A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

The impact of coronary calcium score as an addition to myocardial perfusion imaging in altering clinical management (ICCAMPA trial).

INTRODUCTION: AIM: Myocardial perfusion imaging (MPI) is a key tool for the identification and risk stratification of patients with coronary artery disease. The use of a coronary calcium score further adds to prognostic data above MPI alone. In this study, our aim was to evaluate the extent to which the use of a coronary artery calcium (CAC) score, when co-reported with MPI, impacts changes in clinical management in patients without a history of coronary artery disease (CAD) undergoing functional imaging. METHODS: This is a multicenter international study which incorporated a standardized questionnaire to evaluate changes in clinician management after MPI results were given with and without the additional information of a CAC score. Calcium scoring on a SPECT-CT system was performed via a semiquantitative Shemesh score (0-12) with a 0-3 score from the left main, left anterior descending, left circumflex, and right coronary arteries. CT of the chest was read independently, and non-coronary findings were reported alongside the CAC score. RESULTS: A total of 281 patients were enrolled across 3 international centers (Brazil, Australia, New Zealand). Of the 281 patients, 133 (47%) had management altered after the clinician was made aware of the CAC score. The impact of the CAC in changing clinical management was significant, particularly in patients with a negative MPI (P < 0.0001), but also in MPI-positive patients (P = 0.0021). The most common management change was the addition or intensification of statin therapy. CONCLUSION: The addition of the CAC component to MPI yielded significant management changes in nearly half of all patients undergoing MPI for suspected CAD. This trend was observed across all centers in the three countries involved and was particularly evident in patient with a negative MPI.

Risk Factors of Haematoma Formation Following Cardiac Implantable Electronic Device Procedures.

PURPOSE: A single-centre cohort of 2,100 adults who consecutively underwent cardiac implantable electronic device procedures were retrospectively analysed to identify and quantify risk factors of perioperative pocket haematoma formation. RESULTS: Dual antiplatelet therapy was significantly associated with increased odds of haematoma formation (OR 11.7 for aspirin and clopidogrel, OR 11.8 for aspirin and ticagrelor and OR 104 for aspirin and prasugrel, p<0.05) on multivariate binomial logistic regression analysis. Aspirin monotherapy was also associated with increased bleeding risk (OR 3.02, p<0.01). Direct oral anticoagulants and warfarin were also each associated with increased odds of haematoma formation although to a lesser extent than dual anti platelet therapy (DAPT). Amongst oral anticoagulants, apixaban was associated with the lowest bleeding risk (OR 2.59, p=0.03) whilst dabigatran was associated with the highest (OR 3.81, p=0.04). There was a significant incremental reduction in bleeding risk by 8% per 10x103/µL increase in platelet count. CONCLUSION: DAPT was associated with increased odds of pocket haematoma formation following cardiovascular implantable electronic device (CIED) procedure. This likelihood was higher than with oral anticoagulation therapy. Timely medication reconciliation of P2Y12 inhibitors according to guidelines is important to avoid post-procedural bleeding complications. Perioperative policies which account for the half-life of withheld anticoagulant agents may help reduce the haematoma risk.

Remote Device Interrogation Kiosks (ReDInK) - Pharmacy Kiosk Remote Testing of Pacemakers and Implantable Cardioverter-Defibrillators for Rural Victorians. A Novel Strategy to Tackle COVID-19.

BACKGROUND: In the era of COVID-19, travel restrictions and social distancing measures have changed the landscape for device interrogations of pacemakers and defibrillators for rural Victorians. Previously, device checks were performed infrequently in large volume, face-to-face rural clinics by visiting cardiologists and technicians. Access to remote areas and social distancing restrictions have made these clinics unfeasible to operate. The Cardiac Society of Australia and New Zealand (CSANZ) and Heart Rhythm Society (HRS) COVID-19 consensus statements have suggested the utilisation of remote monitoring to minimise the potential spread of COVID-19 infections between clinicians and high-risk patients. A novel solution to this challenge was the implementation of a remote device interrogation (RI) service located in two kiosks at two rural pharmacies. This service was termed Remote Device Interrogation Kiosks (ReDInK). AIM: This cross-sectional observational study aimed to describe the set-up process, safety and efficacy of RI and customer satisfaction of the ReDInK program. METHODS: Two-hundred-and-ninety-two (292) rurally located patients with implantable cardiac devices were identified via the cardiology department database. Of these, 101 (44%) were enrolled into the ReDInK program across two rurally located pharmacies between April and July 2020. RI was performed and download outcomes were reviewed. A customer satisfaction survey assessed attitudes towards the program and explored options of ongoing service application. RESULTS: Of 101 patients enrolled into ReDInK, 96 (95%) resulted in satisfactory device checks. Four (4) individuals failed-to-attend and one individual experienced technical download issues. Of the 96 satisfactory device checks, three required in-person follow-up for reasons including battery replacement, lead repositioning and in-person programming. No adverse events were reported. A satisfaction telephone survey was conducted with 81 (83%) participants enrolled in ReDInK. Seventy-one (71) individuals (88%) of those surveyed expressed satisfaction and 73 (90%) labelled the process as efficiently conducted. Sixty-nine (69) (85%) participants felt reassured that this service was established during the pandemic. However 47 (58%) participants reported they would still feel comfortable to undergo in-person reviews despite social distancing recommendations. CONCLUSIONS: With the COVID-19 pandemic posing restrictions to social distancing and reducing unnecessary in-person interaction, the ReDInK program emerges as an efficacious and safe solution for patients in rural Victoria. The program's widely positive reception and successful conduction in rural Victoria invites further opportunity for a wider application of similar programs, expanding its role to metropolitan areas.

Muscle mass, strength, and physical performance predicting activities of daily living: a meta-analysis.

Background Activities of daily living (ADLs) and instrumental activities of daily living (IADLs) are essential for independent living and are predictors of morbidity and mortality in older populations. Older adults who are dependent in ADLs and IADLs are also more likely to have poor muscle measures defined as low muscle mass, muscle strength, and physical performance, which further limit their ability to perform activities. The aim of this systematic review and meta-analysis was to determine if muscle measures are predictive of ADL and IADL in older populations. Methods A systematic search was conducted using four databases (MEDLINE, EMBASE, Cochrane, and CINAHL) from date of inception to 7 June 2018. Longitudinal cohorts were included that reported baseline muscle measures defined by muscle mass, muscle strength, and physical performance in conjunction with prospective ADL or IADL in participants aged 65 years and older at follow-up. Meta-analyses were conducted using a random effect model. Results Of the 7760 articles screened, 83 articles were included for the systematic review and involved a total of 108 428 (54.8% female) participants with a follow-up duration ranging from 11 days to 25 years. Low muscle mass was positively associated with ADL dependency in 5/9 articles and 5/5 for IADL dependency. Low muscle strength was associated with ADL dependency in 22/34 articles and IADL dependency in 8/9 articles. Low physical performance was associated with ADL dependency in 37/49 articles and with IADL dependency in 9/11 articles. Forty-five articles were pooled into the meta-analyses, 36 reported ADL, 11 reported IADL, and 2 reported ADL and IADL as a composite outcome. Low muscle mass was associated with worsening ADL (pooled odds ratio (95% confidence interval) 3.19 (1.29-7.92)) and worsening IADL (1.28 (1.02-1.61)). Low handgrip strength was associated with both worsening ADL and IADL (1.51 (1.34-1.70); 1.59 (1.04-2.31) respectively). Low scores on the short physical performance battery and gait speed were associated with worsening ADL (3.49 (2.47-4.92); 2.33 (1.58-3.44) respectively) and IADL (3.09 (1.06-8.98); 1.93 (1.69-2.21) respectively). Low one leg balance (2.74 (1.31-5.72)), timed up and go (3.41 (1.86-6.28)), and chair stand test time (1.90 (1.63-2.21)) were associated with worsening ADL. Conclusions Muscle measures at baseline are predictors of future ADL and IADL dependence in the older adult population.

Counteract of bone marrow of blotchy mice against the increases of plasma copper levels induced by high-fat diets in LDLR-/- mice.

BACKGROUND: Bone marrow of blotchy mouse (blotchy marrow) reflects the function of transmembrane domain and relevant intramembrane sites of ATP7A in myeloid cells. By chronic infusion of angiotensin II, we previously found that blotchy marrow plays a minor role in regulating plasma copper. Moreover, the recipients of blotchy marrow presented a moderate reduction of plasma lipids and inflammatory mediator production. Little is known about whether these changes are a specific response to angiotensin II or reveal a more general role of ATP7A. OBJECTIVE AND DESIGN: We investigated if blotchy marrow reduces plasma lipids and inflammatory mediators induced by high-fat diets. To test this hypothesis, blotchy and control marrows were reconstituted to the recipient mice (irradiated male LDLR-/- mice), followed by high-fat-diet feeding for 4 months. At the end points, plasma metals (copper, zinc and iron), lipid profiling (cholesterol, triglyceride, phospholipids and lipoprotein) and six inflammatory mediators (lymphotacin, MCP3, MCP5, TIMP1, VEGF-A and IP-10) were measured. Parallel experiments were performed using male LDLR-/- mice fed either high-fat diets or chow diets for 4 months. RESULTS: In addition to hyperlipidemia and low-grade inflammation, high-fat diets selectively increased plasma copper concentration compared to chow diets in LDLR-/- mice. After high-fat-diet feeding, the recipients with blotchy marrow showed a decrease in plasma copper (p < 0.01) and an increase in plasma iron (p < 0.05). The recipients with blotchy marrow also presented decreases in cholesterol (p < 0.01) and phospholipids (p < 0.05) in plasma. Surprisingly, plasma levels of MCP3 (p < 0.05), MCP5 (p < 0.05), TIMP1 (p < 0.01), VEGF-A (p < 0.01) and IP-10 (p < 0.01) were significantly increased in the recipients with blotchy marrow compared to controls; the increased levels of MCP3, MCP5 and TIMP1 were more than 50%. CONCLUSION: Our studies showed that blotchy marrow counteracts the increased copper levels induced by high-fat diets, indicating that circulating myeloid cells can regulate blood copper levels via ATP7A. Moreover, transplantation of blotchy marrow followed by high-fat diets leads to a decrease in lipid profile and an increase in inflammatory mediator production. Overall, blotchy marrow mediates divergent responses to angiotensin II and high-fat diets in vivo.