Identification of malignant early repolarization pattern by late QRS activity in high-resolution magnetocardiography.

BACKGROUND: The early repolarization pattern (ERP) in electrocardiography (ECG) has been considered as a risk for ventricular fibrillation (VF), but effective methods for identification of malignant ERP are still required. We investigated whether high spatiotemporal resolution 64-channel magnetocardiography (MCG) would enable distinction between benign and malignant ERPs. METHODS: Among all 2,636 subjects who received MCG in our facility, we identified 116 subjects (43 ± 18 years old, 54% male) with inferior and/or lateral ERP in ECG and without structural heart disease, including 13 survivors of VF (ERP-VF(+)) and 103 with no history of VF (ERP-VF(-)). We measured the following MCG parameters in a time-domain waveform of relative current magnitude: (a) QRS duration (MCG-QRSD), (b) root-mean-square of the last 40 ms (MCG-RMS40), and (c) low amplitude (<10% of maximal) signal duration (MCG-LAS). RESULTS: Compared to ERP-VF(-), ERP-VF(+) subjects presented a significantly longer MCG-QRS (108 ± 24 vs. 91 ± 23 ms, p = .02) and lower MCG-RMS40 (0.10 ± 0.08 vs. 0.25 ± 0.20, p = .01) but no difference in MCG-LAS (38 ± 22 vs. 29 ± 23 ms, p = .17). MCG-QRSD and MCG-RMS40 showed significantly larger area under the ROC curve compared to J-peak amplitude in ECG (0.72 and 0.71 vs. 0.50; p = .04 and 0.03). The sensitivity, specificity, and odds ratio for identifying VF(+) based on MCG-QRSD ≥ 100 ms and MCG-RMS40 ≤ 0.24 were 69%, 74%, and 6.33 (95% CI, 1.80-22.3), and 92%, 48%, and 10.9 (95% CI, 1.37-86.8), respectively. CONCLUSION: Magnetocardiography is an effective tool to distinguish malignant and benign ERPs.

Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve.

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

Derangement of open-loop static and dynamic characteristics of the carotid sinus baroreflex in streptozotocin-induced type 1 diabetic rats.

Although diabetes mellitus (DM) is a major risk factor for cardiovascular diseases, changes in open-loop static and dynamic characteristics of the arterial baroreflex in the early phase of DM remain to be clarified. We performed an open-loop systems analysis of the carotid sinus baroreflex in type 1 DM rats 4 to 5 wk after intraperitoneal streptozotocin injection ( n = 9) and we compared the results with control rats ( n = 9). The operating-point baroreflex gain was maintained in the DM rats compared with the control rats (2.07 ± 0.67 vs. 2.66 ± 0.22 mmHg/mmHg, P = 0.666). However, the range of arterial pressure (AP) control was narrower in the DM than in the control group (48.0 ± 5.0 vs. 77.1 ± 4.5 mmHg, P = 0.001), suggesting that the reserve for AP buffering is lost in DM. Although baroreflex dynamic characteristics were relatively preserved, coherences were lower in the DM than in the control group. The decreased coherence in the neural arc may be related to the narrowed quasi-linear range in the static relationship between carotid sinus pressure and sympathetic nerve activity in the DM group. Although the reason for the decreased coherences in the peripheral arc and the total reflex arc was inconclusive, the finding may indicate a loss of integrity of the baroreflex-mediated sympathetic AP control in the DM group. The derangement of the baroreflex dynamic characteristics is progressing occultly in this early stage of type 1 DM in a manner where dynamic gains are relatively preserved around the normal operating point.

Myocardial interstitial levels of serotonin and its major metabolite 5-hydroxyindole acetic acid during ischemia-reperfusion.

The aim of this study was to examine the accumulation of serotonin (5-HT) and degradation of 5-HT taken up into cells in the ischemic region during myocardial ischemia-reperfusion. Using microdialysis technique in anesthetized rats, we monitored myocardial interstitial levels of 5-HT and its metabolite produced by monoamine oxidase (MAO), 5-hydroxyindole acetic acid (5-HIAA), during 30-min coronary occlusion followed by 45-min reperfusion, and investigated the effects of local administration of the MAO inhibitor pargyline and the 5-HT uptake inhibitor fluoxetine. In the vehicle group, the dialysate 5-HT concentration increased from 1.3 ± 0.2 nM at baseline to 29.6 ± 2.8 nM at 22.5-30 min of occlusion, but the dialysate 5-HIAA concentration did not change from baseline (9.9 ± 1.1 nM). Upon reperfusion, the dialysate 5-HT concentration increased further to a peak (34.2 ± 4.2 nM) at 0-7.5 min and then declined. The dialysate 5-HIAA concentration increased to 31.9 ± 5.2 nM at 7.5-15 min of reperfusion and maintained this high level until 45 min. Pargyline markedly suppressed the increase in dialysate 5-HIAA concentration after reperfusion and increased the averaged dialysate 5-HT concentration during the reperfusion period. Fluoxetine suppressed the increase in dialysate 5-HT concentration during occlusion but did not change dialysate 5-HT or 5-HIAA concentration after reperfusion. During ischemia, 5-HT secreted from ischemic tissues accumulates but 5-HT degradation by MAO is suppressed. After reperfusion, degradation of 5-HT taken up into cells is enhanced and contributes to the clearance of accumulated 5-HT. This degradation following cellular uptake is dependent on MAO activity but not the fluoxetine-sensitive uptake transporter. NEW & NOTEWORTHY: By monitoring myocardial interstitial levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid, we investigated 5-HT kinetics during myocardial ischemia-reperfusion. 5-HT accumulates but 5-HT degradation is suppressed during ischemia. After reperfusion, 5-HT degradation is enhanced and this degradation is dependent on monoamine oxidase activity but not fluoxetine-sensitive uptake transporter.

The Current Status of Cardiovascular Medicine in Japan　- Analysis of a Large Number of Health Records From a Nationwide Claim-Based Database, JROAD-DPC.

BACKGROUND: Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records' data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range [IQR], 76.9-88.0%), there were wide variations in the proportions of patients prescribed ß-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6-55.7%; ACEI/ARB, 52.0%, IQR 40.3-62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8-47.6%; ACEI/ARB, 41.0%, IQR 31.7-49.1%). CONCLUSIONS: A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327-2335).

Hybrid stage I palliation for hypoplastic left heart syndrome has no advantage on ventricular energetics: a theoretical analysis.

A hybrid procedure combining bilateral pulmonary artery banding with ductal stenting has recently been used as stage I palliation for hypoplastic left heart syndrome. However, the advantage of the hybrid procedure over the Norwood procedure on ventricular energetics remains unclear. To clarify this, we performed a computational analysis with a combination of time-varying elastance chamber model and modified three-element Windkessel vascular model. Although mean pulmonary artery (PA) pressure, pulmonary flow, and oxygen saturation were almost equivalent with the Norwood procedure, the hybrid procedure delivered higher systolic and lower diastolic systemic arterial pressures compared to the Norwood procedure with right ventricle (RV) to PA shunt. As a result, the hybrid procedure yielded increased systolic pressure-volume area and impaired mechanical efficiency. Therefore, the hybrid procedure has probably no advantage on ventricular energetics compared to the Norwood procedure with a RV-PA shunt.

Medetomidine suppresses cardiac and gastric sympathetic nerve activities but selectively activates cardiac vagus nerve.

BACKGROUND: To identify a pharmacological agent that can selectively activate cardiac vagus nerve for potential use in vagal activation therapy against heart failure, the effects of medetomidine on autonomic nerve activities in both the heart and stomach were examined. METHODS AND RESULTS: In anesthetized rabbits, microdialysis probes were implanted into both the right atrial and gastric walls. Dialysate acetylcholine (ACh) and norepinephrine (NE) concentrations were measured by high-performance liquid chromatography. First, the effects of 100µg/kg of intravenous medetomidine on vagal ACh and sympathetic NE releases were examined. Medetomidine significantly increased cardiac ACh release (4.7±1.1 to 7.8±0.9nmol/L, P<0.05), but suppressed gastric ACh release (8.0±2.6 to 3.5±1.5nmol/L, P<0.01). In contrast, medetomidine suppressed both cardiac and gastric NE releases. Second, the effects of medetomidine on ACh releases induced by electrical vagus nerve stimulation (VNS; 10Hz) were examined. Electrical VNS significantly increased both cardiac (6.7±1.2 to 14.8±1.8nmol/L, P<0.01) and gastric (3.8±0.8 to 181.3±65.6nmol/L, P<0.01) ACh releases. Medetomidine did not alter the VNS-induced increases in ACh release. CONCLUSIONS: Medetomidine suppresses both cardiac and gastric sympathetic nerve activities. In contrast, medetomidine activates cardiac vagus nerve but inhibits gastric vagal activity. Medetomidine might be one of the potential pharmacological agents for vagal activation therapy against heart failure without the risk of gastric adverse effects.

Effects of dapagliflozin on myoglobin efflux from cardiomyocyte during myocardial ischemia/reperfusion in anesthetized rats.

It has been suggested that sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardioprotective effects during myocardial ischemia/reperfusion (I/R) independent of glucose-lowering action. However, the effects of SGLT2 inhibitors on structural damage to cardiomyocytes in the ischemic region during I/R remain unknown. We applied a microdialysis technique to the heart of anesthetized rats and investigated the effects of an SGLT2 inhibitor, dapagliflozin, on myocardial interstitial myoglobin levels in the ischemic region during coronary occlusion followed by reperfusion. Dapagliflozin was administered systemically (40 µg/body iv) or locally via a dialysis probe (100 µM and 1 mM) 30 min before coronary occlusion. In the vehicle group, coronary occlusion increased the dialysate myoglobin concentration in the ischemic region. Reperfusion further increased the dialysate myoglobin concentration. Intravenous administration of dapagliflozin reduced dialysate myoglobin concentration during ischemia and at 0-15 min after reperfusion, but local administration (100 µM and 1 mM) did not. Therefore, acute systemic administration of dapagliflozin prior to ischemia has cardioprotective effects on structural damage during I/R.

Donepezil markedly improves long-term survival in rats with chronic heart failure after extensive myocardial infarction.

BACKGROUND: Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats. METHODS AND RESULTS: At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325 ± 6 vs. 355 ± 10 beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dtmax: +18%, P<0.01; left ventricular end-diastolic pressue: -26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73 ± 0.04 vs. 3.06 ± 0.08 g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers. CONCLUSIONS: Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.

Medetomidine, an α(2)-adrenergic agonist, activates cardiac vagal nerve through modulation of baroreflex control.

BACKGROUND: Although α(2)-adrenergic agonists have been reported to induce a vagal-dominant condition through suppression of sympathetic nerve activity, there is little direct evidence that they directly increase cardiac vagal nerve activity. Using a cardiac microdialysis technique, we investigated the effects of medetomidine, an α(2)-adrenergic agonist, on norepinephrine (NE) and acetylcholine (ACh) release from cardiac nerve endings. METHODS AND RESULTS: A microdialysis probe was implanted into the right atrial wall near the sinoatrial node in anesthetized rabbits and perfused with Ringer's solution containing eserine. Dialysate NE and ACh concentrations were measured using high-performance liquid chromatography. Both 10 and 100µg/kg of intravenous medetomidine significantly decreased mean blood pressure (BP) and the dialysate NE concentration, but only 100µg/kg of medetomidine enhanced ACh release. Combined administration of medetomidine and phenylephrine maintained mean BP at baseline level, and augmented the medetomidine-induced ACh release. When we varied the mean BP using intravenous administration of phenylephrine, treatment with medetomidine significantly steepened the slope of the regression line between mean BP and log ACh concentration. CONCLUSIONS: Medetomidine increased ACh release from cardiac vagal nerve endings and augmented baroreflex control of vagal nerve activity.

Adaptation of the respiratory controller contributes to the attenuation of exercise hyperpnea in endurance-trained athletes.

We have reported that minute ventilation [[Formula: see text]] and end-tidal CO(2) tension [[Formula: see text]] are determined by the interaction between central controller and peripheral plant properties. During exercise, the controller curve shifts upward with unchanged central chemoreflex threshold to compensate for the plant curve shift accompanying increased metabolism. This effectively stabilizes [Formula: see text] within the normal range at the expense of exercise hyperpnea. In the present study, we investigated how endurance-trained athletes reduce this exercise hyperpnea. Nine exercise-trained and seven untrained healthy males were studied. To characterize the controller, we induced hypercapnia by changing the inspiratory CO(2) fraction with a background of hyperoxia and measured the linear [Formula: see text] relation [[Formula: see text]]. To characterize the plant, we instructed the subjects to alter [Formula: see text] voluntarily and measured the hyperbolic [Formula: see text] relation ([Formula: see text]). We characterized these relations both at rest and during light exercise. Regular exercise training did not affect the characteristics of either controller or plant at rest. Exercise stimulus increased the controller gain (S) both in untrained and trained subjects. On the other hand, the [Formula: see text]-intercept (B) during exercise was greater in trained than in untrained subjects, indicating that exercise-induced upward shift of the controller property was less in trained than in untrained subjects. The results suggest that the additive exercise drive to breathe was less in trained subjects, without necessarily a change in central chemoreflex threshold. The hyperbolic plant property shifted rightward and upward during exercise as predicted by increased metabolism, with little difference between two groups. The [Formula: see text] during exercise in trained subjects was 21% lower than that in untrained subjects (P < 0.01). These results indicate that an adaptation of the controller, but not that of plant, contributes to the attenuation of exercise hyperpnea at an iso-metabolic rate in trained subjects. However, whether training induces changes in neural drive originating from the central nervous system, afferents from the working limbs, or afferents from the heart, which is additive to the chemoreflex drive to breathe, cannot be determined from these results.

Exercise training augments the dynamic heart rate response to vagal but not sympathetic stimulation in rats.

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 ± 1.5 vs. 4.5 ± 1.5 beats·min(-1)·Hz(-1); natural frequency, 0.07 ± 0.01 vs. 0.08 ± 0.01 Hz; damping coefficient, 1.96 ± 0.55 vs. 1.69 ± 0.15; and lag time, 0.7 ± 0.1 vs. 0.6 ± 0.1 s; sedentary vs. exercise trained, respectively, means ± SD). The transfer gain from vagal stimulation to HR response was 6.1 ± 3.0 in the sedentary and 9.7 ± 5.1 beats·min(-1)·Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 ± 0.05 vs. 0.17 ± 0.09 Hz) and lag time (0.1 ± 0.1 vs. 0.2 ± 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.

Dynamic characteristics of heart rate control by the autonomic nervous system in rats.

We estimated the transfer function of autonomic heart rate (HR) control by using random binary sympathetic or vagal nerve stimulation in anaesthetized rats. The transfer function from sympathetic stimulation to HR response approximated a second-order, low-pass filter with a lag time (gain, 4.29 +/- 1.55 beats min(1) Hz(1); natural frequency, 0.07 +/- 0.03 Hz; damping coefficient, 1.96 +/- 0.64; and lag time, 0.73 +/- 0.12 s). The transfer function from vagal stimulation to HR response approximated a first-order, low-pass filter with a lag time (gain, 8.84 +/- 4.51 beats min(1) Hz(1); corner frequency, 0.12 +/- 0.06 Hz; and lag time, 0.12 +/- 0.08 s). These results suggest that the dynamic characteristics of HR control by the autonomic nervous system in rats are similar to those of larger mammals.

Acute effects of intravenous carvedilol versus metoprolol on baroreflex-mediated sympathetic circulatory regulation in rats.

AIMS: To compare the effects of metoprolol and carvedilol on baroreflex-mediated sympathetic circulatory regulation. METHODS: In anesthetized Wistar-Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA), arterial pressure (AP), heart rate (HR), and aortic flow (AoF) in response to a staircase-wise pressure input were examined before (control) and after intravenous injection of low-dose metoprolol (2 mg/kg), high-dose metoprolol (10 mg/kg), or carvedilol (0.67 mg/kg) (n = 6 each). Peripheral vascular resistance (PVR) was calculated from mean AP divided by mean AoF. RESULTS: Low-dose metoprolol had limited effect on sympathetic AP regulation compared to control [operating-point AP (drug vs. control): 88.7 ±â€¯7.1 vs. 98.3 ±â€¯3.3 mm Hg, not significant] despite a significant bradycardic effect. Although high-dose metoprolol showed central sympathoinhibition, it increased PVR at a given SNA as a peripheral effect. Consequently, high-dose metoprolol decreased the operating-point AP slightly (96.1 ±â€¯2.7 vs. 101.9 ±â€¯2.7 mm Hg, P < 0.01). Carvedilol showed no significant central sympathoinhibition at the dose examined in this study, but significantly reduced PVR at a given SNA, leading to a marked reduction in the operating-point AP (71.9 ±â€¯8.2 vs. 112.6 ±â€¯7.6 mm Hg, P < 0.05). CONCLUSION: Low-dose metoprolol has limited hypotensive effect despite blockade of sympathetic HR regulation. Although high-dose metoprolol induces central sympathoinhibition, it also induces peripheral vasoconstriction that antagonizes the hypotensive effect. In contrast, carvedilol exhibits hypotensive effect mainly through peripheral vasodilation. Although carvedilol is frequently classified as a ß-blocker, its vasodilatory effect via α1-adrenergic blockade plays an important role in AP reduction or heart failure treatment.

Central activation of cardiac vagal nerve by α2-adrenergic stimulation is impaired in streptozotocin-induced type 1 diabetic rats.

To elucidate the abnormality of cardiac vagal control in streptozotocin-induced type 1 diabetic rats, we measured left ventricular myocardial interstitial acetylcholine (ACh) release in response to α2-adrenergic stimulation as an index of in vivo cardiac vagal nerve activity. A cardiac microdialysis technique was applied to the rat left ventricle, and the effect of α2-adrenergic stimulation by intravenous medetomidine (100 µg/kg) on myocardial interstitial ACh levels was examined in anesthetized diabetic rats (4-6 weeks after intraperitoneal streptozotocin) and age-matched control rats (protocol 1). The effect of electrical vagal nerve stimulation on ACh levels was also examined in separate rats (protocol 2). In protocol 1, medetomidine increased the ACh levels in control (from 1.76 ±â€¯0.65 to 3.13 ±â€¯1.41 nM, P < 0.05, n = 7) but not in diabetic rats (from 2.01 ±â€¯0.47 to 1.62 ±â€¯0.34 nM, not significant, n = 7). In protocol 2, electrical vagal nerve stimulation at 20 Hz significantly increased the ACh levels in both control (from 1.49 ±â€¯0.26 to 6.39 ±â€¯1.81 nM, P < 0.001, n = 6) and diabetic rats (from 1.77 ±â€¯0.54 to 6.98 ±â€¯1.38 nM, P < 0.001, n = 6). In conclusion, medetomidine-induced central vagal activation was impaired in diabetic rats, whereas peripheral cardiac vagal control of ACh release was preserved. The impairment of central vagal activation may lead to relative sympathetic predominance and promote cardiovascular complications in diabetes.

Ivabradine preserves dynamic sympathetic control of heart rate despite inducing significant bradycardia in rats.

Ivabradine is a selective bradycardic agent that inhibits hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. HCN channels play a key role in mediating the positive chronotropic response to sympathetic nerve stimulation (SNS). We examined whether ivabradine would interfere with dynamic sympathetic control of heart rate (HR). The effect of intravenous ivabradine (2 mg/kg, n = 7) or metoprolol (10 mg/kg, n = 6) on the transfer function from SNS to HR was examined in anesthetized rats. Ivabradine preserved the asymptotic dynamic gain of the HR transfer function and nearly doubled the asymptotic dynamic gain of the transfer function from SNS to the R-R interval. In contrast, metoprolol abolished dynamic sympathetic control of HR. Preserved dynamic sympathetic control of HR, with coexisting bradycardia, may contribute to some of the beneficial effects of ivabradine previously reported in clinical application.

Prescription Rates of Guideline-Directed Medications Are Associated With In-Hospital Mortality Among Japanese Patients With Acute Myocardial Infarction: A Report From JROAD - DPC Study.

Background The JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination) is a nationwide claims database comprised of the Japanese DPC /Per Diem Payment System. This study aimed to investigate the relationship between prescription rates of guideline-directed medications in each hospital and in-hospital mortality among patients with acute myocardial infarction. Methods and Results A total of 61 838 Japanese patients from 741 hospitals with acute myocardial infarction between 2012 and 2013 were enrolled. The relationship between prescription rates of 4 guideline-directed medications for acute myocardial infarction and in-hospital mortality was analyzed. There were variations in the prescription ratio of ß-blockers on admission (median prescription rate 23% [interquartile range 11% to 38%]) and at discharge (51% [36% to 63%]), and of angiotensin converting enzyme/receptor blocker (60% [47% to 70%]). The highest prescription rate quartile of each medication was associated with a significantly lower mortality compared with the lowest prescription rate quartile (aspirin on admission, incidence rate ratio 0.67 [95% CI 0.61-0.74], P<0.001; aspirin at discharge, incidence rate ratio 0.50 [95% CI 0.46-0.55], P<0.001; ß-blocker on admission, 0.83 [0.76-0.92], P<0.001; ß-blocker at discharge, 0.78 [0.71-0.85], P<0.001; angiotensin converting enzyme/receptor blocker, 0.68 [0.62-0.75], P<0.001; statin, 0.63 [0.57-0.70], P<0.001). The composite prescription score was inversely associated with in-hospital mortality (ß coefficient=-0.48, P<0.001) and was closer to the plateau in the high-score range (median mortality for composite prescription scores of 6, 15, and 24 were 10.6%, 6.8%, and 4.6%, respectively). Conclusions The prescription rates of guideline-directed medications for treatment of Japanese acute myocardial infarction patients were inversely associated with in-hospital mortality.

Lumped parameter model for hemodynamic simulation of congenital heart diseases.

The recent development of computer technology has made it possible to simulate the hemodynamics of congenital heart diseases on a desktop computer. However, multi-scale modeling of the cardiovascular system based on computed tomographic and magnetic resonance images still requires long simulation times. The lumped parameter model is potentially beneficial for real-time bedside simulation of congenital heart diseases. In this review, we introduce the basics of the lumped parameter model (time-varying elastance chamber model combined with modified Windkessel vasculature model) and illustrate its usage in hemodynamic simulation of congenital heart diseases using examples such as hypoplastic left heart syndrome and Fontan circulation. We also discuss the advantages of the lumped parameter model and the problems for clinical use.

Correction to: Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases.

The article Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases, written by Kenji Shigemi, Soichiro Fuke, Dai Une, Keita Saku, Shuji Shimizu, Toru Kawada, Toshiaki Shishido, Kenji Sunagawa and Masaru Sugimachi, was originally published Online First without open access.

Regional difference in ischaemia-induced myocardial interstitial noradrenaline and acetylcholine releases.

Knowledge of the regional differences in myocardial interstitial noradrenaline (NA) and acetylcholine (ACh) levels during ischaemia would be important to understand the abnormality of neuronal environment surrounding the ischaemic heart. Using a cardiac microdialysis technique, we compared ischaemia-induced changes in the myocardial interstitial NA and ACh levels among three groups of anesthetized cats: the anterior free wall of the left ventricle (ANT group, n=7; the left anterior descending coronary artery was occluded), the posterior free wall of the left ventricle (POST group, n=6; the left circumflex coronary artery was occluded), and the right ventricle (RV group, n=6; the right coronary artery was occluded). The maximum NA level was not different between the ANT and POST groups but was significantly lower in the RV group (P<0.01) [70 nM (SD 37), 106 nM (SD 99), and 7 nM (SD 10), respectively]. The maximum ACh level was not different between the ANT and POST groups but was significantly lower in the RV group (P<0.05) [16 nM (SD 7), 20 nM (SD 15), and 6 nM (SD 2), respectively]. In contrast, there were no significant differences in NA or ACh release in response to a local administration of ouabain (10 mM) among the ANT, POST, and RV groups (n=6 each). In conclusion, the regional difference of the ischaemic effects, rather than the regional difference in the functional distributions of sympathetic and vagal efferent nerve terminals, might contribute to the lower levels of ischaemia-induced NA and ACh releases in the RV group.