Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen.

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling.

Inhibition of Na+/H+ Exchanger With EMD 87580 does not Confer Greater Cardioprotection Beyond Preconditioning on Ischemia-Reperfusion Injury in Normal Dogs.

Postischemic accumulation of intracellular Na+ promotes calcium overload and contributes to cellular necrosis. Cardioprotection afforded by pharmacologic blockade of the sodium-hydrogen exchanger subtype 1 (NHE1) is thought to be more remarkable than that obtained by ischemic conditioning (IC). The window of protection provided by IC pretreatment is maintained even when performed up to 48 hours before ischemia. In addition, the perception exists that combined NHE1 inhibition plus IC produces greater than additive protection against ischemic injury. The current study compared the efficacy of NHE1 blockade by N-[2-methyl-4,5-bis(methylsulfonyl)-benzoyl]-guanidine (EMD 87580 5 mg/kg) combined with first- or second-window IC on ischemic tolerance in dogs subject to 90-minute acute ischemia and 180-minute reperfusion. Infarct size (tetrazolium staining), vascular responses, and myocardial perfusion (microspheres) were assessed. EMD 87580 given before ischemia or before reperfusion did not reduce infarct size (compared to vehicle-treated group). Significant protection against tissue necrosis was obtained by both first- and second-window IC, but additive cardioprotection (ie, greater than that afforded by IC) was not observed by treatment with EMD 87580. Vascular reactivity in the infarct-related artery was not preserved after ischemia-reperfusion in any of the experimental groups. Likewise, either the pharmacologic or the nonpharmacologic interventions did not modify myocardial perfusion. These data demonstrate that EMD 87580 did not protect against ischemia-reperfusion injury regardless of the time of drug administration. Combined EMD 87580 and IC did not antagonize protection that was achieved by either first- or second-window IC alone; no additive protection beyond preconditioning was obtained. Further study is necessary to assess the value of NHE1 blockers as protective agents against myocardial injury.

Renocardiac syndromes: physiopathology and treatment stratagems.

PURPOSE OF REVIEW: Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. SOURCES OF INFORMATION: Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. FINDINGS: The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. LIMITATIONS: Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. IMPLICATIONS: Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes.

OBJECTIFS DE LA RÉVISION: Les interactions bidirectionnelles entre organes adjacents sont essentielles au bon fonctionnement du corps humain mais sont aussi susceptibles de provoquer des conditions adverses sur des organes plus éloignés. Cette revue offre un compte rendu sommaire de l'épidémiologie, des mécanismes physiopathologiques et du traitement clinique des patients atteints à la fois d'insuffisance rénale et de cardiopathie, ou tel que récemment désignés, atteints du syndrome cardiorénal de type 3 ou de type 4. La revue examine également des résultats obtenus en recherche fondamentale en utilisant des modèles animaux présentant des cas similaires de comorbidité. SOURCES: Les articles pertinents ont été répertoriés à la suite d'une recherche dans la littérature sur PubMed, MEDLINE et « Google Scholar ¼. Des données complémentaires provenant  d'études du laboratoire de recherche de l'auteur ont aussi été consultées. CONSTATATIONS: Le vieillissement de la population en plus de facteurs de risque incluant l'hypertension, le diabète et la dyslipidémie augmente en partie la prévalence du syndrome cardiorénal à travers le monde. La pathogenèse de ce désordre implique de multiples interactions bidirectionnelles entre le cœur et les reins; cependant, la participation d'organes périphériques n'est tout de même pas à exclure. Nos travaux soutiennent l'hypothèse selon laquelle l'environnement urémique résultant de la dysfonction rénale serait responsable d'altérations majeures dans la régulation de la pression, particulièrement au niveau des microvaisseaux. En résultent une perfusion sanguine altérée et une distribution insuffisante d'oxygène vers les organes. LIMITES DE L'ÉTUDE: La littérature clinique récente comporte de nombreux articles traitant de la nécessité d'identifier et de caractériser de façon plus élaborée les causes du syndrome cardiorénal dans la perspective d'améliorer le traitement clinique des patients qui en sont atteints. Par contre, puisqu'il existe encore très peu d'informations sur l'étiologie du syndrome cardiorénal, les patients ne sont pris en charge qu'après son apparition. Qui plus est, la compréhension des mécanismes impliqués dans la pathogenèse résultant des interactions entre organes demeure un objectif difficile à atteindre, en partie parce que la recherche fondamentale est limitée étant donné la rareté des modèles animaux pour cette pathologie. CONSÉQUENCES: À la lumière des données disponibles à ce jour, il apparait que la préservation de l'intégrité du système vasculaire, particulièrement au niveau des microvaisseaux, est un facteur-clé pour restreindre le développement de désordres impliquant plusieurs organes tel le syndrome cardiorénal. Davantage d'études en recherche fondamentale sont requises pour faire la lumière sur les mécanismes physiopathologiques de ce syndrome et développer des traitements efficaces pour en améliorer les résultats cliniques.

Nitric oxide bioavailability affects cardiovascular regulation dependent on cardiac nerve status.

The sympathetic nervous system and nitric oxide (NO) contribute to regulation of vascular tone, blood flow regulation and cardiac function. Intrinsic cardiac neurons are tonically influenced by locally released NO and exogenous NO donors; however, the role of intact central neural connections remains controversial. We investigated the effects of S-nitroso-N-acetylpenicillamine (SNAP) administered into an intracoronary artery near the ventral interventricular ganglionated plexus (VIVGP) to evaluate distribution of myocardial blood flow (MBF) and ventricular function in normal and acute cardiac decentralized dogs. MBF was measured with microspheres during infusion of SNAP (100µM, IC) after systemic administration of 7-nitroindazole (nNOS blocker) followed by N(ω)-nitro-L-arginine methyl ester (LN; non-selective NOS blocker). Cardiac dynamics were not significantly affected by cardiac decentralization; several of these parameters (aortic systolic and diastolic pressures) were significantly increased after systemic administration of LN. Overall SNAP administered to the VIVGP increased blood flow in the anterior LV wall (vs. posterior LV wall) without affecting other cardiodynamic factors. In cardiac decentralized dogs subepicardial blood flow to the anterior LV wall during LN+SNAP was diminished resulting in a significantly higher inner:outer blood flow ratio (index of blood flow uniformity across the LV wall). LV function was not affected by acute cardiac decentralization; however, LV ejection fraction decreased markedly after LN (reduced NO bioavailability). These results validate earlier claims that reduced NO bioavailability imposes an upper limit on myocardial blood flow regulation and its transmural distribution. These effects are exacerbated after disconnection of intrinsic cardiac neurons from intact central neuron connections.

Complications after hip arthroplasty and the association with hospital procedure volume.

BACKGROUND AND PURPOSE: It has been suggested that a higher procedure volume is associated with less complications after hip arthroplasty. In order to investigate the incidence of serious negative outcomes and a possible association with procedure volume, we performed a retrospective nationwide cohort study on total hip replacements in all Dutch hospitals. METHODS: All total hip replacements (n = 50,080) that were identified as primary intervention in all general and university medical centers between January 1, 2002 and October 1, 2004 were included. Primary endpoints of follow-up were mortality and complications during admission, and re-admission within 3 months due to complications. Variables that were assessed as potential risk factor were age, sex, duration of (preoperative) admission, specific diagnosis, acute/non-planned admission, co-morbidity, and hospital procedure volume. RESULTS: Age, sex, and comorbidity were associated with complications and mortality. Additionally, acute admission was a risk factor for mortality but not for complications. There was no linear trend indicating that decreasing volume led to an increasing number of complications, and no statistically sginificant effect for mortality was found. INTERPRETATION: After adjustment for several risk factors, we found that the hospitals performing most hip procedures every year had fewer complications during index admission, but that they did not have a lower mortality than groups performing fewer procedures. The lack of a linear trend may be explained by the fact that almost all Dutch hospitals perform a high number of hip arthroplasties each year.

Modulation of nitric oxide affects myocardial perfusion-contraction matching in anaesthetized dogs with recurrent no-flow ischaemia.

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Eccentric overload training in patients with chronic Achilles tendinopathy: a systematic review.

BACKGROUND: Eccentric overload training seems to be a promising conservative intervention in patients with chronic Achilles tendinopathy. The efficacy of eccentric overload training on the outcome measures of pain and physical functioning are not exactly clear. STUDY DESIGN: Systematic review of the literature. METHODS: Electronic databases were searched for randomised clinical trials concerning eccentric overload training in patients with chronic Achilles tendinopathy. The Delphi list was used to assess the methodological quality of the studies. RESULTS: Nine clinical trials were included. Only one study had sufficient methodological quality. The included trials showed an improvement in pain after eccentric overload training. Because of the methodological shortcomings of the trials, no definite conclusion can be drawn concerning the effects of eccentric overload training in patients with chronic Achilles tendinopathy. CONCLUSION: The effects of eccentric exercise training in patients with chronic Achilles tendinopathy on pain are promising; however, the magnitude of the effects cannot be determined. Large, methodologically sound studies from multiple sites in which functional outcome measures are included are warranted.

Corticosteroids and the risk of atrial fibrillation.

BACKGROUND: High-dose (pulse) corticosteroid therapy has been associated with the development of atrial fibrillation. This association, however, is mainly based on case reports. METHODS: To test the hypothesis that high-dose corticosteroid exposure increases the risk of new-onset atrial fibrillation, we performed a nested case-control study within the Rotterdam Study, a population-based cohort study among 7983 older adults. Cases were defined as persons with incident atrial fibrillation between July 1, 1991, and January 1, 2000. Their date of diagnosis was defined as the index date. All noncases within the Rotterdam Study who were alive and eligible on this index date were used as controls. Subsequently, we compared the proportion of cases and controls that received a corticosteroid prescription within 1 month preceding the index date. Corticosteroid exposure was categorized into high-dose exposure (oral or parenteral steroid at a daily dose > or =7.5 mg of prednisone equivalents) and low-intermediate-dose exposure (<7.5 mg of prednisone equivalents or inhaled corticosteroids). RESULTS: There were 385 eligible cases of new-onset atrial fibrillation during the study period. The risk of new-onset atrial fibrillation was significantly higher for persons who received a corticosteroid prescription within 1 month before the index date than for those without (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.38-5.87). However, only high-dose corticosteroid use was associated with an increased risk (OR, 6.07; 95% CI, 3.90-9.42), whereas low-intermediate-dose use was not (OR, 1.42; 95% CI, 0.72-2.82). The association of atrial fibrillation with high-dose corticosteroid use was largely independent of the indication for corticosteroid therapy, since the risk of new-onset atrial fibrillation was not only increased in patients with asthma or chronic obstructive pulmonary disease (OR, 4.02; 95% CI, 2.07-7.81) but also in patients with rheumatic, allergic, or malignant hematologic diseases (OR, 7.90; 95% CI, 4.47-13.98). CONCLUSION: Our findings strongly suggest that patients receiving high-dose corticosteroid therapy are at increased risk of developing atrial fibrillation.

Prolonged QTc interval and risk of sudden cardiac death in a population of older adults.

OBJECTIVES: This study sought to investigate whether prolongation of the heart rate-corrected QT (QTc) interval is a risk factor for sudden cardiac death in the general population. BACKGROUND: In developed countries, sudden cardiac death is a major cause of cardiovascular mortality. Prolongation of the QTc interval has been associated with ventricular arrhythmias, but in most population-based studies no consistent association was found between QTc prolongation and total or cardiovascular mortality. Only very few of these studies specifically addressed sudden cardiac death. METHODS: This study was conducted as part of the Rotterdam Study, a prospective population-based cohort study that comprises 3,105 men and 4,878 women aged 55 years and older. The QTc interval on the electrocardiogram was determined during the baseline visit (1990 to 1993) and the first follow-up examination (1993 to 1995). The association between a prolonged QTc interval and sudden cardiac death was estimated using Cox proportional hazards analysis. RESULTS: During an average follow-up period of 6.7 years (standard deviation, 2.3 years) 125 patients died of sudden cardiac death. An abnormally prolonged QTc interval (>450 ms in men, >470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3). CONCLUSIONS: Abnormal QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death.

Mortality in patients with hypertension on angiotensin-I converting enzyme (ACE)-inhibitor treatment is influenced by the ACE insertion/deletion polymorphism.

BACKGROUND: The response to angiotensin-I converting enzyme (ACE)-inhibitor therapy is highly variable. Residual ACE activity during treatment, potentially modified by the ACE insertion/deletion (I/D) polymorphism, may explain part of this variability. We studied the possible interaction between ACE-inhibitor therapy in patients with hypertension and the ACE I/D polymorphism in incident heart failure and death. METHODS: We studied 3365 hypertensive participants of the population-based Rotterdam Study, without heart failure at baseline for whom ACE-genotyping was successful. Incident heart failure was defined according to established criteria. In addition, total and cardiovascular mortality were studied as endpoints. A Cox regression model with use of ACE-inhibitors defined as time-dependent covariates was used for data-analysis. Interaction was tested in this model assuming an allele-effect relationship. RESULTS: Although we could not demonstrate a beneficial effect of ACE-inhibitors, there was significant interaction between the ACE I/D polymorphism (II-ID-DD) and ACE-inhibitor use in the prediction of total and cardiovascular mortality. Mortality risk associated with treatment increased with the number of D alleles present; e.g. for total mortality in the II genotype group: RR=0.95 (95% CI 0.63-1.45), in the ID genotype group: RR=1.08 (95% CI 0.84-1.38) and in the DD genotype group: RR=1.61 (95% CI 1.18-2.18). No statistically significant interaction was found for incident heart failure. CONCLUSION: The results of our study suggest a relative resistance to ACE-inhibitor therapy in subjects with hypertension and the DD genotype compared to the II genotype, with the ID genotype in an intermediate position.

Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation.

OBJECTIVES: The objectives were to study the absorption kinetics and pharmacodynamics of two oral formulations of flecainide in patients with atrial fibrillation (AF) and to assess the relationship between pharmacokinetic parameters and the efficacy in restoring sinus rhythm. METHODS: The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption. RESULTS: The tablets gave a maximum concentration (C (max\ fit)) of 0.43+/-0.14 mg/l at 2.37+/-1.20 h. The oral solution resulted in a much faster peak concentration at 1.05+/-0.71 h (P<0.0001). The C (max\ fit) of the oral solution of 0.60+/-0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C (max\ fit) were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities. CONCLUSIONS: The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.

Drug-induced atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained rhythm disorder observed in clinical practice and predominantly associated with cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce AF in patients without apparent heart disease or may precipitate the onset of AF in patients with preexisting heart disease. We reviewed the literature on drug-induced AF, using the PubMed/Medline and Micromedex databases and lateral references. Successively, we discuss the potential role in the onset of AF of cardiovascular drugs, respiratory system drugs, cytostatics, central nervous system drugs, genitourinary system drugs, and some miscellaneous agents. Drug-induced AF may play a role in only a minority of the patients presenting with AF. Nevertheless, it is important to recognize drugs or other agents as a potential cause, especially in the elderly, because increasing age is associated with multiple drug use and a high incidence of AF. This may contribute to timely diagnosis and management of drug-induced AF.

Rate control is more cost-effective than rhythm control for patients with persistent atrial fibrillation--results from the RAte Control versus Electrical cardioversion (RACE) study.

Aims To evaluate costs between a rate and rhythm control strategy in persistent atrial fibrillation. Methods and results In a prospective substudy of RACE (Rate control versus electrical cardioversion for persistent atrial fibrillation) in 428 of the total 522 patients (206 rate control and 222 rhythm control), a cost-minimisation and cost-effectiveness analysis was performed to assess cost-effectiveness of the treatment strategies. After a mean follow-up of 2.3+/-0.6 years, the primary endpoint (cardiovascular morbidity and mortality) occurred in 17.5% (36/202) of the rate control patients and in 21.2% (47/222) of the rhythm control patients. Mean costs per patient under rate control were euro 7386 and euro 8284 under rhythm control. Cost-effectiveness analysis showed that per avoided endpoint under rate control, the cost savings were euro 24944. Under rhythm control, more costs were generated due to electrical cardioversions, hospital admissions and anti-arrhythmic medication. Costs were higher in older patients, patients with underlying heart disease, those who reached a primary endpoint and women. Heart rhythm at the end of study, did not influence costs. Conclusions Rate control is more cost-effective than rhythm control for treatment of persistent atrial fibrillation. Underlying heart disease but not heart rhythm largely accounts for costs.

Antipsychotics and the risk of sudden cardiac death.

BACKGROUND: Antipsychotics have been associated with prolongation of the corrected QT interval and sudden cardiac death. Only a few epidemiological studies have investigated this association. We performed a case-control study to investigate the association between use of antipsychotics and sudden cardiac death in a well-defined community-dwelling population. METHODS: We performed a population-based case-control study in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from 150 general practitioners. All instances of death between January 1, 1995, and April 1, 2001, were reviewed. Sudden cardiac death was classified based on time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, sex, date of sudden death, and practice. Exposure at the index date was categorized as 3 mutually exclusive groups of current use, past use, and nonuse. RESULTS: The study population comprised 554 cases of sudden cardiac death. Current use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death. The risk of sudden cardiac death was highest among those using butyrophenone antipsychotics, those with a defined daily dose equivalent of more than 0.5 and short-term (

Oral antiarrhythmic drugs in converting recent onset atrial fibrillation.

AIM: This article reviews clinical studies on oral antiarrhythmic drugs in converting recent onset atrial fibrillation. An oral loading dose of an antiarrhythmic drug for cardioversion of atrial fibrillation could be an option, due to its simplicity, both for patients admitted to outpatient departments and for episodic treatment by self administration outside the hospital. The latter treatment strategy has recently been pointed out by the American College of Cardiology, the American Heart Association and the European Society of Cardiology as the 'pill in the pocket approach'. METHODS: Articles were identified by Medline 1966 to November 2001 and Embase 1966 to November 2001. Randomized studies of oral antiarrhythmic drugs versus placebo or comparative treatment, which are written in the English language, were selected. Non-randomized or non-comparative studies were selected if the results of an analysis to identify predictors for successful conversion are described. The review of clinical trials is followed by a description of pharmacokinetic parameters of the antiarrhythmic drugs. RESULTS: Studies meeting the inclusion criteria were on propafenone, flecainide, sotalol, amiodarone, quinidine, digoxin and verapamil. Conversion rates of a single oral loading dose of 600 mg propafenone varied between 37% and 41% at 4 h after ingestion. Propafenone was more effective than quinidine, amiodarone and placebo. A single oral dose of 300 mg flecainide restored sinus rhythm in 59% and 68% of patients at 3 h. Flecainide was more effective than amiodarone and placebo. Oral sotalol, digoxin and verapamil were not effective in converting atrial fibrillation to sinus rhythm. CONCLUSION: Propafenone and flecainide are effective in converting recent onset atrial fibrillation. No serious ventricular arrhythmia, other serious proarrhythmic effects or serious non cardiac adverse events were observed. Regular supraventricular tachyarrhythmias with 1:1 AV conduction were rare and were also observed in placebo treated patients. Propafenone and flecainide are more effective in patients with atrial fibrillation of less than 24 h. The association between cardioversion and patient characteristics are not consistent between studies. The pharmacokinetics of flecainide, with lower interindividual variability of absorption kinetics, no genetically determined formation of an active metabolite and a more rapid distribution to myocardial tissue, are more favourable for episodic treatment as compared to propafenone. Both flecainide and propafenone are safe in hospitalized patients. Out of hospital self administration of antiarrhythmic drugs, also described as the 'pill in the pocket approach', could be an option for selected patients, after the treatment has proven to be safe in hospital.

Apolipoprotein E epsilon4 allele is associated with left ventricular systolic dysfunction.

BACKGROUND: Apolipoprotein (APOE) epsilon4 allele has been associated with cardiac dysfunction in Alzheimer's disease and beta-thalassemia. We investigated the association between APOE genotypes and left ventricular dysfunction in a population of community-dwelling elderly subjects. METHODS: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly subjects. For 2206 participants, a baseline echocardiogram and blood specimens for APOE typing were available. Cardiac dysfunction was considered present when fractional shortening was or=65 years. CONCLUSION: The APOE epsilon4 allele is an independent risk factor for cardiac dysfunction in elderly people. Besides well-known effects on atherosclerosis and cholesterol levels, there may be other mechanisms, such as apoptosis, through which this allele exerts negative effects on myocardial performance.

Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study.

OBJECTIVES: We studied the influence of rate control or rhythm control in patients with persistent atrial fibrillation (AF) on quality of life (QoL). BACKGROUND: Atrial fibrillation may cause symptoms like fatigue and dyspnea. This can impair QoL. Treatment of AF with either rate or rhythm control may influence QoL. METHOD: Quality of life was assessed in patients included in the Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study (rate vs. rhythm control in persistent AF). Rate control patients (n = 175) were given negative chronotropic drugs and oral anticoagulation. Rhythm control patients (n = 177) received serial electrocardioversion, antiarrhythmic drugs, and oral anticoagulation, as needed. Quality of life was studied using the Short Form (SF)-36 health survey questionnaire at baseline, one year, and the end of the study (after 2 to 3 years of follow-up). At baseline, QoL was compared with that of healthy control subjects. Patient characteristics related to QoL changes were determined. RESULTS: Mean follow-up was 2.3 years. At baseline, QoL was lower in patients than in age-matched healthy controls. At study end, under rate control, three subscales of the SF-36 improved. Under rhythm control, no significant changes occurred compared with baseline. At study end, QoL was comparable between both groups. The presence of complaints of AF at baseline, a short duration of AF, and the presence of sinus rhythm (SR) at the end of follow-up, rather than the assigned strategy, were associated with QoL improvement. CONCLUSIONS: Quality of life is impaired in patients with AF compared with healthy controls. Treatment strategy does not affect QoL. Patients with complaints related to AF, however, may benefit from rhythm control if SR can be maintained.

A randomized study of combining maze surgery for atrial fibrillation with mitral valve surgery.

AIM: Mitral valve surgery seldom suppresses atrial fibrillation (AF), present prior to surgery. Maze III surgery eliminates AF in >80% of cases, the reason why combining this procedure with mitral valve surgery in patients with AF seems worthwhile. We prospectively studied the outcome of combining the Maze III procedure with mitral valve surgery. METHODS: Thirty-five patients with AF and a mean age of 64 years undergoing mitral valve surgery were prospectively randomized according to a 2.5:1 ratio to surgery with (n=25), or without (n=10) maze III and followed for at least 1 year. RESULTS: At discharge and after 12 months freedom from AF was 56% and 92%, respectively, in the maze group, and 0% and 20%, respectively, in patients without maze (group differences at discharge p=0.002, after 12 months p=0.0007). Sinus node incompetence was seen in 1 of 25 maze patients requiring pacing. No in-hospital or late death occurred; stroke was observed in 1 patient (without maze). Quality of life markedly improved after surgery, but did not differ between patients with or without maze surgery. CONCLUSIONS: This first prospective randomized study shows that combining maze III with mitral valve surgery resulted in a significantly better elimination of preoperative AF than mitral valve surgery alone. As the quality of life did not differ between patients with, or without maze surgery, additional maze surgery is primarily recommended in patients in whom anticoagulation therapy can be avoided after surgery, specifically in patients with scheduled mitral valve plasty.