Clinical characteristics of silent myocardial ischemia diagnosed with adenosine stress 99mTc-tetrofosmin myocardial scintigraphy in Japanese patients with acute cerebral infarction.

It is well known that silent myocardial ischemia (SMI) often complicates patients with cerebral infarction and that stroke patients often die of ischemic heart disease. Therefore, it is considered important to treat myocardial ischemia in stroke patients. This study investigated SMI complicating Japanese patients with fresh stroke, using (99m)Tc-tetrofosmin myocardial scintigraphy with pharmacologic stress testing to elucidate their clinical manifestations. This study included 41 patients (26 men, mean age 76.0 ± 10.7 years) with acute cerebral infarction and no history of coronary artery disease. All patients underwent (99m)Tc-tetrofosmin myocardial scintigraphy with intravenous administration of adenosine to diagnose SMI. Of the 41 patients, myocardial ischemia was confirmed in 17 patients (41.5%). Atherosclerotic etiology was the major cause of stroke in the ischemia(+) group and embolic origin was the major cause in the ischemia(-) group. Patients with myocardial ischemia had a higher incidence of diabetes mellitus (52.9 vs 20.8%; P = 0.0323) and more than two conventional cardiovascular risk factors (64.7 vs 25.0%; P = 0.0110) compared with the nonischemic patients. Infarction subtype of atherosclerotic origin was an independent positive predictor of asymptomatic myocardial ischemia in patients with stroke. These findings indicate that the prevalence of asymptomatic myocardial ischemia is relatively high, especially in patients with stroke of atherosclerotic origin. Therefore, it is beneficial for us to narrow the target population who are at the highest risk when screening for SMI in Japanese patients with acute cerebral infarction.

Effective surgical treatment for controlling the acute heart failure induced by acutely progressed mitral regurgitation with nonbacterial thrombotic endocarditis.

A 45-year-old woman complaining of consciousness disturbance demonstrated multiple brain infarctions. Echocardiogram showed vegetation on the posterior mitral leaflet. Infectious endocarditis was initially suspected and we started empirical antibiotics. However, mitral vegetation grew rapidly and caused severe mitral regurgitation. Acute heart failure was so poorly controlled by conservative treatment that we concluded cardiac surgery was indicated. Mitral valve replacement was safely performed, and there was no sign of heart failure or recurrent thromboembolism during the postoperative course. Thereafter, multiple hepatic masses and a solid lesion in the pancreatic head were detected by computed tomography. The patient finally died of multiple organ failure that presumably resulted from malignancy in the terminal stage. The clinical course of this case can be explained by the pathology of nonbacterial thrombotic endocarditis (NBTE). The standard treatment for NBTE consists of systemic anticoagulation as well as controlling the underlying malignancy. However, we could not diagnose this case as NBTE before surgery. Although mitral valve replacement was finally effective to control acute heart failure in this case, NBTE should be exactly diagnosed as quickly as possible and the treatment policy should be deliberated.

Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways.

RATIONALE: It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1beta has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined. OBJECTIVE: We studied the role of hypertrophy signal-mediated IL-1beta/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure. METHODS AND RESULTS: Pressure overload was performed by aortic banding in IL-1beta-deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1beta-deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (approximately 50%) decreased in the IL-1beta-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1beta and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1beta-deficient CFs. IL-1beta released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1beta activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1beta deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them. CONCLUSIONS: We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1beta, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.

Nicorandil regulates Bcl-2 family proteins and protects cardiac myocytes against hypoxia-induced apoptosis.

Nicorandil has been shown to inhibit myocyte apoptosis by opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and nitrate-like effect against oxidative stress. However, the detailed mechanism of nicorandil-mediated cardioprotection under hypoxic conditions remains to be largely unknown. The present study examined whether nicorandil can inhibit apoptosis via regulation of Bcl-2 family proteins in hypoxic myocytes. Neonatal rat cardiac myocytes were exposed to hypoxia for 7 hours. Hypoxia-induced myocyte apoptosis (13.9+/-0.9%) under glucose-rich conditions. Myocyte apoptosis was accompanied by loss of mitochondrial membrane potential (Deltapsi(m)), cytochrome c release from mitochondria into cytosol, and activation of caspase-3. Hypoxia also significantly increased Bax and decreased Bcl-2 mRNA and protein expression, thereby increasing Bax/Bcl-2 ratio. Nicorandil 100 micromol/l significantly decreased the percentage of apoptotic myocytes (7.2+/-0.5%) by inhibiting loss of Deltapsi(m) and translocation of cytochrome c. These effects of nicorandil were partially but significantly inhibited by cotreatment of either 500 micromol/l 5-hydroxydecanoate, a selective mitoK(ATP) channel antagonist, or 10 micromol/l 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Moreover, nicorandil significantly inhibited the hypoxia-induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria. These effects of nicorandil in Bax and Bcl-2 expression were significantly blunted by cotreatment of ODQ and 5-HD, respectively. Cotreatment of KT5823, an inhibitor of protein kinase G, significantly blocked the effect of nicorandil on Bax expression and 8-bromo-cyclic guanosine 3',5' monophosphate (8-bromo-cGMP), a cGMP analog, mimicked the effect of nicorandil on Bax expression. The present study demonstrates that nicorandil regulates Bcl-2 family proteins via opening of mitoK(ATP) channels and nitric oxide-cGMP signaling and inhibits hypoxia-induced mitochondrial death pathway.

[Assessment of microcirculation disturbance in patients with coronary ectasia by ATP-loading 99mTc-tetrofosmin myocardial SPECT].

UNLABELLED: Patients with coronary ectasia often develop chest pain and reveal ischemic changes on electrocardiograms and reduced left ventricular wall motion on left ventriculography, in the absence of epicardial coronary artery stenotic regions. We examined the disturbances in the coronary microcirculation in patients with coronary ectasia using left ventriculography and ATP loading 99mTc-tetrofosmin myocardial single photon emission computed tomography (SPECT) before and after administration of a coronary vasodilator and antiplatelet agents. METHODS: Twenty patients in whom coronary angiography revealed diffuse coronary artery ectasia but no stenotic regions were enrolled in this study. Left ventriculography and ATP loading 99mTc-tetrofosmin myocardial SPECT were performed before and after administration of the coronary vasodilator, nicorandil, as well as that of the antiplatelet agents, aspirin and ticlopidine. RESULTS: (1) The ejection fraction in left ventriculography was 48.3 +/- 17.4% before, and 56.6 +/- 18.3% after the drug administration, the ejection fraction was improved after the drug administration (p < 0.05). (2) Before the drug administration, the total defect scores on 99mTc-tetrofosmin myocardial SPECT were 5.9 +/- 3.1 and 8.8 +/- 2.7 in the ATP-loading and rest images, respectively (p < 0.05), and the corresponding scores after the drug administration were 4.1 +/- 3.0 and 5.4 +/- 3.1, respectively (N.S.). Thus, the total defect scores in the ATP-loading and rest images improved after the drug administration (p < 0.05). CONCLUSION: Myocardial damage in patients with coronary ectasia might be induced by microthrombotic embolism and microcirculation disturbance.