This review discusses the pathogenesis and management of coronary microvascular dysfunction. Factors to consider in clinical management are the cause of the dysfunction and whether it is iatrogenic, whether obstructive coronary artery disease is present, and whether myocardial disease is present.

https://www.nejm.org/doi/suppl/10.1056/NEJMra061889/suppl_file/nejm_camici_830sa1.pdf

Coronary Microvascular Dysfunction

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity) This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease

Diabetic Cardiomyopathy: Evidence, Mechanisms, and Therapeutic Implications

Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

/pdf/cardiovascular-actions-of-insulin-39x6u4o6br.pdf

Cardiovascular actions of insulin.

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.

(CFR), defined as the ratio of coronary blood flow (CBF) at maximal dilation to CBF at baseline, is impaired in patients with CMD. CMD encompasses various clinicopathologic changes that lead to functional and structural abnormalities in the coronary microvasculature. These changes disrupt the ability of the vessels to vasodilate and augment CBF in response to increased myocardial oxygen demand, causing angina and ischemia.14

/pdf/coronary-microvascular-dysfunction-3m29a5l4s1.pdf

Disturbances of coronary circulation have been reported in diabetic patients with microvascular complications but without obstructive coronary atherosclerosis. The aim of the present study was to investigate coronary flow reserve in young adult patients with IDDM but without microalbuminuria and diabetic autonomic neuropathy. Coronary flow reserve was determined in 12 nonsmoking male patients with IDDM (age 30.0 ± 6.6 years) and 12 healthy matched volunteers. Groups were similar with respect to blood pressure and serum lipid concentrations, and no subject had a positive family history of coronary heart disease. The patients with IDDM had normal exercise echocardiography and autonomic nervous function tests. Five patients had minimal background retinopathy, and none had microalbuminuria. Positron emission tomography and [ 15 O]H 2 O were used to measure myocardial blood flow at rest and after dipyridamole administration. The studies were performed during euglycemic hyperinsulinemia (serum insulin ∼70 mU/1). The baseline myocardial blood flow was similar in patients with IDDM and in control subjects (0.84 ± 0.18 vs. 0.88 ± 0.25 ml · g −1 · min −1 , NS). The myocardial blood flow during hyperemia was 29% lower in patients with IDDM (3.17 ± 1.57) compared with the control subjects (4.45 ± 1.37 ml · g −1 · min −1 P P −1 P

Coronary Flow Reserve Is Reduced in Young Men With IDDM

Hyperinsulinemia is a risk factor for coronary artery disease Previous studies have reported that hyperinsulinemia increases cardiac and skeletal muscle sympathetic nerve activity and skeletal muscle blood flow in normal subjects However, little is known about insulin’s effects on myocardial blood flow in humans The purpose of this study was to investigate whether physiological hyperinsulinemia affects myocardial blood flow and flow reserve in healthy subjects Additionally, the role of the sympathetic nervous system in regulating insulin’s effects on coronary perfusion was tested We used positron emission tomography and oxygen-15-labeled water to measure myocardial blood flow and coronary flow reserve in 16 healthy nonobese men (age, 34 ± 4 yr; maximal aerobic capacity, 32 ± 3 mL·g −1·min −1; blood pressure, 118 ± 10/65 ± 8 mm Hg) at fasting and during euglycemic hyperinsulinemic clamp (1 mU·kg−1·min−1 for 80 min) To study the role of the sympathetic nervous system, each subject was studied twice: o

/pdf/insulin-induced-increment-of-coronary-flow-reserve-is-not-1rq3rsjkl8.pdf

Insulin-induced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men.

Objective: To examine the role of the sympathetic nervous system in regulating insulin’s action on coronary perfusion in uncomplicated type 1 diabetes by blocking centrally mediated sympathetic activity with dexamethasone.

Methods: Positron emission tomography and oxygen 15 labelled water were used to quantify myocardial blood flow basally and during adenosine infusion with or without simultaneous euglycaemic physiological hyperinsulinaemia in nine non-smoking men with type 1 diabetes and 12 healthy non-diabetic men. Each patient was studied both with and without previous dexamethasone treatment for two days (2 mg/day).

Results: Insulin increased coronary flow reserve in diabetic (from 4.3 (0.7) to 5.1 (0.6), p < 0.05) and non-diabetic (from 4.3 (0.3) to 5.4 (0.4), p < 0.05) patients. In contrast to non-diabetic patients dexamethasone pretreatment abolished the insulin induced increase in coronary flow reserve in diabetic patients (p < 0.05) leading to lower coronary flow reserve in diabetic than in non-diabetic patients (3.9 (0.6) v 7.1 (0.9), p < 0.05).

Conclusions: These results show that insulin’s ability to modulate coronary perfusion is sustained in young patients with type 1 diabetes without microvascular complications or autonomic neuropathy. Dexamethasone treatment abolished the insulin induced increase in coronary flow reserve in diabetic patients but not in healthy study participants, suggesting that sympathetic activation plays an important part in regulating insulin’s effects on myocardial perfusion in patients with type 1 diabetes.

https://heart.bmj.com/content/heartjnl/90/3/270.full.pdf

Pertti J Koskinen

Papers

Coronary Flow Reserve Is Reduced in Young Men With IDDM

Insulin-induced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men.

Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes.