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.

Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR. We used RHR GWAS summary statistics from 388,237 individuals of European ancestry from UK Biobank and performed fine mapping using publicly available genomic annotation datasets. High-confidence causal variants (accounting for > 75% posterior probability) were identified, and we collated candidate effector genes using a multi-omics approach that combined evidence from colocalisation with molecular quantitative trait loci (QTLs), and long-range chromatin interaction analyses. Finally, we performed druggability analyses to investigate drug repurposing opportunities. The fine mapping pipeline indicated 442 distinct RHR signals. For 90 signals, a single variant was identified as a high-confidence causal variant, of which 22 were annotated as missense. In trait-relevant tissues, 39 signals colocalised with cis-expression QTLs (eQTLs), 3 with cis-protein QTLs (pQTLs), and 75 had promoter interactions via Hi-C. In total, 262 candidate genes were highlighted (79% had promoter interactions, 15% had a colocalised eQTL, 8% had a missense variant and 1% had a colocalised pQTL), and, for the first time, enrichment in nervous system pathways. Druggability analyses highlighted ACHE, CALCRL, MYT1 and TDP1 as potential targets. Our genetic fine-mapping pipeline prioritised 262 candidate genes for RHR that warrant further investigation in functional studies, and we provide potential therapeutic targets to reduce RHR and cardiovascular mortality.

Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders.

The resting QT interval, an electrocardiographic (ECG) measure of ventricular myocardial repolarization, is a heritable risk marker of cardiovascular mortality, but the mechanisms remain incompletely understood. Previously reported candidate genes have provided insights into the regulatory mechanisms of the QT interval. However, there are still important knowledge gaps. We aimed to gain new insights by (i) providing new candidate genes, (ii) identifying pleiotropic associations with other cardiovascular traits, and (iii) scanning for sexually dimorphic genetic effects. We conducted a genome-wide association analysis for resting QT interval with ~9.8 million variants in 52 107 individuals of European ancestry without known cardiovascular disease from the UK Biobank. We identified 40 loci, 13 of which were novel, including 2 potential sex-specific loci, explaining ~11% of the trait variance. Candidate genes at novel loci were involved in myocardial structure and arrhythmogenic cardiomyopathy. Investigation of pleiotropic effects of QT interval variants using phenome-wide association analyses in 302 000 unrelated individuals from the UK Biobank and pairwise genome-wide comparisons with other ECG and cardiac imaging traits revealed genetic overlap with atrial electrical pathology. These findings provide novel insights into how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.

Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.

Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10-8). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.

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.

Electrocardiographic imaging demonstrates electrical synchrony improvement by dynamic atrioventricular delays in patients with left bundle branch block and preserved atrioventricular conduction.

AIMS: Cardiac resynchronization therapy programmed to dynamically fuse pacing with intrinsic conduction using atrioventricular (AV) timing algorithms (e.g. SyncAV) has shown promise; however, mechanistic data are lacking. This study assessed the impact of SyncAV on electrical dyssynchrony across various pacing modalities using non-invasive epicardial electrocardiographic imaging (ECGi). METHODS AND RESULTS: Twenty-five patients with left bundle-branch block (median QRS duration (QRSd) 162.7 ms) and intact AV conduction (PR interval 174.0 ms) were prospectively enrolled. ECGi was performed acutely during biventricular pacing with fixed nominal AV delays (BiV) and using SyncAV (optimized for the narrowest QRSd) during: BiV + SyncAV, LV-only single-site (LVSS + SyncAV), MultiPoint pacing (MPP + SyncAV), and LV-only MPP (LVMPP + SyncAV). Dyssynchrony was quantified via ECGi (LV activation time, LVAT; RV activation time, RVAT; LV electrical dispersion index, LVEDi; ventricular electrical uncoupling index, VEU; and biventricular total activation time, VVtat). Intrinsic conduction LVAT (124 ms) was significantly reduced by BiV pacing (109 ms) (P = 0.001) and further reduced by LVSS + SyncAV (103 ms), BiV + SyncAV (103 ms), LVMPP + SyncAV (95 ms), and MPP + SyncAV (90 ms). Intrinsic RVAT (93 ms), VVtat (130 ms), LVEDi (36 ms), VEU (50 ms), and QRSd (163 ms) were reduced by SyncAV across all pacing modes. More patients exhibited minimal LVAT, VVtat, LVEDi, and QRSd with MPP + SyncAV than any other modality. CONCLUSION: Dynamic AV delay programming targeting fusion with intrinsic conduction significantly reduced dyssynchrony, as quantified by ECGi and QRSd for all evaluated pacing modes. MPP + SyncAV achieved the greatest synchrony overall but not for all patients, highlighting the value of pacing mode individualization during fusion optimization.

Exploiting SMART pass filter deactivation detection to minimize inappropriate subcutaneous implantable cardioverter defibrillator therapies: a real-world single-centre experience and management guide.

AIMS: The SMART Pass™ (SP) algorithm is a high-pass filter that aims to reduce inappropriate therapy (IT) in subcutaneous internal cardiac defibrillator (S-ICD), but SP can deactivate due to low amplitude sensed R waves or asystole. The association between IT and SP deactivation and management strategies were evaluated, hypothesizing SP deactivation increases the risk of IT and device re-programming, or lead/generator re-positioning could reduce this risk. METHODS AND RESULTS: Retrospective single-centre audit of Emblem™ S-ICD devices implanted 2016 to 2020 utilizing health records and remote monitoring data. Cox regression models evaluated associations between SP deactivation and IT. A total of 348 patients (27 ± 16.6 months follow-up) were studied: 73% primary prevention. Thirty-eight patients (11.8%) received 83 shocks with 27 patients (7.8%) receiving a total of 44 IT. Causes of IT were oversensing (98%) and aberrantly conducted atrial fibrillation (2%). SP deactivation occurred in 32 of 348 patients (9%) and was significantly associated with increased risk of IT (hazard ratio 5.36, 95% CI 2.37-12.13). SP deactivation was due to low amplitude R waves (94%), associated with a higher defibrillation threshold at implant and presence of arrhythmogenic right ventricular cardiomyopathy. No further IT occurred 16 ± 15.5 months after corrective interventions, with changing the sensing vector being successful in 59% of cases. CONCLUSION: To reduce the risk of IT, the cause of the SP deactivation should be investigated, and appropriate reprogramming, device, or lead modifications made. Utilizing the alert for SP deactivation and electrograms could pro-actively prevent IT.

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

QT variability unrelated to RR variability during stress testing for identification of coronary artery disease.

Stress test electrocardiogram (ECG) analysis is widely used for coronary artery disease (CAD) diagnosis despite its limited accuracy. Alterations in autonomic modulation of cardiac electrical activity have been reported in CAD patients during acute ischemia. We hypothesized that those alterations could be reflected in changes in ventricular repolarization dynamics during stress testing that could be measured through QT interval variability (QTV). However, QTV is largely dependent on RR interval variability (RRV), which might hinder intrinsic ventricular repolarization dynamics. In this study, we investigated whether different markers accounting for low-frequency (LF) oscillations of QTV unrelated to RRV during stress testing could be used to separate patients with and without CAD. Power spectral density of QTV unrelated to RRV was obtained based on time-frequency coherence estimation. Instantaneous LF power of QTV and QTV unrelated to RRV were obtained. LF power of QTV unrelated to RRV normalized by LF power of QTV was also studied. Stress test ECG of 100 patients were analysed. Patients referred to coronary angiography were classified into non-CAD or CAD group. LF oscillations in QTV did not show significant differences between CAD and non-CAD groups. However, LF oscillations in QTV unrelated to RRV were significantly higher in the CAD group as compared with the non-CAD group when measured during the first phases of exercise and last phases of recovery. ROC analysis of these indices revealed area under the curve values ranging from 61 to 73%. Binomial logistic regression analysis revealed LF power of QTV unrelated to RRV, both during the first phase of exercise and last phase of recovery, as independent predictors of CAD. In conclusion, this study highlights the importance of removing the influence of RRV when measuring QTV during stress testing for CAD identification and supports the added value of LF oscillations of QTV unrelated to RRV to diagnose CAD from the first minutes of exercise. This article is part of the theme issue 'Advanced computation in cardiovascular physiology: new challenges and opportunities'.

Autonomic modulation of the electrical substrate in mice haploinsufficient for cardiac sodium channels: a model of the Brugada syndrome.

A murine line haploinsufficient in the cardiac sodium channel has been used to model human Brugada syndrome: a disease causing sudden cardiac death due to lethal ventricular arrhythmias. We explored the effects of cholinergic tone on electrophysiological parameters in wild-type and genetically modified, heterozygous, Scn5a+/- knockout mice. Scn5a+/- ventricular slices showed longer refractory periods than wild-type both at baseline and during isoprenaline challenge. Scn5a+/- hearts also showed lower conduction velocities and increased mean increase in delay than did littermate controls at baseline and blunted responses to isoprenaline challenge. Carbachol exerted limited effects but reversed the effects of isoprenaline with coapplication. Scn5a+/- mice showed a reduction in conduction reserve in that isoprenaline no longer increased conduction velocity, and this was not antagonized by muscarinic agonists.

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AIMS: Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo. METHODS AND RESULTS: We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans. CONCLUSION: Combined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Prolonged action potential duration and dynamic transmural action potential duration heterogeneity underlie vulnerability to ventricular tachycardia in patients undergoing ventricular tachycardia ablation.

AIMS: Differences of action potential duration (APD) in regions of myocardial scar and their borderzones are poorly defined in the intact human heart. Heterogeneities in APD may play an important role in the generation of ventricular tachycardia (VT) by creating regions of functional block. We aimed to investigate the transmural and planar differences of APD in patients admitted for VT ablation. METHODS AND RESULTS: Six patients (median age 53 years, five male); (median ejection fraction 35%), were studied. Endocardial (Endo) and epicardial (Epi) 3D electroanatomic mapping was performed. A bipolar voltage of <0.5 mV was defined as dense scar, 0.5-1.5 mV as scar borderzone, and >1.5 mV as normal. Decapolar catheters were positioned transmurally across the scar borderzone to assess differences of APD and repolarization time (RT) during restitution pacing from Endo and Epi. Epi APD was 173 ms in normal tissue vs. 187 ms at scar borderzone and 210 ms in dense scar (P < 0.001). Endocardial APD was 210 ms in normal tissue vs. 222 ms in the scar borderzone and 238 ms in dense scar (P < 0.01). This resulted in significant transmural RT dispersion (ΔRT 22 ms across dense transmural scar vs. 5 ms in normal transmural tissue, P < 0.001), dependent on the scar characteristics in the Endo and Epi, and the pacing site. CONCLUSION: Areas of myocardial scar have prolonged APD compared with normal tissue. Heterogeneity of regional transmural and planar APD result in localized dispersion of repolarization, which may play an important role in initiating VT.

In vivo human sock-mapping validation of a simple model that explains unipolar electrogram morphology in relation to conduction-repolarization dynamics.

INTRODUCTION: The unipolar electrogram (UEG) provides local measures of cardiac activation and repolarization and is an important translational link between patient and laboratory. A simple theoretical model of the UEG was previously proposed and tested in silico. METHOD AND RESULTS: The aim of this study was to use epicardial sock-mapping data to validate the simple model's predictions of unipolar electrogram morphology in the in vivo human heart. The simple model conceptualizes the UEG as the difference between a local cardiac action potential and a position-independent component representing remote activity, which is defined as the average of all action potentials. UEGs were recorded in 18 patients using a multielectrode sock containing 240 electrodes and activation (AT) and repolarization time (RT) were measured using standard definitions. For each cardiac site, a simulated local action potential was generated by adjusting a stylized action potential to fit AT and RT measured in vivo. The correlation coefficient (cc) measuring the morphological similarity between 13,637 recorded and simulated UEGs was cc  =  0.89 (0.72-0.95), median (Q1 -Q3 ), for the entire UEG, cc  =  0.90 (0.76-0.95) for QRS complexes, and cc  =  0.83 (0.58-0.92) for T-waves. QRS and T-wave areas from recorded and simulated UEGs showed cc> 0.89 and cc> 0.84, respectively, indicating good agreement between voltage isochrones maps. Simulated UEGs accurately reproduced the interaction between AT and QRS morphology and between RT and T-wave morphology observed in vivo. CONCLUSIONS: Human in vivo whole heart data support the validity of the simple model, which provides a framework for improving the understanding of the UEG and its clinical utility.

In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes.

RATIONALE: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. OBJECTIVE: To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. METHODS AND RESULTS: In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type; P<0.01), because of sarcoplasmic reticulum Ca(2+) ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na(+)/Ca(2+) exchanger current is the main driver in translating Ca(2+) fluctuations into RA. CONCLUSIONS: In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.

Interactive effect of beta-adrenergic stimulation and mechanical stretch on low-frequency oscillations of ventricular action potential duration in humans.

Ventricular repolarization dynamics are crucial to arrhythmogenesis. Low-frequency oscillations of repolarization have recently been reported in humans and the magnitude of these oscillations proposed to be a strong predictor of sudden cardiac death. Available evidence suggests a role of the sympathetic nervous system. We have used biophysically detailed models integrating ventricular electrophysiology, calcium dynamics, mechanics and ß-adrenergic signaling to investigate the underlying mechanisms. The main results were: (1) Phasic beta-adrenergic stimulation (ß-AS) at a Mayer wave frequency between 0.03 and 0.15Hz resulted in a gradual decrease of action potential (AP) duration (APD) with concomitant small APD oscillations. (2) After 3-4minutes of phasic ß-AS, the mean APD adapted and oscillations of APD became apparent. (3) Phasic changes in haemodynamic loading at the same Mayer wave frequency (a known accompaniment of enhanced sympathetic nerve activity), simulated as variations in the sarcomere length, also induced APD oscillations. (4) The effect of phasic ß-AS and haemodynamic loading on the magnitude of APD oscillations was synergistic. (5) The presence of calcium overload and reduced repolarization reserve further enhanced the magnitude of APD oscillations and was accompanied by afterdepolarizations and/or spontaneous APs. In conclusion, low-frequency oscillations of repolarization recently reported in humans were induced by phasic ß-AS and phasic mechanical loading, which acted synergistically, and were greatly enhanced by disease-associated conditions, leading to arrhythmogenic events.

Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart.

The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1-S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope -1.36 ± 1.9 and -0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic.