Impact of myocardial infarction on cardiac autonomic function in diabetic rats

AimsWe evaluated autonomic and hemodynamic parameters and maximal oxygen consumption (VO₂max) as possible determinants of mortality in streptozotocin (STZ) diabetic rats after myocardial infarction (MI).MethodMale Wistar rats were divided into (n = 8 of each): control sham (CS), diabetes sham (DS), MI (I), and diabetes + MI (DI). MI was induced 15 days after STZ induction. VO₂max was measured at 3 (basal), 30, 60, and 91 days after MI. Hemodynamic and autonomic parameters were evaluated 92 days after MI.ResultsMI area was similar in infarcted groups (~ 44%). Mortality rate increased in the DI (70%) compared with I (53%) group. Cardiopulmonary baroreflex, sympathetic (48%) and vagal (33%) tonus, low frequency (LF) band (57%), and LF/high frequency (HF) band ratio (53%) were reduced in DI compared with I animals. Furthermore, cardiac output (CO), peripheral vascular resistance (PVR) impairment, and VO₂max reductions were observed in the DI compared with the I group.ConclusionsOur data suggest that the CO and PVR changes as well as VO₂max reduction were probably associated with additional cardiac autonomic control impairment, and, consequently, increased mortality rate in diabetic rats after a chronic myocardial infarction.     

GYY4137 attenuates remodeling,preserves cardiac function and modulates the natriuretic peptide response to ischemia

AimsMyocardial infarction followed by adverse left ventricular (LV) remodeling is the most frequent proximate cause of heart failure. Hydrogen sulfide (H₂S) is an important endogenous modulator of diverse physiological and pathophysiological processes. Its role in post-ischemic ventricular remodeling and the associated neurohormonal responses has not been defined. Here, we aimed at evaluating whether the slow-releasing water-soluble H₂S donor GYY4137 (GYY) exerts cardioprotective effects and modulates the neurohormonal response to cardiac ischemic injury.Methods and resultsTreatment for 2 or 7 days with GYY (100 mg/Kg/48 h, IP) after acute myocardial infarction (MI) in rats preserved LV dimensions and function in vivo, compared to untreated infarcted (MI), placebo- and dl-propargylglycine- (PAG, an inhibitor of endogenous H₂S synthesis) treated animals (n = 9/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts had significantly less LV fibrosis than MI, placebo and PAG hearts. A higher density of blood vessels was found in the LV scar area of GYY-treated animals compared to all other infarcted groups. Despite preserved LV structure and function, treatment with GYY increased the levels of the natriuretic peptides ANP and BNP in association with enhanced cyclic GMP levels, paralleled by higher cGMP-dependent protein kinase type I (cGKI) protein levels.ConclusionsOur data suggest that the slow-releasing H₂S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro-angiogenic, anti-apoptotic, anti-hypertrophic and anti-fibrotic) effects in part through enhanced early post-ischemic endogenous natriuretic peptide activation.     

Mesenchymal Stem Cells Pretreatment With Stromal-Derived Factor-1 Alpha Augments Cardiac Function and Angiogenesis in Infarcted Myocardium

BackgroundStem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI).MethodsThe influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation.ResultsSDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with ^p240MSC, ^SDF1αMSC, and ^VEGF-A165MSC in comparison to the control group.ConclusionsThese findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.     

Influência do Consumo de Suco de Laranja (Citrus Sinensis) na Remodelação Cardíaca de Ratos Submetidos a Infarto do Miocárdio

BackgroundOrange juice (OJ) is rich in polyphenols with anti-inflammatory and antioxidant properties. After myocardial infarction (MI), complex changes occur in cardiac structure and function, which is known as cardiac remodeling (CR). Oxidative stress and inflammation can modulate this process. We hypothesized that the consumption of OJ attenuates the CR after MI.ObjectivesTo evaluate the influence of OJ on CR after MI by analysis of functional, morphological, oxidative stress, inflammation, and energy metabolism variables.MethodsA total of 242 male rats weighing 200-250 g were submitted to a surgical procedure (coronary artery ligation or simulated surgery). Seven days after surgery, survivors were assigned to one of the four groups 1) SM, sham animals with water and maltodextrin (n= 20); 2) SOJ, sham animals with OJ (n= 20); 3) IM, infarcted animals with water and maltodextrin (n= 40); and 4) IOJ, infarcted animals with OJ (n = 40). Statistical analysis was performed by the two-way ANOVA supplemented by Holm-Sidak. Results are presented as mean ± standard deviation, the level of significance adopted was 5%.ResultsAfter 3 months, MI led to left ventricular (LV) hypertrophy, with systolic and diastolic dysfunction, and increased oxidative stress and inflammatory mediators. OJ intake reduced LV cavity and improved systolic and diastolic function. The OJ animals presented lower activity of glutathione peroxidase and higher expression of heme-oxygenase-1 (HO-1).ConclusionOJ attenuated CR in infarcted rats and HO-1 may be play an important role in this process.     

QGC606: A Best-in-Class Orally Active Centrally Acting Aminopeptidase A Inhibitor Prodrug for Treating Heart Failure Following Myocardial Infarction

BackgroundBlockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI.MethodsTwo days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control.ResultsFour weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice.ConclusionsChronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.     

Efeitos do Exercício Aeróbico Tardio na Remodelação Cardíaca de Ratos com Infarto do Miocárdio Pequeno

Background:Physical exercise has been considered an important non-pharmacological therapy for the prevention and treatment of cardiovascular diseases. However, its effects on minor cardiac remodeling are not clear.Objective:To evaluate the influence of aerobic exercise on the functional capacity, cardiac structure, left ventricular (LV) function, and gene expression of NADPH oxidase subunits in rats with small-sized myocardial infarction (MI).Methods:Three months after MI induction, Wistar rats were divided into three groups: Sham; sedentary MI (MI-SED); and aerobic exercised MI (MI-AE). The rats exercised on a treadmill three times a week for 12 weeks. An echocardiogram was performed before and after training. The infarction size was evaluated by histology, and gene expression was assessed by RT-PCR. The significance level for statistical analysis was set at 5%.Results:Rats with MI lower than 30% of the LV total area were included in the study. Functional capacity was higher in MI-AE than in Sham and MI-SED rats. The infarction size did not differ between groups. Infarcted rats had increased LV diastolic and systolic diameter, left atrial diameter, and LV mass, with systolic dysfunction. Relative wall thickness was lower in MI-SED than in the MI-AE and Sham groups. Gene expression of the NADPH oxidase subunits NOX2, NOX4, p22^phox, and p47^phox did not differ between groups.Conclusion:Small-sized MI changes cardiac structure and LV systolic function. Late aerobic exercise is able to improve functional capacity and cardiac remodeling by preserving the left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small-sized MI.     

Early intervention with a potent endothelin-A/endothelin-B receptor antagonist aggravates left ventricular remodeling after myocardial infarction in rats

Intervention with selective endothelin (ET)A receptor antagonists within 24 h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ET_A/ET_B receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ET_A/ET_B receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg·kg⁻¹ SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48 h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4 ± 0.5 vs 9.1 ± 0.2 mm; LV end-systolic diameter: 8.5 ± 0.4 vs 7.2 ± 0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ET_A/ET_B receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI. Received: 1 September 2001, Returned for revision: 13 September 2001, Revision received: 6 December 2001, Accepted: 21 December 2001     

Prognostic Significance of Diastolic Dysfunction by Tissue Doppler Imaging in Patients With Chronic Heart Failure

BackgroundThis study assesses the prognostic values of left ventricular (LV) filling patterns, as determined by tissue Doppler imaging (TDI), on cardiac events in patients with LV systolic dysfunction. Normally observed in patients with an advanced form of cardiac disease, an abnormal diastolic pattern by Doppler echocardiography reflects a poor prognosis. Recent studies using TDI have significantly contributed to efforts to evaluate diastolic function and demonstrate the prognostic importance of TDI-derived indices of the LV function.Methods and ResultsOne hundred seventy-three consecutive adult patients, mean (standard deviation) age of 62.4 (14.3), with a diagnosis of dilated cardiomyopathy and LV ejection fraction < 45% were enrolled. During a follow-up period of 321 ± 100 days, 9 patients expired from cardiac complications and 29 underwent readmission for decompensated heart failure. in multivariate analysis, only the mean value of early (E_m) and late (A_m) diastolic velocities ratio assessed by TDI, and LV end-diastolic pressure were found to be independent predictors of a cardiac event. The optimal cutoff value for forecasting cardiac event was E_m/A_m ≥ 0.74 with an area under the receiver operating characteristic curve of 0.82; sensitivity and specificity were 84% and 76%, respectively (P < 0.001; standard error = 0.046).ConclusionsE_m/A_m ratio is the important predictor of cardiac event, which allows normalization for other risk factors in patients with a clinical diagnosis of chronic heart failure with LV dysfunction comparing with conventional Doppler echocardiography.     

Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy

OBJECTIVES: We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). METHODS: Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. RESULTS: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition. CONCLUSION: Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.     

Short-term effects of angiotensin receptor-neprilysin inhibitors on diastolic strain and tissue doppler parameters in heart failure patients with reduced ejection fraction: A pilot trial

ObjectiveAlthough sacubitril/valsartan has recently shown its long-term benefits on morbidity and mortality in symptomatic patients with chronic heart failure with reduced ejection fraction (HFrEF), its short-term effects on diastolic function remain uncertain. We sought to assess 30-day effects of sacubitril/valsartan on left ventricular (LV) diastolic paremeters determined by speckle tracking and tissue Doppler imaging (STI and TDI respectively) as well as their association with functional capacity change evaluated by peak oxygen uptake (VO₂max) in stable patients with symptomatic HFrEF.MethodsA total of 35 patients (aged 61 ± 9 years) eligible for sacubitril/valsartan underwent a complete two-dimension (2D) echocardiographic study and a cardiopulmonary exercise test at baseline and 30 days after the initiation of therapy.ResultsSignificant improvements in ratio of trans-mitral inflow early diastolic velocity E to mitral annulus early diastolic velocity E′ (ΔΕ//Ε′ = -35.9%, p = 0.001), peak early diastolic strain rate SRE (ΔSRE = +22.5%, p = 0.024) and ratio E/SRE (ΔE/SRE = -33.2%, p = 0.025) were observed after 1-month therapy. Compared with baseline, VO₂max also increased significantly by 16.7 % (p = 0.001). Baseline E/SRE and ΔE/SRE were the strongest independent predictors of VO₂max improvement (beta = -0.43, p = 0.004 and beta = 0.45, p = 0.021 respectively) in the multivariate analysis.ConclusionSacubitril/valsartan was associated with early improvement in LV diastolic function determined by TDI and 2D STI. Baseline E/SRE was stronger than standard echocardiographic parameters in predicting the early benefit of sacubitril/valsartan therapy.     

Attenuation of Left Ventricular Adverse Remodeling With Epicardial Patching After Myocardial Infarction

BackgroundPrevious studies suggested that epicardial patch applied to the infarcted site after acute myocardial infarction (MI) can alleviate left ventricular (LV) remodeling and improve cardiac performance; however, the effects of regional epicardial patch on chronic phase of LV remodeling remain unclear.Methods and ResultsWe studied 20 pigs with MI induced by distal embolization and impaired LV ejection fraction (LVEF <45%) as detected by gadolinium-enhanced cardiac magnetic resonance imaging (MRI). Eight weeks post-MI, all animal underwent open chest procedure for sham surgery (control, n = 12) or patch implantation over the infarcted lateral LV wall (patch group, n = 12). In the patch group, +dP/dt increased and LV end-diastolic pressure decreased at 20 weeks compared with immediately post-MI and at 8 weeks (P < .05), but not in the control group (P > .05). As determined by cardiac MRI, LV end-diastolic and end-systolic volumes increased at 20 weeks compared with 8 weeks in both groups (P < .05). However, the increase in LV end-diastolic volume (+14.1 ± 1.8% vs. +6.6 ± 2.1%, P = .015) and LV end-systolic volume (+12.1 ± 2.4% vs. ?4.7 ± 3.7%, P = .0015) were significantly greater in the control group compared with the patch group. Furthermore, the percentage increase in LVEF (+17.3 ± 4.9% vs. +4.1 ± 3.9%, P = .048) from 8 to 20 weeks was significantly greater in the patch group compared with the control group. Histological examination showed that LV wall thickness at the infarct region and adjacent peri-infarct regions were significantly greater in the patch group compared with the control group (P < .05).ConclusionRegional application of a simple, passive synthetic epicardial patch increased LV wall thickness at the infarct region, attenuated LV dilation, and improved LVEF and +dP/dt in a large animal model of MI.     

Left ventricular systolic dyssynchrony index by three-dimensional echocardiography in patients with decreased left ventricular function: comparison with tissue Doppler echocardiography

Background: Three‐dimensional echocardiography (3DE) can simultaneously assess left ventricular (LV) regional systolic motion and global LV mechanical dyssynchrony. Methods: We used 3DE to measure systolic dyssynchrony index (SDI) (standard deviation of the time from cardiac cycle onset to minimum systolic volume in 17 LV segments) in 100 patients and analyzed the association of SDI with other parameters for LV systolic function or dyssynchrony. Eighteen patients who underwent cardiac resynchronization therapy (CRT) were also evaluated at 6 months after CRT, and the association of baseline SDI and tissue Doppler imaging (TDI) dyssynchrony index (Ts‐SD) with the change of LV end‐systolic volume (ESV) analyzed. Ts‐SD was calculated using the standard deviation of the time from the QRS complex to peak systolic velocity. Results: There was a significant inverse correlation between LVEF and SDI (r =?0.686, P < 0.0001). QRS duration was also significantly correlated to SDI (r = 0.407, P < 0.0001). There was a significant positive correlation between baseline SDI and the decrease in LVESV after CRT (r = 0.42). Baseline SDI was significantly greater in responders (10 patients) than in nonresponders (16.4 ± 5.1 vs. 7.9 ± 2.4%, P < 0.01), but there was no significant difference in Ts‐SD. SDI > 11.9% predicted CRT response with a sensitivity of 90% and a specificity of 75%. Conclusions: SDI derived from 3DE is a useful parameter to assess global LV systolic dyssynchrony and predict responses to CRT. (Echocardiography 2012;29:346‐352)     

Effect of Matrix Metalloproteinase Inhibition by Doxycycline on Myocardial Healing and Remodeling after Myocardial Infarction

Summary The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm² ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm², respectively; p < 0.05). Our work suggest that effective MMPs’ inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.     

Infarct Size Reduction and Attenuation of Global Left Ventricular Remodeling with the CorCap<Superscript>TM</Superscript> Cardiac Support Device Following Acute Myocardial Infarction in Sheep

Background:Whether mechanical restraint of the left ventricle (LV) can influence remodeling following myocardial infarction (MI) remains poorly understood. The following discussion details three studies examining the effects of surgically placing a cardiac support device (CSD) over the entire epicardial surface, on infarct expansion, global cardiac function and myocyte geometry and function post-MI. Methods: The effects of passive constraint on infarct expansion and global cardiac function/myocardial energetics were investigated in 10 sheep (5 MI only; 5 MI + CSD) using pressure-volume analysis and magnetic resonance imaging (MRI). Additionally, 11 sheep (5 MI only; 6 MI + CSD) were used to study the effects of passive restraint on myocyte geometry and function post-MI, with 10 additional uninstrumented sheep serving as controls. Baseline data was collected followed by the creation of an anterior infarct. 1 week post-infarct the animals underwent a second set of data collection studies followed by placement of the CSD in the experimental groups. Additional data was collected at 2 and 3 months post-MI. The animals in the myocyte function group underwent additional studies immediately following the 3 month time point. Results: Infarct expansion was diminished as a result of the CSD. At 1 week post-MI the akinetic area was similar in both groups. At the terminal time-point, the akinetic area in the control group was similar to the 1-week time-point whereas, in the CSD group, the area of akinesis decreased (P = 0.001). A comparison of the two groups at the terminal time-point demonstrates a significantly diminished area of akinesis in the CSD group (P = 0.004). The relative area of akinesis followed a similar pattern. The CSD group also exhibited a decrease in end-diastolic volume (control 110.3 ± 19.8 mL vs. CSD 67.6 ± 4.7 mL, P = .006) and an improved ejection fraction (control 15.5% ± 5.7% vs. CSD 29.46% ± 4.42%, P = .008) relative to the control group. Myocardial energetics were also enhanced in the CSD group as evidenced by significant improvements in potential energy (control 2015 ± 503 mL ⋅ mm Hg/beat vs. CSD 885 ± 220 mL ⋅ Hg/beat, P = .006), efficiency (control 39.4% ± 13.6% vs. CSD 59.8% ± 8.5%, P = .044), and oxygen consumption (control 0.072 ± 0.013 mL O₂/beat vs. CSD 0.052 ± 0.007 mL O₂/beat, P = .034). Isolated LV myocyte shortening velocity was reduced by 35% from control values (P < 0.05) in both MI groups. LV myocyte β-adrenergic response was reduced with MI, but normalized in the MI + CSD group. Relative collagen content was increased and matrix metalloproteinase-9 was decreased within the MI border region of the CSD group. Conclusions:The CorCap cardiac support device retarded infarct expansion, improved global and regional cardiac function and beneficially modified LV and myocyte remodeling post-MI. These findings provide evidence that non-pharmacological strategies can interrupt adverse LV remodeling post-MI.     

Differential expression of vascular endothelial growth factor isoforms and receptor subtypes in the infarcted heart

Aims

The vascular endothelial growth factor (VEGF) family contains four major isoforms and three receptor subtypes. The expressions of each VEGF isoform and receptor subtype in cardiac repair/remodeling after myocardial infarction (MI) remain uncertain and are investigated in the current study.

Methods and results

Temporal and spatial expressions of VEGF isoforms and VEGFR subtypes were examined in the infarcted rat heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all VEGF isoforms. Following MI, VEGF-A was only increased in the border zone at day 1 and was significantly decreased in the infarcted heart during the 42 day observation period afterwards. VEGF-B was significantly suppressed in the infarcted heart. VEGF-C and VEGF-D were markedly increased in the infarcted heart in both early and late stages of MI. VEGFR-1 and 2 were significantly decreased in the infarcted heart, while VEGFR-3 was significantly increased, which was primarily expressed in blood vessels and myofibroblasts (myoFb).

Conclusions

VEGF isoforms and VEGFR subtypes are differentially expressed in the infarcted heart. Increased VEGF-A in the very early stage of MI suggests the potential role in initiating the cardiac angiogenic response. Suppressed cardiac VEGF-B postMI suggests that it may not be critical to cardiac repair. The presence of enhanced VEGF‐C and VEGF-D along with its receptor, VEGFR-3, in various cell types of the infarcted heart suggest that these isoforms may regulate multiple responses during cardiac repair/remodeling.     

The incremental value of regional dyssynchrony in determining functional mitral regurgitation beyond left ventricular geometry after narrow QRS anterior myocardial infarction: a real time three-dimensional echocardiography study

Background: Determinants of functional mitral regurgitation (FMR) severity after acute anterior myocardial infarction (MI) remained unclear. Our aim was to: (1) test whether LV dyssynchrony upon real time three‐dimensional echocardiography (RT‐3DE) is independently associated with FMR severity; and (2) to investigate the role of regional systolic dyssynchrony index (SDI) in identifying FMR severity. Methods: RT‐3DE was successfully performed on 64 consecutive patients following acute anterior MI with a narrow QRS complex (<130 ms) and another 30 healthy volunteers. MR severity was assessed using vena contracta method. SDI was derived from the dispersion of the time to minimum regional volume for all 16 LV segments. Multiple linear regression analysis was used to identify the independent relationship between FMR and SDI with and without multivariate adjustment. Results: The mean LV ejection fraction was 49.6%± 11.9% in the MI group. All regional (except apical) and global SDIs were associated with regional LV remodeling and were significantly correlated with FMR even after multivariate adjustment, with midwall SDI being most strongly associated with MR severity (R²= 0.55, P < 0.001). Regional midwall SDI superimposed on LV global geometry and mitral leaflet deformation substantially expanded the area under curve in identifying FMR (AUC increased from 0.69 to 0.93, c‐statistics: P = 0.041). Conclusions: While both global and regional dyssynchrony following anterior MI were independently related to FMR severity, regional midwall dyssynchrony further added incremental value in predicting FMR severity beyond traditional parameters. This finding provides a new insight into the understanding of FMR after anterior MI and may further potentiate specific therapeutic approaches. (Echocardiography 2011;28:665‐675)     

Effect of Cilazapril on Ventricular Remodeling Assessed by Doppler-Echocardiographic Assessment and Cardiac Gene Expression

The purpose of this study is to determine whether the administration of the ACE inhibitor cilazapril can lessen the adverse effects of ventricular remodeling, including systolic and diastolic dysfunction, modulation of fetal gene expression, increase of collagen genes, and depression of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase gene in a myocardial infarcted (MI) rat model. At 1 day after MI, the animals were randomly assigned to cilazapril treatment or no treatment. We performed Doppler-echocardiographic examinations and measured cardiac mRNA in rats at 1 month and 3 months after MI (each group n = 8). The weights of the right (RV) and left ventricles (LV) in 1- and 3-month MI rats were significantly larger than those of the control rats. Cilazapril significantly prevented the increase. The MI rats showed systolic dysfunction, as evidenced by decreased fractional shortening (control, 34 ± 3% vs. MI, 17 ± 3%; P <0.01) and ejection fraction measured by the modified Simpsons method (control, 61 ± 2% vs. MI, 36 ± 3%; P < 0.01) in rats at 1 month after operation. MI rats showed diastolic dysfunction, defined as increased peak early filling velocity, increased deceleration rate of the early filling wave, decreased late filling velocity, and an increase in the ratio of early filling to late filling velocity. Cilazapril significantly prevented systolic and diastolic dysfunction in rats after MI. The increases in -MHC, -skeletal actin, ANP, and collagen I and III mRNAs in the nonischemic LV and RV were significantly suppressed by treatment with cilazapril. Depressed SR Ca²⁺-ATPase mRNA (nonischemic LV, 0.7-fold, P < 0.05 vs. control; RV, 0.5-fold, P < 0.05 vs. control) at 3 months after MI was significantly restored to normal levels by cilazapril. Cilazapril improved the adverse remodeling process by attenuating the progression of systolic and diastolic dysfunction, and prevented abnormal cardiac gene expression following MI.     

Clenbuterol Plus Granulocyte Colony-Stimulating Factor Regulates Stem/Progenitor Cell Mobilization and Exerts Beneficial Effect by Increasing Neovascularization in Rats With Heart Failure

BackgroundTreatment of beta₂-adrenergic receptor agonists with myeloid cytokines, such as granulocyte colony-stimulating factor (G-CSF) has been reported to enhance stem/progenitor cell mobilization and proliferation in ischemic myocardium. However, whether the combination therapy of G-CSF and clenbuterol (Clen) contributes to improved left ventricular (LV) function remains uncertain. We investigated whether this combination therapy induced bone marrow–derived stem/progenitor cell mobilization, neovascularization, and altered LV function after acute myocardial infarction (MI).Methods and ResultsFollowing MI, rats were treated with single Clen, high-dose Clen, and G-CSF + Clen. We evaluated LV function and remodeling with the use of echocardiography in addition to hemodynamics 3 weeks after MI. Treatment with G-CSF + Clen increased (P < .05), compared with no treatment, LV ejection fraction 46 ± 3% vs 34 ± 2%, LV dP/dt 5,789 ± 394 mm Hg vs 4,503 ± 283 mm Hg, and the percentage of circulating CD34+ cells, appearing to correlate with improvements in LV function.ConclusionsCombination therapy improved LV function 3 weeks after MI, suggesting that G-CSF + Clen might augment stem/progenitor cell migration, contributing to tissue healing. These data raise the possibility that enhancing endogenous bone marrow–derived stem/progenitor cell mobilization may be a new treatment for ischemic heart failure after MI.