Arterial Function Research Articles

11C]PS13 Demonstrates Pharmacologically Selective and Substantial Binding to Cyclooxygenase-1 in the Human Brain.

Our laboratory recently developed [11C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [11C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling. This study sought to quantify the specific binding of [11C]PS13 to COX-1 in healthy human brain using scans performed with arterial input function at baseline and after blockade by the COX-1-selective inhibitor ketoprofen. Methods: Eight healthy volunteers underwent two 90-min [11C]PS13 PET scans with radiometabolite-corrected arterial input function, at baseline and about 2 h after oral administration of ketoprofen (75 mg). Results: Two-tissue compartment modeling effectively identified the total uptake of radioactivity in the brain (as distribution volume), showing the highest densities in the hippocampus, the occipital cortex, and the banks of the central sulcus. All brain regions exhibited displaceable and specific binding, and thus none could be used as a reference region. Ketoprofen blocked approximately 84% of the binding sites on COX-1 in the whole brain. After full occupancy was extrapolated, the average whole-brain values of [11C]PS13 were 1.6 ± 0.8 mL·cm-3 for specific uptake, 1.7 ± 0.6 mL·cm-3 for background uptake, and 1.1 ± 0.5 for the specific-to-background ratio. The hippocampus had the highest specific-to-background ratio value of 2.7 ± 0.9. Conclusion: [11C]PS13 exhibited high specific binding to COX-1 in the human brain, but its quantification requires arterial blood sampling.

Abstract 4140139: Cardio-ankle vascular index (CAVI) in prediction of chronic coronary artery disease: risk, coronary artery lesions, and cardiovascular disease events

Introduction: The cardio-ankle vascular index (CAVI) is a significant metric for evaluating arterial function. The test measures the stiffness of the arteries from the beginning of the aorta to the ankle, and the algorithm used is not influenced by blood pressure. Recent statistics indicate that a high CAVI score has the potential to predict future cardiovascular disease (CVD) occurrences. However, no research has been conducted in Vietnam to investigate this matter. Methods: A prospective study was conducted on 222 patients. Out of these, 162 patients had chronic coronary artery disease (CAD), while the remaining 62 patients were free of CAD. The study took place between October 2019 and December 2022. Participants who fulfilled the criteria were evaluated using the CAVI baseline measurement and clinical and paraclinical parameters. A total of 162 patients with chronic coronary artery disease (CAD) were monitored for cardiovascular disease (CVD) events over a period of 2 years. Results: CAVI in chronic CAD patients (9.21±0.79) was significantly higher compared to those in free-CAD patients (8.48 ± 0.62) with p<0.001. CAVI with a cut-off point ≥ 8.83 was a significant predictor for chronic CAD (OR = 9.6; 95%CI: 4.0-18.8). The Area under the curve (AUC) of CAVI for chronic CAD was 0.796 (95% CI: 0.736-0.856 ; p<0.001). In addition, CAVI has a statistically significant increase in severe stenosis (≥75%) and multivessel coronary artery disease. CAVI in the CVD events group (9.77±1.06) was significantly higher than CAVI in the free–CVD events group (9.13±0.72) group (p=0.009). The patients with CAVI ≥9.63 have significantly higher CVD events (HR=6.4 ; 95% CI: 1.9-21.9, p=0.046). Conclusion: CAVI is higher in chronic CAD and can predict chronic CAD with a cut-off point ≥ 8.83. In chronic CAD, CAVI is higher in severe stenosis and multivessel coronary artery disease. Increased CAVI was significantly associated with CVD events.

NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY

Abstract BACKGROUND Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation. METHODS A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts. RESULTS Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement. CONCLUSION Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.

Effects of Continuous Positive Airway Pressure Treatment on Vascular Function in a Real-Life Cohort of Elderly Patients with Obstructive Sleep Apnoea Syndrome

Background: Obstructive sleep apnoea syndrome (OSAS) is an independent risk factor for cardiovascular morbidity and mortality and has a detrimental effect on vascular function, in particular on arterial stiffness and endothelial function. Continuous positive airway pressure (CPAP) is the gold-standard therapy for OSAS and its effects on arterial stiffness and endothelial function have been demonstrated in non-elderly patients. Objectives: The objective of this study was to evaluate the effect of one year of CPAP treatment on arterial stiffness, through assessment of carotid–femoral pulse wave velocity (cf-PWV), and on endothelial function, through the reactive hyperaemia index (RHi), in a real-life cohort of elderly patients with moderate-to-severe OSAS and several comorbidities. Methods: In this nonrandomised prospective study, we enrolled 469 consecutive elderly patients affected by moderate-to-severe OSAS distributed in two groups: CPAP-treated (n = 225) and untreated patients (n = 244). Results: At one-year follow-up, in the treated group emerged an important improvement in poligraphics (AHI, ODI, TC90, mean SpO2%), laboratory (HOMA index, eGFR, hs-CRP) and vascular function parameters: cf-PWV. The stepwise multivariate linear regression demonstrated a significant correlation between the delta of the polygraph parameters and the delta of PWV and RHi. Conclusions: Our study confirmed the favourable effects of CPAP therapy in a cohort of elderly patients affected by OSAS and several comorbidities on sleep respiratory parameters and vascular function; early diagnosis and treatment with CPAP might be beneficial to delay or prevent the occurrence of cardiovascular events in these groups of patients.

Associations of Cardiovascular Health Metrics in Childhood and Adolescence With Arterial Health Indicators in Adolescence: The PANIC Study.

Our aim was to assess the relationships of cardiovascular health metrics, cardiorespiratory fitness, lean mass, and fat percentage with arterial structure and function from childhood to adolescence. Five hundred four children aged 6 to 9 years were examined in the PANIC (Physical Activity and Nutrition in Children) study at baseline, 2 and 8 years later. The associations of adjusted American Heart Association cardiovascular health metrics (smoking status, body mass index-SD score, moderate-to-vigorous physical activity, diet quality, plasma total cholesterol, systolic blood pressure, plasma glucose categorized into poor, intermediate, and ideal), the American Heart Association cardiovascular health score, cardiorespiratory fitness measured by maximal oxygen uptake in a bicycle exercise test, lean mass and fat percentage with carotid intima-media thickness (cIMT) and pulse wave velocity (PWV) were analyzed cross-sectionally and longitudinally in 277 participants at age 15 to 17 years. Higher American Heart Association cardiovascular health score at baseline was associated with lower PWV at 8-year follow-up (ß, -0.19 [95% CI, -0.32 to -0.05]). Higher body mass index-SD score and systolic blood pressure were associated with higher cIMT (ß, 0.18 [95% CI, 0.05-0.31]); and (ß, 0.13 [95% CI, 0.00-0.25]; respectively) and PWV (ß, 0.20 [95% CI, 0.07-0.34]) and (ß, 0.13 [95% CI, 0.00-0.26]; respectively) at 8-year follow-up. Higher moderate-to-vigorous physical activity was associated with higher cIMT (ß, 0.25 [95% CI, 0.07-0.43]); yet lower PWV (ß, -0.25 [95% CI, -0.44 to -0.06]) at 8-year follow-up. Better cardiorespiratory fitness (ß, 0.29 [95% CI, 0.08-0.51]) and higher lean mass (ß, 0.51 [95% CI, 0.03-0.98]) were associated with higher cIMT after accounting for American Heart Association cardiovascular health score at 8-year follow-up. While our results suggest that higher cardiometabolic risk factors in childhood may exert unfavorable effects on arterial health during adolescence, we demonstrated the complexity of relationships between cardiovascular health metrics and arterial health indicators in childhood and adolescence. We found different associations of cardiovascular health metrics with cIMT and PWV in childhood and adolescence, calling for caution when interpreting the results of various cardiovascular risk factors with measures of arterial health, particularly in youth. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01803776.

Coronary Spasm Due to Pulsed Field Ablation: A State-of-the-Art Review.

With the ever-growing population of patients undergoing cardiac ablation with pulsed electric fields, there is a need to understand secondary effects from the therapy. Coronary artery spasm is one such effect that has recently emerged as the subject of further investigation in electrophysiology literature. This review aims to elucidate the basic anatomy underlying vascular spasm due to pulsed electric fields and the effects of irreversible electroporation on coronary arteries. This review also aims to gather the current preclinical and clinical data regarding the physiology and function of coronary arteries following electroporation.

Central Pulse Wave Velocity and Augmentation Index Are Repeatable and Reproducible Measures of Arterial Function.

Arterial function (specifically arterial stiffness) is an important cardiovascular risk factor. Pulse wave velocity (PWV) and augmentation index (Al ) are established indicators of arterial function. The present study aimed to evaluate the repeatability and reproducibility of PWV and Al in healthy individuals. Forty healthy participants (age 33 ± 11 years, 17 females) underwent resting supine PWV and Al assessments. Measurements were made in triplicate and repeated 1 week apart. Al was measured by brachial occlusion and PWV was measured from the carotid artery to the femoral artery via the tonometer-oscillometric method. Repeatability and reproducibility were assessed using the intraclass correlation coefficient (ICC). Interoperator reproducibility was performed on 10 participants. The average values for week-to-week visits for PWV and Al were 6.20 ± 0.91 versus 6.13 ± 0.91 ms-1 and 14.0 ± 11.8 versus 16.3 ± 12.2% respectively. For same-day measurements, both PWV and Al showed excellent repeatability (PWV: ICC = 0.96, 95% CI: 0.92-0.98, p < 0.01; Al : ICC = 0.90, 95% CI: 0.84-0.94, p < 0.01) and interoperator reproducibility (PWV: ICC = 0.98, 95% CI: 0.93-1.00, p < 0.01; Al : ICC = 0.93, 95% CI: 0.69-0.98, p < 0.01). Measurements were repeated 1 week apart and showed good reproducibility (PWV: ICC = 0.77, 95% CI: 0.61-0.87, p ≤ 0.01; Al : ICC = 0.73, 95% CI: 0.73-0.86, p < 0.01). PWV and Al demonstrate excellent repeatability and good reproducibility. Considering these variables are noninvasive and easy-to-measure, arterial function assessment may have a role in routine clinical practice to facilitate risk stratification in cardiovascular diseases.

Effects of SGLT-2i and GLP-1RA in vascular function parameters: the impact of the weight loss

Abstract Background Arterial stiffness and endothelial function markers flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness and endothelial function as well as the metabolic parameters of HbA1c and Weight in T2DM patients. Patients and Methods: We enrolled 99 consecutive patients under stable antidiabetic therapy who did not reach therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Glycosylated hemoglobin (Hba1c) and weight expressed through Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) and flow-mediated dilatation (FMD), as biomarkers of arterial stiffness and endothelial function accordingly, were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups in traditional risk factors of age and sex or baseline HbA1c, BMI, PWV, and FMD levels (ps=NS for all). In both groups PWV values displayed a statistically significant improvement from 11.2±2.5 to 9.3±2.2 m/sec (p&amp;lt;0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group, as presented in Figure 1 through the differences in the values of PWV. FMD values were also significantly improve in both groups from baseline to follow-up; from 6.04±1.22 to 6.50±1.26% (p&amp;lt;0,001) for the GLP-1RA group and from 6.38±1.21 to 6.81±1.29% (p&amp;lt;0.001) for the SGLT-2i group. Moreover, both groups achieved better weight management goals in terms of BMI values between baseline and follow-up; from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group (p&amp;lt;0.001) and from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p&amp;lt;0.001), in addition to achieving better glycemic control in terms of HbA1c values, as seen in their paired differences: for GLP-1RA: 1.3±0.7% and for SGLT-2i: 0.8±0.5%. Interestingly, in the SGLT-2i group the magnitude of the PWV improvement was correlated with the weight loss (r=0.368, p=0.007). Conclusion These data provide evidence that the newer antidiabetic drugs, both GLP1-RA and SGLT-2i, have actions that benefit both vascular function, endothelium as well as metabolic parameters. Interestingly, in the patients receiving SGLT-2i the magnitude of the PWV improvement was correlated with the weight loss.delta PWV for SGLT-2i &amp; GLP-1RA groupsCorrelation of deltaWeight &amp; deltaPWV

The interplay between coronary microvascular resistance, arterial reservoir function and coronary flow reserve: unravelling the significance of high microvascular resistance

Abstract Background Beyond the observation that patients with low CFR indicating presence of coronary microvascular dysfunction (CMD) have an unfavourable prognosis compared to patients with preserved CFR, recent large multicentre trials [1-2] have shown that increased minimal hyperaemic microvascular resistance (HMR or IMR) ,neither on top of the low CFR nor alone, does not play a role as a prognostic factor for ischemia in nonobstructive coronary artery disease (INOCA) patients. Purpose This study investigates the pathophysiological interactive processes in CMD and no-CMD groups with high and low HMR taking into account potential adaptive mechanisms that alter arterial reservoir function [3] associated with microvascular resistance and systemic vasomotor response in INOCA patients. Methods Analysis was conducted on 312 unique unobstructed vessels (FFR&amp;gt;0.80) from 258 patients (73% male) enrolled in the DEFINE-FLOW [4] study. CFR and HMR were quantified using intracoronary Doppler and pressure measurements. Vessels were categorized into four groups based on high and low CFR and HMR using the best available cut-off values (2.5 for both). Arterial reservoir capacity (ARC) and related parameters [3] were quantified using reservoir-excess pressure (Preservoir and Pexcess) analysis of averaged aortic and distal coronary pressure waveforms in CMD (CFR&amp;lt;2.5) and no-CMD (CFR≥2.5) subgroups. (Figure 1-2) Results Compared to vessels without CMD, functional and structural CMD have increased Pexcess (p:0.007) and a rapid decline in diastolic pressure (DRCcoronary p&amp;lt;0.001, DRCaortic, p&amp;lt;0.05), indicating the ongoing systemic hemodynamic superfluous state despite locally suppressed resting blood flow in the structural CMD. Higher baseline microvascular resistance (BMR) was associated with increased reservoir pressure (r:0.302, p&amp;lt;0.001). The vessels with preserved CFR despite high HMR are characterised by uniquely increased ARC (p:0.014), effectively diminished Pexcess (p:0.010), which parallels the local (highest BMR p&amp;lt;0.001) and global (lowest DRCaortic, p&amp;lt;0.05) vasomotor response, that normalizes the systemic and local hyperperfusion, and ultimately regains an adequate flow reserve (CFR) (p&amp;lt;0.001). The high HMR in this group was mainly due to increased resting tonus unlike structural CMD, evident by the highest RRR (BMR/HMR).(p&amp;lt;0.001) (Figure 1-2) Conclusion(s) The high HMR despite preserved CFR vessels form a unique-adaptive group, characterised by substantially increased arterial reservoir capacity and effectively diminished Pexcess, by means of an adaptive vasomotor response which manifests locally in the coronary bed as pronouncedly augmented BMR &amp; RRR, and globally as reduced DRC in the aortic pressure waveform. This adaptive myogenic response normalising resting flow and ongoing systemic and local hyperperfusion ultimately regains an adequate flow reserve (CFR).Figure 1.Methods and Main FindingsFigure 2.Visual Abstract

Effect of antiretroviral treatment on myocardial work and arterial function of treatment-naive patients with HIV

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&amp;lt;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&amp;lt;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.

Inhibiting chondroitin sulfate synthase 1 ameliorates hyperplastic arterial remodelling

Abstract Introduction Hyperplastic arterial remodelling is characterized by intima-media thickening, lumen narrowing, inflammation and increased extracellular matrix (ECM) deposition. Chondroitin sulfate (CS) glycosaminoglycans, the unbranched polysaccharide chains of proteoglycans, are important components of ECM. We previously found CS accumulated in adversely remodelled heart and artery, aggravating cardiac deterioration. Objective We aim to explore a therapeutic strategy to interfere with CS synthesis and investigate its potential in ameliorating hyperplastic arterial remodelling. Methods Through single-cell RNA sequencing of non-cardiomyocytes cardiac cells from mouse myocardial infarction model, chondroitin sulfate synthase 1 (CHSY1) was identified as the primary CS synthase and was increased during disease progression. A Chsy1 knockout (KO) mouse strain was generated. Fibrosis and arterial remodelling were induced using: (i) 4 weeks of angiotensin II/phenylephrine (AngII/PE) infusion through subcutaneous osmotic minipumps; and (ii) transverse aortic constriction surgery. To assess the therapeutic potential of CHSY1 inhibition in ameliorating hyperplastic arterial remodelling, Chsy1 was knockdown by dsiRNA post disease onset. Mechanism of action was investigated using primary vascular smooth muscle cells (VSMCs). Results Chsy1 KO reduced CS and its stereoisomer dermatan sulfate in the heart to 42 ± 22% and 36 ± 7% respectively, whereas other types of glycosaminoglycans remain intact. KO mice were protected against phenotypes of hyperplastic arterial remodelling induced by the two disease models in both the coronary and carotid arteries. For example, 90.1% of coronary arterial fibrosis and 79.7% of macrophage infiltration induced by AngII/PE was declined in KO mice compared to WT mice, while cardiac function as stroke volume was augmented by 41.3%. Concomitantly, carotid arterial wall thickening was lower by 36.5% and distensibility was higher by 36.7%, validating Chsy1 as a potent target. As a therapeutic approach, weekly intravenous injection of dsiRNA achieved Chsy1 reduced to 30.2 ± 5.5% in the carotid artery and 72.5 ± 4.7% in the heart. Post disease onset, Chsy1 KD therapy reduced fibrosis by 59.9% in the coronary artery (P = 0.006) and improved stroke volume by 25.6% (P = 0.036). The structural integrity and function of carotid arteries were well-reserved, manifesting as improved distensibility (29%, P = 0.016), increased elastin/perimeter ratio (15%, P = 0.002), and reduced macrophage infiltration (38%, P = 0.029). In vitro, CHSY1 inhibition suppressed migration and cytokine production of macrophages, fibroblast-to-myofibroblast transition, and VSMC hyperproliferation. NOTCH3 signalling was found to be positively correlated with CHSY1 modulation. Conclusions We demonstrated that inhibiting CHSY1 is necessary and sufficient to block CS synthesis. Chsy1 KD by dsiRNA is an effective therapy to ameliorate hyperplastic arterial remodelling.

Association between echocardiographic parameters and abnormal spirometry among chronic heart failure patients

Abstract Background A significant proportion (10-40%) of heart failure (HF) patients have concomitant pulmonary disease which have negative effects on cardiovascular outcome of patients. Because of the similarities in symptoms between HF and pulmonary disease, the prevalence of concomitant pulmonary disease may be underestimated. Early detection manage accordingly may improve outcomes of HF patients. We aimed to study clinical and echocardiographic parameters identifying HF patients with concomitant pulmonary disease. Methods This cross-sectional study included adults (age≥18 years) who were diagnosed with HF. The echocardiogram, arterial blood gas and pulmonary function test (PFT) were performed. The patients were classified into normal and abnormal (obstructive and restrictive) PFT patterns. The primary outcome was the association between echocardiographic parameters and abnormal PFT. The receiver operating characteristic (ROC) curve was performed to evaluate diagnostic performance of echocardiographic parameter in detecting abnormal PFT. Results A total of 57 patients was enrolled, of which 32 patients (56.14%) had normal PFT, 14 patients (24.56%) had obstructive PFT, and 11 patients (19.30%) had restrictive PFT. The clinical characteristics were not different between groups. ROC curve demonstrated that only left atrial volume index (LAVI) and main pulmonary artery (MPA) diameter had significant diagnostic accuracy to predict abnormal PFT with AUC of 0.72 (95%CI 0.57-0.87) and 0.66 (95%CI 0.51-0.80) respectively. Using combination of LAVI (cutoff 40mm2/m2) and MPA diameter (cutoff 22.0 mm) had a sensitivity of 95.7% (95%CI 78.05-99.89%) and specificity of 41.94% (95%CI 24.55-60.92%) in detection patients with abnormal PFT. Conclusion Almost half of HF had concomitant abnormal PFT. The combination of LAVI and MPA diameter can identify patients with abnormal PFT with high negative predictive value and should be considered as screening parameters in HF patients.

Early impairment of endothelial and myocardial function in patients with hidradenitis suppurativa

Abstract Background/Introduction Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating, inflammatory skin disease manifested by painful, deep-seated, inflamed lesions of the apocrine gland-bearing areas of the body (axillae, submammary folds, inguinal and anogenital region). HS has been associated, among others, with an increased cardiovascular risk. Purpose We aimed to investigate the endothelial, arterial and left ventricular (LV) myocardial function in patients with severe HS. Methods Twenty-eight, not previously treated patients (mean age: 36 ± 13 years) with Hurley stage III disease and a mean score of 19±8 on the International Hidradenitis Suppurativa Severity Score System (IHS4) scale, were studied. Twenty healthy sex-, age- and body mass index -matched individuals, who were also weighted for common cardiovascular risk factors, served as the control group. Both patients and controls were evaluated for: a) perfused boundary region (PBR) of the sublingual microvessels with a diameter of 5-25 μm (an increased PBR value is considered as an indicator of a decrease in thickness of the endothelial glycocalyx), using a dedicated camera (Microscan, GlycoCheck), b) carotid-femoral pulse wave velocity (PWV-Complior), c) flow-mediated dilation (FMD) of the brachial artery and d) LV global longitudinal strain (GLS) using the speckle-tracking echocardiography. Results Compared to healthy controls, HS patients had increased PBR value (2.32 ± 0.19 vs. 1.99 ± 0.14 μm, p &amp;lt; 0.001) and decreased FMD (5.7 ± 2.9 vs. 10.3 ± 1.9 %, p &amp;lt; 0.001) and GLS values (-18.6 ± 2.8 vs. -22.5 ± 2.3 %, p &amp;lt; 0.001). In contrast, similar PWV values (9.2 ± 2 vs. 9.1 ± 1.9 m/s, p = 0.937) were recorded between patients and controls (Table). Increased IHS4 score (more severe disease) was associated with increased PBR values (r = 0.42, p = 0.026) and decreased FMD values (r = -0.37, p = 0.045). Conclusion Patients with HS show early impairment of endothelial and LV myocardial function, which correlates with the severity of the underlying systemic inflammation.Table

Impact of right ventricular - pulmonary arterial coupling on mortality after transcatheter aortic valve implantation in patients with aortic stenosis

Abstract Background Aortic stenosis (AS) leads to left ventricle (LV) pressure overload. In more advanced stages of the disease, this pressure, which is transmitted through the pulmonary vasculature, may result in right ventricle (RV) remodeling and eventual dilatation and disfunction. RV failure is associated with impair prognosis, even after relief of the obstruction. The interplay of pulmonary arterial (PA) pressure and RV function can be assess using RV-PA coupling index; in a compensate state RV function is coupled with pulmonary pressure, and this function has a proper response to an increase in pulmonary afterload; in contrast, when RV function uncouples with pulmonary pressure it means that RV function can no longer sustain PA afterload, leading to a decompensate state. RV-PA uncoupling has already been associated with poor prognosis in other heart conditions, such as heart failure or pulmonary hypertension; however, there is still not much evidence on how RV-PA uncoupling prior transcatheter aortic valve implantation (TAVI) impacts on mortality. Purpose Assess the impact of RV-PA uncoupling on all-cause mortality after TAVI in patients with aortic stenosis. Methods In a prospective TAVI registry, patients were included if they had an adequate echocardiographic evaluation prior TAVI. All-cause mortality after the procedure was analyzed in two subgroups, according to their RV-PA coupling status. RV-PA was assess using tricuspid annular plane systolic excursion (TAPSE) and pulmonary arterial systolic pressure (PASP). The cut-off value was 0.39, consistent with other studies. Hazard ratios (HR) are calculated by univariate and multivariate Cox proportional hazard model. Multivariate adjustment included baseline characteristics – including age, gender, hypertension, diabetes, dyslipidemia, atrial fibrillation, and serum albumin –, and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) and European System for Cardiac Operative Risk Evaluation (EUROSCORE) II. Results A total of 1190 patients underwent TAVI from January 2011 to December 2023; 315 patients were eligible, with mean age 82,24 years (± 8,0), 52% being women, and a mean EUROSCORE II score of 4.0 (± 9,3). The RV-PA cut-off value of 0.39 stratified patients into groups of RV-PA coupling (n = 194/63,6 %) or uncoupling (n = 121/38,4 %). During follow-up time (35,94 months ±25,6), patients with unpaired coupling had a 64% more risk of all-cause mortality in univariate analysis and, after adjusting for the parameters above, a 58% increased risk in multivariate analysis. Table. Conclusions Patients with significant aortic stenosis who had an impair RV-PA coupling prior TAVI had a significant increased risk of all-cause mortality. This suggests the need to incorporate this parameter to our right-side hemodynamics evaluation prior the procedure. Broader experience to determine its application and cut-off value are still needed.

[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients

BackgroundP-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.MethodsEight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2).ResultsDRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).Conclusions[11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.Trial registrationEudraCT 2019-003137-42. Registered 28 February 2020.

Functional improvement of non-infarct related coronary artery stenosis by extensive LDL-C reduction with a PCSK9 antibody: the FITTER trial, microvascular function analysis

Abstract Background Atherosclerosis and microvascular dysfunction are closely linked. Moreover, impaired microvascular function is strongly associated with increased risk on major adverse cardiac events. In patients presenting with acute coronary syndrome (ACS), microvascular function is reduced. PCSK9-inhibitors have shown to reduce plaque burden and lipid load in epicardial vessels and might exhibit similar results on microvascular vessels, thereby improving microvascular function. The FITTER trial offers the unique opportunity to test this hypothesis. Methods The FITTER trial is a multi-center, randomized, double blind, placebo controlled clinical trial for patients presenting with ACS and multi-vessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) measurement of non-infarct related artery (non-IRA) lesions was performed. Patients with intermediate, non-critical lesions (FFR: 0.67-0.85) were included in this trial. For exploratory purpose, additional physiological assessment of the non-IRA included coronary flow reserve (CFR) and microvascular resistance index (IMR) measurements. Microvascular function was evaluated using a pressure- and temperature-sensitive guidewire and a bolus thermodilution method. Participants were randomized and treated for 12 weeks with either evolocumab or placebo in addition to high-intensity statin therapy. Staged reevaluation was done at 12 weeks. After repeated physiology testing, PCI was performed if deemed necessary. Pre-defined exploratory analysis includes the absolute and relative difference in change between CFR and IMR from baseline to follow up in the non-IRA. PCSK9 inhibition might result in a relatively larger increase of CFR and larger decrease of IMR. Results Between March 2020 and August 2023, a total of 150 patients were included in the trial. In 61 patients (88.5% male, age 65.3 ± 9.1 years, 23.0% STEMI, 70.5% non-STEMI, 6.6% UAP) successful baseline and follow-up measurements of microvascular function were performed. Complete results will be available at the beginning of March 2024. The primary- and secondary endpoints will be submitted for late-breaking clinical trials selection. The results of this abstract will include a per vessel analysis of coronary artery microvascular function. Conclusion The FITTER trial will provide new insights on the potential of extensive LDL-C reduction with a PCSK9 antibody on microvascular coronary artery function in patients presenting with ACS and MVD.

Maternal adiponectin restores cholinergic vasodilation in resistance vessels from adult offspring exposed to maternal obesity in utero.

Maternal obesity increases the risk of cardiovascular and metabolic disease in the offspring both during childhood and adult life. Pregnant women and mice with obesity have lower circulating levels of adiponectin (ADN) compared to lean controls. ADN is an adipokine involved in regulating energy metabolism, vascular function, and placental function. We hypothesized that offspring of obese mice have impaired resistance artery function, which can be prevented by restoration of normal circulating ADN levels in obese dams during late pregnancy. Adult female mice were fed either control or obesogenic diet and mated with control diet-fed males. Control dams received a continuous infusion of phosphate saline buffer (PBS) during late pregnancy whereas obese females received either PBS or ADN. After weaning, offspring were fed a control diet. Mesenteric arteries (MsA) were dissected from adult offspring and mounted in a wire myograph or fixed for histology. MsA responses to vasoconstrictors (phenylephrine and endothelin-1) were not different between infusion groups. However, the vasodilatory responses to acetylcholine were reduced in offspring from obese dams as compared to control-fed dams. ADN supplementation during pregnancy restored the cholinergic vasodilatory responses of resistance vessels in offspring from obese dams. These observations suggest a target during obese pregnancy for the prevention of the long-lasting vascular effects in the offspring.

Effect of 5β-dihydrotestosterone on vasodilator function and on cell proliferation.

Aging is one of the main factors associated with cardiovascular diseases. Androgens exert beneficial effects on the cardiovascular system and testosterone (TES) replacement therapy improves cardiometabolic risk factors. However, TES is contraindicated in patients with prostate cancer due to its proliferative effects on prostatic tumor cells. Additionally, TES and its reduced metabolites 5α- and 5β-dihydrotestosterone (5α-DHT and 5β-DHT) exert vasodilatory effects. Since androgen levels decrease during aging and 5β-DHT lacks genomic effects, this study is focused on analyzing its effect on vasodilator function and the proliferation rate of prostatic tumor and vascular smooth muscle cells. To study the vascular function, mesenteric arteries from aged-orchidectomized Sprague-Dawley rats were used. Mesenteric segments were divided into one control (without treatment) and three groups with the androgens (10 nM, 30 min) to analyze: acetylcholine- and sodium nitroprusside-induced responses and nitric oxide and superoxide anion production. To analyze cell proliferation, the effect of androgens on cell viability was determined. The results showed that 5β-DHT improves vasodilator function in arteries from aged-orchidectomized rats and induces antioxidant action, while the proliferation rate of the androgen-dependent prostatic tumor cells remains unaltered. These results make 5β-DHT a promising therapeutic agent for the treatment of cardiovascular pathologies.

Measurement variability of blood-brain barrier permeability using dynamic contrast-enhanced magnetic resonance imaging.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is used to quantify the blood-brain barrier (BBB) permeability-surface area product. Serial measurements can indicate changes in BBB health, of interest to the study of normal physiology, neurological disease, and the effect of therapeutics. We performed a scan-rescan study to inform both sample size calculation for future studies and an appropriate reference change value for patient care. The final dataset included 28 healthy individuals (mean age 53.0 years, 82% female) scanned twice with mean interval 9.9 weeks. DCE-MRI was performed at 3T using a 3D gradient echo sequence with whole brain coverage, T1 mapping using variable flip angles, and a 16-min dynamic sequence with a 3.2-s time resolution. Segmentation of white and grey matter (WM/GM) was performed using a 3D magnetization-prepared gradient echo image. The influx constant Ki was calculated using the Patlak method. The primary outcome was the within-subject coefficient of variation (CV) of Ki in both WM and GM. Ki values followed biological expectations in relation to known GM/WM differences in cerebral blood volume (CBV) and consequently vascular surface area. Subject-derived arterial input functions showed marked within-subject variability which were significantly reduced by using a venous input function (CV of area under the curve 46 vs. 12%, p < 0.001). Use of the venous input function significantly improved the CV of Ki in both WM (30 vs. 59%, p < 0.001) and GM (21 vs. 53%, p < 0.001). Further improvement was obtained using motion correction, scaling the venous input function by the artery, and using the median rather than the mean of individual voxel data. The final method gave CV of 27% and 17% in WM and GM, respectively. No further improvement was obtained by replacing the subject-derived input function by one standard population input function. CV of Ki was shown to be highly sensitive to dynamic sequence duration, with shorter measurement periods giving marked deterioration especially in WM. In conclusion, measurement variability of 3D brain DCE-MRI is sensitive to analysis method and a large precision improvement is obtained using a venous input function.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice.

Aging, an independent risk factor for cardiometabolic diseases, refers to a progressive deterioration in physiological function, characterized by 12 established hallmarks. Vascular aging is driven by endothelial dysfunction, telomere dysfunction, oxidative stress, and vascular inflammation. This study investigated whether aged gut microbiome promotes vascular aging and metabolic impairment. Fecal microbiome transfer (FMT) was conducted from aged (>75 weeks old) to young C57BL/6 mice (8 weeks old) for 6 weeks. Wire myography was used to evaluate endothelial function in aortas and mesenteric arteries. ROS levels were measured by dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence. Vascular and intestinal telomere function, in terms of relative telomere length, telomerase reverse transcriptase expression and telomerase activity, were measured. Systemic inflammation, endotoxemia and intestinal integrity of mice were assessed. Gut microbiome profiles were studied by 16S rRNA sequencing. Some middle-aged mice (40-42 weeks old) were subjected to chronic metformin treatment and exercise training for 4 weeks to evaluate their anti-aging benefits. Six-week FMT impaired glucose homeostasis and caused vascular dysfunction in aortas and mesenteric arteries in young mice. FMT triggered vascular inflammation and oxidative stress, along with declined telomerase activity and shorter telomere length in aortas. Additionally, FMT impaired intestinal integrity, and triggered AMPK inactivation and telomere dysfunction in intestines, potentially attributed to the altered gut microbial profiles. Metformin treatment and moderate exercise improved integrity, AMPK activation and telomere function in mouse intestines. Our data highlight aged microbiome as a mechanism that accelerates intestinal and vascular aging, suggesting the gut-vascular connection as a potential intervention target against cardiovascular aging and complications.