Eigil Fossum

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

Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease

BACKGROUND Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life. METHODS We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life. RESULTS At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups. CONCLUSIONS In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

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.

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.

Opposite effects of losartan and atenolol on natriuretic peptides in patients with hypertension and left ventricular hypertrophy: a LIFE substudy.

Background Secretion of natriuretic peptides is related to cardiac wall stress and influenced by the renin–angiotensin system. Therefore, we investigated the influence of blood pressure (BP) reduction with losartan versus atenolol on N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP). Methods In 183 patients with hypertension and electrocardiographic left ventricular (LV) hypertrophy, enrolled in the LIFE Study, we measured BP and serum Nt-proANP and Nt-proBNP by immunoassay after 2 weeks of placebo treatment and after 1, 2, 4, 6, 12, 24, 36 and 48 months of randomized treatment with losartan- or atenolol-based antihypertensive regimens. Results There was no significant difference in BP at any time point between the two treatment groups. In patients treated with losartan, median Nt-proANP decreased gradually throughout the study, reaching significance after 6 months of treatment (1125–1060 pmol/l, P < 0.001), and Nt-proBNP decreased within the first month (24.7–18.7 pmol/l, P < 0.01) and stayed reduced throughout the study. During losartan-based antihypertensive treatment, Nt-proANP and Nt-proBNP as a percentage of baseline values were correlated to reductions in systolic BP (r = 0.11, P < 0.01 and r = 0.10, P = 0.01) and diastolic BP (r = 0.17, P < 0.001 and r = 0.07, P = 0.09). In atenolol-treated patients, Nt-proANP (1100–1640 pmol/l, P < 0.001) and Nt-proBNP (20.0–37.7 pmol/l, P < 0.001) increased during the first month, and remained elevated throughout the study. During atenolol-based antihypertensive treatment, changes in Nt-proANP (r = −0.16, P < 0.001) and Nt-proBNP (r = −0.07, P = 0.08) were negatively related to change in heart rate. Conclusion Nt-proANP and Nt-proBNP were reduced in parallel with BP in losartan-treated patients whereas they increased in parallel with decreased heart rate in atenolol-treated patients.

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.

Insulin Sensitivity Is Related to Physical Fitness and Exercise Blood Pressure to Structural Vascular Properties in Young Men

Insulin resistance is related to physical inactivity, which is a risk factor for cardiovascular disease and death. Moreover, blood pressure responses during the first 6 minutes of an exercise test (600 kilo/pound/meter [kpm] per min) are more predictive for cardiovascular morbidity and mortality than blood pressure at rest, which could reflect that exercise blood pressure correlates more closely to peripheral structural vascular changes than casual blood pressure. We have recently shown a correlation between insulin resistance and minimal forearm vascular resistance (MFVR) in young men recruited from the highest blood pressure percentiles during a military draft session. In the present study, we tested the hypotheses that insulin sensitivity relates to physical fitness and that blood pressure responses during an exercise test relate to peripheral structural vascular changes in these men; we also tested whether these findings were interrelated. We assessed insulin sensitivity and physical fitness in 27 young men randomly selected from the cohort having a blood pressure of 140/90 mm Hg or higher during the compulsory military draft session in Oslo. Insulin sensitivity correlated with physical fitness (r=0.58, P=0.002). Systolic blood pressure after 6 minutes of exercise (600 kpm/min) correlated with MFVR (r=0.46, P=0.015). MFVR and physical fitness independently explained 60% of the variation in insulin sensitivity, and MFVR independently explained 19% of the variation of systolic blood pressure after 6 minutes of exercise. In conclusion, insulin sensitivity is related to physical fitness and exercise blood pressure to structural vascular properties in these young men.

Relations between insulin sensitivity, fitness and autonomic cardiac regulation in healthy, young men.

Objectives We hypothesized that insulin sensitivity and vagal cardiac control are independently related in young men after adjustment for fitness and other confounding variables. Design Male volunteers aged 21–24 years with high (borderline hypertensive; n = 20) and low–normal (normotensive; n = 21) screening blood pressure (BP) were studied cross-sectionally. Methods Mean R–R interval (RR) and heart rate variability (HRV) were computed from 30-min ECGs, and baroreflex sensitivity (BRS) and latency (phase shift) from 15-min beat-to-beat finger blood pressure (BP) and heart rate recordings. Insulin-adjusted glucose disposal rate (GDR/I) was measured with a 90-min hyperinsulinaemic glucose clamp and fitness by peak oxygen uptake (VO2peak) during a treadmill test. Results HRV, baroreflex function, GDR/I, and VO2peak did not differ between the groups. GDR/I correlated positively with time and frequency domain HRV, including high-frequency power (HF) (r = 0.40, P = 0.01) and root-mean squared successive differences (RMSSD) (r = 0.43, P = 0.005), but not BRS or phase shift. GDR/I correlated with VO2peak (r = 0.70, P < 0.0001) and was explained (R2 = 0.56) by VO2peak (β = 0.57, P < 0.0001) and RR (β = 0.29, P = 0.03), independently of HRV and measures of obesity. Conversely, RR (β = 0.55, P = 0.0004) and HRV, including HF (β = 0.44, P = 0.006) and RMSSD (β = 0.46, P = 0.004) were explained by GDR/I, independently of VO2peak. Conclusions Insulin sensitivity and autonomic cardiac control are related independently of physical fitness in young men.