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PubMed2002

Bi-atrial mapping of atrial arrhythmias.

Cardiac mapping of atrial activation was originally performed in animals during open chest preparations, using epicardial electrodes. The development of endocardial egg-shaped multiple electrodes provided detailed assessment of the minimum number of wavelengths required to sustain atrial fibrillation (AF), as well as the role of interatrial connections during AF. Subsequently, several studies on bi-atrial epicardial high-density mapping in animals and humans also reported on the importance of interatrial connections, as well as the specific characteristics of the left atrium as compared with the right atrium during chronic AF. Endocardial bi-atrial mapping studies using electrode catheters were reported using basket-shaped catheters carrying 64 electrodes. Animal studies suggested that septal activation was asynchronous and discordant, while a human study outlined the multiple origins of atrial ectopic beats following DC cardioversion in patients with chronic atrial fibrillation. The advent of non-fluoroscopic mapping systems significantly changed our approach to percutaneous endocardial mapping. Simultaneous bi-atrial studies using electroanatomic mapping were performed in sinus rhythm as well as in atrial flutter. These studies demonstrated the predominance of interatrial conduction over Bachmann's Bundle and the coronary sinus-left atrial connection during respectively, sinus rhythm and atrial flutter. Simultaneous bi-atrial non-contact mapping was initially performed during porcine studies and later in humans, demonstrating asynchronous and discordant septal activation both during sinus rhythm or left lateral atrial pacing. Preliminary studies from simultaneous bi-atrial non-contact mapping in humans in whom AF occurred spontaneously or was induced suggests three main types of atrial activation, consisting of left atrial drivers causing the right atrium to fibrillate following conduction over interatrial connections, the right atrium independently sustaining AF, even after pulmonary vein disconnection, and both atria fibrillating independently without activation over interatrial connections. Bi-atrial mapping has been essential for our understanding of normal and abnormal atrial activation, and ultimately may provide new approaches for ablation of atrial fibrillation.

Animals↗
PubMed1999

Vagal nerve activity recording in the awake condition for the control of an artificial heart system.

To detect useful information for an artificial heart control system, we paid attention to the autonomic nervous system. For stable recording, we used vagal nerve activity in chronic animal experiments using healthy adult goats in an awake condition because this nerve was sufficiently bold and large enough. Vagal nerve discharges were successfully recorded from awake goats. They were synchronized with respiration and responded to the hemodynamic changes induced by drug administration, suggesting that they may provide useful information for an artificial heart control algorithm. For automatic control, some time delay plays a vitally important role. Thus, predictive control for an artificial heart system may be desirable. It may be embodied by the use of autonomic nerve information.

Action Potentials↗
PubMed2001

Reduction in atrial defibrillation threshold by a single linear ablation lesion.

INTRODUCTION: This study investigated a hybrid approach to reduce the atrial defibrillation threshold (ADFT) by determining the effect of a single linear radiofrequency ablation (RFA) lesion on both the ADFT and activation patterns during atrial fibrillation (AF). METHODS AND RESULTS: In 18 open chest sheep (45 to 57 kg), coil defibrillation electrodes were placed in a superior vena cava/right ventricular configuration. AF was induced by burst pacing and maintained with acetyl beta-methylcholine (2 to 42 microL/min). ADFTs were obtained before and after a linear RFA lesion was created in the left atrium (LAL; n = 6), right atrium (RAL; n = 6), or neither atrium as a control (n = 6). In animals receiving an LAL, a 504-unipolar-electrode plaque was sutured to the LA. For animals receiving an RAL, two 504-electrode plaques were placed, one each on the LA and RA. From each plaque, activations were recorded before and after ADFT shocks, and organizational characteristics of activations were analyzed using algorithms that track individual wavefronts. In sham-treated controls, the ADFT did not change. In contrast, LAL reduced ADFT energy 29%, from 4.5 +/- 2.3 J to 3.2 +/- 2.0 J (P < 0.05). RAL reduced ADFT energy 25%, from 2.0 +/- 0.9 J to 1.5 +/- 0.7 J (P < 0.05). AF activation was substantially more organized after RFA than before RFA for both the RAL- and LAL-treated animals. CONCLUSION: A single RFA lesion in either the RA or LA reduces the ADFT in this sheep model. This decrease is associated with an increase in fibrillatory organization.

Animals↗
PubMed2000

Evidence of heterogeneous remodeling in canine atrial fibrillation.

Although electrophysiologic changes occur during atrial remodeling, little is known how remodeling affects atrial fibrillation (AF) organization. We hypothesized that, in animals with long-term rapid atrial rates and a rapid ventricular response, AF would be more disorganized than in animals with rapid atrial rates only. In 8 dogs, chronic AF was created by 6 weeks of continuous rapid atrial pacing. In this group, the ventricular response to AF was spontaneous and unaltered. Twenty-one epochs of AF were epicardially mapped from the right and left atria. In 6 dogs, chronic AF was also created with rapid atrial pacing, however, the AV node was ablated and the ventricles were VVI paced at 80 BPM. Only 1 epoch of AF per dog was mapped. Atrial cycle length (CL) and spatial organization were compared. In chronic AF with a spontaneous ventricular rate, left atrial CL (96+/-14 ms) averaged 24 ms shorter than right atrial CL (121+/-18 ms) (P < .0001). With VVI pacing, AF CL was longer than in the dogs with the spontaneous ventricular rate. However, the left atrial CL (109+/-30 ms) was still significantly shorter than the right atrial CL (145+/-43 ms) (P < .001). Spatial organization values showed that during chronic AF with a spontaneous ventricular rate, the left atrium is more disorganized (2593+/-497) than the right atrium (2052+/-732) (P < .0001). With VVI pacing, the left atrium (2202+/-597) is still more disorganized than the right (1620+/-936) (P < .05). However, with VVI pacing, both atria appear less disorganized than dogs with VVI pacing. Atrial remodeling caused by heart failure that is superimposed on the remodeling due to rapid atrial rates causes the atria to be more disorganized than remodeling due to rapid atrial rates alone. However, in either case the left atrium is faster and more disorganized than the right atrium. Atrial fibrosis caused by the heart failure may increase the disorganization of AF activation.

Animals↗
PubMed1993

Nonuniformity of AH intervals during stimulation at different left atrial sites.

Studies in humans have found left atrial stimulation via the coronary sinus (CS) to elicit significantly shorter atrium-His (AH) intervals as compared to right atrial stimulation, but whether pacing at different left atrial sites (anterior vs posterior left atrium, i.e., far distal vs proximal CS) affects the AH interval has not been studied. Hence, in 22 patients, we compared the effects of stimulation from various atrial sites, including anterior high right atrium (HRA), distal CS, mid-CS, and proximal CS, on: stimulus-atrium (SA), AH, and stimulus-His intervals on the His bundle electrogram. Paced cycle length differed for each patient (range 900-350 msec, mean 532 +/- 140 msec), but conduction intervals from different atrial sites were compared using identical cycle length in each patient. The mean SA intervals were 34 +/- 10 msec, 57 +/- 10 msec, 44 +/- 11 msec, and 32 +/- 8 msec with stimulation, respectively, from HRA, distal CS, mid-CS, and proximal CS (each significantly different except for HRA vs proximal CS). The mean AH intervals were 123 +/- 23 msec, 104 +/- 28 msec, 95 +/- 15 msec, and 90 +/- 18 msec with stimulation, respectively, from HRA, distal CS, mid-CS, and proximal CS (each significantly different except for mid-CS vs proximal CS). In 13 patients, the discrepancy in AH intervals during distal versus proximal CS stimulation was > or = 15 msec; in 9 patients this difference was only < or = 10 msec, considered within the range of measurement error. Thus, in a significant portion of patients, discrepant AH intervals were demonstrated during stimulation from the distal versus proximal CS. These previously undescribed observations suggest that electrophysiological studies on atrioventricular nodal conduction that involve left atrial stimulation must take into account actual location of the stimulation site (anterior or posterior) in order to properly interpret the findings.

Adolescent↗
PubMed2000

The influence of right atrial septal pacing on the interatrial contraction sequence.

UNLABELLED: Right atrial septal pacing yields shorter interatrial conduction delays than conventional right atrial pacing at the free wall or the right atrial appendage. However, the hemodynamic effects of right atrial septal pacing are less well known. This study measured the delay between right and left atrial contractions during right atrial septal pacing (n = 21), conventional right atrial pacing (n = 32) and atrial multisite pacing (n = 6) by pulse Doppler echocardiography of transtricuspidal and transmitral blood flow. The effects of right atrial septal pacing (n = 14) versus conventional right atrial pacing (n = 22) on the optimal AV delay during dual chamber pacing was examined in patients with high degree atrioventricular (AV) block. Compared to sinus rhythm, conventional right atrial pacing increased P wave duration from 119 +/- 21 ms to 137 +/- 24 ms (P < 0.001), whereas both right atrial septal pacing (119 +/- 10 ms before, 106 +/- 13 ms during pacing, P = 0.002) and atrial multisite pacing (123 +/- 20 ms before, 112 +/- 11 ms during pacing, P = 0.5) shortened P wave duration. Atrial pacing caused a significant (P < 0.002) prolongation of atrial contraction [corrected] delays from 24 +/- 21 ms to 41 +/- 26 ms during conventional right atrial pacing, and reversed the right-to-left into a left-to-right contraction sequence in 20 of 21 patients during right atrial septal pacing (atrial conduction delay during sinus rhythm: 34 +/- 23 ms vs -37 [corrected] +/- 26 ms during atrial pacing, P < 0.0001). Atrial multisite pacing caused a nonsignificant shortening of the usual right-to-left contraction delay from 22 +/- 34 ms to 11 +/- 18 ms. The optimal left heart AV delay during AV sequential pacing was significantly (P = 0.002) shorter during right atrial septal pacing (108 +/- 38 ms) than during conventional right atrial pacing (152 +/- 33 ms). During conventional right atrial pacing the optimal right heart AV delay was significantly (P = 0.029) shorter than the optimal left heart AV delay. The opposite relation was observed for right atrial septal pacing (P = 0.033). CONCLUSIONS: Interatrial septal pacing does not synchronize right and left atrial contractions. It reverses the atrial mechanical timing from a right-to-left to a left-to-right contraction sequence, and requires the setting of shorter AV delays during dual chamber pacing if based on the optimization of left heart timing. Interatrial septal pacing is a technique which allows pacing of the left atrium from a right atrial site, rather than a single site approach to biatrial pacing.

Adolescent↗
PubMed1993

Significance of increased atrial pressure on stroke volume during atrial fibrillation in anaesthetized pigs.

During atrial fibrillation synchronized atrial contraction is lost and cardiac output declines. Concomitantly, atrial pressure increases. The significance of the increase in atrial pressure on stroke volume was examined before and after blood volume expansion. Atrial fibrillation was induced by rapid atrial pacing in seven anaesthetized, open-chest pigs. The increase in right atrial pressure subsequently was counteracted by an appropriate constriction of the inferior vena cava. To avoid the confounding effect of a rapid and irregular heart rate, ventricular rate was kept constant by separate His bundle pacing after complete atrioventricular block. When atrial fibrillation was induced, right and left atrial pressure at the top of the v-wave increased both during normovolaemia and during hypervolaemia. Concomitantly, stroke volume declined. When the increase in atrial pressure was prevented during atrial fibrillation, stroke volume declined further: by 35 (21-50) and 9 (2-17)% (difference: P = 0.01), during normo- and hypervolaemia, respectively. Thus, the increase in atrial pressure counteracts the decline in stroke volume after induction of atrial fibrillation and thereby represents an important compensatory mechanism. This mechanism is more important with normal blood volume than during hypervolaemia.

Animals↗
PubMed1971

Reflex effects on the heart of stimulating left atrial receptors.

1. Stimulation of left atrial receptors, by distension of the pulmonary vein/left atrial junctions, is known to cause a reflex increase in heart rate; the efferent pathway is known to be solely in the sympathetic nerves.2. In expectation of a concomitant positive inotropic response the effect of stimulating the left atrial receptors on the inotropic state of the left ventricle was studied, using as a known sensitive index of inotropic changes the maximal rate of rise of pressure in the left ventricle (dP/dt max).3. Stimulation of left atrial receptors resulted in an increase in heart rate but there were no significant concomitant changes in dP/dt max.4. It is concluded that activity in this discrete efferent pathway does not include an inotropic effect on the left ventricle and therefore the reflex involves only those sympathetic nerves which innervate the sinu-atrial node.5. The possible function of atrial receptors in the regulation of heart volumes is discussed.

Animals↗
PubMed1994

Does endogenous adenosine have a role in the cardiac responses to isoprenaline and in the rapid fade of the inotropic response of perfused heart?

The role of endogenous adenosine during the beta-adrenoceptor responses to isoprenaline of guinea-pig isolated cardiac preparations was examined. Insignificant effects of adenosine deaminase (0.3 U.mL-1) on cumulative concentration--response curves for isoprenaline on isolated left and right atria and papillary muscles indicated a negligible depressant effect of endogenous adenosine during these responses. The increase in force of contraction to an infusion of isoprenaline (14 nM) in perfused spontaneously beating hearts rapidly waned while the infusion continued, whereas the increase in rate of contraction remained constant throughout the infusion. The degree of fade was less in paced preparations (5 Hz), indicating that it was only in part due to the rate increase exerting some mechanical constraint on the force of contraction. The P1-purinoceptor antagonist 8-phenyltheophylline (12 microM) and adenosine deaminase (0.3 U.mL-1) did not enhance the peak responses to the isoprenaline infusion. The fade of the inotropic response in both spontaneous and paced hearts was also not attenuated by the presence of 8-phenyltheophylline or adenosine deaminase. The fade was not, therefore, due to release of endogenous adenosine exerting a depressant effect. Whether this declining inotropic response represents a form of rapid desensitization remains to be determined.

Adenosine↗
PubMed1993

Estrogen-induced left ventricular chamber enlargement in ewes.

We studied the chronic effect of administration of a single large intramuscular dose of 17 beta-estradiol on left ventricular chamber size and output in the ewe. Fourteen oophorectomized ewes were successfully instrumented and studied, with measurements made of left ventricular, aortic, right and left atrial pressures, left ventricular stroke volume, and left ventricular minor axis dimension. Unanesthetized ewes were studied before and 1, 2, and 3 wk after intramuscular administration of 0.6 mg/kg 17 beta-estradiol (7 ewes) or 1.5 ml sesame oil placebo (7 ewes). Left ventricular end-diastolic pressure-end-diastolic dimension (LVEDP-EDD) and left ventricular end-diastolic pressure-stroke volume (LVEDP-SV) relationships were quantified during graded inferior vena caval occlusion and volume infusion. Left ventricular end-diastolic diameter was larger after estrogen but not after placebo administration. The LVEDP-EDD relationship shifted progressively rightward, indicating left ventricular chamber enlargement in the estrogen group but was unchanged in the placebo group. The plateau limb of the LVEDP-SV relationship in the estrogen group shifted up from a mean stroke volume of 77.1-89.5 ml/beat and did not change in the placebo group. We conclude that administration of a single large intramuscular dose of 17 beta-estradiol resulted in left ventricular chamber enlargement and increased stroke volume in the ewe.

Animals↗
PubMed2006

Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: a comparison in canine models of structural and electrical atrial remodeling.

Several animal models of atrial fibrillation (AF) have been developed that demonstrate either atrial structural remodeling or atrial electrical remodeling, but the characteristics and spatiotemporal organization of the AF between the models have not been compared. Thirty-nine dogs were divided into five groups: rapid atrial pacing (RAP), chronic mitral regurgitation (MR), congestive heart failure (CHF), methylcholine (Meth), and control. Right and left atria (RA and LA, respectively) were simultaneously mapped during episodes of AF in each animal using high-density (240 electrodes) epicardial arrays. Multiple 30-s AF epochs were recorded in each dog. Fast Fourier transform was calculated every 1 s over a sliding 2-s window, and dominant frequency (DF) was determined. Stable, discrete, high-frequency areas were seen in none of the RAP or control dogs, four of nine MR dogs, four of six CHF dogs, and seven of nine Meth dogs in either the RA or LA or both. Average DFs in the Meth model were significantly greater than in all other models in both LA and RA except LA DFs in the RAP model. The RAP model was the only one with a consistent LA-to-RA DF gradient (9.5 +/- 0.2 vs. 8.3 +/- 0.3 Hz, P < 0.00005). The Meth model had a higher spatial and temporal variance of DFs and lower measured organization levels compared with the other AF models, and it was the only model to show a linear relationship between the highest DF and dispersion (R(2) = 0.86). These data indicate that structural remodeling of atria (models known to have predominantly altered conduction) leads to an AF characterized by a stable high-frequency area, whereas electrical remodeling of atria (models known to have predominantly shortened refractoriness without significant conduction abnormalities) leads to an AF characterized by multiple high-frequency areas and multiple wavelets.

Animals↗
PubMed1993

Effects of atrial fibrillation on left and right atrial dimensions, pressures, and compliances.

The effects of atrial fibrillation on left and right atrial dimensions, pressures, and compliances were examined in two groups of seven barbiturate-anesthetized open-chest pigs. Atrial diameters and pressures were recorded during atrioventricular (AV) pace and thereafter during atrial fibrillation. Both rhythms were studied with constant ventricular rate after complete AV block. Left atrial maximal diameter, which appeared at the end of the atrial filling phase, decreased from 32.4 (28.9-36.7; median and 95% confidence interval) to 31.3 (28.4-35.7) mm after induction of atrial fibrillation. The right atrial maximal diameter also decreased, although not significantly. Atrial pressure at the peak of the v wave rose from 7.0 (5.5-8.5) to 9.6 (8.3-11.2) mmHg in the left atrium and from 5.0 (4.3-5.6) to 7.3 (6.2-8.7) mmHg in the right atrium. Left and right atrial chamber stiffness constants increased from 0.25 (0.19-0.48) to 0.41 (0.28-0.66) mm-1 and from 0.21 (0.11-0.31) to 0.33 (0.30-0.39) mm-1, respectively. Instantaneous diastolic atrial compliance decreased in both atria after induction of atrial fibrillation. Thus, during atrial fibrillation with regular ventricular rate, changes in atrial diameter, pressure, and compliance take place.

Animals↗
PubMed1999

Atrial involvement in patients with progressive systemic sclerosis: relationship between ultrasonic tissue characterization of the atrium and interatrial conduction.

OBJECTIVE: The aim of this study was to assess atrial lesions using ultrasonic tissue characterization and to determine the contribution of atrial lesions to the interatrial electromechanical coupling conduction time in patients with progressive systemic sclerosis (PSS). METHODS: Twenty patients with PSS and 20 age-matched healthy controls were evaluated. The cyclic variation in integrated backscatter value (CV-IB) was measured at the interatrial septum (IAS) from apical four chamber view. M-modes of ventricular long axis motion along with phono- and electrocardiograms were recorded simultaneously at the right lateral (RT) and left lateral (LT) sites of the atrioventricular (AV) rings and central fibrous body (CFB) in the apical four-chamber view. Intervals from the P wave on ECG to the echocardiographic onset of atrial contraction as a point of inflection in long axis M-mode echocardiogram were measured at the RT and LT sites of AV rings and CFB (P-RT, P-LT, P-SEP, respectively). Interatrial electromechanical coupling conduction time was determined as [(P-LT) - (P-RT)]. RESULTS: In patients with PSS compared to normal controls, P-RT, P-SEP, P-LT, and interatrial conduction time were greater, while CV-IB in IAS decreased. Furthermore, CV-IB in IAS correlated well with interatrial conduction time (r = 0.7, p < 0.01) in patients with PSS. CONCLUSIONS: Interatrial electromechanical coupling times may be prolonged due to atrial tissue damage in patients with PSS.

Adult↗
PubMed2006

AVE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat.

BACKGROUND: The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF. METHODS AND RESULTS: Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 microg x kg(-1) x min(-1)), the Ca2+ sensitizer EMD57033 (1 mg x kg(-1) x min(-1)), the L-type Ca2+ channel agonist BayY5959 (0.1 mg x kg(-1) x min(-1)), and AVE0118 (0.01 to 0.2 mg x kg(-1) x min(-1)). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to <10%. Digoxin and dobutamine failed to increase atrial contractility. EMD57033 restored 41% and BayY5959 restored 48% of atrial contractility at baseline. BayY5959 significantly prolonged QT duration by 24.7%. AVE0118 enhanced atrial contraction to 156% of the baseline value. The positive inotropic effect was accompanied by a pronounced prolongation of atrial action potential duration and refractoriness, whereas QT duration remained unchanged. CONCLUSIONS: Conventional positive inotropic drugs showed limited effect on atrial contractility after cardioversion of AF or produced QT prolongation. In contrast, the I(to)/I(Kur) blocker AVE0118 fully restored atrial contraction without proarrhythmic effects on the ventricle.

Action Potentials↗
PubMed2001

Potential ionic mechanism for repolarization differences between canine right and left atrium.

Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current (I(Kr)) was greater in the LA (eg, 1.83+/-0.10 pA/pF at +20 mV) than in the RA (1.15+/-0.07 pA/pF, P<0.01; n=16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca(2+), and transient outward K(+) currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go-related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD- and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I(Kr) than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I(Kr) may participate in the ability of the LA to act as a "driver region" for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy.

Action Potentials↗
PubMed2006

Differences in the aging-associated trends of the monophasic action potential duration and effective refractory period of the right and left atria of the rat.

BACKGROUND: The incidence of atrial fibrillation (AF) increases with aging, but the aging-associated electrophysiological changes of atrial myocardium are poorly understood. METHODS AND RESULTS: Based on the hypothesis that aging of the atrium enhances AF susceptibility, 30 Wistar rats were divided into 3 age groups: adult, middle-aged, and aged (n=20 per group). Their hearts were isolated and perfused by Langendorff apparatus. Monophasic action potential duration at 90% repolarization (MAPD(90)) and effective refractory period (ERP) at the basic stimulation cycle length (BCL: 400 ms), and MAPD(90) at other different stimulation cycle lengths in each age group were measured. At the BCL, the MAPD (90) of the right atrial myocardium was prolonged from the adult to the aged group, that of the left atrial myocardium was prolonged from the adult to middle-aged group, and the MAPD(90) of the left atrial myocardium in the aged group were shorter than that in the adult and middle-aged groups. The ERP of the atrial myocardium showed the same age-associated trend as MAPD(90). As the stimulation frequency increased, the MAPD(90) of both the left and right atrial myocardium shortened correspondingly in the adult and middle-aged groups, but in the aged group the MAPD(90) of the right atrial myocardium shortened markedly more than that of the left atrial myocardium. CONCLUSIONS: There are different aging-associated electrophysiological changes in the right and left atrium, and the older heart is more vulnerable to developing the substrate for AF.

Action Potentials↗
PubMed1995

Structure-activity relationships of alkylxanthines: alkyl chain elongation at the N1- or N7-position decreases cardiotonic activity in the isolated guinea pig heart.

Relationships between the alkyl substitutions (C1-C6) and cardiac inotropic activities of xanthine derivatives were studied in isolated guinea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elongation of alkyl chain at the N3-position but decreased by substitution of a long alkyl group at the N1- or N7-position of the xanthine skeleton. Although positive inotropic activity in the right ventricular papillary muscle was also increased by longer alkyl groups at the N3-position, the inotropic activity became negative with an increment in alkyl chain length at the N1- or N7-position. The positive inotropic activity of alkylxanthines was correlated with their inhibitory activity on the phosphodiesterase (PDE) III isoenzyme. Adenosine A1 antagonism and PDE IV inhibitory activity were also partly associated with the inotropic activity because H-89, an inhibitor of cyclic AMP-dependent protein kinase, diminished the positive inotropic action and potentiated the negative inotropic action. These results indicate that the positive inotropic activity of alkylxanthines becomes weak with elongation of alkyl chains at the N1- and N7-positions; In particular, xanthines having two long alkyl chains show a negative inotropic activity on the right ventricular papillary muscle, an effect that could not be elucidated from their cyclic AMP-dependent action.

Adenosine↗