Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

AIMS: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. METHODS AND RESULTS: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. CONCLUSION: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

The Guideline-Policy Gap in Direct-Acting Oral Anticoagulants Usage in Atrial Fibrillation: Evidence, Practice, and Public Policy Considerations.

Atrial fibrillation has a high disease burden-both in prevalence and associated consequences. Despite anticoagulation being an effective treatment in atrial fibrillation, stroke prevention is slow to reflect evidence-based practice. Real-world data reveal a substantial portion of patients who would benefit from anticoagulation, yet do not receive it adequately or at all. A large part of this suboptimal treatment is due to the underutilization of direct oral anticoagulants (DOACs). In response to abundant evidence published over a short timeframe, international guidelines have adopted DOAC usage ahead of policy and fund holders. This paper reviews the evidence and values that influence published guidelines, patient-physician decision making, and policy framework on DOAC usage. An important factor is the access gap between patients who qualify for DOAC according to evidence-based guidelines and the subset of this cohort who are eligible for DOAC based on government funded policy. We analyse the Canadian health system in detail-including drug approval and funding process. Health care systems in other countries are explored, with emphasis on similar universal health care systems that may help overcome barriers common to Canada. We will discuss strategies to: (1) improve awareness of the risk and preventability of stroke; (2) enable physicians to provide evidence-based DOAC usage; (3) empower patients to improve adherence and persistence; (4) collect real-life data that encourages patient self-monitoring, physician outcomes auditing, and building evidence that is useful for policy makers; and (5) use postmarketing data in negotiating shared risk management between pharmaceuticals and government to improve access to DOACs.

Current Practices and Attitudes of Canadian Team Physicians Toward Cardiovascular Preparticipation Screening.

To determine the current cardiovascular preparticipation screening practices and attitudes of team physicians for Canadian University and Major Junior Hockey Athletes, a 13-question survey was distributed to lead physicians of each organization. The response rate was 47% (48% [27 of 56] for the Canadian Interuniversity Sport and 55% [11 of 20] for the Ontario Hockey League). Ninety-two percent of physicians reported some form of preparticipation screening, with 22% currently using 12-lead electrocardiogram. Substantial inter- and intraorganization variability existed. Physicians not performing electrocardiogram screening reported lack of evidence (45%) and lack of cost-effectiveness (28%) as their rationale. To our knowledge, this is the first study to investigate Canadian athletic screening practices, and highlights the need for national guidelines.

Single-entry models (SEMs) for scheduled services: Towards a roadmap for the implementation of recommended practices.

BACKGROUND: Long waiting times for elective services continue to be a challenging issue. Single-entry models (SEMs) are used to increase access to and flow through the healthcare system. This paper provides a roadmap for healthcare decision-makers, managers, physicians, and researchers to guide implementation and management of successful and sustainable SEMs. METHODS: The roadmap was informed by an inductive qualitative synthesis of the findings from a deliberative process (a symposium on SEMs, with clinicians, researchers, senior policy-makers, healthcare managers, and patient representatives) and focus groups with the symposium participants. RESULTS: SEMs are a promising strategy to improve the management of referrals and represent one approach to reduce waiting times. The SEMs roadmap outlines current knowledge about SEMs and critical success factors for SEMs' implementation and management. CONCLUSIONS: This SEM roadmap is intended to help clinicians, decision-makers, managers, and researchers interested in developing new or strengthening existing SEMs. We consider this roadmap to be a living document that will continue to evolve as we learn more about implementing and managing sustainable SEMs.

Adherence to process of care quality indicators after percutaneous coronary intervention in Ontario, Canada: a retrospective observational cohort study.

BACKGROUND: Public reporting of percutaneous coronary intervention (PCI) outcomes has been established in many jurisdictions to ensure optimal delivery of care. The majority of PCI report cards examine in-hospital mortality, but relatively little is known regarding the adherence to processes of care. METHODS: A modified Delphi panel comprising cardiovascular experts was assembled to develop a set of PCI quality indicators. Indicators such as prescription of aspirin, dual antiplatelet therapy, statins and smoking cessation counselling were identified to represent high-quality PCI care. Chart abstraction was performed at 13 PCI hospitals in Ontario, Canada from 2009 to 2010 with at least 200 PCI patients randomly selected from each hospital. RESULTS: Our study sample included 3041 patients, of whom 18% had stable coronary artery disease (CAD) and 82% had an acute coronary syndrome (ACS). Their mean age was 63±12.4 years and 29% of patients were female. Prior to PCI, 89% were prescribed aspirin, and after PCI 98.7% were prescribed aspirin, 95.1% were prescribed dual antiplatelet therapy for 12 months after drug-eluting stents, and 94.9% were prescribed statins. The lowest performing quality indicator was smoking cessation counselling, observed in only 42% of current and past smokers (18% in patients with stable CAD and 47% in ACS). CONCLUSIONS: Our study demonstrates high levels of adherence to most quality indicators for patients undergoing PCI procedures in Ontario. In conclusion, smoking cessation counselling was not consistently performed across hospitals and represents an opportunity for future quality improvement efforts.

Incidence, predictors, and procedural results of upgrade to resynchronization therapy: the RAFT upgrade substudy.

BACKGROUND: The resynchronization-defibrillation for ambulatory heart failure trial (RAFT) study demonstrated that adding cardiac resynchronization therapy (CRT) in selected patients requiring de novo implantable cardiac defibrillators (ICD) reduced mortality as compared with ICD therapy alone, despite an increase in procedure-related adverse events. Data are lacking regarding the management of patients with ICD therapy who develop an indication for CRT upgrade. METHODS AND RESULTS: Participating RAFT centers provided data regarding de novo CRT-D (CRT with ICD) implant, upgrade to CRT-D during RAFT (study upgrade), and upgrade within 6 months after presentation of study results (substudy). Substudy centers enrolled 1346 (74.9%) patients in RAFT, including 644 de novo, 80 study upgrade, and 60 substudy CRT attempts. The success rate (initial plus repeat attempts) was 95.2% for de novo versus 96.3% for study upgrade and 90.0% for substudy CRT attempts (P=0.402). Acute complications occurred among 26.2% of de novo versus 18.8% of study upgrade and 3.4% of substudy CRT implantation attempts (P<0.001). The most common complication was left ventricular lead dislodgement. The principal reasons for not yet attempting upgrade in the substudy were patient preference (31.9%), New York Heart Association Class I (17.0%), and a QRS<150 ms (13.1%). CONCLUSIONS: Among a broad group of implant physicians, CRT upgrades were performed in patients with an ICD in situ with no difference in implant success rate and a reduced acute complication rate as compared with a de novo CRT implant. Decisions to upgrade were influenced by predictors of benefit in subgroup analyses of the RAFT study and other trials.

Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT).

BACKGROUND: Cardiac resynchronization (CRT) prolongs survival in patients with systolic heart failure and QRS prolongation. However, most trials excluded patients with permanent atrial fibrillation. METHODS AND RESULTS: The Resynchronization for Ambulatory Heart Failure Trial (RAFT) randomized patients to an implantable cardioverter defibrillator (ICD) or ICD+CRT, stratified by the presence of permanent atrial fibrillation. Patients with permanent atrial fibrillation were randomized to CRT-ICD (n=114) or ICD (n=115). Patients receiving a CRT-ICD were similar to those receiving an ICD: age (71.6±7.3 versus 70.4±7.7 years), left ventricular ejection fraction (22.9±5.3% versus 22.3±5.1%), and QRS duration (151.0±23.6 versus 153.4±24.7 ms). There was no difference in the primary outcome of death or heart failure hospitalization between those assigned to CRT-ICD versus ICD (hazard ratio, 0.96; 95% CI, 0.65-1.41; P=0.82). Cardiovascular death was similar between treatment arms (hazard ratio, 0.97; 95% CI, 0.55-1.71; P=0.91); however, there was a trend for fewer heart failure hospitalizations with CRT-ICD (hazard ratio, 0.58; 95% CI, 0.38-1.01; P=0.052). The change in 6-minute hall walk duration between baseline and 12 months was not different between treatment arms (CRT-ICD: 19±84 m versus ICD: 16±76 m; P=0.88). Patients treated with CRT-ICD showed a trend for a greater improvement in Minnesota Living with Heart Failure score between baseline and 6 months (CRT-ICD: 41±21 to 31±21; ICD: 33±20 to 28±20; P=0.057). CONCLUSIONS: Patients with permanent atrial fibrillation who are otherwise CRT candidates appear to gain minimal benefit from CRT-ICD compared with a standard ICD.

Do small (6.6 Fr.) active and passive fixation defibrillation leads perform as well as larger sized leads? A multi-centre analysis.

AIMS: The 6.6 Fr. Sprint Fidelis lead family may allow multiple lead implantation procedures with reduced risk of venous obstruction. METHODS AND RESULTS: Two prospective, historically controlled, multi-centre studies were conducted in Europe (80 patients) and Canada (79 patients). The purpose was to assess the ventricular lead-related adverse events (LRAEs) and performance of the small Models 6948 and 6949 defibrillation leads, respectively, in patients with a standard indication for an ICD implant. Safety was assessed by demonstrating equivalence of the LRAE free rate at 1 month to comparable but larger leads (Models 6942, 6943, 6944, 6947and 4074). Seventy-five of 80 patients with a 6948 lead (93.8%) remained free of LRAEs. Seventy-four out of 79 patients (93.7%) with the 6949 lead remained free of LRAEs. The 95% lower confidence bounds were above the critical difference limits. Thus, safety of the Sprint Fidelis((R)) leads is similar to that of larger leads. Electrical performance through 1-month follow-up proved to be acceptable in comparison with other established leads. CONCLUSION: These multi-centre studies confirm that smaller defibrillation leads offer similar safety and efficacy features to widely used larger leads; they have low LRAE rates and defibrillation thresholds, while providing the advantage of a smaller introducer size and reduced venous obstruction.