Adverse influence of bisoprolol on central blood pressure in the upright position: a double-blind placebo-controlled cross-over study.

Treatment with beta-blockers is characterized by inferior reduction of central versus peripheral blood pressure. We examined changes in blood pressure, cardiac function, and vascular resistance after 3 weeks of bisoprolol treatment (5 mg/day) during passive head-up tilt in 16 never-treated Caucasian males with grade I-II primary hypertension. A double-blind, randomized, placebo-controlled cross-over design was applied, and hemodynamics were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased blood pressure in the aorta (~8/10 mmHg, p ≤ 0.032) and radial artery (~10/9 mmHg, p ≤ 0.037), but upright aortic systolic blood pressure was not significantly reduced (p = 0.085). Bisoprolol reduced heart rate and left cardiac work, and increased subendocardial viability index in supine and upright positions (p ≤ 0.044 for all). Bisoprolol increased stroke volume in the supine (~11 ml, p = 0.02) but not in the upright position, while only upright (~1 l/min, p = 0.007) but not supine cardiac output was reduced. Upright elevation in systemic vascular resistance was increased 2.7-fold (p = 0.002), while upright pulse pressure amplification was decreased by ~20% (p = 0.002) after bisoprolol. Aortic augmentation index, augmentation pressure, and pulse pressure were not changed in the supine position but were increased in the upright position (from 9% to 17%, 3-6 mmHg, and 30-34 mmHg, respectively, p ≤ 0.016 for all). In conclusion, although bisoprolol treatment reduced peripheral blood pressure, central systolic blood pressure in the upright position was not decreased. Importantly, the harmful influences of bisoprolol on central pulse pressure and pressure wave reflection were manifested in the upright position.

Haemodynamic Influences of Bisoprolol in Hypertensive Middle-Aged Men: A Double-Blind, Randomized, Placebo-Controlled Cross-Over Study.

Treatment with beta-blockers appears to show inferior reduction in central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta-blockade. Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/day) in a double-blind, randomized, placebo-controlled cross-over trial in never-treated 16 Caucasian males with grade I-II primary hypertension using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p < 0.05 for all). Ejection duration (336 versus 316 ms) and stroke volume (109 versus 98 ml) were increased (p < 0.01 for all), while cardiac output was not significantly changed (6.2 versus 6.6 l/min). Bisoprolol decreased pulse wave velocity (7.8 versus 8.9 m/s, p < 0.001), but after adjustment for blood pressure, the decrease was not significant (8.16 versus 8.52 m/s, p = 0.464). The treatment reduced pulse pressure amplification from central to peripheral circulation (30 versus 38%, p = 0.002). No differences were observed in systemic vascular resistance, augmentation index, aortic characteristic impedance or total arterial stiffness after bisoprolol versus placebo. Bisoprolol decreased central and peripheral blood pressure and pulse wave velocity in male individuals with grade I to grade II hypertension. The decrease in pulse wave velocity was related to the antihypertensive effect. Reduced pulse pressure amplification indicates that peripheral blood pressure was reduced more efficiently than central blood pressure.

Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

OBJECTIVE: Diabetic men have lowered overall prostate cancer (PCa) risk, while their risk of high-grade disease may be elevated. The antidiabetic drug metformin may reduce the risk. This study evaluated PCa incidence among users of metformin and other antidiabetic drugs in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). METHODS: The study population (78,615 men) was linked to the national prescription database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PCa were estimated using Cox regression, with medication use as a time-dependent variable. The effect of diabetes was estimated by comparing antidiabetic drug users to non-users, while drug-specific effects were evaluated within antidiabetic drug users. Analyses were performed in both study arms of FinRSPC. RESULTS: Compared to non-users, men using antidiabetic drugs had lowered overall PCa risk (HR 0.85, 95% CI 0.79-0.92), and this association was not affected by PCa screening. However, the risk of metastatic PCa was increased (HR 1.44, 95% CI 1.09-1.91). Among antidiabetic drug users, metformin decreased overall PCa risk (HR 0.81, 95% CI 0.69-0.95) in a dose-dependent manner. When stratified by FinRSPC study arm, the risk reduction was observed only in the screening arm. Sulphonylureas increased the risk of metastatic PCa (HR 2.04, 95% CI 1.11-3.77). Use of thiazoledenediones or insulin was not associated with PCa risk. CONCLUSION: Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa.

Central wave reflection is associated with peripheral arterial resistance in addition to arterial stiffness in subjects without antihypertensive medication.

BACKGROUND: Augmentation index, a marker of central wave reflection, is influenced by age, sex, height, blood pressure, heart rate, and arterial stiffness. However, the detailed haemodynamic determinants of augmentation index, and their relations, remain uncertain. We examined the association of augmentation index with vascular resistance and other haemodynamic and non-haemodynamic factors. METHODS: Background information, laboratory values, and haemodynamics of 488 subjects (239 men, 249 women) without antihypertensive medication were obtained. Indices of central wave reflection, systemic vascular resistance, cardiac function, and pulse wave velocity were measured using continuous radial pulse wave analysis and whole-body impedance cardiography. RESULTS: In a regression model including only haemodynamic variables, augmentation index in males and female subjects, respectively, was associated with systemic vascular resistance (ß = 0.425, ß = 0.336), pulse wave velocity (ß = 0.409, ß = 0.400) (P < 0.001 for all), stroke volume (ß = 0.256, ß = 0.278) (P = 0.001 for both) and heart rate (ß = -0.150, ß = -0.156) (P = 0.049 and P = 0.036). When age, height, weight, smoking habits, and laboratory values were included in the regression model, the most significant explanatory variables for augmentation index in males and females, respectively, were age (ß = 0.577, ß = 0.557) and systemic vascular resistance (ß = 0.437, ß = 0.295) (P < 0.001 for all). In the final regression model, pulse wave velocity was not a significant explanatory variable for augmentation index, probably due to the high correlation of this variable with age (Spearman's correlation ≥0.617). CONCLUSION: Augmentation index is strongly associated with systemic vascular resistance in addition to arterial stiffness. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01742702 .

Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin.

BACKGROUND: Energy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear. OBJECTIVE: We explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association. DESIGN, SETTING, AND PARTICIPANTS: The PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5×10(-3). Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses. RESULTS AND LIMITATIONS: A total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p<0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population. CONCLUSIONS: SNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death. PATIENT SUMMARY: Genetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes.

Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects.

BACKGROUND: High resting heart rate (HR) is associated with increased cardiovascular risk in general populations, possibly due to elevated blood pressure (BP) or sympathetic over-activity. We studied the association of resting HR with cardiovascular function, and examined whether the hemodynamics remained similar during passive head-up tilt. METHODS: Hemodynamics were recorded using whole-body impedance cardiography and continuous radial pulse wave analysis in 522 subjects (age 20-72 years, 261 males) without medication influencing HR or BP, or diagnosed diabetes, coronary artery, renal, peripheral arterial, or cerebrovascular disease. Correlations were calculated, and results analysed according to resting HR tertiles. RESULTS: Higher resting HR was associated with elevated systolic and diastolic BP, lower stroke volume but higher cardiac output and work, and lower systemic vascular resistance, both supine and upright (p < 0.05 for all). Subjects with higher HR also showed lower supine and upright aortic pulse pressure and augmentation index, and increased resting pulse wave velocity (p < 0.001). Upright stroke volume decreased less in subjects with highest resting HR (p < 0.05), and cardiac output decreased less in subjects with lowest resting HR (p < 0.009), but clear hemodynamic differences between the tertiles persisted both supine and upright. CONCLUSIONS: Supine and upright hemodynamic profile associated with higher resting HR is characterized by higher cardiac output and lower systemic vascular resistance. Higher resting HR was associated with reduced central wave reflection, in spite of elevated BP and arterial stiffness. The increased cardiac workload, higher BP and arterial stiffness, may explain why higher HR is associated with less favourable prognosis in populations.

Hemodynamic alterations in hypertensive patients at rest and during passive head-up tilt.

OBJECTIVE: Hypertension is characterized by increased vascular resistance and arterial stiffness, but information about upright hemodynamics is scarce. We compared hemodynamics in hypertensive versus normotensive patients at rest and during passive head-up tilt. METHODS: Volunteers (n = 387, 19-72 years) without antihypertensive medication were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Seated office blood pressure was 4/10  mmHg (systolic/diastolic) higher than average supine values during hemodynamic measurements. As there is no accepted cut-off for hypertension during tilt-table tests, supine level at least 135/85  mmHg defined hypertension (n = 155) versus normotension (n = 232). Age, BMI, and proportion of men were higher among hypertensives (49 vs. 42 years, 28 vs. 25, 55 vs. 38%, respectively), and analyses were adjusted for these differences. RESULTS: Both at rest and during head-up tilt radial and aortic blood pressure and pulse pressure, cardiac index (CI) and work, systemic vascular resistance (SVR), and augmentation pressure were higher in hypertensive patients (P < 0.05 for all). Adjusted linear regression analyses showed that during passive head-up tilt aortic SBP and pulse pressure, stroke index, and left cardiac work index decreased less; heart rate increased less; and aortic DBP and SVR increased more in hypertensive patients (P < 0.05 for all); whereas reduction in CI and augmentation index did not differ between the groups. CONCLUSION: Not only supine hemodynamics, but also responses to head-up tilt differed between normotensive and hypertensive patients, indicating functional alterations beyond increased vascular resistance and higher arterial stiffness in hypertension.