Takotsubo syndrome in a heart transplant recipient with poor cardiac sympathetic reinnervation.

Takotsubo syndrome (TTS), also referred to as stress cardiomyopathy, is characterized by transient left ventricular apical ballooning in the absence of obstructive coronary artery disease. Catecholamine-induced cardiac injury or vasospasm has been implicated in this pathophysiology. We present a case of a 67-year-old man 10 years after heart transplantation diagnosed with TTS. Sympathetic reinnervation could not be detected by iodine-123 meta iodobenzylguanidine uptake, suggesting that TTS can occur in the absence of functional sympathetic nerve systems reconstruction.

Anomalous origin of the coronary artery coursing between the great vessels presenting with a cardiovascular event (J-CONOMALY Registry).

AIMS: Anomalous origin of the coronary artery (AOCA) with an inter-arterial course (IAC) between the great vessels poses a risk for a life-threatening cardiovascular event. We assessed, in a registry-based study, the clinical features, treatment strategies, and prognoses of life-threatening cardiovascular events ensuant to AOCA. METHODS AND RESULTS: Included were 65 AOCA patients (48 men/17 women, aged 41 ± 23 years) from 40 clinical centres who had experienced sudden cardiac arrest (SCA) (n = 30), acute myocardial infarction (AMI) (n = 5), angina (n = 23), or syncope (n = 7). The anomalous vessel was the right coronary artery in 72% of patients and left coronary artery in 28%; the ostium was slit-like in 42%. Coronary luminal narrowing ≥75% was absent in patients with SCA or syncope (86% and 57%, respectively), but occlusion or narrowing was seen in those with AMI (100%) or angina (52%). Age ≤40 years, male sex, sporting activity, absence of prodromal symptoms, acutely angled (≤30°) take-off from the aorta, and absence of luminal narrowing of the IAC segment were associated with SCA in this patient group. Coronary vasospasm was inducible in 12 of 17 patients without coronary narrowing. Management included surgical revascularization (n = 26) percutaneous coronary intervention (n = 9), and medical treatment (n = 26). Four SCA patients died while hospitalized; no others died during the median 5.0 (range, 1.8-7.0)-year follow-up period. CONCLUSIONS: In patients with AOCA, age ≤40 years, male sex, sporting activity, and an acute take-off angle appear to be risk factors for SCA. Appropriate management can be beneficial. Confirmation in a large-scale study is warranted.

A fatal case of acute progression of generalized edema and simultaneous flash pulmonary edema in a patient with idiopathic systemic capillary leak syndrome: a case report.

INTRODUCTION: Idiopathic systemic capillary leak syndrome is a rare and fatal disease due to the unexplained episodic attacks of capillary leakage of plasma from the intravascular into the interstitial space. The attack consists of three phases, a prodromal phase, peripheral leak phase and recruitment phase. During the peripheral leak phase, generalized edema, mainly in the trunk and extremities, with hemoconcentration and hypoalbuminemia occurs, while usually the visceral organs like lungs, brain, heart and kidneys seem not to be involved. Treatment of the acute phase is supportive, focusing on adequate but not overzealous fluid resuscitation, because pulmonary edema usually occurs in the recruitment phase. CASE PRESENTATION: A 65-year-old Japanese woman was admitted to our hospital because of severe hypovolemic shock with metabolic acidosis and hemoconcentration and hypoalbuminemia. Although she was considered to be in the peripheral leak phase of idiopathic systemic capillary leak syndrome, which could not be diagnosed during the treatment, the generalized edema worsened further, severe flash pulmonary edema progressed rapidly after fluid resuscitation and she died. The autopsy showed generalized edema, especially alveolar pulmonary edema without endothelial apoptosis. CONCLUSIONS: Because hypovolemic shock and fatal pulmonary edema may progress rapidly together even in the peripheral leak phase of idiopathic systemic capillary leak syndrome, we should keep in mind this rare and fatal disease and recognize the pathophysiology to treat it effectively when the patient has hypovolemia with metabolic acidosis.

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.

Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) are implicated in the development and further progression of heart failure, which might be, at least in part, mediated by the production of reactive oxygen species (ROS). However, the cause and consequences of this agonist-mediated ROS production in cardiac myocytes have not been well defined. Recently, we demonstrated that increased ROS production was associated with mitochondrial DNA (mtDNA) damage and dysfunction in failing hearts. We thus investigated whether the direct exposure of cardiac myocytes to TNF-alpha and Ang II in vitro could induce mtDNA damage via production of ROS. METHODS AND RESULTS: TNF-alpha increased ROS production within cultured neonatal rat ventricular myocytes after 1 hour, as assessed by 2',7'-dichlorofluorescin diacetate fluorescence microscopy. TNF-alpha also decreased mtDNA copy number by Southern blot analysis in association with complex III activity, which was prevented in the presence of the antioxidant alpha-tocopherol. A direct exposure of myocytes to H2O2 caused a similar decrease in mtDNA copy number. In contrast, Ang II did not affect mtDNA copy number, despite the similar increase in ROS production. TNF-alpha-mediated ROS production and a decrease in mtDNA copy number were inhibited by the sphingomyelinase inhibitor D609. Furthermore, N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analogue, increased myocyte ROS production, suggesting that TNF-alpha-mediated ROS production and subsequent mtDNA damage were mediated by the sphingomyelin-ceramide signaling pathway. CONCLUSIONS: The intimate link between TNF-alpha, ROS, and mtDNA damage might play an important role in myocardial remodeling and failure.

Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma activators have recently been implicated as regulators of cellular proliferation and inflammatory response such as cytokine expression. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of pioglitazone treatment in an experimental model of chronic heart failure. METHODS AND RESULTS: Mice with extensive anterior MI were treated with placebo or pioglitazone (3 mg x kg(-1) x d(-1)) as a dietary supplement for 4 weeks starting 6 hours after surgery. Infarct size and glucose levels were similar among all groups. LV cavity dilatation and dysfunction by echocardiography were significantly attenuated in MI mice given pioglitazone. LV end-diastolic pressure was increased in MI mice and was significantly reduced by pioglitazone treatment. Pioglitazone partially normalized LV dP/dt(max) and dP/dt(min), indices of LV contractile function, which were significantly reduced in MI mice. Improvement of LV function by pioglitazone was accompanied by a decrease in myocyte hypertrophy and interstitial fibrosis and a reduced expression of tumor necrosis factor-alpha, transforming growth factor-beta, and monocyte chemoattractant protein-1 genes in the noninfarcted LV from MI mice. LV inducible nitric oxide synthase and gelatinase B protein levels were increased in MI and were not altered by pioglitazone treatment. CONCLUSIONS: Pioglitazone improved LV remodeling and function in mice with post-MI heart failure. This effect was associated with an attenuated LV expression of inflammatory cytokines and chemokines. Peroxisome proliferator-activated receptor-gamma ligands have promise as preventive and therapeutic agents against heart failure.

Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation.

BACKGROUND: Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF. METHODS AND RESULTS: We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltration, monocyte chemoattractant protein-1 expression, and renin-angiotensin system and matrix metalloproteinase activity. Probucol treatment prevented increases in oxidative stress, inflammation, and matrix metalloproteinase activity and attenuated LV dysfunction and remodeling. CONCLUSIONS: Probucol attenuated LV dysfunction and remodeling, possibly through its antioxidant and/or antiinflammatory effects in ventricular pacing-induced HF. These data suggest that inflammatory disorders, which cause an abnormal interaction between failing myocardium and activated monocytes, have an important role in the progression of HF.

Greater oxidative stress in healthy young men compared with premenopausal women.

Coronary risk factors, including age, hypertension, diabetes mellitus, hyperlipidemia, and smoking, are associated with enhanced oxidative stress, which is implicated as a potential mechanism for atherogenesis and atherosclerotic cardiovascular diseases. Male sex is one of the well-known cardiovascular risk factors. We tested the hypothesis that oxidative stress is greater in men than in women. Plasma thiobarbituric acid-reactive substances (TBARS) and urinary 8-isoprostaglandin F2alpha (8-iso-PGF2alpha) were measured in 52 young men and 51 age-matched women. The subjects were healthy, were not smokers, and were not taking any medications or vitamins. Age, blood pressure, plasma cholesterol, and glucose did not differ between the groups. Baseline TBARS (2.32 +/- 0.11 [men] versus 1.87 +/- 0.09 [women] nmol/mL, P<0.01) and 8-iso-PGF2alpha (292 +/- 56 [men] versus 164 +/- 25 [women] pg/mg creatinine, P<0.05) were higher in men than in women. Supplementation of antioxidant vitamins for 4 weeks in men produced a significant reduction in TBARS and 8-iso-PGF2alpha by 34% (P<0.01) and 48% (P<0.05), respectively. Plasma superoxide dismutase, catalase, and vitamin E levels were comparable between the groups. Enhanced oxidative stress in men may provide a biochemical link between male sex and atherosclerotic diseases related to oxidative stress.

Severe pulmonary hypertension in a patient with systemic lupus erythematosus and minimal lupus activity.

Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 l/min/m2). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction.

BACKGROUND: Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown. METHODS AND RESULTS: Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; P<0.05) without affecting the infarct size (52+/-2% versus 49+/-3%; P=NS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice. CONCLUSIONS: Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.