Significant Correlates of Nocturnal Hypertension in Patients With Hypertension Who Are Treated With Antihypertensive Drugs.

BACKGROUND: Nocturnal hypertension assessed by a home blood pressure monitoring (HBPM) device is associated with an increased risk of cardiovascular events. However, it is still difficult to assess nighttime blood pressure (BP) frequently. The purpose of this cross-sectional study was to identify significant correlates of nocturnal hypertension assessed by an HBPM device in patients with hypertension who are treated with antihypertensive drugs. METHODS: We measured nighttime BP, morning BP, and evening BP by an HBPM device for 7 consecutive days in 365 medicated patients with hypertension. RESULTS: Of the 365 subjects, 138 (37.8%) had nocturnal hypertension defined as a mean nighttime systolic BP of ≥ 120 mm Hg. Receiver operating characteristic curve analyses showed that the diagnostic accuracy of morning systolic BP for subjects with nocturnal hypertension was significantly superior to that of evening systolic BP (P = 0.04) and that of office systolic BP (P < 0.001). Multivariate analysis revealed that morning systolic BP of 125-<135 mm Hg (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.13-4.58; P = 0.02), morning systolic BP of ≥ 135 mm Hg (OR, 16.4; 95% CI, 8.20-32.7; P < 0.001), and a history of cerebrovascular disease (OR, 3.99; 95% CI, 1.75-9.13; P = 0.001) were significantly associated with a higher risk of nocturnal hypertension and that bedtime dosing of antihypertensive drugs was significantly associated with a lower risk of nocturnal hypertension (OR, 0.56; 95% CI, 0.32-0.97; P = 0.04). CONCLUSIONS: Morning systolic BP of ≥ 125 mm Hg, a history of cerebrovascular disease, and bedtime dosing were significant correlates of nocturnal hypertension in medicated patients with hypertension, and may help detect this risky BP condition. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN000019173).

Effects of the Dipeptidyl Peptidase 4 Inhibitor Alogliptin on Blood Pressure in Hypertensive Patients with Type 2 Diabetes Mellitus.

BACKGROUND: The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM). METHODS: Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM. RESULTS: After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%). CONCLUSIONS: Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM. CLINICAL TRIALS REGISTRATION: Registration Number for Clinical Trial: UMIN000007722.

Relationship between home blood pressure and vascular function in patients receiving antihypertensive drug treatment.

Hypertension is associated with vascular failure, such as increased arterial stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. The purpose of this study was to investigate the relationship between out-of-office blood pressure and vascular function in patients receiving antihypertensive drugs. We assessed out-of-office blood pressure, including daytime and night-time blood pressure, by home blood pressure monitoring and performed vascular function tests, including brachial-ankle pulse wave velocity (baPWV), flow-mediated vasodilation (FMD), and nitroglycerine-induced vasodilation (NID), in 169 patients receiving antihypertensive drugs, of whom 86 (50.9%) had normotension, 23 (13.6%) had isolated nocturnal hypertension (night-time systolic blood pressure ≥120 mm Hg), 26 (15.4%) had isolated daytime hypertension (daytime systolic blood pressure ≥135 mm Hg), and 34 (20.1%) had sustained hypertension (daytime and nocturnal hypertension). baPWV was significantly higher in patients with sustained hypertension than in those without sustained hypertension (1585 ± 257 cm/s in normotension; 1687 ± 267 cm/s in isolated nocturnal hypertension; 1688 ± 313 cm/s in isolated daytime hypertension; and 1923 ± 399 cm/s in sustained hypertension; P < 0.001). baPWV above the cutoff value of 1858 cm/s, derived from receiver operating characteristic curve analysis to diagnose patients with sustained hypertension, was significantly associated with sustained hypertension after adjustment of other confounding factors (odds ratio, 5.01; 95% confidence interval, 1.94-13.41; P < 0.001). In contrast, there was no significant association of home blood pressure status with FMD or NID in these patients. In patients receiving antihypertensive drugs, baPWV was significantly associated with sustained hypertension, whereas FMD and NID were impaired regardless of the home blood pressure status.

Skull Bone Regeneration Using Chitosan⁻Siloxane Porous Hybrids-Long-Term Implantation.

Burr holes in craniotomy are not self-repairing bone defects. To regenerate new bone at the sites of these defects, a good scaffold is required. Biodegradable hybrids including silica or siloxane networks have been investigated as bone tissue scaffolds. This study examined skull bone regeneration using chitosan-siloxane hybrids after long-term implantation (two and three years). After implantation of the hybrids, the surrounding cells migrated and formed fibrous tissues and blood vessels. Then, bone formation occurred from the surrounding blood vessels. Addition of calcium ions and coating with hydroxyapatite improved bone regeneration. Finally, the regenerated tissue area became smaller than the initial hole, and some areas changed to completed bone tissues.

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Comparison between a novel and conventional artificial pancreas for perioperative glycemic control using a closed-loop system.

This clinical study aimed to compare a novel and conventional artificial pancreas (AP) used in surgical patients for perioperative glycemic control, with respect to usability, blood glucose measurements, and glycemic control characteristics. From July in 2010 to March in 2015, 177 patients underwent perioperative glycemic control using a novel AP. Among them, 166 patients were eligible for inclusion in this study. Intensive insulin therapy (IIT) targeting a blood glucose range of 80-110 mg/dL was implemented in 82 patients (49 %), and the remaining 84 patients (51 %) received a less-intensive regime of insulin therapy. Data were collected prospectively and were reviewed or analyzed retrospectively. A comparison study of 324 patients undergoing IIT for glycemic control using a novel (n = 82) or conventional AP (n = 242) was conducted retrospectively. All patients had no hypoglycemia. The comparison study revealed no significant differences in perioperative mean blood glucose level, achievement rates for target blood glucose range, and variability in blood glucose level achieved with IIT between the novel AP and conventional AP groups. The usability, performance with respect to blood glucose measurement, and glycemic control characteristics of IIT were comparable between novel and conventional AP systems. However, the novel AP was easier to manipulate than the conventional AP due to its smaller size, lower weight, and shorter time for preparation. In the near future, this novel AP system might be accepted worldwide as a safe and useful device for use in perioperative glycemic control.

A method for deciding the optimal anticoagulant infusion dose for blood purification therapy.

BACKGROUND: The incidence of iatrogenic pseudoaneurysms has recently increased due to the more frequent use of high doses of anticoagulants in apheresis therapy. The reason why the decision for an appropriate dose of the anticoagulant is difficult is that such information about the material properties of adsorbers is not provided. OBJECTIVE: To investigate the calculations to determine the optimal dose of heparin sodium to administer during apheresis. METHODS: The calculations were based on experimental data obtained during an in vivo test using dogs and theoretical pharmacokinetics data obtained using a one compartment model. RESULTS: When information regarding the adsorption isotherm of the adsorbent material that takes competitive adsorption into consideration was provided, the required anticoagulant dose for apheresis could be determined. CONCLUSIONS: It is important to decide the optimal dose of anticoagulant that Information about the material's characteristics including data about its adsorption isotherm that takes competitive adsorption into consideration are provided before therapy. Then, if so, the calculation for required dose must be possible.

Perioperative intensive insulin therapy using an artificial endocrine pancreas with closed-loop glycemic control system: the effects of no hypoglycemia.

BACKGROUND: We examined whether perioperative intensive insulin therapy (IIT) using an artificial pancreas (AP) with a closed-loop glycemic control system can be used to prevent hypoglycemia in surgical patients. METHODS: Between 2006 and 2012, perioperative glycemic control using an AP was performed in 427 patients undergoing general surgery. A total of 305 patients undergoing IIT using an AP in the target blood glucose range of 80 to 110 mg/dL were enrolled in the study. Data were collected prospectively and were reviewed or analyzed retrospectively. RESULTS: No patients had hypoglycemia. Perioperative mean blood glucose level and achievement rates in target blood glucose range of 80 to 110 mg/dL were 100.5 ± 11.9 mg/dL and 88.1% ± 16.0%, respectively. For the 3 primary operative methods, including hepatic, pancreatic, and esophageal resections, there were no significant differences in glycemic control stability between the types of surgery. CONCLUSION: Perioperative IIT using an AP with a closed-loop glycemic control system can be used to prevent hypoglycemia and maintain stable glycemic control with less variability of blood glucose concentration.

Evaluation of a novel artificial pancreas: closed loop glycemic control system with continuous blood glucose monitoring.

A closed-loop glycemic control system using an artificial pancreas has been applied with many clinical benefits in Japan since 1987. To update this system incorporating user-friendly features, we developed a novel artificial pancreas (STG-55). The purpose of this study was to evaluate STG-55 for device usability, performance of blood glucose measurement, glycemic control characteristics in vivo in animal experiments, and evaluate its clinical feasibility. There are several features for usability improvement based on the design concepts, such as compactness, display monitor, batteries, guidance function, and reduction of the preparation time. All animal study data were compared with a clinically available artificial pancreas system in Japan (control device: STG-22). We examined correlations of both blood glucose levels between two groups (STG-55 vs. control) using Clarke's error grid analysis, and also compared mean glucose infusion rate (GIR) during glucose clamp. The results showed strong correlation in blood glucose concentrations (Pearson's product-moment correlation coefficient: 0.97; n = 1636). Clarke's error grid analysis showed that 98.4% of the data fell in Zones A and B, which represent clinically accurate or benign errors, respectively. The difference in mean GIRs was less than 0.2 mg/kg/min, which was considered not significant. Clinical feasibility study demonstrated sufficient glycemic control maintaining target glucose range between 80 and 110 (mg/dL), and between 140 and 160 without any hypoglycemia. In conclusion, STG-55 was a clinically acceptable artificial pancreas with improved interface and usability. A closed-loop glycemic control system with STG-55 would be a useful tool for surgical and critical patients in intensive care units, as well as diabetic patients.

Perioperative glycemic control using an artificial endocrine pancreas in patients undergoing total pancreatectomy: tight glycemic control may be justified in order to avoid brittle diabetes.

I dedicate this paper to the late Prof. Yukihiko Nosé with all my heart. In 2001, under the direction of Prof. Nosé and Prof. Brunicardi at Baylor College of Medicine, we published a review article entitled "Artificial endocrine pancreas" in JACS. Subsequently, we reported that perioperative tight glycemic control (TGC) using an artificial pancreas (AP) with a closed-loop system could stably maintain near-normoglycemia in total-pancreatectomized dogs. Based on this experimental study in Houston, since 2006, we have introduced perioperative TGC using an AP into clinical use in Kochi. As of 2011, this novel TGC method has provided safe and stable blood glucose levels in more than 400 surgical patients. In this paper, we report new clinical findings regarding perioperative TGC using an AP in total-pancreatectomized patients. TGC using an AP enables us to achieve stable glycemic control not only without hypoglycemia and hyperglycemia but also with less variation in blood glucose concentration from the target blood glucose range, even in patients with the most serious form of diabetes, so-called "brittle diabetes", undergoing total pancreatectomy. To the best of our knowledge, this is the first clinical report of TGC using an AP in patients undergoing total pancreatic resection.

Blood compatibility of the adsorptive device filled with poly arylate beads.

The clinical treatments with blood purification therapy is most suitable in which a blood compatible adsorbent is employed. In the present study, two kinds of adsorber with different filling ratio (% rate with a bulk volume in the column volume (v)) with 83% (PAB-83) and 100% (PAB-100) were prepared, respectively. The adsorbent (PAB - Poly Arylate Beads), which was filled up in the column, was prepared with the phase-inversion method. Usually the major problems of blood purification therapy are blood clotting and the residual blood in the column during/after therapy process. The therapy should be interrupted when the internal pressure of the column dramatically go up by such problems. We concluded that PAB does not affect the blood clotting formation in terms of endogenous clotting parameters, i.e., activated partial thromboplastin time (APTT), prothrombin time (PT) and the amount of fibrinogen (Fib). They lead to not dramatically decreasing of the essential protein. These adsorbers might be available to use as the adsorptive device for the blood purification therapy.

Differential brain cooling induced by transarterial perfusion of cooled crystalloid solution in canines.

OBJECTIVE: We investigated the possibility of differential brain cooling by an endovascular method, perfusing cooled crystalloid solution transarterially. METHODS: Fifteen healthy adult hybrid dogs were divided into three groups according to different crystalloid infusion rates: Group 1 received 1.5 ml/kg/min (n=6), Group 2 received 3.0 ml/kg/min (n=6) and Group 3 received 5.0 ml/kg/min (n=3). A four-French angiographic catheter was placed into the right common carotid artery to infuse cooled Ringer's solution. A six-French angiographic catheter was placed into the right jugular vein to withdraw hemodiluted blood. Excessive fluid was eliminated using a dialyzer in a venovenous extracorporeal circuit. Hypothermic perfusion was continued for 30 minutes. A Swan-Ganz catheter was inserted to measure cardiac output. Temperatures were monitored in the cerebral hemispheres and rectum. RESULTS: The cooling rates of the right cerebral hemisphere were 1.8 +/- 0.9 degrees C/30 min in Group 1 and 4.7 +/- 1.0 degrees C/30 min in Group 2. The cooling rates of the left cerebral hemisphere and rectum were 1.4 +/- 0.5 and 1.5 +/- 0.7 degrees C/30 min in Group 1, and 3.5 +/- 0.5 and 3.4 +/- 0.8 degrees C/30 min in Group 2, respectively. In Group 3, two dogs died after the experiment. Systemic hemodynamics was stable throughout the experiment in Group 1, while arterial blood pressure, heart rate and cardiac output changed significantly after perfusion in Group 2. CONCLUSION: Transarterial perfusion of cooled crystalloid solution achieved differential cooling between the target and other sites. However, the difference was small and further refinements are necessary to achieve beneficial effects.

Rapid induction of brain hypothermia by endovascular intra-arterial perfusion.

OBJECTIVES: Achieving rapid, brain cooling has potentially important clinical implications. To investigate potential practicalities, we induced brain hypothermia in canines by perfusing cooled crystalloid solution into the carotid artery using an extracorporeal cooling-filtration system. METHODS: Ringer's solution cooled to approximately 6.5 degrees C was infused at a rate of 3 ml/kg/min for 30 minutes into the right common carotid artery through an angiographic catheter via the right femoral artery in six adult canines (13.81 +/- 0.60 kg). Excessive fluid was ultrafiltrated through a venovenous extracorporeal circuit via the right femoral vein. Temperature was monitored in the cerebral hemispheres, the rectum and the vena cava. The extracellular lactate concentrations were measured by microdialysis in the frontal lobes. RESULTS: Right brain temperature decreased to 33.6 +/- 2.0 degrees C from 37.7 +/- 1.1 degrees C 30 minutes after initiation of perfusion, while left brain and rectal temperatures were 34.3 +/- 1.7 and 34.1 +/- 1.3 degrees C, respectively. The cooling rate of the right cerebral hemisphere was 4.2 +/- 1.1 degrees C/ 30 minutes and advanced compared with the rectum (p<0.01), the left cerebral hemisphere and the vena cava (both p<0.05). There was no significant increase in the extracellular lactate concentrations in the cerebral hemispheres. Hemoglobin, hematocrit and cardiac function significantly changed during perfusion (p<0.05). CONCLUSIONS: Brain hypothermia was rapidly and safely induced using an intra-arterial crystalloid infusion and an extracorporeal cooing-filtration system. With refinement and further assessment of metabolic and physiologic parameters, the method holds a potential for clinical utility.

The analysis and diagnosis of unstable behavior of the blood vessel wall with an aneurysm based on noise science.

Previously, one of the authors developed a noninvasive measurement method of acceleration and deceleration during the expansion process of the blood vessel wall under pulsatile pressure flow by measuring the strain rate of the blood vessel wall using a supersonic Doppler effect sensor aided by computer analysis (DPC method). In this paper, on the basis of the analysis of chaos theory, that is, the complexity of science, the unstable behavior of the blood vessel wall with an aneurysm was investigated by identifying the characteristic DPC wave forms induced by the onset and progression of aneurysm. These results showed that unstable dynamic behavior of the blood vessel wall occurs due to the progression of the aneurysm. Furthermore, using the theoretical analysis of chaos, this unstable behavior of the blood vessel wall was quantified and the fundamental principle of a noninvasive diagnostic method of the progressive degree of aneurysm was proposed.