Asynchronisme cardiaque chez le sujet à QRS fin. Étude par échocardiographie Doppler tissulaire

ObjectiveTo assess the prevalence of different types of cardiac dyssynchrony by pulsed Doppler ultrasound and Doppler tissue in patients with narrow QRS with or without left ventricular systolic dysfunction.MethodologyProspective, cross-sectional survey at the Institute of Cardiology of Abidjan, from January to April 2012, in subjects with narrow QRS. Group 1: patients with dilated cardiomyopathy with severe left ventricular dysfunction (left ventricular end diastolic diameter greater than 60 mm and/or 30 mm/m² and ejection fraction less than 35% NYHA stage IV). Group 2: normal subjects with normal echocardiography. All patients underwent an evaluation including tissue Doppler search for different types of dyssynchrony (atrioventricular, interventricular and left intraventricular).ResultsPatients in group 1 were significantly older (51.5 ± 15.8 vs. 35.8 ± 7.8, P = 0.03), with larger left ventricular diameters and significantly higher pulmonary systolic pressure. The prevalence of different types of dyssynchrony in group 1 were: atrioventricular dyssynchrony 43.7%, interventricular dyssynchrony 37.5%, left ventricular dyssynchrony 65.6%. Group 2: atrioventricular dyssynchrony 0%, interventricular dyssynchrony 0%, left ventricular dyssynchrony 35%.ConclusionA large proportion of patients with left ventricular systolic dysfunction and narrow QRS have cardiac dyssynchrony and left ventricular dyssynchrony can be found in healthy patients. This raises the problem of the specificity of Doppler ultrasound criteria using cardiac tissue Doppler to assess cardiac dyssynchrony.     

The Use of a Quadripolar Left Ventricular Lead Increases Successful Implantation Rates in Patients with Phrenic Nerve Stimulation and/or High Pacing Thresholds Undergoing Cardiac Resynchronisation Therapy with Conventional Bipolar Leads

BackgroundPhrenic nerve stimulation (PNS) and high pacing thresholds (HPT) hinder biventricular stimulation in patients (pts) undergoing cardiac resynchronization therapy (CRT). A new quadripolar left ventricular (LV) lead (Quartet 1458Q, St. Jude Medical) with increased number of pacing configuration, might overcome this problem.MethodsAll consecutive pts in whom a standard bipolar lead intraoperatively resulted in PNS and/or HPT (≥ 4.00 V/1 mV), received, during the same implant, a quadripolar LV lead. Aim of the study was to evaluate acute and short term outcome.Results26 pts [24 (92%) male, mean age 74 ± 6 years)] with PNS (22 pts; 85%) and HPT (4 pts; 15%) were included. Permanent right ventricular pacing was the reason for broad QRS complex in 4 (15%) pts, whereas all other pts had a left bundle branch block. Severely symptomatic (NYHA Class ≥ 3) heart failure with reduced ejection fraction (EF 31 ± 9%) was mostly caused by ischemic heart disease (14 pts; 54%). Idiopathic dilated cardiomyopathy and valvular heart disease were diagnosed in 6 (23%) pts each. In most (24/26, 92%) pts the use of the Quartet lead led to successful biventricular pacing due to a significant reduction in intraoperative pacing threshold (5.2 V/1.0 ms vs. 1.4 V/0.8 ms; p = 0.03), which was maintained (1.2 V/0.7 ms) at follow-up. PNS never represented reason for failed LV pacing, neither acutely nor during follow-up.ConclusionsExcessively HPT and/or PNS are frequently encountered when conventional bipolar leads are used for CRT. A new quadripolar LV lead increases the rate of successful biventricular stimulation. Lower pacing threshold and freedom from PNS are maintained at follow-up.     

The AV synchrogram: A novel approach to quantify atrioventricular coupling during atrial arrhythmias

The generation of ventricular response during atrial arrhythmias and its dependence on atrial activity is poorly understood. This paper introduces the atrioventricular (AV) synchrogram, a novel method for the beat-to-beat assessment of AV coupling during atrial arrhythmias, based on the stroboscopic observation of the ventricular phase at times triggered by atrial activation. The method was applied on a database of 120 atrial electrograms and ECG signals recorded in patients during typical atrial flutter (AFL), rapid atrial flutter (rAFL), and atrial fibrillation (AF). Synchronized epochs of different n:m order were automatically detected in the AV synchrogram and characterized in terms of percentage of significantly coupled beats (p_lb), maximal length of coupling segments (l_max), average conduction ratio (CR). Synchrogram analysis demonstrated that AV coupling and degree of conduction were significantly affected by the rate and regularity of atrial activity. The occurrence and stability of AV coupled epochs was maximal during regular atrial activation in AFL (median (interquartile range) of p_lb = 100 (100–100)%, l_max = 29.0 (28.5–29.4) s), and significantly (p < 0.001) decreased at faster atrial rates in rAFL (p_lb = 74.3 (57.6–100)%, l_max = 7.4 (3.9–28.7) s). A further decrease of coupling indexes occurred at higher irregularity of atrial activity in AF (p_lb = 25.7 (19.9–30.2)%, l_max = 2.1 (1.8–2.6) s). The increase of atrial rate led to a significant (p < 0.001) reduction of CRs from 0.50 (0.29–0.50) in AFL to 0.25 (0.22–0.25) in rAFL and 0.30 (0.24–0.35) in AF. Application of the analysis to the time course of AF showed the presence of a Farey sequence structure in n:m coupling patterns at increasing atrial rate, which was consistent with the scaling effect of nodal recovery on atrial beats. In conclusion, AV synchrogram analysis enables beat-to-beat assessment of AV coupling and dynamical tracking of AV response during atrial arrhythmias, which may favor mechanistic insight about the genesis of ventricular rhythms and potentially the development of efficacious rate control strategies.     

Alternative alert system for Ganga river eutrophication using alkaline phosphatase as a level determinant

Short-term variations in phosphorus (P) concentrations must be considered while assessing the long-term changes in trophic status and estimating the P load and export. Furthermore, given the challenges of conventional monitoring of river systems, a sediment-specific biomonitoring tool may be more successful inferring P related human controls. In this study, conducted along a 37 km river channel representing up-and downstream urban control, and through a trajectory from a major point source (Assi drain), we tested the patterns of concordance between alkaline phosphatase (AP) activity and soluble reactive-P (SRP) and between AP activity and trophic status in the Ganga River. To validate data comparison, we selected a reference site at Dev Prayag, situated ∼1130 km upstream to the main study stretch. Samples were collected for three consecutive year (March 2013 to February 2016) with respect to atmospheric deposition, surface runoff, point source loading, river water and sediment analysis. For trajectory analysis, samples were collected from 15 locations starting from the drain outlet (zero distance) upto 1.5 km downstream with sampling location 100 m away from the preceding one. We found marked spatial and temporal variations in P concentrations which could be traced by quantifying the AP activity. The AP activity, recorded highest at reference site, declined with increases in P; and at drain mouth it was close to zero reflecting strong influence of P level on alkaline phosphatase activity in the river. We used canonical correlation analysis (CCorA) to test the degrees of concordance and similarity in different variables. Most of the environmental variables and indicators of eutrophy appear largely clustered at one side of the coordinate separating AP activity and dissolved oxygen towards opposite side of the axis. The dynamic fit function relating AP activity with different variables showed significant positive correlation with DO (R² = 0.67; p < 0.001) and negative correlations with BOD (R² = 0.82; p < 0.001), Chl a biomass (R² = 0.52; p < 0.001) and trophic status index (R² = 0.54 (Chl a), 0.96 (DRP); p < 0.001). Furthermore, the enzyme activity did not show significant negative correlation with heavy metals in sediment. Because anthropogenic activities continue to enhance P loads; AP is inhibited directly by P availability; and eutrophy feedbacks sediment P release, our observations on P-AP activity relationship provide a valuable alternative means for detecting P related controls on water quality, trophic status and biogeochemical feedbacks in human impacted rivers.     

Intérêt potentiel des images paramétriques des temps d’éjection et de relaxation en tomoscintigraphie des cavités cardiaques dans l’évaluation des cardiopathies asynchrones

Intraleft dyssynchrony is strongly correlated to contractile dysfunction associated to severe heart failure. Dyssynchrony is also a predictive marker for cardiac resynchronization therapy response. We measured dyssynchrony values for both ventricles from gated blood pool SPECT images.Material and methodsThree groups of patients were sampled from normal patients (n = 7), mild heart failure patients (n = 24) and severe heart failure patients (n = 9). Time-derivative parametric images were obtained from 24-time bins gated blood pool SPECT data. We measured intraleft and interventricular contractile and relaxing dyssynchrony values from these images.ResultsIntraleft dispersions values linked to ventricular peak emptying rate were 107 ± 21 ms, 141 ± 58 ms and 515 ± 104 ms for each of the three groups. The values linked to left ventricular peak filling rate were 122 ± 62 ms, 219 ± 117 ms and 603 ± 164 ms respectively. Statistical significant differences (p < 0.01) were observed both for contractile and relaxing phases for severe heart failure patients. Mild heart failure patients had isolated statistical significant (p < 0.01) alterations of the ventricular relaxing phase. Correlation between isotopic dyssynchrony values and left ejection fraction led to a R square coefficient of 0.71 and 0.64 for time to peak emptying and to peak filling respectively. Correlation to QRS width values led to a R square coefficient of 0.76 and 0.62 respectively.ConclusionVentricular dyssynchrony correlated to the importance of the ventricular mechanical dysfunctions is a robust predictor of heart failure. Separate analysis of contractile and relaxing dyssynchrony may lead to a better understanding and characterization of the mechanical dysfunctions involved in heart failure.     

Effect of cholesterol content on affinity and stability of factor VIII and annexin V binding to a liposomal bilayer membrane

To investigate the effect of cholesterol composition on the binding of factor VIII (FVIII) and annexin V (AV) to membranes, liposomal membranes with phospholipid bilayers of various compositions of phosphatidylcholine (PC), phosphatidylserine (PS), and cholesterol were constructed. A surface plasmon resonance (SPR) biosensor system was employed to measure the equilibrium and rate constants of the bindings. As expected, PS was found to play a dominant role in the binding of AV; its binding level was directly proportional to the PS composition in a liposome. The binding levels of FVIII and AV to liposome increased with an increase in cholesterol composition in liposome. It seemed to suggest that cholesterol in liposome acts as a ‘phospholipid arrangement’ factor by inducing the formation of PS-rich microdomains. However, in the absence of PS (20% on a mole basis), cholesterol could not exert the binding enhancement effect, which again confirmed the critical role of PS in the bindings. Stability of the AV binding was significantly improved by the increase in cholesterol content; for AV, the dissociation rate constant was decreased approximately fivefold, from 1.7 × 10^?3 s^?1 in the absence of cholesterol to 3.3 × 10^?4 s^?1 in the presence of only 10% cholesterol. But, for FVIII the binding stability was not so much influenced by the cholesterol addition (up to 50% on a mole basis). In summary, by using liposomes on an SPR system, we were able to demonstrate quantitatively the apparent effects of cholesterol on the binding affinity and stability of the membrane-binding proteins.     

Serum interleukin-6 and C-reactive protein are markedly elevated in acute decompensated heart failure patients with left ventricular systolic dysfunction

Cytokines play important roles in heart failure (HF). We examined whether cytokine levels are different in acute decompensated heart failure (ADHF) patients between with left ventricular systolic dysfunction (LVSDF) and with preserved LV ejection function (PLVEF). We studied 81 HF patients who were admitted to our hospital with acute decompensation. They were divided into two groups: LVSDF (LVEF) < 45% and PLVEF (LVEF ? 45%). Serum interleukin-6 (IL-6), highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), and IL-18 and plasma brain natriuretic peptide (BNP) were measured on admission and at discharge. On admission, IL-6 and hsCRP were higher in LVSDF than in PLVEF. IL-6 and hsCRP decreased after treatment in LVSDF, but not in PLVEF, while plasma BNP levels decreased in both HF with treatment. There was no difference in TNF-α or in IL-18 level between LVSDF and PLVEF, and they did not change after treatment in either group. In conclusion, cytokine profiles were different in ADHF between those with LVSDF and PLVEF. Activation of IL-6–hsCRP pathway may play a specific role in ADHF with LVSDF.     

Variance-based signal conditioning technique: Comparison to a wavelet-based technique to improve spike detection in multiunit intrafascicular recordings

Detection of single unit action potentials (APs) from peripheral nerve recordings is complicated by low signal-to-noise ratio (SNR) due to the activity of nearby muscles, interference from more distant nerve fibers, and thermal noise from the neural interface. In this study, we propose a novel signal conditioning technique for multiunit signals (i.e. a signal comprised of multiple units coming from different nerve fibers), based on the variance to be applied prior to detection of APs. The proposed technique was tested on experimental and simulated intrafascicular recordings; and was compared to a wavelet-based conditioning (also applied before AP detection). The outputs of both conditioning schemes were sent to an AP detection algorithm that used a simple threshold (equal to the standard deviation of the signal). The overall performance of the detection phase was superior when using the wavelet-based conditioned signal especially for SNR ≤ 2 dB. However, when using the variance-based conditioned signal, the AP detection phase resulted in lower number of false positives for SNR > 2 dB. The novel variance-based method improves the SNR by attenuating the background noise between APs and can be applied as pre-conditioning processing for AP detection.     

Influence of kinematics on the wear of a total ankle replacement

Total ankle replacement (TAR) is an alternative to fusion, replacing the degenerated joint with a mechanical motion-preserving alternative. Minimal pre-clinical testing has been reported to date and existing wear testing standards lack definition. Ankle gait is complex, therefore the aim of this study was to investigate the effect on wear of a range of different ankle gait kinematic inputs. Five Zenith (Corin Group) TARs were tested in a modified knee simulator for twelve million cycles (Mc). Different combinations of IR rotation and AP displacement were applied every 2Mc to understand the effects of the individual kinematics. Wear was assessed gravimetrically every Mc and surface profilometry undertaken after each condition. With the initial unidirectional input with no AP displacement the wear rate measured 1.2±0.6 mm³/Mc. The addition of 11° rotation and 9 mm of AP displacement caused a statistically significant increase in the wear rate to 25.8±3.1 mm³/Mc. These inputs seen a significant decrease in the surface roughness at the tibial articulation. Following polishing three displacement values were tested; 0, 4 and 9 mm with no significant difference in wear rate ranging 11.8–15.2 mm³/Mc. TAR wear rates were shown to be highly dependent on the addition of internal/external rotation within the gait profile with multidirectional kinematics proving vital in the accurate wear testing of TARs. Prior to surface polishing wear rates were significantly higher but once in a steady state the AP displacement had no significant effect on the wear.     

Recurrent Takotsubo Cardiomyopathy Associated with Pheochromocytoma

ObjectiveTo describe a case of recurrent takotsubo cardiomyopathy in a patient with pheochromocytoma.MethodsWe present a case report, including clinical and laboratory data. In addition, the current relevant literature pertaining to pheochromocytoma and takotsubo syndrome is reviewed and summarized.ResultsIn 2004, an 81-year-old woman with no history of cardiac disease presented with chest discomfort, and takotsubo syndrome was diagnosed. No emotional or physical stressors were identified at that time. Her left ventricular systolic function normalized during that hospitalization. In 2007, the patient was readmitted to the hospital with chest discomfort and ST-segment elevation. Cardiac catheterization demonstrated only minor nonobstructive coronary artery disease. She was again found to have takotsubo syndrome with a classic apical hypokinetic segment. Treatment with a heart failure regimen was initiated, and she was screened for pheochromocytoma as the precipitant for her recurrent takotsubo cardiomyopathy. A 24-hour urine collection showed minimally elevated normetanephrine excretion of 719 μg (reference range, 148 to 560) and vanillylmandelic acid of 8.3 mg (reference range, < 8.0). The plasma normetanephrine level was 1.57pg/mL (reference range, < 0.9). Subsequent magnetic resonance imaging revealed a left adrenal mass (2 cm by 1 cm). Ultimately, the patient underwent left adrenalectomy, and the pathology report was consistent with pheochromocytoma. She has been asymptomatic since then, and a repeated echocardiogram demonstrated normal left ventricular systolic function.ConclusionIn patients presenting with takotsubo cardiomyopathy, a precipitating factor, such as emotional or physical stress, can often be identified. In some patients (such as our current case), however, pheochromocytoma may be the underlying disease and should be considered. (Endocr Pract. 2009;15:560-562)     

Rapid cloning,expression and purification of a novel high-activity alkaline phosphatase with detoxification of lipopolysaccharide

Lipopolysaccharide (LPS) is a bacterial endotoxin leading to endotoxemia. Its virulence factor ‘diphosphoryl lipid A’ can be abolished by alkaline phosphatase (AP). A novel AP gene (without introns) was cloned from Saccharomyces boulardii ATCC MYA-796 with a GenBank accession number KF471017, and the recombinant AP (rAP) was expressed as a soluble protein in Pichia pastoris X-33 with a yield of 43.66 mg/l at the end of 120 h of induction in a shaker flask. After purification by affinity-column chromatography, the purity of rAP was over 90%. The optimal reaction conditions of rAP were pH 9.6, temperature at 60 °C and 2 mM Mg²⁺ in diethanolamine buffer, and EDTA was a potent inhibitor of rAP activity. The specific activity of rAP was 9912.01 U/mg under the optimal conditions. Furthermore, rAP showed a broad dephosphorylation activity to LPS over a broad pH range (pH 2–10) in vitro and peaked at pH 4 in Tris–HCl buffer. After LPS dephosphorylated by rAP was injected intraperitoneally into mice, the serum level of tumor necrosis factor (TNF)-α was significantly reduced compared to that of the LPS group (p < 0.01). These findings suggest that rAP has great potential to cure diseases caused by LPS.     

Prognostic value of circulating levels of stem cell growth factor beta (SCGF beta) in patients with Chagas’ disease and idiopathic dilated cardiomyopathy

Chagas’ disease (CD) often leads to dilated cardiomyopathy (DCM), and during its chronic stage hematopoietic stem or progenitor cells are involved in its pathological process. However, it is not clear whether stem cell growth factor (SCGF) beta can be regulated in patients with CD and idiopathic DCM. In present study, we aim to investigate the plasma SCGF beta concentration and its correlation with echocardiographic parameters and clinical outcome.In this prospective cohort study, SCGF beta levels were quantified in patients with CD (n = 94), DCM (n = 48), and control healthy subjects (n = 25). In comparison with healthy subjects, no statistical difference can be detected in NYHA classes I–II patients. However, SCGF beta was significantly increased in advanced heart failure patients (NYHA III–IV), compared to CD patients without heart failure. There was no group difference between CD and DCM. However, despite this significant increase in advanced heart failure patients, SCGF beta had no significant correlation with echocardiographic parameters, and it cannot be used as a prognostic marker for mortality and heart transplantation.To our best knowledge, this is the first report of SCGF beta in heart failure patients. Although it is significantly increased in advanced heart failure patients caused by CD or DCM, its prognostic value for end points is minor.     

Serum interleukin-6 concentration reflects the extent of asymptomatic left ventricular dysfunction and predicts progression to heart failure in patients with stable coronary artery disease

BackgroundLeft ventricular ejection fraction (LVEF) remains one of the strongest predictors of long-term prognosis in patients with stable coronary artery disease (CAD). Asymptomatic left ventricular systolic dysfunction (LVSD) often precedes clinically overt heart failure (HF) and is an area of extensive research nowadays. We studied the association between serum IL-6 concentrations and the extent of LV dysfunction in patients with asymptomatic LVSD. We aimed to investigate the diagnostic value of serum IL-6 concentrations in predicting the risk of progression to HF. Seventy-one patients entered the study and were divided into three groups based on LVEF: group 1 – patients with LVEF <30% (N = 7), group 2 – patients with LVEF 30–50% (N = 37) and group 3 – patients with LVEF >50% (N = 27).ResultsDemographics were similar in all three groups. IL-6 concentration was the highest in group 1 (median 8.6 pg/mL) and the lowest in group 3 (median 2.6 pg/mL), whereas IL-6 concentration in group 2 was intermediate (median 3.7 pg/mL) (P = 0.002). We found a significant, inverse correlation between IL-6 concentration and ejection fraction. During 18-month follow-up clinically overt HF developed in 71.4% of patients in group 1 and in 37.5% of patients in group 2. None of the patients in group 3 manifested HF symptoms (P < 0.001). ROC analysis revealed high diagnostic value of serum IL-6 and LVEF in predicting progression to HF. We also found a strong, inverse correlation between IL-6 and the time of progression to HF.ConclusionsThere is a strong correlation between IL-6 and the extent of asymptomatic LVSD in patients with documented CAD. Elevated IL-6 concentrations preceded progression to clinically overt HF. Moreover, the higher the IL-6 concentration the earlier the manifestation of HF symptoms.     

Increased plasma levels of osteopontin are associated with activation of the renin–aldosterone system and with myocardial and coronary microvascular damage in dilated cardiomyopathy

In patients with dilated cardiomyopathy (DCM) abnormal myocardial blood flow (MBF) has been associated with coronary microvascular dysfunction. The aim of this study was to test the hypothesis that osteopontin (OPN) plasma levels could be associated with the activation of the renin–aldosterone system (RAS) in these patients and be involved in mediating myocardial and coronary damage. In 66 patients with idiopathic left ventricular dysfunction of variable severity the plasma levels of OPN were correlated with biomarkers of systemic metabolism, RAS activation, myocardial dysfunction and with clinical indexes of left ventricle (LV) function and perfusion obtained by 2D-echocardiography and PET. As compared to controls, patients showed a significant increase of inflammatory markers (OPN: 508 ± 30.8 ng/ml vs. 426.9 ± 16.4, p < 0.05 and interleukin (IL)-6: 1.71 ± 0.29 pg/ml vs. 0.38 ± 0.03 pg/ml, p < 0.001) and of indexes of cardiac damage. OPN levels were significantly correlated with the extent of microvascular dysfunction (MBF at rest: p = 0.01; during dipyridamole: p = 0.0003) and with plasma renin activity (PRA) (r = 0.26, p = 0.04). Both in patients with milder or more severe LV dysfunction lower MBF values were associated with higher OPN levels and PRA. These results suggest a interdependent role of RAS and vascular inflammation in cardiomyopathy.     

Celery oil modulates DEHP-induced reproductive toxicity in male rats

The objective of the study was to investigate the protective effect of Apium graveolens (AP) against di-(2-ethylhexyl) phthalate (DEHP)-induced testes injury in rats. Adult rats were divided into nine groups: (1) control group (no treatment); (2) corn oil (60 μg/kg body weight – bwt); (3) AP (50 μg/kg bwt); (4) 300 mg DEHP/kg bwt; (5) 500 mg DEHP/kg bwt; (6) 1000 mg DEHP/kg bwt; (7) 300 mg DEHP/kg bwt + AP; (8) 500 mg DEHP/kg bwt + AP; and (9) 1000 mg DEHP/kg bwt + AP. Oral administration of treatments was performed daily for 6 weeks. DEHP decreased (p < 0.01) body weight, testis weight and serum concentrations of testosterone, cholesterol and total proteins. Moreover, DEHP increased (p < 0.001) total antioxidant capacity in the testis and plasma DEHP level. In addition, DEHP decreased mRNA expression of two testicular steroidogenic enzymes: 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. DEHP also caused atrophy, vacuolar degeneration and aspermia of the seminiferous tubules. AP administered concurrently with DEHP effectively alleviated most of the DEHP-induced effects. In conclusion, in male rats, DEHP had adverse effects on the testis including inhibition of androgen production. A concurrent administration of A. graveolens (celery oil) protected the testis against DEHP-induced toxicity.     

Atrioventricular nodal function during atrial fibrillation: Model building and robust estimation

Statistical modeling of atrioventricular (AV) nodal function during atrial fibrillation (AF) is revisited for the purpose of defining model properties and improving parameter estimation. The characterization of AV nodal pathways is made more detailed and the number of pathways is now determined by the Bayesian information criterion, rather than just producing a probability as was previously done. Robust estimation of the shorter refractory period (i.e., of the slow pathway) is accomplished by a Hough-based technique which is applied to a Poincaré plot of RR intervals. The performance is evaluated on simulated data as well as on ECG data acquired from AF patients during rest and head-up tilt test. The simulation results suggest that the refractory period of the slow pathway can be accurately estimated even in the presence of many artifacts. They also show that the number of pathways can be accurately determined. The results from ECG data show that the refined AV node model provides significantly better fit than did the original model, increasing from 85 ± 5% to 88 ± 4% during rest, and from 86 ± 5% to 87 ± 3% during tilt. When assessing the effect of sympathetic stimulation, the AF frequency increased significantly during tilt (6.25 ± 0.58 Hz vs. 6.32 ± 0.61 Hz, p < 0.05, rest vs. tilt) and the prolongation of the refractory periods of both pathways decreased significantly (slow pathway: 0.23 ± 0.20 s vs. 0.11 ± 0.10 s, p < 0.001, rest vs. tilt; fast pathway: 0.24 ± 0.31 s vs. 0.16 ± 0.19 s, p < 0.05, rest vs. tilt). The results show that AV node characteristics can be assessed noninvasively for the purpose of quantifying changes induced by autonomic stimulation.     

Fluorescent properties of oligonucleotides doubly modified with an indole-fused cytosine analog and 2-aminopurine

Single- and double-stranded oligodeoxynucleotides (ODNs) incorporating both 2-aminopurine (2AP) and an indole-fused cytosine analog (PPI) were prepared and studied for their fluorescence properties. PPI and 2AP can be excited simultaneously by irradiation at 300 nm, with emission observed at 500 nm for PPI and 370 nm for 2AP. We demonstrated the utility of these properties in the dual fluorescence labeling of ODNs giving well-separated emission peaks. In addition, both of the fluorescence signals of a doubly modified ODN changed independently, reflecting the local duplex formation at the regions containing 2AP or PPI. Potential applications of this strategy for the dual fluorescence labeling of oligonucleotides with 2AP and PPI include monitoring local structure alterations of functional nucleic acids and the multiplex detection of biologically important nucleic acids.     

Efficacy of olmesartan and nifedipine on recurrent hypoxia-induced left ventricular remodeling in diabetic mice

AimsRecurrent hypoxia due to sleep apnea syndrome is implicated in cardiovascular events, especially in diabetic patients, but the underlying mechanisms remain controversial. We previously reported that angiotensin II receptor blockers can improve hypoxia-induced left ventricular remodeling. The aim of this study was to examine the effect on left ventricular remodeling of adding a calcium channel blocker to angiotensin II receptor blocker therapy in diabetic mice exposed to recurrent hypoxia.Main methodsMale db/db mice (8-week-old) and age-matched control db/+ mice were fed a Western diet and subjected to recurrent hypoxia (oxygen at 10 ± 0.5% for 8 h daily during the daytime) or normoxia for 3 weeks. Hypoxic db/db mice were treated with the vehicle, olmesartan (3 mg/kg/day), nifedipine (10 mg/kg/day), or both drugs.Key findingsRecurrent hypoxia caused hypertrophy of cardiomyocytes, interstitial fibrosis, and a significant increase in expression of the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in the left ventricular myocardium. Treatment with olmesartan, nifedipine, or both drugs had no effect on systolic blood pressure, and each treatment achieved similar suppression of 4-HNE expression. Olmesartan and the combination with olmesartan and nifedipine significantly prevented cardiomyocyte hypertrophy more than treatment with nifedipine alone. On the other hand, olmesartan combined with nifedipine significantly reduced cytokine expression, superoxide production and matrix metalloproteinase (MMP)-9 activity, and significantly suppressed interstitial fibrosis in the left ventricular myocardium.SignificanceThe combination with olmesartan and nifedipine, as well as a monotherapy with olmesartan, exerts preferable cardioprotection in diabetic mice exposed to recurrent hypoxia.     

Quantitative transdermal behavior of pellitorine from Anacyclus pyrethrum extract

The plant Anacyclus pyrethrum (AP) consists of several N-alkylamides with pellitorine as main constituent. AP extracts are known to be biologically active and some products for topical administration containing AP plant extracts are already commercially available with functional cosmeceutical claims. However, no transdermal data for pellitorine are currently available. Therefore, our general goal was to investigate the local skin pharmacokinetics of the plant N-alkylamide pellitorine using a Franz diffusion cell set-up. Two different forms were applied on human skin: purified pellitorine and the AP extract. Our study demonstrated that pellitorine is able to cross the stratum corneum and the subsequent skin layers. A significantly higher permeability coefficient was observed when the AP extract (K_p = 2.3 × 10⁻⁴ cm/h) was administered, compared to purified pellitorine (K_p = 1.1 × 10⁻⁴ cm/h). With the obtained pellitorine concentrations in the skin layers and the receptor fluid, it is concluded that local and systemic effects can be expected after topical application. Due to these findings and as a regulatory consequence, products containing reasonable concentrations of pellitorine are recommended to be classified as a medicinal product.     

Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis

BackgroundEndothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction.Methods and resultsWe conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41 months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African–Brazilians (p = 0.043). African–Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value = 0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR = 0.11; 95% CI = 0.01–0.83; p = 0.03).ConclusionsThe -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African–Brazilian patients.