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.
Mone, Pasquale, Klara Komici, Germano Guerra, Tommaso Dazzetti, Urna Kansakar, Gianluca Gennarelli, Antonio Rainone, et al. “Stress Hyperglycemia Ratio and Physical Frailty in HFpEF.”. Cardiovascular Diabetology, 2025. https://doi.org/10.1186/s12933-025-03020-z.
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.
Mhamedi, El Cheima, Florent Hubé, Suresh K Alahari, Francisco J Enguita, Barbara Pardini, Mark W Feinberg, Laura Poliseno, et al. “The Non-Coding RNA Journal Club: Highlights on Recent Papers-14.”. Non-Coding RNA 11, no. 6 (2025). https://doi.org/10.3390/ncrna11060075.
The field of non-coding RNA research is advancing at a breathtaking pace, continually uncovering new layers of regulatory complexity and functional diversity [...].
BACKGROUND: Statin therapy has been associated with increased risk of type 2 diabetes (T2D). We investigated the relationship between Low-Density Lipoprotein Cholesterol (LDL-C) plasma concentrations and incident T2D and evaluated the modifying effect of statin therapy in a large population-based cohort.
METHODS: Individuals free of T2D and cardiovascular disease at baseline were followed longitudinally for the development of new-onset T2D. Cox proportional hazards models were applied to evaluate the associations of LDL-C levels and statin therapy with T2D risk.
RESULTS: From a population of 202,545 individuals, we selected 13,674 participants free of T2D and cardiovascular disease (of whom 52% were on statins), who were followed for a median of 71.6 months (IQR 34.5-149.9), during which 1,819 (13%) developed incident T2D. Cox multiple regression analysis revealed a significant inverse association between LDL-C plasma levels and incident T2D (p < 0.001). When stratifying LDL-C into quartiles [i.e. low (< 84 mg/dL), medium (≥ 84 to < 107 mg/dL), high (≥ 107 to < 131 mg/dL), and very high (≥ 131 mg/dL)], we observed that patients with LDL-C < 84 mg/dL had the highest risk of developing T2D. The interaction between statin therapy and T2D incidence was significant only in the very high LDL-C group, where statin users had a greater risk than non-users (p = 0.018); in the other three LDL-C groups, statin therapy did not significantly modify the association between LDL-C and T2D risk.
CONCLUSIONS: Taken together, our findings demonstrate a strong inverse association between LDL-C and incident T2D in the general population. The increased risk of T2D at lower LDL-C levels appears to be independent of statin use, supporting the role of LDL-C as a potential biomarker of T2D susceptibility.
Wang, Brandon, Stanislovas S Jankauskas, Pasquale Mone, Fahimeh Varzideh, and Gaetano Santulli. “Immunology of Heart Failure With Preserved Ejection Fraction.”. Expert Review of Clinical Immunology, 2025. https://doi.org/10.1080/1744666X.2025.2587180.
INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction, systemic comorbidities, and chronic low-grade inflammation. Emerging evidence suggests that immune dysregulation plays a central role in its pathophysiology. Both innate and adaptive immune responses contribute to myocardial remodeling, endothelial dysfunction, and comorbidity-driven inflammation that are hallmarks of HFpEF.
AREAS COVERED: We summarize current evidence on the contribution of immunological pathways to HFpEF, including the role of proinflammatory cytokines, immune cell infiltration (particularly macrophages, mast cells, and T cells), and immune - endothelial interactions. We also highlight findings from experimental models linking systemic metabolic inflammation to myocardial fibrosis, coronary microvascular dysfunction, and cardiomyocyte stiffness in HFpEF. Finally, we explore potential immunomodulatory therapeutic approaches currently under investigation and discuss biomarkers of immune activation with potential clinical relevance.
EXPERT OPINION: While no immunologically targeted therapy is yet approved for HFpEF, interventions that modulate inflammation - such as IL-1 blockade, mast cell stabilization, or myeloid-targeted therapies - offer promise. Future clinical trials should incorporate immune profiling to enable patient stratification and personalized treatment approaches. A deeper understanding of immune-mediated mechanisms in HFpEF will be essential to advance therapeutic innovation and improve outcomes in this challenging and growing patient population.
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral artery disease (PAD), remains a leading cause of morbidity and limb loss. Effective vascular regeneration strategies will require increased understanding of molecular mechanisms underlying angiogenesis. Recent evidence revealed a new role for the vascular smooth muscle cell-enriched (VSMC-enriched) long noncoding RNA (lncRNA) CARMN in endothelial angiogenesis and postischemic vascular repair. CARMN was downregulated in both human CLTI muscle tissue and murine ischemia models. In VSMCs, CARMN deficiency suppressed a specific miRNA-mediated paracrine signaling axis that regulates Hedgehog signaling. In mice, deleting CARMN caused impariment in capillary growth and blood flow recovery after limb ischemia, an effect that was reversed by restoring miR-143-3p or silencing the Hedgehog inhibitor HHIP. The identification of lncRNA-mediated crosstalk between VSMCs and endothelial cells in PAD pathophysiology reveals possible therapeutic targets for CLTI and underscores the translational potential of RNA-based strategies in ischemic vascular disease.
Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer's disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline.
Santulli, Gaetano, Shivangi Pande, Pasquale Mone, and Fahimeh Varzideh. “Decoding the Coronary Paradox of Obesity: Not All Fat Is Equal!”. International Journal of Cardiology. Heart & Vasculature 61 (2025): 101807. https://doi.org/10.1016/j.ijcha.2025.101807.
BACKGROUND: Recent evidence suggests that inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis, has beneficial effects on lipid metabolism and blood pressure (BP), but detrimental consequences on glycemia. Nutraceuticals (NUTs) containing both Monacolin K (MK) and Morus alba have been shown to be more effective in lowering lipids compared to NUT formulations containing only MK. However, the effects of these NUTs on glucose homeostasis have not been fully determined.
METHODS: To evaluate the association between LDL-C-lowering therapy and glycemia in patients receiving NUT combinations with or without Morus alba, we analyzed data from a prospective, randomized, active-treatment controlled trial (NCT02898805), which enrolled 359 patients to compare the effects of a NUT combination containing MK alone (Formulation 1, F1; n = 170) versus one containing MK and Morus alba (Formulation 1, F2; n = 189).
RESULTS: Participants in the two treatment arms (F1 vs. F2) were comparable in terms of sex, age, metabolic parameters, and BP. After 3 months, both groups experienced significant reductions in LDL-C, fasting plasma glucose, HbA1c, and HOMA index. F2 treatment led to a significantly greater reduction in glycemic levels compared to F1 treatment (b = - 16, p < 0.001). Notably, a divergent trend emerged over time: an inverse relationship between LDL-C and glycemic levels was observed in the F1 group, while a significant direct association between LDL-C and glycemic levels was detected in the F2 group (b = 0.06, p = 0.002).
CONCLUSIONS: Taken together, our findings indicate that the treatment with a NUT combination containing Morus alba simultaneously reduces plasma levels of LDL-C and glucose.
Hypertension remains a major contributor to cardiovascular and renal complications in patients with diabetes mellitus, increasing the risk of macrovascular and microvascular disease. The 2025 AHA/ACC hypertension guidelines maintain a diagnostic and treatment threshold of 130/80 mmHg, emphasizing earlier and more intensive blood pressure control to reduce cardiovascular events, stroke, heart failure, and progression of diabetic nephropathy. Evidence from clinical trials and meta-analyses supports the benefits of tighter blood pressure targets, while acknowledging potential risks such as hypotension, electrolyte disturbances, and acute kidney injury. Management strategies combine pharmacologic therapy with lifestyle interventions including dietary modification, physical activity, weight management, and smoking cessation. Individualized blood pressure targets are recommended for older or frail patients to balance safety and benefit. Home and ambulatory blood pressure monitoring are highlighted for detecting masked or nocturnal hypertension, enhancing risk stratification, and supporting treatment titration. The guidelines also emphasize integrated risk assessment and multidisciplinary management. The 2025 AHA/ACC hypertension guidelines provide an evidence-based, patient-centered framework to optimize cardiovascular and renal outcomes in patients with diabetes, promoting early intervention, individualized therapy, and comprehensive risk reduction.
