Felice Paleari

Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus

Summary Diabetic autonomic dysfunction is associated with a high risk of mortality which makes its early identification clinically important. The aim of our study was to compare the detection of autonomic dysfunction provided by classical laboratory autonomic function tests with that obtained through computer assessment of the spontaneous sensitivity of the baroreceptor-heart rate reflex (BRS) by time domain and frequency domain techniques. In 20 normotensive diabetic patients (mean age ± SD 41.9 ± 8.1 years) with no evidence of autonomic dysfunction on laboratory autonomic testing (D0) blood pressure (BP) and ECG were continuously monitored over 15 min in the supine position. BRS was assessed as the slope of the regression line between spontaneous increases or reductions in systolic BP and linearly related lengthening or shortening in RR interval over sequences of at least 4 consecutive beats (sequence method), or as the squared ratio between RR interval and systolic BP spectral powers around 0.1 Hz. We compared the results with those of 32 age-matched normotensive diabetic patients with abnormal autonomic function tests (D1) and with those of 24 healthy age-matched control subjects with normal autonomic function tests (C). Compared to C, BRS was markedly less in D1 when assessed by both the slope of the two types of sequences (data pooled) and by the spectral method (–71.3 % and –60.2 % respectively, both p < 0.01). However, BRS was consistently although somewhat less markedly reduced in D0, the reduction being clearly evident for all the estimates (–57.0 % and –43.5 %, both p < 0.01). The effects were more evident than those obtained by the simple quantification of the RR interval variability. These data suggest that time and frequency domain estimates of spontaneous BRS allow earlier detection of diabetic autonomic dysfunction than classical laboratory autonomic tests. The estimates can be obtained by short non-invasive recording of the BP and RR interval signals in the supine patient, i. e. under conditions suitable for routine outpatient evaluation. [Diabetologia (1997) 40: 1470–1475]

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

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]

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

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]

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

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.

Lacidipine and blood pressure variability in diabetic hypertensive patients.

The aim of our study was to assess the effects of lacidipine, a long-acting calcium antagonist, on 24-hour average blood pressure, blood pressure variability, and baroreflex sensitivity. In 10 mildly to moderately hypertensive patients with type II diabetes mellitus (aged 18 to 65 years), 24-hour ambulatory blood pressure was continuously monitored noninvasively (Portapres device) after a 3-week pretreatment with placebo and a subsequent 4-week once daily lacidipine (4 mg) or placebo treatment (double-blind crossover design). Systolic blood pressure, diastolic blood pressure, and heart rate means were computed each hour for 24 hours (day and night) at the end of each treatment period. Similar assessments were also made for blood pressure and heart rate variability (standard deviation and variation coefficient) and for 24-hour baroreflex sensitivity, which was quantified (1) in the time domain by the slope of the spontaneous sequences characterized by progressive increases or reductions of systolic blood pressure and RR interval and (2) in the frequency domain by the squared ratio of RR interval and systolic blood pressure spectral power ≈0.1 and 0.3 Hz over the 24 hours. Compared with placebo, lacidipine reduced the 24-hour, daytime, and nighttime systolic and diastolic blood pressure (P <0.05) with no significant change in heart rate. It also reduced 24-hour, daytime, and nighttime standard deviation (−19.6%, −14.4%, and −24.0%, respectively;P <0.05) and their variation coefficient. The 24-hour average slope of all sequences (7.7±1.7 ms/mm Hg) seen during placebo was significantly increased by lacidipine (8.7±1.8 ms/mm Hg, P <0.01), with a significant increase being obtained also for the 24-hour average &agr; coefficient at 0.1 Hz (from 5.7±1.5 to 6.4±1.3 ms/mm Hg, P <0.01). Thus, in diabetic hypertensive patients, lacidipine reduced not only 24-hour blood pressure means but also blood pressure variability. This reduction was accompanied by an improvement of baroreflex sensitivity. Computer analysis of beat-to-beat 24-hour noninvasive blood pressure monitoring may offer valuable information about the effects of antihypertensive drugs on hemodynamic and autonomic parameters in daily life.

Emotional and affective disturbances in patients with epilepsy

We sought to assess whether epilepsy is associated with a higher risk of emotional reactions to frustrating stimuli, aggressive behavior, apathy, and depression, and whether these psychiatric patterns are specific to the epileptic condition. The study population consisted of referral patients 17 years and older with idiopathic or cryptogenic epilepsy (i.e., epilepsy not caused by a detectable brain lesion) without significant cognitive dysfunction. A first control was selected for each patient among patients with insulin-dependent diabetes and a second among normal blood donors. Aggressiveness in response to stressful stimuli was assessed with the Picture Frustration Study (PFS). Depression was tested by the Beck Depression Inventory. The Aggressive Behavior Scale (assessing irritability and rumination) and the Apathy Scale were also used. Odds Ratios (ORs) with 95% Confidence Intervals (95% CI) were used as the risk measure. Statistical analysis included between-group comparisons. In patients with epilepsy, the test scores were correlated to the main demographic (age, sex, education, marital status, and occupation) and clinical features (seizure types, disease duration, seizure control, and treatments). The sample included 55 patients with epilepsy, 56 diabetics, and 59 normal individuals. Patients with epilepsy and the two control groups had similar PFS scores and similar aggressiveness. Scores were also similar for the Aggressive Behavior and Apathy Scales, with similar numbers of individuals with aggressive conduct and excess rumination. Patients with epilepsy had higher depression scores. Moderate to severe depression was present in 9 cases (diabetes, 2; blood donors, 1) (P=0.004). Relative to blood donors, the OR for moderate to severe depression (95% CI) was 2.1 (0.1-61.7) for diabetes and 11.3 (1.4-247.8) for epilepsy. No significant correlation was detectable between test scores and patient and disease characteristics.

Increased Arterial Stiffness in Normoglycemic Normotensive Offspring of Type 2 Diabetic Parents

Diabetes is associated with a reduction of arterial distensibility. Limited information exists regarding whether or how early this appears in the course of the disease. We studied 54 normoglycemic, normotensive, healthy offspring of 2 parents with type 2 diabetes mellitus and 55 age- and sex-matched healthy control subjects. Carotid diastolic diameter and systodiastolic change were measured by echo tracking (Wall Track System) and wall thickness by echocolor Doppler (Sonos 5500, Philips). Pulse pressure was measured by a semiautomatic device positioned on the brachial artery and arterial distensibility calculated by Reneman formula. Blood pressure, blood glucose, glycohemoglobin, and insulin sensitivity (homeostasis model assessment index) were normal or only slightly elevated and by and large similar in the 2 groups. Compared with control subjects, offspring of diabetic parents showed similar carotid diameters at diastole and a reduced increase in carotid diameter at systole (−16%), a reduced carotid artery distensibility (−30%), and an increased pulse pressure (+21.8%), all differences being statistically significant (P<0.05) and persisting in subgroups with elevated or normal body mass index values (<25 and ≥25 kg/m2). Carotid artery wall thickness was not different between the 2 groups. Thus, subjects with predisposition to diabetes show carotid artery stiffening even in the absence of blood pressure alterations, as well as substantial alterations of glucose metabolism, body mass index, and changes in carotid wall thickness. This suggests that, in diabetes, alterations in arterial mechanical properties represent an early phenomenon, which may occur in the absence of metabolic and blood pressure alterations.

Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus

Abstract Aims. Diabetes mellitus is characterized by structural and functional alterations of the large- and medium-size arteries. Whether blood glucose variability, i.e. the glycemic oscillations occurring during the 24-h period, represents a risk factor for vascular alterations additional to and independent on HbA1c in type 1 diabetes mellitus is still undefined. The present study was carried out with the aim at investigating the impact of different measures of blood glucose variability on arterial structure and function. We studied 17 non-complicated type 1 diabetic patients (11 males, six females) with an age of 40.8 ± 7.6 years (mean ± SD). In each patient, 24-h glucose profile was obtained by continuous glucose monitoring system and glucose variability was expressed as mean ± SD of 24-h blood glucose levels, mean amplitude of glycemic excursions and postprandial hyperglycemic spikes. Arterial structure and function was measured as carotid IMT and stiffness. Major findings. The different approaches to assessing blood glucose variability well correlated between and with HbA1c. Carotid IMT and stiffness showed significant correlations with age, blood pressure, heart rate and daily insulin intake but a non- significant correlation with blood glucose variability. Principal conclusion. Thus, in type 1 diabetes mellitus, measures of glycemic variability are useful in predicting both actual and long-lasting glycemic control. In absence of diabetes-related complications and of any intima-media thickness alterations, the major predictors of arterial distensibility are represented by traditional risk factors beside glycemic 24-h control.

Effect of Amlodipine on Insulin Secretion, Glucose, Lipid Profile and Urinary Albumin Excretion in Patients with Mild Hypertension and Non-Insulin-Dependent Diabetes

SummaryThe effects of amlodipine 5 to 10 mg/day on hypertension and metabolic indices was assessed in 113 patients with recently diagnosed untreated mild hypertension, and non-insulin-dependent diabetes mellitus (NIDDM). Comparisons were made with normotensive patients matched with similar demographic and clinical characteristics.Amlodipine showed notable antihypertensive efficacy without affecting heart rate. It had no negative effect on glucose homeostasis (HbA1c and blood glucose levels), β-cell secretion or serum lipid profile, although lipoprotein A levels increased. No progression of ocular or cardiac disease was noted during treatment with the drug, indicating a possible protective effect. Eight of 82 (9.7%) treated hypertensive patients and 6 of 78 (7.7%) normotensive patients with normal urinary albumin excretion rates (AER) at baseline developed microalbuminuria after 52 weeks. No patient with microalbuminuria developed proteinuria. Opposing significant intergroup differences in AER were noted for normotensive (increased; p < 0.05) and hypertensive (decreased; not significant) patients with baseline microalbuminuria. Together, these results suggest a renoprotective role for amlodipine in this setting.In conclusion, amlodipine is an effective antihypertensive agent that has no negative long term effect on glucose homeostasis, β-cell secretion or lipid profile in patients with mild hypertension and NIDDM.