Exercise training-induced bradycardia: evidence for enhanced parasympathetic regulation without changes in intrinsic sinoatrial node function.

The mechanisms responsible for exercise-induced reductions in baseline heart rate (HR), known as training bradycardia, remain controversial. Therefore, changes in cardiac autonomic regulation and intrinsic sinoatrial nodal (SAN) rate were evaluated using dogs randomly assigned to either a 10- to 12-wk exercise training (Ex, n = 15) or an equivalent sedentary period (Sed, n = 10). Intrinsic HR was revealed by combined autonomic nervous system (ANS) blockade (propranolol + atropine, iv) before and after completion of the study. At the end of the study, SAN function was further evaluated by examining the SAN recovery time (SNRT) following rapid atrial pacing and the response to adenosine in anesthetized animals. As expected, both the response to submaximal exercise and baseline HR significantly (P < 0.01) decreased, and heart rate variability (HRV; e.g., high-frequency R-R interval variability) significantly (P < 0.01) increased in the Ex group but did not change in the Sed group. Atropine also induced significantly (P < 0.01) greater reductions in HRV in the Ex group compared with the Sed group; propranolol elicited similar HR and HRV changes in both groups. In contrast, neither intrinsic HR (Ex before, 141.2 ± 6.7; Ex after, 146.0 ± 8.0 vs. Sed before, 143.3 ± 11.1; Sed after, 141.0 ± 11.3 beats per minute), the response to adenosine, corrected SNRT, nor atrial fibrosis and atrial fibrillation inducibility differed in the Ex group vs. the Sed group. These data suggest that in a large-animal model, training bradycardia results from an enhanced cardiac parasympathetic regulation and not from changes in intrinsic properties of the SAN.

Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping.

BACKGROUND: Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF. METHODS AND RESULTS: We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 µmol/L) markedly prolonged postpacing SAN conduction time in HF by 206 ± 99 milliseconds (versus 66 ± 21 milliseconds in controls; P=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (P=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1 ± 28.9 versus 1.5 ± 1.3 seconds; P<0.001). Furthermore, 10 µmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (P=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 µmol/L theophylline/1 µmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47 ± 19%) and surrounding atrial myocardium (by 90 ± 40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38 ± 4% versus 23 ± 4%; P<0.001). CONCLUSIONS: In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.

The effects of omega-3 polyunsaturated fatty acids on cardiac rhythm: a critical reassessment.

Although epidemiological studies provide strong evidence for an inverse relationship between omega-3 polyunsaturated fatty acids (n-3 PUFAs) and cardiac mortality, inconsistent and often conflicting results have been obtained from both animal studies and clinical prevention trials. Despite these heterogeneous results, some general conclusions can be drawn from these studies: 1) n-PUFAs have potent effects on ion channels and calcium regulatory proteins that vary depending on the route of administration. Circulating (acute administration) n-3 PUFAs affect ion channels directly while incorporation (long-term supplementation) of these lipids into cell membranes indirectly alter cardiac electrical activity via alteration of membrane properties. 2) n-3 PUFAs reduce baseline HR and increase HRV via alterations in intrinsic pacemaker rate rather than from changes in cardiac autonomic neural regulation. 3) n-3 PUFAs may be only effective if given before electrophysiological or structural remodeling has begun and have no efficacy against atrial fibrillation. 5) Despite initial encouraging results, more recent clinical prevention and animal studies have not only failed to reduce sudden cardiac death but actually increased mortality in angina patients and increased rather than decreased malignant arrhythmias in animal models of regional ischemia. 6) Given the inconsistent benefits reported in clinical and experimental studies and the potential adverse actions on cardiac rhythm noted during myocardial ischemia, n-3 PUFA must be prescribed with caution and generalized recommendations to increase fish intake or to take n-3 PUFA supplements need to be reconsidered.

Tachy-brady arrhythmias: the critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses.

BACKGROUND: In patients with sinoatrial nodal (SAN) dysfunction, atrial pauses lasting several seconds may follow rapid atrial pacing or paroxysmal tachycardia (tachy-brady arrhythmias). Clinical studies suggest that adenosine may play an important role in SAN dysfunction, but the mechanism remains unclear. OBJECTIVE: To define the mechanism of SAN dysfunction induced by the combination of adenosine and tachycardia. METHODS: We studied the mechanism of SAN dysfunction produced by a combination of adenosine and rapid atrial pacing in isolated coronary-perfused canine atrial preparations by using high-resolution optical mapping (n = 9). Sinus cycle length and sinoatrial conduction time (SACT) were measured during adenosine (1-100 µM) and DPCPX (1 µM; A1 receptor antagonist; n = 7) perfusion. Sinoatrial node recovery time was measured after 1 minute of "slow" pacing (3.3 Hz) or tachypacing (7-9 Hz). RESULTS: Adenosine significantly increased sinus cycle length (477 ± 62 ms vs 778 ± 114 ms; P<.01) and SACT during sinus rhythm (41 ± 11 ms vs 86 ± 16 ms; P<.01) in a dose-dependent manner. Adenosine dramatically affected SACT of the first SAN beat after tachypacing (41 ± 5 ms vs 221 ± 98 ms; P<.01). Moreover, at high concentrations of adenosine (10-100 µM), termination of tachypacing or atrial flutter/fibrillation produced atrial pauses of 4.2 ± 3.4 seconds (n = 5) owing to conduction block between the SAN and the atria, despite a stable SAN intrinsic rate. Conduction block was preferentially related to depressed excitability in SAN conduction pathways. Adenosine-induced changes were reversible on washout or DPCPX treatment. CONCLUSIONS: These data directly demonstrate that adenosine contributes to post-tachycardia atrial pauses through SAN exit block rather than slowed pacemaker automaticity. Thus, these data suggest an important modulatory role of adenosine in tachy-brady syndrome.

Effect of dietary omega-3 polyunsaturated Fatty acids on heart rate and heart rate variability in animals susceptible or resistant to ventricular fibrillation.

The consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been reported to reduce cardiac mortality following myocardial infarction as well as to decrease resting heart rate (HR) and increase HR variability (HRV). However, it has not been established whether n-3 PUFAs exhibit the same actions on HR and HRV in individuals known to be either susceptible or resistant to ventricular fibrillation (VF). Therefore, HR and HRV (high frequency and total R-R interval variability) were evaluated before and 3 months after n-3 PUFA treatment in dogs with healed myocardial infarction that were either susceptible (VF+, n = 31) or resistant (VF-, n = 31) to ventricular tachyarrhythmias induced by a 2-min coronary artery occlusion during the last minute of a submaximal exercise test. HR and HRV were evaluated at rest, during submaximal exercise and in response to acute myocardial ischemia at rest before and after either placebo (1 g/day, corn oil, VF+, n = 9; VF- n = 8) or n-3 PUFA (docosahexaenoic acid + eicosapentaenoic acid ethyl esters, 1-4 g/day, VF+, n = 22; VF-, n = 23) treatment for 3 months. The n-3 PUFA treatment elicited similar increases in red blood cell membrane, right atrial, and left ventricular n-3 PUFA levels in both the VF+ and VF- dogs. The n-3 PUFA treatment also provoked similar reductions in baseline HR and increases in baseline HRV in both groups that resulted in parallel shifts in the response to either exercise or acute myocardial ischemia (that is, the change in these variables induced by physiological challenges was not altered after n-3 PUFA treatment). These data demonstrate that dietary n-3 PUFA decreased HR and increased HRV to a similar extent in animals known to be prone to or resistant to malignant cardiac tachyarrhythmias.

Endurance exercise training reduces cardiac sodium/calcium exchanger expression in animals susceptible to ventricular fibrillation.

AIM: Increased sodium/calcium exchanger activity (NCX1, an important regulator of cardiomyocyte cystolic calcium) may provoke arrhythmias. Exercise training can decrease NCX1 expression in animals with heart failure improving cytosolic calcium regulation, and could thereby reduce the risk for ventricular fibrillation (VF). METHODS: To test this hypothesis, a 2-min coronary occlusion was made during the last minute of exercise in dogs with healed myocardial infarctions; 23 had VF (S, susceptible) and 13 did not (R, resistant). The animals were randomly assigned to either 10-week exercise training (progressively increasing treadmill running; S n = 9; R n = 8) or 10-week sedentary (S n = 14; R n = 5) groups. At the end of the 10-week period, the exercise + ischemia test provoked VF in sedentary but not trained susceptible dogs. On a subsequent day, cardiac tissue was harvested and NCX1 protein expression was determined by Western blot. RESULTS: In the sedentary group, NCX1 expression was significantly (ANOVA, P < 0.05) higher in susceptible compared to resistant dogs. In contrast, NCX1 levels were similar in the exercise trained resistant and susceptible animals. CONCLUSION: These data suggest that exercise training can restore a more normal NCX1 level in dogs susceptible to VF, improving cystolic calcium regulation and could thereby reduce the risk for sudden death following myocardial infarction.

Vernakalant, a mixed sodium and potassium ion channel antagonist that blocks K(v)1.5 channels, for the potential treatment of atrial fibrillation.

Despite being the most common arrhythmia currently treated by cardiologists, safe and effective treatments for atrial fibrillation (AF) remain elusive. To address this issue, Astellas Pharma Inc, Merck & Co Inc and Cardiome Pharma Corp are developing vernakalant (RSD-1235), a drug which dose-dependently inhibits sodium channels and several potassium repolarizing currents. Of particular note, vernakalant inhibits I(Kur) (K(v)1.5), a current that is more predominant in atrial than in ventricular tissue. Consistent with this observation, vernakalant produced increases in atrial refractory period with minimal actions on QTc interval or ventricular refractory period in both humans and animals. Intravenous vernakalant terminated recent-onset AF in several animal models, and also in patients with short-duration AF or AF following cardiac surgery enrolled in phase II and III clinical trials. Vernakalant was well tolerated and adverse reactions were transient and mild. Thus, vernakalant holds considerable promise for the treatment of recent-onset AF; however, given its relatively short half-life, continuous dosing may be required in order to maintain sinus rhythm following conversion from AF. The efficacy and safety of vernakalant for the long-term management of AF remains to be determined. Phase III clinical trials with intravenous vernakalant are ongoing, and phase II clinical trials are also being conducted with an oral formulation intended for chronic use.

Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training.

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, both the identification of factors contributing to ventricular fibrillation as well as the development of safe and effective antiarrhythmic agents remain elusive. Subnormal cardiac parasympathetic regulation coupled with an elevated cardiac sympathetic activation may allow for the formation of malignant ventricular arrhythmias. In particular, myocardial infarction can reduce cardiac parasympathetic regulation and alter beta-adrenoceptor subtype expression enhancing beta(2)-adrenoceptor sensitivity that can lead to intracellular calcium dysregulation and arrhythmias. As such, myocardial infarction can induce a remodeling of cardiac autonomic regulation that may be required to maintain cardiac pump function. If alterations in cardiac autonomic regulation play an important role in the genesis of life-threatening arrhythmias, then one would predict that interventions designed to either augment parasympathetic activity and/or reduce cardiac adrenergic activity would also protect against ventricular fibrillation. Recently, studies using a canine model of sudden death demonstrate that endurance exercise training (treadmill running) enhanced cardiac parasympathetic regulation (increased heart rate variability), restored a more normal beta-adrenoceptor balance (i.e., reduced beta(2)-adrenoceptor sensitivity and expression), and protected against ventricular fibrillation induced by acute myocardial ischemia. Thus exercise training may reverse the autonomic neural remodeling induced by myocardial infarction and thereby enhance the electrical stability of the heart in individuals shown to be at an increased risk for sudden cardiac death.

The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy.

The activation of cardiac cell membrane ATP-sensitive potassium channels during myocardial ischemia promotes potassium efflux, reductions in action potential duration, and heterogeneities in repolarization, thereby creating a substrate for re-entrant arrhythmias. Drugs that block this channel should be particularly effective anti-arrhythmic agents. Indeed, non-selective ATP-sensitive potassium channel antagonists, (e.g., glibenclamide) can prevent arrhythmias associated with myocardial ischemia. However, these non-selective antagonists have important non-cardiac actions that promote insulin release and hypoglycemia (pancreatic beta-cells), reduce coronary blood flow (vascular smooth muscle cells), prevent ischemia preconditioning (cardiac mitochondrial channels) and depress cardiac contractile function. The ATP-sensitive potassium channel consists of a pore forming inward rectifying potassium channel (Kir6.1 or Kir6.2) and a regulatory subunit (sulfonylurea receptors, SUR1, SUR2A &SUR2B). The Kir6.2/SUR2A combination appears to be preferentially expressed on cardiac cell membranes. As such, it should be possible to develop agents selective for cardiac sarcolemmal ATP-sensitive potassium channels. The novel compounds HMR 1883 (or its sodium salt HMR 1098) or HMR 1402 have been shown to block selectively the cardiac sarcolemmal ATP-sensitive potassium channels. These drugs attenuated ischemically-induced changes in cardiac electrical properties and prevented malignant arrhythmias without the untoward effects of other drugs. Since the ATP-sensitive potassium channel only becomes active as ATP levels fall, these drugs have the added advantage that they would have effects only on ischemic tissue with little or no effect noted on normal tissue. Thus, selective antagonists of the cardiac cell surface ATP-sensitive potassium channel may represent a new class of ischemia selective anti-arrhythmic medications.

Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation.

Parasympathetic activity during acute coronary artery occlusion (CAO) can protect against ischaemia-induced malignant arrhythmias; nonetheless, the mechanism mediating this protection remains unclear. During CAO, myocardial electrotonic uncoupling is associated with autonomically mediated immediate (i.e. type 1A) arrhythmias and can modulate pro-arrhythmic dispersion of repolarization. Therefore, the effects of acutely enhanced or decreased cardiac parasympathetic activity on early electrotonic coupling during CAO, as measured by myocardial electrical impedance (MEI), were investigated. Anaesthetized dogs were instrumented for MEI measurements, and left circumflex coronary arterial occlusions were performed in intact (CTRL) and vagotomized (VAG) animals. The CAO was followed by either vagotomy (CTRL) or vagal nerve stimulation (VNS, 10 Hz, 10 V) in the VAG dogs. Vagal nerve stimulation was studied in two additional sets of animals. In one set heart rate (HR) was maintained by pacing (220 beats min(-1)), while in the other set bilateral stellectomy preceded CAO. The MEI increased after CAO in all animals. A larger MEI increase was observed in vagotomized animals (+85 +/- 9 Omega, from 611 +/- 24 Omega, n = 16) when compared with intact control dogs (+43 +/- 5 Omega, from 620 +/- 20 Omega, n = 7). Acute vagotomy during ischaemia abruptly increased HR (from 155 +/- 11 to 193 +/- 15 beats min(-1)) and MEI (+12 +/- 1.1 Omega, from 663 +/- 18 Omega). In contrast, VNS during ischaemia (n = 11) abruptly reduced HR (from 206 +/- 6 to 73 +/- 9 beats min(-1)) and MEI (-16 +/- 2 Omega, from 700 +/- 44 Omega). These effects of VNS were eliminated by pacing but not by bilateral stellectomy. Vagal nerve stimulation during CAO also attenuated ECG-derived indices of ischaemia (e.g. ST segment, 0.22 +/- 0.03 versus 0.15 +/- 0.03 mV) and of rate-corrected repolarization dispersion [terminal portion of T wave (TPEc), 84.5 +/- 4.2 versus 65.8 +/- 5.9 ms; QTc, 340 +/- 8 versus 254 +/- 16 ms]. Vagal nerve stimulation during myocardial ischaemia exerts negative chronotropic effects, limiting early ischaemic electrotonic uncoupling and dispersion of repolarization, possibly via a decreased myocardial metabolic demand.

Novel transient outward and ultra-rapid delayed rectifier current antagonist, AVE0118, protects against ventricular fibrillation induced by myocardial ischemia.

AVE0118 is a novel drug that blocks the transient outward current (Ito), the ultra rapid component of the delayed rectifier current (IKur), and the acetylcholine dependent potassium channel (IKach). The latter 2 channels are more abundant in atrial tissue. It is possible that AVE0118 could reduce regional differences in repolarization and thereby prevent malignant arrhythmias provoked by ischemia. To test this hypothesis, ventricular fibrillation was induced by a 2-minute occlusion of the left circumflex coronary artery during the last min of exercise in dogs with healed myocardial infarctions (n = 9). On a subsequent day, this exercise plus ischemia test was repeated after pretreatment with AVE0118 (1.0 mg/kg, IV). AVE0118 did not change QTc (Van de Water's correction) interval [245 +/- 6.0 ms (control) versus 242 +/- 2.3 ms (AVE)] and attenuated the dispersion of repolarization as measured by the duration of the descending portion of the T wave (Tpeak - Tend) induced by ischemia [ischemic changes: +11.1 +/- 2.4 ms (no drug) versus +2.2 +/- 3.7 ms (AVE)]. AVE0118 also significantly reduced the incidence of ventricular fibrillation, protecting 7 of 9 animals. Thus, AVE0118 abolished ischemically induced repolarization abnormalities and prevented malignant arrhythmias induced by ischemia without altering QTc interval.

A comprehensive review and analysis of 25 years of data from an in vivo canine model of sudden cardiac death: implications for future anti-arrhythmic drug development.

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, the development of safe and effective anti-arrhythmic agents remains elusive. The identification of effective anti-arrhythmic agents is critically dependent upon the use of appropriate animal models of human disease. During the last 25 years, a canine model of sudden cardiac death has proven to be useful in both the identification of factors contributing to ventricular fibrillation (VF) and the evaluation of potential anti-arrhythmic therapies. The present review provides a detailed retrospective analysis of the data obtained with this model. Briefly, VF was reliably and reproducibly induced by the combination of acute myocardial ischemia at site distant from a previous myocardial infarction during submaximal exercise (to activate the autonomic nervous system). This exercise plus ischemia test identified 2 stable populations of dogs: those that development malignant arrhythmias (susceptible, n=303) and those that rarely developed even single premature ventricular activation (resistant, n=209). The susceptible animals exhibited an elevated sympathetic activation (due to an enhanced beta2-adrenoceptor responsiveness) and a subnormal parasympathetic regulation. Several interventions have proven to be particularly effective in preventing VF in the susceptible dogs; including calcium channel antagonists, left stellate ganglion disruption, ATP-sensitive potassium channel antagonists, beta-adrenoceptor antagonists, and non-pharmacological interventions (endurance exercise training and dietary omega-3 fatty acids).

Heart rate response to onset of exercise: evidence for enhanced cardiac sympathetic activity in animals susceptible to ventricular fibrillation.

A large heart rate (HR) increase at the onset of exercise has been linked to an increased risk for adverse cardiovascular events, including cardiac death. However, the relationship between changes in cardiac autonomic regulation induced by exercise onset and the confirmed susceptibility to ventricular fibrillation (VF) has not been established. Therefore, a retrospective analysis of the HR response to exercise onset was made in mongrel dogs with healed myocardial infarctions that were either susceptible (S, n = 131) or resistant (R, n = 114) to VF (induced by a 2-min occlusion of the left circumflex artery during the last minute of exercise). The ECG was recorded, and time series analysis of HR variability (vagal activity index, the 0.24-1.04-Hz frequency component of R-R interval variability) was measured before and 30, 60, and 120 s after the onset of exercise (treadmill running). Exercise elicited significantly (ANOVA, P < 0.0001) greater increases in HR in susceptible dogs at all three times (e.g., at 60 s: R, 46.8 +/- 2.3 vs. S, 57.1 +/- 2.2 beats/min). However, the vagal activity index decreased to a similar extent in both groups of dogs (at 60 s: R, -2.8 +/- 0.1 vs. S, -3.0 +/- 0.2 ln ms2). Beta-adrenoceptor blockade (BB, propranolol 1.0 mg/kg iv) reduced the HR increase and eliminated the differences noted between the groups [at 60 s: R (n = 26), 40.4 +/- 3.2 vs. S (n = 31), 37.5 +/- 2.4 beats/min]. After BB, exercise once again elicited similar declines in vagal activity in both groups (at 60 s: R, -3.6 +/- 0.5 vs. S, -3.2 +/- 0.4 ln ms2). When considered together, these data suggest that at the onset of exercise HR increases to a greater extent in animals prone to VF compared with dogs resistant to this malignant arrhythmia due to an enhanced cardiac sympathetic activation in the susceptible dogs.