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      Diastolic Dysfunction Is Associated with Insulin Resistance, but Not with Aldosterone Level in Normotensive Offspring of Hypertensive Families

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          Background and Aims: We investigated left ventricular (LV) morphology and function in association with insulin level/insulin resistance (IR) and aldosterone level in normotensive offspring of subjects with essential hypertension (familial trait, FT). Methods: The study encompassed 76 volunteers of whom 44 were normotensive with FT (aged 28–39 years) and 32 age-matched controls without FT. LV mass and function were measured using conventional echocardiography and tissue Doppler imaging. LV diastolic function was reported as peak septal annular velocities (E<sub>m</sub> and E<sub>m</sub>/A<sub>m</sub> ratio) in tissue Doppler imaging. Fasting insulin and aldosterone were determined. Results: In subjects with FT, the LV mass was higher than in controls (92.14 ± 24.02 vs. 70.08 ± 20.58 g; p < 0.001). The study group had a worse LV diastolic function than control subjects (lower E<sub>m</sub> and E<sub>m</sub>/A<sub>m</sub> ratio; p < 0.001). In subjects with FT, the E<sub>m</sub>/A<sub>m</sub> ratio was independently associated with IR (partial p = 0.029 in multivariate model, R<sup>2</sup> = 0.51), but not with LV mass. The aldosterone level was comparable in both groups. Conclusions: In normotensive individuals with FT, LV morphological and functional abnormalities were found. LV dysfunction but not an increase in LV mass is associated with IR. The aldosterone level is probably not responsible for the development of early hypertensive heart disease.

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          Most cited references 30

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          Serum aldosterone and the incidence of hypertension in nonhypertensive persons.

          Primary hyperaldosteronism is a well-recognized cause of secondary hypertension. It is unknown whether serum aldosterone levels within the physiologic range influence the risk of hypertension. We investigated the relation of baseline serum aldosterone levels to increases in blood pressure and the incidence of hypertension after four years in 1688 nonhypertensive participants in the Framingham Offspring Study (mean age, 55 years), 58 percent of whom were women. We defined an increase in blood pressure as an increment of at least one blood-pressure category (as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and defined hypertension as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or the use of antihypertensive medications. At follow-up, the blood-pressure category had increased in 33.6 percent of the participants, and hypertension had developed in 14.8 percent. In multivariable models, a 16 percent increase in the risk of an elevation in blood pressure (P=0.002) and a 17 percent increase in the risk of hypertension (P=0.03) were observed per quartile increment in the serum aldosterone level. The highest serum aldosterone quartile, relative to the lowest, was associated with a 1.60-fold risk of an elevation in blood pressure (95 percent confidence interval, 1.19 to 2.14) and a 1.61-fold risk of hypertension (95 percent confidence interval, 1.05 to 2.46). The associations between the serum aldosterone level and blood-pressure outcomes were not significantly affected by adjustment for urinary sodium excretion or left ventricular thickness or internal dimensions. In our community-based sample, increased aldosterone levels within the physiologic range predisposed persons to the development of hypertension. Copyright 2004 Massachusetts Medical Society
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            Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats.

            Diabetic cardiomyopathy (DCM) is common in type 2 diabetes. In DCM, insulin resistance may alter cardiac substrate supply and utilisation leading to changes in myocardial metabolism and cardiac function. In rats, exposure to excessive alimentary fat, inducing a type 2 diabetic phenotype, may result in myocardial insulin resistance and cardiac functional changes resembling DCM. Rats received high-fat (HFD) or low-fat (LFD) diets for 7 weeks. Prior to killing, insulin or saline was injected i.p. Contractile function and insulin signalling were assessed in papillary muscles and ventricular lysates, respectively. Fasting and post-load blood glucose levels were increased in HFD- vs LFD-rats (all p < 0.02). Mean heart weight, but not body weight, was increased in HFD-rats (p < 0.01). HFD-hearts showed structural changes and triglyceride accumulation. HFD-muscles developed higher baseline and maximum forces, but showed impaired recovery from higher workloads. Insulin-associated modulation of Ca2+-induced force augmentation was abolished in HFD-muscles. HFD reduced insulin-stimulated IRS1-associated phosphatidylinositol 3'-kinase activity and phosphorylation of protein kinase B, glycogen synthase kinase-3beta, endothelial nitric oxide synthase, and forkhead transcription factors by 40-60% (all p < 0.05). Insulin-mediated phosphorylation of phospholamban, a critical regulator of myocardial contractility, was decreased in HFD-hearts (p < 0.05). HFD induced a hypertrophy-like cardiac phenotype, characterised by a higher basal contractile force, an impaired recovery from increased workloads and decreased insulin-mediated protection against Ca2+ overload. Cardiac dysfunction was associated with myocardial insulin resistance and phospholamban hypophosphorylation. Our data suggest that myocardial insulin resistance, resulting from exposure to excessive alimentary fat, may contribute to the pathogenesis of diabetes-related heart disease.
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              Insulin resistance is a characteristic feature of primary hypertension independent of obesity.

               T Pollare,  C Berne,  H Lithell (1990)
              The relationship between abnormalities in carbohydrate metabolism and hypertension was studied in 143 newly detected hypertensive patients (59% obese) of both sexes (90 males, 53 females) and compared with 51 normotensive controls. Insulin-mediated glucose disposal assessed with the euglycemic insulin clamp technique was significantly decreased in both non-obese (7.2 +/- 2.1 mg/kg/min; P less than .05) and obese hypertensives (5.1 +/- 2.1 mg/kg/min; P less than .01) compared with the controls (8.4 +/- 1.8 mg/kg/min). The decrease in insulin sensitivity and increase in basal insulin as well as a decreased rate of glucose disposal after an intravenous glucose tolerance test (IVGTT) were verified also after statistical adjustment for sex, age, body mass index, and waist-hip ratio. The insulin index (ratio between peak and basal insulin) during IVGTT was significantly decreased in the hypertensive patients (P less than .001). After the statistical adjustment for the factors mentioned the following lipid abnormalities were still significant: total cholesterol (6.25 +/- 1.12 mmol/L non-obese; 6.06 +/- 1.20 mmol/L obese; 5.41 +/- 1.02 mmol/L controls), triglycerides (1.70 +/- 0.74 mmol/L nonobese; 2.26 +/- 1.13 mmol/L obese; 1.24 +/- 0.53 mmol/L controls) and free fatty acids (0.57 +/- 0.20 mmol/L nonobese; 0.59 +/- 0.20 mmol/L obese; 0.48 +/- 0.15 mmol/L controls). This study shows that after correction for a series of probable confounding variables, hypertension emerges as part of a syndrome characterized by major abnormalities of carbohydrate, insulin, and lipid metabolism, which independently or in concert may act as important risk factors for cardiovascular disease.

                Author and article information

                S. Karger AG
                July 2008
                01 February 2008
                : 111
                : 1
                : 8-15
                Department of Angiology, University Medical Centre, Ljubljana, Slovenia
                113420 Cardiology 2008;111:8–15
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 4, References: 61, Pages: 8
                Original Research


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