A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats.

BACKGROUND: Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the angiogenic response to hypoxia. METHODS: We studied the effects of adenoviral vectors expressing a constitutively active HIF-1 alpha hybrid (Ad2/HIF-1 alpha/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia. RESULTS: After the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin-1 and angiopietin-4 in the calf muscles, as measured by Taqman reverse transcriptase-polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post-mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF-1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans-blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF-1 alpha/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content. CONCLUSIONS: The endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down-regulation of angiogenic factors. Ad2/HIF-1 alpha/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 alpha angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity.

Impact of pulmonary vein isolation on the autonomic modulation in patients with paroxysmal atrial fibrillation and prolonged sinus pauses.

AIMS: The efficacy of catheter-based pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (AF) and prolonged sinus pauses [bradycardia-tachycardia syndrome (BTS)] has been already described. However, the effects of PVI on autonomic modulation in BTS patients remain to be determined. We, therefore, examined the alteration in the autonomic modulation through the PVI procedure by using a heart rate variability (HRV) analysis of 24 h ambulatory monitoring. METHODS AND RESULTS: This study consisted of 26 symptomatic paroxysmal AF patients either with prolonged sinus pauses on termination of AF (>3.0 s, BTS group, n = 11) or without any evidence of sinus node dysfunction (control group, matched for sex and age, n = 15) who underwent PVI. All 11 BTS patients became free from both AF and prolonged sinus pauses without pacemaker implantation (23 +/- 14 months of observation). The mean heart rate significantly increased in the control group (P < 0.05), but not in the BTS group after the PVI procedure, although the HRV parameters of root-mean-square successive differences in the adjacent NN intervals, standard deviation of the NN intervals, and high frequency did significantly decrease in both groups (P < 0.05). CONCLUSION: Although the parasympathetic modulation was significantly attenuated after the PVI procedure, the mean heart rate did not increase in the BTS patients, probably due to the pre-existing sinus node dysfunction.

Myocardial Ca2+ handling and cell-to-cell coupling, key factors in prevention of sudden cardiac death.

Using whole-heart preparations, we tested our hypothesis that Ca(2+) handling is closely related to cell-to-cell coupling at the gap junctions and that both are critical for the development and particularly the termination of ventricular fibrillation (VF) and hence the prevention of sudden arrhythmic death. Intracellular free calcium concentration ([Ca(2+)](i)), ECG, and left ventricular pressure were continuously monitored in isolated guinea pig hearts before and during development of low K(+)-induced sustained VF and during its conversion into sinus rhythm facilitated by stobadine. We also examined myocardial ultrastructure to detect cell-to-cell coupling alterations. We demonstrated that VF occurrence was preceded by a 55.9% +/- 6.2% increase in diastolic [Ca(2+)](i), which was associated with subcellular alterations indicating Ca(2+) overload of the cardiomyocytes and disorders in coupling among the cells. Moreover, VF itself further increased [Ca(2+)](i) by 58.2% +/- 3.4% and deteriorated subcellular and cell-to-cell coupling abnormalities that were heterogeneously distributed throughout the myocardium. In contrast, termination of VF and its conversion into sinus rhythm was marked by restoration of basal [Ca(2+)](i), resulting in recovery of intercellular coupling linked with synchronous contraction. Furthermore, we have shown that hearts exhibiting lower SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) activity and abnormal intercellular coupling (as in older guinea pigs) are more prone to develop Ca(2+) overload associated with cell-to-cell uncoupling than hearts with higher SERCA2a activity (as in young guinea pigs). Consequently, young animals are better able to terminate VF spontaneously. These findings indicate the crucial role of Ca(2+) handling in relation to cell-to-cell coupling in both the occurrence and termination of malignant arrhythmia.

Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study.

BACKGROUND: Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease. METHODS: We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20-79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40-160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328. FINDINGS: After a median follow-up of 3.1 years (range 1-3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1000 patient years; hazard ratio 0.61, 95% CI 0.47-0.79, p=0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38-0.95, p=0.028), angina pectoris (19 vs 53; 0.35, 0.20-0.58, p<0.0001), and heart failure (19 vs 36; 0.53, 0.31-0.94, p=0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups. INTERPRETATION: The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Reduction of AF recurrence after pulmonary vein isolation by eliminating ATP-induced transient venous re-conduction.

BACKGROUND: Recent evidence has suggested that the transient re-conduction of the isolated pulmonary vein (PV) induced by the intravenous injection of adenosine (dormant PV conduction) might predict the incidence of subsequent venous reconnection after the procedure, which is the main cause of the atrial fibrillation (AF) recurrence after PV isolation (PVI). We tested the hypothesis that the elimination of these dormant PV conductions by additional radiofrequency (RF) applications can improve the efficacy of the PVI. METHODS AND RESULTS: One hundred forty-eight patients (124 males; mean age 53 +/- 9 years) with drug-refractory AF underwent the PVI procedure. The standard PVI was performed in 94 patients (Group A), whereas the elimination of adenosine triphosphate (ATP)-induced dormant conduction using additional RF energy was performed in addition to the standard PVI in other 54 patients (Group B). Dormant conduction was observed in 56% of the patients (30/54) in Group B and 95% of these transient re-conductions were successfully eliminated by additional RF applications (mean: 1.5 +/- 1.0 times). During the mean follow-up period of 20 months, recurrences of AF after the procedures were observed significantly less frequently in Group B (20%) than in Group A (40%) (P < 0.05). CONCLUSION: The use of additional RF applications to eliminate transient PV reconnection induced by ATP injection led to a reduction of AF recurrence after PVI, most likely due to the minimization of the subsequent PV reconnection.

Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats.

BACKGROUND: Sensitivity to ischemia and its underlying mechanisms in type 2 diabetic hearts are still largely unknown. Especially, correlation between reperfusion induced ventricular arrhythmia and changes in intracellular pH has not been elucidated. METHODS AND RESULTS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 16 and 32 weeks of age were used along with age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. Hearts from rats in these 4 groups were perfused in the working heart mode, thus inducing whole heart ischemia. At 16 weeks of age, no differences in blood glucose levels or incidence and duration of reperfusion arrhythmia were found between the strains. At 32 weeks of age, both impaired glucose tolerance and obesity were observed in the OLETF rats. Further, the duration of reperfusion-induced ventricular fibrillation (VF) was significantly longer in the OLETF rats, while the pH level was significantly lower and proton contents were significantly higher in coronary effluent during ischemia in those rats. Following treatment with troglitazone, improvements in pH and proton level in coronary effluent during ischemia were observed, as was the duration of reperfusion-induced VF in OLETF rats at 32 weeks of age. CONCLUSION: The hearts of spontaneously diabetic OLETF rats were found to be more susceptible to ischemic insult. Troglitazone treatment improved ischemic tolerance by improving glucose metabolism in the myocardium of those rats.

Elevated plasma brain natriuretic peptide level in cardiac sarcoidosis patients with preserved ejection fraction.

We sought to examine whether the plasma brain natriuretic peptide (BNP) levels are elevated in the cardiac sarcoidosis patients even with a preserved ejection fraction. The data from the patients with either pulmonary sarcoidosis without any evidence of cardiac involvement (n = 13) or cardiac sarcoidosis (n = 8) with a preserved ejection fraction (>55%) on echocardiography were analyzed. The median plasma BNP levels were significantly higher in the patients with cardiac sarcoidosis than in those with pulmonary sarcoidosis (101.5 +/- 65.1 vs. 15.6 +/- 10.5 pg/ml, p < 0.001), although there was no significant difference in left ventricular ejection fraction between the two populations. The plasma BNP level is thus considered to be a useful non-invasive biomarker for identifying a possible cardiac involvement in the sarcoidosis patients with a preserved ejection fraction.

Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial.

BACKGROUND AND PURPOSE: Although the efficacy of anticoagulant therapy for primary prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) has been established, efficacy of antiplatelet therapy for low-risk patients is disputable in Japanese patients because of the frequent hemorrhagic complications. We examined the efficacy and safety of aspirin therapy in Japanese patients with NVAF in a prospective randomized multicenter trial. METHODS: Patients with NVAF were randomized to an aspirin group (aspirin at 150 to 200 mg per day) or a control group without antiplatelet or anticoagulant therapy. Primary end points included cardiovascular death, symptomatic brain infarction, or transient ischemic attack. RESULTS: A total of 426 patients were randomized to aspirin group and 445 to no treatment. The trial was stopped earlier because there were 27 primary end point events (3.1% per year; 95% CI, 2.1% to 4.6% per year) in the aspirin group versus 23 (2.4% per year; 95% CI, 1.5% to 3.5% per year) in the control group, suggesting a low possibility of superiority of the aspirin treatment for prevention of the primary end point. In addition, treatment with aspirin caused a marginally increased risk of major bleeding (7 patients; 1.6%) compared with the control group (2 patients; 0.4%; Fisher exact test P=0.101). CONCLUSIONS: For prevention of stroke in patients with NVAF, aspirin at 150 to 200 mg per day does not seem to be either effective or safe. Further prospective studies are needed to determine the best preventive therapy for cerebrovascular events in Japanese patients with NVAF.

Post-transcriptional downregulation of sarcolipin mRNA by triiodothyronine in the atrial myocardium.

Thyroid hormone-mediated positive cardiotropic effects are differently regulated between the atria and ventricles. This regulation is, at least in part, dependent on sarcoplasmic reticulum (SR) proteins. Sarcolipin, a homologue of phospholamban, has been recently identified as an atrium-specific SR protein. The expression of sarcolipin mRNA was significantly decreased in the atria of mice with hyperthyroidism and in 3,5,3'-triiodo-l-thyronine-treated neonatal rat atrial myocytes. Promoter activity and mRNA stability analyses revealed that thyroid hormone post-transcriptionally down regulated the expression of sarcolipin mRNA. The atrium-specific effect of thyroid hormone may occur in part through the regulation of atrial sarcolipin gene expression.

Behavior of atrial ectopic beats before and after pulmonary vein isolation in patients with atrial fibrillation: a reduction in the number and arrhythmogenicity of ectopic firings.

BACKGROUND: No studies evaluating in a quantitative manner the effect of pulmonary vein (PV) isolation on the behavior of atrial premature beats have been reported. OBJECTIVES: The purpose of this study was to reveal the behavior of atrial premature beats before and after PV isolation in patients with paroxysmal atrial fibrillation (AF). METHODS: In 108 patients free from AF following PV isolation, both the number of atrial premature beats and their coupling intervals before and following PV isolation were evaluated with periodic 24-hour ambulatory monitoring. RESULTS: After a successful PV isolation procedure (group 1, n = 78), the number of atrial premature beats significantly decreased with two distinct time courses: an acute reduction on the following day and a subsequent gradual decrease throughout the whole observation period. The mean atrial premature beat coupling interval at baseline was 420 +/- 30 ms, which was significantly prolonged to 560 +/- 100 ms at 3 months after PV isolation (P <.01). Although patients with AF recurrence after PV isolation (group 2, n = 30) had transiently depressed atrial premature beats shortly after the procedure, they recovered to the former level 3 months after PV isolation. Repeat PV isolation targeting the reconnected PVs successfully suppressed these residual atrial premature beats both in their number and the coupling interval in a manner similar to those in group 1. CONCLUSION: Successful PV isolation reduced the number of atrial premature beats with both rapid and gradual time courses. The residual atrial premature beats appeared less arrhythmogenic, with longer coupling intervals than those at baseline. AF recurrences after PV isolation were associated with increased atrial premature beat number and shortened coupling interval, which were depressed by reisolation of reconnected PVs.

Effects of eplerenone and salt intake on left ventricular remodeling after myocardial infarction in rats.

Eplerenone, a selective aldosterone blocker, has been shown to attenuate cardiac fibrosis and decrease cardiovascular events in both experimental and clinical studies. We examined the cardioprotective effect of eplerenone in myocardial infarction (MI) rats receiving different levels of salt in their diet. The MI rats were randomly divided into five groups: Group CL, animals received a low-salt diet (0.015%); Group EpL, a low-salt diet with eplerenone (100 mg/kg/day in food); Group CH, a high-salt diet (0.9%); Group EpH, a high-salt diet with eplerenone; and Group C, a normal salt diet (0.3%). These diets were continued for 4 weeks. Echocardiographic and histomorphological examinations revealed that the administration of eplerenone significantly improved the cardiac function, significantly suppressed compensatory cardiac hypertrophy and significantly reduced cardiac fibrosis in both the interstitial and the perivascular areas in the high-salt diet group (Group EpH). However, eplerenone had no observable effects in the low-salt diet group (Group EpL). Also, these examinations demonstrated that the left ventricular remodeling after MI was suppressed and the cardiac function was improved in the group receiving a low-salt diet without eplerenone (Group CL), even though there was a significant increase of aldosterone level in blood, in comparison to the group receiving a high-salt diet without eplerenone (Group CH). These results indicate that the cardioprotective effect of eplerenone varies depending on the salt intake.

Delayed in vivo catabolism of intermediate-density lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis.

OBJECTIVE: Premature cardiovascular disease is the leading cause of death in patients with end-stage renal disease treated by hemodialysis (HD). Low-density lipoprotein (LDL) levels are not generally increased in HD patients, but their LDL metabolism is still poorly understood. We therefore investigated the in vivo metabolism of apoB-containing lipoproteins in two different ethnic populations of HD patients and controls. METHODS AND RESULTS: We performed stable isotope kinetic studies using a primed constant infusion of deuterated leucine in 12 HD patients and 13 healthy controls. Tracer/tracee ratio of apoB was determined by means of gas chromatography/mass spectrometry, and the modeling program SAAMII was used to estimate the fractional catabolic rate (FCR) of apoB. Mean LDL-apoB plasma concentrations were almost identical in both groups (HD: 95+/-30 mg/dL, controls: 91+/-40 mg/dL), whereas LDL-apoB FCR was 50% lower in HD patients as compared with controls (0.22+/-0.12 days(-1) versus 0.46+/-0.20 days(-1), P=0.001) with concomitantly decreased production rates of LDL. Compared with controls, intermediate-density lipoprotein (IDL)-apoB FCR was 65% lower (2.87+/-1.02 days(-1) versus 8.89+/-4.94 days(-1), P=0.014), accompanied by 1.5-fold higher IDL-apoB levels in HD. Very low-density lipoprotein metabolism was similar in both study groups. CONCLUSIONS: In vivo catabolism of LDL and IDL is severely impaired in HD patients but misleadingly masked by normal plasma cholesterol levels. The resulting markedly prolonged residence times of both IDL and LDL particles might thus significantly contribute to the well-documented high risk for premature cardiovascular disease in HD patients.

Complete deficiency of the low-density lipoprotein receptor is associated with increased apolipoprotein B-100 production.

OBJECTIVE: We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans. METHODS AND RESULTS: Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. The FCRs of very-low-density lipoprotein 1 (VLDL1), VLDL2, intermediate-density lipoprotein (IDL), and LDL apoB were lower in FH than in controls, with the LDL apoB FCR being significantly lower (0.148+/-0.049 versus 0.499+/-0.099 pools x d(-1); P=0.008). Whereas receptor-defective FH patients had a total apoB PR similar to controls, receptor-null FH patients had a significantly greater total apoB PR than controls (35.97+/-10.51 versus 21.32+/-4.21 mg x kg(-1) x d(-1), respectively; P=0.02). CONCLUSIONS: This first study of apoB metabolism in homozygous FH using endogenous labeling with stable isotopes demonstrates that the LDL receptor contributes significantly to the clearance of LDL from plasma but plays a lesser role in the clearance of larger apoB-containing lipoproteins. Furthermore, these data also indicate that absence of a LDL receptor in humans substantially influences the apoB PR in vivo.

New diagnostic technique in multi-slice computed tomography for in-stent restenosis: pixel count method.

OBJECTIVES: A diagnostic technique to objectively determine coronary in-stent stenosis was developed with multi(16)-slice computed tomography (MSCT), and it was compared with coronary angiography (CAG) in clinical cases. BACKGROUND: MSCT is expected to replace coronary angiography as a new non-invasive examination. Evaluation of highly calcified or in-stent lesions with CT is generally thought to be difficult. METHODS: Twenty lesions among 16 consecutive patients that were implanted with coronary stents were examined with both MSCT and CAG at follow-up. The minor axis cross sections of the stents were reconstructed at intervals of 1.5 mm with multiplanar reformation (MPR). The pixel with a higher CT value than the lowest CT value in the standard cross section at the proximal site out of stent was counted to determine the presence/absence of a stenotic lesion. RESULTS: Among 20 lesions, one case was not able to be evaluated with MSCT. MSCT correctly detected 3 of 4 cases with in-stent stenosis (sensitivity 75%), and 14 of 16 cases with no in-stent stenosis (specificity 88%, negative predictive value 93%, positive predictive value 75%). If analysis was made per-artery, sensitivity and specificity were 100% (3 of 3) and 87% (13 of 15), respectively, for detection of in-stent stenosis. CONCLUSIONS: This study was performed to examine a unique diagnostic technique: pixel count method, for coronary in-stent stenosis with MSCT. It showed that the coronary in-stent stenosis could be determined when stent struts were clearly imaged. Further examination is required with various stents, especially those with a diameter of 3.0 mm or smaller.

Dual mechanisms underlying pulmonary vein tachycardias in a patient with paroxysmal atrial fibrillation.

We report a case of a 46-year-old man with paroxysmal atrial fibrillation who underwent pulmonary vein isolation. After a complete isolation of each pulmonary vein was performed, two different types of pulmonary vein tachycardia appeared: a regular tachycardia in the left inferior pulmonary vein with a supposed reentrant mechanism, and an irregular tachycardia in the right superior PV showing a nonreentrant character.

Glucose intolerance is common in Japanese patients with acute coronary syndrome who were not previously diagnosed with diabetes.

OBJECTIVE: Postprandial hyperglycemia has emerged as a new glycometabolic condition associated with an excessive risk for coronary artery disease. We therefore attempted to evaluate the frequency of postchallenge hyperglycemia in patients with acute coronary syndrome (ACS) who were not previously diagnosed to have diabetes and did not have a fasting glucose concentration of > or =7 mmol/l or an HbA(1c) level >6.0%. We further correlated the presence of postchallenge hyperglycemia with the extent of coronary atherosclerosis. RESEARCH DESIGN AND METHODS: In all, 134 consecutive ACS patients who met the above inclusion criteria were studied. An oral glucose tolerance test was performed before discharge. RESULTS: The mean age, fasting glucose, and HbA(1c) were 60 years, 5.15 mmol/l, and 5.4%, respectively. Among ACS patients, impaired glucose tolerance (IGT) and diabetes were found in 50 (37%) and 13 patients (10%), respectively. The homeostasis model assessment for insulin resistance did not differ substantially among the normal glucose tolerance (NGT), IGT, and diabetic groups. Insulinogenic index, however, was lower and the number of stenosed vessels higher in diabetic patients compared with NGT patients. CONCLUSIONS: Postchallenge hyperglycemia, caused primarily by impaired initial insulin secretion, is commonly found in Japanese ACS patients who have not been previously diagnosed with diabetes, and this phenomenon is considered to be associated with advanced coronary atherosclerosis. Therefore, the present study strongly supports the notion that oral glucose tolerance test assessment of postchallenge hyperglycemia is essential to identify any previously undiagnosed diabetes cases among Japanese ACS patients.

Evaluation of the cross-bridge-dependent change in the Ca2+ affinity of troponin C in aequorin-injected ferret ventricular muscles.

Ca2+ affinity of cardiac troponin C (TnC) is regulated by the active cross-bridges (downstream-dependent mechanism). In the present study, we showed one of the methods to evaluate the downstream-dependent change in the Ca2+ affinity of TnC during contraction using the aequorin-injected ferret papillary muscle. For this purpose, the tension-dependent change in the extra-Ca2+ (a transient increase in the intracellular Ca2+ concentration ([Ca2+]i) in response to a quick length reduction) was measured under various conditions. We examined whether the regression line between the magnitude of tension reduction and the magnitude of the normalized extra-Ca2+ (the extra-Ca2+ was divided by [Ca2+]i immediately before length change) (the normalized extra-Ca2+-tension relation) in twitch contraction can be used for the estimation of the downstream-dependent change in the Ca2+ affinity of TnC. The normalized extra-Ca2+-tension relation became shallow by EMD 57033 (EMD) (one of the Ca2+ sensitizers) and by an increase in Ca2+ concentration in the solution ([Ca2+]o) in a concentration-dependent manner. However, 2,3-butanedione monoxime (BDM) (one of the desensitizers) antagonized the effects of EMD and higher [Ca2+]o in a concentration-dependent manner. These effects of EMD and BDM were also observed in the normalized extra-Ca2+-tension relation in tetanic contraction. The normalized extra-Ca2+-tension relation became steep by shortening the initial muscle length before contraction in tetanic contraction. Length-tension relation in twitch contraction was significantly shifted upward by higher [Ca2+]o and EMD, but BDM showed the opposite effects on them in a concentration-dependent manner. Thus, the downstream-dependent change in the Ca2+ affinity of TnC which physiologically functions in intact cardiac muscle can be evaluated using the normalized extra-Ca2+-tension relation.

Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts.

To study the cardioprotective effects of vanadate on ischemia-reperfusion (I/R) injury, isolated rat hearts perfused at constant flow were subjected to global ischemia for 30 min followed by reperfusion for 30 min. In this experimental model, I/R markedly decreased ventricular developed pressure and increased end-diastolic pressure. Pretreatment of hearts with 4 microM vanadate attenuated I/R-induced cardiac dysfunction. The reduction in sarcoplasmic reticulum (SR) Ca2+ uptake and Ca2+ release, as well as SR protein contents for Ca2+-pump ATPase and Ca2+-release channel, was also prevented by vanadate. Pretreatment of hearts with an antioxidant mixture containing superoxide dismutase + catalase exerted effects similar to those of vanadate in I/R hearts. Postischemic treatment of hearts with vanadate or superoxide dismutase + catalase also had beneficial effects on I/R-induced changes in cardiac performance and SR function. Alterations in cardiac function and SR Ca2+ transport due to an oxyradical-generating system (xanthine + xanthine oxidase) or an oxidant (H2O2) were attenuated by treatment with vanadate. These results suggest that vanadate may exert beneficial effects on cardiac performance and SR function in I/R hearts because of its antioxidant action.

Effects of bezafibrate on lipoprotein subclasses and inflammatory markers in patients with hypertriglyceridemia--a nuclear magnetic resonance study.

BACKGROUND: Hypertriglyceridemia is often associated with elevated remnants, small dense LDL and decreased HDL-cholesterol (C). The objective of this study was to investigate the efficacy of bezafibrate on lipoprotein subfractions profile and inflammation markers in patients with hypertriglyceridemia. METHODS: Twenty-four hypertriglyceridemic subjects took bezafibrate, 400 mg daily, for 4 weeks. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy. Inflammation markers including C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) were also determined. RESULTS: Bezafibrate lowered triglyceride (TG) by 59% and increased HDL-C by 20%. NMR analysis revealed that bezafibrate lowered large TG-rich lipoproteins and IDL by 81% and 46%, respectively. Small LDL was selectively decreased by 53% with increase in large to intermediate LDL, thus altering the LDL distribution towards the larger particles (mean diameter 19.9 to 20.7 nm, p = 0.0001). Small (HDL1) and intermediate (HDL3) HDL significantly increased by 168% and 70%, whereby resulting in a significant reduction of the mean HDL particle size from 9.0 to 8.7 nm (p = 0.026). None of inflammation makers showed significant change by bezafibrate. CONCLUSIONS: Bezafibrate effectively ameliorates atherogenic dyslipidemia by reducing remnants and small LDL as well as by increasing HDL particles in hypertriglyceridemic subjects.

Atrial pacing failure following termination of atrial fibrillation by acute administration of disopyramide phosphate.

Atrial pacing failure occurred after termination of atrial fibrillation by acute administration of disopyramide phosphate in a 71-year-old woman implanted with an AAI pacemaker for sick sinus syndrome. The atrial pacing threshold showed an 810% increase; however, the serum concentration of disopyramide corresponded to therapeutic level. Infusion of the same dose of disopyramide phosphate used during the period of atrial pacing rhythm did not increase the atrial pacing threshold. In the present patient, we supposed that atrial pacing failure did not occur by the effect of disopyramide alone, but rather was a reciprocal action in response to atrial fibrillation.