“Cardiac resynchronisation therapy”: Does the haemodynamic improvement of biventricular pacing truly arise from cardiac resynchronisation?

In this thesis I have explored some of the fundamental concepts which underpin biventricular pacing (commonly called cardiac resynchronisation therapy, CRT). As a therapy, its impact on survival, and symptoms is impressive. By adopting the name cardiac resynchronisation therapy, a common assumption is that these benefits come from ensuring resynchronisation of the ventricles in the failing heart. In this thesis I explore how biventricular pacing delivers its benefit, and whether there are other dimensions beyond resynchronisation which deserve more attention. I first performed a meta-analysis to quantify what the actual symptomatic benefit from biventricular pacing is in the randomised controlled trials. A non-response rate of one-third is often quoted to biventricular pacing, but my analysis demonstrated that once the effect seen in the control arms is deducted the incremental symptomatic response rate is closer to 15%. I explored more acute markers of response, and how they are used for optimisation of biventricular pacing. I composed a review of different technologies available for optimisation, and a developed a step wise approach to develop the ideal optimisation scheme. Left ventricular outflow tract (LVOT) Doppler is one commonly used measure for optimisation, and my analysis concluded that a much larger number of beats is required for precise optimisation., I evaluated a novel method to acquire and trace around large numbers of LVOT Doppler velocities, and assessed whether breath holding is required. I discovered that breath holding did not have a significant impact on the magnitude or variability of measurements, and quiet breathing may be the easier way to acquire a larger number of beats for precise measurements. An algorithm using multiple alternations of systolic blood pressure between reference and tested pacing setting has been developed by my supervisors for reproducible AV optimisation, I used this technology to explore current techniques, and explore concepts in biventricular pacing: I evaluate the different methods for manufacturer specific electrogram-based AV optimisation. I found that agreement between the different methods is poor, and none agree with the haemodynamic optimum. I explored the apparent discrepancy studies have reported on the effect of VV optimisation. By performing VV optimisation by using four different methods for holding the AV delay constant (A-LV constant, A-RV constant, time to first ventricular lead constant, and time to second ventricular lead constant), I discovered that the acute haemodynamic effect was predominantly determined by the time to the first paced ventricle. To explore the influence of pure AV optimisation in heart failure I examined a group of patients with PR prolongation and demonstrated a significant improvement in acute haemodynamic response with AV optimised pacing of the His bundle. Temporary pacing of the His allows us to maintain the same, narrow QRS morphology and thus examine the pure effect of AV optimisation, an mean increment of 4 mmHg in systolic pressure is seen, approximately 60% of that seen in heart failure with LBBB. This also demonstrates the pure effect of AV shortening without an associated adverse haemodynamic effect of right ventricular pacing. I explored the role of lead position and whether the AV optimum varies between different LV lead positions. The AV optimum, did not significantly differ, suggesting high precision measurements at one AV delay could be used to determine the best lead position which in my study was occasionally in a position which would usually be considered non-conventional (anterior basal wall). I finally explored the role of biventricular pacing in non-LBBB morphologies looking at outcome studies. My analysis showed that biventricular pacing has a harmful effect in narrow QRS and the effect increases with the duration of time, indicating that this is due to a physiologically adverse effect of pacing. As this is the case, one can make a case for switching off biventricular pacing in such patients.Open Acces

Erectile dysfunction: prevalence, risk factors and involvement of antihypertensive drugs intervention

Purpose: To explore the literature regarding prevalance, risk factors and the involvement of antihypertensive drugs in erectile dysfunction (ED).Methods: Original research articles, reviews, editorials and case reports published in English language on the prevalence of sexual/erectile dysfunction in hypertensive men taking antihypertensive drugs and risk factors were identified through a search of four bibliographic databases, namely, PubMed, EMBASE, CINAHL and EBSCO Health.Results: Recent analyses suggest that hypertensive men of almost all age groups suffer from ED but it is more prevalent in elderly male patients. The involvement of β-blockers was found to be controversial. Nevertheless, some evidence had been found regarding the use of propranolol in high doses.Conclusion: The present review indicates the need for research to unravel the role of β-blockers in the manifestation of ED in hypertensive males, whom there are no contributory factors such as sedentary lifestyle, aging, stress and anxiety, etc.Keywords: Hypertension, Antihypertensive drugs, β-Blockers, Propranolol, Erectile dysfunction, Life style, Risk factor

On Time-Dependent Rheology of Sutterby Nanofluid Transport across a Rotating Cone with Anisotropic Slip Constraints and Bioconvection

The purpose and novelty of our study include the scrutinization of the unsteady flow and heat characteristics of the unsteady Sutterby nano-fluid flow across an elongated cone using slip boundary conditions. The bioconvection of gyrotactic micro-organisms, Cattaneo-Christov, and thermal radiative fluxes with magnetic fields are significant physical aspects of the study. Anisotropic constraints on the cone surface are taken into account. The leading formulation is transmuted into ordinary differential formate via similarity functions. Five coupled equations with nonlinear terms are resolved numerically through the utilization of a MATLAB code for the Runge-Kutta procedure. The parameters of buoyancy ratio, the porosity of medium, and bioconvection Rayleigh number decrease x-direction velocity. The slip parameter retard y-direction velocity. The temperature for Sutterby fluids is at a hotter level, but its velocity is vividly slower compared to those of nanofluids. The temperature profile improves directly with thermophoresis, v-velocity slip, and random motion of nanoentities. 2022 by the authors.This research was supported by Taif University, Researchers Supporting Project Number (TURSP-2020/217), Taif University, Taif, Saudi Arabia. Open Access funding provided by the Qatar National Library.Scopu

Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. Methods and Results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. Clinical Trial Registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov

Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) trial:HOPE HF Trial rationale and design

Aims In patients with heart failure and a pathologically prolonged PR interval, left ventricular (LV) filling can be improved by shortening atrioventricular delay using His‐bundle pacing. His‐bundle pacing delivers physiological ventricular activation and has been shown to improve acute haemodynamic function in this group of patients. In the HOPE‐HF (His Optimized Pacing Evaluated for Heart Failure) trial, we are investigating whether these acute haemodynamic improvements translate into improvements in exercise capacity and heart failure symptoms. Methods and results This multicentre, double‐blind, randomized, crossover study aims to randomize 160 patients with PR prolongation (≥200 ms), LV impairment (EF ≤ 40%), and either narrow QRS (≤140 ms) or right bundle branch block. All patients receive a cardiac device with leads positioned in the right atrium and the His bundle. Eligible patients also receive a defibrillator lead. Those not eligible for implantable cardioverter defibrillator have a backup pacing lead positioned in an LV branch of the coronary sinus. Patients are allocated in random order to 6 months of (i) haemodynamically optimized dual chamber His‐bundle pacing and (ii) backup pacing only, using the non‐His ventricular lead. The primary endpoint is change in exercise capacity assessed by peak oxygen uptake. Secondary endpoints include change in ejection fraction, quality of life scores, B‐type natriuretic peptide, daily patient activity levels, and safety and feasibility assessments of His‐bundle pacing. Conclusions Hope‐HF aims to determine whether correcting PR prolongation in patients with heart failure and narrow QRS or right bundle branch block using haemodynamically optimized dual chamber His‐bundle pacing improves exercise capacity and symptoms. We aim to complete recruitment by the end of 2018 and report in 2020

Automated aortic Doppler flow tracing for reproducible research and clinical measurements

In clinical practice, echocardiographers are often unkeen to make the significant time investment to make additional multiple measurements of Doppler velocity. Main hurdle to obtaining multiple measurements is the time required to manually trace a series of Doppler traces. To make it easier to analyze more beats, we present the description of an application system for automated aortic Doppler envelope quantification, compatible with a range of hardware platforms. It analyses long Doppler strips, spanning many heartbeats, and does not require electrocardiogram to separate individual beats. We tested its measurement of velocity-time-integral and peak-velocity against the reference standard defined as the average of three experts who each made three separate measurements. The automated measurements of velocity-time-integral showed strong correspondence (R2 = 0.94) and good Bland-Altman agreement (SD = 1.39 cm) with the reference consensus expert values, and indeed performed as well as the individual experts ( R2 = 0.90 to 0.96, SD = 1.05 to 1.53 cm). The same performance was observed for peak-velocities; ( R2 = 0.98, SD = 3.07 cm/s) and ( R2 = 0.93 to 0.98, SD = 2.96 to 5.18 cm/s). This automated technology allows > 10 times as many beats to be analyzed compared to the conventional manual approach. This would make clinical and research protocols more precise for the same operator effort

Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy:The BRAVO Trial

Objectives: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method. Background: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform. Methods: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro–B-type natriuretic peptide. Results: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro–B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms. Conclusions: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829

What shape do UK trainees want their training to be? Results of a cross-sectional study

OBJECTIVES: The British Government is acting on recommendations to overhaul postgraduate training to meet the needs of the changing population, to produce generalist doctors undergoing shorter broad-based training (Greenaway Review). Only 45 doctors in training were involved in the consultation process. This study aims to obtain a focused perspective on the proposed reforms by doctors in training from across specialities. DESIGN: Prospective, questionnaire-based cross-sectional study. SETTING/PARTICIPANTS: Following validation, a 31-item electronic questionnaire was distributed via trainee organisations and Postgraduate Local Education and Training Board (LETB) mailing lists. Throughout the 10-week study period, the survey was publicised on several social media platforms. RESULTS: Of the 3603 demographically representative respondents, 69% knew about proposed changes. Of the respondents, 73% expressed a desire to specialise, with 54% keen to provide general emergency cover. A small proportion (12%) stated that current training pathway length is too long, although 86% felt that it is impossible to achieve independent practitioner-level proficiency in a shorter period of time than is currently required. Opinions regarding credentialing were mixed, but tended towards disagreement. The vast majority (97%) felt credentialing should not be funded by doctors in training. Respondents preferred longer placement lengths with increasing career progression. Doctors in training value early generalised training (65%), with suggestions for further improvement. CONCLUSIONS: This is the first large-scale cross-specialty study regarding the Shape of Training Review. Although there are recommendations which trainees support, it is clear that one size does not fit all. Most trainees are keen to provide a specialist service on an emergency generalist background. Credentialing is a contentious issue; however, we believe removing aspects from curricula into post-Certificate of Completion of Training (CCT) credentialing programmes with shortened specialty training routes only degrades the current consultant expertise, and does not serve the population. Educational needs, not political winds, should drive changes in postgraduate medical education and all stakeholders should be involved

Daily angina documentation versus subsequent recall: development of a symptom smartphone app

Aims: The traditional approach to documenting angina outcomes in clinical trials is to ask the patient to recall their symptoms at the end of a month. With the ubiquitous availability of smartphones and tablets, daily contemporaneous documentation might be possible. Methods and results: The ORBITA-2 symptom smartphone app was developed with a user-centred iterative design and testing cycle involving a focus group of previous ORBITA participants. The feasibility and acceptability were assessed in an internal pilot of participants in the ongoing ORBITA-2 trial. Seven days of app entries by ORBITA-2 participants were compared with subsequent participant recall at the end of the 7-day period. The design focus group tested a prototype app. They reported that the final version captured their symptoms and was easy to use. In the completion assessment group, 141 of 142 (99%) completed the app in full and 47 of 141 (33%) without reminders. In the recall assessment group, 29 of 29 (100%) participants said they could recall the previous day’s symptoms, and 82% of them recalled correctly. For 2 days previously, 88% said they could recall and of those, 87% recalled correctly. The proportion saying they could recall their symptoms fell progressively thereafter: 89, 67, 61, 50%, and at 7 days, 55% (P < 0.001 for trend). The proportion of recalling correctly also fell progressively to 55% at 7 days (P = 0.04 for trend). Conclusion: Episode counts of angina are difficult to recall after a few days. For trials such as ORBITA-2 focusing on angina, daily symptom collection via a smartphone app will increase the validity of the results