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Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated failing heart

Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated... Vagal nerve stimulation (VNS) induces bradycardia in chronic heart failure (CHF). We hypothesized that beta-blocker would cover the beneficial effects of VNS on CHF if the anti-beta-adrenergic effect was the main VNS effect. This study investigated the effects of VNS on cardiac remodeling in rats with CHF treated with metoprolol. Two weeks after myocardial infarction, surviving rats were randomly assigned to groups of sham stimulation (SS), sham stimulation with metoprolol (SSM), or VNS with metoprolol (VSM). Compared to the SS group, heart rate was significantly reduced in the SSM and VSM groups. Hemodynamic assessments showed that VSM rats maintained better cardiac pump function and presented higher cardiac index and lower heart weight than SSM rats. VSM was also associated with lower plasma brain natriuretic peptide and nor- epinephrine levels than SSM. VSM but not SSM improved the 50-day survival rate compared with the SS group. The results suggest that VNS may exert its beneficial effects on the failing heart independently of its anti-beta-adrenergic mechanism. Keywords Vagal nerve stimulation · Beta-blocker · Myocardial infarction · Cardiac remodeling · Chronic heart failure Introduction of patients with CHF remains poor, and new therapeutic strategies are necessary. In contrast to sympathetic acti- Left ventricular remodeling after acute myocardial infarc- vation, clinical evidence from the Autonomic Tone and tion (MI) plays a crucial role in progressive left ventricular Reflexes After Myocardial Infarction [ 7] and Cardiac Insuf- dysfunction and subsequent heart failure [1]. The degree of ficiency Bisoprolol Study II [ 8] indicated that diminished ventricular enlargement is an important predictor of survival cardiac vagal activity and increased heart rate (HR) predict in patients with coronary artery disease and chronic heart a high mortality rate among patients with CHF. This natu- failure (CHF) [2, 3]. Left ventricular systolic dysfunction rally raised a question of whether augmentation of vagal tone is associated with activation of neurohumoral compensa- would be a new target for the treatment of CHF. We firstly tory mechanisms such as sympathetic and renin–angioten- demonstrated that electrical vagal nerve stimulation (VNS) sin–aldosterone systems [4]. Chronic activation of these significantly improves the long-term survival of rats with mechanisms exerts deleterious hemodynamic and direct CHF by preventing the progression of pump failure and car- cardiotoxic effects and contributes to progressive deteriora - diac remodeling [9]. Several clinical trials of chronic VNS tion of ventricular function. Conversely, attenuation of these treatment for patients with CHF have been evaluated and mechanisms improves the survival of patients with CHF. reported the safety and improvement of life quality [10–12]. This has been demonstrated for angiotensin-converting- By contrast, improvements in the efficacy endpoints were enzyme inhibitors (ACEI), angiotensin II receptor blockers unconfirmed in the population with severe CHF. Because (ARB), and beta-blockers [5, 6]. Despite the development of these studies were conducted in a different population with pharmacological therapy and devices, the overall prognosis various strong pharmaceutical therapeutic backgrounds with inconsistent protocols for VNS, the dissimilar conclusion contrasting with animal studies is not surprising. Knowl- * Can Zheng edge on widely acceptable mechanisms for VNS treatment zhengcan@ncvc.go.jp is still lacking. Therefore, clarification of the mechanisms for Department of Cardiovascular Dynamics, National Cerebral VNS-mediated beneficial effects remains important for suc - and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, cessful clinical translation. HR reduction by vagal efferent Osaka 565-8565, Japan Vol.:(0123456789) 1 3 296 The Journal of Physiological Sciences (2019) 69:295–303 activation may partly account for the beneficial effects [13]. Subject Committee in the National Cerebral and Cardiovas- However, beta-blocker is the most used drug in the above- cular Center. mentioned trials. If VNS treatment exerts benefits mainly Male Sprague–Dawley rats (n = 100, body weight : through its anti-beta-adrenergic action, beta-blockade should 250–280  g; SLC, Hamamatsu, Japan) were anesthetized cover these effects. Clinical study is difficult to verify this with halothane (3% at induction and 1.2% during surgery) hypothesis. There is no literature but a conference report inhalation, and extensive MI was induced by proximal left concerning combination therapy of beta-blocker with VNS coronary artery ligation [9, 15]. Mortality in animals with in an animal study [14]. Therefore, we hypothesized that MI was 54% (n = 54) within the first 24 h. This high mortal- VNS exerts the beneficial effects via mechanisms beyond ity was related to the extensive MI size. We confirmed the its anti-beta-adrenergic action in CHF rats. In this study, we infarct size by postmortem examination. aimed to investigate the effects of chronic VNS on cardiac remodeling and dysfunction in rats with MI treated with metoprolol. Fabrication of the electrode We used the same electrode as in our previous studies [9, Materials and methods 16]. The neck is one of the most active body parts in rats. To increase the flexibility and endurance of the lead, we Experimental chronic heart failure model designed a coil structure using a thin stainless wire (OD 0.03 mm, coated with polyurethane; Unique Medical Co., The care of animals and all animal experiments were per- Ltd., Tokyo, Japan). A segment (4 mm) of a commercially formed in strict accordance with the Guide for the Care and available silicone tube (OD 1 mm, ID 0.5 mm) was used as Use of Laboratory Animals published by the US National a cuff around the nerve. A longitudinal slit was made on the Institutes of Health (NIH Publication No. 85-23, revised tube, through which the nerve was placed. The wires were 1996), and the Guiding Principles for the Care and Use penetrated through the thin wall and bent against the cuff, of Animals in the Field of Physiological Sciences, which parallel to the cuff’s long axis. The other ends of the leads have been approved by the Physiological Society of Japan. were welded (KTH-MWS, Kondo Technology, Inc., Tokyo, All protocols were reviewed and approved by the Animal Japan) to the output lead of the generator (Fig. 1a, b). Fig. 1 Design of the silicone tube-based cuff bipolar elec- trodes and the hemodynamic responses to right cervical vagal nerve stimulation (VNS) in free-moving rats. a Schematic representation of the structure of the cuff electrode. b Image of the implanted electrode with the cervical vagal nerve. The sample electrode was removed 3 months after the implanta- tion surgery. c Representa- tive recording of HR and AP response to VNS in a conscious rat with CHF (stimulation inten- sity: current, 0.1 mA; pulse, 0.2 ms; frequency, 20 Hz). This panel shows the VNS treatment protocol after the adjustment of the stimulation intensity, which was 0.1 mA. In c, black boxes indicate VNS 1 3 The Journal of Physiological Sciences (2019) 69:295–303 297 the cervical vein for neurohumoral assays. Plasma catecho- Implantable remote‑controlled pulse generator lamine concentrations were measured by high-performance liquid chromatography with electrochemical detection after As described previously [9], we selected an implantable, real-time remote-controlled system, which consisted of alumina adsorption. The plasma level of brain natriuretic peptide (BNP) was determined using enzyme-linked immu- an implantable pulse generator (ISE1000SA; Unimec Inc., Tokyo, Japan) and a command transmission board nosorbent assay (BNP-32 Enzyme Immunoassay Kit; Penin- sula Laboratory, Inc. Ann Arbor, MI, USA). (ISE1010C; Unimec Inc., Japan). The pulse generator weighed 8 g with a total volume of 5 ml. The working out- Cardiac remodeling and dysfunction study put current range was 0.1–1.0 mA, and the working space of the transmission board was suited for the standard cage To evaluate the effect of VNS on cardiac remodeling, after (L 37.0  cm, W 28.5  cm, and H 9.3  cm). We previously tested a hemodynamic response to VNS in conscious CHF 1-week recovery following the last blood sampling, we measured hemodynamics in anesthetized rats with CHF rats (Fig. 1c). We regulated the intensity by pulse current (0.1–0.13 mA) to a submaximal level at which the animals (SS, SSM, and VSM). The anesthesia was maintained using 1.2% halothane during surgical procedures and 0.6% halo- did not show stress-like behavior when the stimulation was conducted. In this manner, VNS did not affect food or water thane during data recording. Left ventricular pressure, AP, and right atrial pressure (RAP) were measured with a 2-Fr consumption with normal growth rate. During VNS, usually but not always, HR decreased by 20–30 bpm without great catheter-tip micromanometer (SPC-320; Millar Instruments, Inc., Houston, TX, USA) and aortic flow with a transonic changes of the arterial pressure (AP) in rats with CHF. flow probe (T-206 flow probe #2.5 ss66; Transonic Systems Inc., Ithaca, NY, USA), as described previously [9, 15, 17]. Experimental protocols All signals were digitized at a rate of 500 Hz for 1–2 min. One week after inducing MI, survivors were randomly assigned to sham stimulation without metoprolol (SS, Determination of infarct size and organ weights n = 18), sham stimulation with metoprolol (SSM, n = 15), or VNS with metoprolol group (VSM, n = 13). The rats in After hemodynamic measurements, the lung and liver were immediately excised and weighed; the heart was excised for the VSM group were implanted with the above-described electrode around the right cervical vagus and the pulse gen- subsequent determination of infarct size. As described in previous studies [9, 15, 17], the biventricles were dissected, erator in the back. Similarly, the rats in the SS or SSM group were implanted with a dummy. At the same time, to evaluate weighed, cut from the apex to the base into three transverse slices, and fixed in 4% phosphate-buffered paraformalde- the long-term effects of metoprolol with or without VNS on hemodynamics under non-stressful conditions, we implanted hyde solution. Four-micrometer-thick sections were cut and stained using the Masson trichrome method. Histological the 46 rats with a blood pressure transmitter (TA11PA-C40; DSI, St. Paul, MN, USA). The Teflon tube of the transmit- images were digitized through a frame grabber and analyzed. Infarct size was calculated from the three slices by dividing ter was inserted into the abdominal aorta to record blood pressure and HR in real time. The recording was sampled at the sum of the endocardial lengths of infarcted regions by the sum of the total endocardial circumferences. 500 Hz. After another week recovery, we started VNS and selected a pulse frequency of 20 Hz, a pulse width of 0.2 ms, Prognosis study using a duty cycle of 16.7% (10-s on/50-s off, Fig.  1c) for 24 h and continued VNS for 6 weeks (limited by battery life To examine the outcome of VNS- and metoprolol-treated of the generator). The effectiveness of VNS was checked weekly by the behavioral and hemodynamic responses in rats with CHF, we observed a 50-day survival rate in over- all treatment time. The rats were inspected daily, and gross each rat. Metoprolol (Sigma-Aldrich, St. Louis, MO, USA) was added to drinking water (0.7 g/l, average dose 70 mg/kg/ postmortem examination was conducted on the dead rats. The heart was removed for subsequent measurements of day) in the SSM and VSM groups, but not in the SS group. The metoprolol dose was selected to decrease the HR by heart weight and infarct size. 20–30 bpm in rats with MI without significant influence on normal growth, according to the findings in a preliminary Statistical analysis study. Metoprolol treatment continued until the end of study (7 weeks). At the end of the 6-week stimulation and observa- All data were presented as mean and SE values. Data of long-term recorded HR and mean blood pressure (MBP) tion period, the animals were anesthetized with halothane (3% for induction, 1% for 5-min blood sampling operation). before and during treatment in each group were examined using one-way analysis of variance (ANOVA) with repeated Under anesthesia, 3 ml of blood was quickly sampled from 1 3 298 The Journal of Physiological Sciences (2019) 69:295–303 measurements, followed by post hoc Dunnett’s test. Differ - Hemodynamics and cardiac remodeling ences among the three groups were examined with one-way ANOVA, followed by post hoc Dunnett’s test. For hemo- Acute hemodynamics and cardiac remodeling parameters dynamic and remodeling study data, differences among the were measured in anesthetized rats with CHF at the end of three groups were tested by ANOVA, with Scheffé’s mul- the 7-week treatment (Fig. 3). Although no differences were tiple comparison test. For neurohumoral data, differences found in MBP and HR among the three groups (Fig. 3a, b), among the three groups were tested by ANOVA, followed VSM-treated rats with CHF showed signic fi antly higher car - by post hoc Student–Newman–Keuls test. Survival data are diac index (Fig. 3c), higher maximum left ventricular pres- presented as Kaplan–Meier curves, and the effect of treat- sure dP/dt (Fig. 3d), and lower left ventricular end-diastolic ment on a 50-day survival was analyzed using a log-rank pressure (Fig. 3e), and RAP (Fig. 3f) than the SS and SSM- test. For all statistical analyses, the difference was consid- treated rats with CHF. Further improvement of cardiac func- ered significant when P < 0.05. tion in VSM rats was accompanied by a significant decrease in normalized biventricular weight (Table 1). However, sig- nificant differences were not noted in body weight, infarct size, or normalized lung and liver weights among the SS, Results SSM, and VSM-treated rats with CHF (Table 1). Telemetric hemodynamic measurements Analysis of plasma neurohumoral levels in conscious rats with CHF and prognosis after treatment The SSM (n = 11) and VSM (n = 12) groups showed a sig- The VSM group showed a lower plasma norepinephrine nificant reduction in average HR from the first week com- level than the SS and SSM groups (Fig.  4a). Meanwhile, pared with the untreated SS group (n = 11) and maintained the SSM and VSM groups had lower plasma epinephrine a low level in the following weeks (Fig. 2a). The difference than the SS group (Fig. 4b). Although the SSM and VSM in HR between the SSM and SS groups or between the VSM groups had a lower concentration of plasma BNP than the and SS groups reached more than 40 bpm at the end of the SS group, the VSM group showed a further decrease in the 6-week treatment. However, significant difference was not BNP level than the SSM group (Fig. 4c). During the 7-week noted between the VSM and SSM groups. Although no sta- observation period, VSM therapy significantly suppressed tistically significant differences were found, MBP tended the mortality rate of rats with CHF (Fig. 5). The number of to be higher in the VSM than in the SSM and SS groups deaths in the VSM group was only one, which was signifi- (Fig. 2b). cantly lower than that in the SS group (Table 1). Fig. 2 Effects of a 6-week treatment with sham stimulation (SS, CHF. Each point presented the weekly averaged heart rate (a) and the white circles, n = 11), sham stimulation plus metoprolol (SSM, gray weekly averaged mean blood pressure (b) of rats with CHF. Data are circles, n = 11), and vagal stimulation plus metoprolol (VSM, black expressed as mean ± SEM. *P < 0.05; **P < 0.01 vs. the pre-treat- circles, n = 12) on telemetry hemodynamics in conscious rats with ment value of each group (week 0); P < 0.01 vs. SS group 1 3 The Journal of Physiological Sciences (2019) 69:295–303 299 Fig. 3 Effects of treatment with SS (white bars, n = 11), SSM (gray bars, n = 11), and VSM (black bars, n = 12) on a MBP, mean blood pressure; b HR, heart rate; c cardiac index; d LV + dP/dt , maximum dP/ max dt of left-ventricular pressure; e LVEDP, left ventricular end-diastolic pressure; and f RAP, right atrial pressure in anesthetized rats with CHF (chronic heart failure). The assessment was made at the end of a 7-week treatment (1-week recovery after blood sam- pling). *P < 0.05 vs. SS group; P < 0.05 vs. SSM group Table 1 The characteristics SS group (n = 11) SSM group (n = 11) VSM group (n = 12) after 7-week treatment in rats with chronic heart failure BW (g) 432 ± 14 427 ± 16 425 ± 8 Infarct size (%) 44 ± 2 45 ± 2 44 ± 1 *,# HW (g/kg) 3.26 ± 0.19 2.96 ± 0.06 2.67 ± 0.08 Lung W (g/kg) 7.51 ± 0.45 9.49 ± 0.83 7.46 ± 0.85 Liver W (g/kg) 29.38 ± 0.90 33.49 ± 1.33 31.14 ± 0.80 Death number 7 (7/18, 39%) 4 (4/15, 27%) 1 (1/13, 8%) Values are mean ± SEM. For data of BW, HW, lung W, liver W and infarct size, differences among three groups were tested by ANOVA, with Scheffé’s multiple comparison test. The effect of treatment on 50-day survival was analyzed by a log-rank test BW body weight, HW biventricular weight normalized by body weight, lung W lung weight normalized by body weight, liver W liver weight normalized by body weight *P < 0.05 vs. SS group P < 0.05 vs. SSM group Fig. 4 Comparison of plasma neurohumoral levels after a 6-week Plasma levels of norepinephrine. b Plasma levels of epinephrine. c treatment with SS (white circles, n = 11), SSM (gray circles, n = 11), Plasma levels of brain natriuretic peptide (BNP). **P < 0.01 vs. SS # ## and VSM (black circles, n = 12) in rats with chronic heart failure. a group; P < 0.05; P < 0.01 vs. SSM group 1 3 300 The Journal of Physiological Sciences (2019) 69:295–303 patients with CHF. Considerable evidence is available showing that beta-blockade reduces mortality and morbidity in patients with CHF. Nevertheless, the effects of VNS and beta-blockade could be different. As an example, previous studies indicated that VNS improves baroreflex neural arc in CHF rats [19] while metoprolol abolished dynamic sympathetic control of HR [20]. Moreover, beta-blockers can unmask an alpha-adren- ergic vasoconstrictive effect, which can reduce coronary blood flow during sympathetic activation [21]. These mechanisms may partly contribute to the different outcomes between SSM and VSM. In the present study, we created permanent MI and started treatments 2 weeks after MI. At this stage, MI might have been fixed, resulting in no significant difference in the MI size among the three groups. Because the observation period was relatively short (50 days), there was less edema, which resulted in no differences in body weight, lung weight, Fig. 5 Effects of treatment with SS (gray dotted line, n = 18), SSM or liver weight among the three groups. SSM treatment (gray solid line, n = 15), and VSM (black solid line, n = 13) on the decreased plasma epinephrine and BNP levels, which may survival curves of rats with chronic heart failure. Treatment started partially contribute to the improvement in cardiac function. 14  days after myocardial infarction (MI) induced by coronary artery In patients with CHF, compensatory cardiac sympathetic ligation. Compared with the SS group, VSM significantly (P = 0.022) improved the survival rate for a 50-day observation. No significant activation that resulted from cardiac dysfunction is associ- difference was found between the VSM and SSM groups ated with poor prognosis [22]; plasma norepinephrine level is a univariate predictor of all-cause and cardiac mortality, and beta-blocker treatment correlates with lower mortality Discussion [23]. However, the VSM group not only had significantly lower heart weight than the SS and SSM groups, but also The major results of the present study are as follows. SSM prevented cardiac dysfunction, and decreased norepineph- reduced HR, ameliorated cardiac dysfunction, improved rine and BNP levels more than the SSM. These results cardiac index, and decreased plasma neurohumoral lev- suggest that VSM may decrease sympathetic outflow and els, although no difference in normalized heart weight was improve neurohumoral state, and then effectively prevent found compared with SS. On the other hand, VSM further cardiac remodeling. For the survival rate, although there was prevented the progression of cardiac remodeling and dys- no difference between VSM and SSM groups (92 vs. 73%, function and effectively suppressed mortality and plasma P = 0.163), VSM markedly improved the 50-day survival (92 catecholamine and BNP, compared with SSM. These results vs. 61%, P = 0.022) compared with the SS group. suggest that VNS exerts its cardioprotective effects on the Meanwhile, when we adopted data from our previous failing heart independently of its anti-beta-adrenergic study [9], VSM therapy provided the similar treatment mechanism. effects to that attained by VNS alone (normalized biventricu- lar weight: 2.67 ± 0.08 vs. 2.75 ± 0.08; LVEDP: 16 ± 1 vs. Eec ff ts of beta‑blockade and VNS treatment on CHF 17 ± 2; LV + dp/dt : 5036 ± 172 vs. 4152 ± 75 mmHg/s), max and from the viewpoint of 50-day survival, 92 vs. 91% in The present study evaluated the long-term hemodynamics CHF rats. These results indicated that the effect of VNS in rats with CHF by using telemetry. Both SSM and VSM was not enhanced by metoprolol, i.e., there would be no therapies similarly reduced HR compared with the SS. The significant synergistic effect between VNS and beta-blocker extent of HR reduction was also similar to our previous report therapy. The difference between VSM and SSM may be that examined the effect of VNS without beta-blockade in rats attributable to mechanisms unique to VNS independent of with CHF [9]. These results imply that chronic VNS does not ant-beta-adrenergic mechanism. induce an additional bradycardic effect beyond the bradycardic effect attained by beta-blockade. Hence, chronic VNS may Possible treatment mechanisms involved in VNS contribute to the reduction of averaged HR mainly through therapy decreasing or inhibiting cardiac sympathetic activity. HR has been proven to be the best predictor for prognosis after MI in The vagal nerve is an ancient nerve in evolution; it is com- patients with congestive heart failure [18]. By inducing brady- posed of afferent and efferent fibers to govern many visceral cardia, beta-blockers have become very important in treating 1 3 The Journal of Physiological Sciences (2019) 69:295–303 301 reflexes. In small animals, such as mice, rats, and rabbits, the have proven that the vagal afferent nerves exert a significant vagal nerve in the cervical region can be surgically separated tonic inhibitory influence on AVP secretion in anesthetic and from other nerves (e.g., aortic nerve and sympathetic nerve). conscious dogs [33, 34]. AVP is reportedly upregulated and Because various nerve fibers in the vagal nerve have differ - exhibits a defective response to physiological stimulation ent trigger levels to evoke action potential, responses to VNS in CHF [35, 36]. Although AVP was not measured in the rely on stimulus strength. Early acute VNS intervention for present study, we have previously demonstrated that chronic cardiac protection is considered as vagal efferent effect [24]. VNS decreases AVP secretion and sodium ingestion in CHF However, reviewing over 10 years of research on VNS for rats with MI [16]. Therefore, we postulate that decreasing CHF including experimental and clinical studies, it may be the AVP secretion may be a contributing mechanism of VNS worth focusing on the role of the vagal afferent pathway therapy for CHF. in the VNS therapy. We applied telemetry recording and remote controlling systems to evaluate behavioral and hemo- Clinical implications dynamic responses to VNS in free-moving rats. In the pre- liminary test for selecting VNS intensity, we observed that The diversity of disease conditions in patients with CHF is animals could sense the VNS even at very low intensity (cur- one of the biggest challenges in clinical studies. According rent) and make behavioral responses such as holding breath to therapeutic ethics, numerous clinical studies had to be per- and displaying alertness. These phenomena suggest that at formed in the presence of a routine therapeutic background. least a part of the vagal afferent fibers can be stimulated by These therapeutic factors may obscure the real effects of the a low current, which may be lower than the trigger level of intervention to be evaluated. All the VNS clinical trials were efferent fibers to control HR [25]. The titration for chronic conducted with the standard treatment background includ- VNS had to be set below a tolerable level in an experimental ing beta-blockers, ACEI or/and ARB, aldosterone antago- study [26] or a clinical trial [27]. nists, and diuretic agents. In particular, most of the patients At least three aspects of vagal afferent action should be (92–100%) used beta-blockers. The results of this study considered. First, vagal afferent stimulation may inhibit sym- showed that VNS did not further decrease mean HR under pathetic nerve activity through the input to the brainstem the beta-blocker treatment background while it exerted addi- (the nucleus tractus solitarius) [28, 29]. This effect is pos- tional benefits for CHF. Hence, beta-blockers should not be a sibly one of the most important mechanisms of VNS benefits malefactor of obstructing the VNS benefits in clinical trials. for CHF, because persistent compensatory sympathetic acti- In a previous study, we demonstrated that pharmacologi- vation for cardiac dysfunction leads to an increased secretion cal vagal activation by donepezil (an acetylcholinesterase of neurohumoral factors such as vasopressin and adrenocor- inhibitor) combined with losartan exerts synergic treatment ticoid. This increased secretion, in turn, further activates effects in rats with CHF [17]. Therefore, ACEI or ARB may compensatory mechanisms to form a vicious cycle. We also be excluded from a malefactor list. We suspect that diuretic observed that VNS treatment significantly improved the agents could interfere with the VNS effects. Clinical stud- ability of the carotid sinus baroreflex to reduce sympathetic ies reported that diuretics increase sympathetic outflow and nerve activity in rats with CHF [19]. Second, electrical VNS AVP secretion, without improving the long-term outcome decreases the release of various cytokines including tumor in patients with CHF [37–41]. Diuretics may antagonize the necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This above-mentioned VNS-induced prevention of AVP secre- effect involves both afferent and efferent fibers and is called tion. However, detailed data analysis to evaluate the VNS the cholinergic anti-inflammatory reflex [30]. Although this effects in diuretic-free patients with CHF is still lacking. The study did not evaluate these inflammatory factors, a previ- ongoing clinical trial ANTHEM-HFpEF has been designed ous study indicated that VNS in the anesthetized rodent fol- to conduct VNS in patients with CHF with preserved and lowing myocardial ischemia and reperfusion reduced infarct mid-range left ventricular ejection fraction [42]. Patients size, through the alpha-7 nicotinic acetylcholine receptor- in these categories were less frequently prescribed diuretic dependent anti-inflammation mechanism [31]. In the canine agents than in subjects with severe CHF enrolled in previ- model of CHF, both TNF-α and IL-6 in plasma and in car- ous VNS trials. We hope this prospective clinical study may diac tissue are elevated more than in normal dogs, and they provide new insights into diuretic influence on VNS therapy. were attenuated by long-term monotherapy with VNS [32]. Third, vagal afferent stimulation may inhibit arginine vaso- Study limitations pressin (AVP) secretion. This field rarely has attracted the attention of researchers in VNS therapy studies for patients The present study has several limitations. First, it applied with CHF. AVP is the most important neurohormone to VNS to a rat model of MI-induced CHF. These rats were maintain circulatory volume and fluid balance through reg- in the early stage of progression of cardiac remodeling and ulation of water reabsorption in the kidney. Early studies further development to CHF. However, the patients enrolled 1 3 302 The Journal of Physiological Sciences (2019) 69:295–303 3. Likoff MJ, Chandler SL, Kay HR (1987) Clinical determinants in clinical trials were usually in the late stage of CHF. There- of mortality in chronic congestive heart failure secondary to idi- fore, the therapeutic effects may be different and associated opathic dilated or to ischemic cardiomyopathy. Am J Cardiol with different outcomes. Second, rodents and humans have 59:634–638 different vagal nerve anatomy in the cervical area, which 4. Vaughan DE, Pfeffer MA (1994) Angiotensin converting enzyme inhibitors and cardiovascular remodelling. Cardiovasc Res may cause varied functional effects of VNS. Third, they 28:159–165 greatly differ in breath rate and HR. Finally, titration of VNS 5. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, should be adjusted according to the response of the patients. Gilbert EM, Shusterman NH (1996) The effect of carvedilol For example, a VNS frequency of 20 Hz had been selected on morbidity and mortality in patients with chronic heart fail- ure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med for the rat, which may not be the best frequency for humans. 334:1349–1355 The new ongoing ANTHEM-HFpEF trial using a frequency 6. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi of 5–10 Hz (near the natural discharge frequency of vagal) P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz [42] is the new challenge. MK, DeMets DL (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658 7. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ (1998) Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarc- Conclusions tion. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 351:478–484 VSM therapy further prevented cardiac remodeling, pre- 8. Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Wer- hlen-Grandjean M, Pochmalicki G, Dargie H (2001) Heart rate served cardiac output, and improved 50-day survival rate and cardiac rhythm relationships with bisoprolol benefit in chronic despite the background of beta-blockade in rats with CHF. heart failure in CIBIS II trial. Circulation 103:1428–1433 The results suggest that VNS may exert its beneficial effects 9. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K on the failing heart independently of its anti-beta-adrenergic (2004) Vagal nerve stimulation markedly improves long-term sur- vival after chronic heart failure in rats. Circulation 109:120–124 mechanism. The VNS therapy may be applied to patients 10. De Ferrari GM, Stolen C, Tuinenburg AE, Wright DJ, Brugada with CHF taking beta-blockers. J, Butter C, Klein H, Neuzil P, Botman C, Castel MA, D’Onofrio A, de Borst GJ, Solomon S, Stein KM, Schubert B, Stalsberg K, Acknowledgements This study was partly supported by JSPS KAK- Wold N, Ruble S, Zannad F (2017) Long-term vagal stimulation ENHI (Grant Number: C—26461099, 17K09544). for heart failure: eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int J Cardiol Author contributions ML, CZ, and MS designed the study. ML and 244:229–234 CZ performed the measurements and statistical analysis, and drafted 11. Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo the manuscript. KT, MI, and KU joined in interpreting the data. All SH, Lieberman RA, Milasinovic G, Berman BJ, Djordjevic S, authors have read and approved the final manuscript. Neelagaru S, Schwartz PJ, Starling RC, Mann DL (2016) Vagus nerve stimulation for the treatment of heart failure: the INOVATE- HF trial. J Am Coll Cardiol 68:149–158 Compliance with ethical standards 12. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Conflict of interest The author(s) declare that they have no competing Anand IS (2014) Autonomic regulation therapy via left or right interests. cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail 20:808–816 Research involving animals The care of animals and all animal experi- 13. Gronda E, Vanoli E (2016) Autonomic modulation with barore- ments were performed in strict accordance with the Guide for the Care flex activation therapy in heart failure. Curr Heart Fail Rep and Use of Laboratory Animals published by the US National Institutes 13:273–280 of Health (NIH Publication No. 85-23, revised 1996), and the Guiding 14. 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Pfeffer MA (1995) Left ventricular remodeling after acute myo- and sodium ingestion in heart failure rats after myocardial infarc- cardial infarction. Annu Rev Med 46:455–466 tion. Conf Proc IEEE Eng Med Biol Soc 4:3962–3965 2. Hammermeister KE, DeRouen TA, Dodge HT (1979) Variables 17. Li M, Zheng C, Kawada T, Inagaki M, Uemura K, Sugimachi M predictive of survival in patients with coronary disease. Selec- (2014) Adding the acetylcholinesterase inhibitor, donepezil, to tion by univariate and multivariate analyses from the clinical, losartan treatment markedly improves long-term survival in rats electrocardiographic, exercise, arteriographic, and quantitative with chronic heart failure. Eur J Heart Fail 16:1056–1065 angiographic evaluations. Circulation 59:421–430 1 3 The Journal of Physiological Sciences (2019) 69:295–303 303 18. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Pon- 30. Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859 ikowski P, Voors AA, Dominjon F, Henon-Goburdhun C, Pannaux 31. Kiss A, Tratsiakovich Y, Mahdi A, Yang J, Gonon AT, Podesser M, Bohm M, prEserve DlvefchFwisI (2017) Effect of ivabradine BK, Pernow J (2017) Vagal nerve stimulation reduces infarct size in patients with heart failure with preserved ejection fraction: via a mechanism involving the alpha-7 nicotinic acetylcholine the EDIFY randomized placebo-controlled trial. Eur J Heart Fail receptor and downregulation of cardiac and vascular arginase. 19:1495–1503 Acta Physiol (Oxf) 221:174–181 19. Kawada T, Li M, Zheng C, Shimizu S, Uemura K, Turner MJ, 32. Hamann JJ, Ruble SB, Stolen C, Wang M, Gupta RC, Rastogi S, Yamamoto H, Sugimachi M (2014) Chronic vagal nerve stimula- Sabbah HN (2013) Vagus nerve stimulation improves left ven- tion improves baroreflex neural arc function in heart failure rats. tricular function in a canine model of chronic heart failure. Eur J J Appl Physiol (1985) 116:1308–1314 Heart Fail 15:1319–1326 20. Kawada T, Shimizu S, Uemura K, Hayama Y, Yamamoto H, 33. Morita H, Manders WT, Skelton MM, Cowley AW Jr, Vatner SF Shishido T, Nishikawa T, Sugimachi M (2018) Ivabradine pre- (1986) Vagal regulation of arginine vasopressin in conscious dogs. serves dynamic sympathetic control of heart rate despite induc- Am J Physiol 251:H19–H23 ing significant bradycardia in rats. J Physiol Sci. h t t p s : / / d o i . 34. Thames MD, Schmid PG (1981) Interaction between carotid and org/10.1007/s1257 6-018-0636-2 cardiopulmonary baroreflexes in control of plasma ADH. Am J 21. Guth BD, Heusch G, Seitelberger R, Ross J Jr (1987) Mecha- Physiol 241:H431–H434 nism of beneficial effect of beta-adrenergic blockade on exer - 35. Goldsmith SR (1992) Baroreflex loading maneuvers do not sup- cise-induced myocardial ischemia in conscious dogs. 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Eur J Heart Fail furosemide in patients with chronic congestive heart failure. Acti- 10:884–891 vation of the neurohumoral axis. Ann Intern Med 103:1–6 28. Saku K, Kishi T, Sakamoto K, Hosokawa K, Sakamoto T, Muray- 42. DiCarlo LA, Libbus I, Kumar HU, Mittal S, Premchand RK, ama Y, Kakino T, Ikeda M, Ide T, Sunagawa K (2014) Afferent Amurthur B, KenKnight BH, Ardell JL, Anand IS (2018) Auto- vagal nerve stimulation resets baroreflex neural arc and inhibits nomic regulation therapy to enhance myocardial function in heart sympathetic nerve activity. Physiol Rep 2:e12136 failure patients: the ANTHEM-HFpEF study. ESC Heart Fail 29. Smith BN, Dou P, Barber WD, Dudek FE (1998) Vagally evoked 5:95–100 synaptic currents in the immature rat nucleus tractus solitarii in an intact in vitro preparation. J Physiol 512(Pt 1):149–162 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Physiological Sciences Springer Journals

Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated failing heart

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Springer Journals
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Copyright © 2018 by The Physiological Society of Japan and Springer Japan KK, part of Springer Nature
Subject
Biomedicine; Human Physiology; Neurosciences; Animal Biochemistry; Animal Physiology; Cell Physiology; Neurobiology
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1880-6546
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1880-6562
DOI
10.1007/s12576-018-0646-0
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Abstract

Vagal nerve stimulation (VNS) induces bradycardia in chronic heart failure (CHF). We hypothesized that beta-blocker would cover the beneficial effects of VNS on CHF if the anti-beta-adrenergic effect was the main VNS effect. This study investigated the effects of VNS on cardiac remodeling in rats with CHF treated with metoprolol. Two weeks after myocardial infarction, surviving rats were randomly assigned to groups of sham stimulation (SS), sham stimulation with metoprolol (SSM), or VNS with metoprolol (VSM). Compared to the SS group, heart rate was significantly reduced in the SSM and VSM groups. Hemodynamic assessments showed that VSM rats maintained better cardiac pump function and presented higher cardiac index and lower heart weight than SSM rats. VSM was also associated with lower plasma brain natriuretic peptide and nor- epinephrine levels than SSM. VSM but not SSM improved the 50-day survival rate compared with the SS group. The results suggest that VNS may exert its beneficial effects on the failing heart independently of its anti-beta-adrenergic mechanism. Keywords Vagal nerve stimulation · Beta-blocker · Myocardial infarction · Cardiac remodeling · Chronic heart failure Introduction of patients with CHF remains poor, and new therapeutic strategies are necessary. In contrast to sympathetic acti- Left ventricular remodeling after acute myocardial infarc- vation, clinical evidence from the Autonomic Tone and tion (MI) plays a crucial role in progressive left ventricular Reflexes After Myocardial Infarction [ 7] and Cardiac Insuf- dysfunction and subsequent heart failure [1]. The degree of ficiency Bisoprolol Study II [ 8] indicated that diminished ventricular enlargement is an important predictor of survival cardiac vagal activity and increased heart rate (HR) predict in patients with coronary artery disease and chronic heart a high mortality rate among patients with CHF. This natu- failure (CHF) [2, 3]. Left ventricular systolic dysfunction rally raised a question of whether augmentation of vagal tone is associated with activation of neurohumoral compensa- would be a new target for the treatment of CHF. We firstly tory mechanisms such as sympathetic and renin–angioten- demonstrated that electrical vagal nerve stimulation (VNS) sin–aldosterone systems [4]. Chronic activation of these significantly improves the long-term survival of rats with mechanisms exerts deleterious hemodynamic and direct CHF by preventing the progression of pump failure and car- cardiotoxic effects and contributes to progressive deteriora - diac remodeling [9]. Several clinical trials of chronic VNS tion of ventricular function. Conversely, attenuation of these treatment for patients with CHF have been evaluated and mechanisms improves the survival of patients with CHF. reported the safety and improvement of life quality [10–12]. This has been demonstrated for angiotensin-converting- By contrast, improvements in the efficacy endpoints were enzyme inhibitors (ACEI), angiotensin II receptor blockers unconfirmed in the population with severe CHF. Because (ARB), and beta-blockers [5, 6]. Despite the development of these studies were conducted in a different population with pharmacological therapy and devices, the overall prognosis various strong pharmaceutical therapeutic backgrounds with inconsistent protocols for VNS, the dissimilar conclusion contrasting with animal studies is not surprising. Knowl- * Can Zheng edge on widely acceptable mechanisms for VNS treatment zhengcan@ncvc.go.jp is still lacking. Therefore, clarification of the mechanisms for Department of Cardiovascular Dynamics, National Cerebral VNS-mediated beneficial effects remains important for suc - and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, cessful clinical translation. HR reduction by vagal efferent Osaka 565-8565, Japan Vol.:(0123456789) 1 3 296 The Journal of Physiological Sciences (2019) 69:295–303 activation may partly account for the beneficial effects [13]. Subject Committee in the National Cerebral and Cardiovas- However, beta-blocker is the most used drug in the above- cular Center. mentioned trials. If VNS treatment exerts benefits mainly Male Sprague–Dawley rats (n = 100, body weight : through its anti-beta-adrenergic action, beta-blockade should 250–280  g; SLC, Hamamatsu, Japan) were anesthetized cover these effects. Clinical study is difficult to verify this with halothane (3% at induction and 1.2% during surgery) hypothesis. There is no literature but a conference report inhalation, and extensive MI was induced by proximal left concerning combination therapy of beta-blocker with VNS coronary artery ligation [9, 15]. Mortality in animals with in an animal study [14]. Therefore, we hypothesized that MI was 54% (n = 54) within the first 24 h. This high mortal- VNS exerts the beneficial effects via mechanisms beyond ity was related to the extensive MI size. We confirmed the its anti-beta-adrenergic action in CHF rats. In this study, we infarct size by postmortem examination. aimed to investigate the effects of chronic VNS on cardiac remodeling and dysfunction in rats with MI treated with metoprolol. Fabrication of the electrode We used the same electrode as in our previous studies [9, Materials and methods 16]. The neck is one of the most active body parts in rats. To increase the flexibility and endurance of the lead, we Experimental chronic heart failure model designed a coil structure using a thin stainless wire (OD 0.03 mm, coated with polyurethane; Unique Medical Co., The care of animals and all animal experiments were per- Ltd., Tokyo, Japan). A segment (4 mm) of a commercially formed in strict accordance with the Guide for the Care and available silicone tube (OD 1 mm, ID 0.5 mm) was used as Use of Laboratory Animals published by the US National a cuff around the nerve. A longitudinal slit was made on the Institutes of Health (NIH Publication No. 85-23, revised tube, through which the nerve was placed. The wires were 1996), and the Guiding Principles for the Care and Use penetrated through the thin wall and bent against the cuff, of Animals in the Field of Physiological Sciences, which parallel to the cuff’s long axis. The other ends of the leads have been approved by the Physiological Society of Japan. were welded (KTH-MWS, Kondo Technology, Inc., Tokyo, All protocols were reviewed and approved by the Animal Japan) to the output lead of the generator (Fig. 1a, b). Fig. 1 Design of the silicone tube-based cuff bipolar elec- trodes and the hemodynamic responses to right cervical vagal nerve stimulation (VNS) in free-moving rats. a Schematic representation of the structure of the cuff electrode. b Image of the implanted electrode with the cervical vagal nerve. The sample electrode was removed 3 months after the implanta- tion surgery. c Representa- tive recording of HR and AP response to VNS in a conscious rat with CHF (stimulation inten- sity: current, 0.1 mA; pulse, 0.2 ms; frequency, 20 Hz). This panel shows the VNS treatment protocol after the adjustment of the stimulation intensity, which was 0.1 mA. In c, black boxes indicate VNS 1 3 The Journal of Physiological Sciences (2019) 69:295–303 297 the cervical vein for neurohumoral assays. Plasma catecho- Implantable remote‑controlled pulse generator lamine concentrations were measured by high-performance liquid chromatography with electrochemical detection after As described previously [9], we selected an implantable, real-time remote-controlled system, which consisted of alumina adsorption. The plasma level of brain natriuretic peptide (BNP) was determined using enzyme-linked immu- an implantable pulse generator (ISE1000SA; Unimec Inc., Tokyo, Japan) and a command transmission board nosorbent assay (BNP-32 Enzyme Immunoassay Kit; Penin- sula Laboratory, Inc. Ann Arbor, MI, USA). (ISE1010C; Unimec Inc., Japan). The pulse generator weighed 8 g with a total volume of 5 ml. The working out- Cardiac remodeling and dysfunction study put current range was 0.1–1.0 mA, and the working space of the transmission board was suited for the standard cage To evaluate the effect of VNS on cardiac remodeling, after (L 37.0  cm, W 28.5  cm, and H 9.3  cm). We previously tested a hemodynamic response to VNS in conscious CHF 1-week recovery following the last blood sampling, we measured hemodynamics in anesthetized rats with CHF rats (Fig. 1c). We regulated the intensity by pulse current (0.1–0.13 mA) to a submaximal level at which the animals (SS, SSM, and VSM). The anesthesia was maintained using 1.2% halothane during surgical procedures and 0.6% halo- did not show stress-like behavior when the stimulation was conducted. In this manner, VNS did not affect food or water thane during data recording. Left ventricular pressure, AP, and right atrial pressure (RAP) were measured with a 2-Fr consumption with normal growth rate. During VNS, usually but not always, HR decreased by 20–30 bpm without great catheter-tip micromanometer (SPC-320; Millar Instruments, Inc., Houston, TX, USA) and aortic flow with a transonic changes of the arterial pressure (AP) in rats with CHF. flow probe (T-206 flow probe #2.5 ss66; Transonic Systems Inc., Ithaca, NY, USA), as described previously [9, 15, 17]. Experimental protocols All signals were digitized at a rate of 500 Hz for 1–2 min. One week after inducing MI, survivors were randomly assigned to sham stimulation without metoprolol (SS, Determination of infarct size and organ weights n = 18), sham stimulation with metoprolol (SSM, n = 15), or VNS with metoprolol group (VSM, n = 13). The rats in After hemodynamic measurements, the lung and liver were immediately excised and weighed; the heart was excised for the VSM group were implanted with the above-described electrode around the right cervical vagus and the pulse gen- subsequent determination of infarct size. As described in previous studies [9, 15, 17], the biventricles were dissected, erator in the back. Similarly, the rats in the SS or SSM group were implanted with a dummy. At the same time, to evaluate weighed, cut from the apex to the base into three transverse slices, and fixed in 4% phosphate-buffered paraformalde- the long-term effects of metoprolol with or without VNS on hemodynamics under non-stressful conditions, we implanted hyde solution. Four-micrometer-thick sections were cut and stained using the Masson trichrome method. Histological the 46 rats with a blood pressure transmitter (TA11PA-C40; DSI, St. Paul, MN, USA). The Teflon tube of the transmit- images were digitized through a frame grabber and analyzed. Infarct size was calculated from the three slices by dividing ter was inserted into the abdominal aorta to record blood pressure and HR in real time. The recording was sampled at the sum of the endocardial lengths of infarcted regions by the sum of the total endocardial circumferences. 500 Hz. After another week recovery, we started VNS and selected a pulse frequency of 20 Hz, a pulse width of 0.2 ms, Prognosis study using a duty cycle of 16.7% (10-s on/50-s off, Fig.  1c) for 24 h and continued VNS for 6 weeks (limited by battery life To examine the outcome of VNS- and metoprolol-treated of the generator). The effectiveness of VNS was checked weekly by the behavioral and hemodynamic responses in rats with CHF, we observed a 50-day survival rate in over- all treatment time. The rats were inspected daily, and gross each rat. Metoprolol (Sigma-Aldrich, St. Louis, MO, USA) was added to drinking water (0.7 g/l, average dose 70 mg/kg/ postmortem examination was conducted on the dead rats. The heart was removed for subsequent measurements of day) in the SSM and VSM groups, but not in the SS group. The metoprolol dose was selected to decrease the HR by heart weight and infarct size. 20–30 bpm in rats with MI without significant influence on normal growth, according to the findings in a preliminary Statistical analysis study. Metoprolol treatment continued until the end of study (7 weeks). At the end of the 6-week stimulation and observa- All data were presented as mean and SE values. Data of long-term recorded HR and mean blood pressure (MBP) tion period, the animals were anesthetized with halothane (3% for induction, 1% for 5-min blood sampling operation). before and during treatment in each group were examined using one-way analysis of variance (ANOVA) with repeated Under anesthesia, 3 ml of blood was quickly sampled from 1 3 298 The Journal of Physiological Sciences (2019) 69:295–303 measurements, followed by post hoc Dunnett’s test. Differ - Hemodynamics and cardiac remodeling ences among the three groups were examined with one-way ANOVA, followed by post hoc Dunnett’s test. For hemo- Acute hemodynamics and cardiac remodeling parameters dynamic and remodeling study data, differences among the were measured in anesthetized rats with CHF at the end of three groups were tested by ANOVA, with Scheffé’s mul- the 7-week treatment (Fig. 3). Although no differences were tiple comparison test. For neurohumoral data, differences found in MBP and HR among the three groups (Fig. 3a, b), among the three groups were tested by ANOVA, followed VSM-treated rats with CHF showed signic fi antly higher car - by post hoc Student–Newman–Keuls test. Survival data are diac index (Fig. 3c), higher maximum left ventricular pres- presented as Kaplan–Meier curves, and the effect of treat- sure dP/dt (Fig. 3d), and lower left ventricular end-diastolic ment on a 50-day survival was analyzed using a log-rank pressure (Fig. 3e), and RAP (Fig. 3f) than the SS and SSM- test. For all statistical analyses, the difference was consid- treated rats with CHF. Further improvement of cardiac func- ered significant when P < 0.05. tion in VSM rats was accompanied by a significant decrease in normalized biventricular weight (Table 1). However, sig- nificant differences were not noted in body weight, infarct size, or normalized lung and liver weights among the SS, Results SSM, and VSM-treated rats with CHF (Table 1). Telemetric hemodynamic measurements Analysis of plasma neurohumoral levels in conscious rats with CHF and prognosis after treatment The SSM (n = 11) and VSM (n = 12) groups showed a sig- The VSM group showed a lower plasma norepinephrine nificant reduction in average HR from the first week com- level than the SS and SSM groups (Fig.  4a). Meanwhile, pared with the untreated SS group (n = 11) and maintained the SSM and VSM groups had lower plasma epinephrine a low level in the following weeks (Fig. 2a). The difference than the SS group (Fig. 4b). Although the SSM and VSM in HR between the SSM and SS groups or between the VSM groups had a lower concentration of plasma BNP than the and SS groups reached more than 40 bpm at the end of the SS group, the VSM group showed a further decrease in the 6-week treatment. However, significant difference was not BNP level than the SSM group (Fig. 4c). During the 7-week noted between the VSM and SSM groups. Although no sta- observation period, VSM therapy significantly suppressed tistically significant differences were found, MBP tended the mortality rate of rats with CHF (Fig. 5). The number of to be higher in the VSM than in the SSM and SS groups deaths in the VSM group was only one, which was signifi- (Fig. 2b). cantly lower than that in the SS group (Table 1). Fig. 2 Effects of a 6-week treatment with sham stimulation (SS, CHF. Each point presented the weekly averaged heart rate (a) and the white circles, n = 11), sham stimulation plus metoprolol (SSM, gray weekly averaged mean blood pressure (b) of rats with CHF. Data are circles, n = 11), and vagal stimulation plus metoprolol (VSM, black expressed as mean ± SEM. *P < 0.05; **P < 0.01 vs. the pre-treat- circles, n = 12) on telemetry hemodynamics in conscious rats with ment value of each group (week 0); P < 0.01 vs. SS group 1 3 The Journal of Physiological Sciences (2019) 69:295–303 299 Fig. 3 Effects of treatment with SS (white bars, n = 11), SSM (gray bars, n = 11), and VSM (black bars, n = 12) on a MBP, mean blood pressure; b HR, heart rate; c cardiac index; d LV + dP/dt , maximum dP/ max dt of left-ventricular pressure; e LVEDP, left ventricular end-diastolic pressure; and f RAP, right atrial pressure in anesthetized rats with CHF (chronic heart failure). The assessment was made at the end of a 7-week treatment (1-week recovery after blood sam- pling). *P < 0.05 vs. SS group; P < 0.05 vs. SSM group Table 1 The characteristics SS group (n = 11) SSM group (n = 11) VSM group (n = 12) after 7-week treatment in rats with chronic heart failure BW (g) 432 ± 14 427 ± 16 425 ± 8 Infarct size (%) 44 ± 2 45 ± 2 44 ± 1 *,# HW (g/kg) 3.26 ± 0.19 2.96 ± 0.06 2.67 ± 0.08 Lung W (g/kg) 7.51 ± 0.45 9.49 ± 0.83 7.46 ± 0.85 Liver W (g/kg) 29.38 ± 0.90 33.49 ± 1.33 31.14 ± 0.80 Death number 7 (7/18, 39%) 4 (4/15, 27%) 1 (1/13, 8%) Values are mean ± SEM. For data of BW, HW, lung W, liver W and infarct size, differences among three groups were tested by ANOVA, with Scheffé’s multiple comparison test. The effect of treatment on 50-day survival was analyzed by a log-rank test BW body weight, HW biventricular weight normalized by body weight, lung W lung weight normalized by body weight, liver W liver weight normalized by body weight *P < 0.05 vs. SS group P < 0.05 vs. SSM group Fig. 4 Comparison of plasma neurohumoral levels after a 6-week Plasma levels of norepinephrine. b Plasma levels of epinephrine. c treatment with SS (white circles, n = 11), SSM (gray circles, n = 11), Plasma levels of brain natriuretic peptide (BNP). **P < 0.01 vs. SS # ## and VSM (black circles, n = 12) in rats with chronic heart failure. a group; P < 0.05; P < 0.01 vs. SSM group 1 3 300 The Journal of Physiological Sciences (2019) 69:295–303 patients with CHF. Considerable evidence is available showing that beta-blockade reduces mortality and morbidity in patients with CHF. Nevertheless, the effects of VNS and beta-blockade could be different. As an example, previous studies indicated that VNS improves baroreflex neural arc in CHF rats [19] while metoprolol abolished dynamic sympathetic control of HR [20]. Moreover, beta-blockers can unmask an alpha-adren- ergic vasoconstrictive effect, which can reduce coronary blood flow during sympathetic activation [21]. These mechanisms may partly contribute to the different outcomes between SSM and VSM. In the present study, we created permanent MI and started treatments 2 weeks after MI. At this stage, MI might have been fixed, resulting in no significant difference in the MI size among the three groups. Because the observation period was relatively short (50 days), there was less edema, which resulted in no differences in body weight, lung weight, Fig. 5 Effects of treatment with SS (gray dotted line, n = 18), SSM or liver weight among the three groups. SSM treatment (gray solid line, n = 15), and VSM (black solid line, n = 13) on the decreased plasma epinephrine and BNP levels, which may survival curves of rats with chronic heart failure. Treatment started partially contribute to the improvement in cardiac function. 14  days after myocardial infarction (MI) induced by coronary artery In patients with CHF, compensatory cardiac sympathetic ligation. Compared with the SS group, VSM significantly (P = 0.022) improved the survival rate for a 50-day observation. No significant activation that resulted from cardiac dysfunction is associ- difference was found between the VSM and SSM groups ated with poor prognosis [22]; plasma norepinephrine level is a univariate predictor of all-cause and cardiac mortality, and beta-blocker treatment correlates with lower mortality Discussion [23]. However, the VSM group not only had significantly lower heart weight than the SS and SSM groups, but also The major results of the present study are as follows. SSM prevented cardiac dysfunction, and decreased norepineph- reduced HR, ameliorated cardiac dysfunction, improved rine and BNP levels more than the SSM. These results cardiac index, and decreased plasma neurohumoral lev- suggest that VSM may decrease sympathetic outflow and els, although no difference in normalized heart weight was improve neurohumoral state, and then effectively prevent found compared with SS. On the other hand, VSM further cardiac remodeling. For the survival rate, although there was prevented the progression of cardiac remodeling and dys- no difference between VSM and SSM groups (92 vs. 73%, function and effectively suppressed mortality and plasma P = 0.163), VSM markedly improved the 50-day survival (92 catecholamine and BNP, compared with SSM. These results vs. 61%, P = 0.022) compared with the SS group. suggest that VNS exerts its cardioprotective effects on the Meanwhile, when we adopted data from our previous failing heart independently of its anti-beta-adrenergic study [9], VSM therapy provided the similar treatment mechanism. effects to that attained by VNS alone (normalized biventricu- lar weight: 2.67 ± 0.08 vs. 2.75 ± 0.08; LVEDP: 16 ± 1 vs. Eec ff ts of beta‑blockade and VNS treatment on CHF 17 ± 2; LV + dp/dt : 5036 ± 172 vs. 4152 ± 75 mmHg/s), max and from the viewpoint of 50-day survival, 92 vs. 91% in The present study evaluated the long-term hemodynamics CHF rats. These results indicated that the effect of VNS in rats with CHF by using telemetry. Both SSM and VSM was not enhanced by metoprolol, i.e., there would be no therapies similarly reduced HR compared with the SS. The significant synergistic effect between VNS and beta-blocker extent of HR reduction was also similar to our previous report therapy. The difference between VSM and SSM may be that examined the effect of VNS without beta-blockade in rats attributable to mechanisms unique to VNS independent of with CHF [9]. These results imply that chronic VNS does not ant-beta-adrenergic mechanism. induce an additional bradycardic effect beyond the bradycardic effect attained by beta-blockade. Hence, chronic VNS may Possible treatment mechanisms involved in VNS contribute to the reduction of averaged HR mainly through therapy decreasing or inhibiting cardiac sympathetic activity. HR has been proven to be the best predictor for prognosis after MI in The vagal nerve is an ancient nerve in evolution; it is com- patients with congestive heart failure [18]. By inducing brady- posed of afferent and efferent fibers to govern many visceral cardia, beta-blockers have become very important in treating 1 3 The Journal of Physiological Sciences (2019) 69:295–303 301 reflexes. In small animals, such as mice, rats, and rabbits, the have proven that the vagal afferent nerves exert a significant vagal nerve in the cervical region can be surgically separated tonic inhibitory influence on AVP secretion in anesthetic and from other nerves (e.g., aortic nerve and sympathetic nerve). conscious dogs [33, 34]. AVP is reportedly upregulated and Because various nerve fibers in the vagal nerve have differ - exhibits a defective response to physiological stimulation ent trigger levels to evoke action potential, responses to VNS in CHF [35, 36]. Although AVP was not measured in the rely on stimulus strength. Early acute VNS intervention for present study, we have previously demonstrated that chronic cardiac protection is considered as vagal efferent effect [24]. VNS decreases AVP secretion and sodium ingestion in CHF However, reviewing over 10 years of research on VNS for rats with MI [16]. Therefore, we postulate that decreasing CHF including experimental and clinical studies, it may be the AVP secretion may be a contributing mechanism of VNS worth focusing on the role of the vagal afferent pathway therapy for CHF. in the VNS therapy. We applied telemetry recording and remote controlling systems to evaluate behavioral and hemo- Clinical implications dynamic responses to VNS in free-moving rats. In the pre- liminary test for selecting VNS intensity, we observed that The diversity of disease conditions in patients with CHF is animals could sense the VNS even at very low intensity (cur- one of the biggest challenges in clinical studies. According rent) and make behavioral responses such as holding breath to therapeutic ethics, numerous clinical studies had to be per- and displaying alertness. These phenomena suggest that at formed in the presence of a routine therapeutic background. least a part of the vagal afferent fibers can be stimulated by These therapeutic factors may obscure the real effects of the a low current, which may be lower than the trigger level of intervention to be evaluated. All the VNS clinical trials were efferent fibers to control HR [25]. The titration for chronic conducted with the standard treatment background includ- VNS had to be set below a tolerable level in an experimental ing beta-blockers, ACEI or/and ARB, aldosterone antago- study [26] or a clinical trial [27]. nists, and diuretic agents. In particular, most of the patients At least three aspects of vagal afferent action should be (92–100%) used beta-blockers. The results of this study considered. First, vagal afferent stimulation may inhibit sym- showed that VNS did not further decrease mean HR under pathetic nerve activity through the input to the brainstem the beta-blocker treatment background while it exerted addi- (the nucleus tractus solitarius) [28, 29]. This effect is pos- tional benefits for CHF. Hence, beta-blockers should not be a sibly one of the most important mechanisms of VNS benefits malefactor of obstructing the VNS benefits in clinical trials. for CHF, because persistent compensatory sympathetic acti- In a previous study, we demonstrated that pharmacologi- vation for cardiac dysfunction leads to an increased secretion cal vagal activation by donepezil (an acetylcholinesterase of neurohumoral factors such as vasopressin and adrenocor- inhibitor) combined with losartan exerts synergic treatment ticoid. This increased secretion, in turn, further activates effects in rats with CHF [17]. Therefore, ACEI or ARB may compensatory mechanisms to form a vicious cycle. We also be excluded from a malefactor list. We suspect that diuretic observed that VNS treatment significantly improved the agents could interfere with the VNS effects. Clinical stud- ability of the carotid sinus baroreflex to reduce sympathetic ies reported that diuretics increase sympathetic outflow and nerve activity in rats with CHF [19]. Second, electrical VNS AVP secretion, without improving the long-term outcome decreases the release of various cytokines including tumor in patients with CHF [37–41]. Diuretics may antagonize the necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This above-mentioned VNS-induced prevention of AVP secre- effect involves both afferent and efferent fibers and is called tion. However, detailed data analysis to evaluate the VNS the cholinergic anti-inflammatory reflex [30]. Although this effects in diuretic-free patients with CHF is still lacking. The study did not evaluate these inflammatory factors, a previ- ongoing clinical trial ANTHEM-HFpEF has been designed ous study indicated that VNS in the anesthetized rodent fol- to conduct VNS in patients with CHF with preserved and lowing myocardial ischemia and reperfusion reduced infarct mid-range left ventricular ejection fraction [42]. Patients size, through the alpha-7 nicotinic acetylcholine receptor- in these categories were less frequently prescribed diuretic dependent anti-inflammation mechanism [31]. In the canine agents than in subjects with severe CHF enrolled in previ- model of CHF, both TNF-α and IL-6 in plasma and in car- ous VNS trials. We hope this prospective clinical study may diac tissue are elevated more than in normal dogs, and they provide new insights into diuretic influence on VNS therapy. were attenuated by long-term monotherapy with VNS [32]. Third, vagal afferent stimulation may inhibit arginine vaso- Study limitations pressin (AVP) secretion. 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Published: Nov 9, 2018

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