Effects of buflomedil on skin blood flow in patients with type 2 diabetes mellitus without overt micro- or macroangiopathy.

AIM: The aim of this study was to assess the effects of buflomedil on the peripheral microcirculation in patients with type 2 diabetes mellitus (T2DM) without overt micro- or macroangiopathy. METHODS: Twenty-three patients with T2DM were randomly assigned to receive buflomedil 600 mg/day for six months (N.=12) or no medication (N.=11). Skin blood flow in the lower limbs was assessed at baseline and after 3 and 6 months using Laser Doppler. We measured the following laser Doppler parameters: volume, flow and velocity. RESULTS: In patients treated with buflomedil, there was a significant increase in volume (P=0.039) and a trend for an increase in both flow and velocity (P=0.097 for both parameters). In contrast, significant decreases in volume and flow were observed in the control group (P=0.045 and P=0.027, respectively) whereas velocity did not change (P=0.150). CONCLUSION: In conclusion, buflomedil appears to have a beneficial effect on the peripheral microcirculation in patients with T2DM.

Stroke and conditions that mimic it: a protocol secures a safe early recognition.

OBJECTIVE: Certain disorders may be falsely diagnosed as stroke. We examined the efficacy of the diagnostic protocol that is followed in our stroke unit and was designed in order to early differentiate more efficiently between stroke and conditions that mimic it. METHODS-PATIENTS: Three hundred sixty-two elderly patients (196 male, 166 female with average age 74.56 years), who were hospitalized at our stroke center between January of 2005 and June of 2007 and diagnosed at admission as stroke patients, were retrospectively studied in order to investigate if the final diagnosis agreed with the initial diagnosis of stroke on admission.Our diagnostic protocol included medical history of the patient, assessment of state of consciousness, blood pressure, electrocardiogram, complete blood cell count (hematocrit/hemoglobin, leukocytes, platelets), clotting mechanism (prothrombin time, activated partial thromboplastin time), glucose, electrolytes (Na, K, Ca), renal (blood urea nitrogen, creatinine) and liver function (SGOT, SGPT), as well as imaging methods like chest X-Ray and brain CT scan. RESULTS: In 95% of patients, the final diagnosis agreed with the initial diagnosis of stroke at admission. According to final diagnosis, 344 (95%) of them had stroke -either hemorrhagic or ischemic-, while from the rest 18 (5%), 12 (66.7%) were found to have metastatic neoplasm of brain, 3 (18.7%) had primal tumour of brain, whereas 3 (18.7%) suffered from other diseases (respiratory infection, meningoencephalitis, thyrotoxicosis). The principal symptoms of the conditions that mimicked a stroke were: aphasic disturbances (27.3%), dizziness/fainting (27.3%), headache/diplopia (11.1%), dysarthria (11.1%), hiccup and/or swallow disturbances (5.6%). CONCLUSION: Our diagnostic protocol seems to ensure a high degree of differential diagnosis between stroke and conditions that mimic it.

Inflammatory cytokines in insulin-treated patients with type 2 diabetes.

OBJECTIVE: An association between type 2 diabetes mellitus and inflammation has been described in several studies. The aim of this study was to search for the presence of low-grade inflammation in a special group of insulin-treated patients with type 2 diabetes, and to investigate a possible correlation between inflammation and obesity, glucose homeostasis and insulin requirement (IU insulin/kg body weight, BW). METHODS: We studied 85 subjects with type 2 diabetes that were receiving insulin treatment (group A) and 32 receiving sulfonylurea treatment (group B), and 57 subjects without diabetes (group C). Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), and the soluble TNF-alpha receptors sTNFR-60 and sTNFR-80 were measured in serum samples taken from all patients. RESULTS: The mean serum cytokine levels in group A vs. group B were: IL-6, 8.54+/-11 vs. 2.71+/-1.9 pg/ml (p=0.000); TNF-alpha, 14.33+/-24 vs. 5.12+/-15 pg/ml (p=0.016); sTNFR60, 3.9+/-2.8 vs. 2.36+/-1.4 ng/ml (p=0.000); and sTNFR80, 11.9+/-7 vs. 9.4+/-6 ng/ml (p=0.080). The mean serum cytokine levels in group A vs. group C were: IL-6, 8.54+/-11 vs. 4.74+/-7 pg/ml (p=0.017); TNF-alpha, 14.33+/-24 vs. 5.94+/-3.4 pg/ml (p=0.003); sTNFR60, 3.9+/-2.8 vs. 2.54+/-1.4 ng/ml (p=0.000); and sTNFR80, 11.9+/-7 vs. 10.85+/-8 ng/ml (p=0.470). A positive association between waist circumference and IL-6 (r=0.165, p=0.030) and sTNFR-60 (r=0.276, p=0.000) was detected. A significant correlation coefficient was observed between haemoglobin A1c (HbA1c) and both IL-6 (r=0.278, p=0.000) and sTNFR-60 (r=0.293, p=0.000), when the groups were studied as one. No correlation between inflammation and units of insulin/kg BW was found. In conclusion, low-grade chronic inflammation, as estimated by the relative levels of inflammatory cytokines, was present in patients with type 2 diabetes that were receiving insulin treatment, with significantly higher cytokine levels recorded compared to sulfonylurea-treated patients. In addition, an association between inflammation and both obesity and glucose homeostasis was detected.

Parathyroid crisis as first manifestation of primary hyperparathyroidism.

We report the case of a 61-year-old woman who suffered a parathyroid crisis due to a parathyroid adenoma. The patient presented with the typical clinical symptoms of hypercalcemia. Ca(+2) and PTH were markedly increased. Initially, she was treated conservatively until Ca(+2) returned to normal levels. Then, she underwent surgical excision of a newly diagnosed parathyroid adenoma. Parathyroid crisis (PC), also known as parathyroid storm or acute primary hyperparathyroidism, is a rare and serious complication of primary hyperparathyroidism (PH). Fewer than 200 cases have been described in the literature. Prognosis is poor: mortality is 100% in non-operable cases and 20% in cases in which parathyroidectomy is performed. We emphasize the importance of early diagnosis and aggressive treatment.

Usefulness of colour tissue Doppler imaging in assessing aortic elastic properties in Type 1 diabetic patients.

AIMS: Diabetes mellitus (DM) is associated with macrovascular disease and impaired aortic function. We hypothesized that the change in aortic elastic properties could be investigated with colour tissue Doppler imaging (CTDI) in Type 1 diabetic patients and that these findings could be related to the aortic stiffness index. METHODS: We examined by echocardiography 66 patients with Type 1 DM (mean age 35 +/- 10 years, mean duration of disease 20 +/- 9 years) without a history of arterial hypertension or coronary artery disease (negative thallium-201 stress test) and 66 age- and sex-matched normal subjects. Arterial pressure was measured before echocardiography was performed. Internal aortic systolic and diastolic diameters by M-mode echocardiography and aortic systolic upper wall tissue velocity (Sao, cm/s) by CTDI were measured 3 cm above the aortic valve. Aortic distensibility and aortic stiffness index were calculated using accepted formulae. RESULTS: Aortic stiffness, distensibility and Sao velocity differed significantly between the studied groups. In the diabetic group, duration of diabetes correlated with aortic stiffness (r = 0.53, P < 0.001), distensibility (r = -0.61, P < 0.001) and Sao velocity (r = -0.48, P < 0.001). There was a negative correlation between aortic stiffness and Sao velocity (r = -0.49, P < 0.001). Multiple stepwise linear regression analysis in the diabetic group revealed that aortic S velocity (beta = 0.30, P = 0.005) and duration of diabetes (beta = -0.49, P = 0.001) were the main predictors of aortic distensibility (overall R(2) = 0.48). CONCLUSIONS: Aortic elastic properties can be directly assessed by measuring the movements in the upper aortic wall. Reduced aortic S velocity is associated with increased aortic stiffness in Type 1 diabetic patients.

The control of dyslipidemia in outpatient clinics in Greece (OLYMPIC) Study.

The objective of this study was to determine the proportion of Greek patients referred to outpatient clinics for dyslipidemia who achieved the low-density lipoprotein cholesterol (LDL-C) goal defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines, using lifestyle changes, lipid-lowering drug treatment (LLDT), or both. Adult patients with dyslipidemia, who had been receiving a hypolipidemic diet and/or LLDT for at least 3 months were assessed in a multicenter study performed at 66 sites across Greece. Patients were followed up for an additional 3-month treatment period. Lipid levels were recorded at baseline and at the end of the study. The primary endpoint was the proportion of patients achieving their individual LDL-C target at the end of the study, according to their coronary heart disease (CHD) risk status or its equivalents, as defined by the NCEP-ATP III guidelines. Multivariate logistic models were used to identify determinants of undertreatment. The study included 2,660 adults (20-75 years) from 7 regions of Greece. Of the evaluable sample (n = 2,211; men 51%; mean age 62 +/-9 years) 81% were receiving LLDT (96% with statins and 3% with fibrates), 44% had a history of CHD, 61% arterial hypertension, 36% diabetes, and 26% a family history of premature CHD. Overall, 6% were at low CHD risk, 30% at medium CHD risk, and 63% at high CHD risk. At the end of the study, 26% of all patients and 30% of those receiving LLDT achieved the NCEP-specified LDL-C target levels. The percentage of patients at LDL-C goal according to CHD risk status was: low risk 67% (95% CI = 59-75), medium risk 29% (95% CI = 26-33), and high risk 20% (95% CI = 18-22). Statins proved to be more effective than fibrates (p <0.0001). Atorvastatin-treated subjects (n = 1,222, mean dose 19 mg/day) attained the LDL-C target (31% of the cases) at a higher rate than those receiving other LLDT (n = 574, 26% at target, p <0.01) or not receiving drug treatment (n = 415, 8%, p <0.001). This outcome was more evident in the high-CHD risk group (n = 1,402, 26% with atorvastatin vs 16% with other LLDT and 3% not receiving LLDT attained the LDL-C goal, ANOVA, p <0.001). The majority of dyslipidemic patients receiving LLDT, mainly those with high-CHD risk, are not achieving the NCEP LDL-C target. This is mainly explained by inadequate dose titration to ensure target goals are met. Promoting healthy lifestyle and appropriate LLDT (potent statins with sufficient dose titration) must be implemented to ensure that patients attain LDL-C treatment goals and thus benefit from the reduction in individual CHD risk.

The burden of the rheumatic diseases in the general adult population of Greece: the ESORDIG study.

OBJECTIVE: To estimate the burden of rheumatic diseases in terms of disability and health-care utilization in the Greek general adult population. METHODS: The study was conducted on the total adult population of seven communities (8547 subjects), as well as on 2100 out of 5686 randomly selected subjects in an additional two communities. Rheumatologists visited the participants at their homes to assess the prevalence of six morbidity indicators concerning disability and health-care utilization associated with rheumatic diseases or other major disease groups. RESULTS: The participation rate in the study was 82.1%. The prevalence of chronic health problems, long-term disability, short-term disability, physician office visits and prescription or non-prescription drug use due to rheumatic diseases in the total target adult population was 14.3, 4.3, 2.9, 2.8, 7.2 and 2.0%, respectively. Compared with all other major disease groups, rheumatic diseases were the most common cause of chronic health problems (38.7%), long-term disability (47.2%), short-term disability (26.2%) and physician office visits (20.5%), while they ranked second for the use of prescription (24.0%) or non-prescription drugs (17.7%). Rheumatic diseases were the main cause of morbidity in five out of six indicators in subjects aged < or =65 yr. Logistic regression analysis revealed an association of female gender, age > or =45 yr and obesity with almost all morbidity indicators related to rheumatic diseases. CONCLUSION: These findings suggest that rheumatic diseases constitute a major public health problem and should be considered in planning undergraduate and postgraduate medical education, research and health-care services.

Coincidence of high antiislet and antithyroid autoantibody titles in first-degree relatives of patients with type 1 diabetes.

An association between thyroid and islet autoantibodies has been reported for patients with type 1 diabetes and their first-degree relatives. However no general agreement on this association has been reached since several studies reported controversial data. In the present study, sera from 429 healthy first-degree relatives of type 1 diabetic patients have been examined for the presence of thyroid and islet autoantibodies. Autoantibodies against glutamate decarboxylase (GAD65Ab) and tyrosine-phosphatase IA-2 (IA-2/ICA512Ab) have been detected by radioimmunoassay techniques with in vitro translated recombinant human 35S-autoantigens. The presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has been estimated by commercial radioimmunoassay kits. An increased frequency of TgAb was found in subjects who were positive for GAD65Ab (p=0.0257). However, no significant association between TPOAb and GAD65Ab or IA-2Ab or between TgAb and IA-2Ab could be established. These data indicate an increased rate of coincidence between TgAb and GAD65Ab in healthy first-degree relatives of type 1 diabetic patients. Accordingly a common genetic background leading to the appearance of both TgAb and GAD65Ab may be suggested.

The ORLIstat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORLICARDIA) Study.

BACKGROUND: Metabolic syndrome (MetSyn) is associated with a marked increase in the risk of cardiovascular disease, especially in patients with type 2 diabetes mellitus (DM). AIM: To investigate the effect of orlistat plus hypocaloric diet (HCD) vs HCD alone on the cardiovascular risk profile in patients with both MetSyn (National Cholesterol Educational Program--NCEP--Adult Treatment Panel III definition) and type 2 DM. METHODS: This was a prospective, multicentre, open-label, randomized, controlled study. One hundred and twenty-six patients, free of cardiovascular disease at baseline, were included in the final analysis. Ninety-four (73%) patients were treated with orlistat (360 mg/day) and HCD for a 6-month period, while 34 (27%) were on HCD alone. Analysis of covariance was used to assess differences between the treatment groups over time. MAIN OUTCOME MEASURES: Components of the MetSyn criteria assessed were: waist circumference; systolic and diastolic blood pressure; fasting glucose, triglycerides; high-density lipoprotein cholesterol (HDL-C) plus body mass index; glycosylated haemoglobin (HbA1C); homeostasis model for assessment of insulin resistance (HOMA) index; and total and low-density lipoprotein cholesterol (LDL-C). RESULTS: By protocol, all patients had MetSyn at baseline. After a 6 month treatment period there were significant differences between the orlistat plus HCD vs the HCD-alone groups in body weight (p = 0.0001), waist circumference (p < 0.0001), fasting glucose (p < 0.0001), HbA(1C) (p < 0.0001), systolic blood pressure (p = 0.024), total cholesterol (p < 0.0001), LDL-C (p = 0.034), and HOMA index (p = 0.022), while there were no significant differences in triglycerides and HDL-C. Orlistat was well tolerated. By the end of the study, 65% of the patients on orlistat plus HCD were still meeting the MetSyn criteria and 41% had four to five MetSyn components vs 91% (p < 0.0001) and 53% (p = 0.017), respectively, of those on HCD alone. CONCLUSIONS: Orlistat plus HCD favourably modified several cardiovascular risk factors in patients with both MetSyn and type 2 DM. These effects might partly offset the excess cardiovascular risk and improve outcome in this patient population.

Thyroid disease associated with rheumatoid arthritis is not adequately screened with a sensitive chemiluminescence thyrotrophin assay.

The objective of this study was to screen for thyroidopathies in patients with rheumatoid arthritis (RA). Screening for thyroid disorders is advocated in patients with autoimmune diseases, and rheumatoid arthritis has been linked to thyroid autoimmune disorders, more particularly Hashimoto's thyroiditis and sometimes Graves' disease. We performed thyroid disease screening in 69 patients with RA free of medication for at least a 2 weeks period, not in remission, and in 65 patients with osteoarthritis (OA). The latter were studied as a control group of non-autoimmune arthritis patients. Basal levels of thyrotrophin (TSH) were measured using a sensitive chemiluminescence serum TSH assay. Serum antithyroperoxidase and antithyroglobulin (anti-Tg) autoantibodies were measured as well. If TSH values were found to be outside the normal limits, serum total thyroxine, total triiodothyronine (T3), resin T3 uptake, the free thyroxine index (FT4I) and free triiodothyronine index (FT3I) were evaluated. Rheumatoid arthritis patients exhibited statistically significant lower mean TSH values as compared to OA patients. However, RA patients with low TSH values did not have elevated FT4I. Previous use of corticosteroids in some of the RA patients may be responsible for these results. The autoantibodies levels did not differ between the two groups. We conclude that thyroid function screening with sensitive TSH assays is not sufficient for assessment of early stages of autoimmune thyroidopathies in patients with RA. Thyroid hormones should also be estimated.

Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus.

The aim of this study was to determine whether the levels of serum cytokines IL-6 and TNFalpha and of the soluble receptors p55 srTNFalpha, p75 srTNFalpha and srIL-2ac are valuable markers of disease activity in patients with systemic lupus erythematosus (SLE) compared with the established parameters of anti-dsDNA, C3, C4 and CH50. Forty patients with SLE, 19 ambulatory and 21 hospitalised, were included in this study. On the day of blood sampling a clinical examination was performed and SLEDAI and ECLAM disease activity scores were used to assess disease activity. Nineteen patients had inactive disease and 21 patients had active disease. Thirteen patients from the second group developed nephritis. In these patients the blood sampling and disease activity assessment were performed twice (at presentation and 6 months after treatment). Serum levels of cytokines and soluble receptors were measured by ELISA. Serum levels of cytokines and soluble receptors of patients with active disease were significantly higher than in patients with inactive disease (IL-6 p = 0.0004, TNFalpha p = 0.0015, srIL-2c p<0.0001, p55 srTNFalpha p<0.0001, p75 srTNFalpha p<0.0001). Serum soluble receptor levels of patients with inactive disease were higher than those of healthy controls (p55 srTNFalpha p<0.0001, p75 srTNFalpha p = 0.0002, srIL-2alpha p = 0.0012). No significant difference was found for TNFalpha and IL-6 (TNFalpha p=0.015, IL-6 p=0.019). Serum TNFalpha levels and especially srIL-2alpha, p55 srTNFalpha( and p75 srTNFalpha levels correlated strongly with SLEDAI and ECLAM disease activity scores, anti-dsDNA, C3, C4 and CH50 (p<0.0001). Serum soluble receptor (srIL-2alphac, p55 srTNFa, p75 srTNFalpha) levels were higher in patients with nephritis before treatment and decreased significantly 6 months after treatment (p=0.005). The same trend was noticed with SLEDAI and ECLAM disease activity scores (p = 0.005) and anti-dsDNA (p = 0.008). In contrast, no significant differences were observed for C3 and C4 levels before and after treatment, which suggests that soluble receptors of cytokines are more sensitive markers of disease activity than C3 or C4 in predicting improvement. Serum levels of srIL-2alpha, p55 srTNFalpha and p75 srTNFalpha could provide useful information about disease activity in SLE patients, especially in cases where the other markers do not.

Adaptive denoising and multiscale detection of the V wave in brainstem auditory evoked potentials.

This paper describes a wavelet-transform-based system for the V wave identification in brainstem auditory evoked potentials (BAEP). The system combines signal denoising and rule-based localization modules. The signal denoising module has the potential of effective noise reduction after signal averaging. It analyses adaptively the evolution of the wavelet transform maxima across scales. The singularities of the signal create wavelet maxima with different properties from those of the induced noise. A non-linear filtering process implemented with a neural network extracts out the noise-induced maxima. The filtered wavelet details are subsequently analysed by the rule-based localization module for the automatic identification of the V wave. In the first phase, it implements a set of statistical observations as well as heuristic criteria used by human experts in order to classify the IV-V complex. At the second phase, using a multiscale focusing algorithm, the IV and V waves are positioned on the BAEP signal. Our experiments revealed that the system provides accurate results even for signals exhibiting unclear IV-V complexes.

Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy.

OBJECTIVE: Autonomic nervous system function in patients with diabetes mellitus (DM), especially those with diabetic autonomic neuropathy (DAN), displays an abnormal circadian pattern compared to normal subjects; this probably plays an important role in the onset of acute cardiovascular syndromes, which display a similar pattern of occurrence with a blunted late morning peak, and an increase of episodes during the night, in comparison to non-diabetic subjects. This study was undertaken to investigate the effect of an angiotensin-converting enzyme inhibitor, quinapril, on the circadian pattern of heart rate variability (HRV), a reliable index of sympathovagal interactions, in patients with definite DAN. METHODS & RESULTS: Normalised HRV frequency domain indices [high frequency power (HFP), reflecting vagal tone, low frequency power (LFP), reflecting both vagal and sympathetic (predominantly) modulation, and their ratio (LFP/HFP), indicative of sympathovagal balance] were assessed in 60 patients with DAN at baseline and one year after therapy with quinapril (n = 30), or placebo (n = 30) on a 24-hour 2-channel electrocardiogram with a solid state Holter monitor. Normal subjects (n = 30) and patients with DM without DAN (n = 30), were used as controls. The baseline circadian variation of fractional normalised power in DAN patients was abolished, with pronounced dominance of LFP over HFP during the whole 24-hour period. After one year of treatment, quinapril increased HFP, decreased LFP and improved their ratio, in the morning (07.00 a.m. to 15.00 p.m.) and night (23.00 p.m. to 07.00 a.m.) time intervals, with maximal effect in the night time interval (HFP = 20%, LFP = -8%, LFP/HFP = -31%; for all comparisons p < 0.05 vs baseline values and p < 0.001 vs one year of placebo). CONCLUSIONS: Quinapril increased HFP and decreased LFP as well as their ratio, all indicative of sympathetic predominance reduction, in patients with DAN at time intervals these indices were most adversely affected (morning and night). Since autonomic function is an important contributor in the pathogenesis of acute coronary events, malignant arrhythmias and sudden cardiac death, improvement of indices related to autonomic function in DAN patients in these time intervals may prove beneficial in clinical practice.

Prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes.

OBJECTIVE: The purpose of the present study was to determine the prevalence of oral lichen planus (OLP) in a population of patients with diabetes mellitus (DM) as compared with a control population. DESIGN: A clinicopathologic study. SUBJECTS AND METHODS: One hundred and thirty-nine patients with type I DM, 353 patients with type II DM and 274 controls were examined for clinical evidence of OLP. The clinical evidence of OLP in the diabetic and control patients was confirmed by histopathological examination. RESULTS: The prevalence of OLP in type I diabetic patients was 5.76%, in type II 2.83%, and 1.82% in the controls. The prevalence of OLP was significantly higher in patients with type I DM and slightly higher in patients with type II DM in comparison to the prevalence in the control sample. CONCLUSIONS: The above findings and the fact that type I diabetes and OLP are characterized by autoimmune phenomena and T cell immune responses respectively, suggest that the immune system may play a critical role in the appearance of OLP in patients with type I DM.

Effect of aldose reductase inhibition on cardiovascular reflex tests in patients with definite diabetic autonomic neuropathy over a period of 2 years.

The potential of the aldose reductase inhibitor tolrestat to ameliorate definite diabetic autonomic neuropathy (DAN), as defined by standard cardiovascular autonomic function tests, was evaluated in 35 patients over a period of 2 years, with repeated measurements at 3-month intervals. The effect of tolrestat (200 mg a day) was compared with that of placebo on 35 controls with diabetes mellitus, of similar age, gender, and glycemic control. In the placebo group, a significant deterioration of the indices, with the exception of Valsalva ratio, was recorded, while tolrestat induced a significant beneficial change in the values of most standard cardiovascular reflex tests, in comparison to baseline and placebo. The deep breathing tests (expiration-inspiration ratio, standard deviation, and mean circular resultant of R-R intervals), postural index, and postural hypotension were favorably affected. Three of 35 patients on tolrestat (8.6%) developed high transaminases levels (more than threefold the upper normal limit) and were withdrawn from the study. In conclusion, tolrestat improved autonomic nervous system function in patients with definite DAN, in comparison to baseline and placebo. The clinical importance of this finding needs further investigation.

The natural history of recently diagnosed autonomic neuropathy over a period of 2 years.

BACKGROUND: Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with normals or diabetic patients without DAN. Indices of standard cardiovascular autonomic function tests and heart rate variability (HRV) are reliable markers of the presence and severity of DAN. OBJECTIVE: The present prospective study investigated the natural history of values of HRV indices and cardiovascular reflex tests in patients with recently diagnosed asymptomatic DAN, over a period of 2 years, at 3 month intervals. PATIENTS AND METHODS: A total of 30 consecutive patients (nine men and 21 women), of median age 51 (range 25-65) years, eight with type 1 and 22 with Type 2 diabetes mellitus, were included in the study, at the time that the presence of DAN was confirmed, as this was established if at least two of cardiovascular autonomic function tests became abnormal. The expiration/inspiration (E/I) ratio. S.D. and mean circular resultant of R-R intervals, the Valsalva index, the 30:15 ratio, and the blood pressure response to standing as well as normalised spectral power indices of HRV were used. RESULTS: All measured indices, except the Valsalva index, deteriorated in all 30 patients during the 2 year follow-up. Most of HRV indices values deteriorated significantly in comparison to baseline at month 12, while the values of cardiovascular reflex tests displayed significant deterioration, in comparison to baseline, between months 15 and 21. Fourteen patients developed symptoms of DAN during the 2 year period. Patients with better glycemic control exhibited deterioration of DAN markers at the same time period with those with poor glycemic control. CONCLUSIONS: Our data suggest that the progression of DAN is significant during the 2 years subsequent to its discovery. This was defined by the deterioration of the mean values of HRV indices and standard cardiovascular autonomic function tests, and by the development of autonomic symptoms in some patients. HRV indices are the earlier markers of DAN deterioration.

Effect of aldose reductase inhibition on heart rate variability in patients with severe or moderate diabetic autonomic neuropathy.

Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with diabetic patients without DAN. Heart rate variability (HRV) time and frequency domain indices are strong predictors of malignant arrhythmias and sudden cardiac death. This prospective, randomised, double-blind, placebo-controlled study analysed the long-term effect of an aldose reductase inhibitor, tolrestat, on HRV time and frequency domain variables in 45 patients with diabetes mellitus (DM) and DAN. Patients were randomised into tolrestat (n = 22) and placebo (n = 23) groups. Tolrestat (200 mg/day) or placebo were administered, respectively, for a period of 12 months. HRV was assessed at months 0, 3, 6, 9 and 12. The HRV level of the 45 patients was compared with that of 20 patients with DM, with analogous glycaemic control, without DAN and 20 healthy controls, of similar age and gender. At the twelfth month, tolrestat, compared with placebo, had a beneficial effect on HRV indices related to vagal tone. Compared with baseline, HRV time and frequency domain indices showed no significant improvement. Moreover, at the twelfth month of tolrestat administration, HRV indices remained less than that of patients with DM but without DAN, and healthy controls. The 12 patients of the 22 with moderate DAN benefited more than the 10 patients of the 22 with severe DAN. At the twelfth month no patient showed deterioration in HRV indices with tolrestat as was seen with placebo. Our data suggest that tolrestat slows down the progression of DAN compared with placebo. This effect of an aldose reductase inhibitor may contribute to a reduction in risk for malignant ventricular arrhythmias. The early detection of DAN is imperative for successful intervention.

Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy.

OBJECTIVE: Heart rate variability (HRV) time and frequency domain indexes are strong predictors of malignant arrhythmias and sudden cardiac death. Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with diabetic patients without DAN. RESEARCH DESIGN AND METHODS: The present double-blind, randomized, and placebo-controlled study analyzed the effect of quinapril, an ACE inhibitor, on HRV time and frequency domain variables in patients with DAN. Forty patients (17 men and 23 women) of a mean age of 51 (range 19-68) years, free of coronary artery disease and arterial hypertension, were randomized into a quinapril or placebo group. HRV was recorded at months 0, 3, and 6. The parameters measured were 1) time domain indexes: SD of all 24-h R-R intervals (intervals between consecutive electrocardiogram R waves), or SDNN/24-h; mean of SD of R-R intervals of all 5-min segements (SDNN/5-min); root-mean-square of the differences of successive R-R intervals (RMSSD); and percentage of the R-R intervals differing more than 50 ms (pNN50); and 2) frequency domain indexes: total power (TP), high-frequency power (HFP), low-frequency power (LFP), and very-low-frequency power (VLFP). HRV level of the 40 patients were compared with one of 20 matched diabetic patients, of analogous glycemic control without DAN, and 20 healthy control subjects. RESULTS: Quinapril, compared with placebo, increased total HRV: SDNN/24-h (P < 0.05), TP (P < 0.05), and HRV parameters related to parasympathetic activity: pNN50 (P < 0.01). RMSSD (P < 0.05), and HFP in absolute and normalized units (P < 0.01). LFP/HFP ratio was decreased (P < 0.01). Despite the beneficial effect of quinapril on parasympathetic variables of HRV these remained less than those of diabetic patients without DAN and healthy control subjects. CONCLUSIONS: Our findings suggest that quinapril significantly increases parasympathetic activity in patients with DAN 3 months after treatment initiation and sustains this effect until the 6th month. This might contribute to the reduction of the risk for malignant ventricular arrhythmias in these patients.