Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking / 生理学报

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.

Grass height and transmission ecology of Echinococcus multilocularis in Tibetan communities, China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Alveolar echinococcosis is a major zoonosis of public health significance in western China. Overgrazing was recently assumed as a potential risk factor for transmission of alveolar echinococcosis. The research was designed to further test the overgrazing hypothesis by investigating how overgrazing influenced the burrow density of intermediate host small mammals and how the burrow density of small mammals was associated with dog Echinococcus multilocularis infection.</p><p><b>METHODS</b>The study sites were chosen by previous studies which found areas where the alveolar echinococcosis was prevalent. The data, including grass height, burrow density of intermediate host small mammals, dog and fox fecal samples as well as Global Positioning System (GPS) position, were collected from field investigations in Shiqu County, Sichuan Province, China. The fecal samples were analyzed using copro-PCR. The worms, teeth, bones and hairs in the fecal samples were visually examined. Single factor and multifactor analyses tools including chi square and generalized linear models were applied to these data.</p><p><b>RESULTS</b>By using grass height as a proxy of grazing pressure in the homogenous pasture, this study found that taller grass in the pasture led to lower small mammals' burrow density (chi(2) = 4.670, P = 0.031, coefficient = -1.570). The Echinococcus multilocularis worm burden in dogs was statistically significantly related to the maximum density of the intermediate host Ochotona spp. (chi(2) = 5.250, P = 0.022, coefficient = 0.028). The prevalence in owned dogs was positively correlated to the number of stray dogs seen within a 200 meter radius (Wald chi(2) = 8.375, P = 0.004, odds ratio = 1.198).</p><p><b>CONCLUSIONS</b>Our findings support the hypothesis that overgrazing promotes transmission of alveolar echinococcosis and confirm the role of stray dogs in the transmission of alveolar echinococcosis.</p>

Impact of overgrazing on the transmission of Echinococcus multilocularis in Tibetan pastoral communities of Sichuan Province, China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Overgrazing was assumed to increase the population density of small mammals that are the intermediate hosts of Echinococcus multilocularis, the pathogen of alveolar echinococcosis in the Qinghai Tibet Plateau. This research tested the hypothesis that overgrazing might promote Echinococcus multilocularis transmission through increasing populations of small mammal, intermediate hosts in Tibetan pastoral communities.</p><p><b>METHODS</b>Grazing practices, small mammal indices and dog Echinococcus multilocularis infection data were collected to analyze the relation between overgrazing and Echinococcus multilocularis transmission using nonparametric tests and multiple stepwise logistic regression.</p><p><b>RESULTS</b>In the investigated area, raising livestock was a key industry. The communal pastures existed and the available forage was deficient for grazing. Open (common) pastures were overgrazed and had higher burrow density of small mammals compared with neighboring fenced (private) pastures; this high overgrazing pressure on the open pastures measured by neighboring fenced area led to higher burrow density of small mammals in open pastures. The median burrow density of small mammals in open pastures was independently associated with nearby canine Echinococcus multilocularis infection (P = 0.003, OR = 1.048).</p><p><b>CONCLUSION</b>Overgrazing may promote the transmission of Echinococcus multilocularis through increasing the population density of small mammals.</p>

Biological approaches to generating cardiac biopacemaker for bradycardia / 生理学报

Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been investigated for generating cardiac biopacers. This article summarizes the progresses in research on recreation of cardiac biopacemakers. Genetically engineered biological pacemaker holds great promise to potentially cure severe bradycardia if critical issues, such as their stability and longevity, are properly solved.

Embryonic stem cells cultured in biodegradable scaffold repair infarcted myocardium in mice / 生理学报

Our previous findings demonstrated that directly injecting embryonic stem cells (ESCs) into ischemic region of the heart improved cardiac function in animals with experimental myocardial infarction (MI). Tissue engineering with stem cells may provide tissue creation and repair. This study was designed to investigate the effectiveness of grafting of ESC-seeded biodegradable patch on infarcted heart. MI in mice was induced by ligation of the left coronary artery. Mouse ESCs were seeded on polyglycolic-acid (PGA) material patches. Three days after culture, an ESC-seeded patch was transplanted on the surface of ischemic and peri-ischemic myocardium. Eight weeks after MI operation and patch transplantation, hemodynamics and cardiac function were evaluated in four (sham-operated, MI, MI + cell-free patch, and MI + ESC-patch) groups of mice. The blood pressure and left ventricular function were significantly reduced in the MI animals. Compared with MI alone and MI + cell-free patch groups, the animals received MI + ESC-seeded patches significantly improved blood pressure and ventricular function. The survival rate of the MI mice grafted with MI + ESC-seeded patches was markedly higher than that in MI alone or MI + cell-free patch animals. GFP-positive tissue was detected in infarcted area with grafting of ESC-seeded patch, which suggests the survivors of ESCs and possible myocardial regeneration. Our data demonstrate that grafting of ESC-seeded bioabsorbable patch can repair infarcted myocardium and improve cardiac function in MI mice. This novel approach of combining stem cells and biodegradable materials may provide a therapeutic modality for repairing injured heart.

Cardiac application of embryonic stem cells / 生理学报

Cardiomyocytes deceased during myocardial infarction (MI) are replaced with non-contractile scar tissue, which has a great chance to cause heart failure. Repair of dead or injured myocardium and improvement of cardiac function remain a serious challenge for the therapy of heart failure. Recently, stem cells have been transplanted in experimental settings to replace lost myocardium. This article summarizes the recent experimental findings on transplantation of embryonic stem cells (ESCs) and their derived cells in animals with myocardial injury and highlights the progresses in research of these particular cell types. Beneficial effects of cell transplantation with other cell types in injured hearts have been detailed in other reviews. ESCs are pluripotent cells derived from early mammalian embryos at the blasto-stage. These cells have the capacity for prolonged undifferentiated proliferation or differentiation into all of specialized somatic cell types of the body in culture, including cardiomyocytes. Because of the great ability of proliferation and differentiation to mature tissues, ESCs are a potential valuable resource for cell therapy targeting regeneration of functional myocardium in diseased hearts. In recent animal studies intramyocardial transplantation of ESCs or their differentiated cardiac-like cells regenerated injured myocardium and improved heart function in infarcted animal models. In addition, intravenous infusion of ESCs significantly increased the survival rate and attenuated myocardial injury in viral myocarditic mice. Development and characterization of cardiomyocytes in vitro from human ESCs have been reported recently. However, many ethical, political, and scientific barriers have to be overcome before clinical utilization of human ESCs and their differentiated cells for treating end-stage cardiac diseases.

Effects of polyunsaturated fatty acids on cardiac voltage-activated K(+) currents in adult ferret cardiomyocytes / 生理学报

This study was carried out in adult ferret cardiomyocytes to investigate the effects of the n-3 polyunsaturated fatty acids (PUFAs) on voltage-gated K(+) currents. We report that the two outward K(+) currents: the transient outward K(+) current (I(to)) and the delayed rectifier K(+) current (I(K)), are both inhibited by the n-3 PUFAs, while the inwardly rectifying K(+) current (I(K1)) is unaffected by the n-3 PUFAs. Docosahexaenoic acid (C22:6n-3, DHA) produced a concentration dependent suppression of I(to) and I(K) in adult ferret cardiomyocytes with an IC(50) of 7.5 and 20 micromol/L, respectively; but not I(K1). In addition, eicosapentaenoic acid (C20:5n-3, EPA) had the effects on the three K(+) channels similar to DHA. Arachidonic acid (C20:4n-6, AA) at 5 or 10 micromol/L, after an initial inhibitory effect on I(K), caused an activation of I(K),AA which was prevented by pretreatment with indomethacin, a cyclooxygenase inhibitor. Monounsaturated and saturated fatty acids, which are not antiarrhythmic, lack the effects on these K(+) currents. Our results demonstrate that the n-3 PUFAs inhibit cardiac I(to) and I(K) with much less potency compared to their effects on cardiac Na(+) and Ca(2+) currents as we reported previously. This inhibition of the cardiac ion currents by the n-3 PUFAs may contribute to their antiarrhythmic actions.