Yuji Wakayama

Electrocardiographic Characteristics of the Variants of Idiopathic Left Ventricular Outflow Tract Ventricular Tachyarrhythmias

Background: Despite similar QRS morphology, idiopathic repetitive monomorphic ventricular tachyarrhythmias (VTs) of left ventricular outflow tract (LVOT) are known to have the variants of different adjacent origins, including the aorto‐mitral continuity (AMC), anterior site around the mitral annulus (MA), aortic sinus cusps (ASC), and epicardium. However, the electrocardiographic characteristics of those variants previously have not been evaluated fully.

Spatial Nonuniformity of Excitation–Contraction Coupling Causes Arrhythmogenic Ca2+ Waves in Rat Cardiac Muscle

Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation–contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 &mgr;m) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23°C; [Ca2+]o=2.0 mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of Ca2+ waves.

Sarcomere mechanics in uniform and non-uniform cardiac muscle: A link between pump function and arrhythmias

Starlings Law and the well-known end-systolic pressure-volume relationship (ESPVR) of the left ventricle reflect the effect of sarcomere length (SL) on stress (sigma) development and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL-[Ca2+]free relationships (sigma-SL-CaR) at submaximal [Ca2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-CaR using a kinetic model where we assumed that the rates of Ca2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C-Ca2+ affinity, XB kinetics or, unitary XB-force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C-Ca2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the sigma-SL-CaR and the time course of twitch-stress as well as the time course of intracellular [Ca2+]i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca2+ waves arise from weakened areas in cardiac muscle. These Ca2+ waves can reversibly be induced in muscle with non-uniform excitation contraction coupling (ECC) by the cycle of stretch and release in the border zone between the damaged and intact regions. Stimulus trains induced propagating Ca2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). These observations suggest the unifying hypothesis that force feedback to Ca2+ binding by Tn-C is responsible for Starlings Law and the ESPVR in uniform myocardium and leads in non-uniform myocardium to a surge of Ca2+ released by the myofilaments during relaxation, which initiates arrhythmogenic propagating Ca2+ release by the SR.

Role of sarcomere mechanics and Ca2+ overload in Ca2+ waves and arrhythmias in rat cardiac muscle

Abstract:  Ca2+ release from the sarcoplasmic reticulum (SR) depends on the sarcoplasmic reticulum (SR) Ca2+ load and the cytosolic Ca2+ level. Arrhythmogenic Ca2+ waves underlying triggered propagated contractions arise from Ca2+ overloaded regions near damaged areas in the cardiac muscle. Ca2+ waves can also be induced in undamaged muscle, in regions with nonuniform excitation–contraction (EC) coupling by the cycle of stretch and release in the border zone between the damaged and intact regions. We hypothesize that rapid shortening of sarcomeres in the border zone during relaxation causes Ca2+ release from troponin C (TnC) on thin filaments and initiates Ca2+ waves. Elimination of this shortening will inhibit the initiation of Ca2+ waves, while SR Ca2+ overload will enhance the waves. Force, sarcomere length (SL), and [Ca2+]i were measured and muscle length was controlled. A small jet of Hepes solution with an extracellular [Ca2+] 10 mM (HC), or HC containing BDM, was used to weaken a 300 μm long muscle segment. Trains of electrical stimuli were used to induce Ca2+ waves. The effects of small exponential stretches on triggered propagatory contraction (TPC) amplitude and propagation velocity of Ca2+ waves (Vprop) were studied. Sarcomere shortening was uniform prior to activation. HC induced spontaneous diastolic sarcomere contractions in the jet region and attenuated twitch sarcomere shortening; HC+ butanedione monoxime (BDM) caused stretch only in the jet region. Stimulus trains induced Ca2+ waves, which started inside the HC jet region during twitch relaxation. Ca2+ waves started in the border zone of the BDM jet. The initial local [Ca2+]i rise of the waves by HC was twice that by BDM. The waves propagated at a Vprop of 2.0 ± 0.2 mm/sec. Arrhythmias occurred frequently in trabeculae following exposure to the HC jet. Stretch early during relaxation, which reduced sarcomere shortening in the weakened regions, substantially decreased force of the TPC (FTPC) and delayed Ca2+ waves, and reduced Vprop commensurate with the reduction FTPC. These results are consistent with the hypothesis that Ca2+ release from the myofilaments initiates arrhythmogenic propagating Ca2+ release. Prevention of sarcomere shortening, by itself, did not inhibit Ca2+ wave generation. SR Ca2+ overload potentiated initiation and propagation of Ca2+ waves.

Delayed enhancement on cardiac magnetic resonance imaging is a poor prognostic factor in patients with cardiac sarcoidosis

BACKGROUND Predictors of ventricular arrhythmias (VA) in patients with cardiac sarcoidosis (CS) remain unclear. METHODS AND RESULTS We examined 61 consecutive CS patients who were admitted to our hospital from April 2002 to March 2012 with a mean follow-up period of 45 ± 31 months for the relationship between delayed enhancement on cardiac magnetic resonance imaging (DE-MRI) and VA or a composite endpoint, including VA, heart failure hospitalization, and cardiovascular mortality. Although there was no significant difference in baseline clinical characteristics between patients with VA and those without it, the former group was characterized as compared with the latter by lower left ventricular (LV) ejection fraction (p<0.05), larger LV systolic/diastolic dimensions (both p<0.05), and a significant association with DE-MRI (p<0.05). Furthermore, the patients with DE-MRI (n=26), as compared with those without it (n=11), had a significantly higher composite endpoint event rate (41% vs. 0%, p<0.05) and a trend toward higher VA (29% vs. 0%, p=0.12). Univariate analysis also showed that impaired LV systolic function was significantly associated with composite events on follow-up. CONCLUSIONS These results indicate that the presence of DE-MRI is a significant predictor of VA events and poor outcome in CS patients.

Spatial Non-uniformity of Excitation-Contraction Coupling Can Enhance Arrhythmogenic Delayed Afterdepolarizations in Rat Cardiac Muscle

AIMS We examined whether non-uniform muscle contraction affects delayed afterdepolarizations (DADs) by dissociating Ca(2+) from myofilaments within the border zone (BZ) between contracting and stretched regions. METHODS AND RESULTS Force, sarcomere length (SL), membrane potential, and [Ca(2+)](i) dynamics were measured in 31 ventricular trabeculae from rat hearts. Non-uniform muscle contraction was produced by exposing a restricted region of muscle to a jet of solution containing 20 mmol/L 2,3-butanedione monoxime (BDM). DADs were induced by 7.5 s-2 Hz stimulus trains at an SL of 2.0 microm (24 degrees C, [Ca(2+)](o) 2.0 mmol/L). The BDM jet enhanced DADs (n = 6, P < 0.05) and aftercontractions (n = 6, P < 0.05) with or without 100 micromol/L streptomycin and occasionally elicited an action potential. A stretch pulse from an SL of 2.0 microm to 2.1 or 2.2 microm during the last stimulated twitch of the trains accelerated Ca(2+) waves in proportion to the increment of force by the stretch (P < 0.01) with or without streptomycin. In the presence of 1 mmol/L caffeine, rapid shortening of the muscle after the stretch pulse increased [Ca(2+)](i) within the BZ, whose amplitude correlated with the increment of force by the stretch (n = 15, P < 0.01). CONCLUSION These results suggest that non-uniform muscle contraction can enhance DADs by dissociating Ca(2+) from myofilaments within the BZ and thereby cause triggered arrhythmias.

Contribution of Na+/Ca2+ exchange current to the formation of delayed afterdepolarizations in intact rat ventricular muscle.

Aim: To evaluate the role of the Na+-Ca2+ exchange current in the induction of arrhythmias during Ca2+ waves, we investigated the relationship between Ca2+ waves and delayed afterdepolarizations (DADs) and further investigated the effect of KB-R7943, an Na+-Ca2+ exchange inhibitor, on such relationship in multicellular muscle. Methods: Force, sarcomere length, membrane potential, and [Ca2+]i dynamics were measured in 32 ventricular trabeculae from rat hearts. After the induction of Ca2+ waves by trains of electrical stimuli (400, 500, or 600 ms intervals) for 7.5 seconds, 23 Ca2+ waves in the absence of KB-R7943 and cilnidipine ([Ca2+]o = 2.3 ± 0.2 mmol/L), 11 Ca2+ waves in the presence of 10 μmol/L KB-R7943 ([Ca2+]o = 2.5 ± 0.5 mmol/L), and 8 Ca2+ waves in the presence of 1 μmol/L cilnidipine ([Ca2+]o = 4.1 ± 0.3 mmol/L) were measured at a sarcomere length of 2.1 μm (23.9 ± 0.8°C). Results: The amplitude of DADs correlated with the velocity (r = 0.90) and the amplitude (r = 0.90) of Ca2+ waves. The amplitude of DADs was significantly decreased to ~40% of the initial value by 10 μmol/L KB-R7943. Conclusions: These results suggest that the velocity and the amplitude of Ca2+ waves determine the formation of DADs principally through the activation of the Na+-Ca2+ exchange current, thereby inducing triggered arrhythmias in multicellular ventricular muscle.

Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats

Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca2+ ([Ca2+]i) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca2+ content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca2+ ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca2+ transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca2+]i, and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca2+ uptake and reduced reserve of the trans-sarcolemmal Ca2+ transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.

Spatial Nonuniformity of Contraction Causes Arrhythmogenic Ca2+ Waves in Rat Cardiac Muscle

Abstract: Landesberg and Sidemans four state model of the cardiac cross‐bridge (XB) hypothesizes a feedback of force development to Ca2+ binding by troponin C (TnC). We have further modeled this behavior and observed that the force (F)‐Ca2+ relationship as well as the F‐sarcomere length (SL) relationship and the time course of F and Ca2+ transients in cardiac muscle can be reproduced faithfully by a single effect of F on deformation of the TnC‐Ca complex and, thereby, on the dissociation rate of Ca2+. Furthermore, this feedback predicts that rapid decline of F in the activated sarcomere causes release of Ca2+ from TnC‐Ca2+, which is sufficient to initiate arrhythmogenic Ca2+ release from the sarcoplasmic reticulum (SR). This work investigated the initiation of Ca2+ waves underlying triggered propagated contractions (TPCs) in rat cardiac trabeculae under conditions that simulate functional nonuniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution that reduces excitation‐contraction coupling in myocytes within that segment. Force was measured, and SL as well as [Ca2+]i were measured regionally. When the jet contained caffeine, 2,3‐butanedione monoxime or low‐[Ca2+], muscle‐twitch F decreased and the sarcomeres in the exposed segment were stretched by shortening the normal regions outside the jet. During relaxation, the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca2+ waves to rise from the borders exposed to the jet. Ca2+ waves started during F relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were triggered when the amplitude of the Ca2+ wave increased by raising [Ca2+]o. The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. These results show that nonuniform contraction can cause Ca2+ waves underlying TPCs, and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca2+ waves.

High-density materials do not always induce artifacts on PET/CT: what is responsible for the difference?

ObjectivePET/CT often show increased uptake at sites of high-density materials. However, some materials seldom demonstrate increased uptake on PET/CT, such as the materials used in hip prostheses. We hypothesized that the motion of materials may be crucial for such artifacts. Here, we present representative cases, and validate our hypothesis based on the results of phantom studies. MethodsA standard cylinder, 20 cm in diameter, was filled with approximately 37 MBq of 18F-based activity, and a pacemaker was attached to the side of the cylinder. This phantom was placed on the bed with the pacemaker side facing the scanner. PET scans were performed using a Biograph LSO DUO. CT scans were performed first for transmission scans, followed by acquisition of emission scans. The phantom was first scanned (protocol 1). The phantom was then moved about 2 cm closer to the distal edge of the bed just after transmission CT scan, and the emission scan was performed (protocol 2). ResultsHomogenous uptake was seen in the cylinder in protocol 1, and there was no visible uptake at the site of the pacemaker. In contrast, a clear hotspot was seen at the site of the pacemaker in protocol 2. The uptake in the cylinder was inhomogeneous; that on the pacemaker side of the cylinder was low, while that on the opposite side was high. ConclusionsHigh-density materials do not show false increased uptake without motion on PET/CT. Motion of these materials surrounded by radioactive organs may play an important role in inducing false increased uptake on PET/CT.