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Anti-apoptotic therapy for cardiomyocytes could be an effective strategy for preventing or treating heart failure. Notably, however, morphological evidence definitively demonstrating cardiomyocyte apoptosis has been very rare in actual heart diseases such as acute myocardial infarction and heart failure. By contrast, within the postinfarction heart, interstitial noncardiomyocytes such as granulation tissue cells do die via apoptosis to form scar tissue. Blockade of this apoptosis improves survival and mitigates ventricular remodeling and dysfunction during the chronic stage. Possible mechanisms to explain this benefit might be preservation of infarcted wall thickness and preservation of myofibroblasts, which could promote infarct shrinkage; both would reduce wall stress through Laplace's law. On the other hand, autophagy is an intracellular degradation mechanism that compensates for energy insufficiency by digesting and recycling intracellular components, and is often observed in cardiomyocytes within failing hearts with various origins including postinfarction. Starvation strongly induces and activates autophagic degeneration within cardiomyocytes. When that activation is inhibited, the starved animals suffer from heart failure. Promoting autophagy through caloric restriction or several reagents not only reduces the acute infarct size but also mitigates postinfarction cardiac remodeling and dysfunction during chronic stages. Moreover, augmenting autophagy by the treatment with resveratrol or exercise can bring about reverse remodeling in failing hearts with a large old myocardial infarction. In conclusion, we propose two strategies for managing postinfarction heart failure through control of cell death/degeneration: (1) anti-apoptosis in granulation tissue noncardiomyocytes; and (2) pro-autophagy in salvaged cardiomyocytes.

Recently, a new generation of multi-detector row computed tomography (CT) with 320-detector rows (DR) has become available in the clinical settings. The purpose of the present study was to determine the cutoff values of Hounsfield unit (HU) for discrimination of plaque components by comparing HU of coronary plaques with integrated backscatter intravascular ultrasound (IB-IVUS) serving as a gold standard. Seventy-seven coronary atherosclerotic lesions in 77 patients with angina were visualized by both 320-DR CT (Aquilion One, Toshiba, Japan) and IB-IVUS at the same site. To determine the thresholds for discrimination of plaque components, we compared HU with IB values as a gold standard. Optimal thresholds were determined from receiver operating characteristic (ROC) curves analysis. The HU values of lipid pool (n = 115), fibrosis (n = 93), vessel lumen and calcification (n = 73) were 28 ± 19 HU (range −18 to 69 HU), 98 ± 31 HU (44 to 195 HU), 357 ± 65 HU (227 to 534 HU) and 998 ± 236 HU (366 to 1,489 HU), respectively. The thresholds of 56 HU, 210 HU and 490 HU were the most reliable predictors of lipid pool, fibrosis, vessel lumen and calcification, respectively. Lipid volume measured by 320-DR CT was correlated with that measured by IB-IVUS (r = 0.63, p

The effect of β-blockers in ST-elevation myocardial infarction (STEMI) patients who have undergone primary percutaneous coronary intervention (PCI) has not been adequately evaluated. Using a large multi-center registry in Japan, we identified 3,692 patients who underwent PCI within 24 h from onset of STEMI and were discharged alive from 2005 to 2007. Three-year cardiovascular outcomes were compared between the 2 groups of patients with (N = 1,614) or without (N = 2,078) β-blocker prescription at discharge. Compared with patients in the no-β group, patients in the β group were younger, more frequently male, more often had hypertension and atrial fibrillation but less often had chronic obstructive pulmonary disease than in the no-β group. Statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were more frequently prescribed in the β group. Crude incidence of cardiac death and/or recurrent myocardial infarction (cardiac death/MI) tended to be higher in the β group (7.6 vs. 6.2 %, log-rank p = 0.1). After adjusting for potential confounders, β-blockers were associated with significantly higher risk for cardiac death/MI (hazard ratio 1.43, 95 % CI: 1.06–1.94, p = 0.01). β-Blocker prescription at discharge was not associated with better cardiovascular outcomes in patients who underwent PCI after STEMI. Large-scale randomized controlled trials are needed to evaluate the role of β-blocker therapy in these patients.

Long-term safety and efficacy of drug-eluting stents remains controversial. The CREDO-Kyoto registry cohort-2 is a physician-initiated non-company sponsored multi-center registry enrolling consecutive patients undergoing first coronary revascularization in 26 centers in Japan. We compared 3-year outcome between patients treated with sirolimus-eluting stent (SES) only (5092 patients) and bare-metal stent (BMS) only (5405 patients). SES-use as compared with BMS-use was associated with significantly lower adjusted risk for all-cause death [hazard ratio (HR) [95% confidence interval (CI)] 0.72 (0.59–0.87), P = 0.0007], which was mainly driven by the reduction in non-cardiac death [HR (95% CI) 0.64 (0.48–0.85), P = 0.002]. The risk of cardiac death [HR (95% CI) 0.82 (0.63–1.07), P = 0.15], myocardial infarction [HR (95% CI) 0.73 (0.51–1.03), P = 0.07] and definite stent thrombosis [HR (95% CI) 0.62 (0.35–1.09), P = 0.1] was not different between the two groups. Despite longer duration of thienopyridine administration, SES-use was associated with significantly lower risk for bleeding [HR (95% CI) 0.75 (0.6–0.95), P = 0.02] and similar risk for stroke [HR (95% CI) 1.0 (0.75–1.34), P = 1.0]. The risk for target-lesion revascularization (TLR) was markedly lower in the SES group [HR (95% CI) 0.42 (0.36–0.48), P < 0.0001]. The direction and magnitude of the effect of SES relative to BMS in patients presenting acute myocardial infarction (AMI) were similar to those in patients presenting otherwise. In conclusion, SES-use as compared with BMS-use was associated with marked reduction of TLR without any increases in death, myocardial infarction, stent thrombosis, stroke and bleeding in real world clinical practice regardless of clinical presentation including AMI.

Previous studies have shown inconsistent results regarding the effects of concomitant use of clopidogrel and proton pump inhibitors (PPI) on cardiovascular outcomes. We sought to evaluate the clinical impact of PPI-use in patients treated with thienopyridines after percutaneous coronary intervention (PCI) in a large Japanese observational database. Among 12446 patients discharged alive on thienopyridines (ticlopidine 90.4% and clopidogrel 9.6%), 3223 patients were treated with PPIs and 9223 patients without PPI at the time of hospital discharge. The PPI group included more patients with co-morbidities than the non-PPI group. The adjusted hazard ratio (HR) of PPI-use for a composite of cardiovascular death, myocardial infarction, and stroke was 1.26 (95% confidence interval (CI) 1.09-1.47, p = 0.002). The adjusted HR of PPI-use for bleeding was 1.26 (95% CI 1.05-1.52, p = 0.013). Cardiovascular and bleeding outcomes were not different among the three groups receiving three different types of PPI. The negative effect of PPI on cardiovascular outcome was consistently seen in both drug-eluting stent (DES) [HR 1.31 (95% CI 1.07-1.6, p = 0.0097)] and non-DES strata [HR 1.25 (95% CI: 0.99-1.57, p = 0.057)] (Interaction p = 0.79) despite the fact that the duration of thienopyridine administration was significantly longer in patients receiving DES. In conclusion, cardiovascular outcomes after PCI were significantly worse in patients with PPI than in patients without PPI in the Japanese real clinical practice. However, the observed poorer cardiovascular outcome in patients receiving PPI was most likely to be related to residual confounding and seemed not causally related to attenuation of antiplatelet effect of thienopyridine through interaction with PPI.

To address whether adult rat ventricular cardiomyocytes (ARVCs) exposed to oxidant stress die via apoptosis (secondarily by necrosis) or primarily by necrosis, we exposed ARVCs to hydrogen peroxide (H2O2; 0.1-100 microM) for up to 24 h and then compared them with isoproterenol-induced apoptotic and Triton X-induced necrotic controls. Cellular shrinkage preceded plasma membrane disruption, reflected by trypan blue uptake in ARVCs exposed to lower concentrations of H2O2 (1 microM; an apoptotic pattern), but the order was reversed in cells exposed to higher concentrations of H2O2 (1 microM; a necrotic pattern). DNA fragmentation, caspase-3 activation, mitochondrial membrane potential preservation, and ATP preservation were all apparent in ARVCs treated with low H2O2 (0.5 microM), but not in those treated with high H2O2 (10 microM). In addition, electron microscopy revealed unique morphology in H2O2-treated ARVCs; i.e., the nuclei had a homogeneous ground glass-like appearance that was never accompanied by chromatin condensation. Apparently, high concentrations of H2O2 caused primary necrosis in ARVCs, whereas low concentrations induced biochemically comparable apoptosis, although the latter did not satisfy the morphological criteria of apoptosis. These findings caution against the use of oxidant stress, H2O2 in particular, as an inducer of apoptosis in ARVCs.

Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin–angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN. In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4–12 mg/day) or benazepril hydrochrolide (benazepril, 2.5–10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased. Dual blockade decreased proteinuria more than single blockade with ARB (−42.3 vs. −60.5%, P

Gated single-photon emission computed tomography (G-SPECT) was used to evaluate cardiac risk associated with noncardiac surgery and determine the benefits and indications of this technique for this type of surgery.Patients scheduled to undergo noncardiac surgery under the supervision of anesthesiologists and subjected to preoperative cardiac evaluation using G-SPECT during the 26-month period between June 2000 and August 2002 were followed for the presence/absence of cardiac events (i.e., cardiac death, myocardial infarction, unstable angina, congestive heart failure, or fatal arrhythmia) during surgery and the postoperative period until discharged. Relationships between the occurrence of cardiac events and preoperative G-SPECT findings were evaluated.A total of 39 patients underwent G-SPECT; 6 of the 39 exhibited abnormal ejection fraction (left ventricular ejection fraction, LVEFor=50%) and end-systolic volume (ESVor=50 ml). Surgery was suspended for three of these six patients and cardiac events developed in the remaining three patients. Both abnormal perfusion images (PI) and abnormal wall thickening (WT) were observed in all six patients. All six patients exhibited abnormal LVEF and/or ESV. Three patients had either abnormal PI or WT, and a cardiac event occurred in one of them. Of the five patients who experienced cardiac events during or after surgery, two exhibited a short run of ventricular tachycardia requiring a continuous administering of antiarrhythmic drugs, whereas the remaining three patients exhibited cardiac failure requiring inotropic support following surgery.The results of this study indicate that the occurrence of perioperative cardiac events can be predicted by considering the severity of expected surgical stress and preoperative G-SPECT findings for LVEF, PI, and WT. We conclude that G-SPECT is quite useful for cardiac risk assessment in patients undergoing noncardiac surgery.

Recent studies suggest transplanted bone marrow cells (BMCs) can be used to reconstitute coronary vessels and myocardium following acute myocardial infarction, thereby improving cardiac function. We sought to investigate the therapeutic potential of BMC transplantation in the treatment of nonischemic cardiomyopathy. Experimental cardiomyopathy was produced by treating rabbits for 8 weeks with doxorubicin (2 mg/kg per week). Two weeks after the treatment was finished, freshly aspirated BMCs or an equivalent volume of phosphate-buffered saline was injected directly into the left ventricular free wall. Four weeks later, heart function was examined during perfusion on a Langendorff apparatus. Left ventricular developed pressure and +/-dp/dt were significantly better in the transplantation group, among which echocardiography also showed significantly better ejection fractions. In addition, left ventricular weights as a fraction of body weight and left ventricular wall thicknesses were both lower in rabbits transplanted with BMCs than in controls. Immunohistochemical analyses carried out 2 weeks after transplantation showed no new myocardium and a very small number of endothelial cells originating from BMCs. On the other hand, immunoblotting revealed upregulated expression of transforming growth factor-beta1 and downregulated expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha following BMC transplantation. In conclusion, autologous BMC transplantation into cardiomyopathic rabbit hearts ameliorates the decline in ventricular function without regenerating cardiomyocytes, most likely by altering expression of various cytokines.

We examined whether pharmacological inhibition of glycogenolysis by N-methyl-1-deoxynojirimycin (MOR-14), a new compound which reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase activity of the glycogen-debranching enzyme, can protect the heart against postischemic left ventricular dysfunction. The hearts of male Sprague-Dawley rats were excised, and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during the ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s), and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min including a 30-min preischemic period followed by a 30-min episode of global ischemia and 60 min reperfusion. with or without 0.5 or 2 mM of MOR-14 during the 30-min preischemic period or the first 30 min of reperfusion. In another series of experiments, the myocardial content of glycogen and lactate was measured during the 30-min episode of ischemia in groups treated with and without 2mM of MOR-14. Preischemic but not postischemic treatment with MOR-14 significantly improved LVDP and +/-dP/dt without altering coronary flow during reperfusion in a dose-dependent manner. MOR-14 significantly preserved the glycogen content and significantly attenuated the lactate accumulation during the 30-min episode of ischemia. Preischemic treatment with MOR-14 is protective against postischemic left ventricular dysfunction through the inhibition of glycogenolysis in the isolated rat heart.

Recent studies have indicated the key role of adenosine receptor activation as a trigger for ischemic preconditioning (PC). Hence, the augmentation of endogenous adenosine may potentiate the cardioprotective effects of PC. In this study, we aimed to test the hypothesis that dilazep dihydrochloride, an adenosine transport inhibitor, potentiates the PC effect. Protocol 1: Infarcts were produced in open-chest anesthetized rabbits by 30-min occlusion of a coronary artery and 2 days' reperfusion. PC was elicited by a preceding 5-min occlusion and either 5, 40, or 120 min of reperfusion. PC with the 5-min reperfusion markedly limited the infarct size after the 30-min ischemia (infarct size to area at risk (IS): 10% ± 3% vs 41% ± 3%, P < 0.05). PC was not protective when the reperfusion periods were 40 or 120 min (IS: 47% ± 5% and 44% ± 3%, P = not significant (NS) vs control, respectively). However, concomitant treatment with dilazep (0.2 mg/kg) preserved the PC effect in the 40-min reperfusion group (18% ± 5%, P < 0.05 vs control) but not in the 120-min reperfusion group (43% ± 4%, P = NS vs control). Protocol 2: Infarct was produced in a similar rabbit model by either a 45- or 50-min occlusion of a coronary artery and 2 days of reperfusion. PC was elicited by a preceding 5-min occlusion and a 5-min reperfusion. PC was protective in the 45-min occlusion group (30% ± 7% vs 67% ± 3%, P < 0.05) but not in the 50-min occlusion group (74% ± 4% vs 79% ± 5%, P = NS). Treatment with dilazep (0.2 mg/kg) failed to retrieve protection in this preconditioned group (77% ± 6%, P = NS vs 50-min occlusion group without PC). Thus, dilazep prolonged the infarct size-limiting effect of PC, but failed to retrieve protection in the group with a longer sustained ischemia.

In the present study, we investigated whether gallic acid (GA) can induce death in cultured vascular smooth muscle cells (VSMCs), and whether production of the hydroxyl radical (.OH) is involved in the process of GA action. GA killed cultured VSMCs from rat aorta, in a dosc- and time-dependent manner. Cytoplasmic shrinkage and nuclear condensation were observed light microscopically in GA-treated VSMCs, which appeared apoptotic. However, the ultrastructure of the VSMC was not typical of apoptosis: nuclear condensation was not glossy, and the plasma membrane and subccellular organelles were disrupted. Although the VSMC were positive for in situ nick end-labeling (TUNEL). they did not show a DNA ladder pattern on gel electrophoresis and were negative for T aq polymerase-based in situ ligation, which is more specific for apoptosis than TUNEL. Moreover. GA-induced cell death was not prevented by Boc-Asp-fmk (a pan-caspase inhibitor). Production of OH was detected in GA-treated VSMCs using high-performance liquid chromatography with salicylic acid as a trapping agent. Lipid peroxidation was also observed. The production of .OH was inhibited by catalase (CAT) and deferoxamine (DFX), and these treatments completely rescued VSMCs from cell death. In a cell-free system, GA produced .OH in the presence of Fe2+-EDTA, which was quenched by CAT and DFX, suggesting involvement of the Haber-Weiss reaction. Oxidative stress by reactive oxygen species, .OH in particular, is one of the mechanisms of GA-induced death of VSMCs, the mode of which was different from typical apoptosis.

To evaluate cardiac sympathetic activity, a simple method should be developed to replace such complex methods as the spillover rate of tritiated norepinephrine (3H-norepinephrine) or microneurography of sympathetic nerve activity. The goal of this study is to evaluate cardiac sympathetic activities by analyzing the washout of I-123 meta-iodobenzylguanidine (123I-MIBG), a radiolabeled norepinephrine analogue, in Dahl salt-sensitive (DS) rats as it relates to the progression of hypertension.Dahl salt-resistant (DR) rats and DS rats were fed an 8 % salt diet starting at age 5 weeks. Marked hypertension and cardiac hypertrophy developed in the DS rats, whereas DR rats remained normotensive. Then the time-activity curves of 123I-MIBG from 15 to 200 minutes were obtained from both DS and DR strains at ages 8, 11, and 13 weeks using dynamic scintigraphic analysis. We also examined the nonneuronal washout of 123I-MIBG using dynamic scintigraphic studies in desipramine pretreated normal rats. In the preliminary study with desipramine pretreatment, the majority of the nonneuronal 123I-MIBG washout occurred by 90 minutes after injection. Therefore the late-phase washout in the control rats was found to reflect the neuronal washout. We then applied exponential curve fitting to the time activity curves acquired in the 90- to 200-minute period after 123I-MIBG injection in both DR and DS rats. When we compared the coefficients of these washout curves in the DS and DR rats as an index of cardiac sympathetic activities, the coefficient values remained high during all stages in DS rats, whereas they decreased with age in DR rats.Measurement of late-phase 123I-MIBG washout may be a useful tool for assessing the change in sympathetic activity in the progression of hypertension without the influence of extraneuronal washout of 123I-MIBG and left ventricular hypertrophy.

We examined whether the Inoue endovascular graft could be used as a device for the treatment of aortic dissection. This graft consists of a cylinder made from a thin Dacron sheet suspended by several extra-flexible wire rings. Aortic dissections were experimentally created in 11 dogs. Using aortography and intravascular ultrasound imaging (IVUS), we selected the size of the graft diameter according to the diameter of the normal descending aorta (distal to aortic dissection) in 5 dogs (group I) and according to the diameter of the true lumen of the aorta within the aneurysm in 6 dogs (group II). The graft was deployed transfemorally through a 15-F long sheath into the aneurysm to close the entry site, immediately after creation of the aortic dissection. The entry was completely closed in all dogs after immediate implantation. All 5 dogs in group I died within 11 days (mean, 7 days) after graft deployment. However, all grafts in group II were tolerated very well and followed up for as long as 5 months. After the follow up, IVUS and aortography showed no rupture of the aortic aneurysmal wall and no migration, leakage, or damage to the graft in any of the 6 dogs. These 6 dogs were sacrificed and autopsy showed that the graft was covered by a thin, translucent, neointima, effectively recreating a new aortic lumen and completely closing the entry of the aneurysm. The Inoue endovascular graft proved to be effective in the long-term treatment of aortic dissection without surgery, when the size of the graft was selected according to the diameter of the true lumen of the aorta within the aneurysm.

Because it is not metabolized as is norepinephrine (NE), most of the metaiodobenzylguanidine (MIBG) taken up by the heart is considered to be lost subsequently by release concomitant with sympathetic stimulation. Therefore we examined whether the washout of MIBG is influenced by sympathetic tone, which we modulated by using immobilization stress or activation of the renin-angiotensin system (RAS).In 175 male ddY mice, left ventricular radioactivity was counted 30 minutes or 4 hours after injection of 74 kBq (2 microCi) of iodine 125- or iodine 131-labeled MIBG (125I- or 131I-MIBG). The washout rates of MIBG were determined under immobilization stress or under sodium loading or restriction in combination with losartan (10 mg/kg) or cilazapril (1 mg/kg) pretreatment. Immobilization enhanced the washout of 125I-MIBG (80.9% vs 57.9% in the control animals); this was determined to be related to washout from the neuronal compartment, because the nonneuronal component assessed through desipramine pretreatment was not affected. Pretreatment with losartan or cilazapril decreased the facilitation of 125I-MIBG washout in sodium-restricted mice (40.9% and 33.7%, respectively, vs 43.5% in the control animals), but not in sodium-loaded mice.Measurement of MIBG washout may be feasible for determining the changes in sympathetic tone caused by immobilization stress or activation of the RAS.

Isolated mitral regurgitation without supravalvular aortic stenosis is rarely identified in Williams syndrome. We describe the case of a 24-year-old man with isolated mitral regurgitation in Williams syndrome. Severe regurgitation due to prolapse of the anterior leaflet was noted in an echocardiogram and color Doppler, and a left ventriculogram showed grade IV regurgitation. No pressure gradient between the left ventricle and the ascending aorta was found. Mitral regurgitation had been noted since his birth, and pediatricians suspected Williams syndrome because of postnatal growth deficiency, mental deficiency, unusual personality, and unusual facial features in his childhood. The diagnosis was confirmed by demonstration of the hemizygous deletion of 7q11.23 in the karyotype by the fluorescent in situ hybridization technique after his admission to our department. The patient underwent mitral valve replacement, and microscopic examination of the excised valve revealed myxomatous degeneration.