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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., (© 2024. The Author(s).)

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., (Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine 2024.)

A hypercalcemic crisis due to primary hyperparathyroidism is a life-threatening condition. We herein report a 71-years-old man with hypercalcemic crisis due to primary hyperparathyroidism with parathyroid adenoma. Generally, hemodialysis or continuous hemodiafiltration using calcium-free or low-calcium dialysate is performed early for hypercalcemic crisis. In this case, continuous hemodialysis with a common calcium concentration dialysate improved the hypercalcemic crisis, and parathyroidectomy was performed. The patient recovered sufficiently. Prediction of hypercalcemia crisis, appropriate introduction and methods of blood purification therapy, and timing decisions for parathyroidectomy are required for therapeutic management of hypercalcemic crisis with parathyroid adenoma.

Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation., (© 2024. The Author(s).)

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 β (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., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Latin America (LATAM) children offer special insight into Severe Acute Respiratory Syndrome Coronavirus 2 (SARS COV2) due to high-risk race/ethnicity, variability in medical resources, diverse socioeconomic background, and numerous involved organ systems. This multinational study of LATAM youth examined the distinguishing features of acute or late multisystem SARS COV2 with versus without cardiac involvement. A consecutive sample of youth 0-18 years old (N = 98;50% male) presenting with multisystem SARS COV2 to 32 centers in 10 Latin American countries participating in a pediatric cardiac multi-imaging society were grouped as with versus without cardiac involvement, defined as abnormal echocardiographic findings or arrhythmia. Collected clinical data were analyzed by Student's t-test or Fisher's exact test. Cardiac (N = 48, 50% male) versus no cardiac (N = 50, 50% male) were similar in age; weight; nonrespiratory symptoms; and medical history. The cardiac group had 1 death and symptoms including coronary artery dilation, ejection fraction <50%, pericardial effusion, peripheral edema, arrhythmia, and pulmonary artery thrombus. The cardiac group had higher risk of ICU admission (77% vs 54%, p = 0.02); invasive ventilation (23% vs 4%,p = 0.007); vasoactive infusions (27% vs 4%, p = 0.002); prominent respiratory symptoms (60% vs 36%, p < 0.03); abnormal chest imaging (69% vs 34%, p = 0.001); troponin (33% vs 12%, p = 0.01); alanine aminotransferase (33% vs 12%, p = 0.02); and thrombocytopenia (46% vs 22%, p = 0.02). Receiver operating curve analysis showed that abnormal laboratories had 94% sensitivity and 98% negative predictive value on the need for ICU interventions.Conclusion: In LATAM children with multisystem SARS COV2, cardiac involvement was prevalent. Cardiac involvement was more likely to require ICU interventions, certain abnormal labs, and respiratory involvement. What is Known: • SARS COV2 can be asymptomatic in children but in some cases can have serious multisystemic involvement. • Hispanic ethnicity is purportedly at high risk of SARS COV2 in nations where they are often disadvantaged minority populations. What is New: • Latin American children presenting with multisystem SARS COV2 frequently have cardiac involvement which was associated with ICU interventions; prominent respiratory symptoms; abnormal chest X-ray; elevated troponin, ALT, and thrombocytopenia. • Elevated troponin, ALT or thrombocytopenia had high sensitivity and negative predictive value on the need for intensive care interventions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We assessed the expression profile of Mg(2+)-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg(2+) excretion. Urine Mg(2+) excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg(2+) excretion: 0.16 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old LETO rats and 0.28 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 ± 5.6% in 34-wk-old LETO rats and 63.0 ± 3.5% in 34-wk-old OLETF rats) concomitant with Na(+)-Cl(-) cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 ± 0.04% in 16-wk-old LETO rats, 0.10 ± 0.01% in 16-wk-old OLETF rats, 0.52 ± 0.03% in 24-wk-old LETO rats, 0.10 ± 0.01% in 24-wk-old OLETF rats, 0.48 ± 0.02% in 34-wk-old LETO rats, and 0.12 ± 0.02% in 34-wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy., (Copyright © 2015 the American Physiological Society.)