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Although vagal nerve stimulation (VNS) benefits patients with chronic heart failure (CHF), the optimal dose of VNS remains unknown. In clinical trials, adverse symptoms limited up-titration. In this study, we evaluated the impact of various voltages of VNS which were titrated below symptom threshold on cardiac function and CHF parameters in rat myocardial infarction (MI) models.We randomly allocated MI rats to vagal (VNS; n = 41) and sham (Sham; n = 16) stimulation groups. We stimulated the right vagal nerve with 20 Hz at 3 different voltages for 4 weeks. We defined Max as the highest voltage that did not evoke any symptom, Half as one-half of Max, and Quarter as one-fourth of Max. All 3 VNS groups significantly reduced biventricular weight compared with Sham (P .05). In contrast, only Half decreased left ventricular (LV) end-diastolic pressure (Half: 17.5 ± 2.0 mm Hg; Sham: 24.2 ± 1.2 mm Hg; P .05) and increased LV ejection fraction (Half: 37.9 ± 3.1%; Sham: 28.4 ± 2.3%,-P .05) and LV maximum +dP/dt (Half: 5918.6 ± 2.0 mm/Hg/s; Sham: 5001.2 ± 563.2 mm Hg/s; P .05). The number of large vagal nerve fibers was reduced with Max (Max: 163.1 ± 43.0 counts/bundle; Sham: 360.0 ±61.6 counts/bundle; P .05), indicating significant neural damage by VNS.The optimal titration of VNS would maximize benefits for CHF and minimize adverse effects.

Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF, the central mechanism remains unclear. Since VNS exerts powerful anti-inflammatory effects, we investigated how VNS impacts on the inflammatory regulation and the development of CHF. Methods: In 8 weeks old Sprague-Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI. We adjusted the intensity of VNS below the threshold of bradycardia (20 Hz, 1.5±0.9 volts, 10 sec on, 50 sec off). In the first group (EARLY) (CHF: n=8, VNS: n=13), we continued VNS for 3 days and evaluated the early impact of VNS on inflammation on the 3rd day. In the second group (LATE) (CHF: n=13, VNS: n=13), we continued VNS for 4 weeks and evaluated cardiac remodeling and function on the last day. Results: In EARLY, hemodynamic parameters or plasma BNP as an index of CHF did not change significantly. In contrast, VNS halved the invasion of CD 68 positive cells in the left ventricle (LV) (CHF: 295.1±142.1, VNS: 110.7±59.6 counts/mm2, p Conclusion: VNS significantly decreased the invasion of macrophage, IL-1β and TGF-β production from the beginning of VNS initiation, and resulted in the decrease of cardiac fibrosis and the improvement of cardiac remodeling as well as cardiac function. VNS induced early suppression of the excessive inflammatory response may lead to its late beneficial effects on CHF.

BACKGROUND: Enhanced sympathetic nerve activity (SNA) plays a pivotal role in the pathogenesis of pulmonary hypertension (PH). Since carotid body denervation (CBD) inhibits excessive sympatho-excit...

Background: We previously showed that volume loading activates low pressure baroreflex (L-BARO) and causes biphasic change in sympathetic nerve activity (SNA). We examine if chronic heart failure (...

Background: The hypersensitive peripheral chemoreflex induces sympathoexcitation and vagolysis and is known to associate with the poor prognosis of chronic heart failure (CHF). We hypothesized that denervation of carotid body (CBD) improves CHF and restore the normal autonomic balance in a rat model of myocardial infarction (MI)-induced CHF. Methods: We created MI-induced CHF in rats. Surviving rats at 4 weeks after MI were randomized into CBD (n=10) and sham-operated (Sham; n=10) group. To establish CBD, we removed the tissues around the carotid bifurcation. Two months after CBD, we evaluated physiological and histological findings. Results: CBD significantly reduced biventricular weight (2.9±0.1 vs. 3.3±0.1 g/kg, p

Background: Although VNS is known to have a powerful anti-infarct effect, the technical difficulty associated with VNS precludes its application under emergent settings of AMI. We developed a novel...

Background Because the prevalence of coronary artery calcification is lower among Japanese than among Western individuals, aspects of the Japanese lifestyle might be related to the development of calcification. We aimed to clarify the relationship between coronary artery calcium scores in Japanese patients and various lifestyle factors among the Japanese population. Methods Study subjects were patients aged ≥20 years who underwent multidetector-row computed tomography. A total of 201 patients agreed to take part in this study and answered a questionnaire regarding lifestyle, medical history, and other factors. Results Old age, current and former smoking, sedentary work, short sleep time, coronary artery stenosis, treatment with statins, medical history of cerebrovascular disease, medical history of angina pectoris, medical history of ischemic heart disease, and medical history of dyslipidemia were associated with higher odds ratios than the other factors examined, while the Japanese-style breakfast (e.g. boiled rice, miso soup, grilled fish) was associated with lower odds ratios. Conclusions In this study, smoking, sedentary work, short sleep time, and the Japanese-style breakfast were lifestyle factors related to coronary artery calcification. The lifestyle of Japanese people may be related to coronary calcification.

Background: We aimed to elucidate the prognostic impacts of atrial fibrillation (AF) in patients with chronic heart failure (CHF). Methods and Results: We examined 4,818 consecutive patients with Stage C/D CHF registered in our CHART-2 Study (N510,219). Among them, 1,859 (38.6%) had AF at enrollment. As compared with the remaining 2,953 patients with sinus rhythm at enrollment, patients with AF were characterized by higher age (71 vs. 68 yrs.), lower esti- mated glomerular filtration rate (58.9 vs. 61.9 ml/min/1.73m 2 ), higher brain natri- uretic peptide (BNP) levels (152 vs. 74.5 pg/ml), comparable LVEF (56.8 vs 56.5%) and similar prescription rate of beta-blocker (48.1 vs. 50.6%) and renin- angiotensin system (RAS) inhibitor (72.9 vs. 71.6%). Among the patients with si- nus rhythm at enrollment, 106 (3.6%) developed de-novo AF (dnAF) during the median follow-up for 3.2 years, which was associated with an increased mortality (adjusted hazard ratio (HR) 1.72, P50.013). In contrast, neither paroxysmal AF (pAF) nor chronic AF (cAF) at enrollment was associated with mortality (pAF, adjusted HR 1.10, P50.491; cAF, adjusted HR 1.00, P 50.992). IPTW analysis revealed that neither beta-blockers nor RAS inhibitors was associated with reduced mortality in AF patients, regardless of pAF or cAF. Conclusions: These results indicate that development of dnAF, but not pAF or cAF at enrollment, was associated with increased mortality in CHF patients. Background: We previously reported that the activation of low-pressure baroreflex (LBARO) by volume infusion biphasically altered sympathetic nerve activity (SNA). We examined whether chronic heart failure (CHF) changed LBARO. Methods: In 14 anesthetized Sprague-Dawley rats, we created CHF by myocardial infarction. We isolated carotid sinuses to abolish the arterial baroreflex. We infused blood stepwise to activate LBARO, and recorded SNA and hemodynamics. Result: In the normal group (n56), volume loading increased both central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP) and biphasically changed SNA with a maximal response of 48621%. In contrast, CHF (n58) markedly reduced the maximum response (1567%, p!0.05) and abolished the biphasic change of SNA (Figure). Conclusions: CHF induces the L-BARO failure. How the LBARO failure impacts the pathophysiology of CHF remains to be investigated.

Purpose: Although the augmented sympathetic nerve activity (SNA) is a salient feature of heart failure, while vagal nerve stimulation (VNS) benefits patients with heart failure. How the VNS impacts on SNA remains unknown. Since the vagal trunk has both efferent and afferent fibers, we hypothesized that the vagal afferent stimulation (AVNS) impacts on baroreflex control of SNA. Methods and results: In 6 anesthetized, ventilated rats, we controlled the pressure of isolated, bilateral carotid sinuses (CSP) and measured celiac SNA and arterial pressure (AP). Under a constant CSP at 100 mmHg, increasing the voltage of AVNS captured the vagal afferent nerves at 2-4 volts and dose dependently decreased SNA and AP. The averaged maximal inhibition of SNA were -27.3±5.3% (Fig. 1). To examine the impact of AVNS on the baroreflex system, we changed CSP stepwise and measured the response of SNA and AP with/without AVNS. AVNS reset the sigmoidal CSP-SNA relation (neural arc) downward, whereas unaffected the linear SNA-AP relation (peripheral arc) (Fig. 2). To evaluate the dynamic impacts of AVNS on SNA, we randomly stimulated AVNS with binary white noise sequences, and identified the transfer function from AVNS to SNA and that from SNA to AP. We also identified transfer function of native baroreflex from CSP to SNA and from SNA to AP. The transfer functions from AVNS to SNA strikingly resembled that from CSP to SNA. The transfer functions from SNA to AP were indistinguishable whether we perturbed CSP or AVNS indicating that they share the common central and peripheral neural mechanism. ![Figure][1] Conclusions: AVNS resets the baroreflex neural arc and induces sympathoinhibition just like the native baroreflex. The AVNS induced sympathoinhibition may in part attribute to the beneficial impacts of VNS on heart failure. [1]: pending:yes