Loureirin B alleviates cardiac fibrosis by suppressing Pin1/TGF-ß1 signaling.

It is well-established that cardiac fibrosis contributes to cardiac dysfunction and adverse outcomes. However, the underlying mechanisms remain elusive, warranting further studies to develop new therapeutic strategies. It has been suggested that loureirin B can ameliorate the progression of fibrotic diseases. This study investigated the effects of loureirin B on cardiac fibrosis and explored the underlying mechanisms. Transverse aortic constriction (TAC) was performed to induce cardiac fibrosis in mice. Loureirin B (10 mg/kg/day) or saline was continuously delivered via subcutaneous osmotic mini-pumps. Cardiac fibroblasts (CFs) were treated with angiotensin II (Ang II, 100 nM, 24 h) to simulate fibrosis in vitro. Immunochemistry, echocardiography, and Sircol collagen assays were conducted to evaluate the cardioprotective effects. Quantitative real-time polymerase chain reaction, Western blot, and transfection techniques were performed to elucidate the mechanisms. Results showed that loureirin B prevented cardiac fibrosis and improved cardiac function in mice subjected to TAC. Treatment with loureirin B inhibited the elevation of inflammatory factors (interleukin-1ß, interleukin-6, and tumor necrosis factor-α), transforming growth factor-ß1 (TGF-ß1), and Pin1 induced by TAC. Furthermore, loureirin B treatment inhibited the increased fibroblast activation and collagen synthesis induced by Ang II in CFs. In addition, loureirin B inhibited increased expression of TGF-ß1 and Pin1 induced by Ang II or TAC. Mechanistically, overexpression of Pin1 induced increased TGF-ß1 expression and blocked the anti-fibrotic effects in Ang II-induced CFs treated with loureirin B. Loureirin B ameliorated cardiac fibrosis and dysfunction both in vitro and in vivo probably through the Pin1/TGF-ß1 signaling pathway.

[A woman with a chronic cough and dyspnoea]. / En kvinne med kronisk hoste og dyspné.

A previously healthy woman in her forties with a six-month history of persistent coughing, breathlessness and fatigue was referred to our hospital for further evaluation. She was initially treated with antibiotics for a possible respiratory tract infection but with only minor effect. A chest x-ray and computer tomography (CT) of the thorax demonstrated a solid tumour in the right lung hilus. Bronchoscopy revealed slight oedema of the bronchial mucous membrane in the area in question. Cytological examination of bronchoalveolar lavage fluid (BAL) showed normal respiratory epithelial cells. Histological examination of a needle biopsy from the tumour showed lymphoproliferative changes of uncertain cause. Magnetic resonance imaging (MRI) of the thorax provided no further information. An electrocardiogram (ECG) revealed signs of left ventricular hypertrophy and sinus bradycardia. Her complaints were palpitations, mild exertional dyspnoea and attenuated heart rate response to exercise. Echocardiography showed increased wall thickness with heterogeneous echogenicity in both ventricles, a slightly enlarged left atrium and mild mitral regurgitation. Tissue Doppler measurements showed impaired relaxation. These findings were suggestive of restrictive cardiomyopathy with diastolic dysfunction. Cardiac MRI confirmed the echocardiographic findings. The tumour was removed by thoracotomy and was shown to be made up of lymphatic tissue with granulomas, consistent with sarcoidosis. The restrictive cardiomyopathy was regarded as a cardiac manifestation of sarcoidosis. The patient was treated with corticosteroids. Clinical follow up with cardiac MRI and echocardiography did not reveal any progression of the cardiac involvement. Cardiac sarcoidosis must be considered in all sarcoid patients because of its significance for prognosis and treatment.

Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease--an overview.

In recent years, diabetes and its associated complications have come to represent a major public health concern. It is a complex disease characterized by multiple metabolic derangements and is known to impair cardiac function by disrupting the balance between pro-oxidants and antioxidants at the cellular level. The subsequent generation of reactive oxygen species (ROS) and accompanying oxidative stress are hallmarks of the molecular mechanisms responsible for cardiovascular disease. Among several oxidative stress-mediated mechanisms that have been proposed, ROS-mediated oxidative stress has received the most attention. ROS have been shown to interact with proteins, lipids, and DNA, causing damage to the cellular macromolecules and subsequently, deterioration of cellular function. Induction of thioredoxin-1 (Trx1) gene expression has been demonstrated to protect the diabetic myocardium from dysfunction by reducing oxidative stress and enhancing the expression of heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF). The failure of antioxidants to consistently demonstrate clinical benefit necessitates further investigation of the role of oxidative stress in diabetes-mediated cardiovascular disease.

Coffin-Lowry syndrome and left ventricular noncompaction cardiomyopathy with a restrictive pattern.

Coffin-Lowry syndrome (CLS) is an X-linked dominant condition characterized by moderate to severe mental retardation, characteristic facies, and hand and skeletal malformations. The syndrome is due to mutations in the gene that encodes the ribosomal protein S6 kinase-2, a growth factor-regulating protein kinase located on Xp22.2. Cardiac anomalies are known to be associated with CLS. Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by left ventricular (LV) myocardial trabeculations and intertrabecular recesses that communicate with the LV cavity. Patients may present with a variety of clinical phenotypes, ranging from a complete absence of symptoms to a rapid, progressive decline in LV systolic and diastolic function, resulting in congestive heart failure, malignant ventricular tachyarrhythmias, and systemic thromboembolic events. Restrictive cardiomyopathy is an uncommon primary cardiomyopathy characterized by biatrial enlargement, normal or decreased biventricular volume, impaired ventricular filling, and normal or near-normal systolic function. We describe a patient with CLS and LVNC with a restrictive pattern, as documented by echocardiography and cardiac catheterization. To our knowledge, there have been no previous reports of concomitant CLS and LVNC. On the basis of our case, we suggest that patients with CLS be screened not only for congenital structural heart defects but also for LVNC cardiomyopathy.

Restrictive cardiomyopathy as a cardiac manifestation of myofibrillar myopathy.

OBJECTIVES: Restrictive cardiomyopathy (RCM) has been repeatedly reported as a cardiac manifestation of certain neuromuscular disorders, but only in single patients with myofibrillar myopathy (MFMP). CASE REPORT: In a 19-year-old woman with a history of short stature, tiptoe-walking since childhood, fixed joint contractures, severe scoliosis requiring surgical correction, elevated levels of creatine kinase, and RCM, MFMP was diagnosed based on her clinical presentation, her elevated muscle enzymes and a muscle biopsy. An electrocardiogram showed an atrioventricular-block I, paroxysmal sinus-tachycardia, biphasic P-waves, right-axis deviation, abnormal repolarization, and episodes of supraventricular tachycardia. Echocardiography confirmed her RCM. Her respiratory function was markedly reduced, despite surgical correction of her severe scoliosis at age 14 years. After an aggravation of heart failure because of atrial flutter, the patient profited from successful cardioversion and diuretics. CONCLUSION: Electrocardiographic abnormalities such as atrial flutter and RCM represent cardiac manifestations of MFMP. Cardioversion can be successful, and oral anticoagulation may prevent cardioembolic events.

[Original case report of amyloidosis with pleural involvement: the role of echocardiography in the diagnosis]. / Un cas original d'amylose pleurale: apport de l'échocardiographie au diagnostic.

INTRODUCTION: Amyloidosis is often difficult to diagnose and cardiac involvement worsens the prognosis. CLINICAL CASE: We report the case of a 72-year old man consulting for cardiac failure with pleural effusion. A restrictive cardiomyopathy was discovered by echocardiography, and amyloidosis was then suspected. First histological localization was pleural. Cardiac involvement was confirmed. The diagnosis was supported by digestive and cutaneous localizations. It was an AL amyloidosis. Treatment with melphalan and dexamethasone allowed stabilization during more than six months. DISCUSSION: This is an original case report, because of the first clinical signs (cardiac failure), the histological proof (pleural histology). Echocardiography is particularly helpful in internal medicine.

[Idiopathic hypereosinophilia with cardiac involvement]. / Idiopathische Hypereosinophilie mit kardialer Beteiligung.

HISTORY AND CLINICAL FINDINGS: A 34-year-old previously healthy woman was admitted to another hospital because of abdominal pain, cough and dyspnea. Peripheral eosinophilia was present. Two months later she was admitted to the cardiology department with signs of mitral regurgitation. Dyspnea, fatigue, skin rashes with pruritus and a systolic murmur were noted. INVESTIGATIONS: Laboratory tests showed 11.4/nl leukocytes (normal range 4.8-10.8/nl) with an eosinophilia of 19% (normal range < 4%) corresponding to 2.2/nl. Cardiac magnetic resonance imaging revealed endomyocardial fibrosis involving the posterior mitral leaflet with resulting valvular regurgitation. Doppler ultrasound showed restrictive heart failure. DIAGNOSIS, THERAPY AND FURTHER COURSE: The diagnosis of idiopathic hypereosinophilia most likely as part of hypereosinophilic syndrome with cardiac involvement was made. The patient was treated with digitalis, diuretics and peptidyl dipeptidase (PDP) inhibitor. The treatment with glucocorticoids and cytotoxic agent to achieve a reduction of eosinophil count was ended by the patient a few weeks later. CONCLUSION: The hypereosinophilic syndrome with endomyocardial fibrosis is rare, and its prognosis is grave. The pathophysiological mechanisms are not entirely clear, nearly 70 years after Löffler first described fibrous endocarditis with eosinophilia. Patients receive symptomatic medical therapies. Additional surgical treatment has been reported,. Antihypereosinophilic therapy is used to control the disease.

Favorable response to high-dose interferon-alpha in idiopathic hypereosinophilic syndrome with restrictive cardiomyopathy--case report and literature review.

The idiopathic hypereosinophilic syndrome is characterized by a prolonged overproduction of eosinophils of unknown cause in addition to specific organ damage due to eosinophil-derivated protein toxicity. Its prognosis is correlated with heart involvement that results in a restrictive cardiomyopathy. This is frequently biventricular. Isolated left ventricular infiltration has rarely been reported. The authors report a case of idiopathic hypereosinophilic syndrome with cardiac involvement obliterating the left ventricular cavity with a favorable clinical outcome following a combination therapy with interferon-alpha, hydroxyurea and prednisone. Data from other studies dealing with the treatment of idiopathic hypereosinophilic syndrome with interferon-alpha are reviewed and discussed.

Reversible restrictive cardiomyopathy due to light-chain deposition disease.

Systemic light-chain deposition due to plasma cell dyscrasias manifests as a form of restrictive cardiomyopathy with diastolic ventricular dysfunction. Although these manifestations are likely to be cardiac amyloidosis, whether these pathological conditions are reversible after treatment of the underlying plasma cell disorders is unknown. To our knowledge, we describe the first patient with cardiac light-chain deposition due to multiple myeloma in whom echocardiographic and biochemical factors of cardiac function were ameliorated dramatically after remission of this disorder. We emphasize that restrictive cardiomyopathy due to light-chain deposition may be reversible and have a relatively better prognosis after remission of plasma cell dyscrasias.

Idiopathic myocardial vasculitis presenting as restrictive cardiomyopathy.

A previously unreported case of small-vessel myocardial vasculitis presenting as restrictive cardiomyopathy and congestive heart failure is described. The hemodynamic study, showing severely increased and equalized diastolic pressures in atrial and ventricular chambers, and cardiac MRI, showing normal pericardium and ventricular endomyocardial biopsy, not including myocardial vascular component, were insufficient to make a diagnosis. This made a thoracotomy and surgical cardiac biopsy necessary. Steroids and cyclophosphamide, introduced after histologic evidence of necrotizing vasculitis, unassociated with a systemic disease, became available and improved the clinical profile and the diastolic dysfunction at two-dimensional echocardiographic Doppler analysis.

Occult restrictive hemodynamics after pediatric heart transplantation.

BACKGROUND: Although resting hemodynamics after pediatric heart transplantation are generally within normal limits, we hypothesized that occult restrictive hemodynamics suggesting diastolic dysfunction may be unmasked by acute volume loading (fluid challenge) during cardiac catheterization. We wished to determine the incidence of diastolic dysfunction and to assess whether it progressed over time. METHODS: From 1988 through 1993, a total of 100 fluid challenges were performed at the time of surveillance endomyocardial biopsy in 31 survivors of orthotopic heart transplantation. Cyclosporine-based immunosuppression was used in 16 patients, and FK506 was used in 15 patients. Right heart hemodynamics and cardiac output (thermodilution) were obtained at baseline and after a fluid challenge with 10 ml/kg of normal saline solution. The data were analyzed to determine whether type of immunosuppression or time elapsed since transplantation predicted the response to fluid challenge. RESULTS: Baseline hemodynamics were normal; however, a marked increase in atrial filling pressures occurred after fluid challenge (p < 0.001). Findings were similar in cyclosporine- and FK506-treated patients. Hemodynamic response to fluid challenge was not related to duration of time since transplantation, including studies on patients surviving more than 4 years. CONCLUSIONS: Diastolic dysfunction after heart transplantation is common; however, the abnormalities do not progress in severity, suggesting stable long-term graft function.