Background:Poor survival outcomes for patients with severe heart failure (HF) and the donor shortage for heart transplantation warrant the development of myocardial regenerative therapy. We performed ...a multicenter, phase II study to evaluate the safety and efficacy of autologous skeletal myoblast sheets (TCD-51073).Methods and Results:In 3 study sites, we enrolled 7 patients with severe chronic HF due to ischemic heart disease despite maximal therapy, all of whom underwent transplantation of TCD-51073. No serious arrhythmia was reported, and no changes were noted in the frequency of ventricular extrasystole frequency. The primary efficacy endpoint of the change in left ventricular ejection fraction (LVEF) on gated blood-pool scintigraphy at 26 weeks after transplantation showed that 5 subjects were responders (classified as “improved” or “unchanged”). In addition, LVEF on echocardiography improved over time, with a change in LVEF of 7.1±2.8% at 26 weeks posttransplantation. Among the 7 subjects, 6 showed improvement in New York Heart Association functional class by at least 1 class. The 6-min walk distance was 410.1±136.1 m before transplantation and 455.4±103.7 m at 26 weeks after transplantation.Conclusions:This study demonstrated the feasibility and safety of the transplantation of TCD-51073 in the patients with severe chronic HF due to ischemic heart disease, suggesting that TCD-51073 might maintain or improve cardiac function, symptoms, and physical function. (Circ J 2015; 79: 991–999)
Background: Robot-assisted valve surgery represents the latest development in the field of minimally invasive approaches. Robotic assistance may provide greater visualization, enhanced dexterity, and ...greater precision than traditional mini-thoracotomy aortic valve replacement.Methods and Results: Aortic valve replacement operations using the da Vinci Xi Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA) were performed on 2 patients, 1 with severe aortic insufficiency and the other with aortic stenosis. Both patients had an uneventful postoperative course and were discharged without any adverse events.Conclusions: Robot-assisted assisted aortic valve replacement appears feasible and safe in limited cases.
Background:This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic mitral porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods ...and Results:The medical records of 390 patients who underwent mitral valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999–2014) were reviewed. Patient data were collected using the Research Electronic Data Capture software. Patient survival was determined using the Kaplan-Meier method. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined using actuarial methods. The median (interquartile range IQR) age of the cohort was 73 (69–77) years. The median (IQR) follow-up period was 4.83 (1.84–8.26) years. The longest follow-up period was 15.8 years. The 30-day mortality rate was 5.4%. The 12-year actuarial survival rate was 54.1±4.5%, and the freedom from valve-related death was 85.3±3.4%. The freedom from reoperation at 12 years was 74.3±5.7%. The freedom from SVD at 12 years was 81.4±6.6% for patients aged ≥65 years and 71.6±11.1% for those aged <65 years. The median (IQR) mean pressure gradient was 4.1 (3.0–6.0) and 5.6 (4.0–6.7) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.7 (1.4–2.0) and 1.4 (1.2–1.6) cm2at 1 and 10 years, respectively.Conclusions:The Mosaic porcine bioprosthesis offered satisfactory long-term outcomes for up to 12 years.
When transplanted into failing heart, autologous somatic tissue-derived cells yield functional recovery via paracrine effects that enhance native regeneration. However, the therapeutic effects are ...modest. We developed a method in which scaffold-free cell sheets are attached to the epicardial surface to maximize paracrine effects. This Phase I clinical trial tested whether transplanting autologous cell-sheets derived from skeletal muscle is feasible, safe, and effective for treating severe congestive heart failure.
Fifteen ischemic cardiomyopathy patients and 12 patients with dilated cardiomyopathy, who were in New York Heart Association functional class II or III and had been treated with the maximum medical and/or interventional therapies available, were enrolled. Scaffold-free cell sheets of 3 to 9×10
cells derived from autologous muscle were transplanted over the LV free wall via left thoracotomy, without additional interventional treatments. There were no procedure-related major complications during follow-up. The majority of the ischemic cardiomyopathy patients showed marked symptomatic improvement in New York Heart Association classification (pre: 2.9±0.5 versus 6 months: 2.1±0.4,
<0.01; 1 year: 1.9±0.3,
<0.01) and the Six-Minute Walk Test with significant reduction of serum brain natriuretic peptide level (pre: 308±72 pg/mL versus 6 months: 191±56 versus 1 year: 182±46,
<0.05), pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress after transplantation instead of limited efficacy in dilated cardiomyopathy patients.
Cell-sheet transplantation as a sole therapy was feasible for treating cardiomyopathy. Promising results in the safety and functional recovery warrant further clinical follow-up and larger studies to confirm this treatment's efficacy for severe congestive heart failure.
URL: http://www.umin.ac.jp/english/. Unique identifier: UMIN000003273.
Background:Blood stream infection is thought to increase the risk of hemorrhagic stroke, a major adverse event with devastating outcome, in patients with continuous-flow left ventricular assist ...devices (LVADs). We analyzed the risk factors of hemorrhagic stroke in LVAD patients, as well as the time relationship between systemic bacteremia and hemorrhagic stroke.Methods and Results:We evaluated the incidence of systemic bacteremia and stroke in 164 patients who underwent continuous-flow LVAD implantation between 2005 and 2016. At 1 and 2 years after implantation, the incidence of bacteremia was 29% and 36%, and the incidence of hemorrhagic stroke was 22% and 22% in patients without bacteremia, and 32% and 44% in those with bacteremia, respectively (P=0.035). This higher prevalence of hemorrhagic stroke in patients with bacteremia was notable particularly in the chronic phase (>90 days after implantation). Multivariate analysis revealed that bacteremia was an independent risk factor of hemorrhagic stroke in the chronic phase hazard ratio, 2.36 (1.02–5.62); P=0.044. The hazard rate was the highest immediately after the onset of bacteremia, and the risk steadily declined by 90 days after the last episode of bacteremia and flattened thereafter.Conclusions:Bacteremia was an independent risk factor of hemorrhagic stroke in patients in the chronic phase, with the highest risk seen in the early phase following an episode of bacteremia.
Background and purpose
Despite promising experimental results, clinically, intramyocardial myoblast injection failed to reverse remodeling and it induced arrhythmogenicity. In contrast, scaffold-free ...skeletal muscle-derived cell (SC) sheets attenuated cardiac dysfunction and arrhythmogenicity via paracrine effects. We report the first clinical trial of SC sheet implantation (SCSI) conducted in four patients with dilated cardiomyopathy (DCM) supported by a left ventricular assist device (LVAD).
Methods
SC sheets were made from muscle fibers and multi-layered SC sheets were applied to the left ventricular (LV) anterolateral surface via left thoracotomy.
Results
There were no major cardiac adverse events. Ventricular arrhythmia decreased in all except one patient, in whom global LV function did not improve. The LV volume decreased and LV ejection fraction improved in all except the same patient. Systolic wall thickening, reflecting regional wall motion, improved in the sheet-implanted areas, and vessels in the LV apex increased in all patients, suggesting angiogenesis. The LVAD was successfully removed in two patients.
Conclusions
SCSI induced reverse remodeling and angiogenesis, and improved LV function, allowing LVAD removal in two patients, although functional recovery failed to improve in the one non-responder, even with angiogenesis. SCSI is a promising regenerative therapy for DCM patients responsive to this strategy, even with LVAD assistance.
We evaluated the cardiac function recovery following skeletal myoblast cell-sheet transplantation and the long-term outcomes after applying this treatment in 23 patients with ischemic cardiomyopathy. ...We defined patients as “responders” when their left ventricular ejection fraction remained unchanged or improved at 6 months after treatment. At 6 months, 16 (69.6%) patients were defined as responders, and the average increase in left ventricular ejection fraction was 4.9%. The responders achieved greater improvement degrees in left ventricular and hemodynamic function parameters, and they presented improved exercise capacity. During the follow-up period (56 ± 28 months), there were four deaths and the overall 5-year survival rate was 95%. Although the responders showed higher freedom from mortality and/or heart failure admission (5-year, 81% versus 0%; p = 0.0002), both groups presented an excellent 5-year survival rate (5-year, 93% versus 100%; p = 0.297) that was higher than that predicted using the Seattle Heart Failure Model. The stepwise logistic regression analysis showed that the preoperative estimated glomerular filtration rate and the left ventricular end-systolic volume index were independently associated with the recovery progress. Approximately 70% of patients with “no-option” ischemic cardiomyopathy responded well to the cell-sheet transplantation. Preoperative renal and left ventricular function might predict the patients’ response to this treatment.
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This study demonstrated that approximately 70% of patients with “no-option” ischemic cardiomyopathy responded well to cell-sheet transplantation in terms of LV unloading and improvements in LV systolic and hemodynamic functions and functional capacity. Preoperative renal and LV function might predict the patients’ response to this treatment.
Background:We describe our original left ventricular assist device (LVAD) speed ramp and volume loading test designed to evaluate native heart function under continuous-flow LVAD support.Methods and ...Results:LVAD speed was decreased in 4 stages from the patient’s optimal speed to the minimum setting for each device. Under minimal LVAD support, patients were subjected to saline loading (body weight kg×10 mL in 15 min). Echocardiographic and hemodynamic data were obtained at each stage of the LVAD speed ramp and every 3 min during saline loading. Patients were divided into Recovery (with successful LVAD removal; n=8) and Non-recovery (others; n=31) groups. During testing, increased pulmonary capillary wedge pressure caused by volume loading was milder in the Recovery than Non-recovery group (repeated measures analysis of variance; group effect, P=0.0069; time effect, P<0.0001; interaction effect, P=0.0173). Increased cardiac output from volume loading was significantly higher in the Recovery than Non-recovery group (group effect, P=0.0124; time effect, P<0.0001; interaction effect, P=0.0091). Therefore, the Frank-Starling curve of the Recovery group was located upward and to the left of that of the Non-recovery group.Conclusions:The LVAD speed ramp and volume loading test facilitates the precise evaluation of native heart function during continuous-flow LVAD support.
GPR84 is a G protein-coupled receptor for medium-chain fatty acids. Capric acid and 3,3'-diindolylmethane are specific agonists for GPR84. We built a homology model of a GPR84-capric acid complex to ...investigate the ligand-binding mode using the crystal structure of human active-state β2-adrenergic receptor. We performed site-directed mutagenesis to subject ligand-binding sites to our model using GPR84-Giα fusion proteins and a (35)SGTPγS-binding assay. We compared the activity of the wild type and mutated forms of GPR84 by (35)SGTPγS binding to capric acid and diindolylmethane. The mutations L100D `Ballesteros-Weinstein numbering: 3.32), F101Y (3.33) and N104Q (3.36) in the transmembrane helix III and N357D (7.39) in the transmembrane helix VII resulted in reduced capric acid activity but maintained the diindolylmethane responses. Y186F (5.46) and Y186H (5.46) mutations had no characteristic effect on capric acid but with diindolylmethane they significantly affected the G protein activation efficiency. The L100D (3.32) mutant responded to decylamine, a fatty amine, instead of a natural agonist, the fatty acid capric acid, suggesting that we have identified a mutated G protein-coupled receptor-artificial ligand pairing. Our molecular model provides an explanation for these results and interactions between GPR84 and capric acid. Further, from the results of a double stimulation assay, we concluded that diindolylmethane was a positive allosteric modulator for GPR84.
Background:This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic aortic porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods ...and Results:We reviewed the records of 1,202 patients who underwent aortic valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999–2014). Patient data were collected using Research Electronic Data Capture. Patient survival was determined by Kaplan-Meier methodology. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined by actuarial methods. The median (interquartile range IQR) age of the cohort was 76 (70–80) years. The median (IQR) follow-up period was 3.52 (1.71–5.35) years. The longest follow-up was 15.8 years. The 30-day mortality rate was 2.3%. The 12-year actuarial survival rate was 59.9±7.5%, and the freedom from valve-related death was 81.1±7.9%. The freedom from reoperation was 86.4±2.6% at 12 years. The freedom from SVD at 12 years was 93.5±2.9% for patients aged ≥65 years and 98.2±1.8% for those aged <65 years. The median (IQR) systolic pressure gradient was 17 (12–23) and 19 (12–25) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.2 (1.1–1.5) and 1.1 (1–1.5) cm2at 1 and 10 years, respectively.Conclusions:The Mosaic porcine bioprosthesis showed satisfactory long-term outcomes over 12 years.
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