Marcello Disertori

Valsartan for Prevention of Recurrent Atrial Fibrillation

BACKGROUND Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation. METHODS We conducted a large, randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation. We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes, or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo. The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year. RESULTS A total of 1442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P=0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P=0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting-enzyme inhibitors. CONCLUSIONS Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation. (ClinicalTrials.gov number, NCT00376272.)

Management of syncope referred urgently to general hospitals with and without syncope units

OBJECTIVE We tested the hypothesis that management of patients with syncope admitted urgently to a general hospital may be influenced by the presence of an in-hospital structured syncope unit. BACKGROUND The management of syncope is not standardized. Methods We compared six hospitals equipped with a syncope unit organized inside the department of cardiology with six matched hospitals without such facilities. The study enroled all consecutive patients referred to the emergency room from 5 November 2001 to 7 December 2001 who were affected by transient loss of consciousness as their principal symptom. RESULTS There were 279 patients in the syncope unit hospitals and 274 in the control hospitals. In the study group, 30 (11%) patients were referred to the syncope unit for evaluation. In the study group, 12% fewer patients were hospitalized (43 vs 49%, not significant) and 8% fewer tests were performed (3.3+/-2.2 vs 3.6+/-2.2 per patient, not significant). In particular, the study group patients underwent fewer basic laboratory tests (75 vs 86%, P=0.002), fewer brain-imaging examinations (17 vs 24%, P=0.05), fewer echocardiograms (11 vs 16%, P=0.04), more carotid sinus massage (13 vs 8%, P=0.03) and more tilt testing (8 vs 1%, P=0.000). In the study group, there was a +56% rate of final diagnosis of neurally mediated syncope (56 vs 36%, P=0.000). CONCLUSION Although only a minority of patients admitted as an emergency are referred to the syncope unit, overall management is substantially affected. It is speculated that the use of a standardized approach, such as that typically adopted in the syncope unit, is able to influence overall practice in the hospital.

Rationale and design of the GISSI-Atrial Fibrillation Trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence.

Background The possibility of preventing atrial fibrillation recurrence with anti-arrhythmic agents is very limited, given the discouraging results obtained with current drugs in many patients. Data from experimental studies suggest that angiotensin II AT1-receptor blockers can influence atrial remodelling, a key factor in atrial fibrillation initiation and maintenance. Moreover, some preliminary clinical data show that angiotensin II AT1-receptor blockers can prevent atrial fibrillation episodes. The GISSI-Atrial Fibrillation (AF) trial is a randomized, prospective, parallel group, placebo-controlled, multicentre study designed to test whether angiotensin II AT1-receptor blockers can reduce atrial fibrillation recurrence. Objectives and Methods The primary objective of the study is to demonstrate that, in patients with a history of recent atrial fibrillation who are treated with the best recommended therapies, the addition of the angiotensin II AT1-receptor blocker valsartan (titrated up to 320 mg) is superior to placebo in reducing atrial fibrillation recurrence. A substudy will analyse the effect of valsartan on left atrial dimensions and on neurohormones. The study population consists of patients with symptomatic atrial fibrillation (at least two electrocardiogram documented atrial fibrillation episodes in the previous 6 months or successful cardioversion in the last 2 weeks) with underlying cardiovascular diseases or comorbidities. With approximately 100 centres participating in Italy, a total of 1402 patients are randomized in a 1: 1 ratio to receive valsartan or placebo. The enrolment period will last 12 months and the patients will be followed for 12 months from study entry. Conclusions The GISSI-AF is the largest trial aimed at assessing the role of angiotensin receptor blockade in reducing the recurrence of atrial fibrillation and its possible mechanisms of action in terms of its effects on atrium remodelling and neurohormones.

Ventricular beats induce variations in cycle length of rapid (type II) atrial flutter in humans. Evidence of leading circle reentry.

BACKGROUND Slight variation in cycle lengths of common and rapid atrial flutter in humans is an established phenomenon, but its mechanisms have not been completely clarified. In a previous study, we demonstrated that in common atrial flutter the variations in atrial cycle length were due to atrial stretch affecting the revolution time of a reentrant circuit. In the present study, we investigate the nature of atrial cycle length variations in the rapid type of human atrial flutter. METHODS AND RESULTS Atrial interval variations of 17 episodes of rapid atrial flutter in 14 patients were investigated by measuring the sequence of atrial intervals from intraesophageal or intra-atrial leads and the onset of QRS complexes from a surface lead (V1). To study whether interval variation in flutter cycle was related to ventricular activity, a phase plot was constructed in which the flutter cycle length was plotted against the time after the previous QRS complex. This showed that the interval fluctuations were strictly coupled to the moment of ventricular activation. After the onset of the QRS complex, the rapid atrial flutter interval gradually decreased by an average of 4.1% (P < .001) and reached a minimum value after 300 to 600 milliseconds. Thereafter, the intervals increased again until the next ventricular beat occurred. In 10 patients developing both common and rapid atrial flutter, two different phase relations were found. Whereas during common atrial flutter the atrial interval increased after the QRS complex, it decreased during rapid atrial flutter. In three patients, intra-atrial pressure was recorded together with the electrical activity during both common and rapid atrial flutter episodes. This showed that variations in atrial flutter cycle length were associated with the rise of atrial pressure during ventricular contraction. CONCLUSIONS These findings indicate a role of contraction-excitation feedback caused by atrial stretch after a ventricular activation. The shortening of the atrial interval after the onset of the QRS complex as found in patients during rapid atrial flutter can be explained by stretch-induced shortening of atrial refractoriness and consequent shortening of the revolution time of a functionally determined intra-atrial circuit.

Deterioration of Organization in the First Minutes of Atrial Fibrillation: A Beat-to-Beat Analysis of Cycle Length and Wave Similarity

Introduction: It has been recently suggested that many episodes of atrial fibrillation (AF) may be partially organized at the onset and thus more suitable for antitachycardia pacing therapy. Nevertheless, the time course of organization in the first minutes of AF has not been quantified yet.

Acute Atrial Dilatation Slows Conduction and Increases AF Vulnerability in the Human Atrium

Stretch Slows Conduction in the Human Atrium. Introduction: The mechanisms by which atrial stretch favors the development of a substrate for atrial fibrillation (AF) are not fully understood. In this study, the role of stretch‐induced conduction changes in the creation of a proarrhythmic substrate has been investigated by quantifying the spatial distribution of local conduction velocities (CVs) in the human atrium during acute atrial dilatation.

Transesophageal atrial pacing: A first-choice technique in atrial flutter therapy

Here we report on a study of 181 episodes of spontaneous atrial flutter (AF) (mean atrial cycle length 250 +/- 32 msec) treated by transesophageal atrial pacing (TAP) in 138 patients (92 men and 46 women; mean age 59.5 +/- 12.6 years). TAP was effective in 163 episodes (90%); sinus rhythm resumption was immediate in 36 (19.9%) and followed a short period of atrial fibrillation in 64 (35.3%); in 63 episodes (34.8%) a stable atrial fibrillation was obtained. TAP was unsuccessful in 18 cases (10%). All the patients tolerated the procedure well. A statistical elaboration with the Fisher exact test did not evidence a correlation between efficacy and age, sex, atrial cycle length, or underlying heart disease but showed a significant correlation between efficacy and AF duration of less than 1 day (p less than 0.05) and absence of antiarrhythmic pharmacologic pretreatment (p less than 0.01). These data strongly support the immediate first-choice use of TAP in AF therapy.

Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

Background—Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. Methods and Results—We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Conclusions—Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial

Background Inflammation may play a significant role in the pathogenesis of atrial fibrillation (AF). Objectives To examine the roles of three systemic inflammatory markers in predicting recurrent AF. Methods The association between the plasma concentrations of high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6) and pentraxin-3 (PTX3) with echocardiographic parameters and with the time to first recurrence of AF was tested in 382 patients with a history of AF but in sinus rhythm at randomisation, enrolled in the GISSI-AF biohumoral study. Results Baseline PTX3 was related to left atrial, but not to left ventricular chamber volume. During one year of follow-up, 204 patients (53.1%) had a recurrent AF. There were no significant differences in baseline median [Q1–Q3] plasma concentrations of IL-6, hsCRP and PTX3 among patients with (2.11 [1.47–3.74] pg/ml, 3.30 [1.40–6.80] mg/l and 4.66 [3.27–6.97] ng/ml, respectively) or without recurrent AF (2.09 [1.37–2.90] pg/ml, p=0.182; 3.00 [1.10–6.20] mg/l, p=0.333; 5.09 [3.22–7.98] ng/ml, p=0.637). At 6 and 12 months follow-up, AF patients had significantly higher concentrations of IL-6 and PTX3 than those in sinus rhythm, and those with most recent episodes of AF had higher hsCRP. Baseline levels of IL-6, hsCRP or PTX3 were not significantly associated with a higher risk of recurrence of AF. Conclusion In patients with a history of AF, but without significant left ventricular dysfunction or heart failure, inflammatory biomarkers may be raised but are, at best, weak predictors of the risk for first recurrence of AF.

Thromboembolic event rate in paroxysmal and persistent atrial fibrillation: Data from the GISSI-AF trial

BackgroundFew data on the thromboembolic (TE) risk of paroxysmal and persistent atrial fibrillation (AF) are available. This study aimed to assess the incidence of TE events in paroxysmal and persistent AF.MethodsWe performed a subset post hoc analysis of 771 patients with paroxysmal and 463 with persistent AF enrolled in the multicenter, prospective, randomized, double-blind, placebo-controlled GISSI-AF trial - comparing the efficacy of valsartan versus placebo in preventing AF recurrences – where the choice of antithrombotic treatment was left to the judgment of the referring physician. TE and major outcome events were centrally validated. AF recurrences were detected by frequent clinic visits and a transtelephonic monitoring device with weekly and symptomatic transmissions.ResultsEighty-five percent of patients had a history of hypertension, and the 7.7% had heart failure, left ventricular dysfunction, or both. The mean CHADS2 score was 1.41±0.84. TE and major bleeding events were observed at a low incidence among the overall population at 1-year follow-up (0.97% and 0.81%, respectively). The univariate and multivariable analyses revealed no statistically significant differences in the incidence of TE, major bleeding events or mortality in paroxysmal and persistent AF patients. TE events were more common among women than men (p=0.02). The follow-up examination showed under- or overtreatment with warfarin in many patients, according to guideline suggestions. Warfarin was more frequently prescribed to patients with persistent AF (p<0.0001) and patients with AF recurrences (p<0.0001). AF recurrences were noninvasively detected in 632 (51.2%) patients. In patients without AF recurrences, the TE event rate was 0.5% versus 1.74%, 1.28%, and 1.18% for those with only symptomatic, only asymptomatic or both symptomatic and asymptomatic AF recurrences, respectively, but the difference was not statistically significant, even after adjusting for warfarin treatment and the CHADS2 score (HR 2.93; CI 95%; 0.8-10.9; p=0.11).ConclusionsTE and major bleeding events showed a very low incidence in the GISSI-AF trial population, despite under- or overtreatment with warfarin in many patients. TE events had a similar rate in paroxysmal and persistent AF.Trial registrationTrial registration number: NCT00376272