Takeshi Kashimura

Spatiotemporal changes of coxsackievirus and adenovirus receptor in rat hearts during postnatal development and in cultured cardiomyocytes of neonatal rat

Coxsackievirus B is the most common cause of viral myocarditis and is particularly virulent in neonates and children. Adenovirus is also a leading cause of the disease. The determinant of tropism for both viruses is considered to be the expression of coxsackievirus and adenovirus receptor (CAR) in target organs. However, developmental change and physiological localization of CAR in the heart are unknown. We examined expression levels of CAR in rat hearts by quantitative real-time polymerase chain reaction and Western blot analysis and found that CAR decreased gradually during postnatal development, although CAR was detectable, even in adults. Immunohistochemistry revealed CAR on the whole surface of cardiomyocytes in immature rat hearts. In contrast, CAR was detected predominantly on intercalated disks in the adult heart and was accumulated especially at the contact point between the cultured cardiomyocytes, even though they were prepared from the neonatal rat heart. In conclusion, CAR was expressed abundantly on the whole surface of cardiomyocytes in immature rat hearts. Both the expression level and the localization of CAR are possible determinants of the susceptibility to viral myocarditis of neonates and children.

Guidewire-induced coronary artery perforation treated with transcatheter delivery of subcutaneous tissue.

In three cases of small coronary artery perforation by guidewires during percutaneous coronary intervention, coronary leakage continued despite prolonged balloon inflation and reversal of heparin. Subcutaneous tissue was selectively delivered to perforated vessels by means of microcatheters in a successful attempt to stop leakage. This method appears to be extremely effective for treating guidewire‐induced perforations of distal coronary arteries.

Amiodarone Improves Cardiac Sympathetic Nerve Function to Hold Norepinephrine in the Heart, Prevents Left Ventricular Remodeling, and Improves Cardiac Function in Rat Dilated Cardiomyopathy

Background—It is unclear how amiodarone therapy exerts its effects on left ventricular remodeling and cardiac sympathetic nerve function in chronic heart failure. We investigated long-term effects of amiodarone on rat dilated cardiomyopathy after healing of cardiac myosin–induced autoimmune myocarditis. Methods and Results—Rats were treated with oral amiodarone or vehicle for 6 weeks. We determined cardiac function, left ventricular remodeling, and cardiac sympathetic nerve function with iodine-125–labeled metaiodobenzylguanidine ([I125]MIBG). Amiodarone treatment improved left ventricular pressure, central venous pressure, and rate of isovolumetric contraction and decreased ventricular weight (P<0.005). Expression of cytokine mRNA was unchanged; expression of atrial natriuretic peptide, collagen III, and transforming growth factor-&bgr;1 mRNA was decreased in amiodarone-treated rats (P<0.05). Phenotype of myosin heavy chain was moved toward that of normal rats by amiodarone. Initial myocardial uptake of MIBG decreased by 67% (P<0.001) and washout rate accelerated by 221% in rats with chronic heart failure compared with normal rats. Whereas amiodarone decreased the initial uptake by 71% in normal rats, amiodarone decelerated the early washout and the late washout and improved the late myocardial distribution of MIBG in rats with chronic heart failure (257% compared with vehicle-treated rats with chronic heart failure; P<0.01). In proportion to MIBG distributions, cardiac tissue catecholamines were increased by amiodarone treatment. Conclusions—Long-term amiodarone treatment prevented left ventricular remodeling and improved cardiac function in rat dilated cardiomyopathy. Long-term amiodarone treatment also restored cardiac sympathetic tone to hold norepinephrine in the heart.

Effects of angiotensin-II receptor blocker candesartan cilexetil in rats with dilated cardiomyopathy.

We examined effects of an angiotensin-II receptor blockers, candesartan cilexetil, in rats with dilated cardiomyopathy after autoimmune myocarditis. Candesartan cilexetil showed angiotensin-II blocking action in a dose-dependent manner in rats with dilated cardiomyopathy. Twenty-eight days after immunization, surviving Lewis rats were divided into four groups and given candesartan cilexetil at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg per day (Group-C0.05, n = 15, Group-C0.5, n = 15 and Group-C5, n = 15, respectively) or vehicle alone (Group-V, n = 15). After oral administration for 1 month, the left ventricular end-diastolic pressure and heart weight/body weight ratio were lower in Group-C0.05 (13.3± 1.1 mmHg and 3.7± 0.2 g/kg, respectively), in Group-C0.5 (8.0± 0.9 mmHg and 3.3± 0.1 g/kg, respectively) and in Group-C5 (5.5± 1 mmHg and 3.1± 0.1 g/kg, respectively) than in Group-V (13.5± 1.0 mmHg and 3.8± 0.2 g/kg, respectively). The area of myocardial fibrosis was also lower in Group-C0.05 (25± 3%), in Group-C0.5 (20± 3%), and in Group-C5 (12± 1%) than in Group-V (32± 4%). Furthermore, expressions of transforming growth factor-β1 and collagen-III mRNA were suppressed in Group-C0.05 (349± 23% and 395± 22%, respectively), Group-C0.5 (292± 81% and 364± 42%, respectively) and in Group-C5 (204± 63% and 259± 33%, respectively) compared with those in Group-V (367± 26% and 437± 18%, respectively). These results suggest that candesartan cilexetil can improve the function of inefficient heart. (Mol Cell Biochem 269: 137–142, 2005)

Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

BACKGROUND Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. METHODS AND RESULTS LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. CONCLUSIONS We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin.

Leiomyosarcoma of the abdominal aorta : A rare cause of renovascular hypertension

We describe the case of a 44-year-old woman who presented with renovascular hypertension caused by primary leiomyosarcoma of the abdominal aorta that had metastasized into the renal arteries. Despite an extensive radiological evaluation, the diagnosis was mistaken first for Takayasus arteritis and then for retroperitoneal hematoma or neoplasm. The patient developed renal failure due to bilateral renal infarction, and died 3 months after her initial presentation with ischemic colitis. Postmortem examination confirmed the diagnosis.

Ventricular Fibrillation in Two Cases with Dilated Cardiomyopathy and Mechanical Alternans

Clinical implication of mechanical alternans is yet unclear. It may suggest the risk for sudden death in patients with chronic heart failure. Two cases with dilated cardiomyopathy showed mechanical alternans during diagnostic cardiac catheterization. They suddenly died due to ventricular fibrillation before the induction of β‐blocker therapy. Patients with mechanical alternans should be treated under intense monitoring until the induction of β‐blocker therapy.

Improved cardiac function after sirolimus-eluting stent placement in diabetic patients by pioglitazone: Combination therapy with statin

BACKGROUND Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are used as anti-diabetic drugs, and their pleiotrophic action has been reported to improve endothelial function leading to cardioprotective effects. In this study we evaluated the long-term effect of pioglitazone on cardiac function in diabetic patients after percutaneous coronary intervention (PCI) by drug-eluting stent (DES). METHODS AND RESULTS We investigated 54 diabetic patients who received PCI using a sirolimus-eluting stent. We excluded cases of acute myocardial infarction. They were divided into two groups: Group C received only conventional therapy (n=26) and Group P received additionally pioglitazone 15 mg/day (n=28). The left ventricular ejection fraction (LVEF) was measured by left ventriculography and analyzed before and 8 months after PCI. In Group C, LVEF did not change significantly: 55.6% vs. 56.7%, before and after PCI respectively (p=0.58). However, pioglitazone significantly improved LVEF: 54.4% vs. 60.0% (p=0.014). Multiple linear regression analysis showed that DeltaLVEF was significantly related to pioglitazone therapy (p=0.037). In particular, the combination of pioglitazone and statin improved LVEF (DeltaLVEF 9.6% with vs. 2.2% without statin). CONCLUSIONS Pioglitazone improved cardiac function after PCI using SES in diabetic patients, especially in combination with a statin.

Mechanical alternans in human idiopathic dilated cardiomyopathy is caused with impaired force-frequency relationship and enhanced poststimulation potentiation.

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular dP/dt during pacing-induced tachycardia was assessed as the force gain in the force–frequency relationship (FG-FFR), and the maximal increase in left ventricular dP/dt of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(−)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(−) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force–frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia.

Improvement of anemia with decreasing hepcidin levels following valve replacement for severe tricuspid regurgitation

To the Editor: Severe right heart failure is occasionally accompanied by anemia (1, 2), but the underlying mechanisms for this association remain unknown. Hepcidin, a circulating hormone that is synthesized mainly by the liver, has emerged as a key regulator of systemic iron homeostasis (3). Hepcidin suppresses the expression of the iron transporter, ferroportin-1, thereby inhibiting the absorption of iron from the duodenum and the release of iron from the reticuloendothelial system. Therefore, the excessive production of hepcidin decreases serum iron levels, consequently causing and consequently causes anemia (3). Here, we report on a sixty-two-year-old woman of severe tricuspid regurgitation with refractory anemia in a patient with a very high serum hepcidin level who recovered from anemia after valve replacement, which was accompanied by a decrease in the hepcidin level. She had undergone mitral valve replacement for mitral stenosis 24 yrs before this episode. An echocardiogram revealed severe tricuspid regurgitation and dilatation of the right atrium. Right heart catheterization was performed after admission. Her right atrial pressure (RAP) was high (mean RAP, 15 mmHg; prominent V wave, 21 mmHg). Abdominal CT revealed hepatic vein dilatation and massive ascites. She received drug therapy for right heart failure, but this failed to reduce the massive ascites. She also had normocytic, normochromic anemia, but fecal occult blood tests were negative, and no bleeding source was found. She received oral iron preparation and red blood cell transfusions; however, her anemia did not resolve. As the massive ascites and progressive abdominal distension were believed to be life threatening, we decided to perform valve replacement surgery. The patient’s preoperative hemoglobin (Hb) level was 7.9 g ⁄dL, red blood cell (RBC) count was 271 million ⁄L, hematocrit (Ht) was 25.0%, serum iron level was low (26 lg ⁄dL), and serum ferritin level was high (724 ng ⁄mL; Table 1). Moreover, using a hepcidin EIA kit (Bachem Americans Inc., San Carlos, CA, USA), we found that her serum hepcidin levels (828 ng ⁄mL) were very high compared with the normal range (normal range, 1.8– 48.7 ng ⁄mL). Her preoperative serum C-reactive protein (CRP) level (15.91 mg ⁄dL) and interleukin-6 (IL-6) level (695 pg ⁄mL) were very high, but infectious disease was not found in any region of her body. Tricuspid valve replacement for severe tricuspid valve regurgitation and mitral valve replacement for the old ball valve were performed on July 1, 2010. Three months after the operation, the massive ascites completely disappeared. Postoperative right heart catheterization showed a decrease in RAP (mean RAP, 7 mmHg; V wave, 9 mmHg). Serum