1. Laurence Watkins, M.D., M.P.H., F.A.C.C.
DIABETIC ATHEROTHROMBOSIS AND ACCELERATED AGING: INTERVENTION STRATEGIES
Laurence Watkins, M.D., M.P.H., F.A.C.C.
Healthy Heart Center
Port St. Lucie, FL

2. Modernization Leads To Increased Prevalence of Diabetes
Intermittent Starvation + High-Protein Diet + Physical Activity
Genetic Selection
Metabolic Efficiency = "Thrifty Genes"
Acute Modernization (calories, dietary fat, physical activity)
Neel. Am J Human Genet. 1962;826.
Tsunehara et al. Am J Clin Nutr. 1990;52:731.
Obesity, Insulin Resistance, And Type 2 Diabetes

3. GLUCOSE INTOLERANCE IN POPULATIONS OF WEST AFRICAN ORIGIN
Age Standardized Prevalence of Diabetes
MEN
WOMEN
1.0
0.5
11.0
14.8
0.5
2.3
11.5
14.6
PREVALENCE
(188) (138) (199) (181)
(196) (157) (198) (224)
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5. November 20, 2018

6. AGE-ADJUSTED PREVALENCE OF DIABETES: ST. JAMES CARDIOVASCULAR STUDY
November 20, 2018

7. PREVALENCE OF DIABETES IN MEN BY AGE AND ETHNIC GROUP ST
PREVALENCE OF DIABETES IN MEN BY AGE AND ETHNIC GROUP ST. JAMES CARDIOVASCULAR STUDY
AGE GROUP
November 20, 2018

8. PREVALENCE OF DIABETES IN WOMEN BY AGE AND ETHNIC GROUP ST
PREVALENCE OF DIABETES IN WOMEN BY AGE AND ETHNIC GROUP ST. JAMES CARDIOVASCULAR STUDY
AGE GROUP
November 20, 2018

9. DIABETES ESTIMATES AND PROJECTION
Persons with Diabetes
COUNTRY
2000
2030
Bahamas
11,519
26,040
Barbados
11,064
22,466
Dominica
2,692
4,306
Grenada
4,169
7,160
Jamaica
80,631
197,573
St. Lucia
5,238
11,327
St. Vincent
5,050
8,886
Trinidad and Tobago
60,259
124,780
USA
17,701,942
30,312,264
November 20, 2018

10. Two-Thirds of People with Diabetes Die of Cardiovascular Disease
November 20, 2018

11. November 20, 2018

12. High Risk of Cardiovascular Events in Type 2 Diabetes
Type 2 diabetes is associated with a marked increase in the risk of cardiovascular (CV) disease. Diabetic individuals without prior myocardial infarction (MI) have as high a CV risk as nondiabetic individuals with previous MI.
In a Finnish population-based cohort, the 7-year incidences of fatal or nonfatal MI, fatal or nonfatal stroke, and death from CV causes among 1373 nondiabetic subjects were compared with the incidences among 1059 subjects with type 2 diabetes.
Both the presence of diabetes and the history of a previous MI at baseline were associated with an increased incidence of CV events.
Diabetic subjects without prior MI had as high a CV risk as nondiabetic subjects with previous MI.
References
Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:
November 20, 2018

13. DIABETES IN TRINIDAD AND TOBAGO MORTALITY STATISTICS
In 1980, highest death rates for DM in the Americas
In 1986, fourth leading cause of death, 52 per 100,000
Greater contribution in women 8%, 25%, 14% for ages 25-44, 45-64, 65 and over
November 20, 2018

14. Atherosclerosis Timeline
Inter-mediate lesion
Foam cells
Fatty streak
Athe-roma
Fibrous plaque
Complicated lesion / rupture
Atherosclerosis timeline
Content Points:
The pathological effects of atherosclerosis occur over decades. A subtle injury to the endothelium initiates the atherosclerotic process.3 Endothelial dysfunction underlies many stages in the progression of atherosclerosis from earliest onset to the lesions that result in coronary heart disease (CHD).4
Foam cells may infiltrate the vessel, progressing to a fatty streak. As the lesion progresses, small pools of extracellular lipid form within the smooth muscle layers, disrupting the intimal lining of the vessel. Progression to an advanced lesion, or atheroma, occurs when accumulated lipid, cells, and other plaque components disrupt the arterial wall.
Progression of atheroma involves accumulation of smooth muscle cells that elaborate extracellular matrix macromolecules. Once the plaque becomes fibrous, the danger of rupture increases. This type of advanced lesion can be found beginning in the fourth decade of life.
The clinically important complication of atheroma usually involve thrombosis. Arterial stenoses by themselves seldom cause acute unstable angina or acute myocardial infarction. Indeed, sizable atheroma may remain silent for decades or produce only stable symptoms, such as angina, precipitated by increased demand.
Thrombus formation usually occurs because of physical disruption of atherosclerotic plaque. The majority of coronary thromboses result from a rupture of the plaque’s protective fibrous cap, which permits contact between blood and the highly thrombogenic material located in the lesion’s lipid core.
The endothelium participates in the atherosclerotic process and remodeling through secretion of specific compounds.1 These will be discussed in later slides.
(Adapted from Pepine CJ. Am J Cardiol )
November 20, 2018

15. Potential Mechanisms of Atherogenesis in Diabetes
Abnormalities in apoprotein and lipoprotein particle distribution
Glycosylation and advanced glycation of proteins in plasma and arterial wall
“Glycoxidation” and oxidation
Procoagulant state
Insulin resistance and hyperinsulinemia
Hormone, growth-factor, and cytokine-enhanced SMC proliferation and foam cell formation
SMC=smooth muscle cell.
Adapted from Bierman EL. Arterioscler Thromb. 1992;12:
November 20, 2018

16. Angina and Coronary Artery Disease in Patients with Diabetes Mellitus
In diabetes, hyperglycemia, excess free fatty acid release, and insulin resistance engender adverse metabolic events within the endothelial cell. Activation of these systems impairs endothelial function, augments vasoconstriction, increases inflammation, and promotes thrombosis and thus renders arteries susceptible to atherosclerosis.1
Postprandial increases in plasma glucose, free fatty acids, and insulin concentrations in diabetic patients suppress endothelium-mediated vasodilation by decreasing bioavailability of endothelium-derived nitric oxide.1
In patients with type 2 diabetes, this suppression of endothelium-mediated vasodilation is of greater severity and longer duration than in individuals with normal glucose tolerance.2
Postprandial increases in serum glucose, low-density lipoprotein cholesterol, and insulin concentrations can also lead to vasoconstriction mediated by increased expression of endothelin-1, angiotensin II, and prostanoids.2
These changes augment immune and inflammatory responses that contribute to atherogenesis.
[1] Beckman, et al. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002; 287:
[2] Nesto. Correlation between cardiovascular disease and diabetes mellitus: current concepts. Am J Med. 2004; 116(suppl 5A):11S-22S
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Angina and Coronary Artery Disease in Patients with Diabetes Mellitus

17. Atherosclerosis: Lesion Initiation
L-Selectin, Integrins
Monocyte
VCAM-1, ICAM-1
LDL
E-Selectin, P-Selectin
MCP-1
Intima
OxLDL
Oxidation of low-density lipoprotein (LDL) initiates the atherosclerotic process in the vessel wall by acting as a potent stimulus for the induction of inflammatory gene products in vascular endothelial cells. By activating the NFB transcription factor, oxidized LDL (oxLDL) stimulates increased expression of cellular adhesion molecules. There are several different types of adhesion molecules with specific functions in the endothelial leukocyte interaction: The selectins tether and trap monocytes and other leukocytes. Importantly, vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate firm attachment of these leukocytes to the endothelial layer.
OxLDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF). MCP-1 mediates the attraction of monocytes and leukocytes and their diapedesis through the endothelium into the intima. M-CSF plays an important role in the transformation of monocytes to macrophage foam cells. Macrophages express scavenger receptors and take up and internalize oxLDL in their transformation into foam cells. Migration of smooth muscle cells (SMCs) from the intima into the media is another early event initiating a sequence that leads to formation of a fibrous atheroma.
Kinlay et al. J Cardiovasc Pharmacol. 1998;32(suppl 3)S62-S66.
Newby et al. J Cardiovasc Res. 1999:
M-CSF
Macrophage
Activation & Division
Media
Smooth Muscle Cell
Migration
November 20, 2018
Kinlay S, Selwyn AP, Libby P, Ganz P. Inflammation, the endothelium, and the acute coronary syndromes. J Cardiovasc Pharmacol (suppl 3):S62-S66.
Newby AC, Zaltsman AB. Fibrous cap formation or destruction—the critical importance of vascular smooth muscle cell proliferation, migration, and matrix formation. Cardiovasc Res. 1999;41:
SLIDE 4

18. Atherosclerosis: An Inflammatory Disorder
Adherence and entry of leukocytes
VSMC migration
Adherence and aggregation of platelets
Foam-cell formation
T-cell activation
November 20, 2018
VSMC, vascular smooth muscle cell migration.

19. EARLY STAGES OF DIABETIC ATHEROSCLEROSIS
Overproduction of Reactive Oxygen Species causes Endothelial Dysfunction via
Decreased bioavailability of NO,
Increased synthesis of Endothelin
Increased vascular permeability
Increased production of VascularEndothelial Growth factor(promotes angiogenesis and microangiopathy)
Hyperglycemia-induced endothelial damage
Increased Advanced Glycation End-product formation
Activation of Proinflammatory Nuclear Factor Kappa B
November 20, 2018

20. ADVANCED STAGES OF DIABETIC ATHEROSCLEROSIS
Diabetes-induced Oxidative Stress stimulates
-Adventitial Inflammation
-Vasa vasorum neovascularization
End Result
-Intraplaque hemorrhage
-Macrophage activation
-Lipid core expansion
Increased potential for plaque rupture
Insulin Resistance induces in MACROPHAGES
-upregulation of CD36 protein
-increased uptake of Ox-LDL
-increased Matrix Metalloproteinase production
-infiltration into plaque
November 20, 2018

21. Nature of Coronary Artery Disease (CAD) in Diabetes
Normal glycemia (n=291)
Disease both mild and diffuse
Impaired Fasting Glucose (IFG) (n=82)
“Mild” diabetes (n=20)
WHO-defined diabetes (n=73)
P for linear trend=0.0001 ns
P=0.06
P for linear trend=0.001
P=0.05 ns
P for linear trend=0.05 ns ns
Mean Number of Affected Segments
Mean Number of Affected Segments
Mean Number of Affected Segments
This slide demonstrates the distribution of coronary segments by severity grade and by categories of hyperglycemia.1
Only mildly severe (25% to 49% diameter stenosis) lesions were significantly more prevalent in patients with “mild” diabetes than they were in patients with normal plasma glucose and were as prevalent as in the WHO-defined patients with diabetes.1
Patients with higher numbers of normal segments had a greater likelihood of being normoglycemic.1
Patients with mildly diseased segments were generally more likely to have “mild” diabetes (1997 ADA definition – fasting plasma glucose (FPG)>126 mg/dL).1
It has been previously thought that patients with T2DM have more severe atherosclerotic disease. Many patients with T2DM actually have mild/moderate atherosclerotic disease.1
Mild disease is associated with softer plaque, which is in essence more vulnerable to rupture. This finding may explain the increased event rate in patients with diabetes, even in those who are asymptomatic.1
1. Ledru F, Ducimetiere P, Battaglia S, et al. New diagnostic criteria for diabetes and coronary artery disease: insights from an angiographic study. J Am Coll Cardiol. 2001;37(6):
Normal segments <25%
Mildly diseased segments (26% to 50%)
Severely diseased segments (76% to 99%)
Ledru F, et al. J Am Coll Cardiol. 2001;37(6):
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22. November 20, 2018

23. Several age-associated cardiovascular changes directly impact the development and progression of atherosclerosis and CAD.1 Over a century ago, it was recognized that arterial walls stiffen with age in both animals and man. Major aging changes in the arterial wall include increased calcium and collagen content and loss of elastin fibers. An increase in collagen cross-linking also occurs. Greater wall thickness is observed in both central and peripheral arteries and can be detected by ultrasound as increased intima-medial thickness. The loss in arterial resiliency results in increases in the systolic blood pressure and pulse pressure, both of which are potent cardiovascular and coronary risk factors in older patients. Pulse wave velocity, a more direct measure of arterial stiffness, also increases with age. The central arterial pressure wave contour is also altered with age, typically demonstrating late systolic augmentation, thought to represent the effects of early wave reflection returning from the periphery. Stiffer arteries with higher systolic and pulse pressures coupled with late systolic pressure augmentation combine to increase the left ventricular (LV) pulsatile load with age.
Thus, the older adult heart requires greater LV stroke work, wall tension and myocardial oxygen consumption during systole than does the younger heart, thereby increasing the risk of ischemia, even in the absence of CAD. In addition, vascular wall stress is increased, predisposing to vascular injury, an important stimulus to the development and progression of atherosclerosis.
[1] Lakatta EG, et al. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises – part I: aging arteries: a “set up” for vascular disease. Circulation. 2003; 107:139–146
[2] Lakatta EG, et al. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises – part II: the aging heart in health: links to heart disease. Circulation. 2003; 107:346–354
November 20, 2018
Chronic Coronary Artery Disease in the Elderly

24. Visceral Fat Distribution: Normal vs Type 2 Diabetes
Slide 13
Visceral Fat Distribution:
Normal vs Type 2 Diabetes
As seen in computed tomographic (CT) scans, the distribution of visceral fat (white areas) differs in a subject with normal glucose tolerance (left) and in a subject with type 2 diabetes (right). The two subjects had similar waist circumferences, but the individual with type 2 diabetes had a larger amount of visceral fat than did the subject with normal glucose tolerance. The amount of subcutaneous fat was larger in the subject with normal glucose tolerance than in the subject with type 2 diabetes.
November 20, 2018