Anti-arrhythmic and anti-heart failure effects of low-level electrical stimulation on aortic root ventricular ganglionated plexi.

BACKGROUND: It remains uncertain whether low-level electrical stimulation (LL-ES) of the ventricular ganglionated plexi (GP) improves heart function. This study investigated the anti-arrhythmic and anti-heart failure effects of LL-ES of the aortic root ventricular GP (ARVGP). METHODS: Thirty dogs were divided randomly into control, drug, and LL-ES groups after performing rapid right ventricular pacing to establish a heart failure (HF) model. The inducing rate of arrhythmia; levels of bioactive factors influencing HF, including angiotensin II type I receptor (AT-1R), transforming growth factor-beta (TGF-ß), matrix metalloproteinase (MMP), and phosphorylated extracellular signal-regulated kinase (p-ERK1/2); left ventricular stroke volume (LVSV), and left ventricular ejection fraction (LVEF)were measured after treatment with placebo, drugs, and LL-ES. RESULTS: The inducing rate of atrial arrhythmia decreased from 60% in the control group to 50% in the drug group and 10% in the LL-ES group (p = .033 vs. drug group) after 1 week of treatment. The ventricular effective refractory period was prolonged from 139 ± 8 ms in the drug group to 166 ± 13 ms in the LL-ES group (p = .001). Compared to the drug group, the expressions of AT-1R, TGF-ß, and MMP proteins were down-regulated in the LL-ES group, whereas that of p-ERK1/2 was significantly increased (all p = .001). Moreover, in the LL-ES group, LVSV increased markedly from 13.16 ± 0.22 to 16.86 ± 0.27 mL, relative to that in the drug group (p = .001), and LVEF increased significantly from 38.48% ± 0.53% to 48.94% ± 0.57% during the same time frame (p = .001). CONCLUSION: Short-term LL-ES of ARVGP had both anti-arrhythmic and anti-inflammatory effects and contributed to the treatment of tachycardia-induced HF and its associated arrhythmia.

Left Stellate Ganglion Ablation Inhibits Ventricular Arrhythmias through Macrophage Regulation in Canines with Acute Ischemic Stroke.

AIMS: To investigate the potential mechanism of ventricular arrhythmias (VAs) after acute ischemic stroke and explore the effects of left stellate gangling (LSG) ablation on VAs induced by stroke in canines. Materials and Methods: Twenty canines were randomly divided into the sham-operated group (n=6), AS group (n=7) and SGA group (n=7). Cerebral ischemic model was established in the AS group and the SGA group by right acute middle cerebral artery occlusion (MCAO). LSG ablation was performed in the SGA group as soon as MCAO. After 3 days, atrial electrophysiology and neural activity were measured in vivo. The levels of norepinephrine (NE) in plasma and ventricle were detected by ELISA. The levels of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and NF-κB p65 in ventricle were detected by western blotting. The pro-inflammatory polarization of macrophages in ventricle was detected by immunofluorescence. Results: Higher ventricular tachycardia (VT) inducibility and lower ventricular fibrillation threshold (VFT) were observed in the AS group compared with those in the sham-operated group, associated with higher LSG activity and NE levels, increased number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Compared with the AS group, the SGA group had lower VT inducibility and higher VFT, combined with lower NE levels, and reduced number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Conclusion: LSG ablation could reduce VAs vulnerability after acute stroke by preventing the macrophages polarization and activation induced by sympathetic hyperactivity.

Focal reduction in left ventricular 123I-metaiodobenzylguanidine uptake and impairment in systolic function in patients with Anderson-Fabry disease.

BACKGROUND: Abnormalities of cardiac sympathetic innervation have been demonstrated in Anderson-Fabry disease (AFD). We aimed to investigate the relationship between regional left ventricular (LV) denervation and regional function abnormalities. METHODS: Twenty-four AFD patients (43.7 ± 12.8 years) were studied by 123I-metaiodobenzylguanidine (MIBG) cardiac imaging and speckle-tracking echocardiography. Segmental tracer uptake was estimated according to 0 to 4 score, and total defect score (TDS) was calculated for each patient. RESULTS: Segmental longitudinal strain worsened as MIBG uptake score increased (P < 0.001). By ROC analysis, a segmental longitudinal strain > - 16.2% predicted a segmental MIBG uptake score ≥1, with 79.7% sensitivity and 65.3% specificity. Segmental MIBG uptake defects were found in 13 out 24 AFD patients. LV mass index (60.8 ± 10.1 vs. 41.4 ± 9.8 g/h2.7), relative wall thickness (0.51 ± 0.06 vs. 0.40 ± 0.06), systolic pulmonary artery pressure (35.2 ± 6.7 vs. 27.2 ± 4.2 mmHg), and longitudinal strain (- 14.3 ± 2.7 vs. -19.4 ± 1.8%) were significantly higher in patients with segmental defect (all P < 0.01). At multivariate linear regression analysis, global longitudinal strain was independently associated with TDS (B = 3.007, 95% confidence interval 1.384 to 4.630, P = 0.001). CONCLUSIONS: Reduced cardiac MIBG uptake reflects the severity of cardiac involvement in AFD patients. LV longitudinal function impairment seems to be an earlier disease feature than regional myocardial denervation.

Cells of the adult human heart.

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

Effect of sympathetic autonomic stress from the cold pressor test on left ventricular function in young healthy adults.

There is a dearth of studies investigating the effect of sympathetic activation on left ventricular function. This study aimed to investigate the effect of sympathetic autonomic stress on left ventricular function in young healthy adults. Fifty-six normotensive healthy participants (age 23.55 ± 3.82 years) took part in the study after giving informed consent. After obtaining baseline measurements, heart rate (HR), blood pressure (BP), peripheral saturation of oxygen (SpO2) and left ventricular function (assessed by means of ejection fraction (EF) obtained by transthoracic 2-D echocardiography) were determined before and following sympathetic activation using cold pressor test (CPT). Exposure to CPT led to significant increase (P < 0.0001) in HR (70.4 ± 10.7 bpm to 91.6 ± 14.8 bpm), SBP (118 ± 8 mmHg to 138 ± 14 mmHg) and DBP (71 ± 7 mmHg to 91 ± 11 mmHg). Participants' EDV (101.1 ± 15.8 ml to 104.2 ± 19.3 mL), ESV (38.7 ± 9.1 mL to 40.3 ± 11.6 mL), SpO2 (99.5 ± 0.79% to 99.5 ± 0.77%) and EF (61.9 ± 5.9% to 60.9 ± 6.4%) were only slightly changed (P > 0.05). However, cardiac output (4.3 ± 0.9 L/min to 5.4 ± 1.4 L/min) and cardiac index (3.7 ± 0.8 L/min per m2 to 4.5 ± 1.4 L/min per m2 ) increased significantly (P < 0.0001). We conclude that sympathetic stress induced by cold pressor test has marginal effect on ejection fraction and fractional shortening while increasing cardiac output and cardiac index in young healthy adults.

Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity.

Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.

Blocking the Nav1.8 channel in the left stellate ganglion suppresses ventricular arrhythmia induced by acute ischemia in a canine model.

Left stellate ganglion (LSG) hyperactivity promotes ischemia induced ventricular arrhythmia (VA). Blocking the Nav1.8 channel decreases neuron activity. Therefore, the present study aimed to investigate whether blocking the Nav1.8 channel with its specific blocker A-803467 in the LSG reduces sympathetic activity and exerts anti-arrhythmic effects. Forty canines were divided into dimethylsulfoxide (DMSO) group and 10 mM, 15 mM, and 20 mM A-803467 groups. A volume of 0.1 ml of A-803467 or DMSO was injected into the LSG. The ventricular electrophysiological parameters, LSG function were measured before and 30 min after the injection. VA was assessed for 60 min after ischemia and then LSG tissues were collected for molecular biological experiments. Compared with DMSO, concentration-dependent prolonged action potential duration and effective refractory period, decreased LSG function were identified after A-803467 treatment. Moreover, the severity of ischemia induced VA was decreased in A-803467 groups. Furthermore, decreased nerve growth factor, decreased c-fos and increased sympathetic neuron apoptosis were found in the LSG after A-803467 injection. In conclusion, blocking the Nav1.8 channel could significantly attenuate ischemia-induced VA, primarily by suppressing LSG activity.

Correlation between the high-frequency content of the QRS on murine surface electrocardiogram and the sympathetic nerves density in left ventricle after myocardial infarction: Experimental study.

Denervated post-infarct scar is arrhythmogenic. Our aim was to compare QRS frequency content in denervated and innervated left ventricular (LV) scar. In-vivo single lead ECG telemetry device was implanted in 17 heterozygous PTPσ (HET) and 7 lacking PTPσ (KO) transgenic mice. Myocardial infarction (MI) with reperfusion and sham surgery was performed. HET mice developed a denervated scar, whereas KO mice developed innervated scar. The power spectral density was used to assess the QRS frequency content. Denervated as compared to innervated post-MI scar was characterized by the higher relative contribution of 300-500 Hz (14 ± 1 vs. 9 ± 1%; P = 0.001) but reduced relative contribution of 200-300 Hz (86 ± 1 vs. 91 ± 1%; P = 0.001). Norepinephrine concentration in peri-infarct zone correlated with both 1-200 Hz (r = 0.75; P = 0.03) and 200-500 Hz QRS power (r = 0.73; P = 0.04). Sympathetic fiber density within the infarct correlated with 200-300/200-500 Hz QRS power ratio (r = 0.56; P = 0.005). Intracellular sigma peptide injections in post-MI HET mice restored the QRS power.

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.

Bilateral sympathectomy improves postinfarction left ventricular remodeling and function.

OBJECTIVES: To evaluate the influence of bilateral or left sympathectomy on left ventricular remodeling and function after myocardial infarction in rats. METHODS: Myocardial infarction was induced in rats by ligation of the left anterior descending coronary. Seven days later, rats were divided into 4 groups: the myocardial infarction, myocardial infarction with left sympathectomy, myocardial infarction with bilateral sympathectomy, and sham groups. After 8 weeks, left ventricular function was evaluated with the use of a pressure-volume conductance catheter under steady-state conditions and pharmacological stress. Infarct size and extracellular matrix fibrosis were evaluated, and cardiac matrix metalloproteinases and myocardial inflammatory markers were analyzed. RESULTS: The myocardial infarction and left sympathectomy group had an increased end diastolic volume, whereas the bilateral sympathectomy group had a mean end-diastolic volume similar to that of the sham group (P < .002). Significant reduction in ejection fraction was observed in the myocardial infarction and left sympathectomy group, whereas it was preserved after bilateral sympathectomy (P < .001). In response to dobutamine, left ventricular contractility increased in sham rats, rising stroke work, cardiac output, systolic volume, end-diastolic volume, ejection fraction, and dP/dt max. Only bilateral sympathectomy rats had significant increases in ejection fraction (P < .001) with dobutamine. Fibrotic tissue and matrix metalloproteinase expression decreased in the bilateral sympathectomy group compared to that in the myocardial infarction group (P < .001) and was associated with left ventricular wall thickness maintenance and better apoptotic markers in noninfarcted myocardium. CONCLUSIONS: Bilateral sympathectomy effectively attenuated left ventricular remodeling and preserved systolic function after myocardial infarction induction in rats.

Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Patients with Hereditary Ventricular Arrhythmias.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) has been underutilized in patients with hereditary ventricular arrhythmia syndromes such as congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The purpose of this study was to investigate the safety and efficacy of video-assisted thoracoscopic (VATS) LCSD in such patients. METHODS: Fifteen patients (four men, 24.6 ± 10.5 years old) who underwent VATS-LCSD between November 2010 and January 2015 for hereditary ventricular arrhythmia syndromes at Kyungpook National University Hospital were enrolled in this study. The safety and efficacy of VATS-LCSD were evaluated by periprocedural epinephrine tests and assessing the development of complications and cardiac events during follow-up. RESULTS: Fourteen patients with LQTS and one patient with CPVT underwent VATS-LCSD. Six and one patients developed ventricular tachyarrhythmia during preprocedural and postprocedural epinephrine test, respectively (P = 0.063). No serious complications such as Horner syndrome, pneumothorax, or bleeding developed after LCSD. Mean hospital stay after VATS-LCSD was 3.7 ± 1.5 days. During a mean follow-up of 927 ± 350 days, one LQTS patient and one CPVT patient, neither of whom manifested tachyarrhythmia during post-LCSD epinephrine test, developed torsades de pointes and syncope, respectively. The annual event rates of six patients who were symptomatic during the period preceding LCSD decreased from 0.97 to 0.19 events/year (P = 0.045). CONCLUSIONS: VATS-LCSD was a safe, and effective procedure for patients with hereditary ventricular tachycardia syndrome, with no serious adverse events and with short hospital stay.

Heart rate variability in patients undergoing univentricular heart repair.

OBJECTIVE: Altered cardiac autonomic control may play a role in the long-term outcome of patients undergoing univentricular heart repair. This study was undertaken to compare bidirectional superior cavopulmonary anastomosis with preserved antegrade pulmonary blood flow and total cavopulmonary connection, with regard to their effects on cardiac autonomic activity, as measured by heart rate variability indices, prior to and early after surgery. METHODS: This prospective study included 46 patients (27 with bidirectional superior cavopulmonary anastomosis and 19 with total cavopulmonary connection. Heart rate variability was measured preoperatively and at 2 and 9 months postoperatively. The heart rate variability was measured by a 900-s electrocardiogram recording. Comparisons were drawn between and within groups, using standard statistical methods. RESULTS: All heart rate variability parameters were comparable in the 2 groups preoperatively. At the first follow-up, all heart rate variability parameters had decreased in both groups, but the decreases were not statistically significant. Between-group comparisons showed significantly higher parasympathetic and lower sympathetic tone in the bidirectional superior cavopulmonary anastomosis group. At the second follow-up, the bidirectional superior cavopulmonary anastomosis group had a significant increase in overall cardiac autonomic tone, and the total cavopulmonary connection group had a significant increase in parasympathetic tone, compared to the first follow-up. Between-group comparisons showed higher cardiac autonomic tone in the bidirectional superior cavopulmonary anastomosis group. CONCLUSION: Total cavopulmonary connection leads to a significant reduction in overall cardiac autonomic tone, compared to bidirectional superior cavopulmonary anastomosis with antegrade pulmonary blood flow.

Vagal modulation of cardiac ventricular arrhythmia.

NEW FINDINGS: What is the topic of this review? This article addresses the relationship between vagus nerve activity and malignant ventricular arrhythmias. It focuses on the clinical association of an impaired vagal tone in cardiac disease states with high mortality from sudden cardiac death and the potential underlying mechanisms. What advances does it highlight? The article summarizes the mounting evidence that vagal innervation in the cardiac ventricle plays a key direct role in the prevention of the initiation of ventricular fibrillation. Data are presented on the role that nitric oxide plays in mediating the effects of vagal protection against ventricular fibrillation, supporting the notion that a separate non-muscarinic, nitrergic population of vagal neurons is responsible for this protection. Sudden cardiac death remains a significant unresolved clinical problem, with many of the deaths being due to malignant ventricular arrhythmias. Markers of abnormal autonomic function have been shown to be strong prognostic predictors, highlighting the important relationship between reduced vagal tone and malignant ventricular arrhythmias, such as ventricular fibrillation, in cardiac patients. Exploring the mechanisms underlying the autonomic modulation of ventricular fibrillation, my group has shown that vagus nerve stimulation protects against ventricular fibrillation in the innervated isolated heart preparation. We have provided direct evidence that nitric oxide is released in the ventricle with cervical vagus nerve stimulation and NO mediates the antifibrillatory actions of vagus nerve stimulation in the ventricle. Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors and, dogmatically, that there is little vagal effect in the ventricle, as innervation was believed to be sparse. Mounting evidence from many species now supports the presence of a rich vagal innervation in the ventricle. Data from my group showing that the protective actions of vagus nerve stimulation against ventricular fibrillation and NO release are preserved in the presence of muscarinic block support the notion that a population of nitrergic neurons could be responsible. This potentially exploitable downstream pathway together with the availability of vagus nerve stimulators make it an exciting time to investigate the development of an effective strategy of vagal protection against ventricular fibrillation in the clinical setting.

Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia.

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2-T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32-3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 µmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin.

Optimizing the parameters of vagus nerve stimulation by uniform design in rats with acute myocardial infarction.

Vagus nerve stimulation (VNS) has been shown to improve left ventricular function and survival in rats with acute myocardial infarction (AMI), and this maneuver has also been adopted clinically for the treatment of patients with chronic heart failure (CHF). Recent in vitro and in vivo studies have suggested that VNS can modulate the level of pro-inflammatory factors. Despite the beneficial effects of VNS, the stimulation parameters for obtaining favorable outcomes appear highly variable. To optimize VNS parameters, we set up different stimulation protocols with different pulse width (1-2 ms), frequency (1-6 Hz), voltage (1-6 V) and duration (40-240 min) of VNS by uniform design (UD). Rats were divided into seven groups with (Group1-Group6) or without VNS (MI group). Our results demonstrate that (1) the parameter sets in Group1, Group2 and Group3 yield the best post-MI protection by VNS, while the protective role were not observed in Group4, Group5 and Group6; (2) baroreflex sensitivity and the α7 nicotinic acetylcholine receptor level were also increased in Group1, Group2 and Group3. (3) the parameter set in Group1 (G1:1 ms, 2 Hz, 3 V, 240 min) is judged the most optimal parameter in this study as rats in this group not only showed a reduced myocardial injury with better-preserved cardiac function compared with other groups, more important, but also exhibited minimal heart rate (HR) reduction. (4) the duration of VNS plays an important role in determining the protection effect of VNS. In conclusion, VNS displays a beneficial role in Group1, Group2 and Group3. Of note, the parameter set in Group1 provides the most optimal cardioprotective effect. These results may provide insight into development of novel treatment for ischemic heart diseases.

LMI1195 PET imaging in evaluation of regional cardiac sympathetic denervation and its potential role in antiarrhythmic drug treatment.

PURPOSE: Regional cardiac sympathetic denervation (RCSD) associated with reduced noradrenaline transporter (NAT) function has been linked to cardiac arrhythmia. This study examined the association of LMI1195, an (18)F-labeled NAT substrate developed for positron emission tomography (PET) imaging, with NAT in vitro, and its imaging to detect RCSD and guide antiarrhythmic drug treatment in vivo. METHODS: LMI1195 association with NAT was assessed in comparison with other substrates, noradrenaline (NA) and (123)I-metaiodobenzylguanidine (MIBG), in NAT-expressing cells. LMI1195 cardiac imaging was performed for evaluation of RCSD in a rabbit model surgically developed by regional phenol application on the left ventricular (LV) wall. The normal LV areas in images were quantified as regions with radioactivity ≥50 % maximum. Potential impact of RCSD on dofetilide, an antiarrhythmic drug, induced ECG changes was assessed. RESULTS: NAT blockade with desipramine reduced LMI1195 cell uptake by 90 ± 3 %, similar to NA and MIBG. NA, MIBG, or self inhibited LMI1195 cell uptake concentration-dependently with comparable IC(50) values (1.09, 0.21, and 0.90 µM). LMI1195 cardiac imaging differentiated innervated and denervated areas in RCSD rabbits. The surgery resulted in a large denervated LV area at 2 weeks which was partially recovered at 12 weeks. Myocardial perfusion imaging with flurpiridaz F 18 showed normal perfusion in RCSD areas. Dofetilide induced more prominent QTc prolongation in RCSD than control animals. However, changes in heart rate were comparable. CONCLUSION: LMI1195 exhibits high association with NAT and can be used for imaging RCSD. The detected RCSD increases cardiac risks to the antiarrhythmic drug, dofetilide, by inducing more QTc prolongation.

Left ventricular assist device as bridge to recovery for anthracycline-induced terminal heart failure.

Anthracycline treatments are hampered by dose-related cardiotoxicity, frequently leading to heart failure (HF) with a very poor prognosis. The authors report a case of a 19-year-old man developing HF after anthracycline treatment for Ewing sarcoma. Despite medical treatment, his condition deteriorated to terminal HF, leading to implantation of a mechanical left ventricular assist device (LVAD). His heart function recovered, allowing explantation of the device 14 months after implantation. Heart transplantation is often contraindicated in the first years after treatment for cancers, and LVAD as "bridge to recovery" may be warranted in similar patients.

Cancer induces cardiomyocyte remodeling and hypoinnervation in the left ventricle of the mouse heart.

Cancer is often associated with cachexia, cardiovascular symptoms and autonomic dysregulation. We tested whether extracardiac cancer directly affects the innervation of left ventricular myocardium. Mice injected with Lewis lung carcinoma cells (tumor group, TG) or PBS (control group, CG) were analyzed after 21 days. Cardiac function (echocardiography), serum levels of TNF-α and Il-6 (ELISA), structural alterations of cardiomyocytes and their innervation (design-based stereology) and levels of innervation-related mRNA (quantitative RT-PCR) were analysed. The groups did not differ in various functional parameters. Serum levels of TNF-α and Il-6 were elevated in TG. The total length of axons in the left ventricle was reduced. The number of dense core vesicles per axon profile was reduced. Decreased myofibrillar volume, increased sarcoplasmic volume and increased volume of lipid droplets were indicative of metabolic alterations of TG cardiomyocytes. In the heart, the mRNA level of nerve growth factor was reduced whereas that of ß1-adrenergic receptor was unchanged in TG. In the stellate ganglion of TG, mRNA levels of nerve growth factor and neuropeptide Y were decreased and that of tyrosine hydroxylase was increased. In summary, cancer induces a systemic pro-inflammatory state, a significant reduction in myocardial innervation and a catabolic phenotype of cardiomyocytes in the mouse. Reduced expression of nerve growth factor may account for the reduced myocardial innervation.