Publications by Nikolaos Stergiopulos

Cardiac output estimated from an uncalibrated radial blood pressure waveform: validation in an in-silico-generated population

Vasiliki Bikia, Georgios Rovas, Nikolaos Stergiopulos

Background: Cardiac output is essential for patient management in critically ill patients. The state-of-the-art for cardiac output monitoring bears limitations that pertain to the invasive nature of the method, high costs, and associated complications. Hence, the determination of cardiac output in a non-invasive, accurate, and reliable way remains an unmet need. The advent of wearable technologies has directed research towards the exploitation of wearable-sensed data to improve hemodynamical monitoring.Methods: We developed an artificial neural networks (ANN)-enabled modelling approach to estimate cardiac output from radial blood pressure waveform. In silico data including a variety of arterial pulse waves and cardiovascular parameters from 3,818 virtual subjects were used for the analysis. Of particular interest was to investigate whether the uncalibrated, namely, normalized between 0 and 1, radial blood pressure waveform contains sufficient information to derive cardiac output accurately in an in silico population. Specifically, a training/testing pipeline was adopted for the development of two artificial neural networks models using as input: the calibrated radial blood pressure waveform (ANN(calradBP)), or the uncalibrated radial blood pressure waveform (ANN(uncalradBP)).Results: Artificial neural networks models provided precise cardiac output estimations across the extensive range of cardiovascular profiles, with accuracy being higher for the ANN(calradBP). Pearson's correlation coefficient and limits of agreement were found to be equal to [0.98 and (-0.44, 0.53) L/min] and [0.95 and (-0.84, 0.73) L/min] for ANN(calradBP) and ANN(uncalradBP), respectively. The method's sensitivity to major cardiovascular parameters, such as heart rate, aortic blood pressure, and total arterial compliance was evaluated.Discussion: The study findings indicate that the uncalibrated radial blood pressure waveform provides sample information for accurately deriving cardiac output in an in silico population of virtual subjects. Validation of our results using in vivo human data will verify the clinical utility of the proposed model, while it will enable research applications for the integration of the model in wearable sensing systems, such as smartwatches or other consumer devices.

FRONTIERS MEDIA SA2023

Effect of the structural modification of Candesartan with Zinc on hypertension and left ventricular hypertrophy

Valeria Romina Martinez, Augusto Martins Lima, Nikolaos Stergiopulos

Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.

ELSEVIER2023

In Memoriam of Nico Westerhof (1937-2022)

Patrick Segers, Nikolaos Stergiopulos

BMC2023

Quantification of the Phenomena Affecting Reflective Arterial Photoplethysmography

Vasiliki Bikia, Georgios Rovas, Nikolaos Stergiopulos

Photoplethysmography (PPG) is a widely emerging method to assess vascular health in humans. The origins of the signal of reflective PPG on peripheral arteries have not been thoroughly investigated. We aimed to identify and quantify the optical and biomechanical processes that influence the reflective PPG signal. We developed a theoretical model to describe the dependence of reflected light on the pressure, flow rate, and the hemorheological properties of erythrocytes. To verify the theory, we designed a silicone model of a human radial artery, inserted it in a mock circulatory circuit filled with porcine blood, and imposed static and pulsatile flow conditions. We found a positive, linear relationship between the pressure and the PPG and a negative, non-linear relationship, of comparable magnitude, between the flow and the PPG. Additionally, we quantified the effects of the erythrocyte disorientation and aggregation. The theoretical model based on pressure and flow rate yielded more accurate predictions, compared to the model using pressure alone. Our results indicate that the PPG waveform is not a suitable surrogate for intraluminal pressure and that flow rate significantly affects PPG. Further validation of the proposed methodology in vivo could enable the non-invasive estimation of arterial pressure from PPG and increase the accuracy of health-monitoring devices.

MDPI2023

The Impact of Left Ventricular Performance and Afterload on the Evaluation of Aortic Valve Stenosis: A 1D Mathematical Modeling Approach

Nikolaos Stergiopulos

The transaortic valvular pressure gradient (TPG) plays a central role in decision-making for patients suffering from severe aortic stenosis. However, the flow-dependence nature of the TPG makes the diagnosis of aortic stenosis challenging since the markers of cardiac performance and afterload present high physiological interdependence and thus, isolated effects cannot be measured directly in vivo. We used a validated 1D mathematical model of the cardiovascular system, coupled with a model of aortic stenosis, to assess and quantify the independent effect of the main left ventricular performance parameters (end-systolic (E-es) and end-diastolic (E-ed) elastance) and principal afterload indices (total vascular resistance (TVR) and total arterial compliance (TAC)) on the TPG for different levels of aortic stenosis. In patients with critical aortic stenosis (aortic valve area (AVA)

MDPI2023

Arterial Wave Reflection and Aortic Valve Stenosis: Diagnostic Challenges and Prognostic Significance

Vasiliki Bikia, Stamatia Zoi Pagoulatou, Georgios Rovas, Nikolaos Stergiopulos

IntroductionArterial wave reflection is an important component of the left ventricular afterload, affecting both pressure and flow to the aorta. The aim of the present study was to evaluate the impact of wave reflection on transvalvular pressure gradients (TPG), a key parameter for the evaluation of aortic valve stenosis (AS), as well as its prognostic significance in patients with AS undergoing a transcatheter aortic valve replacement (TAVR). Materials and MethodsThe study population consisted of 351 patients with AS (mean age 84 +/- 6 years, 43% males) who underwent a complete hemodynamic evaluation before the TAVR. The baseline assessment included right and left heart catheterization, transthoracic echocardiography, and a thorough evaluation of the left ventricular afterload by means of wave separation analysis. The cohort was divided into quartiles according to the transit time of the backward pressure wave (BWTT). Primary endpoint was all-cause mortality at 1 year. ResultsEarly arrival of the backward pressure wave was related to lower cardiac output (Q1: 3.7 +/- 0.9 lt/min vs Q4: 4.4 +/- 1.0 lt/min, p < 0.001) and higher aortic systolic blood pressure (Q1: 132 +/- 26 mmHg vs Q4: 117 +/- 26 mmHg, p < 0.001). TPG was significantly related to the BWTT, patients in the arrival group exhibiting the lowest TPG (mean TPG, Q1: 37.6 +/- 12.7 mmHg vs Q4: 44.8 +/- 14.7 mmHg, p = 0.005) for the same aortic valve area (AVA) (Q1: 0.58 +/- 0.35 cm(2) vs 0.61 +/- 0.22 cm(2), p = 0.303). In multivariate analysis, BWTT remained an independent determinant of mean TPG (beta 0.3, p = 0.002). Moreover, the prevalence of low-flow, low-gradient AS with preserved ejection fraction was higher in patients with early arterial reflection arrival (Q1: 33.3% vs Q4: 14.9%, p = 0.033). Finally, patients with early arrival of the reflected wave (Q1) exhibited higher all-cause mortality at 1 year after the TAVR (unadjusted HR: 2.33, 95% CI: 1.17-4.65, p = 0.016). ConclusionEarly reflected wave arrival to the aortic root is associated with poor prognosis and significant aortic hemodynamic alterations in patients undergoing a TAVR for AS. This is related to a significant decrease in TPG for a given AVA, leading to a possible underestimation of the AS severity.

FRONTIERS MEDIA SA2022

Assessment Of Stiffness Of Large To Small Arteries In Multi-Stage Renal Disease: A Numerical Study

Vasiliki Bikia, Patrick Segers, Nikolaos Stergiopulos

LIPPINCOTT WILLIAMS & WILKINS2022

Assessment of Stiffness of Large to Small Arteries in Multistage Renal Disease Model: A Numerical Study

Vasiliki Bikia, Patrick Segers, Nikolaos Stergiopulos

Arterial stiffness (AS), as assessed via pulse wave velocity (PWV), is a major biomarker for cardiovascular risk assessment in patients with chronic kidney disease (CKD). However, the mechanisms responsible for the changes in PWV in the presence of kidney disease are not yet fully elucidated. In the present study, we aimed to investigate the direct effects attributable to biomechanical changes in the arterial tree caused by staged renal removal, independent of any biochemical or compensatory effects. Particularly, we simulated arterial pressure and flow using a previously validated one-dimensional (1-D) model of the cardiovascular system with different kidney configurations: two kidneys (2KDN), one single kidney (1KDN), no kidneys (0KDN), and a transplanted kidney (TX) attached to the external iliac artery. We evaluated the respective variations in blood pressure (BP), as well as AS of large-, medium-, and small-sized arteries via carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and radial-digital PWV (rdPWV), respectively. Our results showed that BP was increased in 1KDN and 0KDN, and that systolic BP values were restored in the TX configuration. Furthermore, a rise was reported in all PWVs for all tested configurations. The relative difference in stiffness from 2KDN to 0KDN was higher in the case of crPWV (15%) in comparison with the increase observed for cfPWV (11%). In TX, we observed a restoration of the PWVs to values close to 1KDN. Globally, it was demonstrated that alterations of the outflow boundaries to the renal arteries with staged kidney removal led to changes in BP and central and peripheral PWV in line with previously reported clinical data. Our findings suggest that the PWV variations observed in clinical practice with different stages of kidney disease may be partially attributed to biomechanical alterations of the arterial tree and their effect on BP.

FRONTIERS MEDIA SA2022

Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

Nikolaos Stergiopulos, Mikaël Nils Sturny

Background: Neurogenic erectile dysfunction (ED) following radical prostatectomy (RP) is a frequent complication often leading to erectile tissue remodeling and permanent ED. Low-intensity electrostimulation (LIES) has been shown to enhance peripheral nerve regeneration, however, its application on cavernous nerves (CN) has never been investigated. Aims: To investigate whether LIES enhances CN regeneration, improves erectile function (EF) recovery, and prevents corpora cavernosal remodeling after CN injury, which is a principal factor for ED following RP. Methods: Adult male Sprague-Dawley rats were divided into Sham, Bilateral Cavernous Nerve Injury (BCNI), and BCNI + LIES (1V, 0.1ms, 12Hz, 1h/day). After 7days, EF was assessed (ICP measurement). Penes and CN were collected formolecular analyses of TGF-beta 1, Il-6, CRP, eNOS, ERK and AKT protein levels in corpus cavernosum (CC), and immunohistological analysis of DHE, total collagen and alpha-SMA in CC and S-100, Tub-III, DAPI, TUNEL, and nNOS in CN. Outcomes: Effects of LIES on EF, erectile tissue remodeling and CN structure. Results: EF was decreased (P < .05) 7 days after BCNI and increased (P < .05) by LIES. Intracavernosal reactive oxygen species (DHE) was increased (P < .05) after BCNI and normalized by LIES. Protein expressions of TGF-beta 1, IL-6, and CRP were increased in the penis (P < .05) after BCNI and normalized by LIES. The alpha-SMA and/or total collagen ratio was decreased (P < .05) after BCNI in the penis and normalized by LIES. Protein expression ratio of p-ERK/ERK and p-AKT/AKT did not change after BCNI but increased (P

ELSEVIER SCI LTD2022

, ,

Aims:Diminazene aceturate, a putative ACE2 activator, is susceptible to cleavage resulting in the formation of paminobenzamidine (PAB). This study aimed to investigate the effects of PAB in addressing cardiovascular dysfunctions in spontaneously hypertensive rats (SHR). Main methods:Acute effects of PAB on mean arterial pressure (MAP), heart rate (HR), and aortic (AVC) and mesenteric vascular conductance (MVC) were evaluated in anesthetized SHR. Isolated aortic rings and the Langendorff technique were used to investigate the acute and chronic effects of PAB in the artery and heart. Chronic treatment with PAB (1 mg/kg, gavage) was carried out for 60 days. During this period, systolic blood pressure (SBP) and HR were measured by tail-cuff plethysmography. After the treatment, the left ventricle was collected for histology analyses, western blotting, and ACE2 activity. Key findings:Bolus infusion of PAB acutely reduced MAP and increased both AVC and MVC in SHR. Additionally, PAB induced coronary and aorta vasodilation in isolated organs from Wistar and SHR in an endothelialdependent manner. The chronic PAB treatment in SHR significantly attenuated the increase of SBP and improved the aorta vasorelaxation induced by acetylcholine and bradykinin-induced coronary vasodilation. In addition, chronic treatment with PAB attenuated the cardiomyocyte hypertrophy and extracellular matrix deposition in hearts from SHR. PAB did not alter the protein expression of the AT1, AT2, Mas, ACE, ACE2, or ACE2 activity. Significance:PAB induced beneficial effects on cardiovascular dysfunctions induced by hypertension, suggesting that this molecule could be used in the development of new drugs for the treatment of cardiovascular diseases.

PERGAMON-ELSEVIER SCIENCE LTD2022