Effects of telmisartan and losartan on cardiovascular protection in Japanese hypertensive patients.

The Telmisartan and Losartan Cardiac Evaluation Trial, a multicenter, prospective, randomized, open-labeled, blinded-endpoint trial, was designed to compare the effects of two angiotensin II receptor blockers (ARBs), telmisartan and losartan, on cardiovascular protection in Japanese patients with mild to moderate essential hypertension. We compared the effects of telmisartan and losartan on left ventricular (LV) hypertrophy, cardiac function, atherosclerosis of carotid arteries and surrogate markers related to the actions of peroxisome proliferator-activated receptor-γ. A total of 58 patients were enrolled in the present trial and the follow-up period was 1 year. There were no significant differences in blood pressure (BP) levels between the telmisartan group and the losartan group throughout the trial. The percentage of the patients treated with ARB monotherapy was significantly higher in the telmisartan group compared with the losartan group. In addition, the progression of intima-media thickness of common carotid artery was significantly inhibited in the telmisartan group compared with the losartan group. Neither group experienced significant changes in cardiac function and LV mass index. There were no differences between the groups with respect to changes in surrogate markers such as serum adiponectin, creatinine, homeostasis model assessment index, plasminogen activator inhibitor-1 and high sensitivity C-reactive protein. Although BP levels were equal and well controlled in both groups, telmisartan showed more protective vascular effects than losartan.

Abdominal aortic pseudoaneurysm caused by prolonged methicillin-resistant Staphylococcus aureus sepsis.

The mechanism of pseudoaneurysm formation caused by prolonged sepsis is thought to be related to the vascular endothelium being directly invaded and broken by bacteria. Moreover, matrix metalloproteinases (MMPs) which are up-regulated by chronic inflammation have been reported to be implicated in the pathogenesis of aneurysm development through increased proteolysis of extracellular matrix proteins. An effective treatment for infected pseudoaneurysm remains unsettled. Surgery is generally performed, however, because the patients in most of these cases are in very poor physical condition, the operation is associated with high morbidity and mortality. A more successful alternative is endovascular treatment. Recent reports indicate low morbidity and mortality rates with this treatment. If the patient in this case had been in better condition, we could have selected endovascular stent-grafting for her treatment.

Takayasu arteritis evaluated by multi-slice computed tomography in an old man.

In the case of patients with Takayasu arteritis (TA), they consult a doctor for the first time when they have a slight fever, shoulder pain, chest pain, back pain, or headache, or when they are pointed out to have high CRP or anemia by chance in medical check-up. In TA, they are usually young women. In our case, the very old patient had bilateral massive pleural effusion and aortic aneurysm with a 64-slice computed tomography (CT). TA commonly affects primarily large elastic arteries such as the aorta and its main branches. Steroid was very effective for suppression of inflammatory symptom being dose-dependent. His pleural effusion had been decreasing without reducing the size of aortic aneurysm. Multi-slice CT was a very useful tool to detect unexpected lesion in Takayasu arteritis in a non-invasive manner.

Transferring images via the wireless messaging network using camera phones shortens the time required to diagnose acute coronary syndrome.

BACKGROUND: Clear images can be sent via e-mail using camera phones. We examined whether camera phones are useful to transmit electrocardiogram (ECG) images. METHODS AND RESULTS: ECG images were taken of 20 patients suspected to have acute coronary syndrome. Ten images were sent to a cardiologist by fax. The other 10 images were transmitted using a camera phone. The total time elapsed between image transmission to diagnosis by cardiologists was shorter in the camera phone group than in the fax group. CONCLUSIONS: ECG image transmission by camera phone can be efficiently used in the diagnosis of acute coronary syndrome.

Coronary aneurysm reduced after coronary stenting.

We describe as case of a 70-year-old man who underwent a percutaneous coronary intervention with stenting, for a severe stenosis complicated by a coronary aneurysm just distal to the stenotic site. Notably, coronary angiogram showed an immediate and progressive reduction in the size of coronary aneurysm. Curved planar reconstruction images of the enhanced CT showed no thrombus and no dissection of the coronary aneurysm. We speculate that coronary stenting might decrease the velocity of coronary flow through the stenosis. Consequently, stenting might attenuate the hydrodynamic wall stress on the aneurysm, and, in addition, improve the degradation of the extracellular matrix structure through the regulation of matrix metalloproteinases. Regression of coronary aneurysm after stenting requires further investigations, because stenting may become a potential means for treating post-stenotic aneurysms.

G-CSF prevents the progression of atherosclerosis and neointimal formation in rabbits.

Granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling after myocardial infarction, but its effect on atherosclerosis is unknown. We examined two kinds of rabbit atherosclerosis models. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were treated with G-CSF or saline for 7 days from 14 months old. The vascular injury models were created by inflating angioplasty balloon in the iliac artery of rabbits and were divided into G-CSF and saline group. G-CSF significantly reduced the stenosis score of coronary artery and lipid plaque area of thoracic aorta in WHHL-MI rabbits at 4 weeks after the treatment. In the vascular injury model, G-CSF significantly prevented an increase in neointima/media ratio at 4 weeks after the treatment. G-CSF accelerated the reendothelialization of denuded arteries, and the pretreatment with nitric oxide synthase inhibitor significantly inhibited it. These results suggest that G-CSF has a therapeutic potential for the progression of atherosclerosis.

Granulocyte colony stimulating factor directly inhibits myocardial ischemia-reperfusion injury through Akt-endothelial NO synthase pathway.

OBJECTIVE: Granulocyte colony stimulating factor (G-CSF) has been reported recently to prevent cardiac remodeling and dysfunction after acute myocardial infarction through signal transducer and activator of transcription 3 (STAT3). In this study, we examined acute effects of G-CSF on the heart against ischemia-reperfusion injury. METHODS AND RESULTS: Rat hearts were subjected to global 35-minute ischemia and 120-minute reperfusion in Langendorff system with or without G-CSF (300 ng/mL). G-CSF administration was started at the onset of reperfusion. Triphenyltetrazolium chloride staining revealed that G-CSF markedly reduced the infarct size. G-CSF strongly activated Janus kinase 2 (Jak2), STAT3, extracellular signal-regulated kinase (ERK), Akt, and endothelial NO synthase (NOS) in the hearts subjected to ischemia followed by 15-minute reperfusion. The G-CSF-induced reduction in infarct size was abolished by inhibitors of phosphatidylinositol 3-kinase, Jak2, and NOS but not of mitogen-activated protein kinase kinase (MEK). CONCLUSIONS: These results suggest that G-CSF acts directly on the myocardium during ischemia-reperfusion injury and has acute nongenomic cardioprotective effects through the Akt-endothelial NOS pathway.

Cardioprotective effects of granulocyte colony-stimulating factor in swine with chronic myocardial ischemia.

OBJECTIVES: The aim of this study was to investigate the effect of granulocyte colony-stimulating factor (G-CSF) on chronic myocardial ischemia in swine. BACKGROUND: We recently have reported that G-CSF prevents cardiac remodeling and dysfunction after acute myocardial infarction in mice and swine. It remains unclear whether G-CSF has beneficial effects on chronic myocardial ischemia. METHODS: An ameroid constrictor was placed on left circumflex coronary artery of swine. The presence of myocardial ischemia was verified at four weeks after the operation, and the animals were randomly assigned into the following two groups: 1) administration of vehicle (control group, n = 10), and 2) administration of G-CSF (10 microg/kg/day) for seven days (G-CSF group, n = 10). RESULTS: Echocardiographic examination revealed that the G-CSF treatment prevented left ventricular dilation and dysfunction at eight weeks after the operation. Stress echocardiography revealed that G-CSF ameliorated the regional contractility of chronic myocardial ischemia. Morphological analysis revealed that the extent of myocardial fibrosis of the ischemic region was less in the G-CSF group than in control group. There were more vessels and less apoptotic cells at the ischemic region of the heart of the G-CSF group than control group. Moreover, Akt1 was more strongly activated in the heart of the G-CSF group than control group. CONCLUSIONS: These findings suggest that G-CSF improves cardiac function of chronic myocardial ischemia through decreases in fibrosis and apoptotic death and an increase in vascular density in the ischemic region.

Effects of G-CSF on left ventricular remodeling and heart failure after acute myocardial infarction.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophil progenitors. G-CSF also possesses immunomodulatory properties. G-CSF-induced hematopoietic stem cell mobilization is widely used clinically for transplantation. After it was recently reported that G-CSF mobilizes bone marrow stem cells (BMSCs) into the infarcted hearts and accelerates the differentiation into vascular cells and cardiac myocytes, myocardial regeneration utilizing mobilization of BMSCs by G-CSF is attracting the attention of investigators. In animal models, G-CSF prevents left ventricular remodeling and dysfunction after acute myocardial infarction, at least in part, through a decrease in apoptotic cells and an increase in vascular cells. Although it is controversial whether BMSCs mobilized by G-CSF can differentiate into cardiac myocytes, G-CSF-induced angiogenesis is indeed recognized in infarcted heart. The cardioprotective effects of G-CSF are recognized even in isolated perfused heart. In addition, G-CSF activates various signaling pathways such as Akt, extracellular signal-regulated kinase, and Janus kinase 2/signal transducer and activator of transcription 3 through G-CSF receptors in cardiac myocytes. These observations suggest that G-CSF not only induces mobilization of stem cells and progenitor cells but also acts directly on cardiomyocytes. Therefore, G-CSF may be utilized as a novel agent to have protective and regenerative effects on injured myocardium. Although the effects of G-CSF on the progression of atherosclerosis are still unclear, there is a possibility that G-CSF will become a promising therapy for ischemic heart diseases.

G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes.

Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.

Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine.

We examined whether granulocyte colony-stimulating factor (G-CSF) prevents cardiac dysfunction and remodeling after myocardial infarction (MI) in large animals. MI was produced by ligation of left anterior descending coronary artery in swine. G-CSF (10 microg/kg/day, once a day) was injected subcutaneously from 24h after ligation for 7 days. Echocardiographic examination revealed that the G-CSF treatment induced improvement of cardiac function and attenuation of cardiac remodeling at 4 weeks after MI. In the ischemic region, the number of apoptotic endothelial cells was smaller and the number of vessels was larger in the G-CSF treatment group than in control group. Moreover, vascular endothelial growth factor was more abundantly expressed and Akt was more strongly activated in the ischemic region of the G-CSF treatment group than of control group. These findings suggest that G-CSF prevents cardiac dysfunction and remodeling after MI in large animals.

Forefront of Na+/Ca2+ exchanger studies: role of Na+/Ca2+ exchanger--lessons from knockout mice.

We used Na+/Ca2+ exchanger (NCX) knockout mice to evaluate the effects of NCX in cardiac function and the infarct size after ischemia/reperfusion injury. The contractile function in NCX KO mice hearts was significantly better than that in wild type (WT) mouse hearts after ischemia/reperfusion and the infracted size was significantly smaller in NCX KO mice hearts compared with that in WT mice hearts. NCX is critically involved in the development of ischemia/reperfusion-induced myocardial injury, and therefore the inhibition of NCX function may contribute to cardioprotection against ischemia/reperfusion injury.

Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization.

Pretreatment with a combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) has been reported to attenuate left ventricular (LV) remodeling after acute myocardial infarction (MI). We here examined whether the cytokine treatment started after MI has also beneficial effects. Anterior MI was created in the recipient mice whose bone marrow had been replaced with that of transgenic mice expressing enhanced green fluorescent protein (GFP). We categorized mice into five groups according to the following treatment: 1) saline; 2) administration of G-CSF and SCF from 5 days before MI through 3 days after; 3) administration of G-CSF and SCF for 5 days after MI; 4) administration of G-CSF alone for 5 days after MI; 5) administration of SCF alone for 5 days after MI. All the three treatment groups with G-CSF showed less LV remodeling and improved cardiac function and survival rate after MI. The number of capillaries, which express GFP, was increased and the number of apoptotic cells was decreased in the border area of all the treatment groups with G-CSF. Even if the cytokine treatment is started after MI, it could prevent LV remodeling and dysfunction after MI--at least in part--through an increase in neovascularization and a decrease in apoptosis in the border area.

Role of Na+-Ca2+ exchanger in myocardial ischemia/reperfusion injury: evaluation using a heterozygous Na+-Ca2+ exchanger knockout mouse model.

We used Na(+)-Ca(2+) exchanger (NCX) knockout mice to evaluate the effects of NCX in cardiac function and the infarct size after ischemia/reperfusion injury. The contractile function in NCX KO mice hearts was significantly better than that in wild type (WT) mice hearts after ischemia/reperfusion and the infarct size was significantly small in NCX KO mice hearts compared with that in WT mice hearts. NCX is critically involved in the development of ischemia/reperfusion-induced myocardial injury and therefore the inhibition of NCX function may contribute to cardioprotection against ischemia/reperfusion injury.

Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction.

Many cytokines have been reported to be increased in human and animal models with cardiovascular diseases. Myocardial infarction (MI) is accompanied with an inflammatory reaction which induces cardiac dysfunction and remodeling. The inflammatory reaction has been investigated in animal models of MI or myocardial ischemia-reperfusion injury. The mechanisms by which cytokine cascade is activated in the infarcted myocardium have been recently elucidated. Several hematopoietic growth factors including interleukin-3 (IL-3), IL-6, granulocyte-macrophage colony-stimulating factors (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) have been reported to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. G-CSF plays a critical role in regulation of proliferation, differentiation, and survival of myeloid progenitor cells. G-CSF also causes a marked increase in the release of hematopoietic stem cells (HSCs) into the peripheral blood circulation, a process termed mobilization. Although cardiac myocytes have been considered as terminally differentiated cells, it has been recently reported that there are many proliferating cardiac myocytes after MI in human heart. After it was demonstrated that bone marrow stem cells (BMSCs) can differentiate into cardiac myocytes, myocardial regeneration has been widely investigated. Recently, G-CSF has been reported to improve cardiac function and reduces mortality after acute MI. Although the mechanism by which G-CSF ameliorates cardiac dysfunction is not fully understood, there is the possibility that G-CSF may regenerate cardiac myocytes and blood vessels through mobilization of BMSCs. In the future, cytokine-mediated regeneration therapy may become to be a novel therapeutic strategy for MI.

[Gene therapy for heart failure].

Pharmacological, device, and surgical therapies can be used in the management of heart failure. Because those conventional therapies are not effective in patients with the most severe heart failure, gene therapy is expected to become a viable alternative. The molecular pathways that contribute to the development of heart failure have been clarified in recent years. Specific molecular interventions have been evaluated in heart failure models, and the results indicate the potential for gene transfer strategies that are customized to target the individual molecular defects responsible for heart failure. Gene transfer studies have shown that modulating calcium homeostasis, manipulating beta-adrenergic receptor signaling, and augmenting cardiomyocyte resistance to apoptosis can be expected to be useful therapeutic modalities.