Imperial College London

ProfessorDarrelFrancis

Faculty of MedicineNational Heart & Lung Institute

Professor of Cardiology
 
 
 
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Contact

 

+44 (0)20 7594 3381d.francis Website

 
 
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Assistant

 

Miss Juliet Holmes +44 (0)20 7594 5735

 
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Location

 

Block B Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

616 results found

Mielewczik M, Francis D, Studer B, Simunek MVet al., 2017, Die Rezeption von Gregor Mendels Hybridisierungsversuchen im 19. Jahrhundert–Eine bio-bibliographische Studie, Nova acta Leopoldina : Abhandlungen der Kaiserlich Leopoldinisch-Carolinisch Deutschen Akademie der Naturforscher, Vol: 413, Pages: 83-134, ISSN: 0369-5034

Journal article

Gronda E, Francis D, Zannad F, Hamm C, Brugada J, Vanoli Eet al., 2017, Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction, Journal of Cardiovascular Medicine, Vol: 18, Pages: 641-649, ISSN: 1558-2027

Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.

Journal article

Sikkel MB, Francis DP, Howard J, Gordon F, Rowlands C, Peters NS, Lyon AR, Harding SE, MacLeod KTet al., 2017, Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies, Cardiovascular Research, Vol: 113, Pages: 1743-1752, ISSN: 1755-3245

AimsIt is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests).Methods and resultsCa2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF.Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF.ConclusionCa2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for relia

Journal article

Shun-Shin MJ, Francis DP, 2017, Is this muscle pain caused by my statin?, BMJ, Vol: 357, ISSN: 0959-8138

Journal article

Zaman S, Zaman S, Scholtes T, Shun-Shin MJ, Plymen CM, Francis DP, Cole GDet al., 2017, The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets, European Journal of Heart Failure, Vol: 19, Pages: 1401-1409, ISSN: 1879-0844

Aims: The prescription of optimal medical therapy for heart failure is often delayed despite compelling evidence of the reductions in mortality it may facilitate. We calculated the absolute risk resulting from delayed prescription of therapy. For comparison, we established the threshold applied by clinicians when discussing the risk for death associated with an intervention, and the threshold used in of ficial patient information leaflets.Methods and results:We undertook a meta-analysis of randomized controlled trials to calculate the excess mortality caused by deferral of medical therapy for 1 year. Risk ratios for angiotensin-converting enzyme inhibitors, beta-blockers and aldosterone antagonists were 0.80, 0.73 and 0.77, respectively. In patients who might achieve a 1-year survival rate of 90% if treated, a 1-year deferral of treatment reduced survival to 78% (i.e. an annual absolute increase in mortality of 12 in 100 patients). This corresponds to an additional absolute mortality risk per month of 1%. A survey of clinicians carried out to establish the risk threshold at which they would obtain written consent showed the majority (85%) sought written consent for interventions associated with a 12-fold lower mortality risk: one in 100 patients. A systematic review of UK patient information leaflets to establish the magnitude of risk considered sufficient to be stated explicitly showed that leaflets begin to mention death at a ∼18 000-fold lower mortality risk of just 0.0007 in 100 patients.Conclusions:Deferring heart failure treatment for 1 year carries far greater risk than the level at which most doctors seek written consent, and 18000 times more risk than the level at which patient information leaflets begin to mention death.

Journal article

Zolgharni M, Negoita M, Dhutia NM, Mielewczik M, Manoharan K, Sohaib SMA, Finegold JA, Sacchi S, Cole GD, Francis DPet al., 2017, Automatic detection of end-diastolic and end-systolic frames in 2D echocardiography, ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES, Vol: 34, Pages: 956-967, ISSN: 0742-2822

Background:Correctly selecting the end-diastolic and end-systolic frames on a 2D echocardiogram is important and challenging, for both human experts and automated algorithms. Manual selection is time-consuming and subject to uncertainty, and may affect the results obtained, especially for advanced measurements such as myocardial strain.Methods and Results:We developed and evaluated algorithms which can automatically extract global and regional cardiac velocity, and identify end-diastolic and end-systolic frames. We acquired apical four-chamber 2D echocardiographic video recordings, each at least 10 heartbeats long, acquired twice at frame rates of 52 and 79 frames/s from 19 patients, yielding 38 recordings. Five experienced echocardiographers independently marked end-systolic and end-diastolic frames for the first 10 heartbeats of each recording. The automated algorithm also did this. Using the average of time points identified by five human operators as the reference gold standard, the individual operators had a root mean square difference from that gold standard of 46.5 ms. The algorithm had a root mean square difference from the human gold standard of 40.5 ms (P<.0001). Put another way, the algorithm-identified time point was an outlier in 122/564 heartbeats (21.6%), whereas the average human operator was an outlier in 254/564 heartbeats (45%).Conclusion:An automated algorithm can identify the end-systolic and end-diastolic frames with performance indistinguishable from that of human experts. This saves staff time, which could therefore be invested in assessing more beats, and reduces uncertainty about the reliability of the choice of frame.

Journal article

Cook CM, Petraco R, Shun-Shin MJ, Ahmad Y, Nijjer S, Al-Lamee R, Kikuta Y, Shiono Y, Mayet J, Francis DP, Sen S, Davies JEet al., 2017, Diagnostic accuracy of computed tomography-derived fractional flow reserve a systematic review, JAMA Cardiology, Vol: 2, Pages: 803-810, ISSN: 2380-6591

Importance Computed tomography–derived fractional flow reserve (FFR-CT) is a novel, noninvasive test for myocardial ischemia. Clinicians using FFR-CT must be able to interpret individual FFR-CT results to determine subsequent patient care.Objective To provide clinicians a means of interpreting individual FFR-CT results with respect to the range of invasive FFRs that this interpretation might likely represent.Evidence Review We performed a systematic review in accordance with guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic search of MEDLINE (January 1, 2011, to 2016, week 2) and EMBASE (January 1, 2011, to 2016, week 2) was performed for studies assessing the diagnostic accuracy of FFR-CT. Title words used were computed tomography or computed tomographic and fractional flow reserve or FFR. Results were limited to publications in peer-reviewed journals. Duplicate studies and abstracts from scientific meetings were removed. All of the retrieved studies, including references, were reviewed.Findings There were 908 vessels from 536 patients in 5 studies included in the analysis. A total of 365 (68.1%) were male, and the mean (SD) age was 63.2 (9.5) years. The overall per-vessel diagnostic accuracy of FFR-CT was 81.9% (95% CI, 79.4%-84.4%). For vessels with FFR-CT values below 0.60, 0.60 to 0.70, 0.70 to 0.80, 0.80 to 0.90, and above 0.90, diagnostic accuracy of FFR-CT was 86.4% (95% CI, 78.0%-94.0%), 74.7% (95% CI, 71.9%-77.5%), 46.1% (95% CI, 42.9%-49.3%), 87.3% (95% CI, 85.1%-89.5%), and 97.9% (95% CI, 97.9%-98.8%), respectively. The 82% (overall) diagnostic accuracy threshold was met for FFR-CT values lower than 0.63 or above 0.83. More stringent 95% and 98% diagnostic accuracy thresholds were met for FFR-CT values lower than 0.53 or above 0.93 and lower than 0.47 or above 0.99, respectively.Conclusions and Relevance The diagnostic accuracy of FFR-CT varies markedly across the spectrum of disease. This ana

Journal article

Shun-Shin MJ, Zheng S, Cole G, Howard J, Whinnett Z, Francis Det al., 2017, Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials, European Heart Journal, Vol: 38, Pages: 1738-1746, ISSN: 1522-9645

AimsPrimary prevention implantable cardioverter defibrillators (ICDs) are established therapy for reducing mortality in patients with left ventricular systolic dysfunction and ischaemic heart disease (IHD). However, their efficacy in patients without IHD has been controversial. We undertook a meta-analysis of the totality of the evidence.Methods We systematically identified all RCTs comparing ICD versus no ICD in primary prevention. Eligible RCTs were those that recruited patients with left ventricular dysfunction, reported all-cause mortality, and presented their results stratified by the presence of IHD (or recruited only those with or without). Our primary endpoint was all-cause mortality.ResultsWe identified 11 studies enrolling 8567 participants with left ventricular dysfunction, including 3128 patients without IHD and 5439 patients with IHD. In patients without IHD, ICD therapy reduced mortality by 24% (HR 0.76, 95% CI 0.64 to 0.90 p=0.001). In patients with IHD, ICD implantation (at a dedicated procedure), also reduced mortality by 24% (HR 0.76, 95% CI 0.60 to 0.96, p=0.02).ConclusionsUntil now, it has never been explicitly stated that the patients without IHD in COMPANION showed significant survival benefit from adding ICD therapy (to a background of CRT). Furthermore, even with only the trials before DANISH, meta-analysis shows reduced mortality. DANISH is consistent with these data.With a significant 24% mortality reduction in both aetiologies, it may no longer be necessaryto distinguish between them when deciding on primary prevention ICD implantation.

Journal article

Dhutia NM, Zolgharni M, Mielewczik M, Negoita M, Sacchi S, Manoharan K, Francis DP, Cole GDet al., 2017, Open-source, vendor-independent, automated multi-beat tissue Doppler echocardiography analysis, International Journal of Cardiovascular Imaging, Vol: 33, Pages: 1135-1148, ISSN: 1569-5794

Current guidelines for measuring cardiac function by tissue Doppler recommend using multiple beats, but this has a time cost for human operators. We present an open-source, vendor-independent, drag-and-drop software capable of automating the measurement process. A database of ~8000 tissue Doppler beats (48 patients) from the septal and lateral annuli were analyzed by three expert echocardiographers. We developed an intensity- and gradient-based automated algorithm to measure tissue Doppler velocities. We tested its performance against manual measurements from the expert human operators. Our algorithm showed strong agreement with expert human operators. Performance was indistinguishable from a human operator: for algorithm, mean difference and SDD from the mean of human operators’ estimates 0.48 ± 1.12 cm/s (R2 = 0.82); for the humans individually this was 0.43 ± 1.11 cm/s (R2 = 0.84), −0.88 ± 1.12 cm/s (R2 = 0.84) and 0.41 ± 1.30 cm/s (R2 = 0.78). Agreement between operators and the automated algorithm was preserved when measuring at either the edge or middle of the trace. The algorithm was 10-fold quicker than manual measurements (p < 0.001). This open-source, vendor-independent, drag-and-drop software can make peak velocity measurements from pulsed wave tissue Doppler traces as accurately as human experts. This automation permits rapid, bias-resistant multi-beat analysis from spectral tissue Doppler images.

Journal article

De Pooter J, El Haddad M, De Buyzere M, Aranda HA, Cornelussen R, Stegemann B, Rinaldi CA, Sterlinski M, Sokal A, Francis DP, Jordaens L, Stroobandt RX, Heuverswyn FV, Timmermans Fet al., 2017, Biventricular Paced QRS Area Predicts Acute Hemodynamic CRT Response Better Than QRS Duration or QRS Amplitudes, JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Vol: 28, Pages: 192-200, ISSN: 1045-3873

Journal article

Sands SA, Mebrate Y, Edwards BA, Nernati S, Manisty CH, Desai AS, Wellman A, Willson K, Francis DP, Butler JP, Malhotra Aet al., 2017, Resonance as the mechanism of daytime periodic breathing in patients with heart failure, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 237-246, ISSN: 1073-449X

Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited.Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects.Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation.Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined).Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to r

Journal article

Sands SA, Mebrate Y, Edwards BA, Nemati S, Manisty CH, Desai AS, Wellman A, Willson K, Francis DP, Butler JP, Malhotra Aet al., 2017, Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure., Am J Respir Crit Care Med, Vol: 195, Pages: 237-246

RATIONALE: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. OBJECTIVES: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. METHODS: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. MEASUREMENTS AND MAIN RESULTS: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = -0.68) oscillations (P < 0.001 for all, both groups combined). CONCLUSIONS: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underl

Journal article

Captur G, Karperien AL, Hughes AD, Francis DP, Moon JCet al., 2017, The fractal heart - embracing mathematics in the cardiology clinic, Nature Reviews Cardiology, Vol: 14, Pages: 56-64, ISSN: 1759-5002

For clinicians grappling with quantifying the complex spatial and temporal patterns of cardiac structure and function (such as myocardial trabeculae, coronary microvascular anatomy, tissue perfusion, myocyte histology, electrical conduction, heart rate, and blood-pressure variability), fractal analysis is a powerful, but still underused, mathematical tool. In this Perspectives article, we explain some fundamental principles of fractal geometry and place it in a familiar medical setting. We summarize studies in the cardiovascular sciences in which fractal methods have successfully been used to investigate disease mechanisms, and suggest potential future clinical roles in cardiac imaging and time series measurements. We believe that clinical researchers can deploy innovative fractal solutions to common cardiac problems that might ultimately translate into advancements for patient care.

Journal article

Ahmad T, Bouwman RA, Grigoras I, Aldecoa C, Hofer C, Hoeft A, Holt P, Fleisher LA, Buhre W, Pearse RM, Ferguson M, MacMahon M, Shulman M, Cherian R, Currow H, Kanathiban K, Gillespie D, Pathmanathan E, Phillips K, Reynolds J, Rowley J, Douglas J, Kerridge R, Garg S, Bennett M, Jain M, Alcock D, Terblanche N, Cotter R, Leslie K, Stewart M, Zingerle N, Clyde A, Hambidge O, Rehak A, Cotterell S, Huynh WBQ, McCulloch T, Ben-Menachem E, Egan T, Cope J, Halliwell R, Fellinger P, Haisjackl M, Haselberger S, Holaubek C, Lichtenegger P, Scherz F, Schmid W, Hoffer F, Cakova V, Eichwalder A, Fischbach N, Klug R, Schneider E, Vesely M, Wickenhauser R, Grubmueller KG, Leitgeb M, Lang F, Toro N, Bauer M, Laengle F, Haberl C, Mayrhofer T, Trybus C, Buerkle C, Forstner K, Germann R, Rinoesl H, Schindler E, Trampitsch E, Bogner G, Dankl D, Duenser M, Fritsch G, Gradwohl-Matis I, Hartmann A, Hoelzenbein T, Jaeger T, Landauer F, Lindl G, Lux M, Steindl J, Stundner O, Szabo C, Bidgoli J, Verdoodt H, Forget P, Kahn D, Lois F, Momeni M, Pregardien C, Pospiech A, Steyaert A, Veevaete L, De Kegel D, De Jongh K, Foubert L, Smitz C, Vercauteren M, Poelaert J, Van Mossevelde V, Abeloos J, Bouchez S, Coppens M, De Baerdemaeker L, Deblaere I, De Bruyne A, De Hert S, Fonck K, Heyse B, Jacobs T, Lapage K, Moerman A, Neckebroek M, Parashchanka A, Roels N, Van Den Eynde N, Vandenheuvel M, Van Limmen J, Vanluchene A, Vanpeteghem C, Wouters P, Wyffels P, Huygens C, Vandenbempt P, Van de Velde M, Dylst D, Janssen B, Schreurs E, Aleixo FB, Candido K, Batista HD, Guimaraes M, Guizeline J, Hoffmann J, Lobo S, Marques Lobo FR, Nascimento V, Nishiyama K, Pazetto L, Souza D, Rodrigues RS, Vilela dos Santos AM, Jardim J, Sa Malbouisson LM, Silva J, do Nascimento Junior P, Baio TH, Pereira de Castro GI, Watanabe Oliveira HR, Amendola CP, Cardoso G, Ortega D, Brotto AF, De Oliveira MC, Rea-Neto A, Dias F, Travi ME, Zerman L, Azambuja P, Knibel MF, Martins A, Almeida W, Neder Neto C, Tardelli MA, Caser E, Machaet al., 2016, Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries., British Journal of Anaesthesia, Vol: 117, Pages: 601-+, ISSN: 0007-0912

BackgroundAs global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care.MethodsWe designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries.ResultsA total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2–7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries.ConclusionsPoor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care.

Journal article

Raphael CE, Cooper R, Parker KH, Collinson J, Vassiliou V, Pennell DJ, de Silva R, Hsu LY, Greve AM, Nijjer S, Broyd C, Ali A, Keegan J, Francis DP, Davies JE, Hughes AD, Arai A, Frenneaux M, Stables RH, Di Mario C, Prasad SKet al., 2016, Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance., Journal of the American College of Cardiology, Vol: 68, Pages: 1651-1660, ISSN: 1558-3597

BACKGROUND: Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. OBJECTIVES: Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. METHODS: Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. RESULTS: Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). CONCLUSIONS: Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; th

Journal article

Mereu R, Taraborrelli P, Sau A, Di Toro A, Halim S, Hayat S, Bernardi L, Francis DP, Sutton R, Lim PBet al., 2016, Diagnostic role of head-up tilt test in patients with cough syncope, EUROPACE, Vol: 18, Pages: 1273-1279, ISSN: 1099-5129

Journal article

Jones S, Lumens J, Sohaib SMA, Finegold JA, Kanagaratnam P, Tanner M, Duncan E, Moore P, Leyva F, Frenneaux M, Mason M, Hughes AD, Francis D, Whinnett ZI, the BRAVO Investigators, on behalf of the BRAVO Investigatorset al., 2016, Cardiac Resynchronisation Therapy: mechanisms of action and scope for further improvement in cardiac function, Europace, Vol: 19, Pages: 1178-1186, ISSN: 1532-2092

BackgroundCardiac resynchronisation therapy(CRT) may exert its beneficial hemodynamic effect by improving ventricular synchrony and improving atrioventricular(AV) timing.Aims To establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronisation. Methods 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.ResultsThe simulations suggest 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 201ms and LV activation time is reduced by 25ms (typical for current CRT methods) then AV delay optimisation is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25ms produced an additional 2.6mmHg increase in BP (30% of effect size observed with current CRT).In the clinical population, ventricular fusion significantly shortened QRS duration (∆-27±23ms, P <0.001), and, improved SBP (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.ConclusionsImproving 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 resynchronisation can be developed.

Journal article

Ahmad Y, Cook C, Shun-Shin M, Balu A, Keene D, Nijjer S, Petraco R, Baker CS, Malik IS, Bellamy MF, Sethi A, Mikhail GW, Al-Bustami M, Khan M, Kaprielian R, Foale RA, Mayet J, Davies JE, Francis DP, Sen Set al., 2016, Resolving the paradox of randomised controlled trials and observational studies comparing multi-vessel angioplasty and culprit only angioplasty at the time of STEMI, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 222, Pages: 1-8, ISSN: 0167-5273

Journal article

Negoita M, Zolgharni M, Dadkho E, Pernigo M, Mielewczik M, Cole GD, Dhutia NM, Francis DPet al., 2016, Frame rate required for speckle tracking echocardiography: A quantitative clinical study with open-source, vendor-independent software, International Journal of Cardiology, Vol: 218, Pages: 31-36, ISSN: 1874-1754

ObjectivesTo determine the optimal frame rate at which reliable heart walls velocities can be assessed by speckle tracking.BackgroundAssessing left ventricular function with speckle tracking is useful in patient diagnosis but requires a temporal resolution that can follow myocardial motion. In this study we investigated the effect of different frame rates on the accuracy of speckle tracking results, highlighting the temporal resolution where reliable results can be obtained.Material and methods27 patients were scanned at two different frame rates at their resting heart rate. From all acquired loops, lower temporal resolution image sequences were generated by dropping frames, decreasing the frame rate by up to 10-fold.ResultsTissue velocities were estimated by automated speckle tracking. Above 40 frames/s the peak velocity was reliably measured. When frame rate was lower, the inter-frame interval containing the instant of highest velocity also contained lower velocities, and therefore the average velocity in that interval was an underestimate of the clinically desired instantaneous maximum velocity.ConclusionsThe higher the frame rate, the more accurately maximum velocities are identified by speckle tracking, until the frame rate drops below 40 frames/s, beyond which there is little increase in peak velocity. We provide in an online supplement the vendor-independent software we used for automatic speckle-tracked velocity assessment to help others working in this field.

Journal article

Sterlinski M, Sokal A, Lenarczyk R, Van Heuverswyn F, Rinaldi CA, Vanderheyden M, Khalameizer V, Francis D, Heynens J, Stegemann B, Cornelussen Ret al., 2016, In Heart Failure Patients with Left Bundle Branch Block Single Lead MultiSpot Left Ventricular Pacing Does Not Improve Acute Hemodynamic Response To Conventional Biventricular Pacing. A Multicenter Prospective, Interventional, Non-Randomized Study, PLOS ONE, Vol: 11, ISSN: 1932-6203

Journal article

Francis DP, Cole GD, 2016, Authors' reply to Perry., BMJ, Vol: 353, Pages: i2031-i2031, ISSN: 0959-8138

Journal article

Ghosh AK, Hughes AD, Francis D, Chaturvedi N, Pellerin D, Deanfield J, Kuh D, Mayet J, Hardy R, MRC NSHD Scientific and Data Collection Teamet al., 2016, Midlife blood pressure predicts future diastolic dysfunction independently of blood pressure., Heart, Vol: 102, Pages: 1380-1387, ISSN: 1355-6037

OBJECTIVES: High blood pressure (BP) is associated with diastolic dysfunction, but the consequence of elevated BP over the adult life course on diastolic function is unknown. We hypothesised that high BP in earlier adulthood would be associated with impaired diastolic function independent of current BP. METHODS: Participants in the Medical Research Council National Survey of Health and Development birth cohort (n=1653) underwent investigations including echocardiography at age 60-64 years. The relationships between adult BP, antihypertensive treatment (HTT) and echocardiographic measures of diastolic function were assessed using adjusted regression models. RESULTS: Increased systolic BP (SBP) at ages 36, 43 and 53 years was predictive of increased E/e' and increased left atrial volume. These effects were only partially explained by SBP at 60-64 years and increased left ventricular mass. HTT was also associated with poorer diastolic function after adjustment for SBP at 60-64 years. Faster rates of increase in SBP in midlife were also associated with increased poorer diastolic function. CONCLUSIONS: High SBP in midlife is associated with poorer diastolic function at age 60-64 years. Early identification of individuals with high BP or rapid rises in BP may be important for prevention of impaired cardiac function in later life.

Journal article

Cook CM, Ahmad Y, Shun-Shin MJ, Nijjer S, Petraco R, Al-Lamee R, Mayet J, Francis DP, Sen S, Davies JEet al., 2016, Quantification of the Effect of Pressure Wire Drift on the Diagnostic Performance of Fractional Flow Reserve, Instantaneous Wave-Free Ratio, and Whole-Cycle Pd/Pa, Circulation: Cardiovascular Interventions, Vol: 9, ISSN: 1941-7640

Background—Small drifts in intracoronary pressure measurements (±2 mmHg) can affect stenosis categorization usingpressure indices. This has not previously been assessed for fractional flow reserve (FFR), instantaneous wave-free ratio(iFR), and whole-cycle distal pressure/proximal pressure (Pd/Pa) indices.Methods and Results—Four hundred forty seven stenoses were assessed with FFR, iFR, and whole-cycle Pd/Pa. Cut pointvalues for significance were predefined as ≤0.8, <0.90, and <0.93, respectively. Pressure wire drift was simulated byoffsetting the distal coronary pressure trace by ±2 mmHg. FFR, iFR, and whole-cycle Pd/Pa indices were recalculatedand stenosis misclassification quantified. Median (±median absolute deviation) values for FFR, iFR, and whole-cycle Pd/Pa were 0.81 (±0.11), 0.90 (±0.07), and 0.93 (±0.06), respectively. 34.6% (155), 50.1% (224), and 62.2% (278) of valueslay within ±0.05 U of the cut point for FFR, iFR, and whole-cycle Pd/Pa, respectively. With ±2 mmHg pressure wire drift,21% (94), 25% (110), and 33% (148) of the study population were misclassified with FFR, iFR, and whole-cycle Pd/Pa,respectively. Both FFR and iFR had significantly lower misclassification than whole-cycle Pd/Pa (P<0.001). There wasno statistically significant difference between the diagnostic performance of FFR and iFR (P=0.125).Conclusions—In a substantial proportion of cases, small amounts of pressure wire drift are enough to causestenoses to change classification. Whole-cycle Pd/Pa is more vulnerable to such reclassification than FFR and iFR.

Journal article

Francis DP, Cole GD, 2016, Coronary artery disease: screen or treat?, BMJ, Vol: 352, ISSN: 0959-8138

Journal article

Finegold JA, Shun-Shin M, Cole G, Zaman S, Maznyczka A, Zaman S, al-lamee R, Ye S, Francis Det al., 2016, The distribution of lifespan gain from primary prevention intervention, Open Heart, Vol: 3, ISSN: 2053-3624

Objective: When advising patients about possible initiation of primary prevention treatment, clinicians currently do not have information on expected impact on lifespan, nor how much this increment differs between individuals. 
Methods: First, UK cardiovascular and non-cardiovascular mortality data was used to calculate the mean lifespan gain from an intervention (such as a statin) that reduces cardiovascular mortality by 30%. Second, a new method was developed to calculate the probability distribution of lifespan gain. Third, we performed a survey in 3 UK cities on 11 days between May-June 2014 involving 396 participants (mean age 40 years, 55% male) to assess how individuals evaluate potential benefit from primary prevention therapies. Results: Amongst numerous identical patients the lifespan gain, from an intervention that reduces cardiovascular mortality by 30%, is concentrated within an unpredictable minority. For example, 50-year-old males with national-average cardiovascular risk have mean lifespan gain of 7 months. However, 93% of these identical individuals gain no lifespan, while the remaining 7% gain a mean of 99 months. Many survey respondents preferred a chance of large lifespan gain to the identical life-expectancy gain given as certainty. Indeed, 33% preferred a 2% probability of 10 years to 5-fold more gain, expressed as certainty of 1 year. Conclusions:People who gain lifespan from preventative therapy gain far more than the average for their risk stratum, even if perfectly defined. This may be important in patient decision-making. Looking beyond mortality reduction alone from preventative therapy, the benefits are likely to be even larger.

Journal article

Broyd CJ, Nijjer S, Sen S, Petraco R, Jones S, Al-Lamee R, Foin N, Al-Bustami M, Sethi A, Kaprielian R, Ramrakha P, Khan M, Malik IS, Francis DP, Parker K, Hughes AD, Mikhail GW, Mayet J, Davies JEet al., 2016, Estimation of coronary wave intensity analysis using noninvasive techniques and its application to exercise physiology, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 310, Pages: H619-H627, ISSN: 0363-6135

Journal article

Barron A, Francis DP, Mayet J, Ewert R, Obst A, Mason M, Elkin S, Hughes AD, Wensel Ret al., 2016, Oxygen uptake efficiency slope and breathing reserve, not anaerobic threshold, discriminate between patients with cardiovascular disease over COPD, JACC: Heart Failure, Vol: 4, Pages: 252-261, ISSN: 2213-1779

Objectives To compare the relative discrimination of various cardiopulmonary exercise testing (CPX) variables between cardiac and respiratory disease.Background CPX testing is used in many cardiorespiratory diseases. However discrimination of cardiac and respiratory dysfunction can be problematic. Anaerobic threshold (AT) and oxygen-uptake to work-rate relationship (VO2/WR slope) have been proposed as diagnostic of cardiac dysfunction, but multiple variables have not been compared.Methods 73 patients with chronic obstructive airways disease (COPD, n=25), heart failure with reduced ejection fraction (HFrEF, n=40) or combined COPD and HFrEF (n=8), were recruited and underwent CPX testing on a bicycle ergometer. Following a familiarisation test, each patient underwent a personalised second test aiming for maximal exercise after ~10 minutes. Measurements from this test were used to calculate area under receiver-operator characteristic curve (AUC). Results PeakVO2 was similar between the 2 principal groups (COPD 17.1±4.6ml/min/kg (mean±SD), HFrEF 16.4±3.6ml/min/kg). Breathing reserve (AUC 0.91) and percent predicted oxygen uptake efficiency slope (OUES) (AUC 0.87) had the greatest ability to discriminate between COPD and HFrEF. VO2/WR slope performed significantly worse (AUC 0.68). VO2 at the AT did not discriminate (AUC 0.56 for AT as percent predicted peakVO2). OUES and BR remained strong discriminators when compared with an external cohort of healthy matched controls, and were comparable to B-type natriuretic peptide.Conclusions Breathing reserve and OUES discriminate heart failure from COPD. Despite it being considered an important determinant of cardiac dysfunction, the AT could not discriminate these typical clinical populations whilst the VO2/WR slope showed poor to moderate discriminant ability.

Journal article

Sau A, Mereu R, Taraborrelli P, Dhutia NM, Willson K, Hayat SA, Francis DP, Sutton R, Lim PBet al., 2016, A long-term follow-up of patients with prolonged asystole of greater than 15 s on head-up tilt testing, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 203, Pages: 482-485, ISSN: 0167-5273

Journal article

Howard JP, Shun-Shin MJ, Hartley A, Bhatt DL, Krum H, Francis DPet al., 2016, Quantifying the 3 Biases That Lead to Unintentional Overestimation of the Blood Pressure-Lowering Effect of Renal Denervation., Circulation: Cardiovascular Quality and Outcomes, Vol: 9, Pages: 14-22, ISSN: 1941-7713

BACKGROUND: Studies of renal denervation report disparate results. Meta-analysis by trial design may allow quantitative estimation of sources and magnitude of biases in denervation studies. METHODS AND RESULTS: One hundred forty nonrandomized, 6 randomized open-label, and 2 randomized blinded studies were analyzed for 2 outcomes: (1) blood pressure changes for nonrandomized, open-label randomized, and blinded studies; and (2) quantification of 3 biases potentially contributing to apparent antihypertensive effects: (a) regression to the mean, (b) asymmetrical data handling, and (c) true blood pressure drops caused by something other than the tested therapy (confounding). Nonrandomized studies and open-label randomized trials reported large reductions in office blood pressure of 23.6 mm Hg (95% confidence interval [CI], 22.0 to 25.3) and 29.1 mm Hg (95% CI, 25.2 to 33.1 mm Hg), respectively. They reported smaller reductions in ambulatory blood pressures (11.2 mm Hg; 95% CI, 10.0 to 12.4). The blinded trials found no significant reduction in blood pressure (2.9 mm Hg; 95% CI, -0.4 to 6.3). Analyses of these data indicate the magnitude of the 3 potential sources of bias to be regression to the mean, -1.01 mm Hg (95% CI, 4.24 to -6.27); asymmetrical data handling, -10.8 mm Hg (95% CI, -8.77 to -12.87); and confounding, -8.3 mm Hg (95% CI, -4.73 to -11.83). CONCLUSIONS: Increasingly bias-resistant trial designs report effect sizes of decreasing magnitude. This disparity may be caused by asymmetrical data handling and confounding (eg, increased drug adherence). If these differences are caused by trial design and not by some other differences in patients or procedures, which happen to match the trial design, then randomization alone is not enough: blinding is also needed. This has broad implications across trials of medications and devices.

Journal article

Petraco R, Sen S, Nijjer S, Malik IS, Mikhail GW, Al-Lamee R, Cook C, Baker C, Kaprielian R, Foale RA, Mayet J, Francis DP, Davies JEet al., 2015, ECG-Independent Calculation of Instantaneous Wave-Free Ratio, JACC-CARDIOVASCULAR INTERVENTIONS, Vol: 8, Pages: 2043-2046, ISSN: 1936-8798

Journal article

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