External validation and updating of prediction models of bleeding risk in patients with cancer receiving anticoagulants.

OBJECTIVE: Patients with cancer are at increased bleeding risk, and anticoagulants increase this risk even more. Yet, validated bleeding risk models for prediction of bleeding risk in patients with cancer are lacking. The aim of this study is to predict bleeding risk in anticoagulated patients with cancer. METHODS: We performed a study using the routine healthcare database of the Julius General Practitioners' Network. Five bleeding risk models were selected for external validation. Patients with a new cancer episode during anticoagulant treatment or those initiating anticoagulation during active cancer were included. The outcome was the composite of major bleeding and clinically relevant non-major (CRNM) bleeding. Next, we internally validated an updated bleeding risk model accounting for the competing risk of death. RESULTS: The validation cohort consisted of 1304 patients with cancer, mean age 74.0±10.9 years, 52.2% males. In total 215 (16.5%) patients developed a first major or CRNM bleeding during a mean follow-up of 1.5 years (incidence rate; 11.0 per 100 person-years (95% CI 9.6 to 12.5)). The c-statistics of all selected bleeding risk models were low, around 0.56. Internal validation of an updated model accounting for death as competing risk showed a slightly improved c-statistic of 0.61 (95% CI 0.54 to 0.70). On updating, only age and a history of bleeding appeared to contribute to the prediction of bleeding risk. CONCLUSIONS: Existing bleeding risk models cannot accurately differentiate bleeding risk between patients. Future studies may use our updated model as a starting point for further development of bleeding risk models in patients with cancer.

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Female sex as an independent risk factor for stroke in atrial fibrillation: possible mechanisms.

Atrial fibrillation (AF) is an independent risk factor for thromboembolism and stroke. Women with AF are at a higher overall risk for thromboembolic stroke when compared to men with AF. Recent evidence suggests that female sex, after adjusting for stroke risk profile and sex differences in utilisation of anticoagulation, is an independent stroke risk factor in AF. The inclusion of female sex has improved the accuracy of the CHADS2 stroke risk stratification schema (Congestive heart failure, Hypertension, Age 75 years or greater, Diabetes mellitus, and prior Stroke or TIA). The newly revised and validated schema, CHA2DS2-VASc, dichotomises age and incorporates female sex and vascular disease history. The pathophysiological mechanisms to explain this increased risk in women are not well understood. According to Virchow's triad, thrombosis that leads to stroke in AF should arise from three co-existing phenomena: structural abnormalities, blood stasis, and a hypercoagulable state. Herein, we explore the sex differences in the biological processes that lead to thrombus formation as applied to Virchow's Triad. The objective of this review is to describe the potential mechanisms behind the increased risk of stroke in AF associated with female sex.

[Rhythm control as treatment for patients with medication-resistant atrial fibrillation: maze surgery and percutaneous pulmonary vein isolation by catheter ablation]. / Ritmecontrole als behandeling voor patiënten met medicatieresistent boezemfibrilleren: 'maze'-operatie en percutane longvenekatheterisolatie.

In patients with atrial fibrillation, a decision must be made whether to accept the arrhythmia (rate control) or to pursue maintenance of sinus rhythm (rhythm control). Randomized trials have shown no difference between these strategies with respect to morbidity, mortality, and quality of life. In these studies, morbidity and mortality appeared to be related predominantly to the underlying heart disease rather than to the arrhythmia itself. However, other analyses suggest that long-term sinus rhythm may improve prognosis. At any rate, complaints caused by the arrhythmia may definitely be a reason to strive for rhythm control. If pharmacological rhythm control fails, maze surgery, both in patients with lone atrial fibrillation and as concomitant surgery, is highly successful. This, however, necessitates cardiac surgery. New techniques have now emerged, including pulmonary vein isolation by means of percutaneous catheter ablation. This is less invasive and therefore nowadays the treatment of first choice if pharmacological rhythm control has failed.

[Cardiological (pharmaco)therapy and dental practice]. / Cardiologie en tandheelkunde.

In recent years much progress has been made in the treatment of acute coronary syndromes, heart failure and cardiac rhythm disturbances. Polypharmacy including two antiplatelet drugs (aspirin and clopidogrel) is common in many patients after a percutaneous coronary intervention using a 'stent'. Discontinuation of these drugs for invasive dental treatment may result in coronary rethrombosis. However, in many patients with coronary artery disease, a temporal pause in the use of aspirin appears safe and may decrease the risk of bleeding after a dental procedure. An increasing number of patients with heart failure and/or life threatening rhythm disturbances receive an implantable cardioverter defibrillator (ICD). Such a device, equipped with a left ventricular lead, also stimulates the left ventricle in case of delayed electrical conduction (e.g. a left bundle branch block). This so called cardiac resynchronization therapy decreases morbidity and mortality in selected patients. ICDs are safe in the dental office even in case of discharge. In patients with prosthetic heart valves, endocarditis prophylaxis according to the current guidelines is recommended before invasive dental treatment. Dentists are advised to contact the Dutch Thrombosis Service to discuss the dose of oral ancicoagulants and the required INR value. In case of urgent and/or extended dental procedures, admittence to a hospital must be considered to secure optimal therapy.

[Arrhythmogenic right-ventricular cardiomyopathy: different manifestations as precursors of sudden death which might be prevented]. / Aritmogene rechterventrikelcardiomyopathie: verschillende uitingen als voorbode van mogelijk te voorkomen plotse hartdood.

Two men aged 47 and 56 and one woman aged 21 presented at our cardiology department with presyncope, heart failure and exercise induced palpitations, respectively. Using the criteria of McKenna et al., a diagnosis of arrhythmogenic right-ventricular cardiomyopathy (ARVC) was made. Following implantation of a defibrillator, one of the men experienced seven appropriate interventions within six months and also developed psychological problems. The other man was problem-free and the woman recovered reasonably well, having only one appropriate intervention from the defibrillator one year after implantation. Indications of ARVC were also found in her mother but not in any other family members. Because ARVC manifests itself in various different ways it is difficult to diagnose. It is important to consider ARVC in patients with exercise-induced palpitations, presyncope, and unexplained cardiomyopathies or arrhythmias, especially if there is a family history of unexpected deaths. ARVC is a potentially life-threatening disease, that may require implantation of a cardioverter defibrillator. Furthermore, since genetics play an important role and ARVC can be asymptomatic, evaluation of close relatives for preclinical symptoms is important.

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.

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.

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.

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.

Management of atrial fibrillation in the setting of heart failure.

Heart failure is often complicated by atrial fibrillation. Once atrial fibrillation has started it further enhances heart failure due to uncontrolled rate with shortened filling time and provocation of tachycardiomyopathy. Absent atrial kick and irregularity of the ventricular rhythm also contribute. Considering these mechanisms, restoration of sinus rhythm is most beneficial but is associated with frequent recurrences. Before cardioversion heart failure must be treated. ACE inhibition, initiated before cardioversion, may enhance maintenance of sinus rhythm by reducing neurohumoral activation. As a consequence, arrhythmogenic factors diminish and ventricular function may improve. beta-blockade and amiodarone may have similar effects. If cardioversion fails, adequate rate control is mandatory to prevent progressive ventricular dysfunction. Digitalis is the treatment of first choice, but when the heart rate remains uncontrolled low-dose beta-blockade should be given. If the ventricular rate remains uncontrolled despite drugs, atrioventricular node ablation with implantation of a pacemaker may be considered. Not only patients with idiopathic heart failure and atrial fibrillation, but also those with significant underlying heart disease may benefit from this intervention. In atrial fibrillation patients undergoing cardiac surgery for heart failure due to valvular disease, additional arrhythmia surgery may be contemplated.

Efficacy of serial electrical cardioversion therapy in patients with chronic atrial fibrillation after valve replacement and implications for surgery to cure atrial fibrillation.

Chronic atrial fibrillation (AF) occurs often in the setting of mitral and aortic valve disease. Eventually, these patients undergo valve replacement which improves cardiac function but does not prevent AF. This study investigates which patient may benefit from additional surgery for the cure of AF performed in combination with valve surgery. Seventy-four patients were retrospectively included from our prospective database of patients referred for serial cardioversion therapy between 1986 and 1993. All these patients had chronic AF after valve replacement. After the first electrical cardioversion, patients did not receive antiarrhythmic drugs. Relapses were managed by repeated cardioversions, and then antiarrhythmic drugs were instituted. After a median follow-up of 7 years (range 1.3 to 23), 39 patients had intractable AF. Multivariate analysis revealed that patients with a history of chronic AF before surgery (risk ratio 5.4, confidence intervals 2.5 to 11.3, p = 0.0001) had a poor arrhythmia outcome. In addition, Kaplan-Meier survival analysis demonstrated a lower success rate (p = 0.0017) in patients with mitral valve disease than in those with aortic valve disease. Congestive heart failure (41% vs 6%, p = 0.0007) and cardiovascular mortality (23% vs 9%, p = 0.09) were seen most often in patients with an unsuccessful cardioversion strategy. Thus, patients scheduled for mitral valve surgery with a history of chronic AF should be considered candidates for additional surgery for AF concomitantly performed during valve surgery.

Patency of arm vein grafts used in aorto-coronary bypass surgery.

Arm veins have been used in myocardial revascularisation procedures as a last resort bypass conduit because of their associated low patency. Nevertheless, leg veins and mammary arteries, which are the most commonly used, are sometimes not sufficient, leaving little choice as to the bypass conduit. To assess the properties of arm veins in bypass surgery, we compared a group of 28 patients that underwent an arm vein graft coronary bypass procedure with a matched group of patients in which leg veins were used. In 28 patients, 40 arm vein grafts with 77 distal anastomoses were used (mean 1.9 +/- 0.9; range 1-5). A cerebrovascular accident was the cause of the sole death (2%) during the study period. The mean follow-up was 4.6 years (Standard deviation, SD: 1.5 years). More antianginal medication was used in the arm vein group (P = 0.017). Additionally, the percentage of the expected maximal frequency during exercise testing was lower in the arm vein group as compared to the leg vein group. Digital subtraction angiography showed that the patency of the arm vein bypass grafts was 47% (70% confidence limits, CL: 32%-62%) while the patency of the leg vein grafts was 77% (CL: 64%-87%), which was statistically significant (P = 0.051). Comparison of these figures with the few published reports on arm veins used as coronary bypass grafts reveals similar results. We conclude that the arm vein as a coronary bypass graft is only to be used when mammary arteries and leg veins are not available.