East Asians Variant Mitochondrial Aldehyde Dehydrogenase 2 Genotype Exacerbates Nitrate Tolerance in Patients With Coronary Spastic Angina.

Background: Aldehyde dehydrogenase 2 (ALDH2) plays a central role in the biotransformation of glyceryl trinitrate (GTN) or nitroglycerin, which is widely used for the treatment of coronary artery disease (CAD). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. This study examined whether there are differences in nitroglycerine-mediated dilation (NMD) and flow-mediated dilation (FMD) response between wildALDH2*1/*1and variantALDH2*2patients with CAD.

Sex Differences in Heart Failure With Preserved Ejection Fraction Reflected by B-type Natriuretic Peptide Level.

Background: Prevalence of heart failure with preserved ejection fraction (HFpEF) increases with advancing age, particularly among women. Plasma levels of B-type natriuretic peptide (BNP), a surrogate marker of heart failure, have consistently been shown to be higher in women in the general populations. Whether BNP levels differ as per the sex of HFpEF patients remains largely unknown.

The diabetic heart utilizes ketone bodies as an energy source.

Background: Diabetic heart is characterized by failure of insulin to increase glucose uptake and increasingly relies on free fatty acids (FFAs) as a source of fuel in animal models. However, it is not well known how cardiac energy metabolism is altered in diabetic hearts in humans. We examined cardiac fuel metabolism in the diabetics as compared to non-diabetics who underwent cardiac catheterization for heart diseases.

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction - Relevance to Age-Related Left Ventricular Modeling in Japanese.

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is increasing with aging of the population. Plasma levels of B-type natriuretic peptide (BNP) increase in proportion to the severity of left ventricular (LV) dysfunction. The object of this study was to examine the plasma levels of BNP in HFpEF to better understand the pathogenesis of HFpEF as compared with HF with reduced EF (HFrEF).

East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.

Background: Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese.

Alcohol flushing and positive ethanol patch test in patients with coronary spastic angina: possible role of aldehyde dehydrogenase 2 polymorphisms.

Objective: Coronary spasm plays an important role in the pathogenesis of coronary heart disease (CHD) and angina pectoris caused by coronary spasm or coronary spastic angina (CSA) is prevalent in Japan. However, the precise mechanisms underlying coronary spasm are unclear. Alcohol intolerance is prevalent among East Asians, and we previously reported that coronary spasm could be induced by alcohol intake in CSA patients.

Usefulness of plasma B-type natriuretic peptide as a prognostic marker of cardiac function in senile systemic amyloidosis and in familial amyloidotic polyneuropathy.

Objective: In senile systemic amyloidosis (SSA), a common age-related amyloidosis, wild-type transthyretin accumulates in tissues, with a primary result being cardiac dysfunction. Here, we aimed to clarify the usefulness of B-type natriuretic peptide (BNP) as a prognostic marker of cardiac function in SSA and in familial amyloidotic polyneuropathy (FAP).

Methods And Results: We studied 13 patients with severe SSA and 14 patients with FAP.

Coronary spastic angina is associated with insulin resistance - possible involvement of endothelial dysfunction.

Objective: In this study, we examined whether coronary spastic angina (CSA) is associated with insulin resistance.

Background: There is increasing evidence that insulin resistance is associated with endothelial dysfunction. Patients with CSA show endothelial dysfunction.

Suppression of primary aldosteronism and resistant hypertension by the peroxisome proliferator-activated receptor gamma agonist pioglitazone.

The peroxisome proliferator-activated receptor gamma (PPAR γ) agonists have been reported to have antiproliferative and tumor-suppressive effects. We report a case of 55-year-old man with primary aldosteronism (PA) whose hyperaldosteronism was suppressed with the PPAR γ agonist pioglitazone. He had drug-resistant hypertension, hypokalemia, and diabetes mellitus.

Novel function of transthyretin in pancreatic alpha cells.

Although transthyretin (TTR) is expressed in pancreatic alpha (glucagon) cells in the islets of Langerhans, the function of TTR in pancreatic alpha cells remains unknown. In this study, by using TTR knockout (TTR KO) mice, we determined the novel role of TTR in glucose homeostasis. We demonstrated that TTR KO mice evidenced impaired recovery of blood glucose and glucagon levels.

Potential use of glucuronylglucosyl-β-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy.

Transthyretin (TTR)-related familial amyloidotic polyneuropathy, which is induced by amyloidogenic transthyretin (ATTR), is characterized by systemic accumulation of amyloid fibrils. Although it is believed that protein misfolding of monomeric form of TTR is a rate-limiting step for TTR amyloid formation, no effective therapy targeting this misfolding step is available. Our recent studies revealed that cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, might interact with TTR and prevent the protein misfolding.

Antibody therapy for familial amyloidotic polyneuropathy.

Although it is believed that altered conformations exposing cryptic regions are intermediary and critical steps in the mechanism of transthyretin (TTR) amyloid formation, no effective therapy targeting this step is available. In this study, to establish the antibody therapy for familial amyloidotic polyneuropathy (FAP), we generated a monoclonal anti-TTR antibody, which specifically reacts with surface epitopes of TTR (MAb ATTR) and evaluated its binding affinity and specificity for TTR amyloid fibrils. MAb ATTR showed specific binding affinity for TTR amyloid fibrils, but not for native form of TTR.

Clinicopathological features of senile systemic amyloidosis: an ante- and post-mortem study.

Senile systemic amyloidosis is a common age-related amyloidosis that involves accumulation of wild-type transthyretin, with cardiac dysfunction being a predominant result. The importance of obtaining an accurate diagnosis of senile systemic amyloidosis has been increasingly recognized, so that novel treatments are being developed. However, the clinicopathological features of senile systemic amyloidosis remain to be completely understood.

Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis.

TTR (transthyretin), a β-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation.

Spinal multifocal amyloidosis derived from wild-type transthyretin.

Abstract Spinal amyloidosis can occur as a part of systemic amyloidosis or as localized amyloidomas. However, the exact pathogenesis of the spinal amyloidosis remains to be fully understood. Transthyretin (TTR) is an amyloidogenic protein causing two kinds of amyloid diseases.

Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy.

Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process.

Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism.

Recent studies clearly demonstrated that several types of pathogenic amyloid proteins acted as agents that could transmit amyloidosis by means of a prion-like mechanism. Systemic AA amyloidosis is one of the most severe complications of chronic inflammatory disorders, particularly rheumatoid arthritis. It is well known that, similar to an infectious prion protein, amyloid-enhancing factor (AEF) acts as a transmissible agent in AA amyloidosis.

Low responsiveness to thienopyridine in hemodialysis patients.

We sought to evaluate whether thienopyridine low responsiveness, a predictor of stent thrombosis, is found in hemodialysis patients. We measured platelet aggregation at the site of implantation of drug-eluting stents in 333 patients with angina pectoris undergoing dual anti-platelet therapy. Thirty-one patients were on hemodialysis (HD group), and 302 were not (N-HD group).

Sorafenib-induced acute myocardial infarction due to coronary artery spasm.

A 65-year-old man with advanced renal cell carcinoma was admitted due to continuing chest pain at rest. Two weeks before his admission, sorafenib had been started. He was diagnosed with non-ST-elevation myocardial infarction by laboratory data and electrocardiogram.

The endothelial nitric oxide synthase gene -786T/C polymorphism is a predictive factor for reattacks of coronary spasm.

Objective: We previously found a -786T/C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is strongly associated with coronary spasm. In this study, we examined whether the polymorphism is a prognostic marker in coronary spasm patients.

Methods And Results: We examined the clinical courses of 201 consecutive patients with coronary spasm who were admitted to our institution: 146 patients with the -786T/T genotype; 50 patients with the -786C/T genotype; and five patients with the -786C/C genotype.

Predominant effect of A-type natriuretic peptide on reduction of oxidative stress during the treatment of patients with heart failure.

Background: Oxidative stress plays an important role in the pathogenesis of heart failure and was investigated in the present study of the role of exogenous A-type natriuretic peptide (ANP) in the patients with heart failure and in cultured neonatal rat cardiomyocytes.

Methods And Results: The first protocol was to examine if an infusion of human ANP (carperitide) changed serum levels of TRX (thioredoxin) during the treatment of patients with heart failure compared with conventional therapy using furosemide. Protocol 2 investigated whether ANP had a direct antioxidant action on the failing heart by measuring TRX gene expression and reactive oxygen species (ROS) production in cultured neonatal rat cardiomyocytes.

A -786T>C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine.

We identified a -786T>C polymorphism in the eNOS gene, and this polymorphism was strongly associated with coronary spasm. The present study aimed to elucidate whether the -786T>C polymorphism or acetylcholine (ACh)-induced coronary spasm affects serum nitrite/nitrate (NOx) levels. The study population comprised three groups: (i) 26 patients without coronary spasm in the left anterior descending coronary artery (LAD) with the T/T genotype (group A); (ii) 20 patients with coronary spasm in the LAD with the T/T genotype (group B); and (iii) 16 patients with coronary spasm in the LAD with the C/T genotype (group C).