Induction of human cardiomyocyte-like cells from fibroblasts by defined factors.

Heart disease remains a leading cause of death worldwide. Owing to the limited regenerative capacity of heart tissue, cardiac regenerative therapy has emerged as an attractive approach. Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. In the present study, we sought to determine whether human fibroblasts also could be converted to iCMs by defined factors. Our initial finding that GMT was not sufficient for cardiac induction in HCFs prompted us to screen for additional factors to promote cardiac reprogramming by analyzing multiple cardiac-specific gene induction with quantitative RT-PCR. The addition of Mesp1 and Myocd to GMT up-regulated a broader spectrum of cardiac genes in HCFs more efficiently compared with GMT alone. The HCFs and human dermal fibroblasts transduced with GMT, Mesp1, and Myocd (GMTMM) changed the cell morphology from a spindle shape to a rod-like or polygonal shape, expressed multiple cardiac-specific proteins, increased a broad range of cardiac genes and concomitantly suppressed fibroblast genes, and exhibited spontaneous Ca(2+) oscillations. Moreover, the cells matured to exhibit action potentials and contract synchronously in coculture with murine cardiomyocytes. A 5-ethynyl-2'-deoxyuridine assay revealed that the iCMs thus generated do not pass through a mitotic cell state. These findings demonstrate that human fibroblasts can be directly converted to iCMs by defined factors, which may facilitate future applications in regenerative medicine.

Time to revisit role of transcatheter balloon aortic valvuloplasty: a bridge-therapy to subsequent treatment case report.

Recently there has been a noticeable resurgence in the usage of percutaneous balloon aortic valvuloplasty (BAV) by the development of less invasive endovascular therapies including transcatheter aortic valve implantation (TAVI). We performed BAV in a 91-year-old man with end-stage severe symptomatic aortic stenosis (AS) and an impending abdominal aortic aneurysm (AAA) rupture who had been refused surgical treatment because of the comorbidities with stage V chronic kidney disease (CKD) and severe left ventricular dysfunction. Improvement in hemodynamics and kidney function was observed after BAV. Subsequently, we performed endovascular aneurysm repair (EVAR) successfully for AAA using iodinated contrast. No deterioration of kidney function was confirmed after the procedure. The patient was discharged without any adverse events. At present, the possibilities of TAVI or surgical aortic valve replacement (s-AVR) are under consideration as the definitive therapy for the upcoming aortic valve restenosis. In conclusion, this inoperable patient with multiple comorbidities was successfully treated, at lower risk, by catheter-based two-stage therapy.

[Efficacy of surgical left ventricular restoration for the patients with ischemic cardiomyopathy; comparison with the surgical treatments for ischemic heart failure (STICH) trial].

The efficacy of surgical left ventricular restoration (LVR) for the patients with ischemic cardiomyopathy was denied by the surgical treatments for ischemic heart failure (STICH) trial. But the conclusion of the STICH trial is wrong and real message of the STICH trial is as follows. LVR is not effective procedure for the patients with poor left ventricular function and small left ventricular dilatation. In the STICH trial, volume reduction rate of the patients with LVR is too little. Based on the low of Laplace, little volume reduction rate do not contribute the improvement of the ventricular function. In our 33 cases of LVR, the survival rates at 5, 7, and 10 years after LVR were 80%, 76% and 76%. On the other hand, the corresponding cardiac event-free rates were 55%. 44%, and 44%. These discrepancies of the value suggest the importance of both the preoperative strategy and the intensive therapy during the postoperative period. We observed some cases that re-enlarged left ventricle after LVR induced heart failure or ventricular arrhythmia. The timing of operation, left ventricular reconstruction of appropriate size and shape considering the function of residual myocardium has significant effect on prognosis. Postoperative ventricular tachycardia (VT) was the major factor influenced the survival rate. After preoperative or intraoperative three-dimensional electrical mapping by CARTO system to detect focus of VT, endocardiectomy combined with cryoablation at the VT focus is performed and postoperative antiarrhythmic medication is added routinely. If LVR will be performed after appreciation of its concept, indication and method, excellent long term prognosis will be expected.

Omentopexy enhances graft function in myocardial cell sheet transplantation.

Myocardial cell sheets (MCS) are a potentially valuable tool for tissue engineering aimed at heart regeneration. Several methods have recently been established for the fabrication of MCS. However, the lack of a sufficient blood supply has inhibited functional recovery of the MCS. To address this challenge, we combined MCS transplantation with omentopexy (OP), which utilizes omental tissue as a surgical flap. Rats were divided into five groups: sham, myocardial infarction (MI), MCS transplantation, OP, and MCS+OP. Histologic analysis revealed that MCS+OP drastically reversed MI-induced cardiac remodeling. Echocardiography revealed that MCS increased cardiac function, while OP had a synergistic beneficial effect with MCS transplantation. Immunofluorescence imaging showed that OP increased the survival of transplanted cardiomyocytes, and increased the blood supply through enhancement of angiogenesis and migration of small arteries into the MCS. Taken together, we concluded that OP is a promising strategy for the enhancement of graft function in MCS transplantation.

Feasibility of mitral valve repair using the loop technique.

PURPOSE: The most difficult aspect of chordal replacement in a mitral valve repair using expanded polytetrafluoroethylene (ePTFE) sutures, is determining the appropriate length of artificial chorda and ligation of the ePTFE sutures without the knot sliding. PATIENTS AND METHODS: We adopted a loop technique reported by Mohr et al. in 12 consecutive cases from October 2005. Nine cases were comparative broad-range prolapses of the posterior leaflet, 2 cases were anterior and the posterior leaflet and 1 case was vegetation of the anterior leaflet. Chordal replacement was done by 4 loops in 11 cases and by 8 loops in 1 case. RESULTS: Postoperative echocardiography showed more physiological movement of the posterior leaflet than by the resection suture method. When comparing of the peak pressure gradient across the mitral valve on echocardiography between the loop technique group and the non-loop technique group, the gradient in the loop technique group (n=11) was 1.8+/-0.7 mmHg and in the non-loop technique group (n=18) was 3.2+/-1.0 mm Hg. There was a significant statistical difference between 2 groups. The loop technique also seemed to be superior procedure hemodynamically. CONCLUSION: This technique may be useful through both port-access minimally invasive cardiac surgery (MICS) and a conventional approach to the mitral valve, and simplifying chordal replacement. We report on the feasibility of the loop technique based on our experience.

Atrophic degeneration and loss of myocytes of residual left ventricular myocardium after Dor operation for ischemic cardiomyopathy associated with left ventricular remodeling.

A 32-year-old male with familial hypercholesterolemia suffered from severe left ventricular dysfunction caused by left ventricular remodeling after myocardial infarction (ischemic cardiomyopathy), and endoventricular circular patch plasty (Dor operation) was performed. The patient's postoperative recovery was favorable. Postoperative left ventricular function was significantly improved and the patient was discharged from our hospital. However, about 5 months later, the patient developed congestive heart failure, which progressed rapidly and irreversibly, with death at postoperative month 6. At autopsy, atrophic degeneration and loss of myocytes of the residual left ventricular myocardium were suggested to be the cause of irreversible heart failure. The postoperative balance between function of the residual myocardium and reduced left ventricular volume should be considered in cases of Dor operation for ischemic cardiomyopathy with left ventricular remodeling.

Efficacy of endoventricular circular patch plasty: will this procedure improve the prognosis of patients with ischemic cardiomyopathy?

OBJECTIVES: We report hemodynamic and clinical results of our series of endoventricular circular patch plasty (Dor operation) and consider some advantages of this procedure for patients with ischemic cardiomyopathy. METHODS: Between 1996 and 2001, 23 consecutive patients with left ventricular aneurysm and/ or ischemic cardiomyopathy after myocardial infarction who underwent Dor operation were included in this study. Hemodynamic and clinical results of Dor operation were analyzed periodically. Patients were divided into two groups according to the extent of asynergy, more than 60% or not, i.e., an ischemic cardiomyopathy group (ICM group) or a simple left ventricular aneurysm group (sLVA group). RESULTS: Hospital mortality was 4.4%. Postoperative New York Heart Association functional class was improved in all survivors to class I or II. Postoperative ejection fraction (EF) increased and postoperative left ventricular (LV) volume decreased in all survivors. In both groups, early and 1 year postoperative EF increased significantly. Additionally, end-diastolic and end-systolic volumes decreased significantly in the early postoperative period. Postoperative LV volume had re-enlarged in the cases in which preoperative left ventricular end-systolic volume index was more than 90 mL/m2, though left ventricular ejection fraction was maintained or rather improved at 1 year postoperatively. The survival rates after 3 years of the operation in the sLVA and ICM groups were 85.7% and 81.3%. CONCLUSION: Though patients with ischemic cardiomyopathy with severe LV dysfunction may benefit the most from Dor operation, postoperative LV re-dilatation may deteriorate late mortality. At operation, whether optimal LV size and shape can be reconstructed and the timing of operation are the important issues because they affect prognoses.

Changes in left ventricular volume and predictors of cardiac events after endoventricular circular patch plasty.

OBJECTIVE: The aim of this study was to identify predictors of cardiac events after endoventricular circular patch plasty (Dor operation) by analyzing our experience with Dor operation. METHODS: Thirty patients with left ventricular aneurysm and/or ischemic cardiomyopathy who underwent Dor operation were included in this study. Hemodynamic and clinical results were analyzed, and the predictors of cardiac events were examined. RESULTS: Hospital mortality was 3.3%. Postoperative clinical status and left ventricular (LV) function in all survivors significantly improved. The survival rates at 1, 3, and 5 years after operation were 93%, 89% and 89%. The corresponding cardiac event-free rates were 75%, 67% and 49%. Pre- and postoperative LV function and volume did not differ significantly between patients with or without cardiac events. However, the proportion of reduced end-diastolic volume index (EDVI) (preoperative EDVI-postoperative EDVI) to preoperative EDVI was significantly higher in patients with cardiac events than in cardiac event-free patients. Postoperative LV volume re-increased in the cases with cardiac events during follow-up. Cox regression analysis confirmed that preoperative clinical premature ventricular contraction and end-systolic volume index (ESVI), postoperative EDVI, ESVI, and ejection fraction were independent predictors of late cardiac events. There was a significant positive correlation between preoperative ESVI and postoperative EDVI. CONCLUSION: Though LV function significantly improved after Dor operation, LV reconstruction with excessive reduction can cause restarting LV remodeling and increasing mortality and morbidity. Therefore, LV reconstruction of appropriate sizes and shapes, considering the function of residual myocardium, has a significant effect on prognosis. It is highly reasonable to expect that preoperative ESVI can predict the optimal size of reconstructed left ventricle.

Risk scores for predicting mortality after surgical ventricular reconstruction for ischemic cardiomyopathy: results of a Japanese multicenter study.

OBJECTIVES: Surgical ventricular reconstruction has been believed to be beneficial for those with ischemic cardiomyopathy. However, the effectiveness of surgical ventricular reconstruction was not proved by a large-scale trial, and no report has clearly demonstrated the exact indications and limitations of surgical ventricular reconstruction. The purpose of this study was to elucidate predictive factors of mortality after surgical ventricular reconstruction and to develop a prognostic model by calculating risk scores. METHODS: The study subjects were 596 patients who underwent surgical ventricular reconstruction for chronic ischemic heart failure in 11 Japanese cardiovascular hospitals between 2000 and 2010. Potential predictors of postoperative mortality were assessed using the Cox proportional hazards model, and a risk score was calculated. RESULTS: Forty-one patients died before discharge, and 81 patients died during a mean follow-up time of 2.9 years. Four independent predictors of mortality were identified: age, Interagency Registry for Mechanically Assisted Circulatory Support profile, left ventricular ejection fraction, and severity of mitral regurgitation. Each variable was assigned a number of points proportional to its regression coefficient. A risk score was calculated using the point scores for each patient, and 3 risk groups were developed: a low-risk group (0-4 points), an intermediate-risk group (5-6 points), and a high-risk group (7-12 points). Their 3-year survivals were 93%, 81%, and 44%, respectively (log-rank P < .001). Harrell's C-index of the predictive model was 0.69. CONCLUSIONS: A simple prognostic model was developed to predict mortality after surgical ventricular reconstruction. It can be useful in clinical practice to select treatment options for ischemic heart failure.

Impact of left ventricular remodelling on outcomes after left ventriculoplasty for ischaemic cardiomyopathy: Japanese surgical ventricular reconstruction group experience.

OBJECTIVES: Surgical ventricular reconstruction (SVR) for patients with severe left ventricular (LV) remodelling due to ischaemic cardiomyopathy is still controversial, because the Surgical Treatment for Ischaemic Heart Failure (STICH) trial demonstrated that SVR not only has no beneficial effect on survival compared with coronary artery bypass grafting (CABG) alone, but also is worse for those with a larger LV. Therefore, we assessed the impact of LV remodelling on the outcomes after SVR for ischaemic cardiomyopathy in Japan, using Di Donato's LV shape classification. METHODS: From 2000 to 2010, 627 patients underwent SVR for ischaemic heart failure in 11 Japanese hospitals. To assess the patients with an LV ejection fraction (LVEF) of ≤ 35% like the STICH trial, considering the severity of LV remodelling, the patients with a preoperative LVEF of >35%, no preoperative LV volume assessment and no preoperative LV shape classification were excluded. Finally, 323 patients were selected as the study subjects. The LV shape was divided into three types according to Di Donato's classification. Types 1 and 3 indicate the aneurysmal and globally akinetic LV, respectively. Type 2 is the intermediate shape. RESULTS: Type 1, 2 and 3 LV shapes were observed in 85 (26%), 104 (32%) and 134 (42%) of the patients, respectively. The preoperative LV volume and diameter increased if the LV became more akinetic (Type 3 > 2 > 1, P < 0.001). LVEF was lower in those with more akinetic LV (P = 0.002). The preoperative LV end-diastolic volume index and LVEF in Type 3 patients were 133 ± 47 ml/m(2) and 22 ± 7%, respectively. Mitral valve repair was more frequently performed for patients with the Type 3 LV shape (65%) than for the others (P < 0.001). The hospital mortality rates were 2.4, 2.9 and 7.4% for Type 1, 2 and 3 patients, respectively (P = 0.16). Kaplan-Meier analysis demonstrated no significant difference in mortality among the three groups (log-rank P = 0.37). The 5-year survival rates were 81, 70 and 73% for Type 1, 2 and 3 patients, respectively. CONCLUSIONS: The severity of LV remodelling did not affect survival after SVR plus CABG. The results of SVR were acceptable even for those with globally akinetic LV due to ischaemic cardiomyopathy.

Double-bar application decreases postoperative pain after the Nuss procedure.

OBJECTIVE: This biomechanical study aims to elucidate whether additional bar application increases postoperative pain after the Nuss procedure for pectus excavatum. METHODS: Clinical evaluation: The intensity of postoperative pain was compared between patients for whom a single-bar was used (single-bar group: n = 14) and those for whom double bars (double-bar group: n = 10) were used to correct the thoracic deformity. The evaluation was performed by referring to the frequency with which local anesthetics were self-injected in a patient-controlled anesthetic system and how many days were needed for the patients to resume ambulation. Theoretical evaluation: An original simulation system for the Nuss procedure was developed by producing 3-dimensional finite element analysis models from computed tomographic data of patients with pectus excavatum. With this system, single-bar and double-bar placement was simulated separately for the thorax models of the double-bar group. The stresses occurring on the thoraces were then compared between the two situations. RESULTS: Clinical evaluation: Self-injection of local anesthetic was more frequent for the single-bar group than for the double-bar group; single-bar patients restarted ambulation later than the double-bar group. Theoretical evaluation: Stresses on the thoraces were smaller when double bars were applied than when a single bar was applied. CONCLUSIONS: Performing double-bar placement decreases postoperative pain. Therefore, surgeons should not hesitate to perform double-bar correction in patients in whom the deformity extends to multiple intercostal spaces, requiring correction of the thorax shape at multiple sites.

Aortic insufficiency and cardiac herniation associated with blunt chest trauma.

Aortic insufficiency and cardiac herniation due to pericardial rupture after blunt chest trauma are rare complications and are usually associated with high mortality. We report on a patient with simultaneous aortic insufficiency and cardiac herniation. He was involved in a falling accident, but initially presented no symptoms associated with the heart. At a later stage, he developed dyspnea on effort and a final diagnosis was completed. He was successfully treated surgically.

Examination of mitral valve repair with port-access method--Aiming at early and less invasive mitral valve repair--.

OBJECTIVE: We reviewed the results of mitral valvuloplasty by port-access minimally invasive cardiac surgery to examine the validity of operating during an early phase. METHODS: From 1988 through March 2007, a total of 126 patients requiring mitral valvuloplasty were treated with port-access minimally invasive cardiac surgery. Their mean age was 51 +/- 13 years, and 88 were male. The operative procedures were resection-suture in 51 cases, artificial chordal replacement in 5 cases, chordal translocation in 3 cases, leaflet plication in 3 cases, and artificial chordal reconstruction by the loop technique in 64 cases. RESULTS: There was one hospital death, and two patients required reoperation at 1 and 21 postoperative days because of hemolysis and intractable systolic anterior motion, respectively. Except for the two patients undergoing reoperation, the duration of the postoperative hospital stay was 9.7 +/- 3 days. The results of the other cases were satisfactory during each follow-up period. CONCLUSION: Complete valvuloplasty with port-access MIS is thought to be an increasingly important procedure for treating mitral regurgitation.

A case report of surgical correction for congenital mitral regurgitation with subvalvular apparatus abnormality.

We report a successful complex mitral valve plasty using port access minimally invasive cardiac surgery for congenital mitral regurgitation that presented as an abnormality of the subvalvular apparatus. A 16-year-old male patient received a diagnosis of mitral regurgitation resulting from tethering of the anterior mitral leaflet and posterior mitral leaflet caused by an abnormality in papillary muscle insertion and a hypoplastic chordae tendineae. The posterior leaflet was closely tethered to the tips of the papillary muscle with essentially no chordae tendineae. The flexibility of the leaflet was restored by surgically removing the abnormal chordae, and reconstruction of chordae tendinae of the anterior leaflet was carried out using three loops and of the posterior leaflet using one loop with a loop technique method. As an additional procedure for persistent regurgitation, an edge-to-edge technique to the posterior commissure side was performed, after which the mitral regurgitation disappeared.

Extrinsic compression of the left main coronary artery by atrial septal defect.

On rare occasions, extrinsic compression of the coronary artery can cause significant stenosis. We report a 42-year-old woman who was referred to our hospital for surgical repair of atrial septal defect. Cardiac 64-slice multi-detector computed tomography before the operation revealed the extrinsic compression of the proximal left main coronary artery by the marked dilatation of pulmonary trunk. The patient eventually underwent atrial septal defect closure and coronary artery bypass simultaneously. Four months after the operation, multi-detector computed tomographic scan revealed reduction of pulmonary trunk diameter and resolution of left main coronary artery narrowing.

Experience with nifekalant hydrochloride in a patient with ischemic cardiomyopathy and severe ventricular dysfunction after dor operation.

A 52-year-old male with ischemic cardiomyopathy and severe ventricular dysfunction underwent coronary artery bypass grafting and left ventricular reconstruction (Dor operation). The patient developed acute onset of incessant ventricular tachycardia in the early postoperative period that was refractory to therapy with class I antiarrhythmic agents, and multiple attempts at electrical cardioversion were required. A combination of intravenous nifekalant hydrochloride and enteral amiodarone was elected as treatment for this recurrent incessant ventricular tachycardia. Nifekalant hydrochloride was administered as a loading dose (0.3 mg/kg/5 min), followed by an intravenous infusion (0.4 mg/kg/hr). Several days after initiating therapy, the patient no longer experienced episodes of ventricular tachycardia, and there was no compromise in hemodynamics. We conclude that nifekalant hydrochloride is a useful agent for suppression of ventricular tachycardia in patients with severe left ventricular dysfunction, especially during the early postoperative period.