Arterial Vascular Resistance Research Articles

Unmasking an Intracardiac Shunt in a Case of Persistent Unexplained Hypoxia: A Case Report

Background and Clinical Significance: Pulmonary hypertension (PH) is characterized by an increase in mean pulmonary arterial pressure and pulmonary vascular resistance. It is frequently encountered in patients with significant intracardiac shunts, often necessitating the implementation of a closure device or surgical correction. Nevertheless, the occurrence of a concomitant atrial septal defect (ASD) with a right-to-left shunt inducing left ventricular dysfunction is a rare phenomenon. Case Presentation: A 69-year-old female patient with a history of heart failure (with preserved ejection fraction) and end-stage renal disease on hemodialysis presented to an outside facility, with syncope and hypoxia. She was recently diagnosed with severe pulmonary hypertension (measuring 86 mmHg). Right heart catheterization (RHC) revealed precapillary pulmonary hypertension (88/37/54 mmHg), prompting the initiation of intravenous epoprostenol. Nevertheless, the patient was persistently hypoxic, raising the possibility of a concomitant diagnosis. Upon review of the prior echocardiogram, which included a bubble study, an intracardiac shunt was identified. It was hypothesized that a combination of right ventricular failure and the right-to-left shunt resulting from the ASD contributed to the persistent hypoxemia. In light of this, prostacyclin therapy was continued alongside adjunctive vasopressors, resulting in clinical stabilization. The patient was eventually discharged with a treatment regimen that included subcutaneous Treprostinil. Conclusions: It is important to recognize that the consequences of PH are extensive, and that a rare yet significant etiology for persistent hypoxemia may be attributed to right-to-left shunting.

Capillary refill time paradoxically decreases in a blood loss shock model

BackgroundThis study aimed to investigate whether changes in capillary refill (CR) time precede macrovascular signs of deterioration in a human model of blood loss shock. The study was conducted at the Department of Emergency Medicine in Linköping, Sweden, and involved 42 healthy volunteers aged 18–45. Participants were randomized into two provocations of applied lower body negative pressure (LBNP): a stepwise escalation protocol and a direct application protocol, to simulate gradual and acute blood loss. The main outcome measure was CR time. Systolic, diastolic, and mean arterial pressures, heart rate, cardiac output, and systemic vascular resistance were measured continuously. CR time was assessed on the finger pulp using a standardized pressure and measured with a polarized reflectance imaging system.ResultsThe provocation elicited pre-syncope reactions and clear decrease in blood pressure for all participants, yet two-thirds of the participants in both protocols reacted with shorter CR times at maximum provocation, and the overall median CR time decreased by 0.2 s (Wilcoxon W = − 395.0, range: − 6.3 to 3.2, IQR − 1.3 to 0.1, P = 0.0070). Participants with shorter CR times exhibited comparatively greater increases in systemic vascular resistance and a more pronounced decrease in cardiac output.ConclusionsOur findings reveal that finger CR time paradoxically decreases in a majority of healthy volunteers in a lower body negative pressure model of blood loss, challenging traditional assumptions about the CR test’s reliability as a shock indicator in its present interpretation.

Systemic Circulation in Advanced Heart Failure and Cardiogenic Shock: State-of-the-Art Review.

The integrative physiology of the left ventricle and systemic circulation is fundamental to our understanding of advanced heart failure and cardiogenic shock. In simplest terms, any increase in aortic stiffness increases the vascular afterload presented to the failing left ventricle. The net effect is increased myocardial oxygen demand and reduced coronary perfusion pressure, thereby further deteriorating contractile function. Although mechanical circulatory support devices should theoretically work in concert with guideline-directed medical therapy, cardiac resynchronization and inotropic and vasopressor agents designed to support myocardial performance and enhance left ventricle recovery, this does not always occur. Each therapy and intervention may result in vastly different and sometimes deleterious effects on vascular afterload. Although best described by a combination of both steady-state and pulsatile components, the latter is frequently overlooked when mean arterial pressure or systemic vascular resistance alone is used to quantify vascular afterload in advanced heart failure and cardiogenic shock. In this state-of-the-art review, we examine what is known about vascular afterload in advanced heart failure and cardiogenic shock, including the use of temporary and permanent mechanical circulatory support systems. Importantly, we outline 4 key components for a more complete assessment of vascular afterload. Unlike previous discussions on this topic, we set aside considerations of venous return and ventricular preload, as important as they are, to focus exclusively on the hydraulic load within the systemic circulation against which the impaired left ventricle must contract.

Progress in pediatric pulmonary hypertension management in Saudi Arabia: bridging current challenges with emerging solutions

Pulmonary hypertension (PH) in pediatrics is a rare illness that is known by progressive structural alterations with accompanied elevation in arterial pressure and vascular resistance that leads to right heart failure and mortality. PH in pediatrics has a poor prognosis and is a life-threatening illness that necessitates early and appropriate management. This review was established to overview the progress made in pediatric PH management in Saudi Arabia. Hence, the search process for obtaining relevant articles was conducted using scientific websites and databases with related keywords. Eligible articles included those focused on the research topic, originating from Saudi Arabia or other regions for comparative insights. Pulmonary arterial hypertension (PAH) is a potential disease among the pediatric population with significant adverse outcomes and poor prognosis; however, this disease gained low focus in the research field and clinical trials with a lack of prevalence and incidence data globally and in Saudi Arabia. Saudi Arabia published a guideline on the management of PAH among children in the year 2014; however, since then, there has been no progression noted in the management of PAH children in Saudi Arabia due to the lack of research and clinical trials reporting the outcomes and the impacts of different therapeutic regimens. Furthermore, it cannot be deduced which ideal treatment is for the pediatric population as the treatment of this population is mainly based on the research conducted on the adult population.

When pulmonary arterial hypertension and pregnancy meet: a multidisciplinary clinical experts review.

Pulmonary hypertension (PH) is a rare condition characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, potentially leading to right ventricular failure. Pulmonary arterial hypertension (PAH) is the most common type of PH in women of childbearing age and, as per the modified World Health Organization (mWHO) classification of maternal cardiovascular risk, it falls into mWHO class IV and pregnancy is contraindicated. These patients face an exceptionally high risk of maternal mortality and morbidity, with estimated maternal cardiac event rates ranging from 40 to 100% during pregnancy, because physiological changes happening in pregnancy exacerbate the disorder. Despite these recommendations, there is a growing incidence of pregnancy among women with PAH. Early referral to specialized centers, personalized therapies and expert multidisciplinary care involving pulmonary hypertension specialists, obstetricians, critical care specialists, anesthesiologists, and neonatologists are crucial steps to ensure positive outcomes for both mother and fetus. This review aims to examine the current understanding of pregnancy in patients with PAH, drawing on the experience of our center in the multidisciplinary management of pregnant women with this condition. In particular, we want to focus the attention of clinicians on the following aspects: early referral of pregnant patients to specialized centers, detailed counseling on the implications of pregnancy, initiation of therapy in treatment-naive patients and potential adjustment of therapy in non-naive patients, periodic risk assessment, evaluation of the appropriate timing of delivery, multidisciplinary management of the most critical periods, which are delivery and the post-partum phase.

Abstract 4138793: Impact of diabetes mellitus on the severity and long-term outcomes of chronic thromboembolic pulmonary hypertension: a retrospective cohort study

Background: Previous studies have indicated that diabetes mellitus (DM) is linked to the severity and mortality of both pulmonary thromboembolism and pulmonary arterial hypertension. But the relationships between diabetes and chronic thromboembolic pulmonary hypertension (CTEPH) have not been discussed. This study aims to investigate the relationships of DM with disease severity and clinical worsening events in patients with CTEPH. Methods: We analysed data of patients with CTEPH from the National Center for Cardiovascular Diseases in China between January 1, 2013 and August 31, 2023. A 2-group propensity score matching was conducted to adjust for differences between CTEPH patients with and without DM, employing a 1:1 pairing algorithm. The association between DM and long-term adverse outcomes was appraised utilizing multivariable Cox regression models. Subgroup analyses, predicated on age, sex, World Health Organization functional class (WHO-FC) and body mass index, were carried out to evaluated interaction effects. Results: In total, 489 consecutive CTEPH patients were included in the study, with 25.97% diagnosed with DM. Subsequent matched analysis comprised 127 patients with DM and 127 without DM. CTEPH patients with DM exhibited inferior WHO-FC as well as cardiac index, elevated N-terminal pro–brain natriuretic peptide levels, pericardial effusion, tricuspid annular plane systolic excursion / systolic pulmonary arterial pressure ratio and pulmonary vascular resistance. After adjusting for confounding factors, DM remained independently associated with adverse outcomes in patients with CTEPH. In addition, further subgroup analyses disclosed a more robust association in patients without overweight or obesity. Conclusions: DM correlates with heightened severity of CTEPH and serves as an autonomous predictor of long-term prognosis in CTEPH. Moreover, this correlation is more pronounced in individuals devoid of overweight or obesity.

Echocardiographic profiles of patients with CPCPH and IPCPH in HFpEF: insights from the PHHF study

Abstract Background The 2022 ESC/ERS guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Yet, the echocardiographic profile of HF with preserved ejection fraction (PEF) patients according to their mPAP and RVP is not known. Objectives To investigate the echocardiographic profile of HFPEF patients according to their mPAP and RVP. Methods Stable HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed-up in this multicenter study. All patients had a right heart catheterization and an echocardiography within the 24 hours. PcPH was characterized by a pulmonary wedge pressure exceeding 20 mm Hg and mean mPAP greater than 20 mm Hg, from an isolated state when PVR was less than 2 Wood units (WU, IpcPH) to a combined form when PVR exceeded 2 WU (CpcPH). Results Out of 662 HF patients included in PHHF study, 268 (40%) were classified as having HFpEF (35% male, median age 71 yo). Compared to IpcPH patients, CpcPH patients had higher tricuspid regurgitation peak velocity (sPAP, 3.53 vs 3.00 m/s, p<0.01), lower S tricuspid tissue Doppler velocity (10 vs. 11 cm/s, p 0.01) and TAPSE (18 vs. 21 mm, p< 0.01) and lower TAPSE/sPAP ratio (0.3 vs. 0.4, p<0.01). There were no differences between groups regarding both right ventricle and right atrial diameter and area. Conclusion In HFpEF patients with PH, CpcPH patients had worse right ventricular function despite similar remodeling when compared to IpcPH patients

Hemodynamic effects of vericiguat in symptomaticHFrEF patients: insights from right heart catheterization study

Abstract Background Vericiguat is recommended in the guidelines as Class IIb for patients with heart failure with reduced ejection fraction (HFrEF) who continue to have persistent symptoms despite receiving standard therapy. However, the precise effects of vericiguat on pulmonary and systemic hemodynamics and cardiac performance remain unclear. Purpose This study aimed to investigate the hemodynamic impact of vericiguat in 12 symptomatic HFrEF patients who experienced worsening HF despite receiving standard therapy with the four foundational heart failure medications, using right heart catheterization (RHC). Methods On day 1, RHC was performed via the right internal jugular vein and a balloon-tripped pulmonary artery thermodilution catheter was placed. On day 2 and 3, RHC data were measured at 15min before and 30min, 1hr, 2hr, 3hr and 5hr after intake of 2.5mg vericiguat. RHC data on day 2 and 3 were averaged and the catheter was removed after the RHC measurements on day 3. RHC was repeated on a median day of 105(quartiles 37,168). The acute hemodynamic effects of vericiguat were assessed using a comparison of six RHC measures, including pulmonary artery wedge pressure (PAWP), mean pulmonary artery pressure (MPAP), mean arterial blood pressures (MABP), pulmonary (PVR) and systemic vascular resistances (SVR) and cardiac index (CI), at 15minutes before intake of vericiguat 2.5mg with those at 30minutes to 5hours after that. The chronic hemodynamic effects of vericiguat were evaluated by comparing the six RHC measures on day 1 with those on day 105(37,168). Results Participant characteristics on day 1 were age 63.5(53.5,70)yrs., 16.7%(N=2) women, height 164.3(155,171.3)cm, weight 64.6(54.8,75.1)kg, body mass index 23.8(20,26.3), systolic 101.5(90.5,111.5)mmHg and diastolic blood pressures 60.2(53.5,65)mmHg, heart rate 65.5(56,72)bpm, New York Heart Association functional class Ⅱ 50%(N=6), Ⅲ 16.7%(N=2) and Ⅳ 33.3%(N=4), estimated glomerular filtration rate 44.5(34.5,53.5)mL/min/1.73m2, left-ventricular ejection fraction 19.9(14.5,24.5)% and diastolic diameter 68(60.5,72.5)mm, left-atrial diameter 45(36.5,50.5)mm and brain natriuretic peptide level 419(254,479)pg/mL. Oral intake of vericiguat 2.5mg decreased PAWP (11[7.5,15]mmHg) and MPAP (19.3[14.3,26.8]mmHg) before the intake to PAWP (9.3[6.8,14]mmHg) and MPAP (17.5[12.5,24]mmHg) at 30min after that (both P<0.05[crude P<0.0017])(Figure A) while comparable changes in MABP, PVR, SVR and CI and the other timepoints (all P>0.05[crude P<0.0017]). Vericiguat was titrated to 2.5mg 25% (N=3), 5mg 50% (N=6) and 10mg 25% (N=3) on day 105 (37,168), in which PAWP (9.5[6.5,12.5]mmHg) was decreased from PAWP (14.5[9.5,19.5]mmHg) on day 1 (P<0.05[crude P<0.0083])(Figure B) while comparable changes in the other RHC parameters (all P>0.05[crude P<0.0083]). Conclusions The consistent reduction in PAWP underscores vericiguat's well-tolerated nature and potential to enhance cardiac performance in patients with HFrEF.

Noninvasive Assessment of Temporal Dynamics in Sympathetic and Parasympathetic Baroreflex Responses.

The baroreflex system is crucial for cardiovascular regulation and autonomic homeostasis. A comprehensive assessment requires understanding the simultaneous temporal dynamics of its multiple functional branches, which traditional methods often overlook. To develop and validate a noninvasive method for simultaneously assessing the temporal dynamics of sympathetic and parasympathetic baroreflexes using pulse contour analysis and the sequence method. Beat-to-beat blood pressure and ECG recordings were analyzed from 55 preoperative cardiothoracic surgery patients in the supine position and 21 subjects from the EUROBAVAR dataset in both supine and standing positions. Systolic arterial pressure (SAP), interbeat interval (IBI), cardiac output (CO), myocardial contraction (dP/dtmax), and systemic vascular resistance (SVR) were estimated using pulse contour analysis. Baroreflex sensitivity (BRS) was calculated via the sequence method and correlated with hemodynamic and heart rate variability (HRV) parameters. Parasympathetic BRS for IBI was correlated with the root mean square of successive differences of ECG RR intervals (RMSSD-HRV) at 0-beat delay. Sympathetic BRS for SVR strongly correlated with SVR, CO, and RMSSD-HRV, particularly at 3-beat delay, and was uniquely associated with SAP at 1-beat delay. Sympathetic BRS for dP/dtmax correlated with dP/dtmax at 1-beat delay. In contrast, BRS for CO correlated with CO and SVR at 0- and 3-beat delays. Postural changes mainly affected parasympathetically-mediated BRS for IBI and, to a lesser extent, the sympathetic vascular and myocardial branches. This method effectively captures multiple baroreflex responses and their temporal dynamics, revealing distinct autonomic mechanisms and the impact of postural changes. Further validation is warranted.

Small changes in the transducer position cause a systematic change in cardiac output readings: implications for clinical practice.

To systematically evaluate the effect of small changes in transducer position on key hemodynamic variables including CO generated by 4th generation FloTrac software. After cardiac surgery, cardiac output, mean arterial pressure, systemic vascular resistance, and stroke volume variation were measured with 4 generation Flotrac software. The transducer position was randomly placed at the midaxillary plane, 4cm higher than the midaxillary plane or 4cm lower than the midaxillary plane. Averages of three measurements were used. Data was available from 20 patients. Cardiac output increased from 4.59L/min (± 0.92) to 4.78L/min (± 0.99) with the transducer position at the midaxillary plane to 4cm higher than the midaxillary plane, and cardiac output decreased to 4.43L/min (± 0.90) with the transducer 4cm lower than midaxillary plane (P < 0.001). On the relative scale, CO increased 4.1% (95% CI 3.1-5.0) when comparing the higher transducer level with the midaxillary plane position, and CO decreased 3.4% (95% CI 2.4-4.4) when comparing the midaxillary plane position with the lower transducer level, correspondiong to changes in CO of ≈ 1% per 1cm change in transducer position. Mean arterial pressure and systemic vascular resistance both changed significantly with transducer position (both P < 0.001), whereas no statistically or clinically significant effect was seen on stroke volume variation (P = 0.98). A four-centimeter change in vertical transducer position induced clinically significant changes in cardiac output measurements by 4th generation FloTrac software. Definitions of optimal cardiac output in goal-directed therapy algorithms require meticulous transducer adjustment and can only be used in the reference patient position.

Correlation Analysis of Activity Levels and Risk Factors in Patients with Stroke: Variations in Cardiac Function According to the Longshi Scale.

This study examined the link between physical activity levels, as measured by the Longshi Scale, and cardiac function and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in stroke patients, aiming to find correlations with stroke risk factors. The study involved 123 apoplexy patients divided into four groups based on the Longshi Scale: bedridden (31), domestic (32), community (30), and health (30). Clinical data was collected, and hemodynamic assessments were performed using impedance cardiography. Cardiac output time index (CTI) and estimated ejection fraction (EF est) were significantly reduced in both the domestic and community groups compared to the health group (P < 0.05), while diastolic arterial blood pressure (DABP) and systemic vascular resistance index (SVRi) were increased. In the bedridden group, stroke volume (SV), cardiac output (CO), CTI, left cardiac work index (LCWi), and EF est were all lower compared to the health group (P < 0.05), with SVRI and NT-proBNP levels being higher. Additionally, the bedridden group exhibited lower SV, CO, DABP, LCWi, CTI, and EF est when compared to the domestic and community groups (P < 0.05), but higher end-diastolic filling rate (EDFR) and NT-proBNP levels. The Longshi Scale grading positively correlated with SV (r = 0.536, P < 0.01), and NT-proBNP, EF, and cognitive dysfunction were found to be associated with activity levels in stroke patients. The Longshi Scale correlates with cardiac function indicators like NT-proBNP and EF, and can help identify stroke patients at risk of cardiac dysfunction. Moreover, cognitive dysfunction was identified as a significant factor influencing the range of activity in patients with stroke.

The Right Ventricular-Arterial Compliance Index: A Novel Hemodynamic Marker to Predict Right Heart Failure Following Left Ventricular Assist Device.

The development of right heart failure (RHF) in patients with advanced heart failure following left ventricular assist device (LVAD) implantation remains difficult to predict. We proposed a novel composite hemodynamic index-the right ventricular-arterial compliance index (RVACi), derived from pulmonary artery pulse pressure (PAPP), ejection time (ET), heart rate (HR), and cardiac output (CO), with and expressed as mm Hg·s/L. We then conducted a retrospective, single-center analysis comparing the predictive value of RVACi for the development of RHF or unplanned right ventricular (RV) mechanical circulatory support following LVAD implantation against existing hemodynamic indices. One hundred patients were enrolled after screening 232 patients over a 10 year period, with 74 patients having complete hemodynamic data for RVACi calculation. There was good correlation between pulmonary arterial capacitance (R² = 0.48) and pulmonary vascular resistance (R² = 0.63) with RVACi, but not RV stroke work index or pulmonary artery pulsatility index. Reduced baseline RVACi (52 ± 23 vs. 92 ± 55 mm Hg·s/L; p = 0.02) was the strongest hemodynamic predictor of unplanned RV mechanical circulatory support requirement in patients following LVAD insertion. Composite pulsatile hemodynamic indices including RVACi may provide additional insight over existing hemodynamic indices for the prediction of RHF and need for RV mechanical circulatory support.

BMP10 reflects pre-capillary pulmonary hemodynamics: association of biomarkers and hemodynamic parameters in pulmonary hypertension

Abstract Background and aims The role of biomarkers in diagnosing pulmonary hypertension (PH) and distinguishing between pre- and post-capillary PH remains poorly understood. We aimed to identify biomarkers with a strong association with mean pulmonary arterial pressure, mPAP (PH diagnosis) and pulmonary vascular resistance, PVR (pre-capillary component), but not with pulmonary arterial wedge pressure, PAWP (post-capillary component). Methods Blood samples were collected in patients undergoing right heart catheterization within a prospective cross-sectional study. Biomarkers measured included BMP10, NT-proBNP, ANG2, ESM1/endocan, FGF23, GDF15, IGFBP7, IL6, MyBPC3, proC3, and proC6/endotrophin. Primary outcomes were mPAP, PVR, and PAWP, while secondary outcomes included PH diagnosis (mPAP &gt; 20 mmHg) and elevated PVR (&gt; 2 Wood units). Multivariable linear and logistic regression models were used to assess the relationship between biomarkers and outcomes. Results Of the 127 patients included (age 66 ± 13 years, 54% female), 73% were diagnosed with PH. BMP10, NT-proBNP, ANG2, MyBPC3, and FGF23 showed a strong association with mPAP (p &lt; 0.001). BMP10 and NT-proBNP were strongly associated with PVR (p &lt; 0.001), while NT-proBNP and ANG2 were strongly associated with PAWP (p &lt; 0.001). NT-proBNP had the strongest association with the diagnosis of PH (area under the curve = 0.76). BMP10 was the only biomarker associated with elevated PVR (OR 1.60, 95%CI 1.01–2.54, p = 0.04) but not with PAWP (p = 0.86). Conclusions Several biomarkers were strongly associated with mPAP, PAWP, and PVR. BMP10 was the only biomarker strongly associated with mPAP and PVR, but not with PAWP, thus reflecting the pre-capillary PH component. Measurement of BMP10 along with NT-proBNP may aid in diagnosing PH. Graphical abstract

Do we have our FACTTs straight about cor pulmonale in acute respiratory distress syndrome?

The incidence of cor pulmonale in acute respiratory distress syndrome is roughly 20-25% and is associated with nearly 50% increase in mortality risk. Our primary aim was to quantify the association of traditional cor pulmonale risk factors {pH, PaO2:FiO2 ratio, PaCO2, and driving pressure [plateau pressure minus the positive end-expiratory pressure (PEEP)]} and PEEP with the mentioned cor pulmonale parameters. Using data from the FACTT trial, we examined four cor pulmonale parameters. In addition to pulmonary arterial compliance (Cpa) and pulmonary vascular resistance index (PVRi), we assessed pulmonary artery pulsatility index (PAPi) and effective arterial elastance (Ea) of the pulmonary circulation. Median [interquartile range (IQR)] Cpa on study day 1 was 4.28 mL/mmHg (3.14, 6.08). Increasing pH and P:F were associated with an increase in Cpa. Median (IQR) Ea on Day 1 was 0.48 mmHg/mL (0.36, 0.66). Increase of pH, PaCO2, and P:F were associated with a decrease in Ea, while an increase in PEEP was associated with an increase in Ea. Median (IQR) PAPi on Day 1 was 1.58 (1.13, 2.38). Increase in pH was associated with an increase in PAPi, while increase in PEEP was associated with a decrease in PAPi. Median (IQR) PVRi on Day 1 was 3.86 WU*m2 (2.45, 4.79). Increases in PaCO2 and P:F were associated with a decrease in PVRi, while increasing driving pressure and PEEP were associated with an increase in PVRi. While the FACTT data demonstrate neither a clear nor a consistent relationship between right ventricular-pulmonary arterial function and traditional risk factors, this does not indicate their unimportance.

Definition, classification and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is a haemodynamic condition characterised by elevation of mean pulmonary arterial pressure (mPAP) >20 mmHg, assessed by right heart catheterisation. Pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) distinguish pre-capillary PH (PAWP ≤15 mmHg, PVR >2 Wood Units (WU)), isolated post-capillary PH (PAWP >15 mmHg, PVR ≤2 WU) and combined post- and pre-capillary PH (PAWP >15 mmHg, PVR >2 WU). Exercise PH is a haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during exercise, defined as a mPAP/cardiac output slope >3 mmHg/L/min between rest and exercise. The core structure of the clinical classification of PH has been retained, including the five major groups. However, some changes are presented herewith, such as the re-introduction of "long-term responders to calcium channel blockers" as a subgroup of idiopathic pulmonary arterial hypertension, the addition of subgroups in group 2 PH and the differentiation of group 3 PH subgroups based on pulmonary diseases instead of functional abnormalities. Mitomycin-C and carfilzomib have been added to the list of drugs with "definite association" with PAH. For diagnosis of PH, we propose a stepwise approach with the main aim of discerning those patients who need to be referred to a PH centre and who should undergo invasive haemodynamic assessment. In case of high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, a fast-track referral to a PH centre is recommended at any point during the clinical workup.

Circulating Endothelin 1 but Not Transforming Growth Factor-β Levels Are Reduced after Pulmonary Endarterectomy in Subjects Affected by Chronic Thromboembolic Pulmonary Hypertension: A Prospective Cohort Study.

Background and objectives: Endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) play a pivotal role in the pathophysiology and vascular remodeling of chronic thromboembolic pulmonary hypertension (CTEPH) which is an under-diagnosed complication of acute pulmonary embolism (PE). Currently, pulmonary endarterectomy (PEA) is still the treatment of choice for selected patients suffering from CTEPH. The aim of this study was to evaluate the preoperative and postoperative circulating levels of ET-1 and TGF-β in subjects affected by CTEPH undergoing successful surgical treatment by PEA. Methods: The data from patients diagnosed with CTEPH who underwent PEA at the Foundation IRCCS Policlinico San Matteo Hospital (Pavia, Italy) were prospectively recorded in the Institutional database. Circulating ET-1 and TGF-β levels were assessed by an ELISA commercial kit before PEA, at 3 months and 1 year after PEA. The demographic data, preoperatory mean pulmonary arterial pressure (mPAP), cardiac output (CO), and pulmonary vascular resistance (PVR) were also recorded. Univariate and multivariate analyses were performed. Results: The analysis included 340 patients with complete ET-1 measurements and 206 patients with complete TGF-β measurements. ET-1 significantly decreased both at 3 months (p < 0.001) and at 1 year (p = 0.009) after PEA. On the other hand, preoperatory TGF-β levels did not significantly change after PEA. Furthermore, ET-1, but not TGF-β, was a good predictor for increased mPAP in multivariate analyses (p < 0.05). Conclusions: ET-1 but not TGF β was significantly modulated by PEA in subjects affected by CTEPH up to 1 year after surgery. The mechanisms leading to prolonged elevated circulating TGF-β levels and their clinical significance have to be further elucidated.

Animal models of pulmonary arterial hypertension associated with atrial septal defect

Pulmonary arterial hypertension (PAH) is a well-known complication of congenital heart disease (CHD). The lack of a satisfactory animal model for PAH associated with CHD (PAH-CHD) has limited progress in understanding the pathogenesis of PAH and the development of therapeutic agents. The development of a rat model for PAH associated with atrial septal defect (ASD) was achieved through atrial septal puncture and thermal ablation. Two and 4 weeks after modeling, hematoxylin and eosin staining showed that the vascular thickness, vascular thickness index, vascular area, and vascular area index in pulmonary arteries with an outer diameter of 50–300 μm in the PAH-ASD 2 and 4 weeks group were higher than those in the sham group (all P < 0.05). Alpha-smooth muscle actin (ɑ-SMA) staining showed that the medial thickness, medial thickness index, medial area, and medial area index in pulmonary arteries with an outer diameter of 50–300 µm at 2 and 4 weeks after modeling were significantly higher than those in the sham group (all P < 0.05). Additionally, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in the PAH-ASD 2 and 4 weeks groups were significantly higher than those in the sham group (both P < 0.05). Elastin van Gieson staining showed that the vascular obstruction score in the PAH-ASD 2 and 4 weeks group was significantly higher than that in the sham group (both P < 0.05). The PAH-ASD rats were successfully generated. These findings suggest that our model would be useful for further research into the pathogenesis, prevention, and treatment of PAH-ASD.

A Comparative Investigation of the Pulmonary Vasodilating Effects of Inhaled NO Gas Therapy and Inhalation of a New Drug Formulation Containing a NO Donor Metabolite (SIN-1A).

Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.

Changes in cerebral hemodynamics after week 32 of gestation in fetuses with late-onset fetal growth restriction

BACKGROUND: Late-onset fetal growth restriction is characterized by changes in fetal cerebral hemodynamic patterns. Blood flow parameters in the anterior, middle, and posterior cerebral arteries have been studied previously, and there was shown a relationship between changes in certain cerebral artery vascular resistance parameters and increased risk of adverse perinatal outcomes such as fetal hypoxia in labor, cesarean section, and stillbirth. AIM: The aim of this study was to search for cerebral hemodynamic patterns in fetuses with late-onset fetal growth restriction after week 32 of gestation. MATERIALS AND METHODS: This prospective study included 110 pregnant women at week 32 or more of gestation who underwent fetal ultrasound (fetometry and Doppler with additional measurement of vascular resistance parameters in the anterior and posterior cerebral arteries). Ultrasound findings were assessed for the presence of late-onset fetal growth restriction. The systole-diastolic ratio, resistance index, and pulsatility index were evaluated in appropriate-for-gestational-age fetuses and in fetuses with late-onset fetal growth restriction. RESULTS: A total of 128 middle, 86 anterior, and 87 posterior cerebral arteries measurements were included in the calculations. From weeks 32–33 to preterm gestation in appropriate-for-gestational-age fetuses, a decrease in the middle cerebral artery parameters was observed, while in the anterior and posterior cerebral arteries, the vascular resistance parameters remained at the same level or slightly increased. A nonlinear trend of blood flow changes in the anterior and posterior cerebral arteries was observed in fetuses with fetal growth restriction — the values increased by weeks 34–36 of gestation and decreased in preterm gestation. At the same time, differences (р 0.05) were found between the median values of the systolic-diastolic ratio, resistance index and pulsatility index in the anterior and posterior cerebral arteries at weeks 34–36 and those at preterm gestation. CONCLUSIONS: Changes in fetal cerebral hemodynamics in fetal growth restriction, in particular, a shift in the peak values of vascular resistance parameters to later gestational periods may be associated with changes in the development of integrative functions of the central nervous system and neurovascular development of the fetal brain (cortex), which occurs predominantly in the third trimester of pregnancy.

The Impact of Highly Selective Thoracic Sympathectomy on the Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by persistently elevated pulmonary artery pressure and vascular resistance. Sympathetic overactivity in hypertension participates in pulmonary vascular remodeling and heart failure. The present study aims to explore the efficacy of highly selective thoracic sympathectomy (HSTS) on lowering pulmonary artery pressure, reversing pulmonary vascular remodeling, and improving right ventricular function in rats. A total of 24 Sprague-Dawley rats were randomly assigned into the control group (n = 8) and experimental group (n = 16). Rats in the control group were intraperitoneally injected with 0.9% normal saline, and those in the experimental group were similarly administered with received monocrotaline (MCT) injections at 60 mg/kg. Two weeks later, rats in the experimental group were further subdivided randomly into the MCT-HSTS group (n = 8) and MCT-sham group (n = 8), and they were surgically treated with HSTS and sham operation, respectively. Two weeks later, significantly lowered mean pulmonary artery pressure (mPAP), pulmonary artery systolic pressure (sPAP), and the ratio of sPAP to femoral artery systolic pressure (sFAP) were detected in the MCT-HSTS group than those of the MCT-sham group. In addition, rats in the MCT-HSTS group presented a significantly lower ratio of vascular wall area to the total vascular area (WT%), right ventricular hypertrophy index, and degrees of right ventricular fibrosis and lung fibrosis in comparison to those of the MCT-sham group. HSTS significantly downregulated protein levels of inflammasomes in pulmonary artery smooth muscle cells (PASMCs). Collectively, HSTS effectively reduces pulmonary artery pressure, pulmonary arteriolar media hypertrophy, and right ventricular hypertrophy in MCT-induced PAH rats. It also exerts an anti-inflammatory effect on PASMCs in PAH rats by suppressing inflammasomes and the subsequent release of inflammatory cytokines.