Ivabradine: pre-clinical and clinical evidence in the setting of ventricular arrhythmias.

BACKGROUND: Ivabradine, an agent lowering the heart rate, acting as a funny current (If) specific inhibitor, is responsible for the sinoatrial node's spontaneous depolarization. According to current guidelines, it is indicated in specific heart failure populations and as a second-line treatment option to improve angina in chronic coronary syndromes. REVIEW OF LITERATURE: The role of ivabradine in the setting of ventricular arrhythmias has been studied in both experimental and clinical studies. Specifically, experimental studies have examined the role of ivabradine in acute myocardial ischemia, reperfusion, digitalis-induced ventricular arrhythmias, and catecholaminergic polymorphic ventricular tachycardia showing promising results. In addition, clinical studies have shown a beneficial role of ivabradine in reducing ventricular arrhythmias. Ivabradine reduced premature ventricular contractions in combination with beta-blockers in dilated cardiomyopathy patients. Similarly, in catecholaminergic polymorphic ventricular tachycardia, ivabradine reduced dobutamine-induced premature ventricular complexes and improved ventricular arrhythmias burden. On the other hand, current data show no beneficial role of ivabradine in reducing ventricular arrhythmias in myocardial ischemia. CONCLUSIONS: Randomized clinical trials are needed to elucidate the role of ivabradine in reducing the burden of ventricular arrhythmias in various clinical settings. HIPPOKRATIA 2022, 26 (2):49-54.

The association of hematological indices with the response to cardiac resynchronization therapy: a single-center study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapeutic option for patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≤35 % who meet specific criteria according to current guidelines. However, up to 40 % of patients have no response to CRT. Our study aimed to investigate the association between different hematological and biochemical indices and response to CRT. METHODS: Patients with HF due to ischemic or dilated cardiomyopathy referred to our hospital for CRT implantation from January 2013 to November 2017 were included in the study. Response to CRT was defined as an increase in LVEF ≥10 % or a decrease in left ventricular end-systolic volume (LVESV) ≥15 % at six months of follow-up. RESULTS: A total of 48 patients (mean age: 66.2 ± 9.5 years, 81.3 % males) were included in the study. Of these HF patients, 29 (60.4 %) had ischemic cardiomyopathy, and 19 (39.6 %) had dilated cardiomyopathy. At six months of follow-up, 37 patients (77.1 %) had responded to CRT. Ten patients (20.8 %) had ventricular tachycardia (VT), 24 (50 %) patients were hospitalized, and two patients (4.2 %) died during the follow-up period. Multivariate analysis demonstrated that age (p =0.03) and creatinine levels (p =0.02) were independent predictors of the response to CRT. No significant associations between hematological markers (white blood cells, neutrophils, lymphocytes, platelets, neutrophil to lymphocyte ratio, red blood cells distribution width) and CRT response were observed. CONCLUSIONS: A smaller increase in LVEF and a smaller decrease in LVESV were predictive for VT occurrence and hospitalizations in patients receiving CRT. No significant association between hematological markers and response to CRT was found. HIPPOKRATIA 2019, 23(3): 118-125.

Differences in cardiac structure assessed by echocardiography between renal transplant recipients and chronic kidney disease patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in predialysis chronic kidney disease (CKD) and dialysis patients as well as in renal transplant recipients (RTRs). Left ventricular hypertrophy (LVH) starts early during the course of CKD and is a strong predictor of CVD in this population. Regression of LVH after a successful renal transplantation remains a debatable issue among investigators, whereas there is little data comparing echocardiographic measurements between patients with predialysis CKD and RTRs. AIM: The aim of this study was to compare echocardiographic measurements of LV structure and function between predialysis CKD patients and RTRs of similar renal function level. PATIENTS AND METHODS: We conducted a case control study with individual (1:2) matching from the Renal Transplant and the predialysis CKD Outpatient Clinic. For each of the 36 RTRs, two matched for gender, age and estimated glomerular filtration rate (eGFR) predialysis CKD outpatients (72 patients) were included. All patients underwent transthoracic echocardiography and LV mass, LV mass index [LVM and LVMI = LVM/BSA g/m(2)] and indices of systolic function were measured. In a subgroup of 12 RTRs we retrospectively assessed and compared the LVMI measurements at three different time points, during predialysis, dialysis and post transplant period. RESULTS: The prevalence of LVH was 33% in RTRs and 52% in CKD patients (ns). RTRs had significantly lower LVM and LVMI levels compared with predialysis CKD patients (P = .006 and P = .008) while the other echocardiographic indices did not differ. In the subgroup of 12 RTRs, post-transplant LVMI levels (105 ± 25 g/m(2)) were significantly lower in comparison with predialysis (147 ± 57 g/m(2)) and dialysis LVMI levels (169 ± 72 g/m(2)) (P = .01, P = .01, respectively). CONCLUSION: RTRs had significantly lower LVMI compared with predialysis CKD patients of similar age, renal function, hemoglobin and blood pressure level.

Hsp70 regulates the doxorubicin-mediated heart failure in Hsp70-transgenic mice.

The aim of this study was to investigate the potential protective effect of the Hsp70 protein in the cardiac dysfunction induced by doxorubicin (DOX) and the mechanisms of its action. For this purpose, we used both wild-type mice (F1/F1) and Hsp70-transgenic mice (Tg/Tg) overexpressing human HSP70. Both types were subjected to chronic DOX administration (3 mg/kg intraperitoneally every week for 10 weeks, with an interval from weeks 4 to 6). Primary cell cultures isolated from embryos of these mice were also studied. During DOX administration, the mortality rate as well as weight reduction were lower in Tg/Tg compared to F1/F1 mice (P < 0.05). In vivo cardiac function assessment by transthoracic echocardiography showed that the reduction in left ventricular systolic function observed after DOX administration was lower in Tg/Tg mice (P < 0.05). The study in primary embryonic cell lines showed that the apoptosis after incubation with DOX was reduced in cells overexpressing Hsp70 (Tg/Tg), while the apoptotic pathway that was activated by DOX administration involved activated protein factors such as p53, Bax, caspase-9, caspase-3, and PARP-1. In myocardial protein extracts from identical mice with DOX-induced heart failure, the particular activated apoptotic pathway was confirmed, while the presence of Hsp70 appeared to inhibit the apoptotic pathway upstream of the p53 activation. Our results, in this DOX-induced heart failure model, indicate that Hsp70 overexpression in Tg/Tg transgenic mice provides protection from myocardial damage via an Hsp70-block in p53 activation, thus reducing the subsequent apoptotic mechanism.

TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells.

Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-α) is a proinflammatory cytokine, and polymorphism in the TNF-α gene increases the risk of gastric cancer. We herein investigated the role of TNF-α in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-α (Tnf) or TNF-α receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf-/- Gan and Tnfrsf1a-/- Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf-/- Gan mice and Tnfrsf1a-/- Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf+/+ or Tnfrsf1a+/+ Gan mice. These results indicate that TNF-α signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-α expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-α-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-α/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-α/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

Factors affecting psychological stress in children who cooperate with dental treatment: a pilot study.

AIM: Few studies have examined psychological stress and personal anxiety in children exhibiting cooperative behaviour during dental treatment. We assessed psychological stress and personal anxiety during dental treatment in cooperative children, and investigated the influence of various factors. MATERIALS AND METHODS: We measured pre- and post-treatment salivary alpha amylase (sAA) levels of 28 children aged 8-13 years and their parents. Children completed the State-Trait Anxiety Inventory for Children (STAIC); their parents completed the STAI. The IA group included children whose sAA levels increased >10%, whereas the DA group included children whose sAA levels decreased >10%. We used regression models to calculate the power of variables to predict children's psychological stress. RESULTS: The mean anxiety trait score in the IA group was significantly higher than in the DA group (t-test, P = 0.021). For children with higher STAIC-Trait scores, the OR for increasing sAA was 1.16 (95% CI [1.02-1.31]). Parental or treatment factors did not significantly contribute to incremental sAA levels in children. CONCLUSION: Well-behaved children with high anxiety traits may experience high stress levels during dental treatment; however, parental and dental treatment factors may not affect psychological stress in these children.

3D reconstruction of coronary arteries using frequency domain optical coherence tomography images and biplane angiography.

The aim of this study is to describe a new method for three-dimensional (3D) reconstruction of coronary arteries using Frequency Domain Optical Coherence Tomography (FD-OCT) images. The rationale is to fuse the information about the curvature of the artery, derived from biplane angiographies, with the information regarding the lumen wall, which is produced from the FD-OCT examination. The method is based on a three step approach. In the first step the lumen borders in FD-OCT images are detected. In the second step a 3D curve is produced using the center line of the vessel from the two biplane projections. Finally in the third step the detected lumen borders are placed perpendicularly onto the path based on the centroid of each lumen border. The result is a 3D reconstructed artery produced by all the lumen borders of the FD-OCT pullback representing the 3D arterial geometry of the vessel.

Multiscale-patient-specific artery and atherogenesis models.

In this work, we present a platform for the development of multiscale patient-specific artery and atherogenesis models. The platform, called ARTool, integrates technologies of 3-D image reconstruction from various image modalities, blood flow and biological models of mass transfer, plaque characterization, and plaque growth. Patient images are acquired for the development of the 3-D model of the patient specific arteries. Then, blood flow is modeled within the arterial models for the calculation of the wall shear stress distribution (WSS). WSS is combined with other patient-specific parameters for the development of the plaque progression models. Real-time simulation can be performed for same cases in grid environment. The platform is evaluated using both animal and human data.

Atherosclerotic plaque characterization in Optical Coherence Tomography images.

Optical Coherence Tomography (OCT) is a fiber--optic imaging modality which produces high resolution tomographic images of the coronary lumen and outer vessel wall. While OCT images present morphological information in highly resolved detail, the characterization of the various plaque components relies on trained readers. The aim of this study is to extract a set of features in grayscale OCT images and to use them in order to classify the atherosclerotic plaque. Intensity and texture based features we used in order to classify the plaque in four plaque types: Calcium (C), Lipid Pool (LP), Fibrous Tissue (FT) and Mixed Plaque (MP). 50 OCT annotated images from 3 patients were used to train and test the proposed plaque characterization method. Using a Random Forests classifier overall classification accuracy 80.41% is reported.

A non-invasive methodology for fetal monitoring during pregnancy.

OBJECTIVES: This paper describes a methodology for the monitoring of the fetal cardiac health status during pregnancy, through the effective and non-invasive monitoring of the abdominal ECG signals (abdECG) of the mother. METHODS: For this purpose, a three-stage methodology has been developed. In the first stage, the fetal heart rate (fHR) is extracted from the abdECG signals, using nonlinear analysis. Also, the eliminated ECG (eECG) is calculated, which is the abdECG after the maternal QRSs elimination. In the second stage, a blind source separation technique is applied to the eECG signals and the fetal ECG (fECG) is obtained. Finally, monitoring of the fetus is implemented using features extracted from the fHR and fECG, such as the T/QRS ratio and the characterization of the fetal ST waveforms. RESULTS: The methodology is evaluated using a dataset of simulated multichannel abdECG signals: 94.79% accuracy for fHR extraction, 92.49% accuracy in T/QRS ratio calculation and 79.87% in ST waveform classification. CONCLUSIONS: The novel non-invasive proposed methodology is advantageous since it offers automated identification of fHR and fECG and automated ST waveform analysis, exhibiting a high diagnostic accuracy.

Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation.

OBJECTIVE: To assess the effectiveness and safety of pharmacological conversion of persistent atrial fibrillation (AF) with a combined propafenone plus ibutilide regimen. METHODS AND RESULTS: 100 consecutive patients (66 men, mean (SD) age 65 (10) years) with persistent AF (mean (SD) duration 99 (92) days) admitted for elective pharmacological cardioversion were randomly assigned to treatment with either intravenous ibutilide (1 mg plus an additional 1 mg, if required; n = 51) or oral propafenone (600 mg) plus intravenous ibutilide at the same dose (n = 49). Success rates were 41.1% (21 of 51 patients) for ibutilide alone and 71.4% (35 of 49 patients) for propafenone plus ibutilide (p = 0.0044). However, cardioversion occurred earlier in the ibutilide alone group (55 (20) minutes) compared with the combination group (81 (32) minutes, p = 0.0019). A comparable increase in the QTc interval was observed in both groups but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group. No other complications were noted during the hospitalisation period. CONCLUSION: Concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent AF is safe and more effective than ibutilide alone.

Treatment of acute lower limb ischemia following the use of the Duett sealing device: report of three cases and review of the literature.

Three cases of local thrombolysis in the treatment of acute lower limb ischemia complicating the utilization of the Duett sealing device are presented. Routine usage of several vascular closure devices after cardiac catheterization and percutaneous coronary intervention (PCI) has been adopted in our institution during the last 3 years (September 1999 to April 2003). The Duett closure device has been used in 420 patients (post-coronary angiography, 359; post-PCI, 61). Three patients (0.7%) demonstrated acute leg ischemia used by inadvertent intravascular administration of the sealing material related to this device. All three were treated successfully by catheter-directed local thromolysis (tissue plasminogen activator 5 mg bolus followed initially by 1 mg/hr and consequently by 0.5-1.0 mg/hr depending upon the development of significant hematoma and lasting for 24 hr). In conclusion, interventional treatment using local thrombolysis should be the first-line treatment in acute lower limb ischemia complicating the utilization of the Duett sealing device.

Preparation of a purified fibrinogen calibration material for Clauss method and turbidimetric immunoassay possessing biological activity and antigenicity.

Fibrinogen plays a major role in basic coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT). These show high interlaboratory variation because of inaccurate instrumental calibration. The same is true of the fibrinogen assay, despite its being a quantitative assay. Most medical laboratories use automated coagulometers and commercially available calibration materials (calibrators) to obtain an accurate fibrinogen value, but, when checked, calibrators have been found to deviate from the assigned value. The Japan Society of Laboratory Medicine (JSLM) has identified the need for a reliable plasma fibrinogen standard. To enhance the reliability of calibrator fibrinogen values and thereby remedy the poor precision and accuracy of plasma fibrinogen testing, we undertook the preparation of a standard calibration material applicable to both the Clauss method and turbidimetric immunoassay (TIA). The calibrator was prepared from fresh human plasma by glycine precipitation and virus inactivation followed by affinity chromatography to remove contaminated plasminogen. In the resulting product, clottable fibrinogen accounted for 95% of total protein and within-run precision showed a CV of less than 1.8%. We believe the preparation will become a candidate material for laboratory and manufacturer use in Japan.

Effects of delayed (24 h postintervention) beta-irradiation therapy after coronary angioplasty and stenting in de novo native coronary artery lesions; Results of a randomized clinical and intravascular ultrasound study.

BACKGROUND: The effects of brachytherapy performed 24 h postintervention in de novo native coronary artery lesions. METHODS AND RESULTS: Thirty-nine patients with 39 de novo coronary artery lesions were randomised to prompt (immediately after intervention, n=21) or delayed (24 h later, n=18) beta brachytherapy ((90)Sr/(90)Y) after been successfully revascularized with stenting. Clinical follow-up data up to 21 months (median time) were compared. After irradiation and at 6-month follow-up, paired volumetric analysis of the stented segment and the 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque, and media (external elastic membrane minus lumen), stent and intima hyperplasia (stent minus lumen). Baseline clinical and angiographic characteristics were similar in the two groups. Postintervention measurements of stent, lumen, and intima hyperplasia volumes as well as postintervention minimum lumen cross-sectional areas were not different. In the stented segments and in the segments 5 mm proximal and distal to the stent, similar changes of all IVUS measurements were measured in the two patient groups, but in the lumen volume at the proximal stent edge of patients irradiated 24 h postinjury. At 21 months median follow-up time, target lesion revascularization (TLR) was performed in 8 patients (38%) in the prompt irradiation group compared with 3 (17%) in the delayed (P=.17). CONCLUSION: Beta irradiation is similarly effective whether performed immediately after percutaneous coronary intervention or 24 h later.

Fractal dimensions of laser doppler flowmetry time series.

Laser Doppler flowmetry (LDF) provides a non-invasive method of assessing cutaneous perfusion. As the microvasculature under the probe is not defined the measured flux cannot be given absolute units, but the technique has nevertheless proved valuable for assessing relative changes in perfusion in response to physiological stress. LDF signals normally show pronounced temporal variability, both as a consequence of the pulsatile nature of blood flow and local changes in dynamic vasomotor activity. The aim of the present study was to investigate the use of methods of nonlinear analysis in characterizing temporal fluctuations in LDF signals. Data were collected under standardised conditions from the forearm of 16 normal subjects at rest, during exercise and on recovery. Surrogate data was then generated from the original time series by phase randomization. Dispersional analysis demonstrated that the LDF data was fractal with two distinct scaling regions, thus allowing the calculation of a fractal dimension which decreased significantly from 1.23 +/- 0.09 to 1.04 +/- 0.02 during exercise. By contrast, dispersional analysis of the surrogate data showed no scaling region.

Wavelet and receiver operating characteristic analysis of heart rate variability.

Multiresolution wavelet analysis has been used to study the heart rate variability in two classes of patients with different pathological conditions. The scale dependent measure of Thurner et al. was found to be statistically significant in discriminating patients suffering from hypercardiomyopathy from a control set of normal subjects. We have performed Receiver Operating Characteristc (ROC) analysis and found the ROC area to be a useful measure by which to label the significance of the discrimination, as well as to describe the severity of heart dysfunction.

Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide.

Flow-mediated dilatation (FMD) of the brachial artery assessed by high-resolution ultrasound is widely used to measure endothelial function. However, the technique is not standardized, with different groups using occlusion of either the wrist or the upper arm to induce increased blood flow. The validity of the test as a marker of endothelial function rests on the assumption that the dilatation observed is endothelium-dependent and mediated by nitric oxide (NO). We sought to compare the NO component of brachial artery dilatation observed following wrist or upper arm occlusion. Dilatation was assessed before and during intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) following occlusion of (i) the wrist (distal to ultrasound probe) and (ii) the upper arm (proximal to ultrasound probe) for 5 min in ten healthy males. Dilatation was significantly greater after upper arm occlusion (upper arm, 11.62+/-3.17%; wrist, 7.25+/-2.49%; P=0.003). During L-NMMA infusion, dilatation after wrist occlusion was abolished (from 7.25+/-2.49% to 0.16+/-2.24%; P<0.001), whereas dilatation after upper arm occlusion was only partially attenuated (from 11.62+/-3.17% to 7.51+/-2.34%; P=0.006). The peak flow stimulus was similar after wrist and upper arm occlusion. We conclude that dilatation following upper arm occlusion is greater than that observed after wrist occlusion, despite a similar peak flow stimulus. L-NMMA infusion revealed that FMD following wrist occlusion is mediated exclusively by NO, while dilatation following upper arm occlusion comprises a substantial component not mediated by NO, most probably related to tissue ischaemia around the brachial artery. FMD following wrist occlusion may be a more valid marker of endothelial function than dilatation following upper arm occlusion.

Adsorption effect of activated charcoal on enterohemorrhagic Escherichia coli.

The adsorption property of activated charcoal on verotoxin (VT)-producing Escherichia coli (VTEC) was examined using E. coli O157:H7. In the present study, E. coli O157:H7 strains were effectively adsorbed by activated charcoal. Adsorption was dose-dependent, and the maximum adsorption occurred within 5 min. At 10 mg of activated charcoal, bacteria tested were completely adsorbed. Activated charcoal also had the capacity to adsorb toxin (verotoxin 2) activity from the bacterial extract. Furthermore, the adsorption efficiency of activated charcoal for the normal bacterial flora in the intestine was assessed using Enterococcus faecium, Bifidobacterium thermophilum, and Lactobacillus acidophilus. Activated charcoal showed lower binding capacity to the normal bacterial flora tested than that to E. coli O157:H7 strains. These results suggest that activated charcoal could be a good adsorbent system for the removal of VTEC and verotoxin.