BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

M double-stranded RNA (MdsRNA) plasmid mutants were obtained by mutagenesis and screening of a diploid killer culture partially heat cured of the plasmid, so that a high proportion of the cells could be expected to have only one M plasmid. Mutants with neutral (nonkiller [K-], immune [R+]) or suicide (killer [K+], sensitive [R-]) phenotypes were examined. All mutants became K-Rsensitives on heat curing of the MdsRNA plasmid, and showed cytoplasmic inheritance by random spore analysis. In some cases, M plasmid mutations were indicated by altered mobility of the MdsRNA by agarose gel electrophoresis or by altered size of in vitro translation products from denatured dsRNA. Neutral mutants were of two types: nonsecretors of the toxin protein or secretors of an inactive toxin. Of three neutral nonsecretors examined, one (NLP-1), probably a nonsense mutation, made a smaller protoxin precursor in vitro and in vivo, and two made full-size protoxin molecules. The in vivo protoxin of 43,000 molecular weight was unstable in the wild type and kinetically showed a precursor-product relationship to the processed, secreted 11,000-molecular-weight toxin. In one nonsecretor (N1), the protoxin appeared more stable in a pulse-chase experiment, and could be altered in a recognition site required for protein processing.Killer strains of the yeast Saccharomyces cerevisiae contain M double-stranded RNA (MdsRNA) plasmids encapsidated in a virus-like particle. This MdsRNA codes for a protein toxin and an immunity component. The toxin is secreted and kills sensitive yeast cells devoid of the plasmid (see references 5, 7, and 28 for recent reviews). The toxin appears to be membrane acting (9); it interacts initially with a cell wall receptor (8) and then, in an energy-dependent reaction, causes membrane damage (23). In vitro, in a phospholipid bilayer system, the toxin inserts into the bilayer and forms a pore (B. Kagan, personal communication), and, as in the case of the membrane-acting colicin K (21), this is likely to be the mechanism of action in vivo.The killer toxin system is a useful model for secretion and for events in the interaction of a protein with the cell surface. The existence of mutants in the MdsRNA plasmid that affect toxin or immunity function permits us to make a genetic approach to these problems and to extend work done with chromosomal mutants (1). Although MdsRNA mutations have been described previously (24-26), none but the suppressive sensitive deletions (10) have been examined in detail. Here we examine nine mutants, six defective in toxin activity or secretion and three partially defective in the immunity component. MATERIALS AND METHODSYeast stains and media. The diploid killer strain T158C/S14a (8) was used as the wild type for the production of mutants and as the killer strain in phenotype tests. Sensitive strains used were S6, K19.10, and A8207NK. Neutral mutants Ni and N2 were also used (24).Growth medium was the minimal medium of Halvorson (11) plus 0.5% yeast extract, 0.5% peptone, and 2% dextrose [YEPD ...

In patients with unexplained syncope, the early use of an ILR has a superior diagnostic yield compared with the conventional evaluation strategy, with lower healthcare-related costs.

AAIsafeR2 mode seems to be safe and reliable in patients with infrequent slowing or pauses in ventricular activity, while maintaining ventricular pacing below 1%.

Despite the low long-term incidence of high-degree atrioventricular (AV) block and the known negative effects of ventricular pacing, programming of the AAI mode in patients with sinus node dysfunction (SND) remains exceptional. A new pacing mode was, therefore, designed to combine the advantages of AAI with the safety of DDD pacing. AAIsafeR behaves like the AAI mode in absence of AV block. First- and second-degree AV blocks are tolerated up to a predetermined, programmable limit, and conversion to DDD takes place in case of high-degree AV block. From DDD, the device may switch back to AAI, provided AV conduction has returned. The safety of AAIsafeR was examined in 43 recipients (70 +/- 12-year old, 24 men) of dual chamber pacemakers implanted for SND or paroxysmal AV block. All patients underwent 24-hour ambulatory electrocardiographic recordings before hospital discharge and at 1 month of follow-up with the AAIsafeR mode activated. No AAIsafeR-related adverse event was observed. At 1 month, the device was functioning in AAIsafeR in 28 patients (65%), and the mean rate of ventricular pacing was 0.2%+/- 0.4%. Appropriate switches to DDD occurred in 15 patients (35%) for frequent, unexpected AV block. AAIsafeR mode was safe and preserved ventricular function during paroxysmal AV block, while maintaining a very low rate of ventricular pacing. The performance of this new pacing mode in the prevention of atrial fibrillation will be examined in a large, controlled study.