Assessment of elevation of and rapid change in left ventricular filling pressure using a novel global strain imaging diastolic index.

BACKGROUND: The aim of this study was to determine whether global strain imaging diastolic index (SIDI) obtained using 2-D speckle tracking imaging (2DSI) could predict elevation in and rapid change of LV filling pressure. METHODS AND RESULTS: Patients (n=126) underwent echocardiography and 2DSI during simultaneous cardiac catheterization. There were 60 patients in whom the same measurements were repeated 5min after i.v. glyceryl trinitrate. LV pre-atrial contraction pressure (pre-A) was measured as a surrogate of LV filling pressure. SIDI was defined as the change of LV longitudinal strain measured using 2DSI during the first one-third of diastole. Then, longitudinal global SIDI (L-global SIDI) was calculated as the mean SIDI of 18 LV segments. Mitral inflow and tissue Doppler imaging were also assessed. Among 126 patients, 93 patients had LV pre-A ≥15mmHg. L-global SIDI had a better correlation with LV pre-A (P<0.001, r=-0.56) than E/e' (P<0.01, r=0.35). On receiver operating characteristic curve analysis, L-global SIDI <0.48 was the optimum cut-off to predict LV pre-A ≥15mmHg (sensitivity, 82%; specificity, 68%). In addition, the ratio of L-global SIDI (after nitrate/before nitrate) was correlated with the ratio of LV pre-A (after nitrate/before nitrate; P=0.02, r=-0.34). CONCLUSIONS: A novel L-global SIDI derived from 2DSI may reflect elevated LV filling pressure and its rapid change better than conventional diastolic parameters.

Prognostic value of coronary flow reserve assessed by transthoracic Doppler echocardiography on long-term outcome in asymptomatic patients with type 2 diabetes without overt coronary artery disease.

BACKGROUND: Cardiovascular risk stratification of asymptomatic diabetic patients is important and remains a difficult clinical problem. Our aim was to test the hypothesis that coronary flow reserve (CFR) assessed by noninvasive transthoracic Doppler echocardiography predicts prognosis in those patients. METHODS: From February 2002 to January 2005, we evaluated 135 consecutive asymptomatic patients (74 male; mean age, 63 ± 9 years) with type 2 diabetes without a history of coronary artery disease. Adenosine triphosphate (0.14 mg/kg/min) stress Doppler echocardiography was performed to evaluate CFR of the left anterior descending artery. Patients with a CFR < 2.0 were also excluded based on the suspicion of significant coronary artery stenosis in the left anterior descending artery. RESULTS: There were 111 patients (60 male; mean age, 64 ± 9 years) enrolled. During a median follow-up of 79 months, 20 events (5 deaths, 7 acute coronary syndromes, 8 coronary revascularizations) occurred. The optimal cut-off value of CFR to predict events was 2.5 (area under the receiver-operating characteristic curve = 0.65). Multivariate analysis showed that the independent prognostic indicators were male gender (p < 0.05) and a CFR < 2.5 (p < 0.01). Kaplan-Mayer analysis revealed that the event rate was significantly higher (log-lank, p < 0.01) in patients with CFR < 2.5 than in those with CFR ≥ 2.5. CONCLUSIONS: CFR obtained by transthoracic Doppler echocardiography provides independent prognostic information in asymptomatic patients with type 2 diabetes without overt coronary artery disease. Patients with CFR < 2.5 had a worse long-term outcome.

Prediction of coronary artery stenosis at rest in patients with normal left ventricular wall motion. Segmental analyses using strain imaging diastolic index.

Noninvasive detection of coronary artery stenosis usually requires a stress test in patients without left ventricular (LV) regional wall motion abnormalities (RWMA). In contrast, abnormal regional LV relaxation caused by ischemia may persist beyond recovery from transient ischemia. The aim of the present study was to determine whether segmental analysis of abnormal regional LV relaxation using the strain imaging diastolic index (SI-DI) at rest could predict coronary artery stenosis in the three major vessels in patients without LV dysfunction or RWMA. We performed 2D speckle tracking echocardiography and coronary angiography in 85 patients without RWMA with suspected coronary artery disease. Patients with LV dysfunction or acute coronary syndrome were excluded. Echocardiographic images of the LV were obtained in the apical 2-, 3-, and 4-chamber views and divided into 6 segments. In each segment, SI-DI derived from transverse strain imaging was determined. Forty-eight patients had significant coronary artery stenosis (≥ 70%). The optimal cutoff values of SI-DI were 60.5% in the mid anteroseptal segment for detecting left anterior descending artery stenosis (sensitivity, 83.3%; specificity, 81.1%), 60.5% in the basal anterolateral segment for detecting left circumflex artery stenosis (sensitivity, 80.9%; specificity, 90.3%), and 61.5% in the basal inferior segment for detecting right coronary artery stenosis (sensitivity, 74.1%; specificity, 77.8%). A segmental analysis of SI-DI at rest predicted coronary artery stenosis in the three major vessels in patients without RWMA. This noninvasive method may be useful for detecting coronary artery stenosis without a stress test.

A case report of pulmonary artery intimal sarcoma negative for 18F-FDG mimicking pulmonary thromboembolism.

Background: Pulmonary artery sarcoma is a rare malignant neoplasm arising from intimal mesenchymal cells in the pulmonary artery wall and is often difficult to differentiate from pulmonary embolism, however, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be useful for a differential diagnosis. Here, we present a rare case of pulmonary sarcoma undetectable by PET. Case summary: A 77-year-old woman who had worsening dyspnoea on effort for a month and progressive chest discomfort with nocturnal cough for a week presented to our hospital. Contrast-enhanced computed tomography (CT) demonstrated a massive filling defect in the left pulmonary artery (PA). Two major differential diagnoses were considered; pulmonary thromboembolism and tumour-like lesions. Positron emission tomography-computed tomography (PET-CT) revealed that there was no abnormal accumulation of 18F-FDG in the mass. However, even after effective anti-thrombotic treatment for 3 weeks, a follow-up CT showed no reduction at all in the size of the lesion in the pulmonary artery. Therefore, surgery for diagnostic therapeutic purposes was performed. Discussion: The present case is informative because it supports the idea that being aware of PA angiosarcoma as a potential differential diagnosis of pulmonary thromboembolism is essential, particularly in cases of no evident peripheral venous thrombosis and a negative D-dimer test, even if neither heterogenous contrast enhancement in CT and magnetic resonance imaging nor accumulation of 18-FDG in PET-CT is evident.

Atypical Shone's Complex Diagnosed at 70 Years Old: Presenting with Double-orifice Mitral Valve, Bicuspid Aortic Valve, and Aortic Coarctation.

Atypical Shone's complex is a rare congenital anomaly involving a left-sided obstructive lesion of two or three cardiovascular levels. A 70-year-old man with dyspnea on exertion was diagnosed with severe aortic stenosis (AS) with a bicuspid valve, complicated by severe aortic coarctation (CoA) and a double-orifice mitral valve. He underwent surgery for AS and CoA in one session. It is important to search for complicated malformations, even in cases of bicuspid aortic valve found in old age.

Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function--a crossover trial (AGENT).

BACKGROUND: Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice. METHODS: Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT. RESULTS: Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016). CONCLUSIONS: These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

Different responses to oxidized low-density lipoproteins in human polarized macrophages.

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) uptake by macrophages plays an important role in foam cell formation. It has been suggested the presence of heterogeneous subsets of macrophage, such as M1 and M2, in human atherosclerotic lesions. To evaluate which types of macrophages contribute to atherogenesis, we performed cDNA microarray analysis to determine oxLDL-induced transcriptional alterations of each subset of macrophages. RESULTS: Human monocyte-derived macrophages were polarized toward the M1 or M2 subset, followed by treatment with oxLDL. Then gene expression levels during oxLDL treatment in each subset of macrophages were evaluated by cDNA microarray analysis and quantitative real-time RT-PCR. In terms of high-ranking upregulated genes and functional ontologies, the alterations during oxLDL treatment in M2 macrophages were similar to those in nonpolarized macrophages (M0). Molecular network analysis showed that most of the molecules in the oxLDL-induced highest scoring molecular network of M1 macrophages were directly or indirectly related to transforming growth factor (TGF)-ß1. Hierarchical cluster analysis revealed commonly upregulated genes in all subset of macrophages, some of which contained antioxidant response elements (ARE) in their promoter regions. A cluster of genes that were specifically upregulated in M1 macrophages included those encoding molecules related to nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. Quantitative real-time RT-PCR showed that the gene expression of interleukin (IL)-8 after oxLDL treatment in M2 macrophages was markedly lower than those in M0 and M1 cells. HMOX1 gene expression levels were almost the same in all 3 subsets of macrophages even after oxLDL treatment. CONCLUSIONS: The present study demonstrated transcriptional alterations in polarized macrophages during oxLDL treatment. The data suggested that oxLDL uptake may affect TGF-ß1- and NF-κB-mediated functions of M1 macrophages, but not those of M0 or M2 macrophages. It is likely that M1 macrophages characteristically respond to oxLDL.

Single administration of alpha-glucosidase inhibitors on endothelial function and incretin secretion in diabetic patients with coronary artery disease - Juntendo University trial: effects of miglitol on endothelial vascular reactivity in type 2 diabetic patients with coronary heart disease (J-MACH) -.

BACKGROUND: Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on alpha-glucosidase inhibitors (alpha-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of alpha-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear. METHODS AND RESULTS: The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P<0.01). GLP-1 levels were significantly higher at 120 min (P<0.05) and GIP levels were significantly lower at 30 min and 60 min (P<0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups. CONCLUSIONS: A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).

Estrogen variation during the menstrual cycle does not influence left ventricular diastolic function and untwisting rate in premenopausal women.

BACKGROUND: Although a cardioprotective effect of estrogen has been suggested by experimental studies, clinical data on the influence of estrogen on left ventricular (LV) diastolic function are sparse. The LV untwisting rate obtained by 2D speckle tracking echocardiography (2D-STE) is correlated with the time constant of LV pressure decay (tau), and this correlation is independent of left atrial pressure. Therefore, we used conventional Doppler echocardiography and 2D-STE to investigate changes in LV diastolic function during a single menstrual cycle in premenopausal women. METHODS: Twenty healthy premenopausal woman (mean age, 28.1±2.7 years) were enrolled. Clinical and echocardiographic data were obtained during the follicular phase (F-phase) and luteal phase (L-phase) of a single menstrual cycle. We compared the clinical and echocardiographic data, and estrogen levels between the two phases. RESULTS: There were no significant differences in LV diastolic parameters derived from Doppler echocardiography (E/A, p=0.295; E/e', p=0.449, DcT, p=0.178) or 2D-STE (peak untwisting rate, p=0.892; time-to-peak untwisting, p=0.951) between the two phases of the menstrual cycle. However, there was a significant decrease in estrogen levels between the F- and L-phases (177±119pg/ml vs. 35±12pg/ml, p<0.0001). CONCLUSIONS: LV diastolic function in healthy premenopausal women did not significantly change during the menstrual cycle. Estrogen does not appear to have a significant acute effect on LV diastolic function in premenopausal woman.

High levels of very long-chain saturated fatty acid in erythrocytes correlates with atherogenic lipoprotein profiles in subjects with metabolic syndrome.

AIM: Very long chain saturated fatty acid (VLCFA) levels in erythrocytes are associated with metabolic syndrome (MS). However, the relationship between levels of the VLCFA ligonoceric acid (C24:0) in erythrocytes and the atherogenic lipoprotein profiles and inflammatory state in MS remain unclear. METHODS: Based on the International Diabetes Federation (IDF) definition of MS, 195 apparently healthy males were assigned to either an MS group (n=38) or a non-MS group (n=157). Fatty acid composition of erythrocytes was determined by gas liquid chromatography. RESULTS: Erythrocytes from the MS group had a significantly higher level of C24:0 than cells from the non-MS group (4.06±0.48% versus 3.88±0.34%; p=0.03). C24:0 levels were significantly correlated with several components of MS. The C24:0 levels showed a significant negative correlation with LDL and HDL particle size. Multivariate linear regression analysis showed that C24:0 levels were independently correlated with LDL particle size after adjusting for age and each MS criterion. C24:0 levels were also positively correlated with log-transformed high-sensitivity CRP levels (p=0.04). CONCLUSION: C24:0 levels in erythrocytes are associated with specific atherogenic lipoprotein profiles and inflammation status in subjects with MS.

Clinical significance of the measurements of urinary liver-type fatty acid binding protein levels in patients with acute coronary syndrome.

BACKGROUND: Recently, much attention has been focused on cardio-renal interaction. Urinary liver-type fatty acid binding protein (U-L-FABP), which is produced in the proximal tubule by renal hypoxia and oxidative stress, has been identified as a useful marker for diagnosis of acute kidney disease and a predictor of future events in chronic kidney disease. However, the clinical significance of U-L-FABP measurements in patients with acute coronary syndrome (ACS) has not been completely evaluated. METHODS AND RESULTS: This study included 50 consecutive patients with ACS [37 with acute myocardial infarction (AMI) and 13 with unstable angina pectoris (UAP)] and 47 subjects without coronary artery disease (control group). U-L-FABP levels, urinary albumin (U-Alb), and other serum parameters were measured at admission and at 24 h after percutaneous coronary intervention. RESULTS: U-L-FABP levels in patients with AMI were significantly higher (p=0.0019), than in control subjects, while patients with UAP did not exhibit such an increase. U-L-FABP levels at admission were positively correlated with brain natriuretic protein levels (p=0.001) and duration of hospitalization (p=0.025). At follow-up angiography, patients with restenosis had significantly higher U-L-FABP (p=0.047) and U-Alb levels (p<0.0001) than those without restenosis. After a median follow-up of 42 months, U-L-FABP levels at second measurement in patients with major adverse cardiocerebrovascular events (MACCEs) were significantly higher than those in patients without MACCEs (p=0.028). After adjusting for confounding factors, high U-L-FABP levels at second measurement were found to be independent factors for MACCEs (p=0.019). CONCLUSIONS: These data suggest that patients with ACS, especially those with AMI, have high U-L-FABP levels, and that U-L-FABP measurements may be useful in identifying high-risk patients for future cardiovascular events after ACS.

Involvement of cholesterol-enriched microdomains in class A scavenger receptor-mediated responses in human macrophages.

OBJECTIVE: Lipid rafts are cholesterol-enriched microdomains on cell membranes. We hypothesized that these microdomains could involve modified low-density lipoprotein (LDL) uptake. METHODS AND RESULTS: Co-localizations of cholesterol-enriched microdomains and CD204 during the uptake of acetyl LDL (AcLDL) and oxidized LDL were observed using Alexa488-labeled polyethylene glycol cholesteryl ester, which is a sensitive probe used to analyze the dynamics of cholesterol-rich lipid microdomains in living cells. The lipid raft disruptors, methyl-ß cyclodextrin and filipin, inhibited the uptake of AcLDL. CD204 siRNA treatments significantly reduced AcLDL uptake by 80%. We also demonstrated the presence of CD204 in the detergent-resistant membrane fraction (DRM) by immunoblotting analysis. The ratio of CD204/flotillin-1 in DRM was increased 11.5-fold by modified LDL administration. The PI3 kinase inhibitor LY294002, but not the Src kinase inhibitor PP1 or the Gαi/o inhibitor pertussis toxin, inhibited modified LDL uptake. The production of interleukin (IL)-8, but not CCL2, CXCL2, CXCL3, IL-6 or tumor necrosis factor-α was increased by AcLDL administration. The AcLDL-induced IL-8 production was inhibited by LY294002 and filipin. CONCLUSIONS: These data firstly demonstrated that PI3 kinase-associated cholesterol-enriched microdomains are involved in CD204-mediated modified LDL uptake in human macrophages. Cholesterol-enriched microdomains may play a critical role in inflammatory processes.

Clinical significance of the measurements of plasma N-terminal pro-B-type natriuretic peptide levels in patients with coronary artery disease who have undergone elective drug-eluting stent implantation.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a diagnostic biomarker for patients with congestive heart failure (CHF). However, the clinical significance of measurements of NT-proBNP levels in patients with coronary artery disease (CAD) who have undergone drug-eluting stent (DES) implantation has not been fully elucidated. METHODS AND RESULTS: We recruited 280 patients with documented CAD who were scheduled for elective coronary intervention and also age- and gender-matched 140 healthy subjects. Subjects with acute coronary syndrome, ongoing CHF, and stage IV or V chronic kidney disease were excluded. We measured the plasma NT-proBNP levels and followed the CAD patients who have undergone DES implantation for up to 62 months until occurrence of major adverse cardiovascular events (MACE). Plasma NT-proBNP levels were significantly higher in CAD patients compared to control subjects (p<0.0001). In the CAD group, 25 patients developed MACE and the NT-proBNP levels in the MACE group were significantly higher compared to that in the non-MACE group (p=0.005). After adjusting for the confounding factors, high NT-proBNP levels were observed to be independent factors for CAD (p<0.0001) and MACE (p=0.021). CONCLUSIONS: These results demonstrated that the measurements of NT-proBNP levels may be useful in identifying high-risk subjects among CAD patients who have undergone elective DES implantation.

Voluntary exercise ameliorates the progression of atherosclerotic lesion formation via anti-inflammatory effects in apolipoprotein E-deficient mice.

AIM: A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood. METHODS AND RESULTS: Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p<0.001). There was a strong negative correlation between atherosclerotic areas and the mean running distance per day in the HFD+Ex group (r=-0.90, p=0.01). Endothelial function was significantly preserved in the HFD+Ex group (p<0.05). Serum interleukin-6 and macrophage chemoattractant protein-1 levels were significantly lower and those of adiponectin were significantly higher in the HFD+Ex group than in the HFD group (p<0.05). CONCLUSIONS: These results suggest that Ex ameliorates the progression of endothelial dysfunction and atherosclerotic lesion formation through anti-inflammatory effects, despite continued consumption of HFD.

Polyunsaturated fatty acid levels of serum and red blood cells in apparently healthy Japanese subjects living in an urban area.

AIM: We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area. METHODS: We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3+/-9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1 <35y, G2 35y-<45y, G3 45y-<55y, G4 55y-<65y, G5>or=65y). RESULTS: No significant differences in EPA, DHA, AA, or EPA/AA were observed between males and females. After dividing into generations, stepwise increases in EPA and DHA, but not DGLA or AA, were observed in serum (all p<0.0001). EPA/AA ratios were stepwisely increased in serum (mean: G1:0.26, G2:0.29, G3:0.43, G4:0.58, G5:0.68, p<0.0001) and RBCs (mean: G1:0.10, G2:0.09, G3:0.15, G4:0.20, G5:0.23, p<0.0001). Positive correlations of EPA (r=0.83), DHA (r=0.55), DGLA (r=0.54), AA (r=0.29), and EPA/AA (r=0.91) were demonstrated between serum and RBCs. In addition, a significant positive correlation between EPA/AA ratios and insulin sensitivity as well as a negative correlation between those ratios and insulin resistance were observed in subjects with metabolic syndrome. CONCLUSION: Low levels of EPA/AA, which were associated with insulin resistance, were demonstrated in young Japanese adults living in an urban area.