Dimitrios T. Karamitsos

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 < 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.

The ORlistat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORliCARDIA) study

SUMMARY 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), HbA1C ( 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.

Effect of various treatments on leptin, adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus

Introduction: Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM). Areas covered: The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM. Expert opinion: Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated.

Impact of autonomic neuropathy on left ventricular function in normotensive type 1 diabetic patients: a tissue Doppler echocardiographic study.

Cardiovascular autonomic neuropathy (CAN) is one of the most serious complications of diabetes and has been weakly linked with left ventricular (LV) diastolic dysfunction. Previous studies that explored this association either suffer from inadequate definition of CAN or have mainly used conventional Doppler or nuclear techniques to investigate LV diastolic function. Tissue Doppler imaging (TDI) has evolved as a new quantitative tool for the assessment of cardiac systolic function, diastolic function, and the hemodynamics of LV filling. We sought to investigate conventional and TDI-derived indexes of LV systolic and diastolic function in type 1 diabetic patients with and without CAN and also in normal control subjects. Our findings suggest that the presence of CAN seems to have an additive effect on LV diastolic dysfunction in type 1 diabetes.

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.

Diabetes mellitus and cerebrovascular disease: which are the actual data?

Cerebrovascular disease (CeVD) represents a major cause of morbidity and mortality worldwide. Diabetes mellitus (DM) represents an independent risk factor for CeVD. The aim of the present review is to describe the epidemiology of CeVD in patients with DM and to explain how DM and diabetic autonomic neuropathy can increase the risk of CeVD. The prevention and management of CeVD in the diabetic population are also analyzed.

Evaluation of use of proton pump inhibitors in Greece

INTRODUCTION Proton pump inhibitors (PPIs) are widely used for acid-related gastric diseases. However, several national studies reported increasing use of PPIs for yet unlicensed indications. AIM The aim of our study was to evaluate the extent of PPIs prescription in a Greek tertiary hospital, as well as the adherence to licensed indications according to the Greek National Drug Organization. METHODS We retrospectively studied the discharge letters of 1693 adult patients who were admitted at the First Propedeutic Department of Internal Medicine at AHEPA hospital in Thessaloniki, Greece between July 2005 and December 2006. We studied their discharge letters in order to record all cases in which antisecretory therapy (PPIs or H(2) antagonists) was prescribed, as well as to collect data about indication of PPI treatment and the type of PPI prescribed for each patient. RESULTS PPIs were prescribed in 430 patients (25.4%). In 349 patients, PPIs were prescribed for an improper indication (81.2%), mainly for prophylaxis against medications such as steroids, non-steroidal anti-inflammatory drugs, antiplatelets and warfarin. The most commonly prescribed PPI was omeprazole. CONCLUSIONS PPIs are inappropriately prescribed in Greece. In most cases, physicians prescribe PPIs for unlicensed indications and usually, they do not give specific instructions about the duration of the treatment.

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.

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.

Effect of Aldose Reductase Inhibition on Heart Rate Variability in Patients with Severe or Moderate Diabetic Autonomic Neuropathy

SummaryPatients 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.