Susumu Nishikawa

Aldosterone Directly Induces Myocyte Apoptosis Through Calcineurin-Dependent Pathways

Background—Aldosterone has recently attracted considerable attention for its involvement in the pathophysiology of heart failure, in which apoptotic cell loss plays a critical role. This study examined whether aldosterone directly induces myocyte apoptosis via its specific receptors. Methods and Results—Neonatal rat cardiac myocytes were exposed to aldosterone (10−8 to 10−5 mol/L). Nuclear staining with Hoechst 33258 showed that aldosterone induced myocyte apoptosis in a dose- and time-dependent fashion. Treatment of myocytes with 10−5 mol/L aldosterone significantly increased the percentage of apoptosis (15.5±1.4%) compared with serum-deprived control (7.3±0.6%). Radio ligand binding assay revealed the existence of plasma membrane receptor with high affinity (Kd, 0.2 nmol/L) for aldosterone in cardiac myocytes but not in fibroblasts. Aldosterone rapidly (≈30 seconds) mobilized [Ca2+]i that was blocked by neomycin. Aldosterone induced dephosphorylation of the proapoptotic protein Bad, enhancement of mitochondrial permeability transition, decrease in mitochondrial membrane potential, and release of cytochrome c from the mitochondria into the cytosol with concomitant activation of caspase-3. These effects of aldosterone were inhibited by concurrent treatment with either an L-type Ca2+ channel antagonist, nifedipine, or inhibitors for the Ca2+-dependent phosphatase calcineurin, cyclosporin A and FK506. Conclusions—The present study demonstrates for the first time that the specific plasma membrane receptor (coupled with phospholipase C) for aldosterone is present on cardiac myocytes and that aldosterone accelerates the mitochondrial apoptotic pathway through activation of calcineurin and dephosphorylation of Bad, suggesting that the proapoptotic action of aldosterone may directly contribute to the progression of heart failure.

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-1&bgr; 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-1&bgr;/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-1&bgr;–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-1&bgr;–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 (≈50%) decreased in the IL-1&bgr;–deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1&bgr; and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1&bgr;–deficient CFs. IL-1&bgr; 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-1&bgr; activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1&bgr; 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-1&bgr;, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

Aldosterone antagonists have been reported to prevent ventricular remodeling after myocardial infarction (MI) via their action to extracellular matrix (ECM). However, it remains largely unknown whether aldosterone antagonists attenuate myocyte loss in the remodeling process. The present study examined whether spironolactone prevents myocyte apoptosis and improves post-infarct ventricular remodeling in rats. MI was achieved by permanent occlusion of the left coronary artery. Administration of spironolactone (100 mg/kg/day) was started immediately after MI. Sprague-Dawley rats were divided into four groups: 1) sham, 2) spironolactone-treated sham, 3) untreated MI, 4) spironolactone-treated MI. Echocardiographic parameters (left ventricular [LV] diastolic dimension [LVDd], fractional shortening [%FS]), hemodynamic parameters (LV systolic pressure [LVSP], LV end-diastolic pressure [LVEDP], dP/dtmax and dP/dtmin) and collagen accumulation quantitated by Massons Trichrome staining were significantly improved in the spironolactone-treated MI group on the 14th day, compared with the untreated MI group. Moreover, the percentage of apoptotic myocytes evaluated by terminal deoxynucleotide transferase–mediated dUTP nick end labeling (TUNEL) assay was significantly lower in the spironolactone-treated MI group on the 2nd (3.54% vs. 5.79% in untreated MI group), 7th (0.65% vs. 1.37% in untreated MI group) and 14th days (0.11% vs. 0.16% in untreated MI group). Real time reverse transcription–polymerase chain reaction (RT-PCR) analysis showed that the expression of mineralocorticoid receptor (MR) mRNA and that of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) mRNA, which is known to confer aldosterone selectivity on MR, were upregulated in the untreated MI group, and that spironolactone significantly suppressed the expression of these genes. Moreover, spironolactone significantly inhibited aldosterone-induced apoptosis in cultured rat cardiac myocytes in a dose-dependent fashion. Our study demonstrates that, in addition to their effect on ECM, aldosterone antagonists inhibit myocyte apoptosis and prevent post-infarct ventricular remodeling by modulating the expression levels of MR and 11β-HSD2, which are enhanced in the remodeling heart.

Subacutely progressed extensive aortic dissection complicated with catheter-induced dissection in left main coronary artery.

A 64-year-old man complaining of resting angina underwent emergent coronary angiogram and significant stenosis in the mid-left anterior descending artery was discovered. Although deployment of the drug-eluting Cypher stent relieved the stenosis, the guiding catheter accidentally induced coronary dissection in the left main coronary artery (LMCA). Then, deployment of another Cypher stent at the lesion successfully managed the complication. 20 days later, although asymptomatic, extensive aortic dissection was detected from the coronary sinus of Valsalva to the femoral artery. 64-Row multidetector computed tomography demonstrated that the dissection originated from the LMCA and retrogradely expanded to the aorta. This type of dissection is a rare complication related to coronary intervention and even in such a clinical setting, asymptomatic delayed progression of retrograde aortic dissection has not previously been reported to our knowledge.

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 99mTc-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 99mTc-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.

Clinical manifestations and effects of primary percutaneous coronary intervention for patients with delayed pre-hospital time in acute myocardial infarction

BACKGROUND Prolonged pre-hospital time for acute myocardial infarction (AMI) is associated with decreased indication for primary percutaneous coronary intervention (PCI). However, the efficacy of primary PCI in AMI patients with prolonged pre-hospital time has not been fully investigated in Japan. METHODS AND RESULTS A total of 3010 consecutive AMI patients admitted to AMI-Kyoto Multi-Center Risk Study Group hospitals were retrospectively analyzed, and the clinical characteristics and in-hospital prognosis of these patients were reviewed. Patients with pre-hospital delay [elapsed time (ET)>12 h] had a lower frequency of Killip≥3 (9.3%) and less frequently received primary PCI (77.7%) compared with patients with ET≤12 h. In the ET>12 h group, older patients or patients with MI history tended to be complicated by heart failure. Primary PCI was performed for patients with ET>12 h, irrespective of the severity of heart failure [Killip 1 (78.7%) vs Killip≥2 (74.0%); p=0.3827]. On multivariate logistic regression analysis, age [odds ratio (OR) 1.053], MI history (OR 2.860), Killip≥2 (OR 10.235), and multi-vessels or left main coronary artery as culprit (OR 11.712) were significant independent positive predictors of in-hospital mortality for patients with ET>12 h. Practice of primary PCI was not a significant negative predictor for patients with ET>12 h (OR 0.812), but it was for patients with ET≤12 h (OR 0.425). CONCLUSIONS These findings indicate that patients with ET>12 h have a less severe condition and less frequently receive primary PCI compared with patients with ET≤12 h. Although primary PCI is often performed for these patients irrespective of the severity of heart failure, no preferable effect of primary PCI on the in-hospital mortality is demonstrated. In contrary, practice of primary PCI is a significant negative predictor of in-hospital mortality for patients with ET≤12 h.

Increasing myocardial123I-BMIPP uptake in non-ischemic area in a patient with acute myocardial ischemia

The subject was a 65-year-old woman with chest pain. An electrocardiogram revealed T-wave-inversion in leads III, aVF, V1–V5.99mTc-tetrofosmin myocardial SPECT showed mildly reduced uptake in the anteroseptal wall and the apex. These findings suggested acute myocardial ischemia. Coronary angiography did not show any stenotic lesions, but diffuse coronary ectasia was noted in three vessels. Coronary flow velocity was remarkably reduced on coronary angiography. Epicardial coronary spasm was not provoked by ergonovine loading test. Left ventriculography showed diffuse hypokinesis.123I-BMIPP myocardial SPECT showed mildly reduced uptake in the anteroseptal wall and the apex on the early images. But 4-hour delayed images showed an increase of 8% in myocardial123I-BMIPP uptake. We treated this patient with ticlopidine and nicorandil. After drug therapy her symptoms and left ventriculography improved.123I-BMIPP myocardial SPECT findings on the early images improved, whereas delayed images showed a decrease of 28% in myocardial123I-BMIPP uptake after two weeks and 36% after four weeks. These dynamic changes in123I-BMIPP findings might be a reflection of myocardial fatty acid metabolism in patients with acute myocardial ischemia. Delayed123I-BMIPP myocardial SPECT images are useful for the assessment of fatty acid metabolism.

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.