Wearable Piezoelectric-Based System for Continuous Beat-to-Beat Blood Pressure Measurement

Non-invasive continuous blood pressure measurement is an emerging issue that potentially can be applied to cardiovascular disease monitoring and prediction. Recently, many groups have proposed the pulse transition time (PTT) method to estimate blood pressure for long-term monitoring. However, the PTT-based methods for blood pressure estimation are limited by non-specific estimation models and require multiple calibrations. This study aims to develop a low-cost wearable piezoelectric-based system for continuous beat-to-beat blood pressure measurement. The pressure change in the radial artery was extracted by systolic and diastolic feature points in pressure pulse wave (PPW) and the pressure sensitivity of the sensor. The proposed system showed a reliable accuracy of systolic blood pressure (SBP) (mean absolute error (MAE) ± standard deviation (SD) 1.52 ± 0.30 mmHg) and diastolic blood pressure (DBP, MAE ± SD 1.83 ± 0.50), and its performance agreed with standard criteria of MAE within 5 mmHg and SD within ±8 mmHg. In conclusion, this study successfully developed a low-cost, high-accuracy piezoelectric-based system for continuous beat-to-beat SBP and DBP measurement without multiple calibrations and complex regression analysis. The system is potentially suitable for continuous, long-term blood pressure-monitoring applications

The Calcium and Voltage Clocks in Sinoatrial Node Automaticity

Recent evidence indicates that the voltage (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release) jointly regulate sinoatrial node (SAN) automaticity. Since the intact SAN is a heterogeneous structure that includes multiple different cell types interacting with each other, the relative importance of the voltage and Ca2+ clocks for pacemaking may be variable in different regions of the SAN. Recently, we performed optical mapping in isolated and Langendorff-perfused canine right atria. We mapped the intracellular calcium (Cai) and membrane potentials of the intact SAN simultaneously. Using previously described criteria of the timing of the late diastolic Cai elevation (LDCAE) relative to the action potential upstroke to detect Ca2+ clock activity, we demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with the robust LDCAE during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic SR Ca2+ release and was closely related with heart rate changes. We conclude that the Ca2+ and voltage clocks work synergistically to generate SAN automaticity

Electrical coupling between ventricular myocytes and myofibroblasts in the infarcted mouse heart

Aims: Recent studies have demonstrated electrotonic coupling between scar tissue and the surrounding myocardium in cryoinjured hearts. However, the electrical dynamics occurring at the myocyte-nonmyocyte interface in the fibrotic heart remain undefined. Here, we sought to develop an assay to interrogate the nonmyocyte cell type contributing to heterocellular coupling and to characterize, on a cellular scale, its voltage response in the infarct border zone of living hearts. Methods and results: We used two-photon laser scanning microscopy in conjunction with a voltage-sensitive dye to record transmembrane voltage changes simultaneously from cardiomyocytes and adjoined nonmyocytes in Langendorff-perfused mouse hearts with healing myocardial infarction. Transgenic mice with cardiomyocyte-restricted expression of a green fluorescent reporter protein underwent permanent coronary artery ligation and their hearts were subjected to voltage imaging 7-10 days later. Reporter-negative cells, i.e. nonmyocytes, in the infarct border zone exhibited depolarizing transients at a 1:1 coupling ratio with action potentials recorded simultaneously from adjacent, reporter-positive ventricular myocytes. The electrotonic responses in the nonmyocytes exhibited slower rates of de- and repolarization compared to the action potential waveform of juxtaposed myocytes. Voltage imaging in infarcted hearts expressing a fluorescent reporter specifically in myofibroblasts revealed that the latter were electrically coupled to border zone myocytes. Their voltage transient properties were indistinguishable from those of nonmyocytes in hearts with cardiomyocyte-restricted reporter expression. The density of connexin43 expression at myofibroblast-cardiomyocyte junctions was ∼5% of that in the intercalated disc regions of paired ventricular myocytes in the remote, uninjured myocardium, whereas the ratio of connexin45 to connexin43 expression levels at heterocellular contacts was ∼1%. Conclusion: Myofibroblasts contribute to the population of electrically coupled nonmyocytes in the infarct border zone. The slower kinetics of myofibroblast voltage responses may reflect low electrical conductivity across heterocellular junctions, in accordance with the paucity of connexin expression at myofibroblast-cardiomyocyte contacts

Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review we focus on the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches and biological therapies. While the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future

Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs

AIMS: We hypothesized that carvedilol can effectively suppress autonomic nerve activity (ANA) in ambulatory dogs during sinus rhythm and atrial fibrillation (AF), and that carvedilol withdrawal can lead to rebound elevation of ANA. Carvedilol is known to block pre-junctional β2-adrenoceptor responsible for norepinephrine release. METHODS AND RESULTS: We implanted radiotransmitters to record stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and superior left ganglionated plexi nerve activity (SLGPNA) in 12 ambulatory dogs. Carvedilol (12.5 mg orally twice a day) was given for 7 days during sinus rhythm (n = 8). Four of the eight dogs and an additional four dogs were paced into persistent AF. Carvedilol reduced heart rate [from 103 b.p.m. (95% confidence interval (CI), 100-105) to 100 b.p.m. (95% CI, 98-102), P = 0.044], suppressed integrated nerve activities (Int-NAs, SGNA by 17%, VNA by 19%, and SLGPNA by 12%; all P < 0.05 vs. the baseline), and significantly reduced the incidence (from 8 ± 6 to 3 ± 3 episodes/day, P < 0.05) and total duration (from 68 ± 64 to 16 ± 21 s/day, P < 0.05) of paroxysmal atrial tachycardia (PAT). Following the development of persistent AF, carvedilol loading was associated with AF termination in three dogs. In the remaining five dogs, Int-NAs were not significantly suppressed by carvedilol, but SGNA significantly increased by 16% after carvedilol withdrawal (P < 0.001). CONCLUSION: Carvedilol suppresses ANA and PAT in ambulatory dogs during sinus rhythm

Effects of Stellate Ganglion Cryoablation on Subcutaneous Nerve Activity and Atrial Tachyarrhythmias in a Canine Model of Pacing-Induced Heart Failure

OBJECTIVES: This study aimed to test the hypothesis that subcutaneous nerve activity (SCNA) can adequately estimate the cardiac sympathetic tone and the effects of cryoablation of the stellate ganglion in dogs with pacing-induced heart failure (HF). BACKGROUND: Recording of SCNA is a new method to estimate sympathetic tone in dogs. HF is known to increase sympathetic tone and atrial arrhythmias. METHODS: Twelve dogs with pacing-induced HF were studied using implanted radiotransmitters to record the stellate ganglia nerve activity (SGNA), vagal nerve activity, and SCNA. Of these, 6 dogs (ablation group) underwent bilateral stellate ganglia cryoablation before the rapid ventricular pacing; the remaining 6 dogs (control group) had rapid ventricular pacing only. In both groups, SCNA was compared with SGNA and the occurrence of arrhythmias. RESULTS: SCNA invariably increased before the 360 identified atrial tachyarrhythmia episodes in the 6 control dogs before and after HF induction. SCNA and SGNA correlated in all dogs with an average correlation coefficient of 0.64 (95% confidence interval: 0.58 to 0.70). Cryoablation of bilateral stellate ganglia significantly reduced SCNA from 0.34 ± 0.033 μV to 0.25 ± 0.028 μV (p = 0.03) and eliminated all atrial tachyarrhythmias. CONCLUSIONS: SCNA can be used to estimate cardiac sympathetic tone in dogs with pacing-induced HF. Cryoablation of the stellate ganglia reduced SCNA and arrhythmia vulnerability

Phospholamban Regulates Nuclear Ca2+ Stores and Inositol 1,4,5-Trisphosphate Mediated Nuclear Ca2+ Cycling in Cardiomyocytes

AIMS: Phospholamban (PLB) is the key regulator of the cardiac Ca2+ pump (SERCA2a)-mediated sarcoplasmic reticulum Ca2+ stores. We recently reported that PLB is highly concentrated in the nuclear envelope (NE) from where it can modulate perinuclear Ca2+ handling of the cardiomyocytes (CMs). Since inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) mediates nuclear Ca2+ release, we examined whether the nuclear pool of PLB regulates IP3-induced nuclear Ca2+ handling. METHODS AND RESULTS: Fluo-4 based confocal Ca2+ imaging was performed to measure Ca2+ dynamics across both nucleus and cytosol in saponin-permeabilized CMs isolated from wild-type (WT) or PLB-knockout (PLB-KO) mice. At diastolic intracellular Ca2+ ([Ca2+]i = 100 nM), the Fab fragment of the monoclonal PLB antibody (anti-PLB Fab) facilitated the formation and increased the length of spontaneous Ca2+ waves (SCWs) originating from the nuclear region in CMs from WT but not from PLB-KO mice. We next examined nuclear Ca2+ activities at basal condition and after sequential addition of IP3, anti-PLB Fab, and the IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) at a series of [Ca2+]i. In WT mice, at 10 nM [Ca2+]i where ryanodine receptor (RyR2) based spontaneous Ca2+ sparks rarely occurred, IP3 increased fluorescence amplitude (F/F0) of overall nuclear region to 1.19 ± 0.02. Subsequent addition of anti-PLB Fab significantly decreased F/F0 to 1.09 ± 0.02. At 50 nM [Ca2+]i, anti-PLB Fab not only decreased the overall nuclear F/F0 previously elevated by IP3, but also increased the amplitude and duration of spark-like nuclear Ca2+ release events. These nuclear Ca2+ releases were blocked by 2-APB. At 100 nM [Ca2+]i, IP3 induced short SCWs originating from nucleus. Anti-PLB Fab transformed those short waves into long SCWs with propagation from the nucleus into the cytosol. In contrast, neither nuclear nor cytosolic Ca2+ dynamics was affected by anti-PLB Fab in CMs from PLB-KO mice in all these conditions. Furthermore, in WT CMs pretreated with RyR2 blocker tetracaine, IP3 and anti-PLB Fab still increased the magnitude of nuclear Ca2+ release but failed to regenerate SCWs. Finally, anti-PLB Fab increased low Ca2+ affinity mag-fluo 4 fluorescence intensity in the lumen of NE of nuclei isolated from WT but not in PLB-KO mice. CONCLUSION: PLB regulates nuclear Ca2+ handling. By increasing Ca2+ uptake into lumen of the NE and perhaps other perinuclear membranes, the acute reversal of PLB inhibition decreases global Ca2+ concentration at rest in the nucleoplasm, and increases Ca2+ release into the nucleus, through mechanisms involving IP3R and RyR2 in the vicinity

Method for Detection and Quantification of Non-Invasive Skin Sympathetic Nerve Activity

Sympathetic nerve activity is an important trigger of cardiac arrhythmia. Our laboratory recently developed a new method for non-invasive recording of the skin sympathetic nerve activity (SKNA) using conventional electrocardiography (ECG) patch electrodes. Recent studies showed that SKNA can adequately estimate sympathetic tone in humans. In order to improve the analysis of SKNA, we developed automatic standard assessment system based on the concept of microneurography and applied to non-invasive SKNA recording via 4 steps of signal processing. Every parameters in procedures can be manually selected by users in order to meet requirements. After using these signal processing, the results obtained by this system show improved nerve burst morphology and trend. Intuitive nerve discharge pattern and occurrence frequency can be automatically generated. Verification of the method with the cold water pressor test data further established the reliability and usefulness of the system. This new method offered a convenient tool to evaluate SKNA for comprehensive and detailed application in neurocardiology. The analysis system may facilitate the study between SKNA and cardiac arrhythmia, thus advance the field of neurocardiology research

Subcutaneous nerve activity is more accurate than heart rate variability in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction

BACKGROUND: We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone. OBJECTIVE: The purpose of this study was to test the hypothesis that left thoracic SCNA is more accurate than heart rate variability (HRV) in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction (MI). METHODS: We used an implanted radiotransmitter to study left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and thoracic SCNA in 9 dogs at baseline and up to 8 weeks after MI. HRV was determined based on time-domain, frequency-domain, and nonlinear analyses. RESULTS: The correlation coefficients between integrated SGNA and SCNA averaged 0.74 (95% confidence interval [CI] 0.41-1.06) at baseline and 0.82 (95% CI, 0.63-1.01) after MI (P <.05 for both). The absolute values of the correlation coefficients were significantly larger than that between SGNA and HRV analysis based on time-domain, frequency-domain, and nonlinear analyses, respectively, at baseline (P <.05 for all) and after MI (P <.05 for all). There was a clear increment of SGNA and SCNA at 2, 4, 6, and 8 weeks after MI, whereas HRV parameters showed no significant changes. Significant circadian variations were noted in SCNA, SGNA, and all HRV parameters at baseline and after MI, respectively. Atrial tachycardia (AT) episodes were invariably preceded by SCNA and SGNA, which were progressively increased from 120th, 90th, 60th, to 30th seconds before AT onset. No such changes of HRV parameters were observed before AT onset. CONCLUSION: SCNA is more accurate than HRV in estimating cardiac sympathetic tone in ambulatory dogs with MI

Sex‐specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles

Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin‐sensitive small conductance Ca2+‐activated K+ (SK) current (IKAS) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. IKAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD25) more prominently than APD at the level of 80% repolarization (APD80), consequently reversing isoproterenol‐induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. IKAS in males did not respond to the L‐type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7‐tetrabromobenzotriazole. In addition, whole‐cell outward IKAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. IKAS activation in females induced negative intracellular Ca2+–voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca2+–voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β‐adrenergic stimulation activates ventricular IKAS in females to a much greater extent than in males. IKAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation