Haruo Mitani

In Vivo klotho Gene Transfer Ameliorates Angiotensin II-Induced Renal Damage

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3×1010 plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.

Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat

Administration of angiotensin II to rats decreases renal expression of klotho, an aging‐related gene, and also causes abnormal iron deposition in renal cells. Here we have examined the effects of iron overload and iron chelation on renal expression of klotho in untreated rats and rats treated with angiotensin II. Administration of iron–dextran caused a downregulation of klotho expression, and iron chelation suppressed the angiotensin II‐induced downregulation of this gene. In addition, a free radical scavenger (T‐0970), which effectively decreased plasma levels of 8‐epi‐prostaglandin F2α (8‐epi‐PGF2α), suppressed angiotensin II‐induced downregulation of klotho. Collectively, these findings suggest that abnormal iron metabolism and increased oxidative stress are involved in the mechanism of angiotensin II‐mediated modulation of klotho expression.

Iron overload augments angiotensin II-induced cardiac fibrosis and promotes neointima formation.

Background—Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II–induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results—Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II–infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions—Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II. In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

Takotsubo cardiomyopathy in a patient undergoing hemodialysis

A 61-year-old woman hospitalized following surgery for cervical spondylosis developed severe chest pain and dyspnea during a hemodialysis session. She had been receiving chronic hemodialysis for 20 years secondary to glomerulonephritis. Electrocardiography (ECG) revealed ST-segment elevation in the precordial leads, and Q waves in the anterior and inferior leads. The creatine kinase MB and troponin I concentrations were slightly elevated. Echocardiography showed an apical wall motion abnormality. These findings were compatible with acute anterior wall myocardial infarction (MI). Emergent coronary angiography demonstrated normal coronary arteries. Left ventricular angiography revealed apical ballooning of the left ventricle in the systolic phase (Figure 1), not typical of the wall motion abnormality seen after acute MI. A diagnosis of Takotsubo cardiomyopathy was made based on the presence of this characteristic finding (Takotsubo is a Japanese octopus trap). The cardiomyopathy resolved spontaneously after 1 month, with normalization of the ECG. Takotsubo cardiomyopathy (transient left ventricular apical ballooning syndrome) is increasingly being recognized worldwide. In the setting of cardiogenic shock, recognition of Takotsubo cardiomyopathy is important to distinguish this cardiomyopathy from acute MI, which is especially relevant in end-stage renal disease patients because of their high cardiovascular risk. Although the etiology of Takotsubo cardiomyopathy remains uncertain in most patients, long-term outcomes appear favorable compared with myocardial infarction.

Alcohol-induced Ventricular Fibrillation in Brugada Syndrome

A 37‐year‐old man lost consciousness suddenly due to ventricular fibrillation (VF). After cardioversion, twelve‐lead ECG showed a pattern characteristic of type 1 Brugada. An implantable cardioverter defibrillator (ICD) was implanted for Brugada syndrome. In the following three years, VF occurred eight times after consumption of alcohol. Association between the Brugada syndrome and alcohol consumption has rarely been reported. Recently, it was reported that alcohol has inhibitory effect on single cardiac sodium channel gating and it may be that alcohol acted as a sodium channel blocker in this patient. Here we report a case of alcohol‐induced VF in Brugada syndrome.

The efficacy of bare metal stent implantation for patients with acute myocardial infarction in the drug-eluting stent era

BACKGROUND Although several trials have demonstrated the safety of drug-eluting stent (DES) implantation for acute myocardial infarction (AMI) patients, care must be exercised when DES are implanted in AMI cases because of the risk of in-stent thrombosis or adverse side effects of antiplatelet agents. On the other hand, recently, there has been much improvement in bare metal stents (BMSs), and thus, the efficacy of BMS implantation should be reevaluated. METHODS We investigated the primary and long-term outcome of BMS implantation for AMI patients in the DES era (July 2004 to December 2006; n=97 [Group 1]) and compared the results with those in the pre-DES era (January 2002 to June 2004; n=81 [Group 2]), retrospectively. RESULTS The most frequently used BMS in Group 1 was the Driver stent (63.9%) and in Group 2 the Duraflex stent (44.4%). Stent length and diameter were not significantly different between Group 1 and Group 2. The rates of in-stent restenosis, and target lesion revascularization were lower in Group 1 than in Group 2. Restenosis frequently occurred in small vessel lesions and in lesions that had required more than 10atm fully to dilate the pre-dilatation balloon at the primary PCI. CONCLUSIONS Currently available BMSs are much more effective than old-type BMSs. However, DES implantation may be considered for small vessel diseases and lesions that need high pressure to dilate.

P940Retrieval of leadless pacemaker embolizes to the lungs

Result : The patient is a man with pacemaker using unipolar lead. Because ERI, we elected to proceed with placement of a leadless pacemaker (Micra). The Micra was deployed successfully, and had 3 of the 4 tines engaged. I cut and pulled the tether out of the system. And then the pacing threshold became unstable. We decided to remove the device, by using a snare and a steerable introducer. Snaring the retrieval head was challenging because the head was too close to septum. Using an electrode catheter, we attempted to turn the device in some other direction, so that the retrieval head was accessible. In the next instant, the Micra had dislodged and embolized to the left pulmonary artery. We snared 2 of the 4 tines (Figure1), the device was gently pulled to the right atrium. Finally, we snared the retrieval head with another snare and successfully retrieved without any complications. (Figure2)

Successful Resuscitation from Cardiopulmonary Arrest: 5-FU Cardiotoxicity

A 61-year-old man with 5-fluorouracil (5-FU) chemotherapy suffered a cardiopulmonary arrest (CPA). The electrocardiogram showed changes consistent with myocardial infarction only during CPA that was normalized 30 minutes after cardiopulmonary resuscitation. Coronary angiography showed no significant stenosis. We suspected the cause of CPA to be vasospastic angina due to 5-FU and administered Benidipine, Diltiazem, and Isosorbide mononitrate to prevent recurrence of vasospasm.