Doron Aronson

How hyperglycemia promotes atherosclerosis: molecular mechanisms

Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease. Atherosclerosis accounts for virtually 80% of all deaths among diabetic patients. Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. Animal and human studies have elucidated three major mechanisms that encompass most of the pathological alterations observed in the diabetic vasculature: 1) Nonenzymatic glycosylation of proteins and lipids which can interfere with their normal function by disrupting molecular conformation, alter enzymatic activity, reduce degradative capacity, and interfere with receptor recognition. In addition, glycosylated proteins interact with a specific receptor present on all cells relevant to the atherosclerotic process, including monocyte-derived macrophages, endothelial cells, and smooth muscle cells. The interaction of glycosylated proteins with their receptor results in the induction of oxidative stress and proinflammatory responses 2) oxidative stress 3) protein kinase C (PKC) activation with subsequent alteration in growth factor expression. Importantly, these mechanisms may be interrelated. For example, hyperglycemia-induced oxidative stress promotes both the formation of advanced glycosylation end products and PKC activation.

Mechanisms Determining Course and Outcome of Diabetic Patients Who Have Had Acute Myocardial Infarction

Cardiovascular disease is a leading cause of death in diabetic patients; it accounts for almost 80% of all deaths among diabetic patients in North America [1]. Three quarters of these deaths result from coronary artery disease. Acute myocardial infarction is the cause of death in a substantial proportion of these patients [2]. Diabetic patients who have had myocardial infarction have a higher mortality rate than do nondiabetic patients, both in the acute phase [3, 4] and on long-term follow-up [5, 6]. We examine the mechanisms that may contribute to adverse outcome in diabetic patients who have had myocardial infarction. Course of Acute Myocardial Infarction in the Prethrombolytic Era Studies done before the introduction of fibrinolytic therapy have consistently shown that the in-hospital mortality rates of diabetic patients who have had myocardial infarction are 1.5 to 2 times higher than those of nondiabetic patients [3, 4, 7-15]. Diabetic women have a particularly poor prognosis; their mortality rates are nearly twofold higher than those of diabetic men [4, 7, 13]. The risk conferred by diabetes also affects young diabetic patients who have good cardiovascular status at baseline [9, 16]. Most studies have shown no relation between the duration of known diabetes and in-hospital mortality after myocardial infarction [4, 15, 17]. The excess in-hospital mortality of diabetic patients is primarily caused by an increased incidence of congestive heart failure [3, 4, 7, 10, 11, 14, 15, 18, 19]. Other contributing causes include increased rates of reinfarction, infarction extension, and recurrent ischemia [4, 12, 14, 20]. Most studies have found no excess of ventricular arrhythmias among diabetic patients [4, 11, 12, 14, 15, 21, 22]. It has been well established that survival after myocardial infarction is related to residual left ventricular function and thus to the amount of damaged myocardium [23, 24]. However, congestive heart failure and cardiogenic shock in diabetic patients are more common and more severe than would be predicted from infarction size [3, 7, 18, 19, 21, 25-27]. Studies have found no evidence that diabetic patients have more extensive infarctions than do nondiabetic patients, whether infarction size is assessed by serial determinations of total creatine kinase activity [3, 4, 14, 18, 19, 22], radionuclide ventriculography [7, 27], or echocardiography [11]. Additional pathogenic processes thus compromise myocardial function [4] (Figure 1). Figure 1. Probable mechanisms promoting congestive heart failure and associated in-hospital mortality in diabetic patients who have had acute myocardial infarction. Diabetic Cardiomyopathy The higher incidence of pump failure among diabetic patients has generally been ascribed to a preexisting subclinical impairment of left ventricular function [4, 28]. During acute ischemia, patients show compensatory hyperkinesis of the noninfarcted myocardium; this hyperkinesis may normalize global ejection fraction and correlates with hemodynamic status and survival [29, 30]. Several studies have shown a reduction in left ventricular ejection fraction [11, 4, 27, 31] and regional ejection fraction of the noninfarcted myocardium [27, 31] after myocardial infarction in diabetic patients compared with nondiabetic patients. Results of early angiography in the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) trials [13] showed that ventricular function was worse in noninfarcted areas in diabetic patients. Nevertheless, a considerable increase in the clinical manifestations of heart failure occurs with a modest decrease in left ventricular ejection fraction, indicating that the diastolic component is a major culprit of congestive symptoms [4]. Indeed, the cardiomyopathic process associated with diabetes initially manifests as diminished left ventricular compliance in the presence of normal systolic function [32-38]. Diastolic abnormalities occur in 27% to 69% of asymptomatic diabetic patients in the absence of or with only mild microvascular complications [32, 33, 36, 37]. Coexistent hypertension, which occurs about twice as frequently in diabetic patients as in the general population [39], results in more severe cardiomyopathy [40]. Hypertension leads to left ventricular hypertrophy and contributes to decreased left ventricular compliance [40]. However, impaired diastolic relaxation has been shown in the absence of concomitant hypertension in diabetic patients [32, 35-37, 41]. A lower ejection fraction in response to exercise in the presence of normal resting ejection fraction has also been shown in several studies [37, 38, 42, 43], suggesting that the contractile reserve is decreased in asymptomatic patients. Frank systolic dysfunction usually appears in patients with longstanding disease who have advanced microvascular complications or coexistent hypertension [35, 38, 40]. Subclinical diabetic cardiomyopathy that is unrelated to large-vessel atherosclerosis therefore reduces the compensatory ability of the noninfarcted myocardium. In a diabetic patient who has a given degree of myocardial necrosis, the clinical picture is likely to reflect the extent of the cardiomyopathic process. Patients with preexisting diastolic dysfunction may develop clinical heart failure with a relatively preserved ejection fraction. It should be emphasized, however, that indices of left ventricular diastolic function provide prognostic information independent of ejection fraction [30, 44]. Patients with more advanced cardiomyopathy manifest congestive heart failure with decreased ejection fraction and possibly cardiogenic shock. Reduced Blood Flow to the Noninfarcted Myocardium The global effect of acute coronary occlusion is partly determined by the extent of coronary disease and its effect on the contraction of the surviving myocardium. Stenosis of more than 50% in noninfarction vessels is related to lack of hyperkinesis of noninfarcted areas [29, 45]. Both the GUSTO (Global Utilization of Streptokinase and t-PA [tissue plasminogen activator] for Occluded Coronary Arteries) [45] and the TAMI [46] trials have shown that the presence of multivessel coronary artery disease predicts short-term mortality in patients who have had acute myocardial infarction. Autopsy studies have shown that diabetic patients have more extensive coronary atherosclerosis than do controls without diabetes [47, 48]. Large angiographic studies indicate that diabetic patients who have established coronary artery disease have significantly more severe proximal and distal coronary artery disease [13, 49-51] (Table 1). Concomitant hypertension [40], atherogenic lipoprotein profile [52], and abdominal obesity [53] contribute to the accelerated atherosclerosis. Table 1. Angiographic Studies in Patients with Diabetes* Angiographic assessment of epicardial stenoses does not fully reflect the adequacy of myocardial perfusion. In the normal heart, a balance between increased oxygen demand and supply is obtained by the dilatation of epicardial coronary arteries and small (resistance) arterioles. In diabetes, the capacity of the vascular bed to meet myocardial demand may also be impaired by abnormal epicardial vessel tone and microvascular dysfunction. Dilatation of epicardial arteries in response to hypoxia mainly relies on the release of endothelium-dependent relaxing factor [54]. Impaired endothelium-dependent relaxation is consistently found in diabetic patients [55-57] and occurs in various vascular beds, including the coronary arteries [58]. Hyperglycemia is the primary mediator of diabetic endothelial dysfunction. Impaired endothelium-dependent relaxation can be induced by brief exposure (several hours) to high glucose concentrations [56, 57] and can be reversed by pancreatic islet transplantation [59], implying a metabolic defect rather than irreversible damage to endothelial cells [55]. Endothelial dysfunction is thought to result primarily from increased generation of free radicals [56, 57, 60, 61] and the presence of advanced glycosylation end products [62] that deactivate nitric oxide. The abnormal vasodilatory response associated with diabetes also extends to the microcirculation. Locally regulated microvascular dilatation permits efficient distribution of blood flow in the myocardium [54]. Coronary arterial microvessels dilate in response to graded reductions in coronary perfusion. This autoregulatory response is blunted in hyperglycemic animals [63, 64] and diabetic patients [65]. This functional abnormality may also be related to endothelial dysfunction [66] and can be worsened by structural abnormalities of the coronary microcirculation [28]. Severe and diffuse atherosclerotic disease, endothelial dysfunction of coronary arteries, impaired autoregulatory response of microvessels to increased myocardial demand, and structural changes in the coronary microvasculature can all lead to myocardial ischemia in the surviving myocardium, rendering it unable to compensate efficiently. In view of the above discussion, why do diabetic patients not have larger infarctions? Recent animal studies suggest that the hearts of diabetic patients are more tolerant to ischemic insults, such as coronary occlusion [67, 68]. Although the mechanism of this protection is unknown, it may be related to ischemic preconditioning [69]. Abnormal Myocardial Substrate Metabolism Energy-independent transport of glucose across cell membranes is catalyzed by members of the facilitative glucose transporter family. The most important glucose transporter in cardiac myocytes is GLUT4, the insulin-responsive glucose transporter. Most of GLUT4 resides in intracellular membrane compartments, where it is prevented from contributing to cellular glucose transport. Insulin stimulates translocation of GLUT4 from the intracellular pool to the plasma membrane, resulting in increased glucose uptake by myocardial cells. GLUT4 also translocates to the plasma memb

Relation Between Red Cell Distribution Width and Clinical Outcomes After Acute Myocardial Infarction

Increased red blood cell distribution width (RDW) has been associated with adverse outcomes in heart failure and stable coronary disease. We studied the association between baseline RDW and changes in RDW during hospital course with clinical outcomes in patients with acute myocardial infarction (AMI). Baseline RDW and RDW change during hospital course were determined in 1,709 patients with AMI who were followed for a median of 27 months (range 6 to 48). The relation between RDW and clinical outcomes after hospital discharge were tested using Cox regression models, adjusting for clinical variables, baseline hemoglobin, mean corpuscular volume, and left ventricular ejection fraction. Compared to patients in the first RDW quintile, the adjusted hazard ratios for death progressively increased with higher quintiles of RDW (second quintile 1.1, 95% confidence interval [CI] 0.6 to 2.1; third quintile 1.8, 95% CI 1.0 to 3.2; fourth quintile 2.0, 95% CI 1.1 to 3.4; fifth quintile 2.8, 95% CI 1.6 to 4.7, p for trend <0.0001). An increase in RDW during hospital course was also associated with subsequent mortality (adjusted hazard ratio 1.13 for 1-SD increase in RDW, 95% CI 1.02 to 1.25). Similar results were obtained for the end point of heart failure. The association between increased RDW and worse outcome was evident in patients with and without anemia. In conclusion, there is a graded, independent association between increased RDW and mortality after AMI. An increase in RDW during hospitalization also portends adverse clinical outcome.

Hyperglycemia and the Pathobiology of Diabetic Complications

Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease. Atherosclerosis accounts for virtually 80% of a

Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.

Objective—Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). The Hp gene is polymorphic with 2 common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product. We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population. Methods and Results—1434 DM individuals ≥55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; P=0.01) and led to early termination of the study. Conclusions—Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2-2 genotype (ClinicalTrials.gov NCT00220831).

Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study.

Background—Stress hyperglycemia in patients with acute myocardial infarction has been associated with increased mortality. Most studies looked at the relationship between admission glucose (AG) and outcome; limited information is available about the clinical significance of fasting glucose (FG). Methods and Results—We prospectively studied the relationship between FG and 30-day mortality in 735 nondiabetic patients with acute myocardial infarction. FG (≥8-hour fast within 24 hours of admission) and AG were measured in each patient. At 30 days, 9 deaths (2%) occurred in patients with normal FG, and 11 (10%), 14 (13%), and 31 (29%) deaths occurred in the first, second, and third tertiles of elevated FG, respectively. Compared with normal FG (<110 mg/dL), the adjusted OR for 30-day mortality progressively increased with higher tertiles of elevated FG (first tertile, 4.6; 95% CI, 1.7 to 12.7; P=0.003; second tertile, 6.4; 95% CI, 2.5 to 16.6; P<0.0001; third tertile, 11.5; 95% CI, 4.7 to 20.0; P<0.0001). Compared with patients categorized as having normal AG (<140 mg/d), the adjusted ORs for tertiles of elevated AG were as follows: first tertile, 1.4 (95% CI, 0.5 to 3.8; P=0.54); second tertile, 3.0 (95% CI, 1.3 to 7.0; P=0.01); and third tertile, 4.4 (95% CI, 2.0 to 9.7; P<0.0001). Compared with patients with normal FG and AG, the adjusted ORs for 30-day mortality were 0.71 (95% CI, 0.15 to 3.4; P=0.67) in patients with elevated AG and normal FG, 3.4 (95% CI, 1.1 to 10.4; P=0.03) for patients with normal AG glucose and elevated FG, and 9.6 (95% CI, 3.5 to 26.0; P<0.0001) for patients with both elevated FG and AG. Comparing nested models showed that including AG failed to improve the prediction of the model based on FG (&khgr;2=5.4, 3 df, P=0.15). In contrast, the addition of FG classes to the model based on AG improved model prediction (&khgr;2=22.4, 3 df, P<0.0001). Conclusions—There is a graded relation between elevated FG and AG and 30-day mortality in patients with acute myocardial infarction. FG is superior to AG in the assessment of short-term risk. (Circulation. 2005;111:754-760.)

Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome

OBJECTIVE: To investigate the relationship between C-reactive protein (CRP) and various characteristics of the metabolic syndrome.DESIGN: Population-based cross-sectional study.SUBJECTS: A total of 1929 subjects undergoing a medical examination in a preventive medicine clinic (age, 50±10 y; 63% males).RESULTS: The proportion of subjects with CRP levels above the cut point generally used to indicate an obvious source of infection or inflammation (>10 mg/l) was 3, 7, and 15% in subjects who were normal weight, overweight, and obese, respectively. Subjects with obesity had markedly higher CRP level compared to patients without obesity regardless of whether they had the metabolic syndrome. However, there was no significant difference in CRP levels between nonobese subjects without the metabolic syndrome and subjects in whom the diagnosis of the metabolic syndrome was based on criteria other than obesity (adjusted geometric mean CRP 1.75 vs 2.08 mg/l, P=0.79). Similarly, CRP levels did not differ among obese subjects with and without the metabolic syndrome (adjusted geometric mean CRP 3.22 vs 3.49 mg/l, P=0.99). There was a linear increase in CRP levels with an increase in the number of metabolic disorders (P trend <0.0001), which was substantially diminished after controlling for body mass index (BMI) (P trend=0.1). Stepwise multivariate linear regression analysis identified BMI, triglyceride levels, HDL cholesterol levels (inversely), and fasting glucose as independently related to CRP levels. However, BMI accounted for 15% of the variability in CRP levels, whereas triglycerides, HDL cholesterol and fasting glucose levels accounted for only ∼1% of the variability in CRP levels.CONCLUSION: Obesity is the major factor associated with elevated CRP in individuals with the metabolic syndrome. CRP levels in the range suggesting a source of infection or inflammation (>10 mg/l) are more common among obese subjects than in nonobese subjects.

Association Between Elevated Liver Enzymes and C-Reactive Protein. Possible Hepatic Contribution to Systemic Inflammation in the Metabolic Syndrome

Objective— The objective of this study was to test whether the frequent association between liver enzyme elevations and various components of the metabolic syndrome is associated with higher C-reactive protein (CRP) levels. Methods and Results— Alanine aminotransferase (ALT), alkaline phosphatase (Alk-P), and high-sensitivity CRP were measured in 1740 subjects. Adjusted geometric mean CRP was calculated for subjects with normal and elevated ALT and for subjects with normal and elevated Alk-P, adjusting for age, sex, smoking, physical activity, body mass index, fasting glucose, triglycerides, the presence of hypertension and low HDL cholesterol, and use of aspirin or hormone replacement therapy. Adjusted CRP levels were higher in subjects with elevated ALT (2.21 versus 1.94 mg/L, P=0.028) or elevated Alk-P (2.58 versus 1.66 mg/L, P<0.0001). Logistic regression showed that compared with subjects with normal liver function tests, the adjusted odds for high-risk CRP (>3 mg/L) were significantly higher in subjects with elevated ALT (OR, 1.5; 95% CI, 1.2 to 1.9, P=0.002) or elevated Alk-P (OR, 2.1; 95% CI, 1.7 to 2.6, P<0.0001). Conclusions— Elevations of liver enzymes are associated with higher CRP concentrations. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome.

Functional Tricuspid Regurgitation in Patients With Pulmonary Hypertension: Is Pulmonary Artery Pressure the Only Determinant of Regurgitation Severity?

BACKGROUND Pulmonary hypertension is a common cause of functional tricuspid regurgitation (TR), but other factors play a role in determining TR severity. The objectives of our study were to determine the distribution of TR severity in relation to pulmonary artery systolic pressure (PASP) and to define the determinants of TR severity. METHODS The echocardiographic reports and selected echocardiographic studies of patients with echocardiographic estimation of PASP were reviewed. Patients with organic tricuspid valve (TV) disease were excluded from the analysis. RESULTS Among 2,139 patients, the frequency of moderate or severe TR was progressively greater in patients with higher PASP. Nevertheless, TR was only mild in a substantial proportion of patients with high PASP (mild TR in 65.4% of patients with PASP 50-69 mm Hg and in 45.6% of patients with PASP >or= 70 mm Hg). By multivariate analysis, age, female gender, PASP (odds ratio, 2.26 per 10-mm Hg increase; 95% confidence interval, 1.95 to 2.61), pacemaker lead, right atrial (RA) and right ventricular enlargement, left atrial enlargement, and organic mitral valve disease were independently associated with greater degrees of TR. In patients with PASP >or= 70 mm Hg, RA size, tricuspid annular diameter, and TV tethering area were greater in patients with greater degrees of TR. CONCLUSIONS PASP is a strong determinant of TR severity, but many patients with pulmonary hypertension do not exhibit significant TR. In addition to PASP, demographic characteristics, mechanical factors, remodeling of the right heart cavities, and other factors (possibly reflecting the presence of atrial fibrillation or occult organic TV disease) are predictive of TR severity.

Relationship Between Reactive Pulmonary Hypertension and Mortality in Patients With Acute Decompensated Heart Failure

Background— In patients with heart failure, pulmonary hypertension (PH) predicts higher risk for morbidity and mortality. However, few data are available on the prognostic implications of reactive (precapillary) PH superimposed on passive (postcapillary) PH. Methods and Results— We performed a subgroup analysis of 242 patients with acute decompensated heart failure assigned to pulmonary artery catheter placement in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Patients were classified into 3 groups, using the final (posttreatment) hemodynamic measurements: (1) no PH (mean pulmonary artery pressure ⩽25 mm Hg; (2) passive PH (mean pulmonary artery pressure >25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance⩽3 Wood units); and (3) reactive PH (mean pulmonary artery pressure >25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance >3 Wood units). Fifty-eight patients were classified as normal mean pulmonary artery pressure, 124 with passive PH and 60 with reactive PH. During follow-up of 6 months, 5 (8.6%), 27 (21.8%), and 29 (48.3%) deaths occurred in patients without PH, patients with passive PH, and with reactive PH, respectively (P<0.0001). After multivariable adjustments, reactive PH remained an independent predictor of death, with an adjusted hazard ratio of 4.8 compared with patients without PH, and 2.8 compared with patients with passive PH (95% confidence interval, 1.7 to 4.7, P=0.0001). Similar results were obtained when reactive PH was defined on the basis of transpulmonary gradient. Conclusions— Reactive PH is common among patients with acute decompensated heart failure after initial diuretic and vasodilator therapy. The adverse outcome associated with PH is predominantly due to increased mortality rates in the subgroup of patients with reactive PH.