Role of Cardiac Magnetic Resonance Imaging in the Evaluation of Athletes with Premature Ventricular Beats

Premature ventricular beats (PVBs) in athletes are not rare. The risk of PVBs depends on the presence of an underlying pathological myocardial substrate predisposing the subject to sudden cardiac death. The standard diagnostic work-up of athletes with PVBs includes an examination of family and personal history, resting electrocardiogram (ECG), 24 h ambulatory ECG (possibly with a 12-lead configuration and including a training session), maximal exercise testing and echocardiography. Despite its fundamental role in the diagnostic assessment of athletes with PVBs, echocardiography has very limited sensitivity in detecting the presence of non-ischemic left ventricular scars, which can be revealed only through more in-depth studies, particularly with the use of contrast-enhanced cardiac magnetic resonance (CMR) imaging. The morphology, complexity and exercise inducibility of PVBs can help estimate the probability of an underlying heart disease. Based on these features, CMR imaging may be indicated even when echocardiography is normal. This review focuses on interpreting PVBs, and on the indication and role of CMR imaging in the diagnostic evaluation of athletes, with a special focus on non-ischemic left ventricular scars that are an emerging substrate of cardiac arrest during sport.

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

Time-efficient three-dimensional transmural scar assessment provides relevant substrate characterization for ventricular tachycardia features and long-term recurrences in ischemic cardiomyopathy

Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection.

Abstract P445: A Combinatorial Approach Comprehensively Improves The Maturation Of Human Induced Pluripotent Stem Cell Derived Atrial Cardiomyocytes

Introduction: The limited success of pharmacological approaches to atrial fibrillation ( AF ) is due to limitations of in vitro and in vivo models and inaccessibility of human atrial tissue. Patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are a robust platform to model the heterogeneous myocardial substrate of AF, but their immaturity limits their fidelity. Objective: We hypothesized that a combinatorial approach of biochemical (triiodothyronine [ T3 ], insulin-like growth factor-1 [ IGF-1 ], and dexamethasone; collectively TID ), bioenergetic (fatty acids [ FA ]), and electrical stimulation ( ES ) will enhance electrophysiological ( EP ), structural, and metabolic maturity of iPSC- a CMs. Methods: We assessed maturation with whole cell patch clamping, calcium transients, immunofluorescence (IF), Seahorse Analyzer, contractility assay, RT-PCR, Western Blotting, and RNA sequencing (RNAseq). Using a time series with RNAseq we identified signaling pathways and transcriptional regulation that drive EP, structural, and metabolic atrial development and compared iPSC-aCM maturity with human aCMs (haCMs) obtained from the same patient. Results: TID+FA+ES significantly improved structural organization and cell morphology ( Fig. 1a ), enhanced membrane potential stability and improved depolarization ( Fig. 1b ), improved Ca 2+ kinetics with faster and increased Ca 2+ release from sarcoplasmic reticulum ( Fig. 1c ), and increased expression of Na + , Ca 2+ , and K + channels, markers of structural maturity, FA metabolism, and oxidative phosphorylation ( Fig. 1d ). There was no difference in each parameter between TID+FA+ES iPSC-aCMs and haCMs from the same patient. Conclusion: Our optimized, combinatorial TID+FA+ES approach markedly enhanced EP, structural, and metabolic maturity of human iPSC-aCMs, which will be useful for elucidating the genetic basis of AF developing precision drug therapies.

Simultaneous orthogonal bipole mapping compared to conventional electrode configurations and impact on ablation strategies: results from a real world observational study

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Abbott Background 3D mapping systems are pivotal to identify low voltage areas and to define ablation strategies. In this context, high-density multipolar mapping catheters with varying electrode configurations are used for accurate myocardial substrate definition. High density mapping using a grid shaped catheter allows for use of simultaneous analysis of adjacent orthogonal bipolar signals that may assist in more accurate substrate characterization and ablation strategy decisions. Purpose This was a prospective, multicenter observational study to characterize the utility of electroanatomical mapping with a high density grid-style mapping catheter (HD Grid) in subjects undergoing catheter ablation for persistent atrial fibrillation (PersAF) or ventricular tachycardia (VT) in real-world clinical settings. Methods Mapping was performed with the HD Grid catheter to generate high-density maps of cardiac chambers in order to assess the potential influence of the simultaneous orthogonal bipole configuration on PersAF and VT ablation strategies. Differences in substrate identification between simultaneous orthogonal bipole configuration and standard along-the-spline electrode configuration, and potential effects on ablation strategies were investigated. Results During the study period (January 2019 through April 2020), 367 subjects underwent catheter ablation for PersAF (N = 333, average age 64.1yr, 75% male) or VT (N = 34, average age = 64.3yr, 85.3% male). In total, 494 maps were generated to treat patients undergoing PersAF ablation and 57 to treat patients undergoing VT ablation. Compared to standard along-the-spline configuration, mapping with the simultaneous orthogonal bipole configuration showed differences in 57.8% (178/308) of maps generated, with the greatest difference noticed in surface area of low voltage (62.9%) and location of low voltage (55.6%). In comparisons performed live during the procedure (n = 50), simultaneous orthogonal bipole configuration assisted in identification of ablation targets in 70.0% of cases, changing the ablation strategy compared to that identified with along-the-spline configuration in 34.3%. In comparisons performed retrospectively after the procedure (n = 258), the ablation strategy identified with simultaneous orthogonal bipole configuration differed from along-the-spline configuration in 21.7% of maps. Even compared to a higher-density electrode configuration using all-bipoles rather than along-the-spline bipoles, simultaneous orthogonal bipole configuration identified differences in 57.1% of maps. Conclusion The HD grid catheter combined with simultaneous orthogonal bipole configuration can define myocardial substrate more accurately compared to standard along-the-spline configuration. The difference in substrate identification has potential impact on ablation strategy. Further clinical trials are needed to elucidate the role of orthogonal bipole configuration mapping and improved ablation success rates.

MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury

Rationale: The mechanistic target of rapamycin complex-1 (mTORC1) controls metabolism and protein homeostasis, and is activated following ischemic reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little studied. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied prior to ischemic stress. This can be circumvented by regulating one serine (S1365) on tuberous sclerosis complex (TSC2) to achieve bi-directional mTORC1 modulation but only with TCS2-regulated co-stimulation. Objective: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and IPC by amplifying mTORC1 activity to favor glycolytic metabolism. Methods and Results: Mice with either S1365A (TSC2 SA ; phospho-null) or S1365E (TSC2 SE ; phosphomimetic) knock-in mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2 SA mice had amplified mTORC1 activation and improved heart function compared to WT and TSC2 SE hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2 SE hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2 SA , with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acyl-carnitine levels declined during ischemia. The relative IR protection in TSC2 SA was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in WT and TSC2 SE but not TSC2 SA which had the worst post-IR function under these conditions. Conclusions: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC.