Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease.

Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),　hemoglobin, and lipid peroxide (LPO) {standardized ß (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.

Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling.

Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2 stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (ANG II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in ANG II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated ANG II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with 13C-labeled glutamine, we observed glutamine metabolic flux in ANG II-treated RNCMs and RNCFs. The incorporation of 13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied hearts. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.

Critical role of glutamine metabolism in cardiomyocytes under oxidative stress.

BACKGROUND: Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates α-ketoglutarate (αKG) derived from glutamine into the tricarboxylic acid (TCA) cycle. It is well known that cancer cells depend on glutamine for their increased energy demand and proliferation; however, the physiological roles of glutamine metabolism in failing hearts remain unclear. OBJECTIVE: To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium. METHODS AND RESULTS: The intracellular levels of glutamine, glutamate, and αKG were significantly decreased by H2O2 stimulation in rat neonatal cardiomyocytes (RNCMs). To better understand the metabolic flux in failing myocardium, we performed a stable isotope tracing study and found that glutaminolysis was upregulated in RNCMs under oxidative stress. Consistent with this, the enzymatic activity of glutaminase (Gls), which converts glutamine to glutamate, was augmented in RNCMs treated with H2O2. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of αKG. Furthermore, the inhibition of Gls reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with H2O2 stimulation. Finally, we evaluated the effects of αKG on failing myocardium and observed that dimethyl α-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels. CONCLUSION: Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of αKG and its replenishment into the TCA cycle, thereby exerting cardioprotective effects by maintaining ATP and GSH levels. Modulation of glutamine metabolism in failing hearts might provide a new therapeutic strategy for HF.

Imatinib Dramatically Improved Pulmonary Hypertension Caused by Pulmonary Tumor Thrombotic Microangiopathy (PTTM) Associated with Metastatic Breast Cancer.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, showing rapid progression of respiratory dysfunction and pulmonary hypertension (PH). Accumulating evidence suggests that imatinib, a platelet-derived growth factor (PDGF) receptor-tyrosine kinase inhibitor, might be effective and improve severe PH in patients with PTTM associated with gastric cancer. However, its efficacy in PTTM with breast cancer is generally believed as very limited. We experienced a rare case of PTTM associated with metastatic breast cancer, a rare case who were treated with imatinib, exhibiting significant improvement of respiratory dysfunction and PH.

Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy.

The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.

Impaired Cholesterol Uptake Capacity in Patients with Hypertriglyceridemia and Diabetes Mellitus.

BACKGROUND: Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the "cholesterol uptake capacity (CUC)" as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus. METHODS: The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital. RESULTS: The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = -0.30, P < 0.001). CONCLUSIONS: The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality.

[Palliative care workshop primarily aimed for physicians and nurses in order to improve the care of the end-of- life homecare patient].

Since 2008, we held a palliative care workshop primarily aimed for physicians, who engaged in clinical practice for cancer treatment. In order to improve the end-of-life stage patient care at home, we made all sorts of efforts not only for physicians, but we also made a workshop available for healthcare professionals to participate. There were more than 60 people participated the workshop: our 20% of physicians and 24% of nurses, 13% of nearby hospital and clinic physicians, 12% of pharmacists and 17% of nurses. According to our questionnaire survey, more than 90% of the participants were satisfied with the workshop. Only 8% of the participants expressed that the workshop was rather difficult. From our analysis of the results, it was clear that we attained a high level of participants' satisfaction.

Effects of Elaidic Acid on HDL Cholesterol Uptake Capacity.

Recently we established a cell-free assay to evaluate "cholesterol uptake capacity (CUC)" as a novel concept for high-density lipoprotein (HDL) functionality and demonstrated the feasibility of CUC for coronary risk stratification, although its regulatory mechanism remains unclear. HDL fluidity affects cholesterol efflux, and trans fatty acids (TFA) reduce lipid membrane fluidity when incorporated into phospholipids (PL). This study aimed to clarify the effect of TFA in HDL-PL on CUC. Serum was collected from 264 patients after coronary angiography or percutaneous coronary intervention to measure CUC and elaidic acid levels in HDL-PL, and in vitro analysis using reconstituted HDL (rHDL) was used to determine the HDL-PL mechanism affecting CUC. CUC was positively associated with HDL-PL levels but negatively associated with the proportion of elaidic acid in HDL-PL (elaidic acid in HDL-PL/HDL-PL ratio). Increased elaidic acid-phosphatidylcholine (PC) content in rHDL exhibited no change in particle size or CUC compared to rHDL containing oleic acid in PC. Recombinant human lecithin-cholesterol acyltransferase (LCAT) enhanced CUC, and LCAT-dependent enhancement of CUC and LCAT-dependent cholesterol esterification were suppressed in rHDL containing elaidic acid in PC. Therefore, CUC is affected by HDL-PL concentration, HDL-PL acyl group composition, and LCAT-dependent cholesterol esterification. Elaidic acid precipitated an inhibition of cholesterol uptake and maturation of HDL; therefore, modulation of HDL-PL acyl groups could improve CUC.

[For the seamless care of home ALS patient on a mechanical ventilator--the importance of reducing the sputum].

Recently, many of the ALS patients on mechanical ventilator have been shifting to home based care from hospitals, and these ALS patients are increasing in trend. In doing a seamless transition from hospital to home based care, it is important that the burden of the family caregiver should be reduced while the patient is still in the hospital prior to discharge. We experienced one ALS patient on ventilator who could be cared at home smoothly by several measures for a reduction of sputum. The following procedural measures are thought to be efficient: 1 set the tidal volume of ventilator rather high, 2 treat the underlying lung disease for the cause of sputum increase, and 3 keep a good sleep to prevent a sputum increase in the night by the patient's body movements.

[The experiences of elderly patients' successful resumption of oral ingestion with home parenteral nutrition and multi-professional team approach].

There are many elderly patients with poor oral intake when they are hospitalized with pneumonia or urinary tract infection, and we often need to consider their proper feeding method, such as percutaneous endoscopic gastrostomy(PEG)or total parenteral nutrition(TPN). However, it is difficult to receive homecare services for patients who rely highly upon medical treatment. Meanwhile, a prolonged hospitalization is a serious social problem. Here, we report two cases of elderly patients who were able to eat because home parenteral nutrition care and seamless approach were provided by multi-professional team.

[Three cases of live-alone patients received an end-of-life care at home].

Many people hope to receive an end-of-life care at home. Due to the trend toward the nuclear family and aging society, most people, however, would end up in medical institutions. The low ADLs of patients, in addition to medical treatment such as home oxygen therapy and intravenous injection, make it difficult to spend an end-of-life care at home alone. We have experienced and reported here three cases of live-alone patients who could remain at home owing to the evaluation of domestic care ability by a Home Care Score and the appropriate introduction of social health care services.

[Infection control measures for multidrug-resistant Pseudomonas aeruginosa (MDRP) carrier at home--a trial production of infection control manual of our hospital].

It is thought that there is no effective traditional antibiotic therapy for MDRP, and a prevention of its transmission is the most important strategy for controlling infection. In practicing standard precautions for MDRP patients at home, we noticed some sort of anxiety and confusion among the healthcare workers and family caregivers. We made our experimental manual and unified our procedures for MDRP carriers at home to reduce such problems. Consequently, healthcare workers' stress was alleviated and the teamwork could be enhanced better. We think that it is significant to make a common manual for MDRP control to improve mutual understandings and to have a better cooperation among the concerned home care workers.

[A case report of a patient whose sputum culture of multidrug-resistant Pseudomonas aeruginosa (MDRP) disappeared after administration of green tea by gastric tube].

It costs a lot of burden to take care of MDRP carriers at home as well as preventing MDRP transmission to caregivers. It is reported that epigallocatechin gallate (EGCG), the most abundant chemical contained in tea catechin, is chemically similar to trimethoprim (TMP) and inhibits S. maltophilia growth by antifolate acitivity. In this report, we present a case of a patient, whose sputum culture of MDRP disappeared after a green tea administration by gastric tube. We thought that catechin escaped from a drug efflux mechanism(s) of MDRP and could act on its growth.

[Three elderly patient cases maintained by home hypodermoclysis--a practical hydrating method performed by family members].

Hypodermoclysis, the subcutaneous infusion of fluids, has been reevaluated as a useful hydration technique for elderly patients. In the care of end-of-life elderly patients who are unable to take adequate fluids orally, hypodermoclysis is a less stressful means for patients and family than an intravenous hydration. Further more, it shortens the duration of hospitalization. We report three cases of patients who could remain at home stably for a relatively long period of time because of hypodermoclysis administered by family members.

An Unusual Case of Inferior Vena Cava Thrombosis in a Healthy Male Bodybuilder.

Inferior vena cava (IVC) thrombosis is very rare, particularly in the absence of an apparent congenital caval abnormality or hypercoagulable state. We herein report an unusual case of a healthy and active 62-year-old male bodybuilder with a mass-like IVC thrombus. We placed an IVC filter and began treatment with rivaroxaban. The patient recovered successfully, and the IVC thrombus completely disappeared three months later. This case suggested that extrinsic compression of IVC by a tightened weightlifting belt around the abdomen is a triggering factor of IVC thrombosis, and rivaroxaban, a new oral anticoagulant, may be a useful option for treatment.

Dasatinib-Induced Pulmonary Arterial Hypertension Treated with Upfront Combination Therapy.

Pulmonary arterial hypertension (PAH) is a rare complication of dasatinib that was approved as a first-line therapy for chronic myelocytic leukemia (CML). A 24-year-old man presenting dyspnea at rest and leg edema was admitted to our hospital. He had been diagnosed with CML and prescribed dasatinib for 4 years. Chest X-ray showed significant bilateral pleural effusion and heart enlargement. Echocardiography revealed interventricular septal compression and elevated peak tricuspid regurgitation pressure gradient of 66.7 mmHg indicating severe pulmonary hypertension. After the other specific diseases to provoke PAH were excluded, he was diagnosed with dasatinib-induced PAH. Despite discontinuation of dasatinib and intravenous administration of diuretic for two weeks, World Health Organization (WHO) functional class was still II and mean pulmonary arterial pressure (PAP) was high at 37 mmHg. Therefore, we administered sildenafil and bosentan together as an upfront combination therapy three weeks after dasatinib discontinuation. Six months later, his symptoms improved to WHO functional class I and mean PAP was decreased to 31 mmHg. Although PAH is a rare complication of dasatinib, symptomatic patients prescribed with dasatinib should have an echocardiogram for PAH screening. Moreover, the upfront combination therapy would be a useful option for symptomatic patients after discontinuation of dasatinib.

Acute pulmonary edema in patients with reduced left ventricular ejection fraction is associated with concentric left ventricular geometry.

Although acute pulmonary edema (APE) is common in patients with heart failure (HF) with preserved ejection fraction (EF), its pathogenesis in patients with HF with reduced EF (HFrEF) is not completely understood. The purpose of our study was to explore the contributions of left ventricular (LV) geometry to understand the difference between HFrEF patients with or without APE. We studied 122 consecutive acute decompensated HF patients with HFrEF (≤40%). APE was defined as acute-onset dyspnea and radiographic alveolar edema requiring immediate airway intervention. LV geometry was determined from a combination of the LV mass index and relative wall thickness (RWT). Long-term unfavorable outcome events were tracked during a follow-up of a median of 21 months (interquartile range, 10-28 months), during which APE was observed in 29 patients (24%). Compared to those without APE, hospitalized patients with APE had a higher systolic blood pressure, RWT, and LVEF and lower end-diastolic dimension. Among echocardiographic variables, a multivariate logistic regression analysis identified RWT as the only independent determinant of APE (hazard ratio: 2.46, p < 0.001). Those with concentric geometry (n = 25; RWT > 0.42) had a higher incidence of APE relative to those with non-concentric geometry. Furthermore, among patients with APE, mortality was significantly higher among those with concentric geometry (log-rank, p = 0.008). Compared with non-concentric geometry, concentric geometry (increased RWT, not LV mass) was strongly associated with APE onset and a poorer outcome among APE patients. An easily obtained echocardiographic RWT index may facilitate the risk stratification of patients.