Chronic Stage Of Myocardial Infarction Research Articles

Factors predicting resolution of left ventricular thrombus in different time windows after myocardial infarction

BackgroundLeft ventricular thrombus (LVT) is a serious complication after myocardial infarction. However, due to its asymptomatic nature, early detection is challenging. We aimed to explore the differences in clinical correlates of LVT found in acute to subacute and chronic phases of myocardial infarction.MethodsWe collected data from 153 patients who were diagnosed with LVT after myocardial infarction at the Affiliated Hospital of Qingdao University from January 2013 to December 2022. Baseline information, inflammatory markers, transthoracic echocardiograph (TTE) data and other clinical correlates were collected. Patients were categorized into acute to subacute phase group (< 30 days) and chronic phase group (30 days and after) according to the time at which echocardiograph was performed. The resolution of thrombus within 90 days is regarded as the primary endpoint event. We fitted logistic regression models to relating clinical correlates with phase-specific thrombus resolution.ResultsFor acute to subacute phase thrombus patients: C-reactive protein levels (OR: 0.95, 95% CI: 0.918–0.983, p = 0.003) were significantly associated with thrombus resolution. For chronic phase thrombus patients: anticoagulant treatment was associated with 5.717-fold odds of thrombus resolution (OR: 5.717, 95% CI: 1.543–21.18, p = 0.009).ConclusionsHigher levels of CRP were associated with lower likelihood of LVT resolution in acute phase myocardial infarction; Anticoagulant therapy is still needed for thrombus in the chronic stage of myocardial infarction.

Biomechanical properties of acellular scar ECM during the acute to chronic stages of myocardial infarction

After myocardial infarction (MI), the infarcted tissue undergoes dynamic and time-dependent changes. Previous knowledge on MI biomechanical alterations has been obtained by studying the explanted scar tissues. In this study, we decellularized MI scar tissue and characterized the biomechanics of the obtained pure scar ECM. By thoroughly removing the cellular content in the MI scar tissue, we were able to avoid its confounding effects. Rat MI hearts were obtained from a reliable and reproducible model based on permanent left coronary artery ligation (PLCAL). MI heart explants at various time points (15min, 1 week, 2 weeks, 4 weeks, and 12 weeks) were subjected to decellularization with 0.1% sodium dodecyl sulfate solution for ~1-2 weeks to obtain acellular scar ECM. A biaxial mechanical testing system was used to characterize the acellular scar ECM under physiologically relevant loading conditions. After decellularization, large decrease in wall thickness was observed in the native heart ECM and 15min scar ECM, implying the collapse of cardiomyocyte lacunae after removal of heart muscle fibers. For scar ECM 1 week, 2 weeks, and 4 weeks post infarction, the decrease in wall thickness after decellularization was small. For scar ECM 12 weeks post infarction, the reduction amount of wall thickness due to decellularization was minimal. We found that the scar ECM preserved the overall mechanical anisotropy of the native ventricle wall and MI scar tissue, in which the longitudinal direction is more extensible. Acellular scar ECM from 15min to 12 weeks post infarction showed an overall stiffening trend in biaxial behavior, in which longitudinal direction was mostly affected and manifested with a decreased extensibility and increased modulus. This reduction trend of longitudinal extensibility also led to a decreased anisotropy index in the scar ECM from the acute to chronic stages of MI. The post-MI change in biomechanical properties of the scar ECM reflected the alterations of collagen fiber network, confirmed by the histology of scar ECM. In short, the reported structure-property relationship reveals how scar ECM biophysical properties evolve from the acute to chronic stages of MI. The obtained information will help establish a knowledge basis about the dynamics of scar ECM to better understand post-MI cardiac remodeling.

Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway.

Blockade of hypoxia-caused nonmyocytes apoptosis helps improve survival and mitigate ventricular remodeling and dysfunction during the chronic stage of myocardial infarction. But tools affecting nonmyocyte apoptosis are very rare. Sphingosylphosphorylcholine (SPC), a naturally occurring bioactive sphingolipid in plasma, was proved to protect cardiomyocyte against apoptosis in an ischemic model in our previous study. Here, we showed that SPC also inhibited hypoxia-induced apoptosis in myofibroblasts, an important type of nonmyocytes in the heart. Calmodulin (CaM) is an identified receptor of SPC. We clarified that SPC inhibited myofibroblast apoptosis through CaM as evidenced by decreased cleaved caspase 3, PARP1 and condensed nucleus. Furthermore, the employment of inhibitor and agonist of p38 and STAT3 suggests that SPC inhibits myofibroblast apoptosis by regulating the phosphorylation of p38 and STAT3, and they act as downstream of CaM. The present work may provide new evidence on the regulation of myofibroblasts apoptosis by SPC and a novel target for heart remodeling after hypoxia.

Personalized Cardiac Computational Models: From Clinical Data to Simulation of Infarct-Related Ventricular Tachycardia.

In the chronic stage of myocardial infarction, a significant number of patients develop life-threatening ventricular tachycardias (VT) due to the arrhythmogenic nature of the remodeled myocardium. Radiofrequency ablation (RFA) is a common procedure to isolate reentry pathways across the infarct scar that are responsible for VT. Unfortunately, this strategy show relatively low success rates; up to 50% of patients experience recurrent VT after the procedure. In the last decade, intensive research in the field of computational cardiac electrophysiology (EP) has demonstrated the ability of three-dimensional (3D) cardiac computational models to perform in-silico EP studies. However, the personalization and modeling of certain key components remain challenging, particularly in the case of the infarct border zone (BZ). In this study, we used a clinical dataset from a patient with a history of infarct-related VT to build an image-based 3D ventricular model aimed at computational simulation of cardiac EP, including detailed patient-specific cardiac anatomy and infarct scar geometry. We modeled the BZ in eight different ways by combining the presence or absence of electrical remodeling with four different levels of image-based patchy fibrosis (0, 10, 20, and 30%). A 3D torso model was also constructed to compute the ECG. Patient-specific sinus activation patterns were simulated and validated against the patient's ECG. Subsequently, the pacing protocol used to induce reentrant VTs in the EP laboratory was reproduced in-silico. The clinical VT was induced with different versions of the model and from different pacing points, thus identifying the slow conducting channel responsible for such VT. Finally, the real patient's ECG recorded during VT episodes was used to validate our simulation results and to assess different strategies to model the BZ. Our study showed that reduced conduction velocities and heterogeneity in action potential duration in the BZ are the main factors in promoting reentrant activity. Either electrical remodeling or fibrosis in a degree of at least 30% in the BZ were required to initiate VT. Moreover, this proof-of-concept study confirms the feasibility of developing 3D computational models for cardiac EP able to reproduce cardiac activation in sinus rhythm and during VT, using exclusively non-invasive clinical data.

Runx1 deficiency preserves LV systolic function post-MI in the chronic stages of MI in mice with large infarcts

Background: Myocardial infarction (MI) resulting in adverse cardiac remodelling leads to heart failure and is a major cause of mortality worldwide. Novel therapeutic targets that can limit this progression are urgently required.

Abstract 368: Biomechanical Properties of Scar ECM: from the Acute to Chronic Stages of Myocardial Infarction

Introduction: Myocardial infarction (MI) affects more than 8 million Americans, causing massive heart cell death and heart function decrease. To better understand the scar biomechanics, we characterized the mechanical properties of pure scar ECM, obtained by decellularizing the MI tissues. Materials and Methods: Infarcted rat hearts were generated by a permanent left coronary artery ligation (PLCAL) and harvested at 15 min, 1, 2, and 4 weeks (per acute to chronic stages of MI)(N = 6 each). Scar ECM were obtained by decellularizing the infarcted hearts in 0.1% sodium dodecyl sulfate (SDS) solution for 3 weeks. Scar ECM specimens were trimmed into square shape, and then subjected to biaxial testing with one edge aligned with the circumferential direction and the other edge aligned with the longitudinal direction of the rat heart. After 10 cycle preconditioning, an equibiaxial tension protocol of T circ : T rad = 30:30 N/m was performed to capture the tissue biaxial behavior. Results and Discussion: Scar ECM 15 minutes through 4 weeks post infarction showed a stiffening biaxial behavior along with the time (Fig.1). The decrease of extensibility along longitudinal direction was more noticeable than circumferential direction, which led to a decrease in degree of anisotropy. Conclusions: Scar ECM biomechanics showed a stiffening behavior with a marked reduction in extensibility (longitudinal) with time. This change in biomechanical properties can be correlated to the collagen structure changes with progression of MI. Knowledge of the structural-mechanical relationship of scar ECM will help us understand MI progression and help formulate regenerative therapies.

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.

OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling.

Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction.

Inhibition of glycogen synthase kinase-3β prevents sympathetic hyperinnervation in infarcted rats.

We have demonstrated that nerve growth factor (NGF) expression in the myocardium is selectively increased during chronic stage of myocardial infarction, resulting in sympathetic hyperinnervation. Glycogen synthase kinase-3 (GSK-3) signal has been shown to play key roles in the regulation of cytoskeletal assembly during axon regeneration. We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction through attenuated NGF expression and Tau expression. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to either LiCl or SB216763, chemically unrelated inhibitors of GSK-3β, a combination of LiCl and SB216763, or vehicle for four weeks. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for sympathetic nerve also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administering either LiCl, SB216763, or combination. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those treated with GSK-3 inhibitors. Addition of SB216763 did not have additional beneficial effects compared with those seen in rats treated with LiCl alone. Furthermore, lithium treatment increased Tau1 and decreased AT8 and AT180 levels. Chronic use of lithium after infarction, resulting in attenuated sympathetic reinnervation by GSK-3 inhibition, may modify the arrhythmogenic response to programmed electrical stimulation.

Chronic ischemic mitral regurgitation – adiagnostic and therapeutic challenge

Chronic ischemic mitral regurgitation (IMR) is a valvular disorder caused by left ventricular dysfunction due to chronic coronary artery disease. It represents a valvular consequence of left ventricular contractile dysfunction and/or pathologic remodeling that indirectly impairs appropriate closing of the mitral valve. IMR is not caused by a structural change of the mitral valve. Acute postinfarction mitral regurgitation is also differentiated from chronic IMR. Chronic IMR occurs in the chronic stage of myocardial infarction in 20–50 % of the patients; its prevalence in the population is increasing. In patients after myocardial infarction, impaired contractility and mitral regurgitation are the most important negative prognostic factors. Furthermore, regurgitation that would be considered mild in patients with organic mitral valve disease already has a negative prognostic implication in patients with IMR. Echocardiogram is the fundamental tool for diagnostic evaluation and treatment planning in patients with IMR. The key parameters that have to be assessed include left ventricular contractile dysfunction, degree of left ventricular remodeling, pathologic changes in mitral valve geometry and quantification of regurgitation severity. In some patients, significant IMR can only be identified by stress echocardiography. Although IMR has an important negative impact on prognosis, indications for treatment and best treatment options have still not been well defined. According to the European and American guidelines, significant IMR should be treated, particularly in patients who are candidates for surgical coronary artery revascularisation. However, there is still no conclusive evidence that any surgical or percutaneous treatment of IMR improves patients’ prognosis.

Lipomatous metaplasia identified in rabbits with reperfused myocardial infarction by 3.0 T magnetic resonance imaging and histopathology

BackgroundCardiac lipomatous metaplasia (LM) occurs in patients with chronic ischemic heart disease and heart failure with unclear mechanisms. We studied coronary occlusion/reperfusion-induced myocardial infarction (MI) in rabbits during a 9-months follow-up using 3.0 T magnetic resonance scanner, and confirmed the presence of MI in acute phase and LM in chronic phase using histopathology.MethodsMI was surgically induced in 10 rabbits by 90-min coronary artery occlusion and reperfusion. Forty-eight hours later, multiparametric cardiac magnetic resonance imaging (cMRI) was performed at a 3.0 T clinical scanner for MI diagnosis and cardiac function analysis. Afterwards, seven rabbits were scarified for histochemical staining with triphenyltetrazolium chloride (TTC), and hematoxylin-eosin (HE), and 3 were scanned with cMRI at 2 days, 2 weeks, 2 months and 9 months for longitudinal observations of morphological and functional changes, and the fate of the animals. Post-mortem TTC, HE and Masson's trichrome (MTC) were studied for chronic stage of MI.ResultsThe size of acute MI correlated well between cMRI and TTC staining (r2=0.83). Global cardiac morphology-function analysis showed significant correlation between increasing acute MI size and decreasing ejection fraction (p<0.001). During 9 months, cMRI documented evolving morphological and functional changes from acute MI to chronic scar transformation and fat deposition with a definite diagnosis of LM established by histopathology.ConclusionsAcute MI and chronic LM were induced in rabbits and monitored with 3.0 T MRI. Studies on this platform may help investigate the mechanisms and therapeutic interventions for LM.

Noninvasive Parameters for Evaluation of Activation Delay in Arrhythmogenic Cardiomyopathy

Prolonged electric activation delay between 2 sites in the heart is due to slow conduction, lengthening of conduction pathways, or both. In the presence of unidirectional block and triggers, enhanced delay promotes reentrant circuits as substrate of arrhythmogenesis in various supraventricular and ventricular arrhythmias. This mechanism is well-known in the chronic stage of myocardial infarction and other types of structural heart disease, including arrhythmogenic cardiomyopathy (AC).1–3 Article see p 475 AC can be defined as, ultimately, a structural heart disease, with signs of heart failure preceded in the early stages by electrophysiological alteration that result in electrocardiographic abnormalities and ventricular arrhythmias. AC includes primarily right ventricular, primarily left ventricular, or biventricular abnormalities.4,5 Arrhythmogenic right ventricular dysplasia/cardiomyopathy is well-known nomenclature for the right-sided variant. However, although histopathological and functional predominance of right ventricular abnormalities are frequently found, the left ventricle is affected in most patients as well. Moreover, at the molecular level, both ventricles are affected by altered expression and distribution of intercalated disk proteins.6–8 Because of these considerations, AC has recently become the favored terminology of this group of frequently difficult-to-distinguish disorders. AC is considered a genetic disorder primarily associated with gene mutations encoding desmosomal proteins, although nondesmosomal genes are also involved in a minority, but substantial number of cases.9–11 Accumulating evidence suggests that gene mutation-related changes or distribution of desmosomal proteins give rise to altered expression and distribution of other intercalated disk proteins, including gap junction and ion channel proteins, resulting in mechanical and electric uncoupling …

The Antiapoptotic Effect of Granulocyte Colony-stimulating Factor Reduces Infarct Size and Prevents Heart Failure Development in Rats

Background/Aim. Granulocyte colony-stimulating factor (G-CSF) reduces myocardial injury and improves cardiac function after myocardial infarction (MI). We investigated the early alterations provided by G-CSF and the chronic repercussions in infarcted rats. Methods. Male Wistar rats (200-250g) received vehicle (MI) or G-CSF (MI-GCSF) (50 µg/kg, sc) at 7, 3 and 1 days before MI surgery. Afterwards MI was produced and infarct size was measured 1 and 15 days after surgery. Expression of anti- and proapoptotic proteins was evaluated immediately before surgery. 24 hours after surgery, apoptotic nuclei were evaluated. Two weeks after MI, left ventricular (LV) function was evaluated, followed by in situ LV diastolic pressure-volume evaluation. Results. Infarct size was decreased by 1 day pre-treatment before occlusion (36±2.8 vs. 44±2.1% in MI; P<0.05) and remained reduced at 15 days after infarction (28±2.2 vs. 36±1.4% in MI; P<0.05). G-CSF pretreatment increased Bcl-2 and Bcl-xL protein expression, but did not alter Bax in LV. Apoptotic nuclei were reduced by treatment (Sham: 0.46±0.42, MI: 15.5±2.43, MI-GCSF: 5.34±3.34%; P<0.05). Fifteen days after MI, cardiac function remained preserved in G-CSF pretreated rats. The LV dilation was reduced in MI-G-CSF group as compared to MI rats, being closely associated with infarct size. Conclusion. The early beneficial effects of G-CSF were essentials to preserve cardiac function at a chronic stage of myocardial infarction.

Comparison of multidetector CT with F-18-FDG-PET and SPECT in the assessment of myocardial viability in patients with myocardial infarction: A preliminary study

Objective To evaluate the ability of MDCT to detect a nonviable myocardium in patients with myocardial infarction (MI). Methods and material This study included 17 patients with MI in the acute ( n = 13) or chronic stage ( n = 4). MDCT, SPECT, and F-18-FDG-PET were performed in 10 patients during the acute stage and in 2 during the chronic stage of MI. MDCT and SPECT were performed in 13 patients with acute stage and in 4 with chronic stage of MI. Sixteen-slice MDCT was performed 10 min after injection of 120 mL of nonionic contrast media. MDCT, SPECT and PET images were analyzed using a 17-segment model. The depth of hyperenhancement >2/3 was defined as nonviable at MDCT. Results MDCT and SPECT were concordant in localizing the MI in 84.2% (272/323 segments) and were discordant in 15.8% (51/323). MDCT and PET were concordant in localizing MI in 89.2% (182/204) and discordant in 10.8% (22/204). The sensitivity, specificity and diagnostic accuracy of MDCT in determining the nonviable segments were 70.4%, 85.3%, 81.4% as compared with PET, respectively, and 69.4%, 81.8%, 79.9% compared with SPECT, respectively, and 73.5%, 79.4%, 78.4% compared with combined PET and SPECT, respectively. MDCT findings suggested nonviability in additional 16 segments (5.0%) and 7 segments (3.4%) where MI was not detected on SPECT and FDG-PET, respectively. Conclusion MDCT is useful for determining myocardial viability in patients with myocardial infarction and more sensitive than SPECT and FDG-PET in detecting a nonviable myocardium.

Effect on Outcome of an Increase of Serum Cardiac Troponin T in Patients With Healing or Healed ST-Elevation Myocardial Infarction

Recently, an association between minimally elevated cardiac troponin levels and cardiovascular risk in the general population has been reported. However, the prevalence and clinical importance of elevated cardiac troponin T (cTnT) levels remain unclear in patients with histories of myocardial infarction (MI). In this study, 1,807 consecutive patients with ST-segment elevation MIs were prospectively studied (77.1% men; mean age 64.4 years). Venous blood samples were obtained in the chronic stage of MI (28 +/- 7 days after onset), and serum cTnT levels were determined. During the average follow-up of 1,042 days, 84 patients died and 83 had nonfatal reinfarctions. Patients with cTnT levels in the highest quartile (> or = 0.040 ng/ml [n = 353]) had a higher incidence of all-cause death (8.2% vs 5.2%, p = 0.049) and nonfatal reinfarction (8.3% vs 5.1%, p = 0.048) than patients with cTnT levels from the lower 3 quartiles (<0.040 ng/ml [n = 1,064]). Multivariate Cox regression analysis revealed that a minimally elevated cTnT level (> or =0.040 ng/ml) was a significant predictor of all-cause mortality (hazard ratio 1.79, 95% confidence interval 1.10 to 2.90, p <0.02) and nonfatal reinfarction (hazard ratio 1.50, 95% confidence interval 1.13 to 2.20, p <0.03). Subgroup analysis showed that an elevated cTnT level was also a predictor of all-cause mortality and nonfatal reinfarction in patients without heart failure. In conclusion, minimally elevated cTnT levels in the chronic stage of MI predicted long-term adverse clinical outcomes.

Oozing type of left ventricular rupture via subepicardial aneurysm diagnosed 5 months after myocardial infarction

A 71-year-old man visited our hospital complaining of increasing fatigue and exertional dyspnea. He had had severe epigastric pain for the past 5 months. On admission, chest radiogram showed marked cardiac dilatation and echocardiogram massive pericardial effusion with a small subepicardial aneurysm at the posterior wall of the left ventricle. An urgent pericardiocentesis removed 1300 ml of bloody effusion. The red blood cell count of the pericardial effusion was similar to that of the peripheral blood, and there were no abnormal findings on cytologic and bacteriological examinations. Coronary angiography showed a blunt occlusion of the mid-portion of the circumflex artery. Left ventricular angiogram revealed aneurysmal deformity of the left ventricular posterior wall. These findings suggested that an oozing type of left ventricular rupture via a subepicardial aneurysm had occurred after the onset of myocardial infarction (MI), resulting in massive accumulation of pericardial effusion. The patient is presently doing well without any clinical symptoms 18 months after pericardiocentesis. This is the first case report in which a subepicardial aneurysm with massive pericardial effusion was detected in the chronic stage of MI and successfully managed without surgical repair.

G-CSF upregulates myocardial akt and improves function of the hearts with established heart failure due to large old myocardial infarction

We recently reported the beneficial effects of granulocyte colony-stimulating factor (G-CSF) that was started on the next day of acute myocardial infarction (MI) upon post-infarct ventricular remodeling and heart failure. However, the effect of G-CSF is unknown on the hearts with established heart failure due to old large MI. In the present study, we examined the potential therapeutic effects of G-CSF on post-infarct ventricular remodeling and heart failure at the chronic stage. To the mice with 12 week-old MI showing marked ventricular remodeling and established heart failure, G-CSF (10 microg/kg/day) was subcutaneous injected for 5 days/week for 4 weeks. According to echocardiography and hemodynamic measurement, the G-CSF treated group showed significantly alleviated left ventricular remodeling and dysfunction at 16 weeks post-infarction, compared with the distilled water-treated control group. Immunohistochemically, G-CSF receptor was overexpressed on plasma membrane of the surviving cardiomyocytes of hearts with old MI. Western blot analysis of cardiac tissues revealed a significant up-regulation of Akt and phospho-Akt in the G-CSF-treated group. However, in the other set of experiments using chimera mice transplanted GFP-positive bone marrow beforehand, no GFP-positive, bone marrow-derived cardiomyocytes was found in each group. The present findings may imply a novel therapeutic strategy against post-infarct heart failure, which is applicable during the chronic stage of MI.

Beat-to-beat repolarization variability measured by T wave spectral variance index in chronic infarcted animals.

Recent experimental and clinical studies have shown that beat-to-beat variability of repolarization morphology is associated with an increased risk for developing malignant ventricular arrhythmias. However, few data exist on the relationship between beat-to-beat repolarization variability and myocardial infarction itself. In the present work we tested the algorithm of T wave spectral variance (TWSV) using the two dimension fast Fourier transform, in an animal model of myocardial infarction to extend the evidences that support the existence of beat-to-beat alteration in repolarization during the chronic stage of myocardial infarction. Thirty-four New Zealand rabbits were included in the study and divided in two groups. Group I (N = 24) exposed to surgical ligation of the left anterior descendent coronary artery. Group II (N = 10) sham operated animals. The TWSV index was calculated before and after 15 and 45 days of surgery. Both groups showed significant increments in TWSV after 15 days postsurgery. However, while the sham animals return to its control value, the infarcted group exhibited values of the TWSV index that remains significantly high after 45 days of surgery, with a mean increment of 28.7% (P < 0.05 against sham). Moreover, when the infarcted group was qualitatively divided in three subgroups, according to its infarction areas, a trend was found in the correlation between the magnitude of the infarcted area and the TWSV index. This noninvasive measure confirms the presence of temporal repolarization variability associated with chronic myocardial infarction and further contributes to identify the infarcted animals.

Differential expression of alpha 1, alpha 3 and alpha 5 integrin subunits in acute and chronic stages of myocardial infarction in rats.

Anchoring cardiac myocytes to extracellular matrix, which is mediated mainly by integrins on their surfaces, is important for maintaining the architecture of myocardial tissues and transmitting mechanical force. We evaluated the expression of alpha integrin subunits on myocytes and the accumulation of interstitial collagen and fibronectin at acute and chronic stages after myocardial infarction. Myocardial infarction was induced by ligation of left coronary arteries in rats. The expression of alpha 1, alpha 3 and alpha 5 integrin subunits, and accumulation of collagen and fibronectin were analyzed with immunohistochemistry or sirius-red staining. In hearts without infarction, moderate expression of the alpha 3 subunit and only slight expression of the alpha 5 subunit were observed on myocytes. In the first week after infarction, the alpha 1 subunit, collagen and fibronectin were increased only in the peri-infarcted area, while the alpha 5 subunit was increased both in peri-infarcted and non-infarcted areas. At day 42, the expression of the alpha 1 subunit and collagen were still increased, although the alpha 5 subunit and fibronectin were decreased. The expression of the alpha 3 subunit was not altered throughout the experimental period. These data suggest that integrin subunits play an important role in healing and remodeling processes after myocardial infarction.

BMIPP imaging to assess functional outcome in patients with acute and chronic left ventricular dysfunction.

Assessment of myocardial viability is an important clinical issue for patient management during the acute and chronic stages of myocardial infarction. BMIPP (15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid) is a free fatty acid analogue which is trapped in the myocardium, thus permitting for metabolic imaging with single photon emission computerized tomography (SPECT). Less BMIPP than flow tracers that may be observed in the areas of infarction, may reflect the metabolic shift from fatty acid to glucose utilization in ischaemic myocardium. In this sense, the combined imaging of BMIPP and a flow tracer with SPECT may provide similar and important information as fluoro-18 deoxyglucose (FDG) and positron emission tomography (PET) regarding the assessment of myocardial viability. The purpose of this article is to review the clinical impact of BMIPP in patients with acute and with chronic left ventricular dysfunction for the identification of jeopardized but viable myocardium and the prediction of the functional outcome.