Liraglutide improves cardiac function in patients with type 2 diabetes and chronic heart failure.

PURPOSE: To compare the effect of liraglutide, sitagliptin and insulin glargine added to standard therapy on left ventricular function in post-ischemic type-2 diabetes mellitus patients. METHODS: We evaluated 32 type-2 diabetes mellitus Caucasians with history of post-ischemic chronic heart failure NYHA class II/III and/or left ventricular ejection fraction ≤45 %. Participants underwent laboratory determinations, electrocardiogram, echocardiogram, Minnesota Living with Heart Failure questionnaire and 6 min walking test at baseline and following 52 weeks treatment. Patients were treated with standard therapy for chronic heart failure and were randomized to receive liraglutide, sitagliptin and glargine in addition to metformin and/or sulfonylurea. RESULTS: Liraglutide treatment induced an improvement in left ventricular ejection fraction from 41.5 ± 2.2 to 46.3 ± 3 %; P = 0.001). On the contrary, treatment with sitagliptin and glargine induced no changes in left ventricular ejection fraction (41.8 ± 2.6 vs. 42.5 ± 2.5 % and 42 ± 1.5 vs. 42 ± 1.6 %, respectively; P = NS). Indexed end-systolic LV volume was reduced only in liraglutide-treated patients (51 ± 9 vs. 43 ± 8 ml/m2; P < 0.05). Liraglutide treatment induced also a significant increase in the anterograde stroke volume (39 ± 9 vs. 49 ± 11 ml; P < 0.05), whereas no differences were observed in the other two groups. Cardiac output and cardiac index showed a significant increase only in liraglutide-treated patients (4.4 ± 0.5 vs. 5.0 ± 0.6 L/min; P < 0.05 and 1.23 ± 0.26 vs. 1.62 ± 0.29 L/m2; P = 0.005, respectively). Liraglutide treatment was also associated with an improvement of functional capacity and an improvement of quality of life. CONCLUSIONS: These data provide evidence that treatment with liraglutide is associated with improvement of cardiac function and functional capacity in failing post-ischemic type-2 diabetes mellitus patients.

[Hyperglycaemia and Acute Coronary Syndrome]. / L'iperglicemia nelle Sindromi Coronariche Acute.

Hyperglycaemia in patients with Acute Coronary Syndrome (ACS)is common, and is an independent predictor of mortality and morbidity in patients both with and without diabetes mellitus. Hyperglycaemia may be a marker of pre-existing diabetes or glucose intolerance or may also represent a transient stress response mediated through the autonomic nervous system with release of adrenal corticosteroids and catecholamines. Several evidences suggest that an intensive control of hyperglycaemia results in a significant improvement of the adverse outcomes in the short and long term. In fact, an intensive metabolic treatment can counteract the negative effects of hyperglycaemia. However, the main difficulty to intensive glucose control in patients with ACS remains hypoglycaemia that is associated with an increased risk of mortality and myocardial re-infarction. No definitive data are available about the beneficial effects of insulin intensive treatment. Therefore, randomized multicenter clinical trials will be needed to definitively establish whether intensive glucose control will reduce the associated increased mortality rate and higher rates of complications in hospitalized ACS patients with hyperglycaemia.

Relationship between angiotensin-converting enzyme gene polymorphism and insulin resistance in never-treated hypertensive patients.

The association between angiotensin-converting enzyme (ACE) gene polymorphism and insulin resistance (IR) in hypertensive subjects remains controversial. Thus, we evaluated the possible association between IR and ACE gene polymorphism in a group of hypertensive, never-treated patients compared with that in a normotensive control group. We enrolled 200 (114 men and 86 women; age, 45.5 +/- 4.7 yr) hypertensive patients and 96 (54 men and 42 women; age, 44.0 +/- 4.7 yr) normotensive subjects. A double PCR assay was used to identify ACE genotypes. We determined fasting glucose and insulin by the glucose oxidase method and using a standard RIA technique. IR was estimated using the homeostasis model assessment (HOMA(IR)). Both fasting glucose (5.0 +/- 0.3 vs. 4.7 +/- 0.3 mmol/L; P < 0.0001), insulin levels (12.3 +/- 4.7 vs. 4.9 +/- 1.5 muU/mL; P < 0.0001), and HOMA(IR) (2.7 +/- 1.1 vs. 1.1 +/- 0.3; P < 0.0001) were significantly higher in hypertensive patients than in the normotensive control group. When we subdivided hypertensive patients according to ACE genotype, we observed that fasting insulin and HOMA(IR) were 16.3 +/- 3.3 and 3.6 +/- 0.8 in the DD genotype, 9.4 +/- 3.1 and 2.1 +/- 0.7 in the ID genotype, and 8.3 +/- 2.8 and 1.9 +/- 0.7 muU/mL in the II group (P < 0.0001, by ANOVA). No significant differences were observed in the normotensive control group. In conclusion, we extended previous data regarding the relationship of hypertension and IR by demonstrating a dependence of this relationship upon the ACE gene polymorphism.

Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients.

We tested the effects of vitamin C and atorvastatin treatment on endothelium-dependent and endothelium-independent vasodilation in 18 hypercholesterolemic patients (ten men and eight women, aged 20-46 years) in comparison with 12 normal volunteers (seven men and five women, aged 20-45 years). The responses of the forearm blood flow (FBF) to acetylcholine (ACh) (7.5, 15 and 30 microg/min), sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) and L-NMMA (2, 4, 8 micromol/min) were evaluated at baseline and after 1 month of atorvastatin (10 mg/day) treatment. Drugs were infused into the brachial artery and FBF was measured by strain-gauge plethysmography. At baseline, the response to ACh was significantly attenuated in hypercholesterolemics versus controls: at the highest dose (30 microg/min), FBF was 27.0+/-3.4 versus 11.5+/-1.9 ml.100 ml tissue(-1).min(-1) respectively (P<0.0001). No significant differences were found between groups during SNP infusion. The atorvastatin treatment significantly improved ACh-stimulated FBF: at highest dose the FBF increased to 14.9+/-1.5 ml.100 ml tissue(-1). min(-1) (P<0.0001). Similarly, the L-NMMA endothelial effects were significantly enhanced by lipid-lowering treatment, supporting the improvement of basal nitric oxide. Vitamin C increased ACh-vasodilation in the same way before and after atorvastatin treatment. In conclusion, the endothelial dysfunction in hypercholesterolemics is due to an oxidative stress and atorvastatin rapidly improves both basal and stimulated endothelium-dependent vasodilation.

Relationship between left ventricular mass and endothelium-dependent vasodilation in never-treated hypertensive patients.

BACKGROUND: Hypertensive patients are characterized by development of both left ventricular hypertrophy (LVH) and endothelial dysfunction METHODS AND RESULTS: We enrolled 65 never-treated hypertensive patients (36 men and 29 women aged 45.6+/-6.0 years) to assess the possible relationship between echocardiographic left ventricular mass (LVM) and endothelium-dependent vasodilation. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography and the Penn Convention. LVM was calculated with the Devereux formula and indexed by body surface area and height raised to the 2.7th power. The endothelial function was tested as responses of forearm vasculature to acetylcholine (ACh), an endothelium-dependent vasodilator (7.5, 15, and 30 microg. mL-1. min-1, each for 5 minutes), and sodium nitroprusside (SNP), an endothelium-independent vasodilator (0.8, 1.6, and 3.2 microg. mL-1. min-1, each for 5 minutes). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by strain-gauge plethysmography. A negative significant relationship between indexed LVM and peak of increase in FBF was found during ACh infusions (r=-0. 554; P<0.0001). In addition, hypertrophic patients had a significantly lower responsive to ACh than patients without LVH (the peak increase in FBF was 9.9+/-3.7 versus 16.1+/-8.1 mL per 100 mL of tissue per minute; P<0.0001). No significant correlation was observed between LVM and FBF during SNP infusion. CONCLUSIONS: Our data provide the first evidence that echocardiographic LVM in hypertensive patients is inversely related to FBF responses to the endothelium-dependent vasodilating agent ACh, but it is likely that both endothelium and LVM are damaged by hypertension.

Anti-hypertensive effect of manidipine: 24 hours monitoring evaluation and Doppler-echocardiographic remarks.

In order to evaluate the antihypertensive effects of manidipine, at the dosage of 10 or 20 mg once daily, we studied 36 patients (12 males and 24 females, mean age 54.3 years) with mild hypertension. After a wash-out period of 2 weeks and another 2 week run-in period with placebo, all the patients were assigned to a treatment with manidipine 10 mg/ day. After 2 weeks of treatment, the non-normalized (diastolic BP > 90 mmHg) and the non-responders (BP fall < 10 mmHg) received an increase in dosage to 20 mg/day. The drug effects were assessed by casual blood pressure (BP) measurement at baseline and after 4, 8, 12, 24, 36 and 52 weeks. At baseline and after 1 year of treatment a 24-h BP monitoring and a Doppler echocardiogram were performed. Routine laboratory tests were performed at baseline, after 6 months and after 1 year of treatment. At the end of the observation period, both casual systolic (p < 0.01) and diastolic (p < 0.001) BP were significantly reduced; 24-h BP monitoring showed a significant decrease in systolic (p < 0.05) and diastolic (p < 0.01) pressure, systolic and diastolic (p < 0.001) daytime and night-time measurements. The peak to through ratio was 67%. No difference was found in heart rate. Reduced interventricular septum thickness (p < 0.05), increased fractional shortening (p < 0.02), reduced end-systolic stress (p < 0.005) and systemic vascular resistances (p < 0.001), and lower values of atrial filling fraction (AFF) (p < 0.001) after 1 year of treatment have been shown at the Doppler-Echo evaluation. A multilinear regression analysis showed a relation between delta %AFF and delta %24-h systolic BP (R = 0.74; F = 7.5: p < 0.05) and with delta % daytime systolic BP (R = 0.77; F = 9.2; p < 0.02). No abnormal changes were observed in laboratory tests. Three non-responder patients and three patients with adverse effects (1 flushing and 2 ankle oedema) dropped out and were excluded from the final analysis. In conclusion, manidipine at an individualized dose of 10 or 20 mg. was effective and safe in the management of arterial hypertension. Hemodynamic evaluations after 1 year of treatment confirmed an improvement of systolic and diastolic function, with an evident reduction of afterload.

Evaluation of antihypertensive effects of once-a-day isradipine and fosinopril: a double-blind crossover study by means of ambulatory blood pressure monitoring.

We compared the efficacy and tolerability of isradipine (ISR) and fosinopril (FOS) once-a-day administration in 17 outpatients, 9 men and 8 women, aged 35-65 years (mean +/- SD = 58 +/- 10 years), affected by mild to moderate primary systemic hypertension. The patients were given single-blind placebo for 2 weeks and thereafter, in double-blind, randomized, crossover sequence, ISR (5 mg) and FOS (20 mg), both for 4 weeks. At the end of each period, patients underwent 24-h noninvasive blood pressure (BP) monitoring by means of an A&D TM 2420 Monitor Model 7, with readings taken very 10 min during the day (from 7 A.M. to 11 P.M.), and every 20 min during the night (from 11 P.M. to 7 A.M.) Similarly, BP load (BPL) as percentage of systolic and diastolic BP reading > 140 and > 90 mmHg was investigated. Both ISR and FOS induced a highly significant (p < 0.0001) decrease in BP from 158/96 +/- 7/6 mmHg to 133/86 +/- 6/6 and to 132/83 +/- 10/7 mmHg, respectively. Mean BP decreased from 117 +/- 6 mmHg to 102 +/- 6 mmHg (ISR) (p < 0.0001) and to 99 +/- 8 mmHg (FOS) (p < 0.0001). Both ISR and FOS significantly (p < 0.0001) reduced systolic BPL from 78 +/- 16% to 44 +/- 13% and 28 +/- 12%, respectively, and diastolic BPL from 70 +/- 15% to 40 +/- 13% (p < 0.0001) and 35 +/- 13% (p < 0.0001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of torsade de pointes occurring in a newborn with persistent 2:1 atrioventricular block.

A case of QT interval prolongation with ventricular tachycardia and torsade de pointes is reported. Arrhythmias occurred in a baby with persistent 2:1 atrioventricular block and long QT interval 2 days after birth and were self-limiting. No structural cardiac defect was present. Serum levels of sodium, potassium, magnesium and calcium were in the normal range. Finally, the pathogenetic mechanism of cardiac block is discussed.

New data on the antiarrhythmic value of parenteral magnesium treatment: magnesium and ventricular arrhythmias.

Antiarrhythmic magnesium (Mg) therapy was evaluated in 20 normomagnesaemic patients affected by ischaemic dilated cardiomyopathy (ID) and severe ventricular arrhythmias, and in 10 patients with torsade de pointes (TdP) occurring in the setting of acquired QT interval prolongation. In the group with IDC, magnesium sulphate was given as slow infusions (50 mg/min over 60 min) twice a day for 7 d. This was antiarrhythmic in all of the patients: ventricular premature contractions and couplets decreased from 13,979 +/- 8964 (mean +/- SD) to 382 +/- 265 (P < 0.001), and from 516 +/- 274 to 9 +/- 6 (P < 0.001), respectively; runs of ventricular tachycardia (41.9 +/- 14.2) disappeared by the fifth day of treatment. The efficacy of antiarrhythmic treatment was evaluated by 24 h Holter monitoring obtained in baseline conditions and after 3, 5 and 10 d from beginning of therapy. In patients with TdP, Mg infusions were instituted at a slow rate (50 mg/min) and continued for 2 h after disappearance of Tdp, which occurred within 20 to 30 min from the start of the Mg infusions. These were followed by prophylactic infusions at rate of 30 mg/min for 90 min twice a day over the next 3 to 4 d. No side effects were observed, and heart rate and QTc remained unchanged from baseline values. In conclusion, Mg infusions may be an effective antiarrhythmic treatment for short and medium-term control of severe ventricular arrhythmias associated with IDC, and may prove useful in the acute treatment of TdP, especially in situations where conventional therapy might prove deleterious or difficult.