scholarly journals Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas

2021 ◽  
Vol 128 (9) ◽  
pp. 1279-1296
Author(s):  
Peter Hanna ◽  
Michael J. Dacey ◽  
Jaclyn Brennan ◽  
Alison Moss ◽  
Shaina Robbins ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Neural Control ◽  
Sinoatrial Node ◽  
Phenotypic Diversity ◽  
Functional Characterization ◽  
Geographic Region ◽  
Left Ventricular ◽  
Cholinergic Innervation ◽  
Right Atrial ◽  
Ventricular Contractility

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

scholarly journals Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas

2020 ◽  
Author(s):  
Peter Hanna ◽  
Michael J. Dacey ◽  
Jaclyn Brennan ◽  
Alison Moss ◽  
Shaina Robbins ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Neural Control ◽  
Sinoatrial Node ◽  
Phenotypic Diversity ◽  
Functional Characterization ◽  
Tissue Level ◽  
Geographic Region ◽  
Left Ventricular ◽  
Cholinergic Innervation ◽  
Right Atrial

AbstractCardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node as an initial discovery step. Here, we report an in-depth, multi-scale structural and functional characterization of the innervation of the sinoatrial node (SAN) by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies including tissue clearing, immunohistochemical and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiologic mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular (AV) conduction and left ventricular (LV) contractility. For the first time, we demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. This provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

Long-Term Prospective Follow-Up Study of Cardiac Function After Cardiotoxic Therapy for Malignancy in Children

2003 ◽  
Vol 21 (12) ◽  
pp. 2349-2356 ◽  
Author(s):  
Tuija Poutanen ◽  
Tero Tikanoja ◽  
Pekka Riikonen ◽  
Annuli Silvast ◽  
Mikko Perkkiö
Keyword(s):  
Cardiac Function ◽  
Natriuretic Peptide ◽  
Three Dimensional ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Childhood Malignancy ◽  
Group I ◽  
Group Ii ◽  
Anthracycline Dose

Purpose: To evaluate cardiac function by means of conventional and three-dimensional echocardiography (3DE) and measurement of natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria. Patients and Methods: Thirty-nine survivors of childhood malignancy were examined in 1994 and 1998. The mean time from the diagnosis was 8.6 (3.9 to 16.8) years and between cardiac evaluations was 4.1 (3.3 to 5.1) years. Patients were divided into two groups according to therapies given (group I (n = 30): no cardiac irradiation, median cumulative anthracycline dose 210 mg/m2; group II (n = 9): irradiation in the cardiac region, median cumulative anthracycline dose 180 mg/m2). Results: Fractional shortening (FS) in 1994 was higher than in 1998 (32.5 ± 4.3 vs. 30.3% ± 3.3%, P = .009). 33% of patients in group I and 56% in group II in 1994 and 30% of patients in group I and 67% in group II in 1998 had N-terminal of the propeptide-atrial natriuretic peptide (NT-proANP) levels exceeding the 90th percentile of controls. In 1998, both groups (I and II) had lower ejection fraction (EF) measured by 3DE than their matched controls (52.9 ± 5.2 vs. 58.8% ± 3.1%, P < .001 and 50.0 ± 6.6 vs. 60.8% ± 3.2%, P = .024, respectively). Left atrial maximum volumes/body surface area were smaller in the patients than in controls. B-Type natriuretic peptide values did not differ significantly in either group. Conclusion: Left ventricular contractility decreases slowly even years after cardiotoxic cancer therapy in children. 3DE and NT-proANP measurements are effective methods to evaluate the cardiac function in these patients.

Parasympathetic control of the heart. II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate

2004 ◽  
Vol 96 (6) ◽  
pp. 2273-2278 ◽  
Author(s):  
Alrich L. Gray ◽  
Tannis A. Johnson ◽  
Jeffrey L. Ardell ◽  
V. John Massari
Keyword(s):  
Neural Control ◽  
Dorsal Surface ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Cardiac Rate ◽  
Cardiac Functions ◽  
Av Conduction ◽  
Parasympathetic Control ◽  
Intracardiac Ganglia ◽  
The Right

Intracardiac pathways mediating the parasympathetic control of various cardiac functions are incompletely understood. Several intracardiac ganglia have been demonstrated to potently influence cardiac rate [the sinoatrial (SA) ganglion], atrioventricular (AV) conduction (the AV ganglion), or left ventricular contractility (the cranioventricular ganglion). However, there are numerous ganglia found throughout the heart whose functions are poorly characterized. One such ganglion, the posterior atrial (PA) ganglion, is found in a fat pad on the rostral dorsal surface of the right atrium. We have investigated the potential impact of this ganglion on cardiac rate and AV conduction. We report that microinjections of a ganglionic blocker into the PA ganglion significantly attenuates the negative chronotropic effects of vagal stimulation without significantly influencing negative dromotropic effects. Because prior evidence indicates that the PA ganglion does not project to the SA node, we neuroanatomically tested the hypothesis that the PA ganglion mediates its effect on cardiac rate through an interganglionic projection to the SA ganglion. Subsequent to microinjections of the retrograde tracer fast blue into the SA ganglion, >70% of the retrogradely labeled neurons found within five intracardiac ganglia throughout the heart were observed in the PA ganglion. The neuroanatomic data further indicate that intraganglionic neuronal circuits are found within the SA ganglion. The present data support the hypothesis that two interacting cardiac centers, i.e., the SA and PA ganglia, mediate the peripheral parasympathetic control of cardiac rate. These data further support the emerging concept of an intrinsic cardiac nervous system.

scholarly journals A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model

2020 ◽  
Vol 7 (4) ◽  
pp. 53
Author(s):  
Jeffrey E. Cohen ◽  
Andrew B. Goldstone ◽  
Hanjay Wang ◽  
Brendan P. Purcell ◽  
Yasuhiro Shudo ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Coronary Artery Ligation ◽  
Large Animal ◽  
Ventricular Contractility ◽  
Intramyocardial Injection ◽  
Ventricular Ejection Fraction ◽  
Scar Size

The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats

2005 ◽  
Vol 99 (4) ◽  
pp. 1378-1383 ◽  
Author(s):  
Jason D. Gardner ◽  
Gregory L. Brower ◽  
Joseph S. Janicki
Keyword(s):  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Isolated Heart ◽  
Systolic Pressure ◽  
Volume Overload ◽  
Left Ventricular ◽  
Female Rats ◽  
Ventricular Contractility ◽  
Ventricular Compliance ◽  
Chronic Volume Overload

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(−)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 ± 229 mg Fist-P(−) and 1,079 ± 199 mg Fist-P(+) vs. 620 ± 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(−) rats (428 ± 16 vs. 300 ± 14 μl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 ± 17 μl). Fist-P(−) rats developed increased ventricular compliance (5.3 ± 0.8 vs. 2.3 ± 0.3 μl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 ± 0.4 μl/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced ( P < 0.001) in the Fist-P(−) rats [systolic pressure-volume slope: 1.04 ± 0.03, 0.60 ± 0.06, and 0.99 ± 0.08 mmHg/μl, for Fist-P(+), Fist-P(−), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.

scholarly journals Simultaneous variation of ventricular pacing site and timing with biventricular pacing in acute ventricular failure improves function by interventricular assist

2009 ◽  
Vol 297 (6) ◽  
pp. H2220-H2226 ◽  
Author(s):  
T. Alexander Quinn ◽  
Santos E. Cabreriza ◽  
Marc E. Richmond ◽  
Alan D. Weinberg ◽  
Jeffrey W. Holmes ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Maximum Rate ◽  
Systolic Function ◽  
Biventricular Pacing ◽  
Pressure Change ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Right Atrial ◽  
Hemodynamic Effects ◽  
Ventricular Failure

The goal of this work was to investigate the hemodynamic effects of simultaneous left ventricular (LV) pacing site (LVPS) and interventricular pacing delay (VVD) variation with biventricular pacing (BiVP) during acute LV failure. Simultaneously varying LVPS and VVD with BiVP has been shown to improve hemodynamics during acute right ventricular (RV) failure. However, effects during acute LV failure have not been reported. In six open-chest pigs, acute LV volume overload was induced by regurgitant flow via an aortic-LV conduit. Epicardial BiVP was implemented with right atrial and ventricular leads and a custom LV pacing array. Fifty-four LVPS-VVD combinations were tested in random order. Cardiac output was evaluated by aortic flow probe, ventricular systolic function by maximum rate of ventricular pressure change, and mechanical interventricular synchrony by normalized RV-LV pressure diagram area. Simultaneous LVPS-VVD variation improved all measures of cardiac function. The observed effect was different for each functional index, with evidence of LVPS-VVD interaction. Compared with effects of LVPS-VVD variation in a model of acute RV failure, hemodynamic changes were markedly different. However, in both models, maximum rate of ventricular pressure change of the failing ventricle was improved with synchronous interventricular contraction, suggesting that, in acute ventricular failure, BiVP can recruit the unstressed ventricle to support systolic function of the failing one. Thus simultaneously varying LVPS and VVD with BiVP during acute ventricular failure can improve cardiac function by “interventricular assist”, with hemodynamic effects dependent on the type of failure. This supports the potential utility of temporary BiVP for the treatment of acute ventricular failure commonly seen after cardiac surgery.

Cardiac function and pulmonary hypertension in Central Asian highlanders at 3250 m

2020 ◽  
Vol 56 (2) ◽  
pp. 1902474 ◽  
Author(s):  
Mona Lichtblau ◽  
Stéphanie Saxer ◽  
Michael Furian ◽  
Laura Mayer ◽  
Patrick R. Bader ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Function ◽  
High Altitude ◽  
Chronic Exposure ◽  
Left Ventricular ◽  
Right Atrial ◽  
Volume Index ◽  
Left Ventricular Ejection ◽  
Central Asian ◽  
Definition Of

The question addressed by the studyChronic exposure to hypoxia increases pulmonary artery pressure (PAP) in highlanders, but the criteria for diagnosis of high-altitude pulmonary hypertension (HAPH) are debated. We assessed cardiac function and PAP in highlanders at 3250 m and explored HAPH prevalence using different definitions.Patients and methodsCentral Asian highlanders free of overt cardiorespiratory disease, permanently living at 2500–3500 m compared to age-matched lowlanders living <800 m. Participants underwent echocardiography close to their altitude of residence (at 3250 m versus 760 m).Results173 participants (97 highlanders, 76 lowlanders), mean±sd age 49±9 years (49% females) completed the study. Results in lowlanders versus highlanders were systolic PAP (23±5 versus 30±10 mmHg), right ventricular fractional area change (42±6% versus 39±8%), tricuspid annular plane systolic excursion (2.1±0.3 versus 2.0±0.3 cm), right atrial volume index (20±6 versus 23±8 mL·m−2), left ventricular ejection fraction (62±4% versus 57±5%) and stroke volume (64±10 versus 57±11 mL); all between-group comparisons p<0.05. Depending on criteria, HAPH prevalence varied between 6% and 35%.The answer to the questionChronic exposure to hypoxia in highlanders is associated with higher PAP and slight alterations in right and left heart function compared to lowlanders. The prevalence of HAPH in this large highlander cohort varies between 6% according to expert consensus definition of chronic high-altitude disease to 35% according to the most recent definition of pulmonary hypertension proposed for lowlanders.

scholarly journals Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

2021 ◽  
Author(s):  
U. Gergs ◽  
J. Weisgut ◽  
K. Griethe ◽  
N. Mißlinger ◽  
U. Kirchhefer ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Antiarrhythmic Drugs ◽  
Positive Inotropic Effect ◽  
Drug Application ◽  
Histamine Receptor ◽  
Left Ventricular ◽  
Histamine Receptors ◽  
Inotropic Effect ◽  
Right Atrial ◽  
Ventricular Contractility

AbstractHistamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2-histamine receptors in a cardiac-specific way (H2-TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H2-TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H2-TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H2-TG could be blocked by the H2-histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H2 and not H1-histamine receptors) more often induced arrhythmias in right atrial preparations from H2-TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H2-TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H2-TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H2-TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H2-TG than from WT. In summary, we noted that overexpression of human H2-histamine receptors in a novel transgenic animal model can lead to arrhythmias. We suggest that this model might be useful to understand the mechanism(s) of histamine-induced cardiac arrhythmias in humans better in a molecular way and may be of value to screen novel antiarrhythmic drugs.

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