Six-month supplementation with high dose coenzyme Q10 improves liver steatosis, endothelial, vascular and myocardial function in patients with metabolic-dysfunction associated steatotic liver disease: a randomized double-blind, placebo-controlled trial.

BACKROUND: Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) has been associated with increased cardiovascular risk. The aim of this Randomized Double-blind clinical Trial was to evaluate the effects of coenzyme-Q10 supplementation in patients with MASLD in terms of endothelial, vascular and myocardial function. METHODS: Sixty patients with MASLD were randomized to receive daily 240 mg of coenzyme-Q10 or placebo. At baseline and at 6-months, the a)Perfused boundary region of sublingual vessels using the Sideview Darkfield imaging technique, b)pulse-wave-velocity, c)flow-mediated dilation of the brachial artery, d)left ventricular global longitudinal strain, e)coronary flow reserve of the left anterior descending coronary artery and f)controlled attenuation parameter for the quantification of liver steatosis were evaluated. RESULTS: Six months post-treatment, patients under coenzyme-Q10 showed reduced Perfused boundary region (2.18 ± 0.23vs.2.29 ± 0.18 µm), pulse-wave-velocity (9.5 ± 2vs.10.2 ± 2.3 m/s), controlled attenuation parameter (280.9 ± 33.4vs.304.8 ± 37.4dB/m), and increased flow-mediated dilation (6.1 ± 3.8vs.4.3 ± 2.8%), global longitudinal strain (-19.6 ± 1.6vs.-18.8 ± 1.9%) and coronary flow reserve (3.1 ± 0.4vs.2.8 ± 0.4) compared to baseline (p < 0.05). The placebo group exhibited no improvement during the 6-month follow-up period (p > 0.05). In patients under coenzyme-Q10, the reduction in controlled attenuation parameter score was positively related to the reduction in Perfused boundary region and pulse wave velocity and reversely related to the increase in coronary flow reserve and flow-mediated dilation (p < 0.05 for all relations). CONCLUSIONS: Six-month treatment with high-dose coenzyme-Q10 reduces liver steatosis and improves endothelial, vascular and left ventricle myocardial function in patients with MASLD, demonstrating significant improvements in micro- and macro-vasculature function. TRIAL REGISTRATION: NCT05941910.

Association of aortic stiffness early post myocardial infarction with left ventricular remodelling.

BACKGROUND: Adverse left ventricular (LV) remodelling after myocardial infarction is associated with heart failure. We investigated whether aortic stiffness during acute ST-segment elevation myocardial infarction is associated with LV remodelling at long-term follow-up. METHODS: In 109 patients within 48 h of myocardial infarction post-primary percutaneous coronary intervention and after 2 years, we measured: (a) carotid to femoral pulse wave velocity (PWV), (b) LV global longitudinal strain (GLS) and left atrial strain using speckle-tracking echocardiography, (c) PWV/GLS ratio as a surrogate marker of ventricular-arterial interaction, and (d) LV end-diastolic and end-systolic volumes. A > 15% decrease from the baseline in LV end-systolic volume at 2-year follow-up was considered as a criterion of reverse LV remodelling. RESULTS: Compared with baseline, all patients had reduced PWV, LV end-diastolic and end-systolic volumes while PWV/GLS, GLS and reservoir left atrial strain were improved (p < .05) after 2 years. Baseline values of PWV, GLS, PWV/GLS ratio and reservoir left atrial strain were associated with percentage change of LV end-systolic volume at 2 years (p < .05). Multivariable analysis revealed that lower baseline values of PWV and a less impaired GLS and PWV/GLS were independently associated with reverse LV remodelling at 2 years with a C-statistic of .748, .711 and .787, respectively. CONCLUSION: Aortic stiffness early post-infarction determines LV remodelling after 2 years of the ischemic event despite post successful revascularization. CLINICAL TRIAL REGISTRATION-URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT03984123, 30/04/2020.

Effects of Liraglutide, Empagliflozin and Their Combination on Left Atrial Strain and Arterial Function.

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are cardioprotective drugs. We investigated their effects on left atrial function, a major determinant of cardiac diastolic dysfunction in type 2 diabetes mellitus. We also explored the association of changes in arterial stiffness with those of the LA strain after treatment. Materials and Methods: A total of 200 patients (59.5 ± 9.1 year old, 151 male) with type 2 diabetes mellitus treated with metformin were randomized to insulin (n = 50 served as controls), liraglutide (n = 50), empagliflozin (n = 50) or their combination (liraglutide + empagliflozin) (n = 50). We measured at baseline and 6 months post-treatment: (a) left atrial and global left ventricular longitudinal strain by speckle tracking echocardiography; (b) pulse wave velocity (PWV) and central systolic blood pressure. Results: At baseline, there was a correlation of the LA reservoir strain with PWV (r = -0.209, p = 0.008), central SBP (r = -0.151, p = 0.030), EF (r = 0.214, p = 0.004) and GLS (r = -0.279, p = 0.009). The LA reservoir change 6 months post-treatment was correlated with the PWV change in all groups (r = -0.242, p = 0.028). The LA reservoir change 6 months post-treatment was correlated with the GLS change in all groups (r = -0.322, p = 0.004). Six months after intervention, patients treated with liraglutide, empagliflozin and their combination improved the left atrial reservoir strain (GLP1RA 30.7 ± 9.3 vs. 33.9 ± 9.7%, p = 0.011, SGLT2i 30 ± 8.3 vs. 32.3 ± 7.3%, p = 0.04, GLP1&SGLT2i 29.1 ± 8.7 vs. 31.3 ± 8.2, p = 0.007) compared to those treated with insulin (33 ± 8.3% vs. 32.8 ± 7.4, p = 0.829). Also, patients treated with liraglutide and the combination liraglutide and empagliflozin had improved left atrial conduction strain (p < 0.05). Empagliflozin or the combination liraglutide and empagliflozin showed a greater decrease of PWV and central and brachial systolic blood pressure than insulin or GLP-1RA. (p < 0.05). Conclusions: Impaired aortic elastic properties are associated with a decreased LA strain in type 2 diabetics. Treatment with liraglutide, empagliflozin and their combination for 6 months showed a greater improvement of left atrial function compared to insulin treatment in parallel with the improvement of arterial and myocardial functions.

Association of hydroxytyrosol enriched olive oil with vascular function in chronic coronary disease.

BACKGROUND: Hydroxytyrosol reduces low-density lipoprotein oxidation, contributing to prevention of atherosclerosis progression. METHODS: In a prospective, crossover, double-blind, placebo-controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1 month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow-mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment. RESULTS: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 ± .3 vs. 1.7 ± .4 µm, p = .040, 3.7 ± 2.1 vs. 6.5% ± 2.3%, p < .001, 2.3 ± .4 vs. 2.5 ± .4, p = .030 and 11.1 ± 1.8 vs. 11.8 ± 2.3 m/s, p = .002) while there was no effect after placebo (p = NS). No effect of OOHT treatment was observed on blood pressure. There was a parallel improvement of E' of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p < .05) but not after placebo. Compared to baseline, treatment with OOHT reduced malondialdehyde, a marker of lipid peroxidation, oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p < .05) in contrast to placebo. CONCLUSIONS: Hydroxytyrosol-enriched olive oil may have beneficial effects on endothelial, arterial and LV diastolic function likely by reducing oxidative and inflammatory burden in CCAS, though further studies are needed to confirm this mechanism.

Point of care transthoracic echocardiography for the prediction of post - spinal anesthesia hypotension in elderly patients with cardiac diseases and left ventricular dysfunction : Inferior vena cava and post-spinal anesthesia hypotension in elderly patients.

In elderly patients with cardiac diseases, changes in cardiovascular physiology diminish cardiovascular reserve and predispose to hemodynamic instability after spinal anesthesia; hence, such patients could be at risk of postoperative complications. Additionally, transthoracic echocardiography (TTE) is used in clinical practice to evaluate cardiovascular hemodynamics. Therefore, we hypothesized that echocardiographic measurements could display significant diagnostic power in the prediction of post - spinal anesthesia hypotension in elderly patients with cardiac diseases and reduced left ventricular ejection fraction (LV-EF). Therefore, sixty-one elderly orthopedic-trauma patients were recruited. Prior to spinal anesthesia a TTE examination was performed. The LV-EF, the stroke volume index (SVI), the peripheral vascular resistance (PVR), the LV filling pressures (E/Em ratio), the right ventricular function [tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TASV) and fractional area change (FAC)], as well as inferior vena cava (IVC) measurements, such as IVCCI (collapsibility index of the IVC) and dIVCmax (maximum diameter of IVC)-to-IVCCI ratio were assessed. Twenty-six out of sixty-one patients manifested hypotension. Preoperative dIVCmax-to-IVCCI ratio demonstrated the greatest performance amongst echocardiographic indices in predicting post - spinal anesthesia hypotension. The dIVCmax-to-IVCCI ratio < 48 had significantly higher diagnostic power than IVCCI > 0.28, FAC > 42, E/Em ratio < 9 and SVI < 32 (receiver operator characteristic curve analysis). The gray zone for the dIVCmax-to-IVCCI ratio (40-49) showed the lowest number of inconclusive measurements among echocardiographic variables. The preoperative dIVCmax-to-IVCCI ratio could be a reliable echocardiographic index to predict post - spinal anesthesia hypotension in elderly patients with left ventricular dysfunction.

Cardiac imaging in cardiotoxicity: a focus on clinical practice.

Cancer therapeutics induced cardiotoxicity has emerged as an important factor of long-term adverse cardiovascular outcomes in survivors of various malignant diseases. Early detection of myocardial injury in the setting of cancer treatment is important for the initiation of targeted cardioprotective therapy, in order to prevent irreversible cardiac dysfunction and heart failure, while not withholding a potentially life-saving cancer therapy. Cardiac imaging techniques including echocardiography, cardiac magnetic resonance, and nuclear cardiac imaging are the main tools for the identification of cardiotoxicity. There is also growing evidence for the detection of subclinical cardiac dysfunction in cancer patients by speckle tracking echocardiography. In this review article, we focus on current and emerging data regarding the role of cardiac imaging for the detection of changes in myocardial function related with cancer treatment in clinical practice.

ß-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

BACKGROUND AND AIMS: Increased ß-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. PATIENTS AND METHODS: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) ß-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. RESULTS: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with ß-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, ß-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and ß-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and ß-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. CONCLUSIONS: Increased ß-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.

Echocardiography, an Indispensable Tool for the Management of Diabetics, with or without Coronary Artery Disease, in Clinical Practice.

Diabetes mellitus is a major factor contributing to the development of cardiovascular disease. As morbidity and mortality rates rise dramatically, when target organ damage develops pre-symptomatic assessment is critical for the management of diabetic patients. Echocardiography is a noninvasive and reproducible method that may aid in risk stratification and in evaluation of treatment effects. The aim of this review is to analyze the echocardiographic techniques which can detect early alteration in cardiac function in patients with diabetes.

Combination antiplatelet treatment in coronary artery disease patients: A necessary evil or an overzealous practice?

In seeking to improve care in coronary artery disease patients, further platelet inhibition has been occasionally applied beyond that provided by aspirin and a P2Y12 receptor antagonist. This review aims to offer insights about the rationale, the efficacy and safety of combination antiplatelet therapy, involving three or more agents. Overall, the use of glycoprotein (GP) IIb/IIIa inhibitors did not significantly modify the treatment effect of different antiplatelet strategies, including double vs standard clopidogrel, prasugrel vs clopidogrel, ticagrelor vs clopidogrel, cangrelor vs clopidogrel, and vorapaxar vs placebo. With the caveat that the use of GP IIb/IIIa inhibitor was not randomized, adding such an agent to aspirin and a P2Y12 receptor antagonist appears to carry a significantly increased bleeding potential. Moreover, adding vorapaxar to aspirin- and clopidogrel-treated patients is associated with more bleeding events, while the bleeding potential is further exacerbated in cases of quadruplicate antiplatelet treatment including aspirin, clopidogrel, vorapaxar, and a GP IIb/IIIa inhibitor. In ST-segment elevation, myocardial infarction patients' administration of an intravenous antiplatelet agent (GP IIb/IIIa inhibitor or cangrelor), in addition to aspirin and a P2Y12 receptor antagonist, efficiently bridges the pharmacodynamic gap of oral agents. Cilostazol on top of aspirin and clopidogrel appears to be safe, although of questionable clinical benefit. In conclusion, combination antiplatelet therapy should be reserved only for selected cases and following thoughtful consideration of the associated risk/benefit ratio.

Semaglutide Concurrently Improves Vascular and Liver Indices in Patients With Type 2 Diabetes and Fatty Liver Disease.

Context: The cardiovascular benefits of semaglutide are established; however, its effects on surrogate vascular markers and liver function are not known. Objective: To investigate the effects of semaglutide on vascular, endothelial, and liver function in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Methods: Overall, 75 consecutive subjects with T2DM and NAFLD were enrolled: 50 patients received semaglutide 1 mg (treatment group) and 25 patients received dipeptidyl peptidase 4 inhibitors (control group). All patients underwent a clinical, vascular, and hepatic examination with Fibroscan elastography at 4 and 12 months after inclusion in the study. Results: Treatment with semaglutide resulted in a reduction of Controlled Attenuation Parameter (CAP) score, E fibrosis score, NAFLD fibrosis score, Fibrosis-4 (FIB-4) score and perfused boundary region (PBR) at 4 and at 12 months (P < .05), contrary to controls. Patients treated with semaglutide showed a greater decrease of central systolic blood pressure (SBP) (-6% vs -4%, P = .048 and -11% vs -9%, P = .039), augmentation index (AIx) (-59% vs -52%, P = .041 and -70% vs -57%, P = .022), and pulse wave velocity (PWV) (-6% vs -3.5%, P = .019 and -12% vs -10%, P = .036) at 4 and at 12 months, respectively. In all patients, ΔPWV and ΔPBR were correlated with a corresponding reduction of CAP, E fibrosis, NAFLD fibrosis, and FIB-4 scores. Conclusion: Twelve-month treatment with semaglutide simultaneously improves arterial stiffness, endothelial function, and liver steatosis and fibrosis in patients with T2DM and NAFLD.

Left Atrial Deformation in Heart Failure: A Clinical Update.

Despite left ventricular global longitudinal strain is an eminent and validated marker of cardiovascular disease, assessment of left atrial size and function may have incremental role in diagnosis and management of cardiovascular disease. Left atrial strain, measured by 2-dimensional speckle tracking echocardiography, is a non-invasive biomarker for the assessment of left atrial function. This novel marker, has additional value to traditional echocardiography markers of left atrial function such as left atrial diameter and volume for the diagnosis and management of left ventricular diastolic dysfunction, heart failure with preserved ejection fraction, atrial fibrillation and valvular disease. However, there are potent limitations for its use in the daily clinical practice, regarding loading conditions, image acquisition and heart rate. The aim of this review is to summarize the published evidence about left atrial strain, as assessed by speckle tracking imaging, and to discuss its clinical implications and its potent limitations.

Additive prognostic value of longitudinal myocardial deformation to SCORE2 in psoriasis.

Aims: Psoriasis has been associated with increased cardiovascular (CV) risk. We investigated whether markers of CV function and their change after treatment have a prognostic value for adverse outcomes. Methods and results: In a prospective study, at baseline and after 6 months of treatment with biological agents, we assessed in 298 psoriasis patients (i) left ventricular global longitudinal strain (GLS) and (ii) carotid-femoral pulse wave velocity (PWV), to evaluate their prognostic value for major adverse cardiovascular events (MACEs), including coronary artery disease, stroke, hospitalization for heart failure, and all-cause death over a 4-year follow-up period. During follow-up, 26 (8.7%) MACEs were recorded. By univariate analysis, decreasing absolute GLS values [hazard ratio (HR): 0.73, P < 0.001], decreasing GLS change after treatment (HR: 0.53, P = 0.008), and increasing PWV values (HR: 1.16, P = 0.049) were associated with adverse outcomes. Baseline GLS and its change post-treatment remained independent predictors of adverse events after adjusting for several confounders (P < 0.05). The addition of baseline GLS and its absolute change post-treatment to SCORE2 increased Harrell's C from 0.882 to 0.941. By multivariable analysis, for each 1% increase in absolute baseline GLS values, the risk of MACE decreased by 33% and for each 1% absolute increase of GLS post-treatment compared with the baseline value, the risk of MACE decreased by 58%. Conclusion: Global longitudinal strain has an independent and additive prognostic value to SCORE2 for adverse CV events in psoriasis, providing timely decision-making for intensive anti-inflammatory treatment and aggressive modification of risk factors to reduce CV risk.

Cardiac mechanics in response to proteasome inhibition: a prospective study.

AIM: Ubiquitin-Proteasome System (UPS) is of paramount importance regarding the function of the myocardial cell. Consistently, inhibition of this system has been found to affect myocardium in experimental models; yet, the clinical impact of UPS inhibition on cardiac function has not been comprehensively examined. Our aim was to gain insight into the effect of proteasome inhibition on myocardial mechanics in humans. METHODS AND RESULTS: We prospectively evaluated 48 patients with multiple myeloma and an indication to receive carfilzomib, an irreversible proteasome inhibitor. All patients were initially evaluated and underwent echocardiography with speckle tracking analysis. Carfilzomib was administered according to Kd treatment protocol. Follow-up echocardiography was performed at the 3rd and 6th month. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells.At 3 months after treatment, we observed early left ventricular (LV) segmental dysfunction and deterioration of left atrial (LA) remodelling, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, LV and right ventricular functions were additionally attenuated (P < 0.05 for all). These changes were independent of blood pressure, endothelial function, inflammation, and cardiac injury levels. Changes in PrA were associated with changes in global longitudinal strain (GLS), segmental LV strain, and LA markers (P < 0.05 for all). Finally, baseline GLS < -18% or LA strain rate > 1.71 were associated with null hypertension events. CONCLUSION: Inhibition of the UPS induced global deterioration of cardiac function.

Fagerstrom score predicts smoking status six months after hospitalization for acute myocardial infarction: a prospective study.

BACKGROUND: Fagerstrom score is a validated marker of nicotine addiction in smokers. METHODS: In a prospective study, we investigated a) the predictive value of Fagerstrom score for the smoking status in patients early after acute myocardial infarction (AMI) and b) the effectiveness of medically assisted smoking cessation programs in the prevention of relapsing to smoking post discharge. In 103 smokers (58 ± 12 years, 79.6% males), we assessed Fagerstrom score during hospitalization for AMI. Patients filled a dedicated questionnaire including data on family, marital and educational status, habits related to smoking and were followed-up at 3 and 6 months after discharge. RESULTS: Twenty-eight patients (27.2%) did not quit smoking throughout the 6-months follow-up period (Fagerstrom score:8.1 ± 1.6), 39 patients (37.8%) ceased smoking at 3 months but relapsed to smoking at 6 months (score:6.8 ± 2.1), and only 34 patients (33%) had ceased smoking for 6 consecutive months (score:5.2 ± 2 p < 0.05 for all comparisons between subgroups). By multivariate analysis, Fagerstrom score remained a significant predictor of smoking cessation at 6 months (OR: 0.72, 95%CI: 0.60--0.86, p < 0.001). Out of 73 patients who abstained from smoking for the first 3 months post-AMI, those who participated in a smoking cessation program displayed lower rate of relapsing to smoking compared with those who opted to cease smoking without any support (33.3% vs 61.8% p = 0.012). CONCLUSION: Fagerstrom score is a useful predictor of smoking cessation 6 months post-AMI. Patients participating in a smoking cessation program display lower relapse rates post-discharge suggesting the need of well-organized smoking cessation clinics for secondary prevention of heart disease.

Endothelial glycocalyx integrity in oncological patients.

BACKGROUND: Cancer is associated with early changes in the cardiovascular system (CV) before overt cardiotoxicity. Endothelial dysfunction is induced by chemotherapeutic regimens but there is no data for endothelial glycocalyx in cancer. METHODS: Sixty-four patients with cancer (65.6% with solid tumors and 34.4% with hematological malignancies) and 32 controls from the outpatient cardiology clinic were included in the study. The perfused boundary region (PBR) of the sublingual arterial microvessels, Pulse Wave Velocity (PWV) and augmentation index (AI) were measured. A standard transthoracic echocardiogram plus assessment of global longitudinal strain (GLS) of all cardiac chambers were performed. RESULTS: There was no difference in the baseline profile (age, sex, smoking, hypertension, diabetes, hyperlipidemia and coronary artery disease) and in the echocardiographic parameters between the two groups, with the exception of left atrial volume (33.3 ± 13 in cancer patients vs 27.6 ± 6.5 ml/m2 in controls). PBR 5-25 and PBR 20-25 were significantly increased in cancer patients vs controls (2.11 ± 0.36 vs 1.97 ± 0.21 µm, p = 0.025 and 2.65 ± 0.48 vs 2.40 ± 0.36 µm, p = 0.012, respectively). Endothelial glycocalyx thickness impairment was independent of traditional CV risk factors and anticancer therapy, but proportional to disease stage (r = 0.337, p = 0.044). However, there was no difference in arterial stiffness between the two groups (PWV 10.74 ± 4.11 vs 11.26 ± 3.38 m/s, p = 0.539 and AI 11.28 ± 28.87 vs 15.38 ± 18.8 %, p = 0.470). CONCLUSIONS: Endothelial function as assessed by endothelial glycocalyx thickness is significantly impaired in cancer patients without overt cardiotoxicity. This implies that PBR might be useful for the early assessment of microvascular and endothelial toxicity of cancer.

Endothelial Dysfunction Is Associated with Decreased Nitric Oxide Bioavailability in Dysglycaemic Subjects and First-Degree Relatives of Type 2 Diabetic Patients.

Oxidative stress plays an important role in the pathogenesis of diabetes. We investigated oxidative stress and nitrite/nitrate concentrations at baseline and during postprandial hyperglycaemia in 40 first-degree relatives (FDRs) of diabetic patients with normal oral glucose tolerance test (OGTT) results, 40 subjects with abnormal OGTT results (dysglycaemic) and 20 subjects with normal OGTT results (normoglycaemic). Malondialdehyde (MDA), protein carbonyls (PCs), nitrite/nitrate plasma levels, the perfused boundary region (PBR­Glycocheck) of the sublingual microvessels, a marker of glycocalyx integrity, coronary flow reserve (CFR) and left ventricular global longitudinal strain (GLS) were assessed at 0 and 120 min of the OGTT. Insulin sensitivity was evaluated using Matsuda and the insulin sensitivity index (ISI). In all subjects, there were no significant changes in MDA or PC after the OGTT (p > 0.05). Compared with normoglycaemic subjects, FDRs and dysglycaemic subjects had significantly decreased nitrite/nitrate levels (−3% vs. −24% vs. −30%, respectively), an increased PBR and reduced CFR and GLS at 120 min (p < 0.05). The percent reduction in nitrite/nitrate was associated with abnormal Matsuda and ISI results, reversely related with the percent increase in PBR (r = −0.60) and positively related with the percent decrease in CFR (r = 0.39) and GLS (r = 0.48) (p < 0.05). Insulin resistance is associated with reduced nitric oxide bioavailability and coronary and myocardial dysfunction in FDRs and dysglycaemic subjects.

Apremilast Improves Endothelial Glycocalyx Integrity, Vascular and Left Ventricular Myocardial Function in Psoriasis.

The phosphodiesterase 4 inhibitor apremilast is used for the treatment of psoriasis. We investigated the effects of apremilast on endothelial glycocalyx, vascular and left ventricular (LV) myocardial function in psoriasis. One hundred and fifty psoriatic patients were randomized to apremilast (n = 50), anti-tumor necrosis factor-α (etanercept; n = 50), or cyclosporine (n = 50). At baseline and 4 months post-treatment, we measured: (1) Perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter 5-25 µm using a Sidestream Dark Field camera (GlycoCheck). Increased PBR indicates damaged glycocalyx. Functional microvascular density, an index of microvascular perfusion, was also measured. (2) Pulse wave velocity (PWV-Complior) and (3) LV global longitudinal strain (GLS) using speckle-tracking echocardiography. Compared with baseline, PBR5-25 µm decreased only after apremilast (-12% at 4 months, p < 0.05) whereas no significant changes in PBR5-25 µm were observed after etanercept or cyclosporine treatment. Compared with etanercept and cyclosporine, apremilast resulted in a greater increase of functional microvascular density (+14% versus +1% versus -1%) and in a higher reduction of PWV. Apremilast showed a greater increase of GLS (+13.5% versus +7% versus +2%) than etanercept and cyclosporine (p < 0.05). In conclusion, apremilast restores glycocalyx integrity and confers a greater improvement of vascular and myocardial function compared with etanercept or cyclosporine after 4 months.

Endothelial glycocalyx and microvascular perfusion are associated with carotid intima-media thickness and impaired myocardial deformation in psoriatic disease.

Psoriatic disease is associated with vascular and myocardial dysfunction. We aimed to evaluate endothelial glycocalyx barrier properties and microvascular perfusion in psoriatic patients, as well as their correlation with carotid intima-media thickness (cIMT) and markers of left ventricular (LV) myocardial deformation. We examined 297 psoriatic patients and 150 controls, adjusted for age, sex, and atherosclerotic risk factors. The severity of psoriatic disease was estimated using the psoriasis area and severity index (PASI). Perfused boundary region (PBR), a marker of glycocalyx barrier function, was measured non-invasively in sublingual microvessels with a diameter 5-25 µm using Sidestream Dark Field camera (Microscan, GlycoCheck). Increased PBR indicates reduced glycocalyx thickness. Indexes of microvascular perfusion, including red blood cells filling (RBCF) and functional microvascular density, were also calculated. We measured cIMT, coronary flow reserve (CFR) and markers of myocardial deformation by speckle-tracking imaging, namely global longitudinal strain (GLS) and percentage changes between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO). Compared to controls, psoriatic patients had higher PBR5-25µm (2.13 ± 0.29µm versus 1.78 ± 0.25µm, p < 0.001) and lower RBCF and functional microvascular density (p < 0.001). Increased PASI was associated with elevated PBR and more impaired cIMT and GLS (p < 0.05). There was an inverse association of PBR with RBCF and functional microvascular density (p < 0.001). In psoriatic population, increased PBR was related to increased cIMT, reduced CFR, impaired GLS and decreased %dpTw-UtwMVO (p < 0.001). Glycocalyx thickness is reduced in psoriatic patients, which in turn impairs microvascular perfusion, and is associated with carotid IMT and impaired coronary and myocardial function.Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT02144857.

Impaired Endothelial Glycocalyx Predicts Adverse Outcome in Subjects Without Overt Cardiovascular Disease: a 6-Year Follow-up Study.

We investigated whether disturbance of glycocalyx integrity is related with increased cardiovascular risk. In 600 healthy subjects, we measured perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter ranging 5-25 µm using a dedicated camera (Sideview Darkfield Imaging). Increased PBR indicates reduced glycocalyx thickness. We prospectively monitored the occurrence of cardiovascular events (MACE-death, myocardial infarction, and stroke) during a 6-year follow-up. Fifty-seven MACE were documented. Increased values of PBR5-25 predicted higher risk for MACE in a model including sex, age, hyperlipidemia, diabetes, hypertension, smoking, family history of coronary disease, treatment with ACEi/ARBs, or lipid-lowering agents (hazard ratio (HR), 6.44, p = 0.011; net reclassification improvement (NRI), 28%; C-statistic: 0.761). PBR5-25 was an independent and additive predictor of outcome when added in a model including the European Heart SCORE, diabetes, family history of CAD, and medication (HR, 4.71; NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01).Glycocalyx integrity is an independent and additive predictor to risk factors for MACE at 6-year follow-up in individuals without cardiovascular disease. ClinicalTrials.govIdentifier:NCT04646252. PBR5-25 was an independent and additive predictor of adverse cardiovascular events in a model including the European Heart SCORE, diabetes, family history of coronary disease, and medication (HR: 4.71, NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01, NRI:37.9%).

Differential effects of heat-not-burn and conventional cigarettes on coronary flow, myocardial and vascular function.

We compared the effects of Heat-not-Burn cigarette (HNBC) to those of tobacco cigarette (Tcig), on myocardial, coronary and arterial function as well as on oxidative stress and platelet activation in 75 smokers. In the acute study, 50 smokers were randomised into smoking a single Tcig or a HNBC and after 60 min were crossed-over to the alternate smoking. For chronic phase, 50 smokers were switched to HNBC and were compared with an external group of 25 Tcig smokers before and after 1 month. Exhaled carbon monoxide (CO), pulse wave velocity (PWV), malondialdehyde (MDA) and thromboxane B2 (TxB2) were assessed in the acute and chronic study. Global longitudinal strain (GLS), myocardial work index (GWI), wasted myocardial work (GWW), coronary flow reserve (CFR), total arterial compliance (TAC) and flow-mediated dilation (FMD) were assessed in the chronic study. Acute HNBC smoking caused a smaller increase of PWV than Tcig (change 1.1 vs 0.54 m/s, p < 0.05) without change in CO and biomarkers in contrast to Tcig. Compared to Tcig, switching to HNBC for 1-month improved CO, FMD, CFR, TAC, GLS, GWW, MDA, TxB2 (differences 10.42 ppm, 4.3%, 0.98, 1.8 mL/mmHg, 2.35%, 19.72 mmHg%, 0.38 nmol/L and 45 pg/mL respectively, p < 0.05). HNBCs exert a less detrimental effect on vascular and cardiac function than tobacco cigarettes.Trial registration Registered on https://clinicaltrials.gov/ (NCT03452124, 02/03/2018).