Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma.

Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.

Great Saphenous Vein Flow Pattern as a Simple Ultrasonographic Sign of Early Recanalization of Deep Vein Thrombosis: A Case Series Report.

We retrospectively examined patients with ultrasonographically occlusive acute proximal deep vein thrombosis (DVT). All patients were categorized into two groups on the basis of whether great saphenous vein (GSV) flow toward the common femoral vein was detected (flow [+]; n=10) or undetected (flow [-]; n=10). We investigated the relationship between the GSV flow pattern and DVT recanalization. Thrombus recanalization, which is defined as diameter reduction to lower than 40% of the vessel diameter, was confirmed in seven of the flow (+), and none of the flow (-). This study proposes that the GSV flow pattern may be a simple marker for the recanalization of proximal occlusive DVT.

Preliminary report on a cost-utility analysis of revascularization by percutaneous coronary intervention for ischemic heart disease.

Few socioeconomic studies have so far reported on revascularization for stable ischemic heart disease in Japan. This study aimed to validate the sensitivity of the health-related quality of life (HRQOL) scale for determining the pathology and medical technology to be used and to validate the application of a cost-utility analysis model. We studied 32 patients who had undergone percutaneous coronary intervention (PCI) (mean age 67.9 ± 7.3 years). For HRQOL, utility and quality of life (QOL) were examined using the EuroQol 5 Dimension (EQ-5D) and EuroQol Visual Analogue Scale (EQ-VAS), respectively. The changes in the utility index before and after PCI were compared between the PCI and coronary angiography (CAG) groups to determine the sensitivity of the EQ-5D that was used to calculate quality-adjusted life years (QALY). Additionally, to estimate the cost-utility of PCI 120 months after the procedure, we analyzed our study results and the results of previous reports using the Markov chain model. The utility index was found to improve in the PCI group (0.08 ± 0.15), whereas it decreased in the CAG group (-0.02 ± 0.11) (p = 0.049). The estimated result of the cost-utility analysis as the increase in utility above baseline level was the expected value, that is, 70,000 US$/QALY. Our findings suggest that QALY may be valid as a utility index in the clinical and economic evaluation of PCI in Japan.

A novel homemade snare, safe, economical and size-adjustable.

AIMS: Snaring has recently been reported as being effective in catching the retrograde guidewire (GW) in retrograde percutaneous coronary intervention (PCI) for chronic total occlusion. However, commercially available snares and previously reported homemade snares have a number of drawbacks, such as additional cost, limited size adjustability, risk of vessel injury and difficult handling. We report here a novel method to create easily an inexpensive, safe and size-adjustable snare. METHODS AND RESULTS: Our newly developed homemade snare consists of a conventional 0.014" GW, a PCI balloon, and a guiding catheter (GC). In most cases, no extra cost is needed. As the snare is created by the soft wire tip, vascular injury is negligible. To adjust the size of the snare loop, the snare wire is simply pulled backwards and pushed forwards. Using this snare technique, we succeeded in the total revascularisation of a CTO in the left main trunk with a retrograde approach. CONCLUSIONS: We report a novel method to create easily an inexpensive, safe and size-adjustable snare, and demonstrate its use in a retrograde CTO intervention. In some cases where a conventional snare is indicated, such as removal of intravascular iatrogenic foreign bodies, this novel homemade snare would be preferable because of its advantages.

Endothelial Gab1 deletion accelerates angiotensin II-dependent vascular inflammation and atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis. METHODS AND RESULTS: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Krüppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice. CONCLUSIONS: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4.

Maximum carotid intima-media thickness improves the prediction ability of coronary artery stenosis in type 2 diabetic patients without history of coronary artery disease.

OBJECTIVE: Carotid intima-media thickness (CIMT), a marker of early atherosclerosis and vascular remodelling, is one of the independent predictors of coronary artery disease (CAD). However, it is unknown whether ultrasonic assessment of carotid atherosclerosis, including CIMT, improves the prediction ability for CAD over and above conventional coronary risk factors in the diabetic patients. METHODS: Ultrasonic scanning of the common carotid artery (CCA), the carotid bulb (Bul), and the internal carotid artery (ICA) was performed. The site with the greatest IMT, including plaque lesions, was sought along the arterial walls and max-IMT (the greatest IMT in the observation-possible areas of the CCA, Bul and ICA) was measured. The association of max-IMT with coronary artery stenosis assessed by coronary computed tomography angiography and the incremental effect of adding max-IMT to the conventional risk factors for predicting coronary artery stenosis were evaluated in 241 asymptomatic type 2 diabetic patients. RESULTS: Multiple logistic regression analyses showed that max-IMT was significantly associated with coronary artery stenosis even after adjustment for conventional risk factors. ROC curve analysis revealed that the AUC significantly increased after addition of max-IMT to conventional coronary risk factors [from 0.64 (95% CI; 0.57-0.71) to 0.74 (95% CI; 0.67-0.80), p = 0.020]. The addition of max-IMT to conventional coronary risk factors increased the AUC in obese patients (from 0.58 to 0.76, p = 0.012) but not in non-obese patients (from 0.68 to 0.72, NS). CONCLUSIONS: In type 2 diabetic patients without apparent cardiovascular disease, the addition of max-IMT to conventional risk factors substantially improves the risk stratification for CAD.

Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-met signaling.

RATIONALE: Grb2-associated binder (Gab) docking proteins, consisting of Gab1, Gab2, and Gab3, have crucial roles in growth factor-dependent signaling. Various proangiogenic growth factors regulate angiogenesis and endothelial function. However, the roles of Gab proteins in angiogenesis remain elusive. OBJECTIVE: To elucidate the role of Gab proteins in postnatal angiogenesis. METHODS AND RESULTS: Endothelium-specific Gab1 knockout (Gab1ECKO) mice were viable and showed no obvious defects in vascular development. Therefore, we analyzed a hindlimb ischemia (HLI) model of control, Gab1ECKO, or conventional Gab2 knockout (Gab2KO) mice. Intriguingly, impaired blood flow recovery and necrosis in the operated limb was observed in all of Gab1ECKO, but not in control or Gab2KO mice. Among several proangiogenic growth factors, hepatocyte growth factor (HGF) induced the most prominent tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 with SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) and phosphatidylinositol 3-kinase subunit p85 in human endothelial cells (ECs). Gab1-SHP2 complex was required for HGF-induced migration and proliferation of ECs via extracellular signal-regulated kinase (ERK)1/2 pathway and for HGF-induced stabilization of ECs via ERK5. In contrast, Gab1-p85 complex regulated activation of AKT and contributed partially to migration of ECs after HGF stimulation. Microarray analysis demonstrated that HGF upregulated angiogenesis-related genes such as KLF2 (Krüppel-like factor 2) and Egr1 (early growth response 1) via Gab1-SHP2 complex in human ECs. In Gab1ECKO mice, gene transfer of vascular endothelial growth factor, but not HGF, improved blood flow recovery and ameliorated limb necrosis after HLI. CONCLUSION: Gab1 is essential for postnatal angiogenesis after ischemia via HGF/c-Met signaling.

Relationship between carotid intima-media thickness and the presence and extent of coronary stenosis in type 2 diabetic patients with carotid atherosclerosis but without history of coronary artery disease.

OBJECTIVE: We examined the relationship between the presence and extent of coronary stenosis and carotid intima-media thickness (CIMT) in type 2 diabetic patients without history of coronary artery disease (CAD) but with carotid atherosclerosis. RESEARCH DESIGN AND METHODS: A total of 91 type 2 diabetic patients underwent multi-slice computed tomography coronary angiography. RESULTS: Max-IMT in the ≥ 50% stenosis group by multi-slice computed tomography coronary angiography estimation was significantly greater than the 0-25 and 25-50% stenosis group (2.68 ± 0.77 vs. 1.61 ± 0.49 mm, P < 0.0005, and 2.14 ± 0.81 mm, P < 0.05, respectively), and max-IMT in the 25-50% stenosis group was significantly greater than the 0-25% stenosis group (P < 0.05) after adjustment for age, sex, duration of type 2 diabetes, hypertension, and dyslipidemia. In the analysis for trend through the categories of max-IMT, as max-IMT increased, the percentage of ≥ 50% stenosis increased and the percentage of 0-25% stenosis decreased. CONCLUSIONS: Our data suggest that max-IMT might be closely associated with the extent of coronary stenosis in type 2 diabetic patients without history of CAD but with carotid atherosclerosis.

SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene.

Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal alpha-actin (alpha-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in alpha-SKA gene expression. Thus, alpha-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of alpha-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in alpha-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes alpha-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate alpha-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2(WT)), dominant-negative SHP2 (SHP2(C/S)), or beta-galactosidase (beta-gal), on alpha-SKA gene expression. LIF did not upregulate alpha-SKA mRNA in cardiomyocytes overexpressing either beta-gal or SHP2(WT). In cardiomyocytes overexpressing SHP2(C/S), LIF induced upregulation of alpha-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2(C/S), but not in myocytes overexpressing beta-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates alpha-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.

Clinical significance of plasma endothelin-1 level after bosentan administration in pulmonary arterial hypertension.

BACKGROUND: Endothelin (ET)-1 has been shown to play a significant pathogenic role in pulmonary arterial hypertension (PAH). However, the pathobiological significance of increased ET-1 concentration after administration of ET receptor antagonist in patients with PAH has not yet been fully examined. METHODS: In 16 PAH patients, plasma ET-1 concentration was measured at 0, 1, 3, 6, and 24h after a single 62.5mg dose of bosentan, a dual ET receptor antagonist, and the peak and 24-h change in ET-1 concentration from baseline were examined. The severity of PAH was evaluated by hemodynamic parameters, 6-min walk distance, New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP). RESULTS: Plasma ET-1 concentration significantly increased from 1.93+/-0.12 to 3.36+/-0.18 pg/ml after bosentan administration in PAH patients (p<0.01). The peak-to-baseline ratio of ET-1 concentration after bosentan administration showed a significant positive correlation with baseline ET-1 concentration (p<0.05). After 4-week bosentan administration, NYHA functional class improved in 7 patients but was not changed in 9 patients. The optimal cut-off point of % change of ET-1 concentration at 24h for discriminating the two groups was 30%. According to this cut-off point, patients were divided into the higher (n=7) and the lower (n=9) groups. NYHA functional class did not change in the lower group, but significantly improved (p<0.01) in the higher group after 4-week bosentan administration. In addition, plasma BNP levels significantly decreased from baseline in the higher group compared with those in the lower group after 12-week bosentan administration (-44+/-11% vs. 7+/-20%, p<0.05). CONCLUSIONS: Although the population in this study is small and heterogeneous, measurement of plasma ET-1 concentration after bosentan administration might predict the responsiveness to bosentan treatment, and be useful in the determination of effective therapy in treatment of PAH patients.

Carbacyclin induces carnitine palmitoyltransferase-1 in cardiomyocytes via peroxisome proliferator-activated receptor (PPAR) delta independent of the IP receptor signaling pathway.

Prostacyclin (PGI2) and its analogues exert cardioprotective effects via the rhodopsin type membrane PGI2 receptor, IP. Peroxisome proliferator-activated receptor (PPAR) delta is a nuclear receptor abundantly expressed in cardiomyocytes and plays a pivotal role in maintaining constitutive mitochondrial fatty acid beta-oxidation (FAO). Recently, a novel signaling pathway of PGI2 via PPARdelta has been demonstrated in non-cardiac tissues. We therefore examined whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARdelta in cardiomyocytes. Intraperitoneal injection of cPGI2 increased CPT-1 mRNA expression in murine hearts. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a concentration-dependent manner, where PPRE has been mapped to the promoter region of the CPT-1 gene. Moreover, the elevation of CPT-1 mRNA expression and PPRE promoter activity by cPGI2 was not abolished by H-89, a potent protein kinase A inhibitor, but was significantly inhibited in cardiomyocytes over-expressing a dominant-negative type of PPARdelta. Furthermore, electrophoretic mobility shift assays demonstrated that binding of PPARdelta to PPRE in the CPT-1 gene promoter is enhanced in response to cPGI2 stimulation. In addition, down-regulation of CPT-1 mRNA expression in cardiomyocytes subjected to hypoxia was attenuated by cPGI2. These results indicate that cPGI2 induces CPT-1 mRNA expression through PPARdelta, independent of the IP receptor signaling pathway, suggesting a possibility that cPGI2 modulates cardiac energy metabolism by activating FAO via PPARdelta.

Effect of bosentan on plasma endothelin-1 concentration in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with high mortality. An orally active dual endothelin (ET) receptor antagonist, bosentan, has been reported to improve exercise capacity and survival in patients with PAH. Plasma ET-1 concentration is known to be increased in PAH patients; however, the effect of bosentan on ET-1 concentration has not yet been investigated. METHODS AND RESULTS: The concentration of ET-1 after bosentan administration was examined in 7 PAH patients, including 2 primary and 5 secondary cases. They were clinically assessed by pulmonary artery pressure (PAP), 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration. Baseline ET-1 concentration was significantly higher in patients with PAH than in normal individuals (2.19+/-0.71 pg/ml vs 1.45+/-0.10 pg/ml, p<0.05) and was significantly correlated with 6MWD and BNP. A single dose of 62.5 mg bosentan in patients with PAH significantly increased plasma ET-1 concentration to 2.04 times the basal concentration (p<0.01) with a peak at 8.1 h. The peak to base ratio of ET-1 after bosentan administration correlated negatively with severity of PAH as assessed by PAP. CONCLUSIONS: The present study is the first study to show that bosentan administration increases plasma ET-1 in patients with PAH. The response of plasma ET-1 to bosentan administration might be useful for determining the severity of PAH.

Sildenafil as adjunct therapy to high-dose epoprostenol in a patient with pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease is refractory to medical treatment and is generally associated with a poor prognosis. Treatment with vasodilators, such as prostacyclin, of patients with PVOD is controversial because of concerns regarding hemodynamic deterioration. Although a preferential pulmonary vasodilatory effect of a specific phosphodiesterase-5 inhibitor, sildenafil, has recently been reported in patients with primary pulmonary hypertension, little information is available regarding the effect of sildenafil on patients with pulmonary veno-occlusive disease. In the present case, remarkable improvement of hemodynamics and of clinical course was produced by adjunctive use of oral sildenafil in association with intravenous high-dose epoprostenol. These findings suggest that sildenafil may be a therapeutic option in the medical treatment of pulmonary veno-occlusive disease.

Cross-talk between bone morphogenetic protein 2 and leukemia inhibitory factor through ERK 1/2 and Smad1 in protection against doxorubicin-induced injury of cardiomyocytes.

The survival of cardiomyocytes is regulated by growth factors and cytokines such as bone morphogenetic protein (BMP) 2 and leukemia inhibitory factor (LIF). BMP2 and LIF induce distinct signal transduction pathways that each activate a different transcription factor [Smad1 and signal transducing activating transcriptional factor (Stat) 3, respectively] and common signal pathway [mitogen-activated protein kinase (MAPK)]. We previously demonstrated that BMP2 and LIF protect cardiomyocytes via Smad1 and STAT3 signaling pathways, respectively. On the other hand, these signals are known to act in synergy via synergistic integration of signaling pathways. Here, we examined interaction between BMP2 and LIF in primary cultured neonatal rat cardiomyocytes. LIF sustained phosphorylation/activation of Smad1 by BMP2. The role of extracellular signal-regulated kinase (ERK) 1/2 cascade activated by LIF was highlighted by the use of a MAPK/ERK kinase (MEK) 1/2 inhibitor, U0126, or overexpression of dominant-negative form of MEK1 that abolished sustained phosphorylation of Smad1 and cell survival effect induced by co-stimulation of LIF with BMP2, while BMP2 alone did not activate ERK1/2. Conversely, overexpression of the constitutive-active form of MEK1 increased BMP2-induced phosphoration of Smad1 without additional LIF. Moreover, BMP2 and LIF synergistically induced bcl-xL mRNA in doxorubicin (DOX)-injured cardiomyocytes. These findings suggest that the ERK1/2 pathway downstream of LIF is involved in sustained phosphorylation/activation of Smad1 by BMP2 and provide a possible mechanism for cooperation between intracellular signals activated by LIF and BMP2 in protection against DOX-induced injury of cardiomyocytes.

AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress.

Oxygen deprivation leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), causing ER stress. Under conditions of ER stress, inhibition of protein synthesis and up-regulation of ER chaperone expression reduce the misfolded proteins in the ER. AMP-activated protein kinase (AMPK) is a key regulatory enzyme involved in energy homeostasis during hypoxia. It has been shown that AMPK activation is associated with inhibition of protein synthesis via phosphorylation of elongation factor 2 (eEF2) in cardiomyocytes. We therefore examined whether AMPK attenuates hypoxia-induced ER stress in neonatal rat cardiomyocytes. We found that hypoxia induced ER stress, as assessed by the expression of CHOP and BiP and cleavage of caspase 12. Knockdown of CHOP or caspase 12 through small interfering RNA (siRNA) resulted in decreased expression of cleaved poly(ADP-ribose) polymerase following exposure to hypoxia. We also found that hypoxia-induced CHOP expression and cleavage of caspase 12 were significantly inhibited by pretreatment with 5-aminoimidazole-4-carboxyamide-1-beta-D-ribofuranoside (AICAR), a pharmacological activator of AMPK. In parallel, adenovirus expressing dominant-negative AMPK significantly attenuated the cardioprotective effects of AICAR. Knockdown of eEF2 phosphorylation using eEF2 kinase siRNA abolished these cardioprotective effects of AICAR. Taken together, these findings demonstrate that activation of AMPK contributes to protection of the heart against hypoxic injury through attenuation of ER stress and that attenuation of protein synthesis via eEF2 inactivation may be the mechanism of cardioprotection by AMPK.

Smad1 protects cardiomyocytes from ischemia-reperfusion injury.

BACKGROUND: We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury. METHODS AND RESULTS: The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the alpha-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene-positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and beta-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT. CONCLUSIONS: These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.

Solitary right ventricle metastasis by renal cell carcinoma.

A 57-year-old man with a history of renal cell carcinoma presented with presyncope. He underwent nephrectomy years earlier followed by HLA-matched allogeneic peripheral-blood stem-cell transplantation. Echocardiographic investigation revealed a solitary right ventricle mass without contiguous vena caval or right atrial involvement. The mass was pathologically confirmed to be metastatic carcinoma in the right ventricular cavity. This case highlights the need to consider an underlying neoplastic syndrome in patients presenting isolated right ventricle mass by echocardiography.

Detection of TIMI-3 flow before mechanical reperfusion with ultrasonic tissue characterization in patients with anterior wall acute myocardial infarction.

BACKGROUND: Spontaneous coronary reperfusion with TIMI-3 flow is associated with favorable clinical outcomes in patients with acute myocardial infarction (AMI). We investigated the ability of analyzing cardiac cycle-dependent variation of myocardial integrated backscatter (IBS) for predicting spontaneous reperfusion in anterior AMI. METHODS AND RESULTS: We recorded IBS images on admission in 104 patients with first anterior wall AMI and subsequently performed coronary angiography and coronary intervention. We measured the cyclic variation of IBS within the infarct zone and expressed its magnitude as phase-corrected magnitude (PCM) by giving positive and negative values when it showed synchronous and asynchronous contraction, respectively. Twenty-three patients showing TIMI-3 flow at the initial coronary angiography had smaller peak creatine kinase value than 57 patients with initial TIMI-0/1 flow (864+/-961 versus 2358+/-1757 IU/L; P=0.0002) and better percent wall thickening within risk area (36.1+/-15.1%) than those with TIMI-2 (16.7+/-12.8%, P<0.0001) or TIMI-0/1 (5.1+/-11.6, P<0.0001). The patients with initial TIMI-3 had higher PCM (2.7+/-1.3 dB) than those with TIMI-2 (-0.3+/-2.2 dB, P<0.0001) or those with TIMI-0/1 (-1.1+/-2.4 dB, P<0.0001). Using PCM=1.0 dB as the cutoff point, PCM detected TIMI-3 flow with 95.7% sensitivity and 90.1% specificity. Multivariable logistic regression analysis revealed that only PCM is an independent predictor for spontaneous reperfusion among the hemodynamic, echocardiographic, and electrocardiographic variables. CONCLUSIONS: Analysis of myocardial IBS could detect spontaneous reperfusion noninvasively in the emergent stage of anterior AMI.

Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction.

OBJECTIVES: We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). BACKGROUND: Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. METHODS: A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom onset. Two-dimensional echocardiography was recorded on day 1 and three months later to determine the change in the wall motion score (DeltaWMS; sum of 16 segmental scores; dyskinesia = 4 to normokinesia = 0). RESULTS: The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose level on hospital admission was significantly higher than that of patients who did not exhibit this phenomenon (209 +/- 79 vs. 159 +/- 56 mg/dl; p < 0.0001). There was no difference in glycosylated hemoglobin or in the incidence of diabetes mellitus between the two subsets. The no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia (>/=160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2,497 +/- 1,603 vs. 1,804 +/- 1,300 IU/l; p = 0.005) and a lower DeltaWMS (3.7 +/- 4.8 vs. 5.7 +/- 4.3; p = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the culprit lesion, and anterior AMI. CONCLUSIONS: Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.