n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet.

AIMS/HYPOTHESIS: Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. METHODS: Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). RESULTS: DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. CONCLUSIONS/INTERPRETATION: DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.

The bioavailability and pharmacodynamics of different concentrations of omega-3 acid ethyl esters.

Omega-3 fatty acids have a long history of use as dietary supplements and more recently for therapeutic applications as prescription pharmaceuticals. Achieving a high concentration is critical for developing convenient, practical therapeutic formulations. The objective of the study was to explore the uptake and effects of different concentrations of omega-3 acid ethyl esters. Three different omega-3 concentrations were investigated in a clinical study with 101 subjects. All participants were dosed for 14 days with 5.1g per day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters provided in three concentrations: 62.5%, 80% and 85% of total fatty acids. Key endpoints of the study were serum phospholipids and standard fasting lipid panels at day 14. Although administered the same quantity of omega-3 fatty acids, the patients taking the more concentrated formulations had higher levels of EPA/DHA in serum phospholipids and greater reductions in serum triglyceride and VLDL cholesterol levels. Total and non-HDL cholesterol were significantly reduced from baseline with all three formulations. In conclusion the concentration of omega-3 fatty acids of the formulations studied had independent effects on the uptake and effect outcomes during short-term administration. Very high concentrations of omega-3 acid ethyl esters (80%) appear to have higher uptake and are more potent for reducing triglycerides (TGs) and VLDL-cholesterol than formulations with lower concentrations.

Left ventricular diastolic and systolic function during isometric exercise: an echocardiographic study.

Normal subjects of both sexes between 20 and 63 years were examined with M-mode echocardiography. Blood pressure (BP), heart rate (HR), and left ventricular (LV) diastolic and systolic function were measured at rest and at the end of a standardized maximal isometric handgrip test. BP and HR increased about 25%. This increase in cardiac work had no significant influence on LV systolic function. Diastolic function (myocardial relaxation and maximum rate of LV filling), however, improved significantly. Isometric handgrip test is a suitable exercise test in combination with M-mode echocardiography. Studies on LV function during exercise may improve the sensitivity for detection of mild LV dysfunction.

Effects of verapamil on left ventricular diastolic function at rest and during isometric exercise in patients with hypertrophic cardiomyopathy.

Ten patients with hypertrophic cardiomyopathy were examined with echocardiography before and during verapamil treatment to evaluate short-term and long-term effects of verapamil on left ventricular diastolic function. All patients were in sinus rhythm and in NYHA functional class I. Effects on filling and myocardial relaxation were documented by digitized echocardiography obtained at rest and during isometric exercise before treatment, after two weeks (short-term) and four months (long-term) treatment, respectively. At rest a significant decrease of the myocardial relaxation time was found during verapamil treatment. A few patients, however, returned to almost baseline conditions after an initial improvement. A small increase in the peak rate of dimension change, a parameter of filling, reached statistical significance at the end of the long-term treatment period. Isometric exercise did not induce any changes in the diastolic parameters during verapamil treatment. A positive effect of verapamil was thus seen on both myocardial relaxation and left ventricular filling, but only in resting conditions.

Noninvasive findings in patients with hypertrophic and dilative cardiomyopathy: a combined echocardiographic and radionuclide angiographic study.

Fifteen patients with hypertrophic (HCM) and 15 with dilative cardiomyopathy (DCM) were examined with radionuclide angiography and M-mode echocardiography to evaluate the combination of two noninvasive methods for measuring left ventricular performance. The patients with HCM had delayed myocardial relaxation and rapid filling time with preserved peak rate of early ventricular filling. DCM patients, on the contrary, had low values of left ventricular systolic performance and low peak filling rate. Myocardial relaxation and rapid filling time, however, were short, indicating compensatory mechanisms in the failing ventricle improving rapid filling.

The mitral valve mechanism with normal and prolapsed leaflets in the light of a dynamic model.

A dynamic model was presented to explain some of the clinical and morphologic findings in primary mitral valve prolapse. In normal cases, the leaflets, chorda tendinae, the annular ring, and the papillary muscles represent a functional entity balanced by the pressure force acting upon the leaflets. When the leaflets are larger, as in primary mitral valve prolapse, a negative interference with this balance is achieved, causing an increased traction on the papillary muscles and a concomitant dilatation of the annular ring.

Nocturnal hypoxaemia and cor pulmonale in severe chronic lung disease.

The relation between daytime and nocturnal hypoxaemia on one hand and right ventricular failure (RVF) and hypertrophy (RVH) on the other was studied in 21 patients with severely reduced ventilatory capacity. RVH was assessed by myocardial scintigraphy, vector cardiography and echocardiography. Seven patients had suffered from acute RVF at least once. They had lower vital capacity and PaO2 and higher PaCO2 than patients without a history of RVF. They also had a more severe nocturnal hypoxaemia. They did not, however, have more severe RVH than patients without a history of RVF. Blood gases during daytime were not related to RVH. Oxygen saturation during sleep had a weak inverse relationship to RVH determined with scintigraphy, but not with the other methods. Nocturnal hypoxaemia was closely related to hypoxaemia and hypercapnia during daytime. A difference between daytime PaO2 and PaCO2 less than 2 kPa could with reasonable accuracy identify patients with nocturnal hypoxaemia.

Abnormal left ventricular filling in patients with sustained myocardial relaxation: assessment of diastolic parameters using radionuclide angiography and echocardiography.

Parameters of left ventricular filling obtained from time-activity curves of radionuclide angiograms were compared with parameters of myocardial relaxation from digitized M-mode curves of the free wall endocardium in 25 consecutive patients. Eight patients had normal left ventricular systolic and diastolic function. Five patients with low ejection fraction (EF less than 50%) also had abnormal values of peak filling rate (PFR), time to peak filling rate (Tr), and/or time constant of endocardial retraction (Te). Twelve patients with normal EF had three (40%), two (40%), or one (20%) of the diastolic parameters within the pathological range. Tr correlated significantly with Te (r = 0.88, p less than 0.001), and patients with Te prolongation always had high values of Tr. One of the diastolic parameters (PFR) correlated significantly with EF (r = 0.60, p less than 0.01). Parameters of left ventricular filling and myocardial relaxation are thus abnormal in many patients with normal systolic function, indicating that diastolic parameters may be more sensitive to myocardial deterioration.

Echocardiographic assessment of left ventricular diastolic function in a normal population and a group of patients with myocardial hypertrophy.

In order to study left ventricular diastolic function, digitized M-mode echocardiograms of the free wall endocardium were analyzed. A population of 117 healthy individuals was compared with a group of 22 patients with myocardial hypertrophy due to aortic stenosis (AS), and a group of 21 with hypertrophic cardiomyopathy (HCMP). The time constant Te of endocardial retraction in normals (66 +/- 13 ms) differed significantly from Te in the patients (AS, 105 +/- 23 ms, p less than 0.001; HCMP, 113 +/- 31 ms, p less than 0.001). Peak velocity of endocardial retraction (peak neg. dEnd/dt, in the normals 8.6 +/- 2.7 s-1) did not differ between normals and patients (AS, 7.0 +/- 2.3 s-1; HCMP, 7.3 +/- 2.4 s-1). Fractional shortening (FS) of the internal diameter, a parameter of left ventricular systolic function, tended to be higher in the AS patients than in the normal group, but was on the average significantly increased in the group of HCMP. However, most patients in the hypertrophic groups had FS within normal limits +/- 2 SD. The discrepancy between normal or supernormal systolic function and a pathological prolonged time constant Te in myocardial hypertrophy demonstrates the importance of diastolic parameters in left ventricular characterization. Te is a useful parameter of left ventricular diastolic function which can be provided noninvasively from echocardiographic M-mode curves of the free wall endocardium.

The prevalence of mitral valve prolapse in healthy men and women in Sweden. An echocardiographic study.

An asymptomatic population of 100 women and 101 men was studied with M-mode echocardiogram to determine the prevalence of mitral valve prolapse (MVP). One of the two patterns characteristic for MVP was found in 8% of the females and 7% of the males. The diastolic mitral valve excursion was significantly higher in the MVP group (p less than or equal to 0.001). A typical M-mode pattern in combination with a high mitral valve excursion probably enhances the diagnostic specificity.