Atrial remodeling in atrial fibrillation : Epidemiological, clinical and magnetocardiographic aspects

Atrial fibrillation is the most common arrhythmia requiring treatment. This Thesis investigated atrial fibrillation (AF) with a specific emphasis on atrial remodeling which was analysed from epidemiological, clinical and magnetocardiographic (MCG) perspectives. In the first study we evaluated in real-life clinical practice a population-based cohort of AF patients referred for their first elective cardioversion (CV). 183 consecutive patients were included of whom in 153 (84%) sinus rhythm (SR) was restored. Only 39 (25%) of those maintained SR for one year. Shorter duration of AF and the use of sotalol were the only characteristics associated with better restoration and maintenance of SR. During the one-year follow-up 40% of the patients ended up in permanent AF. Female gender and older age were associated with the acceptance of permanent AF. The LIFE-trial was a prospective, randomised, double-blinded study that evaluated losartan and atenolol in patients with hypertension and left ventricular hypertrophy (LVH). Of the 8,851 patients with SR at baseline and without a history of AF 371 patients developed new-onset AF during the study. Patients with new-onset AF had an increased risk of cardiac events, stroke, and increased rate of hospitalisation for heart failure. Younger age, female gender, lower systolic blood pressure, lesser LVH in ECG and randomisation to losartan therapy were independently associated with lower frequency of new-onset AF. The impact of AF on morbidity and mortality was evaluated in a post-hoc analysis of the OPTIMAAL trial that compared losartan with captopril in patients with acute myocardial infarction (AMI) and evidence of LV dysfunction. Of the 5,477 randomised patients 655 had AF at baseline, and 345 patients developed new AF during the follow-up period, median 3.0 years. Older patients and patients with signs of more serious heart disease had and developed AF more often. Patients with AF at baseline had an increased risk of mortality (hazard ratio (HR) of 1.32) and stroke (HR 1.77). New-onset AF was associated with increased mortality (HR 1.82) and stroke (HR of 2.29). In the fourth study we assessed the reproducibility of our MCG method. This method was used in the fifth study where 26 patients with persistent AF had immediately after the CV longer P-wave duration and higher energy of the last portion of atrial signal (RMS40) in MCG, increased P-wave dispersion in SAECG and decreased pump function of the atria as well as enlarged atrial diameter in echocardiography compared to age- and disease-matched controls. After one month in SR, P-wave duration in MCG still remained longer and left atrial (LA) diameter greater compared to the controls, while the other measurements had returned to the same level as in the control group. In conclusion is not a rare condition in either general population or patients with hypertension or AMI, and it is associated with increased risk of morbidity and mortality. Therefore, atrial remodeling that increases the likelihood of AF and also seems to be relatively stable has to be identified and prevented. MCG was found to be an encouraging new method to study electrical atrial remodeling and reverse remodeling. RAAS-suppressing medications appear to be the most promising method to prevent atrial remodeling and AF.

Thrombophilia and direct thrombin inhibitor lepirudin clinical and monitoring aspects

Thrombophilia (TF) predisposes both to venous and arterial thrombosis at a young age. TF may also impact the thrombosis or stenosis of hemodialysis (HD) vascular access in patients with end-stage renal disease (ESRD). When involved in severe thrombosis TF may associate with inappropriate response to anticoagulation. Lepirudin, a potent direct thrombin inhibitor (DTI), indicated for heparin-induced thrombocytopenia-related thrombosis, could offer a treatment alternative in TF. Monitoring of narrow-ranged lepirudin demands new insights also in laboratory. The above issues constitute the targets in this thesis. We evaluated the prevalence of TF in patients with ESRD and its impact upon thrombosis- or stenosis-free survival of the vascular access. Altogether 237 ESRD patients were prospectively screened for TF and thrombogenic risk factors prior to HD access surgery in 2002-2004 (mean follow-up of 3.6 years). TF was evident in 43 (18%) of the ESRD patients, more often in males (23 vs. 9%, p=0.009). Known gene mutations of FV Leiden and FII G20210A occurred in 4%. Vascular access sufficiently matured in 226 (95%). The 1-year thrombosis- and stenosis-free access survival was 72%. Female gender (hazards ratio, HR, 2.5; 95% CI 1.6-3.9) and TF (HR 1.9, 95% CI 1.1-3.3) were independent risk factors for the shortened thrombosis- and stenosis-free survival. Additionally, TF or thrombogenic background was found in relatively young patients having severe thrombosis either in hepatic veins (Budd-Chiari syndrome, BCS, one patient) or inoperable critical limb ischemia (CLI, six patients). Lepirudin was evaluated in an off-label setting in the severe thrombosis after inefficacious traditional anticoagulation without other treatment options except severe invasive procedures, such as lower extremity amputation. Lepirudin treatments were repeatedly monitored clinically and with laboratory assessments (e.g. activated partial thromboplastin time, APTT). Our preliminary studies with lepirudin in thrombotic calamities appeared safe, and no bleeds occurred. An effective DTI lepirudin calmed thrombosis as all patients gradually recovered. Only one limb amputation was performed 3 years later during the follow-up (mean 4 years). Furthermore, we aimed to overcome the limitations of APTT and confounding effects of warfarin (INR of 1.5-3.9) and lupus anticoagulant (LA). Lepirudin responses were assessed in vitro by five specific laboratory methods. Ecarin chromogenic assay (ECA) or anti-Factor IIa (anti-FIIa) correlated precisely (r=0.99) with each other and with spiked lepirudin in all plasma pools: normal, warfarin, and LA-containing plasma. In contrast, in the presence of warfarin and LA both APTT and prothrombinase-induced clotting time (PiCT®) were limited by non-linear and imprecise dose responses. As a global coagulation test APTT is useful in parallel to the precise chromogenic methods ECA or Anti-FIIa in challenging clinical situations. Lepirudin treatment requires multidisciplinary approach to ensure appropriate patient selection, interpretation of laboratory monitoring, and treatment safety. TF seemed to be associated with complicated thrombotic events, in venous (BCS), arterial (CLI), and vascular access systems. TF screening should be aimed to patients with repeated access complications or prior unprovoked thromboembolic events. Lepirudin inhibits free and clot-bound thrombin which heparin fails to inhibit. Lepirudin seems to offer a potent and safe option for treatment of severe thrombosis. Multi-centered randomized trials are necessary to assess the possible management of complicated thrombotic events with DTIs like lepirudin and seek prevention options against access complications.