Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE-HF randomized controlled trial.

AIMS: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO2max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes. METHODS AND RESULTS: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO2max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. CONCLUSIONS: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed.

Coronary artery disease and outcomes following transcatheter aortic valve implantation.

BACKGROUND: Aortic stenosis is a life-limiting condition for which transcatheter aortic valve implantation (TAVI) is an established therapy. Coronary artery disease (CAD) is frequently found in this patient group and optimal management in these patients remains uncertain. OBJECTIVES: We sought to examine the association of coexistent CAD on mortality and hospital readmission in patients undergoing TAVI. METHODS: In this observational cohort study, we examined patients who underwent TAVI and segregated them by the presence of obstructive epicardial CAD. The primary outcome was 3-year mortality with secondary outcomes being readmission for (1) all-causes, (2) a MACE (Major Adverse Cardiovascular Event) composite endpoint and (3) acute coronary syndrome. Subsidiary outcomes included patient angina and breathlessness scores. RESULTS: 898 patients underwent TAVI, of which 488 (54.3%) had unobstructed coronary arteries and 410 (45.7%) had obstructive CAD. Overall, n=298 (33.2%) patients experienced the primary mortality endpoint with no significant difference when stratified according to CAD (n=160 (32.9%) vs n=136 (33.2%), HR 0.98, CI 0.78 to 1.24). After multivariate analysis, the presence of CAD had no effect on the primary outcome (HR 0.98, CI 0.68 to 1.40). There was no significant difference in readmission for any cause (n=181, 37.1% (CAD) vs n=169, 41.2% (no CAD), p=0.23), including no significant difference on readmission for MACE (n=48, 9.8% (CAD) vs n=45, 11.0% (no CAD), p=0.11). CAD at the time of TAVI also did not alter breathlessness or angina scores before/after TAVI (p>0.05). CONCLUSION: Coexistent CAD had no significant association with mortality, any-cause readmission or symptoms for patients undergoing TAVI in our cohort.

Cardiac rehabilitation for heart failure and atrial fibrillation: a propensity- matched study.

BACKGROUND: Atrial fibrillation (AF) is common in individuals with heart failure (HF). Individuals with HF and AF may have a reduced functional capacity and quality of life (QoL) which leads to hospital admission and burden on clinical services. Evidence supported the effect of exercise training in individuals with HF. However, there is no existing data on the effectiveness of comprehensive cardiac rehabilitation (CR) in individuals with coexisting HF and AF. AIM: To explore the effect of CR in individuals with HF and AF compared with those with HF and no-coexisting AF. METHODS: Using CR database, individuals with HF and AF were identified and propensity matched to those with no coexisting AF. The change in incremental shuttle walking test, Heart Disease Quality of Life questionnaire, Hospital Anxiety and Depression Scores were compared between groups pre-CR and post-CR. RESULTS: 149 individuals were propensity matched from each group. The mean±SD age of the matched sample was 73.4±8 years, body mass index 29±5.5 kg/m2, left ventricular ejection fraction 35.2±9.8% and 56% were male.A statistically significant improvements in exercise capacity, heart disease QoL, anxiety and depression scores were observed within each group. There were no significant differences between groups for any of these outcome measures. CONCLUSIONS: Individuals with HF and AF gain a similar improvement in exercise capacity and health related QoL outcomes as individuals with no coexisting AF following CR. The presence of AF did not compromise the effectiveness of CR.

Effects of haemodynamically atrio-ventricular optimized His bundle pacing on heart failure symptoms and exercise capacity: the His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) randomized, double-blind, cross-over trial.

AIMS: Excessive prolongation of PR interval impairs coupling of atrio-ventricular (AV) contraction, which reduces left ventricular pre-load and stroke volume, and worsens symptoms. His bundle pacing allows AV delay shortening while maintaining normal ventricular activation. HOPE-HF evaluated whether AV optimized His pacing is preferable to no-pacing, in a double-blind cross-over fashion, in patients with heart failure, left ventricular ejection fraction (LVEF) ≤40%, PR interval ≥200 ms and either QRS ≤140 ms or right bundle branch block. METHODS AND RESULTS: Patients had atrial and His bundle leads implanted (and an implantable cardioverter-defibrillator lead if clinically indicated) and were randomized to 6 months of pacing and 6 months of no-pacing utilizing a cross-over design. The primary outcome was peak oxygen uptake during symptom-limited exercise. Quality of life, LVEF and patients' holistic symptomatic preference between arms were secondary outcomes. Overall, 167 patients were randomized: 90% men, 69 ± 10 years, QRS duration 124 ± 26 ms, PR interval 249 ± 59 ms, LVEF 33 ± 9%. Neither peak oxygen uptake (+0.25 ml/kg/min, 95% confidence interval [CI] -0.23 to +0.73, p = 0.3) nor LVEF (+0.5%, 95% CI -0.7 to 1.6, p = 0.4) changed with pacing but Minnesota Living with Heart Failure quality of life improved significantly (-3.7, 95% CI -7.1 to -0.3, p = 0.03). Seventy-six percent of patients preferred His bundle pacing-on and 24% pacing-off (p < 0.0001). CONCLUSION: His bundle pacing did not increase peak oxygen uptake but, under double-blind conditions, significantly improved quality of life and was symptomatically preferred by the clear majority of patients. Ventricular pacing delivered via the His bundle did not adversely impact ventricular function during the 6 months.

A Novel Lipase from Lasiodiplodia theobromae Efficiently Hydrolyses C8-C10 Methyl Esters for the Preparation of Medium-Chain Triglycerides' Precursors.

Medium-chain triglycerides (MCTs) are an emerging choice to treat neurodegenerative disorders such as Alzheimer's disease. They are triesters of glycerol and three medium-chain fatty acids, such as capric (C8) and caprylic (C10) acids. The availability of C8-C10 methyl esters (C8-C10 ME) from vegetable oil processes has presented an opportunity to use methyl esters as raw materials for the synthesis of MCTs. However, there are few reports on enzymes that can efficiently hydrolyse C8-C10 ME to industrial specifications. Here, we report the discovery and identification of a novel lipase from Lasiodiplodia theobromae fungus (LTL1), which hydrolyses C8-C10 ME efficiently. LTL1 can perform hydrolysis over pH ranges from 3.0 to 9.0 and maintain thermotolerance up to 70 °C. It has high selectivity for monoesters over triesters and displays higher activity over commercially available lipases for C8-C10 ME to achieve 96.17% hydrolysis within 31 h. Structural analysis by protein X-ray crystallography revealed LTL1's well-conserved lipase core domain, together with a partially resolved N-terminal subdomain and an inserted loop, which may suggest its hydrolytic preference for monoesters. In conclusion, our results suggest that LTL1 provides a tractable route towards to production of C8-C10 fatty acids from methyl esters for the synthesis of MCTs.

Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure.

BACKGROUND: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction. METHODS: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%. RESULTS: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P=0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P=0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P=0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure. CONCLUSIONS: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Zymography for Picogram Detection of Lipase and Esterase Activities.

Lipases and esterases are important catalysts with wide varieties of industrial applications. Although many methods have been established for detecting their activities, a simple and sensitive approach for picogram detection of lipolytic enzyme quantity is still highly desirable. Here we report a lipase detection assay which is 1000-fold more sensitive than previously reported methods. Our assay enables the detection of as low as 5 pg and 180 pg of lipolytic activity by direct spotting and zymography, respectively. Furthermore, we demonstrated that the detection sensitivity was adjustable by varying the buffering capacity, which allows for screening of both high and low abundance lipolytic enzymes. Coupled with liquid chromatography-mass spectrometry, our method provides a useful tool for sensitive detection and identification of lipolytic enzymes.

Evaluating the use of a mobile device for detection of atrial fibrillation in primary care.

A trial fibrillation (AF) increases cardio-embolic stroke risk, yet AF diagnosis and subsequent prophylactic anticoagulant prescription rates are suboptimal globally. This project aimed to increase AF diagnosis and subsequent anticoagulation prescription rates in East Midlands Clinical Commissioning Groups (CCGs). This service improvement evaluation of the East Midlands AF Advance programme investigated the implementation of mobile AF detection devices (Kardia, AliveCor) into primary-care practices within East Midlands CCGs, along with audit tools and clinician upskilling workshops designed to increase AF diagnosis and anticoagulation prescription rates. AF prevalence and prescription data were collected quarterly from July to September (Q3) 2017/18 to April to June/July to September (Q2/3) 2018/19. AF prevalence increased from 1.9% (22,975 diagnoses) in Q3 2017/18 to 2.4% (24,246 diagnoses) in Q2 2018/19 (p=0.026), while the percentage of high-risk AF patients receiving anticoagulants increased from 80.5% in Q3 2017/18 to 86.9% in Q3 2018/19 (p=0.57), surpassing the Public Health England 2019 target of 85%. The East Midlands AF Advance programme increased AF diagnosis and anticoagulation rates, which is expected to be of significant clinical benefit. The mobile AF detection devices provide a more practical alternative to traditional 12-lead electrocardiograms (ECGs) and should be incorporated into routine clinical practice for opportunistic AF detection, in combination with medication reviews to increase anticoagulant prescription.

A Validation Study: How Predictive Is a Diagnostic Coding Algorithm at Identifying Rheumatic Heart Disease in Western Australian Hospital Data?

BACKGROUND: International Classification of Diseases codes for rheumatic heart disease (RHD) (ICD-10 I05-I08) include valvular heart disease of unspecified origin, limiting their usefulness for estimating RHD burden. An expert opinion-based algorithm was developed to increase their accuracy for epidemiological case ascertainment. The algorithm included codes not defaulting to RHD ('probable') plus selected codes pertaining to mitral valve involvement in patients <60 years ('possible'). We aimed to determine the positive predictive value (PPV) for RHD of algorithm-selected hospital admissions. METHODS: Chart reviews of RHD-coded admissions (n=368) to Western Australian tertiary hospitals (2009-2016) authenticated RHD diagnosis. We selected all cases with algorithm-positive codes from populations at high-risk of RHD and an age-stratified random sample from low-risk groups. RHD status was determined from echocardiographic reports or clinical diagnosis in charts. PPVs were compared by population risk status (high-risk/low-risk), age group, gender, principal/secondary diagnosis and probable/possible codes. RESULTS: High-risk patients had higher PPVs than low-risk patients (83.8% vs 54.9%, p<0.0001). PPVs were 91.5% and 51.5% respectively for algorithm-defined 'probable RHD' and 'possible' codes (p<0.0001). The PPVs in low-risk patients were higher for principal diagnoses than secondary diagnoses (84.5% vs 44.8%, weighted p<0.0001) but were similar in high-risk patients (92.5% vs 81.7%, p=0.096). CONCLUSION: The algorithm performs well for RHD coded as a principal diagnosis, 'probable' codes or in populations at high risk of RHD. Refinement is needed for identifying true RHD in low-risk groups.

Rheumatic heart disease in pregnancy: Profile of women admitted to a Western Australian tertiary obstetric hospital.

This retrospective study assessed maternal and perinatal outcomes for women with rheumatic heart disease (RHD) admitted to the largest tertiary obstetric hospital in Western Australia from 2009 to 2016. Of 54 women identified, 75.9% were Indigenous, 59.3% lived in rural areas and 40.7% had severe RHD. Heart failure developed in 10% who gave birth. Indigenous women were younger, had higher gravidity (P = 0.0305), were more likely to receive secondary prophylaxis (P = 0.0041) and have sub-optimal antenatal clinic attendance (P = 0.0078). There were no maternal deaths and two perinatal deaths (4.0%), reflecting vigilance in the obstetric management of women with RHD in Western Australia.

Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection.

Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In the present study, we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative reverse transcription-PCR (RT-PCR), immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors (OXR). In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11, d-Leu15]-Orexin B) exerted similar effects as OR-B, whereas a specific orexin receptor-1 (OX1R) antagonist (SB-408124) did not alter the responsiveness of OR-B. Treatment of the same model with OR-B resulted in a dose-dependent increase in myosin light chain and troponin-I (TnI) phosphorylation. Following ischaemia/reperfusion in the isolated Langendorff perfused rat heart model, OR-B, but not OR-A, exerts a cardioprotective effect; mirrored in an in vivo model as well. Unlike OR-A, OR-B was also able to induce extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2) and Akt phosphorylation in rat myocardial tissue and ERK1/2 phosphorylation in human heart samples. These findings were further corroborated in an in vivo rat model. In human subjects with heart failure, there is a significant negative correlation between the expression of OX2R and the severity of the disease clinical symptoms, as assessed by the New York Heart Association (NYHA) functional classification. Collectively, we provide evidence of a distinct orexin system in the heart that exerts a cardioprotective role via an OR-B/OX2R pathway.

Evaluation of mobile learning: students' experiences in a new rural-based medical school.

BACKGROUND: Mobile learning (ML) is an emerging educational method with success dependent on many factors including the ML device, physical infrastructure and user characteristics. At Gippsland Medical School (GMS), students are given a laptop at the commencement of their four-year degree. We evaluated the educational impact of the ML program from students' perspectives. METHODS: Questionnaires and individual interviews explored students' experiences of ML. All students were invited to complete questionnaires. Convenience sampling was used for interviews. Quantitative data was entered to SPSS 17.0 and descriptive statistics computed. Free text comments from questionnaires and transcriptions of interviews were thematically analysed. RESULTS: Fifty students completed the questionnaire (response rate 88%). Six students participated in interviews. More than half the students owned a laptop prior to commencing studies, would recommend the laptop and took the laptop to GMS daily. Modal daily use of laptops was four hours. Most frequent use was for access to the internet and email while the most frequently used applications were Microsoft Word and PowerPoint. Students appreciated the laptops for several reasons. The reduced financial burden was valued. Students were largely satisfied with the laptop specifications. Design elements of teaching spaces limited functionality. Although students valued aspects of the virtual learning environment (VLE), they also made many suggestions for improvement. CONCLUSIONS: Students reported many educational benefits from school provision of laptops. In particular, the quick and easy access to electronic educational resources as and when they were needed. Improved design of physical facilities would enhance laptop use together with a more logical layout of the VLE, new computer-based resources and activities promoting interaction.

Video-assisted thoracoscopic implantation of the left ventricular pacing lead for cardiac resynchronization therapy.

BACKGROUND: To study the feasibility and efficacy of video-assisted thoracoscopic (VAT) placement of the left ventricular pacing lead for cardiac resynchronization therapy (CRT) where the conventional transvenous coronary sinus approach has failed. METHODS: Seventeen patients underwent the VAT procedure. Indications for CRT were ischemic cardiomyopathy in six patients and nonischemic cardiomyopathy in 11. The procedure was performed under general anesthesia with single-lung ventilation. Three 2-cm incisions were used on the left chest wall to place the screw-in lead near the obtuse marginal arteries high on the lateral wall of the left ventricle (LV). RESULTS: The VATS approach was successful in 13/17 (76%) patients. Median procedure time was 75 minutes (range 55-135). A learning curve was observed that appeared to plateau at 75 minutes procedure time after four cases. Median length of hospital stay was 2 days (range 2-8) with one patient requiring intensive care. Satisfactory thresholds and impedances of 2.3 +/- 0.9 V/0.5 ms and 560 ohms, respectively, were achieved at mean follow-up of 226 days. All patients reported symptomatic benefit with reduction in New York Heart Association score from III preoperatively to II postoperatively. CONCLUSIONS: VAT placement of the epicardial pacing lead is feasible, safe, and efficacious. It should be considered in cases where the transvenous route has failed or as an alternative in prolonged or hazardous transvenous procedures.