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"Vascular Insulin Resistance: The Syndrome X Files"

Dr. Ross Feldman (biography)
English - 2002-04-26 - 29 minutes
(25 slides)

Summary :
The relationship between insulin resistance and disordered vascular regulation predisposing to hypertension has been appreciated for more than a decade. The causal relationship linking these phenomenons remains unclear.

Initially, investigators in the field focused on the potential impact of hyperinsulinemia on vascular regulation. However, at least in regards to acute vascular effects, insulin is vasodilator-an effect shared with most agents that activate vascular receptor tyrosine kinases. The primary mechanism for these acute vasodilator effects of insulin is endothelial, in part by activation of NOS via a PI3 kinase-dependent mechanism. Notably, other mechanisms, including activation of adenylyl cyclase isoforms selectively coupled to raf-1, have also been implicated in this vascular effect.

Studies from our laboratory as well as those of others have characterized vascular insulin effects and their alterations in settings of vascular disease/insulin resistance. Resistance to the vascular effects of insulin: parallel resistance to the glucoregulatory effects of insulin. Further, impaired vascular sensitivity to insulin has been reported in patients with diabetes mellitus, with hypertension, with obesity and with aging. Vascular insulin resistance has been reported to be worsened by dietary salt restriction and improved with ACE-inhibitor therapy.

Vascular insulin resistance appears to be of a syndrome complex characterized by a more global defect in endothelial function. That is, in settings where vascular insulin resistance has been reported, this impairment has been seen to be generalized to more global indices of "endothelial dysfunction" (ie, flow-mediated vasodilation and acetylcholine-mediated vasodilation). A number of mechanisms (many probably interdependent) have been suggested to play a role in orchestrating these defects, including: disordered free fatty acid metabolism, hyperglycemia, oxidative stress and the effects of prolonged hyperinsulinemia. Further, the selective targeting of some of these mechanisms has been shown to reverse the pattern of endothelial dysfunction characteristic of patients with insulin resistance.

Learning objectives :
The participant will learn how:
1. insulin mediates vasodilation
2. this vasodilation is disrupted by insulin resistance
3. vascular insulin resistance parallels both systemic insulin resistance and global indices of endothelial dysfunction
4. vascular insulin resistance is reversible

Bibliographic references :
The 2001 Canadian recommendations for the management of hypertension: Part one--Assessment for diagnosis, cardiovascular risk, causes and lifestyle modification.

Zarnke KB, McAlister FA, Campbell NR, Levine M, Schiffrin EL, Grover S, McKay DW, Myers MG, Wilson TW, Rabkin SW, Feldman RD, Burgess E, Bolli P, Honos G, Lebel M, Mann K, Abbott C, Tobe S, Petrella R, Touyz RM; Canadian Hypertension Recommendations Working Group.

London Health Sciences Centre, University Hospital Campus, London, Canada.

OBJECTIVE: To provide updated, evidence-based recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. OPTIONS: For persons in whom a high blood pressure value is recorded, hypertension is diagnosed based on the appropriate measurement of blood pressure, the level of the blood pressure elevation and the duration of follow-up. In addition, the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases must be assessed to determine the urgency, intensity and type of treatment. For persons receiving a diagnosis of hypertension, defining the overall risk of adverse cardiovascular outcomes requires an assessment of concomitant vascular risk factors, including laboratory testing, a search for target organ damage and an assessment for modifiable causes of hypertension. Home and ambulatory blood pressure assessment and echocardiography are options for selected patients. OUTCOMES: The outcomes were: the identification of persons at increased risk of adverse cardiovascular outcomes; the quantification of overall cardiovascular risk; and the identification of persons with potentially modifiable causes of hypertension. Evidence: Medline searches were conducted from one year before the period of the last revision of the Canadian recommendations for the management of hypertension (May 1999 to May 2001). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. Identified articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. In addition to an update of the previous year's review, new sections on assessing overall cardiovascular risk and endocrine causes are provided. VALUES: A high value was placed on the identification of persons at increased risk of cardiovascular morbidity and mortality, and of persons with identifiable causes of hypertension. BENEFITS, HARMS AND COSTS: The identification of persons at higher risk of cardiovascular disease will permit counseling for lifestyle manoeuvres and introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. The identification of specific causes of hypertension may permit the use of cause-specific interventions. In certain subgroups of patients, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity or mortality. RECOMMENDATIONS: The present document contains recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, the role of echocardiography and lifestyle modifications. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only those recommendations achieving high levels of consensus are reported. These guidelines will be updated annually. ENDORSEMENT: These guidelines are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control, Health Canada.

Can J Cardiol 2002 Jun;18(6):604-24


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