Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction

Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood.The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n = 88) and MMP-9 null (MMP-9^−/−; n = 92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n = 42). At day 7 post-MI, WT LVs displayed a 3-fold increase in end-diastolic volume, while MMP-9^−/− showed only a 2-fold increase (p < 0.05). Biaxial mechanical testing revealed that MMP-9^−/− infarcts were stiffer than WT infarcts, as indicated by a 1.3-fold reduction in predicted in vivo circumferential stretch (p < 0.05). Paradoxically, MMP-9^−/− infarcts had a 1.8-fold reduction in collagen deposition (p < 0.05). This apparent contradiction was explained by a 3.1-fold increase in lysyl oxidase (p < 0.05) in MMP-9^−/− infarcts, indicating that MMP-9 deletion increased collagen cross-linking activity. Furthermore, MMP-9 deletion led to a 3.0-fold increase in bone morphogenetic protein-1, the metalloproteinase that cleaves pro-collagen and pro-lysyl oxidase (p < 0.05) and reduced fibronectin fragmentation by 49% (p < 0.05) to enhance lysyl oxidase activity. We conclude that MMP-9 deletion increases infarct stiffness and prevents LV dilation by reducing collagen degradation and facilitating collagen assembly and cross-linking through preservation of the fibronectin network and activation of lysyl oxidase.     

Prospective study of matrix metalloproteinase-9 and risk of myocardial infarction and stroke in older men and women

ObjectivesThe endopeptidase matrix metalloproteinase-9 (MMP-9) is implicated in atherosclerotic plaque rupture. We investigate prospective associations between MMP-9 and MI or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.MethodsBaseline serum MMP-9 was measured in incident MI (n = 368) and stroke (n = 299) cases and two controls per case, ‘nested’ in prospective studies of 4252 men and 4286 women aged 60–79 years, sampled from General Practices in Britain in 1998–2000, with 7-year follow-up for fatal and non-fatal MI and stroke.ResultsGeometric mean MMP-9 was 528 ng/mL (IQR 397, 743) in MI cases compared to 501 ng/mL (IQR 370, 743) in controls, p = 0.10. Participants in the top compared to bottom third of MMP-9 levels had an age-adjusted odds ratio for MI of 1.53 (95% CI 1.09, 2.13), which attenuated to 1.18 (95% CI 0.81, 1.70) after adjustment for established and novel cardiovascular risk factors. There was weak evidence that OR differed according to pre-existing CVD; the OR for MI in 187 participants with pre-existing CVD was 2.20 (1.04, 4.64) and 1.24 (0.84, 1.82) in 715 participants without (LR test for interaction p = 0.06). Geometric mean MMP-9 levels were higher in stroke cases than controls; 522 ng/mL (IQR 363, 673) vs 487 (IQR 393, 704), p = 0.045; however adjustments similarly attenuated the associations.ConclusionsWhile serum MMP-9 is univariately associated with risk of MI and stroke, it is not a strong independent risk marker for either.     

Percutaneous Implantation of an Intraventricular Device for the Treatment of Heart Failure: Experimental Results and Proof of Concept

BackgroundA percutaneous system to implant a ventricular partitioning device (VPD) has been developed to partition the left ventricular (LV) cavity for treating regional wall motion abnormalities associated with post-left anterior descending (LAD) infarction, dilated left ventricle, and systolic dysfunction. The hemodynamic effects of this novel approach were evaluated in an ovine model with an anteroapical infarction created by a coil placed in the LAD.Methods and ResultsLV anteroapical infarction (MI) was induced in 10 animals. The VPD device was implanted at 6 weeks after MI in 5 animals. The hemodynamic status of each animal was evaluated at 30 weeks post-MI in treated (“VPD + MI” group, n = 5) and nontreated (“MI” group, n = 5). The comparison of end-point hemodynamic variables shows a significantly smaller end-systolic LV volume in the animals receiving the implant (70.1 ± 9.0 mL in “VPD + MI” group vs. 102.9 ± 10.3 mL in “MI” group, P < .02), improved ejection fraction (46.9 ± 5.2% in “VPD + MI” group vs. 34.7 ± 6.8% in “MI” group, P < .04) and preserved cardiac output (5.2 ± 0.7 L/min in “VPD + MI” group vs. 5.0 ± 1.8 L/min in “MI” group, P = NS), suggesting more efficient mechanical performance of the LV with the implanted VPD.ConclusionsA significant reduction in LV volumes and corresponding improvement in LV function occurred after device implantation indicating a potential beneficial effect of this new device in treatment of post MI LV dilation.     

Biomarkers of airway and systemic inflammation in obese asthmatic paediatric patients

BackgroundIt is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment.ObjectiveThis study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation.MethodsThe study included patients aged 6–16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n = 43), obese non-asthmatic (n = 45), and non-obese non-asthmatic (control group, n = 30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups.ResultsNo statistically significant differences were observed in 25(OH)-vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP-9.ConclusionThis is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children.     

Gender specific associations between matrix metalloproteinases and inflammatory markers in post myocardial infarction patients

ObjectiveAtherothrombotic disease in the coronary arteries leads to myocardial infarction (MI) through plaque rupture or erosion of the endothelium, the former mechanism predominating in men and the latter in women. Inflammation is a key feature of these processes, and the interplay between inflammation and matrix metalloproteinases (MMPs) in this context is not fully understood. In this study, we investigated the association between inflammatory markers and MMPs in men and women.MethodsBlood samples were drawn 3 months after a first MI in 387 patients and 387 sex- and age-matched controls (82% men). C-reactive protein (CRP), interleukin-6 (IL-6), IL-8, -18, tumour necrosis factor-α (TNF-α), macrophage chemoattractant protein-1 (MCP-1), MMP-1, -3 and -9 were measured. Coronary angiography was performed in 243 of the patients, and they were classified into 0-, 1-, 2- or 3-vessel disease groups.ResultsCRP, IL-6, -8, -18 and TNF-α were higher, and MMP-3 and -9 were lower, in patients than in controls. A greater proportion of women (49%) had 0-vessel disease than men (16%, p < 0.0001). A gender specific pattern of associations between inflammatory markers and MMPs was found as IL-6 (r_S = 0.29, p < 0.05), IL-18 (r_S = 0.34, p < 0.01) and MCP-1 (r_S = 0.35, p < 0.01) correlated with MMP-3 in female patients, whereas CRP (r_S = 0.23, p < 0.0001), IL-6 (r_S = 0.13, p < 0.05) and IL-8 (r_S = ?0.21, p < 0.01) correlated with MMP-9 in male patients.ConclusionsThe present study demonstrates different patterns of association between inflammatory markers and MMPs in men and women, strengthening the hypothesis of gender specific differences in pathophysiological mechanisms of MI.     

MMP-9 in atrial remodeling in patients with atrial fibrillation

IntroductionAtrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. The impact of matrix metalloproteinases (MMPs) on structural atrial remodeling and sustainment of AF in patients with persistent and permanent AF is unresolved.ObjectivesThe aim was to evaluate MMP-9 and its tissue inhibitor-1 (TIMP-1) as markers of atrial remodeling in patients with persistent AF (PAF) who underwent electrical cardioversion (ECV) and in patients with permanent AF (continuous AF, CAF).Patients and methodsPlasma levels of MMP-9 and TIMP-1, clinical findings, and echocardiographic parameters were evaluated in 39 patients with AF and in 14 controls with sinus rhythm.ResultsThe concentrations of MMP-9 were significantly higher in patients with PAF and CAF compared to controls. There was a significant increase of MMP-9 after ECV in the persistent AF group. The values of TIMP-1 were not significantly different between the groups. In patients with AF, MMP-9 levels were positively related to posterior wall thickness of the LV (r = 0.356, P = 0.049) and body mass index (r = 0.367, P = 0.046).ConclusionElevated levels of MMP-9 were related to the occurrence and maintenance of AF. This suggests that MMP-9 can be a marker of atrial remodeling in patients with AF. Regulation of the extracellular collagen matrix might be a potential therapeutic target in AF.     

Induction of matrix metalloproteinase-2 and -9 via Erk1/2-NF-κB pathway in human astroglia infected with Toxoplasma gondii

Matrix metalloproteinase (MMP)-2 and MMP-9 can cleave fibronectin, allowing leukocyte migration to the site of Toxoplasma gondii infection during toxoplasmic encephalitis. The aim of this study was to investigate the association between extracellular signal-regulated kinase (Erk)1/2-nuclear factor (NF)-κB pathway and MMP-2/-9 expression in astroglia infected with T. gondii tachyzoite in vitro. Our results showed that phosphorylated (p)-Erk1/2 transiently increased 1 h post-infection (PI) and p-NF-κB significantly increased from 1 h PI to 12 h PI in cell homogenates. NF-κB was bound directly to oligonucleotides containing putative NF-κB binding sites for the MMP-9 promoter. Additionally, expression of p-NF-κB, MMP-2, and MMP-9 was significantly decreased by MG132, an indirect NF-κB inhibitor. Treatment with PD98059, an Erk kinase inhibitor, efficiently reduced p-Erk1/2, p-NF-κB, MMP-2, and MMP-9 expression. These results suggest that suppression of the Erk1/2-NF-κB signaling pathway causes reductions in MMP-2 and MMP-9 activities in astroglia response to T. gondii infection. Thus, inhibiting this signaling intermediate involved in MMP-2 and MMP-9 expression may be a potential method for controlling inflammatory development of T. gondii-induced encephalitis.     

High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction

IntroductionThe purpose of this study was to compare serum matrix metalloproteinase (MMP)-9 levels in a population of type 2 diabetic versus non-diabetic patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and to examine the relationship between serum MMP-9 levels and the incidence of in-hospital cardiac events, including death and cardiogenic shock.MethodsWe recruited 120 patients with STEMI, of whom 48 were type 2 diabetic and 72 non-diabetic. Serum MMP-9 levels were measured on admission, using a commercially available ELISA. The primary study endpoint was cardiac death in-hospital and cardiogenic shock.ResultsMean serum MMP-9 levels were significantly higher in type 2 diabetic patients compared to non-diabetic patients (240 ± 52 ng/mL versus 185 ± 47 ng/mL; P < 0.0001). In multivariable analysis, type 2 diabetes was an independent factor for mortality [OR: 1.75 (1.40–2.30); P = 0.005] and cardiogenic shock [OR: 1.55 (1.20–1.70); P = 0.03] when the variable MMP-9 level was not introduced into the model, but it was less significantly associated with mortality [OR: 1.60 (1.40–2.10); P = 0.01] and no longer associated with cardiogenic shock when MMP-9 was in the model.ConclusionAfter STEMI, type 2 diabetes is independently associated with high serum MMP-9 levels. This elevated MMP-9 is strongly associated with the increased incidence of in-hospital mortality and cardiogenic shock observed in type 2 diabetes. Our findings clearly indicate that serum MMP-9 provides a highly valuable prognostic information on in-hospital outcome after STEMI, in particular in type 2 diabetic patients.     

Different Substrates of Non-Sustained Ventricular Tachycardia in Post-infarction Patients With and Without Left Ventricular Dilatation

BackgroundWe investigated the relationship between nonsustained ventricular tachycardia (NSVT) and left ventricular (LV) dilatation, function, remodeling, and scar tissue extent in patients with previous myocardial infarction (MI).Methods and ResultsEighty-two patients (ages 64 ± 10 years) with first previous MI were referred for 24-hour electrocardiogram recording and cine and delayed enhancement (DE) cardiac magnetic resonance (CMR). LV volumes, ejection fraction, systolic wall thickening, sphericity index, and core and peri-infarctual areas of scar tissue by CMR were evaluated. LV dilatation was observed in 39 patients. Episodes of NSVT were recorded in 32 patients: 23 with LV dilatation and 9 without. In the entire population, NSVT was related to ejection fraction, LV volumes, LV mass, and sphericity index; end-systolic volume (P = .001) resulted in the only independent predictor at multivariate analysis. In patients without LV dilatation, the occurrence of NSVT was only positively related with percentage of contracting segments with DE (P = .008). Conversely, in patients with LV dilatation, increase in LV mass (P = .020) and end-systolic volume (P = .038) were independent predictors of NSVT.ConclusionsNecrotic and viable myocardium coexistence within the same wall segments predicted occurrence of NSVT in patients without LV dilatation, whereas LV mass and end-systolic volume were predictors of NSVT in those with LV dilatation.     

Plasma metalloproteinase-9 and restrictive filling pattern as major predictors of outcome in patients with ischemic cardiomyopathy

ObjectiveAssessment of plasma matrix metalloproteinase-9 (MMP-9) and Doppler markers of increased left ventricular (LV) filling pressure may be added to risk stratify patients with ischemic cardiomyopathy (IC). Therefore, we aimed at investigating the value of plasma MMP-9 and restrictive filling pattern (RFP) in IC patients.MethodsEighty-eight consecutive patients hospitalized for heart failure (LV ejection fraction ≤ 40%) due to IC were enrolled. A complete M-mode and two-dimensional echo-Doppler examination were performed. Patients were defined as having RFP if they had a mitral E wave deceleration time < 150 ms. Plasma MMP-9 and N-terminal protype-B natriuretic peptide levels were assessed at the time of the index echocardiogram. The end point was all-cause mortality or hospitalization for worsening HF. Follow-up period was 25 ± 17 months.ResultsMedian value of MMP-9 was 714 ng/ml. On univariate analysis, a number of measurements predicted the composite end point: NYHA class > 2, RFP, MMP-9 > 60.5 ng/ml, LV ejection fraction < 27%, anemia, pulmonary pressure ≥ 35 mm Hg, N-terminal protype-B natriuretic peptide > 1742 pg/ml, and glomerular filtration rate < 60 ml/min/1.73 m². Independent variables of outcome were anemia (HR = 1.9, p = 0.031), and the combination of plasma MMP-9 and RFP (HR = 3.2, p = 0.004). On Kaplan–Meier survival curves, patients with elevated MMP-9 levels and RFP had the lowest event-free survival rate (log-rank: 29.0, p < 0.0001). The net reclassification improvement showed a significant increase in the prediction model when elevated MMP-9 and RFP were added to the base model that included clinical, biochemical and echocardiographic parameters (p < 0.0001).ConclusionMMP-9 levels and RFP have an incremental predictive value to risk classify IC patients.     

Serum levels of MMP-9 and TIMP-1 in primary hypertension and effect of antihypertensive treatment

BackgroundMatrix metalloproteinases, a family of proteolytic enzymes are thought to be involved in extracellular matrix accumulation during development of hypertensive target organ disease. The present study was designed to compare hypertensive patients with normotensive individuals with respect to serum levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and to search for the effect of antihypertensive treatment on the serum enzyme levels.MethodsThirty-three patients with stage 1 primary hypertension and sixteen age- and sexmatched control subjects were enrolled into the study. Serum MMP-9 and TIMP-1 levels were assessed in the hypertensive group before and after a 3-month-antihypertensive treatment (candesartan 8 mg/day to 17 patients and lisinopril 10 mg/day to 16 patients).ResultsPre-treatment serum MMP-9 levels were higher in the hypertensive group (p = 0.309) while serum TIMP-1 levels were lower (p = 0.296). Serum MMP-9 levels were decreased (p < 0.001) and TIMP-1 levels were increased (p = 0.022) after the antihypertensive treatment.ConclusionsIn hypertensive patients, increased MMP-9 activity could result in increased degradation of elastin relative to collagen and non-elasticity, while decreased TIMP-1 activity could lead to accumulation of poorly cross-linked, immature and unstable fibril degradation products, which result in misdirected deposition of collagen. Our study is important for revealing the role of the MMP enzyme system in the pathogenesis of hypertensive target organ disease.     

Increased intestinal permeability,measured by serum zonulin,is associated with metabolic risk markers in overweight pregnant women

BackgroundIncreased intestinal permeability with subsequent metabolic endotoxemia, i.e., elevated circulating levels of bacterial lipopolysaccharide, LPS, has been introduced as a novel initiator of obesity related metabolic disturbances in non-pregnant individuals. The objective was to investigate the extent to which intestinal permeability, measured by serum zonulin concentration, is related to metabolic endotoxemia and metabolic risk markers in overweight pregnant women.MethodsThis was a cross-sectional study including 100 pregnant overweight women in early pregnancy. Serum zonulin was analyzed using ELISA, and markers for metabolic endotoxemia (LPS), inflammation (high-sensitive C-reactive protein and glycoprotein acetylation GlyA), glucose metabolism (fasting glucose and insulin), and lipid metabolism were measured.ResultsHigher serum zonulin concentration associated positively with LPS (P = 0.02), inflammatory markers (P < 0.001), insulin (P < 0.001), insulin resistance (P < 0.001), and triglycerides (P = 0.001), and negatively with insulin sensitivity (P = 0.001) (ANOVA with Tukey's corrections or Kruskal–Wallis nonparametric test with Bonferroni correction for zonulin quartiles). All the observed associations were confirmed (P < 0.015) in a linear regression model adjusted with potential confounding factors. Both LPS and GlycA showed positive relationship with insulin resistance, serum insulin, triglycerides, total and LDL-cholesterol and negative relationship with insulin sensitivity (P ≤ 0.03) in the univariate linear regression. Positive relationship was also found between LPS and HDL-cholesterol (P = 0.03).ConclusionsOur findings suggest that increased serum zonulin concentration, i.e., increased intestinal permeability, contributes to metabolic endotoxemia, systemic inflammation, and insulin resistance in overweight pregnant women. By reinforcing intestinal barrier, it may be possible to manipulate maternal metabolism during pregnancy with subsequent health benefits.     

QT-interval dispersion in type 2 diabetic and non-diabetic patients with post-myocardial infarction

Background and aimsQT-interval dispersion (QTD), which reflects spatial ventricular repolarization inhomogeneity, has been reported to increase and to have a prognostic value in patients with either myocardial infarction or diabetes. Our aim was to compare increases in QTD in type 2 diabetic and non-diabetic patients following post-myocardial infarction (post-MI). We also compared QTD in type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone.Methods and resultsWe determined the rate corrected QT-interval (QTc) dispersion (QTcD) in 178 consecutive post-MI patients, including 48 type 2 diabetic and 130 non-diabetic patients. The QTcD, measured with software (QTD-1), was defined as the difference in the minimum and maximum QTc in any of the 12 standard electrocardiographic leads. There were no significant differences in age, gender, left ventricular end-diastolic diameter, ejection fraction, or minimum QTc between type 2 diabetic and non-diabetic patients with post-MI. Compared with post-MI patients without diabetes, those with type 2 diabetes had higher maximum QTc (481 ± 37 vs. 459 ± 43 ms, P < 0.05) and QTcD (67 ± 18 vs. 58 ± 16 ms, P < 0.05). Among type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone, the QTcD (81 ± 18 vs. 64 ± 16 vs. 62 ± 17 ms, P < 0.05, respectively) was significantly greater and the R-R interval was shorter in the insulin therapy group.ConclusionsType 2 diabetes is associated with an additional increase in the QTD in post-MI patients. This additional increase in spatial repolarization inhomogeneity might be implicated in the increased mortality risk in post-MI patients with type 2 diabetes. These findings were thought to be more striking in the insulin therapy group.     

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

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

Asociación entre disminución de la función renal y actividad metaloproteinasa-9 en el paciente hipertenso

Background and objective

Matrix metalloproteinases (MMPs) are involved in deleterious tissue remodeling associated with target organ damage in renal disease. The aim of this study was to study the association between renal dysfunction and activity of the inflammatory metalloproteinase MMP-9 in hypertensive patients with mild-moderate chronic kidney disease (CKD).

Plasma MMP-2, MMP-9 and N-BNP in long-term survivors following complicated myocardial infarction: relation to cardiac magnetic resonance imaging measures of left ventricular structure and function

BackgroundAltered activity of the matrix metalloproteinases (MMP-2 and -9), has been implicated in the left ventricular (LV) remodeling process occurring after myocardial infarction (MI). In the acute phase, a relation between plasma MMP-9 levels and parameters of LV dysfunction has been demonstrated. The relationship in long-term survivors has not been investigated. We studied the relationships of these biochemical markers, and N-terminal pro-B-type natriuretic peptide (N-BNP), with measures of long-term LV remodeling.Methods and ResultsPlasma levels of N-BNP, MMP-2, and MMP-9 were measured at randomization, 1 month, 1 year, and >4 years after complicated AMI. Contrast-enhanced cardiac magnetic resonance (CMR) was performed at 4.4 (±0.4) years in 52 clinically stable long-term survivors of the index AMI. We assessed the relationships of plasma N-BNP, MMP-2, and MMP-9 with myocardial scarring, and measures of long-term LV remodeling. Compared with a reference population, N-BNP and MMP-9 levels were increased at all time points from the acute phase until >4 years after MI. Plasma N-BNP and MMP-9 correlated only in the subacute phase (randomization, mean 3.3 days after MI) days after acute MI (r = 0.38, P = .006). At CMR assessment ≥4 years, log MMP-9 level was inversely related to LV ejection fraction (P = .002) and nonscarred myocardial mass (P = .008). This relationship was independent of MMP-2. Log N-BNP was related to end diastolic volume index (P = .0002). There was no correlation between log MMP-9 and LV volumes.ConclusionThere is a time-dependent relationship between plasma N-BNP and MMP-9 levels, these peptides correlating only in the acute phase after MI. In long-term follow-up, plasma MMP-9 and N-BNP levels were related to different parameters of LV remodeling. These findings suggest that in long-term survivors of complicated MI, different mechanisms modulate plasma levels of MMP-9 and N-BNP.     

Effects of omega-3 polyunsaturated fatty acids on metabolically active hormones in patients post-myocardial infarction

BackgroundLong-chain omega-3 polyunsaturated fatty acids (PUFA) supplementation is used as a therapeutic secondary prevention strategy among post-myocardial infarction (MI) patients. The effects of omega-3 PUFA on markers of energy homeostasis among post-MI patients are unclear.MethodsWe investigated the effects of Omacor (a pharmaceutical capsule formulation of highly refined, concentrated omega-3 PUFA; Solvay Healthcare, Southampton, UK; 1 g/day) in addition to usual care (cardiovascular therapy) in a pilot randomised study of 35 post-MI men. Following randomisation to Omacor (n = 16), or ‘usual care’ controls (n = 19), fasting levels of insulin, non-esterified fatty acids (NEFA), triglycerides, glucose and adipocytokines (adiponectin, leptin and tumour necrosis factor (TNF)-α), as indices of markers of energy homeostasis, were measured at baseline and after 3-month treatment.ResultsThere were no baseline differences in age, body mass index, blood pressure, fasting triglycerides, plasma glucose, NEFA and adipocytokines between the two treatment arms (P = 0.07). There were no significant changes in metabolically active hormones within groups after 3-month treatment. Across arms, the direction of baseline to follow-up changes in insulin levels were significantly different (P =  0.03), with a mean increase with Omacor (+ 3.39 mU/ml) and a decrease among controls (− 17.6 mU/ml), without associated deteriorating changes in triglycerides, NEFA or plasma glucose.ConclusionThis pilot study suggests that Omacor had little effect on glycaemic control among male post-MI patients. However, Omacor was associated with raised insulin levels, compared to usual care; thus, a metabolic basis for the cardioprotective action of Omacor, outside of its lipid lowering effects, merits further investigation.     

Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat

OBJECTIVE: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2, -3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP-1, -2, -3, and -4) upregulation during left ventricular (LV) remodeling following myocardial infarction (MI) in rats. METHODS: The descending left coronary artery of male rats (Rattus norvegicus) was ligated to produce a MI. LV function and dilation were assessed from 1 day to 16 weeks post-MI. Protein and mRNA extraction was done on LV samples containing scar and myocardium together. Gelatinase activity was measured by zymography. Westerns were run on the MMPs known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as TIMP-1, -2, and -4. RESULTS: Average infarct size was 38.6+/-1.1%, and produced LV dysfunction and progressive LV dilation. Thoracic ascites, a marker of congestive heart failure (HF), was not present until 12 weeks post-MI. Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at different timepoints during HF progression. Increased MMP protein levels occurred sometimes without a corresponding elevation in mRNA levels, and increased TIMP mRNA levels without increased protein levels. MMP-13 active form was elevated during the first 2 weeks post-MI while TIMP-1 and TIMP-2 protein levels were not significantly elevated until 2 weeks post-MI. MMP-8 and MMP-14 protein levels increased later during heart failure progression. CONCLUSION: MMP/TIMP upregulation evolves over time following infarction in the rat LV. Some MMPs were significantly elevated during the first week post-MI (MMP-13, -2, and -9) and another was not until 16 weeks post-MI (MMP-14). The dissociation between LV MMP/TIMP mRNA and protein levels shows that post-translation processing occurs in the rat heart.