Anaphylactic Shock Due to Technetium (99mTc)-Tetrofosmin During Myocardial Perfusion Scintigraphy: A Case Report.

Myocardial perfusion scintigraphy is a popular minimally invasive method for evaluating chronic coronary disease (CCD). We performed myocardial scintigraphy to assess CCD in a 74-year-old man with a history of allergy to contrast media. The patient developed anaphylactic shock immediately after the administration of the technetium (99mTc)-tetrofosmin preparation. This is the first report of anaphylactic shock due to 99mTc-tetrofosmin administration during myocardial perfusion scintigraphy.

Balloon venoplasty for disdialysis syndrome due to pacemaker-related superior vena cava syndrome with chylothorax post-bacteraemia: A case report.

BACKGROUND: Although superior vena cava (SVC) syndrome has also been reported as a late complication of pacemaker (PM) implantation, acute onset of SVC syndrome caused by disdialysis syndrome in patients with PM implantation is very rare. There are no specific therapies or guidelines. CASE SUMMARY: A 96-year-old woman receiving dialysis was implanted with a PM due to sick sinus syndrome. She was referred to our facility for chest discomfort experienced during dialysis. Upon examination, unilateral pleural effusion on the right side was cloudy with a foul odour. The patient was diagnosed with pyothorax and treated with antibiotics. After the effusion was reduced, it gradually reaggravated and remained cloudy. In this case, SVC syndrome, which is generally considered a late complication after PM implantation, rapidly developed following the bacteraemia, resulting in impaired venous return, chylothorax, and disdialysis syndrome. After catheter intervention for SVC stenosis, the patient's symptoms promptly improved. The patient has been recurrence-free for a year. CONCLUSION: Acute SVC syndrome can cause dysdialysis in PM-implanted patients. Catheter intervention alone has improved this condition for a traceable period.

Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23) Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23) is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK) activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus.

Loss of apoptosis regulator through modulating IAP expression (ARIA) protects blood vessels from atherosclerosis.

Atherosclerosis is the primary cause for cardiovascular disease. Here we identified a novel mechanism underlying atherosclerosis, which is provided by ARIA (apoptosis regulator through modulating IAP expression), the transmembrane protein that we recently identified. ARIA is expressed in macrophages present in human atherosclerotic plaque as well as in mouse peritoneal macrophages. When challenged with acetylated LDL, peritoneal macrophages isolated from ARIA-deficient mice showed substantially reduced foam cell formation, whereas the uptake did not differ from that in wild-type macrophages. Mechanistically, loss of ARIA enhanced PI3K/Akt signaling and consequently reduced the expression of acyl coenzyme A:cholesterol acyltransferase-1 (ACAT-1), an enzyme that esterifies cholesterol and promotes its storage, in macrophages. Inhibition of PI3K abolished the reduction in ACAT-1 expression and foam cell formation in ARIA-deficient macrophages. In contrast, overexpression of ARIA reduced Akt activity and enhanced foam cell formation in RAW264.7 macrophages, which was abrogated by treatment with ACAT inhibitor. Of note, genetic deletion of ARIA significantly reduced the atherosclerosis in ApoE-deficient mice. Oil red-O-positive lipid-rich lesion was reduced, which was accompanied by an increase of collagen fiber and decrease of necrotic core lesion in atherosclerotic plaque in ARIA/ApoE double-deficient mice. Analysis of bone marrow chimeric mice revealed that loss of ARIA in bone marrow cells was sufficient to reduce the atherosclerogenesis in ApoE-deficient mice. Together, we identified a unique role of ARIA in the pathogenesis of atherosclerosis at least partly by modulating macrophage foam cell formation. Our results indicate that ARIA could serve as a novel pharmacotherapeutic target for the treatment of atherosclerotic diseases.

Aging differentially alters the expression of angiogenic genes in a tissue-dependent manner.

Organ functions are altered and impaired during aging, thereby resulting in increased morbidity of age-related diseases such as Alzheimer's disease, diabetes, and heart failure in the elderly. Angiogenesis plays a crucial role in the maintenance of tissue homeostasis, and aging is known to reduce the angiogenic capacity in many tissues. Here, we report the differential effects of aging on the expression of angiogenic factors in different tissues, representing a potentially causes for age-related metabolic disorders. PCR-array analysis revealed that many of angiogenic genes were down-regulated in the white adipose tissue (WAT) of aged mice, whereas they were largely up-regulated in the skeletal muscle (SM) of aged mice compared to that in young mice. Consistently, blood vessel density was substantially reduced and hypoxia was exacerbated in WAT of aged mice compared to that in young mice. In contrast, blood vessel density in SM of aged mice was well preserved and was not different from that in young mice. Moreover, we identified that endoplasmic reticulum (ER) stress was strongly induced in both WAT and SM during aging in vivo. We also found that ER stress significantly reduced the expression of angiogenic genes in 3T3-L1 adipocytes, whereas it increased their expression in C2C12 myotubes in vitro. These results collectively indicate that aging differentially affects the expression of angiogenic genes in different tissues, and that aging-associated down-regulation of angiogenic genes in WAT, at least in part through ER stress, is potentially involved in the age-related adipose tissue dysfunction.

Manipulation of cardiac phosphatidylinositol 3-kinase (PI3K)/Akt signaling by apoptosis regulator through modulating IAP expression (ARIA) regulates cardiomyocyte death during doxorubicin-induced cardiomyopathy.

PI3K/Akt signaling plays an important role in the regulation of cardiomyocyte death machinery, which can cause stress-induced cardiac dysfunction. Here, we report that apoptosis regulator through modulating IAP expression (ARIA), a recently identified transmembrane protein, regulates the cardiac PI3K/Akt signaling and thus modifies the progression of doxorubicin (DOX)-induced cardiomyopathy. ARIA is highly expressed in the mouse heart relative to other tissues, and it is also expressed in isolated rat cardiomyocytes. The stable expression of ARIA in H9c2 cardiac muscle cells increased the levels of membrane-associated PTEN and subsequently reduced the PI3K/Akt signaling and the downstream phosphorylation of Bad, a proapoptotic BH3-only protein. When challenged with DOX, ARIA-expressing H9c2 cells exhibited enhanced apoptosis, which was reversed by the siRNA-mediated silencing of Bad. ARIA-deficient mice exhibited normal heart morphology and function. However, DOX-induced cardiac dysfunction was significantly ameliorated in conjunction with reduced cardiomyocyte death and cardiac fibrosis in ARIA-deficient mice. Phosphorylation of Akt and Bad was substantially enhanced in the heart of ARIA-deficient mice even after treatment with DOX. Moreover, repressing the PI3K by cardiomyocyte-specific expression of dominant-negative PI3K (p110α) abolished the cardioprotective effects of ARIA deletion. Notably, targeted activation of ARIA in cardiomyocytes but not in endothelial cells reduced the cardiac PI3K/Akt signaling and exacerbated the DOX-induced cardiac dysfunction. These studies, therefore, revealed a previously undescribed mode of manipulating cardiac PI3K/Akt signaling by ARIA, thus identifying ARIA as an attractive new target for the prevention of stress-induced myocardial dysfunction.

Macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells.

Vascular calcification is a major risk factor for the cardiovascular disease, yet its underlying molecular mechanisms remain to be elucidated. Recently, we identified that osteogenic signals via bone morphogenetic protein (BMP)-2 exerted by vascular smooth muscle cells (VSMCs) play a crucial role in the formation of atherosclerotic plaque calcification. Here we report a synergistic interaction between macrophages and VSMCs with respect to plaque calcification. Treatment with conditioned medium (CM) of macrophages dramatically enhanced BMP-2 expression in VSMCs, while it substantially reduced the expression of matrix Gla-protein (MGP) that inhibits the BMP-2 osteogenic signaling. As a result, macrophages significantly accelerated the osteoblastic differentiation of C2C12 cells induced by VSMC-CM. In contrast, macrophage-CM did not enhance the osteoblastic gene expressions in VSMCs, indicating that macrophages unlikely induced the osteoblastic trans-differentiation of VSMCs. We then examined the effect of recombinant TNF-α and IL-1ß on the VSMC-derived osteogenic signals. Similar to the macrophage-CM, both cytokines enhanced BMP-2 expression and reduced MGP expression in VSMCs. Nevertheless, only the neutralization of TNF-α but not IL-1ß attenuated the effect of macrophage-CM on the expression of these genes in VSMCs, due to the very low concentration of IL-1ß in the macrophage-CM. On the other hand, VSMCs significantly enhanced IL-1ß expression in macrophages, which might in turn accelerate the VSMC-mediated osteogenic signals. Together, we identified a unique role of macrophages in the formation of plaque calcification in coordination with VSMCs. This interaction between macrophages and VSMCs is a potential therapeutic target to treat and prevent the atherosclerotic plaque calcification.

Importance of measuring the fractional flow reserve in patients receiving hemodialysis.

Angiography is not always an accurate indicator of physiologically significant stenosis. We examined the usefulness of functional evaluation of coronary stenosis severity by determining the fractional flow reserve (FFR) using a pressure wire in patients who received hemodialysis with angiographically intermediate lesions. We recruited 44 patients with intermediate lesions; of these, 22 were undergoing hemodialysis while 22 were not. Quantitative coronary angiography (QCA) was performed to measure the minimal lumen diameter (MLD) and calculate the percent diameter stenosis (%DS). The FFR was calculated as the ratio of the coronary pressure at the distal stenotic site to the mean aortic pressure during maximum hyperemia. In each group, we investigated the relationship between the FFR and %DS and FFR and MLD. The patients in the hemodialysis group were significantly younger and had more calcified and type B2/C lesions than those in the non-dialysis group. Although the FFR was correlated with both %DS (r = 0.71, p < 0.01) and MLD (r = 0.58, p < 0.01) in the non-dialysis group, the FFR was not correlated with either MLD or %DS in the hemodialysis group. In the hemodialysis group, there was a discordance between the QCA- and FFR-based assessments of the severity of coronary stenosis. In patients receiving hemodialysis, both anatomical and functional assessments should be conducted to determine the physiological significance of the stenosis accurately.

[Clinical characteristics of patients diagnosed as high cardiac event probability by "Heart Risk View"].

"Heart Risk View" is the software to evaluate the cardiac event probability, and it is based on the results of the prospective cohort study (J-ACCESS). We examined the usefulness of this software. Study population consisted of 83 patients, who were diagnosed that cardiac event probability was over 20% by "Heart Risk View." During the follow-up period (596 +/- 356 days), cardiac event occurred in 23 patients (27.7%), including 7 patients death. No significant differences were observed in the ejection fraction by Quantitative Gated SPECT, total defect score calculated from SPECT, and the percentage of stress perfusion abnormality detected by SPECT between event and non-event groups. However, the percentage of cardiac revascularization therapy based on the SPECT was significantly lower in the event group (9 vs. 38%, p = 0.03). In conclusion, cardiac event probability calculated by "Heart Risk View" was reliable in our study cohort. Cardiac event strongly depended on the cardiac ischemia, for which the therapy was difficult because of lesion complexity or combined diseases.

A case report: 201Tl/99mTc-Pyrophosphate dual-isotope myocardial SPECT for detecting annular subendocardial infarction induced by a transient shock.

The patient was a 74-year-old woman with angina pectoris, who had undergone percutaneous coronary intervention with stent placement in the right coronary artery on October 2, 2007. On November 12 of the same year, she suffered from paroxysmal atrial fibrillation. She was treated with pilsicainide hydrochloride administered by intravenous injection, which was followed by a sudden sinus standstill, with marked bradycardia and a shock state. The patient was then treated with a catecholamine, however, the shock state persisted for about an hour. An electrocardiogram revealed persistent ST depression in leads V4-6 along with elevation of the serum creatinine kinase. A coronary angiography performed on the admission day revealed no abnormality. On the third hospital day, a dual-isotope myocardial SPECT using 201Tl and 99mTc-pyrophosphate demonstrated an annular accumulation of 99mTc-pyrophosphate concordant with the endocardium from apex to the mid-portion of the left ventricle, suggestive of subendocardial infarction. The case is reported here, as there are few reports of subendocardial infarction developing due to ischemia arising from a shock state.