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Aims Dilated cardiomyopathy (DCM) is a severe disorder defined by ventricular dilation and contractile dysfunction. Abnormal Ca2+ handling is hypothesized to play a critical pathological role in DCM progression. The transient receptor potential vanilloid 2 (TRPV2) has been previously suggested as a candidate pathway for enhanced Ca2+ entry. Here, we examined the sarcolemmal accumulation of TRPV2 in various heart-failure model animals and DCM patients, and assessed whether presently available inhibitory tools against TRPV2 ameliorate DCM symptoms. Methods and results Immunological and cell physiological analyses revealed that TRPV2 is highly concentrated and activated in the ventricular sarcolemma of DCM patients and three animal models—δ-sarcoglycan-deficient hamsters (J2N-k), transgenic mice over-expressing sialytransferase (4C30), and doxorubicin (DOX)-induced DCM mice. Over-expression of the amino-terminal (NT) domain of TRPV2 could block the plasma membrane accumulation and influx of Ca2+ via TRPV2. Transgenic (Tg) or adenoviral expression of the NT domain in DCM animals caused effective removal of sarcolemmal TRPV2 along with reduction in the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and reactive oxygen species (ROS) production, which were activated in DCM; further, it prevented ventricular dilation and fibrosis, ameliorated contractile dysfunction in DCM, and improved survival of the affected animals. The TRPV2 inhibitor tranilast markedly suppressed DCM progression. Conclusion Sarcolemmal TRPV2 accumulation appears to have considerable pathological impact on DCM progression, and blockade of this channel may be a promising therapeutic strategy for treating advanced heart failure. [ABSTRACT FROM AUTHOR]

Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of β-adrenergic receptors, and worsens heart failure. To test whether a histamine H receptor blocker had a beneficial effect in addition to β-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H receptor blocker, in dogs receiving a β-blocker. We induced heart failure in dogs by rapid ventricular pacing (230 beats/min). Animals received no drugs (control group), famotidine (1 mg/kg daily), carvedilol (0.1 mg/kg daily), or carvedilol plus famotidine. Both cardiac catheterization and echocardiography were performed before and 4 weeks after the initiation of pacing. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks of pacing. In the control group, the left ventricular ejection fraction (LVEF) was decreased after 4 weeks compared with before pacing (71 ± 2 vs. 27 ± 2%, p < 0.05) and mean pulmonary capillary wedge pressure (PCWP) was increased (8 ± 1 vs. 19 ± 3 mmHg). Famotidine ameliorated the decrease of LVEF and increase of PCWP, while the combination of carvedilol plus famotidine further improved both parameters compared with the carvedilol groups. These beneficial effects of famotidine were associated with a decrease of the myocardial cAMP level. Histamine H receptor blockade preserves cardiac systolic function in dogs with pacing-induced heart failure, even in the presence of β-adrenergic receptor blockade. This finding strengthens the rationale for using histamine H blockers in the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Non-invasive diagnosis of rejection is a major objective in the management of heart transplant recipients. The ability of strain rate (SR) imaging on echocardiograms to detect rejection in heart transplant recipients was investigated. Methods: A total of 396 endomyocardial biopsies, right-heart catheterisation and echocardiograms were performed in 35 heart transplant recipients. Mean values of systolic strain (ɛ sys), peak systolic SR (SRsys), and peak early diastolic SR (SRdia) obtained from eight left ventricular segments were calculated. Results: According to the conventional International Society for Heart and Lung Transplantation criteria, 351 biopsies showed a rejection grade (acute rejection, AR) of 0 or 1a (group AR−) whereas 45 biopsies showed a grade of 1b or higher (group AR+). The ɛ sys, SRsys and SRdia were significantly different between group AR+ and group AR− (−20.7±8.0 vs −32.6±6.3%, p <0.0001, 2.5±1.8 vs 3.6±1.1/s, p <0.0001, and −1.9±1.6 vs −3.5±1.3/s, p <0.001, respectively). Multivariate analysis identified ɛ sys (p <0.0001) as a strong predictor for group AR+, and ɛ sys cut-off value of −27.4% was associated with a predictive accuracy of 82.3%. The combination of ɛ sys and SRdia discriminated group AR+ from group AR− with a predictive accuracy of 84.8%. The pulmonary artery wedge pressure was higher in group AR+ than that in group AR− (7.4±3.0 vs 9.4±4.4mmHg, p <0.05). Conclusion: SR imaging is of potential clinical value for monitoring acute rejection in heart transplant recipients. [Copyright &y& Elsevier]

Abstract: Neuropilin-1 (NRP1) is a multifunctional transmembrane protein which has a short cytoplasmic region with no particular functional domain, and is considered to act as a co-receptor for both VEGFs and semaphorins. However, the molecular mechanisms by which NRP1 carries out such versatile functions are still poorly understood. Here we identified protein kinase CK2 holoenzyme as a novel NRP1 binding protein by our combined purification strategy using epitope-tag immunoprecipitation followed by reverse-phase column chromatography. Further we showed that CK2 binds to the extracellular domain of NRP1 which is also phosphorylated by CK2 both in vitro and in vivo. Our findings of novel molecular interactions and modification of NRP1 may provide a new clue to understand the diverse functions of NRP1. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to investigate whether liposomal adenosine has stronger cardioprotective effects and fewer side effects than free adenosine. Background: Liposomes are nanoparticles that can deliver various agents to target tissues and delay degradation of these agents. Liposomes coated with polyethylene glycol (PEG) prolong the residence time of drugs in the blood. Although adenosine reduces the myocardial infarct (MI) size in clinical trials, it also causes hypotension and bradycardia. Methods: We prepared PEGylated liposomal adenosine (mean diameter 134 ± 21 nm) by the hydration method. In rats, we evaluated the myocardial accumulation of liposomes and MI size at 3 h after 30 min of ischemia followed by reperfusion. Results: The electron microscopy and ex vivo bioluminescence imaging showed the specific accumulation of liposomes in ischemic/reperfused myocardium. Investigation of radioisotope-labeled adenosine encapsulated in PEGylated liposomes revealed a prolonged blood residence time. An intravenous infusion of PEGylated liposomal adenosine (450 μg/kg/min) had a weaker effect on blood pressure and heart rate than the corresponding dose of free adenosine. An intravenous infusion of PEGylated liposomal adenosine (450 μg/kg/min) for 10 min from 5 min before the onset of reperfusion significantly reduced MI size (29.5 ± 6.5%) compared with an infusion of saline (53.2 ± 3.5%, p < 0.05). The antagonist of adenosine A1, A2a, A2b, or A3 subtype receptor blocked cardioprotection observed in the PEGylated liposomal adenosine-treated group. Conclusions: An infusion as PEGylated liposomes augmented the cardioprotective effects of adenosine against ischemia/reperfusion injury and reduced its unfavorable hemodynamic effects. Liposomes are promising for developing new treatments for acute MI. [Copyright &y& Elsevier]

Abstract: Accurate measurement of the biomagnetic signals from a rat or a mouse crucially benefits the development of new medicines and pathologies. In previous studies, MEG/MCG systems developed for humans were used to obtain small animal biomagnetic signals, but we only partially succeeded. The accuracy and efficiency of the results were insufficient because the systems were not designed to measure small animal MEG or MCG. In order to improve the efficiency and accuracy of small animal measurements, we have developed a biomagnetism measurement system suitable for small animals. The newly developed integrated 9ch Low-Tc SQUIDs magnetometer array is designed to improve spatial resolution. It has a 2.5 mm diameter pickup coil on each sensor and covers 8 mm×8 mm measurement area. A single measurement by the sensor provides sufficient data for the analysis of small animal biosignals. Measurement efficiency and replicability has also been improved compared to conventional systems by the addition of a removable table and the 3-axis linear stage. The removable nonmagnetic table is attached to a 3-axis linear stage and its temperature is controlled by circulating hot water in order to keep subject stable while recording. The principal components of this system are integrated into a small transportable chassis. The dimension of the whole system is 1.4 m in width, 0.7 m in depth, 1.8 m in height. The small sized biomagnetism measurement system is easy to place in a typical lab space. [Copyright &y& Elsevier]

Abstract: Cell-free hemoglobin (Hb) derivatives that have been developed as Hb-based artificial oxygen carrier cause both coronary vasoconstriction and platelet aggregation due to the scavenging actions of nitric oxide (NO). Recently, native Hb is found to undergo S-nitrosylation, which regulates blood flow, whereas artificial oxygen carriers are lacking of S-nitrosylation. Therefore, S-nitrosylated and pegylated hemoglobin (SNO-PEG-Hb) was prepared to overcome the above defects, where pegylation was included to avoid extravasation and to prolong the circulatory half-live. Since SNO-PEG-Hb possesses SNO property, we tested whether SNO-PEG-Hb increases coronary blood flow (CBF) and improves the severity of myocardial ischemia. In 19 open chest dogs, the left anterior descending coronary artery was perfused with blood from the carotid artery via the bypass tube, and then CBF and coronary perfusion pressure (CPP) were measured. After hemodynamic stabilization, CPP was reduced so that CBF decreased to 33% of the baseline and thereafter CPP was maintained constant. Ten minutes after the onset of coronary hypoperfusion, we infused 10% SNO-PEG-Hb into the coronary artery (2.5 ml/min). SNO-PEG-Hb increased CBF (28.1±3.3 to 43.3±3.9 ml/100 g/min, p <0.05), fractional shortening (4.6±1.2 to 16.6±2.4%, p <0.01) and lactate extraction ratio (−38.5±8.6 to 25.5±1.3%, p <0.01). Thus, we conclude that SNO-PEG-Hb increases coronary blood flow and improves the contractile and metabolic dysfunction of the ischemic myocardium. SNO-PEG-Hb, a newly developed artificial oxygen carrier, may mediate a cardioprotection in ischemic heart diseases in addition to blood supplementation. [Copyright &y& Elsevier]

Objectives: The goal of this work was to determine whether the blockade of histamine H2 receptors is beneficial for the pathophysiology of chronic heart failure (CHF). Background: Because CHF is one of the major life-threatening diseases, we need to find a novel effective therapy. Intriguingly, our previous study, which predicts the involvement of histamine in CHF, suggests that we should test this hypothesis in patients with CHF. Methods: We selected 159 patients who received famotidine among symptomatic CHF patients for the retrospective study. We blindly selected age- and gender-matched CHF patients receiving drugs for gastritis other than histamine H2 receptor blockers as a control group. For the prospective study, 50 symptomatic CHF patients were randomly divided into 2 groups. One group received famotidine of 30 mg/day for 6 months, and the other group received teprenone. Results: In the retrospective study, famotidine of 20 to 40 mg decreased both left ventricular end-diastolic and end-systolic lengths (LVDd and LVDs, respectively) and the plasma B-type natriuretic peptide (BNP) levels (182 ± 21 vs. 259 ± 25 pg/ml, p < 0.05) with unaltered fractional shortening (FS). In a randomized, open-label study, compared with teprenone, famotidine of 30 mg prospectively decreased both New York Heart Association functional class (p < 0.05) and plasma BNP levels (183 ± 26 pg/ml vs. 285 ± 41 pg/ml, p < 0.05); this corresponded to decreasing both LVDd (57 ± 2 mm vs. 64 ± 2 mm, p < 0.05) and LVDs (47 ± 2 mm vs. 55 ± 2 mm, p < 0.05) with unaltered FS (15 ± 1% vs. 17 ± 1%). The frequency of readmission because of worsening of CHF was lower in the famotidine group (4% and 24%, p < 0.05). On the other hand, teprenone had no effects on CHF. Conclusions: Famotidine improved both cardiac symptoms and ventricular remodeling associated with CHF. Histamine H2 receptor blockers may have therapeutic benefits for CHF. [Copyright &y& Elsevier]

Objectives: We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI). Background: Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs). Methods: We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation. Results: The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 ± 6.0% vs. 22.9 ± 2.2%). One week after MI, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 ± 1.9%) group was significantly higher than that in either the control (41.9 ± 0.9%) or the EPO(1wk) (42.6 ± 1.2%) group but significantly lower than that in the EPO(0) group (56.1 ± 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups. Conclusions: In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations. [Copyright &y& Elsevier]

Abstract: We have previously reported that histamine H2 blockers may be cardioprotective in patients with chronic heart failure. Since both endogenous histamine and histamine H2 receptors are present in heart tissue, we tested the hypothesis that the blockade of histamine H2 receptors mediates protection against reversible or irreversible ischemia and reperfusion injury. In open-chest dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Administration of famotidine and cimetidine from 10 minutes before occlusion until after 1 hour of reperfusion reduced infarct size (17.0±4.1% and 17.8±2.9% vs. 36.9±5.9% of the solvent group, respectively) Famotidine administration only during the reperfusion period for 1 hour also attenuated infarct size (22.5±3.5%). There were no differences in either area at risk or collateral flow among the groups. In another set of experiments, we decreased coronary perfusion pressure in dogs so that the coronary blood flow decreased to 50% of the non-ischemic level. In such conditions, we observed the increases in histamine release compared with non-ischemic conditions (0.04±0.03 to 0.28±0.13 ng/ml, p<0.05). Famotidine improved anaerobic myocardial metabolism gauged by both lactate extraction ratio and myocardial oxygen consumption. We conclude that the blockade of histamine H2 receptors mediates improvements in the anaerobic myocardial metabolism, and thus protects against ischemia and reperfusion injury. [Copyright &y& Elsevier]

Presents a novel mechanism of myocyte degeneration involving a growth factor-regulated channel permeable to calcium. Disruption of the dystrophin-glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans; Implications on cell biology.

This article reports changes in tacrolimus (FK506) blood levels connected with carbamazepine (CBZ). A drug interaction between FK506 and CBZ was investigated in a woman, who was in her 40s, who underwent heart transplantation. Pharmacokinetic parameters were measured, including dose and trough blood levels (C0), area under the serum concentration-time curve from 0 to 12 hours (AUC0–12h), and apparent clearance of oral FK506 (CL/F) for FK506 alone (about 3 months before starting CBZ) and combined with CBZ (11 days and about 3 months after starting CBZ). FK506 C0 levels were decreased within 7 days of CBZ treatment. FK506 dosing required a 1.3- to 1.4-fold increase to maintain adequate blood levels while taking 200 mg CBZ daily. The AUC0–12h/dose 11 days after CBZ treatment was about 50% of the value before CBZ, and was about 70% at 3 months after CBZ treatment. The CL/F at 11 days and about 3 months after starting CBZ treatment was about 2 times higher than before CBZ therapy. FK506 C0 levels are decreased by CBZ treatment, and blood levels should be closely monitored. [Copyright &y& Elsevier]

In older adults, chronic obstructive pulmonary disease (COPD) is commonly associated with heart failure with reduced ejection fraction (HFrEF), and the high prevalence of this combination suggests that customized treatment is highly necessary in patients with COPD and HFrEF. To investigate whether the treatment of COPD with tiotropium, an anticholinergic bronchodilator, reduces the severity of heart failure in patients with HFrEF complicated by mild to moderate COPD, forty consecutive participants were randomly divided into two groups and enrolled in a crossover design study. Group A inhaled 18 μg tiotropium daily for 28 days and underwent observation for another 28 days. Group B completed the 28-day observation period first and then received tiotropium inhalation therapy for 28 days. Pulmonary and cardiac functions were measured on days 1, 29, and 56. In both groups, 28 days of tiotropium inhalation therapy substantially improved the left ventricular ejection fraction (from 36.3 ± 2.4% to 41.8 ± 5.9%, p < 0.01, in group A; from 35.7 ± 3.8% to 41.6 ± 3.8%, p < 0.01, in group B) and plasma brain natriuretic peptide levels (from 374 ± 94 to 263 ± 92 pg/mL, p < 0.01, in group A; from 358 ± 110 to 246 ± 101 pg/mL, p < 0.01, in group B). Tiotropium inhalation therapy improves pulmonary function as well as cardiac function, and reduces the severity of heart failure in patients with compensated HFrEF with concomitant mild to moderate COPD., Competing Interests: The authors declare no conflict of interest.

Left ventricular (LV) dyssynchrony is a causal factor in LV dysfunction and thought to be associated with LV twisting motion. We tested whether three-dimensional speckle tracking (3DT) can be used to evaluate the relationship between LV twisting motion and dyssynchrony. We examined 25 patients with sick sinus syndrome who had received dual chamber pacemakers. The acute effects of ventricular pacing on LV wall motion after the switch from atrial to ventricular pacing were assessed. LV twisting motion and dyssynchrony during each pacing mode were measured using 3DT. LV dyssynchrony was calculated from the time to the minimum peak systolic area strain of 16 LV imaging segments. Ventricular pacing increased LV dyssynchrony and decreased twist and torsion. A significant correlation was observed between changes in LV dyssynchrony and changes in torsion (r = -0.65, p < 0.01). Evaluation of LV twisting motion can potentially be used for diagnosing LV dyssynchrony.

In 1990, takotsubo cardiomyopathy (TCM) was first discovered and reported by a Japanese cardiovascular specialist. Since then, this heart disease has gained worldwide acceptance as an independent disease entity. TCM is an important entity that differs from acute myocardial infarction. It occurs more often in postmenopausal elderly women, is characterized by a transient hypokinesis of the left ventricular (LV) apex, and is associated with emotional or physical stress. Wall motion abnormality of the LV apex is generally transient and resolves within a few days to several weeks. Its prognosis is generally good. However, there are some reports of serious TCM complications, including hypotension, heart failure, ventricular rupture, thrombosis involving the LV apex, and torsade de pointes. It has been suggested that coronary spasm, coronary microvascular dysfunction, catecholamine toxicity and myocarditis might contribute to the pathogenesis of TCM. However, its pathophysiology is not clearly understood.

An 80-year-old man visited our hospital because of dyspnea on exertion from 6 months ago. Echo Doppler study showed severe calcification in the aortic valve with restricted movement and the sigmoid septum causing obstruction at the LV outflow tract (LVOT). Considering the aortic valve area (AVA) might have been inaccurately estimated, we carried out beta-blocker stress echocardiography. The transaortic pressure gradient and AVA were respectively calculated as 52 mmHg and 0.90 cm(2) before propranolol administration and as 64 mmHg and 0.86 cm(2) after propranolol administration. Thus, beta-blocker stress echocardiography may provide an accurate assessment of AS if the LVOT obstruction is concomitant.

Background: Plasma aldosterone concentration (PAC) is related to cardiac remodeling in patients with hypertension. However, we do not know the detailed relationship between changes in PAC and regression of left atrial (LA) volume following long-term treatment with angiotensin II receptor blocker (ARB) or calcium-channel blocker (CCB)., Objective: The aim of this study was to investigate the effects of anti-hypertensive monotherapy, an ARB irbesartan or a CCB amlodipine, on PAC and LA reverse remodeling in hypertensive patients., Methods: A total of 48 patients with untreated hypertension were randomly assigned to irbesartan (ARB group, n=26) and amlodipine (CCB group, n=22). We examined the correlation between LA volume index (LAVI) and other echocardiographic parameters or PAC (n=40) at the baseline and after 12 months of treatment., Results: After 12 months, blood pressure (BP) decreased similarly in both groups. LAVI and PAC significantly decreased in the ARB group, but not in the CCB group (-16±8% vs. 22±9%, p<0.01, -16±9% vs. 11±9%, p<0.05). Larger %-decrease in PAC was associated with larger %-reduction of LAVI in the ARB group (r=0.54, p<0.05), but not in the CCB group., Conclusions: While BP reduction was similar between the two groups, decrease in LA volume was larger in the ARB group than in the CCB group. Decrease in LA volume was larger in patients with a greater decrease in PAC than in those with smaller decrease in PAC. ARB may facilitate reverse remodeling of LA through decreases in PAC in hypertensive patients., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Thyroid hormone is associated with arterial stiffness and left ventricular diastolic function in hypothyroid disease. The relationship of thyroid hormone level to cardio-ankle vascular index (CAVI) and left ventricular diastolic function, however, remains unclear in subjects with subclinical hypothyroidism., Methods and Results: We conducted a cross-sectional study of 83 patients with untreated subclinical hypothyroidism and compared them with 83 randomly selected controls from health check-ups. Log N-terminal prohormone of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and arterial stiffness were measured. In addition, we measured early diastolic mitral annular velocity (E') in 43 participants with subclinical hypothyroidism and in 40 controls. When compared with the control group, patients with subclinical hypothyroidism had higher logNT-proBNP (1.9±0.5 vs. 1.7±0.3pg/ml, P<0.05), CRP (0.22±0.04 vs. 0.09±0.06mg/dl, P<0.05), and CAVI (8.8±1.7 vs. 7.8±1.4, P<0.001) and lower E' (5.8±1.7 vs. 7.5±2.1cm/s, P<0.001). CAVI was significantly associated with logNT-proBNP, CRP and E' in the subclinical hypothyroidism group., Conclusions: High logNT-proBNP was associated with a raised CAVI in patients with subclinical hypothyroidism. Subclinical hypothyroidism may be a risk factor for cardiovascular events related to arterial stiffening and left ventricular diastolic dysfunction.

Pathophysiology of heart failure has been considered to be a damaged state of systolic function of the heart followed by a state of low cardiac output that is, systolic heart failure. Even if systolic function is preserved, left ventricular filling in diastole can be impeded and resulted in elevation of filling pressure and symptoms of heart failure. This kind of heart failure is called diastolic heart failure. Nowadays, diastolic heart failure is referred to as heart failure with preserved ejection fraction (HFpEF), whereas systolic heart failure is referred to as heart failure with reduced ejection fraction (HFrEF). In this paper, the similarities and differences between the pathogenesis and pathophysiology of diastolic and systolic heart failure were reviewed. Although diastolic heart failure is a common condition of heart failure worldwide, its pathophysiology has not been sufficiently elucidated. This is thought to be the most significant reason for a lack of established treatment methods for diastolic heart failure. We hope to proceed with future studies on this topic.

Heart failure with preserved ejection fraction is recently highlighted as a major health problem, and diastolic dysfunction associated with hypertension has a dominant role in the development of heart failure with preserved ejection fraction. Osteopontin (OPN) is a secreted phosphoprotein, which mediates fibrosis. In animal models, OPN is upregulated in response to pressure overload and is thought to be involved in systolic dysfunction. However, the functional role of OPN in diastolic dysfunction is unknown. The guanine base insertion polymorphism at -156 position of the OPN promoter is postulated to upregulate the transcription of OPN in human. To investigate whether -156del/G polymorphism of OPN promoter is associated with diastolic dysfunction in hypertensive hearts, the patients with hypertension have been genotyped for variants of -156del/G polymorphism by genomic sequencing. Diastolic function of the left ventricle was estimated as the ratio of early to atrial filling (E/A ratio), obtained by pulsed-Doppler derived transmitral flow in echocardiographic analysis. The patients with -156G allele displayed lower E/A ratio compared with those with -156del/del genotype, suggesting exacerbated diastolic function. Notably, in case of the population with diabetes mellitus, the patients with -156G allele showed significant association with lower E/A ratio, compared with -156del/-156del patients. Multiple linear regression analysis revealed that prevalence of -156G allele was an independent factor for lowering E/A ratio. The -156del/G genetic variants of OPN promoter were associated with decreased E/A ratio in hypertensive patients. These results suggest that OPN has a functional role in the development of diastolic dysfunction in hypertensive hearts.

Background: Reduced left ventricular torsion (LV-tor) has been reported to be associated with acute rejection in heart transplant (HTx) recipients. We investigated the utility of LV-tor analysis derived from 2-dimensional speckle-tracking echocardiography (2D-STE) for detecting allograft rejection., Methods: A total of 301 endomyocardial biopsies (EMBs), right heart catheterizations and echocardiograms were performed in 32 HTx recipients. Echocardiography was done within 3 hours from EMB or simultaneously with the procedures. The LV-tor was defined as the difference between apical and basal end-systolic rotations. The LV-tor values with and without cellular rejection were compared. In addition, we investigated whether the change in LV-tor values predicts the change in rejection grade in each patient. The baseline LV-tor value in each patient was defined as a mean value of the first 3 LV-tor measurements obtained when the patient was free from rejection., Results: According to the conventional International Society for Heart and Lung Transplantation criteria, 274 biopsies showed a rejection Grade of 0, 1a or 1b (Group AR(-)), whereas 27 biopsies were Grade 2 or higher (Group AR(+)). LV-tor decreased more in Group AR(+) than in Group AR(-) (9.3 ± 0.7 vs 12.2 ± 0.2 degrees, p < 0.0001). In the LV-tor measurement for each patient, the 25% reduction in LV-tor value from baseline predicted Grade 2 or higher rejection with a predictive accuracy of 92.9%., Conclusion: LV-tor derived from 2D-STE could be of clinical value for non-invasive monitoring of acute rejection in HTx recipients., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Evaluating donor heart as accurately as possible upon the organ procurement would help lead careful post-transplant heart management. Our institution (National Cerebral and Cardiovascular Center, Osaka, Japan) has sent a transplant cardiologist upon the organ procurement for evaluating a donor heart ever since our first case of heart transplantation., Methods: Thirteen consecutive bedside echocardiograms obtained from donors upon the organ procurement and post-transplant echocardiograms obtained from their recipients were retrospectively reviewed. The impact of donor echocardiograms on their recipients' post-transplant time course was analyzed and both the donor echocardiographic parameters and their recipients' parameters within 1 week after the heart transplant were compared., Results: Both the left ventricular end-diastolic diameter and the ventricular wall thickness of donors correlated well with those parameters of their corresponding recipients (r(2)=0.740, p<0.0001, r(2)=0.704, p<0.0001, respectively). The information on coronary flow of the donor heart with risk factors for ischemic heart disease was useful for judging the availability for heart transplantation. The information on the pre-existing localized wall motion abnormality of donor hearts was useful for ruling out a possibility of rejection and other causes of wall motion abnormality after transplantation. The mean time required for bedside echocardiography for the donor heart was only 3.7 min. None of the recipients either developed primary graft failure or required treatment for cellular rejection., Conclusions: Detailed observation of donor hearts by bedside echocardiograms upon the organ procurement is of clinical benefit., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Cerebrovascular accident (CVA) is a major adverse event following left ventricular assist device (LVAD) surgery. This study investigates pre- and post-operative factors associated with CVA in this population., Methods and Results: A total of 118 consecutive patients who underwent LVAD surgery at our institution between April 1994 and April 2009 were retrospectively reviewed. Clinical characteristics, hemodynamic data, and laboratory indexes associated with CVA after LVAD surgery were analyzed. In total, 57 (48.3%) patients developed CVA 133.5 ± 184.7 days after surgery. The combination of baseline heart disease, type of LVAD surgery, mean right atrial pressure (mRA), serum total bilirubin and total protein concentration, and right ventricular end-diastolic dimension (RVEDd) was associated with CVA at any time after LVAD surgery, with a discriminant probability of 718%. With regard to CVA development later than 3 months after surgery, the combination of mRA and RVEDd before surgery [odds ratio (OR), 1.24, 1.20; 95% confidential interval (CI), 1.07-1.42, 1.06-1.34; P = 0.004, P = 0.006, respectively], positive blood culture, and C-reactive protein after surgery (OR, 7.66, 2.19; 95%CI, 1.50-39.0, 1.47-3.25; P = 0.015, P < 0.0001, respectively) was associated with CVA with a discriminant probability of 85.9%., Conclusions: Patients' general condition including malnutrition, in addition to device selection, contributed to overall CVA development after surgery. In the chronic phase after surgery, pre-LVAD right heart failure and post-LVAD systemic infection were highly associated with CVA development.

We transfected naked HGF plasmid DNA into cultured cardiomyocytes using a sonoporation method consisting of ultrasound-triggered bubble liposome destruction. We examined the effects on transfection efficiency of three concentrations of bubble liposome (1 × 10(6), 1 × 10(7), 1 × 10(8)/mL), three concentrations of HGF DNA (60, 120, 180 μg/mL), two insonification times (30, 60 sec), and three incubation times (15, 60, 120 min). We found that low concentrations of bubble liposome and low concentrations of DNA provided the largest amount of the HGF protein expression by the sonoporated cardiomyocytes. Variation of insonification and incubation times did not affect the amount of product. Following insonification, cardiomyocytes showed cellular injury, as determined by a dye exclusion test. The extent of injury was most severe with the highest concentration of bubble liposome. In conclusion, there are some trade-offs between gene transfection efficiency and cellular injury using ultrasound-triggered bubble liposome destruction as a method for gene transfection.

Background and Purpose: The majority of heart transplant (HTx) candidates require left ventricular assist device (LVAD) support for more than 2 years before transplantation in Japan. However, the only currently available device is the extracorporeal pulsatile LVAD. The long-term management of extracorporeal LVAD support has improved remarkably over the years. To determine which post-operative management factors are related to the long-term survival of patients on such LVAD, we retrospectively compared the incidence of complications and their management strategies between the initial and recent eras of LVAD use, classified by the year of LVAD surgery., Methods: Sixty-nine consecutive patients supported by extracorporeal pulsatile LVAD as a bridge to HTx between 1994 and 2007 were reviewed retrospectively. The patients were assigned according to the time of LVAD surgery to either group A (n=30; between 1994 and 2000) or group B (n=39; between 2001 and 2007)., Results: Patients in group B survived significantly longer on LVAD support than those in group A (674.6 vs. 369.3 days; p<0.001). The 1- and 2-year survival rates were significantly higher in group B than that in group A (82% vs. 48%, p<0.0001; 68% vs. 23%, p<0.0001, respectively). The proportion of deaths due to cerebrovascular accidents was lower (17% vs. 50%, p<0.001) in group B compared with group A. The incidences of systemic infection were similar in both groups, but the proportions of patients alive and achieving transplant surgery after systemic infection were higher in group B than those in group A (55% vs. 14%, p<0.01; 14% vs. 36%, p<0.05, respectively)., Conclusions: The long-term survival of patients even on "first-generation" extracorporeal LVAD has improved significantly in the recent era. Careful management of cerebrovascular accidents and systemic infection will play important roles in the long-term LVAD management., (Copyright © 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The number of heart transplant (HTx) surgeries in Japan is expected to increase under the Revised Organ Transplant Law. To date, among 69 HTx surgeries performed in Japan, 27 operations (39.1%) were performed at our institution, the National Cardiovascular Center (NCVC), located in Osaka. We have reviewed the outcomes of HTx conducted at NCVC during a 10 year period (May 1999 to January 2009). Among 27 heart transplant recipients at NCVC, the clinical charts of 26 recipients whose post-HTx period exceeded 1 year were retrospectively reviewed and compared to data from the International Society for Heart and Lung Transplantation (ISHLT) Registry. The survival rate of our recipients was 96.2% at 10.8 years, which was excellent even compared to the ISHLT Registry. The immunosuppressive regimen at NCVC was equivalent to that of the ISHLT Registry, except for more frequent use of Muromonab-CD3 (26.9% versus 3.3%, P < 0.0001) and an initial CSA-based regimen (65.3% versus 34.4%, P < 0.001). The drug we use for induction therapy has been recently changed from Muromonab-CD3 to Basiliximab. The incidences of post-HTx hypertension, diabetes, hyperlipidemia, and renal insufficiency were significantly less in patients at NCVC compared to those in the ISHLT Registry, however, the incidence of transplant coronary artery disease (TxCAD) was almost identical. Clinical review of post-HTx outcome at NCVC can provide useful information for Japanese transplant cardiologists who will engage in HTx management.

The aim of the present study was to investigate the relationship between rejections and gene expression of Ca(2+)-handling proteins in heart transplant recipients. Thirty-seven heart transplant recipients underwent routine endomyocardial biopsy. Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and ryanodine receptor-2 mRNAs in endomyocardial tissue were quantified by a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Rejections were diagnosed according to the conventional International Society for Heart and Lung Transplantation criteria. Patients were classified as follows; group AR(+) (n = 9) with rejection grade of 2 or higher versus group AR(-) (n = 28) with rejection grade of 0, 1a or 1b at the time of biopsy, and group Rec-AR(+) (n = 6) with a history of more than 4 episodes of treatment required rejection versus group Rec-AR(-) (n = 31) without history of recurrent rejection. The mRNA levels of the SERCA2/GAPDH ratio and ryanodine receptor-2/GAPDH ratio were not different between group AR(+) and group AR(-); however, they were reduced in group Rec-AR(+) more than in group Rec-AR(-) (0.83 +/- 0.07 versus 0.90 +/- 0.07, P = 0.034, 0.74 +/- 0.06 versus 0.84 +/- 0.10, P = 0.027, respectively). A single episode of on-going rejection would not affect myocardial Ca(2+)-handling proteins; however, cumulative rejection episodes might alter the gene expression of myocardial Ca(2+)-handling proteins in heart transplant recipients.