Koichi Toda

Enhanced Survival of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes by the Combination of Cell Sheets With the Pedicled Omental Flap Technique in a Porcine Heart

Background— Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply. Methods and Results— Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide–labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T–positive cells surrounded by vascular-rich structures. Conclusions— The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.

Late Aortic Insufficiency Related to Poor Prognosis During Left Ventricular Assist Device Support

BACKGROUND Management of native aortic insufficiency (AI) during left ventricular assist device (LVAD) support is challenging. We investigated the occurrence of de novo AI during long-term LVAD support to identify its effect on late clinical and echocardiographic outcomes. METHODS Left ventricular assist devices were implanted in 99 patients with dilated cardiomyopathy, of whom 47 without preoperative AI were investigated using serial echocardiography examinations for more than 1 year after the operation. RESULTS The mean duration of LVAD support was 838±327 days, and 26 patients (55%) were supported for more than 2 years. Twenty-nine patients (62%) had no AI (group A), whereas de novo AI developed in the remaining 18 (38%; group B) at 1 year after LVAD implantation (≥grade 2 in 5, grade 1 in 13). The LV end-diastolic diameter was significantly reduced after LVAD implantation in both groups, with no significant difference between them. Overall survival was better in group A (p=0.0195). Multivariate analysis revealed that preoperative mitral regurgitation of more than grade 2 (odds ratio, 7.8; 95% confidence interval, 1.2 to 48.6; p=0.028) and an aortic valve that remained closed at 1 month after implantation (odds ratio, 6.7; 95% confidence interval, 1.0 to 43.9; p=0.048) were significant independent predictors of de novo AI at 1 year after LVAD implantation. CONCLUSIONS Survival was significantly worse when de novo AI developed in patients during long-term LVAD. Our findings indicate that preoperative functional mitral regurgitation and postoperative aortic valve opening are related to the progression of AI during long-term LVAD support.

Distribution of Porphyromonas gingivalis fimA genotypes in cardiovascular specimens from Japanese patients.

INTRODUCTION Porphyromonas gingivalis, a major periodontal pathogen, is gaining increasing attention for its possible association with cardiovascular diseases. Its fimbriae are classified into six genotypes (types I-V and Ib) based on the diversity of the fimA genes encoding the fimbrial subunits. In this study, fimA genotypic distribution was analyzed in P. gingivalis-infected cardiovascular specimens. METHODS A total of 112 heart valves and 80 atheromatous plaque specimens were collected from patients undergoing cardiovascular surgery, as well as 56 dental plaque specimens. Bacterial DNA was extracted from each, and polymerase chain reaction analysis was carried out with a P. gingivalis-specific set of primers. P. gingivalis-positive specimens were further analyzed to discriminate the fimA genotype using polymerase chain reaction with fimA type-specific primer sets. RESULTS P. gingivalis was detected in 10.4% of the cardiovascular specimens and 50.0% of the dental plaque samples. In the latter, type II was most frequently detected (35.7%), followed by types I (28.6%) and IV (21.4%), while types IV and II were detected with considerable frequencies of 45.0% and 30.0%, respectively, in the cardiovascular specimens. In contrast, the occurrence of type I was limited (5.0%) in the cardiovascular specimens. CONCLUSION These results suggest that specific fimA genotypic clones, which are reportedly associated with periodontitis, are also frequently harbored in cardiovascular specimens, indicating the possible involvement of type II and IV clones in the initiation and progression of cardiovascular diseases.

Risk Analysis of Bloodstream Infection During Long-Term Left Ventricular Assist Device Support

BACKGROUND Infection during left ventricular assist device (LVAD) support is associated with a high mortality. This study investigated the effect of bloodstream infection on survival of patients with LVAD support and assessed risk factors for survival in LVAD patients with bloodstream infection. METHODS Between 1999 and 2010, 109 consecutive patients with end-stage heart failure were supported by an LVAD as a bridge to transplantation. Overall survival was compared between those with and without a bloodstream infection. Risk factors for survival of patients with bloodstream infection were analyzed. RESULTS A bloodstream infection developed in 65 patients (60%) during 584 ± 389 days of LVAD support. Compared with patients without a bloodstream infection, overall survival was significantly worse in those with bloodstream infection (68% vs 84% at 2 years after LVAD implantation, p = 0.0117). However, of 22 patients bridged to transplantation, none had bloodstream infection recurrence after transplantation, and their 3-year survival rate after transplantation was 100%. Cox multivariate analysis (hazard ratio [95% confidence interval]) identified postoperative right ventricular failure (2.890 [1.238 to 6.757]; p = 0.0141) and bloodstream infection caused by a pathogen other than gram-positive cocci (3.336 [1.390 to 8.006] p = 0.0070) as significant risk factors for death in LVAD patients with a bloodstream infection. CONCLUSIONS Bloodstream infection had a significant effect on survival after LVAD implantation. Our results suggest that urgent cardiac transplantation should be considered for LVAD patients with a bloodstream infection based on the causative organism and right ventricular function.

Revascularization in severe ventricular dysfunction (15% ≤ LVEF ≤ 30%): a comparison of bypass grafting and percutaneous intervention

BACKGROUND We sought to determine the optimal approach to revascularization of patients with severe left ventricular (LV) dysfunction. METHODS We conducted a single-center observational study of 117 consecutive patients who had severe LV dysfunction (15% < OR = LV ejection fraction < OR = 30%) and underwent either coronary artery bypass grafting (CABG, n = 69) or percutaneous revascularization (n = 48) between 1992 and 1997. RESULTS The CABG group was younger (62 versus 67 years, p = 0.026), and fewer previous bypasses (7% versus 40%, p < 0.0001) and fewer prior percutaneous revascularizations (16% versus 42%, p = 0.0019) were noted. More vessels were revascularized (3 +/- 0.8 versus 1.5 +/- 0.7, p < 0.0001), and revascularization was more complete by CABG (84% versus 48%, p < 0.0001). Morbidity and mortality at 30 days were similar, and there was no significant difference in 3-year survival (73% versus 67%), although 3-year cardiac event-free survival (52% versus 25%, p = 0.0011) and 3-year target vessel revascularization-free survival (71% versus 41%, p < 0.0001) were significantly better in the CABG group, and LV ejection fraction was significantly improved after CABG. In the subgroup of patients 65 years of age or older and those without proximal left anterior descending coronary artery lesions, significant benefit of CABG in cardiac event-free and target vessel revascularization-free survival disappeared. CONCLUSIONS We found that in clinically selected patients with severe ventricular dysfunction, CABG compared with percutaneous revascularization achieves more complete revascularization, improved LV function, fewer cardiac events, and fewer target vessel revascularizations, but does not affect mid-term survival. A prospective controlled trial with defined criteria for treatment assignment is warranted to confirm our results regarding the two revascularization strategies in patients with severe LV dysfunction.

Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates.

Summary Induced pluripotent stem cells (iPSCs) can serve as a source of cardiomyocytes (CMs) to treat end-stage heart failure; however, transplantation of genetically dissimilar iPSCs even within species (allogeneic) can induce immune rejection. We hypothesized that this might be limited by matching the major histocompatibility complex (MHC) antigens between the donor and the recipient. We therefore transplanted fluorescence-labeled (GFP) iPSC-CMs donated from a macaque with homozygous MHC haplotypes into the subcutaneous tissue and hearts of macaques having heterozygous MHC haplotypes (MHC-matched; group I) or without identical MHC alleles (group II) in conjunction with immune suppression. Group I displayed a higher GFP intensity and less immune-cell infiltration in the graft than group II. However, MHC-matched transplantation with single or no immune-suppressive drugs still induced a substantial host immune response to the graft. Thus, the immunogenicity of allogeneic iPSC-CMs was reduced by MHC-matched transplantation although a requirement for appropriate immune suppression was retained for successful engraftment.

Valve surgery in active endocarditis patients complicated by intracranial haemorrhage: the influence of the timing of surgery on neurological outcomes

OBJECTIVES The risk of neurological deterioration during valve surgery using cardiopulmonary bypass under systemic heparinization in infective endocarditis (IE) patients with intracranial haemorrhage (ICH) is unknown. The objective of this retrospective study was to investigate the stratified risk related to the timing of valve surgery on neurological outcomes in patients with active IE and preoperative ICH. METHODS From 2004 to 2012, 246 patients underwent valve surgery for IE in hospitals enrolled in the Osaka Cardiovascular Research Group. Of these, a group of 30 patients had preoperative ICH, and they included 18 patients with cerebral haemorrhage, 8 with subarachnoid haemorrhage and 4 with haemorrhagic infarction. The preoperative characteristics, neurological statuses and postoperative results of these patients were retrospectively explored to analyse the effects of the timing of surgery on neurological outcomes. RESULTS Twenty-one patients had symptomatic ICH, and the median modified Rankin score was 1.5 (95% confidence interval [CI] 1.2-2.8). Eight patients were diagnosed with mycotic aneurysms, and 7 of these patients underwent aneurysm resection or clipping before valve surgery. All 30 patients underwent valve surgery, and the median interval between ICH onset and surgery was 22.5 (95% CI 15.5-39.4) days. Four patients died of multiple organ dysfunction or heart failure. The interval between ICH onset and valve surgery was within 7 days for 5 cases, between 8 and 14 days for 6, between 15 and 28 days for 9 and >29 days for 10. Postoperative neuroimaging showed that neither neurological deterioration nor exacerbation of haemorrhagic lesions had occurred among the 30 patients, regardless of the timing of surgery. However, 2 cases who underwent valve surgery 8 and 81 days after the onset of ICH developed new ectopic asymptomatic haemorrhages postoperatively. CONCLUSIONS The risk of postoperative neurological deterioration resulting from the exacerbation of haemorrhagic lesions seemed relatively low, even in IE patients who underwent valve surgery within 2 weeks of ICH onset. However, further evaluation of the sizes and aetiologies of haemorrhagic lesions is vital to establish a safe interval between the ICH onset and surgery.

Usefulness of transient elastography for noninvasive and reliable estimation of right-sided filling pressure in heart failure.

Accurate noninvasive assessment of right atrial pressure (RAP) is important for volume management in patients with heart failure (HF). Transient elastography is a noninvasive and reliable method to assess liver stiffness (LS). We investigated the value of LS for evaluation of RAP in patients with HF without structural liver disease. We measured LS using transient elastography (Fibroscan) in 31 patients undergoing right-sided cardiac catheterization (test group). The relation between LS and RAP found in the test group was used to derive the best-fit model to predict RAP. The applicability of the model was then tested in a validation group of 49 additional patients. There was an excellent correlation between LS and RAP in the test group (r = 0.95, p <0.0001; RAP = -5.8 + 6.7 × ln [LS]). Natural log transformation (ln) of LS provided the regression equation to predict RAP. When the equation model derived from the test group was applied to the validation group, predicted RAP correlated excellently with actual RAP (r = 0.90, p <0.0001). The receiver operating characteristic curve analyses in the test group showed that LS favorably compared with echocardiography for detecting RAP >10 mm Hg (area under the curve 0.958 vs 0.800, respectively, p = 0.047). In the validation group, LS with a cut-off value of 10.6 kPa for identifying RAP >10 mm Hg had a higher sensitivity and accuracy (p = 0.046 and p = 0.049, respectively) than echocardiography. In conclusion, LS may offer an accurate noninvasive diagnostic method to assess RAP in patients with HF.

Long-term outcome of combined valve repair and maze procedure for nonrheumatic mitral regurgitation.

OBJECTIVE The long-term outcomes of combined mitral repair and maze procedure for patients with nonrheumatic mitral regurgitation and chronic atrial fibrillation were evaluated. METHODS Between June 1992 and December 2008, 187 patients underwent a combined mitral repair and maze procedure. The mean follow-up period was 7.4 ± 4.3 years. Chordal reconstruction was performed in 69 patients, leaflet resection in 91, edge-to-edge leaflet suture in 30, and ring annuloplasty in 156. In addition, a cryo-maze procedure was applied in 110, and a Cox-Kosakai maze and radiofrequency maze were applied in the others. RESULTS There were 2 operative deaths and the 15-year survival was 71%. The 15-year freedom from greater than grade 3 mitral regurgitation was 61%; rates of freedom from heart failure (New York Heart Association class ≥ III) and reoperations were 79% and 91%, respectively. Cardiac function was improved and left ventricular size was decreased significantly postoperatively. Multivariate analysis showed that a large left ventricular diastolic diameter (≥65 mm) was an independent risk factor for recurrent mitral regurgitation. Eleven thromboembolic episodes (0.79%/patient-year) were detected during follow-up examinations, of which 7 occurred in patients with recurrent atrial fibrillation. Sinus rhythm was regained in 86% after 6 months and in 63% after 15 years. Multivariate analysis showed that a small-voltage f wave was an independent risk factor for AF recurrence. CONCLUSIONS A combined mitral valve repair and maze procedure provided low rates of morbidity and mortality and led to well-preserved cardiac function. Left ventricular diastolic diameter and f-wave voltage can be accurate predictors of good long-term outcome.

New Self-Expanding Transcatheter Aortic Valve Device for Transfemoral Implantation – Early Results of the First-in-Asia Implantation of the ACURATE Neo/TF TM System –

BACKGROUND Feasibility and early results of transfemoral aortic valve implantation using the ACURATE neo/TF(TM)self-expanding stent are reported. METHODS AND RESULTS The study group of 15 patients (mean age 83.3±6.0) was enrolled with a mean EuroSCORE and STS score of 21.9±11.6% and 7.5±3.1%, respectively. Clinical and echocardiographic evaluations were performed at baseline, discharge, 30 days and 6 months. The primary endpoint was all-cause mortality at 30 days. Transcatheter aortic valve implantation (TAVI) using the ACURATE neo/TF device was successful in 14 patients; 1 patient underwent valve-in-valve implantation because the prosthetic valve embolized during withdrawal of the delivery system. Conversion to surgery, coronary obstruction, peri-operative stroke, and pacemaker implantation did not occur at 30 days. Mean transvalvular gradients at discharge significantly decreased from 44.2±10.5 mmHg (preprocedural) to 7.7±3.1 mmHg (P<0.0001) and effective orifice area significantly increased from 0.77±0.12 to 1.69±0.25 cm(2)(P<0.0001). None or trace paravalvular leak was revealed in 50.0%, and no patient exhibited moderate or higher paravalvular leak. The overall mortality at 30 days and 6 months was 0% and 6.7%, respectively. CONCLUSIONS A new self-expanding TF TAVI device, ACURATE neo/TF, is safe and effective in the treatment of severe aortic stenosis in elderly patients at high risk for surgery.