Right ventricular function and long-term clinical outcomes after cardiac resynchronization therapy: A cardiovascular magnetic resonance study.

BACKGROUND: Right ventricular (RV) dysfunction has been linked to a poor response to cardiac resynchronization therapy (CRT). We sought to determine whether cardiovascular magnetic resonance (CMR)-derived measures of RV function influence clinical outcomes after CRT. METHODS: In this retrospective study, we used CMR to assess pre-implant RV volumes and RV ejection fraction (RVEF) in relation to clinical outcomes after CRT implantation. RESULTS: Among 243 patients (age: 70.3 ± 10.8 years [mean ± SD]; 68.7% male; 121 [49.8%]) with ischemic cardiomyopathy and 122 (50.2%) with nonischemic cardiomyopathy, 141 (58%) after CRT-defibrillation (CRT-D) and 102 (42%) after CRT-pacing (CRT-P), 101 (41.6.0%) patients died, 61 (25.1%) from cardiac causes and 24 (9.88%) from noncardiac causes, over 5.87 years (median; interquartile range: 4.35-7.73). Two (0.82%) patients underwent cardiac transplantation and four (1.64%) had a left ventricular assist device (LVAD). A total of 41 (16.9%) met the composite endpoint of sudden cardiac death (SCD), ventricular tachycardia, or ventricular fibrillation. In univariate analyses, no measure of RV function was associated with total mortality or the arrhythmic endpoint. RVEF was associated with cardiac mortality on univariate analyses (HR per 10%: 0.82, 95% CI 0.70-0.96), but not on multivariate analyses that included left ventricular ejection fraction. CONCLUSIONS: There is no relationship between measures of RV function, such as RV volumes and RVEF, and the long-term clinical outcome of CRT. These findings indicate that such measures should not be considered in patient selection.

Acute Hemodynamic Effects of Simultaneous and Sequential Multi-Point Pacing in Heart Failure Patients With an Expected Higher Rate of Sub-response to Cardiac Resynchronization Therapy: Results of Multicenter SYNSEQ Study.

The aim of the SYNSEQ (Left Ventricular Synchronous vs. Sequential MultiSpot Pacing for CRT) study was to evaluate the acute hemodynamic response (AHR) of simultaneous (3P-MPP syn) or sequential (3P-MPP seq) multi-3-point-left-ventricular (LV) pacing vs. single point pacing (SPP) in a group of patients at risk of a suboptimal response to cardiac resynchronization therapy (CRT). Twenty five patients with myocardial scar or QRS ≤ 150 or the absence of LBBB (age: 66 ± 12 years, QRS: 159 ± 12 ms, NYHA class II/III, LVEF ≤ 35%) underwent acute hemodynamic assessment by LV + dP/dtmax with a variety of LV pacing configurations at an optimized AV delay. The change in LV + dP/dt max (%ΔLV + dP/dt max) with 3P-MPP syn (15.6%, 95% CI: 8.8%-22.5%) was neither statistically significantly different to 3P-MPP seq (11.8%, 95% CI: 7.6-16.0%) nor to SPP basal (11.5%, 95% CI:7.1-15.9%) or SPP mid (12.2%, 95% CI:7.9-16.5%), but higher than SPP apical (10.6%, 95% CI:5.3-15.9%, p = 0.03). AHR (defined as a %ΔLV + dP/dt max ≥ 10%) varied between pacing configurations: 36% (9/25) for SPP apical, 44% (11/25) for SPP basal, 54% (13/24) for SPP mid, 56% (14/25) for 3P-MPP syn and 48% (11/23) for 3P-MPP seq.Fifteen patients (15/25, 60%) had an AHR in at least one pacing configuration. AHR was observed in 10/13 (77%) patients with a LBBB but only in 5/12 (42%) patients with a non-LBBB (p = 0.11). To conclude, simultaneous or sequential multipoint pacing compared to single point pacing did not improve the acute hemodynamic effect in a suboptimal CRT response population. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02914457.

Myocardial Fibrosis Predicts Ventricular Arrhythmias and Sudden Death After Cardiac Electronic Device Implantation.

BACKGROUND: Increasing evidence supports a link between myocardial fibrosis (MF) and ventricular arrhythmias. OBJECTIVES: The purpose of this study was to determine whether presence of myocardial fibrosis on visual assessment (MFVA) and gray zone fibrosis (GZF) mass predicts sudden cardiac death (SCD) and ventricular fibrillation/sustained ventricular tachycardia after cardiac implantable electronic device (CIED) implantation. METHODS: In this prospective study, total fibrosis and GZF mass, quantified using cardiovascular magnetic resonance, was assessed in relation to the primary endpoint of SCD and the secondary, arrhythmic endpoint of SCD or ventricular arrhythmias after CIED implantation. RESULTS: Among 700 patients (age 68.0 ± 12.0 years), 27 (3.85%) experienced a SCD and 121 (17.3%) met the arrhythmic endpoint over median 6.93 years (IQR: 5.82-9.32 years). MFVA predicted SCD (HR: 26.3; 95% CI: 3.7-3,337; negative predictive value: 100%). In competing risk analyses, MFVA also predicted the arrhythmic endpoint (subdistribution HR: 19.9; 95% CI: 6.4-61.9; negative predictive value: 98.6%). Compared with no MFVA, a GZF mass measured with the 5SD method (GZF5SD) >17 g was associated with highest risk of SCD (HR: 44.6; 95% CI: 6.12-5,685) and the arrhythmic endpoint (subdistribution HR: 30.3; 95% CI: 9.6-95.8). Adding GZF5SD mass to MFVA led to reclassification of 39% for SCD and 50.2% for the arrhythmic endpoint. In contrast, LVEF did not predict either endpoint. CONCLUSIONS: In CIED recipients, MFVA excluded patients at risk of SCD and virtually excluded ventricular arrhythmias. Quantified GZF5SD mass added predictive value in relation to SCD and the arrhythmic endpoint.

Greyzone myocardial fibrosis and ventricular arrhythmias in patients with a left ventricular ejection fraction >35.

AIMS: To determine whether myocardial fibrosis and greyzone fibrosis (GZF) on cardiovascular magnetic resonance (CMR) is associated with ventricular arrhythmias in patients with coronary artery disease (CAD) and a left ventricular ejection fraction (LVEF) >35%. METHODS AND RESULTS: In this retrospective study of CAD patients, GZF mass using the 3SD method (GZF3SD) and total fibrosis mass using the 2SD method (TF2SD) on CMR were assessed in relation to the primary, combined endpoint of sudden cardiac death, ventricular tachycardia, ventricular fibrillation, or resuscitated cardiac arrest. Among 701 patients [age: 65.8 ± 12.3 years (mean ± SD)], 28 (3.99%) patients met the primary endpoint over 5.91 years (median; interquartile range 4.42-7.64). In competing risks analysis, a GZF3SD mass ≥5.0 g was strongly associated with the primary endpoint [subdistribution hazard ratio (sHR): 17.4 (95% confidence interval, CI 6.64-45.5); area under receiver operator characteristic curve (AUC): 0.85, P < 0.001]. A weaker association was observed for TF2SD mass ≥23 g [sHR 10.4 (95% CI 4.22-25.8); AUC: 0.80, P < 0.001]. The range of sHRs for GZF3SD mass (1-527) was wider than for TF2SD mass (1-37.6). CONCLUSIONS: In CAD patients with an LVEF >35%, GZF3SD mass was strongly associated with the arrhythmic endpoint. These findings hold promise for its use in identifying patients with CAD and an LVEF >35% at risk of arrhythmic events.

Cardiac operations and interventions during the COVID-19 pandemic: a nationwide perspective.

AIMS: The COVID-19 pandemic has led to a decline in hospitalizations for non-COVID-19-related conditions. We explored the impact of the COVID-19 pandemic on cardiac operations and interventions undertaken in England. METHODS AND RESULTS: An administrative database covering hospital activity for England, the Health Episodes Statistics, was used to assess a total of 286 697 hospitalizations for cardiac operations and interventions, as well as 227 257 hospitalizations for myocardial infarction (MI) and 453 799 for heart failure (HF) from 7 January 2019 to 26 July 2020. Over the 3 months of 'lockdown', total numbers and mean reductions in weekly rates [n (-%)], compared with the same time period in 2019, were: coronary artery bypass grafting [-2507 (-64%)]; percutaneous coronary intervention [-5245 (-28%)]; surgical [-1324 (-41%)] and transcatheter [-284 (-21%)] aortic valve replacement; mitral valve replacement; implantation of pacemakers [-6450 (-44%)], cardiac resynchronization therapy with [-356 (-42%)] or without [-491 (-46%)] defibrillation devices, and implantable cardioverter-defibrillators [-501 (-45%)]; atrial fibrillation ablation [-1902 (-83%)], and other ablations [-1712 (-64%)] (all P < 0.001). Over this period, there were 21 038 fewer procedures than in the reference period in 2019 (P < 0.001). These changes paralleled reductions in hospitalizations for MI [-10 794 (-27%)] and HF [-63 058 (-28%)] (both P < 0.001). CONCLUSIONS: The COVID-19 pandemic has led to substantial reductions in the number of cardiac operations and interventions undertaken. An alternative strategy for healthcare delivery to patients with cardiac conditions during the COVID-19 pandemic is urgently needed.

Myocardial Fibrosis as a Predictor of Sudden Death in Patients With Coronary Artery Disease.

BACKGROUND: The "gray zone" of myocardial fibrosis (GZF) on cardiovascular magnetic resonance may be a substrate for ventricular arrhythmias (VAs). OBJECTIVES: The purpose of this study was to determine whether GZF predicts sudden cardiac death (SCD) and VAs (ventricular fibrillation or sustained ventricular tachycardia) in patients with coronary artery disease (CAD) and a wide range of left ventricular ejection fractions (LVEFs). METHODS: In this retrospective study of CAD patients, the presence of myocardial fibrosis on visual assessment (MFVA) and GZF mass in patients with MFVA were assessed in relation to SCD and the composite, arrhythmic endpoint of SCD or VAs. RESULTS: Among 979 patients (mean age [± SD]: 65.8 ± 12.3 years), 29 (2.96%) experienced SCD and 80 (8.17%) met the arrhythmic endpoint over median 5.82 years (interquartile range: 4.1 to 7.3 years). In the whole cohort, MFVA was strongly associated with SCD (hazard ratio: 10.1; 95% confidence interval [CI]: 1.42 to 1,278.9) and the arrhythmic endpoint (hazard ratio: 28.0; 95% CI: 4.07 to 3,525.4). In competing risks analyses, associations between LVEF <35% and SCD (subdistribution hazard ratio [sHR]: 2.99; 95% CI: 1.42 to 6.31) and the arrhythmic endpoint (sHR: 4.71; 95% CI: 2.97 to 7.47) were weaker. In competing risk analyses of the MFVA subcohort (n = 832), GZF using the 3SD method (GZF3SD) >5.0 g was strongly associated with SCD (sHR: 10.8; 95% CI: 3.74 to 30.9) and the arrhythmic endpoint (sHR: 7.40; 95% CI: 4.29 to 12.8). Associations between LVEF <35% and SCD (sHR: 2.62; 95% CI: 1.24 to 5.52) and the arrhythmic endpoint (sHR: 4.14; 95% CI: 2.61 to 6.57) were weaker. CONCLUSIONS: In CAD patients, MFVA plus quantified GZF3SD mass was more strongly associated with SCD and VAs than LVEF. In selecting patients for implantable cardioverter-defibrillators, assessment of MFVA followed by quantification of GZF3SD mass may be preferable to LVEF.

Effect of QRS area reduction and myocardial scar on the hemodynamic response to cardiac resynchronization therapy.

BACKGROUND: Vectorcardiographic QRS area (QRSarea) predicts clinical outcomes after cardiac resynchronization therapy (CRT). Myocardial scar adversely affects clinical outcomes after CRT. OBJECTIVE: The purpose of this study in patients with an ideally deployed quadripolar left ventricular (LV) lead (QUAD) was to determine whether reducing QRSarea leads to an acute hemodynamic response (AHR) and whether scar affects this interaction. METHODS: Patients (n = 26; age 69.2 ± 9.12 years [mean ± SD]) underwent assessment of the maximum rate of change of LV pressure (ΔLV dP/dtmax) during CRT using various left ventricular pacing locations (LVPLs). Cardiac magnetic resonance (CMR) scan was used to localize LV myocardial scar. RESULTS: Interindividually, ΔQRSarea (area under the receiver operating characteristic curve [AUC] 0.81; P <.001) and change in QRS duration (ΔQRSd) (AUC 0.76; P <.001) predicted ΔLV dP/dtmax after CRT. Scar burden correlated with ΔQRSarea (r = 0.35; P = .003), ΔQRSarea (r = 0.35; P = .003), and ΔQRSd (r = 0.46; P <.001). A reduction in QRSarea was observed with LVPLs remote from scar (-3.28 ± 38.1 µVs) or in LVPLs in patients with no scar at all (-43.8 ± 36.8 µVs), whereas LVPLs over scar increased QRSarea (22.2 ± 58.4 µVs) (P <.001 for all comparisons). LVPLs within 1 scarred LV segment were associated with lower ΔLV dP/dtmax (-2.21% ± 11.5%) than LVPLs remote from scar (5.23% ± 10.3%; P <.001) or LVPLs in patients with no scar at all (10.2% ± 7.75%) (both P <.001). CONCLUSION: Reducing QRSarea improves the AHR to CRT. Myocardial scar adversely affects ΔQRSarea and the AHR. These findings may support the use of ΔQRSarea and CMR in optimizing CRT using QUAD.

Prognosis of incidental left bundle branch block.

AIMS: Incidental left bundle branch block (iLBBB) is a frequent cause for cardiology referrals. In such instances, there is uncertainty as to its prognosis. We sought to determine the utility of cardiovascular magnetic resonance (CMR) in the risk stratification of patients with iLBBB. METHODS AND RESULTS: Clinical events were collected in patients with iLBBB who had CMR. Controls had no cardiac symptoms or cardiac disease, a normal CMR scan and electrocardiogram. Amongst patients with iLBBB [n = 193, aged 62.7 ± 12.6 years (mean ± SD)], 110/193 (56.9%) had an abnormal phenotype (iLBBBCMR+) and 83/110 (43.0%) had a normal phenotype (iLBBBCMR-). Over 3.75 years (median; inter-quartile range: 2.7-5.5), iLBBBCMR+ had a higher total mortality [adjusted hazard ratio (aHR) 6.49, 95% confidence interval (CI) 1.91-22.0] and total mortality or major adverse cardiac events (MACEs; aHR 9.15, 95% CI 2.56-32.6) than controls (n = 107). In contrast, iLBBBCMR- had a similar risk of total mortality compared with controls, but total mortality or MACEs was higher (aHR 4.24, 95% CI 1.17-15.4; P = 0.028). Amongst iLBBB patients, both myocardial fibrosis (aHR 5.15, 95% CI 1.53-17.4) and left ventricular ejection fraction (LVEF) ≤ 50% (aHR 3.88, 95% CI 1.67-9.06) predicted total mortality. Myocardial fibrosis plus LVEF ≤50% was associated with the highest risk of total mortality (aHR: 9.87, 95% CI 2.99-32.6) and total mortality or MACEs (aHR 3.98, 95% CI 1.73-9.11). CONCLUSIONS: Outcomes in iLBBBCMR+ were poor whereas survival in iLBBBCMR- was comparable with controls. Myocardial fibrosis and LVEF <50% had an additive effect on the risk of clinical outcomes. A CMR scan is pivotal in risk-stratifying patients with iLBBB.

Changes in QRS Area and QRS Duration After Cardiac Resynchronization Therapy Predict Cardiac Mortality, Heart Failure Hospitalizations, and Ventricular Arrhythmias.

Background Predicting clinical outcomes after cardiac resynchronization therapy (CRT) and its optimization remain a challenge. We sought to determine whether pre- and postimplantation QRS area (QRSarea) predict clinical outcomes after CRT. Methods and Results In this retrospective study, QRSarea, derived from pre- and postimplantation vectorcardiography, were assessed in relation to the primary end point of cardiac mortality after CRT with or without defibrillation. Other end points included total mortality, total mortality or heart failure (HF) hospitalization, total mortality or major adverse cardiac events, and the arrhythmic end point of sudden cardiac death or ventricular arrhythmias with or without a shock. In patients (n=380, age 72.0±12.4 years, 68.7% male) undergoing CRT over 7.7 years (median follow-up: 3.8 years [interquartile range 2.3-5.3]), preimplantation QRSarea ≥102 µVs predicted cardiac mortality (HR: 0.36; P<0.001), independent of QRS duration (QRSd) and morphology (P<0.001). A QRSarea reduction ≥45 µVs after CRT predicted cardiac mortality (HR: 0.19), total mortality (HR: 0.50), total mortality or heart failure hospitalization (HR: 0.44), total mortality or major adverse cardiac events (HR: 0.43) (all P<0.001) and the arrhythmic end point (HR: 0.26; P<0.001). A concomitant reduction in QRSarea and QRSd was associated with the lowest risk of cardiac mortality and the arrhythmic end point (both HR: 0.12, P<0.001). Conclusions Pre-implantation QRSarea, derived from vectorcardiography, was superior to QRSd and QRS morphology in predicting cardiac mortality after CRT. A postimplant reduction in both QRSarea and QRSd was associated with the best outcomes, including the arrhythmic end point.

Survival after cardiac resynchronization therapy: results from 50 084 implantations.

AIMS: Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT. METHODS AND RESULTS: A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3-4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76-0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74-0.84) or without (aHR 0.82, 95% CI 0.74-0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76-3.34). Relative survival was higher in 2015-2017 than in 2009-2011 (aHR 0.64, 95% CI 0.59-0.69). CONCLUSION: Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017.

Allopurinol as a therapeutic option in cardiovascular disease.

Epidemiological studies indicate that hyperuricaemia is an independent risk factor for cardiovascular disease. Alongside uric acid formation, increased xanthine oxidase activity also results in the formation of oxidative free radicals and superoxide particles. Oxidative stress significantly contributes to the development of cardiovascular disease, including endothelial cell dysfunction, atherosclerosis, vascular calcification and impaired myocardial energetics. Allopurinol, a competitive xanthine oxidase inhibitor, in addition to reducing serum uric acid levels, can act as a free radical scavenger. Although traditionally used for the management of gout, there has been renewed interest in the role of allopurinol in the management of cardiovascular disease. In this review, we summarise the role of the xanthine oxidase pathway in the generation of oxidative stress and evaluate the current body of evidence assessing the clinical effects of allopurinol in patients with cardiovascular disease. A number of small clinical studies have shown a beneficial effect of allopurinol in reducing ischemia-reperfusion injury in the setting of bypass surgery and coronary angioplasty. Additionally, studies in heart failure indicate a potential favourable effect of allopurinol on endothelial dysfunction, LV function and haemodynamic indices, particularly in those with raised serum uric acid levels. Whilst this cheap and readily available pharmacological option may offer a very cost effective therapeutic option, large-scale prospective studies are required to better delineate its role in reducing hard clinical end-points.

Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702-2167]s vs. 1435[347-1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226-2069]s vs. 1539[561-2316]s, p = 0.499; rivaroxaban 2085[1366-2428]s vs. 1885[724-2420]s, p = 0.295) but not with warfarin (1490[1206-1960]s vs. 1776[1545-2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.

Endogenous Fibrinolysis: An Important Mediator of Thrombus Formation and Cardiovascular Risk.

Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.