A Narrow QRS Is Not Always Normal.

A narrow QRS complex is a hallmark of a normal beat, although this common assumption is questioned in the findings of the present case. This electrocardiographic challenge investigates the unique mechanism of a narrow QRS and the clinical importance of discovering this phenomenon. (Level of Difficulty: Intermediate.).

Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice.

Tenascin-C (TN-C) is an extracellular matrix glycoprotein with high bioactivity. It is expressed at low levels in normal adult heart, but upregulated under pathological conditions, such as myocardial infarction (MI). Recently, we (Ref. 34) reported that MI patients with high serum levels of TN-C have a greater incidence of maladaptive cardiac remodeling and a worse prognosis. We hypothesized that TN-C may aggravate left ventricular remodeling. To examine the effects of TN-C, MI was induced by ligating coronary arteries of TN-C knockout (KO) mice under anesthesia and comparing them with sibling wild-type (WT) mice. In WT+MI mice, TN-C expression was upregulated at day 1, peaked at day 5, downregulated and disappeared by day 28, and the molecule was localized in the border zone between intact myocardium and infarct lesions. The morphometrically determined infarct size and survival rate on day 28 were comparable between the WT+MI and KO+MI groups. Echocardiography and hemodynamic analyses demonstrated left ventricular end-diastolic diameter, myocardial stiffness, and left ventricular end-diastolic pressure to be significantly increased in both WT+MI and KO+MI mice compared with sham-operated mice. However, end-diastolic pressure and dimension and myocardial stiffness of KO+MI were lower than those of the WT+MI mice. Histological examination revealed normal tissue healing, but interstitial fibrosis in the residual myocardium in peri-infarcted areas was significantly less pronounced in KO+MI mice than in WT+MI mice. TN-C may thus accelerate adverse ventricular remodeling, cardiac failure, and fibrosis in the residual myocardium after MI.

Prevalence and clinical implication of metabolic syndrome in chronic heart failure.

BACKGROUND: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities. METHODS AND RESULTS: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan. First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non-ischemic CHF patients. CONCLUSIONS: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF.

Radiofrequency catheter ablation of atrial fibrillation through an implanted inferior vena cava filter.

Pulmonary vein isolation (PVI), which creates electrical blocks between pulmonary veins and left atrium, is an established way of catheter ablation for atrial fibrillation (AF). PVI is usually performed via the femoral vein access, using two or three long preshaped sheaths, followed by atrial-septal puncture to approach the left atrium. Here, we treated an AF patient with a permanently implanted inferior vena cava filter (IVC-F) due to deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE). The patient had symptomatic paroxysmal AF for over a decade, which was not controlled under antiarrhythmic drugs including beta-blockers. Therefore, we recommended PVI to treat the AF. However, as the IVC-F was an obstacle to perform conventional PVI, we changed the combination of vascular access sites and devices to perform it safely. Notably, insertions of a single steerable sheath through IVC-F and an intracardiac ultrasound catheter from the right internal jugular vein were useful for the successful completion of the procedure. .

A case of congenital left ventricular diverticulum in a patient with autosomal dominant polycystic kidney disease: possible mechanistic link between polycystin and ventricular diverticulum.

A 40-year-old woman had been followed as an outpatient to manage chronic kidney disease secondary to autosomal dominant polycystic kidney disease (ADPKD). Atrial premature contraction was found incidentally on an electrocardiogram during her regular follow-up examination. Subsequent transthoracic echocardiography detected an abnormal structure located very close to the left ventricular outflow tract (23 mm long × 15 mm wide in diastole). The structure was finally diagnosed as congenital left ventricular diverticulum (CLVD) using transesophageal echocardiography, contrast-enhanced computed tomography, and magnetic resonance imaging. Although CLVD occasionally causes intraventricular coagulation, lethal arrhythmia, and congestive heart failure, the size and location of her diverticulum remained unchanged over time and a 24-h Holter electrocardiogram showed no lethal arrhythmias. Accordingly, neither anticoagulation therapy nor surgical resection of the diverticulum was performed. To the best of our knowledge, ours is the first case of CLVD in a patient with ADPKD. Because gene abnormalities in polycystin coding are mechanistically related to the development of colonic diverticulum and abnormal cyst formation in ADPKD patients, we suspected that CLVD and abnormal cyst formation were related to the same gene abnormality in ADPKD. More case reports, case series studies, and basic research are required to determine whether CLVD in ADPKD is mechanistically associated with abnormal polycystin or just a coincidence.

Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice.

BACKGROUND: Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process. METHODS AND RESULTS: We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean+/-SEM, 1.5+/-0.2 vs 2.2+/-0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56+/-1% vs 55+/-1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice. CONCLUSIONS: Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.

Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice.

OBJECTIVE: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts. METHODS: Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n = 28) mice and sibling wild-type (p53(+/+); n = 29) mice by ligating the left coronary artery. RESULTS: By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P = NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P = NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423+/-86 vs. 1330 +/- 275/10(5) cells, P < 0.01). CONCLUSIONS: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients.

Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction.

BACKGROUND: Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. METHODS AND RESULTS: We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV. CONCLUSIONS: Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.

Complete atrioventricular block improved by balloon aortic valvuloplasty for severe aortic stenosis: Usefulness of sheathless technique in the retrograde approach.

An 86-year-old man was admitted to our hospital for treatment of congestive heart failure with severe aortic stenosis and advanced atrioventricular (AV) block. Despite pharmacological therapy, he developed complete AV block and resultant acute pulmonary edema requiring temporary pacing and tracheal intubation. We urgently performed retrograde balloon aortic valvuloplasty (BAV) with a sheathless technique. The AV block disappeared soon after the procedure; this was probably attributable to the correction of relative myocardial ischemia, obtained by BAV. Thus, he successfully recovered from a critical condition. .

Successful recovery of tachycardia-induced cardiomyopathy with severely depressed left ventricular systolic function by catheter ablation with mechanical hemodynamic support: a case report.

We describe the case that persistent atrial fibrillation refractory to rhythm control by pharmacotherapy and electrical cardioversions caused tachycardia-induced cardiomyopathy with low ejection fraction and hemodynamic instability. Mechanical hemodynamic support using an intra-aortic balloon pump is one of the choices of hemodynamic support during catheter ablation by pulmonary vein isolation.

Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice.

BACKGROUND: Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI). METHODS AND RESULTS: We created MI in 12- to 16-week-old, male GSHPx transgenic mice (TG+MI) and nontransgenic wild-type littermates (WT+MI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid-reactive substances measured in TG+MI at 4 weeks were significantly lower than those in WT+MI. The survival rate during 4 weeks of MI was significantly higher in TG+MI than in WT+MI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TG+MI. LV end-diastolic pressure was increased in WT+MI and reduced in TG+MI. Improvement of LV function in TG+MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WT+MI after 3 days but were attenuated in TG+MI. CONCLUSIONS: Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.

Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction.

BACKGROUND: Increased expression of monocyte chemoattractant protein-1 (MCP-1) has recently been described in clinical and experimental failing heart. However, its pathophysiological significance in heart failure remains obscure. We thus determined whether MCP-1 is increased in post-myocardial infarction (MI) hearts and its blockade can attenuate the development of left ventricular (LV) remodeling and failure. METHODS AND RESULTS: Anterior MI was produced in mice by ligating the left coronary artery. After 4 weeks, MI mice exerted LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV. MCP-1 mRNA levels were increased by 40-fold in noninfarcted LV 1 day after ligation, which persisted until 28 days. To block the MCP-1 signals, an N-terminal deletion mutant of the human MCP-1 gene was transfected into the limb skeletal muscle 3 days before and 14 days after ligation. This method improved the survival rate of mice with MI at 4 weeks (61% versus 87%, P<0.05) as well as attenuated LV cavity dilatation and contractile dysfunction, interstitial fibrosis, recruitment of macrophages, and myocardial gene expression of tumor necrosis factor-alpha and transforming growth factor-beta compared with the nontreated MI mice despite the comparable infarct size calculated as percent LV circumference. CONCLUSIONS: The activation of MCP-1 expression contributes to the LV remodeling and failure after MI. An anti-MCP-1 gene therapy can be a useful novel strategy for preventing post-MI heart failure.

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.

Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction.

OBJECTIVE: Transforming growth factor (TGF)-beta promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. METHODS: Anterior MI was produced in mice by ligating the left coronary artery. TGF-beta mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-beta signaling during the early phase of MI, an extracellular domain of TGF-beta type II receptor (TbetaIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. RESULTS: TbetaIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-beta signaling during the later phase, TbetaIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TbetaIIR. CONCLUSIONS: The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

Right-sided infective endocarditis with a ruptured sinus of Valsalva and multiple septic pulmonary emboli in a patient with atopic dermatitis.

We herein report the case of 34-year-old woman with acute tricuspid valve infective endocarditis (IE) associated with a ruptured sinus of Valsalva and multiple septic pulmonary emboli. She had no history of medical problems, except for atopic dermatitis (AD). Blood cultures identified methicillin-sensitive Staphylococcus aureus. Despite the administration of two months of antibiotic therapy, the patient experienced recurrent pulmonary emboli and developed heart failure due to a left-to-right shunt, whereas the area of vegetation did not change in size. She subsequently underwent surgery for shunt closure and tricuspid valve replacement. The AD was thought to be the cause of the patient's bacteremia, which consequently resulted in aggressive right-sided IE.

Angiotensin II type 1 receptor blocker attenuates exacerbated left ventricular remodeling and failure in diabetes-associated myocardial infarction.

Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI.

Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload.

Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.

Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart.

Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H(2)O(2) in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG+DM) and nontransgenic wildtype littermates (WT+DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG+DM at 8 wk were significantly lower than those in WT+DM (58 +/- 3 vs. 71 +/- 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT+DM and TG+DM mice. In contrast, diastolic function was impaired in WT+DM and was improved in TG+DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms, P < 0.01). The TG+DM values were comparable with those of WT+Control (tau; 7.8 +/- 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM.

Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy.

Tumor necrosis factor-alpha (TNF-alpha) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase (MMP)-2 is involved in extracellular matrix remodeling. Recent evidence suggests a protective role for this protease against tissue inflammation. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that ablation of the MMP-2 gene could affect cardiac remodeling and failure in TNF-alpha-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-alpha (TG) with MMP-2 knockout (KO) mice. Four groups of male and female mice were studied: wild-type (WT) with wild MMP-2 (WT/MMP(+/+)), WT with MMP-2 KO (WT/MMP(-/-)), TNF-alpha TG with wild MMP-2 (TG/MMP(+/+)), and TG with MMP-2 KO (TG/MMP(-/-)). The upregulation of MMP-2 zymographic activity in TG/MMP(+/+) mice was completely abolished in TG/MMP(-/-) mice, and other MMPs and tissue inhibitors of metalloproteinase were comparable between groups. Survival was shorter for male TG/MMP(-/-) than TG/MMP(+/+) mice. Female TG/MMP(-/-) mice were more severely affected than TG/MMP(+/+) mice with diminished cardiac function. Myocardial TNF-alpha and other proinflammatory cytokines were increased in TG/MMP(+/+) mice, and this increase was similarly observed in TG/MMP(-/-) mice. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP(-/-) than in TG/MMP(+/+) mice. Selective ablation of the MMP-2 gene reduces survival and exacerbates cardiac failure in association with the increased level of myocardial inflammation. MMP-2 may play a cardioprotective role in the pathogenesis of cytokine-induced cardiomyopathy.

Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction.

Matrix metalloproteinase-2 (MMP-2) is prominently overexpressed both after myocardial infarction (MI) and in heart failure. However, its pathophysiological significance in these conditions is still unclear. We thus examined the effects of targeted deletion of MMP-2 on post-MI left ventricular (LV) remodeling and failure. Anterior MI was produced in 10- to 12-wk-old male MMP-2 knockout (KO) and sibling wild-type (WT) mice by ligating the left coronary artery. By day 28, MI resulted in a significant increase in mortality in association with LV cavity dilatation and dysfunction. The MMP-2 KO mice had a significantly better survival rate than WT mice (56% vs. 85%, P < 0.05), despite a comparable infarct size (50 +/- 3% vs. 51 +/- 3%, P = not significant), heart rate, and arterial blood pressure. The KO mice had a significantly lower incidence of LV rupture (10% vs. 39%, P < 0.05), which occurred within 7 days of MI. The KO mice exerted less LV cavity dilatation and improved fractional shortening after MI by echocardiography. The LV zymographic MMP-2 level significantly increased in WT mice after coronary artery ligation; however, this was completely prevented in KO mice. In contrast, the increase in the LV zymographic MMP-9 level after MI was similar between KO and WT mice. MMP-2 activation is therefore considered to contribute to an early cardiac rupture as well as late LV remodeling after MI. The inhibition of MMP-2 activation may therefore be a potentially useful therapeutic strategy to manage post-MI hearts.