Association of fasting plasma free fatty acid concentration and frequency of ventricular premature complexes in nonischemic non-insulin-dependent diabetic patients.

We investigated the association between free fatty acid (FFA) concentration and ventricular premature complexes (VPCs) in nonischemic patients with non-insulin-dependent diabetes mellitus using 3 approaches: cross-sectional analysis (n = 142), intervention including induction of elevated FFA levels with Intralipid heparin (n = 15), and reduction in FFA levels with Acipimox (n = 34) and a longitudinal follow-up study (n = 59). Patients at the third tertile of fasting plasma FFA concentration had the strongest increase in VPCs. Independently of age, sex, body mass index (BMI), waist/hip ratio, left ventricular mass index, glycated hemoglobin, fasting plasma insulin and triglyceride concentration, and daily physical activity, FFA concentration and VPCs were significantly correlated (r = 0.21 p <0.01). At multiple logistic regression analysis independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, glycated hemoglobin, fasting plasma insulin, triglycerides and potassium concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity, plasma FFA concentration was a significant determinant of VPCs (odds ratio 1.2, 95% confidence interval 1.0 to 2.3). Intralipid infusion (10% in 24 hours) (n = 15) and acipimox administration (250 mg, 4 times/day) (n = 34) increased, and decreased fasting plasma FFA concentration, respectively. In those studies, change in VPCs paralleled the effects on plasma FFA. In the longitudinal study (n = 59), plasma FFA concentration predicted the development of VPCs (RR 1.4 95% confidence interval 1.0 to 1.9) independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, fasting plasma triglyceride concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity. In conclusion, in nonischemic patients with non-insulin-dependent diabetes mellitus, plasma FFA concentration is associated with the frequency of ventricular premature complexes.

Effects of magnesium and nifedipine infusions on insulin action, substrate oxidation, and blood pressure in aged hypertensive patients.

Eight aged (70.1 +/- 2.1 years), nonobese (body mass index [BMI] = 26.3 +/- 0.4), hypertensive (systolic blood pressure [SBP] = 184 +/- 4.1; diastolic blood pressure [DBP] = 105 +/- 2.4 mm Hg) subjects underwent a euglycemic hyperinsulinemic (7.1 pmol/kg x min during 240 min) glucose clamp with four different infusions: a) 0.9% NaCl; b) 1.0 micrograms/kg x min nifedipine; c) 100 mumol/min magnesium; d) 1.0 micrograms/kg x min nifedipine plus 100 mumol/min magnesium. All tests were performed in random order. Simultaneous D-3-H glucose infusion and indirect calorimetry allowed us to determine glucose turnover parameters and substrate oxidation. Insulin infusion per se stimulated erythrocyte magnesium (1.83 +/- 0.04 v 1.98 +/- 0.03 mmol/L, P < .03) and calcium (4.7 +/- 0.3 v 6.2 +/- 0.4 mumol/L, P < .02) accumulation, and enhanced total body glucose disposal oxidative and nonoxidative glucose metabolisms. Infusion of insulin and nifedipine v insulin alone reduced insulin-mediated increase in intracellular calcium (5.4 +/- 0.3 v 6.2 +/- 0.4 mumol/L, P < .02), but potentiated the insulin effect upon nonoxidative glucose (15.4 +/- 0.4 v 11.1 +/- 0.3 mumol/kg lean body mass [LBM] x min, P < .03) metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure.

Congestive heart failure is a condition associated with increased plasma norepinephrine levels. Moreover, norepinephrine has been recently demonstrated to affect glucose homeostasis by decreasing insulin sensitivity. In the present study, eight patients suffering from chronic congestive heart failure and 10 healthy age- and body mass index-matched subjected were submitted to both an oral glucose tolerance test (OGTT; 75 g) and a euglycemic hyperinsulinemic glucose clamp. During the 360 minutes of the glucose clamp, insulin was infused at three different rates (25, 50, and 100 mU/kg/h), while D-3H glucose infusion allowed determination of glucose turnover. In basal conditions, patients versus controls had similar plasma glucose (5.2 +/- 0.1 v 4.9 +/- 0.2 mmol/L,P = NS), but higher plasma insulin (125.7 +/- 9.2 v 35.7 +/- 3.3 pmol/L,P less than .01), norepinephrine (5.39 +/- 0.13 v 1.47 +/- 0.22 nmol/L,P less than .001), and free fatty acid (FFA) (927 +/- 79 v 792 +/- 88 mumol/L,P less than .05) levels. In patients, basal plasma norepinephrine correlated with FFA levels (r = .65, P less than .025). After loading glucose, plasma glucose and insulin levels were still significantly higher in patients than controls. Euglycemic hyperinsulinemic glucose clamp produced a lower insulin-mediated inhibition of endogenous (hepatic) glucose production (HGP) and a greater increase in both glucose disappearance rate (Rd) and glucose metabolic clearance rate (gMCR) in patients than in controls during the first two insulin infusion rates (25 and 50 mU/kg/h). By contrast, these differences disappeared during the highest insulin infusion rate (100 mU/kg/h). Insulin-mediated decrease in plasma FFA levels was also lower in patients than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperinsulinemia is associated with ventricular premature complexes.

The study investigated a possible association between fasting plasma insulin (FPI) levels and ventricular premature complexes (VPCs). One hundred eighty-six subjects without coronary artery disease (CAD), diabetes, hypertension, and left ventricular hypertrophy were recruited. All subjects underwent 24-hour electrocardiographic monitoring and oral glucose tolerance testing. The subjects were slightly overweight, normotensive, and nondiabetic. Subjects at the third tertile of FPI concentrations were the oldest and heaviest, with prevalent upper-body fat distribution, and had enhanced fasting plasma triglyceride and potassium concentrations, lower fasting plasma high-density lipoprotein (HDL) cholesterol concentration, and a greater number of VPCs versus subjects at the first and second tertiles. Independently of age, sex, body mass index (BMI), and waist to hip ratio (WHR), VPCs were correlated with FPI concentration (r = .19, P < .01). Multiple logistic regression analyses in which the presence or absence of VPCs was the dependent variable demonstrated that FPI concentrations were associated with VPCs independently of age, sex, BMI, WHR, daily physical activity (DPA), left ventricular mass index (LVMI), plasma low-density lipoprotein (LDL)/HDL cholesterol ratio, and triglyceride concentration (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0 to 1.6). After addition to the model of fasting plasma free fatty acids ([FFA] OR, 0.7; 95% CI, 0.6 to 1.3) or potassium (OR, 0.7; 95% CI, 0.6 to 1.1) concentrations, the association between FPI concentrations and VPCs is no longer significant. In conclusion, FPI concentrations are associated with VPCs in nondiabetic, normotensive, nonischemic subjects.

Total-body and myocardial substrate oxidation in congestive heart failure.

Congestive heart failure is a condition associated with increased plasma norepinephrine levels, which have been demonstrated to impair glucose handling. In the present study, 10 patients suffering from congestive heart failure and 10 healthy age- and body mass index-matched subjects were submitted to a hyperinsulinemic (insulin infusion rate, 0.5 mU/kg.min-1) glucose clamp, while simultaneous D-3H-glucose infusion and indirect calorimetry allowed for determination of glucose turnover parameters and substrate oxidation, respectively. On a separate day, basal local (myocardial) indirect calorimetry was also performed. Our data demonstrate that in congestive heart failure, fasting myocardial glucose oxidation (Gox) was inhibited with a simultaneous increase in lipid oxidation (Lox). In our patients, a significant decrease in total-body insulin-stimulated glucose metabolism (31.0 +/- 0.5 v 20.3 +/- 0.4 mumol/kg.min-1, P < .01) and nonoxidative glucose metabolism (18.9 +/- 1.1 v 11.0 +/- 0.5 mumol/kg.min-1, P < .05) was also found. Such latter changes were also associated with a simultaneous overdrive of Lox (0.4 +/- 0.2 v 1.9 +/- 0.2 mumol/kg.min-1, P < .02) that was correlated with an enhanced availability of plasma free fatty acids (FFAs).

ACE inhibition improves insulin-sensitivity in aged insulin-resistant hypertensive patients.

We have compared the cardiovascular and metabolic responses to five different ACE inhibitors in 86 patients matched for age, body mass index, blood pressure, fasting plasma glucose and insulin levels in a placebo-controlled, double-blind, crossover, randomised trial. In the active drug treatment phase the patients were randomly assigned to one of five ACE inhibitors: captopril (75 mg/day; n = 16); enalapril (20 mg/day; n = 14); quinapril (20 mg/day; n = 17); ramipril (5 mg/day; n = 21) and lisinopril (20 mg/day; n = 18). Placebo and ACE inhibition phases lasted two weeks and were separated by a one week wash-out period. At the end of each treatment period blood pressure and heart rate were recorded and a fasting sample intravenous glucose tolerance test was conducted. Our study demonstrated that ACE inhibition significantly reduces blood pressure and improves insulin sensitivity. All the ACE inhibitors studied had similar cardiovascular responses but lisinopril displayed the larger metabolic response.

Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients.

We investigated the possible role of losartan on insulin-mediated glucose uptake, substrate oxidation and blood flow in insulin-resistant hypertensive patients. Sixteen newly diagnosed patients with mild-to-moderate hypertension were studied. The study design was a single-blind, randomised, placebo-controlled trial. After a 1 week run-in period, each patient was randomly assigned to placebo (n = 7) and losartan (n = 9). Both treatment periods lasted 4 weeks. At baseline, and at the end of the placebo and losartan treatment periods, euglycaemic hyperinsulinaemic glucose clamp and indirect calorimetry were performed. Before and along each glucose clamp, blood flow was also determined in the femoral artery by image-directed duplex ultrasonography combining B-mode imaging and pulse Doppler beams. Losartan vs placebo lowered systolic blood pressure by 163 +/- 3.5 and 147 +/- 4.1 mm Hg (P < 0.001), and diastolic blood pressure by 95 +/- 3.2 and 85 +/- 3.2 mm Hg (P < 0.001). Losartan enhanced glucose metabolic clearance rate by 5.1 +/- 0.3 and 6.3 +/- 0.4 mg/kg x min (P < 0.05), and whole body glucose disposal (WBGD) by 29.2 +/- 0.5 and 38.1 +/- 0.4 mumol/kg free fatty mass (FFM) x min (P < 0.01) but did not affect heart rate. Insulin-mediated change in blood flow was greater after losartan than placebo administration (111 +/- 4 vs 84 +/- 3%, P < 0.01). Per cent change in insulin-mediated stimulation of blood flow and WBGD were also correlated (r = 0.76, P < 0.01). Analysis of substrate oxidation revealed that losartan administration improved insulin action and non-oxidative glucose metabolism (NOGM) (30.8 +/- 2.2 vs 22.8 +/- 2.8 mumol/kg FFM x min, P < 0.05). In conclusion losartan improves insulin-mediated glucose uptake through an increase in NOGM and blood flow in hypertensive patients.

Changes in glucose turnover parameters during muscular exercise: role of age.

In a study of ten young and seven elderly healthy men we have performed an oral glucose tolerance test (75 g) and employed a euglycemic hyperinsulinemic (0.25 mUx kg/min) glucose clamp technique in order to determine insulin sensitivity. This latter experimental protocol consisted of 120 min of euglycemic clamp followed by 60 min in which the clamp and a mild muscular exercise (35% VO(2) (max)) were combined. D-[(3)H]glucose infusion allowed a determination of the glucose turnover parameters. Our results show that in elderly subjects glucose disappearance rate and glucose metabolic clearance rate are significantly lower during both clamp, and clamp + muscular exercise studies. On the contrary, hepatic glucose production was similar under both conditions and was independent of age.

Clinical effects of oral theophylline in elderly patients with sick sinus syndrome.

Theophylline increases the heart rate in patients with normal sinus rhythm and in patients with sick sinus syndrome. This effect is probably connected to the blockade of adenosine receptors by theophylline. This study evaluated the efficacy of theophylline in 34 elderly patients with symptomatic sinus bradycardia (age 68 +/- 11 years). A resting electrocardiogram, a 24-hour recording and treadmill test were performed both before and after administration of slow-release theophylline (700 mg/day). The drug increased resting heart rate (from 43 +/- 6 to 63 +/- 16 beats/min, p < 0.01), mean 24 hour heart rate (from 49 +/- 7 to 65 +/- 17 beats/min, p < 0.01), and minimal 24 hour heart rate (from 34 +/- 5 to 44 +/- 10 beats/min, p < 0.05 ). Cardiac pauses longer than 2.5 seconds were present in 8 patients during control recordings, and disappeared after theophylline. Twenty-six patients were followed for a period of 20 +/- 5 months. Suppression of symptoms was achieved in 24 of them. Asthenia and easy fatigue were reduced markedly by the drug. During long term therapy, the sinus rate was similar to that observed at the steady-state evaluation. In 6 of the 34 patients theophylline had to be discontinued because of gastric intolerance (in 4 cases at the end of the steady-state evaluation and in 2 during long-term therapy). These data suggest that oral theophylline can represent an effective therapy in some elderly patients with symptomatic sinus bradycardia and can avoid or delay the need of a permanent pacemaker.

Isoproterenol test and head-up tilt test for diagnosis of vasovagal syncope in elderly patients.

The elderly can be affected by vasovagal syncope, but they often do not have preceding symptoms. The head-up tilt test (HTT) is successfully used in half of the patients in which the diagnosis is difficult. In young people the association with the isoproterenol test improves the sensitivity of the HTT. In the elderly the effect of such an association is still debated, therefore, the present study was aimed at evaluating the usefulness of the association between the two tests in old subjects to unmask the vasovagal nature of some syncopes of unknown origin. Twenty-four patients with negative HTT (18 males and 6 females; mean age 65 years) 10 with and 14 without organic heart disease were studied. The test protocol consisted of a continuous intravenous infusion of isoproterenol in successive stages starting from a dosage of 1 gamma/min for 5 min in supine position and then for 10 min in passive upright position at 80 (1st stage) up to maximum of 5 gamma/min (5th stage). The results obtained were: 12 patients (50%) had a positive test (reproduction of syncope) with a vasodepressor response in 6 of them and a mixed response in 6 patients. The mean time to syncope was during the 4th min of the 4th stage of treatment. The heart rate increase was 36% between the initial and peak values achieved during the test in patients with a positive test, and 10.5% in patients with negative test (p < 0.05). These results indicate that the isoproterenol test seems to increase the sensitivity of HTT in elderly patients with syncope of unknown origin.

Regression of left ventricular hypertrophy in hypertensive elderly patients with carvedilol.

In hypertensive patients, the development of left ventricular hypertrophy seems to increase the risk of cardiovascular death although some antihypertensive agents have been associated with regression in left ventricular hypertrophy. A few studies have evaluated the carvedilol, a new drug having a balanced pharmacology of vasodilatation and beta-receptor blockade, particularly in elderly hypertensive patients. To test its effects on left ventricular hypertrophy, patients with essential hypertension and left ventricular hypertrophy were studied before and at the end of 6 months of therapy with 25 mg of carvedilol daily. Candidates had to have moderate, uncontrolled essential hypertension with echocardiographically documented left ventricular hypertrophy (left ventricular mass index > 130 g/m2 for men and > 110 g/m2 for women). Of 26 patients selected, 4 dropped out. The remaining 22 patients successfully completed 6 months of therapy. The average age was 69 +/- 8 years. Carvedilol caused a significant reduction of mean systolic blood pressure from 175 to 145 mmHg (p < 0.001), of diastolic blood pressure from 102 to 82 mmHg (p < 0.001), of left ventricular mass index from 148 +/- 24 g/m2 (p < 0.003), and a non significant change of the mean heart rate from 78 to 72 beats/min. In our study, carvedilol was well tolerated in patients with essential hypertension and left ventricular hypertrophy.

Hypertension in the elderly is associated with impaired glucose metabolism independently of obesity and glucose intolerance.

We evaluated insulin secretion, insulin sensitivity and blood pressure changes after oral administration of glucose in hypertensive and normotensive elderly subjects. The hypertensive group consisted of 12 subjects (aged 72.5 +/- 1.9 years, mean +/- s.e.m.) who had a history of hypertension lasting 10-25 years and were not more than 20% above ideal body weight. The normotensive group consisted of 12 subjects matched to the hypertensive group for age, sex and weight. All subjects underwent an oral glucose tolerance test (75 g glucose dissolved in 300 ml water), an intravenous glucose tolerance test (0.33 g/kg of a 50% glucose solution) and a euglycaemic, moderately hyperinsulinaemic glucose clamp. In both groups, oral glucose tolerance was normal according to the criteria of the National Diabetes Data Group; the hypertensive group showed significantly higher plasma glucose and insulin responses to oral glucose than the normotensive group, suggesting insulin resistance. The results of the euglycaemic clamp confirmed the state of reduced insulin sensitivity. Our data demonstrate that oral but not intravenous glucose produces a fall in blood pressure in hypertensive but not in normotensive patients, probably because activation of the sympathetic nervous system is impaired in hypertensive subjects; moreover, hypertension in the elderly seems associated with a state of reduced sensitivity to insulin.

Effects of the angiotensin converting enzyme inhibitor enalapril compared with diuretic therapy in elderly hypertensive patients.

The aim of this study was to evaluate the usefulness of the angiotensin converting enzyme (ACE) inhibitor enalapril in a group of 30 patients (mean age 73.3 years) with moderate hypertension and normal haematological and chemical parameters (170 +/- 8.1 mmHg systolic and 104 +/- 5.8 mmHg diastolic blood pressure), who were receiving diuretic therapy with chlorthalidone (12.5 mg/day). This therapy caused a significant decrease in systolic and diastolic blood pressure (to 165 +/- 6.7 and 98 +/- 4.7 mmHg, respectively; P less than 0.001) but it also induced hypokalaemia (3.04 +/- 0.7 mmol/l; P less than 0.001) and multiple (greater than 10/h) and complex premature ventricular depolarizations (2nd, 3rd and 4th Lown grade). Enalapril treatment (5 mg/day for 5 days and 10 mg thereafter) was added to the diuretic therapy and after 2 months a further decrease in blood pressure was observed (to 158 +/- 5.6 mmHg systolic, P less than 0.001; 87.2 +/- 5.0 mmHg diastolic, P less than 0.001). Moreover, there was a significant reduction in the mean heart rate (from 79 to 72 beats/min, P less than 0.005) and an increase in serum potassium (to 4.19 +/- 0.2 mmol/l; P less than 0.001). In 80% of patients a 24-h dynamic electrocardiogram showed a significant reduction in both the number and complexity of premature ventricular depolarizations. Our findings suggest that ACE inhibitors can be useful in patients developing hypokalaemia during therapy. However, we are not yet able to explain the beneficial effects of enalapril in decreasing the frequency of premature ventricular depolarizations.