Association of free fatty acid binding protein with central aortic stiffness, myocardial dysfunction and preserved ejection fraction heart failure.

There is an established link between cardiometabolic abnormality, central arterial stiffness, and preserved ejection fraction heart failure (HFpEF). Adipocyte free fatty acid binding protein (a-FABP) has been shown to signal endothelial dysfunction through fatty acid toxicity, though its role in mediating ventricular-arterial dysfunction remains unclear. We prospectively examined the associations of a-FABP with central arterial pressure using non-invasive applanation tonometry (SphygmoCor) and cardiac structure/function (i.e., tissue Doppler imaging [TDI] and global longitudinal myocardial strain [GLS]) in patients with cardiometabolic (CM) risk (n = 150) and HFpEF (n = 50), with healthy volunteers (n = 49) serving as a control. We observed a graded increase of a-FABP across the healthy controls, CM individuals, and HFpEF groups (all paired p < 0.05). Higher a-FABP was independently associated with higher central systolic and diastolic blood pressures (CSP/CPP), increased arterial augmentation index (Aix), lower early myocardial relaxation velocity (TDI-e'), higher left ventricle (LV) filling (E/TDI-e') and worsened GLS (all p < 0.05). During a median of 3.85 years (interquartile range: 3.68-4.62 years) follow-up, higher a-FABP (cutoff: 24 ng/mL, adjusted hazard ratio: 1.01, 95% confidence interval: 1.001-1.02, p = 0.04) but not brain natriuretic peptide, and higher central hemodynamic indices were related to the incidence of heart failure (HF) in fully adjusted Cox models. Furthermore, a-FABP improved the HF risk classification over central hemodynamic information. We found a mechanistic pathophysiological link between a-FABP, central arterial stiffness, and myocardial dysfunction. In a population with a high metabolic risk, higher a-FABP accompanied by worsened ventricular-arterial coupling may confer more unfavorable outcomes in HFpEF.

Carotid arterial mechanics as useful biomarker of extracellular matrix turnover and preserved ejection fraction heart failure.

AIMS: We aimed to investigate the functional alterations, diagnostic utilization, and prognostic implication of carotid arterial deformations in subjects with cardiovascular risk factors and heart failure (HF) with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Among 251 prospectively participants (mean age 66.0 ± 9.8 years, 65.7% female) in a single centre between December 2011 and September 2014, carotid artery deformations including circumferential strain (CCS)/strain rate and radial strain were analysed by two-dimensional speckle tracking. We further related these carotid artery deformation indices to HF biomarkers and cardiac structure and function by echocardiography and explored their prognostic values. Significant reductions of CCS, circumferential strain rate, and circumferential radial strain were observed across control (n = 52), high risk (n = 147), and HFpEF (n = 52) (trend P ≤ 0.001). Aging, hypertension, HFpEF, and higher pulse rate showed independent associations with reduced CCS by stepwise multivariate regressions (all P < 0.05). Higher CCS was inversely associated with better cardiac remodelling and functional indices, and lower multiple HF biomarkers (all P ≤ 0.005). After adjustment, higher CCS was independently associated with better global ventricular longitudinal strain/early diastolic strain rate, lower matrix metalloproteinase-2, and N-terminal propeptide of procollagen type III levels (adjusted coef: -0.08 and -19.9, all P < 0.05). During a median follow-up of 1406 days (interquartile range: 1342-1720 days), CCS less than 3.28% as a cut-off had markedly higher HF events [Harrell's C: 0.72, adjusted HR: 2.20 (95% confidence interval: 1.24, 3.16), P = 0.008]. CCS also showed significantly improved risk prediction for HF over global ventricular longitudinal strain (net reclassification index: 48%, P = 0.001; integrated discrimination improvement: 1.8%, P < 0.001). CONCLUSIONS: Carotid artery deformations using two-dimensional speckle-tracking imaging showed novel mechanistic insights on functional arterial alterations reflecting coupled arterial-ventricular pathophysiology. Utilization of such measure may further provide additive prognostic value to advanced myocardial functional assessment.

Segmental arterial stiffness in relation to B-type natriuretic peptide with preserved systolic heart function.

BACKGROUND: Central arterial stiffness has been shown to play a key role in cardiovascular disease. However, evidence regarding such arterial stiffness from various arterial segments in relation to B-type natriuretic peptide (BNP) remains elusive. METHODS: A total of 1255 participants (47.8% men; mean age: 62.6 ± 12.3 [SD] years) with preserved left ventricular function (ejection fraction ≥50%) and ≥1 risk factors were consecutively studied. Arterial pulse wave velocity (PWV) by automatic device (VP-2000; Omron Healthcare) for heart-femoral (hf-PWV), brachial-ankle (ba-PWV), and heart-carotid (hc-PWV) segments were obtained and related to BNP concentrations (Abbott Diagnostics, Abbott Park, IL, USA). RESULTS: Subjects in the highest hf-PWV quartile were older and had worse renal function and higher blood pressure (all P < 0.05). Elevated PWV (m/s) was correlated with elevated BNP (pg/ml) (beta coefficient = 19.3, 12.4, 5.9 for hf-PWV, ba-PWV, hc-PWV respectively, all p < 0.05). After accounting for clinical co-variates and left ventricle mass index (LVMI), both hf-PWV and ba-PWV were correlated with higher BNP (beta coefficient = 8.3, 6.4 respectively, P < 0.01 for each). Adding both hf-PWV and ba-PWV to LVMI significantly expanded ROC in predicting abnormal BNP>100 pg/ml (both P < 0.01), but only hf-PWV presented significant integrated discrimination improvement to predict risk for BNP concentrations (0.7%, P = 0.029). CONCLUSION: A significant segmental PWV associated with biomarker BNP concentrations suggests that arterial stiffness is associated with myocardial damage.

Gender-differences in the associations between circulating creatine kinase, blood pressure, body mass and non-alcoholic fatty liver disease in asymptomatic asians.

BACKGROUND: Creatine kinase (CK) is a pivotal regulatory enzyme in energy metabolism linked to both blood pressure and cardio-metabolic components. However, data is lacking in a large population of asymptomatic Asians. METHODS AND RESULTS: Cardio-metabolic assessment including anthropometric measures and non-alcoholic fatty liver disease (NAFLD) were evaluated by abdominal echo in 4,562 consecutive subjects who underwent an annual health survey. Serum CK levels were related to blood pressure components [systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP)], anthropometric measures, and excessive adiposity in liver as indicated by NAFLD. Circulating CK levels ranged from 4 to 1842 IU/L (mean [SE]: 108.7 [1.1] IU/L) in the study population which consisted of 2522 males (mean age: 48.7 ± 11.2) and 2040 females (mean age: 49.4±11.5). In general, male subjects presented with higher circulating CK levels than females (mean ± SE: 127.3 ± 1.5 vs. 85.5 ± 1.3 IU/L, respectively, p < .001). Gender-differences in circulating CK levels were also observed with increasing age, which showed a more pronounced positive relationship with age in female subjects (gender interaction: p < .05). Furthermore, an elevated circulating CK level was independently associated with higher blood pressure, waist circumference and fat mass (FM), greater body mass index (BMI), increased lower estimated glomerular filtration rate (eGFR) and presence of NAFLD in multivariate analysis (all p < .05), with CK elevation more pronounced with greater BMI and FM in males compared with females (sex interaction: p < .05). CONCLUSION: In a large asymptomatic Asian population, circulating CK levels were increased with more advanced age, higher blood pressure, and greater body mass with gender differences. Our findings may be useful in interpreting elevated CK from subjects free of ongoing myocardial damage.

Phosphoinositide 3-kinase ß, phosphoinositide 3-kinase δ, and phosphoinositide 3-kinase γ mediate the anti-inflammatory effects of magnesium sulfate.

BACKGROUND: We previously demonstrated that inhibiting phosphoinositide 3-kinase (PI3K) or activating L-type calcium channels blocked the anti-inflammatory effects of magnesium sulfate (MgSO4). However, the question as which class I PI3K isoform (PI3Kα, PI3Kß, PI3Kδ, or PI3Kγ) is involved in this regard remains unstudied. The question as whether MgSO4 and L-type calcium channels interact to influence PI3K activation also remains unstudied. We therefore designed this study to test two hypotheses: (1) inhibiting PI3Kα, PI3Kß, PI3Kδ, or PI3Kγ would block the anti-inflammatory effects of MgSO4 and (2) activating L-type calcium channels would block the effects of MgSO4 on activating PI3K. MATERIALS AND METHODS: PI3K isoform investigation: macrophages (RAW264.7 cells) were treated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus the selective inhibitor of PI3Kα (PIK-75), PI3Kß (TGX-221), PI3Kδ (IC-87114), or PI3Kγ (AS-252424). Calcium channel investigation: macrophages were treated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus the L-type calcium channel activator BAY-K8644. RESULTS: The endotoxin plus MgSO4 group presented lower concentrations of inflammatory mediators (macrophage inflammatory protein 2, tumor necrosis factor α, and interleukin 6, lower nuclear concentration of phosphorylated nuclear factor κB, lower cytosolic concentration of phosphorylated inhibitor κBα, and higher concentration of phosphorylated Akt (PI3K activation marker) than the endotoxin group (all P < 0.05). These effects of MgSO4 were significantly reduced by TGX-221, IC-87114, or AS-252424, but not PIK-75. Additionally, BAY-K8644 blocked the effect of MgSO4 on activating PI3K. CONCLUSIONS: MgSO4 exerts its anti-inflammatory effects through activating PI3Kß, PI3Kδ, and PI3Kγ. The underlying mechanism appears to involve inhibition of L-type calcium channels.

Angiotensin Receptor Blockades Effect on Peripheral Muscular and Central Aortic Arterial Stiffness: A Meta-Analysis of Randomized Controlled Trials and Systematic Review.

BACKGROUND: Previous clinical trials have demonstrated the impact of blocking upstream renin-angiotensin-axis with angiotensin converting enzyme inhibitors (ACEIs) on arterial stiffness as evaluated by pulse-wave velocity (PWV). We ran a meta-analysis to evaluate the anti-stiffness effect of powerful downstream angiotensin receptor blockades (ARBs) on peripheral and central arterial stiffness (brachial to ankle, ba-PWV; carotid to femoral, cf-PWV, respectively), using a systematic review to assess the clinical arterial stiffness issues. METHODS: For our study, we searched the PubMed and Cochrane Library databases from inception to June 2013, targeting randomized controlled trials. ARBs along with other antihypertensive agents, ACEIs, calcium channel blockers (CCBs), beta-blockers and diuretics were evaluated to ascertain their comparable effect on ba-PWV and cf-PWV, respectively. A meta-analysis was conducted utilizing the fixed or random effect of the weighted mean change difference between the ARB and comparator groups, depending on the I(2) statistic heterogeneity measurement. RESULTS: In 2 trials treating patients with ARBs (n = 30), the ARBs insignificantly reduced levels of ba-PWV (pooled mean change difference -188, 95% CI -687, 311, p = 0.24 with significant heterogeneity) as compared to other hypertensive agents (ACEIs and CCBs, n = 77). Interestingly, ARBs (n = 20) had a superior capacity to reduce levels of ba-PWV than CCBs (n = 20) in single study results (mean change difference -400, 95% CI -477, -322, p < 0.05). In 7 trials which included a total of 653 patients, treatment with ARBs (n = 308) also insignificantly reduced cf-PWV (pool mean change difference -0.197, 95% CI -0.54, 0.14, p = 0.218) as compared to other anti-hypertensive agents. CONCLUSIONS: Our data suggested that ARBs had a similar effect as other anti-hypertensive agents in reducing ba-PWV and cf-PWV. Upon systematic review, the renin-angiotensin-axis system mechanism seems more significant than the direct vessel dilatation system in anti-arterial stiffness mechanism. KEY WORDS: Angiotension receptor blockage; Arterial stiffness; Meta-analysis; Systematic review.

Comparison of invasive pneumococcal disease caused by serotype 19A and non-19A pneumococci in children: more empyema in serotype 19A invasive pneumococcal disease.

OBJECTIVE: To delineate whether serotype 19A invasive pneumococcal disease (IPD) comprised significantly more necrotizing pneumonia and empyema in children, we compared the clinical characteristics between serotype 19A and non-19A IPD. METHODS: Between January 2007 and December 2011, cases of children with IPD who were treated at the National Taiwan University Hospital were reviewed. Patients were assigned to the 19A group or the non-19A group based on the serotype. Their demographic data, clinical course, laboratory results, diagnosis, complications, and sequelae were collected and analyzed. RESULTS: Overall, 27 patients were included in the 19A group and 29 patients in the non-19A group. Compared with non-19A group, serotype 19A tended to cause IPD in patients without major underlying diseases (p = 0.015). Bacteremia without pneumonia or meningitis was found more frequently in the non-19A group (45% vs. 11%, p = 0.01), and pneumonia with or without empyema occurred significantly more frequently in the 19A group (89% vs. 52%, p = 0.006). Patients in the19A group had longer duration of fever (12 vs. 3 days, p = 0.01), and required more intensive care (78% vs. 41%, p = 0.01) and more video-assisted thoracoscopic surgery (74% vs. 28%, p = 0.001). CONCLUSION: In comparison with the other serotypes, serotype 19A IPD has significantly more empyema which required more video-assisted thoracoscopic surgery and more intensive care.

Multiplexed immunoassay: quantitation and profiling of serum biomarkers using magnetic nanoprobes and MALDI-TOF MS.

Taking advantage of efficient affinity extraction by surface-functionalized magnetic nanoparticles (MNPs) and accurate MALDI-TOF MS readout, we present a multiplexed immunoassay for simultaneous enrichment and quantitation of multiple disease-associated antigens, serum amyloid A (SAA), C-reactive protein (CRP), and serum amyloid P (SAP) from human serum. To obtain reproducible MALDI signal response with direct on-MNP detection, the seed-layer method improved homogeneity of the cocrystallization of MNPs and captured antigens. Our methodology demonstrated good quantitation linearity of targeted analytes (R(2) approximately 0.97) with reduced signal variation (RSD < 10%). The lower limit of quantitation is in the nanogram level with overall assay precision (intraday, 7.0%; interday, 11.3%) and accuracy (intraday, 6.3%; interday, 17.5%) including steps of nanoprobe extraction and MALDI-TOF MS analysis. This triplexed immunoassay showed overexpression of SAA and CRP in patients with cardiac catheterization or gastric cancer (P < 0.05), consistent with single-analyte ELISA and previous studies. Compared to the determination of disease onset by single protein quantitation, our multiplexed immunoassay revealed a distinct triplexed pattern in the control group, patients with gastric cancer, and cardiac catheterization. On the basis of the advantages of flexibility in nanoprobe preparation, high specificity and sensitivity, and rapid screening by MALDI-TOF MS, this platform may provide a new methodology for disease diagnosis.

Inhibition of toll-like receptor-4, nuclear factor-kappaB and mitogen-activated protein kinase by lignocaine may involve voltage-sensitive sodium channels.

We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-kappaB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 micromol/L), LPS + tetrodotoxin (TTX; 1 micromol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 micromol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. We found that LPS significantly increased the concentrations of TLR-4, NF-kappaB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-kappaB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-kappaB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.

Torsade de pointes in severe aortic stenosis: case report.

Aortic stenosis (AS) can develop in a congenitally bicuspid aortic valve, or as the result of an age-related calcific degenerative disease process. Although sudden death occurs in about 20% of patients dying of AS, the mechanisms involved are not well documented. The case is reported of a 67-year-old man who experienced progressive dyspnea and persistent chest tightness for over 60 min after mountain climbing. Cardiac catheterization revealed patent coronary arteries; however, the man had severe AS. On the third day after hospital admission, he experienced a sudden loss of consciousness at the same time that torsade de pointes was recorded on the electrocardiogram. The patient was defibrillated and his vital signs restored. The corrected QT interval (QTc) prolongation seen on admission decreased toward normal after aortic valve replacement. Although the mechanism of sudden cardiac death in severe AS patients remains unclear, ventricular arrhythmia-related syncope may play a role.

Vasodilatation induced by sinomenine lowers blood pressure in spontaneously hypertensive rats.

1. Sinomenine is an alkaloid with a wide range of pharmacological actions. In the present study, we investigated the effect of sinomenine on blood pressure and its possible mechanisms of action. 2. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were given intraperitoneal injections of sinomenine. At 30 min, 2.5-10 mg/kg sinomenine decreased systolic blood pressure (SBP) in a dose-dependent manner in SHR, but had no effect on the SBP in WKY rats. 3. The vascular effect of sinomenine was then examined in aortic rings isolated from Wistar rats. Sinomenine (0.1-10 micromol/L) produced concentration-dependent relaxation in aortic rings precontracted with phenylephrine (10 nmol/L) or KCl (40 mmol/L). Glibenclamide (1-100 micromol/L), a specific inhibitor of ATP-sensitive K(+) channels attenuated the sinomenine-induced relaxation, but this effect was not observed when inhibitors of other types of K(+) channels were used. 4. We further investigated the effects of sinomenine on changes in intracellular Ca(2+) concentrations ([Ca(2+)](i)) in cultured aortic smooth muscle (A7r5) cells by using the Ca(2+)-sensitive dye fura-2 as an indicator. Sinomenine, over the concentration range 0.1-10 micromol/L, decreased the increases in [Ca(2+)](i) elicited by phenylephrine (1 micromol/L) or KCl (40 mmol/L) in a concentration-dependent manner. Glibenclamide (1-100 micromol/L) abolished the effects of sinomenine. 5. In conclusion, sinomenine causes vascular relaxation by opening ATP-sensitive K(+) channels, thus decreasing [Ca(2+)](i).

Reduced expression of endothelial connexins 43 and 37 in hypertensive rats is rectified after 7-day carvedilol treatment.

BACKGROUND: The aim of this study was to clarify the response of endothelial connexins to hypertension and antihypertensive drugs. METHODS: Rats remained normotensive (group 1, N = 10) or were made hypertensive using N(omega)-nitro-L-arginine methyl ester (L-NAME) (groups 2 to 4, N = 10/group). Seven weeks later groups 3 and 4 were respectively fed atenolol or carvedilol daily for 7 days and the aortic endothelial gap junctions were analyzed. In parallel the effects of atenolol, carvedilol, labetalol, vitamin C, and vitamin E on connexin43 (Cx43) in human umbilical vein endothelial cells (HUVEC) were compared. RESULTS: Endothelial Cx43 was reduced by 35% and Cx37 by 59% in hypertensive rats (P < .001). The reduction was recovered fully by carvedilol but only partially by atenolol (P < .05), although both drugs lowered the blood pressure to similar levels. Cx40 remained stationary in all groups. In HUVEC, carvedilol (10 microg/mL) increased Cx43 protein expression by >70% (P < .01), whereas other drugs had minimal effects. The upregulation by carvedilol was associated with increased transcripts and decreased proteolysis of Cx43. CONCLUSIONS: The study showed that L-NAME-induced hypertension has differential effects on endothelial connexins, which respond variously to carvedilol and atenolol. In HUVEC carvedilol directly upregulates endothelial Cx43 and the effect is independent of its antioxidant activity.

Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma.

Macrophage migration inhibitory factor (MIF) has been linked to fundamental processes such as control of cell proliferation, cell survival, angiogenesis, and tumor progression. The expression of MIF has been reported in several tumors. However, the precise role of MIF in tumor cells remains unclear. In the present study, we investigated the expression pattern and the function of MIF in neuroblastoma. Our results showed that intracellular MIF was upregulated in neuroblastoma tumor tissues and cell lines. MIF protein expression significantly correlated with the grade of tumor differentiation. In addition, we found that MIF induced a significant dose-dependent increase of vascular endothelial growth factor and interleukin-8 secretion. We also observed that an increased MIF expression level correlated with N-Myc protein (the N-myc oncogene product) expression in neuroblastoma tissues. MIF increased the expression of N-myc mRNA and N-Myc protein and induced N-Myc translocation from the cytoplasm to nucleus in neuroblastoma cell lines. MIF-induced N-Myc expression was found to be dependent on ERK signaling pathways. The inhibition of ERK activation reduced MIF-mediated N-Myc expression. These results suggest that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors.

Chromobacterium violaceum infection in children: a case of fatal septicemia with nasopharyngeal abscess and literature review.

This previously healthy 5-year-old boy initially presented with fever and purulent conjunctivitis. The course evolved rapidly into preseptal and facial cellulitis, nasopharyngeal abscess and sepsis. Chromobacterium violaceum was isolated from conjunctival exudate and blood cultures. He received intravenous cefazolin therapy for 2 days, followed by penicillin, oxacillin and netilmicin. However, no improvement was noted, and he died on the fifth days of illness.