Transcriptome and Metabolome Analyses Reveal Perfluorooctanoic Acid-Induced Kidney Injury by Interfering with PPAR Signaling Pathway.

Perfluorooctanoic acid (PFOA) is widely used in aviation science and technology, transportation, electronics, kitchenware, and other household products. It is stable in the environment and has potential nephrotoxicity. To investigate the effect of PFOA exposure during pregnancy on the kidneys of offspring mice, a total of 20 mice at day 0 of gestation were randomly divided into two groups (10 mice in each group), and each group was administered 0.2 mL of PFOA at a dose of 3.5 mg/kg or deionized water by gavage during gestation. The kidney weight, kidney index, histopathological observation, serum biochemistry, transcriptomics, and metabolomics of the kidneys of the 35-day offspring mice were analyzed. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels in the kidney were measured. Transcriptome analysis results showed that 387 genes were up-regulated and 283 genes were down-regulated compared with the control group. These differentially expressed genes (DEGs) were mainly concentrated in the peroxisome-proliferator-activated receptor (PPAR) signaling pathway and circadian rhythm. Compared with the control group, 64 and 73 metabolites were up- and down-regulated, respectively, in the PFOA group. The altered metabolites were mainly enriched in the biosynthesis of unsaturated fatty acids. PFOA can affect the expression levels of circadian rhythm-related genes in the kidneys of offspring mice, and this change is influenced by the PPAR signaling pathway. PFOA causes oxidative stress in the kidneys, which is responsible for significant changes in metabolites associated with the biosynthesis of unsaturated fatty acids.

Early diagnosis of coronary microvascular dysfunction by myocardial contrast stress echocardiography.

Coronary microvascular dysfunction (CMD) is one of the basic mechanisms of myocardial ischemia. Myocardial contrast echocardiography (MCE) is a bedside technique that utilises microbubbles which remain entirely within the intravascular space and denotes the status of microvascular perfusion within that region. Some pilot studies suggested that MCE may be used to diagnose CMD, but without further validation. This study is aimed to investigate the diagnostic performance of MCE for the evaluation of CMD. MCE was performed at rest and during adenosine triphosphate stress. ECG triggered real-time frames were acquired in the apical 4-chamber, 3-chamber, 2-chamber, and long-axis imaging planes. These images were imported into Narnar for further processing. Eighty-two participants with suspicion of coronary disease and absence of significant epicardial lesions were prospectively investigated. Thermodilution was used as the gold standard to diagnose CMD. CMD was present in 23 (28%) patients. Myocardial blood flow reserve (MBF) was assessed using MCE. CMD was defined as MBF reserve < 2. The MCE method had a high sensitivity (88.1%) and specificity (95.7%) in the diagnosis of CMD. There was strong agreement with thermodilution (Kappa coefficient was 0.727; 95% CI: 0.57-0.88, p < 0.001). However, the correlation coefficient (r = 0.376; p < 0.001) was not high.

Semantic segmentation method for myocardial contrast echocardiogram based on DeepLabV3+ deep learning architecture.

Myocardial contrast echocardiography (MCE) has been proposed as a method to assess myocardial perfusion for the detection of coronary artery diseases in a non-invasive way. As a critical step of automatic MCE perfusion quantification, myocardium segmentation from the MCE frames faces many challenges due to the low image quality and complex myocardial structure. In this paper, a deep learning semantic segmentation method is proposed based on a modified DeepLabV3+ structure with an atrous convolution and atrous spatial pyramid pooling module. The model was trained separately on three chamber views (apical two-chamber view, apical three-chamber view, and apical four-chamber view) on 100 patients' MCE sequences, divided by a proportion of 7:3 into training and testing datasets. The results evaluated by using the dice coefficient (0.84, 0.84, and 0.86 for three chamber views respectively) and Intersection over Union(0.74, 0.72 and 0.75 for three chamber views respectively) demonstrated the better performance of the proposed method compared to other state-of-the-art methods, including the original DeepLabV3+, PSPnet, and U-net. In addition, we conducted a trade-off comparison between model performance and complexity in different depths of the backbone convolution network, which illustrated model application feasibility.

Mancozeb induces nephrotoxicity by impairing the oxidative phosphorylation pathway: A transcriptome study.

This study analyzed the mechanism underlying mancozeb (MCZ)-induced kidney injury by detecting kidney function indicators, combined with transcriptome and metabolome sequencing. Twenty mice were randomly assigned into two groups (control and MCZ groups) to explore the MCZ-induced kidney toxicity. The control group was gavaged with 0.2 mL of deionized water, and the MCZ group with 0.2 mL of 100 mg/kg MCZ for 30 days. The kidney structure of the MCZ group was damaged, with slight hyaline degeneration in the kidney tubular epithelial envelope. The creatinine (CRE) and uric acid (UA) were significantly increased in the MCZ group than in the control group. Moreover, the reactive oxygen species (ROS) significantly accumulated in the MCZ group kidneys. Compared to the control group, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were significantly decreased in the MCZ group, while the MDA content was substantially increased. The differentially expressed genes (DEGs) in the MCZ group were mainly enriched in the oxidative phosphorylation pathway. Besides, in the MCZ group, ndufs1 and ndufab1 genes were significantly up-regulated, while cox5b, ndufa5, and ndufa6 genes were significantly down-regulated, consistent with the PCR verification results. The metabolomic analysis identified cGMP-PKG signaling pathway of MCZ-induced nephrotoxicity, with Guanosine monophosphate and Adenosine 5'-monophosphate as the main altered metabolites. These results indicated that MCZ impairs the mice kidneys by obstructing the oxidative phosphorylation pathway, which increases oxidative stress in the kidneys, resulting in kidney injury.

Reliable Detection of Myocardial Ischemia Using Machine Learning Based on Temporal-Spatial Characteristics of Electrocardiogram and Vectorcardiogram.

Background: Myocardial ischemia is a common early symptom of cardiovascular disease (CVD). Reliable detection of myocardial ischemia using computer-aided analysis of electrocardiograms (ECG) provides an important reference for early diagnosis of CVD. The vectorcardiogram (VCG) could improve the performance of ECG-based myocardial ischemia detection by affording temporal-spatial characteristics related to myocardial ischemia and capturing subtle changes in ST-T segment in continuous cardiac cycles. We aim to investigate if the combination of ECG and VCG could improve the performance of machine learning algorithms in automatic myocardial ischemia detection. Methods: The ST-T segments of 20-second, 12-lead ECGs, and VCGs were extracted from 377 patients with myocardial ischemia and 52 healthy controls. Then, sample entropy (SampEn, of 12 ECG leads and of three VCG leads), spatial heterogeneity index (SHI, of VCG) and temporal heterogeneity index (THI, of VCG) are calculated. Using a grid search, four SampEn and two features are selected as input signal features for ECG-only and VCG-only models based on support vector machine (SVM), respectively. Similarly, three features (S I , THI, and SHI, where S I is the SampEn of lead I) are further selected for the ECG + VCG model. 5-fold cross validation was used to assess the performance of ECG-only, VCG-only, and ECG + VCG models. To fully evaluate the algorithmic generalization ability, the model with the best performance was selected and tested on a third independent dataset of 148 patients with myocardial ischemia and 52 healthy controls. Results: The ECG + VCG model with three features (S I ,THI, and SHI) yields better classifying results than ECG-only and VCG-only models with the average accuracy of 0.903, sensitivity of 0.903, specificity of 0.905, F1 score of 0.942, and AUC of 0.904, which shows better performance with fewer features compared with existing works. On the third independent dataset, the testing showed an AUC of 0.814. Conclusion: The SVM algorithm based on the ECG + VCG model could reliably detect myocardial ischemia, providing a potential tool to assist cardiologists in the early diagnosis of CVD in routine screening during primary care services.

Effect of microcirculatory dysfunction on coronary hemodynamics: A pilot study based on computational fluid dynamics simulation.

BACKGROUND: Invasively measured fractional flow reserve (FFR) and index of microcirculatory resistance (IMR) are gold standards for the diagnosis of coronary artery disease (CAD) and coronary microcirculatory dysfunction (CMD). However, the interaction between CAD and CMD has not been comprehensively investigated. We aim to non-invasively investigate hemodynamic effect of CMD in nonobstructive CAD cases using computational fluid dynamics (CFD) simulation. METHOD: This study employed CFD simulations on six cases with nonobstructive CAD and CMD in left anterior descending artery (LAD) territories. Two microcirculatory situations were simulated: normal microcirculatory resistance (MR) situation; CMD situation where MR at the outlets of LAD branches were multiplied by the ratio of clinically measured IMR to the cutoff value. Blood flow, translesional pressure drop (Δptl), and simulated FFR (FFRCT) of LAD and non-culprit branches were compared between the two microcirculatory situations using Wilcoxon signed rank test. RESULTS: The results are in accordance with existing studies and clinical measurements. Compared with normal MR, there were significant decreases in outlet flow velocity and increases in FFRCT (p < 0.01 for both in Wilcoxon signed rank tests) in LAD branches with CMD, with minor decreases (0.63-5.64 mmHg) in Δptl. There was no significant influence on outlet flow velocity (< 2%) and FFRCT (< 0.02) in non-culprit branches (p > 0.05 for both). CONCLUSION: IMR-based CFD simulation could estimate hemodynamic effects of CMD. CMD in a coronary artery branch can decrease its blood flow and Δptl, increase its FFR, with little effect on non-culprit branches.

Investigating two kinds of cellular alternans and corresponding TWA induced by impaired calcium cycling in myocardial ischemia.

BACKGROUND: The utility of T wave alternans (TWA) in identifying arrhythmia risk has been demonstrated. During myocardial ischemia (MI), TWA could be induced by cellular alternans. However, the relationship between cellular alternans patterns and TWA patterns in MI has not been investigated thoroughly. METHODS: We set MI conditions to simulate alternans. Either prolonging Ca2+ release or increasing spark-induced sparks (secondary sparks) can give rise to different patterns of APD alternans and TWA. In addition, different ischemic zones and reduced conduction velocity are also considered in one dimensional simulation. RESULTS: Delay of Ca2+ release can produce discordant Ca2+-driven alternans in single cell simulation. Increasing secondary sparks leads to concordant alternans. Correspondingly, morphology and magnitude of TWA vary in two different cellular alternans. Epi ischemia results in alternans concentrating in the first half of T wave. Endo and transmural ischemia lead to fluctuations in the second half of T wave. In addition, slowing conduction velocity has no effect on TWA magnitude. CONCLUSION: Specific ionic channel dysfunction and ischemic zones affect TWA patterns.

Consistency in Geometry Among Coronary Atherosclerotic Plaques Extracted From Computed Tomography Angiography.

Background: The three-dimensional (3D) geometry of coronary atherosclerotic plaques is associated with plaque growth and the occurrence of coronary artery disease. However, there is a lack of studies on the 3D geometric properties of coronary plaques. We aim to investigate if coronary plaques of different sizes are consistent in geometric properties. Methods: Nineteen cases with symptomatic stenosis caused by atherosclerotic plaques in the left coronary artery were included. Based on attenuation values on computed tomography angiography images, coronary atherosclerotic plaques and calcifications were identified, 3D reconstructed, and manually revised. Multidimensional geometric parameters were measured on the 3D models of plaques and calcifications. Linear and non-linear (i.e., power function) fittings were used to investigate the relationship between multidimensional geometric parameters (length, surface area, volume, etc.). Pearson correlation coefficient (r), R-squared, and p-values were used to evaluate the significance of the relationship. The analysis was performed based on cases and plaques, respectively. Significant linear relationship was defined as R-squared > 0.25 and p < 0.05. Results: In total, 49 atherosclerotic plaques and 56 calcifications were extracted. In the case-based analysis, significant linear relationships were found between number of plaques and number of calcifications (r = 0.650, p = 0.003) as well as total volume of plaques (r = 0.538, p = 0.018), between number of calcifications and total volume of plaques (r = 0.703, p = 0.001) as well as total volume of calcification (r = 0.646, p = 0.003), and between the total volumes of plaques and calcifications (r = 0.872, p < 0.001). In plaque-based analysis, the power function showed higher R-squared values than the linear function in fitting the relationships of multidimensional geometric parameters. Two presumptions of plaque geometry in different growth stages were proposed with simplified geometric models developed. In the proposed models, the exponents in the power functions of geometric parameters were in accordance with the fitted values. Conclusion: In patients with coronary artery disease, coronary plaques and calcifications are positively related in number and volume. Different coronary plaques are consistent in the relationship between geometry parameters in different dimensions.

A New Method for Detecting Myocardial Ischemia Based on ECG T-Wave Area Curve (TWAC).

In recent years, coronary heart disease (CHD) has become one of the main diseases that endanger human health, with a high mortality and disability rate. Myocardial ischemia (MI) is the main symptom in the development of CHD. Continuous and severe myocardial ischemia will lead to myocardial infarction. The clinical manifestations of MI are mainly the changes of ST-T segment of ECG, that is, ST segment and T wave. Nearly one third of patients with CHD, however, has no obvious ECG changes. In this paper, a new method for detecting MI based on the T-wave area curve (TWAC) was proposed. Through observation and analysis of clinical data, it was found that there exist significant correlation between the morphology of TWAC and MI. The TWAC morphology of normal subject is smooth and gentle, while the TWAC morphology of patients with coronary stenosis is mostly jagged, and the curve becomes more severe with more severe stenosis. The preliminary test results show that the sensitivity, specificity, and accuracy of the proposed method for detecting MI are 84.3, 83.6, and 84%, respectively. This study shows that the TWAC based approach may be an effective method for detecting MI, especially for the CHD patients with no obvious ECG changes.

Prevalence of abnormal and borderline electrocardiogram changes in 13, 079 Chinese amateur marathon runners.

BACKGROUND: The 12-lead electrocardiogram (ECG) has been adopted as an important component of preparticipation cardiovascular screening. However, there are still controversies in the screening and few studies with a large sample size have reported the results of ECGs of marathon runners. Therefore, the purpose of this study was to assess the prevalence of normal, borderline, and abnormal ECG changes in marathon runners. METHODS: The 12-lead ECG data of 13,079 amateur marathon runners between the ages of 18 and 35 years were included for analysis. The prevalence of ECG abnormalities among different gender groups was compared with chi-square tests. RESULTS: In terms of training-related changes, sinus bradycardia, sinus arrhythmia, and left ventricular high voltage were found in approximately 15, 5, and 3.28% of the participants, respectively. The incidence of right axis deviation in the marathon runners was 1.78%, which was slightly higher than the incidence of left axis deviation (0.88%). No more than 0.1% of the amateur marathon runners exhibited ST-segment depression, T wave inversion (TWI), premature ventricular contraction, pathologic Q waves, and prolonged QT interval. CONCLUSIONS: Training-related ECG changes, including sinus bradycardia, sinus arrhythmia, and left ventricular high voltage, were common in amateur marathon runners. Most abnormal ECG changes, including ST-segment depression, TWI, premature ventricular contraction, pathologic Q waves, and prolonged QT interval, were infrequently found in amateur marathon runners. The data also suggested Chinese amateur marathon runners may have a relatively lower prevalence of ECG abnormalities than black and white runners.

Dataset on blood flow and instantaneous wave-free ratio in normal and stenosed coronary arteries.

Instantaneous wave-free ratio (iFR) has been proposed as a hemodynamic parameter that can reliably reflect the blood flow in stenosed coronary arteries. Currently, there are few investigations on the quantitative analysis of iFR in the patients regarding the variation of microcirculatory resistance (MR). The data aim to provide geometric (cross-section area of branches) and hemodynamic (flow rate and iFR of branches) parameters of normal and stenosed coronary arteries derived from CFD simulation. The CFD simulation was performed on the three-dimensional artery models reconstructed from computed tomography (CT) images of four subjects. The hemodynamic parameters were obtained in six situations of MR to simulate coronary microvascular dysfunction (CMD). This dataset could be used as the reference to estimate the iFR and flow rate in patients with CMD and stenosis in coronary arteries. The geometric parameters could be used in the modelling of coronary arteries.

Effect of microcirculatory resistance on coronary blood flow and instantaneous wave-free ratio: A computational study.

BACKGROUND AND OBJECTIVE: The instantaneous wave-free ratio (iFR) has been proposed to estimate the hemodynamic severity of atherosclerotic stenosis in coronary arteries. The atherosclerotic stenosis in a proximal coronary artery could change its distal microcirculatory resistance (MR). However, there is a lack of investigation about the effect of MR variation on the blood flow and iFR of stenotic coronary arteries. We aim to investigate the changes of blood flow and iFR caused by distal MR variation. METHODS: Four three-dimensional models of coronary arteries were reconstructed from the computed tomography images of two normal cases and two cases with 74.9% and 96.4% (in area) stenoses in a large branch of left anterior descending artery (LAD). Computational fluid dynamics simulation was performed on each model under 6 MR situations: hyperemia as the reference situation, resting when MR was multiplied by 8/3 in all outlet branches, h-one-1.5 and h-one-2 when MR was multiplied by 1.5 and 2.0 in one branch (the stenotic, or the corresponding branch in normal case) of LAD, h-branches-1.5 and h-branches-2 when MR was multiplied by 1.5 and 2.0 in the stenotic/corresponding and its cognate branches. Flow rate and iFR of each outlet branch were then calculated and compared between different MR situations to investigate the effect of MR variation on flow rate and iFR. RESULTS: In the 74.9% stenosed and normal cases, referring to the hyperemia situation, the increase of MR in any branch significantly decreased its flow rate and increased its iFR, with limited effect on the flow rate (<3%) and iFR (<0.01) of other branches. However, in the 96.4% stenosed case, the doubled MR in the stenosed branch (h-one-2) significantly increased the flow rate (>10%) and iFR (>0.05) of its cognate branches. CONCLUSION: The increase of MR in a normal or mildly stenosed branch of coronary artery decreases its blood flow and increases its iFR, with limited effect on other branches. Whereas, the increase of MR in a severely stenotic large branch could significantly increase the flow velocity and iFR of its cognate branches.

Exploring Impaired SERCA Pump-Caused Alternation Occurrence in Ischemia.

Impaired sarcoplasmic reticulum (SR) calcium transport ATPase (SERCA) gives rise to Ca2+ alternans and changes of the Ca2+release amount. These changes in Ca2+ release amount can reveal the mechanism underlying how the interaction between Ca2+ release and Ca2+ uptake induces Ca2+ alternans. This study of alternans by calculating the values of Ca2+ release properties with impaired SERCA has not been explored before. Here, we induced Ca2+ alternans by using an impaired SERCA pump under ischemic conditions. The results showed that the recruitment and refractoriness of the Ca2+ release increased as Ca2+ alternans occurred. This indicates triggering Ca waves. As the propagation of Ca waves is linked to the occurrence of Ca2+ alternans, the "threshold" for Ca waves reflects the key factor in Ca2+ alternans development, and it is still controversial nowadays. We proposed the ratio between the diastolic network SR (NSR) Ca content (Cansr) and the cytoplasmic Ca content (Ca i ) (Cansr/Ca i ) as the "threshold" of Ca waves and Ca2+ alternans. Diastolic Cansr, Ca i , and their ratio were recorded at the onset of Ca2+ alternans. Compared with certain Cansr and Ca i , the "threshold" of the ratio can better explain the comprehensive effects of the Ca2+ release and the Ca2+ uptake on Ca2+ alternans onset. In addition, these ratios are related with the function of SERCA pumps, which vary with different ischemic conditions. Thus, values of these ratios could be used to differentiate Ca2+ alternans from different ischemic cases. This agrees with some experimental results. Therefore, the certain value of diastolic Cansr/Ca i can be the better "threshold" for Ca waves and Ca2+ alternans.

Simulation of inter atrial block based on a human atrial model.

Inter atrial block (IAB) is a prevailing cardiac conduction abnormality that is under-recognized in clinical practice. IAB has strong association with atrial arrhythmia, left atrial enlargement, and electromechanical discordance, increasing the risk of atrial fibrillation (AF) and myocardial ischemia. IAB was generally believed to be caused by impaired conduction along the Bachmann bundle (BB). However, there are three other conduction pathways, including the fibers posteriorly in the vicinity of the right pulmonary veins (VRPV), transseptal fibers in the fossa ovalis (FO), and muscular bundles on the inferior atrial surface near the coronary sinus (CS). We hypothesized that the importance of BB on IAB might have been overestimated. To test this hypothesis, various combinations of conduction pathway blocks were simulated based on a realistic human atrial model to investigate their effects on the index of clinical diagnosis standard of IAB using a simulated 12-lead electrocardiogram (ECG). Firstly, the results showed that the BB block alone could not generate typical P wave morphology of IAB, and that the combination of BB and VRPV pathway block played important roles in the occurrence of IAB. Secondly, although single FO and CS pathways play subordinate roles in inter atrial conduction, their combination with BB and VRPV block could also produce severe IAB. In summary, this simulation study has demonstrated that the combinations of different inter atrial conduction pathways, rather than BB alone, resulted in ECG morphology of IAB. Attention needs to be paid to this in future pathophysiological and clinical studies of IAB.

Potential Maintenance Mechanism in Atrial Fibrillation Patients Subject to Different Treatment Procedures: A Preliminary Study Based on a Human Atrial Model.

Two clinical ablation protocols, 2C3L and stepwise, have been routinely used in our group to treat atrial fibrillation (AF), but with a less than 60% long-term arrhythmia-free outcome achieved in patients. The goal of this study was to examine the underlying mechanism of low success in clinical outcome. MRI images from one patient were used to reconstruct a human atrial anatomical model, and fibrotic tissue was manually added to represent the arrhythmia substrate. AF was induced with standard protocols used in clinical practice. 2C3L and stepwise were then used to test the efficacy of arrhythmia termination in our model. The results showed that re-entries induced in our model could not be terminated by using either 2C3L or the stepwise protocol. Although some of the induced re-entries were terminated, others emerged in new areas. Ablation using only the 2C3L or stepwise method was not sufficient to terminate all re-entries in our model, which may partially explain the poor long-term arrhythmiafree outcomes in clinical practice. Our findings also suggest that computational heart modelling is an important tool to assist in the establishment of optimal ablation strategies.

Cardiodynamicsgram: a novel tool for monitoring cardiac function in exercise training.

This study evaluated the feasibility of cardiodynamicsgram (CDG) for monitoring the cardiac functions of athletes and exercisers. CDG could provide an effective, simple, and economical tool for exercise training. Seventeen middle-distance race athletes aged 14-28 years old were recruited. CDG tests and blood test including creatine kinase (CK), CK-MB isoenzyme, and high-sensitivity troponin I (hsTnI) were performed before a high-intensity prolonged training, as well as 2 and 14 h after training, respectively. The CDG test result was unsatisfactory when the CK test result was used as standard. However, the accuracy of CDG test was about 80% when CK-MB and hsTnI were used as standards. Thus, CDG offers a noninvasive, simple, and economical approach for monitoring the cardiac function of athletes and exercisers during exercise training. Nonetheless, the applicability of CDG needs further investigation.

Electrocardiogram (ECG) patterns of left anterior fascicular block and conduction impairment in ventricular myocardium: a whole-heart model-based simulation study.

Left anterior fascicular block (LAFB) is a heart disease identifiable from an abnormal electrocardiogram (ECG). It has been reported that LAFB is associated with an increased risk of heart failure. Non-specific intraventricular conduction delay due to the lesions of the conduction bundles and slow cell to cell conduction has also been considered as another cause of heart failure. Since the location and mechanism of conduction delay have notable variability between individual patients, we hypothesized that the impaired conduction in the ventricular myocardium may lead to abnormal ECGs similar to LAFB ECG patterns. To test this hypothesis, based on a computer model with a three dimensional whole-heart anatomical structure, we simulated the cardiac exciting sequence map and 12-lead ECG caused by the block in the left anterior fascicle and by the slowed conduction velocity in the ventricular myocardium. The simulation results showed that the typical LAFB ECG patterns can also be observed from cases with slowed conduction velocity in the ventricular myocardium. The main differences were the duration of QRS and wave amplitude. In conclusion, our simulations provide a promising starting point to further investigate the underlying mechanism of heart failure with LAFB, which would provide a potential reference for LAFB diagnosis.

Simulation of Atrial Fibrosis Using Coupled Myocyte-Fibroblast Cellular and Human Atrial Models.

Atrial fibrosis is characterized by expansion of extracellular matrix and increase in the number of fibroblasts which has been associated with the development and maintenance of atrial arrhythmias. However, the mechanisms how the fibrosis contributes to atrial arrhythmia remain incompletely understood. In this study, we used a proposed fibroblast model coupled with the human atrial myocyte to investigate the effects of fibrosis on atrial excitability and repolarization at both cellular and macroscopic levels. The 12-lead electrocardiogram (ECG) was also simulated to explore the index of clinical diagnosis for fibrosis. The simulation results showed that the fibrosis can modify action potential morphology of human atrial myocyte, slow down wave propagation, and have rate adaptation, thus causing the atrial electrical heterogeneity. The fibrosis alone was sufficient to cause arrhythmia, induce reentry wave, and result in low amplitude and wide P waves at normal heart rate and significant prolonged and inverse P waves at high heart rate. All these symptoms aggravated when the level of fibrosis increased. Our simulations demonstrated that fibrosis is the substrate of atrial arrhythmia and thereby may be a potential target in the treatment of atrial arrhythmias.

Circulating MiRNA biomarkers serve as a fingerprint for diabetic atherosclerosis.

Type 2 diabetes mellitus induced atherosclerosis (DA) is regarded as a major cause of disability and death in diabetic patients. The early prediction of atherosclerosis in patients DM is necessary. Therefore, we aimed to identify special plasma microRNAs that can serve as a novel non-invasive screening signature of DA patients with atherosclerosis and test its specificity and sensitivity in the early diagnosis of DA. In total, we obtained plasma samples from 285 diabetic atherosclerosis patients and matched diabetic retinopathy (DR) patients, diabetic nephropathy (DN) patients, diabetes mellitus without complication (DM) and healthy controls. An initial screening of miRNA expression was performed through TaqMan Low Density Array (TLDA). Three miRNAs were significantly increased in patients with DA compared with other groups after the multiple stages. The areas under the receiver operating characteristic (AUC) curves of the validated three-plasma miRNAs signature in DA comparing with NC were 0.881, 0.709 and 0.842 while the merged was 0.940 while DA comparing with DM was 0.879, 0.663, 0.731 and the merged was 0.928. The three miRNA could also distinguish DA from DN with an AUC of 0.894, 0.782, 0.910 and 0.963 (merged) as well as from DR with an AUC of 0.876, 0.815, 0.850 and 0.925 (merged). In conclusion, these data provide evidence that plasma miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of DA. These biomarkers could serve as a dynamic monitoring factor for detecting the progression of DA from DR, DN, DM patients.

In Silico Investigation into Cellular Mechanisms of Cardiac Alternans in Myocardial Ischemia.

Myocardial ischemia is associated with pathophysiological conditions such as hyperkalemia, acidosis, and hypoxia. These physiological disorders may lead to changes on the functions of ionic channels, which in turn form the basis for cardiac alternans. In this paper, we investigated the roles of hyperkalemia and calcium handling components played in the genesis of alternans in ischemia at the cellular level by using computational simulations. The results show that hyperkalemic reduced cell excitability and delayed recovery from inactivation of depolarization currents. The inactivation time constant τf of L-type calcium current (ICaL) increased obviously in hyperkalemia. One cycle length was not enough for ICaL to recover completely. Alternans developed as a result of ICaL responding to stimulation every other beat. Sarcoplasmic reticulum calcium-ATPase (SERCA2a) function decreased in ischemia. This change resulted in intracellular Ca (Ca i ) alternans of small magnitude. A strong Na+-Ca2+ exchange current (INCX) increased the magnitude of Ca i alternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans.