Carotid intima-media thickness (cIMT), amyloid-β1-40 (Aβ1-40), and oxidative stress are markers of vascular aging and cardiovascular risk. We compared the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on the aforementioned markers in type 2 diabetes (T2DM). We prospectively studied 183 metformin-treated T2DM patients, propensity-score-matched to 12-mo treatment with insulin, liraglutide, empagliflozin, or liraglutide plus empagliflozin. Six-segment cIMT and plaque-equivalent lesions (cIMT ≥ 1.5 mm) were assessed at baseline, 6, and 12 mo; plasma Aβ1-40 and malondialdehyde (MDA) were measured. All regimens were associated with reductions in cIMT and Aβ1-40 at 12 mo (P < 0.05). MDA decreased overall with the largest reduction in GLP-1RA-based regimens. Compared with insulin, liraglutide, empagliflozin, and their combination achieved greater reductions in cIMT (-8.2, -5.6, and -10.7% vs. -1.7%, P < 0.05) and in Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%, P < 0.05). Patients achieving cIMT < 1.5 mm at 12 mo was the highest with combination therapy (75%), followed by liraglutide (67%) and empagliflozin (54%) versus insulin (40%; P < 0.05). Patients who regressed <1.5 mm showed greater reduction in Aβ1-40 than those with ≥1.5 mm (-56.2% vs. -25.1%, P = 0.028). Liraglutide, empagliflozin, and their combination induced greater reduction of cIMT (-8.2, -5.6, and -10.7% vs. -1.7%) and Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%; P < 0.05) compared with insulin. cIMT regression was associated with Aβ1-40 and MDA reductions (P < 0.05). In T2DM patients, GLP-1RA and SGLT-2i-particularly in combination-were associated with improvements in carotid atherosclerotic burden, amyloid-related vascular injury, and oxidative stress.NEW & NOTEWORTHY We investigated the effect of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on carotid intima-media thickness (cIMT) and amyloid-β1-40 (Aβ1-40) in diabetes. Twelve-month treatment with GLP-1RA, SGLT-2i, and their combination confers significant reductions in cIMT and Aβ1-40 compared with insulin. cIMT regression was associated with Aβ1-40 and malondialdehyde reductions. Our findings support that newer antidiabetic agents can favorably modify structural and biochemical markers of atherosclerosis.

We investigated potential differences in arterial stiffness, thickness of endothelial glycocalyx, deformation of left atrium and ventricle among various ischemic stroke subtypes and controls.We included 194 ischemic stroke patients (n = 47 lacunar stroke, n = 50 large artery atherosclerotic stroke [LAA], n = 49 cardioembolic stroke, n = 48 with embolic stroke of undetermined source [ESUS]) and 50 matched controls. We measured: (1) perfused boundary region (PBR4-25) of the sublingual microvessels, (marker of endothelial glycocalyx integrity), (2) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (3) left ventricular global longitudinal strain, left atrial (LA) reservoir, conduction and contraction strain, (4) myocardial work indices, by pressure-myocardial loops, and (5) PWV/GLS ratio, to assess ventriculoarterial interaction.Compared with controls, stroke patients displayed affected LA strains, LVGLS, Wasted Work, PBR4-25, cSBP, PWV, and PWV/GLS (p < 0.05). We observed differences in LA strain, PWV, PWV/GLS, and PBR4-25 between different ischemic stroke subtypes (p < 0.05). Participants with lacunar strokes had the most impaired PBR4-25, participants with cardioembolic stroke and ESUS had the most impaired LA strain, and LAA had the most affected PWV and PWV/GLS (p < 0.05). PBR4-25 value of 2.29 μm could discriminate lacunar strokes (AUC: 0.81, 95% CI: 0.74-0.89; p < 0.001), PWV cut-off of 13 m/second could discriminate LAA (AUC: 0.80, 95% CI: 0.72-0.89; p < 0.001) and LA reservoir strain cut-off of 25% could discriminate ESUS/Cardioembolic strokes (AUC: 0.78, 95% CI: 0.71-0.85; p < 0.001).Lacunar strokes exert excessive shedding of endothelial glycocalyx, LAA show aggravated aortic stiffness, while ESUS/Cardioembolic strokes demonstrate worse LA performance. These differences in the underlying pathophysiological mechanisms among stroke subtypes may guide individualized secondary prevention strategies.

Background and Objectives: Patients with type 2 diabetes mellitus (T2DM) and ischemic stroke present with endothelial, vascular and left ventricular (LV) myocardial dysfunction. We investigated the effects of treatment with either glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose contrasporter-2 inhibitors (SGLT-2i) on endothelial glycocalyx, arterial stiffness, and LV myocardial strain in patients with metformin-treated T2DM and a prior ischemic stroke. Materials and Methods: A total of 54 consecutive patients with T2DM and ischemic stroke who attended a cardiometabolic outpatient clinic in Athens, Greece, and received either GLP-1RA (dulaglutide; n = 27) or SGLT-2i (empagliflozin; n = 27) were enrolled in the study. We measured the perfused boundary region (PBR) of the sublingual microvessels, a marker of glycocalyx thickness, as well as carotid-femoral pulse wave velocity (PWV) and LV global longitudinal strain (GLS), at baseline and at 4 and 12 months of treatment. Results: Twelve months after treatment, all patients had reduced glycosylated hemoglobin and body mass index (BMI) (p < 0.001). Patients treated with dulaglutide showed a greater reduction in BMI (-11.8% vs. -4.8%, p < 0.001) compared to those treated with empagliflozin. Compared to baseline, all patients had reduced PBR, PWV and GLS (p < 0.001) after 12 months of treatment. However, empagliflozin presented a greater decrease in PWV (-14% vs. -10.9%, p = 0.041), while dulaglutide resulted in a greater increase in GLS (14.7% vs. 8.3%, p = 0.024) compared to empagliflozin. In all patients, the reduction in PBR at 12 months was correlated with a decrease in PWV and with an increase in GLS (p < 0.05). Conclusions: Both dulaglutide and empagliflozin improve cardiovascular function in T2DM patients with ischemic stroke. Dulaglutide appears to be more effective in the improvement of LV myocardial strain, whereas empagliflozin is more effective in reducing arterial stiffness.

Vascular aging is a key determinant of cardiovascular risk and is characterized by endothelial dysfunction, oxidative stress, inflammation, arterial stiffness, and alterations of the endothelial glycocalyx. In recent years, increasing scientific interest has focused on whether selected nutritional supplements can modulate these mechanisms. The objective of this narrative review is to summarize and critically evaluate the current evidence regarding the effects of selected nutritional supplements on endothelial function and vascular health, with emphasis on their proposed mechanisms of action, available preclinical and clinical evidence, and current limitations. This review examines nutritional supplements targeting nitric oxide biology (L-arginine/L-citrulline and citrulline derived from watermelon), polyphenol-rich foods and extracts (cocoa flavan-3-ols and grape polyphenols), mitochondrial redox balance (coenzyme Q10 and the mitochondria-targeted antioxidant MitoQ), endothelial glycocalyx-supporting formulations, olive-derived bioactive compounds, curcumin, and S-allyl cysteine. Across studies, improvements have been reported primarily in surrogate vascular endpoints, including flow-mediated dilation, pulse wave velocity, and blood pressure, although effect sizes vary and substantial heterogeneity exists among studies. Overall, current evidence suggests that several nutritional supplements may improve surrogate markers of vascular function; however, evidence demonstrating reductions in major cardiovascular events or cardiovascular mortality remains limited. Future research should prioritize adequately powered randomized controlled trials with longer follow-up, standardized supplement formulations, and clinically meaningful cardiovascular outcomes to more clearly define the role of nutritional supplements in cardiovascular prevention.

Aims:We investigated whether the early favourable effects of combined GLP-1 receptor agonist (GLP-1RA) and SGLT2 inhibitor (SGLT2i) therapy in left ventricular deformation is associated with long-term cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). We also addressed the healthcare costs. Methods and results:We enrolled 336 consecutive participants with T2DM, aged 60 ± 10 years old, 252/336 (75%) were males and were categorized into four groups: insulin, liraglutide, empagliflozin, and liraglutide+ empagliflozin. We measured at baseline and at 6 months left ventricular global longitudinal strain (LVGLS) via echocardiography. Patients were followed for 6 years and we recorded the incidence of composite endpoint of non-fatal cardiovascular events (myocardial infarction, heart failure hospitalization, ischaemic stroke, and coronary revascularization). Multivariable Cox regression models were built to assess associations between treatment groups, LVGLS changes, and outcomes. A cost analysis was also conducted. At 6 months LVGLS increased significantly (P = 0.020), with the greatest improvement observed in the combination group compared with insulin, GLP-1RA, and SGLT2i groups (P < 0.05). At 6-year follow-up, 91 events were recorded. Combination therapy was associated with the lowest risk of events (insulin vs. combination: HR = 4.36, 95% CI: 2.04-9.33, P < 0.001; GLP1-RA vs. combination: HR = 2.45, 95% CI: 1.06-5.64, P = 0.035; SGLT2i vs. combination: HR = 3.07, 95% CI: 1.38-6.81, P = 0.006). In combination group, improvement of LVGLS independently predicted reduced event risk (HR = 0.89, 95% CI: 0.79-0.98, P = 0.040). Combination group demonstrated the lowest mean cost per patient per month (insulin: 691€, 95% CI: 472-911; GLP1-RA: 224€, 95% CI: 44-404; SGLT2i: 528€, 95% CI: 305-751; Combination: 175€, 95% CI: 30-321). Conclusion:Combined GLP-1RA and SGLT2i therapy is associated with early improvement in myocardial deformation, which translates into reduced long-term cardiovascular risk and favourable economic outcomes. ClinicalTrials.gov Identifier: NCT03878706.

OBJECTIVE:Patients with type 1 diabetes (T1D) present early subclinical signs of vascular and endothelial dysfunction. Hybrid closed-loop systems (HCLSs) are the gold standard for glycemic management; however, their cardiovascular benefits remain unclear. The aim of this study is to determine whether HCLS improves vascular and endothelial function compared with multiple daily injections (MDIs) or sodium glucose cotransporter 2 inhibitors (SGLT-2is) in T1D. RESEARCH DESIGN AND METHODS:Ninety consecutive patients with poorly controlled T1D under MDI treatment were categorized into three groups according to the treatment approach: (1) HCLS or (2) SGLT-2i added to MDI or (3) intensification of MDI treatment. We assessed at baseline and 6 and 12 months posttreatment: (1) continuous glucose monitoring metrics, (2) pulse wave velocity (PWV) and central systolic blood pressure (cSBP) and central diastolic blood pressure (cDBP) as markers of vascular function, and (3) the perfused boundary region (PBR) of the sublingual arterial microvessels, as a marker of endothelial glycocalyx integrity. RESULTS:At 6 months, HCLS demonstrated the most significant increase in time in range (TIR) followed by SGLT-2i (+28.61 vs +10.91, P = 0.026) compared with MDI group (+2.11, P < 0.001 for all comparisons). At 12 months, patients on HCLS showed a 2-fold and a 4-fold higher increase in TIR compared with SGLT-2i (P = 0.026) and MDI group (P < 0.001), respectively. At 12 months, HCLS and SGLT-2i group displayed the most significant decrease in PWV (-15.71% and -10.14%), cSBP (-8.15% and -6.88%), and PBR (-6.98% and -8.98%) compared with MDI (+5.67%, +1.49%, and +1.99%, respectively; P < 0.05). The absolute change of PWV, PBR, and cSBP was associated with the absolute change of TIR (P < 0.05). CONCLUSIONS:MiniMedTM 780G HCLS demonstrated superiority over MDI or SGLT-2i in terms of glycemic control and cardiovascular function in T1D. These results support HCLS as a preferred therapeutic option for the prevention of cardiometabolic disease in individuals with T1D, in a population whose cardiovascular burden is often underrecognized in both research and clinical practice.

Aim: To investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular function and hepatic metabolism in patients with type 2 diabetes mellitus (T2DM) and metabolic-dysfunction associated steatotic liver disease (MASLD). Methods: This is an unblinded real-world study using propensity score analysis of consecutive patients with T2DM and MASLD received either SGLT-2i (dapagliflozin; n = 21), GLP-1RA (dulaglutide; n = 21), or dipeptidyl peptidase-4 inhibitors (DPP-4i; n = 20). At baseline and after 12 months, we assessed the perfused boundary region (PBR) as a marker of glycocalyx thickness, peripheral and central systolic blood pressure (cSBP), pulse wave velocity (PWV), coronary flow reserve (CFR), left ventricular global longitudinal strain (GLS), controlled attenuation parameter (CAP), and liver stiffness (E). Results: At 12 months, all patients had reduced glycosylated hemoglobin and body mass index compared to baseline ( P < 0.001), as well as a significant reduction in cSBP, PBR, PWV, CAP, E, and increase in CFR and GLS ( P < 0.01). The percentage decrease in peripheral and central SBP was related with the improvement in PBR, PWV, CFR, and GLS at 12 months ( P < 0.01). Dulaglutide showed greater improvement in GLS (22.6% vs. 8.5%, vs. 5.9%, P = 0.015) and PBR ( P = 0.037) than dapagliflozin and DDP-4i. Both dulaglutide and dapagliflozin showed a greater increase in CFR than DDP-4i post-treatment. The percentage reduction in CAP was associated with the decrease in PBR, PWV and with the increase in GLS ( P < 0.05). Conclusion: Twelve-month treatment with either SGLT-2i or GLP-1RA improves central hemodynamics, coronary flow and reduces hepatic steatosis in T2DM individuals with MASLD.

Type 2 diabetes mellitus is a chronic metabolic disorder associated with microvascular and macrovascular complications. Hyperglycemia and insulin resistance are core pathophysiological components of diabetes, linked to subclinical inflammation and persistent oxidative stress, which result in endothelial dysfunction and subsequent atherogenesis. Nowadays, several arrows in the diabetologist's quiver are available for the management of diabetes, providing flexibility and the ability to adopt a personalized approach tailored to each patient's needs. Two of the most commonly prescribed antidiabetic drugs are sodium-glucose cotransporter 2 inhibitors and glucagon- like peptide-1 receptor agonists. Both agents are associated with beneficial metabolic, cardioand nephro-protective effects independent of their antidiabetic properties; thus, their indications have and are continuously expanding over and beyond the treatment of diabetes. Given that these two drug classes have different mechanisms of action, the use of their combination achieves a synergistic interaction and confers additional benefits. The aim of this review is to provide a summary of current knowledge regarding the use of these two drug classes, shed light on the available evidence on their combination, and discuss future perspectives on optimal therapeutic decisions in clinical practice. Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in combination therapy are a promising therapeutic duo and are expected to influence future guidelines and decision-making in everyday clinical practice.

BACKGROUND:Coronavirus disease 2019 (COVID-19) has been associated with impaired endothelial and vascular function. We investigated whether intervention with glycocalyx dietary supplement (GDS), containing glucosamine sulfate and fucoidan, improves endothelial glycocalyx and vascular function after COVID-19 infection. METHODS:Fifty-seven convalescent patients 14 days after mild-to-moderate COVID-19 infection managed in an outpatient setting were randomized to receive GDS (n = 29) or placebo (n = 28) for 4 consecutive months. We measured at baseline and at 4 months: (a) perfused boundary region (PBR) of the sublingual microvessels with a diameter range of 4-25 μm, as a marker of endothelial glycocalyx integrity, (b) pulse wave velocity and augmentation index, (c) coronary flow reserve using Doppler echocardiography, and (d) malondialdehyde and protein carbonyls as oxidative stress markers. RESULTS:Four months after treatment, patients who received GDS showed a greater reduction in PBR 4-25 μm (-6.8% vs. -1.3%), pulse wave velocity (-13.2% vs. -3%), augmentation index (-28.5% vs. -2.5%), malondialdehyde (-26% vs. -2.9%), protein carbonyls (-31.3% vs. -1%) and a greater increase in coronary flow reserve (12.9% vs. 1.6%) compared to placebo (p < .05). In the GDS group, the reduction in PBR 4-25 μm was associated with the corresponding decrease in pulse wave velocity (r = .31, p = .047), malondialdehyde, and protein carbonyls, as well as with the increase in coronary flow reserve (r = -.59, p = .008) at follow-up. Post-treatment, none of the patients under GDS reported post-COVID symptoms compared to 21.4% of the patients under placebo. CONCLUSION:Four-month treatment with GDS may improve endothelial glycocalyx and vascular function after COVID-19 infection. CLINICAL TRIAL REGISTRATION:URL: https://www. CLINICALTRIALS:gov. Unique identifier: NCT05185934.

Background: Retinal vein occlusion (RVO) is a relatively uncommon condition with a complex pathophysiology. However, its association with traditional cardiovascular risk factors is well established. In this study, we compared arterial stiffness and endothelial function between patients with RVO and healthy controls. Methods: We enrolled 28 consecutive patients with RVO, either central (CRVO) or branch (BRVO), and 30 healthy controls. We measured: (i) perfused boundary region of the sublingual arterial microvessels (a marker of endothelial glycocalyx thickness), (ii) pulse wave velocity (PWV), augmentation index (AIx), and central systolic blood pressure (cSBP). Results: No statistically significant differences regarding age, gender, and major cardiovascular risk factors were noted between patients and controls. Compared to controls, patients with RVO had higher PBR, PWV, AIx, and cSBP values (p < 0.05). For each of these indices, no statistically significant differences were noted between patients with CRVO and BRVO (p > 0.05). Conclusions: Patients with RVO demonstrated reduced endothelial glycocalyx thickness and increased arterial stiffness compared to healthy controls. These findings further elucidate the role of atherosclerosis and endothelial dysfunction in the pathophysiology of the disease and indicate the need for the evaluation of subclinical cardiovascular disease in such patients.

Polycystic ovary syndrome (PCOS) is a complex endocrine disease. This study investigates the relationship between endothelial function, insulin resistance, and hormonal profiles in women with PCOS. Forty women with PCOS were included: metformin (n = 20), GLP1-RAs (n = 10), and oral contraceptive pills (n = 10). A 75 g oral glucose tolerance test (OGTT) was performed, and the 0, 60, and 120 min insulin, glucose, and endothelial functions were evaluated. The postprandial and fasting state Matsuda Index and HOMA Index were measured. All measurements were performed at baseline and at a 6-month follow-up. At baseline, the percentage change in the Perfused Boundary Region (PBR) was associated with the percentage change in glucose at 120 min of the OGTT (r = 0.42, p < 0.05). The Matsuda Index, Homa Index, and testosterone levels were associated with the PBR (2.91 ± 0.1 μm) at 120 min of the OGTT (r = 0.41, r = 0.38 and r = 0.28, respectively). MMP9 levels were associated with the Matsuda and Homa Index (r = 0.45, p < 0.05 and r = 0.41, p < 0.05, respectively). At the 6-month follow-up, all the participants presented improvements of the Matsuda Index (7 ± 0.31 vs. 9.1 ± 0.2), Homa Index (5.3 ± 0.8 vs. 2.91 ± 0.1), MMP9 (210 ± 30 vs. 178 ± 28 ng/mL), and testosterone levels (44.2 ± 5 vs. 39.1 ± 2 ng/dL) compared to the baseline (p < 0.05 for all the comparisons). Patients who received GLP1-RA agonists presented the greatest improvement in MMP9 levels. Postprandial hyperglycemia, insulin resistance, and testosterone levels are associated with an impaired glycocalyx thickness in women with PCOS.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

ST elevation myocardial infarction (STEMI) patients display endothelial dysfunction. We investigated whether endothelial glycocalyx thickness is affected in STEMI patients and may predict left ventricular performance post event. We examined 278 STEMI patients and 140 matched controls. We measured: (a) perfused boundary region (PBR) of the sublingual microvessels (range 4 to 25 μm; increased value indicates reduced endothelial glycocalyx integrity) at baseline; (b) left ventricular ejection fraction (LVEF) and global longitudinal strain (LVGLS), at baseline and at 12 months, (c) the percentage change of left ventricular end-systolic volume (ΔLVESV) at 12 months. Compared with matched controls, STEMI patients had higher PBR4–25 (2.11 ± 0.17 μm vs. 1.98 ± 0.20 μm, p < 0.001). In a model including age, sex, hypertension, diabetes, hyperlipidemia, smoking, family history of coronary artery disease, number of diseased vessels, location of STEMI medication, and high-sensitivity troponin T (hs-troponin), PBR4–25 was independently associated with LVEF and LVGLS at 48 hours post-MI (for LVEF: unstandardized β coefficient: −4.71, 95% CI: −8.53 to −0.71, p = 0.019 and for LVGLS: 2.89, 95%CI: 1.63–4.16, p < 0.001). Using multivariable analysis, PBR4–25 remained a significant predictor of the percentage change in LVEF, LVGLS, and ΔLVESV at 12-month follow-up (LVEF change: unstandardized β coefficient: −1.38, 95% CI: −1.80 to −0.96, p < 0.001; for LV GLS change: −0.66, 95% CI: −1.14 to −0.18, p = 0.007 and for ΔLVESV: 1.42, 95% CI: 0.06–2.93, p = 0.039). A PBR4–25 cut-off value of 2.29 μm could detect LV EF less than 45% at 48 h as well as at 12 months (AUC: 0.82, p < 0.001 and AUC: 0.80; p < 0.001). Endothelial glycocalyx assessment is associated with myocardial performance after STEMI.

Background We investigated the effects of the combined treatment with glucagon like peptide‐1 receptor agonists (GLP‐1RA) and sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) on NT‐proBNP (N‐terminal pro‐brain natriuretic peptide), GDF‐15 (growth differentiation factor 15), and MOTS‐c (mitochondrial‐derived peptide‐c) in patients with type 2 diabetes (T2D) and high or very high cardiovascular risk. Methods We studied 163 consecutive patients with type 2 diabetes who were treated with insulin (n=40), liraglutide (n=41), empagliflozin (n=42), or their combination (GLP‐1RA+SGLT‐2i) (n=40) and were matched using propensity score analysis. We measured the following at baseline and 4 and 12 months of treatment: (1) NT‐proBNP, GDF‐15, and MOTS‐c; (2) 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid), and (3) left ventricular global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index using speckle‐tracking imaging. Results At 12 months, GLP‐1RA, SGLT‐2i, and their combination showed a greater reduction of NT‐proBNP (−43.1% versus −54.2% versus −56.9% versus −14.7%) and GDF‐15 than insulin. Only treatment with SGLT‐2i and GLP‐1RA+SGLT‐2i improved MOTS‐c. GLP‐1RA, SGLT‐2i, or GLP‐1RA+SGLT‐2i provided an increase of global longitudinal strain, left atrial strain, and global work index compared with insulin. In all patients, the reduction of NT‐proBNP was associated with the improvement of global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index; the decrease of GDF‐15 with the increase of ABTS and MOTS‐c; and the increase of MOTs‐c with improved global longitudinal strain and constructive myocardial work at 12 months (P<0.05). Conclusions Twelve‐month treatment with combination of GLP‐1RA+SGLT‐2i was associated with a greater reduction of neurohumoral markers and increase of antioxidant ability than each treatment alone and insulin. SGLT‐2i appear more effective in the improvement of neurohumoral and mitochondrial activation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03878706.

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/ Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca2⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs.

Abstract Background Arterial stiffness has been shown to be an independent additive predictor to several traditional risk factors regarding cardiovascular events. Purpose We studied in a prospective cohort whether arterial stiffness has an additive value to SCORE2 in predicting cardiovascular risk. Methods In 747 healthy subjects, we measured carotid-to-femoral pulse wave velocity (PWV), a marker of aortic stiffness. We prospectively documented the incidence of cardiovascular events (major adverse cardiovascular events [MACE]-death, stroke and myocardial infarction) during a 6-year follow-up period. Results Sixty MACE were recorded. Increased values of PWV predicted greater risk for MACE in a model including diabetes, smoking, hypertension, hyperlipidemia, sex and age (hazard ratio (HR)=1.09; 95%CI=1.03 – 1.14; p<0.001, Chi-square change = 8.05; p=0.004; c-statistic increased from 0.74 (0.66 – 0.81) to 0.77 (0.71 – 0.83), p=0.025). PWV was an independent and additive predictor of events when added in a model encompassing the SCORE2 and diabetes (HR=1.07; 95%CI=1.04 – 1.11; p<0.001, Chi-square change = 43.12; p<0.001, c-statistic increased from 0.73 (0.66 - 0.80) to 0.76 (0.70 - 0.82); p=0.014). Also PWV predicted significantly the occurrence of events in all subgroups of each risk factor (for smokers and non-smokers: HR=1.31 and HR=1.11 respectively; for participants with hypertension and participants without hypertension: HR=1.23 and HR=1.12 respectively; for participants with hyperlipidemia vs participants without hyperlipidemia: HR=1.19 and HR=1.12 respectively; for participants with diabetes and participants without diabetes HR=1.19 and HR=1.12 respectively) (p<0.05 for all subgroups). Conclusion PWV confers an additive prognostic value to SCORE2 in primary prevention.

Abstract Background/Aim HIV infection is related with cardiovascular adverse events. We investigated the effects of antiretroviral treatment in myocardial and vascular function of newly diagnosed patients with HIV. Patients and methods A total of 70 newly diagnosed HIV patients (41.2±8.7 years old, 87 % male) were enrolled. Patients were randomized to the newer integrase inhibitor Dolutegravir or to the older protease inhibitor Darunavir/Cobicistat. We measured at baseline and 12 months posttreatment: (a) Left Ventricular (LV) Global Longitudinal Strain (GLS), (b) LV Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE), (c) Coronary Flow Reserve (CFR) of Left Anterior Descending Artery. At baseline, we compared the HIV patients with 35 healthy matched controls. Results At baseline patients with HIV had impaired myocardial function, endothelial function and endothelial glycocalyx compared with healthy controls. Twelve months after intervention HIV patients improved myocardial function, as assessed by GLS, GWI, GCW, GWW and GWE (p<0.05). Moreover, twelve months after intervention HIV patients improved endothelial function, as evaluated by an increase in CFR and a decrease in PBR5-25 (p<0.05). Response to therapy was similar between the two groups of treatment. Nevertheless, in HIV patients 12 months post treatment myocardial, endothelial function and endothelial glycocaylyx was impaired in comparison with healthy controls. Conclusions Treatment with antiretroviral therapy partially improves myocardial and arterial function 12 months post treatment.