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Background/Introduction Biomarkers of oxidative stress burden are found increased in Type-2 diabetes mellitus (T2DM) patients. An imbalance between oxidative and antioxidative plasma factors is implicated in the pathway of cardiovascular disease in diabetics. Novel antidiabetic agents with cardioprotective effects are glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Purpose We investigated the effect of liraglutide (GLP1-RA),empagliflozin (SGLT-2i) and their combination on plasma levels of oxidative and antioxidative factors. Methods A hundred-sixty T2DM patients were randomly assigned and received: a) insulin (n=40), b) liraglutide (n=40), c) empagliflozin (n=40) and d) the combination liraglutide and empagliflozin (n=40) for 1 year. We measured at baseline and after 1 year of treatment the following antioxidative markers: a) Reducing Power (RP), b) 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), c) Total Antioxidant Capacity (TAC) and also Thiobarbituric acid reactive substances (TBARS) as a marker of oxidative burden. Results After 1 year of treatment all subjects achieved successful glycemic regulation, as estimated by Hemoglobin A1c (HbA1c) levels (8±0.5 vs 6.65±0.5, p Conclusion One year treatment with the GLP1-RA liraglutide and SGLT2i empagliflozin resulted in improvement of plasma levels of oxidative and antioxidative biomarkers compared to administration of insulin and the changes were more outstanding in patients that received the combination of GLP1-RA and SGLT2i, despite similar glycemic regulation in all participants. Thus the favorable cardiovascular effects of these novel factors may be partly explained by alterations in equilibrium between oxidative and antioxidative circulating biomarkers. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Oxidative stress plays an important role in the pathogenesis of type 2 diabetes. Purpose We investigated oxidative stress in first-degree relatives of type-2 diabetes patients (FDR) since they are more prone to develop type-2 diabetes, at baseline and during postprandial hyperglycemia in comparison with dysglycaemic or normoglycaemic subjects. We evaluated these results in relation to vascular function. Methods We studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic) with similar demographical and clinical characteristics. Glucose and insulin levels, pulse wave velocity (PWV-Complior, ALAM), central systolic blood pressure (cSBP) and augmentation index (AI) were measured at baseline, 30, 60, 90 and 120min during OGTT. Perfused boundary region (PBR-Microscan, Glycocheck) of the sublingual arterial microvessels (high PBR values represent reduced glycocalyx thickness), plasma concentrations of malondialdehyde (MDA) and protein carbonyls (PCs) as markers of lipid peroxidation and protein oxidation, respectively, and nitrite/nitrates levels as markers for NO biosynthesis, were assessed at baseline and at 120min of OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). Results FDR and dysglycaemics patients had higher fasting insulin, reduced ISI, Matsuda index as well as increased PBR (2.5±0.5 vs. 2.5±0.6 vs. 2.4±0.3μm), increased PWV (8.9±1.1 vs. 10.3±2.4 vs. 8.0±1.5m/s), AI, MDA, PCs and nitrite/nitrate than normoglycaemic subjects (p Conclusions Insulin resistance determines acute endothelial responses during postprandial hyperglycemia leading to reduced NO production and thus facilitating augmentation of oxidative stress during postprandial hyperglycemia in dysglycaemic patients and FDR of diabetic patients. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Type-2 diabetes mellitus (T2DM) exacerbates mechanisms of atherosclerosis and heart failure. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on LV myocardial function of T2DM patients. Methods A hundred-sixty T2DM patients (age: 58±10 years) were randomized to insulin (n=40), liraglutide (n=40), empagliflozin (n=40) or their combination (GLP-1RA+SGLT-2i) (n=40) as add-on to metformin. We measured at baseline, 4 and 12 months post-treatment: a) global LV longitudinal strain (GLS), systolic (LongSr) and diastolic (LongSrE) strain rate, global circumferential (GCS) and radial (GRS) strain, peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel), b) global myocardial global work index (GWI), global constructive (GCW) and global wasted myocardial work (GWW) derived by pressure-myocardial strain loops using speckle tracking imaging. Results At 4 and 12 months post-treatment, all patients improved GLS, GCS, GRS and pUtwVel (p Conclusions Twelve-month treatment with GLP-1RA or combination of GLP-1RA and SGLT-2i showed a greater improvement of myocardial deformation and effective cardiac work than insulin or SGLT-2i treatment in T2DM. The combined therapy as second line was superior to either insulin, or GLP-1RA and SGLT-2i separately. Funding Acknowledgement Type of funding source: None

Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with endothelial and myocardial dysfunction. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on vascular and cardiac function of T2DM patients. Methods A hundred-sixty T2DM patients were randomized to insulin (n=40), liraglutide (n=40), empagliflozin (n=40) or their combination (GLP-1RA+SGLT-2i) (n=40) as add-on to metformin. We measured at baseline, 4 and 12 months post-treatment: a) perfused boundary region (PBR) of the sublingual arterial microvessels (marker of glycocalyx thickness), b) pulse wave velocity (PWV), central systolic blood pressure (cSBP), c) global LV longitudinal (GLS), circumferential (GCS) and radial (GRS) strain, d) the ratio PWV/GLS, as an index of ventricular-arterial interaction, e) myocardial work index (GWI) using speckle tracking imaging. Results Twelve months post-treatment, all patients improved PBR, PWV, GLS, GCS and GRS (p Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination showed a greater improvement of vascular markers and effective cardiac work than insulin in T2DM. The combined therapy was superior to either insulin, or GLP-1RA and SGLT-2i separately. Funding Acknowledgement Type of funding source: None

Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with endothelial and arterial dysfunction. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i)and their combination on endothelial and arterial function of T2DM patients. Methods A hundred-sixty T2DM patients (age: 58±10 years) were randomized to insulin (n=40), liraglutide (n=40), empagliflozin (n=40) or their combination (GLP-1RA+SGLT-2i) (n=40)as add-on to metformin. We measured at baseline, 4 and 12 months post-treatment: a) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5 to 25μm) using Sideview Darkfield imaging. Increased PBR indicates reduced glucocalyx thickness, b) pulse wave velocity (PWV-Complior), central systolic blood pressure (cSBP) and augmentation index (AI) of the aortic pulse wave. Results Twelve months post-treatment, all patients improved PBR, PWV and AI (p Conclusions Twelve-month treatment with SGLT-2i and its combination with GLP-1RA, showed a greater improvement on arterial elastic properties than GLP1RA or insulin treatment in T2DM. The combined therapy as second line was superior to either insulin, or GLP-1RA and SGLT-2i separately. Funding Acknowledgement Type of funding source: None

Introduction Sodium glucose cotransporters inhibitors (SGLT2i) are currently used in the treatment of patients with type 2 diabetes mellitus (T2DM) who pose high cardiovascular risk. However their effects on arterial stiffness, endothelial function and ventriculoarterial coupling have not been described. Methods We recruited 120 patients with T2DM. They received either the SGLT2i empagliflozin (n=60) or insulin (n=60). We measured at baseline and after 1 year of treatment: 1) Perfused Boundary Region (PBR 5–25μm) to evaluate endothelial glycocalyx integrity via Glycocheck, 2) Pulse wave Velocity (PWVc-f), 3)central systolic blood pressure (cSBP), 4) central Pulse Pressure (cPP) via Complior,5) the ratio PWV/GLS by echocardiography to assess ventriculoarterial coupling (VA coupling). Results The patients were matched for age, gender, smoking, hypertension and hyperlipidemia (p=NS). Hemoglobin A1c was deteriorated in both groups (8.1% vs 8.2%, p=NS). The baseline measurements of aforementioned markers did not differ between the 2 groups (p=NS). PWV was correlated with cSBP (r=0.4.p Conclusion 1 year treatment with empagliflozin resulted in improved markers of arterial stiffness, ventriculoarterial coupling and endothelial function, independently of glycemic control. Funding Acknowledgement Type of funding source: None

Background and aims Chemotherapy is known for its potential adverse effects on myocardium. Optimal medical treatment for heart failure may reverse myocardial dysfunction in the early stages of toxicity development. We hypothesized that early initiation of treatment with Angiotensin Converter Enzyme inhibitor (ACE-i) enalapril could prevent cardiotoxicity. Patients and methods 60 patients (mean age 46,3±12,9 years old, 19 male) with preserved ejection fraction, who suffered from hematologic malignancies (lymphoma, leukemia) and underwent bone marrow transplantation and were randomized to receive 2,5 mg enalapril bid daily or placebo. We measured at baseline, before transplantation, and after three months: i) Global Longitudinal Strain of left ventricle (LV) (GLS), ii) Left Ventricular Epicardial Strain (GLSepi), iii) Left Ventricular Endocardial Strain GLSendo), by speckle tracking imagind iv) Left Ventricular End Diastolic Volume, Left Ventricular End Systolic Volume and Left Ventricular Ejection Fraction (LVEF-Simpson's Method). Results The two treatment groups had similar age, sex atherosclerotic risk factors and cardiotoxic medication befeor and after bone marroe transplantation. Compared to baseline, patients treated with enalapril did not show a deterioration of LV GLS and GLSepi [(GLS = −20.2±3.6% vs 19.7±3.7%, p=0.540), (GLSepi = −17.9±3.1% vs −17.2±3.2%, p=0.422)], Conversely, patients treated with placebo group, presented a significant impairment of LV GLS and GLSepi [(GLS = −20.2±1.8% vs 18.9±2.1%, p=0.041, GLSepi = −17.8±1.5% vs −16.6±1.7%, p=0.028)] three months after bone marrow transplantation. No significant changes were found in LVEF after treatment with enalapril (58.6±17.6% vs 59.4±9.2%, p=0.692) or the placebo (59.4±6.6% vs 59.7±6.8%, p=0.892). Conclusions Treatment with enalapril prevented deterioration of myocardial deformation three months after bone marrow transplantation in patients with hematologic malignancies and preserved ejection fraction. Funding Acknowledgement Type of funding source: None

Background/Introduction Tocilizumab, an interleukin-6 receptor blocker is used for the treatment of rheumatoid arthritis (RA). Purpose We investigated the effects of tocilizumab on endothelial glycocalyx and myocardial function in patients with RA. Methods Eighty patients with RA (age: 64±9 years) were randomized to tocilizumab (n=40) or prednisolone (n=40)for 3 months. We measured at baseline and 3 months post-treatment: a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), b) pulse wave velocity (PWV-Complior), central systolic blood pressure (cSBP) and augmentation index (AI), c) global LV longitudinal strain (GLS), longitudinal systolic (LongSr) and diastolic (LongSrE) strain rate, d) global myocardial work index (GWI), global constructive (GCW) and global wasted work (GWW) using speckle tracking imaging. Results At baseline, all patients had similar disease activity score and markers of vascular and myocardial function. Compared with baseline, patients under tocilizumab had reduced PBR (2.14±0.2 vs. 1.97±0.2μm), PWV (11±3 vs. 10.3±2m/s), cSBP (134±18 vs. 129±16mmHg) and LongSrE (0.91±0.3 vs. 1±0.3 1/s) at 3 months (p0.05) (Table). Compared with prednisolone, tocilizumab treatment achieved a greater increase of GLS (8.5% vs. 2.4%), GWI (12.2% vs. 2.7%), GCW (10.3% vs. 5.9%) and a greater reduction of GWW (−30% vs. −13%) (p Conclusions IL-6 inhibition by tocilizumab improves endothelial and vascular function leading to a greater increase of effective myocardial work compared to prednisolone in patients with RA. Funding Acknowledgement Type of funding source: None

Background Cardiopulmonary exercise testing (CPET) has been recognized as a valuable tool regarding the integrated estimation of exercise ability in patients with several cardiopulmonary diseases, dilated cardiomyopathy (DCM) included. Left ventricular (LV) abnormal myocardial deformation might be studied by newer echocardiography techniques. Aim of this study is to explore differences of LV myocardial deformation in DCM patients during a CPET session. Methods Forty-four DCM patients (mean age 53±13 years, 34 men) with an ejection fraction Results All patients finished uneventfully CPET (peakVO2 = 20±7 ml/min/kg) and improved GLS at peak exercise (GLS difference = 1.5±2). We found that at peak exercise, systolic blood pressure (SBP) was increased (119±14 vs. 159±23 mmHg, p Relationship between GLS dif and CPET Conclusions Patients with dilated cardiomyopathy and ejection fraction

Background Cardiovascular risk estimation in arterial hypertension includes the investigation for target organ damage indices (TOD). 24h ambulatory blood pressure monitoring (ABPM) represents the gold standard method for the confirmation of the arterial hypertension disease. Dipping phenomenon, defined as blood pressure decrease >10% during night-time measurements, leads to hypertension burden reduce during night and carries a positive prognostic significance. However, there are doubts regarding its prognosis when it becomes augmented (extreme dipping defined as blood pressure decrease >20% during night-time measurements). Aim of our study is to explore TOD existence between extreme dipper and dipper hypertensive patients with newly diagnosed and never treated arterial hypertension. Methods From the 480 total patients with newly diagnosed and never treated arterial hypertension who subjected to ABPM, we excluded 190 non-dipper patients and we divided the rest 290 hypertensives (mean age 49±11 years, 193 males) in normal dippers (n=245, mean age 49±11 years, 160 males) and extreme dippers (n=45, mean age 49±10 years, 33 males). Both groups were subjected to the following measurements: arterial stiffness (PWV), 24h microalbumin levels (MAU), carotid intima-media thickness (IMT), diastolic dysfunction (E/Ea), left ventricular mass index (LVMI) and coronary flow reserve (CFR). Results We did not find any differences within groups regarding age, sex distribution, BMI, office SBP/DBP, cenrtal SBP/DBP and daytime average SBP/DBP as well as PWV, MAU, IMT, E/Ea and CFR. We noticed that extreme dippers had reduced 24h average SBP/DBP (p=0.001 and p=0.02, respectively) and increased LVMI (86±18 vs. 79±20 gr/m2, p=0.04) compared to normal dippers. Differences in LVMI Conclusions Extreme dipper hypertensive patients have an increased LVMI, probably as a result of myocardial hypoxia due to severe blood pressure reduction over night. Our results point to the possible increased cardiovascular risk in this group of hypertensive patients.

Glucagon like peptide-1 analogues (GLP-1A) and sodium-glucose co-transporter 2 (SGLT2) are used in the treatment of type 2 diabetes mellitus (T2DM) We investigated whether the effects of treatment with GLP-1A and SGLT2 and their combination on vascular and cardiac function. Methods A hundred twenty, patients with type 2 diabetes were randomized to receive the insulin +/− metformin (n=30), GLP-1A, liraglutide (n=30), the SGLT-2, empagliflozin (n=30) or their combination (GLP-1R+SGLT-2) for 3 months (n=30). We measured at baseline and after treatment a) pulse wave velocity (PWV), central systolic blood pressure (cSBP) b) the perfusion boundary region (PBR-micrometers) of the sublingual arterial microvessels, as a marker of endothelial glycocalyx thickness. c) global LV longitundinal strain (GLS), peak LV untwisting velocity and global myocardial work index (GWI) derived by pressure–myocardial strain loops using speckle tracking imaging and PWV to GLS ratio, as a marker of ventricular-arterial coupling Results All treatment groups had similar vascular and cardiac markers, glucose levels and HbA1 at inclusion (p>0.05). After treatment, all patients had improved GLS, PWV and increased LV twisting-untwisting velocities (p N=120 Insulin GLP-1A SGLT-2 GLP-1A + SGLT-2 P 3-months N=30 N=30 N=30 N=30 PBR, μm 2.27±0.3 2.17±0.3 2.17±0.3 1.99±0.2 Conclusion Three-month treatment with GLP-1A, SGLT-2 and their combination showed a greater improvement of vascular markers, ventricular-arterial coupling and effective cardiac work than insulin treatment in type 2 diabetes.

Background Blood pressure variability (BPV) has been associated with development, progression and severity of cardiac and vascular organ damage and with an increased risk of cardiovascular events and mortality, independently adding to cardiovascular risk, over and above the contribution of elevated mean BP levels. We aimed to explore any correlation between differences in BPV and target organ damage indices (TOD) in hypertensive patients three years after medical treatment initiation. Methods At baseline and before medical treatment initiation, we measured 24h average SBP and DBP as well as 24h systolic BPV after 24h ambulatory blood pressure monitoring (ABPM) in newly diagnosed and never treated hypertensive patients (n=171, mean age=52+12 years, 110 males, 24h average SBP/DBP=138+10/87+9 mmHg, 24h systolic BPV=15+3) who were also subjected to arterial stiffness by carotid-femoral pulse wave velocity (PWV), left ventricular hypertrophy by left ventricular mass index (LVMI) and coronary flow reserve (CFR) estimations. All the above tests were repeated approximately three years later after treatment initiation. Results Patients were characterized as controlled (n=113, mean age=54+12 years, 62 males, 24h average SBP/DBP=118+6/71+6 mmHg) or non-controlled hyperensives (n=58, mean age=48+11 years, 48 males, 24h average SBP/DBP=133+8/83+7 mmHg) based on ABPM results three years later (controlled BP=24h average BP Correlation between BPV and LVMI Conclusions It seems that antihypertensive-induced systolic BPV improvement relate with cardiovascular risk decrease occur only in the setting of blood pressure treated within normal limits and confirmed by ABPM. Our study confirms that left ventricular mass between other TOD primarily improves due to successful antihypertensive treatment.