Advanced Cross-Correlation Function Application to Identify Arterial Baroreflex Sensitivity Variations From Healthy to Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic disease characterized by elevated blood glucose levels, which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. DM is of two types-types 1 or 2. In type 1, there is a problem with insulin secretion, and in type 2-insulin resistance. About 463 million people worldwide have diabetes, and 80% of the majority live in low- and middle-income countries, and 1.5 million deaths are directly attributed to diabetes each year. Autonomic neuropathy (AN) is one of the common diabetic complications, leading to failure in blood pressure (BP) control and causing cardiovascular disease. Therefore, early detection of AN becomes crucial to optimize treatment. We propose an advanced cross-correlation function (ACCF) between BP and heart rate with suitable threshold parameters to analyze and detect early changes in baroreflex sensitivity (BRS) in DM with AN (DM+). We studied heart rate (HR) and systolic BP responses during tilt in 16 patients with diabetes mellitus only (DM-), 19 diabetes mellitus with autonomic dysfunction (DM+), and 10 healthy subjects. The ACCF analysis revealed that the healthy and DM groups had different filtered percentages of significant maximum cross-correlation function (CCF) value (p < 0.05), and the maximum CCF value after thresholds was significantly reduced during tilt in the DM+ group (p < 0.05). The maximum CCF index, a parameter for the phase between HR and BP, separated the healthy group from the DM groups (p < 0.05). Due to the maximum CCF index in DM groups being located in the positive range and significantly different from healthy ones, it could be speculated that BRS dysfunction in DM and AN could cause a phase change from lead to lag. ACCF could detect and separate DM+ from DM groups. This fact could represent an advantage of the ACCF algorithm. A common cross-correlation analysis was not easy to distinguish between DM- and DM+. This pilot study demonstrates that ACCF analysis with suitable threshold parameters could explore hidden changes in baroreflex control in DM+ and DM-. Furthermore, the superiority of this ACCF algorithm is useful in distinguishing whether AN is present or not in DM.

Hypertension and Stroke Cardiovascular Control Evaluation by Analyzing Blood Pressure, Cerebral Blood Flow, Blood Vessel Resistance and Baroreflex.

Cardiovascular diseases have been the leading causes of mortality in Taiwan and the world at large for decades. The composition of cardiovascular and cerebrovascular systems is quite complicated. Therefore, it is difficult to detect or trace the related signs of cardiovascular and cerebrovascular diseases. The characteristics and changes in cardiopulmonary system disease can be used to track cardiovascular and cerebrovascular disease prevention and diagnosis. This can effectively reduce the occurrence of cardiovascular and cerebrovascular diseases. This study analyzes the variability in blood pressure, cerebral blood flow velocity and the interaction characteristics using linear and nonlinear approaches in stroke, hypertension and healthy groups to identify the differences in cardiovascular control in these groups. The results showed that the blood pressure and cerebral blood flow of stroke patients and hypertensive patients were significantly higher than those of healthy people (statistical differences (p < 0.05). The cerebrovascular resistance (CVR) shows that the CVR of hypertensive patients is higher than that of healthy people and stroke patients (p < 0.1), indicating that the cerebral vascular resistance of hypertensive patients is slightly higher. From the patient's blood flow and vascular characteristics, it can be observed that the cardiovascular system is different from those in healthy people. Baroreflex sensitivity (BRS) decreased in stroke patients (p < 0.05). Chaotic analysis revealed that the blood pressure disturbance in hypertensive patients has a higher chaotic behavior change and the difference in initial state sensitivity. Cross-correlation (CCF) analysis shows that as the course of healthy→hypertension→stroke progresses, the maximum CCF value decreases significantly (p < 0.05). That means that blood pressure and cerebral blood flow are gradually not well controlled by the self-regulation mechanism. In conclusion, cardiovascular control performance in hypertensive and stroke patients displays greater variation. This can be observed by the bio-signal analysis. This analysis could identify a measure for detecting and preventing the risk for hypertension and stroke in clinical practice. This is a pilot study to analyze cardiovascular control variation in healthy, hypertensive and stroke groups.

Comparisons of the Nonlinear Relationship of Cerebral Blood Flow Response and Cerebral Vasomotor Reactivity to Carbon Dioxide under Hyperventilation between Postural Orthostatic Tachycardia Syndrome Patients and Healthy Subjects.

Postural orthostatic tachycardia syndrome (POTS) typically occurs in youths, and early accurate POTS diagnosis is challenging. A recent hypothesis suggests that upright cognitive impairment in POTS occurs because reduced cerebral blood flow velocity (CBFV) and cerebrovascular response to carbon dioxide (CO2) are nonlinear during transient changes in end-tidal CO2 (PETCO2). This novel study aimed to reveal the interaction between cerebral autoregulation and ventilatory control in POTS patients by using tilt table and hyperventilation to alter the CO2 tension between 10 and 30 mmHg. The cerebral blood flow velocity (CBFV), partial pressure of end-tidal carbon dioxide (PETCO2), and other cardiopulmonary signals were recorded for POTS patients and two healthy groups including those aged >45 years (Healthy-Elder) and aged <45 years (Healthy-Youth) throughout the experiment. Two nonlinear regression functions, Models I and II, were applied to evaluate their CBFV-PETCO2 relationship and cerebral vasomotor reactivity (CVMR). Among the estimated parameters, the curve-fitting Model I for CBFV and CVMR responses to CO2 for POTS patients demonstrated an observable dissimilarity in CBFVmax (p = 0.011), mid-PETCO2 (p = 0.013), and PETCO2 range (p = 0.023) compared with those of Healthy-Youth and in CBFVmax (p = 0.015) and CVMRmax compared with those of Healthy-Elder. With curve-fitting Model II for POTS patients, the fit parameters of curvilinear (p = 0.036) and PETCO2 level (p = 0.033) displayed significant difference in comparison with Healthy-Youth parameters; range of change (p = 0.042), PETCO2 level, and CBFVmax also displayed a significant difference in comparison with Healthy-Elder parameters. The results of this study contribute toward developing an early accurate diagnosis of impaired CBFV responses to CO2 for POTS patients.

Cost-effectiveness of statin therapy for secondary prevention among patients with coronary artery disease and baseline LDL-C 70-100 mg/dL in Taiwan.

BACKGROUND: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70-100 mg/dL in Taiwan could be cost-effective. METHODS: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. RESULTS: Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER. CONCLUSION: Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.

Intravenous Thrombolysis Administration 3-4.5 h After Acute Ischemic Stroke: A Retrospective, Multicenter Study.

Background and Objectives: Intravenous recombinant tissue plasminogen activator (rt-PA) has been approved for acute ischemic stroke (AIS) within 3 h after onset and the treatment was then extended to 4.5 h. However, the Food and Drug Administration did not approve the indication in the expanded time window. This retrospective, matched cohort study aims to investigate the effectiveness and safety of rt-PA in AIS at 3-4.5 h after onset. Materials and Methods: The treatment group included AIS patients receiving rt-PA at 3-4.5 h after onset, otherwise complying with the regulation, in the stroke registries in 16 hospitals between 2008 and 2017. The control group included age- and sex-matched patients not receiving intravenous thrombolysis from the same registries, excluding those with contraindications. The primary outcome was modified Rankin Scale (mRS) 0-1 at day 90. The safety outcomes were any intracerebral hemorrhage (ICH), early neurological deterioration and 3-month mortality. Results: Each group had 374 patients. There were 34.0% of patients with 3-month mRS 0-1 in the treatment group vs. 22.7% in the control group with an odds ratio of 1.75 (95% confidence intervals, 1.27 to 2.42, P = 0.001). There was no difference in symptomatic ICH, early neurological deterioration and 3-month mortality rates between two groups. The 3-month mRS and symptomatic ICH did not differ significantly in patients receiving standard dose or low dose of rt-PA. Conclusions: Our results support the prescription of rt-PA in AIS patients 3-4.5 h after onset as an effective and tolerable treatment in their functional recovery.

The analysis of cardio-respiratory signals and cerebral autoregulation based on CO2 reactivity with healthy subjects and Parkinson's patients.

Current paper focus on Parkinson's patients with autonomic dysfunction and how their interactions between cerebral autoregulation and ventilatory control are affected. The experimental data of dynamic CA assessment from the ANS Laboratory of CCGH was accessed for further processing and analysis. The subjects were classified into the groups of healthy and with Parkinson's disease. Based on the accessed ventilation and CBF data, the percentage changes in ventilation and CBF responses to PETCO2 were examined. To minimize effects of changes in ABP on cerebral vasomotor reactivity (CVMR) estimation, cerebrovascular conductance index (CVCi) was calculated, and CBFV-PETCO2 and CVCi-PETCO2 relationships were quantified by nonlinear logistic regression. The interaction between ventilation responses and CBF autoregulation will be modeled and parameters will be validated.

The analysis of cardio-respiratory signals and cerebral autoregulation based on CO2 reactivity with healthy subjects and Parkinson's patients.

Current paper focus on Parkinson's patients with autonomic dysfunction and how their interactions between cerebral autoregulation and ventilatory control are affected. The experimental data of dynamic CA assessment from the ANS Laboratory of CCGH was accessed for further processing and analysis. The subjects were classified into the groups of healthy and with Parkinson's disease. Based on the accessed ventilation and CBF data, the percentage changes in ventilation and CBF responses to PETCO2 were examined. To minimize effects of changes in ABP on cerebral vasomotor reactivity (CVMR) estimation, cerebrovascular conductance index (CVCi) was calculated, and CBFV-PETCO2 and CVCi-PETCO2 relationships were quantified by nonlinear logistic regression. The interaction between ventilation responses and CBF autoregulation will be modeled and parameters will be validated.

Onset headache predicts good outcome in patients with first-ever ischemic stroke.

BACKGROUND AND PURPOSE: The study aimed to assess whether onset headache is an ominous sign in patients with first-ever ischemic stroke. METHODS: A large population of ischemic stroke patients was obtained from the Taiwan Stroke Registry. Stroke subtypes were classified by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of the International Classification of Headache Disorders, second version, onset headache was defined as a new headache that developed at the onset of ischemic stroke. Clinical features and impact on stroke outcomes, including in-hospital stroke in evolution, changes in National Institutes of Health Stroke Scale on discharge, and Barthel index and modified Rankin scale ≤6 months after stroke were compared between those with and without onset headache. RESULTS: Among 11 523 patients with first-ever ischemic stroke, 848 had onset headache (7.4%). Patients with specific cause, large-artery atherosclerosis, or cardioembolism were more likely to have onset headache. Patients with onset headache were younger, predominantly female, and more likely to have posterior circulation ischemic lesions. Compared with patients without onset headache, those with onset headache had a lower frequency of stroke in evolution (4.5% versus 6.7%; adjusted relative risk, 0.64; 95% confidence interval, 0.52-0.79), greater improvement in National Institutes of Health Stroke Scale score on discharge (0.08 versus -0.20; P=0.02), higher mean Barthel index scores (86.5±20.0 versus 83.9±23.3; adjusted difference, 1.43; 95% confidence interval, 0.28-2.89), and a lower frequency of modified Rankin scale higher than 2 (27.6% versus 31.5%; adjusted relative risk, 0.85; 95% confidence interval, 0.72-0.95) at 1-month follow-up. There was also a trend for better functional outcome in 3- and 6-month follow-ups. CONCLUSIONS: By adopting standard classification criteria, this large-scale study demonstrated that onset headache was associated with modest but significantly better outcomes after ischemic stroke.

Dynamic cerebral autoregulation assessment using chaotic analysis in diabetic autonomic neuropathy.

Cerebral autoregulation (CA) was assessed by chaotic analysis based on mean arterial blood pressure (MABP) and mean cerebral blood flow velocity (MCBFV) in 19 diabetics with autonomic neuropathy (AN) and 11 age-matched normal subjects. MABP in diabetics dropped significantly in response to tilting (91.6 +/- 14.9 vs. 74.1 +/- 13.4 mmHg, P < 0.05). Valsalva ratio of heart rate was reduced in diabetics compared to normal (1.1 +/- 0.1 vs. 1.5 +/- 0.2, P < 0.05). It indicated AN affects the vasomotor tone of peripheral vessels and baroreflex. Nonlinear results showed higher correlation dimension values of MABP and MCBFV in diabetics compared to normal, especially MABP (3.7 +/- 2.3 vs. 2.0 +/- 0.8, P < 0.05). It indicated CA is more complicated in diabetics. The lower Lyapunov exponent and the higher Kolmogorov entropy values in diabetics indicated less predictable behavior and higher chaotic degree. This study suggests impaired autoregulation would be more chaotic and less predictable.

Correlation of common carotid artery intima media thickness, intracranial arterial stenosis and post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: Atherosclerosis of the intracranial arteries is a well-recognized cause of ischemic stroke in Asians, and extracranial carotid artery disease is more often seen in western countries. The relationship of common carotid artery intima-media thickness (CCA-IMT), intracranial arteries stenosis (ICS) and vascular cognitive impairment (VCI) after ischemic stroke has not been fully elucidated. In this study, we investigated the relationship between CCA-IMT and the severity of ICS and VCI. METHODS: We recruited patients from December 2004, to June 2005, with the inclusion criteria: (1) first-ever ischemic stroke, (2) admission within 3 days of stroke onset, (3) under 80 years old, and (4) no previous dementia history. We excluded patients with stroke scores greater than an NIHSS of 15; those with recurrent stroke, and those with extracranial internal carotid artery stenosis > 50%. All the patients underwent brain MR angiography, carotid ultrasonography and neuropsychological testing during hospitalization and at 3 months after stroke. We defined the percent of ICS using the method of Warfarin-Aspirin Symptomatic Intracranial Disease. Measurement of CCA-IMT was made on the far wall of the common carotid artery, 1.5 cm proximal to the bifurcation at a point free of plaques. Cognitive performance was assessed using the Cognition Assessment State Instrument (CASI). RESULTS: Thirty patients (21M/9F, mean age 65.97 +/- 10.33 years) were studied. The initial CCA-IMT was 1.04 +/- 0.59 mm and the initial CASI was 64.73 +/- 14.75. The ICS was 70 +/- 26%. At 3 months after stroke, the CCA-IMT was 1.06 +/- 0.59 mm; and CASI was 70.07 +/- 18.50. Compared with patients with CCA-IMT > 0.87 mm, those with CCA-IMT < or = 0.87 mm had lower ICS (57 +/- 23% vs. 81 +/- 24%, p = 0.013), but similar initial CASI score (67.92 +/- 13.52 vs. 61.93 +/- 16.64, p = 0.28). The improvement of CASI score at 3 months was significantly higher in patients with CCA-IMT < or = 0.87 mm (67.92 +/- 13.52 vs. 77.36 +/- 14.12, p = 0.001), than those with CCA-IMT > 0.87 mm (61.93 +/- 16.64 vs. 63.69 +/- 19.89, p = 0.612). CONCLUSIONS: CCA-IMT might be associated with the severity of ICS and VCI at 3 months after the first-ever ischemic stroke. The patients with lower CCA-IMT had a better CASI evaluation at 3 months after stroke. A larger scale of study to explore the association of CCA-IMT, VCI and ICS at 3 months after stroke might help farther delineation of these relationships.

Correlation between striatal dopamine D2/D3 receptor binding and cardiovascular activity in healthy subjects.

BACKGROUND: The relationship between the striatal dopaminergic system and cardiovascular activity is not well known. The aim of this study is to investigate the relationship between striatal D2/D3 receptor binding and cardiovascular activity. METHODS: The striatal D2/D3 receptor binding of 34 healthy volunteers was assessed by the single-photon emission computed tomography (SPECT) imaging method with the [123I]-iodobenzoamide (IBZM) ligand. The ratio of the radioactivity in the striatum (St) and the frontal cortex (Fc) (St/Fc ratio) was used as the marker for striatal D2/D3 receptor binding. Their cardiac autonomic functions were measured by continuously monitoring their heart rate and blood pressure (BP) in supine position during 10 min. The heart rate variability (HRV) was analyzed by spectral analysis and the geometric method. RESULTS: The St/Fc ratio of striatal dopamine D2/D3 receptor binding correlated negatively with heart rate (HR), and positively with cardiac vagal index (CVI) and low frequency (LF) power in healthy subjects who were in a supine resting position. CONCLUSIONS: Striatal dopamine D2/D3 receptors may play a part in cardiovascular regulation.

Monitoring perspiration from palms of hypohidrosis patients with a stopped-flow conductometric mini-system.

BACKGROUND: Sensitive and real-time methods are required to characterize the symptoms and resolve the complicated pathology of hypohidrosis. METHOD: We constructed a conductometric humidity sensor and a stopped-flow manifold with suitable dynamic range for monitoring impaired perspiration. The mini-sensor was coated with a water-absorbing polymer of poly-(2-acrylamido-2-methylpropane sulfonate). RESULTS: Perspiration from palms of normal individuals and hypohidrosis patients were monitored and compared. Tangent slopes of the sensorograms were capable of discriminating hypohidrosis patients from normal individuals. CONCLUSION: The conductometric min-sensor and the stopped-flow manifold were proven to be useful as a diagnostic tool for hypohidrosis.