Refractory Periods In Patients Research Articles

Refractory periods in SUNCT

Sir, The refractory period in patients with SUNCT is studied by Pareja JA and group, and we deeply appreciate their contribution in today’s understanding of SUNCT. SUNCT has a resemblance with first division trigeminal neuralgia, but SUNCT can be distinguished by the presence of marked autonomic symptoms like conjunctival injection and tearing. However, we do not have clear understanding of the underlying pathophysiological divide between trigeminal neuralgia and SUNCT. Trigeminal autonomic reflex with central disinhibition of variable extent is believed to bring autonomic symptoms in an otherwise trigeminal neuralgia-like illness. So, the trigeminal neuralgia, SUNA and SUNCT may actually be a continuum [1]. It may still be worthwhile to differentiate trigeminal neuralgia from SUNCT, as the presence or absence of autonomic symptoms may actually point towards the underlying pathophysiology. However, trigeminal neuralgia (ophthalmic division) with florid autonomic features irrespective of refractory period as in our cases represents a spectrum of SUNCT [2]. Over a period of time, these patients may show variable attack severity and fluctuating duration of refractory period. Therefore, we referred to Cohn et al. [3] in our paper, not mistakenly though, as they recommended the application of absent refractory period to diagnostic criteria of SUNCT. We believe that refractory period may be present/relative in milder disease and may become absent with severe disease (saw tooth pattern or very frequent spontaneous attacks) [4, 5]. Once, refractory period is studied in a large cohort of SUNCT patients in respect to attack severity, disease chronicity, primary versus secondary disease or natural course versus on-medication course, it would be more authentic to apply absent refractory period to the diagnostic criteria of SUNCT.

Correlations among the frequencies of atrial activity on the surface electrocardiogram, intracardiac atrial electrograms, and the atrial effective refractory period in patients with atrial fibrillation

BackgroundThe frequency of surface atrial electrocardiogram (ECG) depolarization has been postulated to reflect the atrial effective refractory period (AERP). MethodsFrequency analysis of surface ECGs after QRST subtraction and of electrograms from 4 right atrium and 4 coronary sinus electrode pairs was performed in 38 patients in atrial fibrillation. The AERP was measured in the right atrium and coronary sinus 10 minutes after cardioversion. ResultsThe correlation between the dominant frequencies of intracardiac electrograms and atrial activity in leads I, II, and V1 were 0.89, 0.85, and 0.88, respectively (all P < .001). The correlation between the average AERP and the frequency of atrial activity in the surface leads was 0.50, 0.45, and 0.47 (all P < .005). ConclusionIn atrial fibrillation, the frequency of atrial depolarization measured from the surface ECG is highly correlated with intracardiac atrial frequency. However, the correlation between the frequency of surface atrial activity and atrial refractoriness, although significant, is not strong.

From ECG to mutation: Programmed ventricular stimulation providing a link to genetics of cardiac channelopathies

Intracardiac recordings and programmed atrial and ventricular stimulation have contributed substantially to our understanding of cardiac electrophysiology (EP) over the last decades. Intracardiac placed diagnostic multipolar catheters enabled us to link endocardial signals to anatomic structures and to understand conduction through healthy and diseased myocardial tissue. Furthermore, programmed atrial and ventricular stimulation extended our knowledge about the mechanisms of arrhythmias and opened the door for a specific and curative treatment of a variety of arrhythmias with the introduction of radiofrequency ablation therapy. 1 Programmed ventricular stimulation has been used for risk stratification. However, several studies suggested that induction of sustained ventricular tachyarrhythmias and EPguided antiarrhythmic drug therapy in patients with ischemic cardiomyopathy were not predictive for the occurrence of ventricular tachyarrhythmias. Thus, EP testing for risk stratification of patients with prior myocardial infarction has been abandoned. Until now, even in patients with primary electrical diseases, EP studies are not standard procedures for predicting the occurrence of malignant ventricular tachyarrhythmias. In patients with long QT syndrome, EP studies carry no predictive value. 2 In patients with Brugada syndrome, EP studies, especially in asymptomatic patients, remain controversial. 3 In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), EP testing is considered of no value in diagnosis and clinical management. 2 However, the detection of significantly shortened atrial and/or ventricular refractory periods in patients with short QT syndrome recently revealed a new and disease specific finding of EP studies and contributed to the understanding of the disease. 4 Whether the induction of sustained ventricular tachyarrhythmias in short QT syndrome represents a predictive value of future events remains to be examined in larger patient cohorts. In this issue of HeartRhythm, Nof et al 5 describe a further

CAN SLEEP-DISORDERED BREATHING BE AN INDEPENDENT PREDICTOR OF MALIGNANT VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH HEART FAILURE?

Background: Sleep-disordered breathing (SDB) is common and increases mortality rate independently in patients with heart failure (HF). Furthermore, current research suggests that SDB might be an independent predictor of life-threatening ventricular arrhythmias. However, it is still unknown whether SDB have a role to play in electrophysiological background in patient with HF. We assessed the hypothesis that SDB plays an important role in electrophysiological background and contributes to the risk of life-threatening ventricular arrhythmia in patients with HF. Methods: We performed both sleep study and electrophysiologic study in consecutive 33 HF patients and analyzed the relationship between SDB and electrophysiologic data such as AV conduction, ventricular effective refractory period and the inducibility of sustained ventricular tachycardia or fibrillation. All patients had an ejection fraction 10 events/hour on the sleep study. Results: SDB was diagnosed in 22 of 33 patients (67%). There were no statistical differences between patients with and without SDB in baseline characteristics with respect to age, male gender, NYHA class, left ventricular ejection fraction, underlying cardiac disease and medications. AV nodal conduction and ventricular effective refractory period were not significantly differences among two groups. However, the induciblity of ventricular tachyarrhythmia was significantly higher in patients with SDB than those without SDB (73%vs.27%, p=0.013). Conclusions: The present study suggests that SDB can be a risk factor of malignant ventricular arrhythmias without affecting ventricular refractory period in patients with HF.

Pathology‐specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation

This study was designed to establish the pathology-specific inhibitory effects of the IKur/Ito/IK,ACh blocker AVE0118 on atrium-selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF). Outward K+-currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole-cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting. Four components of outward K+-currents and AF-specific alterations in their properties were identified. Ito was smaller in cAF than in SR, and AVE0118 (10 microM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of IKur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non-inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF-related constitutively active IK,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF. In atrial myocytes of cAF patients, we detected reduced function of distinct IKur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active IK,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.

In vivo Effects of Mutant HERG K+ Channel Inhibition by Disopyramide in Patients with a Short QT‐1 Syndrome: A Pilot Study

Quinidine has been evaluated in patients with a short QT-1 syndrome caused by an IKr gain-of-function mutation of HERG. Recently, in vitro data with disopyramide showed an even stronger effect on the N588K mutant current. The aim of the present study was to test the in vivo effects of disopyramide in patients with short QT-1 syndrome caused by a N588K mutation in HERG. Repetitive ECGs were recorded in two female patients with short QT-1 syndrome with a N588K-HERG mutation off drugs, on oral quinidine, and on oral disopyramide. One patient underwent exercise testing on drugs to determine the QT interval to heart rate relation, whereas the QT interval was calculated to the peak of the T wave in lead V3. In the same patient, drug-induced changes in ventricular effective refractory periods were determined by programmed ventricular stimulation via the ICD lead. Disopyramide increased the QT interval from QTc 329 ms/QTc 315 ms, respectively, off drugs to QTc 358 ms/QTc 333 ms in both patients and restored the heart rate dependence of the QT interval toward normal subjects (-0.39 ms/bpm off drugs, -0.58 ms/bpm on disopyramide vs. 1.29 +/- 0.33 ms/bpm in normal subjects). The ventricular effective refractory period increased under disopyramide by 40 ms. These preliminary observations suggest that oral disopyramide may be a suitable alternative to quinidine for prolonging the QT interval and ventricular effective refractory periods in patients with short QT-1 syndrome. Further studies of this pharmacologic approach are warranted.

Abstract 2378: The MinK G38S Polymorphism Associates with Atrial Arrhythmias after Subarachnoid Hemorrhage

Background: Subarachnoid hemorrhage (SAH) leads to significant death and disability. Cardiac abnormalities after SAH include atrial arrhythmias (AAs). The MinK (KCNE1) G38S polymorphism has been associated with atrial fibrillation, with the G38 allele being linked to increased action potential duration in heterologous expression systems. The relationship of AAs and ion channel polymorphisms after SAH is not known. Methods: In 148 patients admitted for acute, aneurysmal SAH, EKG parameters, 24-hour Holter monitors, serum troponin (TnI), potassium (K), magnesium (Mg), and echocardiograms (ejection fraction [EF] and left atrial diameter [LA D]) were examined. MinK G38S was genotyped using fluorescent primers and analyzed with an ABI Prism 7000. Results: No patient had AAs on presentation, but AAs developed in 101 (68%) patients: SVT (95; 64%); fibrillation (9; 6%); flutter (4; 3%); idioventricular rhythm (2; 1%); and 3° block (1; 1%). AAs were not associated with PR or QTc intervals, TnI, K, Mg, EF, LA D, or stroke severity. AAs were associated with older age (58±9 vs 51±10yrs; p&lt;0.001), lower heart rate (HR; 80±10 vs 84±14bpm; p=0.02), and higher HR variability (SDNN; 97±34 vs 85±32; p=0.05). The MinK S38 allele was associated with AAs (Figure ; GS &amp; SS 70% vs GG 51%; p=0.02), but not LA D. Conclusions: Atrial arrhythmias are common following SAH and the MinK S38 allele is associated with an increased frequency of atrial arrhythmias. The SAH-induced catecholamine surge, followed by increased parasympathetic activity, may enhance the shortening of the atrial effective refractory period in patients carrying the MinK S38 allele and increase susceptibility to atrial arrhythmias.

P15.18 Absolute and relative refractory periods in patients with carpal tunnel syndrome

P15.18 Absolute and relative refractory periods in patients with carpal tunnel syndrome

1438 Absolute and relative refractory periods in patients with Carpal Tunnel Syndrome

1438 Absolute and relative refractory periods in patients with Carpal Tunnel Syndrome

Méthodes et intérêt clinique de la mesure de la période réfractaire nerveuse périphérique chez l'homme

Immediately after action potential occurrence, owing to transient sodium channel inactivation, axon excitability is reduced for a short period of time, including the absolute refractory period, a first period of total inexcitability, followed by the relative refractory period. There are basically two different stimulation protocols to estimate axonal refractoriness, i.e. "paired-pulse" and "collision" techniques. Refractory period has been assessed in various conditions and appeared to depend on several physiological or methodological factors, featuring the type of nerve or the characteristics of the subject, but also the technique of stimulation or the method of data analysis. In addition, refractory periods can be altered by pathological conditions. Several studies showed prolonged refractory periods in patients suffering from alcoholic, diabetic or toxic neuropathies. Refractory period abnormality is a sensitive marker of axonal dysfunction as observed in Guillain-Barré syndrome, carpal tunnel syndrome or multiple sclerosis. Thus, the measurement of the refractory periods is a valuable tool to study the pathophysiology of peripheral nerves, complementary to standard nerve conduction studies. However, the application of these techniques in the routine practice of clinical neurophysiology remains limited.

Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

We assessed the feasibility of cardiac contractility modulation (CCM) by electric currents applied during the refractory period in patients with heart failure (HF). Extracellular electric currents modulating action potential and calcium transients have been shown to potentiate myocardial contractility in vitro and in animal models of chronic HF. CCM signals were biphasic square-wave pulses with adjustable amplitude, duration, and time delay from sensing of local electric activity. Signals were applied to the left ventricle through an epicardial vein (in 12 patients) or to the right ventricular (RV) aspect of the septum endocardially (in 6 patients). Simultaneous left ventricular (LV) and aortic pressure measurements were performed using a Millar catheter (Millar Instruments, Houston, Texas). Hemodynamics during RV temporary dual-chamber pacing was regarded as the control condition. Both LV and RV CCM stimulation increased dP/dt max to a similar degree (9.1 ± 4.5% and 7.1 ± 0.8%, respectively; p <0.01 vs controls), with associated aortic pulse pressure changes of 10.3 ± 7.2% and 10.8 ± 1.1% (p <0.01 vs controls). Regional systolic wall motion assessed quantitatively by color kinesis echocardiography was markedly enhanced near the CCM electrode, and the area of increased contractility involved 4.6 ± 1.2 segments per patient. In 6 patients with HF with left bundle branch block, CCM signals delivered during biventricular pacing (BVP) produced an additional 16.1 ± 3.7% increase in dP/dt max and a 17.0 ± 7.5% increase in pulse pressure compared with BVP alone (p <0.01). CCM stimulation in patients with HF enhanced regional and global measures of LV systolic function, regardless of the varied delivery chamber or whether modulation was performed during RV pacing or BVP.

Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation.

Sustained shortening of the atrial effective refractory period (AERP), probably due to reduction in the L-type calcium current, is a major factor in the initiation and maintenance of atrial fibrillation (AF). We investigated underlying molecular changes by studying the relation between gene expression of the L-type calcium channel and potassium channels and AERP in patients with AF. mRNA and protein expression were determined in the left and right atrial appendages of patients with paroxysmal (n=13) or persistent (n=16) AF and of 13 controls in sinus rhythm using reverse transcription polymerase chain reaction and slot-blot, respectively. The mRNA content of almost all investigated ion channel genes was reduced in persistent but not in paroxysmal AF. Protein levels for the L-type Ca(2+) channel and 5 potassium channels (Kv4.3, Kv1.5, HERG, minK, and Kir3.1) were significantly reduced in both persistent and paroxysmal AF. Furthermore, AERPs were determined intraoperatively at 5 basic cycle lengths between 250 and 600 ms. Patients with persistent and paroxysmal AF displayed significant shorter AERPs. Protein levels of all ion channels investigated correlated positively with the AERP and with the rate adaptation of AERP. Patients with reduced ion channel protein expression had a shorter AERP duration and poorer rate adaptation. AF is predominantly accompanied by decreased protein contents of the L-type Ca(2+) channel and several potassium channels. Reductions in L-type Ca(2+) channel correlated with AERP and rate adaptation, and they represent a probable explanation for the electrophysiological changes during AF.

Attenuation of electrical remodelling in chronic atrial fibrillation following oral treatment with verapamil.

Electrical remodelling with shortening of the atrial refractory period and increased fibrillatory rate occurs after onset of atrial fibrillation and can be attenuated by pre-treatment with intravenous verapamil. The aim of the present study was to investigate whether already established fibrillatory-induced shortening of atrial fibrillatory cycle length could be reversed with oral verapamil. Thirteen patients (nine men; mean age 67 years) with chronic atrial fibrillation (CAF) were studied. The dominant atrial cycle length (DACL) was estimated non-invasively using the frequency analysis of fibrillatory ECG (FAF-ECG) method. Measurements were repeated following treatment with slow release oral verapamil. DACL increased from 147 +/- 13 ms to 156 +/- 21 ms after 1 day (P=0.02), to 164 +/- 18 ms after 5 days (P=0.005) and finally to 160 +/- 16 ms after 6 weeks (P=0.008). Long-term oral treatment with verapamil increases the DACL significantly in patients with CAF. The prolongation is evident after 1 day and is further developed during the first 5 days of treatment. Since DACL is believed to be an index of refractoriness, the findings of the present study suggest that this treatment increases the atrial refractory period in patients with CAF.

Effects of levosimendan on cardiac arrhythmia: electrophysiologic and ambulatory electrocardiographic findings in phase II and phase III clinical studies in cardiac failure

Levosimendan is a novel inotropic and vasodilating agent that enhances the calcium sensitivity of myofilaments by binding to troponin C. Unlike other calcium sensitizers, it is highly dependent on the intracellular concentration of calcium. As a result of this unique property, levosimendan might be expected to increase cardiac contractile force without significantly impairing ventricular relaxation. The electrophysiologic effects of intravenously infused levosimendan were examined in healthy volunteers, and its effects on the surface electrocardiogram and on arrhythmia were recorded on 24-hour Holter recorders in patients with heart failure. Levosimendan had no significant effects on heart rate when data were pooled from the 24-hour electrocardiograms of patients receiving various dose levels, although increases were noted at high doses. The uncorrected QT interval remained unchanged, but the rate-corrected QT interval (QT c) was modestly prolonged at doses several-fold higher than that required for therapeutic effect. Atrial and ventricular effective refractory periods in patients with normal heart function were slightly shortened, although the average effect on the ventricles was only 2–5 msec at different pacing rates. No increase in the frequency of nonsustained ventricular tachycardia (VT) was found from the analysis of ambulatory electrocardiograph data from a total of 792 1-day recordings pooled from 10 studies, which included data from 386 heart failure patients. There was no evidence of any increase in the development of new supraventricular or ventricular tachyarrhythmias, including torsade de pointes, in patients who did not exhibit these abnormalities at baseline. The electrophysiologic actions of levosimendan in healthy volunteers and the effects of the drug on the QT interval of the electrocardiogram and on arrhythmia recorded during its intravenous use in patients with severe heart failure demonstrated little potential for the drug to provoke life-threatening proarrhythmic reactions.

Effects of the ATP-sensitive K channel opener nicorandil on the QT interval and the effective refractory period in patients with congenital long QT syndrome

Congenital or idiopathic long QT syndrome is characterized by a frequently lethal ventricular arrhythmia called torsades de pointes (TdP) as well as a prolonged QT interval. The long QT interval related to an abnormal gene of the Na + channel has been shown to be shortened by mexiletine. However, the action of K + channel openers on the QT interval associated with abnormal genes of the K channel has yet to be studied. Seven patients of five families with long QT syndrome were included in this study, of whom six had syncope and six had documented TdP. Either long QT interval or sudden cardiac death had been observed in family members of all seven patients. At 1 to 3 weeks after admission, when TdP or frequent ventricular arrhythmia had subsided, nicorandil, an ATP-sensitive K channel opener, was administered orally at a dose of 15 mg/day in five patients and at 30 mg/day in the remaining two patients, and the effects were assessed on the third day after drug administration. In four patients, the effective refractory period was measured in the right ventricle before and after administration of K channel opener administration. The QT interval (QTc) prior to administration of the K channel opener was 0.60 ± 0.09 ms (mean ± SD) (0.61 ± 0.10 second 1 2 ), which was shortened to 0.54 ± 0.05 ms (0.55 ± 0.06 second 1 2 ) on the third day of drug administration ( P < .05 for both): 10.4 ± 8.0% (8.6 ± 5.5%). The QT interval at varying preceding R-R intervals on Holter electrocardiograms showed a shift toward the right as a result of the drug administration. The effective refractory period showed a significant prolongation, 256 ± 26 ms versus 280 ± 22 ms before and after drug administration, respectively ( P <.05). Intravenous administration of nicorandil resulted in no significant change in heart rate or blood pressure, while QTc showed a tendency to shorten, but nonsignificantly ( P = .08). However, a hump on the monophasic action potential was abolished, especially at the long preceding R-R interval induced by premature stimulation of the ventricle. It is concluded that nicorandil shortens the QT interval slightly when administered orally, whereas the effective refractory period shows a slight prolongation. The physiologic and clinical significance of these effects needs to be studied further.

Ventricular effective refractory period in patients with hypertrophic cardiomyopathy

Ventricular effective refractory period in patients with hypertrophic cardiomyopathy

Prevalence of retrograde conduction in heart block after DDD pacemaker implantation

Electrophysiologic studies were performed before DDD pacemaker implantation in 50 patients with symptomatic heart block. The patients were separated into 2 groups. Group I consisted of patients with intact retrograde conduction and group II consisted of patients with blocked retrograde conduction. After pacemaker implantation, postventricular atrial refractory periods in patients in group I were programmed at 50 to 100 ms, in excess of the retrograde conduction times measured during electrophysiologic studies. In group II patients, postventricular atrial refractory periods were routinely programmed at 300 ms. During follow-up, patients visited the outpatient clinic at 3-month intervals for noninvasive assessment of the prevalence of retrograde conduction, and to test the inducibility of pacemaker-mediated tachycardias. The mean follow-up of group I (15 patients) was 27 ± 10 months, whereas the mean follow-up of group II (35 patients) was 19 ± 9 months. The mean number of noninvasive tests performed during follow-up was 8 ± 3 per patient for group I and 5 ±3 per patient for group II. in group I, retrograde conduction remained intact in 12 patients (p < 0.01). In 29 of 31 patients in group II, retrograde conduction remained absent (p < 0.01). In 4 patients in group II, chronic atrial fibrillation occurred during followup. Chronic atrial fibrillation did not occur in any patient in group I. During serial electrophysiologic testing, no pacemaker-mediated tachycardias could be induced in any patient in group I or II. These results suggest that electrophysiologic studies performed before pacemaker implantation reliably predict the prevalence of retrograde conduction during follow-up of patients with symptomatic heart block and that adjusted atrial refractory periods of the pulse generator at implantation prevent the induction of pacemaker-mediated tachycardias during serial electrophysiologic testing.

Nerve fibre refractory period in patients treated with rubidium and lithium.

Nerve fibre refractory period distributions have been measured on the median nerves of six manic-depressive patients controlled with lithium carbonate, three chronic patients (two manic-depressives and one catatonic schizophrenic) controlled with rubidium chloride, and eight normal volunteers. Rubidium prolonged the refractory periods of all nerve fibres while lithium increased only the longer refractory periods.

Altered refractory periods in patients with short P-R intervals and normal QRS complex

To evaluate the refractory periods of the atrioventricular (A-V) conducting system in patients with a short P-R interval and normal QRS complex, 57 patients with a P-R interval of 110 to 280 msec were studied with His bundle recording and premature atrial stimulation at similar cycle lengths of 660 to 720 msec. In 13 patients with a short P-R interval (120 msec or less) the mean value for the functional refractory period of the A-V node was 368 ± 36 msec (standard deviation), which was significantly lower ( P < 0.01) than the mean value of 415 ± 50 msec in 36 patients with a normal P-R interval (between 120 and 200 msec) and the mean value of 492 ± 57 msec in 8 patients with an increased P-R interval (200 msec or greater). Patients with a short P-R interval had a mean value for the effective refractory period of the A-V conducting system of 247 ± 26 msec, which was significantly lower ( P < 0.01) than the mean values of 297 ± 51 msec in patients with a normal P-R interval and 369 ± 87 msec in patients with an increased P-R interval. The results identify a characteristic conduction abnormality that is compatible with a partial A-V nodal bypass or dual A-V nodal conduction pathways. The relation between the duration of the P-R interval and the refractory period may aid understanding of the clinical significance of the scalar electrocardiogram.