Takumi Toya

Plasma Amino Acid Profiling Identifies Specific Amino Acid Associations with Cardiovascular Function in Patients with Systolic Heart Failure

Background The heart has close interactions with other organs’ functions and concomitant systemic factors such as oxidative stress, nitric oxide (NO), inflammation, and nutrition in systolic heart failure (HF). Recently, plasma amino acid (AA) profiling as a systemic metabolic indicator has attracted considerable attention in predicting the future risk of human cardiometabolic diseases, but it has been scarcely studied in HF. Methods Thirty-eight stable but greater than New York Heart Association class II symptomatic patients with left ventricular (LV) ejection fraction <45% and 33 asymptomatic individuals with normal B-type natriuretic peptide (BNP) value were registered as the HF and control groups, respectively. We analyzed fasting plasma concentrations of 41 AAs using high-performance liquid chromatography, serum NO metabolite concentration, hydroperoxide and high-sensitivity C-reactive protein measurements, echocardiography, and flow-mediated dilatation. Results We found that 17 AAs and two ratios significantly changed in the HF group compared with those in the control group (p < 0.05). In the HF group, subsequent univariate and stepwise multivariate analyses with clinical variables revealed that Fischer ratio and five specific AAs, ie, monoethanolamine, methionine, tyrosine, 1-methylhistidine, and histidine have significant correlation with BNP, LV ejection fraction, LV end-diastolic volume index, inferior vena cava diameter, the ratio of early diastolic velocity of the mitral inflow to mitral annulus, and BNP, respectively (p < 0.05). Interestingly, further exploratory factor analysis categorized these AAs into hepatic-related (monoethanolamine, tyrosine, and Fischer ratio) and skeletal muscle-related (histidine, methionine, and 1-methylhistidine) components. Some categorized AAs showed unique correlations with concomitant factors: monoethanolamine, tyrosine, and Fischer ratio with serum NO concentration; histidine with serum albumin; and 1-methylhistidine with flow-mediated dilatation (p < 0.05). Conclusions Plasma AA profiling identified correlations of specific AAs with cardiac function and concomitant factors, highlighting the cardio-hepatic-skeletal muscle axis in patients with systolic HF.

Arginase inhibition augments nitric oxide production and facilitates left ventricular systolic function in doxorubicin‐induced cardiomyopathy in mice

A metabolizing enzyme arginase can decrease nitric oxide (NO) production by competing with NO synthase for arginine as a substrate, but its pathophysiological role in heart failure remains unknown. We aimed to investigate the effect of pharmacological inhibition of arginase on left ventricular function in doxorubicin‐induced cardiomyopathy in mice. Doxorubicin administration for 5 weeks significantly increased protein expression levels or activity of arginase in the lungs and liver, and caused moderate increase in arginase 2 expression in the aorta. In the lungs, accumulated interstitial cells strongly expressed both arginase 1 and arginase 2 by doxorubicin administration. Echocardiography revealed that administration of a potent, reversible arginase inhibitor N‐omega‐hydroxy‐nor‐l‐arginine completely reversed doxorubicin‐induced decrease in the ejection fraction, in parallel with expression levels of BNP mRNA, without affecting apoptosis, hypertrophy, fibrosis, or macrophage infiltration in the left ventricle. Arginase inhibition reversibly lowered systolic blood pressure, and importantly, it recovered doxorubicin‐induced decline in NO concentration in the serum, lungs, and aorta. Furthermore, arginase inhibition stimulated NO secretion from aortic endothelial cells and peritoneal macrophages in vitro. In conclusion, pharmacological inhibition of arginase augmented NO concentration in the serum, lungs, and aorta, promoted NO‐mediated decrease in afterload for left ventricle, and facilitated left ventricular systolic function in doxorubicin‐induced cardiomyopathy in mice.

Association between brachial-ankle pulse wave velocity and the ratio of l-arginine to asymmetric dimethylarginine in patients undergoing coronary angiography

BACKGROUND Endothelial dysfunction causes vasomotor dysregulation and vascular stiffening in addition to structural changes. By influencing NO synthesis, deficiency of l-arginine relative to asymmetric dimethylarginine (ADMA), which is an l-arginine derivative that acts as a competitive NO synthase inhibitor, may lead to the promotion of arterial stiffness. This study investigated the relationship between the l-arginine/ADMA ratio and brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness. METHODS AND RESULTS This cross-sectional study enrolled 74 patients (62 men, 12 women; mean age, 67±10 years) undergoing elective coronary angiography. A total of 54 (73%) patients had coronary artery disease. Serum l-arginine and ADMA were measured by high-performance liquid chromatography with fluorescence detection. The ratio of l-arginine to ADMA and the serum l-arginine level was associated with baPWV in univariate regression analysis (l-arginine/ADMA ratio: β=-0.323, p=0.005; l-arginine: β=-0.247, p=0.034). In addition, baPWV was related to blood hemoglobin concentration, hematocrit, brain natriuretic peptide level, symmetric dimethylarginine, renal function, blood pressure, and heart rate. In multivariate analysis, the l-arginine/ADMA ratio was a significant predictor of baPWV (β=-0.310, p<0.001). In subgroup analyses, the l-arginine/ADMA ratio was associated with baPWV in elderly patients (n=46, β=-0.359, p=0.004), and in younger patients (n=28, β=-0.412, p=0.006). CONCLUSION A low l-arginine/ADMA ratio may be associated with high baPWV in patients undergoing coronary angiography.

Usefulness of the d-ROMs test for prediction of cardiovascular events

BACKGROUND d-ROMs test developed to determine the degree of individual oxidative stress may predict cardiovascular events. METHODS AND RESULTS 265 patients (204 men, 61 women; age, 65±13years) who had been treated for cardiovascular disease were divided evenly by quartile of baseline d-ROMs levels, and were followed up. During the observation periods of 2.66±1.47years, there were 14 (5%) deaths, 8 (3%) cardiovascular deaths, 13 (5%) major adverse cardiovascular events (MACEs), and 51 (19%) all cardiovascular events including heart failure, cardiovascular surgery, and revascularization. Log-rank tests demonstrated that the patients in the 4th quartile (d-ROMs≧395.00U.CARR) had a higher incidence rate of cardiovascular death than those in the 2nd quartile (d-ROMs 286.00-335.00, p=0.022). In multivariate Cox regression analysis, even after adjustment for age, sex, coronary risk factors, C-reactive protein, and renal function, high d-ROMs was a risk factor for all-cause death [adjusted HR of 4th vs. 1st quartile, 10.791 (95% confidence interval 1.032-112.805), p=0.047], and all cardiovascular events [HR of 4th vs. 1st quartile, 2.651 (95% confidence interval 1.138-6.177), p=0.024]. CONCLUSIONS Our results suggest that d-ROMs is a useful oxidative stress marker to assess prognosis and risk of further cardiovascular events.

A Rare Case of Rush Progression of Purulent Pericarditis by Escherichia coli in a Patient with Malignant Lymphoma

Purulent pericarditis is a rare disease in the antibiotic era. The common pathogens of purulent pericarditis are gram-positive species such as Staphylococcus aureus. Streptococcus pneumoniae, Salmonella, Haemophilus, fungal pathogens/tuberculosis can also result in purulent pericarditis. We report an old male case of purulent pericarditis by Escherichia coli. He came to our hospital suffering from leg edema for 3 months. Echocardiography revealed the large amount of pericardial effusion, and he was admitted to test the cause of pericardial effusion without high fever, tachycardia, and shock vital signs. On the third day, he suddenly presented vital shock. We performed emergency cardiopulmonary resuscitation and pericardiocentesis. Appearance of pericardial effusion was hemorrhagic and purulent. The gram stain revealed remarkable E. coli invasion to pericardial space. Antibiotic therapy was immediately started; however, he died on sixth day with septic shock. The cytological examination of pericardial effusion suggested the invasion of malignant lymphoma to pericardium. This case showed subacute or chronic process of pericarditis without severe clinical and laboratory sings before admission. Nevertheless, bacterial purulent pericarditis usually shows acute clinical manifestation; the first process of this case was very silent. Immunosuppression of malignant lymphoma might make E. coli translocation from gastrointestinal tract to pericardial space, and bacterial pericarditis was progressed to purulent pericarditis. In the latter process, this case showed unexpected rush progression to death by sepsis from purulent pericarditis. Immediate pericardiocentesis should be performed for a prompt diagnosis of purulent pericarditis, and it might have improved the outcome of this case.

Transient right-sided Serratia endocarditis after a percutaneous transhepatic procedure

An 82-year-old man with liver cirrhosis and esophageal varices was referred to our department for sustained fever and chills. He had undergone percutaneous transhepatic portal embolization 11 days before and developed intraperitoneal bleeding and sepsis. There was no history of alcoholism, drug abuse, or intravenous catheter installation. His heart sounds and chest radiography were normal, the CRP level was 13.0 mg/dl, and Serratia marcescens was repeatedly detected in blood culture under cefmetazole and clindamycin treatment. Initial transthoracic echocardiography showed mild tricuspid regurgitation only without vegetation or congenital heart defect (Fig. 1a, supplementary video a). However, re-examination after 3 days revealed swinging, multiple bright particle echoes in the right ventricle (arrows in Fig. 1b, supplementary video b1 and b2), suspicious for right-sided Serratia endocarditis. These echoes rapidly vanished after an 11-day treatment with meropenem (Fig. 1c, supplementary video c) in parallel with alleviation of fever and the CRP level. Chest CT with a contrast agent showed no pulmonary complications. He has been asymptomatic to date. Right-sided endocarditis accounts for 3.8–14 % of all cases of infective endocarditis [1]. The most common predisposing factors are intravenous drug abuse and congenital heart defects as well as long-standing installation of medical devices such as intravenous catheters and pacemaker leads. On the other hand, liver cirrhosis is recognized as another predisposing factor for right-sided bacterial endocarditis, especially because of group D Streptococcus, including Streptococcus bovis, and to other bacteria of intestinal origin [2]. It is partly reasoned that the filter function of the liver is lost in liver cirrhosis. Although the prognosis of right-sided endocarditis is generally better than that of left-sided endocarditis, patients infected with Serratia, Pseudomonas, or fungus have a worse prognosis [3]. Moreover, 10–15 % of right-sided endocarditis complicates a mycotic pulmonary arterial aneurysm, the rupture of which can be fatal [4]. In this case, swinging, bright particle echoes were only transiently observed in the right ventricle without complications. As these echoes look atypical as the vegetation, we have to consider them as air bubbles in the intravenous infusion fluid or non-smoke spontaneous individual contrast (NSSIC) for the differential diagnosis. However, infusion of hypertonic fluid, higher hematocrit and plasma levels of fibrinogen, or transient stasis of the circulation in the right ventricle, which are associated with the generation of bubbles and NSSIC [5, 6], were absent in this case. The favorable clinical course may be due to the prompt diagnosis of rightsided endocarditis at an early stage. Therefore, repetitive transthoracic echocardiography is sometimes crucial to diagnose right-sided infective endocarditis in a patient with liver cirrhosis and esophageal varices.