Large Amplitude Rate-Dependent Mechanical Alternans may Precede Arrhythmogenesis in Human Heart Failure and are Linked to Electrical Alternans via Abnormal Calcium Handling

Abstract

Microvolt T-wave alternans (MTWA) testing identifies patients at risk for lethal ventricular arrhythmias. However, stratification of low and high risk patients with MTWA is challenging due in part to poor signal-to-noise ratio (SNR) of MTWA measurements. Since microscopic systolic pressure alternans (MSPA) has a higher SNR than MTWA, and is also associated with abnormal calcium handling, we hypothesized that rate-dependent MSPA also precedes arrhythmia and may be an alternative approach for arrhythmia risk stratification in heart failure patients. To test this hypothesis, we investigated mechanical alternans, a surrogate for MSPA, and its proposed link to arrhythmogenesis via abnormal calcium handling. Electromechanical models of single human myocytes were constructed. Key features of remodeling were incorporated to simulate abnormal calcium handling in human heart failure. A dynamical pacing protocol was used to investigate intracellular calcium concentration ([Ca]i), voltage, and force for different pacing rates. In normal myocytes, [Ca]i, voltage, and force alternans were not found for pacing rates <200 bpm. In the presence of deranged calcium handling common in heart failure (sarcoplasmic calcium reuptake reduced below 74%), [Ca]i, AP phase II voltage, and force alternans developed at moderate pacing rates <120 bpm and increased in magnitude with increased pacing rate. For all pacing rates, the ratio of force alternans to peak force was at least tenfold larger than the ratio of AP phase II voltage alternans to maximum AP phase II voltage. In conclusion, electrical and mechanical alternans are both rate-dependent and linked via abnormal calcium handling, but mechanical alternans has the greatest amplitude across all pacing rates. Thus, mechanical alternans, due to their greater SNR, may be better predictors for arrhythmogenic propensity in heart failure patients than electrical alternans.