Spontaneous Ca2+ transients in rat pulmonary vein cardiomyocytes are increased in frequency and become more synchronous following electrical stimulation.

The pulmonary veins have an external sleeve of cardiomyocytes that are a widely recognised source of ectopic electrical activity that can lead to atrial fibrillation. Although the mechanisms behind this activity are currently unknown, changes in intracellular calcium (Ca2+) signalling are purported to play a role. Therefore, the intracellular Ca2+ concentration was monitored in the pulmonary vein using fluo-4 and epifluorescence microscopy. Electrical field stimulation evoked a synchronous rise in Ca2+ in neighbouring cardiomyocytes; asynchronous spontaneous Ca2+ transients between electrical stimuli were also present. Immediately following termination of electrical field stimulation at 3 Hz or greater, the frequency of the spontaneous Ca2+ transients was increased from 0.45 ± 0.06 Hz under basal conditions to between 0.59 ± 0.05 and 0.65 ± 0.06 Hz (P < 0.001). Increasing the extracellular Ca2+ concentration enhanced this effect, with the frequency of spontaneous Ca2+ transients increasing from 0.45 ± 0.05 Hz to between 0.75 ± 0.06 and 0.94 ± 0.09 Hz after electrical stimulation at 3 to 9 Hz (P < 0.001), and this was accompanied by a significant increase in the velocity of Ca2+ transients that manifested as waves. Moreover, in the presence of high extracellular Ca2+, the spontaneous Ca2+ transients occurred more synchronously in the initial few seconds following electrical stimulation. The ryanodine receptors, which are the source of spontaneous Ca2+ transients in pulmonary vein cardiomyocytes, were found to be arranged in a striated pattern in the cell interior, as well as along the periphery of cell. Furthermore, labelling the sarcolemma with di-4-ANEPPS showed that over 90% of pulmonary vein cardiomyocytes possessed T-tubules. These findings demonstrate that the frequency of spontaneous Ca2+ transients in the rat pulmonary vein are increased following higher rates of electrical stimulation and increasing the extracellular Ca2+ concentration.

Short runs of atrial arrhythmia and stroke risk: a European-wide online survey among stroke physicians and cardiologists.

A recording of = 30 seconds is required to diagnose paroxysmal atrial fibrillation when using ambulatory ECG monitoring. It is unclear if shorter runs are relevant with regards to stroke risk. Methods An online survey of cardiologists and stroke physicians was carried out to assess current management of patients with short runs of atrial arrhythmia within Europe. Results Respondents included 311 clinicians from 32 countries. To diagnose atrial fibrillation, 80% accepted a single 12-lead ECG and 36% accepted a single run of > 30 seconds on ambulatory monitoring. Stroke physicians were twice as likely to accept < 30 seconds of arrhythmia as being diagnostic of atrial fibrillation (OR 2.43, 95% CI 1.19-4.98). They were also more likely to advocate anticoagulation for hypothetical patients with lower risk; OR 1.9 (95% CI 1.0-3.5) for a patient with CHA2DS2-VASc = 2. Conclusion Short runs of atrial fibrillation create a dilemma for physicians across Europe. Stroke physicians and cardiologists differ in their diagnosis and management of these patients.

Clinically important atrial arrhythmia and stroke risk: a UK-wide online survey among stroke physicians and cardiologists.

BACKGROUND: A recording of ≥30 s is required for diagnosis of paroxysmal atrial fibrillation (AF) when using ambulatory electrocardiography (ECG) monitoring. It is unclear if shorter runs of atrial arrhythmia are relevant with regard to stroke risk. AIM: To assess current management of patients with atrial arrhythmia of <30 s duration detected on ambulatory ECG. DESIGN: Online survey. METHODS: An online survey was sent to cardiologists and stroke physicians in the UK, via their national societies. RESULTS: A total of 205 clinicians responded to the survey (130 stroke physicians, 64 cardiologists, 11 other). Regarding diagnosis of AF, 87% of responders would accept a single 12-lead ECG. In contrast, only 45% would accept a single episode lasting <30 s detected on ambulatory monitoring. There was more agreement with regard to the decision to anticoagulate. When asked whether they would anticoagulate eight hypothetical patients with non-diagnostic paroxysms of AF, there was a mean agreement of responses of 78.6%, with up to 94.1% agreement for high-risk patients. There was a trend suggesting that stroke physicians were more likely to accept an atrial arrhythmia of <30 s as 'AF' than cardiology specialists [OR 1.63 (95% CI 0.88-3.01), P = 0.12]. CONCLUSIONS: There is a lack of consensus on the diagnosis and management of patients with brief runs of atrial arrhythmia detected on ambulatory ECG. Further research is needed to clarify the risk of stroke in this unique population of patients.

An in vitro model for the pro-fibrotic effects of retinoids: mechanisms of action.

BACKGROUND AND PURPOSE: Retinoids, including all-trans retinoic acid (tRA), have dose-dependent pro-fibrotic effects in experimental kidney diseases. To understand and eventually prevent such adverse effects, it is important to establish relevant in vitro models and unravel their mechanisms. EXPERIMENTAL APPROACH: Fibrogenic effects of retinoids were assessed in NRK-49F renal fibroblasts using picro-Sirius red staining for collagens and quantified by spectrophotometric analysis of the eluted stain. Other methods included RT-qPCR, immunoassays and matrix metalloproteinase (MMP) activity assays. KEY RESULTS: With or without TGF-ß1, tRA was dose-dependently pro-fibrotic, notably increasing collagen accumulation. tRA and TGF-ß1 additively suppressed expression of mRNA for MMP2, 3 and 13 and suppressed MMP activity. tRA, in the presence of TGF-ß1, induced plasminogen activator inhibitor-1 (PAI-1) mRNA and they additively induced PAI-1 protein expression. A PAI-1 inhibitor, a pan-retinoic acid receptor (RAR) antagonist and a pan-retinoid X receptor (RXR) antagonist each partially prevented the pro-fibrotic effect of tRA. The dose-dependent pro-fibrotic effects of a pan-RXR agonist were similar to those of tRA. A pan-RAR agonist showed weaker, less dose-dependent pro-fibrotic effects and the pro-fibrotic effects of RARα and RARß-selective agonists were even smaller. An RARγ-selective agonist did not affect fibrogenesis. CONCLUSIONS AND IMPLICATIONS: An in vitro model for the pro-fibrotic effects of retinoids was established in NRK-49F cells. It was associated with reduced MMP activity and increased PAI-1 expression, and was probably mediated by RXR and RAR. To avoid or antagonize the pro-fibrotic activity of tRA, further studies on RAR isotype-selective agonists and PAI-1 inhibitors might be of value.

Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes.

Human atrial transient outward K(+) current (I(TO)) is decreased in a variety of cardiac pathologies, but how I(TO) reduction alters action potentials (APs) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of I(TO) blockers. The aim of this study was to investigate effects of selective I(TO) changes on AP shape and duration (APD), and on afterdepolarisations or abnormal automaticity with ß-adrenergic-stimulation, using the dynamic-clamp technique in atrial cells. Human and rabbit atrial cells were isolated by enzymatic dissociation, and electrical activity recorded by whole-cell-patch clamp (35-37°C). Dynamic-clamp-simulated I(TO) reduction or block slowed AP phase 1 and elevated the plateau, significantly prolonging APD, in both species. In human atrial cells, I(TO) block (100% I(TO) subtraction) increased APD(50) by 31%, APD(90) by 17%, and APD(-61 mV) (reflecting cellular effective refractory period) by 22% (P < 0.05 for each). Interrupting I(TO) block at various time points during repolarisation revealed that the APD(90) increase resulted mainly from plateau-elevation, rather than from phase 1-slowing or any residual I(TO). In rabbit atrial cells, partial I(TO) block (∼40% I(TO) subtraction) reversibly increased the incidence of cellular arrhythmic depolarisations (CADs; afterdepolarisations and/or abnormal automaticity) in the presence of the ß-agonist isoproterenol (0.1 µm; ISO), from 0% to 64% (P < 0.05). ISO-induced CADs were significantly suppressed by dynamic-clamp increase in I(TO) (∼40% I(TO) addition). ISO+I(TO) decrease-induced CADs were abolished by ß(1)-antagonism with atenolol at therapeutic concentration (1 µm). Atrial cell action potential changes from selective I(TO) modulation, shown for the first time using dynamic-clamp, have the potential to influence reentrant and non-reentrant arrhythmia mechanisms, with implications for both the development and treatment of atrial fibrillation.

Walk or run? Is high-intensity exercise more effective than moderate-intensity exercise at reducing cardiovascular risk?

The benefits of exercise in the prevention of cardiovascular disease are irrefutable. However, the optimum 'dose' of exercise in order to derive the maximum cardiovascular benefit is not certain. Current national and international guidelines advocate the benefits of moderate-intensity exercise. The relative benefits of vigorous versus moderate-intensity exercise have been studied in large epidemiological studies, addressing coronary heart disease and mortality, as well as smaller randomized clinical trials which assessed effects on cardiovascular risk factors. There is evidence that exercise intensity, rather than duration or frequency, is the most important variable in determining cardioprotection. Applying this evidence into practice must take into account the impact of baseline fitness, compliance and the independent risk associated with a sedentary lifestyle. This review aims to evaluate the role of exercise intensity in the reduction of cardiovascular risk, and answer the question: should you be advising your patients to walk or run?

Mechanisms of termination and prevention of atrial fibrillation by drug therapy.

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na(+) channel blockers, ß-adrenoceptor antagonists, action potential prolonging drugs, and Ca(2+) channel blockers; the "upstream therapies", e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as "atrial-selective" multiple ion channel blockers, gap junction-enhancers, and intracellular Ca(2+)-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.

The cardiovascular effects of normobaric hyperoxia in patients with heart rate fixed by permanent pacemaker.

To investigate whether the established reductions in heart rate and cardiac output with hyperoxia in humans are primary effects or secondary to increases in systemic vascular resistance, we paced the hearts of nine patients with permanent pacemakers at a fixed rate when breathing either medical air (inspired O(2) fraction 0.21) or oxygen (inspired O(2) fraction 0.80) in a randomised, double-blind fashion. A thoracic bio-impedance machine was used to measure heart rate, stroke volume and blood pressure and calculate cardiac index and systemic vascular resistance index. Oxygen caused no change in cardiac index (p = 0.18), stroke index (p = 0.44) or blood pressure (p = 0.52) but caused a small (5.5%) increase in systemic vascular resistance index (p = 0.03). This suggests that hyperoxia has no direct myocardial depressant effects, but that the changes in cardiac output reported in previous studies are secondary to changes in systemic vascular resistance.

Acute oxalate nephropathy causing late renal transplant dysfunction due to enteric hyperoxaluria.

Calcium oxalate (CaOx) deposition in the renal allograft is an under recognized and important cause of acute tubular injury and early allograft dysfunction. We present a case of late transplant dysfunction due to acute oxalate nephropathy. The patient presented with diarrhea and deteriorating graft function, and a diagnosis of enteric hyperoxaluria secondary to pancreatic insufficiency was made. This had occurred, as the patient had been noncompliant with his pancreatic enzyme replacement therapy. Treatment to reduce his circulating oxalate load was initiated, including twice-daily hemodialysis, low fat and oxalate diet and appropriate administration of pancreatic enzyme supplements. Graft function subsequently recovered. The possibility of fat malabsorption leading to enteric hyperoxaluria should be considered in renal graft recipients presenting with loose stools and graft dysfunction.

Atrial fibrillation ablation in the real world.

While the potential for curative treatment of atrial fibrillation has generated much interest in the role of catheter ablation, its widespread use has been limited by a number of factors.

The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation.

OBJECTIVE: To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes. METHODS: The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (>6 months) AF and 39 patients in sinus rhythm. RESULTS: Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203+/-16 to 104+/-15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca(2+) (I(CaL)) and transient outward K(+) (I(TO)) currents was significantly reduced in cells from patients with AF (by 60-65%), whilst the inward rectifier K(+) current (I(K1)) was increased, and the sustained outward current (I(KSUS)) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228+/-12 vs. 225+/-11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness. CONCLUSION: Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in I(CaL) and I(TO).

Clinical events leading to the progression of heart failure: insights from a national database of hospital discharges.

AIMS: To describe the sequence of clinically apparent events causing readmission and antedating death, subsequent to a first-time hospital admission for heart failure, in order to give insights into the natural history and mechanisms of progression of heart failure. METHODS: A national database of linked hospital discharge and mortality data for Scotland (population 5.1 million) was used. Patients with a first-time admission to hospital with heart failure in 1992 (index population) were identified and, using a record linkage system, hospital readmissions and their cause according to the hospital physician and deaths were recorded over the subsequent 3 years. A flowchart showing the sequence of events leading to death or recurrent admission was constructed. RESULTS: 12 640 patients had first-time admissions with heart failure in 1992; their mean age was 74 years and 46.2% were men. A cohort of 2922 (23%) patients died on their first admission. Among the remaining 9718 patients there were 22 747 readmissions and 4877 deaths over the subsequent 3 years; only 15% had neither event reported. Nine per cent of patients died without any readmission and a further 6% without a further readmission for cardiovascular reasons. A cohort of 5992 (61% of patients at risk) had at least one cardiovascular readmission and half of these had occurred within 6 months. Heart failure without a report of any cardiovascular precipitating event was responsible for 37% (2188 patients) of first cardiovascular readmissions and of these patients approximately 12% had evidence of renal failure or acute respiratory infection as possible triggers for readmission. Acute ischaemic events including myocardial infarction (19%), myocardial infarction alone (8%) and atrial fibrillation (11%) were associated with a substantial number of first readmissions. First readmission precipitated by acute myocardial infarction was associated with a particularly poor prognosis (40% inpatient mortality). CONCLUSIONS: Recurrent ischaemic events and atrial fibrillation may be the predominant mechanisms leading to exacerbation of and progression of heart failure and death. A substantial proportion of readmissions appear related to heart failure alone. Whether this reflects progressive ventricular remodelling leading to worsening heart failure or other unidentified mechanisms cannot be discerned from this data.

Rate-dependency of action potential duration and refractoriness in isolated myocytes from the rabbit AV node and atrium.

During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, I(TO1)to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60+/-1 v-71+/-2 mV), lower V(max)(8+/-2 v 144+/-17 V/s) and higher input resistance [420+/-46 v 65+/-7 MOmega (mean+/-s.eP<0.05 n=9-33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155+/-7 to 135+/-11 ms in AVN cells [P<0.05, n=6] and from 130+/-8 to 106+/-7 ms in atrial cells [P<0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12+/-4% (n=8) and 26+/-7% (n=7), respectively (P<0.05). By contrast, AVN ERP did not shorten at rates >300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD(50)(from 51+/-6 to 29+/-6 ms, P<0. 05). 4-AP (1 m m) significantly prolonged atrial APD(50)at 75 beats/min (P<0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD(50)at any rate. 4-AP also did not affect APD(90)or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. I(TO1)contributed to the APD(50)rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type.

Systematic review of the management of atrial fibrillation in patients with heart failure.

AIMS: To systematically review the management of atrial fibrillation (AF) in patients with heart failure. METHODS: Studies investigating the management of AF in patients with heart failure published between 1967 to 1998 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. RESULTS: Eight studies pertaining to acute and twenty-four pertaining to chronic AF were identified. For patients with acute AF ventricular rate control, anticoagulation and treatment of heart failure should be pursued simultaneously before cardioversion is attempted. Digoxin is relatively ineffective at controlling ventricular response and for cardioversion. Intravenous diltiazem is rapidly effective in controlling ventricular rate and limited evidence suggests it is safe. Amiodarone controls ventricular rate rapidly and increases the rate of cardioversion. There are insufficient data to conclude that immediate anti-coagulation, trans-oesophageal echocardiography to exclude atrial thrombi followed by immediate cardioversion is an appropriate strategy. Patients with chronic AF should be anti-coagulated unless contra-indications exist. It is not clear whether the preferred strategy should be cardioversion and maintenance of sinus rhythm with amiodarone or ventricular rate control of AF combined with anticoagulation to improve outcome including symptoms, morbidity and survival. Electrical cardioversion has a high initial success rate but there is also a high risk of early relapse. Amiodarone currently appears the most effective and safest therapy for maintaining sinus rhythm post-cardioversion. Digoxin is fairly ineffective at controlling ventricular rate during exercise. Addition of a beta-blocker reduces ventricular rate and improves symptoms. Whether digoxin is required in addition to beta-blockade for the control of AF in this setting is currently under investigation. If pharmacological therapy is ineffective or not tolerated then atrio-ventricular node ablation and permanent pacemaker implantation should be considered. CONCLUSION: There is a paucity of controlled clinical trial data for the management of AF among patients with heart failure. The interaction between AF and heart failure means that neither can be treated optimally without treating both. Presently treatment should be on a case by case basis.

Imaging of adenosine bolus transit following intravenous administration: insights into antiarrhythmic efficacy.

OBJECTIVE: To study the effects of the site of intravenous injection of adenosine and to assess the site of action of adenosine in the heart by correlating cardiac effects with bolus transit. METHODS: Ten patients undergoing routine technetium (Tc-99m) gated blood pool ventriculography consented to the coadministration of intravenous adenosine. The dose of adenosine required to produce heart block during sinus rhythm was determined following antecubital vein administration. This dose (6-18 mg) was mixed with Tc-99m and given first into the same antecubital vein (proximal injection) and then repeated into a hand vein (distal injection). The ECG was recorded and the transit of the bolus was imaged using a gamma camera. RESULTS: Heart block occurred in all 10 patients (second degree in seven, first degree in three) at (mean (SEM)) 17.5 (1.0) seconds after the proximal injection of adenosine. Distal injection produced heart block in six patients (second degree in two, first degree in four) at 21.9 (4.4) seconds (p < 0.01). In eight of 10 patients the electrophysiological effects were less with distal injection. The onset of heart block was close to the time of peak bolus Tc-99m activity in the left ventricle. Peak bolus activity was delayed (by about three seconds) and the duration of bolus activity in the left ventricle was increased with distal injection compared with proximal injection, at 17.2 (4.2) v 9.2 (3.1) seconds, p < 0.01. CONCLUSIONS: The lesser electrophysiological effects of adenosine following distal intravenous injections were associated with delay in transit time and dispersion of the bolus. The correlation of adenosine induced heart block with bolus activity in the left heart indicated dependence on coronary arterial delivery of adenosine to the atrioventricular node.

Mechanism of sustained monomorphic ventricular tachycardia in systemic sclerosis.

Three patients with advanced systemic sclerosis and recurrent or incessant monomorphic ventricular tachycardia underwent cardiac electrophysiologic studies. Biventricular transcatheter mapping showed findings most compatible with a reentrant mechanism, which was effectively treated with transcatheter ablation.

Ionic basis of a differential effect of adenosine on refractoriness in rabbit AV nodal and atrial isolated myocytes.

OBJECTIVES: Firstly, to compare effects of adenosine on membrane potential and refractoriness in AV nodal and atrial cells. Secondly, to assess the contribution of the effects of adenosine on IKAdo and ICaL to its effects on the functional electrophysiological properties in the two cell types. METHODS: The whole cell patch clamp technique was used to record action potentials and ion currents in AV nodal and left atrial myocytes isolated enzymatically from rabbit hearts. RESULTS: Adenosine (10 microM) caused similar hyperpolarisation and shortening of the action potential duration (APD) in both cell types: maximum diastolic potential was hyperpolarised from -59 +/- 3 to -66 +/- 2 and from -70 +/- 2 to -76 +/- 2 mV (mean +/- SEM) and APD90 was shortened by 31 +/- 4 and 30 +/- 7% in AV nodal (n = 14) and atrial cells (n = 8), respectively. Adenosine shortened the effective refractory period (ERP) in atrial cells, from 124 +/- 15 to 98 +/- 14 ms (n = 8). In contrast, ERP in AV nodal cells was not significantly affected (112 +/- 13 vs. 102 +/- 12 ms, n = 14), and post-repolarization refractoriness was prolonged. By contrast, current injection, to induce an equal degree of hyperpolarisation to that produced by adenosine, shortened APD and ERP in both cell types, suggesting an additional action of adenosine in AV nodal cells. Adenosine (10 microM) did not affect peak ICaL in AV nodal cells, but significantly altered the biexponential time course of recovery of ICaL from inactivation. The proportion of recovery in the fast phase (time constant, tau = 102 +/- 10 ms) was reduced from 71 +/- 3 to 55 +/- 5%, with shift to the slow phase (tau = 858 +/- 168 ms), without altering tau in either phase. A similar effect of adenosine was seen in left atrial cells. CONCLUSION: Adenosine caused hyperpolarisation, APD-shortening and slowing of recovery of ICaL from inactivation, in both AV nodal and atrial cells, but prolonged post-repolarisation refractoriness in AV nodal cells only. This differential effect of adenosine on refractoriness in the two cell types could not be explained by effects on IKAdo, but may be due to slowed reactivation of ICaL, which is the predominant inward current in AV nodal but not left atrial cells.