Aud Høieggen

Adjusted Drug Treatment Is Superior to Renal Sympathetic Denervation in Patients With True Treatment-Resistant Hypertension

&NA; We aimed to investigate for the first time the blood pressure (BP)–lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (P<0.0005 and P=0.02, SBP and diastolic BP, respectively) and in the RDN group from 156±13/91±15 to 148±7/89±8 mm Hg (P=0.42 and P=0.48, SBP and diastolic BP, respectively). SBP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516

Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension After Witnessed Intake of Medication Before Qualifying Ambulatory Blood Pressure

&NA;It is unknown whether the decline in blood pressure (BP) after renal denervation (RDN) is caused by denervation itself or concomitantly improved drug adherence. We aimed to investigate the BP lowering effect of RDN in true treatment-resistant hypertension by excluding patients with poor drug adherence. Patients with resistant hypertension (n=18) were referred for a thorough clinical and laboratory work-up. Treatment-resistant hypertension was defined as office systolic BP>140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs, including a diuretic. In addition, ambulatory daytime systolic BP>135 mm Hg was required after witnessed intake of antihypertensive drugs to qualify. RDN (n=6) was performed with Symplicity Catheter System. The mean office and ambulatory BPs remained unchanged at 1, 3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings question whether BP falls in response to RDN in patients with true treatment-resistant hypertension. Additional research must aim to verify potential BP lowering effect and identify a priori responders to RDN before this invasive method can routinely be applied to patients with drug-resistant hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

Objective To investigate the metabolic effects of losartan (Cozaar®) in patients with essential hypertension. Methods Twenty patients with mild hypertension (office blood pressure>140/95 mmHg and home diastolic blood pressure>90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). Results Supine blood pressure was reduced from 146 + 3/90 ± 3 mmHg on placebo to 134 ±4/83 ± 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 ± 0.5 mg/kg per min on placebo and 6.4 ± 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 ± 0.3 versus 0.88 ± 0.4 and 341 ± 60 versus 356 ± 60, respectively; arbitary units). Serum cholesterol was 5.3 ± 0.2 mmol/l on placebo and 5.1 ± 0.2 mmol/l with losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 ± 0.1 and 1.5 ± 0.2 mmol/l with placebo, and 1.1 ± 0.1 and 1.4 ± 0.1 mmol/l with losartan treatment. Conclusion In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.

Whole-blood viscosity and the insulin-resistance syndrome

Background In a previous study we found that elevated blood viscosity was linked to the insulin resistance syndrome, and we proposed that high blood viscosity may increase insulin resistance. That study was based on calculated viscosity. Objective To determine whether directly measured whole-blood viscosity was related to the insulin-resistance syndrome in the same way as calculated viscosity had been found to be. Methods Healthy young men were examined with the hyperinsulinemic isoglycemic glucose clamp technique, and we related insulin sensitivity (glucose disposal rate) to other metabolic parameters and to blood viscosity. We established a technique for direct measurement of whole-blood viscosity. Results There were statistically significant negative correlations between glucose disposal rate and whole-blood viscosity at low and high shear rates (r = −0.41, P = 0.007 for both, n = 42). Whole-blood viscosity was correlated positively (n = 15) to serum triglyceride (r = 0.54, P = 0.04) and total cholesterol (r = 0.52, P = 0.05), and negatively with high-density lipoprotein cholesterol (r = −0.53, P = 0.04) concentrations. Insulin sensitivity index was correlated positively to high-density lipoprotein cholesterol (r = 0.54, P = 0.04) and negatively to serum triglyceride (r = −0.69, P = 0.005) and to total cholesterol (r = −0.81, P = 0.0003) concentrations. Conclusions The present results demonstrate for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as a part of the insulin-resistance syndrome. Whole-blood viscosity contributes to the total peripheral resistance, and these results support the hypothesis that insulin resistance has a hemodynamic basis.

Relationship Between Insulin Sensitivity and Maximal Forearm Blood Flow in Young Men

Insulin resistance is a part of the metabolic cardiovascular syndrome. We aimed to test the hemodynamic hypothesis of insulin resistance, which suggests that a decreased skeletal muscle blood supply with subsequent reduced nutritional flow causes insulin resistance in skeletal muscle. We assessed determinants of peripheral blood flow such as maximal forearm blood flow (MFBF), minimal forearm vascular resistance (MFVR), and whole blood viscosity (WBV) in 27 young men with borderline elevation of blood pressure. Insulin sensitivity measured as glucose disposal rate (GDR) correlated with MFBF (r=0.55, P=0.003), MFVR (r=-0.58, P=0. 002), and WBV (r=-0.39, P=0.046 at shear rate 201 s-1). There was no correlation between GDR and myocardial thickness or left ventricular mass. In a stepwise multiple regression analysis, MFVR and WBV explained 54% of the variation in GDR. The relative increase in mean arterial blood pressure during a mental stress test, as a marker of reactivity or an alert reaction, was correlated with MFVR (r=0.56, P=0.002) and inversely with GDR (r=-0.45, P=0.018) and MFBF (r=-0.49, P=0.01) but not with cardiac dimensions. In a stepwise multiple regression analysis, 48% of the increase in blood pressure during a mental stress test was explained by MFVR and WBV. Fasting insulin correlated with MFVR (r=0.41, P=0.036) and GDR (r=-0.62, P=0.001). These data show a positive association between the appearance of peripheral structural vascular changes as quantified through a hemodynamic technique and insulin resistance in young men with borderline elevation of blood pressure. The cause-effect relationship of this finding needs further evaluations.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.

Objective Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. Methods In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. Results Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg × min × 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l2/kg × mmol × min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg × min × 100 and 12.6 versus 11.1 l2/kg × mmol × min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus −14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = −0.16, P < 0.05) independently of the relative change in body mass index (r = −0.29, P < 0.001). Conclusions As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.

Whole Blood Viscosity, Blood Pressure and Cardiovascular Risk Factors in Healthy Blood Donors

Whole blood viscosity contributes to the total peripheral resistance and has been suggested to be a risk factor for cardiovascular disease. Whole blood viscosity was measured using a direct technique in 105 healthy blood donors and in addition to establishing our reference values, the relationship to blood pressure and other cardiovascular risk factors was assessed. Whole blood viscosity correlated with systolic blood pressure (r = 0.29, p = 0.003), cholesterol (r = 0.21, p = 0.034), cholesterol/HDL cholesterol ratio (r = 0.33, p = 0.01), triglycerides (r = 0.37, p < 0.0005), body mass index (r = 0.29, p = 0.003) and waist-hip ratio (r = 0.30, p = 0.002). Subjects with systolic blood pressure > 130 mmHg (n = 16) had higher whole blood viscosity (p = 0.017) than those with lower blood pressure. Whole blood viscosity was significantly lower in women (n = 52) than in men at all shear rates (0.045 > p > 0.001). These results suggest that even in a population of healthy normotensive blood donors of a wide age range and either gender, there are positive correlations between directly assessed whole blood viscosity and a number of the components of the metabolic cardiovascular syndrome including systolic blood pressure, weight and blood lipids.

Evaluation of Adherence Should Become an Integral Part of Assessment of Patients With Apparently Treatment-Resistant Hypertension.

Since the publication of the first Symplicity studies in 2009 to 2010, renal sympathetic denervation gained acceptance as a novel treatment of drug-resistant hypertension. The latter has been defined as a blood pressure (BP) >140/90 mm Hg, despite appropriate lifestyle measures plus a diuretic and 2 other antihypertensive drugs belonging to different classes at adequate doses.1 According to the US definition, patients with controlled BP on ≥4 antihypertensive drugs are also considered as resistant hypertensives.2 However, a substantial proportion of patients with apparently resistant hypertension are in fact poorly adherents to drug treatment. The highly variable BP response to renal denervation (RDN)3–5 prompted to a more rigorous evaluation of eligible patients, with the goal to exclude false resistant hypertension, because of poor adherence to drug treatment.6–8 In particular, several publications documented a high proportion of low drug adherence in patients with apparently resistant hypertension (23%–66%), using witnessed drug intake9 or plasma/urine drug determinations10–18 (Figure 1). Figure 1. Proportion of poor or nonadherence according to drug monitoring in different cohorts of patients with apparently resistant hypertension. Black indicates total nonadherence, whereas gray indicates partial adherence. Partial adherence was defined as the presence of at least one undetectable drug10–12,14,16–18 or as the presence of fewer medications than prescribed.13,15 Furthermore, RDN studies shed the light on the dynamic character of drug adherence. Inclusion in RDN trials may influence drug adherence in various, unpredictable directions.6 In some patients, close follow-up and massive attention devoted to them may lead to improved adherence to lifestyle measures and drug treatment, particularly in the RDN arm (Hawthorne effect). Other patients may stop their medications after RDN according to their perception that the intervention cured their …

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study

Background Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. Methods In 88 unmedicated patients with stage II–III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima–media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. Results IMT was positively correlated to systolic blood pressure (r = 0.26, P < 0.05), whole body glucose uptake index (M/IG; r = 0.22, P < 0.05), age (r = 0.24, P < 0.05) and negatively correlated to body mass index (r = −0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r = −0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = −0.40, P < 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). Conclusions High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Mental stress increases glucose uptake during hyperinsulinemia: Associations with sympathetic and cardiovascular responsiveness

Infusion of epinephrine and norepinephrine reduces insulin-mediated glucose disposal, ie, induces insulin resistance. Mental stress increases concentrations of both plasma catecholamines. However, the effect of acute mental stress on insulin-mediated glucose uptake has not been examined. We observed in pilot studies that a mental stress test (MST) during a euglycemic glucose clamp decreased blood glucose concentration. In a prospective study, euglycemic hyperinsulinemia was established during 120 minutes of glucose clamping; the subjects (N = 74) then underwent 5 minutes of intense mental arithmetics with infusion rates of glucose and insulin kept constant. During MST, plasma epinephrine and norepinephrine increased (by 0.23 +/- 0.02 and 0.50 +/- 0.05 nmol/L) together with blood pressure ([BP] by 18 +/- 8/9 +/- 1 mm Hg) and heart rate ([HR] by 21 +/- 1 beats per minute), with P less than .0001 for all changes. During mental stress, blood glucose concentration decreased by 0.4 +/- 0.1 mmol/L (P < .0001), followed by full recovery after another 10 minutes. Serum insulin was unchanged, indicating an acute but transient increase in glucose uptake. This finding was unrelated to age, sex, body mass, and BP status. Fifty-nine subjects with a decrease in glucose concentrations during MST were characterized by accentuated epinephrine response to MST (a change of 0.25 +/- 0.03 v 0.12 +/- 0.02 nmol/L, P = .001), increase in systolic BP (by 20 +/- 2 v 10 +/- 3 mm Hg, P = .008), and increase in HR (by 23 +/- 2 v 15 +/- 2 beats per minute, P = .008) as compared with 15 subjects with unchanged/increased glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)