Transthoracic ultrasound localization microscopy of myocardial vasculature in patients.

Myocardial microvasculature and haemodynamics are indicative of potential microvascular diseases for patients with symptoms of coronary heart disease in the absence of obstructive coronary arteries. However, imaging microvascular structure and flow within the myocardium is challenging owing to the small size of the vessels and the constant movement of the patient's heart. Here we show the feasibility of transthoracic ultrasound localization microscopy for imaging myocardial microvasculature and haemodynamics in explanted pig hearts and in patients in vivo. Through a customized data-acquisition and processing pipeline with a cardiac phased-array probe, we leveraged motion correction and tracking to reconstruct the dynamics of microcirculation. For four patients, two of whom had impaired myocardial function, we obtained super-resolution images of myocardial vascular structure and flow using data acquired within a breath hold. Myocardial ultrasound localization microscopy may facilitate the understanding of myocardial microcirculation and the management of patients with cardiac microvascular diseases.

T-wave morphology abnormalities in the STREAM stage 1 trial.

BACKGROUND: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate). RESULTS: Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25). CONCLUSIONS: T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.

Predictive value of the PRAETORIAN score for defibrillation test success in patients with subcutaneous ICD: A subanalysis of the PRAETORIAN-DFT trial.

BACKGROUND: The PRAETORIAN score estimates the risk of failure of subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy by using generator and lead positioning on bidirectional chest radiographs. The PRospective randomized compArative trial of subcutanEous implanTable cardiOverter-defibrillatoR ImplANtation with and without DeFibrillation Testing (PRAETORIAN-DFT) investigates whether PRAETORIAN score calculation is noninferior to defibrillation testing (DFT) with regard to first shock efficacy in spontaneous events. OBJECTIVE: This prespecified subanalysis assessed the predictive value of the PRAETORIAN score for defibrillation success in induced ventricular arrhythmias. METHODS: This multicenter investigator-initiated trial randomized 965 patients between DFT and PRAETORIAN score calculation after de novo S-ICD implantation. Successful DFT was defined as conversion of induced ventricular arrhythmia in <5 seconds from shock delivery within 2 attempts. Bidirectional chest radiographs were obtained after implantation. The predictive value of the PRAETORIAN score for DFT success was calculated for patients in the DFT arm. RESULTS: In total, 482 patients were randomized to undergo DFT. Of these patients, 457 (95%) underwent DFT according to protocol, of whom 445 (97%) had successful DFT and 12 (3%) had failed DFT. A PRAETORIAN score of ≥90 had a positive predictive value of 25% for failed DFT, and a PRAETORIAN score of <90 had a negative predictive value of 99% for successful DFT. A PRAETORIAN score of ≥90 was the strongest independent predictor for failed DFT (odds ratio 33.77; confidence interval 6.13-279.95; P < .001). CONCLUSION: A PRAETORIAN score of <90 serves as a reliable indicator for DFT success in patients with S-ICD, and a PRAETORIAN score of ≥90 is a strong predictor for DFT failure.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography.

BACKGROUND: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. OBJECTIVES: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype. METHODS: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. RESULTS: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). CONCLUSIONS: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

The proarrhythmogenic role of autonomics and emerging neuromodulation approaches to prevent sudden death in cardiac ion channelopathies.

Ventricular arrhythmias in cardiac channelopathies are linked to autonomic triggers, which are sub-optimally targeted in current management strategies. Improved molecular understanding of cardiac channelopathies and cellular autonomic signalling could refine autonomic therapies to target the specific signalling pathways relevant to the specific aetiologies as well as the central nervous system centres involved in the cardiac autonomic regulation. This review summarizes key anatomical and physiological aspects of the cardiac autonomic nervous system and its impact on ventricular arrhythmias in primary inherited arrhythmia syndromes. Proarrhythmogenic autonomic effects and potential therapeutic targets in defined conditions including the Brugada syndrome, early repolarization syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia will be examined. Pharmacological and interventional neuromodulation options for these cardiac channelopathies are discussed. Promising new targets for cardiac neuromodulation include inhibitory and excitatory G-protein coupled receptors, neuropeptides, chemorepellents/attractants as well as the vagal and sympathetic nuclei in the central nervous system. Novel therapeutic strategies utilizing invasive and non-invasive deep brain/brain stem stimulation as well as the rapidly growing field of chemo-, opto-, or sonogenetics allowing cell-specific targeting to reduce ventricular arrhythmias are presented.

The BLISTER Score: A Novel, Externally Validated Tool for Predicting Cardiac Implantable Electronic Device Infections, and Its Cost-Utility Implications for Antimicrobial Envelope Use.

BACKGROUND: Antimicrobial envelopes reduce the incidence of cardiac implantable electronic device infections, but their cost restricts routine use in the United Kingdom. Risk scoring could help to identify which patients would most benefit from this technology. METHODS: A novel risk score (BLISTER [Blood results, Long procedure time, Immunosuppressed, Sixty years old (or younger), Type of procedure, Early re-intervention, Repeat procedure]) was derived from multivariate analysis of factors associated with cardiac implantable electronic device infection. Diagnostic utility was assessed against the existing PADIT score (Prior procedure, Age, Depressed renal function, Immunocompromised, Type of procedure) in both standard and high-risk external validation cohorts, and cost-utility models examined different BLISTER and PADIT score thresholds for TYRX (Medtronic; Minneapolis, MN) antimicrobial envelope allocation. RESULTS: In a derivation cohort (n=7383), cardiac implantable electronic device infection occurred in 59 individuals within 12 months of a procedure (event rate, 0.8%). In addition to the PADIT score constituents, lead extraction (hazard ratio, 3.3 [95% CI, 1.9-6.1]; P<0.0001), C-reactive protein >50 mg/L (hazard ratio, 3.0 [95% CI, 1.4-6.4]; P=0.005), reintervention within 2 years (hazard ratio, 10.1 [95% CI, 5.6-17.9]; P<0.0001), and top-quartile procedure duration (hazard ratio, 2.6 [95% CI, 1.6-4.1]; P=0.001) were independent predictors of infection. The BLISTER score demonstrated superior discriminative performance versus PADIT in the standard risk (n=2854, event rate: 0.8%, area under the curve, 0.82 versus 0.71; P=0.001) and high-risk validation cohorts (n=1961, event rate: 2.0%, area under the curve, 0.77 versus 0.69; P=0.001), and in all patients (n=12 198, event rate: 1%, area under the curve, 0.8 versus 0.75, P=0.002). In decision-analytic modeling, the optimum scenario assigned antimicrobial envelopes to patients with BLISTER scores ≥6 (10.8%), delivering a significant reduction in infections (relative risk reduction, 30%; P=0.036) within the National Institute for Health and Care Excellence cost-utility thresholds (incremental cost-effectiveness ratio, £18 446). CONCLUSIONS: The BLISTER score (https://qxmd.com/calculate/calculator_876/the-blister-score-for-cied-infection) was a valid predictor of cardiac implantable electronic device infection, and could facilitate cost-effective antimicrobial envelope allocation to high-risk patients.

The frequency of gene variant reclassification and its impact on clinical management in the inherited arrhythmia clinic.

BACKGROUND: Genetic testing in the inherited arrhythmia clinic informs risk stratification, clinical management, and family screening. Periodic review of variant classification is recommended as supporting evidence accrues over time. However, there is limited reporting of real-world data on the frequency and impact of variant reclassification. OBJECTIVE: The purpose of this study was to determine the burden of variant reclassification in our inherited arrhythmia clinic and the impact on clinical management. METHODS: Genetic testing reports for patients referred to our clinic from 2004-2020 were reviewed. Reported variants were reinvestigated using ClinVar, VarSome, and a literature review. Classification was updated using the American College of Medical Genetics and Genomics (ACMG) criteria and tested for association with arrhythmic events and modification of medical management. RESULTS: We identified 517 patients (median age 37 years) who underwent gene panel testing. A variant of uncertain significance (VUS) was reported for 94 patients (18.2%) and more commonly identified when using large gene panels (P <.001). A total of 28 of 87 unique VUSs (32.2%) were reclassified to pathogenic/likely pathogenic (n = 11) or benign/likely benign (n = 17). Of 138 originally reported pathogenic variants, 7 (5.1%) lacked support using ACMG criteria. Variant reclassification was not associated with arrhythmic events; however, it did impact genotype-specific counseling and future therapeutic options. CONCLUSION: In our large real-world patient cohort, we identify a clinically important proportion of both pathogenic variants and VUSs with evidence for reclassification. These findings highlight the need for informed pretest counseling, a regular structured review of variants reported in genetic testing, and the potential benefits to patients for supporting genotype-guided therapy.

Review of the National Institute for Health and Care Excellence guidelines on the management of atrial and ventricular arrhythmias.

The National Institute for Health and Care Excellence (NICE) guidelines present a synopsis of extensive internal evidence and technology reviews, with a particular focus on clinical efficacy and cost-effectiveness within the NHS in England. This approach has delivered a novel perspective on arrhythmia management, with important distinctions from other policymakers' recommendations. For example, when compared with the European Society of Cardiology (ESC) and the American Heart Association (AHA)/Heart Rhythm Society (HRS)/American College of Cardiology (ACC) guidelines on atrial fibrillation (AF), NICE advocates unique strategies regarding arrhythmia detection, stroke and bleeding risk stratification, and rhythm control (NICE CG 196). Likewise, for patients at risk of sudden cardiac death, NICE TA314 not only recommends device therapy based on New York Heart Association class and ECG findings, but also incorporates quality-adjusted life year data from analysis of key randomised controlled trials.This review examines the NICE guidelines, together with those from the AHA/HRS/ACC and ESC, on the management of AF and ventricular arrhythmias and highlights the key common features and discrepancies between these important documents.

Management of arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations, leading to ventricular arrhythmias and sudden cardiac death. Treating this condition can be challenging due to progressive fibrosis, phenotypic variations and small patient cohorts limiting the feasibility of conducting meaningful clinical trials. Although widely used, the evidence base for anti-arrhythmic drugs is limited. Beta-blockers are theoretically sound, yet their efficacy in reducing arrhythmic risk is not robust. Additionally, the impact of sotalol and amiodarone is inconsistent with studies reporting contradictory results. Emerging evidence suggests that combining flecainide and bisoprolol may be efficacious.Radiofrequency ablation has shown some potential in disrupting ventricular tachycardia circuits, with combined endo and epicardial ablation yielding better results which could be considered at the index procedure. In addition, stereotactic radiotherapy may be a future option that can decrease arrhythmias beyond simple scar formation by altering levels of Nav1.5 channels, Connexin 43 and Wnt signalling, potentially modifying myocardial fibrosis.Future therapies, such as adenoviruses and GSk3b modulation, are still in early-stage research. While implantable cardioverter-defibrillator implantation is a key intervention for reducing arrhythmic death, the risks of inappropriate shocks and device complications must be carefully considered.

DOACs vs Vitamin K Antagonists During Cardiac Rhythm Device Surgery: A Multicenter Propensity-Matched Study.

BACKGROUND: There is a paucity of data comparing vitamin K antagonists (VKAs) to direct oral anticoagulants (DOACs) at the time of cardiac implantable electronic device (CIED) surgery. Furthermore, the best management of DOACs (interruption vs continuation) is yet to be determined. OBJECTIVES: This study aimed to compare the incidence of device-related bleeds and thrombotic events based on anticoagulant type (DOAC vs VKA) and regimen (interrupted vs uninterrupted). METHODS: This was an observational multicenter study. We included patients on chronic oral anticoagulation undergoing CIED surgery. Patients were matched using propensity scoring. RESULTS: We included 1,975 patients (age 73.8 ± 12.4 years). Among 1,326 patients on DOAC, this was interrupted presurgery in 78.2% (n = 1,039) and continued in 21.8% (n = 287). There were 649 patients on continued VKA. The matched population included 861 patients. The rate of any major bleeding was higher with continued DOAC (5.2%) compared to interrupted DOAC (1.7%) and continued VKA (2.1%) (P = 0.03). The rate of perioperative thromboembolism was 1.4% with interrupted DOAC, whereas no thromboembolic events occurred with DOAC or VKA continuation (P = 0.04). The use of dual antiplatelet therapy, DOAC continuation, and male sex were independent predictors of major bleeding on a multivariable analysis. CONCLUSIONS: In this large real-world cohort, a continued DOAC strategy was associated with a higher bleeding risk compared to DOAC interruption or VKA continuation in patients undergoing CIED surgery. However, DOAC interruption was associated with increased thromboembolic risk. Concomitant dual antiplatelet therapy should be avoided whenever clinically possible. A bespoke approach is necessary, with a strategy of minimal DOAC interruption likely to represent the best compromise.

Detecting deceased patients on cardiac device remote monitoring: A case series and management guide for cardiac device services.

BACKGROUND: Remote monitoring (RM) of implantable cardiac devices provides substantial and complex information, presenting new challenges such as detection of a patient's death. OBJECTIVE: This study aims to describe RM transmissions indicating death and propose a management strategy for services. METHODS: The study included consecutive ambulatory outpatients whose deaths were detected via RM. Clinical and device data were collected from electronic records, and ethical approval was obtained from the service's institutional review board. RESULTS: Over a 9-year period (2014-2023), 28 patients were detected. The deceased patients had implantable cardioverter-defibrillators, pacemakers, and implantable loop recorders. In 54% of the cases, the patient's death had already been recognized. Alert transmissions indicating death were commonly related to ventricular arrhythmia events, but also due to lead measurements, and implantable loop recorder battery status. Several diagnostic features may indicate a patient's death. The most reliable was the presenting electrogram, demonstrating base rate pacing with no capture. Device diagnostics, lead parameters, and arrhythmia recordings may indicate death; however, not all cases present with recordings and diagnosis may not be conclusive. A majority (82%) had ventricular arrhythmia at the time of death. In cases where defibrillator shocks were delivered, the arrhythmia reinitiated shortly after successful cardioversion. Delayed therapy was observed, and some patients did not receive defibrillator shocks because of discriminators or because the arrhythmia rate fell below the shock zone. CONCLUSION: Detecting a patient death via RM presents unique challenges and considerations for services. Standard operational policies and legal consultation should be established to address the implications.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Long-term association of ultra-short heart rate variability with cardiovascular events.

Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease. In the National Survey for Health and Development (n = 1337 participants), agreement between 15-s and 6-min HRV, assessed with correlation analysis and Bland-Altman plots, was very good for RMSSD and SDSD and good for PHF. In the UK Biobank (n = 51,628 participants, 64% male, median age 58), after a median follow-up of 11.5 (11.4-11.7) years, incidence of outcomes ranged between 1.7% and 4.3%. Non-linear Cox regression analysis showed that reduced usHRV from 15-, 10- and 5-s ECGs was associated with all outcomes. Individuals with low usHRV (< 20th percentile) had hazard ratios for outcomes between 1.16 and 1.29, p < 0.05, with respect to the reference group. In conclusion, usHRV from ≤ 15-s ECGs correlates with standard short-term HRV and predicts increased risk of cardiovascular events in a large population-representative cohort.

ECGI targeted ablation for persistent AF not responding to pulmonary vein isolation: Results of a two-staged strategy (TARGET AF2).

Background: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear. Objectives: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI). Methods: A total of 100 patients with persistent AF of <2 years' duration underwent cryoballoon PVI (ECGI phenotyping of persistent AF based on driver burden and distribution to predict response to pulmonary vein isolation). Patients with documented recurrence of atrial arrhythmia within 12 months were recruited and underwent repeat PVI (if needed) followed by ablation of potential drivers (PDs) identified by electrocardiographic imaging (ECGI). PDs were defined as rotational activity >1.5 revolutions or focal activations. Cycle lengths were measured pre- and postablation. The primary outcome was freedom from atrial arrhythmia off antiarrhythmic drugs at 1 year as per guidelines. Results: Of 37 patients recruited, 26 had recurrent AF and underwent ECGI-guided ablation of PDs. An average of 6.4 ± 2.7 PDs were targeted per patient. The mean ablation time targeting PDs was 15.5 ± 6.9 minutes. An ablation response occurred in 20 patients (AF termination in 6, cycle length prolongation ≥10% in 14). At 1 year, 14 (54%) of 26 patients were free from arrhythmia, and 12 (46%) of 26 were off antiarrhythmic drugs. Considering the 96 patients who completed follow-up out of the original cohort of 100 patients undergoing cryoablation in this staged strategy, freedom from arrhythmia at 1 year following the last procedure was 72 (75%) of 96, or 70 (73%) of 96 off antiarrhythmic drugs. Conclusions: In patients with recurrent AF despite PVI, ECGI-guided ablation caused an acute response in a majority with reasonable long-term outcomes.

Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.

BACKGROUND: The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality. METHODS: A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy. RESULTS: Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1-5 exercise PVCs, P<0.001) and HR, 1.3 (1-5 recovery PVCs, P<0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, P<0.001) and HR, 1.6 (>5 recovery PVCs, P<0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, P<0.001) and 1.5 (>5 recovery PVCs, P<0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs. CONCLUSIONS: In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy.