Effects of abrupt changes in cycle length on atrial refractory periods in man

While the electrophysiologic effects of sudden changes in cycle length on the His-Purkinje System and ventricular myocardial refractoriness are better known, the behavior of atrial myocardium in this regard is poorly understood. The effects of an abrupt long to short cycle length change (11 patients: group A) and/or short to long cycle length alteration (18 patients: group B) on the atrial effective and functional refractory period were assessed during electrophysiologic studies. The values thus obtained were compared to those observed during the scanning of both constant long and constant short cycle lengths of the same duration. In group A the effective and functional refractory periods of the right atrium measured 250 +/- 38 msec and 296 +/- 31 msec during a constant long cycle length of 709 +/- 80 msec, whereas the same parameters had values of 228 +/- 30 msec and 260 +/- 32 msec, respectively, at a constant short cycle length of 436 +/- 81 msec. With an abrupt change in cycle length from long to short (a change of 273 +/- 75 msec), the effective and functional atrial refractory periods were 225 +/- 29 and 267 +/- 29 msec in that order, and these values closely approximated those seen with a constant short cycle length. Similarly, the two atrial refractory period parameters in group B measured 218 +/- 16 msec and 262 +/- 19 msec during a constant short cycle length of 414 +/- 68 msec and were 236 +/- 17 msec and 284 +/- 21 msec, respectively, at a constant long cycle length of 689 +/- 92 msec.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of activation sequence on ventricular refractory periods of ischemic canine myocardium

Refractory periods were measured in pentobarbital-anesthetized dogs during control periods and one to one and a half hours after distal left anterior descending coronary artery occlusion. The refractory period test site was on the anterior surface of the left ventricle in the distribution of the artery to be occluded. Measurements were made during drive of the refractory period test site, drive of a distant site on the pulmonary conus and during fusion drive in which drive of the test site was delayed with respect to drive of the pulmonary conus. Refractory periods were longer during test site drive than during pulmonary conus or fusion drives in both the control periods and following coronary occlusion. However, the effects of driving mode on refractory periods were greater following coronary occlusion than in the control periods. The findings are likely secondary to different magnitudes of change in electrotonic interactions associated with changes in activation sequence in ischemic and nonischemic myocardium. The greater dependence of repolarization properties in ischemic than nonischemic tissue suggests that inhomogeneity of these properties could be modified considerably by the site of origin of ectopic ventricular complexes.     

Indication of myocardial "memory". Gradual, persisting modulation of myocardial decrease in excitation following change in the activation sequence

It is well established that regional differences in electrical repolarization are responsible for the electrocardiographic T-wave. Regional differences in ventricular repolarization traditionally have been attributed to variance of action potential duration (APD), believed to be an intrinsic property of individual cardiac cells (17, 21, 24). To evaluate whether the excitation sequence influences ventricular repolarization we studied the effect of an altered excitation sequence on the APD distribution in isolated rabbit hearts. We found that APD is not primarily a function of the cell's location in the ventricle but rather is modulated by the sequence with which the ventricles are electrically excited. This excitation sequence-dependent modulation of APD occurs with a very slow time-course, requiring hours to develop and hours to dissipate after resumption of the original excitation sequence. Our findings suggest a new, as of yet unrecognized form of intercellular communication by which the myocardial cells adjust their repolarization sequence to a change in excitation sequence.     

Long-term oral propafenone therapy for suppression of refractory symptomatic atrial fibrillation and atrial flutter

Sixty patients who had recurrent episodes of symptomatic atrial fibrillation or flutter, or both, and who had failed one to five prior drug trials were treated with open label oral propafenone hydrochloride. On a mean maximal tolerated dose of 795 +/- 180 mg/day, actuarial estimates of the percent of individuals free of recurrences of symptomatic atrial fibrillation/flutter during propafenone treatment were: 1 month, 54%; 3 months, 44% and 6 months, 40%. No individual baseline characteristic achieved statistical significance as a correlate of poor response to propafenone. Drug-related adverse reactions were reported in 22% of patients but were severe enough to require termination of propafenone in only 5%. Thus, oral propafenone is a useful and well tolerated drug for long-term suppression of symptomatic recurrences of atrial fibrillation/flutter despite a history of unresponsiveness to prior antiarrhythmic drug treatment.     

Dual effect of disopyramide on atrial and atrioventricular conduction and refractory periods.

Disopyramide has been shown in conditions of cholinergic blockade to have a depressant effect upon sinus node automaticity and the atrial refractoriness. It also prolongs atrioventricular conduction and increases atrioventricular refractoriness. These effects may often be masked in vivo by the anticholinergic effects of the drug.     

Left atrial posterior wall and pulmonary vein refractory periods are associated with atrial fibrillation inducibility in a swine model

INTRODUCTION AND OBJECTIVES: Ectopic activity originating inside the pulmonary veins has been associated with paroxysmal atrial fibrillation in some patients. However, the roles played by the pulmonary veins and the posterior wall of the left atrium in maintaining atrial fibrillation are not well understood. METHODS: Our aim was to determine whether there is a correlation between the refractory period of either the lateral wall of the right atrium, the lateral wall of the left atrium, the posterior wall of the left atrium, or the pulmonary veins, and the inducibility of atrial fibrillation in an experimental swine model. We assessed atrial fibrillation inducibility using programmed atrial stimulation before and after intravenous administration of a high dose of methacholine in 20 pigs. RESULTS: Atrial fibrillation was induced in 17 out of the 20 pigs. Univariate analysis showed that there were negative correlations between all refractory periods and atrial fibrillation inducibility. A short refractory period was associated with greater inducibility. In the multivariate analysis, only the refractory periods of the posterior wall of the left atrium and the pulmonary veins were associated with inducibility. We also investigated the relationship between the local atrial fibrillation cycle length and refractory period; the only significant correlation was with the refractory period of the lateral wall of the right atrium (Pearson correlation coefficient 0.97). CONCLUSIONS: In an experimental swine model, the inducibility of atrial fibrillation was found to be associated with the refractory periods of both the pulmonary veins and the posterior wall of the left atrium.     

Architecture of ribosomal RNA: constraints on the sequence of "tetra-loops".

The four-base loops that cap many double-helical structures in rRNA (the so-called "tetra-loops") exhibit highly invariant to highly variable sequences depending upon their location in the molecule. However, in the vast majority of these cases the sequence of a tetra-loop is independent of its location and conforms to one of three general motifs, GNRA, UNCG, and (more rarely) CUUG. For the most frequently varying of the 16S rRNA tetra-loops, that at position 83 (Escherichia coli numbering), the three sequences CUUG, UUCG, and GCAA account for almost all examples encountered, and each of them has independently arisen at least a dozen times. The closing base pair of tetra-loop hairpins reflects the loop sequence, tending to be C.G for UUCG loops and G.C for CUUG loops.     

Eastern Pacific molluscan provinces and latitudinal diversity gradient: no evidence for "Rapoport's rule"

"Rapoport's rule," which has gained wide acceptance as a potential explanation for latitudinal and other diversity gradients, holds that mean latitudinal range of species decreases toward the equator. We analyzed latitudinal ranges of 2838 eastern Pacific marine molluscan species, a subset of which figured in the original formulation of Rapoport's rule, and failed to find the predicted trends. Instead, species diversity gradients and range magnitudes appear to vary independently, with the spatial distribution of major oceanographic barriers exerting a strong influence on latitudinal ranges. Biogeographic structure should, therefore, be an important element in the assessment of diversity patterns.     

Evaluation of biatrial pacing, right atrial pacing, and no pacing in patients with drug refractory atrial fibrillation.

It has been suggested biatrial pacing may prevent the recurrence of atrial fibrillation (AF). To further evaluate this hypothesis, we performed a randomized, single-blinded study in 19 patients with drug refractory AF. The study compared biatrial pacing with conventional right atrial (RA) pacing and a control period of inhibited pacing. The pacing modes utilized were DDD with a base rate of 70 beats/min for biatrial and RA pace (with and without biatrial resynchronization, respectively) and 40 beats/min for the control period. The duration of each pacing mode was 3 months. The number of AF episodes and their duration were obtained from pacemaker Holter memory (Chorus RM ELA Medical). Comparison of the control period (n = 11) with either pacing strategy showed a significant decrease in the total duration of AF (control 27 +/- 35 days, biatrial 8 +/- 15 days p = 0.02, RA 11 +/- 27 days p = 0.04). However, there was no effect on the number of AF episodes (control 79 +/- 108, biatrial 36 +/- 75 p = 0.32, RA 41 +/- 80 p = 0.11). The total percentage of atrial pacing also significantly increased when the control period (6 +/- 9%) was compared with both RA pace (62 +/- 33%, p = 0.008) and biatrial pace (63 +/- 31, p = 0.003). When biatrial pacing was compared with RA pace (n = 19), there was no significant difference in either the duration of AF (biatrial 16 +/- 26 days vs RA 19 +/- 31 days, p = 0.7) or the number of AF episodes (biatrial 56 +/- 91 vs RA 87 +/- 106, p = 0.34). In conclusion, pacing (either type) at a base rate of 70 beats/min has an antifibrillatory effect when compared with inhibited pacing at 40 beats/min. No additional benefit of biatrial pacing over right atrial pacing was demonstrated in this study.     

Time dependence of ventricular refractory periods: implications for electrophysiologic protocols

Cardiac refractory periods are routinely measured during electrophysiologic testing. Informal observations suggested that the effective refractory period lengthened with a prolongation of the time in sinus rhythm (basic cycle length time) between successive runs of drive stimuli (S1S1s). If this were true, failure to control the basic cycle length time could affect the results and interpretation of electrophysiologic testing. To study this phenomenon, the effective refractory period was studied in 20 patients during sinus rhythm and two ventricular paced rates with up to three extrastimuli, while varying the basic cycle length time from 2 to 3, to 10 to 20 s. With each of the stimulation sequences used, the effective refractory period lengthened as the basic cycle length time increased ("basic cycle length time-effective refractory period effect"). The effect was most pronounced when extrastimuli were used during the two ventricular paced rates. As the basic cycle length time increased from 2 to 3 to 20 s, the mean effective refractory period determined during sinus rhythm increased from 296 to 300 ms; with the first ventricular paced rate, the effective refractory period increased from 259 to 272 ms (p less than 0.0003) and with the second ventricular paced rate, the effective refractory period increased from 250 to 263 ms (p less than 0.01). The basic cycle length time-effective refractory period effect became more pronounced as the number of extrastimuli increased. With the second ventricular paced rate, as basic cycle length was increased from 2 to 3 to 20 s, the mean prolongation in the cumulative effective refractory period (S1 to final extrastimulus) as the number of extrastimuli increased from 1 to 2 to 3, was 13 (p less than 0.01), 42 (p less than 0.0003) and 82 ms (p less than 0.001), respectively. Results were confirmed in 17 instances by redetermining the effective refractory period at the 2 to 3 s basic cycle length time after the final 20 s basic cycle length time determination, and demonstrating that it was similar to the effective refractory period after the initial 2 to 3 s basic cycle length time. No further prolongation of the effective refractory period could be demonstrated by increasing basic cycle length time from 20 to 60 s, and no significant effect of medications on the basic cycle length time-effective refractory period effect could be demonstrated.     

C-reactive protein and atrial fibrillation: "evidence for the presence of inflammation in the perpetuation of the arrhythmia"

BACKGROUND: Atrial fibrillation (AF) is associated to a high risk of systemic embolism. The mechanisms that contribute to thrombogenesis in these patients are still poorly understood. Systemic and/or local inflammation could be involved in the process of thrombogenesis and contribute to the perpetuation of the arrhythmia. The purpose of the study was to evaluate the role of inflammation and its relation to thrombogenesis and cardiac rhythm in AF. METHODS: We prospectively studied 130 patients with newly diagnosed non-valvular AF in absence of antithrombotic therapy. Determinations of C-reactive protein (CRP) and thrombin-antithrombin complex (TAT) plasma levels, along with a transesophageal echocardiogram were performed in all the patients at admission. RESULTS: Mean age of the group was 67+/-14 years. CRP levels were significantly elevated in AF patients versus controls (matched by age, gender and cardiovascular risk factors) (1.0+/-1.8 versus 0.3+/-0.4 mg/dl, respectively, p<0.01). Baseline TAT levels were also significantly elevated in AF patients but no correlation was found between CRP and TAT. At 1-year of follow-up, mean CRP levels were still elevated in patients that remained in AF compared to those who converted to sinus rhythm (1.2+/-1.8 compared to 0.5+/-1.5 mg/dl, p=0.03). CRP was the only biochemical predictor of sinus rhythm maintenance at 1-year follow-up independently of clinical (including adjustment for risk factors and antiarrhythmic drugs), biochemical and echo parameters. CONCLUSIONS: There is evidence for the presence of inflammation in patients with non-valvular AF, which is not related to activation of the coagulation cascade. The persistence of inflammation is associated with chronic AF at 1-year follow up.     

Effect of altered activation sequence on epicardial QRST area and refractory period in dogs

BACKGROUND. We investigated the effects of activation sequence on cardiac surface QRST areas and refractory periods in experiments on dogs. METHODS AND RESULTS. Right and left ventricular pacings were performed, and the pacing site was altered every 6 minutes. After 4 minutes of a given pacing, 54 unipolar electrograms distributed over the entire cardiac surface were recorded. Next, refractory periods at electrode sites near pacing electrodes were measured. Paired right ventricular/left ventricular (RV/LV) pacing data were obtained six or seven times in each sample. Although the QRST isoarea maps during the two activation orders were qualitatively similar, it was recognized consistently from the right ventricle-left ventricle difference map that leads around the RV free wall had positive values and that leads around the LV free wall and apex had negative values. Compared with the same leads at RV and LV pacing, QRST areas were larger when pacing sites were near the leads. The local QRST areas of individual leads at which we measured local refractory period were consistently larger during drive from proximal pacing sites than during drive from distant pacing sites. Refractory periods were consistently longer during proximal pacing than during distal pacing, and there was a positive correlation between change in local QRST area and change in refractory period (r = 0.64) during altered activation sequence, whereas there was an inverse correlation between change in QRST area and change in refractory period (r = -0.91) during localized myocardial warming. CONCLUSIONS. Both local QRST areas and local refractory periods were dependent on the activation sequence, and there was a positive correlation between QRST areas and refractory periods during various activation sequences compared with localized myocardial warming.     

Vasoactive intestinal polypeptide facilitates atrioventricular nodal conduction and shortens atrial and ventricular refractory periods in conscious and anesthetized dogs

Our study was designed to determine the cardiac electrophysiological influence of vasoactive intestinal polypeptide (VIP) in conscious dogs. Dogs (n = 8) were chronically instrumented with arterial and venous catheters, cervical vagal cooling coils, and right atrial and right ventricular bipolar epicardial pacing and recording electrodes. After autonomic blockade (10 mg/kg i.v. hexamethonium, 0.11 mg/kg i.v. atropine, and vagal cold blockade), VIP (50 and 100 pmol/kg/min i.v.) or isoproterenol (ISO) (250 and 500 pmol/kg/min i.v.) increased heart rate (maximum increases: VIP, 81.1 +/- 4.2 beats/min; ISO, 61.3 +/- 8.5 beats/min), decreased the atrial-ventricular interval (during constant atrial pacing) (VIP, -41.9 +/- 6.3 msec; ISO, -34.6 +/- 7.4 msec), shortened the atrial effective refractory period (VIP, -24.4 +/- 2.1 msec; ISO, -30.6 +/- 4.4 msec) and ventricular effective refractory period (VIP, -4.2 +/- 0.7 msec; ISO, -10.0 +/- 2.4 msec), and decreased mean arterial pressure (VIP, -51.9 +/- 4.0 mm Hg; ISO, -26.1 +/- 2.4 mm Hg). beta-Adrenergic blockade with propranolol (1 mg/kg i.v.) eliminated the positive chronotropic and atrioventricular nodal dromotropic responses to bolus doses of ISO (30, 100, 300, and 1,000 pmol/kg i.v.) but did not affect the responses to VIP (10, 30, 100, and 300 pmol/kg i.v.). Comparable blood pressure decreases produced by sodium nitroprusside caused only minimal changes in heart rate, atrial-ventricular conduction times, and atrial and ventricular refractory periods. In three additional anesthetized dogs, after vagotomy and beta-adrenergic blockade (1 mg/kg i.v. propranolol), VIP (100 pmol/kg/min i.v.) shortened the atrial-His interval but did not alter intra-atrial, intraventricular, or His-Purkinje conduction. Our findings combined with the demonstration by others of VIP-immunoreactive nerves innervating canine sinus nodal cells, atrioventricular nodal cells, and atrial and ventricular myocardial cells suggest that endogenous VIP may directly alter the electrical properties of the heart.     

Pulmonary vein paced activation sequence mapping: comparison with activation sequences during onset of focal atrial fibrillation

INTRODUCTION: Atrial fibrillation (AF) may originate from a single focus, with the vast majority observed within the pulmonary veins. To facilitate mapping, we hypothesized that there would be a characteristic right atrial endocardial activation sequence pattern associated with pacing and spontaneous focal activity from each of the four pulmonary veins. METHODS AND RESULTS: In 10 patients with focal AF, a standardized set of catheters was positioned in the right atrium. These included a 20-pole catheter along the crista terminalis, a decapolar catheter in the coronary sinus (CS), and a His-bundle electrode. Pacing (700 and 300 msec) was performed with a mapping catheter from each of the four pulmonary veins. Activation sequence maps were created by measurement of activation times to each of the recording bipoles with the proximal CS bipole as the arbitrary reference point. Similar maps were constructed for the activation sequence of the pulmonary vein ectopic that initiated AF. There was a characteristic right atrial activation map created by pacing each pulmonary vein that corresponded closely with the map from the same pulmonary vein during initiation of focal AF. The pulmonary vein of origin could be distinguished on the basis of this characteristic pattern and some stereotypic observations. CS activation occurred proximal to distal for right pulmonary veins and distal to proximal for left pulmonary veins. Significant differences in activation timing between the CS and crista terminalis differentiated upper from lower pulmonary veins. CONCLUSION: There is a characteristic right atrial activation map for activity arising from each of the four pulmonary veins that corresponded closely with the map from the same pulmonary vein during initiation of focal AF. These findings may facilitate mapping and ablation of focal AF.     

Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin".

We studied the immunohistochemistry of the skin of scleroderma patients to determine the differences (if any) between clinically "affected" and "nonaffected" areas. We examined paired skin biopsy samples from clinically involved forearm skin ("affected") and clinically uninvolved proximal skin ("nonaffected") taken from 19 patients with diffuse scleroderma and from 15 normal control subjects. We stained the sections with antibodies to endothelial leukocyte-adherence molecule type 1 (ELAM-1; to detect endothelial activation) and to procollagen-1 (PC-1; to detect newly formed, unprocessed collagen). There was increased expression of ELAM-1 and PC-1 in sclerodermatous skin as compared with the controls, but there was no difference between clinically affected and nonaffected skin samples. In 10 of 11 patients whose condition was getting worse, endothelial and fibroblast activation preceded fibrosis. Endothelial and fibroblast activation are more widespread in the skin of scleroderma patients than is evident by inspection on physical examination. What appears to be "normal" skin in diffuse scleroderma is already pathologic, as shown by abnormal endothelial activation and procollagen production.     

"Silicone related symptoms" are common in patients with fibromyalgia: no evidence for a new disease.

OBJECTIVE: To ascertain if the symptom content and rate of symptoms in patients with fibromyalgia (FM) are similar to those in what has been called silicone implant associated syndrome (SIAS), and to determine if SIAS is indeed a new disease or whether it is largely recognizable as FM. METHODS: Mailed survey to 901 patients in Wichita, KS, Portland, OR, Los Angeles, CA, Peoria, IL, Boston, MA, San Antonio, TX, and eastern Kansas who were participating in a longterm outcome study of FM. Laboratory data were available from Wichita patients. RESULTS: Content of symptoms was similar to that in SIAS, and rates were generally as high or higher in patients with FM than in SIAS. In patients with FM, 37.2% had all of the following 5 items: arthralgias, myalgias, sicca complex, atypical rash, and symptoms of a peripheral neuropathy; and 55.2% had 4 of the 5 items. CONCLUSION: These data do not suggest that SIAS is an unrecognized new disease, but suggest the opposite, that such symptoms are well known and previously recognized, and are common among those with musculoskeletal complaints and those seen in rheumatology clinics.