Noninfarcted Myocardium Research Articles

ST2 is reduced by high-dose omega-3 fatty acid treatment following acute MI and is correlated with reduction of the extracellular volume fraction of non-infarcted myocardium

ST2 is reduced by high-dose omega-3 fatty acid treatment following acute MI and is correlated with reduction of the extracellular volume fraction of non-infarcted myocardium

4D strain analysis within non-infarcted myocardium of patients with ischemic cardiomyopathy: potential marker for the prediction of adverse cardiac events

4D strain analysis within non-infarcted myocardium of patients with ischemic cardiomyopathy: potential marker for the prediction of adverse cardiac events

Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage.

BackgroundMyocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes.Method and ResultsWe quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than “nonischemic” MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01).Conclusion MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.

Improvement of Left Ventricular Remodelling by Inhibition of NF-κB in a Rat Model of Myocardial Infarction.

To investigate the effects of inhibition of NF-κB activation on left ventricular (LV) remodelling in a rat model of myocardial infarction (MI). The acute MI model was established by ligation of left anterior descending coronary artery. Pyrrolidine dithiocarbamate (PDTC) (20mg/kg, Qd) was administered intraperitoneally to inhibit NF-κB activation. Eight weeks later, the cardiac structure and LV ejection fraction were assessed with echocardiography. The rat body, heart, and LV weights were measured to calculate LV mass indices. Activation of NF-κB in non-infarcted myocardium was detected by a TransAM NF-κB p65 Transcription Factor Assay Kit. Cardiac collagen volume fraction was evaluated by Masson staining. Eight weeks after the MI model was established, the LV posterior wall thickness in PDTC and MI group was 1.75±0.07mm and 1.85±0.07mm respectively (p<0.05). The LV mass index in the PDTC group (2.53±0.09) was lower than in the MI group (2.65±0.08, p<0.05). The LVEF in the PDTC group (63.89%±4.21%) was higher than in the MI group (42.73%±8.94%, p<0.05). The interstitial collagen deposition in the non-infarcted myocardium in the PDTC group was less than in the MI group (7.25%±1.88% vs. 10.09%±2.19%, p<0.05). Inhibition of activation of NF-κB may result in improvement of myocardial remodelling after myocardial infarction, which is possibly attributable to reduced collagen deposition in non-infarcted areas.

Evaluation of Left Ventricle Function by Regional Fractional Area Change (RFAC) in a Mouse Model of Myocardial Infarction Secondary to Valsartan Treatment.

AimLeft ventricle (LV) regional fractional area change (RFAC) measured by cardiac magnetic resonance (CMR) allows the non-invasive localization and quantification of the degree of myocardial infarction (MI), and could be applied to assess the effectiveness of pharmacological or regenerative therapies. Here we investigate the ability of RFAC to identify regional dysfunction and discriminate the effect of pharmacological treatment with valsartan, a selective antagonist of angiotensin II type 1 receptor, in a model of MI.Methods and ResultsC57BL/6N mice, undergoing coronary artery ligation, were divided into two groups: untreated (MI) or treated with valsartan (MI+Val). Sham-operated mice were used as a control. Cardiac dimensions and function were assessed at baseline, 24 hours, 1 and 4 weeks post surgery by CMR and echocardiography. At sacrifice histology and whole-genome gene expression profiling were performed. RFAC was able to detect significant differences between treatment groups whereas the global ejection fraction was not. RFAC showed greater loss of regional contraction in remote non-infarcted myocardium in MI group than in MI+Val group. Consistently, in the same region MI+Val mice showed reduced myocyte hypertrophy, fibroblast proliferation, and fibrosis and modulation of target genes; in addition, left atrium volumes, appendage length and duct contraction were preserved.ConclusionIn this study, RFAC effectively estimated the degree of systolic dysfunction and discriminated the regions preserved by pharmacological treatment. RFAC index is a promising tool to monitor changes in LV contraction and to assess the effectiveness of therapeutic regimens in clinical settings.

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography

AimsLarge animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. Methods and ResultsMale farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [15O]water and oxygen consumption using [11C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. ConclusionsThe chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.

Abstract 372: Regulation of Ski and Scleraxis in the Infarcted Rat Heart

Introduction: Coronary heart disease is causal to myocardial infarction (MI) and cardiac fibrosis. Upon ischemic myocardial injury, resident cardiac fibroblasts phenoconvert to myofibroblasts and synthesize large amounts of fibrillar collagens to produce scar tissue. Although the myofibroblast numbers are reduced in the infarct scar following the completion of wound healing, a sub-population of cells persist in the wounded area, leading to maladaptive chronic remodeling of the scar area and eventually the non-infarcted myocardium. Ski has been identified as a repressor of the TGF-β1 signaling pathway, attenuating the myofibroblast phenotype and its functional properties. Scleraxis has been implicated in canonical TGF-β1 signaling to promote collagen1α2 expression. We investigated how Ski and Scleraxis contribute to physiological and pathological wound healing in vivo. Methods: The study was carried out using 64 male Sprague-Dawley rats. The left anterior descending (LAD) coronary artery was ligated to induce a myocardial infarction. Control (sham) operated animals underwent surgery without ligation of the LAD artery. Animals were sacrificed at 2, 4, and 8 weeks post-MI and tissue collected for Western blot and qPCR studies. Results: Scleraxis mRNA expression remained at baseline at 2 and 8 weeks post-MI, but was significantly increased 4 weeks post-MI. Scleraxis protein expression was down-regulated within the scar area of infarcted hearts when compared to control samples 2 and 4 weeks post-MI. Ski mRNA expression was up-regulated within the scar area of infarcted hearts 2, 4 and 8 weeks after infarction. Conclusions: Scleraxis protein is down-regulated in myofibroblasts of the infarct scar in the chronic stages of myocardial infarction, corresponding to the maturation of the scar. At these stages of wound healing, we have previously published that Ski is up-regulated in the cytosol of these same cells. We suggest reciprocal feedback in the expression of these two proteins exists in myofibroblasts in the infarct scar. We hope to learn more about the Ski/Scleraxis feedback loop in pathological wound healing to identify novel therapeutic targets.

Embolization of the first diagonal branch of the left anterior descending coronary artery as a porcine model of chronic trans-mural myocardial infarction

BackgroundAlthough the incidence of acute death related to coronary artery disease has decreased with the advent of new interventional therapies, myocardial infarction remains one of the leading causes of death in the US. Current animal models developed to replicate this phenomenon have been associated with unacceptably high morbidity and mortality. A new model utilizing the first diagonal branch of the left anterior descending artery (D1-LAD) was developed to provide a clinically relevant lesion, while attempting to minimize the incidence of adverse complications associated with infarct creation.MethodsEight Yucatan miniature pigs underwent percutaneous embolization of the D1-LAD via injection of 90 µm polystyrene micro-spheres. Cardiac structure and function were monitored at baseline, immediately post-operatively, and at 8-weeks post-infarct using transthoracic echocardiography. Post-mortem histopathology and biochemical analyses were performed to evaluate for changes in myocardial structure and extracellular matrix (ECM) composition respectively. Echocardiographic data were evaluated using a repeated measures analysis of variance followed by Tukey’s HSD post hoc test. Biochemical analyses of infarcted to non-infarcted myocardium were compared using analysis of variance.ResultsAll eight pigs successfully underwent echocardiography prior to catheterization. Overall procedural survival rate was 83% (5/6) with one pig excluded due to failure of infarction and another due to deviation from protocol. Ejection fraction significantly decreased from 69.7 ± 7.8% prior to infarction to 50.6 ± 14.7% immediately post-infarction, and progressed to 48.7 ± 8.9% after 8-weeks (p = 0.011). Left ventricular diameter in systole significantly increased from 22.6 ± 3.8 mm pre-operatively to 30.9 ± 5.0 mm at 8 weeks (p = 0.016). Histopathology showed the presence of disorganized fibrosis on hematoxylin and eosin and Picro Sirius red stains. Collagen I and sulfated glycosaminoglycan content were significantly greater in the infarcted region than in normal myocardium (p = 0.007 and p = 0.018, respectively); however, pyridinoline crosslink content per collagen I content in the infarcted region was significantly less than normal myocardium (p = 0.048).ConclusionSystolic dysfunction and changes in ECM composition induced via embolization of the D1-LAD closely mimic those found in individuals with chronic myocardial infarction (MI), and represents a location visible without the need for anesthesia. As a result, this method represents a useful model for studying chronic MI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0547-4) contains supplementary material, which is available to authorized users.

Extracellular volume fraction in coronary chronic total occlusion patients.

(1) To assess extracellular volume fraction (ECV) and regional systolic function in patients presenting with coronary chronic total occlusion (CTO) in areas without significant late gadolinium enhancement (LGE), and (2) to investigate the correlation between angiography collateral flow and ECV in territories supplied by CTO vessels. A total of 50 angiographically documented CTO patients and 15 age- and sex-matched normal controls were recruited to the study. Myocardial ECV, was calculated in infarcted, global non-infarcted and the entire myocardium respectively. Segmental ECV was calculated from myocardial segments within the perfusion territory of a CTO vessel. The global and regional systolic function was evaluated using ejection fraction and percent systolic thickening. ECVs in global myocardium and global non-infarcted myocardium were significantly elevated in comparison with that in controls (29.1 ± 4.2% and 26.6 ± 2.6% vs. 23.3 ± 2.0%, all P < 0.005). Global ECV significantly correlated with LV ejection fraction (r = -0.56, P < 0.001) and ECV inversely correlated with systolic thickening in global non-infarcted myocardium (r = -0.31, P < 0.05). The lower segmental ECV was associated with the presence of well-developed collaterals (P = 0.004), and multivariate binary logistic analysis demonstrated that mean segmental ECV and course of disease were the independent discriminator of collateral flow with overall diagnostic accuracy of 74.4%. In patients with CTO, ECV is found to be increased beyond that observed with LGE, and correlates with LV regional wall motion abnormality, which appears to reflect diffuse myocardial fibrosis. Mean segmental ECV value, combined with course of disease, may serve as good predictors of collateral flow.

Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.

Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor β1 (TGF-β1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-β1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-β1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-β1 expression.

SYMPATHETIC DENERVATION IS ASSOCIATED WITH MICROVASCULAR DYSFUNCTION IN NON-INFARCTED MYOCARDIUM IN PATIENTS WITH CARDIOMYOPATHY

Sympathetic denervation typically occurs in the infarcted myocardium and is associated with sudden cardiac death. Impaired innervation was also demonstrated in non-infarcted myocardium in ischaemic and dilated cardiomyopathy (ICMPandDCMP). Factors affecting sympatheticnerveintegrity inremotemyocardium areunknown. Perfusionabnor- malities,evenintheabsenceofepicardialcoronaryarterydisease,mayrelatetosympatheticdysfunction.Thisstudywas aimed to assess the interrelations of myocardial blood flow (MBF), contractile function, and sympathetic innervation in non-infarcted remote myocardium. Seventy patients with ICMP or DCMP and LVEF ≤35% were included. ( 15 O)H2O- and ( 11 C)hydroxyephedrine (HED)PETwasperformedtoquantify restingMBF,hyperaemicMBF,andsympatheticinnervation.Cardiovascularmag- neticresonance(CMR)imagingwasperformedtoassessleftventricularfunction,mass,wallthickening,andscarsize.Wall thickening, ( 11 C)HED retention index (RI), and MBF wereassessed in remote segments without scar, selected on CMR. ( 11 C)HEDRIwascorrelatedwithrestingMBF(r ¼ 0.41,P , 0.001)andhyperaemicMBF(r ¼ 0.55,P , 0.001)inremote myocardiuminbothICMPandDCMP.Inaddition,LVvolumes(r ¼ 20.40,P ¼ 0.001),LVmass(r ¼ 20.31,P ¼ 0.008), andwallthickening(r ¼ 0.45,P , 0.001)correlatedwithremote( 11 C)HEDRI.Multivariableanalysisrevealedthathyper- aemic MBF (B ¼ 0.79, P , 0.001), wall thickening (B ¼ 0.01, P ¼ 0.03), and LVEDV (B ¼ 20.03, P ¼ 0.02) were inde- pendent predictors for remote ( 11 C)HED RI. Conclusion Hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted remote myocardium in patients with ICMP and DCMP. This suggests that microvascular dysfunction might be an important factor related to sympathetic nerve integrity. Whether impaired hyperaemic MBF is the primary cause of this relation remains unclear.

Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits

Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase activity and endoplasmic reticulum (ER) stress are increased after myocardial infarction (MI). In this study, we proposed to test whether activation of the NADPH oxidase in the remote non-infarcted myocardium mediates ER stress and left ventricular (LV) remodeling after MI. Rabbits with MI or sham operation were randomly assigned to orally receive an NADPH oxidase inhibitor apocynin or placebo for 30days. The agents were administered beginning at 1week after surgery. MI rabbits exhibited decreases in LV fractional shortening, LV ejection fraction and the first derivative of the LV pressure rise, which were abolished by apocynin treatment. NADPH oxidase Nox2 protein and mRNA expressions were increased in the remote non-infarcted myocardium after MI. Immunolabeling further revealed that Nox2 was increased in cardiac myocytes in the remote myocardium. The apocynin treatment prevented increases in the Nox2 expression, NADPH oxidase activity, oxidative stress, myocyte apoptosis and GRP78, CHOP and cleaved caspase 12 protein expression in the remote myocardium. The apocynin treatment also attenuated increases in myocyte diameter and cardiac fibrosis. In cultured H9C2 cardiomyocytes exposed to angiotensin II, an important stimulus for post-MI remodeling, Nox2 knockdown with siRNA significantly inhibited angiotensin II-induced NADPH oxidase activation, reactive oxygen species and GRP78 and CHOP protein expression. We conclude that NADPH oxidase inhibition attenuates increased ER stress in the remote non-infarcted myocardium and LV remodeling late after MI in rabbits. These findings suggest that the activation of NADPH oxidase in the remote non-infarcted myocardium mediates increased ER stress, contributing to myocyte apoptosis and LV remodeling after MI.

Cardiac remodeling and physical training post myocardial infarction.

After myocardial infarction (MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of renin-angiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.

Abstract 14957: Investigation of Myocardial Birefringence using Polarization-Sensitive Optical Coherence Tomography in a Mouse Model of Myocardial Infarction

Introduction: Although several imaging modalities have been utilized to characterize myocardium, the birefringence of myocardium has not been spotlighted. The polarization-sensitive optical coherence tomography (PS-OCT) is a novel imaging method for the characterization of tissue birefringence. Hypothesis: The birefringence of infarcted myocardium would be different from non-infarcted myocardium. We examined the myocardial birefringence in a mouse coronary artery ligation model using PS-OCT. Methods: Male C57B/6 mice (20-30g) underwent thoracotomy and the ligation of left anterior descending artery. At post-myocardial infarction (post-MI) 3 hours or on post-MI day 28, the left anterior wall of the mice was imaged with PS-OCT in vivo and ex vivo. The local phase retardation for tissue birefringence, the local principal axis directional uniformity for tissue orientation, and the degree of polarization uniformity were demonstrated and compared with collagen fiber staining (picrosirius red). For PS-OCT system, wavelength-swept laser with 140 nm bandwidth (center wavelength = 1,280 nm) and 120 kHz A-line rate was used. Results: The endocardial border could be detected by high birefringence of myocardium. There was no difference in the birefringence between systole and diastole. The infarcted anterior wall showed dyskinesia or hypokinesia. The systolic wall thickening was lower in the infarcted wall compared to the normal anterior wall. At post-MI 3 hours, there was no significant change in myocardial birefringence. On day 28, the infarcted myocardium with scar tissue showed low level of local birefringence with irregular tissue orientation compared to the normal myocardium. The 3D reconstructed images were used to differentiate transmural or subendocardial MI. Conclusions: Our study demonstrated that the PS-OCT would be helpful for the evaluation of myocardial function and tissue characterization in myocardial infarction.

Abstract 17328: Ultrasmall Supraparamagnetic Particles of Iron Oxide-enhanced Magnetic Resonance Imaging in the Assessment of Cellular Inflammation after Myocardial Infarction

Introduction: Excessive inflammation after myocardial infarction (MI) can be detrimental to the recovery of cardiac function. Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) can detect myocardial cellular inflammation after MI. We aimed to determine the time course and duration of USPIO-enhancement following acute MI. Methods: Twenty-one patients with acute MI were studied in the 3-month period following acute MI. Repeated T2*-weighted 3T MRI was performed throughout and 24 h after USPIO (ferumoxytol, 4 mg/kg) administration at 4±3, 12±2, 21±4 and 90±9 days. Myocardial regions of interest (ROIs) were drawn and categorised into infarct and non-infarct regions by the presence or absence of late gadolinium enhancement (LGE). R2* values within ROIs were determined to assess the time course and duration of uptake and clearance of USPIO. Results: Following single-dose USPIO administration 2-7 days after acute MI, USPIO uptake is demonstrable at 24 h (p&lt;0.0001) and is cleared within 4-8 days (Figure 1a). Increased USPIO uptake is seen in the infarct region at days 2-7 (p&lt;0.0001), and days 10-14 (p&lt;0.05) compared to non-infarcted myocardium (Figure 1b). Conclusions: For the first time, we have shown USPIO-enhanced MRI can detect and quantify infarct-related cellular inflammation in the first 2 weeks following acute MI.

Mineralocorticoid Receptor Antagonists Modulate Galectin-3 and Interleukin-33/ST2 Signaling in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction

ObjectivesThis study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). BackgroundThe molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. MethodsMI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined. ResultsIn the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. ConclusionsMRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling.

Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction

BackgroundRemote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI). Methods and resultsAt 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions. ConclusionsRepeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.

Effect of Chronic Heart Rate Reduction by I(f) Current Inhibitor Ivabradine on Left Ventricular Remodeling and Systolic Performance in Middle-Aged Rats With Postmyocardial Infarction Heart Failure.

A large myocardial infarction (MI) initiates progressive cardiac remodeling that leads to systolic heart failure (HF). Long-term heart rate reduction (HRR) induced by the I f current inhibitor ivabradine (IVA) ameliorates left ventricular (LV) remodeling and improves systolic performance in young post-MI rats. However, the beneficial effects of chronic IVA treatment in middle-aged rats remain to be determined. A large MI was induced in 12-month-old rats by left coronary artery ligation. Rats were treated with IVA via osmotic pumps intraperitoneal in a dose of 10.5 mg/kg/d (MI + IVA) and compared with MI and sham-operated animals 12 weeks after MI. Heart rate in MI + IVA rats was on average 29% lower than that of rats in the MI group. Left ventricular remodeling was comparable between post-MI groups, although MI + IVA rats did not show the compensatory thickening of the noninfarcted myocardium. Chronic HRR had no effect on transverse cardiac myocyte size and capillary growth, but it reduced the collagen content in noninfarcted myocardium. Left ventricular systolic performance remained similarly impaired in MI and MI + IVA rats. Moreover, abrupt IVA withdrawal led to worsening HF and reduction of coronary reserve. Our data reveal that chronic IVA-induced HRR does not provide sustainable benefits for LV systolic performance in middle-aged rats with post-MI HF.

GW25-e0278 Coronary Flow Reserve in the Remote Myocardium Predict Left Ventricular Remodeling Following Acute Myocardial Infarction

The objective of the present study was to assess whether a relationship exists between CFR in the non-infarcted myocardium and left ventricular remodeling following AMI. We enrolled 42 consecutive patients undergoing PCI. All patients were subjected to two-dimensional echocardiography (2-DE) and

Ultra low-dose of gadobenate dimeglumine for late gadolinium enhancement (LGE) imaging in acute myocardial infarction: A feasibility study

PurposeTo assess the feasibility of using an ultra-low dose (0.05mmol/kg of body weight [BW]) of high relaxivity contrast agent for late gadolinium enhancement (LGE) imaging in patients with acute myocardial infarction (AMI). Materials and methods17 consecutive patients (mean age, 60.1±10.3 years) with ST-segment elevation AMI underwent two randomized cardiac magnetic resonance studies (exam intervals between 24 and 48h) on a 1.5T unit during the first week after the event using gadobenate dimeglumine (Gd-BOPTA) at the dose of 0.1mmol/kg BW (standard dose or SD group) and 0.05mmol/kg BW (half dose or HD group). Image quality was qualitatively assessed. Quantitative analysis of LGE were performed by measuring signal intensity (SI), signal-to-noise ratio (SNR) in the infarcted myocardium (IM), non-infarcted myocardium (N-IM) and left ventricular cavity (LVC) in images acquired at 1, 3, 5, 10, 15 and 20min after administration of Gd-BOPTA using both contrast media protocol. Contrast-to-noise ratio (CNR) between IM and N-IM (CNR IM/N-IM) and between IM and LVC (CNR IM/LVC) were also quantified for each time point. Moreover the extent of infarcted myocardium was measured. Results102 LGE images were evaluated for each dose group. Quality score was significantly higher for SD at 1, 15 and 20min (0.002<p<0.046) and for HD at 5min (p=0.013). SNR has been higher in the SD group compared to the HD group even though not statistically significant at any time-point for both IM (SD vs. HD: 87.7±73 vs. 65±66; 0.15<p<0.38) and N-IM (SD vs. HD: 22±61 vs. 9.9±6.5; 0.09<p<0.43). LVC SNR was significantly higher with SD at 10min (p=0.03), 15min (p=0.001) and 20min (p=0.004). CNR between the IM and N-IM was significantly higher using SD compared to HD (1382.24±1049 vs. 695.4±500; 0.000<p<0.028) at 10, 15 and 20min. No significant differences in CNR IM/LVC were noted for HD acquired 5min after CM administration compared to SD acquired at 10 (p=0.34), 15 (p=0.96) and 20 (p=0.41) min, and between HD at 10min compared to SD acquired at 15min (p=0.78) and 20min (p=0.32). Good correlation between SD and HD (0.56<r2<0.85, p<0.024) was found at all time-points in the measuring of IA. ConclusionThe use of a 0.05mmol/kg dose of gadobenate dimeglumine is feasible for LGE imaging of acute MI and the best image quality is obtained at 5min after contrast administration. It could be beneficial in patient with renal failure and a solution to improve the identification of subendocardial infarction reducing examination time, costs and total gadolinium load. However, the standard dose of 0.1mmol/kg provides overall better image quality, with the best performance obtained at the delay of 10min or more after Gd-BOPTA administration, and it should be routinely preferred.