Evaluation of artificial pancreas technology for continuous blood glucose monitoring in dogs.

Artificial pancreas technology, involving "closed-loop" controls with real-time blood glucose monitoring, has been increasing in reliability as its potential for clinical use and application grows. One such device, based on this technology, is the STG-22 (Nikkiso Co., Ltd., Tokyo, Japan) artificial pancreas apparatus. In order to assess the reliability and accuracy of the device for measuring blood glucose, it is important to compare its readings to those obtained using a 'gold standard' method, such as the hexokinase method. Therefore, in the present study, canine blood [glucose] measurements using the STG-22 were compared to those obtained using a previously established commercial reagent, Quickauto-Neo GLU-HK. Furthermore, two different sample types (whole blood versus plasma constituent) were compared to determine which sample type results in more accurate and optimal readings with the STG-22. Given that the STG-22 was not primarily designed for canine blood samples, results for canine blood samples were not accurate. Measurements performed by the STG-22 with whole blood were significantly lower than reference [glucose] counterparts. Alternatively, an opposite trend was observed with plasma measurements that were significantly higher. A conversion format using the following formula, Hexokinase [glucose] = STG-22 [glucose] × 1.407 + 1.532, was observed with canine samples in our study.

V-shaped trough in autonomic activity is a possible precursor of life-threatening cardiac events.

BACKGROUND: No reliable precursor of sudden cardiac death is known. METHODS AND RESULTS: Holter electrocardiograms of 34 patients experiencing a cardiac event (event group, 20 deaths) were compared with 191 controls (no event group). The event group included 25 patients with ventricular fibrillation or acute myocardial infarction (AMI), and 9 with cardiac arrest due to complete atrioventricular block. The logarithms were calculated of the moving average of 5 successive values for the low-frequency component (LF), the high-frequency component (HF), and the ratio LF/HF of heart rate variability: ln(LF), ln(HF) and ln(LF/HF). A V-shaped trough appeared in the curve of ln(LF/HF) [sV-trough] or ln(HF) [pV-trough] before such an event in 31 patients in the event group. The V-trough was marked by a small variation lasting 2 h, an abrupt descent lasting 30 min, and a sharp ascent for 40 min. An sV-trough was observed in 22 patients before the onset of ventricular fibrillation or AMI. A pV-trough was observed in all 9 patients before the onset of complete atrioventricular block. In the no event group, an sV-trough and a pV-trough were observed in 10 subjects (5%) and 20 subjects (10%), respectively. The positive predictive accuracy of an sV-trough for ventricular fibrillation or AMI and that of a pV-trough for complete atrioventricular block was 88% and 100%, respectively. CONCLUSIONS: A previously unidentified V-trough of autonomic activity is a potential precursor of lethal events.

Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats.

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

Sudden Cardiac Death from the Perspective of Nonlinear Dynamics.

There are some reports that sympathetic nerve activity (SNA) shows a characteristic pattern a few hours before the onset of lethal ventricular arrhythmias. If so, it could be possible to predict sudden cardiac death a few hours in advance of its occurrence. Recently, we reported that a previously unidentified V-trough of SNA is a potential precursor of lethal cardiac events by examining 24-hour ambulatory electrocardiograms in which such an event was recorded by chance. In contrast, the chaotic nature of heart rate variability has been noted recently from the viewpoint of nonlinear dynamics. This study models the hemodynamics, consisting of heart rate, SNA, and blood pressure (BP), by modifying a known chaotic electrical circuit, the Chua circuit. A V-trough of the SNA appears when the resistive element between the SNA and BP in the circuit is increased, which corresponds to the impaired regulation of BP by the SNA. This finding is consistent with an acknowledged finding that a depressed baroreflex (a reflex of the BP by SNA) may trigger a lethal arrhythmia. This study indicates that a V-trough of the SNA is a possible precursor of sudden cardiac death on the basis of experimental and clinical findings as well as mathematical modeling.

Usefulness of Measuring the Serum Elastin Fragment Level in the Diagnosis of an Acute Aortic Dissection.

Previous reports have shown that serum elastin fragments (SEFs) may be a useful biomarker for the diagnosis of an acute aortic dissection (AAD). However, because the reference interval of SEFs has not been established, it has not been determined whether SEFs are really useful for the diagnosis of AAD. The purpose of this study was to determine the usefulness of measuring SEFs for the diagnosis of AAD. A total of 42 consecutive patients aged 68 ± 18 years who were diagnosed with an AAD were studied. Patient background and SEF levels were examined on admission. SEF levels were also measured in patients undergoing a medical examination (n = 531, age 54 ± 17 years) to compare with those with an AAD. In the control group, SEF levels increased with age (R = 0.725, p <0.001). Then, we defined the upper limit of the reference interval of SEF levels as the 97.5th percentile of control SEF grouped by decade of life from the sixth to ninth decade. The overall risk of AAD exceeding the upper limit of the reference interval at each decade was 10% (4 of 42). For patients in their 60s and 70s, median SEF levels in the AAD group (89 [77 to 104], 93 [60 to 123] ng/ml, respectively) were not significantly higher than those in the control group (79 [68 to 92], 90 [79 to 106] ng/ml, respectively; p = 0.081 and 0.990, respectively). Our data suggest that measuring SEF levels may not be useful in the diagnosis of an AAD as the upper limit of the reference interval of the SEF level was unexpectedly higher.

Potentiated sympathetic nervous and renin-angiotensin systems reduce nonlinear correlation between sympathetic activity and blood pressure in conscious spontaneously hypertensive rats.

BACKGROUND: Patients with a reduced nonlinear component of heart rate regulation have a poorer outcome. METHODS AND RESULTS: We investigated whether a nonlinear correlation between renal sympathetic nerve activity (RSNA) and blood pressure or renal blood flow is reduced in conscious, spontaneously hypertensive rats (SHR) by comparing them with normotensive Wistar-Kyoto rats (WKY). We also determined the linearity and nonlinearity of the correlation in SHR who were given an angiotensin II receptor blocker, candesartan, orally for 2 weeks. The RSNA value was higher in SHR than in WKY, and coherence peaks of transfer function were found at 0.05 and 0.80 Hz (ie, below respiratory- and cardiac-related fluctuations). The coherence (linearity) of the transfer function was significantly higher and gain was smaller in SHR than in WKY. Because mutual information values (linear and nonlinear correlation) were similar in both strains, we found the nonlinear correlation to be lower in SHR than in WKY. Time delay values calculated by the mutual information method demonstrated that RSNA preceded blood pressure and renal blood flow by 0.5 to 1.0 s. In SHR given candesartan, the RSNA value was lower, and the linearity was lower and nonlinearity higher than SHR given vehicle. CONCLUSIONS: Linear correlation between RSNA and blood pressure or renal blood flow was higher in SHR than in WKY, whereas the nonlinear correlation was lower. Oral treatment with candesartan increased the nonlinearity and reduced the linearity in SHR. Increased RSNA and the renin-angiotensin system may be responsible for the lower nonlinearity and higher linearity in hypertension.

Artificial myocardium with an artificial baroreflex system using nano technology.

Where is the place which should be helped in a patient with congestive heart failure? The answer may be contraction of the heart. At Tohoku University, development research of "the artificial myocardium" has been conducted, using a ball screw type electromagnetic motor. Furthermore, super-miniaturization is being attempted at present. Thus, a system with shape memory alloy is being developed. The cooling speed problem was solved by the application of the Peltier element. A drive at a speed equal to that of a heartbeat was realized by the application of this system. At present, a ventricular assist device is used for patients waiting for a heart transplant in Japan. An air driven type system disturbs a patient's QOL remarkably because it is connected to the drive device. With our concept, energy is provided by using the electromagnetic force from outside of the body by the use of transcutaneous energy transmission system. Magnetic shielding by amorphous fibers was used at Tohoku University to improve the total efficiency. A natural heart can alter the cardiac output corresponding to the demand. Artificial internal organs must participate in the system of the living body, too. Tohoku University has developed a resistance based artificial heart control algorithm, which simulated a baroreflex system to cope with every demand. Nano level sensing equipment is now under development at Tohoku University. At present, development is being conducted aiming at an "intelligent artificial myocardium".

Low-order chaos in sympathetic nerve activity and scaling of heartbeat intervals.

The mechanism of 1/f scaling of heartbeat intervals remains unknown. We recorded heartbeat intervals, sympathetic nerve activity, and blood pressure in conscious rats with normal or high blood pressure. Using nonlinear analyses, we demonstrate that the dynamics of this system of three variables is low-order chaos, and that sympathetic nerve activity leads to heartbeat interval and blood pressure changes. It is suggested that impaired regulation of blood pressure by sympathetic nerve activity is likely to cause experimentally observable steeper scaling of heartbeat intervals in hypertensive (high blood pressure) rats.

Age-adjusted level of circulating elastin as a cardiovascular risk factor in medical check-up individuals.

AIMS: The level of circulating soluble elastin (CSE) is reported to increase proportionally with the degree of clinical atherosclerosis; however, its diagnostic use is limited because CSE also increases with age. We aimed to investigate whether alterations in CSE concentrations are implicated in potential cardiovascular dysfunctions (indicated by standard physiological parameters) in medical check-up individuals, taking age into consideration. METHODS: In a total of 531 individuals (age 20-89 years), CSE levels were correlated most significantly with age. The groups of male and female individuals were each further divided into two subgroups: those with higher and those with lower CSE levels than the reference values determined by polynomial regression. RESULTS: Male participants with lower CSE levels (n = 128) than the age-adjusted reference baseline levels showed higher serum glucose (P < 0.008), uric acid (P < 0.008) and triglyceride (P < 0.02) levels than those with higher CSE levels (n = 126). However, most of the parameters tested in female participants with lower CSE levels (n = 140) were statistically comparable to those with higher CSE levels (n = 137). The ratio of CSE level to the age-adjusted reference level was calculated in each of the male participants, and declines in the ratio were significantly correlated with increases of serum glucose, uric acid and triglyceride levels (P < 0.005, P < 0.02 and P < 0.006, respectively). CONCLUSION: The decrease in age-adjusted CSE levels is a potential indicator of eventual cardiovascular dysfunction in medical check-up individuals, as predicted by the risk factors dyslipidemia, hyperuricemia or diabetes.

Sudden cardiac arrest recorded during Holter monitoring: prevalence, antecedent electrical events, and outcomes.

BACKGROUND: Causative arrhythmias of sudden cardiac arrest (SCA) are changing in this age of improved coronary care. OBJECTIVE: The purpose of this study was to examine the frequency of terminal arrhythmias and the electrical events prior to SCA. METHODS: We analyzed 24-hour Holter recordings of 132 patients enrolled from 41 institutions who either died (n = 88) or had an aborted death (n = 44). The Holter recordings were obtained for diagnosing and evaluating diseases and arrhythmias in those without any episodes suggestive of SCA. RESULTS: In 97 patients (73%), SCA was associated with ventricular tachyarrhythmias and in 35 (27%) with bradyarrhythmias. The bradyarrhythmia-related SCA patients were older than those with a tachyarrhythmia-related SCA (70 ± 13 years vs. 58 ± 19 years, P < .001). The most common arrhythmia for a tachyarrhythmia-related SCA was ventricular tachycardia degenerating to ventricular fibrillation (45%). The bradyarrhythmia-related SCA was caused by asystole (74%) or AV block (26%). Spontaneous conversion was observed in 37 patients (38%) with ventricular tachyarrhythmias. Of those, 62% of the patients experienced symptoms including syncope, chest pain, or convulsion. Multivariate logistic analysis revealed that independent predictors of mortality for tachyarrhythmia-related SCAs were advanced age (odds ratio 1.04, 95% confidence interval 1.02-1.08) and ST elevation within the hour before SCA (odds ratio 3.54, 95% confidence interval 1.07-13.5). In contrast, the presence of preceding torsades de pointes was associated with spontaneous conversion (odds ratio 0.20, 95% confidence interval 0.05-0.66). CONCLUSION: The most frequent cause of SCA remains ventricular tachyarrhythmias. Advanced age and ST elevation before SCA are risk factors for mortality in tachyarrhythmia-related SCAs.

Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure.

Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy.

Application of heart rate variability analysis to electrocardiogram recorded outside the driver's awareness from an automobile steering wheel.

BACKGROUND: Approximately 5% of motor vehicle deaths are assumed to be occur because of a cardiac event thought to be triggered by multiple factors. One important factor is an imbalance of sympathetic and parasympathetic nervous activities, which can be measured by analyzing heart rate variability (HRV). Therefore, a system has been developed to make electrocardiographic (ECG) recordings outside the driver's awareness from the steering wheel (steering-ECG) with an algorithm to remove noise. METHODS AND RESULTS: Steering-ECG and ECG from a chest lead (chest-ECG) were recorded simultaneously in 10 normal subjects while they were driving for 90 min. For each of 4 parameters (instantaneous heart rate, low- and high-frequency components of HRV, and the ratio of these components in all subjects), mutual information was used to examine whether the fluctuation from the steering-ECG resembled that from the chest-ECG. The mutual information of each parameter was larger than 0.047 with 95% confidence interval (mutual information values vary from 0 to 1; threshold of significance: 0.047). Hence, the fluctuation of each steering-ECG parameter resembled its chest-ECG counterpart. CONCLUSIONS: This system heralds a new driver-safety strategy by reporting alteration of autonomic nervous activity during driving.