Prognostic impact of electrical storm in patients with implantable cardioverter defibrillators: Mechanistic and therapeutic considerations to reduce the risk of death

Electrical storm (ES), characterized by short-term recurrent ventricular tachycardia and fibrillation (VT/VF), is a major clinical problem with substantial mortality in patients with implantable cardioverter– defibrillator (ICD) and left ventricular dysfunction. A meta-analysis of 12 ES-related studies showed that this accounts for a nearly 3-fold increased risk of death and is associated with a 3.39-fold increased risk for the composite endpoint of death, heart transplantation, and hospitalization for heart failure (HF) [1]. The majority of previous studies investigated ischemic heart disease (IHD)-associated ES. Thus whether patients with non-ischemic dilated cardiomyopathy (DCM) have a similar risk of death is unknown.

In this issue of Int. J. Cardiol. Noda et al. [2] analyzed data from the Nippon Storm Study, an observational study cohort in which 1570 ICD-patients were enrolled from 48 cardiovascular centers in Japan. This prospective study evaluated the incidence, the risk factor and the subsequent mortality of ES in 1274 patients with structural heart diseases. ES occurred in 21 (6.1%) out of 374 DCM patients with no difference to IHD patients (24/482 patients, 5.0%). DCM-associated ES survivors were at a 3.9-fold increased risk of death compared to non-ES patients, with only a marginal difference in mortality in IHD patients with and without ES. This study is the first to highlight DCM-associated ES in a large cohort, although information on HF worsening and hospitalization and death was not provided.

Although ES, HF progression and associated death are interconnected, the underlying mechanisms are poorly understood. Myocardial damage by electrical shocks is believed to be one major contributor to poor outcomes. The harmful effects of electrical shocks including transient cardiac dysfunction, mild elevation of serum cardiac troponin-I, and pathological and ultrastructural changes are partially ascribed to electroporation, the disruption of cell membranes by an electrical shock [3]. However, the phenomenon is reversible over seconds to minutes and there are conflicting observations that defibrillation shock-induced electroporation occurs at limited regions only (~4% of the whole ventricles) [4], suggesting that the contribution of electroporation to ES-associated mortality might be minor.

An ICD shock drives the sympathetic nervous system. Systemic catecholamine levels increase three-fold but persist only for ~10 min following an ICD shock for induced VF [5]. Although psychiatric disorders such as anxiety and depression, which are also associated with increased sympathetic activity, are diagnosed in about 30% of patients with ICDs [5], it remains uncertain whether and how adrenergic surges contribute to myocardial damage leading to poor outcomes.

Because VF leads to myocardial ischemia, global ischemic stunning likely causes myocardial depression after defibrillation. Reactive oxygen species formation and cytosolic Ca²⁺-overload due to ischemia/reperfusion can be involved in post-defibrillation stunning, which includes increased proteolysis of troponin I and α-actinin by Ca²⁺-activated calpains, acidosis-induced reduction in myofilament Ca²⁺-responsiveness, and tissue injury mediated by proinflammatory nuclear factor-κB [6]. Electromechanical dissociation, the most common cause of death during VF-induction testing in the clinical practice, often occurs in anesthetized patients with oxygenation. We interpret these observations to suggest that excess cytosolic Ca²⁺ during VF may have important consequences for contractile function, independent of ischemia/reperfusion. We hypothesize that Ca²⁺-overload during ventricular tachyarrhythmia worsens the substrate for HF by activating diverse signaling pathways. This notion is also supported by the clinical observation that the type of ventricular tachyarrhythmia influences ES-associated mortality, with the risk being greatest for VF and lowest for slow VT [7].

Fig. 1 illustrates the critical elements of ES pathophysiology. We suggest that the ventricular tachyarrhythmia per se has a stronger contribution to myocardial damage than both electroporation and adrenergic surge caused by electrical shocks. A potential candidate mediator of increased mortality at the cellular level could be the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). This multifunctional kinase phosphorylates multiple proteins involved in regulating Ca²⁺ storage and release, transcription factors, and ion channels. While CaMKII is reversibly activated upon beat-to-beat elevation of intracellular Ca²⁺ (Ca²⁺-dependent form), it is converted into a constitutively-active Ca²⁺-independent form by cardiac stressors, such as fast activation rate, chronic adrenergic stimulation and oxidative stress [8]. Moreover, there is a synergetic interaction between upregulated CaMKII and functional changes in Na⁺-channels (enhanced late Na⁺-current) and ryanodine receptor channels (increased diastolic sarcoplasmic reticulum Ca²⁺-leak), further augmenting persistent Ca²⁺-independent CaMKII activity via a potentially proarrhythmic CaMKII–Na⁺–Ca²⁺ positive feedback loop [8]. The CaMKII overactivity is connected to a variety of cardiac diseases including HF, myocardial infarction, ischemia/reperfusion and cardiac arrhythmias. Previous findings from an experimental ES model by electrical remodeling (QT-prolongation) due to chronic complete atrioventricular block, featuring repetitive Torsades de Pointes and frequent VF episodes, suggest that VF storm results in pronounced CaMKII-activation and prominent phosphorylation-changes in Ca²⁺-handling proteins and the Na⁺-channel and that selective CaMKII inhibition might represent a promising strategy to reduce ES-related mortality [9,10]. Since biological approaches like gene-transfer of CaMKII inhibitory-peptide or small-molecule technologies targeting specifically CaMKII are in their clinical infancy, testing the effects of clinically-available drugs such as ryanodine-receptor channel stabilizers, late Na⁺-current blockers, and other HF medications that indirectly suppress CaMKII activation in ES patients is expected to provide useful insights that may foster the development of new therapeutic approaches to reduce and ultimately prevent the ES-related risk of death.

Fig. 1.

Proposed pathophysiology and therapy of electrical storm. See details in text.