Per-Erik Andersson

Left ventricular hypertrophy in hypertension is associated with the insulin resistance metabolic syndrome

Objective To investigate whether left ventricular hypertrophy is associated with the insulin resistance syndrome. Methods Fifty patients with untreated hypertension were evaluated by recording office blood pressure during regular antihypertensive treatment and 24-h ambulatory blood pressure and office blood pressure after 4–6 weeks on placebo, echocardiog-raphy with M-mode measurements of left ventricular wall thickness and pulsed-wave Doppler measurements of mitral flow in diastole and the hyperinsulinaemic euglycaemic clamp, for determination of insulin sensitivity. Results The left ventricular wall thickness was found to be significantly related to blood pressure [r = 0.44, P < 0.004 for 24-h ambulatory systolic blood pressure (SBP)], fasting insulin level (r = 0.32, P<0.03) and haematocrit level (r = 0.37, P<0.009) and inversely related to insulin sensitivity (r = −0.59, P<0.0001). Multiple regression analysis with these relationships together with confounding factors age, sex, body mass index and waist: hip ratio as independent variables showed insulin sensitivity to be the only significant variable, explaining 43% of the variation in left ventricular wall thickness, whereas 24-h ambulatory SBP explained a further 7%. Left ventricular diastolic filling, as evaluated by the mitral Doppler early: atrial ratio, was significantly correlated with insulin sensitivity (r = 0.42, P<0.003) and inversely related to blood pressure (r = −0.41, P < 0.02 for 24-h ambulatory SBP), left ventricular wall thickness (r = −0.34, P<0.02) and serum fibrinogen level (r = −0.63, P<0.0001). However, multiple regression analysis showed that insulin sensitivity was more closely related to diastolic filling than to blood pressure or left ventricular wall thickness. Conclusion The present study showed left ventricular wall thickness to be closely associated with insulin resistance. Because diastolic dysfunction of the left ventricle was also related to a decreased insulin sensitivity, these findings suggest that left ventricular hypertrophy and diastolic dysfunction are associated with the insulin resistance metabolic syndrome.

Induction of insulin resistance by beta-blockade but not ACE-inhibition: long-term treatment with atenolol or trandolapril

The effects on glucose metabolism by the beta-blocker atenolol and the angiotensin-converting enzyme (ACE)-inhibitor trandolapril were investigated in a randomised double-blind parallel group study of patients with primary hypertension. Twenty-six patients were treated with 50–100 mg atenolol and 27 patients with 2–4 mg trandolapril o.d. Intravenous glucose tolerance tests, euglycaemic hyperinsulinaemic clamps and serum lipid measurements were performed after 8 and 48 weeks of active treatment. After 48 weeks insulin sensitivity was reduced by 23% by atenolol while it remained unchanged during trandolapril treatment (+0.5%, P = 0.0010 for difference between treatments, ANCOVA). The effect on triglycerides (+22% vs −8.5%) and high-density lipoprotein cholesterol (−13% vs +0.7%) also differed significantly between atenolol and trandolapril. Results after 8 weeks were similar. Glucose tolerance was not affected by either drug. Atenolol reduced diastolic blood pressure (DBP) better than trandolapril (−15.3 mm Hg vs −6.6 mm Hg for supine DBP after 48 weeks, P = 0.012). The difference in effect on insulin sensitivity between the drugs corresponded to 25% of the baseline values of insulin sensitivity, and persisted over 48 weeks of treatment. The choice of antihypertensive treatment could influence the risk of diabetes associated with treated hypertension.

Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men. Relationship to changes in skeletal muscle blood flow

In a previous open study on the metabolic effects of doxazosin in patients with essential hypertension, subgroup analysis indicated that subjects with an accumulation of risk factors for coronary heart disease (high VLDL triglycerides, low HDL cholesterol and high fasting blood glucose) seemed to benefit most from the metabolic actions of doxazosin treatment. Those results formed the basis of this double-blind, parallel-group study undertaken to elucidate the metabolic effects of 6 months of doxazosin and enalapril treatment in patients with both essential hypertension and hypertriglyceridemia. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method. Hemodynamic evaluation included measurements of office and ambulatory blood pressure and ultrasonic measurements of femoral artery blood flow. Both drugs significantly reduced both office BP and 24-h ambulatory BP. Office systolic BP was significantly better reduced by enalapril. Doxazosin, in contrast to enalapril, significantly increased insulin sensitivity (by 21%, P = .02). It also reduced serum-triglycerides (by 23%, P = .01), VLDL triglycerides (by 30%, P = .008) and VLDL cholesterol (by 24%, P = .02). This lipid-lowering effect of doxazosin was accompanied by an increase in both plasma lipoprotein lipase activity and the elimination rate of an intravenous fat emulsion load. Neither treatment significantly increased femoral artery blood flow. It is speculated that without measurably increasing blood flow in conduit vessels such as the femoral artery, doxazosin, by capillary recruitment, may prolong the transit time for the blood over the muscle bed, which could explain the increased glucose disposal and increased lipoprotein lipase activity.

Metabolic effects of long-term angiotensin-converting enzyme inhibition with fosinopril in patients with essential hypertension: relationship to angiotensin-converting enzyme inhibition

Fifty patients with mild to moderate essential hypertension were randomized to receive either 20 mg fosinopril daily for 16 weeks or placebo for 4 weeks followed by 12 weeks of 50 mg atenolol daily. Prior to these 16 weeks there was a placebo wash-out period of 2–6 weeks. Blood pressure measurements, euglycaemic, hyperinsulinaemic glucose clamps, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and after 4 and 16 weeks. Blood lipid status was evaluated at baseline and 16 weeks.The insulin sensitivity index (M/I) increased by 12% during the prolonged placebo period, and subsequently decreased by 12% during treatment with atenolol in that group. A post-hoc analysis of covariance indicated that the increase in insulin sensitivity during the initial 4 weeks may have been due to carry over effects from previous anti-hypertensive treatment. Fosinopril increased glucose disappearance during IVGTT at 4 and 16 weeks (k values 1.46 and 1.33 vs 1.10 at baseline) but had no effect on insulin sensitivity. The change in insulin sensitivity and serum triglycerides during treatment with fosinopril was related to angiotensin-converting enzyme inhibition in serum.In conclusion, carry-over effects from previous anti-hypertensive medication were indicated in this study, probably because of an insufficient wash-out period in many patients. Therefore, 4 weeks of placebo wash-out in all patients is advisable in this kind of investigation.

SKELETAL MUSCLE ANGIOTENSIN-CONVERTING ENZYME AND ITS RELATIONSHIP TO BLOOD PRESSURE IN PRIMARY HYPERTENSION AND HEALTHY ELDERLY MEN

The aim of this study was to investigate the relationships between angiotensin-converting enzyme (ACE) activity in serum and skeletal muscle to blood pressure and the long-term antihypertensive effects of fosinopril and atenolol. We examined 50 hypertensive patients randomized to receive 20 mg fosinopril or 50 mg atenolol daily for 16 weeks. ACE activity was measured in biopsy specimens from skeletal muscle. Measurements of office and ambulatory blood pressure, serum ACE, and left ventricular wall thickness were also performed. The same investigations were performed in a cross-sectional study of 50 healthy elderly men. Muscle ACE correlated inversely to blood pressure in cross-sectional analyses in both populations (p < 0.05). During atenolol treatment muscle ACE activity tended to increase (14%, p = 0.059), and this increase correlated inversely to the changes in standing systolic and diastolic blood pressure (r = -0.62, p = 0.0044, and r = 0.54, p = 0.016, respectively). Muscle ACE was also inversely correlated to left ventricular wall thickness when the two populations were pooled (r =-0.29, p = 0.0053). In the fosinopril group, muscle ACE activity was not different during treatment than at baseline (-2. 1%, p = 0.68). The inverse relationship between blood pressure and muscle ACE levels in this study indicate that muscle tissue ACE levels are influenced by haemodynamic factors in humans.

Insulin resistance in essential hypertension is related to plasma renin activity.

A high plasma renin activity (PRA) has previously been related to several cardiovascular risk factors as well as to later cardiovascular events. As insulin resistance has been suggested as the unifying factor in the insulin resistance metabolic syndrome, insulin resistance was evaluated by the euglycaemic hyperinsulinaemic clamp technique in 50 untreated hypertensive subjects in whom PRA and serum aldosterone were measured together with lipids and an intravenous glucose tolerance test (IVGTT). PRA was inversely related to insulin-mediated glucose disposal during the clamp (r = −0.31, P < 0.05), as well as to fasting insulin (r = 0.32, P < 0.05) and to insulin at 60 min at the ivgtt (r = 0.30, P < 0.05), but not to other risk factors. serum aldosterone was not related to any of the metabolic risk factors. in conclusion, the present investigation showed that insulin resistance is associated with elevated levels of pra in patients with untreated essential hypertension. it thus seems as if a high activity in the renin system should be included in the disturbances included in the insulin resistance metabolic syndrome, a syndrome with a major impact on future cardiovascular events.

Circulating angiotensin converting enzyme levels are increased in concentric, but not eccentric, left ventricular hypertrophy in elderly men

Objective To study the cross-sectional relationship between circulating angiotensin converting enzyme (ACE) activity and echocardiographically determined left ventricular geometry in a study of 380 70-year-old men participating in a health-survey reexamination and 50 patients with hypertension. Methods Two-dimensional guided M-mode and Doppler echocardiography. Fluorometric assay of serum ACE activity. Results The serum ACE activity was higher in the elderly men with left ventricular concentric hypertrophy than it was in men with normal geometry and left ventricular eccentric hypertrophy (32, 27, and 26 U/l, respectively, P < 0.01 for both comparisons before and after adjustment for the 24 h mean arterial pressure, body mass index, and use of antihypertensive medication). The serum ACE activity correlated with the thickness of the left ventricular interventricular septum (r = 0.12, P = 0.0095), the left ventricular relative wall thickness (r = 0.13, P = 0.0053), and the total peripheral resistance (r = 0.16, P = 0.0034), but not with the left ventricular mass (r = −0.039, P = 0.45) of these elderly men. The serum ACE activity in the hypertensive patients also correlated with the left ventricular interventricular septum thickness (r = 0.34, P = 0.020) independently of the 24 h mean arterial blood pressure, age, sex, body mass index, and insulin sensitivity. Conclusion Levels of serum ACE activity are associated with left ventricular geometry.

Regression of left ventricular wall thickness during ACE-inhibitor treatment of essential hypertension is associated with an increase in insulin mediated skeletal muscle blood flow

UNLABELLED Left ventricular hypertrophy (LVH) has been associated with insulin resistance, a condition with an impaired insulin-mediated vasodilation in skeletal muscle. ACE-inhibitors have been reported to be superior to most other antihypertensive drugs in inducing a regression of LVH. In a double-blind study with parallel groups, 50 patients with essential hypertension were randomized to treatment with either fosinopril (20 mg o.d.) or atenolol (50 mg o.d.) for 12-16 weeks. Left ventricle wall thickness (LVWT, defined as the sum of interventricular septum and posterior wall), diastolic function (represented by the ratio between the E-wave and the A-wave of mitral blood flow) and femoral artery blood flow (FBF) were evaluated using ultrasonic measurements. FBF was measured at normoinsulinemia and after 2 h of euglycemic hyperinsulinemia. Before treatment, the insulin-induced increase in FBF was inversely related to the LVWT (r = -0.52, p < 0.02). The reduction in ambulatory 24-h SBP/DBP was 13/9 mmHg for fosinopril and 15/14 for atenolol, ambulatory DBP being significantly more reduced by atenolol (p = 0.03 for difference in treatment effect). However, only fosinopril treatment resulted in a significant reduction in LVWT (from 20.5 mm to 19.4 mm, p < 0.05). The degree of reduction in LVWT was related to the increase in FBF in the fosinopril group (r = -0.45, p < 0.05). For fosinopril (but not for atenolol), there was a positive relationship between the change in E/A ratio and the change in femoral artery stroke volume (r = 0.80, p < 0.01). CONCLUSION Impaired insulin-induced stimulation of leg blood flow was related to an increased LVWT. Furthermore, during fosinopril treatment, regression of LVWT was associated with enhanced skeletal muscle blood flow during hyperinsulinemia. This indicates that impaired peripheral blood flow (and thereby increased afterload) may be a possible mechanism explaining the previously found association between insulin resistance and cardiovascular hypertrophy.

Metabolic effects of carvedilol in hypertensive patients

AbstractObjective: Fifty-six patients with essential hypertension were recruited to study the metabolic effects of carvedilol, a non-selective β-adrenoceptor-blocker with α1-adrenoceptor blocking properties. Methods: The study started with a single-blind, 4–6-week placebo-treatment period followed by an open 6-month active treatment period. There was an option to increase the dose from 25 mg carvedilol to 50 mg daily after 6 weeks. Metabolic investigations were carried out at the end of the placebo period and at the end of the active treatment period. Results: The results show that during carvedilol treatment blood pressure was efficiently lowered. The increase in very low density lipoprotein triglyceride concentration was 13%. Despite this modest increase high density lipoprotein cholesterol was reduced by 11%. The metabolic clearance rate of glucose at the hyperinsulinemic clamp test (adjusted for the prevailing insulin and glucose concentrations) decreased by 17%. At the i.v. glucose tolerance test the insulin area under the curve was increased by 18% and the glucose area by 10%. Conclusion: The α1-adrenoceptor-blocking characteristics of carvedilol probably explain the moderate changes of lipoprotein concentrations and insulin sensitivity gained compared with what is usually obtained with a non-selective β-adrenoceptor-blocker.

The effect of euglucaemic hyperinsulinaemia on forearm blood flow and glucose uptake in the human forearm

Abstract Insulin-mediated stimulation of blood flow to skeletal muscle has been proposed to be of major importance for insulin-mediated glucose uptake. The aim of this study was to investigate the relative importance of blood flow and glucose extraction as determinants of insulin-mediated glucose uptake in the human forearm. Forearm blood flow (FBF), glucose extraction and oxygen consumption were evaluated for 100 min during the euglycaemic hyperinsulinaemic clamp (92 mU/l) in nine healthy subjects. FBF was measured by venous occlusion plethysmography. Forearm glucose uptake increased sevenfold during the hyperinsulinaemia (P<0.001). Forearm glucose extraction showed a minor increase during the first 10 min of hyperinsulinaemia, but the most marked increase took place between 10 and 20 min (+170%). Thereafter, only a minor further increase was seen. During the first 10 min of hyperinsulinaemia FBF was unchanged. Thereafter, FBF increased steadily to a plateau reached after 60 min (+50%, P<0.001). A close relationship between whole body glucose uptake and FBF was seen at the end of the clamp (r = 0.75, P<0.02), but at this time the relationship between whole body glucose uptake and forearm glucose extraction was not significant. The modest increase in O2 consumption seen at the beginning of the clamp (+19%) was not related to FBF during the early phase of the clamp. In conclusion, the early course of insulin-mediated glucose uptake in the human forearm was mainly due to an increase in glucose extraction. However, with time the insulin-mediated increase in blood flow increased in importance and after 100 min of hyperinsulinaemia FBF was the major determinant of glucose uptake.