Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. This review discusses the latest findings in diabetic humans and in animal models and reviews emerging new mechanisms that may be involved in the development and progression of cardiac dysfunction in diabetes.

Diabetic Cardiomyopathy Revisited

Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors

Clinical applications of arterial stiffness; definitions and reference values

Background Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima-media thickness, a measure of atherosclerosis, in a population with type 1 diabetes. Methods As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994-1996 and again in 1998-2000. We assessed the intima-media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment. Results At year 1 of the EDIC study, the carotid intima-media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima-media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima-media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima-media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima-media thickness of the common and internal carotid arteries, -0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima-media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT. Conclusions Intensive therapy during the DCCT resulted in decreased progression of intima-media thickness six years after the end of the trial.

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Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus.

Bio-reactive advanced glycation endproducts (AGE) alter the structure and function of molecules in biological systems and increase oxidative stress. These adverse effects of both exogenous and endogenously derived AGE have been implicated in the pathogenesis of diabetic complications and changes associated with ageing including atherosclerosis, renal, eye and neurological disease. Specific AGE receptors and nonreceptor mechanisms contribute to these processes but also assist in the removal and degradation of AGE. The final disposal of AGE depends on renal clearance. Promising pharmacologic strategies to prevent AGE formation, reduce AGE toxicity, and/or inactivate AGE are under investigation.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2796.2002.00932.x

Diabetes and advanced glycation endproducts.

Aims/hypothesis
Previous studies have shown that alterations in vascular, metabolic, inflammatory and haemocoagulative functions characterise the metabolic syndrome. Whether this is also the case for sympathetic function is not clear. We therefore aimed to clarify this issue and to determine whether metabolic or reflex mechanisms might be responsible for the possible adrenergic dysfunction.

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Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome

Aims/hypothesis. Diabetes mellitus is associated with an increased incidence of atherosclerosis. How early functional and structural alterations of large arteries that may preceed atherosclerosis occur in the course of this disease has, however, never been conclusively documented. Methods. We evaluated arterial wall distensibility in the radial artery, common carotid artery and abdominal aorta in 133 patients (aged 35.4 ± 0.9 years, means ± SEM) with Type I (insulin-dependent) diabetes mellitus and no macrovascular complications. Arterial distensibility was derived from continuous measurements of arterial diameter through echotracking techniques and use of either the Langewouters (radial artery) or the Reneman (carotid artery and aorta) formula. The same echotracking techniques enabled us to obtain radial artery and carotid artery wall thickness. Data were compared with those from 70 age-matched normotensive control subjects. Results. In diabetic patients arterial distensibility was consistently less (p < 0.01) than in control subjects, the reduction averaging 26 %, 14 % and 25 % for the radial artery, carotid artery and aorta, respectively. This was accompanied by an increase (p < 0.01) in both radial and carotid artery wall thickness. The changes were more pronounced in patients with microalbuminuria, retinopathy or neuropathy or both. They were evident also in those without microvascular complications. This was the case also when subjects in whom diabetes was associated with hypertension (n = 30) were excluded from data analysis. Carotid and aortic wall abnormalities showed a relation with the duration of disease and blood pressure whereas radial artery abnormalities showed a relation with glycated haemoglobin. Conclusion/interpretation. Type I diabetes is characterised by diffuse arterial wall stiffening and thickening which progress with the severity of the disease but can clearly be seen also in the absence of any diabetic-related complication. This suggests that in diabetes stiffening and thickening are an early marker of vascular damage. [Diabetologia (1999) 42: 987–994]

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Early impairment of large artery structure and function in Type I diabetes mellitus

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is accompanied by reduced arterial distensibility and increased arterial wall thickness even in normotensive subjects with no micro-macrovascular complications. It is not known whether, and how fast, these subclinical markers of vascular damage develop over time. Methods. We measured arterial wall distensibility in radial, common carotid artery and abdominal aorta in 60 normotensive patients (aged 35.0 ± 1.2 years, means ± SE) with Type I diabetes with no microvascular or macrovascular complications and in 20 healthy control subjects matched for age. Arterial distensibility was determined by continuous measurements of arterial diameter through echotracking techniques and by using either the Langewouters (radial artery) or the Reneman formula (carotid artery and aorta). The same echotracking techniques allowed us to ascertain the radial and carotid artery wall thickness. Data were collected before and after 23 ± 1 months. Results. In the first study, carotid artery distensibility was similar but radial artey and aortic distensibility was less (p < 0.01) in patients with diabetes than in control subjects (–39 % and 25 % respectively). This was accompanied by an increase (p < 0.01) in both radial (42 %) and carotid artery wall thickness (46 %). After 23 ± 1 months diabetic subjects showed a further reduction in arterial distensibility (radial–12 %, p < 0.05; carotid–8 %, NS; aorta–20 % p < 0.05) and an increase in arterial wall thickness (radial + 15 %; carotid 14 %, p < 0,05). No change in distensibility and wall thickness values occurred in control subjects. Conclusion/interpretation. The early reduction in arterial distensibility and increase in arterial wall thickness characterizing uncomplicated normotensive Type I diabetes patients shows a measurable worsening over the short term. [Diabetologia (2001) 44: 203–208]

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Progression of large artery structural and functional alterations in Type I diabetes

Objective We have recently observed that in young, normotensive patients with a type I diabetes mellitus and no macro or microvascular complications, large artery structure and function are already altered. This study has been done to assess whether this condition is also characterized by early alterations in cardiac structure and function, and whether these alterations progress with time. Design and methods In 56 insulin-treated, normotensive uncomplicated type I diabetic patients (age 35.0 +/- 2 years, means +/- SE) in good metabolic control, left ventricular wall thickness and diameter were measured by echocardiography together with left ventricular ejection fraction and diastolic function E/A (ratio between early and late ventricular filling), before and after 23 +/- 1 months. The same measurements were made in 20 age and sex-matched subjects who served as controls (C). Results Compared to C, diabetic patients had a significant increase in left ventricular wall (septal plus posterior wall) thickness (+ 8.4%), left ventricular mass index (+ 11%) and h/r ratio (left ventricular wall thickness/ventricular end diastolic diameter, + 16.0%) whereas they showed a reduction of E/A (-6%). In C, all echocardiographic values were unchanged after 2 years. This was the case also for diabetic patients, except for left ventricular ejection fraction and diastolic diameter which showed a significant reduction (-7.2%) and increase (+ 3.8%), respectively, with a reduction of ratio between LV wall thickness and diameter, h/r (-6.8%). Conclusions Uncomplicated type I diabetes mellitus is characterized by early structural and functional cardiac alterations. Some of these alterations show a measurable progression within a relatively short time span.

Pierluigi Gamba

Papers

Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome

Early impairment of large artery structure and function in Type I diabetes mellitus

Progression of large artery structural and functional alterations in Type I diabetes

Progression of functional and structural cardiac alterations in young normotensive uncomplicated patients with type 1 diabetes mellitus

Emotional and affective disturbances in patients with epilepsy.