Long-term changes in heart rate and electrical remodeling contribute to alternans formation in heart failure: a patient-specific in silico study.

Individuals with chronic heart failure (CHF) have an increased risk of ventricular arrhythmias, which has been linked to pathological cellular remodeling and may also be mediated by changes in heart rate. Heart rate typically fluctuates on a timescale ranging from seconds to hours, termed heart rate variability (HRV). This variability is reduced in CHF, and this HRV reduction is associated with a greater risk for arrhythmias. Furthermore, variations in heart rate influence the formation of proarrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD), or intracellular calcium (Ca). In this study, we investigate how long-term changes in heart rate and electrical remodeling associated with CHF influence alternans formation. We measure key statistical properties of the RR-interval sequences from ECGs of individuals with normal sinus rhythm (NSR) and CHF. Patient-specific RR-interval sequences and synthetic sequences (randomly generated to mimicking these statistical properties) are used as the pacing protocol for a discrete time-coupled map model that governs APD and intracellular Ca handling of a single cardiac myocyte, modified to account for pathological electrical remodeling in CHF. Patient-specific simulations show that beat-to-beat differences in APD vary temporally in both populations, with alternans formation more prevalent in CHF. Parameter studies using synthetic sequences demonstrate that increasing the autocorrelation time or mean RR-interval reduces APD alternations, whereas increasing the RR-interval standard deviation leads to higher alternans magnitudes. Importantly, we find that although both the CHF-associated changes in heart rate and electrical remodeling influence alternans formation, variations in heart rate may be more influential.NEW & NOTEWORTHY Using patient-specific data, we show that both the changes in heart rate and electrical remodeling associated with chronic heart failure influence the formation of proarrhythmic alternans in the heart.

Dual regulation by subcellular calcium heterogeneity and heart rate variability on cardiac electromechanical dynamics.

Heart rate constantly varies under physiological conditions, termed heart rate variability (HRV), and in clinical studies, low HRV is associated with a greater risk of cardiac arrhythmias. Prior work has shown that HRV influences the temporal patterns of electrical activity, specifically the formation of pro-arrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD), or intracellular calcium (Ca) levels. We previously showed that HRV may be anti-arrhythmic by disrupting APD and Ca alternations in a homogeneous cardiac myocyte. Here, we expand on our previous work, incorporating variation in subcellular Ca handling (also known to influence alternans) into a nonlinear map model of a cardiac myocyte composed of diffusively coupled Ca release units (CRUs). Ca-related parameters and initial conditions of each CRU are varied to mimic subcellular Ca heterogeneity, and a stochastic pacing sequence reproduces HRV. We find that subcellular Ca heterogeneity promotes the formation of spatially discordant subcellular alternans patterns, which decreases whole cell Ca and APD alternation for low and moderate HRV, while high subcellular Ca heterogeneity and HRV both promote electromechanical desynchronization. Finally, we find that for low and moderate HRV, both the specific subcellular Ca-related parameters and the pacing sequences influence measures of electromechanical dynamics, while for high HRV, these measures depend predominantly on the pacing sequence. Our results suggest that pro-arrhythmic subcellular discordant alternans tend to form for low levels of HRV, while high HRV may be anti-arrhythmic due to mitigated influence from subcellular Ca heterogeneity and desynchronization of APD from Ca instabilities.

Heart rate variability alters cardiac repolarization and electromechanical dynamics.

Heart rate continuously varies due to autonomic regulation, stochasticity in pacemaking, and circadian rhythm, collectively termed heart rate variability (HRV), during normal physiological conditions. Low HRV is clinically associated with an elevated risk of cardiac arrhythmias. Alternans, a beat-to-beat alternation in action potential duration (APD) and/or intracellular calcium (Ca) transient, is a well-known risk factor associated with cardiac arrhythmias that is typically studied under conditions of a constant pacing rate, i.e., the absence of HRV. In this study, we investigate the effects of HRV on the interplay between APD, Ca, and electromechanical properties, employing a nonlinear discrete-time map model that governs APD and intracellular Ca cycling with a stochastic pacing period. We find that HRV can decrease variation in APD and peak Ca at fast pacing rates for which alternans is present. Further, increased HRV typically disrupts the alternating pattern for both APD and peak Ca and weakens the correlation between APD and peak Ca, thus decoupling Ca-mediated instabilities from repolarization alternation. We find that the efficacy of these effects is regulated by the sarcoplasmic reticulum Ca uptake rate. Overall, these results demonstrate that HRV disrupts arrhythmogenic alternans and suggests that HRV may be a significant factor in preventing life-threatening arrhythmias.