Spontaneous calcium release in tissue from the failing canine heart

Abstract

malities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P Ͻ 0.05] and increased duration (252 vs. 229 s, P Ͻ 0.05) compared with those of normal. Under control conditions and during ␤-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P Ͻ 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P Ͻ 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA. heart failure; arrhythmia; delayed afterdepolarization; triggered activity HEART FAILURE (HF) is a serious public health problem that afflicts millions of people in the United States alone (32). HF is associated with impaired cardiac contractility and relaxation, as well as a high incidence of ventricular arrhythmias and sudden death. Abnormal calcium handling has been implicated as a source of both mechanical and electrical dysfunction observed in HF, making it a key target for investigation and clinical therapy.At the myocyte level, impaired ventricular contractility and relaxation in HF have been attributed to decreased calcium transient amplitude due to diastolic sarcoplasmic reticulum (SR) calcium leak (12,13,35) and reduced SR calcium uptake (3,8,22,24). Calcium dysregulation in human HF has been associated with a significant incidence of nonreentrant arrhythmias (28,30,33) that can occur as the result of early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). At the subcellular level, a DAD is caused by spontaneous calcium release from the SR that activates a transient inward current with a magnitude that depends on the amount of calcium flux (33). While studies in isolated myocytes have provided valuable insight into cellular pathophysiology, the translation of these results to arrhythmogenesis at the tissue level is not straightforward.The fact...

Arrhythmogenic Delayed Afterdepolarizations Are Promoted by Severe Hypothermia But Not Therapeutic Hypothermia

“…The mSCR rise time was defined as the time between the minimal fluorescence after the last paced beat, to the peak fluorescence of the mSCRs. The slope of mSCRs, a determinant of triggered activity, 31 was calculated by dividing mSCR amplitude by mSCR rise time. In any given experiment, under every condition, the 10 sites with the largest mSCR amplitude were analyzed for mSCR and DAD parameters; average data of these sites is presented.…”

“…This is manifest in the biphasic nature of the mSCR slope and DAD amplitude (Figure 2B), both of which are directly related to triggered activity occurrence. 31 In other words, slow RyR release kinetics is the predominant effect during TH, resulting in decreased mSCR slope and DAD amplitude. However, RyR-Po increases exponentially with decreasing temperature, which would make it much more predominant at SH, relative to RyR conductance.…”

Mechanisms of Ca2+-Triggered Arrhythmias

“…This mechanism forms the basis for the typical rate and magnitude dependence of DADs: the faster is the triggering rhythm, the shorter is the interval of the triggered response and the faster are self-sustaining trains of DADs (Katra & Laurita, 2005). In other words, only spontaneous SR Ca 2+ release events of sufficient magnitude and rate occurring at multiple sites synchronously within the cell will trigger DAD-mediated action potentials (Hoeker et al, 2009). The action potential initiation from a DAD is facilitated in cardiac myocytes from failing hearts, because of the increased expression of NCX and the reduction of repolarizing K + currents as a consequence of the electrophysiological remodelling (Tomaselli & Zipes, 2004).…”

“…Simplified electrophysiological mechanism underlying delayed afterdepolarization and triggered activity: spontaneous SR Ca 2+ release ("Ca 2+ leak") through dysfunctional RyR2 activates NCX exchange and causes membrane positive oscillations (DADs), which may escalate into triggered action potentials and sustained triggered activity (adapted from Kockskamper & Pieske, 2006). (Hoeker et al, 2009;Mulder et al, 1989), the mechanisms underlying triggered activity in situ remain elusive. It is unknown whether spontaneous Ca 2+ oscillations originate from the extracellular space through L-type Ca 2+ channels, or from SR via RyR2, or perhaps from other sources (e.g.…”

Activation of .BETA.3-Adrenergic Receptor Inhibits Ventricular Arrhythmia in Heart Failure through Calcium Handling

“…Calcium handling, a term defines as entire process of Ca 2+ entry, store, release and reuptake, is central to the control of heart rhythm and contraction (Gwathmey et al 1987). Thus, it is not surprising that abnormalities in calcium handling have been involved as key elements in many forms of heart disease like VT. A recent study also suggested that irregular calcium handling may induce VT in canines with tachycardia-induced CHF (Hoeker et al 2009). Ca 2+ transport is governed by the"Ca 2+ container" inside heart cells, called sarcoplasmic reticulum (SR) (Levine and Loewen 2006).…”