Chang Ming Chern

Frequency Domain Analysis of Cerebral Blood Flow Velocity and its Correlation with Arterial Blood Pressure

We applied frequency domain analysis to detect and quantify spontaneous fluctuations in the blood flow velocity of the middle cerebral artery (MCAFV). Instantaneous MCAFV of normal volunteers was detected using transcranial Doppler sonography. Spectral and transfer function analyses of MCAFV and arterial blood pressure (ABP) were performed by fast Fourier transform. We found the fluctuations in MCAFV, like ABP, could be diffracted into three components at specific frequency ranges, designated as high-frequency (HF, 0.15 to 0.4 Hz), low-frequency (LF, 0.04 to 0.15 Hz), and very low-frequency (VLF, 0.016 to 0.04 Hz) components. The HF and LF components of MCAFV exhibited high coherence with those of ABP, indicating great similarity of MCAFV and ABP fluctuations within the two frequency ranges. However, it was not the case for the VLF component. Transfer function analysis revealed that the ABP-MCAFV phase angle was frequency-dependent in the LF range (r = −0.79, P < 0.001) but not in the HF range. The time delay between LF fluctuations of ABP and those of MCAFV was evaluated as 2.1 seconds. We conclude that in addition to traditional B-wave equivalents, there are at least two different mechanisms for MCAFV fluctuations: the HF and LF fluctuations of MCAFV are basically secondary to those of ABP, and cerebral autoregulation may operate efficiently in LF rather than HF range. Frequency domain analysis offers an opportunity to explore the nature and underlying mechanism of dynamic regulation in cerebral circulation.

Transfer Function Analysis of Cerebral Hemodynamics in Patients With Carotid Stenosis

This study evaluates the validity of the transfer function analysis of spontaneous fluctuations of arterial blood pressure (ABP) and blood flow velocity of the middle cerebral artery (MCAFV) as a simple, convenient method to assess human cerebral autoregulation in patients with carotid stenosis. Eighty-three consecutive patients with various degrees of carotid stenosis and 37 healthy controls were enrolled. The carotid stenosis was graded based on the diagnostic criteria of duplex ultrasound. Instantaneous bilateral MCAFV and ABP of all participants were assessed noninvasively using transcranial Doppler sonography and the servocontrolled infrared finger plethysmography, respectively. Spectral analyses of ABP and MCAFV were performed by fast Fourier transform. The fluctuations in ABP as well as in MCAFV were diffracted into three components at specific frequency ranges designated as high-frequency (HF; 0.15 to 0.4 Hz), low-frequency (LF; 0.04 to 0.15 Hz), and very low-frequency (VLF; 0.016 to 0.04 Hz). Cross-spectral analysis was applied to quantify the coherence, transfer phase, and magnitude in individual HF, LF, and VLF components. Transcranial Doppler CO2 vasomotor reactivity was measured with 5% CO2 inhalation. The LF phase angle (r = −0.53, P < 0.001); magnitude of VLF (r = −0.29, P = 0.002), LF (r = −0.35, P < 0.001), and HF (r = −0.47, P < 0.001); and CO2 vasomotor reactivity (r = −0.66, P < 0.001) were negatively correlated with the severity of stenosis. Patients with unilateral high-grade (greater than 90% stenosis) carotid stenosis demonstrated significant reduction in LF phase angle (P < 0.001) and HF magnitude (P = 0.018) on the ipsilateral side of the affected vessel compared with their contralateral side. The study also revealed a high sensitivity, specificity, and accuracy using LF phase angle and HF magnitude to detect a high-grade carotid stenosis. A strong correlation existed between the LF phase angle and the CO2 vasomotor reactivity test (r = 0.62, P < 0.001), and the correlation between the HF magnitude and the CO2 vasomotor reactivity (r = 0.44, P < 0.001) was statistically significant as well. We conclude that transfer function analysis of spontaneous fluctuations of MCAFV and ABP could be used to identify hemodynamically significant high-grade carotid stenosis with impaired cerebral autoregulation or vasomotor reserve.

Noninvasive Assessment of Spontaneous Baroreflex Sensitivity and Heart Rate Variability in Patients with Carotid Stenosis

Background: Previous limited observations have suggested that atherosclerosis may affect the distensibility of the carotid sinus and then impair the baroreflex sensitivity (BRS). No studies have been done to compare the BRS and heart rate variability (HRV) in patients with carotid stenosis and normal controls. Methods: A convenience-consecutive sample of 118 patients with transient ischemic attack or minor stroke 3 months to 1 year before (mean 6 months) who met the study criteria were referred to the neurovascular laboratory of the study hospital. Forty-three age-matched healthy adults were recruited as the normal controls. The inclusion criteria for participation were (1) no diabetes mellitus, (2) no history, symptoms or ECG signs of coronary artery disease or myocardial infarction, and (3) presence of carotid stenosis greater than or equal to 50%. The diagnosis of carotid stenosis was made using color-coded duplex ultrasound with published criteria. We categorized the patients into two groups: group 1 had moderate stenosis (50–75%) and group 2 had high-grade stenosis (75–99%). Instantaneous systolic blood pressure (SBP) and heart rate of all participants were assessed noninvasively using servo-controlled infrared finger plethysmography. The fluctuation in SBP as well as the interpulse interval (IPI) was divided into three components at specific frequency ranges by fast Fourier transform as high frequency (HF; 0.15–0.4 Hz), low frequency (LF; 0.04–0.15 Hz) and very low frequency (VLF; 0.004–0.04 Hz). The BRS was expressed as (1) transfer function with its magnitude in the HF and LF ranges, (2) BRS index alpha, and (3) regression coefficient by sequence analysis. The HRV was expressed as total power and power in the three frequency ranges (HF, LF and VLF). Results: The final analysis included 99 patients (mean age 72 ± 6 years, 79 male) and 43 healthy controls (mean age 68 ± 7 years, 30 male). Forty-three patients were classified as group 1 (stenosis 50–75%) and 56 as group 2 (stenosis 75–99%). There was no significant difference in the IPI between patients and controls (p value = 0.8637). We observed a significant decrease in all three HRV components (VLF, LF and HF) in the patients; however, there were no differences between the two patient groups with various degrees of stenosis. All the indices of BRS, including the magnitude of SBP-IPI transfer function at LF and HF, the computed BRS index alpha and the regression coefficient of sequence analysis, revealed similar results. Patients exhibited a significant reduction in the BRS (p < 0.001) compared with controls, and no difference was found between the two groups of patients. Conclusions: Our study linked significant carotid stenosis to two important autonomic markers (BRS and HRV) that may have prognostic value for patients with cardiovascular events. Further prospective studies are needed to explore whether or not the decreased BRS and HRV can be predictors for poor cardiovascular prognosis, or even for shortened life span in general, in patients with significant carotid stenosis.

Mechanisms Underlying Phase Lag between Systemic Arterial Blood Pressure and Cerebral Blood Flow Velocity

To explore the mechanisms underlying the phase lag between oscillations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), ABP and CBFV signals were recorded noninvasively from normal volunteers who lay quietly in a supine position. Mean ABP (MAP) and CBFV (MFV) were calculated beat-to-beat by means of integration. Cerebral vascular resistance (CVR) was calculated by dividing MAP with MFV. Frequency domain analysis of MAP, MFV and CVR signals revealed very-low frequency (VLF, 0.016–0.04 Hz), low-frequency (LF, 0.04–0.15 Hz), and high-frequency (HF, 0.15–0.4 Hz) components. The transfer phase of MAP–CVR coupling in the LF and HF range was frequency-dependent, which is equivalent to a time delay of 2 s. However, the transfer phase differed in the CVR–MFV coupling in that the phase was distributed around 180° across the LF and HF ranges. Cross-correlation analysis revealed a positive relationship between MAP–CVR coupling, with MAP leading by 2 s, and a negative relationship between CVR–MFV coupling, with CVR leading by 0.3 s. We concluded that the phase lag between oscillations in ABP and CBFV was chiefly contributed to by the starting latency of cerebral autoregulation (i.e. cerebral vasomotion, revealed by MAP–CVR coupling). Moreover, the negative correlation of the CVR–MFV coupling could offer a different explanation for the physiologic significance of the phase lead of CBFV–ABP oscillations.

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice

Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalAs protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3β and p25/Cdk5, which in turn upregulated β-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3β/Cdk5 activity to enhance the expression levels of β-catenin/DCX and Bcl-2 for neuroprotection.

Spectral analysis of arterial blood pressure and cerebral blood flow velocity during supine rest and orthostasis

This study evaluates the effect of orthostasis on the low frequency (LF, 0.04 to 0,15 Hz) fluctuations in the blood flow velocity of the middle cerebral artery (MCAFV) in relation to its arterial blood pressure (ABP) equivalent to further define and quantify this relationship in cerebrovascular regulation. Spectral analysis was performed on 22 healthy subjects during supine rest and head-up tilt. The power in the LF range can be used to quantify the LF fluctuations, and four types of LF power data could be obtained for each individual: LF power of supine MCAFV, LF power of supine ABP, LF power of tilt MCAFV, and LF power of tilt ABP. By comparing LF power of MCAFV with LF power of ABP, two power ratios could be generated to describe the flow-pressure relationship during supine rest and head-up tilt, respectively, supine power ratio (LF power of supine MCAFV/LF power of supine ABP) and tilt power ratio (LF power of tilt MCAFV/LF power of tilt ABP). In addition, an index for dynamic autoregulation in response to orthostasis can be calculated from these two power ratios (tilt power ratio/supine power ratio). The authors found that this index was dependent on the extent of orthostatic MCAFV changes, and the dependency could be mathematically expressed (r = 0.61, P = .0001), suggesting its involvement in cerebrovascular regulation. Moreover, these data further support the previous observation that the LF fluctuations of MCAFV might result from modulation of its ABP equivalent, and the modulation effect could be quantified as the power ratio (LF power of MCAFV/LF power of ABP). These observations could be an important step toward further insight into cerebrovascular regulation, which warrants more research in the future.

Sympathetic Hyperactivity, Sleep Fragmentation, and Wake-Related Blood Pressure Surge During Late-Light Sleep in Spontaneously Hypertensive Rats.

BACKGROUNDnMany cardiovascular disease events occur before morning awaking and are more severe in hypertensive patients. Sleep-related cardiovascular regulation has been suggested to play an important role in the pathogenesis. In this study, we explored whether such impairments are exaggerated during late sleep (before the active phase) in spontaneously hypertensive rats (SHRs).nnnMETHODSnPolysomnographic recording was performed through wireless transmission in freely moving SHRs and Wistar-Kyoto rats (WKYs) over 24 hours. The SHRs were injected with saline and an α1-adrenergic antagonist (prazosin: 5 mg/kg) on 2 separate days. Cardiovascular and autonomic functions were assessed by cardiovascular variability and spontaneous baroreflex analysis.nnnRESULTSnCompared with the early-light period (Zeitgeber time (ZT) 0-6 hours), both the WKYs and SHRs during the late-light period (ZT 6-12 hours) showed sleep fragmentation, sympathovagal imbalance, and baroreflex impairment, which were exaggerated and more advanced in the SHRs. Like the morning blood pressure (BP) surge in humans, we found that there was a wake-related blood pressure surge (WBPS) during the late-light period in both groups of rats. The WBPS was also greater and occurred earlier in the SHRs, and was accompanied by a surge in vascular sympathetic index. Under α1-adrenergic antagonism, the late-light period-related sleep fragmentation and BP surge in the SHRs were partially reversed.nnnCONCLUSIONSnOur results reveal that sleep-related sympathetic overactivity, baroreflex sensitivity impairment, WBPS, and sleep fragmentation in SHRs deteriorates during the late-light period can be partially alleviated by treatment with an α1-adrenoceptor antagonist.

Intake of potassium- and magnesium-enriched salt improves functional outcome after stroke: a randomized, multicenter, double-blind controlled trial

Background: Stroke is one of the leading causes of mortality and neurologic deficits. Management measures to improve neurologic outcomes are in great need. Our previous intervention trial in elderly subjects successfully used salt as a carrier for potassium, demonstrating a 41% reduction in cardiovascular mortality by switching to potassium-enriched salt. Dietary magnesium has been associated with lowered diabetes and/or stroke risk in humans and with neuroprotection in animals.Objective: Because a large proportion of Taiwanese individuals are in marginal deficiency states for potassium and for magnesium and salt is a good carrier for minerals, it is justifiable to study whether further enriching salt with magnesium at an amount near the Dietary Reference Intake (DRI) amount may provide additional benefit for stroke recovery.Design: This was a double-blind, randomized controlled trial comprising 291 discharged stroke patients with modified Rankin scale (mRS) ≤4. There were 3 arms: 1) regular salt (Na salt) (n = 99), 2) potassium-enriched salt (K salt) (n = 97), and 3) potassium- and magnesium-enriched salt (K/Mg salt) (n = 95). The NIH Stroke Scale (NIHSS), Barthel Index (BI), and mRS were evaluated at discharge, at 3 mo, and at 6 mo. A good neurologic performance was defined by NIHSS = 0, BI = 100, and mRS ≤1.Results: After the 6-mo intervention, the proportion of patients with good neurologic performance increased in a greater magnitude in the K/Mg salt group than in the K salt group and the Na salt group, in that order. The K/Mg salt group had a significantly increased OR (2.25; 95% CI: 1.09, 4.67) of achieving good neurologic performance compared with the Na salt group. But the effect of K salt alone (OR: 1.58; 95% CI: 0.77, 3.22) was not significant.Conclusions: This study suggests that providing the DRI amount of magnesium and potassium together long term is beneficial for stroke patient recovery from neurologic deficits. This trial was registered at clinicaltrials.gov as NCT02910427.

Cold Exposure Can Induce an Exaggerated Early-Morning Blood Pressure Surge in Young Prehypertensives.

Prehypertension is related to a higher risk of cardiovascular events than normotension. Our previous study reported that cold exposure elevates the amplitude of the morning blood pressure surge (MBPS) and is associated with a sympathetic increase during the final sleep transition, which might be critical for sleep-related cardiovascular events in normotensives. However, few studies have explored the effects of cold exposure on autonomic function during sleep transitions and changes of autonomic function among prehypertensives. Therefore, we conducted an experiment for testing the effects of cold exposure on changes of autonomic function during sleep and the MBPS among young prehypertensives are more exaggerate than among young normotensives. The study groups consisted of 12 normotensive and 12 prehypertensive male adults with mean ages of 23.67 ± 0.70 and 25.25 ± 0.76 years, respectively. The subjects underwent cold (16°C) and warm (23°C) conditions randomly. The room temperature was maintained at either 23°C or 16°C by central air conditioning and recorded by a heat-sensitive sensor placed on the forehead and extended into the air. BP was measured every 30 minutes by using an autonomic BP monitor. Electroencephalograms, electrooculograms, electromyograms, electrocardiograms, and near body temperature were recorded by miniature polysomnography. Under cold exposure, a significantly higher amplitude of MBPS than under the warm condition among normotensives; however, this change was more exaggerated in prehypertensives. Furthermore, there was a significant decrease in parasympathetic-related RR and HF during the final sleep transition and a higher early-morning surge in BP and in LF% among prehypertensives, but no such change was found in normotensives. Our study supports that cold exposure might increase the risk of sleep-related cardiovascular events in prehypertensives.

Differential changes and interactions of autonomic functioning and sleep architecture before and after 50 years of age

We hypothesize that the time when age-related changes in autonomic functioning and in sleep structure occur are different and that autonomic functioning modulates sleep architecture differently before and after 50xa0years of age. Sixty-eight healthy subjects (aged 20 to 79xa0years old, 49 of them women) were enrolled. Correlation analysis revealed that wake after sleep onset, the absolute and relative value of stage 1 (S1; S1%), and relative value of stage 2 (S2) were positively correlated with age; however, sleep efficiency, stage 3 (S3), S3%, and rapid-eye-movement latency (REML) were negatively correlated with age. Significant degenerations of sleep during normal aging were occurred after 50xa0years of age; however, significant declines of autonomic activity were showed before 50xa0years of age. Before 50xa0years of age, vagal function during sleep was negatively correlated with arousal index; however, after 50xa0years of age, it was positively correlated with S1 and S1%. In addition, sympathetic activity during wake stage was positively related to S2% only after 50xa0years of age. Our results imply that the age-related changes in autonomic functioning decline promptly as individuals leave the younger part of their adult life span and that age-related changes in sleep slowly develop as individuals enter the older part of their adult life span. Furthermore, while various aspects of sleep architecture are modulated by both the sympathetic and vagal nervous systems during adult life span, the sleep quality is mainly correlated with the sympathetic division after 50xa0years of age.