scholarly journals Mesenteric lymph from rats with trauma-hemorrhagic shock causes abnormal cardiac myocyte function and induces myocardial contractile dysfunction

2011 ◽  
Vol 111 (3) ◽  
pp. 799-807 ◽  
Author(s):  
Justin T. Sambol ◽  
Marlon A. Lee ◽  
Mingshan Jiang ◽  
Garima Dosi ◽  
Wei Dong ◽  
...  
Keyword(s):  
Action Potential ◽  
Hemorrhagic Shock ◽  
Cardiac Myocytes ◽  
Action Potential Duration ◽  
Contractile Dysfunction ◽  
Inotropic Effects ◽  
Mesenteric Lymph ◽  
Myocyte Function ◽  
Myocardial Contractile ◽  
Induced Changes

Myocardial contractile dysfunction develops following trauma-hemorrhagic shock (T/HS). We have previously shown that, in a rat fixed pressure model of T/HS (mean arterial pressure of 30–35 mmHg for 90 min), mesenteric lymph duct ligation before T/HS prevented T/HS-induced myocardial contractile depression. To determine whether T/HS lymph directly alters myocardial contractility, we examined the functional effects of physiologically relevant concentrations of mesenteric lymph collected from rats undergoing trauma-sham shock (T/SS) or T/HS on both isolated cardiac myocytes and Langendorff-perfused whole hearts. Acute application of T/HS lymph (0.1–2%), but not T/SS lymph, induced dual inotropic effects on myocytes with an immediate increase in the amplitude of cell shortening (1.4 ± 0.1-fold) followed by a complete block of contraction. Similarly, T/HS lymph caused dual, positive and negative effects on cellular Ca2+ transients. These effects were associated with changes in the electrophysiological properties of cardiac myocytes; T/HS lymph initially prolonged the action potential duration (action potential duration at 90% repolarization, 3.3 ± 0.4-fold), and this was followed by a decrease in the plateau potential and membrane depolarization. Furthermore, intravenous infusion of T/HS lymph, but not T/SS lymph, caused myocardial contractile dysfunction at 24 h after injection, which mimicked actual T/HS-induced changes; left ventricular developed pressure (LVDP) and the maximal rate of LVDP rise and fall (±dP/d tmax) were decreased and inotropic response to Ca2+ was blunted. However, the contractile responsiveness to β-adrenergic receptor stimulation in the T/HS lymph-infused hearts remained unchanged. These results suggest that T/HS lymph directly causes negative inotropic effects on the myocardium and that T/HS lymph-induced changes in myocyte function are likely to contribute to the development of T/HS-induced myocardial dysfunction.

Dual effects of mesenteric lymph isolated from rats with burn injury on contractile function in rat ventricular myocytes

2006 ◽  
Vol 290 (2) ◽  
pp. H778-H785 ◽  
Author(s):  
Atsuko Yatani ◽  
Da-Zhong Xu ◽  
Keiichi Irie ◽  
Kazunori Sano ◽  
Anoush Jidarian ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Burn Injury ◽  
Ventricular Myocytes ◽  
Contractile Dysfunction ◽  
Inotropic Effects ◽  
Rat Ventricular Myocytes ◽  
Mesenteric Lymph ◽  
Action Potential Plateau ◽  
Potential Plateau

Gut-derived factors in intestinal lymph have been shown to trigger myocardial contractile dysfunction. However, the underlying cellular mechanisms remain unclear. We examined the effects of physiologically relevant concentrations of mesenteric lymph collected from rats with 40% burn injury (burn lymph) on excitation-contraction coupling in rat ventricular myocytes. Burn lymph (0.1–5%), but not control mesenteric lymph from sham-burn animals, induced dual positive and negative inotropic effects depending on the concentrations used. At lower concentrations (<0.5%), burn lymph increased the amplitude of myocyte contraction (1.6 ± 0.3-fold; n = 12). At higher concentrations (>0.5%), burn lymph initially enhanced myocyte contraction, which was followed by a block of contraction. These effects were partially reversible on washout. The initial positive inotropic effect was associated with a prolongation of action potential duration (measured at 90% repolarization, 2.5 ± 0.6-fold; n = 10), leading to significant increases in the net Ca2+ influx (1.7 ± 0.1-fold; n = 8). There were no significant changes in the resting membrane potential. The negative inotropic effect was accompanied by a decrease in the action potential plateau (overshoot decrease by 69 ± 10%; n = 4) and membrane depolarization. Voltage-clamp experiments revealed that the positive inotropic effects of burn lymph were due to an inhibition of the transient outward K+ currents that prolong action potential duration, and the inhibitory effects were due to a concentration-dependent inhibition of Ca2+ currents that lead to a reduction of action potential plateau. These burn lymph-induced changes in cardiac myocyte Ca2+ handling can contribute to burn-induced contractile dysfunction and ultimately to heart failure.

Abstract 107: Mitochondrial Dysfunction Mediated Myocardial Stunning Following Resuscitation From Cardiac Arrest

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Willard W Sharp ◽  
Lin Piao ◽  
Yong Fang ◽  
David G Beiser ◽  
James K Liao ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Myocardial Stunning ◽  
Mitochondrial Dynamics ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Spontaneous Circulation ◽  
Contractile Dysfunction ◽  
Myocardial Contractile ◽  
Induced Changes

Rationale: Severe myocardial contractile dysfunction following resuscitation from cardiac arrest (CA) is a major contributor to CA mortality. The pathophysiology and etiology of this dysfunction is not known and there are no pharmacological therapies known to improve outcomes. Previously, we demonstrated that Dynamin related protein 1 (Drp1) is activated and recruited to the mitochondria during CA and that the Drp1 inhibitor Mdivi-1 improves post CA survival. Objective: To determine the effects of CA length on myocardial and mitochondrial function. We also sought to determine the effects of Mdivi-1 on post CA outcomes. Methods and Results: Asystolic cardiac arrest (CA) was induced in mice by IV injection of 0.08 mg/g KCL. CPR begun at 4, 8, 12, and 16 minutes post-cardiac arrest had rates of return of spontaneous circulation (ROSC) of 100%(12/12), 93%(14/15), 71%(10/14), and 44% (4/9) and 2-hour survival of 100%(12/12), 67%(10/15), 50%(7/14), and 11%(1/9). Transthoracic echocardiography 15 min post-resuscitation demonstrated percent fractional shortening of 36±4% (Sham,n=6), 30±4% (4 minCA,n=11), 24±5% (8minCA,n=10), 15±2% (12minCA,n=12). In surviving animals, myocardial dysfunction persisted for 2 hours post-resuscitation, but slowly recovered to baseline by 72 hours. No evidence of myocardial necrosis, inflammation, or apoptosis was noted following resuscitation. Progressive increases in mitochondrial derived reactive oxygen species (ROS) during CA was observed by MitoSOX red myocardial tissue staining. Mitochondria isolated from 12 min CA hearts demonstrated decreased substrate coupled and uncoupled respiration. Mdivi-1, a mitochondrial inhibitor of division (fission), improved survival and neurological scores in mice following an 8 min cardiac arrest compared to controls. Conclusions: Severe, time dependent myocardial stunning (contractile dysfunction in the absence of irreversible injury) was observed following asystolic cardiac arrest. This myocardial stunning was associated with mitochondrial injury and improved by an inhibitor of Drp1. Strategies targeting ischemia/reperfusion-induced changes in mitochondrial dynamics hold promise for improving myocardial function and survival following cardiac arrest.

scholarly journals Calcium influx through If channels in rat ventricular myocytes

2007 ◽  
Vol 292 (3) ◽  
pp. C1147-C1155 ◽  
Author(s):  
Xiao Yu ◽  
Xiao-Wei Chen ◽  
Peng Zhou ◽  
Lijun Yao ◽  
Tao Liu ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Myocytes ◽  
Action Potential Duration ◽  
Channel Blocker ◽  
Ventricular Myocytes ◽  
Spontaneously Hypertensive Rat ◽  
Calcium Influx ◽  
Hek293 Cells ◽  
Hcn Channels ◽  
Rat Ventricular Myocytes

The hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, or cardiac ( If)/neuronal ( Ih) time- and voltage-dependent inward cation current channels, are conventionally considered as monovalent-selective channels. Recently we discovered that calcium ions can permeate through HCN4 and Ih channels in neurons. This raises the possibility of Ca2+ permeation in If, the Ih counterpart in cardiac myocytes, because of their structural homology. We performed simultaneous measurement of fura-2 Ca2+ signals and whole cell currents produced by HCN2 and HCN4 channels (the 2 cardiac isoforms present in ventricles) expressed in HEK293 cells and by If in rat ventricular myocytes. We observed Ca2+ influx when HCN/ If channels were activated. Ca2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium, an If channel blocker, inhibited If and Ca2+ influx at the same time. Quantitative analysis revealed that Ca2+ flux contributed to ∼0.5% of current produced by the HCN2 channel or If. The associated increase in Ca2+ influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which If current density is higher than that of normotensive rat ventricle. In the absence of EGTA (a Ca2+ chelator), preactivation of If channels significantly reduced the action potential duration, and the effect was blocked by another selective If channel blocker, ZD-7288. In the presence of EGTA, however, preactivation of If channels had no effects on action potential duration. Our data extend our previous discovery of Ca2+ influx in Ih channels in neurons to If channels in cardiac myocytes.

scholarly journals MicroRNA-365 regulates human cardiac action potential duration

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Dena Esfandyari ◽  
Bio Maria Ghéo Idrissou ◽  
Konstantin Hennis ◽  
Petros Avramopoulos ◽  
Anne Dueck ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Myocytes ◽  
Action Potential Duration ◽  
Ionic Current ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Action Potential ◽  
Patient Specific ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Cardiac Action Potential Duration

AbstractAbnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.

scholarly journals Mesenteric lymph duct ligation prevents trauma/hemorrhage shock-induced cardiac contractile dysfunction

2009 ◽  
Vol 106 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Justin T. Sambol ◽  
Marlon A. Lee ◽  
Francis J. Caputo ◽  
Kentaro Kawai ◽  
Chirag Badami ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Experimental Studies ◽  
Left Ventricular ◽  
Lv Function ◽  
Contractile Dysfunction ◽  
Inotropic Effects ◽  
Arterial Blood ◽  
Mesenteric Lymph ◽  
Duct Ligation ◽  
Lymph Duct

Clinical and experimental studies have shown that trauma combined with hemorrhage shock (T/HS) is associated with myocardial contractile dysfunction. However, the initial events triggering the cardiac dysfunction are not fully elucidated. Thus we tested the hypothesis that factors carried in intestinal (mesenteric) lymph contribute to negative inotropic effects in rats subjected to a laparotomy (T) plus hemorrhagic shock (HS; mean arterial blood pressure of 30–40 Torr for 90 min) using a Langendorff isolated heart preparation. Left ventricular (LV) function was assessed 24 h after trauma plus sham shock (T/SS) or T/HS by recording the LV developed pressure (LVDP) and the maximal rate of LVDP rise and fall ( ± dP/d tmax) in five groups of rats: 1) naive noninstrumented rats, 2) rats subjected to T/SS, 3) rats subjected to T/HS, 4) rats subjected to T/SS with mesenteric lymph duct ligation (T/SS+LDL), or 5) rats subjected to T/HS+LDL. Cardiac function was comparable in hearts from naive, T/SS, and T/SS+LDL rats. Both LVDP and ± dP/d tmax were significantly depressed after T/HS. The T/HS hearts also manifested a blunted responsiveness to increases in coronary flow rates and Ca2+, and this was prevented by LDL preceding T/HS. Although electrocardiograms were normal under physiological conditions, when the T/HS hearts were perfused with low Ca2+ levels (∼0.5 mM), prolonged P-R intervals and second-degree plus Wenckebach-type atrioventricular blocks were observed. No such changes occurred in the control or T/HS+LDL hearts. The effects of T/HS were similar to those of the Ca2+ channel antagonist diltiazem, indicating that an impairment of cellular Ca2+ handling contributes to T/HS-induced cardiac dysfunction. In conclusion, gut-derived factors carried in mesenteric lymph are responsible for acute T/HS-induced cardiac dysfunction.

scholarly journals Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Prasongchai Sattayaprasert ◽  
Sunil K. Vasireddi ◽  
Emre Bektik ◽  
Oju Jeon ◽  
Mohammad Hajjiri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Action Potential ◽  
Induced Pluripotent Stem Cells ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cells ◽  
Action Potential Duration ◽  
Calcium Release ◽  
Prolonged Action ◽  
Induced Pluripotent ◽  
Prolonged Action Potential Duration

Background: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates. Methods: hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results: Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% ( P <0.001, n=15), increased Ca2+ alternans by 300% ( P <0.001, n=18), and promoted spontaneous calcium release activity (n=14, P <0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1β (98%, P <0.0001) and IL-6 (460%, P <0.02) compared with nonfailing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti–IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. Conclusions: We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti–IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.

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