BACKGROUND Sympathetic activation in ischemic heart disease can cause lethal arrhythmias. These often are preceded by premature ventricular complexes (PVCs), which at the cellular level could result from delayed afterdepolarizations.OBJECTIVE The purpose of this study was to identify and map vulnerable areas for arrhythmia initiation after myocardial infarction (MI) and to explore the link between PVCs and cellular events.METHODS Anterior-septal wall MI was induced by 120 minutes of coronary occlusion followed by reperfusion (27 MI and 16 sham pigs). After 4 weeks, EnSiteÔ electroanatomic mapping combined with imaging was performed to precisely locate PVC sites of origin and subsequently record monophasic action potentials. Cardiomyocytes were isolated from different regions to study regional cellular remodeling. Isoproterenol was used as a surrogate for adrenergic stimulation both in vivo and in cardiomyocytes.RESULTS PVCs originated from the MI border zone (BZ) and occurred at discrete areas with clusters of PVCs within the BZ. At these sites, frequent delayed afterdepolarizations and occasional associated spontaneous action potentials translating to a PVC were present. Cardiomyocytes isolated from the MI BZ exhibited more spontaneous action potentials than cardiomyocytes from remote regions. Sensitivity to adrenergic stimulation was increased in MI, in vivo and in cardiomyocytes. In awake, freely moving MI animals, frequent PVCs, ventricular arrhythmia, and sudden cardiac death occurred spontaneously at moderately elevated heart rates.CONCLUSION Post-MI, arrhythmias initiate from discrete vulnerable areas within the BZ, where delayed afterdepolarizations, related to increased adrenergic response of BZ cardiomyocytes, can generate PVCs.

Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy can be effective for ventricular arrhythmias with identifiable culprit lesions. Yet, these approaches are not always successful and come with a considerable cost, while pharmacological management is often poor and ineffective, and occasionally proarrhythmic. Advances in mechanistic insights of arrhythmias and technological innovation have led to improved interventional approaches that are being evaluated clinically, yet pharmacological advancement has remained behind. We review the mechanistic basis for current management and provide a perspective for gaining new insights that centre on the complex tissue architecture of the arrhythmogenic infarct and border zone with surviving cardiac myocytes as the source of triggers and central players in re-entry circuits. Identification of the arrhythmia critical sites and characterisation of the molecular signature unique to these sites can open avenues for targeted therapy and reduce off-target effects that have hampered systemic pharmacotherapy. Such advances are in line with precision medicine and a patient-tailored therapy.

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Background An increase in beat‐to‐beat variability of repolarization (BVR) predicts arrhythmia onset in experimental models, but its clinical translation is not well established. We investigated the temporal changes in BVR before nonsustained ventricular tachycardia (nsVT) in patients with implantable cardioverter defibrillator (ICD). Methods and Results Patients with nsVT on 24‐hour Holter before ICD implantation for ischemic cardiomyopathy (ischemic cardiomyopathy+nsVT, n=43) or dilated cardiomyopathy (dilated cardiomyopathy+nsVT, n=37), matched ICD candidates without nsVT (ischemic cardiomyopathy‐nsVT, n=29 and dilated cardiomyopathy‐nsVT, n=26), and patients without ICD without structural heart disease (n=50) were studied. Digital Holter recordings from these patients were analyzed using a modified fiducial segment averaging technique to detect the QT interval. The nsVT episodes were semi‐automatically identified and QT‐BVR was assessed 1‐, 5‐, and 30‐minutes before nsVT, and at rest (at 3:00  am ). Resting BVR was higher in ICD patients compared with controls without structural heart disease. In ICD patients with nsVT, BVR increased significantly 1‐minute pre‐nsVT in ischemic cardiomyopathy (2.21±0.59 ms, versus 5 minutes pre‐nsVT: 1.78±0.50 ms, P <0.001) and dilated cardiomyopathy (2.09±0.57 ms, versus 5‐minutes pre‐nsVT: 1.58±0.51 ms, P <0.001), but not in patients without nsVT. In multivariable Cox regression analysis, pre‐nsVT BVR was a significant predictor for appropriate therapy during follow‐up. Conclusions Baseline BVR is elevated and temporal changes in BVR predict imminent nsVT events in patients with ICD independent of underlying cause. Real‐time BVR monitoring could be used to predict impending ventricular arrhythmia and allow preventive therapy to be incorporated into ICDs.

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