Background: Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. Objectives: To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors. Methods: A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death). Results: Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not signifi-cantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse). Conclusion: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.

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.

Hemodynamically optimal atrioventricular (AV) delay can be derived by echocardiography or beat‐by‐beat blood pressure (BP) measurements, but analysis is labor intensive. Laser Doppler perfusion monitoring measures blood flow and can be incorporated into future implantable cardiac devices.

Background: People of South Asian and African Caribbean ethnicities living in UK have a high risk of cardiometabolic disease. Limited data exist regarding detailed cardiometabolic phenotyping in this population. Methods enabling this are widely available, but the practical aspects of undertaking such studies in large and diverse samples are seldom reported.Methods: The Southall and Brent Revisited (SABRE) study is the UK's largest tri-ethnic longitudinal cohort. Over 1,400 surviving participants (58–85 years) attended the 2nd study visit (2008–2011); during which, comprehensive cardiovascular phenotyping, including 3D-echocardiography [3D-speckle-tracking (3D-STE)], computed tomography, coronary artery calcium scoring, pulse wave velocity, central blood pressure, carotid artery ultrasound, and retinal imaging, were performed. We describe the methods used with the aim of providing a guide to their feasibility and reproducibility in a large tri-ethnic population-based study of older people.Results: Conventional echocardiography and all vascular measurements showed high feasibility (>90% analyzable of clinic attendees), but 3D-echocardiography (3DE) and 3D-STE were less feasible (71% 3DE acquisition feasibility and 38% 3D-STE feasibility of clinic attendees). 3D-STE feasibility differed by ethnicity, being lowest in South Asian participants and highest in African Caribbean participants (p < 0.0001). Similar trends were observed in men (P < 0.0001) and women (P = 0.005); however, in South Asians, there were more women with unreadable 3D-images compared to men (67 vs. 58%). Intra- and inter-observer variabilities were excellent for most of conventional and advanced echocardiographic measures. The test-retest reproducibility was good-excellent and fair-good for conventional and advanced echocardiographic measures, respectively, but lower than when re-reading the same images. All vascular measures demonstrated excellent or fair-good reproducibility.Conclusions: We describe the feasibility and reproducibility of detailed cardiovascular phenotyping in an ethnically diverse population. The data collected will lead to a better understanding of why people of South Asian and African Caribbean ancestry are at elevated risk of cardiometabolic diseases.

AIMS:A prolonged PR interval may adversely affect ventricular filling and, therefore, cardiac function. AV delay can be corrected using right ventricular pacing (RVP), but this induces ventricular dyssynchrony, itself harmful. Therefore, in intermittent heart block, pacing avoidance algorithms are often implemented. We tested His-bundle pacing (HBP) as an alternative. METHODS:Outpatients with a long PR interval (>200 ms) and intermittent need for ventricular pacing were recruited. We measured within-patient differences in high-precision hemodynamics between AV-optimized RVP and HBP, as well as a pacing avoidance algorithm (Managed Ventricular Pacing [MVP]). RESULTS:We recruited 18 patients. Mean left ventricular ejection fraction was 44.3 ± 9%. Mean intrinsic PR interval was 266 ± 42 ms and QRS duration was 123 ± 29 ms. RVP lengthened QRS duration (+54 ms, 95% CI 42-67 ms, p < .0001) while HBP delivered a shorter QRS duration than RVP (-56 ms, 95% CI -67 to -46 ms, p < .0001). HBP did not increase QRS duration (-2 ms, 95% CI -8 to 13 ms, p = .6). HBP improved acute systolic blood pressure by mean of 5.0 mmHg (95% CI 2.8-7.1 mmHg, p < .0001) compared to RVP and by 3.5 mmHg (95% CI 1.9-5.0 mmHg, p = .0002) compared to the pacing avoidance algorithm. There was no significant difference in hemodynamics between RVP and ventricular pacing avoidance (p = .055). CONCLUSIONS:HBP provides better acute cardiac function than pacing avoidance algorithms and RVP, in patients with prolonged PR intervals. HBP allows normalization of prolonged AV delays (unlike pacing avoidance) and does not cause ventricular dyssynchrony (unlike RVP). Clinical trials may be justified to assess whether these acute improvements translate into longer term clinical benefits in patients with bradycardia indications for pacing.

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 (p(noninferiority) =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; p(noninferiority) = 0.002) and hormonal changes (mean change in N-terminal pro-B-type natriuretic peptide -10 pg/ml; p(noninferiority) = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; p(noninferiority) < 0.001; LV diastolic dimension 0 mm; p(noninferiority) < 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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Objectives: Ethnic minority groups in the UK experience marked differences in cardiovascular disease risk. We investigated differences in arterial central haemodynamics, stiffness, and load in a tri-ethnic population-based cohort. Methods: A total of 1312 participants (70 ± 6 years) underwent echocardiography and measurement of brachial and central blood pressure to assess central arterial haemodynamics including central pulse pressure (cPP), arterial stiffness [cPP/stroke volume (SV)], systemic vascular resistance (SVR), and load (Ea). Results: Brachial and central SBPs were similar in all ethnic groups. Compared with Europeans, cPP, cPP/SV, and Ea were higher in South Asians. In contrast, cPP/SV was lower in African Caribbeans despite higher mean arterial pressure, higher SVR, and higher diabetes prevalence. cPP/SV and Ea remained significantly higher in South Asians and significantly lower in African Caribbeans after multivariate adjustment. Diabetes and higher HbA1c were more strongly associated with higher cPP/SV in South Asians than in Europeans (Pinteraction = 0.045 and 0.005, respectively); higher HbA1c was also more strongly associated with increased Ea in South Asians than Europeans (Pinteraction = 0.01). There was no evidence of an interaction between glycaemia and cPP/SV in African Caribbeans. Conclusions: Compared with Europeans, South Asians have unfavorable arterial function. Diabetes and hyperglycaemia have a more deleterious effect on cPP/SV and Ea in South Asians. In contrast, African Caribbeans have more favourable arterial function than Europeans and South Asians. These differences may contribute to the differential ethnic rates of cardiovascular disease.

Objectives:Aortic (central) blood pressure (BP) differs from brachial BP and may be a superior predictor of cardiovascular events. However, its measurement is currently restricted to research settings, owing to a moderate level of operator dependency. We tested a new noninvasive device in a large UK cohort. The device estimates central BP using measurements obtained with an upper arm cuff inflated to suprasystolic pressure. We compared these estimates with those obtained using radial tonometry as well as with invasively acquired measurements of aortic BP in a limited number of individuals.Methods:Consecutive cuff-based and tonometry-based estimates of the pressure waveform and the central BP were obtained from 1107 individuals (70 +/- 6 years). Short-term and long-term reproducibility studies were performed on 28 individuals. Simultaneous cuff-based and invasively measured pressure traces were acquired and compared in an additional six individuals (65 +/- 20 years).Results:Central systolic BP, as estimated by the cuff-based device, was found to be highly reproducible (coefficient of variation 4 and 8% for short and long-term reproducibility, respectively) and was comparable to that estimated by tonometry (average difference 3 +/- 6 mmHg, intraclass correlation coefficient = 0.91). The cuff-based pressure waveforms were similar to those acquired invasively (cross-correlation coefficient 0.93), and the difference in the estimated central systolic BP was -5 +/- 8 mmHg (P = 0.2).Conclusion:Cuff-based devices show promise to simplify the measurement of central BP, whilst maintaining a similar fidelity to tonometry. This could lead to improved adoption of estimates of central BP in clinical practice.

AIMS:Full-disclosure study describing Doppler patterns during iterative atrioventricular delay (AVD) optimization of biventricular pacemakers (cardiac resynchronization therapy, CRT). METHOD AND RESULTS:Doppler traces of the first 50 eligible patients undergoing iterative Doppler AVD optimization in the BRAVO trial were examined. Three experienced observers classified conformity to guideline-described patterns. Each observer then selected the optimum AVD on two separate occasions: blinded and unblinded to AVD. Four Doppler E-A patterns occurred: A (always merged, 18% of patients), B (incrementally less fusion at short AVDs, 12%), C (full separation at short AVDs, as described by the guidelines, 28%), and D (always separated, 42%). In Groups A and D (60%), the iterative guidelines therefore cannot specify one single AVD. On the kappa scale (0 = chance alone; 1 = perfect agreement), observer agreement for the ideal AVD in Classes B and C was poor (0.32) and appeared worse in Groups A and D (0.22). Blinding caused the scattering of the AVD selected as optimal to widen (standard deviation rising from 37 to 49 ms, P < 0.001). By blinding 28% of the selected optimum AVDs were ≤60 or ≥200 ms. All 50 Doppler datasets are presented, to support future methodological testing. CONCLUSION:In most patients, the iterative method does not clearly specify one AVD. In all the patients, agreement on the ideal AVD between skilled observers viewing identical images is poor. The iterative protocol may successfully exclude some extremely unsuitable AVDs, but so might simply accepting factory default. Irreproducibility of the gold standard also prevents alternative physiological optimization methods from being validated honestly.

Background Echocardiographic optimization of pacemaker settings is the current standard of care for patients treated with cardiac resynchronization therapy. However, the process requires considerable time of expert staff. The BRAVO study is a non-inferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay with an alternative method using non-invasive blood pressure monitoring that can be automated to consume less staff resources. Methods/Design BRAVO is a multi-centre, randomized, cross-over, non-inferiority trial of 400 patients with a previously implanted cardiac resynchronization device. Patients are randomly allocated to six months in each arm. In the echocardiographic arm, AV delay is optimized using the iterative method and VV delay by maximizing LVOT VTI. In the haemodynamic arm AV and VV delay are optimized using non-invasive blood pressure measured using finger photoplethysmography. At the end of each six month arm, patients undergo the primary outcome measure of objective exercise capacity, quantified as peak oxygen uptake (VO 2 ) on a cardiopulmonary exercise test. Secondary outcome measures are echocardiographic measurement of left ventricular remodelling, quality of life score and N-terminal pro B-type Natriuretic Peptide (NT-pro BNP). The study is scheduled to complete recruitment in December 2013 and to complete follow up in December 2014. Discussion If exercise capacity is non-inferior with haemodynamic optimization compared with echocardiographic optimization, it would be proof of concept that haemodynamic optimization is an acceptable alternative which has the potential to be more easily implemented. Trial registration Clinicaltrials.gov NCT01258829

Cardiometabolic risk is elevated in South Asians and African Caribbeans compared with Europeans, yet whether this is associated with ethnic differences in left-ventricular structure is unclear. Conventional M-mode or 2-dimensional echocardiography may be misleading, because they calculate left-ventricular mass and remodeling using geometric assumptions. Left-ventricular structure was compared in a triethnic population-based cohort using conventional and 3-dimensional echocardiography on 895 individuals (aged 55-85 years; 427 European, 325 South Asian, 143 African Caribbean). Left-ventricular mass was indexed, and left-ventricle remodeling index and relative wall thickness were calculated. Anthropometry, blood pressure, and fasting bloods were measured. Three-dimensional left-ventricular mass index did not differ between Europeans (mean ± SE, 29.8 ± 0.3 g/m(2.7)) and African Caribbeans (29.9 ± 0.5 g/m(2.7); P=0.9), but it was significantly lower in South Asians (28.1 ± 0.4 g/m(2.7); P<0.0001) compared with Europeans. These findings persisted on multivariate adjustment. In contrast, conventional left-ventricle mass index was significantly higher in African Caribbeans (46.4 ± 0.9 g/m(2.7)) than in Europeans (41.9 ± 0.5 g/m(2.7); P<0.0001). Left-ventricle remodeling index was the highest in African Caribbeans and the lowest in South Asians. Relative wall thickness was also higher in African Caribbeans, but no different in South Asians, compared with Europeans. Differences in left-ventricle remodeling index were attenuated by adjustment for cardiometabolic factors between African Caribbeans and Europeans only. In conclusion, left-ventricular mass is lower in South Asians and equivalent in African Caribbeans compared with Europeans, even when cardiometabolic risk factors are accounted for. Left-ventricular remodeling rather than hypertrophy may explain the increased risk of heart failure in people of African Caribbean origin.

Background/Objectives Thiazolidinediones (TZDs), such as pioglitazone, are widely used to treat type 2 diabetes but there is evidence that their use is associated with an increased risk of heart failure. We compared the effect of pioglitazone vs. placebo on left ventricular (LV) diastolic and systolic function in people with type 2 diabetes. Methods and results 24 male or female patients with type 2 diabetes were randomized to pioglitazone (45 mg/day) or placebo in addition to current therapy for 12 weeks using a prospective double blind crossover protocol following a run-in period >1 week and a 2 week washout period at crossover. Tissue Doppler early peak velocity (e′), a measure of LV diastolic function, was the primary outcome. Pioglitazone significantly increased e′ by 0.7(0.1, 1.3) cm/s (mean (95% confidence interval); p=0.02) compared with placebo. Pioglitazone also increased E/A and mitral deceleration index, ejection fraction, stroke volume and weight, whereas fasting glucose, HbA1c, total peripheral resistance and LV meridional end systolic stress were decreased. Conclusions Treatment with pioglitazone for 12 weeks improves left ventricular diastolic and systolic function in people with type 2 diabetes.

BackgroundChanges in ventricular rotation measured by two-dimensional speckle tracking echocardiography (2DSTE) are early indicators of cardiac disease. Data on the clinical feasibility of this important measure are scarce and there is no information on the comparability of different software versions. We assessed the feasibility, reproducibility and within patient temporal variability of 2DSTE in a large community based sample of older adults. We additionally compared 2DSTE results to those generated by 3DSTE.Methods and results1408 participants underwent transthoracic echocardiography. Using Philips Qlab 8.1 peak LV rotation at either the base or the apex was analysable in 432 (31%) participants. Peak twist measurements were achieved in 274 (20%) participants. 66 participants were randomly selected for the reproducibility study. 20 additional participants had scans 4-6 weeks apart for temporal variability and 3D echocardiography to assess the agreement between 2DSTE and 3DSTE. Reproducibility was evaluated using the intraclass coefficient of correlation (ICC). Better reproducibility for rotation and twist were obtained when measured at the endocardium, and when using more recent software versions, Peak twist and rotation were significantly different using two versions of the same software. Agreement with 3DSTE was better using newer software.ConclusionFeasibility of 2DSTE is low in this cohort of elderly individuals severely limiting its utility in clinical settings. However if high quality images can be acquired assessment of ventricular rotation by 2DSTE is reproducible. Caution should be taken when comparing measurements of ventricular rotation by software from different vendors or different versions of software from the same vendor.

OBJECTIVE Diabetes is associated with left ventricular (LV) diastolic and systolic dysfunction. South Asians may be at particular risk of developing LV dysfunction owing to a high prevalence of diabetes. We investigated the role of diabetes and hyperglycemia in LV dysfunction in a community-based cohort of older South Asians and white Europeans. RESEARCH DESIGN AND METHODS Conventional and Doppler echocardiography was performed in 999 participants (542 Europeans and 457 South Asians aged 58–86 years) in a population-based study. Anthropometry, fasting bloods, coronary artery calcification scoring, blood pressure, and renal function were measured. RESULTS Diabetes and hyperglycemia across the spectrum of HbA1c had a greater adverse effect on LV function in South Asians than Europeans (N-terminal-probrain natriuretic peptide β ± SE 0.09 ± 0.04, P = 0.01, vs. −0.04 ± 0.05, P = 0.4, P for HbA1c/ethnicity interaction 0.02), diastolic function (E/e′ 0.69 ± 0.12, P < 0.0001, vs. 0.09 ± 0.2, P = 0.6, P for interaction 0.005), and systolic function (s′ −0.11 ± 0.06, P = 0.04, vs. 0.14 ± 0.09, P = 0.1, P for interaction 0.2). Multivariable adjustment for hypertension, microvascular disease, LV mass, coronary disease, and dyslipidemia only partially accounted for the ethnic differences. Adverse LV function in diabetic South Asians could not be accounted for by poorer glycemic control or longer diabetes duration. CONCLUSIONS Diabetes and hyperglycemia have a greater adverse effect on LV function in South Asians than Europeans, incompletely explained by adverse risk factors. South Asians may require earlier and more aggressive treatment of their cardiometabolic risk factors to reduce risks of LV dysfunction.