Ventricular Arrhythmias in Ischemic Cardiomyopathy-New Avenues for Mechanism-Guided Treatment

Abstract

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.

Keywords: action potential; arrhythmias; calcium; cardiac remodelling; fibrosis; hypertrophy; myocardial infarction.

Figure 1

Sudden cardiac death and ischemic heart disease (IHD). (A) Estimated short-term mortality following myocardial infarction (Adapted from [7] and respective clinical trials). β-block–β-blocker therapy; Defib–defibrillation; CCU–coronary care unit; PCI–percutaneous coronary intervention. (B) Sudden cardiac death accounts for the largest proportion of death in IHD (Adapted from [5]). (C) Incidence rates of sudden cardiac death events (sudden cardiac death or resuscitated sudden cardiac death) in the first 6 months after myocardial infarction (Adapted from [3]). CV–cardiovascular.

Figure 2

Risk assessment and management of ventricular arrhythmias after myocardial infarction. The flowchart was derived from [16,22,23]. Abbreviations: GBM–Guideline-based medical therapy; VT–ventricular tachycardia; VF–ventricular fibrillation; EPS–Electrophysiological study; WCD–wearable cardioverter-defibrillator; ILR–implantable loop recorder; ICD–implantable cardioverter-defibrillator. LVEF–left ventricular ejection fraction.

Figure 3

The unique nature of the myocardial infarction border zone. (A) Picture of a pig heart from with ischaemia/reperfusion injury-induced myocardial infarction after 1 month, illustrating the histological fibrotic structure of the scar (left insert) the mixed fibrosis and myocytes in the border zone (middle insert) and the healthy/non-infarcted remote myocardium (right insert) by Picosirius red staining (Adapted from [49]). (B) Schematic diagram illustrating the multicellular milieu of the border zone as transition between scar and myocardium without ischemic damage (remote myocardium).

Figure 4

Arrhythmia mechanisms in vivo. (A) Example of ventricular arrhythmia initiation by a premature ventricular complex (PVC) from ICD recording of a patient. (B) Top: Initiation of ventricular tachycardia by a PVC during increased adrenergic drive from a loop recorder of an awake, freely-moving pig with ICM (top) and mapping of PVCs provoked by adrenergic stimulation in an anesthetised animal. Bottom: probing the site of PVCs utilizing monophasic action potential (MAP) catheters (right) revealed that the dominant mechanism is delayed after depolarisation-triggered activity (Adapted from [49]). (C) MAP recording illustrating beat-to-beat variability of repolarisation, a functional substrate, is increased in the border zone during sympathetic stimulation (Adapted from [89]]). (D) Illustration of the fixed scar substrate: left, example of high-definition ex vivo cardiac magnetic resonance imaging highlighting the infarct (top) used to reconstruct the infarct in 3D (bottom); right reentrant mechanism of tachycardia utilizing channel of surviving myocytes in the BZ (Adapted from [90]).

Figure 5

Differential regional remodelling of cardiomyocytes: propensity for DADs and triggered action potentials as well as lability of repolarisation. (A) Resting membrane potential (RMP) of regional isolated cardiomyocytes, border zone (BZ) cardiomyocytes have a more depolarised RMP. (B) Reduced I_K1 under ISO (isoproterenol) in BZ cardiomyocytes, a contributor to depolarised RMP and propensity for triggered activity. (C) Spontaneous Ca²⁺ release events and triggered action potentials are increased in MI BZ cardiomyocytes during adrenergic stimulation. (D) Spontaneous Ca²⁺ release and delayed afterdepolarisations (DADs) influence action potential duration and resultant beat-to-beat variability of repolarisation (BVR). (Adapted from [49,89]).

Figure 6

Arrhythmia site-directed studies. (A) Left, Electroanatomical mapping of a premature ventricular complex (PVC) preferred site, red arrow (left) and recording of the presence of triggering delayed after depolarisations at this site (right). (B) Corresponding polar map of the spatial localisation of arrhythmogenic and non-arrhythmogenic sites for the electroanatomical map in (A) (left) that can be translated to Imaging-based reconstructions to guide targeted sampling (Adapted from [49]).