A left ventricular (LV) ejection fraction (EF) of ≤ 35% later after myocardial infarction (MI) is principally used to identify patients for implantable cardioverter defibrillator (ICD) therapy. Yet, most patients who die suddenly after MI have LVEFs > 35%. A variety of risk markers have been advocated to identify those at higher risk. Yet, there is a lack of multicenter data to support their use. The Risk Estimation Following Infarction Noninvasive Evaluation - ICD efficacy (REFINE ICD) trial is evaluating whether ICD therapy reduces mortality in post-MI patients with LVEFs of 36% to 50% plus BOTH abnormal cardiac depolarization (T wave alternans; TWA) & impaired autonomic tone (heart rate turbulence; HRT). This ongoing trial includes patients from North America, Europe & the Middle East. Those with both abnormal TWA & HRT are randomized (1:1) to an ICD vs. usual care. In Canada, subjects not eligible for randomization (i.e., normal TWA & / or normal HRT) are followed in a Registry. Hypothesis: We hypothesized that Randomized subjects (i.e., BOTH abnormal TWA & impaired HRT) would have a higher risk of death vs. Registry subjects (i.e., one or both markers normal). Subjects were evaluated 3 to 15 months after MI with a SEER 12 high resolution Holter. Holter data were transmitted to a central core laboratory & analyzed, blinded to clinical data & outcome. Commercial software (MARS) was used to assess TWA & HRT using published criteria. Of 694 subjects, 323 were in the Randomized & 371 in the Registry group. Both the Randomized & Registry groups were enrolled a mean of 7 months after MI, had similar mean ages (64 vs. 60 years) & baseline LVEFs (42% vs. 43%). Randomized subjects were more likely to have prominent heart failure symptoms (6% vs. 2%) & be female (22% vs. 11%). Of the 18 deaths in follow-up, 16 occurred in the Randomized group. The odds of death in Randomized subjects was 9.6 (95% confidence interval 2.8 to 32.5) fold higher vs. Registry subjects (p = 0.0004). The presence of both abnormal cardiac depolarization & impaired autonomic tone in post-MI patients with better-preserved LV function identifies a group with a nearly 10-fold higher risk of death. The REFINE ICD study is testing whether ICD therapy can alter that risk.

Over 250,000 Canadians are living with Cardiac Implantable Electrical Devices (CIEDs). These devices improve survival & reduce morbidity, but their follow-up is resource intensive; both in terms of the healthcare system & recipients (travel, parking & time). Remote Monitoring (RM), CIED follow-up in a patient's home or a centralized area, is an important adjunct to conventional follow-up. Home-based RM has been shown to reduce cost & enhance quality of life without compromising safety. However, centralized RM is less well studied. Centralized RM uses a single device to collect the data from multiple CIEDs centrally (e.g., an emergency department or ED) for the Clinician to review and interpret, similar to a home-based RM encounter. To assess the feasibility, acceptance and impact of CareLink Express[TM], a centralized RM tool, in a large urban region. CareLink Express was implemented at 4 high volume EDs in a large metropolitan area. ED staff identified CIED patients that required evaluation, an ECG technician performed CIED interrogation via CareLink Express & the CIED Clinician on call was notified. The Clinician then reviewed the interrogation from home & reported the results to ED staff and the on call electrophysiologist, as necessary. A total 243 evening and nightshift CareLink Express assessments occurred over 12 months. Most assessments did not require direct assessment by the CIED clinician or electrophysiologist. CareLink Express assessments eliminated an estimated 486 hours of travel and 1,458 hours of Clinician overtime. This resulted in a savings of $54,171. Clinician assessment of CareLink Express was universally positive, with reduced travel time cited as its' main advantage. ECG technician satisfaction was also high. ED length of stay was estimated to be reduced by an average of nearly 4 hours per CareLink Express assessment (total reduction of 785 hours). This reduced ED wait times and resulted in an estimated further cost savings of $51,679. Reliable, comprehensive estimates of costs are complex since our implementation of this tool involved multiple departments, clinics & hospitals. The sources required for costs are being collated and will be available at the time of presentation. Centralized remote monitoring via CareLink Express was easy to implement, perceived as valuable and user friendly & allowed for efficient collection of CIED data. This process reduced staffing costs & travel plus enhanced the care of patients in the ED, resulting in improved ED bed utilization and additional savings.

While many patients exhibit favorable remodeling with cardiac resynchronization therapy (CRT), a significant minority does not. We examined the utility of augmentation of pulse pressure with exercise (reflecting cardiac reserve) to reliably predict remodeling post-CRT. Subjects were studied before and 6 months after CRT in terms of functional class, B-type natriuretic peptide (BNP), 6-minute walk test (6-MWT) distance, left ventricular (LV) ejection fraction (EF) and blood pressure (BP). BP was measured via pulse contour analysis (Nexfin) and inert gas re-breathing Methods (Innocor). LV reverse remodeling was pre-defined as a > 15% reduction in end-systolic volume (ESV). The Mann-Whitney (continuous) and Fisher's exact (categorical) tests were used to compare changes within patients. P-values < 0.05 were considered statistically significant. The median age of the 73 subjects was 68 years, 88% male, 53% had an ischemic etiology, median baseline QRS duration was 155 ms, 88% had class III limitation (median 6MWT distance 296 m) and the median LVEF was 0.27. The 63% with favorable LV remodeling had a median change in pulse pressure post 6MWT of 9.5 mmHg (inter-quartile range [IQR]: 0-18) while those without remodeling had a 2 mmHg change (IQR: -9 - 13); p = 0.047. The 63% of patients with LV remodeling were more likely to have a > 5mm Hg increase in pulse pressure (61%) as compared to the 37% of patients without significant remodeling (37%; p = 0.042). A 5mm Hg or larger augmentation of pulse pressure post exercise categorized patients who went on to have favorable LV remodeling with an accuracy of 74% (negative predictive value of 50%). Augmentation in pulse pressure was associated with a 3.1 fold (95% CI: 1.03-9.3; p=0.044) higher odds of response to CRT, adjusted for age, sex and ischemic etiology. A clinically important augmentation of pulse pressure with exercise (an indirect measure of cardiac reserve) appears useful in predicting an individual's likelihood of favorable LV remodeling post CRT. Measuring the change in pulse pressure after a 6-MWT may provide a simple and reliable method of predicting benefit from CRT.

The expression of calreticulin, a Ca(2+)-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired cardiac development, knockout of the Calreticulin gene is lethal during embryogenesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression of calreticulin in the postnatal heart, by producing transgenic mice that overexpress the protein in the heart. These transgenic animals exhibit decreased systolic function and inward I(Ca,L), low levels of connexin43 and connexin40, sinus bradycardia, and prolonged atrioventricular (AV) node conduction followed by complete heart block and sudden death. We conclude that postnatal downregulation of calreticulin is essential in the development of the cardiac conductive system, in particular in the sinus and AV nodes, when an inward Ca(2+) current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardiac death, which involves high expression of calreticulin in the heart.