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Table of Contents
Year : 2022  |  Volume : 65  |  Issue : 4  |  Page : 171-178

Spectral analysis of cardiovascular oscillations in the 7-day regimen of losartan administration with and without cold stress

1 Department of Psychiatry, Cheng Hsin General Hospital; Department of Physiology, National Defense Medical Center, Taipei, Taiwan
2 Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan
3 Department of Physiology, National Defense Medical Center, Taipei, Taiwan
4 Department of Physiology; Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
5 Department of Physiology, National Defense Medical Center; Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan

Date of Submission23-Feb-2022
Date of Decision19-May-2022
Date of Acceptance08-Jun-2022
Date of Web Publication26-Aug-2022

Correspondence Address:
Prof. Che-Se Tung
Division of Medical Research and Education, Cheng Hsin General Hospital, No. 45, Cheng Hsin St., Beitou, Taipei 11280
Prof. Shi-Hung Tsai
Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0304-4920.354802

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Spectral analysis of heart rate (HR) and blood pressure (BP) variabilities (BPV and HRV) is widely available and utilized in understanding the dynamic cardiovascular autonomic regulation in a variety of pathophysiological conditions. In conscious cold-stressed (CS) rats, we examined the effect of a 7-day regimen administration of losartan, a selective nonpeptide angiotensin AT1 receptor blockade, on BPV and HRV at three frequency components: very-low frequency (VLF), low frequency (LF), and high frequency (HF). Key findings in changes of systolic BP (SBP), HR, and spectral power densities for cardiopulmonary oscillations (HF), sympathetic oscillations (LF), cardiovascular myogenic oscillations (VLF), and overall autonomic activity total power (TP) showed: (I) In the resting PreCS trial, compared with the saline, losartan increased HFBPV, TPHRV, all three HRV frequency powers, and the occurrence of the dicrotic notch (DN). However, it decreased SBP, HR, and the LFBPV frequency power. (II) In the CS trial, losartan significantly decreased SBP and DN occurrence and HR and LF/HFHRV but significantly increased HFHRV, TPBPV, and all three BPV frequency powers. In addition, similar to the saline, losartan showed positively correlated LFBPV and VLFBPV. Conversely, losartan converted the original inverse correlations between LFHRV and LFBPV of CS to a positive correlation. (III) Compared with saline in PreCS and CS trials, losartan detached the corresponding sympathetic oscillations between LFBPV and LFHRV. The overall result indicates that endogenous angiotensin II, through stimulation of the AT1 receptor, augments sympathetic tone but attenuates sympathetic oscillations in rats, particularly under the stressful cooling impacts.

Keywords: Cardiovascular autonomic regulation, cold stress, losartan, spectral analysis, sympathetic oscillations, sympathetic tone

How to cite this article:
Liu YP, Lin YC, Lin CC, Tsai SH, Tung CS. Spectral analysis of cardiovascular oscillations in the 7-day regimen of losartan administration with and without cold stress. Chin J Physiol 2022;65:171-8

How to cite this URL:
Liu YP, Lin YC, Lin CC, Tsai SH, Tung CS. Spectral analysis of cardiovascular oscillations in the 7-day regimen of losartan administration with and without cold stress. Chin J Physiol [serial online] 2022 [cited 2022 Oct 6];65:171-8. Available from: https://www.cjphysiology.org/text.asp?2022/65/4/171/354802

  Introduction Top

Numerous studies have demonstrated that angiotensin II via different areas of the baroreflex circuit enhances the sympathetic tone, i.e., central augmentation, ganglionic transmission enhancement, and facilitation of norepinephrine release from sympathetic nerve terminals.[1],[2],[3],[4],[5] The baroreflex circuit responds rapidly to decrease arterial blood pressure (BP).[6] In contrast, the humoral effects of angiotensin II respond relatively a time lag through activation of the AT1 receptor (AT1R) on vascular resistance.[7],[8],[9] From the point of stressful impact on efferent (outflow) sympathetic nerve activities to increase vascular resistance, the pressor effect (hypertension) might occur after increased vascular resistance via activating central and or peripheral pathways.[8],[10] Stress exposure may also enhance angiotensin II levels.[11] It is intriguing to determine whether plasma angiotensin II level increases may directly activate AT1R to generate relevant stress disorders such as cold stress (CS)-evoked hemodynamic perturbations (CEHP).

Previous studies indicate that dysregulation of humoral and sympathetic responses to aversive stress is causally associated with central and periphery AT1R hyperactivity.[8],[10],[11],[12] Chan and Chan suggested that oxidative stress on the rostral ventrolateral medulla augments sympathetic vasomotor tone and might induce neurogenic hypertension via activation of the AT1R.[13] These reports provide optimism that the blockade of AT1R receptors is a promising therapeutic option for stress disorders. Indeed, AT1R blockades, such as losartan, could alleviate mental health problems such as anxiety and isolation stress.[12],[14]

CS and hypothermia are essential stressors that evoke a widespread humoral response. Rapid CS exposure induces pressor (CIP) and tachycardia (CIT) and increases sympathetic neurotransmissions, called CEHP,[15],[16],[17],[18],[19] a noninvasive maneuver in clinical practice for evaluating autonomic cardiovascular regulation, was first observed by Lewis T.[20],[21] The phenomenon is characterized by hemodynamic instability (irregular BP, heart rate [HR], and cardiovascular oscillations), initial vasoconstriction followed by vasodilatation, and secondary progressive vasoconstriction.

Spectral analysis of cardiovascular variability (BP variability [BPV] and heart rate variability [HRV]) using a frequency domain approach is widely applied to evaluate the autonomic regulation of cardiovascular function in health and disease – a dynamic interplay among ongoing oscillatory BP and HR and compensatory responses, which depends on interactions among complex neurohumoral reflexes. In previous, we have performed a series of studies. We demonstrated that increased sympathetic vasomotor oscillations (as increased low frequency [LF] BPV) could enhance the strength of vasculomyogenic oscillations (as increased very-low frequency [VLF] BPV), implying an increase of perfusion to prevent tissue damage under the acute cooling impact.[16],[17],[18] We understand that angiotensin II could influence distinct frequency domains since the time lag to activate the renin–angiotensin system is longer than to excite the autonomic and baroreflex function. However, few current investigations attribute to the angiotensin II and CEHP relationships. We thus, in this study, employed spectral and cross-spectral analyses in conscious rats to examine whether a 7-day regimen of losartan administration would affect the cardiovascular autonomic regulation with and without CEHP.

  Materials and Methods Top


Adult male Sprague-Dawley rats weighing between 300 and 350 g were received at the Laboratory Animal Center of the National Defense Medical Center (NDMC, Taiwan) 1 week before the experiments. All efforts were made to reduce the number of experimental animals and their suffering in experiments. The rats in the same experimental group were housed together in a temperature- and humidity-controlled holding facility with a 12-hour light/dark cycle (lights on from 07:00 to 19:00) maintained by manual light control switches as required by the experiment. They received food and water ad libitum.

Experimental design

[Figure 1] illustrates the experiment protocol approved by the NDMC animal care committee (IACUC-13-170). Before commencing the study, the time course of the losartan (30 mg/kg) effect was sought using a standard losartan administration method by gastric gavage, where there we confirmed that the losartan 30 mg/kg dose had a BP-lowering effect. Using this gastric gavage losartan dosage, we found that BP decreased significantly on the fourth day and continued to the seventh day. All rats were then divided randomly into two experimental groups for the same stressful cooling procedure. The control group rats received vehicle solution (NS, 0.9% NaCl, n = 8), and the other group rats received losartan (LOS, 30 mg/kg/3.0 mL vehicle, n = 8) seven times a week for one week, including a dose 30 min before the CS trial.
Figure 1: General protocol: (a) the telemetry sensor embedded in the rat 14 days before administration of a testing agent and (b) the sequence of procedures on the testing day, PreCS, CS, and Recovery. The control group of rats has 0.9% NaCl (NS). The other group of rats has losartan. CS: Cold stress, LOS: Losartan, PreCS: Before CS.

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Cooling process

After adjusting to the experimental environments, all rats were taken to an adjacent room and treated with the same cooling process. A maximum of ten rats was tested per day, with five rats tested simultaneously. All experiments were performed between 08:30 and 11:30.

All rats will receive the telemetry sensor (TL11M2-M2-C50-PXT, DSI, St. Paul, MN, USA) implanted into the descending aorta and stitched the implant structure along the abdominal cavity concurrently to record core temperature and BP. Following a complete stabilization of the systolic BP (SBP, mmHg) and HR (beats/min) at room temperature, each rat's glabrous palms and soles were quickly submerged in ice water (4°C) for 10 min (CS). Beat-to-beat SBP signals were recorded continuously at the subsequent trials: the 10-min before CS trial (PreCS) and the 10-min CS trial itself. After the CS trial, the rat was removed from the test cage, dried with a cloth, and placed in a similar animal cage for 10 min to facilitate recovery. In each trial, the results of signals from a 5-min period (min 3–8) were adopted for spectral analyses. Dicrotic notch (Dn) was counted by manual.

Spectrum signal acquisition and processing

Spectrum signal acquisition and processing are adopted from the methods reported in our previous study.[16],[17],[18] Briefly, the series oscillatory signals of SBP and inter-beat interval (IBI) of HR are computed independently to obtain the power density of total power (0.00–3.0 Hz, total power) and three dominant frequencies: VLF (0.02–0.2 Hz, VLF), low frequency (0.20–0.60 Hz, LF), and high frequency (0.60–3.0 Hz, high frequency [HF]). The HRV power LF to HF (LF/HFHRV) as a measure of sympathovagal balance was also calculated. The moduli of the power density for each frequency are BPV (mm Hg2) and HRV (ms2). Further computation was done using the cross-spectral analysis to examine the strength of coherence between BPV and HRV across a given frequency region. An estimated peak value (K2IBI/SBP) >0.58 is considered a significant covary within that specific frequency region.

Statistical analysis

We portray Box plots to show each data group's interquartile values (median, upper and lower quartile) because most data revealed nonparametric distributions. We used the 2 × 2 factorial Analysis of Variance (Kruskal–Wallis two-way ANOVA) with a between-subject factor of the independent “Group” (NS and LOS) and within-subjects factor of the separated periods “Trial” (PreCS and CS) followed by post hoc Dunn's Multiple Comparison Test to confirm where the differences occurred between trials of those two groups. Univariate correlations were calculated using Pearson's correlation analysis to estimate associations between LFHRV and LFBPV and between LFBPV and VLFBPV. The difference was considered significant at P < 0.05. All statistics were made using the SPSS 16.0 for Windows (Chicago, IL, USA).

  Results Top

A representative example of BP and HR tracings for different groups of rats challenged with and without CS is shown in [Figure 2]. [Figure 3], [Figure 4], [Figure 5] and [Table 1] show each data group's median and interquartile values.
Figure 2: Typical examples of the blood pressure tracing for rats treated with: Control vehicle solution (NS, 0.9% NaCl) or losartan (LOS, 30 mg/kg/3.0 mL vehicle). The timeline is 0–60 s of the 4th min (4–5 min). CS (4°C rapid ice-water immersion of the palms and soles). CS: Cold stress, LOS: Losartan, PreCS: Before CS.

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Figure 3: Systolic blood pressure and heart rate changes of control vehicle (NS) or losartan (LOS) group rats throughout the experiment: Measured changes of (I) SBP (upper left panel) and HR (lower left panel), and (II) the occurrence of the Dn. The box plot shows the median for NS (n = 8) and LOS (n = 8), upper and lower quartile, and minimal and maximal values. Differences were assessed by Kruskal–Wallis two-way ANOVA followed by post hoc Dunn's Multiple Comparison Test and are indicated as follows: Differences between group rats (*P < 0.05, **P < 0.01, ***P < 0.001) and differences between the same parameter for CS versus PreCS (###P < 0.001). CS: Cold stress, LOS: Losartan, NS: 0.9% NaCl, Dn: Dicrotic notch, HR: heart rate, SBP: Systolic blood pressure.

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Figure 4: Power spectral density changes of control vehicle (NS) or LOS group rats throughout the experiment: Measured changes of (I) VLF, (II) LF, and (III) HF. The box plot shows the median for NS (n = 8) and LOS (n = 8), upper and lower quartile, and minimal and maximal values. Differences were assessed by Kruskal–Wallis two-way ANOVA followed by post hoc Dunn's Multiple Comparison Test and are indicated as follows: Differences between group rats (*P < 0.05, **P < 0.01, ***P < 0.001) and differences between the same parameter for CS versus PreCS (#P < 0.05, ###P < 0.001). CS, PreCS, BPV (mm Hg2); HRV (ms2). CS: Cold stress, PreCS: Before CS, BPV: Blood pressure variability (mm Hg2), HRV: Heart rate variability (ms2), HF: High frequency, LF: Low frequency, VLF: Very-low frequency, LOS: Losartan, NS: 0.9% NaCl.

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Figure 5: The relationship between systolic blood pressure and heart rate oscillations in regions as assessed by K2IBI/SBP of two group rats throughout the experiment: VLF, LF, and HF. CS: Cold stress, PreCS: Before CS, K2IBI/SBP: Peak coherence value, HF: High frequency, VLF: Very-low frequency, LF: Low frequency.

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Table 1: The overall power spectral density of control vehicle (NS) or losartan group rats

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Responses of systolic blood pressure, heart rate, and dicrotic notch appearance

[Figure 3] (left panel) shows SBP and HR changes. Compared with NS, LOS significantly decreases the magnitudes of SBP and HR (P < 0.05) in the PreCS trial and HR (P < 0.01) in the CS trial, but LOS insignificantly slightly decreases SBP (P = 0.065) in the CS trial. Besides, when both NS and LOS group rats compared their CS with respective PreCS, cooling impact generally induces pressor response, i.e., CIP (NS: P < 0.001; LOS: P < 0.001) and tachycardia response, i.e., CIT (NS: P < 0.001; LOS: P < 0.001), so-called CEHP aforementioned earlier. However, the LOS group rats' two CIP and CIT profiles are lower than those of the NS group rats.

[Figure 3] (right panel) shows the occurrence of Dn. Contrary to NS, LOS shows the Dn occurrence is much more evident in the baseline PreCS trial (P < 0.001). However, like NS, LOS significantly diminished the Dn occurrence in the CS trial (P < 0.001).

Response of spectral powers and coherence function changes

[Table 1] and [Figure 4] show spectral power changes in BPV and HRV of three definite frequency regions. Compared with NS in the PreCS trial, LOS significantly increases HFBPV (P < 0.05) [[Figure 4]III: Lower right], HFHRV (P < 0.001) [[Figure 4]III: Lower left], LFHRV (P < 0.001) [[Figure 4]II: Middle left], VLFHRV (P < 0.001) [[Figure 4]I: Upper left], and TPHRV (P < 0.001) [Table 1] but significantly decreases LFBPV (P = 0.01) [[Figure 4]II: Middle right]. However, compared with the NS in the CS trial, LOS significantly increases HFHRV (P < 0.001), HFBPV (P < 0.001) [[Figure 4]III: Lower right], LFBPV (P < 0.001), VLFBPV (P < 0.001) [[Figure 4]I: Upper right], VLFHRV (P < 0.05), and TPBPV (P < 0.001) [Table 1]. On the other hand, both NS and LOS group rats when compared their CS with respective PreCS, cooling impact generally significant increases HFBPV (NS: P < 0.001; LOS: P < 0.001), LFBPV (LOS: P < 0.001), and VLFBPV (NS: P < 0.001; LOS: P < 0.001), whereas cooling impact generally significant decreases HFHRV (NS: P < 0.05; LOS: P < 0.001), LFBPV (NS: P < 0.001), LFHRV (NS: P < 0.05; LOS: P < 0.001), and VLFHRV (NS: P < 0.05; LOS: P < 0.05).

The strength of associations between LFHRV and LFBPV and between LFBPV and VLFBPV were assessed by univariate analysis. Compared with the NS group rats at the time of CS exposure, the LOS group rats show a similarly positive correlation between the LFBPV and VLFBPV (NS: R = 0.81, P < 0.05; LOS: R = 0.73, P < 0.05) but the original inverse correlation of the NS group rats (r = -0.457, P = 0.225) is converted into a positive correlation of the LOS group rats (r = 0.70, P < 0.05) between the LFHRV and LFBPV.

Finally, the coherence between BPV and HRV at three definite frequency regions is shown in [Figure 5]. Compared with the K2IBI/SBP values of the NS group rats at the LF region (PreCS: 1 out of 8 rats >0.58; CS: 2 out of 8 rats >0.58), the LOS group rats tend to detach, showing of low K2IBI/SBP values (PreCS: 8 out of 8 rats <0.58; CS: 8 out of 8 rats < 0.58). Compared with the HF region in both PreCS and CS trials, the LOS group rats generally show a similar high K2IBI/SBP values to that of the NS group rats (PreCS: 8 out of 8 rats >0.58 [LOS] vs. 8 out of 8 rats >0.58 [NS]; CS: 8 out of 8 rats >0.58 [LOS] vs. 8 out of 8 rats >0.58 [NS]). On the other hand, there are always small K2IBI/SBP values (<0.58) of both NS and LOS group rats at the VLF region throughout the experiment, suggesting both treatments dissociate myogenic oscillations between BPV and HRV.

  Discussion Top

Circulating angiotensin II and baroreflex interactions are widespread through AT1R in various central and periphery regions rich in sympathetic neurons.[4],[5],[22],[23],[24],[25] The present study investigated the role of angiotensin II before and under the anxious CS using losartan, an angiotensin type 1 receptor antagonist. The losartan 7-day administration regime attenuates sympathetic vasomotor tone but strengthens cardiovascular variability, particularly in conscious rats' CEHP. The elevated SBP, detected by arterial baroreceptors, reflexively decreases HR and cardiac output by increasing parasympathetic activity but decreasing sympathetic activity. Conversely, the lessened SBP evokes the opposite responses. We focused on sympathetic vasomotor reactions in this study. SBP is a standard stimulus for baroreflex resulting from the sympathetic vasomotor tone. However, HR is a weak surrogate of cardiac sympathetic outflows due to the complex innervation of the heart by sympathetic and vagal fibers. As a result, the interpretation of HRV spectra is more complicated than that of BPV spectra.[26],[27],[28] The former considers the interplay of sympathetic and vagal influence on the heart, reflecting heart-brain interactions and autonomic neural dynamics.

Compared with the control vehicle in the baseline PreCS trial, losartan showed notable increases in HFBPV and TPHRV, accompanying increases in all three HRV spectral powers. In addition, there was an increase in the Dn occurrence. However, there were significant decreases in SBP, HR, and, in particular, the power of LFBPV [Figure 3] and [Figure 4]. We propose two possible mechanisms below to explain these observations.

First, from the point of view of central sympathetic outflows, we suggest that decreasing both SBP and HR reflects a diminishing of sympathetic drive to the vascular smooth muscle and heart simultaneously increasing parasympathetic drive to the heart; therefore, engendering vasodilation and heart negative chronotropic effect because losartan inhibits the central augmentation effects of angiotensin II on sympathetic outflows.[2],[13] Second, from the point of view of periphery sympathetic nerve innervations, we speculate that losartan inhibits the presynaptic angiotensin II action on sympathetic postganglionic neurons and then lowers the noradrenaline level in the vasculature and heart; therefore, lowering vascular resistance causing vasodilation and heart negative chronotropic effect.[4],[29],[30],[31]

Next, our spotlight turns on the effects of losartan under stressful cooling impact. Compared with the control vehicle in the CS trial, losartan showed notable decreases in SBP, HR, and the Dn occurrence, whereas increases in HFHRV, TPBPV, and all three BPV spectral powers. Besides, similar to the control vehicle, losartan showed a positive correlation between LFBPV and VLFBPV, whereas converted the original inverse correlations between LFHRV and LFBPV of the control vehicle to correlate them positively in the CS trial. In short, losartan caused an apparent inconsistency in hemodynamic changes between PreCS and CS, i.e., a decrease in sympathetic tone (CIP and CIT) but a rise in all three BPV spectral powers under CS. The LFBPV increase indicates sympathetic arousal, while the VLFBPV increase indicates strengthened vasculomyogenic activity. Such phenomena reflect that losartan treatment could be beneficial to increase perfusion to prevent tissue damage under the stressful cooling impact.[17],[18] The inconsistency between the diminishing SBP and HR and the increasing spectral powers (LFBPV and LFHRV) is intriguing. Their involved underlying mechanisms need further discussion.

As described in the previous section, reducing SBP reduces afferent nerve activity from arterial baroreceptors to the brain, thereby increasing sympathetic outflows, manifested by increasing LFBPV and LFHRV powers. Conversely, direct action on innervated resistance vessels via norepinephrine released from sympathetic nerve endings may increase baroreceptor sensitivity to reducing sympathetic outflows. However, other chemical factors such as epinephrine and angiotensin II may also alter the maximum baroreceptor activity independently of sympathetic changes in vascular tone. In addition to baroreflex in the homeostatic regulations, several other aspects of different reflex pathways are involved, such as cardiopulmonary, hepatic/portal, and renorenal reflexes.[32],[33],[34],[35],[36],[37] Renorenal reflex is a kind of inhibitory reflex; activation of afferent renal mechanosensory nerve activity (ARNA) evokes a decrease of efferent renal sympathetic nerve activity (ERSNA), which could prevent ERSNA overactivation and subsequent excessive sodium retention. Renorenal reflex is a kind of inhibitory reflex; activation of ARNA evokes a decrease of ERSNA, which could prevent ERSNA overactivation and subsequent excessive sodium retention.[33],[34] As to such considerations, we propose below two possible underlying mechanisms by which losartan may affect CEHP.

One possible mechanism is that under CS, losartan inhibits endogenous norepinephrine- and or angiotensin II-induced vasoconstriction, engendering vasodilation, thereby weakening the baroreflex effect and causing the increases of both LFBPV and LFHRV powers. The other possible mechanism could be that under CS, the elevation of plasma norepinephrine in plasma might increase the release of renin from the kidneys with subsequently increased formation of angiotensin II. Angiotensin II has known to mediate suppression of the activation of ARNA.[33] As aforementioned, via the inhibitory renorenal reflex, activation of ARNA evokes a decrease of ERSNA; vice versa, inhibition of ARNA increases ERSNA, exhibiting an increase in both LFBPV and LFHRV powers. Therefore, we speculate that the increases in LFBPV and LFHRV powers were because the inhibitory renorenal reflex was blocked after losartan treatment.

Finally, we observed that losartan affects the pressure wave; losartan enhanced the magnitude of the appearance of Dn in PreCS. However, similar to the control vehicle, losartan reduced the Dn occurrence in CS. The presence of Dn indicates vascular tone changes modifying the reflected pressure waves in conduit arteries.[38] As a result, our observation provides additional information about the myogenic responses to the hemodynamic perturbations by angiotensin II. Furthermore, we observed that between LFBPV and LFHRV, the control vehicle's high coherence value (K2IBI/SBP > 0.58) was weakened by losartan throughout the experiment [Figure 5], suggesting that antagonism of AT1R by losartan detached the baroreflex feedback loop.

  Conclusion Top

The current study demonstrates that immediately stressful cooling impacts may elevate circulatory angiotensin II activities. The results implicate an essential role of the renin-angiotensin system in the CEHP development, and the losartan treatments could help reduce the induced pressor and tachycardia and prevent tissue damage after cold exposure. Considering the beneficial actions of AT1 angiotensin II receptor antagonist by other literature reports, further investigation is needed to elucidate the interaction mechanisms between the autonomic cardiovascular regulations and the renin-angiotensin system in the CEHP genesis.

Financial support and sponsorship

This research was funded by the Ministry of Science and Technology and the CHGH–NDMC cooperative research project, Taiwan, R. O. C., grant number: MOST 103-2320-B-350-001, MOST 108-2314-B-016-047-MY3, CH-NDMC-110-6, CH-NDMC-11114.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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