STATE-OF-THE-ART PAPER
Coronary Circulatory Function Abnormalities in Insulin ResistanceInsights From Positron Emission Tomography
Heinrich R. Schelbert, MD, PhD*
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California
Manuscript received April 4, 2008;
revised manuscript received September 16, 2008,
accepted September 29, 2008.
* Reprint requests and correspondence: Dr. Heinrich R. Schelbert, UCLA Molecular and Medical Pharmacology, Box 956948, B2-085J CHS, Los Angeles, California 90095-6948 (Email: hschelbert{at}mednet.ucla.edu).
 |
Abstract
|
|---|
Traditionally, assessment of coronary circulatory function has been complex, requiring invasive techniques, including quantitative coronary angiography, intracoronary flow velocity probes, and pharmacologic stressor agents. However, radiotracer-based techniques for noninvasive measurement of myocardial blood flow are now available. Studies using these new techniques demonstrate that insulin resistance is associated with functional disturbances of the coronary circulation. Conversely, insulin infusion improves coronary flow, even in the setting of type 2 diabetes mellitus and coronary artery disease.
Key Words: diabetes • insulin • myocardial blood flow • positron emission tomography
|
Abbreviations and Acronyms
| | BMI = body mass index | | CPT = cold pressor testing | | CV = cardiovascular | | eNOS = endothelial nitric oxide synthase | | IR = insulin resistance | | NO = nitric oxide | | PET = positron emission tomography | | SPECT = single-photon emission computed tomography | | T2DM = type 2 diabetes mellitus |
|
Pre-diabetic states of insulin resistance (IR), including impaired glucose tolerance and the metabolic syndrome, are associated with clustering of cardiovascular (CV) risk factors, placing patients at increased risk for coronary events (1). Endothelial function is considered a "biomarker of vascular disease" (2) and represents a link between complex phenomena at the molecular level and vascular pathology of atherosclerosis (3). Functional alterations of the peripheral circulation can readily and noninvasively be assessed. One approach employs high spatial resolution ultrasonography to measure flow-mediated brachial artery dilation and flow velocity changes in response to reactive hyperemia and upstream intra-arterially administered vasodilator agents (2). A second approach employs venous impedance plethysmography to evaluate endothelium-related microvascular responses to intra-arterially administered vasoactive agonists (2). Indeed, the presence of functional, mostly endothelium-related, alterations of the peripheral circulation has been demonstrated in persons with mild, pre-diabetic IR (4,5). However, while studies show that brachial artery responses are a surrogate marker for coronary arterial function, this correspondence does not necessarily extend to the microcirculation (6). Thus, direct assessment of the coronary artery circulation is necessary if we are to fully understand the vascular biology of IR and its implications for CV risk.
Initial approaches to directly assessing coronary circulatory function involved invasive techniques, including quantitative angiography, intracoronary flow velocity probes, and pharmacologic stressor agents such as acetylcholine, papavarine, and adenosine (7). The high cost and invasiveness of this approach limit its use, especially in apparently healthy persons with early abnormalities like mild IR. Therefore, coronary function in pre-diabetic persons remained relatively understudied. However, the development of radiotracer-based techniques for measurements of myocardial blood flow offers noninvasive characterization of coronary circulatory function. The following text summarizes observations with this noninvasive, radiotracer-based study approach and critically examines the effects of IR on total integrated coronary function, endothelium-related disturbances, and the implications thereof.
|
Positron Emission Tomography (PET) in Noninvasive Measurement of Coronary Circulatory Function
|
|---|
Myocardial blood flow (in ml/min/g) can be accurately and reproducibly measured with PET and radiotracers of blood flow such as O-15 water, N-13 ammonia, and rubidium-82 (8–11). The ultra-short physical half-life of these radiotracers, ranging from 90 s to 9.8 min, affords repeat flow measurements during a single 1- to 2-h study session so that flow responses to specific stimuli can be evaluated. The short physical half-life of the radiotracers, combined with their high-energy photons, yields relatively low radiation burdens comparable to, or less than, those encountered with clinical stress-rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging with Tc-99m–labeled flow tracers or thallium-201. The high speed and quantitative image acquisition capability of PET are essential for this approach.
The study of coronary function typically entails flow measurements initially in the basal state at rest, during pharmacologically induced hyperemia, and during sympathetic stimulation by cold pressor testing (CPT) (12,13). Each intervention examines a specific component of coronary circulatory function. Adenosine- or dipyridamole-stimulated hyperemia probes the total integrated coronary vasodilator capacity, depending on both vascular smooth muscle and endothelial function. Hyperemic flow responses are mediated by maximum smooth muscle relaxation of pre-arteriolar resistance vessels and are also modulated by endothelium. With normal endothelial function, increases in flow velocity increase endothelial shear stress, prompting release of vasodilator substances that lead to an increase of the epicardial conduit vessel diameter, thereby lowering the resistance to high-velocity flows.
Flow responses to sympathetic stimulation with CPT are a more selective reflection of endothelium-related vascular function. Exposure to cold, as by hand immersion in ice water, prompts an increase in heart rate and blood pressure and, therefore, in cardiac work, which is accompanied by a commensurate rise in myocardial blood flow (in the absence of a coronary stenosis). The flow increase is initiated by a metabolically mediated dilation of the coronary resistance vessels and is modulated by a complex interaction between vascular smooth muscle-related vasoconstrictive and endothelium-related vasodilatory forces. In this scenario, sympathetic stimulation leads to an alpha-adrenergically mediated constriction of the vascular smooth muscle which, under normal conditions, is appropriately offset by shear stress-mediated and, possibly, receptor-mediated endothelial release of vasodilators such as prostacycline and, especially, nitric oxide (NO). In instances of diminished NO bioavailability because of endothelial dysfunction, vasoconstrictor effects can no longer be adequately opposed and coronary flow responses to CPT become attenuated, absent, or paradoxical, (i.e., coronary flow declines) (13).
|
Coronary Circulatory Function in States of IR
|
|---|
Prior et al. (12) studied 120 Mexican-American patients with IR of increasing severity, ranging from normoglycemic IR (by hyperinsulinemic-euglycemic clamping) to impaired glucose tolerance and type 2 diabetes mellitus (T2DM), with and without hypertension. Hyperemic myocardial flow and therefore total vasodilator capacity was reduced only in patients with T2DM (Fig. 1) (12). Coronary vasodilator function was preserved in IR and impaired glucose tolerance, but flow responses to CPT were attenuated. The attenuation of flow response progressively worsened across the spectrum of IR and became paradoxical (decreased) in T2DM with hypertension as the most severe form of IR. These findings indicate the presence of functional impairment in the background of mild IR in pre-diabetes. The functional disturbance is initially confined to endothelium-related vasomotion, increases in severity with more severe states of IR, and eventually compromises total vasodilator capacity.
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Adenosine- or Dipyridamole-Stimulated Hyperemic MBF, and Cold Pressor-Induced Changes in MBF
Comparison of hyperemic myocardial blood flow (MBF) responses to cold pressor testing in insulin-resistant states. (A) Summary of adenosine- or dipyridamole-stimulated hyperemic MBF. (B) Summary of cold pressor-induced change in MBF ( MBF). Note reduction in total vasodilator capacity (A, MBF) only in patients with diabetes mellitus as compared with attenuation of the flow response (B, MBP) to cold pressor testing in insulin-resistant patients. Adapted from Prior et al. (12). DM = diabetes mellitus; DM+HTN = diabetes mellitus and arterial hypertension; IGT = impaired glucose tolerance; IR = normoglycemic insulin resistance; IS = insulin sensitivity.
|
|
Attenuated flow responses to sympathetic stimulation likely reflect decreases in NO bioavailability—due to diminished synthesis, accelerated inactivation, or both. Diminished NO bioavailability likely results from a defect in the insulin-signaling pathway downstream to the insulin receptor and includes phosphorylation of insulin receptor substance protein and activation of phosphatidylinositol 3-kinase, leading to phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production (1). Low insulin receptor substance levels found in IR likely interfere with normal signal transduction, leading to diminished NO synthesis. In the basal state, NO levels may be diminished without affecting resting myocardial flow, as suggested by findings in young healthy volunteers in whom resting flow remained unchanged after inhibition of eNOS with L-nitro-arginine methyl ester (14).
Mechanisms accounting for the progressively worse coronary circulatory functional abnormalities observed in more severe states of IR remain unclear. They may be related to an increased number of vascular stressors, including elevated plasma levels of free fatty acids, triglycerides, oxidized low-density lipoprotein cholesterol, and oxidation-prone small dense low-density lipoproteins. Pro-inflammatory cytokines and inflammatory markers such as C-reactive protein and adipocyte-derived adipokines contribute to further decreases in production and inactivation of NO. Formation of reactive oxygen species in hyperglycemia, together with inactivation of protein kinase C, may further impair vascular function (15,16). The observation of higher hyperemic myocardial flow in T2DM with adequate glycemic control compared with poor glycemic control, independent of IR by hyperinsulinemic-euglycemic clamping (17), underscores the dominant role of hyperglycemia and hyperglycemia-related reactive oxygen species in coronary vascular dysfunction.
It is not clear if functional vasomotor disturbances in overt clinical diabetes also directly affect vascular smooth muscle function. Decreases in total vasodilator capacity in T2DM suggest this possibility; however, comparable reductions in vasodilator capacity ( 30%) have been observed after eNOS inhibition with L-nitro-arginine methyl ester in young normal volunteers (14). This observation suggests that reductions in hyperemic blood flow in T2DM may result from severe reductions in bioavailability alone, possibly related to additive effects of multiple stressors.
Structural vascular alterations may lead to further reductions of the vasodilator capacity in T2DM. As demonstrated with stress-rest SPECT myocardial perfusion imaging, the reductions may remain confined to myocardial territories supplied by coronary vessels with macrovascular disease. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) study of 1,123 patients with T2DM showed that in 522 patients randomly assigned to stress-rest SPECT myocardial perfusion imaging, almost one-quarter (n = 113) had silent ischemia (18). Perfusion defects were noted in 16% of patients, and adenosine stress-induced ischemic electrocardiographic abnormalities or left ventricular dilation or dysfunction occurred in 6% of the patients with normal myocardial perfusion. Microvascular structural alterations affect coronary circulatory function more uniformly, judging from the homogenously reduced hyperemic flow patterns observed in patients with T2DM and diabetic retinopathy or coronary microangiopathy (19,20). Compared with controls, hyperemic myocardial flow was reduced by 28% in patients with T2DM and macrovascular coronary disease, but was reduced by 57% in patients with T2DM and coronary microangiopathy (20). The presence of coronary microangiopathy was demonstrated by an abnormal electrocardiography stress test in the presence of angiographically patent coronary vessels.
Endothelial dysfunction, even in the absence of macrovascular coronary artery lesions, may be responsible for reduction in or failure to appropriately augment coronary flow, leading to myocardial ischemia (21). When coexisting with obstructive coronary artery disease, endothelial dysfunction may cause more severe and extensive stress-induced perfusion abnormalities (22), possibly because of stress-related sympathetically mediated vasoconstriction (23).
Neuronal alterations in patients with diabetes account for additional reductions in the total vasodilator capacity and for more severely reduced flow responses to CPT. Diabetic neuropathy with sympathetic denervation of the left ventricular myocardium, as demonstrated by PET imaging of norepinephrine analog C-11 hydroxyephedrine uptake, has been associated with further reductions in endothelium-dependent flow responses (24,25).
Circulating insulin levels also have important effects on myocardial flow at rest and during pharmacologically stimulated myocardial hyperemia. Infusion of insulin in healthy subjects and in patients with diabetes raises myocardial flow at rest (26,27). Importantly, acute insulin infusion also evokes significant flow increases in patients with coronary artery disease and T2DM (28). Euglycemic-hyperinsulinemic clamping raised plasma insulin levels more than 7-fold and lowered glucose levels by 31%. With perfusion imaging, resting myocardial flow increased 13%, while adenosine-stimulated flow increased 23% in both remote myocardium and regions with stress-induced flow defects (Fig. 2) (28).
View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 Effects of Insulin Infusion on MBF
Effects of insulin infusion on regional myocardial blood flow (MBF) at rest and with adenosine-stimulated hyperemia in patients with type 2 diabetes mellitus and coronary artery disease. Hyperinsulinemia significantly increased resting and adenosine-stimulated blood flow in ischemic (gray bars) and nonischemic (blue bars) myocardial regions. Adapted from Lautamäki et al. (28), with permission from the American Diabetes Association.
|
|
|
Obesity and Coronary Circulatory Function
|
|---|
Obesity is associated with an increased risk of coronary atherosclerosis and CV mortality and is an independent coronary heart disease risk factor. Endothelial dysfunction has been demonstrated in both the peripheral circulation, with forearm blood flow measurements, and in the coronary circulation in obese patients with angiographically normal or only mildly diseased coronary vessels (4,29–31). Endothelial dysfunction, independently associated with obesity, became progressively worse with increased body weight (31). Endothelial dysfunction was confined to the coronary resistance vessels without involving the large epicardial conduit vessels. Because of the coexistence of elevated fasting glucose and triglyceride levels, as components of the metabolic syndrome, IR was considered a possible cause of endothelial dysfunction. More recent observations with PET-based measurements of myocardial flow revealed similar functional alterations of the coronary circulation in obese persons (32). In this study, endothelium-dependent coronary vasomotor function progressively declined with increased body mass index (BMI) (Fig. 3) (32). Total vasodilator capacity remained intact in overweight persons (BMI  25 and <30 kg/m2) but was significantly diminished in obese persons (BMI 30 kg/m2). On multivariate analysis, age and BMI were the only predictors of the attenuated flow response to CPT and, therefore, of endothelial dysfunction. While the reasons for this relation to age remain uncertain, they may be related to IR in the presence of long-term obesity. These data may mechanistically link obesity with increased CV morbidity and mortality.
|
Endothelial Function, Coronary Risk, and Therapeutic Interventions
|
|---|
Multiple studies support an association between endothelial dysfunction and increased coronary risk (33–36). Attenuated or absent PET flow responses to CPT in patients with angiographically normal coronary vessels were associated with a 32% incidence of coronary events (cardiac death, nonfatal myocardial infraction, acute coronary syndromes, revascularization, and stroke) over 66 months compared with a 4.5% incidence with normal flow responses (35).
Strategies that CV specialists may employ to improve endothelium-dependent coronary vasomotion include risk factor modification and pharmacological approaches. Intense risk factor modification for 6 weeks (weight loss, exercise, dietary lipid lowering) was accompanied by a 9% improvement in total vasodilator capacity (37). Insulin-sensitizer treatment with a peroxisome proliferator-activated receptor- agonist also led to improvements in flow-mediated vasodilator responses in patients with T2DM as well as in endothelium-dependent coronary vasomotion in patients with impaired glucose tolerance or diabetes (38–41). Administration of peroxisome proliferator-activated receptor- ligands (rosiglitazone or troglitazone) for 12 weeks improved IR, lowered circulating insulin levels, and restored flow responses to CPT (40). Dietary and metformin-mediated reductions in circulating glucose levels in patients with T2DM were associated with improvements in flow responses to CPT indicative of better endothelial function (42).
Whether pharmacologically mediated improvements in endothelium-dependent vasomotor function of the coronary circulation reduce long-term CV risk remains uncertain (33). Indeed, the role of peroxisome proliferator-activated receptor- ligands in long-term reduction of cardiac morbidity and mortality remains controversial (43,44). In a study of acute coronary syndrome patients, indices of abnormal vasodilator function by forearm plethysmography were predictive of disease progression and CV events (45). Importantly, recovery of endothelium-dependent vasodilator function 8 weeks after the index event was highly predictive of subsequent event-free survival. Another study in pre-menopausal women with mild-to-moderate arterial hypertension and impaired brachial artery reactivity showed that improvements in flow-mediated dilation after 6 months of aggressive antihypertensive treatment were associated with reduced incidence of CV events over 67 months compared with women without such functional improvement (46). However, these findings should be considered hypothesis generating.
|
Conclusions
|
|---|
IR is associated with important functional disturbances of the coronary circulation. The magnitude of these disturbances is proportional to the severity of the IR; in the case of pre-diabetes, IR primarily affects the endothelium-dependent vasomotor function, whereas overt T2DM is associated with diminished total vasodilator capacity. Administration of insulin to modify glycemic control can lead to substantial improvements in total coronary vasodilator capacity, even in the presence of T2DM and coronary artery disease. Normalization of endothelium-related functional abnormalities (which are considered to be independent predictors of coronary risk) is possible with risk-modification treatment (diet and exercise) and insulin-sensitizing agents, although the long-term effects of these agents on CV risk in patients with IR remain to be determined.
|
Acknowledgments
|
|---|
The author would like to thank Victoria Bender for her skillful assistance in preparing this manuscript.
|
Footnotes
|
|---|
Dr. Schelbert has no conflicts of interest to report.
|
References
|
|---|
1. Kim J-A, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms Circulation 2006;113:1888-1904.[Abstract/Free Full Text]2. Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease Circulation 2003;108:2054-2059.[Free Full Text] 3. Rask-Madsen C, King GL. Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes Nat Clin Pract Endocrinol Metab 2007;3:46-56.[CrossRef][Web of Science][Medline] 4. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996;97:2601-2610.[Web of Science][Medline] 5. Balletshofer BM, Rittig K, Enderle, MD, et al. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance Circulation 2000;101:1780-1784.[Abstract/Free Full Text] 6. Bøttcher M, Madsen MMM, Resgaaard J, et al. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve Circulation 2001;103:1109-1114.[Abstract/Free Full Text] 7. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391-401.[Abstract/Free Full Text] 8. Bergmann SR, Herrero P, Markham J, Weinheimer CJ, Walsh MN. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography J Am Coll Cardiol 1989;14:639-652.[Abstract] 9. Krivokapich J, Smith GT, Huang SC, et al. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation 1989;80:1328-1337.[Abstract/Free Full Text] 10. Lortie M, Beanlands RS, Yoshinaga K, Klein R, Dasilva JN, DeKemp RA. Quantification of myocardial blood flow with 82Rb dynamic PET imaging Eur J Nucl Med Mol Imaging 2007;34:1765-1774.[CrossRef][Web of Science][Medline] 11. Schindler TH, Zhang XL, Prior JO, et al. Assessment of intra- and interobserver reproducibility of rest and cold pressor test-stimulated myocardial blood flow with (13)N-ammonia and PET Eur J Nucl Med Mol Imaging 2007;34:1178-1188.[CrossRef][Web of Science][Medline] 12. Prior JO, Quinones MJ, Hernandez-Pampaloni M, et al. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus Circulation 2005;111:2291-2298.[Abstract/Free Full Text] 13. Schindler TH, Nitzsche EU, Olschewski M, et al. PET-measured responses of MBF to cold pressor testing correlate with indices of coronary vasomotion on quantitative coronary angiography J Nucl Med 2004;45:419-428.[Abstract/Free Full Text] 14. Buus NH, Bottcher M, Hermansen F, Sander M, Nielsen TT, Mulvany MJ. Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia Circulation 2001;104:2305-2310.[Abstract/Free Full Text] 15. Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus Circ Res 2001;88:E14-E22.[Web of Science][Medline] 16. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus J Am Coll Cardiol 2001;37:1344-1350.[Abstract/Free Full Text] 17. Yokoyama I, Ohtake T, Momomura S, et al. Hyperglycemia rather than insulin resistance is related to reduced coronary flow reserve in NIDDM Diabetes 1998;47:119-124.[Abstract] 18. Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study Diabetes Care 2004;27:1954-1961.[Abstract/Free Full Text] 19. Sundell J, Janatuinen T, Ronnemaa T, et al. Diabetic background retinopathy is associated with impaired coronary vasoreactivity in people with type 1 diabetes Diabetologia 2004;47:725-731.[CrossRef][Medline] 20. Yokoyama I, Yonekura K, Ohtake T, et al. Coronary microangiopathy in type 2 diabetic patients: relation to glycemic control, sex, and microvascular angina rather than to coronary artery disease J Nucl Med 2000;41:978-985.[Abstract/Free Full Text] 21. Zeiher AM, Krause T, Schachinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia Circulation 1995;91:2345-2352.[Abstract/Free Full Text] 22. Verna E, Ceriani L, Provasoli S, Scotti S, Ghiringhelli S. Larger perfusion defects with exercise compared with dipyridamole SPECT (exercise-dipyridamole mismatch) may reflect differences in epicardial and microvascular coronary dysfunction: when the stressor matters J Nucl Cardiol 2007;14:818-826.[CrossRef][Medline] 23. Hess OM, Buchi M, Kirkeeide R, et al. Potential role of coronary vasoconstriction in ischaemic heart disease: effect of exercise Eur Heart J 1990;11(Suppl B):58-64.[Abstract/Free Full Text] 24. Di Carli MF, Bianco-Battles D, Landa ME, et al. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus Circulation 1999;100:813-819.[Abstract/Free Full Text] 25. Pop-Busui R, Kirkwood I, Schmid H, et al. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction J Am Coll Cardiol 2004;44:2368-2374.[Abstract/Free Full Text] 26. Iozzo P, Chareonthaitawee P, Di Terlizzi M, Betteridge DJ, Ferrannini E, Camici PG. Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans Am J Physiol Endocrinol Metab 2002;282:E1163-E1171.[Abstract/Free Full Text] 27. Sundell J, Laine H, Nuutila P, et al. The effects of insulin and short-term hyperglycaemia on myocardial blood flow in young men with uncomplicated type I diabetes Diabetologia 2002;45:775-782.[CrossRef][Web of Science][Medline] 28. Lautamäki R, Airaksinen KE, Seppänen M, et al. Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease Diabetes 2006;55:511-516.[Abstract/Free Full Text] 29. Hashimoto M, Akishita M, Eto M, et al. The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation Int J Obes Relat Metab Disord 1998;22:477-484.[CrossRef][Web of Science][Medline] 30. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production Diabetes 2000;49:1231-1238.[Abstract] 31. Suwaidi JA, Wright RS, Grill JP, et al. Obesity is associated with premature occurrence of acute myocardial infarction Clin Cardiol 2001;24:542-547.[Web of Science][Medline] 32. Schindler TH, Cardenas J, Prior JO, et al. Relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function J Am Coll Cardiol 2006;47:1188-1195.[Abstract/Free Full Text] 33. Quyyumi AA. Prognostic value of endothelial function Am J Cardiol 2003;91(Suppl):19H-24H.[CrossRef][Web of Science][Medline] 34. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease Circulation 2000;101:1899-1906.[Abstract/Free Full Text] 35. Schindler TH, Nitzsche EU, Schelbert HR, et al. Positron emission tomography-measured abnormal responses of myocardial blood flow to sympathetic stimulation are associated with the risk of developing cardiovascular events J Am Coll Cardiol 2005;45:1505-1512.[Abstract/Free Full Text] 36. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes Jr. DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction Circulation 2000;101:948-954.[Abstract/Free Full Text] 37. Czernin J, Barnard RJ, Sun KT, et al. Effect of short-term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve Circulation 1995;92:197-204.[Abstract/Free Full Text] 38. Hetzel J, Balletshofer B, Rittig K, et al. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers Arterioscler Thromb Vasc Biol 2005;25:1804-1809.[Abstract/Free Full Text] 39. Pistrosch F, Passauer J, Fischer S, Fuecker K, Hanefeld M, Gross P. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control Diabetes Care 2004;27:484-490.[Abstract/Free Full Text] 40. Quinones MJ, Hernandez-Pampaloni M, Schelbert H, et al. Coronary vasomotor abnormalities in insulin-resistant individuals Ann Intern Med 2004;140:700-708.[Abstract/Free Full Text] 41. Sourij H, Zweiker R, Wascher TC. Effects of pioglitazone on endothelial function, insulin sensitivity, and glucose control in subjects with coronary artery disease and new-onset type 2 diabetes Diabetes Care 2006;29:1039-1045.[Abstract/Free Full Text] 42. Schindler TH, Facta AD, Prior JO, et al. Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes Heart 2007;93:345-349.[Abstract/Free Full Text] 43. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials JAMA 2007;298:1180-1188.[Abstract/Free Full Text] 44. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis JAMA 2007;298:1189-1195.[Abstract/Free Full Text] 45. Fichtlscherer S, Breuer S, Zeiher AM. Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the "vulnerable" patient Circulation 2004;110:1926-1932.[Abstract/Free Full Text] 46. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women J Am Coll Cardiol 2002;40:505-510.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
W. S. Aronow, J. L. Fleg, C. J. Pepine, N. T. Artinian, G. Bakris, A. S. Brown, K. C. Ferdinand, M. A. Forciea, W. H. Frishman, C. Jaigobin, et al.
ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents
Circulation,
May 31, 2011;
123(21):
2434 - 2506.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. S. Aronow, J. L. Fleg, C. J. Pepine, N. T. Artinian, G. Bakris, A. S. Brown, K. C. Ferdinand, M. Ann Forciea, W. H. Frishman, C. Jaigobin, et al.
ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents Developed in Collaboration With the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension
J. Am. Coll. Cardiol.,
May 17, 2011;
57(20):
2037 - 2114.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. T. Martin, S. McNitt, R. W. Nesto, M. K. Rutter, and A. J. Moss
Cardiac Resynchronization Therapy Reduces the Risk of Cardiac Events in Patients With Diabetes Enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)
Circ Heart Fail,
May 1, 2011;
4(3):
332 - 338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Pepine, R. D. Anderson, B. L. Sharaf, S. E. Reis, K. M. Smith, E. M. Handberg, B. D. Johnson, G. Sopko, and C. N. Bairey Merz
Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results From the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) Study
J. Am. Coll. Cardiol.,
June 22, 2010;
55(25):
2825 - 2832.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, G. K. Feld, B. H. Greenberg, J. Hall, M. Hlatky, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, et al.
Highlights of the Year in JACC 2009
J. Am. Coll. Cardiol.,
January 26, 2010;
55(4):
380 - 407.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Pepine
Insulin as a Cardiovascular Therapeutic: Improving Glycemic Control in Patients With Coronary Artery Disease
J. Am. Coll. Cardiol.,
February 3, 2009;
53(5_Suppl_S):
S1 - S2.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Positron Emission Tomography...