Significance of the antioxidant factor,thioredoxin, in heart failure

OBJECTIVES: Increases in oxidative stress may be involved in the progression of heart diseases. However, the serum levels of thioredoxin, a redox regulating protein, have been poorly investigated in patients with heart diseases. This study evaluated the clinical significance of the serum thioredoxin levels in patients with heart failure. METHODS: The serum thioredoxin levels were determined with a sandwich enzyme-linked immunosorbent assay in a total of 34 patients with dilated cardiomyopathy (n = 5), acute coronary syndrome (n = 7), and stable angina (n = 18), including effort angina (n = 7) and vasospastic angina (n = 11), and control subjects (n = 4). RESULTS: The serum thioredoxin levels were significantly elevated in patients with acute coronary syndrome (30.6 +/- 4.9 ng/ml, p < 0.001) and dilated cardiomyopathy (36.9 +/- 8.6 ng/ml, p < 0.001), but not in patients with stable angina (16.8 +/- 5.7 ng/ml, p = 0.27) compared with the control subjects (n = 4, 13.0 +/- 4.9 ng/ml). The serum thioredoxin level in patients with III and IV functional classes of the New York Heart Association (n = 8, 33.3 +/- 8.6 ng/ml, p < 0.001) was significantly higher than in the control subjects. In addition, the serum thioredoxin levels were negatively correlated with left ventricular ejection fractions of the patients (r = 0.59, p < 0.001). CONCLUSIONS: These results indicate a possible association between thioredoxin and the severity of heart failure.     

Enhancement of left ventricular contractility after opening of an arteriovenous fistula in dogs

The effect of opening and closing the infrarenal arteriovenous (A-V) fistula on left ventricular (LV) function was analysed in 12 anaesthetised dogs, instrumented with a micromanometer and a pair of ultrasonic crystals for measurement of LV diameter (D). Plasma noradrenaline (NA) levels sampled from the right ventricular cavity were determined using a high-performance liquid chromatographic method. Immediately after opening of the A-V fistula, the peak LV pressure (P) decreased by 4.3 kPa from the control value of 14.4 kPa and returned to the control level within 30 s. End-diastolic diameter did not significantly change immediately after opening the fistula but then gradually augmented to 28.3 mm, at the stable stage 5 min later. End-systolic diameter was significantly reduced from 22.0 to 20.8 mm immediately after opening and remained reduced until the fistula was closed. The percentage shortening of the LVD increased from 17.1 to 20.1% with the initial fall in LVP, and continued to increase to 26.6% with subsequent enlargement of diameter. With closure of the fistula, a directionally opposite response was observed. The end-systolic P-D relation, obtained by superimposing the series of loops and plotting end-systolic pressure against end-systolic diameter, fell on the single function curve during the initial pressure change, and clearly shifted to the left during the stable stage of volume loading and returned to the control relation with closure of the A-V fistula.2+ leftward shift of the end-systolic P-D relation during the stable stage of volume loading.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of in vivo cardiac hypertrophy with insulin-like growth factor-1 and angiotensin-converting enzyme inhibitor: relationship between change in myosin isoform and progression of left ventricular dysfunction

OBJECTIVES: Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload. BACKGROUND: Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans. METHODS: We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group. RESULTS: After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction. CONCLUSIONS: Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.     

Importance of regurgitant fraction for left ventricular end-systolic wall stress to end-systolic volume ratio in patients with chronic mitral regurgitation

End-systolic wall stress to end-systolic volume index (ESWS/ESVI) ratio is an index of myocardial contractility. In the presence of mitral regurgitation (MR), this ratio may be modified by the unloading effect of a leakage of flow into the low pressure left atrium. Therefore, to evaluate whether or not this ratio is an index of myocardial function in patients with MR, we compared the ratio with conventional measurements of myocardial performance in 11 patients with moderate to severe MR. The ESWS/ESVI ratio was 3.9 +/- 1.6 kdyn/cm5 per m2 in MR and slightly lower than the control value of 4.6 +/- 0.6 kdyn/cm5 per m2. The correlation between ESWS/ESVI ratio and ejection fraction was poor (r = 0.05, p:NS), while there was a close inverse correlation between the ratio and regurgitant fraction (r = 0.76, p less than 0.01). These results strongly suggest that ESWS/ESVI ratio is a better indicator of myocardial function than ejection fraction in MR; however, this ratio could be affected by not only the inotropic state of the ventricle, but also by the extent of mitral regurgitation.     

Efficacy of cibenzoline for chest oppression and ventricular arrhythmia during effort and alcohol consumption in a patient with hypertrophic obstructive cardiomyopathy: a case report

A 67-year-old man presented with chest oppression and palpitation during effort and alcohol consumption. Echocardiography demonstrated asymmetric septal hypertrophy and systolic anterior motion of the anterior mitral leaflet with a pressure gradient of 80 mmHg across the left ventricular outflow tract (LVOT), leading to the diagnosis of hypertrophic obstructive cardiomyopathy. During the treadmill exercise test, blood pressure decreased with electrocardiographic ST-segment depression and subsequent frequent premature ventricular contractions. Holter-electrocardiographic monitoring also showed ST-segment depression with premature ventricular contractions during effort and alcohol consumption. Coronary angiography showed no abnormalities and cardiac catheterization at baseline showed a systolic pressure gradient of only 2 mmHg across the LVOT. However, the gradient increased to 33 mmHg after premature ventricular contraction, 27 mmHg at Valsalva maneuver and 75 mmHg with dobutamine infusion (5 micrograms/kg/min) and disappeared with 70 mg of intravenous cibenzoline. Medication with cibenzoline (300 mg/day) for one month reduced the LVOT gradient at rest to 53 mmHg and strikingly improved symptoms and exercise tolerance and also suppressed premature ventricular contractions during exercise and alcohol consumption. We conclude that cibenzoline was effective for reduction of LVOT gradient both at rest and during exercise and alcohol consumption.     

Characterization and subcellular localization of KCNQ1 with a heterozygous mutation in the C terminus

Numerous mutations in KCNQ1, a gene encoding the alpha -subunit of cardiac delayed rectifier potassium channels, have been found in long QT syndrome (LQTS). Among them, several mutations in the C terminus have been shown to cause autosomal recessive or subclinical autosomal dominant LQTS. Here, we report a heterozygous mutation, T587M, which is also in the KCNQ1 C-terminal domain. The same mutation was found in three independent probands that were clearly symptomatic with family history of cardiac sudden death. Functional assay using a heterologous expression system with a mammalian cell line (COS7 cells) revealed that the mutant displayed neither functional channels when expressed alone nor dominant-negative effect when co-expressed with wild-type (WT) KCNQ1. To examine the cellular trafficking of KCNQ1, green fluorescent protein (GFP) was tagged to the cytoplasmic C terminus of WT or mutant KCNQ1. This procedure did not affect the essential properties of expressed WT KCNQ1 channels. On confocal microscopic images, GFP-tagged WT KCNQ1 showed a plasma membrane fluorescence pattern, whereas the GFP-tagged mutant showed a perinuclear fluorescence pattern. Co-expression of the mutant with GFP-tagged WT KCNQ1 did not influence its normal cellular transport. Therefore, the T587M mutant cannot traffic to the plasma membrane and may form no subunit assembly with WT KCNQ1. These findings provide a novel molecular basis for the clinical finding that this C-terminal mutation produced a severe form of RWS-type LQTS.     

Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor–dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate–dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.     

Evaluating Relative Chain Orientation of Amylose and Poly(l‐lactide) in Inclusion Complexes Formed by Vine‐Twining Polymerization Using Primer–Guest Conjugates

The relative chain orientation of amylose and poly(l ‐lactide) (PLLA) in inclusion complexes formed by phosphorylase‐catalyzed enzymatic polymerization is made clear, by using primer–guest conjugates according to a vine‐twining polymerization manner. The conjugates, which have a maltoheptaosyl moiety at COOH‐ or OH‐terminus of poly(l ‐ and d ‐lactide)s, are synthesized by copper(I)‐catalyzed click chemistry using propargyl‐terminated polylactides (PLAs) and maltoheptaosyl azide. The cavity of amylose includes PLLA, regardless of the chain orientation, when the conjugates composed of PLLA are used on the vine‐twining polymerization. On the other hand, amylose–poly(d ‐lactide) (PDLA) diblock copolymers, which are noninclusion products, are produced when the conjugates composed of PDLA are used. X‐ray diffraction (XRD) patterns of products and gel permeation chromatography (GPC) analyses of their alkaline hydrolysates strongly support that the amylose‐PLLA inclusion supramolecular polymers are produced, probably owing to the same helical direction of amylose as that of PLLA, which is responsibly induced by its chirality, regardless of the chain orientation on complexation.