Haruhiko Kondoh

Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium.

Background. We hypothesized that tissue-engineered contractile cardiomyocyte sheets without a scaffold would show histological and electrical integration with impaired myocardium, leading to the regeneration of infarcted myocardium. Methods. Neonatal rat cardiomyocytes were cultured on Poly(N-isopropylacrylamide)-grafted polystyrene dishes and detached as a square cell sheet at 20°C. Two sheets were stacked to make thicker contractile cardiac sheets. In cross-section, the stacked sheets looked like homogeneous heart-like tissue. Two weeks after rats were subjected to left anterior descending (LAD) ligation, two treatments were conducted: 1) cardiomyocyte sheet implantation (T group, n=10), and 2) fibroblast sheet implantation (F group, n=10). The control group underwent no additional treatment (C group, n=10). Results. Echocardiography demonstrated that cardiac performance was significantly ameliorated in the T group 2, 4, and 8 weeks after implantation. The cardiomyocyte sheets became attached to the infarcted myocardium, showed angiogenesis, expressed connexin-43, and appeared as homogeneous tissue in the myocardium Electrophysiological experiments showed a QRS complex with one peak in the treated scar area in the T group, but two peaks, indicative of branch block, in that of the other groups. Furthermore, the threshold for pacing of the recipient heart was lower in the T group than in the other groups. Conclusions. Cardiomyocyte sheets integrated with the impaired myocardium and improved cardiac performance in a model of ischemic myocardium. Techniques using such tissue-engineered cell sheets are introducing the promising concept of tissue cardiomyoplasty to the field of regenerative medicine.

Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats

The goal of the study was to examine if allogenic mesenchymal stem cell (MSC) transplantation is a useful therapy for acute myocardial infarction (AMI). Buffer (control; group C, n=41), MSCs of male ACI rats (allogenic; group A, n=38, 5 x 10(6)), or MSCs of male LEW rats (syngenic; group S, n=40, 5 x 10(6)) were injected into the scar 15 min after myocardial infarction in female LEW rats. After 28 days, fractional left ventricular shortening significantly increased in groups A (21.3+/-1.7%, P=0.0467) and S (23.2+/-1.9%, P=0.0140), compared to group C (17.1+/-0.9%). Fibrosis in groups A and S was significantly lower. Quantitative PCR of the male-specific sry gene showed disappearance of donor cells within 28 days (5195+/-1975 cells). Secretion of vascular endothelial growth factor (VEGF) by MSCs was enhanced under hypoxic conditions in vitro. In groups A and S, the plasma VEGF concentration, VEGF level, and capillary density in recipient hearts increased after 28 days. Flow cytometry revealed the absence of B7 signal molecules on MSCs. A mixed lymphocyte reaction showed that ACI MSCs failed to stimulate proliferation of LEW lymphocytes. After 1 day after cell transplantation, transient increases in interleukin-1 beta and monocyte chemoattractant protein-1 in recipient hearts were enhanced in group A, with macrophage infiltration at the injection site. T cells remained at the level of normal tissue in all groups. We conclude that allogenic MSC transplantation therapy is useful for AMI. The donor MSCs disappear rapidly, but become a trigger of VEGF paracrine effect, without induction of immune rejection.

Does Stringent Restrictive Annuloplasty for Functional Mitral Regurgitation Cause Functional Mitral Stenosis and Pulmonary Hypertension

Background— It remains controversial whether restrictive mitral annuloplasty (RMA) for functional mitral regurgitation (MR) can induce functional mitral stenosis (MS) that may cause postoperative residual pulmonary hypertension (PH). Methods and Results— One hundred eight patients with left ventricular (LV) dysfunction and severe MR underwent RMA with stringent downsizing of the mitral annulus. Systolic pulmonary artery pressure (PAP) and mitral valve performance variables were determined by Doppler echocardiography prospectively and 1 month after RMA. Fifty-eight patients underwent postoperative hemodynamic measurements. Postoperative echocardiography showed a mean pressure half-time of 92±14 ms, a transmitral mean gradient of 2.9±1.1 mm Hg, and a mitral valve effective orifice area of 2.4±0.4 cm2, consistent with functional MS. Doppler-derived systolic PAP was 32±8 mm Hg, which correlated weakly with the transmitral mean gradient (&rgr;=0.23, P=0.02). Postoperative cardiac catheterization also showed significant improvements in LV volume and systolic function, pulmonary capillary wedge pressure, cardiac index, and systolic PAP; the latter was associated with LV end-diastolic pressure [standardized partial regression coefficient (SPRC)=0.51], pulmonary vascular resistance (SPRC=0.47), cardiac index (SPRC=0.37), and transmitral pressure gradient (SPRC=0.20). In a multivariate Cox proportional hazard model, postoperative PH (systolic PAP >40 mm Hg), but not mitral valve performance variables, was strongly associated with adverse cardiac events. Conclusions— RMA for functional MR resulted in varying degrees of functional MS. However, our data were more consistent with the residual PH being caused by LV dysfunction and pulmonary vascular disease than by the functional MS. The residual PH, not functional MS, was the major predictor of post-RMA adverse cardiac events.

Pulmonary hypertension predicts adverse cardiac events after restrictive mitral annuloplasty for severe functional mitral regurgitation

OBJECTIVES Pulmonary hypertension (PH) is an indicator of a poor prognosis in patients with dilated cardiomyopathy. Few studies have investigated the prognostic role of PH in patients undergoing restrictive mitral annuloplasty (RMA) for severe functional mitral regurgitation secondary to advanced cardiomyopathy. METHODS A total of 46 patients undergoing RMA were classified into 3 groups on the basis of the Doppler-derived systolic pulmonary artery pressure (PAP) at baseline. Of the 46 patients, 19 had a systolic PAP less than 40 mm Hg (mild PH group), 17 had a systolic PAP of 40 to 60 mm Hg (moderate PH group), and 10 had a systolic PAP greater than 60 mm Hg (severe PH group). RESULTS Postoperative cardiac catheterization showed that the RMA procedure resulted in a significant reduction of the left ventricular (LV) preload and improvements in LV systolic function in all 3 groups, along with the relief of symptoms. During the follow-up period (mean, 36 ± 19 months), cardiac death occurred in 6 patients, readmission because of heart failure in 3, and fatal arrhythmia in 1. The rate of freedom from these cardiac events at 3 years was 93% ± 7%, 88% ± 8%, and 56% ± 17% in the mild, moderate, and severe PH groups (P < .001). Serial echocardiography showed that significant LV reverse remodeling occurred in 89%, 71%, and 25% of the mild, moderate, and severe PH groups, respectively. Multivariate Cox regression analysis identified severe PH (systolic PAP > 60 mm Hg) as a significant predictor of adverse cardiac events, as well as LV remodeling after RMA. CONCLUSIONS Noninvasive assessment of preoperative PH has a prognostic value in patients undergoing RMA for severe functional mitral regurgitation secondary to advanced cardiomyopathy.

Total arch replacement with long elephant trunk anastomosed at the base of the innominate artery: a single-centre longitudinal experience.

OBJECTIVE Total arch replacement, with a long elephant trunk (ET) anastomosed at the base of the innominate artery using an undersized graft, is performed for a variety of arch aneurysms. We investigated the long-term clinical outcomes of this procedure, as well as its long-term effectiveness for preventing retrograde flow into the aneurysm and further dilation of the descending aorta. METHODS We treated 127 consecutive patients with an arch aneurysm, who were divided into two groups according to the diameter of the descending aorta at the Th6-Th8 thoracic vertebral level: 35 mm or less (Single-ET, n = 94) and >35 mm (Staged-ET, n = 33). The graft diameter was undersized by 10-20% of the distal aortic diameter. ET length was determined by preoperative computed tomography (CT) to locate the distal end at Th6-Th8. Thrombosis around the ET and the descending aorta diameter around the distal end of the ET were evaluated using CT. RESULTS Two patients (1.6%) died within 30 days, while seven (5.5%) died in the hospital, three (2.4%) had a new stroke, three (2.4%) had permanent paraplegia and one (0.8%) had paraparesis. CT demonstrated complete thrombosis of the perigraft space around the ET in 81 patients (86%) in the Single-ET group and 11 (33%) in the Staged-ET group within 1 month after surgery, but not in the remaining 35 patients. Twenty-seven of the 35 patients without complete thrombosis underwent a subsequent second-stage operation. In those, the descending aorta showed no further dilation around the distal end of the ET, while new-onset perigraft perfusion occurred in two patients in the Single-ET group at 14 and 126 months, respectively. Overall survival was 89, 86, 78 and 74% at 1, 3, 5 and 7 years, respectively. CONCLUSIONS Our operative strategy for extensive thoracic aortic aneurysms using a long ET technique yielded satisfactory short- and long-term outcomes.

Mitral Valve Repair for Medically Refractory Functional Mitral Regurgitation in Patients With End-Stage Renal Disease and Advanced Heart Failure

Background— Information regarding patient selection for mitral valve repair for chronic kidney disease or end-stage renal disease (ESRD) with severe heart failure (HF) as well as outcome is limited. Methods and Results— We classified 208 patients with advanced HF symptoms (Stage C/D) undergoing mitral valve repair for functional mitral regurgitation into 3 groups: estimated glomerular filtration rate ≥30 mL/min/1.73 m2 (control group, n=144); estimated glomerular filtration rate <30 mL/min/1.73 m2, not dependent on hemodialysis (late chronic kidney disease group, n=45), and ESRD on hemodialysis (ESRD group, n=19; preoperative hemodialysis duration 83±92 months). Follow-up was completed with a mean duration of 49±25 months. Postoperative (1-month) cardiac catheterization showed that left ventricular end-systolic volume index decreased from 109±38 to 79±41, 103±31 to 81±31, and 123±40 to 76±34 mL/m2, in the control, late chronic kidney disease, and ESRD groups, respectively. Left ventricular end-diastolic pressure decreased, whereas cardiac index increased in all groups with no intergroup differences for those postoperative values. Freedom from mortality and HF readmission at 5 years was 18%±7% in late chronic kidney disease (P<0.0001 versus control, P=0.01 versus ESRD), and 64%±12% in ESRD (P=1 versus control) as compared with 52%±5% in the control group (median event-free survival, 26, 67, and 63 months, respectively). Conclusions— Mitral valve repair for medically refractory functional mitral regurgitation in patients with advanced HF yielded improvements in left ventricular function and hemodynamics irrespective of preoperative renal function status. Patients with ESRD showed favorable late outcome in terms of freedom from mortality and readmission for HF as compared with those with late chronic kidney disease. Further studies are needed to assess the survival benefits of mitral valve repair in patients with ESRD and advanced HF.

B-type natriuretic peptide response and reverse left ventricular remodeling after surgical correction of functional mitral regurgitation in patients with advanced cardiomyopathy

BACKGROUND Restrictive mitral annuloplasty (RMA) can reverse left ventricular (LV) remodeling and reduce plasma B-type natriuretic peptide (BNP), a surrogate biomarker of heart failure. However, the relationship between reverse LV remodeling and plasma BNP changes after RMA is poorly defined. We explored the main hemodynamic factors contributing to change in plasma BNP after RMA in patients with functional mitral regurgitation (MR). METHODS Twenty-four patients with moderate to severe functional MR secondary to LV systolic dysfunction [ejection fraction (EF) <40%] underwent 64-row multidetector computed tomography (MDCT) before and 1.4 months after RMA. LV end-diastolic volume index (EDVI), end-systolic volume index (ESVI), LVEF, and regional and global end-systolic wall stress (ESS) were calculated from 3-dimensional MDCT images, with blood samples for plasma BNP measurement collected the same day. RESULTS After RMA, LV volumes and global ESS were decreased, while LVEF improved (all p<0.01). There were significant correlations between changes in LVEDVI and LVESVI (r=0.90, p<0.0001), LVESVI and global ESS (r=0.54, p=0.006), and global ESS and LVEF (r=-0.60, p=0.002). The median value for the plasma BNP also decreased from 597 pg/ml [interquartile range (IQR), 360-934 pg/ml] to 207 pg/ml (IQR, 124-271 pg/ml), in association with changes in LVEDVI (r=0.47, p=0.019), LVESVI (r=0.56, p=0.004), LVEF (r=-0.60, p=0.002), and global ESS (r=0.74, p<0.0001). Multivariate regression analysis showed that global ESS change was the strongest contributor to change in natural-log-transformed plasma BNP (standardized partial regression coefficient=0.59, p=0.004), indicating a strong association between decrease in LV afterload and reduction in plasma BNP level after RMA. CONCLUSIONS There may be a significant association between LV reverse remodeling and plasma BNP change after RMA. Furthermore, LV end-systolic myocardial stress may be the key mechanical stimulus influencing plasma BNP after surgical correction for functional MR. Whether these favorable BNP responses and reverse remodeling can predict improved survival requires further study.

Restrictive Mitral Annuloplasty With or Without Surgical Ventricular Restoration in Ischemic Dilated Cardiomyopathy With Severe Mitral Regurgitation

Background— We assessed changes in left ventricular (LV) volume and function and in regional myocardial wall stress in noninfarcted segments after restrictive mitral annuloplasty (RMA) with or without surgical ventricular restoration (SVR). Methods and Results— Thirty-nine patients with ischemic cardiomyopathy (ejection fraction ⩽0.35) and severe mitral regurgitation (≥3) were studied before and 2.8 months after surgery with cine-angiographic multidetector computed tomography (cine-MDCT). Eighteen underwent RMA alone (RMA group) and 21 underwent RMA and SVR (RMA+SVR group). In addition to measuring conventional parameters (LV end-diastolic volume index [LVEDVI], LV end-systolic volume index [LVESVI], and LV ejection fraction), we evaluated the regional circumferential end-systolic wall stress and mean circumferential fiber shortening in both the basal and mid-LV regions using 3-dimensional cine-MDCT images. LV end-diastolic and end-systolic volume indexes were significantly greater in the RMA+SVR group than in the RMA group preoperatively, but these values did not differ significantly postoperatively. LV end-diastolic and end-systolic volume indexes decreased significantly, by 21% and 27% after RMA and by 35% and 42% after RMA and SVR, and the percent reductions in LV end-diastolic and end-systolic volume indexes were significantly larger in the RMA+SVR group. Regional end-systolic wall stress decreased and circumferential fiber shortening increased significantly in the noninfarcted regions after RMA with or without SVR. Conclusions— RMA plus SVR showed a potentially greater reduction of LV end-diastolic and end-systolic volume indexes than RMA alone. In selected patients with more advanced LV remodeling, concomitant SVR may favorably affect the LV reverse-remodeling process induced by RMA.

Restrictive mitral annuloplasty with or without surgical ventricular reconstruction in ischaemic cardiomyopathy: impacts on neurohormonal activation, reverse left ventricular remodelling and survival.

In the STICH trial, adding surgical ventricular reconstruction (SVR) to coronary artery bypass grafting (CABG) reduced LV end‐systolic volume index (LVESVI) by 19%, as compared with 6% with CABG alone, providing no survival or functional benefits. Herein, we compared the efficacy of restrictive mitral annuloplasty (RMA) alone with that of RMA combined with SVR in patients with functional mitral regurgitation (MR).

Optimal graft diameter and location reduce postoperative complications after total arch replacement with long elephant trunk for arch aneurysm

OBJECTIVE Total arch replacement with an elephant trunk is a standard treatment for arch aneurysm, but serious complications, such as paraplegia and peripheral embolization caused by flapping of the elephant trunk, remain. Moreover, dilation of the descending aorta and retrograde flow into the peri-graft space at the distal elephant trunk are frequent problems. We hypothesized that optimal graft diameter and location would reduce complications after total arch replacement with a long elephant trunk by achieving complete thrombosis and minimal dilation of the descending aorta around the elephant trunk. METHODS We treated 65 patients with arch aneurysm by total arch replacement with a long elephant trunk anastomosed at the base of the innominate artery. The graft diameter was undersized (10%-20% of the distal aortas diameter). Elephant trunk length was determined by preoperative computed tomography to locate the distal end at Th6 to Th8. Thrombosis around the elephant trunk, diameter of the descending aorta, and distance between the descending aorta and the graft near the distal end of the elephant trunk were evaluated using computed tomography. RESULTS The distal end of the elephant trunk was located at Th 8 ± 1. There were no operative deaths, 3 patients (5%) died in the hospital, and 3 patients (5%) experienced spinal cord injury, including 1 in whom permanent paraplegia developed. Computed tomography revealed complete thrombosis around the elephant trunk in 58 patients (89%). The descending aorta did not dilate further, and distance between the descending aorta and the graft progressively decreased. CONCLUSIONS Optimal graft diameter and location minimized postoperative complications, with complete thrombosis and no dilation of the descending aorta around the long elephant trunk in most patients.