Derivative Of Left Ventricular Pressure Research Articles

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model

ObjectiveLactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. MethodsHearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. ResultsLV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. ConclusionsEnteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Patient-specific heart simulation can identify non-responders to cardiac resynchronization therapy

To identify non-responders to cardiac resynchronization therapy (CRT), various biomarkers have been proposed, but these attempts have not been successful to date. We tested the clinical applicability of computer simulation of CRT for the identification of non-responders. We used the multi-scale heart simulator “UT-Heart,” which can reproduce the electrophysiology and mechanics of the heart based on a molecular model of the excitation–contraction mechanism. Patient-specific heart models were created for eight heart failure patients who were treated with CRT, based on the clinical data recorded before treatment. Using these heart models, bi-ventricular pacing simulations were performed at multiple pacing sites adopted in clinical practice. Improvement in pumping function measured by the relative change of maximum positive derivative of left ventricular pressure (%ΔdP/dtmax) was compared with the clinical outcome. The operators of the simulation were blinded to the clinical outcome. In six patients, the relative reduction in end-systolic volume exceeded 15% in the follow-up echocardiogram at 3 months (responders) and the remaining two patients were judged as non-responders. The simulated %ΔdP/dtmax at the best lead position could identify responders and non-responders successfully. With further refinement of the model, patient-specific simulation could be a useful tool for identifying non-responders to CRT.

Short-Term Hemodynamic and Electrophysiological Effects of Cardiac Resynchronization by Left Ventricular Septal Pacing

BackgroundCardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated. ObjectivesThe authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients. MethodsTemporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax). ResultsAs compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 ± 22 μVs) and SDAT (to 26 ± 7 ms) than BiV (to 93 ± 26 μVs and 31 ± 7 ms; both p < 0.05) and LVs+RV pacing (to 108 ± 37 μVs; p < 0.05; and 29 ± 8 ms; p = 0.05). The increase in LVdP/dtmax was similar during LVs and BiV pacing (17 ± 10% vs. 17 ± 9%, respectively) and larger than during LVs+RV pacing (11 ± 9%; p < 0.05). There were no significant differences between basal, mid-, or apical LVs levels in LVdP/dtmax and SDAT. In a subgroup of 16 patients, changes in QRS area, SDAT, and LVdP/dtmax were comparable between LVs and HB pacing. ConclusionsLVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT.

Cardiovascular effects of DWORF (dwarf open reading frame) peptide in normal and ischaemia/reperfused isolated rat hearts

The novel peptide dwarf open reading frame (DWORF), highly conserved across species and expressed almost exclusively in cardiac ventricular muscle, may play a role in cardiac physiology and pathophysiology. The effect of direct administration of DWORF in the intact heart has not previously been examined. Accordingly, we investigated the cardiac effects of DWORF (1−30 nM) in normal isolated perfused rat hearts and hearts undergoing ischaemia/reperfusion (I/R) injury, and evaluated potential mechanisms of action. Exogenous DWORF at the top dose (30 nM) increased perfusion pressure (PP) in normal hearts, which indicates coronary vasoconstriction; and during post-ischaemic reperfusion, DWORF increased PP in a dose-dependent manner. In I/R hearts, DWORF at the top dose also increased left ventricular end-diastolic pressure and maximum and minimum derivatives of left ventricular pressure noted dP/dt(max) and dP/dt(min), respectively, without affecting developed pressure (DP). Co-infusion of DWORF with Diltiazem, an l-type Ca2+ channel blocker (1μM), in I/R hearts attenuated the falls in DP, dP/dt(max) and dP/dt(min) observed with Diltiazem alone. DWORF co-infusion with both Diltiazem and Y27632 (1μM) (a Rho-Kinase inhibitor) reversed the coronary vasodilator effect of the inhibitors administered alone. In conclusion, we provide the first evidence that DWORF has coronary vasoconstrictor actions in normal hearts and when administered during reperfusion in an ex-vivo model of cardiac I/R injury, and also exhibits positive cardiac inotropic activity in the latter setting. DWORF’s effect on ventricular contractile function appears to be dependent on the l-type Ca2+ channel, whereas Rho-Kinase activity may be related to the coronary vasoconstrictor effects of DWORF.

Involvement of γ-Glutamyl Transpeptidase in Ischemia/Reperfusion-Induced Cardiac Dysfunction in Isolated Rat Hearts.

GGsTop is a highly potent and specific, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor without any influence on glutamine amidotransferases. The aim of the present study was to investigate the involvement of GGT in ischemia/reperfusion-induced cardiac dysfunction by assessing the effects of a treatment with GGsTop. Using a Langendorff apparatus, excised rat hearts underwent 40 min of global ischemia without irrigation and then 30 min of reperfusion. GGT activity was markedly increased in cardiac tissues exposed to ischemia, and was inhibited by the treatment with GGsTop. Exacerbation of cardiac functional parameters caused by ischemia and reperfusion, namely the reduction of left ventricular (LV) developed pressure and the maximum and negative minimum values of the first derivative of LV pressure, and the increment in LV end-diastolic pressure was significantly attenuated by GGsTop treatment. The treatment with GGsTop suppressed excessive norepinephrine release in the coronary perfusate, a marker for myocardial dysfunction, after ischemia/reperfusion. In addition, oxidative stress indicators in myocardium, including superoxide and malondialdehyde, after ischemia/reperfusion were significantly low in the presence of GGsTop. These observations demonstrate that enhanced GGT activity contributes to cardiac damage after myocardial ischemia/reperfusion, possibly via increased oxidative stress and subsequent norepinephrine overflow. GGT inhibitors have potential as a therapeutic strategy to prevent myocardial ischemia/reperfusion injury in vivo.

A Mathematical Model of dP/dt Max for the Evaluation of the Dynamic Control of Heart Contractility in Septic Shock

Septic shock (SS) patients often show elevated heart rate (HR) despite resuscitation, and this condition is considered an early manifestation of myocardial dysfunction due to an impairment of autonomic nervous system (ANS). We aimed at proposing a mathematical model to assess the autonomic control of ventricular contractility (VC) and HR to track changes in heart functionality during an experimental animal model of SS and resuscitation. SS was induced in six adult swine by polymicrobial peritonitis. We analyzed the beat-to-beat variability of the maximum positive time derivative of left ventricular pressure (dP/dt max), heart period (HP), and aortic blood pressure (ABP). We identified the transfer functions relating fluctuations in ABP and HP to dP/dt max to characterize the static and dynamic properties of the arterial baroreflex and the force-frequency relation mechanisms, respectively. Standard indices of autonomic dysfunction have also been considered as HR variability (HRV) and baroreflex sensitivity (BRS). During baseline, the baroreflex is predominant in controlling VC with a gain value of -5.8 (-7.5,-3) s-1, compared to -1.2 (-1.9,-0.5) mmHg/s ms-1 of the force-frequency autoregulation. During shock, both mechanisms increase their extent in VC control (higher gains and slightly faster dynamics for the baroreflex). After resuscitation, the physiological control of VC is not restored and all the animals still exhibit high HR and reduced HRV and BRS. A condition of cardiovascular inefficiency is persistent after resuscitation and this could be due to autonomic dysfunction. The ANS in SS is crucial to restore homeostasis. Our model could be used to evaluate the efficacy of treatments on VC and related control mechanisms.

A Linear Fragment of Unacylated Ghrelin (UAG6-13) Protects Against Myocardial Ischemia/Reperfusion Injury in Mice in a Growth Hormone Secretagogue Receptor-Independent Manner.

Unacylated ghrelin (UAG), the most abundant form of ghrelin in circulation, has been shown to exert cardioprotective effect in experimental cardiopathies. The present study aimed to investigate the cardioprotective effect of a linear bioactive fragment of UAG against myocardial ischemia-induced injury and dysfunction in C57BL/6 wild type mice and the mechanisms involved. Treatments were administered at doses of 100 (UAG), 1,000 and 3,000 (UAG6−13) nmol/kg at 12 h interval during 14 days prior to 30 min left coronary artery ligation and reperfusion for a period of 6 or 48 h. The infarct area was decreased in a dose-dependent manner at 48 h of reperfusion, with a reduction of 54% at the highest dose of UAG6−13 tested. Myocardial hemodynamics were improved as demonstrated by an increase in cardiac output, maximum first derivative of left ventricular pressure, and preload recruitable stroke work, a load-independent contractility index. Six hours after reperfusion, circulating levels of IL-6 and TNF-α pro-inflammatory cytokines were reduced, and the effect was maintained at 48 h for TNF-α. 5′ AMP-activated protein kinase (AMPK) was activated, while acetyl-CoA carboxylase (ACC) activity was inhibited, along with a decrease in apoptotic protein levels. In isolated hearts, the effect of UAG6−13 was unaffected by the presence of D-Lys3-GHRP-6, a ghrelin receptor (GHSR1a) antagonist, suggesting that the peptide acted through a GHSR1a-independent pathway. The results support the therapeutic application of UAG bioactive peptide fragments against myocardial ischemia/reperfusion injury.

Naringenin improves mitochondrial function and reduces cardiac damage following ischemia-reperfusion injury: the role of the AMPK-SIRT3 signaling pathway.

Mitochondrial dysfunction contributed greatly to myocardial ischemia-reperfusion (MI/R)-induced cardiomyocyte apoptosis. Naringenin is a flavonoid exhibiting potential protective effects on myocardial mitochondria under stress conditions. However, the detailed down-stream signaling pathway involved remains uncovered. This study was designed to elucidate naringenin's mitochondrial protective actions during MI/R with a focus on AMPK-SIRT3 signaling. Sprague-Dawley rats were administered with naringenin (50 mg kg-1 d-1) and subjected to MI/R surgery in the presence or absence of compound C (0.25 mg kg-1, Com.C, an AMPK inhibitor) co-treatment. An in vitro study was performed on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were administered with naringenin (80 μmol L-1) with or without SIRT3 siRNA/AMPK1α siRNA transfection. Naringenin improved post-reperfusion left ventricular systolic pressure and the instantaneous first derivative of left ventricular pressure, and reduced the infarction size and myocardial apoptosis index by suppressing mitochondrial oxidative stress damage (as evidenced by decreased mitochondrial cytochrome c release and oxidative markers) and enhancing mitochondrial biogenesis [as evidenced by increased NRF1, TFAM and oxidative phosphorylation subunit complexes (II, III and IV)]. These protective actions were abolished by Com.C (in vivo) or SIRT3 siRNA (in vitro) administration. Further investigation revealed that Com.C (in vivo) or AMPK1α siRNA (in vitro) markedly suppressed PGC-1α and SIRT3 levels while SIRT3 siRNA (in vitro) inhibited SIRT3 expression without significantly changing AMPK phosphorylation and PGC-1α levels. Taken together, we found that naringenin directly inhibits mitochondrial oxidative stress damage and preserves mitochondrial biogenesis, thus attenuating MI/R injury. Importantly, AMPK-SIRT3 signaling played a key role in this process.

Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats.

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.

Contractility surrogates derived from three-dimensional lead motion analysis and prediction of acute haemodynamic response to CRT

BackgroundPatient-specific left ventricular (LV) lead optimisation strategies with immediate feedback on cardiac resynchronisation therapy (CRT) effectiveness are needed. The purpose of this study was to compare contractility surrogates derived from...

Theophylline-Induced Left Ventricular Relaxation Disturbance in Magnesium-Deficient Rats: Improvement by K201, a Novel 1,4-Benzothiazepine Derivative.

Although magnesium deficiency induces left ventricular dysfunction, it is not known whether both systolic and diastolic functions are altered to the same extent. In this study, we investigated the effects of theophylline on left ventricular function in rats fed a normal diet or a magnesium-deficient diet for 1 month, and determined whether K201, a multi-channel blocker, modulated the effects of theophylline. Theophylline was infused at 5 mg/kg/min for 15 min in 6 control rats and 6 magnesium-deficient rats, and hemodynamic measurements were performed. In another 6 magnesium-deficient rats, K201 was infused at 0.1 mg/kg/min for 15 min simultaneously with theophylline. Theophylline induced persistent increases in heart rate, peak positive first derivative of left ventricular pressure (+dP/dt), and a transient increase in left ventricular end-diastolic pressure (LVEDP), but did not affect left ventricular systolic pressure (LVSP) and peak negative first derivative of left ventricular pressure (-dP/dt) in the control rats. In contrast, in the magnesium-deficient rats, there was a persistent decrease in LVSP and a persistent increase in -dP/dt after theophylline infusion, although increases in heart rate, +dP/dt and LVEDP were similar to those in the control rats. When K201 was infused along with theophylline in the magnesium-deficient rats, both the decrease in LVSP and increase in -dP/dt were suppressed. Theophylline impaired left ventricular function in the magnesium-deficient rats, and this was improved by K201. K201 may provide new insights regarding future strategies for heart failure treatment.

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog.

Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility.Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.

Aortic acceleration as noninvasive index of left ventricular contractility

Background: Left ventricular (LV) contractility is assessed with the invasively measured LV pressure derivative (+dP/dtmax), which is a terminal procedure in mice and other similar sized animals. Noninvasive methods to assess LV contractility have been reported in patients, sheep, dogs, and rats. We undertook this study to validate the use of acceleration of aortic flow velocity in lieu of +dP/dtmax to assess LV contractility in mice. Methods: We measured aortic blood flow velocity noninvasively simultaneous with invasive measurement of LV pressure in the anesthetized mouse. Mean, Ym (=Vp/Tp) and peak, Yp (=dV/dtmax) aortic accelerations were calculated and compared to +dP/dtmax (X) calculated from LV pressure. Measurements were made at baseline and post-dobutamine administration (1μg/g BW) in 4 wild type male mice (C57BL6/J). Results: Peak and mean aortic accelerations were compared to +dP/dtmax at several heart rates (range: 387 to 701 bpm, n=18 data points). Linear regression of both, peak aortic acceleration (Yp) versus +dP/dtmax (X) and mean aortic acceleration (Ym) versus +dP/dtmax (X), showed a high correlation - (Yp = 2.8X + 1617; p<0.0001; r2 = 0.896) and (Ym = 1.4X + 1319; p<0.0001; r2 = 0.903), respectively. Conclusion: The high correlation between Yp versus +dP/dtmax is in agreement with that reported in dogs, while that between Ym versus +dP/dtmax is similar to that reported in sheep. Mean acceleration requires measurement of time (Tp) to peak velocity (Vp) which can be difficult at times due to the ambiguity in the location of the peak velocity. Peak aortic acceleration is much easier to measure using the first derivative and is also highly correlated with +dP/dtmax. Preliminary result of this study suggest that both peak and mean aortic acceleration may be used as a noninvasive index of LV contractility in mice. We expect to evaluate these relationships further under various loading conditions.

Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation.

Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states.

Cardiac sympathetic afferents are considered to be essential pathways for transmission of cardiac nociception to the central nervous system during myocardial ischaemia. However, a potential contribution of the CSAR control of cardiac dysfunction in both normal and chronic heart failure (CHF) states remains unknown. We found that activation of the CSAR evokes little increase in cardiac contractility with an exaggerated peripheral vasoconstriction in the CHF state. CSAR inhibition by epicardial lidocaine decreased cardiac contractility to a greater extent in CHF rats than sham rats. Furthermore, we also found that epicardial lidocaine paradoxically decreased left ventricular end-diastolic pressure (LVEDP) and left ventricular end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. Chronic ablation of the CSAR by epicardial application of the afferent neurotoxin, RTX, selectively lowered diastolic blood pressure CHF rats. The observation suggests that CSAR has a differential effect on cardiac function in normal and CHF states. CSAR activation in normal state causes significant increase in cardiac contractility and cardiac output. The enhanced 'cardiac sympathetic afferent reflex' (CSAR) critically contributes to the exaggerated global sympathetic tone in chronic heart failure (CHF). However, a potential contribution of the cardio-cardiac reflex control of cardiac function in both normal and CHF states remains unknown. In this study, we evaluated the effects of direct activation or inhibition of the CSAR on cardiac function by pressure-volume (P-V) loop analysis in ∼12-week sham-operated and myocardial infarcted (MI) rats. In sham rats, acute CSAR activation by epicardial application of bradykinin (BK) increased heart rate (HR), left ventricular systolic pressure (LVSP), the maximum first derivative of left ventricular pressure (dp/dtmax ), and the slope of the end-systolic P-V relationship (ESPVR), suggesting that acute CSAR activation in the normal state enhances myocardial contractility. CSAR activation also decreased left ventricular (LV) systolic and diastolic volumes with little effect on LV end-diastolic pressure (LVEDP) or the end-diastolic P-V relationship (EDPVR) in sham rats. Compared to sham, CHF rats exhibit a reduced increase in the slope of the ESPVR and dp/dtmax in response to BK, indicating a poor contractile response to CSAR activation. Interestingly, BK application in CHF rats increased cardiac systolic and diastolic volumes and further increased the elevated LVEDP, neither of which was seen in sham rats. Following CSAR inhibition by epicardial lidocaine, blood pressure, HR, LVSP, dp/dt, LVEDP and ESPVR decreased in CHF rats whereas lidocaine had little effect in sham rats, indicating that the CSAR is tonically active in CHF and contributes to cardiac dysfunction. Furthermore, we found that epicardial lidocaine paradoxically decreased LV end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. The decreased preload by lidocaine in CHF rats may be due to a reduction in peripheral vascular resistance since epicardial lidocaine significantly lowered peripheral (renal) sympathetic nerve activity in CHF rats but not in sham rats. Furthermore, chronic ablation of CSAR by epicardial application of a selective afferent neurotoxin, resiniferatoxin, selectively lowered diastolic blood pressure both at daytime and night-time with less effect on systolic blood pressure in CHF rats. Our data suggest that there is an imbalance between cardiac and peripheral responses to CSAR in CHF animals compared to sham-operated controls.

Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines With Heart Failure

BackgroundMultisite biventricular pacing (MSP) has been proposed as an alternative strategy to improve the efficiency of conventional biventricular pacing (BVP), but its utility remains unclear. This study sought to investigate whether MSP induced better synchrony and hemodynamic effects in canines with heart failure. Methods and ResultsAfter 3 weeks' rapid right ventricular pacing, 7 canines were sutured with 4 left ventricular (LV) leads on the anterior, lateral, posterior, and apical walls and followed by MSP and BVP. Hemodynamic, electrocardiographic, and echocardiographic parameters were measured. Dyssynchrony was assessed by tissue Doppler imaging for Yu-index (longitudinal direction) and speckle tracking imaging for the standard deviation of time to peak radial strains (SDε, radial direction). Compared with BVP, mean MSP reduced QRS width (P < .05), Yu-index (25.3 ± 1.9 ms vs 31.6 ± 4.3 ms, P = .008), SDε (32.8 ± 5.9 ms vs 37.3 ± 7.9 ms, P = .032), and LV end-diastolic pressure (P < .05). The optimal pacing site combination improved QRS width, Yu-index, SDε, LV end-diastolic pressure, and the maximum derivative of LV pressure (dP/dtmax) significantly (all P < .05), but the worst MSP (with the smallest dP/dtmax) did not show any improvement to BVP. ConclusionsMSP is superior to BVP in reducing dyssynchrony and improving hemodynamics. The pacing site combination has a potential effect on MSP response.

Endomyocardial radial strain rate imaging during dobutamine stress echocardiography for the evaluation of contractile reserve in patients with dilated cardiomyopathy.

Myocardial contractile reserve is associated with clinical prognosis in patients with dilated cardiomyopathy (DCM). We assessed myocardial contractile reserve using tissue Doppler strain rate imaging with dobutamine stress echocardiography in DCM patients. Simultaneous echocardiography and left ventricular (LV) catheterization during dobutamine stress were performed in 20 patients with DCM, and echocardiography was performed in 31 control subjects. Dobutamine was infused at a starting dose of 5 μg/kg/min for 5 minutes and then at 10 μg/kg/min. Peak endomyocardial radial strain (ɛ) and systolic strain rate (SRsys ) measured with echocardiography and the maximum first derivative of LV pressure (LV dP/dtmax ) derived from catheterization were used as indices of contractility. Their percentage change from baseline to the dose of 10 μg/kg/min was calculated. The ɛ and SRsys were significantly smaller in DCM patients than in controls. The LV dP/dtmax , ɛ, and SRsys were significantly higher at the dose of 10 μg/kg/min than at baseline. The percentage change in SRsys was significantly correlated with the percentage change in LV dP/dtmax . Strain rate imaging during dobutamine stress in DCM might prove noninvasively informative for the evaluation of myocardial contractile reserve and provide insight into LV systolic dysfunction. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:555-560, 2016.

Chronic intermittent hypobaric hypoxia attenuates radiation induced heart damage in rats

AimsRadiation-induced heart damage (RIHD) is becoming an increasing concern for patients and clinicians due to the use of radiotherapy for thoracic tumor. Chronic intermittent hypobaric hypoxia (CIHH) preconditioning has been documented to exert a cardioprotective effect. Here we hypothesized that CIHH was capable of attenuating functional and structural damage in a rat model of RIHD. Main methodsMale adult Sprague-Dawley rats were randomly divided into 4 groups: control, radiation, CIHH and CIHH plus radiation. Cardiac function was measured using Langendorff perfusion in in vitro rat hearts. Cardiac fibrosis, oxidative stress and endoplasmic reticulum stress (ERS) was assessed by quantitative analysis of protein expression. Key findingsNo significant difference between any two groups was observed in baseline cardiac function as assessed by left ventricular end diastolic pressure (LVEDP), left ventricular developing pressure (LVDP) and the derivative of left ventricular pressure (±LVdp/dt). When challenged by ischemia/reperfusion, LVEDP was increased but LVDP and ±LVdp/dt was decreased significantly in radiation group compared with controls, accompanied by an enlarged infarct size and decreased coronary flow. Importantly, CIHH dramatically improved radiation-induced damage of cardiac function and blunted radiation-induced cardiac fibrosis in the perivascular and interstitial area. Furthermore, CIHH abrogated radiation-induced increase in malondialdehyde and enhanced total superoxide dismutase activity, as well as downregulated expression levels of ERS markers like GRP78 and CHOP. SignificanceCIHH pretreatment alleviated radiation-induced damage of cardiac function and fibrosis. Such a protective effect was closely associated with suppression of oxidative stress and ERS responses.