Hemodynamic response during standing test after blood donation can predict the late phase vasovagal reaction.

A major complication of blood donation is vasovagal reaction (VVR) with or without syncope. VVR occurs not only in the early phase, but also in the late phase after blood donation. We previously reported the hemodynamic characteristics of blood donors susceptible to early phase VVR. In the present study, we investigated the hemodynamic characteristics of those who developed late VVR. Ninety-six healthy volunteers donating 400 ml of whole blood were studied. After asking about their physical condition or routine questions for blood donation, blood pressure (BP) and heart rate (HR) were recorded while the donors were kept standing up for 3 min before and after blood collection. Questionnaires were distributed to all donors for reporting late VVR symptoms within 24 h. Those with younger age and lower diastolic blood pressure were more susceptible to late VVR (both p < 0.05). Furthermore, we identified the increase in HR during the standing test after blood collection as a good predictor of late VVR (odds ratio 1.063, 95 % CI 1.005-1.124; p = 0.031). Also, analysis of questions asked before donation revealed that significantly more donors considered themselves as sensitive to pain in the late VVR group (Odds ratio 0.070, 95 % CI 0.008-0.586; p = 0.014). Excessive HR response to standing after blood collection and subjective sensitivity to pain as well as younger age and lower diastolic BP may be useful to detect donors at high risk for late VVR.

Toll-like receptor-4 is upregulated in plaque debris of patients with acute coronary syndrome more than Toll-like receptor-2.

Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins, those may lead to acute coronary syndrome (ACS). We investigated the expression level of TLR-4 in ACS, as compared with TLR-2 and patients with stable angina. Fifty-eight consecutive patients who underwent primary percutaneous coronary intervention (PCI, n = 29) because of ACS and elective PCI (n = 29) because of stable angina using a filter-device distal protection device system were prospectively analyzed. mRNA levels of TLR-2 and TLR-4 in debris containing various inflammatory tissues entrapped in the filter device were altogether analyzed using real-time PCR. There were no significant differences in age, sex distribution, between stable angina and ACS groups. TLR-4 expression levels were higher in patients with ACS than in patients with stable angina. TLR-4 might play a more important role than TLR-2 in atherogenesis, especially in ACS.

Gender differences in factors influencing electrocardiographic findings of left ventricular hypertrophy in severe aortic stenosis.

We investigated gender differences in factors influencing the electrocardiographic (ECG) findings of left ventricular hypertrophy (LVH) in patients with severe aortic stenosis (AS). The functional and geometric responses of the left ventricle to chronic pressure overload, such as hypertension and AS, have been reported to be different between men and women. However, gender differences in the factors influencing the ECG findings of LVH in pressure overload remain unknown. We conducted a retrospective observational study in consecutive patients with severe AS (aortic valve area (AVA) assessed by cardiac catheterization <1.0 cm(2)) without concomitant significant aortic regurgitation, mitral stenosis and/or regurgitation, conduction disturbance, or myocardial infarction (n = 35 males, 68 females). The ECG criteria were classified into three categories: (1) high voltage by the Sokolow-Lyon index associated with ST-T wave changes (with no digitalis therapy); (2) high voltage alone; and (3) normal. Groups 1 and 2 were defined as LVH on ECG. We compared the ECG findings in relation to the AS severity between genders. Women were older, but there were no significant differences in the prevalence of hypertension, AVA index (AVAI), mean pressure gradient or peak velocity across the AV, LV mass index (LVMI) derived from echocardiography or the distribution of ECG categories between genders. A multiple logistic regression analysis including age, gender, hypertension, AVAI, mean pressure gradient, and LVMI revealed that the LVMI (P = 0.001) and AVAI (P = 0.0434) were significantly related to the distribution of ECG categories. LVMI significantly predicted LVH on ECG in both genders, but AVAI was a predictive factor in only women. ECG LVH in patients with severe AS may be mainly reflected by LVMI in men and by both LVMI and AVAI in women. Factors other than AVA, such as end-stage disease and/or complicating factors such as hypertension, may underlie the observed differences in ECG findings of LVH between men and women.

Patient factors against stable control of warfarin therapy for Japanese non-valvular atrial fibrillation patients.

INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (<70 and ≥ 70 years; 49.6 ± 24.8% and 77.8 ± 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those ≥ 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 ± 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS: When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control.

Comparison of the reperfusion efficacy of thrombus aspiration with and without distal protection during primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction.

We evaluated a hypothesis that thrombus aspiration with distal protection is superior to simple thrombus aspiration in patients treated with primary percutaneous coronary intervention (PCI). A total of 176 consecutive patients with ST-segment elevation myocardial infarction were enrolled in this study and assigned to either the thrombus aspiration group (A, n = 104) or the thrombus aspiration with distal protection group using a filter device system (A + DP, n = 72). We compared the angiographic reperfusion grade, left ventricular (LV) function, and clinical outcomes between the 2 groups. There were no significant differences in age, gender distribution, the onset-to-reperfusion time, the peak levels of creatine kinase, or 6-month mortality between the 2 groups. The rate of achieving a Thrombolysis In Myocardial Infarction flow grade of 3 and a myocardial blush grade of 3 was higher in the A + DP group than in the A group. Among the patients who underwent follow-up catheterization 6 months after PCI (A, n = 62; A + DP, n = 52), there were no significant differences in the LV end-diastolic volume index, LV end-systolic volume index, or LV ejection fraction between the 2 groups at the time of PCI or 6 months after PCI. In conclusion, thrombus aspiration with distal protection may be more effective in initially restoring the coronary blood flow than thrombus aspiration alone, although it may not be superior to thrombus aspiration in preventing LV remodeling or preserving the LV function in patients with ST-segment elevation myocardial infarction.

A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and RCM.

A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and ring-closing olefin metathesis (RCM) was developed. The Ireland-Claisen rearrangement of a (Z)-3-alkoxyprop-2-en-1-yl glycolate ester having a cyclic ether on the oxygen at C3 of the (Z)-prop-2-en-1-yl group stereoselectively produced an anti-alpha,beta-dialkoxyester, which was successfully transformed to a fused bicyclic ether via a reaction sequence including RCM.

Enhancement of cardiac performance by bilevel positive airway pressure ventilation in heart failure.

BACKGROUND: Recent studies have reported the clinical usefulness of positive airway pressure ventilation therapy with various kinds of pressure support compared with simple continuous positive airway pressure (CPAP) for heart failure patients. However, the mechanism of the favorable effect of CPAP with pressure support can not be explained simply from the mechanical aspect and remains to be elucidated. METHODS AND RESULTS: In 18 stable chronic heart failure patients, we performed stepwise CPAP (4, 8, 12 cm H(2)O) while the cardiac output and intracardiac pressures were continuously monitored, and we compared the effects of 4 cm H(2)O CPAP with those of 4 cm H(2)O CPAP plus 5 cm H(2)O pressure support. Stepwise CPAP decreased cardiac index significantly in patients with pulmonary arterial wedge pressure (PAWP) <12 mm Hg (n = 10), but not in those with PAWP ≥12 mm Hg (n = 8). Ventilation with CPAP plus pressure support increased cardiac index slightly but significantly from 2.2 ± 0.7 to 2.3 ± 0.7 L min(-1) m(-2) (P = .001) compared with CPAP alone, regardless of basal filling condition or cardiac index. CONCLUSIONS: Our results suggest that CPAP plus pressure support is more effective than simple CPAP in heart failure patients and that the enhancement might be induced by neural changes and not simply by alteration of the preload level.

Simple standing test predicts and water ingestion prevents vasovagal reaction in the high-risk blood donors.

BACKGROUND: One of the serious complications of blood donation is vasovagal reaction (VVR) with syncope. This study was performed to determine if the measurement of hemodynamic responses to standing before blood collection (BC) was useful to identify the high-risk donors for VVR and also examined the effect of 300 mL of water ingestion in the prevention of VVR. STUDY DESIGN AND METHODS: Blood pressure and heart rate (HR) during 5 minutes of standing were examined before and after BC in 93 donors. Because HR increase of 6 of 7 donors who developed syncopal VVR during standing after BC was 15 beats per minute (bpm) or greater, those with HR increase of 15 bpm or greater were determined as high-risk donors (n = 31). In another group (n = 117), 45 donors were identified as high risk based on the HR response before BC (15 bpm). The effect of 300 mL of water ingestion 15 minutes before BC on hemodynamic responses to standing and the rate of VVR after BC were analyzed. RESULTS: Water ingestion given to the high-risk donors of the second group reduced HR increase with standing before BC (-6.6 ± 13.6 bpm, p < 0.02 vs. HR increase before water ingestion) and significantly suppressed VVR rate (2 of 45 donors with high risk, 4.4%,p < 0.04 vs. the first group; 6 of 31 high-risk donors, 19.4%). CONCLUSION: HR response to standing before BC may detect the high-risk donors for VVR. For the high-risk donors, 300 mL of water ingestion may be a simple and effective way of prevention against syncopal VVR.

Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-alpha in cardiovascular diseases. The present study aimed to evaluate the effects of soluble TNF receptor treatment on myocardial infarction (MI). METHODS: An adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein (AdTNFR1) was used to neutralize TNF-alpha, and an adenovirus encoding LacZ (AdLacZ) served as control. In the pre-MI treatment protocol, mice were given an intravenous injection of AdTNFR1 or AdLacZ 1 week before left coronary artery ligation to induce MI. In the post-MI treatment protocol, mice were treated with AdTNFR1 or AdLacZ 1 week after left coronary ligation. RESULTS: Treatment with AdTNFR1 neutralized bioactivity of TNF-alpha that was activated after MI and prevented apoptosis of infiltrating cells in infarct myocardium. However, pre-MI treatment with AdTNFR1 promoted ventricular rupture by reducing fibrosis with further activation of matrix metalloproteinase (MMP)-9. Post-MI treatment with AdTNFR1 exacerbated ventricular dysfunction and remodeling, with enhanced fibrosis of non-infarct myocardium with further MMP-2 activation. CONCLUSIONS: Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model. Thus, TNF-alpha may play not only toxic but also protective roles in MI.

Left ventricular false-pseudo and pseudo aneurysm: serial observations by cardiac magnetic resonance imaging.

A case of extensive inferior myocardial infarction complicated by a large ventricular aneurysm is presented. Magnetic resonance (MR) imaging 4 days after the onset showed a small protrusion from the necrotic inferior myocardium, which expanded 10 days after onset with a marked pericardial effusion. The follow-up examination by MR and CT imaging 6 months after the onset revealed a large ventricular aneurysm from the inferior cardiac wall. After the aneurysmectomy, the histological study revealed that the aneurysm wall was made up of 2 different types of walls; the peripheral part was a false-pseudo aneurysm and the central part was a pseudo aneurysm. From the serial MR imaging, it is considered that such an aneurysm is primarily formed from a small discontinuation of the LV wall followed by oozing type rupture. Finally, the ruptured central part of the LV wall, which was covered by the pericardium, formed a pseudo aneurysm and the stretched peripheral area, which contains myocardium, formed a false-pseudo aneurysm afterward and then they extended together. Thus, MR imaging provided the important information for the understanding of the formation process of the pseudo and false pseudo LV aneurysm.

Blockade of NF-kappaB improves cardiac function and survival after myocardial infarction.

NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.

Blockade of NF-kappaB ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II.

OBJECTIVE: Nuclear factor (NF)-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we assessed the hypothesis that blockade of NF-kappaB may ameliorate ventricular hypertrophy in response to chronic infusion of angiotensin II. METHODS: Mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. Male KO and age-matched wild-type (WT) mice were chronically infused with angiotensin II at the rate of 0.2 (low dose) or 2 microg/kg/min (high dose) for 4 weeks. RESULTS: High- but not low-dose angiotensin II significantly increased systemic blood pressure and left ventricular weight in WT mice. In contrast, although the pressor response was slightly but significantly augmented, the hypertrophic effect of angiotensin II was significantly attenuated in KO mice. The attenuated hypertrophic responsiveness was confirmed histologically (cross-sectional area) and transcriptionally (atrial natriuretic peptide). Echocardiography revealed no evidence of cardiac dysfunction in angiotensin II-treated KO mice. Although phosphorylation of MAPKs, including ERK, JNK, or p38-MAPK, was not affected after 4 weeks of angiotensin II treatment in WT mice, phosphorylation of JNK was specifically abrogated in KO mice. Angiotensin II increased myocardial expression of proinflammatory cytokines and chemokines in WT mice, while expression of TNF-alpha and RANTES was paradoxically augmented in KO mice. CONCLUSION: Blockade of NF-kappaB activation attenuated myocardial hypertrophy without deteriorating cardiac function. NF-kappaB may play an important role in cardiac hypertrophy and remodeling besides promoting inflammation.

Blockade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy.

OBJECTIVE: NF-kappaB, a key transcription factor that regulates inflammatory processes, has been shown to be activated in the failing human heart with enhanced expression of proinflammatory cytokines. In the present study, we assessed the hypothesis that cardiotoxic effects of proinflammatory cytokines are mediated by the activation of NF-kappaB. METHODS: Transgenic mice with cardiac-specific overexpression of TNF-alpha were used as a model of cytokine-induced cardiomyopathy. To block the activation of NF-kappaB, transgenic mice (TG/p50(+/+)) were crossed with knockout mice in which the p50 subunit of NF-kappaB was disrupted (WT/p50(-/-)). RESULTS: The electrophoretic mobility shift assay demonstrated that NF-kappaB was activated in the myocardium of TG/p50(+/+) mice, while it was completely abolished in TG/p50(-/-) mice. Male TG mice died of congestive heart failure earlier than females, where the disruption of the p50 subunit significantly improved the survival. Compared with TG/p50(+/+) mice, TG/p50(-/-) mice showed a significant reduction of ventricular dilatation and hypertrophy with preserved fractional shortening. Although the myocardial expression of proinflammatory cytokines or infiltration of inflammatory cells was not affected, increased expression and activity of MMP-9 were significantly suppressed in TG/p50(-/-) mice. CONCLUSION: Blockade of NF-kappaB activation did not ameliorate myocardial inflammation but improved cardiac function and survival in male TNF-alpha TG mice. An inhibition of NF-kappaB may be a new therapeutic strategy for cardiac remodeling and heart failure, especially when proinflammatory cytokines are activated.

Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells.

Recent studies have demonstrated that upregulated Rho-kinase plays an important role in the pathogenesis of arteriosclerosis and vasospasm in both animals and humans. However, little is known about the molecular mechanism(s) involved in the Rho-kinase upregulation. Since inflammatory mechanisms have been implicated in the pathogenesis of arteriosclerosis and vasospasm, we examined whether inflammatory stimuli upregulate Rho-kinase in vitro and in vivo. In cultured human coronary vascular smooth muscle cells (hcVSMC), inflammatory stimuli, such as angiotensin II and interleukin-1beta, increased Rho-kinase expression (at both mRNA and protein levels) and function (as evaluated by the extent of the phosphorylation of the ERM (the ezrin/radixin/moesin) family, substrates of Rho-kinase) in a time- and concentration-dependent manner. The expression of Rho-kinase was inhibited by blockades of protein kinase C (PKC) (by either GF109253 or prolonged treatment with phorbol myristate acetate for 24 h) and an adenovirus-mediated gene transfer of dominant-active Ikappa-B, suggesting an involvement of PKC and NF-kappaB in the intracellular signal transduction pathway for the Rho-kinase expression. Furthermore, coronary vascular lesion formation (characterized by medial thickening and perivascular fibrosis) induced by a long-term administration of angiotensin II was markedly suppressed in NF-kappaB(-/-) mice with reduced expression and activity of Rho-kinase in vivo. These results indicate that the expression and function of Rho-kinase are upregulated by inflammatory stimuli (e.g. angiotensin II and IL-1beta) in hcVSMC with an involvement of PKC and NF-kappaB both in vitro and in vivo.

Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure with myocardial inflammation. The purpose of this study was to investigate the effects of tumor necrosis factor-alpha on reactive oxygen species (ROS) in this mouse model of cardiomyopathy. Myocardial production of hydroxyl radical detected by electron spin resonance spectroscopy was significantly increased in TG. Myocardial expression of Mn-SOD was significantly decreased in TG, whereas that of Cu,Zn-SOD was unaltered. Myocardial expression of catalase was unchanged, whereas that of glutathione peroxidase was significantly increased, in TG. Histological analysis revealed that macrophages and CD4-positive lymphocytes were increased in TG myocardium. To investigate whether these infiltrating inflammatory cells were the source of ROS, we treated TG mice with cyclophosphamide for 7 days. Although cyclophosphamide significantly suppressed the infiltration of inflammatory cells, it did not diminish the production of hydroxyl radical in TG myocardium. Damaged myocytes, but not infiltrating inflammatory cells, may be the source of ROS in TG.

Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates beta-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt(max) was significantly suppressed, and its beta-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved beta-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of beta-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.

Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-alpha develop dilated cardiomyopathy with myocardial inflammation. The purpose of this study was to investigate the role of nitric oxide (NO) in this mouse model of cardiomyopathy. Female TG and wild-type mice at the age of 10 wk were studied. The expression and activity of inducible NO synthase (iNOS) were significantly increased in the TG myocardium, whereas those of endothelial NOS were not altered. The majority of the iNOS protein was isolated in the interstitial cells. The selective iNOS inhibitor (1S,5S,6R,7R)- 7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) was used to examine the effects of iNOS induction on myocardial contractility. Echocardiography and left ventricular pressure measurements were performed. Both fractional shortening and the maximum rate of rise of left ventricular pressure were significantly suppressed in TG mice. Although ONO-1714 did not change hemodynamic parameters or contractility at baseline, it significantly improved beta-adrenergic inotropic responsiveness in TG mice. These results indicate that induction of iNOS may play an important role in the pathogenesis of cardiac dysfunction in this mouse model of cytokine-induced cardiomyopathy.