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.

Effects of hormone replacement therapy on endothelial function, arterial stiffness and myocardial deformation in women with Turner syndrome.

OBJECTIVES: Turner syndrome (TS) is associated with increased cardiovascular risk. We investigated whether hormone replacement therapy (HRT) affects endothelial function, arterial stiffness and myocardial deformation in women with TS. METHODS: Twenty-five women with TS were studied in the estrogen phase of the HRT and two months after discontinuation of HRT. The following measurements were made: flow-mediated dilation (FMD) of the brachial artery, pulse wave velocity (PWV-Complior) and central systolic blood pressure (cSBP), carotid intima-media thickness (cIMT), aortic (Ao) elastic indexes - namely Ao strain, distensibility, stiffness index and pressure strain modulus (Ep) - and left ventricular (LV) global longitudinal strain (GLS) using speckle-tracking echocardiography. Ten healthy female of similar age and BMI served as a control group. RESULTS: Compared to controls, women with TS on HRT had higher PWV (9.1 ±â€Š2.4 vs. 7.5 ±â€Š0.5 m/s), cSBP (130 ±â€Š15 vs. 121 ±â€Š6 mmHg), cIMT (0.66 ±â€Š0.06 vs. 0.55 ±â€Š0.05 mm), aortic stiffness index, Ep and LA strain, and lower FMD (7.2 ±â€Š4 vs. 10.5 ±â€Š2.3%), Ao strain, Ao distensibility and GLS (-18.8 ±â€Š2.7 vs. -21.9 ±â€Š1.5%) (P < 0.05 for all comparisons). Two months after discontinuation of HRT, all women increased FMD (11.7 ±â€Š6 vs. 7.2 ±â€Š4%) and reduced PWV (7.8 ±â€Š1.7 vs. 9.1 ±â€Š2.4 m/s) and cSBP (123 ±â€Š14 vs. 130 ±â€Š15 mmHg). There were no statistically significant changes in BMI, cIMT and GLS (P > 0.05 for all comparisons). The percentage decrease of cSBP was associated with the percentage decrease of PWV (r = 0.54) and reversely related with the percentage increase of FMD (r = -0.57; P < 0.05 for all comparisons). CONCLUSIONS: HRT in women with TS may deteriorate endothelial function contributing to increased arterial stiffness and central arterial blood pressure.

Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study.

AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 µm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.

Echocardiography in Autoimmune Rheumatic Diseases for Diagnosis and Prognosis of Cardiovascular Complications.

Autoimmune rheumatic diseases are systemic diseases frequently affecting the heart and vessels. The main cardiovascular complications are pericarditis, myocarditis, valvular disease, obstructive coronary artery disease and coronary microcirculatory dysfunction, cardiac failure and pulmonary hypertension. Echocardiography, including transthoracic two and three-dimensional echocardiography, Doppler imaging, myocardial deformation and transesophageal echo, is an established and widely available imaging technique for the identification of cardiovascular manifestations that are crucial for prognosis in rheumatic diseases. Echocardiography is also important for monitoring the impact of drug treatment on cardiac function, coronary microcirculatory function, valvular function and pulmonary artery pressures. In this article we summarize established and evolving knowledge on the role of echocardiography for diagnosis and prognosis of cardiovascular abnormalities in rheumatic diseases.

Optimal Blood Pressure Control Improves Left Ventricular Torsional Deformation and Vascular Function in Newly Diagnosed Hypertensives: a 3-Year Follow-up Study.

We investigated the effects of optimizing blood pressure control on cardiac deformation and vascular function. For this purpose, in 200 untreated patients with essential hypertension, we assessed at baseline as well as after 3 years of optimal blood pressure control: arterial stiffness and coronary microcirculatory function as well as longitudinal and torsional deformation parameters. Compared to baseline, after 3 years of optimal blood pressure control, there was an improvement of longitudinal strain, twisting as well as untwisting parameters of the left ventricle. In parallel, there was an improvement in coronary microcirculatory function, arterial stiffness, left ventricular mass, and ventricular-arterial interaction. The reduction of arterial stiffness was independently associated with the respective improvement of cardiac deformation markers and coronary flow reserve after adjusting for blood pressure improvement. Blood pressure optimization improves LV longitudinal and torsional mechanics in hypertensives in parallel with arterial stiffness, resulting in improved ventricular-arterial interaction and coronary flow reserve. Trial registration: ClinicalTrials.gov Identifier: NCT02346695.

Effects of Interleukin 17A Inhibition on Myocardial Deformation and Vascular Function in Psoriasis.

BACKGROUND: Interleukin (IL)-17A activity is implicated in psoriasis. We investigated the effects of IL-17A inhibition on vascular and left ventricular (LV) function in patients with psoriasis. METHODS: A total of 150 patients with psoriasis received either an anti-IL-17A agent (secukinumab, n = 50), cyclosporine (n = 50), or methotrexate treatment (n = 50). At baseline and after 4 and 12 months of treatment, we measured (1) LV global longitudinal strain (GLS), GLS rate (GLSR), GLSR at early diastole, LV twisting, and untwisting; (2) coronary flow reserve (CFR); (3) pulse wave velocity (PWV); and (4) malondialdehyde and protein carbonyl as markers of oxidative stress. RESULTS: Compared with cyclosporine and methotrexate, anti-IL-17A treatment resulted in a greater increase in GLS at 4 and 12 months after treatment (10% and 14% with anti-IL-17A vs 2% and 2% with cyclosporine vs 4% and 4% with methotrexate, respectively), GLSR, GLSR at early diastole (45% and 41% vs 5% and 4% vs 7% and 9%, respectively), and LV twisting (32% and 28% vs 6% and 8% vs 7% and 6%, respectively) (P < 0.05). Anti-IL-17A treatment resulted in greater improvement of CFR and PWV than cyclosporine or methotrexate (P < 0.05). PWV increased after cyclosporine treatment (+11% at 4 and +14% and 12 months) (P < 0.05). Markers of oxidative stress were reduced only after anti-IL-17A treatment (P < 0.05). Changes of myocardial deformation markers and CFR after anti-IL-17A treatment correlated with a concomitant reduction of oxidative stress. CONCLUSIONS: In psoriasis, inhibition of IL-17A results in a greater improvement of vascular and myocardial function compared with cyclosporine or methotrexate treatment, indicating a beneficial effect on overall cardiovascular function.

Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. METHODS: In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. RESULTS: Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 µm of microvessel ranging from 5 to 9 µm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01). CONCLUSION: Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis. CLINICAL TRIAL REGISTRATION: URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.

Effects of Different Antidiabetic Medications on Endothelial Glycocalyx, Myocardial Function, and Vascular Function in Type 2 Diabetic Patients: One Year Follow-Up Study.

BACKGROUND: Poor glycaemic control affects myocardial function. We investigated changes in endothelial function and left ventricular (LV) myocardial deformation in poorly controlled type 2 diabetics before and after glycaemic control intensification. METHODS: In 100 poorly-controlled diabetic patients (age: 51 ± 12 years), we measured at baseline and at 12 months after intensified glycaemic control: (a) Pulse wave velocity (PWV, Complior); (b) flow-mediated dilatation (FMD, %) of the brachial artery; (c) perfused boundary region (PBR) of the sublingual arterial micro-vessels (side-view dark-field imaging, Glycocheck); (d) LV global longitudinal strain (GLS), peak twisting (pTw), peak twisting velocity (pTwVel), and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography, where the ratio of PWV/GLS was used as a marker of ventricular-arterial interaction; and (e) Malondialdehyde (MDA) and protein carbonyls (PCs) plasma levels. RESULTS: Intensified 12-month antidiabetic treatment reduced HbA1c (8.9 ± 1.8% (74 ± 24 mmol/mol) versus 7.1 ± 1.2% (54 ± 14 mmol/mol), p = 0.001), PWV (12 ± 3 versus 10.8 ± 2 m/s), PBR (2.12 ± 0.3 versus 1.98 ± 0.2 µm), MDA, and PCs; meanwhile, the treatment improved GLS (-15.2 versus -16.9%), PWV/GLS, and FMD% (p < 0.05). By multi-variate analysis, incretin-based agents were associated with improved PWV (p = 0.029), GLS (p = 0.037), PBR (p = 0.047), and FMD% (p = 0.034), in addition to a reduction of HbA1c. The patients with a final HbA1c ≤ 7% (≤ 53 mmol/mol) had greater reduction in PWV, PBR, and markers of oxidative stress, with a parallel increase in FMD and GLS, compared to those who had HbA1c > 7% (> 53 mmol/mol). CONCLUSIONS: Intensified glycaemic control, in addition to incretin-based treatment, improves arterial stiffness, endothelial glycocalyx, and myocardial deformation in type 2 diabetes after one year of treatment.

Differential effects of inhibition of interleukin 1 and 6 on myocardial, coronary and vascular function.

BACKGROUND: Anakinra, an interleukin-1 receptor antagonist and tocilizumab, an interleukin-6 receptor blocker, are used for the treatment of rheumatoid arthritis. We investigated the differential effects of anakinra and tocilizumab on myocardial and vascular function in an atherosclerosis model of patients with rheumatoid arthritis. METHODS: 120 patients with rheumatoid arthritis were randomized to anakinra (n = 40), tocilizumab (n = 40) or prednisolone (n = 40) for 3 months. Primary outcome measure was the change of left ventricular longitudinal strain after 3 months of treatment. Additionally, we measured coronary flow reserve, flow-mediated dilatation of the brachial artery, carotid-femoral pulse wave velocity, malondialdehyde and protein carbonyls as oxidative stress markers and C-reactive protein blood levels at baseline and post-treatment. RESULTS: At baseline, patients among the three treatment arms had similar age, sex, disease activity score and atherosclerotic risk factors. Compared with baseline, all patients had improved longitudinal strain (- 16% vs. - 17.8%), coronary flow reserve (2.56 vs. 2.9), malondialdehyde (2.0 vs. 1.5 µM/L), protein carbonyls (0.0132 vs. 0.0115 nmol/mg), and C-reactive protein post-treatment. In all patients, the percent decrease of malondialdehyde was correlated with percent increase of longitudinal strain (p < 0.001). Compared with tocilizumab and prednisolone, anakinra treatment resulted in a greater improvement of longitudinal strain (18.7% vs. 9.7% vs. 6%) and coronary flow reserve (29% vs. 13% vs. 1%), while pulse wave velocity and brachial blood pressure were improved only after tocilizumab treatment (11 ± 3 vs. 10.3 ± 2 m/s p < 0.05 for all comparisons). CONCLUSIONS: Anakinra is associated with an improvement in cardiac function and tocilizumab with improvement in vascular function. CLINICAL TRIAL REGISTRATION: URL: https:// http://www.clinicaltrials.gov . Unique identifier: NCT03288584.

Pulse wave analysis using the Mobil-O-Graph, Arteriograph and Complior device: a comparative study.

PURPOSE: Pulse wave velocity (PWV) is a marker of arterial stiffness with major prognostic value. We compared Arteriograph and Complior devices with the Mobil-O-Graph for assessment of PWV and central systolic blood pressure (cSBP). MATERIALS AND METHODS: We studied 316 consecutive subjects (age: 55 ± 14 years). For each individual, we measured PWV and cSBP with Arteriograph, Complior and Mobil-O-Graph and compared the readings. Differences in values among three devices were calculated for each measurement. We used Bland-Altman analysis, intraclass correlation coefficient (ICC) and coefficient of variation (CV). RESULTS: Bland-Altman analysis indicated a mean difference for PWV: i.0.5 m/s (limits of agreement -1.4-2.4) between Complior and Mobil-O-Graph, ii.0.6 m/s (limits of agreement -1.4-2.6) between Arteriograph and Mobil-O-Graph. cSBP mean difference was 3.8 mmHg between Complior and Mobil-O-Graph (limits of agreement -12.5-20.1) and 9.2 mmHg between Arteriograph and Mobil-O-Graph (limits of agreement -7.6-26). ICC for PWV was 0.86 between Arteriograph and Mobil-O-Graph, 0.87 between Complior and Mobil-O-Graph and for cSBP 0.92 and 0.91 respectively. CV for PWV was 9.5% between Arteriograph and Mobil-O-Graph, 8.8% between Complior and Mobil-O-Graph. Respective values for cSBP were 6.8% and 5.1%. CONCLUSION: Our study shows acceptable agreement among the three devices regarding pulse wave analysis markers though Mobil-O-Graph appears to underestimate the values of these markers. Further studies are needed to explore the agreement between the 3 devices in various clinical settings and patient populations.

Pulse wave velocity to global longitudinal strain ratio in hypertension.

BACKGROUND: Arterial elastance to left ventricular elastance ratio assessed by echocardiography is widely used as a marker of ventricular-arterial coupling. MATERIALS AND METHODS: We investigated whether the ratio of carotid-femoral pulse wave velocity, as a marker of arterial stiffness, to global longitudinal strain, as a marker of left ventricular performance, could be better associated with vascular and cardiac damage than the established arterial elastance/left ventricular elastance index. In 299 newly-diagnosed untreated hypertensives we measured, carotid-femoral pulse wave velocity, and carotid intima-media thickness, coronary-flow reserve, arterial elastance/left ventricular elastance, global longitudinal strain, and markers of left ventricular diastolic function (E/A and E') by echocardiography. RESULTS: Pulse wave velocity-to-global longitudinal strain ratio (PWV/GLS) was lower in hypertensives than controls (-0.61 ± 0.21 vs -0.45 ± 0.11 m/sec%, P < 0.001). Low PWV/GLS values were associated with carotid-intima media thickness > 0.9 mm (P = 0.003), E/A ≤ 0.8 (P = 0.019) and E' ≤ 9 cm/sec (P = 0.002) and coronary-flow reserve < 2.5 (P = 0.017), after adjustment for age, sex and mean arterial pressure. Low PWV/GLS was also associated with increased left ventricular mass and left atrial volume in the univariate (P = 0.003 and 0.038) but not in the multivariate model. In hypertensives, there was no significant association of arterial elastance-to-left ventricular elastance index with carotid intima media thickness, coronary flow reserve, E/A, E', or left atrial volume with the exception of an inverse association with left ventricular mass (P = 0.027). CONCLUSIONS: Pulse wave velocity-to-global longitudinal strain ratio but not the echocardiography-derived arterial elastance-to left ventricular elastance index is related to impaired carotid-intima media thickness, coronary-flow reserve and diastolic function in hypertensives.

Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives.

We investigated the association of endothelial glycocalyx damage with arterial stiffness, impairment of coronary microcirculatory function, and LV myocardial deformation in 320 untreated hypertensives and 160 controls. We measured perfused boundary region (PBR) of the sublingual microvessels, a marker inversely related with glycocalyx thickness, coronary flow reserve (CFR), and Global Longitudinal strain (GLS) by echocardiography, pulse wave velocity (PWV), and central systolic blood pressure (cSBP). Hypertensives had higher PBR, PWV cSBP, and lower CFR and GLS than controls (P < .05). In hypertensives, increased PBR was associated with increased cSBP, PWV, and decreased CFR and GLS after adjustment for age, sex, BMI, smoking LV mass, heart rate, hyperlipidemia, and office SBP (P < .05). PBR had an additive value to PWV, CFR, and office SBP for the prediction of abnormal GLS (x2  = 2.4-3.8, P for change = .03). Endothelial glycocalyx is impaired in untreated hypertensives and is related to arterial stiffness, coronary, and myocardial dysfunction.

Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes.

BACKGROUND: Incretin-based therapies are used in the treatment of type 2 diabetes mellitus (T2DM) and obesity. We investigated the changes in arterial stiffness and left ventricular (LV) myocardial deformation after 6-month treatment with the GLP-1 analogue liraglutide in subjects with newly diagnosed T2DM. METHODS: We randomized 60 patients with newly diagnosed and treatment-naive T2DM to receive either liraglutide (n = 30) or metformin (n = 30) for 6 months. We measured at baseline and after 6-month treatment: (a) carotid-femoral pulse wave velocity (PWV) (b) LV longitudinal strain (GLS), and strain rate (GLSR), peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography. LV untwisting was calculated as the percentage difference between peak twisting and untwisting at MVO (%dpTw-UtwMVO), at peak (%dpTw-UtwPEF) and end of early LV diastolic filling (%dpTw-UtwEDF) (c) Flow mediated dilatation (FMD) of the brachial artery and percentage difference of FMD (FMD%) (d) malondialdehyde (MDA), protein carbonyls (PCs) and NT-proBNP. RESULTS: After 6-months treatment, subjects that received liraglutide presented with a reduced PWV (11.8 ± 2.5 vs. 10.3 ± 3.3 m/s), MDA (0.92 [0.45-2.45] vs. 0.68 [0.43-2.08] nM/L) and NT-proBNP (p < 0.05) in parallel with an increase in GLS (- 15.4 ± 3 vs. - 16.6 ± 2.7), GLSR (0.77 ± 0.2 vs. 0.89 ± 0.2), pUtwVel (- 97 ± 49 vs. - 112 ± 52°, p < 0.05), %dpTw-UtwMVO (31 ± 10 vs. 40 ± 14), %dpTw-UtwPEF (43 ± 19 vs. 53 ± 22) and FMD% (8.9 ± 3 vs. 13.2 ± 6, p < 0.01). There were no statistically significant differences of the measured markers in subjects that received metformin except for an improvement in FMD. In all subjects, PCs levels at baseline were negatively related to the difference of GLS (r = - 0.53) post-treatment and the difference of MDA was associated with the difference of PWV (r = 0.52) (p < 0.05 for all associations) after 6-month treatment. CONCLUSIONS: Six-month treatment with liraglutide improves arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM. ClinicalTrials.gov Identifier NCT03010683.

Lowering Interleukin-12 Activity Improves Myocardial and Vascular Function Compared With Tumor Necrosis Factor-a Antagonism or Cyclosporine in Psoriasis.

BACKGROUND: Interleukin (IL)-12 activity is involved in the pathogenesis of psoriasis and acute coronary syndromes. We investigated the effects of IL-12 inhibition on vascular and left ventricular (LV) function in psoriasis. METHODS AND RESULTS: One hundred fifty psoriasis patients were randomized to receive an anti-IL-12/23 (ustekinumab, n=50), anti-tumor necrosis factor-a (TNF-α; etanercept, n=50), or cyclosporine treatment (n=50). At baseline and 4 months post-treatment, we measured (1) LV global longitudinal strain, twisting, and percent difference between peak twisting and untwisting at mitral valve opening (%untwMVO) using speckle-tracking echocardiography, (2) coronary flow reserve, (3) pulse wave velocity and augmentation index, (4) circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide), TNF-α, IL-6, IL-12, IL-17, malondialdehyde, and fetuin-a. Compared with baseline, all patients had improved global longitudinal strain (median values: -17.7% versus -19.5%), LV twisting (12.4° versus 14°), %untwMVO (27.8% versus 35%), and coronary flow reserve (2.8 versus 3.1) and reduced circulating NT-proBNP, IL-17, TNF-α, and IL-6 post-treatment (P<0.05). Compared with anti-TNF-α and cyclosporine, anti-IL-12/23 treatment resulted in a greater improvement of global longitudinal strain (25% versus 17% versus 6%,), LV twist (27% versus 17% versus 1%), %untwMVO (31% versus 27% versus 17%), and coronary flow reserve (14% versus 11% versus 4%), as well as a greater reduction of IL-12 (-25% versus -4% versus -2%), malondialdehyde (-27% versus +5% versus +26%), and NT-proBNP(-26% versus -13.6% versus 9.1%) and increase of fetuin-a (P<0.01). Pulse wave velocity and augmentation index were improved only after anti-IL-12/23 treatment and correlated with changes in global longitudinal strain, LV twisting-untwisting (P<0.05). CONCLUSIONS: In psoriasis, IL-12/23 inhibition results in a greater improvement of coronary, arterial, and myocardial function than TNF-α inhibition or cyclosporine treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02144857.

Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage.

BACKGROUND: First-degree relatives of type-2 diabetes patients (FDR) present insulin resistance. We investigated whether FDR and dysglycaemic subjects demonstrate abnormal endothelial glycocalyx and LV deformation during postprandial hyperglycemia. 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). At 0 and 120min of OGTT we measured: a) LV longitudinal strain (LS) of subendocardial, mid-myocardial and subepicardial layers, global LS (GLS), peak twisting (pTw), untwisting velocity (pUtwVel), by speckle tracking echocardiography b) perfused boundary region (PBR) of the sublingual arterial microvessels; high PBR values represent reduced glycocalyx thickness. Insulin resistance was evaluated using insulin sensitivity index (ISI). RESULTS: ISI was related with baseline PBR, GLS and pTw in all subjects (p<0.05). Compared to normoglycaemics, FDR and dysglycaemics had higher PBR, lower ISI, GLS (-18.4±2.6 and -16.8±2.0 vs. -19.2±2.4%), subendocardial LS (-19.0±4.2 and -17.9±3.0 vs. -20.1±3.4%), pTw (14.4±4.4 and 15.6±6.4 vs. 16.9±6.5deg) and pUtwVel (p<0.05 for all comparisons). A GLS<-18% identified FDR with LV dysfunction (p=0.016). Post-OGTT, GLS and the subendocardial LS decreased while pTw and pUtwVel increased in FDR and dysglycaemics (p<0.05) indicating prevalence of the motion of the subepicardial over a dysfunctioning subendocardial myocardial helix. Increased PBR was related with impaired deformation markers at baseline and 120min of OGTT (p<0.05). CONCLUSION: First-degree relatives and dysglycaemics have reduced glycocalyx thickness related with impaired LV longitudinal, twisting-untwisting function. Postprandial hyperglycemia when combined with insulin resistance causes LV longitudinal dysfunction leading to increased LV twisting.

Increased levels of circulating platelet-derived microparticles in psoriasis: Possible implications for the associated cardiovascular risk.

AIM: To evaluate platelet activation markers in psoriasis patients, compared to controls, and investigate their association with the inflammatory burden of psoriasis. METHODS: Forty psoriatic patients without cardiovascular disease, and 12 healthy controls were subjected to measurement of baseline platelet CD62P, CD63 and CD42b expression, platelet-leukocyte complexes, i.e., platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC) and platelet-lymphocyte complexes, and concentrations of platelet-derived microparticles (PMPs) using flow cytometry. Both larger-size (0.5-0.9 µm) and smaller-size (< 0.5 µm) PMPs were determined. Serum interleukin (IL)-12 and IL-17 levels were also measured by enzyme-linked immunosorbent assay. The severity of psoriasis was evaluated by the Psoriasis Area Severity Index (PASI). RESULTS: PMP concentrations were significantly higher in psoriasis patients than controls [mean ± standard error of mean (SEM): 22 ± 5/µL vs 11 ± 6/µL; P = 0.018), for both smaller-size (10 ± 2/µL vs 4 ± 2/µL; P = 0.033) and larger-size (12 ± 3/µL vs 6 ± 4/µL; P = 0.014) PMPs. Platelet CD62P, CD63 and CD42b expression and circulating PMC and PNC were similar between the two groups. Lower circulating PLC were observed in psoriasis patients compared to controls (mean ± SEM: 16% ± 3% vs 23% ± 6%; P = 0.047). Larger-size PMPs were related with IL-12 levels (P < 0.001) and smaller-size PMPs with both IL-12 and IL-17 levels (P < 0.001). Total PMPs also correlated with IL-12 (P < 0.001). CD63 expression was positively correlated with both IL-12 and IL-17 (P < 0.05). Increased PASI score was associated with increased levels of larger-size PMPs (r = 0.45; P = 0.011) and increased CD63 expression (r = 0.47; P < 0.01). CONCLUSION: PMPs, known to be predictive of cardiovascular outcomes, are increased in psoriasis patients, and associated with high inflammatory disease burden. Enhanced platelet activation may be the missing link leading to cardiovascular events in psoriatic patients.

Insulin resistance and acute glucose changes determine arterial elastic properties and coronary flow reserve in dysglycaemic and first-degree relatives of diabetic patients.

BACKGROUND: Insulin resistance is linked to endothelial dysfunction. We investigated whether first-degree relatives of type-2 diabetes patients (FDR) present differences in vascular function at baseline and during postprandial hyperglycemia compared to dysglycaemic or normoglycaemic subjects. 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 clinical characteristics. Glucose, insulin, pulse wave velocity (PWV), central systolic blood pressure (cSBP) and augmentation index (AI) were measured at 0, 30, 60, 90 and 120min during OGTT. Coronary flow reserve (CFR) was assessed using Doppler echocardiography at 0 and 120min after OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). RESULTS: FDR and dysglycaemics had higher fasting insulin, reduced ISI, Matsuda index as well as reduced CFR (2.54 ± 0.5 vs. 2.45 ± 0.3 vs. 2.74 ± 0.5), increased PWV, (8.9 ± 1.1 vs. 10.3 ± 2.4vs. 8.0 ± 1.5 m/sec), AI (23.8 ± 13.6 vs. 26.5 ± 14.4vs.17.7  ±  14%) and cSBP than normoglycaemics (p < 0.05 for all comparisons). During OGTT, AI was similarly reduced in both normoglycaemic and FDR (p < 0.05) at peak insulin levels (60 min) though FDR had 2-fold higher insulin than normoglycaemics. AI was increased in dysglycaemics after peak glucose levels, at 120 min (p < 0.05). CFR was reduced by 10% and 15% at 120min in FDR and dysglycaemic respectively, while remained unchanged in normoglycaemics (p < 0.05). The percent reduction of CFR was related with the percent increase of glucose levels, ISI and Matsuda index(p < 0.05). CONCLUSION: First-degree relatives and dysglycaemic patients have impaired arterial and coronary microcirculatory function. Insulin resistance determines acute vascular responses during postprandial hyperglycemia. CLINICALTRIALS. GOV IDENTIFIER: NCT02244736.

Similarities in coronary function and myocardial deformation between psoriasis and coronary artery disease: the role of oxidative stress and inflammation.

BACKGROUND: Psoriasis has been associated with increased risk for coronary artery disease (CAD). We investigated the presence of vascular and subclinical left ventricular (LV) dysfunction in patients with psoriasis compared with patients with CAD. METHODS: We compared 59 patients with psoriasis without evidence of CAD (psoriasis area and severity index [PASI], 11.5 ± 8) with 59 patients with angiographically documented CAD and 40 controls. We measured (1) the carotid-femoral pulse wave velocity (PWVc) and central augmentation index (CAI), (2) coronary flow reserve (CFR) by Doppler echocardiography, (3) flow-mediated dilation (FMD) of the brachial artery and carotid intima media thickness (IMT), (4) LV global longitudinal strain (GLS) and GLS rate (GLSR) using speckle tracking echocardiography, and (5) malondialdehyde (MDA) and interleukin-6 (IL-6) levels. RESULTS: Patients with psoriasis had higher PWVc, CAI, IMT, MDA, and IL-6 levels and lower FMD, CFR, GLS, and GLSR than did controls (P < 0.05), but they had values of these markers that were similar to those of patients with CAD (P > 0.05) after adjustment for atherosclerotic risk factors: (PWVc [m/s], 10.4 ± 1.8 vs 8.6 ± 1.5 vs 10.3 ± 2, respectively; CFR, 2.4 ± 0.1 vs 3.4 ± 0.6 vs 2.6 ± 0.6, respectively; GLS [%], -16.2 ± 4 vs -21.9 ± 1.6 vs -16.6 ± 4.5, respectively; GLSR [L/sec], -0.85 ± 0.2 vs -1.2 ± 0.12 vs -0.9 ± 0.4, respectively; MDA [nM/L], 1.68 vs 1.76 vs 1.01, respectively; IL-6 [pg/mL], 2.26 vs 2.2 vs 1.7, respectively; P < 0.05 for all comparisons). PASI was related to IMT (r = 0.67; P < 0.01). Decreased GLS was associated with increased MDA, IL-6, PWVc, CAI, and reduced CFR (P < 0.05). CONCLUSIONS: Psoriasis and CAD present similar vascular and LV myocardial dysfunction, possibly because of similar underlying inflammatory and oxidative stress processes. Vascular dysfunction in psoriasis is linked to abnormal LV myocardial deformation.