Abstract
Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, [Ca2+]myo and [Ca2+]SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and [Na+]i and thus provides insight into how changes in electrical activity, [Na+]i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in [Na+]i and [Ca2+]myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.
Highlights
The alternating strong and weak beats in the left ventricle are known as pulsus alternans or mechanical alternans which was first described in the 19th century by Traube [1].Another type is electrical alternans which describe the beat-to-beat variation in direction, amplitude, and duration of any components in an ECG waveform [2].The two are distinguished, yet they may both coexist [3,4].Pulsus alternans is associated with different pathophysiological conditions, e.g., aortic stenosis, tachycardia, ischemia, acidosis and hypertrophic cardiomyopathy [5]
calcium release units (CRU)’s states where we examine act-act-the fraction of CRU that activate in beat (i) and conin CRU’s states where we examine act-act—the fraction of CRU that activate in beat (i) and tinue to activate in beat (i + 1), with act-inact, inact-inact, and inact-act (dark continue to activate in beat (i + 1), with act-inact, inact-inact, and inact-act green). (C) The probability of RyR opening at each beat. (D) The fraction. (C) The probability of RyR opening at each beat. (D) The of L-type Camyocyte (LCC) open during each beat
The model helps to explain a modest role of [Ca2+ ]junctional sarcoplasmic reticulum (jSR) in forming alternans, while it’s suggested that disturbing INa, ICaL and membrane potential plays a dominant role in the forming of pulsus alternans
Summary
The alternating strong and weak beats in the left ventricle are known as pulsus alternans or mechanical alternans which was first described in the 19th century by Traube [1].Another type is electrical alternans (or T-wave alternans) which describe the beat-to-beat variation in direction, amplitude, and duration of any components in an ECG waveform [2].The two are distinguished, yet they may both coexist [3,4].Pulsus alternans is associated with different pathophysiological conditions, e.g., aortic stenosis, tachycardia, ischemia, acidosis and hypertrophic cardiomyopathy [5]. The alternating strong and weak beats in the left ventricle are known as pulsus alternans or mechanical alternans which was first described in the 19th century by Traube [1]. Another type is electrical alternans (or T-wave alternans) which describe the beat-to-beat variation in direction, amplitude, and duration of any components in an ECG waveform [2]. Pulsus alternans is associated with different pathophysiological conditions, e.g., aortic stenosis, tachycardia, ischemia, acidosis and hypertrophic cardiomyopathy [5]. Pulsus alternans may lead to pulseless activity, i.e., when there is an electrical activity, but the heart either does not contract, or the contraction is not strong enough to produce a sufficient cardiac output to generate a pulse [8]
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