[Concomitant Operations for Thoracic Aortic Aneurysm and Myasthenia Gravis;Report of a Case].

A 77-year-old man, who had been under medical treatment for myasthenia gravis without thymoma, was diagnosed with aortic arch aneurysm. He underwent total aortic arch replacement and total resection of the thymus through median sternotomy. His symptoms relating to myasthenia gravis dramatically disappeared after the surgery. The serum anti-acetyl chorine receptor antibody decreased from 2.7 to 0.7 nmol/l (N<0.2) with the reduction of oral predonisolone from 12.5 to 5 mg/day at 4 years after the surgery. The concomitant operations significantly improved his quality of life.

[Left ventriculoplasty in a patient with suspected takotsubo cardiomyopathy followed by a left ventricular aneurysm].

A 42-year-old woman was admitted with chest pain. Coronary angiography did not reveal any significant stenosis, but left ventriculography showed akinesis and ballooning of the apex with a hyperkinetic basal segment indicating Takotsubo cardiomyopathy. Cerebral embolism occurred after one and a half years because of a left ventricular thrombus. The apical akinesis had worsened to a left ventricular aneurysm (maximum diameter 43 mm). The left ventricle was reconstructed to avoid repeated thrombus formation and cerebral infarction despite anticoagulant therapy. A pathological assessment revealed a fibrotic myocardium, but the cause of the cardiac aneurysm remained unknown. Although the outcome of Takotsubo cardiomyopathy is relatively good, careful observation and appropriate treatment are needed considering the possibility of aggravation.

[Surgical repair for ascending aortic pseudoaneurysm derived from the proximal anastomotic site of saphenous vein graft after coronary artery bypass grafting; report of a case].

A 61-year-old male had undergone coronary artery bypass grafting (CABG) using a saphenous vein. Postoperative angiography represented an ascending aortic pseudoaneurysm derived from the proximal anastomotic site of the saphenous vein graft( SVG) which was connected to the obtuse marginal branch and left posterior descending branch sequentially. We performed the closure of tear and the plication of pseudoaneurysmal wall through median sternotomy on the 56th postoperative day. A 7mm length longitudinal tear in the ascending aorta close to the proximal anastomotic site of the SVG was observed. This tear was considered to be caused by the intimal injury during the anastomosis of SVG to ascending aorta. Aortic pseudoaneurysm formation close to the proximal anastomotic site of SVG is a rare and potentially lethal complication requiring urgent operation. Postoperative angiography or enhanced 3 dimensional computed tomography after CABG should be performed before hospital discharge.

A surgical case of excision of infected aneurysm arising from anterior interosseal artery following infectious endocarditis.

Infected aneurysm (IA) of the anterior interosseal artery (AIA), the first branch of the ulnar artery, is an infrequent but serious complication of infectious endocarditis (IE). We report a successful case of excision of IA arising from AIA. In this case, the IA expanded and adhered to the ulnar artery, resulting in occlusion of the ulnar artery. Reconstruction of the ulnar artery was not needed by the preoperative evaluation and the intraoperative occlusion testing. We discuss surgical treatment of IA following IE in upper extremities.

Effects of diabetes mellitus on VEGF-induced proliferation response in bone marrow derived endothelial progenitor cells.

BACKGROUND: This study examined effects of diabetes mellitus (DM) on cellular proliferation associated with vascular endothelial growth factor (VEGF) signaling in endothelial progenitor cells (EPCs) and evaluated protein expression involved in cellular proliferation and proapoptotic signaling in chronically ischemic myocardium. METHODS: Insulin-dependent DM was induced in yucatan miniswine with alloxan. Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Seven weeks after ameroid constrictor, perfusion of ischemic territory was measured by isotope-labeled microspheres, and ischemic myocardium was harvested. Bone marrow (BM) samples were harvested from iliac bone and mononuclear cells (MNCs) were cryopreserved. EPCs were isolated from cryopreserved MNCs in control (n = 6) and DM swine (n = 6). EPC proliferation was assessed. RESULTS: EPC proliferation was decreased in DM as compared to control (1.02 ± 0.09, 0.40 ± 0.04, p < 0.01). VEGF-induced EPC proliferation was impaired in DM as compared to control (p < 0.01). Expression of ERK protein, an activator of VEGF-induced cell proliferation, was decreased. AKT activation, an inhibitor of apoptosis, was decreased, while Bad, an activator of proapoptotic signaling, was elevated in the ischemic myocardium from DM. Collateral dependent perfusion was impaired in DM. CONCLUSION: Impaired VEGF-induced proliferation response in EPC as well as an increase in negative myocardial protein expression for cell proliferation and proapoptotic signaling via VEGF could be a therapeutic target to enhance the effects of proangiogenesis therapies in DM and other chronic illnesses.

Impaired coronary microvascular dilation correlates with enhanced vascular smooth muscle MLC phosphorylation in diabetes.

OBJECTIVE: Impaired endothelium-independent vasodilation is a known consequence of types 1 and 2 diabetes, and the mechanism of impaired vasodilation is not well understood. The following study investigated the effects of types 1 and 2 diabetes in endothelial-independent vasodilation associated with coronary vascular smooth muscle (VSM) relaxation and contractile signaling mechanisms. MATERIALS AND METHODS: Type 1 diabetes was induced in Yucatan miniswine via alloxan injection and treated with or without insulin (DM and IDM). Nondiabetic swine served as controls (ND). Expression and/or phosphorylation of determinants of VSM relaxation and contraction signaling were examined in coronary arteries and microvessels. Coronary microvessel relaxation was assessed by using sodium nitroprusside (SNP). In addition, SNP-induced vasodilation and myosin light-chain (MLC) phosphorylation was determined in coronary microvessels isolated from ND and type 2 diabetic human atrial appendage. RESULTS: Diabetic impairment in SNP-induced relaxation was completely normalized by insulin. Soluble guanylate cyclase (sGC) VSM expression decreased in both DM and IDM groups and did not correlate with vasorelaxation. Phosphorylation of MLC and myosin phosphatase increased in the DM group and MLC phosphorylation strongly correlated with impaired VSM relaxation (r=0.670, P<0.01). Coronary microvessels from type 2 diabetic human patients exhibited similarly impaired vasodilation and enhanced VSM MLC phosphorylation. CONCLUSIONS: Impaired vasodilation in type 1 diabetes correlates with enhanced VSM MLC phosphorylation. In addition, enhanced VSM MLC phosphorylation is associated with impaired vasodilation in type 2 diabetes in humans.

Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes.

BACKGROUND: Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. METHODS AND RESULTS: Diabetes was induced in male Yucatan miniswine using a pancreatic beta-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173+/-14 versus 234+/-23 cells/hpf, P=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4+/-0.9-fold increase, P<0.001), and endostatin (2.9+/-0.4-fold increase, P=0.03) were significantly elevated in the diabetic myocardium. CONCLUSIONS: Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.

Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease. Bone marrow cell transplantation is reported to reduce the development of PH by increasing vascular beds in pulmonary circulation. However, adenoviral overexpression of endothelial nitric oxide synthase (eNOS) in the lung is also known to reduce PH. Because mesenchymal stem cells (MSCs) are potential cell sources for neovascularization, the implantation of MSCs overexpressing eNOS (MSCs/eNOS) may further improve the surgical results. We evaluated the efficacy of MSCs/eNOS implantation in monocrotaline (MCT)-induced PH rats. METHODS AND RESULTS: MSCs were isolated from rat bone marrow. PH was induced in rats by subcutaneous injection of MCT. One week after MCT administration, the rats received 3 different treatments: MSCs (MSC group), MSCs/eNOS (MSC/eNOS group), or nontreatment (PH group). As the negative control, rats received saline instead of MCT (control group). Right ventricular (RV) hypertrophy and the elevation of RV systolic pressure (RVSP) were evaluated 3 weeks after MCT administration. Moreover, the effects of MSCs/eNOS on survival were investigated in PH induced by MCT 3 weeks earlier. RVSP in both the MSC and MSC/eNOS groups was significantly lower than the PH group. RVSP in the MSC/eNOS group was significantly lower than the MSC group. The RV weight to body weight ratio was significantly lower in the MSC and MSC/eNOS groups than the PH group. The survival time of rats receiving MSCs/eNOS was significantly longer than the nontreatment rats. CONCLUSIONS: Intravenous implantation of MSCs/eNOS may offer ameliorating effects on PH-related RV impairment and survival time.

Synthetic vascular prosthesis impregnated with mesenchymal stem cells overexpressing endothelial nitric oxide synthase.

BACKGROUND: Endothelial dysfunction is known to exaggerate coronary artery disease, sometimes leading to irreversible myocardial damage. In such cases, repetitive coronary revascularization including coronary artery bypass grafting is needed, which may cause a shortage of graft conduits. On the other hand, endothelial nitric oxide synthase (eNOS) is an attractive target of cardiovascular gene therapy. The vascular prostheses, of which the inner surfaces are covered with mesenchymal stem cells (MSCs) overexpressing eNOS, are expected to offer feasible effects of NO and angiogenic effects of MSCs on the native coronary arterial beds, as well as improvement of self-patency. Herein, we attempted to develop small caliber vascular prostheses generating the bioactive proteins. Also, we attempted to transduce eNOS cDNA into MSCs. METHODS AND RESULTS: The MSCs were isolated from rat bone marrow and transduced with each adenovirus harboring rat eNOS cDNA and beta-galactosidase (beta-gal) (eNOS/MSCs and beta-gal/MSCs). The beta-gal/MSCs were impregnated into vascular prostheses, then the expressions of beta-gal on the inner surfaces of them were evaluated by 5-bromo-4-chloro-3-indolyl beta-D-galactoside staining. The NOS activity of eNOS/MSCs was assayed by monitoring the conversion of 3H-arginine to 3H-citrulline. The inner surfaces of the vascular prostheses were covered with MSCs expressing beta-gal. The amount of the 3H-citrulline increased, and eNOS/MSCs were determined to generate enzymatic activity of eNOS. This activity was completely inhibited by N(G)-nitro-L-arginine methyl ester. CONCLUSIONS: The inner surface of expanded polytetrafluoroethylene vascular prostheses seeded with lacZ gene-transduced MSCs exhibited recombinant proteins. Development of eNOS/MSC-seeded vascular prostheses would promise much longer graft patency and vasculoprotective effects.

Role of stromal-derived factor-1alpha in the induction of circulating CD34+CXCR4+ progenitor cells after cardiac surgery.

BACKGROUND: Cardioplegia and cardiopulmonary bypass (CP/CPB) leads to an increase in circulating progenitor cells. The role of stromal-derived factor-1alpha (SDF-1alpha), a key regulator of progenitor cell mobilization, and other cytokines in this process is not clear. METHODS AND RESULTS: Peripheral blood (n=24), atrial and skeletal tissue (n=6) samples were taken from patients undergoing CP/CPB before (pre-CP/CPB), 4 hours (post-CP/CPB), and 4 days (POD4) after CP/CPB. The number of circulating CD34+CXCR4+ cells increased post-CP/CPB (442+/-53 versus 286+/-27; P=0.04 versus pre-CP/CPB), but not at POD4 (382+/-50; P=0.28 versus pre-CP/CPB). Plasma levels of SDF-1alpha increased post-CP/CPB as compared with pre-CP/CPB (3325+/-325 versus 2911+/-165 pg/mL; P=0.046) but returned to baseline at POD4 (2838+/-224 pg/mL; P=0.90). Plasma levels of vascular endothelial growth factor were similar post-CP/CPB (P=0.90 versus pre-CP/CPB) but increased at POD4 (220+/-40 pg/mL versus 134+/-26 pg/mL; P=0.04 versus pre-CP/CPB). Serum levels of granulocyte-colony stimulating factor (G-CSF) increased early after CP/CPB as compared with pre-CP/CPB (265.0+/-41.7 versus 11.1+/-1.1 pg/mL; P<0.001) and returned to baseline at POD4 (P=0.84 versus pre-CP/CPB). The circulating CD34+CXCR4+ cells were positively correlated with plasma levels of SDF-1alpha early after CP/CPB (r=0.56, P<0.01), but not at other times. Protein expression of SDF-1alpha was elevated in the atrial myocardium after CP/CPB (9.4-fold; P=0.03). CONCLUSIONS: Exposure to CP/CPB leads to an increase in circulating CD34+CXCR4+ progenitor cells, which is associated with increased myocardial SDF-1alpha expression. The numbers of CD34+CXCR4+ progenitor cells positively correlate with the plasma levels of SDF-1alpha post-CP/CPB, suggesting an important role of SDF-1alpha in progenitor cell mobilization.

Indices of apoptosis activation after blood cardioplegia and cardiopulmonary bypass.

BACKGROUND: Cardioplegic arrest (CA) using cold blood cardioplegia (CBC) has been reported to reduce ischemia-reperfusion (IR)-induced myocardial injury via apoptosis. We studied key apoptotic mediators via the caspase-dependent and intrinsic pathways as well as poly(ADP)-ribosylating protein (PARP) activity in myocardial and peripheral tissues after CA and cardiopulmonary bypass (CBP). METHODS AND RESULTS: Right atrial (RA) and skeletal muscle(SM) was harvested from cardiac surgical patients with similar baseline characteristics (N =6) before and after CPB and CBC. Total and modified caspase-3, Bcl-2, Bad, apoptosis-inducing factor (AIF), and PARP were quantified by immunoblotting. Terminal caspase-3 activity was assessed and immunohistochemistry was performed for PARP and AIF. TUNEL staining was used for identification of apoptotic cells. Microarray gene expression analysis was performed using Affymetrix U95 GeneChip. In RA tissue, CA with CBC significantly increased phosphorylation of Bcl-2 (Ser70), Bad (Ser112) (2.63+/-0.4 and 1.77+/-0.3-fold respectively; P<0.05), and cleavage of the downstream caspase 3 (1.45+/-0.1-fold; P<0.05). There was no significant change in total protein levels. Also, there was an increase in mature AIF (57 kDa) levels (1.22+/-0.01-fold; P<0.05) and a trend toward nuclear translocation on histological staining. Caspase 3 activity was increased 1.5+/-0.14-fold (P<0.05). The number of apoptotic cells in atrial tissue increased after compared with before CPB/CA using TUNEL staining (1.55+/-0.66 versus 0.325+/-0.05%, respectively; P=0.03). In contrast, SM samples did not show any of the changes observed in RA tissue after CPB. CONCLUSIONS: Despite optimal current surgical myocardial protection, we found that CA with CBC induced both programmed cell death and survival signaling in myocardial tissue.

High-dose atorvastatin improves hypercholesterolemic coronary endothelial dysfunction without improving the angiogenic response.

BACKGROUND: Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine. METHODS AND RESULTS: Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29+/-3% versus 61+/-6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67+/-2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (-0.27+/-0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (-0.35+/-0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (-68+/-8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210+/-48%; P=0.004 versus NORM). CONCLUSIONS: Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.

Protein kinase C alpha modulates microvascular reactivity in the human coronary and skeletal microcirculation.

BACKGROUND: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) can lead to dysfunction in the coronary and skeletal microcirculation leading to impaired tissue perfusion. alpha-Adrenergic signaling pathways acting on these microcirculatory beds are thought to involve protein kinase C (PKC). We investigate here the role of the conventional PKCs in microvascular function in the setting of CP/CPB. METHODS: Atrial and skeletal muscle was harvested from 30 patients undergoing cardiac surgery before and after CP/CPB. Microvessels were used for Western blotting and immunofluorescent staining against conventional PKCs. Microvascular constriction was assessed in pre- and post-CP/CPB samples in response to alpha-adrenergic stimulation with phenylephrine, with and without a PKC-alpha inhibitor or PKC-alpha activator. PKC activity was assessed in isolated microvessels. RESULTS: Western blotting and immunostaining demonstrated only PKC-alpha in coronary and skeletal microvessels. CP/CPB diminished contractile responses to phenylephrine in coronary and skeletal samples. Inhibition of PKC-alpha reduced phenylephrine induced vasoconstriction in coronary and skeletal microvessels, whereas activation of PKC-alpha-augmented phenylephrine induced responses. PKC activity was decreased in coronary microvessels and to an even greater degree in skeletal microvessels after CP/CPB. CONCLUSIONS: PKC-alpha is the predominant conventional PKC present in the human coronary and skeletal microcirculation. It likely plays a key role in alpha-adrenergic signaling in microvessels and in the vasomotor dysfunction after CP/CPB.

C-Reactive protein and inflammatory response associated to neurocognitive decline following cardiac surgery.

BACKGROUND: It has been recognized that neurocognitive decline (NCD) often occurs as a complication in cardiac surgery. The early inflammatory response and C-reactive protein (CRP) was examined in relation to NCD and to a marker of axonal central nervous system (CNS) injury after cardiopulmonary bypass. METHODS: A cohort of patients undergoing coronary artery bypass grafting and/or valve procedures using cardiopulmonary bypass were administered a neurocognitive battery preoperatively and postoperatively at 6 hours and day 4. CRP, interleukin 1 beta, and interleukin 10 were quantified from serum. Increase of serum tau protein after surgery was used as a marker of axonal CNS damage. RESULTS: The rate of NCD was found to be 40.5% in this group. Surprisingly, known predictors of NCD did not differ significantly between patients with/without NCD. Patients with NCD had an early increase of CRP of a significantly higher magnitude than those without NCD (38.01 +/- 11.4 vs 16.49 +/- 3.5 mg/L, P = .042), interleukin 1ss (2.35 +/- 0.3 vs 1.20 +/- 0.2 pg/mL, P = .002), and interleukin 10 (29.77 +/- 4.7 vs 12.94 +/- 2.2 pg/mL, P < .001). Increase in serum Tau protein was significantly correlated to NCD (r = 0.50, P = .02). CONCLUSION: Perioperative increases in CRP and inflammatory cytokines are associated with NCD in patients after cardiopulmonary bypass. Thus, it appears that inflammation plays a key role in NCD pathophysiology, likely via axonal CNS injury, and could become a target for prevention.

Effects of purified poloxamer 407 gel on vascular occlusion and the coronary endothelium.

OBJECTIVE: Vascular occlusion during off-pump coronary surgery often results in sub-optimal visualization and endothelial damage of the target vessel. We have previously reported the safety of purified poloxamer 407, a gel with reverse thermosensitive properties, in a model of off-pump coronary occlusion. The aim of this study was to evaluate different gel concentrations and their effects on coronary occlusion time, myocardial contractility, endothelial function, and markers of myocardial injury and apoptosis. METHODS: Yorkshire swine (30-35 kg) underwent sternotomy and mid-LAD occlusion using either microvascular clamps (n=6) or varying quantities of three different concentrations (20%; n=6, 22.5%; n=3, and 25%; n=3) of purified poloxamer 407 gel. Distal LAD flow, left ventricular pressure, and in vitro microvascular reactivity were assessed. Molecular markers of myocardial injury and apoptosis were assessed using Western blotting. RESULTS: Duration of ischemia correlated significantly with the amount of injected gel for the 20% and 22.5% formulations (Spearman r=0.64, p=0.02 and r=0.85, p=0.03, respectively) but not for the 25% gel (r=0.22, p=0.66). There were no significant differences in LV contractility (maximum+dp/dt) (p=0.86) as well as LAD flow (p=0.25) during reperfusion in the four groups. Microvessel relaxation to adenosine diphosphate in the ischemic territory was impaired with higher concentrations of the gel, 22.5% (-14.8+/-7.5% vs control at 10(-5)mol/L, p<0.05) and 25% gel (-24.0+/-7.6% vs control at 10(-5)mol/L, p<0.001) but not with the 20% gel. Endothelium-independent relaxation to sodium nitroprusside was preserved in all groups. Cleaved poly(ADP-ribose) polymerase, a marker of myocardial injury and apoptosis, was elevated in the ischemic myocardium in all groups (p=0.02 vs non-ischemic myocardium) with no significant differences between the groups (p=0.70). Phosphorylation of Bad, an anti-apoptotic protein, was significantly reduced in the ischemic territory (p=0.04). No changes were observed in other markers of myocardial apoptosis. CONCLUSIONS: Purified poloxamer 407 gel is effective for temporary coronary vascular occlusion. Coronary artery occlusion time is related to gel concentration and the quantity of gel injected. The higher gel concentrations may cause endothelial dysfunction of the distal vasculature and therefore should be avoided.

Nifedipine enhances the cardioprotective effect of an angiotensin-II receptor blocker in an experimental animal model of heart failure.

This study was designed to examine the hypothesis that a calcium channel blocker nifedipine (CCB) could enhance the cardioprotective effect of an angiotensin-ll receptor blocker candesartan (ARB) in the treatment for heart failure. Isoproterenol (ISP) was injected into male rats at 300 mg/kg to produce progressive heart failure. Three months later, the rats were divided into 4 groups and treated for 4 weeks with 1) vehicle (n = 20), 2) ARB at 0.2 mg/kg/day (n = 6), 3) CCB at 10 mg/kg/day (n = 6), or 4) both drugs (n = 8). Rats injected with saline served as controls (n = 13). ISP caused severe myocardial degeneration and decreased the capillary density (D(cap)) of the left ventricular (LV) myocardium (mean +/- SD: 2,197 +/- 627 vs. 2,847 +/- 298 N/mm2 for normal controls), while increasing plasma thiobarbituric acid-reactive substances (TBARS; 3.6 +/- 1.1 vs. 1.9 +/- 0.5 nmol/ml). Although ARB therapy preserved cardiac morphology, it had little effect on D(cap) or oxidative stress. On the other hand, CCB decreased plasma TBARS and 4-hydroxy-2-nonenal protein expression in LV myocardium. Furthermore, the combination of CCB and ARB increased D(cap) and preserved the ultrastructure of LV myocardium, so this combination may be a useful option for the treatment of heart failure.

Simultaneous onset of mitral regurgitation requiring surgery due to primary chordal rupture in middle-aged identical twins.

Primary chordal rupture is a leading cause of severe mitral regurgitation requiring surgery. It has previously been documented that there is a high probability of the occurrence of primary chordal rupture in patients with histological evidence of myxysomatous changes in the mitral valve. The precise etiology of primary chordal rupture and/or myxysomatous changes remains obscure and the relative contribution of genetic factors is debated. We report a pair of middle-aged identical twins requiring surgery for mitral regurgitation due to primary chordal rupture, and discuss the etiology of primary chordal rupture and/or myxysomatous changes.

A case of the Starr-Edwards ball valve (Model 6120) in the mitral position for 45 years.

A 59-year-old male who had undergone mitral valve replacement with the Starr-Edwards ball valve Model 6120 (S-E ball valve) 45 years ago was admitted to our hospital for hemolytic anemia and heart failure. Echocardiography revealed that there was no valve dysfunction but paravalvular leakage between the annulus of P2 and the sewing ring of the Starr-Edwards ball valve. He underwent mitral valve replacement. The S-E ball valve was successfully replaced with bileaflet mechanical valve. The explanted S-E ball valve was free from signs of structural valve degeneration. This case shows one of the longest durability of the S-E ball valve in mitral position in the world.

HMG-CoA reductase inhibitor cerivastatin prolonged rat cardiac allograft survival by blocking intercellular signals.

BACKGROUND: The development of atherosclerotic cardiovascular complications caused by hyperlipidemia is a common and serious problem for long-term survivors of organ transplantation. However, adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and lymphocyte function-associated antigen (LFA)-1 are involved in allograft rejection, possibly by providing costimulatory signals. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin has been shown to suppress ICAM-1 expression in acute inflammatory responses. METHODS: In this study, we evaluated the immunosuppressive effects of cerivastatin in rat cardiac allografts. The hearts of Fischer rats were transplanted heterotopically into Lewis rats. Cerivastatin (2 mg/kg) was administrated intraperitoneally to recipients for 7 consecutive days from the day before transplantation. RESULTS: Graft survival in the cerivastatin-treated group (n = 8) was significantly longer than in controls (n = 10) (24.6 +/- 2.2 days vs 10.2 +/- 1.3 days, p < 0.05). Mixed lymphocyte reaction (MLR) showed that on Day 8 after grafting, the proliferative response of alloreactive T cells against F344 alloantigen in cerivastatin-treated rats was significantly more suppressed than in Lewis rats. The Interleukin-2 concentration of supernatant in MLR cultures in the cerivastatin-treated group was lower than in the control group. Immunohistochemical analysis showed that the percentage of CD4-positive cells to infiltrating mononuclear cells was less prominent in the cerivastatin-treated group (9.8% +/- 2.2%) than in the control group (20.9% +/- 3.2%). CONCLUSIONS: The HMG-CoA reductase inhibitor cerivastatin effectively suppressed acute graft rejection, possibly by blocking intercellular signals via ICAM/LFA-1, and cerivastatin may be a candidate for treating patients with hyperlipidemia who undergo organ transplantation.

Potent adenylate cyclase agonist forskolin restores myoprotective effects of ischemic preconditioning in rat hearts after myocardial infarction.

BACKGROUND: The purpose of this study was to determine whether ischemic preconditioning (IPC) provides myoprotective effects in post-myocardial infarction (MI) hearts, and whether beta adrenergic signaling is involved in IPC. METHODS: Rats were subjected to either ligation of the left anterior descending coronary artery (LAD) resulting in MI, or a sham operation. Two weeks later, hearts were isolated and perfused. Six groups (n = 7 each) were studied: group 1, control (sham operation); group 2, sham operation + IPC; group 3, post-MI; group 4, post-MI + IPC; group 5, post-MI + forskolin; group 6, post-MI + forskolin + IPC. IPC consisted of two cycles of 5 minutes of global ischemia. The adenylate cyclase agonist forskolin (1.0 x 10(-5) M) was administered in post-MI hearts either alone (group 5) or for 5 minutes before IPC (group 6). All hearts were then subjected to 20 minutes of global ischemia followed by 120 minutes of reperfusion, after which infarct size was measured. Concentrations of endogenous catecholamines and myocardial mRNA expression of beta 2 adrenergic receptor were measured in the post-MI model. RESULTS: (1) IPC reduced infarct size in shams, from 34.7 +/- 5.2% in group 1 to 21.4 +/- 3.8% in group 2, but did not affect infarct size in post-MI hearts (group 3 versus group 4). (2) Forskolin combined with IPC reduced infarct size in post-MI hearts to 29.3 +/- 3.4% (group 6), but not in group 5 where the value was 39.3 +/- 4.8%. (3) Beta 2 adrenergic receptor mRNA expression in post-MI hearts was significantly decreased as compared with sham-operated animals. CONCLUSIONS: The results indicate that downregulation of beta adrenergic receptors in post-MI hearts may be associated with ineffectiveness of IPC, and that beta adrenergic signaling, especially in relation to adenylate cyclase activation, may be required to generate the IPC response in post-MI hearts.