Hospital utilisation and the costs associated with complications of ICD implantation in a contemporary primary prevention cohort.

INTRODUCTION: Implantation of an implantable cardioverter defibrillator (ICD) is standard care for primary prevention of sudden cardiac death. However, ICD-related complications are increasing as the population of ICD recipients grows. METHODS: ICD-related complications in a national DO-IT Registry cohort of 1442 primary prevention ICD patients were assessed in terms of additional use of hospital care resources and costs. RESULTS: During a median follow-up of 28.7 months (IQR 25.2-33.7) one or more complications occurred in 13.5% of patients. A complication resulted in a surgical intervention in 53% of cases and required on average 3.65 additional hospital days. The additional hospital costs were €6,876 per complication or €8,110 per patient, to which clinical re-interventions and additional hospital days contributed most. Per category of complications, infections required most hospital utilisation and were most expensive at an average of €22,892. The mean costs were €5,800 for lead-related complications, €2,291 for pocket-related complications and €5,619 for complications due to other causes. We estimate that the total yearly incidence-based costs in the Netherlands for hospital management of ICD-related complications following ICD implantation for primary prevention are €2.7 million. CONCLUSION: Complications following ICD implantation are related to a substantial additional need for hospital resources. When performing cost-effectiveness analyses of ICD implantation, including the costs associated with complications, one should be aware that real-world complication rates may deviate from trial data. Considering the economic implications, strategies to reduce the incidence of complications are encouraged.

Driving restrictions for Dutch patients with an implantable cardioverter defibrillator : Compliance and associated factors.

BACKGROUND: Dutch patients with an implantable cardioverter defibrillator (ICD) are restricted from driving for two months after implantation or shocks. This requires significant lifestyle adjustments and is one of the primary concerns of ICD patients. Previous studies indicated that compliance with the driving restrictions is poor, but insight in socio-demographic, clinical and psychological factors associated with compliance is limited. Hence, this study aimed to explore compliance with the driving restrictions and associated factors in a large sample of Dutch ICD patients. METHOD: Dutch ICD patients (N = 313) completed an elaborative set of questionnaires at time of implantation and at four months after implantation, assessing socio-demographic, psychological and driving-related characteristics. Clinical data were collected from the patients' medical records. RESULTS: A substantial subgroup (28%) of the patient sample (median age 64 (interquartile range = 55-71), 81% male) reported to have been noncompliant with the driving restrictions. Univariate analysis indicated that noncompliant patients more often considered refusing the ICD due to the restrictions, compared to compliant patients (19% versus 10%, p = 0.02). Multivariate analysis showed that the feeling of understanding the reason behind the driving restrictions was associated with better compliance (odds ratio = 2.16, 95% confidence interval 1.02-4.56, p = 0.04). No other socio-demographic, clinical, psychological or driving-related factors were associated with compliance. CONCLUSION: A large number of ICD patients does not comply with the driving restrictions after implantation. This study emphasised the importance of the patient's feeling of understanding the reason behind the restrictions.

Dutch outcome in implantable cardioverter-defibrillator therapy (DO-IT): registry design and baseline characteristics of a prospective observational cohort study to predict appropriate indication for implantable cardioverter-defibrillator.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are widely used for the prevention of sudden cardiac death. At present, both clinical benefit and cost-effectiveness of ICD therapy in primary prevention patients are topics of discussion, as only a minority of these patients will eventually receive appropriate ICD therapy. METHODS/DESIGN: The DO-IT Registry is a nationwide prospective cohort with a target enrolment of 1,500 primary prevention ICD patients with reduced left ventricular function in a setting of structural heart disease. The primary outcome measures are death and appropriate ICD therapy for ventricular tachyarrhythmias. Secondary outcome measures are inappropriate ICD therapy, death of any cause, hospitalisation for ICD related complications and for cardiovascular reasons. As of December 2016, data on demographic, clinical, and ICD characteristics of 1,468 patients have been collected. Follow-up will continue up to 24 months after inclusion of the last patient. During follow-up, clinical and ICD data are collected based on the normal follow-up of these patients, assuming ICD interrogations take place every six months and clinical follow-up is once a year. At baseline, the mean age was 66 (standard deviation [SD] 10) years and 27% were women. CONCLUSION: The DO-IT Registry represents a real-world nationwide cohort of patients receiving ICDs for primary prevention of sudden cardiac death with reduced left ventricular function in a setting of structural heart disease. The registry investigates the efficacy of the current practice and aims to develop prediction rules to identify subgroups who will not (sufficiently) benefit from ICD implantation and to provide results regarding costs and budget impact of targeted supply of primary preventions ICDs.

"Are CRT upgrade procedures more complex and associated with more complications than de novo CRT implantations?" A single centre experience.

OBJECTIVE: The objective of the study was to examine whether cardiac resynchronisation therapy upgrade procedures are more complex and associated with more complications than de novo implantations. METHOD: We retrospectively compared 134 upgrade procedures performed between 2006-2012 with a random, equally sized, sample of de novo CRT device implantations in the same period. Procedural data and the occurrence of periprocedural (≤ 30 days) and long-term device-related (≤ 1 year) complications were analysed. Complications with consequences were defined as those in need of adjustment of standard care. RESULTS: Median time to upgrade was 57 (31-115) months. There were no significant differences in procedure duration, radiation time or total hospitalisation between upgrades and de novo implantations. Perioperative complications occurred in 6.7 % of upgrade patients and in 9.0 % of de novo patients. The most frequently seen complications were phrenic nerve stimulation, coronary sinus dissection and pocket haematoma. Procedure success was comparable (upgrade: 98.5 % versus de novo: 96.3 %). A total of 236 patients completed 1 year of follow-up. Ten (4.2 %) patients had a long-term device-related complication with consequences including phrenic nerve stimulation, lead dislodgement/dysfunction, and infection (upgrade: 3.5 % versus de novo: 4.9 %). CONCLUSION: Upgrade procedures are not more complex nor associated with more complications than de novo CRT implantations.

Implementation of guidelines for implantable cardioverter-defibrillator therapy in clinical practice: Which patients do benefit?

PURPOSE: Based on multiple large clinical trials conducted over the last decades guidelines for implantable cardioverter-defibrillator (ICD) implantations have been evolving. The increase in primary prophylactic ICD implantations challenges us to be critical towards the indications in certain patient populations. METHODS: We retrospectively collected patient characteristics and rates of appropriate and inappropriate ICD therapy, appropriate and inappropriate ICD shock and mortality of all patients who received an ICD in the University Medical Center Utrecht (UMCU) over the years 2006-2011. RESULTS: A total of 1075 patients were included in this analysis (74 % male, mean age 61 ± 13 years, left ventricular ejection fraction 30 ± 13 %); 61 % had a primary indication and 58 % had ischaemic heart disease. During a mean follow-up period of 31 ± 17 months, 227 of the patients (21 %) received appropriate ICD therapy (149 (14 %) patients received an appropriate ICD shock). Females, patients with a primary prophylactic indication and patients with non-ischaemic heart disease experienced significantly less ICD therapy. Only a few patients (54, 5 %) received inappropriate ICD therapy; 33 (3 %) patients received an inappropriate ICD shock. Fifty-five patients died within one year after ICD implantation and were therefore, in retrospect, not eligible for ICD implantation. CONCLUSION: Our study confirms the benefit of ICD implantation in clinical practice. Nevertheless, certain patients experience less benefit than others. A more patient-tailored risk stratification based on electrophysiological parameters would be lucrative to improve clinical benefit and cost-effectiveness.

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

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels.

OBJECTIVES: Our purpose was to determine whether patients with persistent atrial fibrillation (AF) and patients with paroxysmal AF show alterations in potassium channel expression. BACKGROUND: Persistent AF is associated with a sustained shortening of the atrial action potential duration and atrial refractory period. Underlying molecular changes have not been studied in humans. We investigated whether a changed gene expression of specific potassium channels is associated with these changes in patients with persistent AF and in patients with paroxysmal AF. METHODS: Right atrial appendages were obtained from 8 patients with paroxysmal AF, 10 with persistent AF and 18 matched controls in sinus rhythm. All controls underwent coronary artery bypass surgery, whereas most AF patients underwent Cox's MAZE surgery (atrial arrhythmia surgery to cure AF) (n = 12). All patients had normal left ventricular function. mRNA (ribonucleic acid) levels were measured by semiquantitative polymerase chain reaction and protein content by Western blotting. RESULTS: mRNA levels of transient outward channel (Kv4.3), acetylcholine-dependent potassium channel (Kir3.4) and ATP-dependent potassium channel (Kir6.2) were reduced in patients with persistent AF (-35%, -47% and -36%, respectively, p < 0.05), whereas only Kv4.3 mRNA level was reduced in patients with paroxysmal AF (-29%, p = 0.03). No changes were found for Kv1.5 and HERG mRNA levels in either group. Protein levels of Kv4.3, Kv1.5 and Kir3.1 were reduced both in patients with persistent AF (-39%, -84% and -47%, respectively, p < 0.05) and in those with paroxysmal AF (-57%, -64%, and -40%, respectively, p < 0.05). CONCLUSIONS: Persistent AF is accompanied by reductions in mRNA and protein levels of several potassium channels. In patients with paroxysmal AF these reductions were observed predominantly at the protein level and not at the mRNA level, suggesting a post-transcriptional regulation.

Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation.

OBJECTIVE: Persistent atrial fibrillation (AF) results in an impairment of atrial function. In order to elucidate the mechanism behind this phenomenon, we investigated the gene expression of proteins influencing calcium handling. METHODS: Right atrial appendages were obtained from eight patients with paroxysmal AF, ten with persistent AF (> 8 months) and 18 matched controls in sinus rhythm. All controls underwent coronary artery bypass grafting, whereas most AF patients underwent Cox's MAZE surgery (n = 12). All patients had a normal left ventricular function. Total RNA was isolated and reversely transcribed into cDNA. In a semi-quantitative polymerase chain reaction the cDNA of interest and of glyceraldehyde-3-phosphate dehydrogenase were coamplified and separated by ethidium bromide-stained gel electrophoresis. Slot blot analysis was performed to study protein expression. RESULTS: L-type calcium channel alpha 1 and sarcoplasmic reticulum Ca(2+)-ATPase mRNA (-57%, p = 0.01 and -28%, p = 0.04, respectively) and protein contents (-43%, p = 0.02 and -28%, p = 0.04, respectively) were reduced in patients with persistent AF compared to the controls. mRNA contents of phospholamban, ryanodine receptor type 2 and sodium/calcium exchanger were comparable. No changes were observed in patients with paroxysmal AF. CONCLUSIONS: Alterations in gene expression of proteins involved in the calcium homeostasis occur only in patients with long-term persistent AF. In the absence of underlying heart disease, the changes are rather secondary than primary to AF.

Pharmacologic versus direct-current electrical cardioversion of atrial flutter and fibrillation.

Conversion of atrial flutter and atrial fibrillation (AF) can be achieved by either pharmacologic or direct-current (DC) electrical cardioversion. DC electrical cardioversion is more effective and restores sinus rhythm instantaneously; however, general anesthesia is necessary, which can cause severe complications. On the other hand, pharmacologic cardioversion is less effective. First, time to conversion is unpredictable and may be relatively long, especially with oral drug therapy. Also, the rate of conversion is lower and depends on duration of AF. In addition, safety is an important issue. Adverse drug reactions include bradycardia, paradoxical tachycardia due to enhanced atrioventricular conduction, ventricular proarrhythmia, and acute heart failure. In paroxysmal AF, drug therapy is usually aimed at an acute conversion. Class IA and IC drugs are more efficacious than the class III drugs sotalol, amiodarone, and ibutilide. By contrast, class III drugs are more effective for the conversion of atrial flutter. Acute conversion out-of-hospital ("pill in the pocket approach") should be done only if the drug used appeared effective and safe after a few in-hospital trials. In persistent AF, DC conversion is preferred because drugs are particularly ineffective if the arrhythmia has lasted >24-48 hours. The latter probably relates to electrical and anatomical remodeling of the atria during ongoing atrial fibrillation and flutter. Nevertheless, a wait-and-see approach using, for example, oral amiodarone may be adopted with late DC conversion if the drug fails to convert persistent AF. However, the consequences of remodeling seem to dictate an early conversion. In this respect, echocardiography-guided DC cardioversion may become increasingly important in AF. It will prevent treatment resistance and potentially reduces embolic complications. In a hybrid approach, antiarrhythmic drugs may be used to enhance DC conversion and prevent (sub)acute recurrences of AF. However, it may increase the defibrillation threshold, especially if class IC drugs are used. New treatment options such as automatic defibrillation (implantable atrioverter) are still investigational.

Comparison of plasma neurohormones in congestive heart failure patients with atrial fibrillation versus patients with sinus rhythm.

Plasma atrial natriuretic peptide and endothelin are further elevated in patients with congestive heart failure and atrial fibrillation, compared to those with sinus rhythm. The higher plasma endothelin suggests that vasoconstriction is an important mechanism for hemodynamic compensation in these patients.

Heart failure and atrial fibrillation: current concepts and controversies.

Heart failure and atrial fibrillation are very common, particularly in the elderly. Owing to common risk factors both disorders are often present in the same patient. In addition, there is increasing evidence of a complex, reciprocal relation between heart failure and atrial fibrillation. Thus heart failure may cause atrial fibrillation, with electromechanical feedback and neurohumoral activation playing an important mediating role. In addition, atrial fibrillation may promote heart failure; in particular, when there is an uncontrolled ventricular rate, tachycardiomyopathy may develop and thereby heart failure. Eventually, a vicious circle between heart failure and atrial fibrillation may form, in which neurohumoral activation and subtle derangement of rate control are involved. Treatment should aim at unloading of the heart, adequate control of ventricular rate, and correction of neurohumoral activation. Angiotensin converting enzyme inhibitors may help to achieve these goals. Treatment should also include an attempt to restore sinus rhythm through electrical cardioversion, though appropriate timing of cardioversion is difficult. His bundle ablation may be used to achieve adequate rate control in drug refractory cases.

Cardioversion of atrial fibrillation in the setting of mild to moderate heart failure.

We investigated the effect of electrical cardioversion of atrial fibrillation in patients with heart failure. The study group consisted of 24 patients with mild to moderate heart failure [13 men, mean age 67+/-7 years, mean peak oxygen consumption (peak VO2) 16.3+/-2.8 ml/min/kg] and chronic atrial fibrillation (median duration 19 (1-228) months). Patients were stable on digoxin, diuretics, nitrates and angiotensin converting enzyme inhibitors; no prophylaxis with antiarrhythmics was started after cardioversion. Cardioversion was unsuccessful in 6 patients; of the 18 patients in whom sinus rhythm was obtained 9 had a relapse of atrial fibrillation within 6 weeks after cardioversion. The remaining 9 patients with maintenance of sinus rhythm and the 15 (6+9) patients with atrial fibrillation at follow-up after 6 weeks did not differ with respect to any baseline characteristic, including age, peak VO2, duration of atrial fibrillation, echocardiographic left ventricular and left atrial dimensions, plasma atrial natriuretic peptide and norepinephrine. In the patients with maintenance of sinus rhythm, baseline measurements were repeated at follow-up. Peak VO2 did not change significantly (16.7+/-2.8 to 17.6+/-3.3 ml/min/kg, P=0.29); also, echo parameters, atrial natriuretic peptide and norepinephrine were not significantly affected. These results indicate that it is difficult to achieve lasting sinus rhythm through electrical cardioversion in patients with atrial fibrillation and mild to moderate heart failure. Moreover, in patients with maintenance of sinus rhythm after cardioversion no significant benefit in terms of peak VO2, cardiac dimensions, and neurohumoral status is to be expected. Hence, indiscriminate cardioversion of atrial fibrillation in the setting of heart failure does not appear to be useful.

Impaired autonomic function predicts dizziness at onset of paroxysmal atrial fibrillation.

BACKGROUND: Paroxysmal atrial fibrillation is associated with various symptoms, including dizziness, which presumably reflects hemodynamic deterioration. Given the importance of the autonomic nervous system in mitigating the hemodynamic effect of atrial fibrillation, we hypothesized that autonomic function would be predictive of the severity of dizziness. METHODS: The study group comprised 73 patients with paroxysmal atrial fibrillation (mean age 54.1 years, 51 males). Forty-three (59%) patients had lone atrial fibrillation. Mean ventricular rate during atrial fibrillation was 99+/-16 beats/min. On average, patients had a 3-year history of one paroxysm per week lasting 2 h. Autonomic function was assessed using autonomic function tests, including noninvasive measurement of baroreflex sensitivity. Head up tilting was used to test vasovagal reactivity. Severity of dizziness at onset of atrial fibrillation was quantified by the patients using a five-point scale (1=none; 2=light; 3=mild; 4=moderate; and 5=severe). Multivariate analysis was performed to identify the independent predictors of the severity of dizziness. RESULTS: Mean severity of dizziness was 3.36+/-1.65. Multivariate predictors of moderate-to-severe dizziness as opposed to none-to-mild dizziness were a low 30-15 ratio after standing up and low baroreflex sensitivity. Though syncope was never reported nine patients showed a full vasovagal response during head up tilting. CONCLUSIONS: It is concluded that dizziness in patients with "treated" atrial fibrillation in the setting of none to mild structural heart disease is predicted by impaired autonomic function. Vasovagal reactivity appears not to be involved in this connection.

Effect of timolol on the amplitude and dynamics of accommodation.

There is still debate about whether the ciliary muscle is innervated by the sympathetic nervous system. We investigated the amplitude and the dynamics of accommodation under influence of the non-selective beta-blocker timolol. For this purpose the variations in thickness of the human lens during step-like changes in accommodation were measured with high-resolution A-scan echography. Results showed that the dynamics of accommodation, expressed in the time constants of the response, were affected as well as the amplitude.

Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation.

OBJECTIVE: To investigate the occurrence of heart failure complications, and to identify variables that predict heart failure in patients with (recurrent) persistent atrial fibrillation, treated aggressively with serial electrical cardioversion and antiarrhythmic drugs to maintain sinus rhythm. DESIGN: Non-randomised controlled trial; cohort; case series; mean (SD) follow up duration 3.4 (1.6) years. SETTING: Tertiary care centre. SUBJECTS: Consecutive sampling of 342 patients with persistent atrial fibrillation (defined as > 24 hours duration) considered eligible for electrical cardioversion. INTERVENTIONS: Serial electrical cardioversions and serial antiarrhythmic drug treatment, after identification and treatment of underlying cardiovascular disease. MAIN OUTCOME MEASURES: heart failure complications: development or progression of heart failure requiring the institution or addition of drug treatment, hospital admission, or death from heart failure. RESULTS: Development or progression of heart failure occurred in 38 patients (11%), and 22 patients (6%) died from heart failure. These complications were related to the presence of coronary artery disease (p < 0.001, risk ratio 3.2, 95% confidence interval (CI) 1.6 to 6.5), rheumatic heart disease (p < 0.001, risk ratio 5.0, 95% CI 2.4 to 10.2), cardiomyopathy (p < 0.001, risk ratio 5.0, 95% CI 2.0 to 12.4), atrial fibrillation for < 3 months (p = 0.04, risk ratio 2.0, 95% CI 1.0 to 3.7), and poor exercise tolerance (New York Heart Association class III at inclusion, p < 0.001, risk ratio 3.5, 95% CI 1.9 to 6. 7). No heart failure complications were observed in patients with lone atrial fibrillation. CONCLUSIONS: Aggressive serial electrical cardioversion does not prevent heart failure complications in patients with persistent atrial fibrillation. These complications are predominantly observed in patients with more severe underlying cardiovascular disease. Randomised comparison with rate control treatment is needed to define the optimal treatment for persistent atrial fibrillation in relation to heart failure.

VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation.

INTRODUCTION: Many relapses of atrial fibrillation (AF) occur, especially during the first week(s) after electrical cardioversion (ECV). The aim of the present study was to compare in a randomized design the efficacy of verapamil (intracellular calcium lowering) versus digoxin (calcium increasing) for maintenance of sinus rhythm after ECV. METHODS AND RESULTS: Ninety-seven patients with persistent AF were randomized to verapamil (n = 49) or digoxin (n = 48) for 1 month before and 1 month after ECV. The first month after ECV, patients recorded heart rhythm using daily transtelephonic monitoring. No additional antiarrhythmic drugs were given. Of the 97 patients, 43 patients (20 verapamil) underwent ECV per protocol. Median previous AF duration was 18 and 26 days for verapamil and digoxin, respectively. There were no differences in atrial dimensions and underlying heart disease between the two groups. The success rate of ECV was 75% versus 83% (P = NS). After 1 month, 47% versus 53% (P = NS) had recurrence of AF. Median time to recurrence was 5 days (range 0 to 26) versus 8 days (range 2 to 28) (P = NS), respectively. CONCLUSION: Stand-alone intracellular calcium lowering by verapamil around ECV does not enhance cardioversion outcome.

Mini-maze suffices as adjunct to mitral valve surgery in patients with preoperative atrial fibrillation.

INTRODUCTION: After mitral valve (MV) surgery, preoperative atrial fibrillation (AF) often recurs while cardioversion therapy generally fails. Additional Cox maze surgery improves postoperative arrhythmia outcome, but the extensive nature of such an approach limits general appliance. We investigated the clinical outcome of a simplified, less extensive Cox maze procedure ("mini-maze") as adjunct to MV surgery. METHODS AND RESULTS: Thirteen patients with MV disease and preoperative AF were treated with combined surgery (group 1). Nine control patients without previous AF underwent isolated MV surgery (group 2). We retrospectively compared the results to findings in 23 patients with preoperative AF who had undergone isolated MV surgery (group 3). In group 1, mini-maze took an additional 46 minutes of perfusion time. One 75-year-old patient died of postoperative multiple organ failure. Seven patients showed spontaneously converting (within 2 months) postoperative AF. After 1 year, 82% were in sinus rhythm (SR). No sinus node dysfunction was observed. In group 2, all patients were in SR after 1 year. In group 3, only 53% were in SR after 1 year, despite serial cardioversion and antiarrhythmic drug therapy. Exercise tolerance and heart rate were comparable for groups 1 and 2. Left atrial function was present in all but one patient in group 1 and in all patients in group 2 (after MV reconstruction). CONCLUSION: Adding a relatively simple mini-maze to MV surgery improves arrhythmia outcome in patients with preoperative AF without introducing sinus node dysfunction or persistent absence of left atrial function. The results of this type of combined surgery are encouraging and deserve further attention.

Alterations in gene expression of proteins involved in the calcium handling in patients with atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) leads to a loss of atrial contraction within hours to days. During persistence of AF, cellular dedifferentiation and hypertrophy occur, eventually resulting in degenerative changes and cell death. Abnormalities in the calcium handling in response to tachycardia-induced intracellular calcium overload play a pivotal role in these processes. METHODS AND RESULTS: The purpose was to investigate the mRNA expression of proteins and ion channels influencing the calcium handling in patients with persistent AF. Right atrial appendages were obtained from 18 matched controls in sinus rhythm (group 1) and 18 patients with persistent AF undergoing elective cardiac surgery. Previous duration of AF was < or = 6 months in 9 (group 2) and > 6 months in 9 patients (group 3). In a single semiquantitative polymerase chain reaction, the mRNA of interest and of glyceraldehyde-3-phosphate dehydrogenase, were coamplified and separated by gel electrophoresis. L-type calcium channel alpha1 subunit mRNA content was inversely related to the duration of AF: -26% in group 2 compared to group 1 (P = 0.2), and -49% in group 3 compared to group 1 (P = 0.01). Inhibitory guanine nucleotide binding protein ialpha2 mRNA content was reduced in group 3 compared to group 1 (-30%, P = 0.01). Sarcoplasmic reticulum calcium ATPase, phospholamban and sodium-calcium exchanger mRNA contents were not affected by AF. CONCLUSIONS: AF-induced alterations in mRNA contents of proteins and ion channels involved in the calcium handling seem to occur in relation to the previous duration of AF. In the present patient population, these changes were significant only if AF lasted > 6 months.

Gene expression of the natriuretic peptide system in atrial tissue of patients with paroxysmal and persistent atrial fibrillation.

INTRODUCTION: Circulating cardiac natriuretic peptides play an important role in maintaining volume homeostasis, especially during conditions affecting hemodynamics. During atrial fibrillation (AF), levels of plasma atrial natriuretic peptide (ANP) becomes elevated. The aim of this study was to gather information about gene expression of the natriuretic peptide system on the atrial level in patients with AF. METHODS AND RESULTS: Right atrial appendages of 36 patients with either paroxysmal or persistent AF were compared with 36 case matched controls in sinus rhythm for mRNA expression of pro- atrial natriuretic peptide (pro-ANP), pro-brain natriuretic peptide (pro-BNP), and their natriuretic peptide receptor type-A (NPR-A). We investigated patients without (n = 36) and with (n = 36) valvular disease. Persistent AF was associated with higher mRNA expression of pro-BNP (+66%, P = 0.04, in patients without valvular disease, and +69%, P < 0.01, in patients with valvular disease) and lower mRNA expression of NPR-A (-58%, P = 0.02, in patients without valvular disease, and -62 %, P < 0.01, in patients with valvular disease). The mRNA content of pro-ANP was only increased in patients with valvular disease (+12%, P = 0.03). No changes were observed in patients with paroxysmal AF. CONCLUSION: This study demonstrates that persistent, but not paroxysmal, AF induces alterations in gene expression of pro-BNP and NPR-A on the atrial level. Although AF generally is associated with an increase of plasma ANP level, a change in mRNA content of pro-ANP is only observed in the presence of concomitant valvular disease and is of minor magnitude.

Quality of life in patients with paroxysmal atrial fibrillation and its predictors: importance of the autonomic nervous system.

AIMS: To determine the impact of paroxysmal atrial fibrillation on quality of life and to determine the predictors of quality of life, particularly the role of symptomatology and autonomic function. METHODS AND RESULTS: The study group comprised 73 patients with paroxysmal atrial fibrillation (mean age 54.1 years, 51 males). On average, patients had a 3-year history of one paroxysm per week lasting 2 h. Quality of life was assessed using the SF-36 (Medical Outcomes Study Short-Form Health Survey) and compared with age-matched controls. Autonomic function was assessed using Holter monitoring with analysis of heart rate variability and autonomic function tests. Symptoms during paroxysms of atrial fibrillation were also scored. Multivariate analysis was performed to identify independent predictors of quality of life. Quality of life scores were markedly lower in patients than in controls in four of the eight subscales (P<0.001): physical role function, emotional role function, vitality and general health. Structural heart disease did not predict quality of life, whereas frequency of paroxysms was predictive only of physical role function. In contrast, autonomic variables (baroreflex-sensitivity, total power (heart rate variability), response to deep breathing, 30-15 ratio (standing up)) were predictive in all four respective subscales (P<0.05), depressed vagal function being predictive of low scores. Symptoms, particularly severe perspiration, were also predictive of low scores (P<0.05). CONCLUSIONS: This study shows that paroxysmal atrial fibrillation causes significant impairment of quality of life. Further, symptomatology and autonomic function are important predictors of quality of life in this patient group.