Lower Left Ventricular End-diastolic Pressure Research Articles

Do collaterals to infarct bed in STE-ACS patients undergoing emergent percutaneous coronary revascularization matter? An assessment of a prospective pool for in-hospital course

BackgroundLimited data exist on the role of coronary collaterals circulation (CCC) in patients with ST-elevation acute coronary syndrome (STE-ACS). This study aimed to assess CCC and the in-hospital course of patients with CCC undergoing primary percutaneous coronary intervention (pPCI). MethodsThe study included consecutive STE-ACS patients undergoing pPCI. Good CCC was defined as Rentrop collateral score (RCS) of 2–3. Patients with good and poor CCC were compared regarding clinical characteristics, angiographic patterns, and hospital course. ResultsIn the sample of 4683 patients, mean age was 55.6 ± 11 years, and 78.8 % were male. Good CCC was observed in 499 (10.7 %) patients. The rate of intra-procedure slow-flow/no-reflow (SF/NR) was 29.9 % vs. 20.5 % (p < 0.001), and the rate of composite adverse clinical outcomes (CACO) was 21.2 % vs. 19 % (p = 0.225) for patients with good and poor CCC, respectively. Multivariable analysis identified left ventricular end-diastolic pressure (LVEDP), multi-vessel disease (MVD), and thrombus grade ≥4 as independent predictors of good CCC, with adjusted odds ratios of 0.98 [0.97–0.99], 1.69 [1.35–2.10], and 3.45 [2.64–4.52], respectively. In propensity-matched cohorts, the intra-procedure SF/NR rate was 29.9 % vs. 26.9 % (p = 0.292), and the rate of CACO was 21.2 % vs. 23.4 % (p = 0.403) for patients with good and poor CCC, respectively. ConclusionAngiographic evidence of good CCC in STE-ACS patients was limited. Good CCC was associated with a higher prevalence of MVD, high thrombus burden, and low pre-procedure LVEDP, resulting in a higher incidence of intra-procedure SF/NR. However, the CACO did not differ significantly between patients with good and poor CCC.

Usefulness of P-wave peak time as an electrocardiographic parameter in predicting left ventricular diastolic dysfunction in patients with mitral regurgitation.

Conventional Doppler measurements have limitations in predicting left ventricular diastolic dysfunction (LVDD) in patients with mitral regurgitation (MR). Recently, electrocardiographic P-wave peak time (PWPT) has been proposed as a parameter of detecting LVDD. This study aimed to evaluate the association between PWPT and left ventricular end-diastolic pressure (LVEDP) in patients with MR. We performed echocardiography and cardiac catheterization in 82 patients with moderate or severe MR. We classified patients into two groups: low LVEDP group (L-LVEDP) (LVEDP <16 mmHg, n=40) and high LVEDP group (H-LVEDP) (LVEDP ≥16 mmHg, n=42). We evaluated LVDD and PWPT based on echocardiographic and electrocardiographic findings in both groups. The PWPT in lead II (PWPTII ) was significantly longer in patients in the H-LVEDP group than in those in the L-LVEDP group (67 vs. 47 ms, p < .001). Using correlation analysis, LVEDP was positively correlated with PWPTII (r=.577, p < .001). Using multivariate analysis, PWPTII was found to be an independent predictor of increased LVEDP (95% CI: 0.1030-0.110; p < .001). Using receiver operating characteristic (ROC) curve analysis, the optimal cutoff value of PWPTII for predicting elevated LVEDP was 58.9ms, with a sensitivity of 80.0% and a specificity of 73.8% (area under curve: 0.809, 95% CI: 0.713-0.905). To the best of our knowledge, this is the first study to assess the effect of a significant valvular disease on PWPT in lead II. These findings suggest that prolonged PWPTII may be an independent predictor of increased LVEDP in patients with moderate or severe MR.

The Influence of Ixeris sonchifolia Hance Injection Combined with Isosorbide Mononitrate in Patients with Coronary Heart Disease and Diabetes.

Objective To evaluate the influence of Ixeris sonchifolia Hance injection combined with isosorbide mononitrate in patients with coronary heart disease (CHD) and diabetes. Methods 60 patients with CHD and diabetes mellitus admitted to our hospital between January 2019 and June 2020 were recruited and assigned via the random number table method at a ratio of 1 : 1 to receive either isosorbide mononitrate treatment (control group) or Ixeris sonchifolia Hance injection plus isosorbide mononitrate treatment (observation group). Outcome measures included left ventricular end diastolic pressure (LVEDP), left ventricular end systolic volume (LVESV), left ventricular function (LVEF), brain natriuretic peptide (BNP), and the total treatment efficiency. Results The two groups had similar LVEDP, LVESV, and LVEF before treatment (p > 0.05). After treatment, the LVEDP and LVESV of the two groups declined (p < 0.05), whereas LVEF increased (p < 0.05), with lower LVEDP and LVESV and higher LVEF in the observation group than in the control group (p < 0.05). Before treatment, there were no significant differences in the BNP levels between the two groups (p > 0.05). After treatment, the observation group had a more significant reduction in the BNP levels versus the observation group (p < 0.05). The observation group showed a higher treatment efficacy than the control group (p < 0.05). Conclusion Ixeris sonchifolia Hance plus isosorbide mononitrate may offer a viable alternative in the treatment of patients with CHD and diabetes mellitus. Future trials are, however, required prior to clinical promotion.

Beneficial properties of the biosynthesized silver/chitosan nanoparticles mediated by Mentha piperita in rats with heart failure following myocardial infarction

• The recent bio-nanocomposite has antioxidant activities against DPPH. • The recent bio-nanocomposite has therapeutic activities. • The recent bio-composite has been synthesized as the best. In this study, we report the green synthesis of nontoxic, stable, and small size silver nanoparticle by using chitosan/ Mentha piperita extract with reducing/capping ability without any toxic reducing agents. Mentha piperita was used as a reducing agent for the synthesis of Ag NPs that next stabilized by chitosan polymers. The in situ prepared Ag NPs/CS- Mentha piperita bio-composite were characterized by advanced physicochemical techniques like FE- SEM, TEM, EDX and XRD study. It has been established that Ag NPs/CS- Mentha piperita bio-composite have a spherical shape with a mean diameter from 5 to 15 nm. In heart failure model, the rats were subjected to coronary artery ligation, and orally administered with Ag NPs/CS- Mentha piperita 12.5, 25 and 50 µg kg(-1) daily, from the 7th day after surgery. Administration with Ag NPs/CS- Mentha piperita led to a significant reduction in infarct size and improvement in cardiac function as demonstrated by lower left ventricular end diastolic pressure (LVEDP) and elevated +/-dp/dt(max). We found that Ag NPs/CS- Mentha piperita significantly reduced left ventricular (LV)/body weight ratio, lung/body weight ratio and significantly inhibited neurohormonal activation. The antioxidant activity of Ag NPs/CS- Mentha piperita bio-composite was determined by DPPH method. The Ag NPs/CS- Mentha piperita bio-composite showed the high antioxidant activity according to the IC 50 value.

Del Nido cardioplegia better preserves cardiac diastolic function but histidine-tryptophan-ketoglutarate is better for endothelial function.

The effectiveness of myocardial protection of cardioplegia has been a matter of debate for decades. This study was designed to compare cardiac and endothelial protection of 3 clinically used cardioplegias: del Nido cardioplegia (DNC), histidine-tryptophan-ketoglutarate (HTK) and blood cardioplegia (BC) followed by HTK (BC + HTK) in a rat model of ischaemia/reperfusion (I/R). Sixty male Wistar rats were subjected to either 120 min of global ischaemia at 4°C followed by 90 min of reperfusion (I/R) at 37°C or no I/R (control) in a Langendorff apparatus and were randomly allocated to 5 groups: control, I/R, DNC, HTK and BC + HTK. Cold cardioplegia solutions were administered at doses of 20 ml/kg for DNC and HTK or 10 ml/kg for BC followed by HTK. Haemodynamic parameters were continuously recorded using an intraventricular balloon. The endothelium-dependent relaxation to acetylcholine was measured in the left anterior descending artery using a myograph. Protein expression of cardiac troponin T (cTnT) and creatine kinase MB was determined by western blot. During reperfusion, HTK had higher left ventricular systolic pressure whereas DNC had lower left ventricular end-diastolic pressure, better left ventricular developed pressure and best +dp/dtmax and -dp/dtmax than the other 2 groups but the differences disappeared at the end of the reperfusion. HTK or BC + HTK preserves the acetylcholine-induced endothelium-dependent relaxation better than DNC (Emax = 48.2 ± 8.0% in DNC vs 75.0 ± 8.0% in HTK, P < 0.05; vs 96.9 ± 3.5% in BC + HTK, P < 0.001). The protein levels of cTnT and creatine kinase MB were downregulated in the 3 groups. All 3 cardioplegias prevented myocardial damage against I/R injury at the end of reperfusion. DNC demonstrated better preserved diastolic function of the left ventricle whereas HTK or BC + HTK showed better preserved coronary endothelial function. These findings may suggest that currently no 'perfect' cardioplegia exists and that exploration for the 'perfect' cardioplegia is needed.

Adenine Nucleotide Translocase 1 Expression Modulates the Immune Response in Ischemic Hearts

Adenine nucleotide translocase 1 (ANT1) transfers ATP and ADP over the mitochondrial inner membrane and thus supplies the cell with energy. This study analyzed the role of ANT1 in the immune response of ischemic heart tissue. Ischemic ANT1 overexpressing hearts experienced a shift toward an anti-inflammatory immune response. The shift was characterized by low interleukin (IL)-1β expression and M1 macrophage infiltration, whereas M2 macrophage infiltration and levels of IL-10, IL-4, and transforming growth factor (TGFβ) were increased. The modulated immune response correlated with high mitochondrial integrity, reduced oxidative stress, low left ventricular end-diastolic heart pressure, and a high survival rate. Isolated ANT1-transgenic (ANT1-TG) cardiomyocytes expressed low levels of pro-inflammatory cytokines such as IL-1α, tumor necrosis factor α, and TGFβ. However, they showed increased expression and cellular release of anti-inflammatory immunomodulators such as vascular endothelial growth factor. The secretome from ANT1-TG cardiomyocytes initiated stress resistance when applied to ischemic wild-type cardiomyocytes and endothelial cells. It additionally prevented macrophages from expressing pro-inflammatory cytokines. Additionally, ANT1 expression correlated with genes that are related to cytokine and growth factor pathways in hearts of patients with ischemic cardiomyopathy. In conclusion, ANT1-TG cardiomyocytes secrete soluble factors that influence ischemic cardiac cells and initiate an anti-inflammatory immune response in ischemic hearts.

Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.

Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.

To Vent or Not to Vent: A Loaded Question During Venoarterial Extracorporeal Membrane Oxygenation Support for Cardiogenic Shock

To Vent or Not to Vent: A Loaded Question During Venoarterial Extracorporeal Membrane Oxygenation Support for Cardiogenic Shock

Risk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction.

The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17-55), the median LVEDP was 17 mm Hg (interquartile range, 12-21), and the correlation between them was not statistically significant (r=0.15; P=0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P=0.045) and major adverse cardiac events (n=21 events; P=0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60-21.22] P=0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7-98.2; P=0.033) when LVEDP>18 was added to IMR>32. IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

Dexmedetomidine Relieves Myocardial Ischemia-Reperfusion Injury and Inhibits Apoptosis in Rats via the Janus Kinase 2/Signal Transducers and Activators of Transcription 3 Signaling Pathway

To evaluate the effects of dexmedetomidine on myocardial ischemia-reperfusion injury in rats and its anti-apoptotic role, as well as the mechanism by which it regulates Janus kinase 2/signal transducers and activators of transcription 3 signal. Rats were randomly assigned into sham, model, experimental and control groups. The left anterior descending coronary artery was ligated to construct the model of myocardial ischemia-reperfusion. Sham group only received threading without ligation. At 1 h before operation, 5.0 μg/kg dexmedetomidine and 5.0 μg/kg Janus kinase 2/signal transducers and activators of transcription 3 signaling pathway agonist SC-39100 were intraperitoneally injected into experimental and control groups, respectively, while the same dose of normal saline was injected into sham and model groups. The left ventricular systolic pressure, left ventricular end-diastolic pressure, 1eft ventricular pressure rise (+dP/dtmax) and left ventricular pressure drop (-dP/dtmax) were measured using color Doppler ultrasonography. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay was performed to detect cardiomyocyte apoptosis. The expression levels of phosphorylated Janus kinase 2 and phosphorylated signal transducers and activators of transcription 3 were determined using western blotting. Compared with sham group, model group had significantly decreased left ventricular systolic pressure, +dP/dtmax and -dP/dtmax and raised left ventricular end-diastolic pressure, cardiomyocyte apoptosis rate and phosphorylated Janus kinase 2 and phosphorylated signal transducers and activators of transcription 3 expressions (p<0.05). Experimental and control groups had significantly higher left ventricular systolic pressure, +dP/dtmax, -dP/dtmax and phosphorylated Janus kinase 2 and phosphorylated signal transducers and activators of transcription 3 expressions and lower left ventricular end-diastolic pressure and cardiomyocyte rate than those of model group (p<0.05). Dexmedetomidine pretreatment can obviously relieve myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis in rats probably by activating the Janus kinase 2/signal transducers and activators of transcription 3 signaling pathway.

Effect of Renal Denervation on Cardiac Function and Inflammatory Factors in Heart Failure After Myocardial Infarction

Heart failure (HF) affects around 100 million people and is a staggering burden for health care system worldwide. Rapid and sustained activation of inflammatory response is an important feature of HF after myocardial infarction. Sympathetic overactivation is also an important factor in the occurrence and progression of HF. The beneficial effect of renal denervation (RDN) has been demonstrated in HF. In the current study, we hypothesized that RDN improves cardiac function in HF canine models due to acute myocardial infarction (AMI) and reduced inflammation might be involved. Twenty-four beagles were randomized into the control (n = 8), HF (n = 8), and HF + RDN group (n = 8). The HF model after AMI was established by embolization the anterior descending distal artery with anhydrous ethanol in the HF and HF + RDN group. Bilateral renal artery ablation was performed in the HF + RDN group. Cardiac function, serum creatine kinase, creatine kinase-MB and NT-Pro BNP level, and expression of inflammation-related proteins in myocardial were examined. Because the paraventricular nucleus of the hypothalamus might be involved in inflammation-induced central neural excitation in HF and plays an important role in regulating extracellular fluid volume and sympathetic activity, expression of inflammation-related proteins in hypothalamus was also examined. AMI and post-AMI HF model was created successfully. Compared with the HF group, dogs in the HF + RDN group showed better cardiac function 4 weeks after AMI: lower left ventricular end-diastolic pressure, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension and higher LEVF and left ventricular systolic pressure (P < 0.05 for all) were observed in the HF + RDN group. In addition, dogs in the HF + RDN group had slightly less ventricular fibrosis. Interestingly, RDN had lower expression of inflammation-related proteins including interleukin-6, tumor necrosis factors-α, nuclear factor κB, and monocyte chemotactic protein 1 (P < 0.05 for all) in both myocardial tissue and hypothalamus. RDN can improve cardiac function in dogs with HF after myocardial infarction. Our results suggested that RDN might affect cytokine-induced central neural excitation in HF and later affect sympathetic activity. Our results suggested a potential beneficial mechanism of RDN independent of mechanism involving renal afferent and efferent sympathetic nerves.

P4473Brain renin-angiotensin system blockade with firibastat, an orally active, central acting aminopeptidase A inhibitor prodrug prevents cardiac dysfunction after myocardial infarction in mice

Abstract Introduction Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Brain angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. Purpose We hypothesized that orally administered firibastat (previously named RB150), an orally central acting APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Methods Two days after MI induced by the left anterior descending artery ligation, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI+vehicle), firibastat (150 mg/kg; MI+firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI+enalapril) as a positive control. Results From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment during four weeks after MI normalized brain APA hyperactivity, with a return to the control values measured in the sham group. Four and six weeks after MI, MI+firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI+vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI+firibastat mice displayed lower levels of mRNA for markers of fibrosis such Ctgf and collagen types I and III than MI+vehicle mice. Conclusions Chronic oral firibastat administration after MI in mice normalizes brain APA hyperactivity, thereby normalizing brain RAS hyperactivity, whilst preventing cardiac dysfunction and attenuating cardiac hypertrophy and fibrosis. Acknowledgement/Funding INSERM, College de France, ANR LabCom, and Quantum Genomics

Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure

To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue. Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n= 12) or left coronary artery ligation (n= 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n= 21), or a fibroblasts/hiPSC-CMs patch (n= 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed. Patch-treated rats had decreased (P < .05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e' [ratio of early peak flow velocity to early peak LV velocity] and e'/a' [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P < .05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart. Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression.

Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Rats by Suppressing TGF-β1/Smad Signaling Pathway

To investigate the inhibitory effect of Linggui Zhugan Decoction (LZD, ) on the ventricular remodeling (VR) after acute myocardial infarction (AMI) and related mRNA and proteins expression in transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway, and explain its putative mechanism. A VR model was generated by ligation of coronary artery in mice. Two weeks after surgery, 60 mice were randomly divided into the model group, the sham-operation group (distilled water), the positive control group (2.4 mg/kg simvastatin), and the low-, medium- and high-dose LZD groups (2.1, 4.2, 8.4 g crude drug/kg, respectively) by a random number table, 10 mice in each group. Mice in each group was treated for 4 weeks. Changes of hemodynamics indices and cardiac weight index were detected by the PowerLab data acquisition and analysis recording instrument. Morphology changes of myocardial tissue were observed by hematoxylin-eosin and Masson staining. The expressions of TGF-β1, Smad2, Smad3, p-Smad2 and p-Smad3 in myocardial tissue were detected by Western blotting. The mRNA expressions of TGF-β1, Smad2 and Smad3 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expressions of matrix metalloprotein 2 (MMP2), MMP9, collagen I and collagen III were observed by immunohistochemical methods. VR mice showed significant dysfunction in hemodynamic indices and cardiac structure and function. Compared with the shamoperation group, myocardial tissue damage, interstitial fibrosis occurred in the model mice, left ventricular systolic pressure (LVSP), left ventricular pressure maximum contraction rate (+dp/dtmax) and left ventricular pressure maximum relaxation rate (-dp/dtmax) decreased significantly (all P<0.01), while left ventricular end-diastolic pressure (LVEDP), cardiac weight index and left ventricular weight index elevated significantly, meanwhile TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I, collagen III protein expressions in myocardial tissue and TGF-β1, Smad2 and Smad3 mRNA expressions increased significantly (all P<0.01). Compared with the model group, LZD could significantly improve the pathological changes of myocardial tissue, increase LVSP, +dp/dtmax and -dp/dtmax, lower LVEDP, reduce the whole heart weight index and left ventricular weight index and inhibit the over-expressions of TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I and collagen III proteins in myocardial tissue and mRNA expressions of TGF-β1, Smad2 and Smad3 (P<0.05 or P<0.01). LZD can significantly suppress VR induced by AMI, and its underlying mechanism may be associated with its inhibitory effect on the TGF-β1/Smad signaling pathway.

Cardioprotective effect of erythropoietin in rats with acute myocardial infarction through JNK pathway.

To explore the molecular mechanism of the cardioprotective effect of erythropoietin (EPO) in the rats with acute myocardial infarction (AMI) via the c-Jun N-terminal kinase (JNK) pathway. The rat AMI models were constructed and randomly divided into the EPO group, AMI group, and Sham group. At 2 weeks after successful modeling, the cardiac function-related indicators of rats were determined, and after the rats were sacrificed, the left ventricular weight (LVW) index was measured. The enzyme-linked immunosorbent assay (ELISA) and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were employed to determine the levels of the related serum inflammatory factors and myocardial apoptosis, respectively. The apoptosis and the expression levels of the JNK pathway-related messenger ribonucleic acids (mRNA) and proteins in the myocardial tissues of all groups of rats were determined via Real Time-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry. After intervention with EPO, the EPO group had a substantially lower left ventricular end-diastolic pressure, but a remarkably higher left ventricular systolic pressure than the AMI group (p<0.05), and the LVW and LVW/body weight (BW) notably declined in the EPO group compared with those in AMI group (p<0.05). According to the ELISA results, the inflammatory factors were substantially raised in the AMI group compared with those in the other two groups (p<0.05) and significantly lowered after treatment with EPO (p<0.05). The TUNEL assay results revealed that EPO treatment could reverse the pathological changes in AMI to decrease the apoptosis to a large extent. It was detected via RT-PCR and immunohistochemistry that, compared with those in the Sham group, the expression level of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) was substantially decreased, but the expression levels of pro-apoptosis gene Bcl-2 associated X protein (Bax) and the JNK pathway-related JNK and c-Jun were evidently elevated in the AMI group (p<0.05). Moreover, the expression level of Bcl-2 was remarkably raised (p<0.05) and the expression levels of Bax, JNK, and c-Jun remarkably declined (p<0.05) in the EPO group after intervention with EPO. EPO can inhibit the inflammatory responses and decrease the myocardial apoptosis to protect the heart of the AMI rats, and its mechanism of action is related to the inhibition of the expression of the JNK pathway.

Mimicking Preconditioning by Vagal Stimulation. Effects on Ventricular Function in a Chronic Experimental Model

Background: Previous studies have shown that preischemic vagal electrostimulation (pVS) reduces acute myocardial infarctsize, without a significant improvement on ventricular function within the two-hour reperfusion period. It is unknown whichare the long-term effects of pVS on left ventricular function (LVF).Objectives: The aim of this study was to analyze whether the protective effects of brief pVS on acute infarct size improvesLVF in a chronic myocardial ischemia-reperfusion model.Methods: FVB mice were subjected to 45-minutes regional myocardial ischemia followed by 2 hours of reperfusion or 28-daypost-reperfusion follow-up with or without 10-minutes pVS. Infarct size (IS) was measured with 2,3,5-triphenyltetrazoliumchloride, and LVF was assessed by echocardiography and left ventricular catheterization.Results: Preischemic vagal stimulation reduced IS from 66.8±3.2% to 43.2±1.6% (p <0.001) at 2 hours of reperfusion, without afavorable LVF response. At 28 days, the pVS group exhibited LVF improvement, with lower left ventricular end-diastolic pressure(4.44±1 vs. 6.91±1 mmHg in the control group; p<0.05), higher ejection fraction (69.7±2.8% vs. 59.3±3.2; p<0.05), greatershortening fraction (33.4±2.23 vs. 25.8±1.8%; p<0.05) and lower isovolumic relaxation time (25±0.8 ms vs. 30.3±1.2 ms; p<0.05)Conclusions: In a mice model of myocardial ischemia and reperfusion, mimicking ischemic preconditioning by VS improvesthe chronic outcome of infarction, resulting in greater LVF recovery

Catalpol pretreatment attenuates cardiac dysfunction following myocardial infarction in rats.

Objective:To investigate the effects and mechanisms of catalpol on cardiac function in rats with isoproterenol (ISO)-induced myocardial infarction (MI).Methods:Adult male Wistar rats were divided into four groups: control group, ISO group, catalpol (L, low dose) group, and catalpol (H, high dose) group. Isoproterenol (85 mg/kg) was injected subcutaneously for 2 consecutive days to induce experimental MI. At the end of experiment, the effects of catalpol on cardiac function; apelin levels; apoptosis index; apelin, APJ, Bcl-2, and Bax protein expression; and caspase-3/9 activities were investigated.Results:The rats in the ISO group showed lower left ventricular maximum rate of positive or negative pressure development (±LVdp/dtmax) and left ventricular end-systolic pressure (LVSP) and higher left ventricular end-diastolic pressure (LVEDP) than those in the control group, suggesting severe cardiac dysfunction. Interestingly, catalpol administration significantly ameliorated the ISO-induced cardiac dysfunction. The groups administered low and high dosages catalpol (5 and 10 mg/kg/day, respectively) showed higher ±LVdp/dtmax and LVSP and lower LVEDP than the group administered ISO alone. Catalpol markedly upregulated apelin levels in the plasma and myocardium. Further, catalpol increased the apelin and APJ expression levels in the myocardium of the ISO-treated rats. In addition, catalpol pretreatment inhibited cardiomyocyte apoptosis as indicated by a decrease in the TUNEL-positive cell percentage, alterations in the Bax and Bcl-2 expression levels, and a decline in caspase-3 and caspase-9 activities.Conclusion:Our results revealed that catalpol can improve cardiac function. Its protective effects may be linked to the enhancement of myocardium contractility, regulation of the apelin/APJ pathway, and inhibition of cardiomyocyte apoptosis.

Intracellular Renin Inhibits Mitochondrial Permeability Transition Pore via Activated Mitochondrial Extracellular Signal-Regulated Kinase (ERK) 1/2 during Ischemia in Diabetic Hearts.

Although beneficial effects of non-secreting intracellular renin (ns-renin) against ischemia have been reported, the precise mechanism remains unclear. In this study, we investigated the roles of ns-renin and mitochondrial extracellular signal-related kinase (ERK) 1/2 on mitochondrial permeability transition pore (mPTP) opening during ischemia in diabetes mellitus (DM) hearts. When isolated hearts from Wistar rats (non-DM hearts) and Goto-Kakizaki rats (DM hearts) were subjected to ischemia for 70 min by left anterior descending coronary artery ligation, DM hearts exhibited higher left ventricular (LV) developed pressure and lower LV end-diastolic pressure than non-DM hearts, suggesting ischemic resistance. In addition, DM hearts showed increased intracellular renin (int-renin, including secreting and non-secreting renin) in the ischemic area, and a direct renin inhibitor (DRI; aliskiren) attenuated ischemic resistance in DM hearts. ERK1/2 was significantly phosphorylated after ischemia in both whole cell and mitochondrial fractions in DM hearts. In isolated mitochondria from DM hearts, rat recombinant renin (r-renin) significantly phosphorylated mitochondrial ERK1/2, and hyperpolarized mitochondrial membrane potential (ΔΨm) in a U0126 (an inhibitor of mitogen-activated protein kinases/ERK kinases)-sensitive manner. R-renin also attenuated atractyloside (Atr, an mPTP opener)-induced ΔΨm depolarization and Atr-induced mitochondrial swelling in an U0126-sensitive manner in isolated mitochondria from DM hearts. Furthermore, U0126 attenuated ischemic resistance in DM hearts, whereas it did not alter the hemodynamics in non-DM hearts. Our results suggest that the increased int-renin during ischemia may inhibit mPTP opening through activation of mitochondrial ERK1/2, which may be involved in ischemic resistance in DM hearts.

Antibodies to receptors are associated with biomarkers of inflammation and myocardial damage in heart failure

Naturally occurring antibodies are linked to inflammation, tissue injury and apoptosis, processes also linked to heart failure. Associations between antibodies, inflammation and myocardial damage, have not been elucidated in heart failure. We investigated if 25 antibodies to receptors expressed in the cardiovascular system were associated with troponin-T, biomarkers of inflammation and clinical measures of disease severity, in patients with heart failure. Antibodies in sera from patients (n=191) with ischemic (n=155) or non-ischemic (n=36) heart failure were measured with full-receptor sandwich enzyme-linked immunosorbent assays. All patients underwent coronary angiography with determination of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP). Measured biomarkers included troponin-T, C-reactive protein, erythrocyte sedimentation rate, fibrinogen and neopterin. Stabilin-1-antibodies correlated with troponin-T (β 0.23 p=0.008), soluble endoglin-antibodies with erythrocyte sedimentation rate (β 0.19, p=0.007) and fibrinogen (β 0.28, p<0.001). Platelet-derived growth factor subunit β-antibodies were associated with neopterin (β 0.17, p=0.002). All antibodies were correlated (R 0.26 to 0.91) and formed 4 principal components (PCs). Patients with high CRP and high PC2 had higher NYHA class and patients with high troponin-T and high PC1 had lower LVEDP (interactions, all p<0.05). Antibodies to receptors are correlated and are associated with biomarkers of inflammation and myocardial damage, which further modifies their association with disease severity in heart failure. Their functional activity and immunological function, remain undecided.

Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure.

Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure.