Diverse QRS morphology reflecting variations in lead placement for left bundle branch area pacing.

AIMS: Left bundle branch area pacing (LBBAP) is a potential alternative to His bundle pacing. This study aimed to investigate the impact of different septal locations of pacing leads on the diversity of QRS morphology during non-selective LBBAP. METHODS AND RESULTS: Non-selective LBBAP and left ventricular septal pacing (LVSP) were achieved in 50 and 21 patients with atrioventricular block, respectively. The electrophysiological properties of LBBAP and their relationship with the lead location were investigated. QRS morphology and axis showed broad variations during LBBAP. Echocardiography demonstrated a widespread distribution of LBBAP leads in the septum. During non-selective LBBAP, the qR-wave in lead V1 indicated that the primary location for pacing lead was the inferior septum (93%). The non-selective LBBAP lead was deployed deeper than the LVSP lead in the inferior septum. The Qr-wave in lead V1 with the inferior axis in aVF suggested pacing lead placement in the anterior septum. The penetration depth of the non-selective LBBAP lead in the anterior septum was significantly shallower than that in the inferior septum (72 ± 11 and 87 ± 8%, respectively). In lead V6, the deep S-wave indicated the time lag between the R-wave peak and the latest ventricular activation in the coronary sinus trunk, with pacemaker leads deployed closer to the left ventricular apex. CONCLUSION: Different QRS morphologies and axes were linked to the location of the non-selective LBBAP lead in the septum. Various lead deployments are feasible for LBBAP, allowing diversity in the conduction system capture in patients with atrioventricular block.

Conduction system pacing: Current status and prospects.

Conduction system pacing (CSP), including His bundle pacing (HBP) and left bundle branch area pacing (LBBAP), is the most physiological of all pacing modalities for ventricular capture and a potential alternative to right ventricular pacing. It induces electrical and mechanical dyssynchrony, resulting in left ventricular dysfunction, heart failure hospitalization, and atrial arrhythmia. CSP activates the normal conduction system and restores ventricular synchrony. In 2000, HBP was first performed as permanent ventricular pacing, which improved left ventricular systolic dysfunction. The feasibility of permanent HBP has already been demonstrated in patients with bradycardia, although a high capture threshold and limited efficacy for infra-Hisian conduction diseases remain critical issues. The LBBAP is an alternative pacing form that overcomes the limitations of the HBP. A lower capture threshold was obtained at implantation and preserved during the follow-up period in patients with LBBAP. Cardiac resynchronization therapy with HBP or LBBAP may provide better synchronization than the traditional biventricular pacing. Hybrid therapy utilizing HBP or LBBAP in combination with left ventricular pacing has been introduced to treat patients with heart failure. In this review, we have focused on the clinical implications, limitations, and a literature review on CSP.

Temporal and spatial pacemap parameters for identification of cardiac surfaces with critical sites for ventricular tachycardia.

INTRODUCTION: Multisurface pacemapping may help identify the surface of interest in scar-related ventricular tachycardia (VT). This study aimed to investigate the performance of pacemap parameters for detecting critical sites through multisurface mapping. METHODS AND RESULTS: In 26 patients who underwent scar-related VT ablation, pacemap parameters including a matching score, the difference between the longest and shortest stimulus-QRS intervals (Δs-QRS), and the distance between the good pacemap sites were measured. The parameters were compared between surfaces with and without critical sites and ablation outcomes. A total of 941 pacemap at 56 surfaces targeting 35 VTs were analyzed. A greater Δs-QRS (40 vs. 8 ms, p < .001) and longer distance between two good pacemap sites (24 vs. 13 mm, p < .001) were observed on the surfaces with critical sites. A similar trend was seen in multisurface pacemapping for the same VTs (52 vs. 18 ms in Δs-QRS, p = .021; 37 vs. 12 mm in distance, p = .019), although the best pacemap scores were comparable (94 vs. 87, p = .295). The Δs-QRS > 20 ms and the distance >19 mm showed high positive likelihood ratios (19.8 and 6.1, respectively) for discriminating the surface harboring the critical site. Ablation of VTs fulfilling these parameters was successful on the surfaces, but without the required multisurface ablation. CONCLUSION: Temporal (Δs-QRS) and spatial (distance) parameters for good pacemap match sites were excellent markers for detecting the surface harboring critical sites in scar-related VT. A multisurface pacemapping can successfully identify the surface of interest.

Fluoroscopic predictors of acceptable capture threshold during the implantation of the micra transcatheter pacing system.

INTRODUCTION: Few predictors of low capture threshold before the deployment of the Micra transcatheter pacing system (Micra TPS) have been determined. We aimed to identify fluoroscopic predictors of an acceptable capture threshold before Micra TPS deployment. METHODS: Sixty patients were successfully implanted with Micra TPS. Before deployment, gooseneck appearance of the catheter shaft was quantified using the angle between the tangent line of the shaft and the cup during diastole in the right anterior oblique (RAO) view. The direction of the device cup toward the ventricular septum was evaluated using the angle between the cup and the horizontal plane in the left anterior oblique (LAO) view. RESULTS: Of the 95 deployments we evaluated, 56 achieved an acceptable capture threshold of ≤2.0 V at 0.24 ms. In this acceptable threshold group, the deflection angle of the gooseneck shaft was significantly larger and the device cup was placed more horizontally with a lower elevation angle compared with those in the high threshold group. A deflection angle of ≥6° and an elevation angle of ≤30° were identified as the predictors of an acceptable capture threshold after deployment. An acceptable capture threshold was achieved in 24/31 (77.4%) patients in whom either angle criterion was satisfied at the first deployment. CONCLUSIONS: Diastolic gooseneck appearance of the delivery catheter in the RAO view or near-horizontal direction in the LAO view predicts an acceptable capture threshold after deployment. The shape of the delivery catheter before deployment should be evaluated using multiple fluoroscopic views to ensure successful implantation of Micra TPS.

Accuracy of wristwatch-type photoplethysmography in detecting atrial fibrillation in daily life.

Aims: Detection of asymptomatic paroxysmal atrial fibrillation is challenging. Smartphone- or smartwatch-based photoplethysmography is efficient at detecting irregular rhythms using pulse waves but is too complex for older patients. We aimed to evaluate the detection accuracy of atrial fibrillation by a wristwatch-type continuous pulse wave monitor (PWM) in daily life. Methods and results: Patients at high risk of atrial fibrillation but with no history of atrial fibrillation (n = 163; mean CHADS2 score, 1.9) and patients with known atrial fibrillation (n = 123, including 34 with persistent atrial fibrillation) underwent PWM and telemetry electrocardiogram recording for 3 days. Risk of atrial fibrillation was judged using the 'Kyorin Atrial Fibrillation Risk Score', a scoring system based on previously reported atrial fibrillation risk scoring systems. The PWM assessed the presence of atrial fibrillation at 30 min intervals, and the results were compared with the telemetry electrocardiogram findings. The PWMs accurately diagnosed two patients with paroxysmal atrial fibrillation in the high-risk group. The PWMs accurately diagnosed 48 of the 55 patients with atrial fibrillation in the known-atrial fibrillation group. The PWM accuracy in detecting patients with atrial fibrillation was as follows: sensitivity, 98.0%; specificity, 90.6%; positive predictive value, 69.4%; negative predictive value, 99.5%. The respective values for intervals with atrial fibrillation were 86.9%, 98.8%, 89.6%, and 98.5%. Conclusion: The wristwatch-type PWM has shown feasibility in detecting atrial fibrillation in daily life and showed the possibility of being used as a screening tool.

Left Atrial Reverse Remodeling Following the Modified Box Isolation with Centerline in Patients with Persistent Atrial Fibrillation.

Esophageal injury is a rare but serious complication of atrial fibrillation (AF) ablation. To minimize esophageal injury, our persistent AF (PerAF) protocol involves complete left atrial posterior wall (LAPW) and pulmonary vein (PV) isolation (box isolation), with a centerline away from the esophagus. However, there has been a concern that extensive LA isolation might deteriorate LA function. There has been a paucity of data on LA remodeling after box isolation. Therefore, we compared LA size pre- and post-box isolation with an LAPW centerline in patients with PerAF.Patients who underwent catheter ablation (CA) for PerAF between November 2016 and December 2018 were retrospectively evaluated.The LAPW, including all PVs, was completely isolated in 105 consecutive patients (75 men; mean age: 68 ± 10 years) with PerAF, including 58 patients with long-standing PerAF. During a follow-up of 660 ± 332 days, 76 patients (72%) were arrhythmia-free. The LA dimension (38 ± 6 mm versus 42 ± 7 mm; P < 0.0001) and volume index (38 ± 13 mL/m2 versus 47 ± 14 mL/m2; P < 0.0001) at 6 months post-ablation were significantly decreased in patients who maintained sinus rhythm compared to pre-ablation. In patients with recurrent AF/atrial tachycardia (AT), these parameters were also significantly decreased (P < 0.001, respectively).Box isolation with a posterior centerline has no esophageal complications and a high clinical success rate in patients with PerAF. Reverse remodeling could be achieved even when using extensive isolation of the PV and LAPW in patients with PerAF.

Stellate Ganglion Phototherapy Using Low-Level Laser: A Novel Rescue Therapy for Patients With Refractory Ventricular Arrhythmias.

OBJECTIVES: This study investigates the effect of stellate ganglion (SG) phototherapy in healthy participants and assesses its efficacy in suppressing electrical storm (ES) refractory to antiarrhythmic drugs and catheter ablation. BACKGROUND: Modulation of the autonomic nervous system has been shown to be an effective adjunctive therapy for ES. METHODS: Ten-minute SG phototherapy was performed twice weekly for 4 weeks in 20 healthy volunteers. To evaluate the acute and chronic effects of SG phototherapy, heart rate variability and serum concentrations of adrenaline, noradrenaline, and dopamine were obtained before phototherapy, immediately after the first phototherapy session, after 8 sessions of phototherapy, and 3 months after the first phototherapy session. In addition, the efficacy of SG phototherapy was evaluated in 11 patients with ES refractory to medication, sedation, and catheter ablation. RESULTS: In healthy participants, serum adrenaline concentration significantly decreased after phototherapy, whereas low-frequency power/high-frequency power significantly decreased during phototherapy. Moreover, the effect on heart rate variability did not last beyond 3 months. In the clinical pilot study, 7 patients had a suppression of ES after SG phototherapy; however, without maintenance therapy, 2 patients had a recurrence of ventricular arrhythmias. Furthermore, it did not control ES in 4 patients. CONCLUSIONS: SG phototherapy reduced sympathetic activity and may be a safe and effective adjunctive therapy to control ES in some patients, but its long-term efficacy remains unknown. Chronic phototherapy might help reduce ES recurrence.

Safety of Distal His Bundle Pacing Via the Right Ventricle Backed Up by Adjacent Ventricular Capture.

OBJECTIVES: This study investigated the differences between distal His bundle pacing (HBP) via the right ventricle and proximal HBP via the right atrium with regard to pacing and sensing parameters. BACKGROUND: HBP preserves physiological ventricular activation. The capture threshold of the adjacent ventricle accompanying HBP has not been evaluated after implantation. METHODS: Fifty patients with bradycardia (58% with atrioventricular block) underwent successful HBP and were followed for 1 year. Precise locations of the lead tips were confirmed using follow-up echocardiography. RESULTS: HBP leads were fixed via the right atrium or right ventricle (25 patients each). Overall, the local ventricle and HBP thresholds were elevated during follow-up. The distal HBP thresholds did not significantly differ from the proximal HBP thresholds, although local ventricular thresholds of distal HBP were markedly lower than those of proximal HBP. At 6 months, the accepted ventricular threshold (≤2.5 V) was maintained in 39 patients (78%). An amplitude of ventricular electrogram post-fixation of ≥2.0 mV and a capture threshold of ≤1.1 V at implantation were determined to be optimal values for predicting the accepted threshold at 6 months, with areas under the curve of 0.86 and 0.84, respectively. Atrial oversensing was often detected in proximal HBP but not distal HBP. CONCLUSIONS: Distal HBP via the right ventricle captured the His bundle, similar to proximal HBP via the right atrium, with a superior local ventricular threshold during follow-up. Anatomy and electrophysiological ventricular properties at implantation may be critical for maintaining adjacent ventricle capture to prevent lead revision (Evaluation of Electrophysiological Parameters related to His Bundle Pacing in Patients With Bradyarrhythmias; UMIN000031364).

Assessing the perforation site of cardiac tamponade during radiofrequency catheter ablation using gas analysis of pericardial effusion.

BACKGROUND: The incidence of pericardial effusion (PE) during radiofrequency catheter ablation (CA) for atrial fibrillation is approximately 1%. PE is a major complication during CA, but there has been limited literature about the perforation site responsible. OBJECTIVE: This study aimed to retrospectively investigate the characteristics of the procedure and the patients in whom PE developed during CA. METHODS: Of 1363 consecutive patients who underwent catheter ablation from January 2015 to June 2019 in Kyorin University Hospital, we reviewed patients who developed PE during CA. RESULTS: PE during CA occurred in 18 (1.32%) patients (median age, 71 [interquartile range (IQR) 65-77] years, 7 women). The median body mass index was 24 (IQR 20-27). Target arrhythmias for CA of patients with PE include atrial fibrillation (AF) (n = 13, 72%), premature ventricular contraction (n = 2, 11%), ventricular tachycardia (n = 1, 6%), atrial flutter (n = 1, 6%), and orthodromic reciprocating tachycardia (n = 1, 6%). Seventeen patients required pericardiocentesis, resulting in 300 (IQR 192.5-475) mL of drainage. Two patients required emergency surgical repair, and 1 died from aortic dissection. Based on the gas analysis, the drained blood was of venous origin in 47% of the total events and 54% of AF ablation. CONCLUSION: PE caused by a diagnostic catheter in the right heart is not uncommon, even in AF ablation.

Reducing radiation exposure during atrial fibrillation ablation using lectures to promote awareness.

Objective: Recently, concern has increased regarding the hazards of radiation exposure in patients and laboratory staff. Since the numbers of complex catheter ablations (CA) performed, duration of procedure times, and need for multiple sessions have increased, radiation exposure during each session needs to be minimised. Our study aimed to assess the impact of awareness on radiation exposure during CA for atrial fibrillation (AF). Methods: Mini-course lectures was delivered to the physicians and staff in the electrophysiology division. Its effect on the fluoroscopic time and radiation dose during AF ablation before (Group I, n=70), shortly after (Group II: n=70) and remotely after the mini-lecture (Group III, n=70) were evaluated. Patient demographics, preoperative testing and procedural parameters were collected. Results: The fluoroscopic time significantly reduced after the lecture (Group I and II: 25.1±10.0 and 15.1±7.3 min, respectively (p<0.0001)), and remained so in Group III (13.0±5.4 min), despite the increase in the number of persistent AFs. The radiation dose also significantly reduced (Groups I, II, III: 295.0±263.0, 109.6±103.5 and 110.1±89.6 mGy, respectively (p<0.0001)). Conclusion: Awareness on radiation exposure led to a significant reduction in fluoroscopic time and radiation dose during CA for AF, the effect of which persisted even to remote periods following the procedure.

Deep Negative Deflection in Unipolar His-Bundle Electrogram as a Predictor of Excellent His-Bundle Pacing Threshold Postimplant.

Background His-bundle pacing (HBP) is a physiological form of pacing. Although high capture thresholds are common, few predictors of low HBP threshold have been determined. We aimed to identify electrophysiological predictors. Methods Fifty-one patients (53% with atrioventricular block) underwent HBP for bradycardia with an intrinsic QRS duration of <120 ms. Attempts to anchor the HBP lead were guided by unipolar His-bundle electrograms (HB EGMs) recorded with an electrophysiology recording system. Patients were followed-up for >6 months. Results In total, 153 attempts at anchoring the HBP lead were made, of which, 45 achieved acceptable HBP thresholds (≤2.5 V at 1 ms). The amplitude of negative deflection in HB EGM and the selective HBP form at fixation were independently associated with achieving an acceptable threshold. A negative amplitude of ≥0.060 mV in HB EGM was determined as the optimal value for identifying the acceptable threshold. This deep negative HB EGM was recorded with an HBP threshold of 1.4±1.3 V (in 34 attempts), significantly lower than that of positive HB EGM without deep negative deflection (2.8±1.3 V, in 31 trials; or >5 V, in 38 trials). The permanent HBP lead remained with deep negative (≥0.060 mV) or positive HB EGMs in 28 and 14 patients, respectively, and with positive or negative HB injury current in 19 and 23 patients, respectively. During follow-up, increased HBP threshold of >1 V was significantly more prevalent in the positive HB EGM group. The HBP thresholds of deep negative HB EGM and HB injury current, but not of the selective HBP group, were significantly lower than the other subgroups during follow-up. Conclusions Deep negative HB EGM at fixation was associated with an excellent short-term HBP threshold, similar to HB injury current. Analysis of unipolar HB EGM postfixation may enable prediction of permanent HBP threshold.

Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice.

Severe invasive group A Streptococcus (GAS) infection evades anti-bacterial immunity by attenuating the cellular components of innate immune responses. However, this loss of protection is compensated for by interferon (IFN)-γ-producing immature myeloid cells (γIMCs), which are selectively recruited upon severe invasive GAS infection in mice. Here, we demonstrate that γIMCs provide this IFN-γ-mediated protection by sequentially sensing GAS through two distinct pattern recognition receptors. In a mouse model, GAS is initially recognized by Toll-like receptor 2 (TLR2), which promptly induces interleukin (IL)-6 production in γIMCs. γIMC-derived IL-6 promotes the upregulation of a recently identified GAS-sensing receptor, macrophage-inducible C-type lectin (Mincle), in an autocrine or paracrine manner. Notably, blockade of γIMC-derived IL-6 abrogates Mincle expression, downstream IFN-γ production, and γIMC-mediated protection against severe invasive GAS infection. Thus, γIMCs regulate host protective immunity against severe invasive GAS infection via a TLR2-IL-6-Mincle axis.

Idiopathic Ventricular Arrhythmia Ablation Using Non-Fluoroscopic Catheter Visualization System.

A novel, sensor-based, electromagnetic, non-fluoroscopic catheter visualization (NFCV) system shows tracked catheters directly on pre-acquired fluoroscopy or cine loops. We aimed to evaluate the effectiveness of this system in the setting of catheter ablation for idiopathic premature ventricular contractions/ventricular tachycardia (i-PVC/VT).A total of 30 i-PVC/VT ablation procedures were performed using the NFCV system in conjunction with three-dimensional electroanatomic mapping system (3D-EMS) between January 2013 and April 2017. At the beginning of the procedure, cine loops of right and left anterior oblique views were obtained and replayed for subsequent mapping and ablation. Right ventriculography, aortography, or coronary angiography was performed, depending on the chamber of interest. We reviewed procedural parameters, comparing with the i-PVC/VT ablation procedure using conventional fluoroscopy (CvF) system (pre-, and post-NFCV implementation; 20 and 11 cases, respectively).I-PVC/VTs were successfully eliminated in 26 patients (87%) in the NFCV group and in 26 (84%) in the CvF group (P = 1.000). The procedure time in the NFCV group was comparable to that in the CvF group (119.8 versus 125.0 minutes, respectively, P = 0.868); the total fluoroscopy time was significantly shorter in the NFCV group (3.3 versus 16.6 minutes, P < 0.001). One patient in the CvF group experienced cardiac tamponade, requiring pericardial drainage. No major complications were encountered in the NFCV group.NFCV system, in conjunction with 3D-EMS, was safe and feasible for i-PVC/VT mapping and ablation. The system contributed to dramatically reduced fluoroscopy time, compared with CvF.

Subclinical cardiac perforation caused by a Micra™ leadless pacemaker.

A subclinical cardiac perforation by a device cup of the Micra™ transcatheter pacing system was suspected in a 78-year-old woman. During the procedure, the device cup was placed on the septum. The contrast media was injected before device deployment and remained outside of the myocardium. Later, a cardiac computed tomography scan visualized a protruded diverticular structure on the right ventricle. The contrast material remained in a pouch within the pericardium. To ensure the device is oriented away from the border between the right ventricular septum and the free wall, right anterior oblique view should be carefully reviewed before deployment.

Elongated ascending aorta predicts a short distance between his-bundle potential recording site and coronary sinus ostium.

BACKGROUND: When performing catheter ablation of atrioventricular nodal reentrant tachycardia (AVNRT), it can be difficult to maintain a safe distance from the His recording site to avoid AV block in patients with a short distance between this recording site to the coronary sinus (CS) ostium (small triangle of Koch [TOK]). In this study, we sought to identify parameters predicting small TOK and test these parameters in patients undergoing AVNRT catheter ablation. METHODS: Twenty-eight patients who underwent catheter ablation of atrial fibrillation using a three-dimensional (3D) electroanatomical mapping system (EAM) with computed tomography (CT) merge (23 males; mean age, 65.8±12.1 years) were included. The shortest distance between the CS ostium and His recording sites (His-CSd) was measured on the EAM. Aortic (Ao) unfolding in chest X-ray scan, Ao angle to the LV, Ao length, Ao to the right ventricular distance, size of the Valsalva in the CT scan, and parameters of echocardiogram were evaluated. The identified parameters were subsequently tested as predictors for small TOK in patients undergoing AVNRT ablation. RESULTS: The size of TOK was associated with Ao length (r = -0.70, p<0.01), left ventricular end-systolic dimension (LVDs) (r = -0.51, p<0.01), and Ao unfolding. In patients with AVNRT, only Ao unfolding predicted a smaller TOK. CONCLUSIONS: Small TOK was associated with longer Ao, larger LVDs, and Ao unfolding. Of these, Ao unfolding was associated with smaller TOK in patients with AVNRT.

Outcomes of single- or dual-chamber implantable cardioverter defibrillator systems in Japanese patients.

BACKGROUND: There are no criteria for selecting single- or dual-chamber implantable cardioverter defibrillators (ICDs) in patients without a pacing indication. Recent reports showed no benefit of the dual-chamber system despite its preference in the United States. As data on ICD selection and respective outcomes in Japanese patients are scarce, we investigated trends regarding single- and dual-chamber ICD usage in Japan. METHODS: Data from a total of 205 ICD recipients with structural heart disease (median age, 63 years) in two Japanese university hospitals were reviewed. Patients with bradycardia with a pacing indication and permanent atrial fibrillation at implantation were excluded. RESULTS: Single- and dual-chamber ICDs were implanted in 36 (18%) and 169 (82%) patients, respectively. Non-ischemic cardiomyopathy dominated both groups. Seventeen dual-chamber patients developed atrial pacing-dependency over 4.5 years, and it developed immediately after implantation in 14. Although preoperative testing showed no sign of bradycardia in these patients, their pacing rate was set higher than it was in patients who were pacing-independent (61 vs. 46 paces per min, p<0.01). Two single-chamber patients (5%) underwent atrial lead insertion. While inappropriate shock equally occurred in both groups (7 vs. 21 patients, single- vs. dual-chamber, P=0.285), device-related infection occurred only in dual-chamber patients (0 vs. 9 patients, P=0.155). No differences in death or heart failure hospitalization were observed between groups. CONCLUSIONS: Dual-chamber ICDs were four-fold more common in Japanese patients without a pacing indication. No benefit over single-chamber ICD was observed. Newly developed atrial pacing-dependency seemed to be limited and could have been overestimated due to higher pacing rate settings in dual-chamber patients.

Sudden cardiac arrest and syncope triggered by coronary spasm.

BACKGROUND: Patients with coronary spasm generally have a good prognosis, although it can result in sudden cardiac arrest (SCA) and syncope. We hypothesized that the nature of coronary spasm triggering lethal arrhythmias may be different from that which induces angina-only. METHODS: Clinical characteristics were examined in patients who had experienced SCA (n = 18) or syncope (n = 28) triggered by coronary spasm. These characteristics were compared to those of patients who had coronary spastic angina-only (n = 52). RESULTS: SCA and syncope occurred frequently during daytime in 57% and 68%, respectively. Spontaneous ST-segment changes during daytime were recorded more often in patients with SCA (50%) and syncope (39%) than angina-only patients (4%, p < 0.01 for each). Nocturnal angina occurred less frequently in patients with SCA (33%) and syncope (32%) than angina-only patients (83%, p < 0.01 for each). Severe multivessel spasm, daytime ST-segment changes, and younger age were significant predictors of SCA. Daytime ST-segment changes and active smoking were related to syncope. CONCLUSIONS: The circadian variance of coronary spasm triggering SCA or syncope may be different from that inducing typical coronary spastic angina. The coronary spasm should be evaluated for patients with aborted SCA or recurrent syncope of unknown cause, even though the patients have not experienced the typical nocturnal angina.

Pretreatment of human mesenchymal stem cells with pioglitazone improved efficiency of cardiomyogenic transdifferentiation and cardiac function.

The efficacy of transplantation of default human marrow-derived mesenchymal stem cells (MSCs) was modest. In this study, our challenge was to improve the efficacy of MSC transplantation in vivo by pretreatment of MSCs with pioglitazone. MSCs were cultured with or without medium containing 1 µM of pioglitazone before cardiomyogenic induction. After cardiomyogenic induction in vitro, cardiomyogenic transdifferentiation efficiency (CTE) was calculated by immunocytochemistry using anti-cardiac troponin-I antibody. For the in vivo experiments, myocardial infarction (MI) at the anterior left ventricle was made in nude rats. Two weeks after MI, MSCs pretreated with pioglitazone (p-BM; n = 30) or without pioglitazone (BM; n = 17) were injected, and then survived for 2 weeks. We compared left ventricular function by echocardiogram and immunohistochemistry to observe cardiomyogenic transdifferentiation in vivo. Pretreatment with pioglitazone significantly increased the CTE in vitro (1.9% ± 0.2% n = 47 vs. 39.5% ± 4.7% n = 13, p < .05). Transplantation of pioglitazone pretreated MSCs significantly improved change in left ventricular % fractional shortening (BM; -4.8% ± 2.1%, vs. p-BM; 5.2% ± 1.5%). Immunohistochemistry revealed significant improvement of cardiomyogenic transdifferentiation in p-BM in vivo (BM; 0% ± 0% n = 5, vs. p-BM; 0.077% ± 0.041% n = 5). Transplantation of pioglitazone-pretreated MSCs significantly improved cardiac function and can be a promising cardiac stem cell source to expect cardiomyogenesis.

Xenografted human amniotic membrane-derived mesenchymal stem cells are immunologically tolerated and transdifferentiated into cardiomyocytes.

RATIONALE: Amniotic membrane is known to have the ability to transdifferentiate into multiple organs and is expected to stimulate a reduced immunologic reaction. OBJECTIVE: Determine whether human amniotic membrane-derived mesenchymal cells (hAMCs) can be an ideal allograftable stem cell source for cardiac regenerative medicine. METHODS AND RESULTS: We established hAMCs. After cardiomyogenic induction in vitro, hAMCs beat spontaneously, and the calculated cardiomyogenic transdifferentiation efficiency was 33%. Transplantation of hAMCs 2 weeks after myocardial infarction improved impaired left ventricular fractional shortening measured by echocardiogram (34+/-2% [n=8] to 39+/-2% [n=11]; P<0.05) and decreased myocardial fibrosis area (18+/-1% [n=9] to 13+/-1% [n=10]; P<0.05), significantly. Furthermore hAMCs transplanted into the infarcted myocardium of Wistar rats were transdifferentiated into cardiomyocytes in situ and survived for more than 4 weeks after the transplantation without using any immunosuppressant. Immunologic tolerance was caused by the hAMC-derived HLA-G expression, lack of MHC expression of hAMCs, and activation of FOXP3-positive regulatory T cells. Administration of IL-10 or progesterone, which is known to play an important role in feto-maternal tolerance during pregnancy, markedly increased HLA-G expression in hAMCs in vitro and, surprisingly, also increased cardiomyogenic transdifferentiation efficiency in vitro and in vivo. CONCLUSIONS: Because hAMCs have a high ability to transdifferentiate into cardiomyocytes and to acquire immunologic tolerance in vivo, they can be a promising cellular source for allograftable stem cells for cardiac regenerative medicine.