Cardiac Alternans: From Bedside to Bench and Back

Abstract

Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms. Based on experimental and simulation results, we describe their relevance to mechanisms of arrhythmogenesis under different disease conditions, and their link to electrocardiographic characteristics of alternans observed in patients. Our major conclusion is that alternans is not only a predictor, but also a causal mechanism of potentially lethal ventricular and atrial arrhythmias across the full spectrum of arrhythmia mechanisms that culminate in functional reentry, although less important for anatomic reentry and focal arrhythmias.

Keywords: Brugada syndrome; atrial fibrillation; cardiovascular diseases; long QT syndrome; myocardial ischemia; torsades de pointes; ventricular fibrillation.

Figure 1.

T-wave alternans (TWA) and arrhythmogenesis. A, TWA prevalence and arrhythmias in long QT syndrome (LQTS) patients. Left, TWA prevalence vs corrected QT interval (QTc). Right, Cardiac event rate vs QTc with (black) and without (white) TWA. B, TWA transitioning directly to Torsade de pointes (TdP) without a clear preceding premature ventricular complex (PVC). C, TWA in which TdP is initiated by a PVC falling on the large T-wave of the alternating beats. D, TWA, followed sometime later by TdP initiated by a short-long-short sequence.

Figure 2.

Voltage-driven alternans. A, Steep action potential duration restitution (APDR)-slope–induced action potential duration (APD) alternans. B, Early afterdepolarization (EAD)-induced APD alternans. C, Early repolarization-induced APD alternans. Left, Experimental action potential (AP) recordings for the 3 cases, obtained from frog ventricle by Nolasco and Dhalen (A), a rabbit ventricular myocyte with hypokalemia-induced EADs (B), and canine epicardial ventricular muscle during simulated ischemia-induced early repolarization (C). Middle, APDR curves for the 3 cases obtained from corresponding computer simulations.^,, The intersection of the APDR curve (black) and pacing cycle length (PCL) line (blue) is the equilibrium point (open circle). If the slope of the APDR curve at this point is >1, the equilibrium point is unstable. Using the graphical cobweb approach pioneered by Nolasco and Dhalen, starting from an initial APD and diastolic interval (DI; star symbol), the subsequent APD and DI values alternate in a growing pattern (red dashed lines and arrows), eventually reaching steady-state APD alternans (green dashed box and colored circles). Right, Corresponding plots of APD versus PCL for the 3 cases.^,, For each PCL, more than 20 consecutive APDs are superimposed. Two APD values at the same PCL indicate alternans, and many APD values indicate high periodicity or chaos.

Figure 3.

Cardiac Ca cycling. A, Schematic diagram of a single calcium release unit (CRU) at a T-tubular membrane-sarcoplasmic reticulum (SR) membrane junction. B, A high-resolution image of the Ryanodine receptor (RyR) clusters in individual CRUs located in the T-tubule network of a rat ventricular myocyte. C, Simulation demonstrating the Ca signaling hierarchy of quarks (q), sparks (s), and spark clusters (c) in a computer model of a ventricular myocyte. In the time sequence illustrated, one of the clusters at the left eventually propagates as a mini-wave (w) by recruiting adjacent clusters. D, Primary Ca-driven alternans in a rabbit ventricular myocyte during pacing with a action potential (AP) clamp waveform. E, The fractional SR Ca release curve measured in a rabbit ventricular myocyte. F, Ca transient (CaT) restitution curves at 2 different extracellular [Ca]_o recorded from mouse ventricular myocytes using the S1S2 extrastimulus method. CaM indicates calmodulin; CaMKII, Ca/calmodulin-dependent protein kinase II; and NCX, Na-Ca exchange.

Figure 4.

Mechanisms of Ca-driven alternans. A, Calcium transient (CaT) alternans driven by sarcoplasmic reticulum (SR) Ca load alternans. Plot of the slopes of the fractional SR Ca release curve versus sarco-endoplasmic reticular Ca ATPase (SERCA) pump rate, in which the line indicates the region above which CaT alternans occurs. CaT alternans is promoted by either reducing the SERCA pump rate or increasing the steepness of the fractional SR Ca release curve (arrows). B, Confocal linescans of Ca fluorescence showing Ca mini-waves during alternans recorded in a rat ventricular myocyte (top) and simulated in a computer model (bottom). C, Transition from microscopic CaT alternans to macroscopic alternans as pacing frequency was increased in a rat ventricular myocyte. Left column, Confocal image and traces at the slower pacing rate show microscopic alternans (lower trace) at the site (marked by arrow) in the confocal image above, in the absence of global macroscopic alternans (upper traces). Right column, At the faster pacing rate, both microscopic (lower trace) and macroscopic alternans (upper traces) are present. Moreover, the 2 ends of the myocyte (superimposed black and gray traces in the middle trace) are alternating out-of-phase, forming subcellular discordant alternans.

Figure 5.

Effects of voltage and Ca coupling on alternans dynamics. A–D, Action potential duration (APD)-to-Ca coupling is assumed to be positive and labels refer to Ca-to-APD coupling sign. A, Electromechanically concordant alternans (EMCA) in a rabbit ventricular myocyte with positive Ca-to-APD coupling. B, Electromechanically discordant alternans (EMDA) in a rabbit myocyte after blocking Na-Ca exchange current by SEA0400 to promote negative Ca-to-APD coupling. C, Theoretical stability boundary of alternans for positive Ca-to-APD coupling. Arrows along both axes indicate the directions of increasing instability and dashed lines are the stability boundaries (from stable to unstable) when Ca and APD are not coupled. Solid line is the stability boundary when Ca and APD are coupled, below which the system is stable without alternans and above which alternans occurs in the form of EMCA. D, Same as C but for negative Ca-to-APD coupling. The regions of EMCA, EMDA, and electromechanically quasiperiodic alternans (EMQA) are marked. E, Quasiperiodic APD alternans caused by infusion of erythromycin in guinea pig hearts.

Figure 6.

Spatially discordant alternans (SDA) and regional spatiotemporal chaos in cardiac tissue. A, At a critical heart rate, action potential duration (APD) begins to alternate concordantly in a long-short pattern over the entire simulated 2-dimensional homogeneous tissue (spatially concordant alternans). During either the long or short APD beat, the APD gradient is minimal, but the QT interval alternates in the simulated electrocardiogram (ECG) tracing below. B, As heart rate increases sufficiently to encounter conduction velocity restitution (CVR), APD alternans becomes spatially discordant, exhibiting a short-long pattern in region a and a long-short pattern in region b, separated by a nodal line without alternans (white line). The result is a marked APD gradient which reverses on alternating beats, causing both T-wave alternans (TWA) and QRS alternans (QRSA) in the simulated ECG tracing below. C, Attenuation of the amplitude of APD alternans (Δa) by spatially dyssynchronous calcium transient (CaT) alternans (Δc_i) in a simulated 1-dimensional cable of rabbit ventricular myocytes. APD alternans amplitude is greater when CaT alternans is synchronized in large clusters of adjacent myocytes (left) compared with a more random spatial distribution (right). D, Regional spatiotemporal chaos in a simulated 1-dimensional cable containing a long APD region at the top (red) next to a region with chaotic early afterdepolarizations (EAD) at the bottom (black). The APD variation in the chaotic region causes the repolarization sequence to vary from beat to beat such that the T-wave amplitude, shape and polarity changes chaotically from beat to beat, causing marked T-wave lability, even though the QT interval (determined primarily by the long APD region) remains unchanged.

Figure 7.

R-to-T and R-from-T mechanisms linking T-wave alternans (TWA) to arrhythmogenesis. A, Electrocardiogram showing TWA and an R-on-T event (*) initiating Torsade de pointes. B, Voltage snapshot illustrating the “R-to-T” mechanism in which a premature ventricular complex (PVC) (*) emerging from a separate location (lower corner) propagates towards a central prolonged action potential duration (APD) region that is still repolarizing, where it blocks locally and then proceeds around and reenters the blocked region after it has repolarized (dashed arrows), thereby initiating figure-of-eight reentry. C, Voltage snapshot showing the “R-from-T” mechanism in which the PVC (*) is generated directly by electronic current flow from the central region with delayed repolarization into already repolarized tissue. The PVC then conducts around and reenter the heterogeneous region to initiate figure-of-eight reentry (dashed arrows). This requires the central region to have a longer APD (eg, due to an early afterdepolarization [EAD] or action potential [AP] dome) which repolarizes much later than surrounding tissue (eg, without an EAD or AP dome).

Figure 8.

Clinical examples of alternans on recorded electrocardiograms. A, T-wave alternans (TWA) with long TQ (time interval between the T-wave and the next Q-wave) intervals in a 52-year-old man with amiodarone-induced long QT syndrome (LQTS). RR=QT+TQ. B, TWA with short TQ intervals from a 13-month-old girl with congenital LQTS. C, TWA with T-wave polarity alternans (TWPA) and QRS complex (QRSA). D, TWA with TWPA without QRSA in a 59-year old man with LQTS. E, QRSA without TWA. F, Pulsus alternans without TWA. G, Microvolt TWA detected using frequency-domain analysis (right). H, A 1 year-old girl with Jervell-Lange-Nielson syndrome with multiple episodes of T-wave lability and Torsade de Pointes, who later died suddenly at 2 years of age. FFT indicates fast fourier transform.