Opposite effects of amlodipine and enalapril on infarct collagen and remodelling during healing after reperfused myocardial infarction

OBJECTIVES: To compare the effects of the calcium channel blocker amlodipine versus the angiotensin-converting enzyme inhibitor enalapril with or without reperfusion on infarct collagen and remodelling during healing after anterior myocardial infarction (MI). ANIMALS AND METHODS: In vivo left ventricular (LV) remodelling and function (by quantitative echocardiography) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion (2 h after anterior MI) or no reperfusion to oral amlodipine (5 mg bid, n=6), enalapril (5 mg bid, n=6), placebo (bid, n=6) or sham surgery (n=6) for six weeks. Ex vivo infarct size, infarct collagen (hydroxyproline), collagen volume fraction and LV topography were measured at six weeks. RESULTS: Compared with placebo controls without reperfusion over six weeks in vivo, enalapril or amlodipine with or without reperfusion produced LV unloading and preserved volumes, shape and function, but enalapril limited LV hypertrophy more than amlodipine. However, compared with no reperfusion, amlodipine preserved infarct wall thickness and shape while enalapril decreased infarct wall thickness and increased the shape index. Ex vivo at six weeks, scar size as a percentage of risk was similar in the MI groups. Importantly, enalapril decreased infarct collagen already lowered by reperfusion, while amlodipine preserved infarct collagen after reperfusion and increased collagen volume fraction in spared myocardium. CONCLUSIONS: Preservation of infarct collagen limits infarct remodelling during healing after reperfused MI and preserves LV shape. Amlodipine and enalapril exert opposite effects on infarct collagen and remodelling after reperfused MI.     

Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AT1 receptor blockade

BACKGROUND: Angiotensin II (AngII) modulates the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), and AngII type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and remodeling after acute ischemia-reperfusion (IR). Whether ARBs improve TIMP/MMP balance during IR has not been determined. METHODS AND RESULTS: We measured hemodynamics, LV function, MMP-2 and MMP-9, and TIMP-3 and TIMP-4 in the ischemic zone (IZ) and nonischemic zone (NIZ) after in vivo IR (90 minutes anterior ischemia; 120 minutes reperfusion) in 28 dogs that were randomized to sham, IR controls, and IR plus the ARB valsartan. In controls, IR induced LV dysfunction, infarction, and IZ remodeling; increased MMP-9 and decreased TIMP-3 in the IZ compared with the NIZ (low TIMP-3/MMP-9 ratio); and did not change MMP-2 or TIMP-4. Compared with controls, valsartan (1) limited LV dysfunction, infarct size, and IZ remodeling; (2) increased MMP-2 and MMP-9 and TIMP-3 and -4 in the NIZ; and (3) increased TIMP-3 and the TIMP-3/MMP-9 ratio in the IZ, but did not change MMP-2 and TIMP-4. CONCLUSION: Valsartan-induced cardioprotection after IR is associated with enhanced TIMP-3 expression and improved TIMP-3/MMP-9 balance in the in vivo dog model.     

Early Short-Term Vagal Nerve Stimulation Attenuates Cardiac Remodeling After Reperfused Myocardial Infarction

BackgroundVagal nerve stimulation (VS) has been suggested to be an effective adjunct to reperfusion therapy in myocardial infarction (MI). However, the effect of VS on left ventricular (LV) remodeling after reperfused MI has not been examined.Methods and ResultsWe investigated the effects of early, brief VS on acute inflammatory reactions (study 1) and chronic LV remodeling (study 2) in a rabbit model of reperfused MI. In study 1, rabbits were subjected to 60-minute coronary artery occlusion followed by reperfusion alone (MI, n = 8) or treated with 24-hour VS (MI-VS, n = 8). At 24 hours after ischemia-reperfusion, MI-VS rabbits showed significantly decreased myocardial infiltration of neutrophils and reduced myocardial expressions of tumor necrosis factor-α and matrix metalloproteinase-8 and -9, compared with MI rabbits. Myocardial expression of interleukin-6 was not affected by VS. In study 2, rabbits were subjected to coronary occlusion and reperfusion alone (n = 16) or treated with VS for 3 days (n = 14). At 8 weeks after ischemia-reperfusion, MI-VS rabbits showed significantly improved LV dysfunction and dilatation, and significantly reduced infarct size, infarct wall thinning, and LV weight compared with MI rabbits.ConclusionEarly, short-term VS attenuates LV remodeling after reperfused MI, which may be associated with suppression of acute inflammatory reactions.     

福辛普利、依贝沙坦及二者合用对心肌梗死后心室重塑影响的实验研究

目的：对比福辛普利、依贝沙坦及二合用对大鼠心肌梗死后心室重塑的影响。方法：通过结扎冠状动脉左前降支诱导大鼠心肌梗死，心肌梗死后24h将大鼠随机分为：（1）安慰剂组；（2）福辛普利组；（3）依贝沙坦组；（4）福辛普利＋依贝沙坦组；另设假手术组。2周后检查以下指标：（1）平均动脉压，左室舒张末压；（2）心室重量／体重；（3）非梗死区胶原含量；（4）非梗死区非心肌细胞增生数量。结果：安慰剂组与假手术组相比左室舒张末压增加（P＜0．05），且心室重量／体重、非梗死区胶原含量及非心肌细胞增生数量增加显（P＜0．01）。福辛普利组和依贝沙坦组与安慰剂组相比平均动脉压下降、心室重量／体重及非心肌细胞增生数量下降，二合用与安慰剂组比较以上指标下降显（P＜0．01）；两药单用和合用与安慰剂组相比左室舒张末压下降（P＜0．05）。两药单独和联合应用均阻止了非梗死区胶原沉积（P＜0．01，与安慰剂组相比），两个单独用药组高于假手术组（P＜0．05），而联合治疗组与假手组间无统计学差异。福辛普利组、依贝沙坦组及二合用组三间各指标差异均无统计学意义。结论：福辛普利和依贝沙坦均可限制心肌梗死后心肌肥大、抑制左室非梗死区胶原沉积和非心肌细胞增生；二合用2周未见上述作用更显。     

Effect of left ventricular unloading with captopril on remodelling and function during healing of anterior transmural myocardial infarction in the dog.

OBJECTIVE: To determine whether left ventricular (LV) unloading with captopril between two days and six weeks during healing after transmural anterior acute myocardial infarction might prevent further LV remodelling and preserve function in the canine model. DESIGN: Serial LV topographic and functional parameters (two-dimensional echocardiograms) and hemodynamics over six weeks and scar topography (planimetry) and collagen (hydroxyproline) at six weeks were measured in 34 chronically instrumented dogs; 24 with anterior transmural acute myocardial infarction (coronary artery ligation and collateral obliteration) that had been randomized at two days post infarction to therapy with oral 50 mg bid placebo (n = 12) or captopril (n = 12) for six weeks, and 10 with sham infarction. MAIN RESULTS: At six weeks, captopril and placebo groups had similar scar mass (7.7 versus 8.1% LV), infarct hydroxyproline and transmurality but the captopril group showed significantly less (P less than or equal to 0.05) infarct expansion and thinning, cavity dilation, epicardial and endocardial bulge. Between two days and six weeks, captopril decreased mean left atrial and arterial pressures compared to placebo or sham. Echocardiograms at two days showed similar LV asynergy, ejection fraction, infarct expansion and thinning with placebo and captopril. In contrast, echocardiograms between two days and six weeks showed that: further expansion and thinning occurred with placebo but not captopril; LV volumes increased with placebo but decreased with captopril; total LV asynergy was unchanged with placebo but decreased with captopril; and LV ejection fraction was unchanged with placebo but increased with captopril. At six weeks, LV ejection fraction was 10% higher (45 versus 35%, P less than 0.001) and LV aneurysm was less frequent (33 versus 100%, P less than 0.005) with captopril compared to placebo. CONCLUSIONS: Chronic LV unloading with captopril therapy during healing after canine transmural anterior acute myocardial infarction limits further remodelling, decreases aneurysm formation and improves function.     

Relation of circulating interleukin-6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction

BACKGROUND: During the remodeling process after myocardial infarction (MI), the expression of proinflammatory cytokines is enhanced in the myocardium. However, only a few clinical studies have been conducted on cytokine involvement in left ventricular (LV) remodeling after MI. HYPOTHESIS: Circulating proinflammatory cytokines may be involved in LV remodeling in patients with reperfused MI. METHODS: We studied 25 patients with acute anterior MI who had undergone coronary reperfusion therapy, and 10 normal control subjects with no cardiac disease. In all patients, LV ejection fraction, end-diastolic volume index (EDVI), and end-systolic volume index (ESVI) were determined using left ventriculography at the acute phase and 6 months after onset. The delta EDVI and delta ESVI were calculated as the value of LV volume reduction, suggesting LV reverse remodeling. Serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were measured using enzyme-linked immunosorbent assay. RESULTS: Serum levels of IL-6 and TNF-alpha at the acute phase were significantly higher in patients with MI than in control subjects (both p < 0.05). The IL-6 levels correlated well negatively with delta EDVI (r = 0.779, p = 0.039), whereas no correlation was found for TNF-alpha. According to multivariate analysis, IL-6 at the acute phase was a significant independent predictor for LV remodeling after reperfused MI (p = 0.007). CONCLUSIONS: Circulating IL-6 levels correlated closely with LV geometric changes during the remodeling process in patients with reperfused MI. Our study addresses the usefulness of another marker for LV remodeling after MI.     

Effect of captopril and enalapril on left ventricular geometry, function and collagen during healing after anterior and inferior myocardial infarction in a dog model

Objectives. This study compared the effects of captopril and enalapril on left ventricular geometry, function and mass and on scar collagen and topography during healing after anterior and inferior myocardial infarction in a canine model.

Background. The beneficial effect of prolonged angiotensin-converting enzyme inhibitor therapy on remodeling during healing after myocardial infarction might be greater in anterior than inferior infarcts and more effective with captopril than enalapril therapy.

Methods. The effects of 6 weeks of therapy with captopril (50 mg twice a day), enalapril (2.5 mg twice a day) or placebo on in vivo variables of left ventricular remodeling, function and mass (by echocardiography), hemodynamic function, postmortem topography (by planimetry) and collagen (hydroxyproline levels) were studied in 36 instrumented dogs randomized to receive therapy 48 h after left anterior descending or left circumflex coronary artery occlusion.

Results. Compared with placebo therapy, both captopril and enalapril decreased infarct expansion and thinning, progressive ventricular dilation, ventricular mass and asynergy and infarct collagen levels in anterior and inferior infarcts. Despite similar small scar sizes, the effects on remodeling and dysfunction were greater in anterior than inferior infarcts. In addition, captopril produced greater attenuation of infarct expansion and ventricular enlargement, greater improvement in volume ejection fraction and less decrease in infarct collagen levels than enalapril.

Conclusions. On balance, captopril and enalapril attenuated left ventricular remodeling and preserved function in small anterior and inferior infarcts despite differences in the effects of the drugs on individual remodeling variables. Further studies will be needed to determine whether inhibition of infarct collagen might be harmful, or differences between captopril and enalapril therapy important, in large transmural infarctions.     

Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction

OBJECTIVES: We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin-converting enzyme (ACE) inhibition on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). BACKGROUND: Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure. METHODS: Starting 10 days after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the ACE inhibitor trandolapril (0.3 mg/kg/day), or a combination of both for nine weeks. RESULTS: Both monotherapies attenuated the rise in LV end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVEDP and LVEDV, significantly improved LV function and reduced plasma norepinephrine levels. The time constant of LV pressure isovolumic decay (tau) was prolonged in placebo MI rats, significantly shortened by eplerenone, and normalized by eplerenone/trandolapril. Increased collagen type I gene expression and collagen content in the noninfarcted LV myocardium from MI placebo rats was attenuated by trandolapril, but almost completely prevented by eplerenone and eplerenone/trandolapril. The addition of eplerenone to ACE inhibition prevented sarcoplasmic-reticulum calcium ATPase downregulation and the increases in LV gene expression of beta-MHC and atrial natriuretic factor more effectively than either monotherapy. Furthermore, combination treatment attenuated the increase in myocardial angiotensin II type 1 receptor expression and increased phosphorylated endothelial nitric oxide synthase protein levels. CONCLUSIONS: The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.     

Growth Hormone Attenuates Early Left Ventricular Remodeling and Improves Cardiac Function in Rats With Large Myocardial Infarction

Objectives. We sought to investigate the cardiac effects of growth hormone (GH) administration during the early phase of pathologic remodeling in a rat model of large myocardial infarction (MI).Background. Recent evidence suggests that exogenous administration of GH evokes a hypertrophic response and increases left ventricular (LV) function in vivo in rats with normal or chronically failing hearts. We hypothesized that these effects would attenuate ventricular remodeling early after MI.Methods. Fifty-eight male rats underwent sham operation (n = 19) or had induced MI (n = 39). The day after the operation, the infarcted rats were randomized to receive 3 weeks of treatment with GH, 3 mg/kg body weight per day (n = 19) or placebo (n = 20). Echocardiography, catheterization and isolated whole heart preparations were used to define cardiac structure and function.Results. Growth hormone caused hypertrophy of the noninfarcted myocardium in a concentric pattern, as noted by higher echocardiographic relative wall thickness at 3 weeks and by morphometric histologic examination. Left ventricular dilation was reduced in the GH-treated versus placebo group (echocardiographic LV diastolic diameter to body weight ratio 2.9 ± 0.1 vs. 3.5 ± 0.2 cm/kg; p < 0.05). In vivo and in vitro cardiac function was improved after GH treatment. Despite elevated insulin-like growth factor-1 (IGF-1) serum levels in GH-treated rats, myocardial IGF-1 messenger ribonucleic acid was not different among the three groups, suggesting that an increase in its local expression does not appear necessary to yield the observed effects.Conclusions. These data demonstrate that early treatment of large MI with GH attenuates the early pathologic LV remodeling and improves LV function.(J Am Coll Cardiol 1997;29:1109–16)© 1997 by the American College of Cardiology     

C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction

OBJECTIVES: We assessed the hypothesis that in vivo administration of C-type natriuretic peptide (CNP) might attenuate cardiac remodeling after myocardial infarction (MI) through its antifibrotic and antihypertrophic action. BACKGROUND: Recently, we have shown that CNP has more potent antifibrotic and antihypertrophic effects than atrial natriuretic peptide (ANP) in cultured cardiac fibroblasts and cardiomyocytes. METHODS: Experimental MI was induced by coronary ligation in male Sprague-Dawley rats; CNP at 0.1 mug/kg/min (n = 34) or vehicle (n = 35) was intravenously infused by osmotic mini-pump starting four days after MI. Sham-operated rats (n = 34) served as controls. After two weeks of infusion, the effects of CNP on cardiac remodeling were evaluated by echocardiograpic, hemodynamic, histopathologic, and gene analysis. RESULTS: C-type natriuretic peptide markedly attenuated the left ventricular (LV) enlargement caused by MI (LV end-diastolic dimension, sham: 6.7 +/- 0.1 mm; MI+vehicle; 8.3 +/- 0.1 mm; MI+CNP: 7.7 +/- 0.1 mm, p < 0.01) without affecting arterial pressure. Moreover, there was a substantial decrease in LV end-diastolic pressure, and increases in dP/dt(max), dP/dt(min), and cardiac output in CNP-treated MI rats compared with vehicle-treated MI rats. Importantly, CNP infusion markedly attenuated an increase in morphometrical collagen volume fraction in the noninfarct region (sham: 3.1 +/- 0.2%; MI+vehicle: 5.7 +/- 0.5%; MI+CNP: 3.9 +/- 0.3%, p < 0.01). In addition, CNP significantly reduced an increase in cross-sectional area of the cardiomyocytes. These effects of CNP were accompanied by suppression of MI-induced increases in collagen I, collagen III, ANP, and beta-myosin heavy chain messenger ribonucleic acid levels in the noninfarct region. CONCLUSIONS: These data suggest that CNP may be useful as a novel antiremodeling agent.     

p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat

OBJECTIVES: The aim of this study was to examine the effect of the p38 mitogen-activated protein kinase (MAPK) inhibitor, RWJ-67657 (RWJ), on left ventricular (LV) dysfunction and remodeling post-myocardial infarction (MI) in rats. BACKGROUND: p38 MAPK signaling has been implicated in the progression of chronic heart failure. METHODS: From day 7 post-MI (coronary artery ligation), rats received either RWJ (50 mg/day, by gavage, n = 8, MI+RWJ) or vehicle (by gavage, n = 8, MI+V) for 21 days. Echocardiography was performed on day 6, before the commencement of treatment, and on day 27. In vivo hemodynamic measurements were made on day 28. Sham-operated rats served as controls. RESULTS: The LV end-diastolic pressure and lung/body weight ratio were reduced, whereas the maximum rate of rise of LV pressure was increased towards sham levels in MI+RWJ compared with MI+V. Baseline echocardiographic studies demonstrated uniform LV remodeling and dysfunction in MI rats. Fractional shortening (FS) further deteriorated in MI+V, whereas FS was preserved in MI+RWJ. Progressive LV dilation and infarct expansion observed in MI+V were inhibited in MI+RWJ. MI+RWJ also demonstrated increased myocyte hypertrophy in the peri-infarct and non-infarct zones, and reduced myocardial collagen and alpha-smooth muscle actin (SMA) immunoreactivity compared with MI+V. The antifibrotic effects of RWJ in vivo may reflect direct effects on cardiac fibroblasts, because RWJ attenuated transforming growth factor beta-1-stimulated collagen synthesis and alpha-SMA expression in isolated cardiac fibroblasts. RWJ also protected cultured myocytes from hydrogen peroxide-induced apoptosis. CONCLUSIONS: RWJ-67657 treatment post-MI had beneficial effects on LV remodeling and dysfunction, supporting a key role for p38 MAPK in pathologic cell signaling in these processes and its inhibition as a novel therapy.     

Mineralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST‐Elevation Myocardial Infarction (The MINIMISE STEMI Trial): Rationale and Study Design

Novel therapies capable of reducing myocardial infarct (MI) size when administered prior to reperfusion are required to prevent the onset of heart failure in ST‐segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). Experimental animal studies have demonstrated that mineralocorticoid receptor antagonist (MRA) therapy administered prior to reperfusion can reduce MI size, and MRA therapy prevents adverse left ventricular (LV) remodeling in post‐MI patients with LV impairment. With these 2 benefits in mind, we hypothesize that initiating MRA therapy prior to PPCI, followed by 3 months of oral MRA therapy, will reduce MI size and prevent adverse LV remodeling in STEMI patients. The MINIMISE‐STEMI trial is a prospective, randomized, double‐blind, placebo‐controlled trial that will recruit 150 STEMI patients from four centers in the United Kingdom. Patients will be randomized to receive either an intravenous bolus of MRA therapy (potassium canrenoate 200 mg) or matching placebo prior to PPCI, followed by oral spironolactone 50 mg once daily or matching placebo for 3 months. A cardiac magnetic resonance imaging scan will be performed within 1 week of PPCI and repeated at 3 months to assess MI size and LV remodeling. Enzymatic MI size will be estimated by the 48‐hour area‐under‐the‐curve serum cardiac enzymes. The primary endpoint of the study will be MI size on the 3‐month cardiac magnetic resonance imaging scan. The MINIMISE STEMI trial will investigate whether early MRA therapy, initiated prior to reperfusion, can reduce MI size and prevent adverse post‐MI LV remodeling.     

Influence of reperfusion therapy on left ventricular remodeling after acute myocardial infarction

To determine the relation between reperfusion therapy and left ventricular function and remodeling after acute myocardial infarction (AMI), 75 consecutive patients with anterior AMI were studied. The patients were divided into four groups according to the reperfusion outcome and time to reperfusion from onset of MI: 12 patients with spontaneous reperfusion, 18 patients with early (less than 4th) successful reperfusion, 16 patients with late (greater than or equal to 4th) successful reperfusion and 29 patients with unsuccessful reperfusion. The right oblique left ventriculograms (LVG), which was performed early (n = 19) and late after infarction (n = 75) were analyzed to assess left ventricular (LV) volume and global and regional LV function. At the late examination, spontaneous early and late reperfused patients showed smaller LV volume (endo diastolic and endo-systolic volume index) than unsuccessfully reperfused patients LV volume was similar in both early and late reperfused patients. Spontaneous and early reperfused patients showed higher LV ejection fraction (EF) and better regional wall motion (RWM) than unsuccessfully reperfused patients. Both EF and RWM was similar in late and unsuccessfully reperfused patients at the late examination. Endo-diastolic and endo-systolic volume index increased significantly with time in patients with unsuccessful reperfusion (n = 10), as compared with the index found in the early examination. In patients with late reperfusion (n = 5), end-diastolic volume index increased with time, but end-systolic volume index was unchanged. RMW improved in patients with early reperfusion (n = 4), but was unchanged in patients with late and unsuccessful reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new anti-fibrotic drug attenuates cardiac remodeling and systolic dysfunction following experimental myocardial infarction

Background

Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model.

Methods and results

Collagen synthesis in NCF was determined by ³H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200 mg/kg/day) or vehicle for a further 4 weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment.

Conclusion

Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.     

Biomechanical properties of reperfused transmural myocardial infarcts in rabbits during the first week after infarction. Implications for left ventricular rupture.

Left ventricular (LV) rupture potential was studied after transmural myocardial infarction (MI) in rabbits by measuring 1) the tensile strength of infarcted tissue strips, 2) the force required to initiate a tear (tear threshold) in the central infarcted region, and 3) the intracavitary pressure required to rupture the infarcted ventricle. During the first week after MI, infarcts resulting from a permanent coronary occlusion were compared with infarcts reperfused "late" (i.e., 3 hours) after coronary occlusion with a resultant hemorrhagic transmural infarct but no reduction in infarct size. The reperfused hemorrhagic infarcted strips had less tensile strength than strips from permanently occluded infarcts in the initial 24 hours after MI (16 +/- 1 versus 24 +/- 3 g/mm2, p less than 0.05), but the tear threshold and response to increased LV pressure were not influenced by infarct reperfusion at this time. By 3 days after MI, reperfused infarcts had equal tensile strength, had greater resistance to infarct tearing, and could withstand a greater LV distending pressure compared with permanently occluded infarcts. By 5 days after MI, reperfused infarcts maintained a greater tear threshold but had less tensile strength than permanently occluded infarcts, although all infarct values were equivalent or greater than normal LV values. By 7 days after MI, reperfused and permanently occluded infarcts were equally strong by all measurements. Thus, late reperfusion of transmural infarcts increased resistance to infarct tearing and LV rupture above that of nonreperfused permanently occluded infarcts by 3 days after MI and enhanced tissue strength after an initial 24-hour vulnerable period. These findings suggest that late reperfusion may accelerate myocardial healing after MI.     

辛伐他汀改善心肌梗死后心肌胶原含量变化及机制的实验研究

目的:探讨辛伐他汀对大鼠心肌梗死后心肌胶原含量的影响及其机制. 方法:建立大鼠心肌梗死模型,24 h后存活大鼠随机分成心肌梗死组(n=9)、辛伐他汀20 mg组[20 ms/(kg·d),n=10]和平伐他汀40 mg组[40 ms/(kg·d),n=9],另设假手术组(n=10).4周后观察血脂水平、左心室重指数和天狼猩红染色分析左心室非梗死区心肌胶原容积分数(表达心肌胶原含量),免疫组化检测基质金属蛋白酶-2(MMP-2),免疫印迹杂交方法(Western blot)和逆转录多聚酶链反应(RT-PCR)检测转化生长因子β1(TGF-β1)在非梗死区的表达. 结果:①各组血脂水平差异无统计学意义,心肌梗死组左心室重苗指数、非梗死区Ⅰ型、Ⅲ型胶原容积分数及Ⅰ型与Ⅲ型胶原容积分数比值较假手术组均明显升高(P均<0.05),差异均有统计学意义;辛伐他汀两组左心室重量指数、非梗死区Ⅰ型、Ⅲ型胶原容积分数及Ⅰ型与Ⅲ型胶原容积分数比值较心肌梗死组均卜降,但仍高于假手术组(P均<0.05),差异均有统计学意义.②心肌梗死组MMP-2和TGF-β1表达较假手术组均显著增加(P均<0.05),而辛伐他汀两组表达则明显降低,但仍高于假手术组(P均<0.05),差异均有统计学意义. 结论:辛伐他汀能有效改善大鼠心肌梗死后心肌胶原含量,机制与其渊脂作用无关,可能与下调MMP-2和TGF-β1的表达有关.     

Neutralization of interleukin-1beta in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling.

OBJECTIVES: We sought to examine the role of the pro-inflammatory cytokine, interleukin-1-beta (IL-1beta), in the process of left ventricular (LV) remodeling in the early phase after myocardial infarction (MI). BACKGROUND: Studies have shown that pro-inflammatory cytokines are closely related to the progression of LV remodeling after MI. METHODS: Mice underwent coronary artery ligation, and the time course of LV remodeling was followed up to 20 weeks. The gene expression level of IL-1beta was examined. In a second set of experiments, the mice underwent coronary artery ligation followed by treatment with anti-IL-1beta antibody (100 microg, intravenously), versus control immunoglobulin G (100 microg, intravenously) immediately after the operation. RESULTS: Rapid hypertrophy of noninfarcted myocardium was observed by four weeks, and interstitial fibrosis progressed steadily up to 20 weeks. Anti-IL-1beta treatment increased the occurrence of ventricular rupture and suppressed collagen accumulation in the infarct-related area. At four and eight weeks after the operation, total heart weight and LV end-diastolic dimension were significantly greater in the anti-IL-1beta-treated mice than in the other groups. In the infarct-related area, collagen accumulation was suppressed, whereas in the noninfarcted area, pro-collagen gene expression levels, particularly type III, were decreased in the anti-IL-1beta-treated mice. CONCLUSIONS: Anti-IL-1beta treatment suppressed pro-collagen gene expression and delayed wound healing mechanisms-properties that are likely to lead to progression of LV remodeling. In the acute phase of MI, IL-1beta appears to play a protective role.     

Streptozotocin-induced hyperglycemia exacerbates left ventricular remodeling and failure after experimental myocardial infarction

OBJECTIVES: The aim of the present study was to determine whether streptozotocin (STZ)-induced hyperglycemia exacerbates progressive left ventricular (LV) dilation and dysfunction after myocardial infarction (MI). BACKGROUND: Diabetes mellitus (DM) adversely affects the outcomes in patients with MI. However, it is unknown whether DM can directly affect the development of post-MI LV remodeling and failure. METHODS: Male mice were injected intraperitoneally with STZ (200 mg/kg; DM group) or vehicle only. At two weeks, MI was created in the STZ-injected (DM+MI group) or vehicle-injected mice (MI group) by left coronary artery ligation, and they were followed up for another four weeks. RESULTS: Survival during six weeks was significantly lower in the DM+MI versus MI group (25% vs. 71%; p < 0.01), despite a similar infarct size (60 +/- 2% vs. 61 +/- 2%; p = NS). Echocardiography after two weeks of ligation showed LV dilation and dysfunction with MI, both of which were exaggerated in the DM+MI group. Likewise, LV end-diastolic pressure and lung weight were increased in mice with MI, and this increase was enhanced in the DM+MI group. The myocyte cross-sectional area in the non-infarcted LV increased to a similar degree in the DM+MI and MI groups, whereas the collagen volume fraction was greater in the DM+MI group. Deoxyribonucleic acid laddering was greater in the DM+MI group. CONCLUSIONS: Hyperglycemia decreased survival and exaggerated LV remodeling and failure after MI by increasing interstitial fibrosis and myocyte apoptosis. Diabetes mellitus could be a risk factor for heart failure, independent of coronary artery lesions.     

Effect of a cleavage-resistant collagen mutation on left ventricular remodeling

Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. A total of 64 r/r and 84 littermate wild-type mice (WT) underwent experimental pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI). Echocardiographic, hemodynamic, and histological parameters were evaluated up to 12 weeks after TAC or 21 days after MI. At 4 weeks after TAC, collagen levels, wall thickness, and echocardiographic parameters were similar in the 2 groups. At 12 weeks after TAC, r/r mice had smaller LV dimensions (ESD: 2.7+/-0.2 mm WT versus 1.7+/-0.2 mm r/r, P<0.013; EDD: 3.8+/-0.2 mm WT versus 3.1+/-0.1 mm r/r, P<0.013); better fractional shortening (30+/-2% WT versus 46+/-4% r/r; P<0.013); and lower LV/body weight ratios (7.3+/-0.6 WT and 5.1+/-0.5 r/r; P<0.013). Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collagen cleavage at this site is not the mechanism by which metalloproteinases mediate LV remodeling. Collagen cleavage could, however, have a role in preservation of cardiac function in late remodeling by mechanisms independent of collagen accumulation. We were not able to detect collagen cleavage fragments, and could not, therefore, rule out the possibility of collagen cleavage at additional sites.     

Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction

OBJECTIVES: This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling. BACKGROUND: Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction. METHOD: A 28-day infusion of caspase inhibitor (n = 12) or vehicle (n = 9) was administered to rats immediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry. RESULTS: Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to-body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI. CONCLUSIONS: Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling. These findings may have important therapeutic implications in post-MI HF.