Masataka Eto

Extracorporeal Cardiac Shock Wave Therapy Markedly Ameliorates Ischemia-Induced Myocardial Dysfunction in Pigs in Vivo

Background—Prognosis of ischemic cardiomyopathy still remains poor because of the lack of effective treatments. To develop a noninvasive therapy for the disorder, we examined the in vitro and vivo effects of extracorporeal shock wave (SW) that could enhance angiogenesis. Methods and Results—SW treatment applied to cultured human umbilical vein endothelial cells significantly upregulated mRNA expression of vascular endothelial growth factor and its receptor Flt-1 in vitro. A porcine model of chronic myocardial ischemia was made by placing an ameroid constrictor at the proximal segment of the left circumflex coronary artery, which gradually induced a total occlusion of the artery with sustained myocardial dysfunction but without myocardial infarction in 4 weeks. Thereafter, extracorporeal SW therapy to the ischemic myocardial region (200 shots/spot for 9 spots at 0.09 mJ/mm2) was performed (n=8), which induced a complete recovery of left ventricular ejection fraction (51±2% to 62±2%), wall thickening fraction (13±3% to 30±3%), and regional myocardial blood flow (1.0±0.2 to 1.4±0.3 mL · min−1 · g−1) of the ischemic region in 4 weeks (all P<0.01). By contrast, animals that did not receive the therapy (n=8) had sustained myocardial dysfunction (left ventricular ejection fraction, 48±3% to 48±1%; wall thickening fraction, 13±2% to 9±2%) and regional myocardial blood flow (1.0±0.3 to 0.6±0.1 mL · min−1 · g−1). Neither arrhythmias nor other complications were observed during or after the treatment. SW treatment of the ischemic myocardium significantly upregulated vascular endothelial growth factor expression in vivo. Conclusions—These results suggest that extracorporeal cardiac SW therapy is an effective and noninvasive therapeutic strategy for ischemic heart disease.

Evidence of a Vicious Cycle in Mitral Regurgitation With Prolapse Secondary Tethering Attributed to Primary Prolapse Demonstrated by Three-Dimensional Echocardiography Exacerbates Regurgitation

Background— In patients with mitral valve prolapse, nonprolapsed leaflets are often apically tented. We hypothesized that secondary left ventricular dilatation attributed to primary mitral regurgitation (MR) causes papillary muscle (PM) displacement, resulting in this leaflet tenting/tethering, and that secondary tethering further exacerbates malcoaptation and contributes to MR severity. Methods and Results— Three-dimensional transesophageal echocardiography was performed in 25 patients with posterior mitral leaflet prolapse with an intact anterior mitral leaflet (AML) and 20 controls. From 3D zoom data sets, 11 equidistant antero-posterior cut planes of the mitral valve at midsystole were obtained. In each plane, tenting area of nonprolapsed leaflet and prolapse area of prolapsed leaflet were measured. Prolapse/tenting volume of each region was obtained as the product of interslice distance and the prolapse/tenting area. AML tenting volume and whole leaflet prolapse/tenting volume were then obtained. The PM tethering distance between PM tips and anterior mitral annulus was measured from 3D full-volume data sets. The severity of MR was quantified by vena contracta area extracted from color 3D transesophageal echocardiography data sets. AML tenting volume was significantly larger in patients with posterior mitral leaflet prolapse compared with that in controls (1.2±0.5 versus 0.6±0.2 mL/m2; P<0.001). Multivariate regression analysis identified independent contribution to AML tenting volume from an increase in PM tethering distance. Multivariate regression analysis identified independent contributions to MR severity (vena contracta area) from both whole leaflet tenting volume (r=0.44; P<0.05) and prolapse volume (r=0.44; P<0.05). AML tenting volume decreased along with left ventricular volume and PM tethering distance postrepair (n=8; P<0.01). Conclusions— These results suggest that primary mitral valve prolapse with MR causes secondary mitral leaflet tethering with PM displacement by left ventricular dilatation, which further exacerbates valve leakage, constituting a vicious cycle that would suggest a pathophysiologic rationale for early surgical repair.

A Rho-kinase inhibitor improves cardiac function after 24-hour heart preservation

OBJECTIVE The Rho-kinase signaling pathway is associated with coronary vasculopathy and myocardial dysfunction after cardiac transplantation. This study evaluated whether using a Rho-kinase inhibitor during allograft storage could limit early endothelial dysfunction and improve myocardial performance after reperfusion. METHODS This experiment was performed with an isolated working rabbit heart model and a support rabbit. Donor hearts (control group, n = 8) were arrested with an extracellular type of cardioplegia, preserved with University of Wisconsin solution, and then immersed in University of Wisconsin solution for 24 hours (1 degrees C). The Rho-kinase inhibitor (Rho-kinase inhibitor group, n = 8) was administrated in the cardioplegic solution, the preservation University of Wisconsin solution, and the storage University of Wisconsin solution. Left ventricular performance was evaluated from the modified Frank-Starling curve in the working mode. Coronary blood flow and donor heart rate were measured in Langendorff mode. Effective evaluation of the Rho-kinase inhibitor was inferred from phosphorylated myosin light chain. The expression of endothelial nitric oxide synthase mRNA was analyzed to assess endothelial function. RESULTS The Frank-Starling curve showed a significant left and upward shift in the Rho-kinase inhibitor group compared with the control group (P < .05). The coronary blood flow and heart rate in the Rho-kinase inhibitor group at 120 minutes was significantly higher than in the control group (P < .05). Phosphorylated myosin light chain was significantly suppressed in the Rho-kinase inhibitor group (P < .05). Endothelial nitric oxide synthase mRNA levels in the Rho-kinase inhibitor group increased 4-fold relative to those seen in the control group. CONCLUSIONS Treatment with Rho-kinase inhibitor during allograft harvest and storage enhanced coronary blood flow and ventricular recovery through nitric oxide-dependent endothelial protection after reperfusion. Rho-kinase inhibitor could help prevent early myocardial dysfunction after transplantation.

Transfection With a Dominant-Negative Inhibitor of Monocyte Chemoattractant Protein-1 Gene Improves Cardiac Function After 6 Hours of Cold Preservation

Background—Monocyte chemoattractant protein-1 (MCP-1), a potent chemotactic factor for monocytes, is induced during ischemia-reperfusion. As monocytes might play an important causative role in reperfusion injury, we investigated if inhibition of monocyte activation could attenuate ischemia-reperfusion injury and thereby improve cardiac preservation. To inhibit monocyte activation, we transfected a dominant-negative inhibitor of MCP-1 (7ND) gene in an animal model. Methods and Results—We used an isolated rabbit heart preparation perfused with support-rabbit blood and transfected 7ND genes to skeletal muscle of the support rabbits (n=7) using electroporation technique; causing an elevation of serum 7ND level to 20±7 pg/mL at 5 days after transfection. Animals receiving empty plasmid served as controls (n=7). Five days after transfection, hearts from other rabbits were excised, stored in UW solution for 6hours, and perfused with blood from transfected support rabbits. The 7ND group showed better cardiac output (128.7±17.9 versus 81.6±19.8 mL/min; P <0.01), lower serum CK-MB levels (5.0±1.8 versus 11.1±2.9 ng/mL; P <0.01), lower serum IL-1&bgr; levels (257.2±23.2 versus 311.2±37.4pg/mL; P <0.05), and lower serum TNF-&agr; levels (19.0±8.4 versus 35.1±13.0pg/mL; P <0.05). The numbers of infiltrating cells in myocardium were significantly reduced in the 7ND group. Conclusions—Inhibition of MCP-1 with 7ND gene transfection reduced cytokine activation, attenuated myocardial damage, and improved cardiac function after 6 hours of preservation. These results show that MCP-1 plays an important role in ischemia-reperfusion injury.

Elastomeric surgical sealant for hemostasis of cardiovascular anastomosis under full heparinization

PURPOSE We developed a novel surgical sealant, a viscous diisocyanated prepolymer, applicable to arterial hemostasis. The purpose of this study is to evaluate hemostatic effect of this surgical sealant under heparinized conditions. METHODS The effectiveness of this sealant was verified by applying it to the end-to-end anastomosis of canine carotid arteries. Five mongrel dogs were used. After a complete heparinization, the carotid arteries were clamped, divided, and end-to-end anastomoses were performed with four simple interrupted sutures. The sealant was coated on the anastomosis. After 5 min the clamps were removed and the hemostatic effect was evaluated. Three dogs were immediately subjected to macroscopic evaluation. Two dogs were subjected to angiography after 3 months and 16 months, respectively. RESULTS No bleeding occurred in any of the anastomoses immediately after the removal of the clamp. Macroscopic finding revealed no leakage of the sealant into the lumen. Carotid angiography revealed patent anastomoses without stenosis. CONCLUSION A novel surgical sealant exhibited rapid and potent hemostatic effect on a moisturized tissue under full heparinization.

Surgical Experience of Cardiac Tumors : Early and Late Results

PurposeCardiac tumors include benign and malignant neoplasms that arise within the cardiac chambers or myocardium. This study summarizes our surgical experiences with cardiac tumors.MethodsBetween 1975 and 2003, 51 patients with cardiac tumors were surgically treated.ResultsMyxomas. Forty-seven cardiac myxomas were excised in 46 patients with an average age of 51.7 ± 18 years. The preoperative symptoms included congestive heart failure (37%) and embolism (30%). The incidence of preoperative embolization was significantly higher in the gelatinous and lobated myxomas than in the solid and smooth form (P = 0.017). The early mortality rate was 2.2%. Although the late mortality rate was 9.7%, no patients died from cardiological causes (mean follow-up, 11.2 years). Only 1 patient required surgery for recurrence. Benign nonmyxomatous tumors. Three patients with a mean age of 26.3 ± 19.0 years showed benign nonmyxomatous tumors. There were no perioperative or late deaths. Malignant tumors. Two patients were diagnosed to have malignant tumors and although there was no perioperative death, both died postoperatively within 6 months.ConclusionsCardiac myxomas and nonmyxomatous benign cardiac tumors show excellent results after a surgical excision, with a low morbidity and mortality. A surgical resection should thus be considered as a treatment option for patients with malignant tumors.

A novel electron paramagnetic resonance spin-probe technique demonstrates the relation between the production of hydroxyl radicals and ischemia–reperfusion injury

OBJECTIVE Many previous studies have suggested an increase in hydroxyl radical (OH) production after myocardial ischemia-reperfusion; however, traditional techniques have not been able to conclusively prove this phenomenon. We investigated whether the production of OH was increased during myocardial reperfusion using a novel electron paramagnetic resonance (EPR) technique using an OH-specific spin probe. An OH scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), was used to examine the relationship between OH production and post-ischemic functional recovery or the degree of myocardial injury. METHODS We used an isolated rabbit-heart preparation perfused with support-rabbit blood, and the heart was reperfused after normothermic global ischemia. Heart samples were reacted with the OH-specific spin probe, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxyl-TEMPO). The rate of decay of the EPR signal showed OH production. We investigated the rate of EPR signal decay and cardiac function. RESULTS The rate of signal decay was significantly increased just after reperfusion compared with that of pre-ischemia (2.00×10(-2)±0.77×10(-2)min(-1) vs 0.11×10(-2)±0.02×10(-2)min(-1), p<0.01). Administration of MCI-186 reduced the rate of decay to 0.86×10(-2)±0.14×10(-2)min(-1) just after reperfusion (p<0.01). Cardiac function was significantly improved 60 min after reperfusion using MCI-186 compared without MCI-186 (left ventricular developed pressure was 95±9 mm Hg vs 60±6 mm Hg and the first derivative of the left ventricular pressure (dP/dt) was 1843±200 mm Hg s(-1) vs 1182±127 mm Hg s(-1)). CONCLUSIONS A novel EPR spin-probe technique demonstrated the relation between the production of OH and ischemia-reperfusion injury. We confirmed that OH production influenced cardiac function and myocardial ischemia-reperfusion injury.

Risk evaluation and midterm outcome of cardiac surgery in patients on dialysis.

The medical charts of 54 patients on maintenance dialysis who underwent cardiovascular surgery (37 elective and 17 urgent/emergency) from 1994 to 2004 were retrospectively analyzed. Thirty patients had coronary artery bypass grafting (17 elective and 13 urgent/emergency), 18 had valve replacement (16 elective and 2 urgent/emergency), and 6 underwent aortic surgery (4 elective and 2 urgent/emergency). The overall early mortality rate was 11.1%, comprising 2 patients (5.4%) who had elective operations and 4 (23.5%) who had urgent or emergency operations (p = 0.049). The overall 5-year survival rate was 48.4%. The 5-year survival rate was 67.2% for elective surgery and 10.5% for urgent/emergency surgery (p = 0.0001). The midterm clinical results after elective cardiovascular surgery were acceptable, whereas the results after urgent/emergency surgery were poor. For elective surgery, sufficient and detailed preoperative examinations might have contributed to the better operative outcome. Early diagnosis and consultation to avoid urgent/emergency operations in dialysis patients is recommended.

Basal Left Ventricular Dilatation and Reduced Contraction in Patients With Mitral Valve Prolapse Can Be Secondary to Annular Dilatation Preoperative and Postoperative Speckle-Tracking Echocardiographic Study on Left Ventricle and Mitral Valve Annulus Interaction

Background—Prominent mitral valve (MV) annular dilatation with only modest left ventricular (LV) dilatation in patients with MV prolapse (MVP) suggests predominant dilatation in adjacent basal LV, which may augment regional wall tension and attenuate contraction by Laplace’s law. We hypothesized that MV annular dilatation in patients with MVP is associated with the basal predominance of LV dilatation and attenuated contraction, which can be altered by surgical MV plasty with annulus reduction. Methods and Results—Echocardiography with speckle-tracking analysis to assess regional cross-sectional short-axis area and longitudinal contraction (strain) of basal, middle, and apical LV was performed in 30 controls and 130 patients with MVP. The basal value/averaged middle and apical values (B/M·A ratio) of LV cross-sectional area and strain were obtained. Patients with MVP showed significantly greater MV annular area (6.4±1.6 versus 3.7±0.6 cm2/m2), increased B/M·A LV area ratio (2.4±0.5 versus 1.8±0.2), and reduced B/M·A LV strain ratio (0.83±0.14 versus 0.96±0.09) than controls (P<0.001). Multivariable analyses identified that MV annular dilatation was independently associated with increased B/M·A LV area ratio (&bgr;=0.60, P<0.001), which was associated with reduced B/M·A LV strain ratio (&bgr;=−0.32, P<0.001). In 35 patients with MVP, B/M·A LV area and strain ratio significantly altered after surgical MV plasty with annulus reduction (2.5±0.5–1.8±0.3 and 0.73±0.10–0.89±0.17, P<0.001, respectively). Conclusions—In patients with MVP, MV annular dilatation was associated with the basal predominance of LV dilatation and reduced contraction, which can be altered by surgical MV plasty with annulus reduction, suggesting unfavorable influence from MV annular dilatation on basal LV.Background— Prominent mitral valve (MV) annular dilatation with only modest left ventricular (LV) dilatation in patients with MV prolapse (MVP) suggests predominant dilatation in adjacent basal LV, which may augment regional wall tension and attenuate contraction by Laplace’s law. We hypothesized that MV annular dilatation in patients with MVP is associated with the basal predominance of LV dilatation and attenuated contraction, which can be altered by surgical MV plasty with annulus reduction. Methods and Results— Echocardiography with speckle-tracking analysis to assess regional cross-sectional short-axis area and longitudinal contraction (strain) of basal, middle, and apical LV was performed in 30 controls and 130 patients with MVP. The basal value/averaged middle and apical values (B/M·A ratio) of LV cross-sectional area and strain were obtained. Patients with MVP showed significantly greater MV annular area (6.4±1.6 versus 3.7±0.6 cm2/m2), increased B/M·A LV area ratio (2.4±0.5 versus 1.8±0.2), and reduced B/M·A LV strain ratio (0.83±0.14 versus 0.96±0.09) than controls ( P <0.001). Multivariable analyses identified that MV annular dilatation was independently associated with increased B/M·A LV area ratio (β=0.60, P <0.001), which was associated with reduced B/M·A LV strain ratio (β=−0.32, P <0.001). In 35 patients with MVP, B/M·A LV area and strain ratio significantly altered after surgical MV plasty with annulus reduction (2.5±0.5–1.8±0.3 and 0.73±0.10–0.89±0.17, P <0.001, respectively). Conclusions— In patients with MVP, MV annular dilatation was associated with the basal predominance of LV dilatation and reduced contraction, which can be altered by surgical MV plasty with annulus reduction, suggesting unfavorable influence from MV annular dilatation on basal LV.

Experimental use of an elastomeric surgical sealant for arterial hemostasis and its long-term tissue response

OBJECTIVES Reliable suture line hemostasis should improve the outcome of aortic surgery. We examined the hemostatic effect and the tissue response of a novel elastomeric surgical sealant. METHODS Using porcine internal carotid arteries, we performed 16 end-to-end anastomoses with four stitches of simple interrupted sutures under full heparinization. The anastomoses were divided into two groups (eight anastomoses per group). Either novel sealant or fibrin glue was applied. The amount of bleeding was measured during the 30 s period after removing the vascular clamp. In a separate experiment, we applied the novel sealant around the abdominal aorta of rabbits (n=6) to assess the effect of the elastomeric property of the sealant on arterial wall histology. For comparison, we applied cyanoacrylate, which has no elastomeric property (n=6). A histological study was performed three months after the operation. RESULTS The novel sealant prevented arterial bleeding. The amount of bleeding from the anastomoses applied with novel sealant and fibrin glue was 0.12+/-0.03 g vs. 91.8+/-16.5 g, respectively (P<0.001). Thinning of the rabbit aortic wall was observed in the cyanoacrylate-treated abdominal aorta, whereas no thinning was observed in the novel sealant group. Histological examination revealed neither cell death nor necrosis in the novel sealant group. CONCLUSIONS The novel sealant effectively prevented arterial bleeding from the anastomosis under full heparinization. In addition, the elastomeric property of the sealant prevented thinning of the aortic wall. The novel sealant may be a promising hemostatic agent for arterial anastomosis.