Dromotropic Effects Research Articles

Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: ● What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients at high risk of developing CAD or in those with established CAD? ● Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? ● Are there antihypertensive drugs that have shown particular efficacy in the primary and secondary prevention of IHD? ● Which antihypertensive drugs should be used in patients who have established CAD with stable or unstable angina pectoris, in those with non–ST-elevation myocardial infarction (NSTEMI), and in those with ST-elevation myocardial infarction (STEMI)?

Monitoring of therapeutic effect in heart failure patients: a clinical application of 123I MIBG imaging?

Labelling of metaiodobenzylguanidine (MIBG) with 123I allows scintigraphic visualization of the cardiac sympathetic nervous system and 123I MIBG was the first radiopharmaceutical that allowed imaging of cardiac neurotransmission by single photon emission computed tomography. Norepinephrine (NE) is the major neurotransmitter of the sympathetic nervous system. 123I MIBG, an analogue of NE, and NE have similar molecular structures, and use the same uptake and storage mechanisms in the pre-synaptic sympathetic nerve ending. Uptake-1 is the most important uptake mechanism of MIBG in human, and is sodium- and energy-dependent. Other uptake mechanisms are the non-neuronal uptake-2 mechanism, which is sodium- and energy-independent, and diffusion. The cardiac sympathetic nervous system is mainly involved in preserving circulatory homeostasis during environmental stress. Increase of sympathetic nervous activity or a rise in catecholamine levels result in cardiac adrenergic stimulation and has subsequent chronotropic (increase in heart rate), inotropic (increase in contractility), and dromotropic (enhanced atrioventricular conduction) effects. For the cardiovascular system in general, an increase in sympathetic nervous activity leads to an increase in peripheral vascular resistance, sodium and water retention, and activation of other neurohormonal systems. Although, in acute heart failure, these effects of enhanced sympathetic nervous activity are at first compensatory, prolonged hyperactivity of the sympathetic nervous system is supposed to be harmful in chronic heart failure. Vascular constriction and increased sodium and water retention will take its toll on energy demands of the myocardium. Furthermore, altered sympathetic cardiac adrenergic function may cause arrhythmias, desensitization of post-synaptic s-adrenoceptors, and activation of the renin–angiotensin system. Prolonged exposure to NE may … *Corresponding author. Tel: +31 71 526 2020; fax: +31 71 526 6809. E-mail address: e.e.van\_der\_wall{at}lumc.nl

Unveiling electrocardiographic mysteries

I read with interest the letter from Dewilde and Desmet [1] on mysterious electrocardiographic arrhythmia in an old woman presenting irregular heart rhythm, characterized by idioventricular rhythmic bigeminy with left bundle branch block pattern, and cardiac dysfunction underlying severe hyperkalemia. Hyperkalemia has been known for a long time to be associated to abnormal impulse formation manifested by either acceleration of normal pacemaker or emergence of ectopic pacemakers [2] in atria and ventricles. In limited series studies, conduction disturbances presenting with right bundle branch block (roughly 25% prevalence) are slightly more prevalent than left bundle branch block (17% prevalence) [3–5]. Impulse formation and conduction may co-exist among electrocardiographic findings of hyperkalemia [3,6], determining junctional rhythm with bundle branch block pattern. However, association of abnormal idioventricular rhythm and overt heart failure represents a medical emergency [6], making cardiac life support mandatory on presentation, and perhaps retarding a more accurate diagnostic procedure. Additionally, association of angiotensin II blockers and potassium-sparing diuretics increases the risk of hyperkalemia [7], especially in elderly due to age-related depressed renal function. Finally, disopyramide has been known to be a potent cardiac depressant [8] with negative dromotropic effect and administration to patients with left ventricular systolic dysfunction must be made with extreme caution [8]. In

Lead Design and Initial Applications of a New Lead for Long‐Term Endovascular Vagal Stimulation

Vagal nerve stimulation (VNS) has negative chronotropic and dromotropic effects. We developed and tested an endovascular spiral vagal stimulation lead (ESVL) designed to follow the projection of the cardiac branches of the vagus nerve around the superior vena cava (SVC) to optimize VNS. ESVL contained six 5-mm coil electrodes, spaced 5-mm apart with a spiral guidewire to provide shape. The tightness and diameter of the guidewire were changed before each placement to simulate different lead designs. Various 2-, 3-, and 4-electrode combinations were used and several lead positions were tested each time. Each VNS protocol included 2-12 V, 15-second pulse trains at 20 Hz, with 2 ms pulse duration. A basket catheter (BC) was used as control and to approximate the initial VNS location. The VNS protocol was performed at the optimal location, using first the BC and then several ESVL configurations. VNS caused a voltage-dependent decrease in heart rate (HR). Using the optimal ESVL configuration at 7 V, HR decreased by 30.4% (37.2 bpm) in dog no. 1 and 12.4% (16.6 bpm) in dog no. 2, versus 15.5% (16.6 bpm) and 16.7% (19.5 bpm) with the BC. A new endovascular spiral lead that takes advantage of the anatomy of the cardiac branches of the vagus nerve in the SVC was developed. VNS using ESVL produced significant HR slowing at voltages slightly below the highest pulse generator output of 7.5 V, which may be suitable for long-term implantation.

Arrhythmogenesis in the Developing Heart During Anoxia‐Reoxygenation and Hypothermia‐Rewarming: An In Vitro Model

The spatio-temporal pattern of arrhythmias in the embryonic/fetal heart subjected to a transient hypoxic or hypothermic stress remains to be established. Spontaneously beating hearts or isolated atria, ventricles, and conotruncus from 4-day-old chick embryos were subjected in vitro to 30-minute anoxia and 60-minute reoxygenation. Hearts were also submitted to 30-minute hypothermia (0-4 degrees C) and 60-minute rewarming. ECG disturbances and alterations of atrial and ventricular electromechanical delay (EMD) were systematically investigated. Baseline functional parameters were stable during at least 2 hours. Anoxia induced tachycardia, followed by bradycardia, atrial ectopy, first-, second-, and third-degree atrio-ventricular blocks and, finally, transient electromechanical arrest after 6.8 minutes, interquartile ranges (IQR) 3.1-16.2 (n = 8). Reoxygenation triggered also Wenckebach phenomenon and ventricular escape beats. At the onset of reoxygenation QT, PR, and ventricular EMD increased by 68%, 70%, and 250%, respectively, whereas atrial EMD was not altered. No fibrillations, no ventricular ectopic beats, and no electromechanical dissociation were observed. Arrhythmic activity of the isolated atria persisted throughout anoxia and upon reoxygenation, whereas activity of the isolated ventricles abruptly ceased after 5 minutes of anoxia and resumed after 5 minutes of reoxygenation. During hypothermia-rewarming, cardiac activity stopped at 17.9 degrees C, IQR 16.2-20.6 (n = 4) and resumed at the same temperature with no arrhythmias. All preparations fully recovered after 40 minutes of reoxygenation or rewarming. In the embryonic heart, arrhythmias mainly originated in the sinoatrial tissue and resembled those observed in the adult heart. Furthermore, oxygen readmission was by far more arrhythmogenic than rewarming and the chronotropic, dromotropic, and inotropic effects were fully reversible.

Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study

To characterise the comparative potency of optically pure (R)- and (S)-verapamil as regards negative dromotropic effects on atrioventricular (AV) node conduction and to compare the hemodynamic effects of single doses of the enantiomers in healthy volunteers. Eight healthy volunteers received a single oral dose of 120 mg (S)-verapamil, 480 mg (R)-verapamil, 240 mg racemic verapamil (rac-verapamil) or placebo on 4 separate occasions. Serum concentrations of (R)- and (S)-verapamil were measured up to 24 h. Cardiovascular effects were assessed by electrocardiography, measurement of blood pressure and transthoracic impedance cardiography (cardiac output and total peripheral resistance). The comparative potency of (R)- and (S)-verapamil with regard to prolongation of the PR interval in the surface ECG was estimated by use of the areas under the effect-time and serum concentration-time curves and linear regression analyses of per cent change in PR interval from baseline versus the logarithm of serum (R)- or (S)-verapamil concentration. The PR interval was significantly prolonged after all verapamil treatments as compared with placebo. (S)-verapamil was 20.6-21.8 times more potent than (R)-verapamil with regard to negative dromotropic effects. (R)-verapamil caused a significantly greater maximum reduction in the mean arterial pressure (MAP) than placebo [15.9+/-6.8 versus 8.7+/-3.2 mmHg (mean+/-SD); 95% CI on the difference, 0.79-13.7 mmHg; p<0.05], whereas MAP was not affected by the other verapamil treatments. No significant changes were observed in heart rate, cardiac output and total peripheral resistance after any verapamil treatment as compared with placebo. (S)-verapamil was about 20 times more potent than (R)-verapamil with regard to negative dromotropic effects on AV node conduction. (R)-verapamil but not (S)-verapamil significantly reduced the MAP as compared with placebo.

P2-48: A novel lead design for chronic endovascular vagal stimulation

Vagal nerve stimulation (VNS) has been shown to cause negative chronotropic and dromotropic effects. We developed and tested an endovascular spiral vagal stimulation lead (ESVL) designed to follow the projection of the cardiac branches of the vagus nerve around the superior vena cava (SVC) in order to optimize VNS (Fig A).

Determinants and Effects of Electrical Stimulation of the Inferior Interatrial Parasympathetic Plexus During Atrial Fibrillation

Catheter stimulation of the inferior interatrial ganglionated parasympathetic plexus decreases the ventricular rate during atrial fibrillation (AF) in humans. However, the relatively high stimulation voltages might prevent implementation of neurostimulation in chronic implantable devices. From myocardial electrostimulation it is known that the required impulse energy and charge is lowest at the chronaxie time. In order to lower energy requirements for cardiac neurostimulation, the present study evaluates the impulse-strength versus impulse-duration relationship for a neurostimulation lead that was implanted into the inferior interatrial ganglionated plexus. In nine dogs, permanent epicardial bipolar screw-in electrodes were fixed in the inferior interatrial ganglionated plexus. AF was maintained via rapid atrial pacing. During AF, neural stimulation was performed at various frequencies (1-100 Hz), impulse durations (0.05-2 msec), and voltages (0.02-11.5 V). There was a linear correlation between R-R interval lengthening and stimulus voltage (R = 0.99; P < 0.001) and a bell-shaped relationship between stimulation frequency and negative dromotropic effect with maximum rate slowing at 30-50 Hz. The rheobase for a 50% R-R interval prolongation during AF was 1.81 V and 2.72 V for high-grade AVB yielding a chronaxie time of 0.14 msec and 0.18 msec, respectively. The impulse energy (charge) at the chronaxie time was 4-6 microJ (6-8 microC). Cardiac neurostimulation follows a chronaxie/rheobase behavior. Energy, charge, and voltage values needed to achieve significant negative dromotropic effects are within the limits of conventional cardiac pacemaker outputs, which may allow implementation of neurostimulation capabilities in current pacemaker technology.

Chronic Cardiac Neurostimulation for Ventricular Rate Control During Atrial Fibrillation

The inferior interatrial ganglionated parasympathetic plexus (IIGP) almost exclusively innervates the atrioventricular node. Acute intracardiac stimulation of this plexus with electrode catheters has been shown to decrease the ventricular rate during atrial fibrillation (AF) in humans. The present study reports on the 6 months stimulation effects of a permanent neurostimulation lead which has been implanted transvenously into this IIGP in dogs. In 5 dogs a DDD-pacemaker was implanted and AF induced by rapid pacing. During 6 months intermittent high frequency stimulation of the IIGPP was performed over a second implantable stimulator to assess chronic neurostimulation efficacy. From 1 to 6 months a continuous decrease of the voltage at which atrioventricular block III° could be elicited was observed. At implant/6 months a 1.8/2.5-fold prolongation of the RR interval during AF was achieved at 1 V/1 ms. Dynamic modulations of the magnitude of the negative dromotropic effect could be obtained by varying stimulus frequency, voltage and duration. Selective chronic cardiac neurostimulation for ventricular rate control during AF can be achieved in animals. The results obtained so far justify human studies.

Selective Increase of Cardiac Neuronal Sympathetic Tone: A Catheter-Based Access to Modulate Left Ventricular Contractility

This study was designed to develop a technique to selectively increase the sympathetic tone to the heart by cardiac sympathetic nerve stimulation (SNS). Access to the cardiac sympathetic neurons may allow modulating the adrenergic tone of the heart while avoiding systemic side effects. Cardiac sympathetic nerves course within neural sleeves along the subclavian artery. Because of this proximity, transvascular SNS was attempted with electrode catheters inside the subclavian artery in 16 pigs. Right/left (R-/L-) SNS (20 Hz) during ventricular pacing at 200/min evoked a >100% increase of left ventricular systolic pressure (baseline: 51 +/- 1 mm Hg; L-SNS: 118 +/- 26 mm Hg; R-SNS: 116 +/- 33 mm Hg; p < 0.001) while systemic vascular resistance remained unchanged. There was a sigmoid dose-response curve with rapid on- and offset of the effect during SNS initiation/cessation. Positive inotropic effects persisted for 12 h of continued SNS (n = 4). Besides positive dromotropic effects, L-SNS/R-SNS yielded a 41% and 77% sinus rate increase, respectively. The neural adrenergic tone to the heart can be selectively increased by catheter stimulation of cardiac efferent sympathetic nerves.

New insights into adenosine‐mediated myocardial protection

British Journal of Pharmacology (2005) 145, 701–702. doi:10.1038/sj.bjp.0706262

Trial to Evaluate the Management of Paroxysmal Supraventricular Tachycardia During an Electrophysiology Study With Tecadenoson

Tecadenoson is a potent selective A1-adenosine receptor agonist with a dose-dependent negative dromotropic effect on the AV node. Tecadenoson terminates induced paroxysmal supraventricular tachycardia (PSVT) without the clinically significant side effects caused by stimulation of other adenosine receptors. This trial was designed to determine a safe and effective tecadenoson bolus for termination of electrophysiologically induced PSVT. Patients with a history of symptomatic PSVT and inducible PSVT at the time of a clinically indicated electrophysiology study were randomized into a multicenter, double-blind, placebo-controlled trial. Five 2-dose tecadenoson bolus regimens were evaluated versus placebo (75/150, 150/300, 300/600, 450/900, 900 microg/900 microg). The second bolus was administered only if PSVT persisted for 1 minute after the first bolus. Each tecadenoson regimen resulted in a significant therapeutic conversion rate compared with placebo (range, 50.0% to 90.3%, analysis of all patients dosed; n=181; P<0.0005). Conversion by the first bolus was dose related (range: placebo, 3.3% to 86.7% for 900 microg/900 microg). Time to conversion was dose dependent, with a median time of <1 minute for the 3 highest dose regimens. Postconversion arrhythmias were transient, requiring no additional treatment in 4 regimens (including placebo). Transient second- and third-degree heart block occurred at higher doses (300/600, 450/900, 900 microg/900 microg) and was supported with backup pacing when needed. No effect on blood pressure was observed. Ten patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without bronchospasm. We identified an optimal tecadenoson regimen (300 microg/600 microg) that effectively and rapidly converted 90% (28 of 31) of PSVT patients to normal sinus rhythm with no significant adverse effects.

Comparison of the direct negative dromotropic effect of a new calcium channel blocker, cilnidipine, with that of nicardipine

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.

Vagal control of the heart: central serotonergic (5‐HT) mechanisms

Cardiac vagal preganglionic neurones (CVPNs) are located within the dorsal vagal nucleus (DVN) and the nucleus ambiguus (nA). In mammals, CVPNs within the nA have small myelinated axons and mediate major chronotropic effects, those in the DVN have non-myelinated axons and mediate smaller chronotropic, dromotropic and inotropic effects. Numerous studies demonstrate important influences of serotonin (5-HT) at multiple sites controlling autonomic outflows including the nucleus tractus solitarius (NTS) where cardiorespiratory afferent fibres terminate, and the CVPNs and rostral ventrolateral medulla (RVLM), the location of sympathetic premotor neurones. We have demonstrated roles for some of the numerous 5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) in brainstem regions involved in cardiac control. Intracisternal application of selective ligands was used to study the effect of 5-HT receptors on heart rate and its reflex control. Further electrophysiological studies were also carried out to delineate their location and the mechanisms of action of these ligands. Blocking 5-HT1A receptors attenuated bradycardias evoked by stimulating baroreceptor and cardiopulmonary afferents but not arterial chemoreceptors, whereas antagonizing 5-HT7 receptors markedly attenuated all these reflex bradycardias. Within the DVN, nA and NTS, activation of 5-HT1A receptors could excite or inhibit neurones. In the NTS 5-HT2 receptors also had variable effects; 5-HT2B receptors excite and 5-HT2C receptors inhibit. Antagonism of 5-HT3 receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT3 receptors excite DVN and NTS neurones by a glutamate-dependent mechanism. The origin of the glutamate (neuronal or glial) remains unresolved but glia are a possibility as baroreceptor-sensitive NTS neurones receive few direct 5-HT-containing synaptic contacts. Thus, 5-HT plays a critical role in the control of vagal outflow to the heart; however, why so many different receptors are involved, and their relative functional roles, remains unresolved.

Enzymatic hydrolysis of luminal coronary glycosidic structures uncovers their role in sensing coronary flow

Endothelial luminal glycocalyx (ELG) is a multifunctional complex structure made off of a diversity of glycosilated proteins, and glycosaminoglycans (GAG). Coronary ELG may participate as a sensor of coronary flow (CF) to induce inotropic and dromotropic effects. In isolated perfused guinea pig heart we tested the role of glycosidic groups of glycans bound to proteins and GAG of the ELG on CF-induced inotropic and dromotropic effects. To study the role of saccharide related groups of certain glycans, they were removed by selective enzyme hydrolysis or bound to a selective plant lectin. CF-induced positive inotropic and positive dromotropic control curves were obtained and the effects of intracoronary infusion of enzyme or lectin determined. The analyzed groups were as follow: 1) Fucosidase enzyme and Ulex europeasus lectin; hydrolysis and binding respectively (H&Br) to alpha-linked fucosyl related groups. 2). Endoglycanase-H and Lycopersicon esculentum (H&Br to N-linked beta-1,3GlcNAc related groups). 3) O-glycanase and Arachis hypogea (H&Br to O-linked beta-Gal1, 3GalNac related groups). 4) Sialidase and Maackia amurensis (H&Br to neuraminic acid related groups). In treatments 1-3 both. lectin and corresponding enzyme, equally depressed CF-positive dromotropic effects without affecting positive inotropic effects. In treatment 4 both lectin and enzyme equally depressed CF-positive inotropic effects without dromotropic effects. The differential role of GAG hyaluran or heparan groups on CF-positive inotropism and positive dromotropism respectively was shown. Infusing hyaluranidase removed hyaluran that solely inhibited CF- inotropism while removal of heparan with heparinase solely inhibited CF-dromotropism. Only the effects of hyaluronidase were reversed infusing hyaluronidate. Our results indicate glycans of ELG are elements of complex multimolecular sensors of coronary flow.

Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique

The pharmacokinetics of dextro(+)- and levo(-)-verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (-)- and dideuterated (+)-isomer. (+)-verapamil exhibited approximately five times greater Cmax (+): 240 +/- 81.1 ng/ml, (-): 46.1 +/- 15.7 ng/ml, P less than 0.0001) and AUC than (-)-verapamil. The apparent oral clearance (CLo) for (+)-verapamil was significantly smaller than that for (-)-verapamil (+): 1.72 +/- 0.57 l/min, (-): 7.46 +/- 2.16 l/min, P less than 0.001). The bioavailability of (+)-verapamil (50%) was 2.5 times greater than that of (-)-verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first-pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (-): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (-): 5.38 h, respectively. Whereas the (+)- to (-)-verapamil plasma concentration ratio following oral administration was 4.92 +/- 0.48, the ratio following i.v. administration was approximately 2. (-)-verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)-verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (-)-isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.

Structure–affinity relationships of 5′-aromatic ethers and 5′-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents

Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A1 adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A1 adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A1 adenosine receptor could avoid this deleterious effect. 5′ Phenyl sulfides (e.g., 17, EC50=1.26μM) and phenyl ethers (e.g., 28, EC50=0.2μM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPγS binding data suggesting partial activity of the A1 adenosine receptor, and PK results for 5′ modified adenosine derivatives are shown.

Extracellular potassium dependent negative dromotropic action of nicorandil in guinea pig myocardium.

Although the antiarrhythmic action of nicorandil is drawing an increasing attention, dromotropic effect of this agent is unclear. Therefore, this was investigated by microelectrode technique to the superfused guinea pig papillary muscle to record the action potential and extracellular potential during conduction. The correlation of myocardial internal longitudinal resistance (r1) assumed to reflect the global gap junctional resistance, maximum rate of rise of the action potential upstroke (Vmax), and conduction velocity was examined under the alterations of external potassium concentrations ([K+]e; ranging from 3.0 to 12.0 mM) in the presence or absence of 100 microM nicorandil. In the minimum [K+]e, nicorandil caused significant (p < 0.05) hyperpolarization and reduction in Vmax. Negative dromotropic action of nicorandil was slight but significant (p < 0.05) in low (3.0 mM) [K+]e but was not evident in physiologic (5.4 mM) or elevated (9.0 to 12.0 mM)[K+]e. In conclusion, nicorandil exerts negative dromotropic action as [K+]e decreased, which was accounted for by the cable analysis and may contribute to the prevention of low [K+]e-induced arrhythmia.

Ventricular rate control during atrial fibrillation and AV node modifications: past, present, and future.

Atrial fibrillation (AF) is the most common arrhythmia. Currently there are two broad strategic treatment options for AF: rhythm control and rate control. For rhythm control, the treatment is directed toward restoring and maintaining the sinus rhythm. For rate control, the intention is to slow ventricular rate while allowing AF to continue. In both cases anticoagulation therapy is recommended. The results of currently available clinical trials demonstrated clearly that rate control is not inferior to rhythm control. Thus, rate control is an acceptable primary therapy for many AF patients. The rate control can be achieved essentially by depressing or modifying the filtering properties of the atrioventricular (AV) node. This can be attained by medications that depress the impulse transmission within the AV node, by anatomic modification of the AV communications, as well as by autonomic manipulations that produce AV node negative dromotropic effect. We are reviewing current clinical and newer experimental modalities aimed at enhancing the lifesaving function of this remarkable nodal structure.

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

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.