Atrial ganglionated plexi stimulation may be an effective therapeutic tool for the treatment of heart failure

An autonomic imbalance, i.e., increased sympathetic tone and/or decreased parasympathetic tone is a critical characteristic of heart failure, which is associated with progressive ventricular remodeling, ventricular arrhythmia generation and disease progression. Increasing cardiac parasympathetic tone by vagus nerve stimulation has been shown to significantly improve heart failure symptoms, hemodynamics, left ventricular function and quality of life. However, cervical surgery is needed to position vagal stimulation electrode and vagus nerve stimulation may also cause some undesired side effects. Our recent studies showed that ablation of the main atrial ganglionated plexi (GP) facilitated the occurrence of ventricular arrhythmias in acute myocardial ischemic heart while low-intensity atrial GP stimulation inhibited the occurrence of ventricular arrhythmias during acute myocardial ischemia and ischemia reperfusion. Based on these results, we hypothesize that atrial GP stimulation may ameliorate autonomic dysfunction in heart failure, inhibit heart failure progression and improve heart failure prognosis.     

Artificial neural interfaces for bionic cardiovascular treatments

An artificial nerve, in the broad sense, may be conceptualized as a physical and logical interface system that reestablishes the information traffic between the central nervous system and peripheral organs. Studies on artificial nerves targeting the autonomic nervous system are in progress to explore new treatment strategies for several cardiovascular diseases. In this article, we will review our research targeting the autonomic nervous system to treat cardiovascular diseases. First, we identified the rule for decoding native sympathetic nerve activity into a heart rate using transfer function analysis, and established a framework for a neurally regulated cardiac pacemaker. Second, we designed a bionic baroreflex system to restore the baroreflex buffering function using electrical stimulation of the celiac ganglion in a rat model of orthostatic hypotension. Third, based on the hypothesis that autonomic imbalance aggravates chronic heart failure, we implanted a neural interface into the right vagal nerve and demonstrated that intermittent vagal stimulation significantly improved the survival rate in rats with chronic heart failure following myocardial infarction. Although several practical problems need to be resolved, such as those relating to the development of electrodes feasible for long-term nerve activity recording, studies of artificial neural interfaces with the autonomic nervous system have great possibilities in the field of cardiovascular treatment. We expect further development of artificial neural interfaces as novel strategies to cope with cardiovascular diseases resistant to conventional therapeutics. Part of this article is a translation of an article in Japanese that appeared in Jinkozoki 2006;3(3):352–355     

Cardiac autonomic denervation in congestive heart failure: comparison of Chagas' heart disease with other dilated cardiomyopathy

Congestive heart failure (CHF) is associated with activation of the cardiac sympathetic nerves. However, impairment of the sympathetic nerve terminals in patients with CHF has been indicated by studies showing reduction of cardiac norepinephrine uptake and stores. This investigation studies the histochemical evaluation of the sympathetic nerve terminals in CHF. The cardiac parasympathetic innervation was also studied to address the question of specificity of the presumed sympathetic denervation. Nineteen patients with CHF underwent cardiac transplantation or partial ventriculectomy, which provided the heart tissue. In 11 of them, the dilated cardiomyopathy was associated with Chagas' disease. Inflammatory process and fibrosis were studied histologically. The sympathetic and parasympathetic nerve fibers were visualized through histochemical techniques for, respectively, catecholamines and acetylcholinesterase activity. By using a computer-assisted morphometric program, the inflammation, fibrosis, and parasympathetic innervation were quantified. Moderate to severe fibrosing myocarditis characterized the hearts of the chagasic patients. In cardiomyopathies not associated with Chagas' disease, the inflammation was discrete, if present, but the amount of fibrosis was similar to that found in Chagas' cardiomyopathy. Reduction of both kinds of nerve terminals occurred in the heart of all patients. The parasympathetic denervation was proven to be more severe in chagasic cardiomyopathy. Our data on the heart innervation indicate a progressive autonomic denervation in heart failure. In Chagas' heart disease, the denervation seems to be more severe or rapid, probably because of the sustained inflammatory process.     

岛叶的功能及对心率变异性的影响

心率变异性作为判断心脏自主神经状态的无创性指标常被用来定量分析自主神经的功能状态，其时域及频域降低与恶性心律失常、心功能不全，乃至心源性猝死等有关。人类的岛叶是控制交感神经和副交感神经介导的心血管调节最重要的皮层区域，多数学者在临床实践中发现，岛叶病变会导致心血管功能紊乱及自主神经功能状态的变化，因此岛叶与心脏功能之间的联系倍受重视。     

Beta-adrenergic blockade may prolong life in post-infarction patients in part by increasing vagal cardiac inhibition

Beta-adrenergic blocking drugs prolong lives of post-infarction patients primarily by preventing sudden cardiac death. The mechanisms responsible for this beneficial effect are not understood clearly, since beta-blockers, in doses used in most clinical trials, are only weakly effective against stable ventricular arrhythmias. Arrhythmias during myocardial ischemia may differ from arrhythmias in other clinical settings in that they depend importantly upon autonomic neural factors, including the balance between levels of sympathetic cardiac stimulation and parasympathetic cardiac inhibition. Beta-blockers reduce sympathetic cardiac stimulation, and they may influence this balance favorably in another important way: a well documented, but not generally appreciated property of beta-blocking drugs is that they also increase levels of vagal cardiac inhibition. I propose that beta-blockade prevents arrhythmic deaths in post-infarction patients in part by increasing levels of vagal cardiac inhibition.     

巨噬细胞极化在心血管疾病中的作用

心血管病,尤其是急性心肌梗死和收缩性心功能衰竭已成为西方国家患者死亡的主要原因,在发展中国家也呈明显上升趋势.缺血性的心脏病已经成为普遍现象,是引起病人死亡的主要原因.尽管早期血管再建和药物治疗能够明显提高心肌梗死后的生存率,但仍有大量病人发展成心力衰竭.巨噬细胞除了具有免疫防御和维持组织稳态功能,还在心肌梗死诱导的病理生理过程中发挥重要作用.巨噬细胞的亚群已被证实参与心血管疾病(动脉粥样硬化、心肌梗死、心肌缺血、心肌纤维化)的发生和发展,在心脏损伤和心肌重塑中有重要作用,研究基于巨噬细胞调控治疗心血管疾病的治疗策略很有价值.     

Vagal nerve activity and the high frequency peak of the heart rate variability.

For the Quality of life (QOL) of patients with an artificial heart system, monitoring an information of the cardiovascular control system may be important. We have been evaluating the autonomic nervous system for that purpose. Recently, fluctuations in hemodynamic parameters including heart rate variability (HRV) were evaluated by means of spectral analysis and nonlinear mathematical analysis. Respiratory wavers in HRV were thought to reflect ongoing information of the parasympathetic nerve activity. Is it true? In order to confirm this hypothesis, we recorded vagal nerve activity directly in the chronic animal experiments. Six healthy adult goats were anesthetized with Halothene inhalation and thoracotomy were performed by the fourth lib resection during mechanical ventilation. Arterial blood pressure, right and left atrial pressures were continuously monitored with the catheter insertion. Cardiac output was measured by the electromagnetic flowmeter attached to the ascending aorta. After the chest was closed, incision was made to the left neck and left vagal nerve was separated. Stainless steel electrodes were inserted into the vagal nerve and fixed by the plasticizer. After the incision was closed, the goats were transferred to the cage and extubated after waking. Hemodynamic parameters and vagal nerve activity were measured in the awake condition. The results showed that clear observation of the autonomic nerve discharges were embodied by this experimental system. The vagal nerve discharges were synchronized with heart beat and respiration. The vagal nerve tonus was significantly influenced by the hemodynamic alteration. However in some condition, the respiratory wave was not always consistent with tonus of the vagal nerve activity, thus suggesting that we should check another information to evaluate the parasympathetic tone. We must continue this study to evaluate an autonomic nerve during artificial heart circulation.     

B-type natriuretic peptide is an independent predictor for cardiovascular death in patients with no clinical signs of ventricular dysfunction after acute myocardial infarction

B-type natriuretic peptide (BNP) is released from cardiac ventricles in response to increased wall tension in patients with heart failure. It has been used as a biochemical marker for the diagnosis of congestive heart failure. BNP is also increased in patients with acute myocardial infarction, and is associated with an increased risk of cardiovascular mortality in those with impaired left ventricular function after myocardial infarction. We hypothesized that an increase in BNP soon after acute myocardial infarction is an independent predictor for long-term prognosis in patients with no clinical signs of left ventricular function.     

间充质干细胞移植治疗心血管疾病的应用与进展

背景：间充质干细胞因其具有自我更新、向不同组织分化及免疫调节功能,而被作为治疗急性心肌梗死、心力衰竭等心血管疾病的有效的方法之一。 目的：从间充质干细胞的生物特性,转分化能力、免疫调节、心脏修复的作用机制以及间充质干细胞用于治疗心血管疾病早期的临床实验资料做一简要阐述。 方法：以“间充质干细胞、免疫调控、心肌梗死、心力衰竭”,“MSCs,Immunomodulation,myocardial infarction,heart  failure”为检索词,应用计算机检索维普(VIP)期刊全文数据库及Pubmed 数据库。排除与研究目的无关和内容重复者。保留35篇文献做进一步分析。 结果与结论：间充质干细胞作为理想的种子细胞,除了具备自我更新、多向分化潜能之外,还具有免疫调节功能,避免同种异体移植或异种移植引起的免疫排斥反应。它可以向心肌细胞及脉管系统分化,通过旁分泌作用分泌一系列的细胞活素类物质及生长因子,并且动员内在的心肌干细胞,从而起到改善心功能,诱导逆向重塑,降低心梗面积的作用。相关的临床实验也显示了移植间充质干细胞的可行性和有效性。     

Left ventricular dysfunction and altered autonomic activity: a possible link to sudden cardiac death

There is now a growing body of clinical evidence that suggests a strong association between left ventricular dysfunction and sudden cardiac death in patients recovering from myocardial infarction. The mechanisms underlying this association remain to be determined. Alterations within the autonomic nervous system may represent one factor that links an impairment in cardiac function to an increased mortality. Since ventricular dysfunction would tend to reduce stroke volume, an increased sympathetic and/or decreased parasympathetic efferent activity may compensate for this fall in stroke volume by increasing heart rate and/or the force of contraction (inotropic state) in an attempt to maintain a more normal cardiac output. Similar changes in autonomic activity are, in fact, known to increase the vulnerability to ventricular fibrillation. Therefore, I propose that myocardial infarction induces changes in cardiac function which in turn elicits autonomic efferent changes. As a consequence of these compensatory reflex changes the heart becomes less electrically stable and thereby more prone to lethal arrhythmias.     

脐血单个核细胞移植治疗冠状动脉性心脏病合并心力衰竭的安全性

背景：多项实验和临床研究表明,干细胞移植可能取代坏死心肌、建立新生血管、改善心脏功能,明显改善心血管疾病患者临床症状和预后。 目的：观察新生儿脐血单个核细胞移植治疗冠状动脉性心脏病合并心力衰竭患者的安全性。 方法：共入选冠状动脉性心脏病合并心力衰竭患者(急性心肌梗死合并心力衰竭6例,陈旧心肌梗死合并心力衰竭6例)12例,入院后在常规药物与介入治疗基础上,经皮经腔导管建立冠状动脉通道,利用微导管移植分离的新生儿脐血单个核细胞悬液。细胞移植后1周进行常规抽血检查,与移植前对比血常规、肝肾功能、免疫指标的变化。 结果与结论：脐血单个核细胞移植后有1例发热,不良反应发生率为8.3%,无微栓塞发生,随访1周无移植物抗宿主病发生。与细胞移植治疗前比较,治疗后1周血常规、肝功能、肾功能、C-反应蛋白、IgA、IgG等指标差异无显著性意义。说明新生儿脐血单个核细胞移植治疗冠状动脉性心脏病死合并心功能衰竭在短期是安全的。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Mental stress inhibits pain perception and heart rate variability but not a nociceptive withdrawal reflex

AIM: Do distraction from- or attention to sural nerve stimulation affect pain, heart rate variability, and a spinal withdrawal reflex? MATERIAL AND METHODS: In 26 male volunteers, electrical stimulation at the distal cutaneous receptive field of the sural nerve elicited pain and a nociceptive withdrawal reflex. Intensity of pain was rated on a numeric rating scale. Electromyographic reflex responses were measured from biceps femoris muscle. Cardiac autonomic function was estimated by heart rate variability measures and was expressed in the time domain as mean of RR-intervals for normal heart beats (mean-RR) and standard deviation of all normal RR-intervals (SD-NN) and, in the frequency domain, where pure vagal activity was assessed by high frequency power (0.15-0.4 Hz). Low frequency power (0.04-0.15 Hz) reflects both parasympathetic and sympathetic control. Effect parameters were recorded before and during random distraction and attention. Distraction from sural nerve stimulation was induced by a mental arithmetic test, paced auditory serial addition task (PASAT), while attention was induced by concentrating on painful foot stimulation. RESULTS: Paced auditory serial addition task decreased mean-RR and SD-NN, frequency domain parameters, as well as pain (P<0.001). In contrast, PASAT did not change the spinal withdrawal reflex. Attention did not affect any effect parameter. CONCLUSION: Distraction by PASAT altered autonomic activity and inhibited pain but failed to affect withdrawal reflex responses, while attention had no effect on either parameter. Psychological distraction and attention may have different effects on noxious evoked pain perception and autonomic activity. Pain relief during PASAT probably involves supraspinal mechanisms.     

心肌再生医学的研究进展

心血管疾病是导致人类死亡的主要疾患之一, 其中以冠心病、心肌梗死最为常见。导致心功能衰竭的主要原因是心肌梗死后心肌细胞的大量丢失及内源性修复机制的缺失,受损的心肌被瘢痕组织所替代，从而进一步导致心功能的丧失。心脏移植可以治疗严重心功能衰竭，但这一有效治疗措施受供体来源和免疫排斥反应等的限制。近年来，随着人类对干细胞认识的加深，应用心肌再生治疗心血管疾病已经成为一个新的研究热点。     

心肌再生途径的研究

急性心肌梗死（AMI）已成全球缺血性心血管疾病的主要死因之一。近年来,随着经皮冠状动脉介入治疗和再灌注时间的改善,急性心梗患者死亡率显著降低。但心肌梗死后导致心肌细胞数量减少,纤维瘢痕增生,引起心室结构重建、心肌弹性下降、脏壁扩张变薄和心功能下降等,逐渐形成慢性心力衰竭（CHF）。结合我国人口老龄化及冠心病发病的特点,意味着更多的人会逐渐发展形成CHF,将严重影响患者的预后及生活质量。心肌再生是让受损心肌周围细胞和血管再次增殖分化,从而减轻心室结构重建,改善心功能。本文就促心肌再生方法,包括信号通路调节、干细胞移植治疗、心脏重编码、外泌体旁分泌刺激、新兴组织工程做一综述。     

Cardiac Stem Cells and their Roles in Myocardial Infarction

Myocardial infarction leads to loss of cardiomyocytes, scar formation, ventricular remodeling and eventually deterioration of heart function. Over the past decade, stem cell therapy has emerged as a novel strategy for patients with ischemic heart disease and its beneficial effects have been demonstrated by substantial preclinical and clinical studies. Efficacy of several types of stem cells in the therapy of cardiovascular diseases has already been evaluated. However, repair of injured myocardium through stem cell transplantation is restricted by critical safety issues and ethic concerns. Recently, the discovery of cardiac stem cells (CSCs) that reside in the heart itself brings new prospects for myocardial regeneration and reconstitution of cardiac tissues. CSCs are positive for various stem cell markers and have the potential of self-renewal and multilineage differentiation. They play a pivotal role in the maintenance of heart homeostasis and cardiac repair. Elucidation of their biological characteristics and functions they exert in myocardial infarction are very crucial to further investigations on them. This review will focus on the field of cardiac stem cells and discuss technical and practical issues that may involve in their clinical applications in myocardial infarction.     

Cardiac rehabilitation and artificial heart devices

Recently, cardiac rehabilitation has gained popularity in Japan because beneficial effects on patients’ prognosis have been reported. Another reason is that cardiac rehabilitation has been covered by health insurance since 1988 in Japan. Currently, cardiac rehabilitation is covered for the diseases of angina pectoris, acute myocardial infarction, chronic heart failure (CHF), peripheral arterial disease, and diseases of the aorta and after open-heart surgery. Left ventricular assist devices (LVADs) are sometimes used in patients with progressive CHF symptoms to provide circulatory support, because in most of these patients heart failure does not improve with application of medical therapy, intra-aortic balloon pumping, or a percutaneous cardiopulmonary system. Modern VAD control systems are compact, allowing patients to carry them around without difficulty. Since patient management at the outpatient clinic has become possible, patients are able to expand the scope of their activities. Early active rehabilitation in patients implanted with a LVAD improves their condition, favorably impacts the clinical course while they await heart transplantation, and also improves posttransplant recovery. Exercise therapy is one of the important components in comprehensive cardiac rehabilitation. Exercise therapy is important to improve the quality of life of patients with LVADs. Appropriate exercise therapy is effective for patients with various cardiac conditions who undergo diverse treatments and is practiced actively by many patients. In order to facilitate cardiac rehabilitation safely and effectively for patients with serious conditions, education for health care professionals is essential. In this review, we describe the concept of rehabilitation followed by cardiac rehabilitation for patients with heart failure, patients after open-heart surgery, and patients with implanted LVADs.     

Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, and fatty acid metabolism has been well studied. Short-chain fatty acids (SCFAs) have been less discussed than long-chain fatty acids (LCFAs) in CVDs. However, increasing evidence indicates the importance of SCFAs in regulating cardiac function. Here, we summarize the current understanding of SCFAs in hypertension, ischaemic reperfusion, myocardial infarction, atherosclerosis and heart failure. Most SCFAs exert positive effects in regulating related diseases. Butyrate and propionate can reduce blood pressure, improve I/R injury and decrease the risk of coronary artery disease (CAD) and atherosclerosis. Acetate can also play a positive role in regulating hypertension and preventing atherosclerosis, and malonate can improve cardiac function after MI. They affect these diseases by regulating inflammation, the immune system and related G protein-coupled receptors, with multiple neurohumoural regulation participation. In contrast, succinate can accelerate IR injury, increasing mitochondrial ROS production. SCFAs ultimately affect the regulation of different pathophysiological processes in heart failure. Here, we clarified the importance of short-chain fatty acids in the cardiovascular system and their multiple effects in various pathophysiological processes, providing new insights into their promising clinical application. More research should be conducted to further elucidate the underlying mechanism and different effects of single or multiple SCFA supplementation on the cardiovascular system.     

Sympathetic modulation of vagal chronotropic and arrhythmogenic influences on the heart

In acute experiments on cats, stimulation of the caudal cardiac nerve inhibited tonic and synchronizing components of the vagal chronotropic effects and suppressed arrhythmogenic effect of vagal stimulation. By contrast, stimulation of ansa subclavia potentiated the effects of vagal stimulation. A novel model of vagosympathetic interactions in the heart of mammals is proposed.     

Effect of the cholinesterase inhibitor donepezil on cardiac remodeling and autonomic balance in rats with heart failure

In an earlier study we demonstrated the beneficial effect of direct vagal electrical stimulation on cardiac remodeling and survival. In the study reported here, we attempted to reproduce the effect of vagal enhancement through the administration of an acetylcholinesterase inhibitor, donepezil. A rat model of heart failure following extensive healed myocardial infarction was used. Compared to their nontreated counterparts, rats given donepezil (5 mg/kg/day) in their drinking water had a smaller biventricular weight (3.40 ± 0.13 vs. 3.02 ± 0.21 g/kg body weight, P < 0.05), and maximal rate of rise (3256 ± 955 vs. 3822 ± 389 mmHg/s, P < 0.05) and the end-diastolic value (30.1 ± 5.6 vs. 23.2 ± 5.7 mmHg, P < 0.05) of left ventricular pressure were improved. Neurohumoral factors were suppressed in donepezil-treated rats (norepinephrine 1885 ± 1423 vs. 316 ± 248 pg/ml, P < 0.01; brain natriuretic peptide 457 ± 68 vs. 362 ± 80 ng/ml, P < 0.05), and the high-frequency component of heart rate variability showed a nocturnal increase. These findings indicated that donepezil reproduced the anti-remodeling effect of electrical vagal stimulation. Further studies are warranted to evaluate the clinical usefulness of donepezil in heart failure.     

Central command: control of cardiac sympathetic and vagal efferent nerve activity and the arterial baroreflex during spontaneous motor behaviour in animals

Feedforward control by higher brain centres (termed central command) plays a role in the autonomic regulation of the cardiovascular system during exercise. Over the past 20 years, workers in our laboratory have used the precollicular-premammillary decerebrate animal model to identify the neural circuitry involved in the CNS control of cardiac autonomic outflow and arterial baroreflex function. Contrary to the traditional idea that vagal withdrawal at the onset of exercise causes the increase in heart rate, central command did not decrease cardiac vagal efferent nerve activity but did allow cardiac sympathetic efferent nerve activity to produce cardiac acceleration. In addition, central command-evoked inhibition of the aortic baroreceptor-heart rate reflex blunted the baroreflex-mediated bradycardia elicited by aortic nerve stimulation, further increasing the heart rate at the onset of exercise. Spontaneous motor activity and associated cardiovascular responses disappeared in animals decerebrated at the midcollicular level. These findings indicate that the brain region including the caudal diencephalon and extending to the rostral mesencephalon may play a role in generating central command. Bicuculline microinjected into the midbrain ventral tegmental area of decerebrate rats produced a long-lasting repetitive activation of renal sympathetic nerve activity that was synchronized with the motor nerve discharge. When lidocaine was microinjected into the ventral tegmental area, the spontaneous motor activity and associated cardiovascular responses ceased. From these findings, we conclude that cerebral cortical outputs trigger activation of neural circuits within the caudal brain, including the ventral tegmental area, which causes central command to augment cardiac sympathetic outflow at the onset of exercise in decerebrate animal models.