Publications

BACKGROUND: Dysregulation of lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) is linked to endothelial dysfunction and impaired tissue repair. Nevertheless, the organ-specific modulation of lysolecithin remodeling in T2DM remains unexplored. Here, we investigate the LPC/PC remodeling dynamics in a T2DM model and propose a novel therapeutic approach using an orally bioavailable peptide (SP6) derived from Spirulina platensis.

METHODS: LPC/PC levels were analyzed by UHPLC-HRMS. Membrane fluidity, VEGF/API5, LPCAT1, VE-cadherin, and GLUT1 were evaluated by merocyanine assay, qPCR, immunoblotting, and immunofluorescence. In vivo, T2DM was induced by a high-fat diet and streptozotocin, and SP6 was orally administered. Tissue lipidomics, GLUTs expression, and insulin secretion were assessed, with the latter also spatially characterized in pancreatic tissue by MALDI-MS imaging.

RESULTS: High glucose induced LPC/PC imbalance, enhanced membrane fluidity, impaired VEGF/API5 expression, and hindered wound healing and VE-cadherin localization via LPCAT1 downregulation and subsequent impact on GLUT1 translocation. In vivo analysis of diabetic mice revealed a multi-organ influence of SP6 preserving LPCAT1 mRNA levels in pancreas, liver, skeletal muscle, and adipose tissue and a specific pattern of lysolecithin remodeling, with selective modulation of LPC 16:0, 18:0, and 20:4 in plasma. Finally, its effects in T2DM are mediated by preserving insulin secretion and glycemic control through increased ATP production.

CONCLUSION: These findings reveal tissue-specific lysolecithin reprogramming in T2DM development and identify LPCAT1-mediated lysolecithin remodeling as a mechanism involved in T2DM-related endothelial and metabolic dysfunction. SP6 modulates lipid metabolism, vascular integrity, and glucose regulation at the transcript level, suggesting its potential as a new preventive treatment for T2DM and its complications.

Heart failure continues to impose a major global burden, with limited options for reversing progressive contractile dysfunction despite optimized pharmacologic and device therapy. In this context, the first-in-human trial of AB-1002, a cardiotropic adeno-associated viral (AAV) vector encoding a constitutively active form of protein phosphatase-1 inhibitor (I-1c) represents a major innovation. By releasing SERCA2a from phospholamban-mediated inhibition, this strategy seeks to restore calcium cycling and contractile reserve without introducing exogenous pump proteins. In an open-label phase 1 study of 11 patients with advanced nonischemic cardiomyopathy, intracoronary delivery of AB-1002 was well tolerated, with no serious vector-related adverse events and only mild transient hepatic enzyme elevations. Modest but consistent improvements were observed in LVEF, while myocardial tissue from one explanted heart confirmed successful transgene expression and phospholamban phosphorylation. These results demonstrate the feasibility and biological activity of a phosphatase-inhibition gene-therapy approach for human heart failure. The forthcoming phase 2 GenePHIT trial will determine whether these encouraging mechanistic signals can be translated into tangible clinical benefit. AB-1002 thus represents a cautiously optimistic inflection point-suggesting that, with improved vector design and rigorous evaluation, gene therapy may yet deliver on its long-sought promise of molecular restoration in the failing human heart.

Frailty and cardiometabolic disorders are highly prevalent in the aging population and frequently coexist, amplifying each other's adverse effects. Frailty, defined by decreased physiological reserves and heightened vulnerability to stressors, often occurs alongside cardiometabolic conditions such as diabetes, hypertension, and cardiovascular disease. The intersection of these conditions poses substantial clinical challenges, impacting morbidity, mortality, and quality of life. Understanding the shared pathophysiological mechanisms underlying frailty and cardiometabolic disorders is critical for guiding effective prevention and management strategies. This systematic review, registered in PROSPERO (CRD420251164236), documents current knowledge on the definitions, epidemiology, and pathophysiology of frailty in the context of cardiometabolic disorders and highlights the main clinical implications of their coexistence. Additionally, we discuss evidence-based strategies for assessment, prevention, and management, emphasizing the importance of an integrated approach to improve outcomes in older adults. These insights aim to inform both clinicians and researchers about targeted interventions that can mitigate risk, enhance resilience, and optimize patient care.

BACKGROUND: Stress hyperglycemia, reflected by the stress hyperglycemia ratio (SHR), is increasingly recognized as a marker of adverse cardiovascular outcomes in both diabetic and non-diabetic patients. Stress-induced hyperglycemia arises from acute metabolic and inflammatory stress responses and may signify impaired glycemic resilience. Heart failure with preserved ejection fraction (HFpEF) commonly coexists with metabolic abnormalities such as hyperglycemia, prediabetes, and diabetes, while physical frailty-frequent in older adults-is mechanistically linked to both dysglycemia and HFpEF. In this study, we aimed to investigate the association between SHR and physical performance in frail older adults with HFpEF.

METHODS: We conducted a prospective observational study enrolling consecutive frail adults aged > 65 years with a confirmed diagnosis of HFpEF and Montreal cognitive assessment (MoCA) score < 26. Frailty was defined by ≥ 3 of 5 Fried criteria (low physical activity, unintentional weight loss, exhaustion, weakness, and slowness). SHR was calculated as the ratio of admission plasma glucose (mmol/L) to estimated chronic glucose derived from HbA1c (%). Participants were stratified into two groups: SHR ≤ 1 and SHR > 1. Physical function was assessed by gait speed (m/s).

RESULTS: Of 295 screened individuals, 204 met inclusion criteria and completed the study. Patients with SHR > 1 demonstrated significantly reduced physical performance compared with those with SHR ≤ 1 (mean gait speed 0.65 ± 0.20 m/s vs. 0.72 ± 0.20 m/s, p = 0.0004).

CONCLUSIONS: A higher SHR was independently associated with poorer physical function in frail older adults with HFpEF. These findings suggest that stress-related dysglycemia may contribute to functional decline in this population, highlighting the potential utility of SHR as a metabolic marker of frailty severity and cardiovascular vulnerability.