Angiotensin Receptor Antagonists to Prevent Sudden Death in Heart Failure: Does the Dose Matter?

Figure 1

Molecular mechanisms that link AT₁ receptor and arrhythmia susceptibility are summarized on this picture. The AT₁ receptor downregulates connexin 43 via protein kinase C (PKC), thus favouring fragmentation and electrical reentry of the stimuli that can lead to tachyarrhythmias. Angiotensin II also affects Ca²⁺ homeostasis via the AT₁ receptor by downregulating sarcoplasmic reticulum (SR) Ca²⁺-ATPase pump (SERCA 2a) and altering ryanodine receptor 2 (RyR2) function. Downregulation of SERCA2a through the AT₁ receptor determines defective SR Ca²⁺ reuptake and promotes protein kinase A (PKA) phosphorylation of RyR2, thus leading to diastolic Ca²⁺ leak from the SR. The resultant cytoplasmic Ca²⁺ overload can trigger spontaneous delayed afterdepolarizations and ventricular arrhythmias.