[Stent graft for rapidly growing thoracic mycotic aneurysm in a patient with advanced lung cancer].

We report a compromised patient with mycotic aneurysm, who was successfully treated by urgent placement of a stent graft. A man in his seventies was admitted to our hospital with relapsing high fever and back pain during chemotherapy for advanced squamous cell carcinoma of the lung. Contrast CT demonstrated a saccular aneurysm of the thoracic aorta and left pleural effusion. Blood cultures were positive for Escherichia coli producing extended spectrum beta-lactamase (ESBL). Therefore, thoracic mycotic aneurysm was diagnosed. Because of rapid growth on consecutive examinations, absolute bed rest was required. Therefore, we performed antibiotic therapy combined with stent graft placement, which achieved complete exclusion of the aneurysm. He was discharged in an ambulatory state, and his quality of life remained good at home until just before death from terminal state of the cancer.

A case of biopsy-proven cardiac sarcoidosis without any other extracardiac manifestations.

A 49-year-old woman was referred to our hospital for uncontrollable heart failure. She had never been diagnosed as having sarcoidosis. Chest X-ray showed cardiomegaly without bilateral hilar lymphadenopathy. Echocardiography showed diffuse hypokinesis of the left ventricle mimicking idiopathic dilated cardiomyopathy. No specific manifestations implying sarcoidosis were observed. On cardiac catheterization, coronary angiograms were normal, whereas concurrent routine endomyocardial biopsy showed foci of non-caseating granuloma, indicating sarcoidosis. Pathological finding was the only clue to diagnose cardiac sarcoidosis among our standard examinations for heart failure. No other additional investigations found any extracardiac features of sarcoidosis. All serological and immunological examinations were within normal range. This is a challenging case of biopsy-proven cardiac sarcoidosis without any other extracardiac involvement.

Nifekalant hydrochloride terminated electrical storms after coronary surgery.

An "electrical storm" is a life-threatening condition defined as a recurrent attack of ventricular tachycardia or fibrillation. The current report is a case study of a patient who had electrical storms developing unexpectedly after undergoing coronary artery bypass grafting. The electrical storms were terminated dramatically by the administration of nifekalant hydrochloride. We suggest that nifekalant hydrochloride has great therapeutic potential for the suppression of intractable ventricular tachyarrhythmias refractory to amiodarone.

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.

The C-terminal tail of mitochondrial transcription factor a markedly strengthens its general binding to DNA.

Mitochondrial transcription factor A (TFAM) contains a basic C-terminal tail which is essential for the promoter-specific transcription. TFAM is also a major component of a protein-mitochondrial DNA (mtDNA) complex, called nucleoid, as a non-specific DNA-binding protein. However, little is known about a role of the C-tail in the nucleoid. Overexpression of full-length TFAM decreased the amount of a D-loop form of mtDNA in cells, while overexpression of TFAM lacking its C-tail (TFAM-DeltaC) did not, suggesting that the C-tail is involved in destabilization or formation of the D-loop. An mRNA for mtDNA-derived ND1 was hardly decreased in the former but rather decreased in the latter. Given that the D-loop formation is coupled with the transcription, the decrease in the D-loop is likely due to its destabilization. The recombinant full-length TFAM much strongly unwound DNA than TFAM-DeltaC, which is consistent with the above idea because D-loop is resolved by unwinding of the supercoiling state. Notably, truncation of the C-tail decreased DNA-binding activity of TFAM by three orders of magnitude. Thus, the C-terminal tail of TFAM is important for the strong general binding to mtDNA. This strong DNA-binding conferred by the C-tail may play an important role in the nucleoid structure.

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.

Fatal case of amiodarone-induced acute respiratory distress syndrome in a patient with severe left ventricular dysfunction due to extensive anterior acute myocardial infarction.

We here report a case of 71-year-old man with acute extensive anterior myocardial infarction, who was complicated with ventricular tachycardia (VT) even after successful percutaneous coronary intervention. As intravenous administration of nifekalant terminated VT, we started oral administration of amiodarone (day 1). We gave 400 mg of amiodarone a day for the first week and 200 mg a day from the second week. The patient was stable with normoxia by day 20, in spite of pulmonary congestion-like infiltrates on chest X-ray. On day 21, he was complicated with acute respiratory distress syndrome. Immediate discontinuance of amiodarone and high-dose pulse glucocorticoid therapy with intubation slightly improved the infiltrations on chest X-ray. However, glucocorticoid therapy induced hyperglycemia with an increase in plasma osmolality, complicated with hypoalbuminemia, and gastrointestinal bleeding. Despite treatment with a large amount of saline, high-doses of catecholamines, and blood transfusion, the patient died on day 28. It is sometimes difficult to diagnose congestive heart failure or amiodarone-induced pulmonary infiltrates in patients with severe left ventricular dysfunction.

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.

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 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.

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.

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.

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.

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.