Anti-arrhythmic effect of oral propafenone. Apropos of 70 cases

During a 3 year period, seventy patients aged 53 +/- 16 years with a total of 73 arrhythmias were treated over a mean period of 6.8 months (maximum 27 months) with oral propafenone, the usual dose being 900 mg/day. The study covered the whole spectrum of cardiac arrhythmias (32 supraventricular, 41 ventricular), and their relation to the autonomic nervous system. The efficacy was scored from 1 (no effect) to 5 (complete control) as judged by the clinical response, the results of Holter monitoring (175 control and 133 test recordings on therapy), and a comparison was made between the effects of propafenone and other antiarrhythmics: quinidine-like drugs, beta-blockers and amiodarone. With respect to supraventricular arrhythmias: 9 cases of vagally-induced atrial flutter and fibrillation were unaffected by propafenone (mean score = 1.1). On the other hand, the drug was very effective (mean score = 4.1) in 8 cases of adrenergic atrial arrhythmias. In 12 arrhythmias with more varied mechanisms (extrasystoles, tachysystole, paroxysmal atrial fibrillation) an intermediate score was obtained (2.8). Three cases of resistant junctional tachycardia due to reentry were improved. At ventricular level, 5 cases of extrasystole sensitive to quinidine were also improved by propafenone (4.6); the difference was more clearcut in 8 cases of benign idiopathic tachycardia (propafenone: 4.1, and quinidine: 2.4). This was more marked in 13 cases of more severe arrhythmia in diseased hearts in which the effect of propafenone (4.1) was superior even to that of amiodarone. However, propafenone was less effective (3.3) than amiodarone in 4 cases of severe polymorphic idiopathic ventricular tachycardia closely related to the autonomic nervous system. The antiarrhythmic effect of propafenone was appreciable in 10 cases of resistant post-infarction ventricular tachycardia, eventually in association with amiodarone. Slowing of the sinus rhythm (-11.6%) with no change in the day/night ratio was due to beta-inhibition. However, in toxic doses this may progress to sinoatrial block (9 cases). A lengthening of the PR interval and duration of QRS was common, but this was not complicated by torsade de pointes, one case of which was successfully treated by propafenone. Secondary gastro-intestinal effects and vertigo were rarely severe enough to warrant stopping therapy. In conclusion, these results show that the introduction of propafenone is a valuable therapeutic advance in the treatment of arrhythmias, especially in those with a favoring adrenergic mechanism.     

Role of sympathetic nervous system in non-ischaemic ventricular arrhythmias

Propranolol and nadolol were used in two groups of patients having ventricular arrhythmias. The two groups were characterised by differences in sympathetic drive. The 10 non-adrenergic patients had idiopathic, monomorphic extrasystoles (isolated with fixed coupling or in pairs or salvoes) arising from the right ventricle or the septum. These extrasystoles were chronic and benign, with a slightly increased daytime frequency (day:night = 1.6). They disappeared on exercise. The nine adrenergic patients had less frequent but more complex polymorphic ventricular extrasystoles, and rapid and irregular tachycardias which were resistant. They occurred predominantly during the day and were associated particularly with stress and exercise. They were either idiopathic, or coexisted with mitral valve prolapse (three cases) or hypertrophic subaortic stenosis (one case) in young patients (mean age, 32 years) who did not have coronary heart disease. Nadolol was more effective than propranolol in controlling the arrhythmia, heart rate, and variations in sinus rhythm in the adrenergic group, while the arrhythmia was not controlled in the non-adrenergic group. Using clinical variables, comparison of the frequency of extrasystoles by day and night, and assessment of the antiarrhythmic effect of beta-blockers, the role of the sympathetic tone in non-ischaemic ventricular arrhythmias may be elucidated.     

The QRS morphology in post-myocardial infarction ventricular tachycardia. A study of 100 tracings compared with 70 cases of idiopathic ventricular tachycardia

A hundred tracings of ventricular tachycardia (VT) belongingto 85 patients with myocardial infarction (MI) were comparedwith 70 cases of incessant, benign, idiopathic VT. The two groupsof tracings differed in terms of QRS axis, most often normalin idiopathic VT (75%) and outside normality in MIVT (74%).The sum of QRS amplitude in unipolar limb leads was greaterin idiopathic VT (4.3±1.3 mv, mean±S.D.) thanin MIVT (2.6±0.8 mv, P>0.001). The QRS width was alsodifferent: 135±11 ms in idiopathic VT vs. 171±32ms in MIVT (P>0.001). The QRS morphology in MIVT was characterizedby the presence of a QR pattern in leads other than VR, or aQS pattern in V₅–V₆. These two aspects were constantlyabsent in idiopathic VT, and they were present in 89%of MIVT.In only 38 MIVT tracings were the ECG signs of MI observed inthe same leads during sinus rhythm and during VT. In 51 MIVTtracings the location of the MI indicated by the VT tracingdiffered from that displayed in sinus rhythm. Rather than indicatingan extension of the infarcted area not apparent in the tracingsin sinus rhythm, such a discrepancy suggests that the QRS patternduring VT strongly depends on the point of origin of the VT.Conversely, this explains why the morphology of the QRS is anureliable means for localizing the VT origin if the locationof the MI is not taken into account. We conclude that both factorsshould be taken into consideration, and this might theoreticallypermit a better though complex approach to the VT origin incoronary heart disease using surface tracings.     

A subpopulation of immunoglobulin G in man selectively interacts with the hormone-binding sites of estrogen receptors

Since the binding sites of hormone receptors may be similar to those of antihormone antibodies, we wondered whether the former might not be recognized by the idiotypic network. To test this hypothesis we investigated the interaction of plasma immunoglobulin G (IgG) with the binding sites of estrogen receptors (ER) from uterine or mammary tissue. Using ER isolated from uterine cytosol we found that IgG from normal subjects shifted the position of purified receptor in sucrose gradients and displaced [3H]estradiol (E2) from its receptor-binding sites. Equilibrium studies revealed competitive inhibition by IgG of E2 binding to the ER. IgG isolated by adsorption on a rat uterine cytosol-Blue B matrix gel column also bound to the ER, and this binding was inhibited by an excess of E2. After an 18-h exposure of MCF-7 mammary carcinoma cells in monolayer culture to IgG (2 mg/ml), Scatchard analysis of [3H]E2 binding revealed a reproducible decrease in the available receptor sites from 2.52 +/- 0.56 (+/- SEM) to 0.68 +/- 0.48 fmol/microgram DNA (n = 10). This effect was selective, since enriched anti-ER IgG obtained by adsorption on purified receptor was 20 times more potent than total IgG, whereas IgG identically prepared but not retained by affinity chromatography had no activity. Exposure of the cells to the IgG for 45 min also revealed, as with isolated ER, specific competition of the IgG with E2 for the E2-binding sites; the Kd increased from 10.5 +/- 1.6 to 27.5 +/- 7.2 X 10(-11) M (n = 7). Enriched antireceptor IgG was a 20 times more effective competitor, and the IgG not retained by affinity chromatography had no activity. In conclusion, our observations indicate the presence of ER on the cell surface, interaction of ER with IgG from plasma of normal subjects, and competitive antagonism of these IgG with E2 uptake leading to a decrease in effective ER concentrations.     

Sphingomyelinase-Like Phosphodiesterase 3b Expression Levels Determine Podocyte Injury Phenotypes in Glomerular Disease

Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVβ₃ integrin-dependent migration in vitro. Furthermore, αVβ₃ integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVβ₃ integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVβ₃ integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.     

Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure.

AIMS: Cardiac resynchronization therapy (CRT) is an effective treatment for refractory congestive heart failure (CHF). However, up to 30% of patients do not respond to CRT. The aim of this study was to identify clinical and electrocardiographic (ECG) predictors of a positive response to CRT. METHODS AND RESULTS: This retrospective study included 139 consecutive patients successfully implanted with a CRT device (mean age, 68+/-9 years, 113 men). At baseline, 69% of patients were in New York Heart Association (NYHA) functional class III, and 31% in class IV, mean left ventricular ejection fraction was 21+/-6%, and mean QRS duration was 188+/-28 ms. In each patient, left and right ventricular leads were placed to attain the shortest QRS duration during biventricular stimulation. Patients were classified at 6 months as responders to CRT (n=100) if they were alive, they had not been re-hospitalized for management of CHF, and the NYHA class had decreased by 1 point, and/or peak VO(2) or 6 min hall-walk increased by >10%. All others were classified as non-responders (n=38; one patient was lost to follow-up). Uni- and multivariate logistic regression analyses were performed to detect a pre- or intra-operative predictor of a positive response to CRT. Among multiple demographic, clinical, and ECG variables, the amount of QRS shortening (DeltaQRS) associated with biventricular stimulation was the only independent predictor of a positive (37+/-23 ms) vs. negative (11+/-23 ms) response to CRT (P<0.001). CONCLUSION: A positive response to CRT was observed in 73% of patients at 6 months and predicted only by DeltaQRS.