Pulmonary Artery Stiffness Research Articles

The relationship between vitamin D level and echocardiographically detected pulmonary artery stiffness in young adult patients presenting with dyspnea

The relationship between vitamin D level and echocardiographically detected pulmonary artery stiffness in young adult patients presenting with dyspnea

Pulmonary transit time has close relation with pulmonary pulse wave transit time in normal subjects.

Pulmonary transit time (PTT) and pulmonary pulse wave transit time (pPTT) are useful parameters for the evaluation of cardiopulmonary circulation and vascular alterations, but their relationship remains unknown. The aim of this study was to investigate the correlation between PTT and pPTT. A total of 60 healthy volunteers were involved in this study. They were divided into two groups (30 participants per group): <50 years and >50 years. They all underwent Doppler echocardiography of pulmonary vein flow and contrast echocardiography with the measurement of pPTT and PTT, respectively. The correlation between PTT and pPTT was deduced. Compared with Group of <50 years, there was a significant increment in left atrial volume index, left atrial pressure and pulmonary artery stiffness but a significant reduction in acceleration times of pulmonary artery flow in Group of >50 years (p < 0.05). Group >50 years had longer PTT and but reduced normalized PTT by R-R interval (NPTT), reduced normalized pPTT by R-R interval (NpPTT) than Group <50 years (p < 0.05), while there was no significant difference in pPTT between the two groups (p > 0.05). PTT and NPTT were all negatively correlated with pPTT and NpPTT. The statistically significant strongest correlation was observed between PTT and NpPTT(r = -0.886, p < 0.0001). The regression equation for them was y = 7.4396-13.095x (R2 = 0.785; p < 0.001), where x and y represent NpPTT and PTT, respectively. PTT had close relation with pPTT in normal subjects. From the regression equation for them, we can get the value of PTT simply and easily by non-invasively measured pPTT.

Abstract 13542: Associations of Pulmonary Artery Stiffness With Mortality in Pulmonary Arterial Hypertension

Introduction: Pulsatility, the relative area change of the pulmonary artery (PA) during the cardiac cycle has been associated with impaired prognosis in pulmonary arterial hypertension (PAH), but other measurements of stiffness are not well explored. Hypothesis: Multiple indices of PA stiffness derived from cardiac magnetic resonance (CMR) and right heart catheterization (RHC) predict outcome in PAH Methods: Retrospective chart review on 108 patients with PAH who had a clinically indicated CMR and RHC within 90 days, and for the primary endpoint of all-cause mortality. From CMR and RHC data, PA areas and indexes of stiffness (pulsatility, compliance, capacitance, distensibility, elastic modulus, and the pressure-independent stiffness index beta) were measured. Data was analyzed using Cox-proportional hazards models. Results: We included 108 patients with average age of 51 (+/- 13) years, 79% female with a mean PA pressure of 46 +/-12 mmHg, and a mean right ventricular ejection fraction (RVEF) of 38 +/-14%. After a median follow-up of 6 years, 58 (54%) patients had died. Most indices of increased stiffness were associated with higher mortality after adjusting for age, sex, diuretic use, mean PA pressure and RVEF ( Table ). Conclusions: Among patients with PAH, most measurements of PA stiffness strongly correlated with mortality.

Abstract 10998: Pulmonary Artery Pulsatility Measured by Cardiac Magnetic Resonance Imaging in Over 42,000 Participants Reveals Novel Genetic Risk Loci

Introduction: Pulmonary artery (PA) hemodynamics are important predictors of mortality. However, genetic mechanisms underlying increased PA stiffness in diseases such as pulmonary hypertension are poorly understood, and targeted therapies are limited. Evaluation of PA hemodynamics frequently requires invasive right heart catheterization, limiting large-scale studies. This study leveraged cardiac magnetic resonance (CMR) imaging to non-invasively determine and characterize PA pulsatility, an established measure of pulmonary vascular compliance. Methods and Results: A deep-learning neural network was implemented to determine PA pulsatility, defined as the relative cross-sectional area change from diastole to systole, in 42,774 UK Biobank participants (intraclass correlation 0.94-0.96 compared with human readers). The mean (SD) PA pulsatility was 0.36 (0.11), and pulsatility decreased by 0.035 for every decade increase in age. Reduction in pulsatility by 0.1 was associated with the presence of congestive heart failure (OR 1.55 [95% CI 1.37-⁠1.76]), chronic obstructive pulmonary disease (OR 1.41 [1.29-⁠1.53]), or diabetes (OR 1.18 [1.13-⁠1.23]), and PA pulsatility was associated with increased all-cause mortality (HR 1.13 [1.03-1.23]) after adjusting for age and sex and excluding those with CHF or COPD (Fig A-B). A genome-wide association study of 40,496 participants identified loci on chromosomes 2 (top SNP: rs6738973) and 10 (rs2077218) associated with PA pulsatility at genome-wide significance ( p &lt; 5 х 10 –8 ; Fig C). Integrative fine-mapping analyses identified PKDCC and PLCE1 among likely effector genes. Conclusions: This is the first population-based epidemiologic and genomics study of PA pulsatility. Decreased PA pulsatility is associated with advanced age, increased rates of comorbidities, and higher mortality. The genes PKDCC and PLCE1 are among likely effectors of PA pulsatility and warrant further functional investigation.

Computational modelling of multi-temporal ventricular-vascular interactions during the progression of pulmonary arterial hypertension.

A computational framework is developed to consider the concurrent growth and remodelling (G&R) processes occurring in the large pulmonary artery (PA) and right ventricle (RV), as well as ventricular-vascular interactions during the progression of pulmonary arterial hypertension (PAH). This computational framework couples the RV and the proximal PA in a closed-loop circulatory system that operates in a short timescale of a cardiac cycle, and evolves over a long timescale due to G&R processes in the PA and RV. The framework predicts changes in haemodynamics (e.g. 68.2% increase in mean PA pressure), RV geometry (e.g. 38% increase in RV end-diastolic volume) and PA tissue microstructure (e.g. 90% increase in collagen mass) that are consistent with clinical and experimental measurements of PAH. The framework also predicts that a reduction in RV contractility is associated with long-term RV chamber dilation, a common biomarker observed in the late-stage PAH. Sensitivity analyses on the G&R rate constants show that large PA stiffening (both short and long term) is affected by RV remodelling more than the reverse. This framework can serve as a foundation for the future development of a more predictive and comprehensive cardiovascular G&R model with realistic heart and vascular geometries.

Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling

Pulmonary hypertension (PH) induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Dysfunction of endothelial cells is the hallmark event in the progression of PH. Among various mechanisms, endothelial to mesenchymal transition (EndoMT) has emerged as an important source of endothelial cell dysfunction in PH. However, the mechanisms underlying the EndoMT in PH remain largely unknown. Our results showed that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression was decreased in pulmonary arterial endothelial cells (PAECs) in PH patients and hypoxia-induced PH mouse model compared to the normal controls. Endothelial-specific overexpression of PGC-1α using nanoparticle delivery significantly attenuated the progression of PH, as shown by the significantly decreased right ventricular systolic pressure and diminished artery thickness as well as reduced vascular muscularization. Moreover, Endothelial-specific overexpression of PGC-1α blocked the EndoMT of PAECs during PH, indicating that loss of PGC-1α promotes PH development by mediating EndoMT, which damages the integrity of endothelium. Intriguingly, we found that PGC-1α overexpression rescued the expression of endothelial nitric oxide synthase in mouse lung tissues that was deceased by hypoxia treatment in vivo and in endothelial cells treated with TGF-β in vitro. Consistently, PAECs and vascular smooth muscle co-culture showed that overexpression of PGC-1α in PAECs increases nitric oxide release, which would likely diffuse to smooth muscle cells, where it activates specific protein kinases, and initiates SMC relaxation by diminishing the calcium flux. Endothelial-specific overexpression of PGC-1α also attenuated hypoxia-induced pulmonary artery stiffness which appeared to be caused by both the decreased endothelial nitric oxide production and increased vascular remodeling. Taken together, these results demonstrated that endothelial-specific delivery of PGC-1α prevents PH development by inhibiting EndoMT of PAECs and thus restoring endothelial function and reducing vascular remodeling.

Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening.

Pulmonary hypertension (PH) is a progressive disease that arises from multiple etiologies and ultimately leads to right heart failure as the predominant cause of morbidity and mortality. In patients, distinct inflammatory responses are a prominent feature in different types of PH, and various immunomodulatory interventions have been shown to modulate disease development and progression in animal models. Specifically, PH-associated inflammation comprises infiltration of both innate and adaptive immune cells into the vascular wall of the pulmonary vasculature—specifically in pulmonary vascular lesions—as well as increased levels of cytokines and chemokines in circulating blood and in the perivascular tissue of pulmonary arteries (PAs). Previous studies suggest that altered hemodynamic forces cause lung endothelial dysfunction and, in turn, adherence of immune cells and release of inflammatory mediators, while the resulting perivascular inflammation, in turn, promotes vascular remodeling and the progression of PH. As such, a vicious cycle of endothelial activation, inflammation, and vascular remodeling may develop and drive the disease process. PA stiffening constitutes an emerging research area in PH, with relevance in PH diagnostics, prognostics, and as a therapeutic target. With respect to its prognostic value, PA stiffness rivals the well-established measurement of pulmonary vascular resistance as a predictor of disease outcome. Vascular remodeling of the arterial extracellular matrix (ECM) as well as vascular calcification, smooth muscle cell stiffening, vascular wall thickening, and tissue fibrosis contribute to PA stiffening. While associations between inflammation and vascular stiffening are well-established in systemic vascular diseases such as atherosclerosis or the vascular manifestations of systemic sclerosis, a similar connection between inflammatory processes and PA stiffening has so far not been addressed in the context of PH. In this review, we discuss potential links between inflammation and PA stiffening with a specific focus on vascular calcification and ECM remodeling in PH.

The effect of L-thyroxine treatment on ventricular dysfunction and pulmonary arterial stiffness in patients with subclinical hypothyroidism.

In our study, we aimed at evaluating the change in biventricular functions and pulmonary arterial stiffness (PAS) in patients with subclinical hypothyroidism (SH) in whom euthyroidism was achieved with L-thyroxine therapy. 70 SH patients and 75 healthy volunteers were included in our study consecutively. Baseline demographic and echocardiographic data of the participants were recorded. The data obtained in the control evaluation 6 months after the euthyroidism were achieved in the SH group patients started on L-thyroxine treatment and then compared with the baseline measurements. The mean age of patients in the SH group was 44.1 ± 9.4 years and 47.1% were women. Euthyroidism in SH patients was achieved with a mean daily L-thyroxine treatment of 59 µg/day for a mean of 16.1 ± 4.5 weeks. Positive changes in metabolic and hormonal profiles were achieved after L-thyroxine treatment in SH patients. It was determined that left ventricular and right ventricular isovolumetric relaxation and myocardial performance index were higher in SH patients compared to the control group, and these measurements were observed to decrease significantly with L-thyroxine treatment (p < 0.05 for each). While PAS was 16.9 ± 3.1 kHz/ms in the control group, it was 25.2 ± 5.3 kHz/ms in the SH group (p < 0.05). After L-thyroxine treatment, PAS measurements decreased to 17.2 ± 3.2 kHz/ms (p < 0.05) in the SH group and showed a positive change. Thyroid-stimulating hormone (TSH) change (Δ TSH) with Δ E/A ratio (r: -0.407, p < 0.001), right ventricular myocardial performance index (Δ RV MPI) change (r: 0.404, p < 0.001) and PAS change (Δ PAS) (r: 0.458, p < 0.001) found to be correlated. SH is associated with dysfunction in the biventricular and pulmonary vascular bed. Biventricular functions and PAS change positively in SH patients with L-thyroxine treatment.

A patient-specific image-based approach to estimate pulmonary artery stiffness based on vessel constitutive model.

An accurate non-invasive evaluation of the mechanical properties of the vessel wall is important for a variety of screening protocols and surgical treatments. In this work, we focused on a sectionof the Pulmonary Artery (PA), and developed a patient-specific approach to estimate its stiffness in terms of the Young's modulus along the circumferential direction (E). First, we developed a patient-specific semi-automatic approach to estimate its expected value and standard deviation. To this end, pressure-length curves were derived from magnetic resonance images acquired during the cardiac cycle and information on vessel pressure obtained by catheterization. Then, the estimates of E were derived through a maximum likelihood estimation approach based on a vessel constitutive law. In particular, we analyzed the entire PA boundary and an arc free from surrounding organs. Second, we applied the approach to the study of pulmonary endarterectomy (PEA) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). We observed a decrease in the circumferential E after PEA for the whole boundary, while no clear trend was observed for the free arc. The low standard deviations associated with the estimates showed high accuracy when considering the entire boundary, while greater variability was observed for the free arc, which was however limited. Finally, reliable hysteretic behavior was obtained from the reconstructed pressure-length curves.

Effects of Sodium-Glucose Co-Transporter-2 Inhibition on Pulmonary Arterial Stiffness and Right Ventricular Function in Heart Failure with Reduced Ejection Fraction.

Background and Objectives: In addition to left ventricular (LV) functions, right ventricular (RV) functions and pulmonary arterial stiffness (PAS) may be adversely affected in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy positively affects LV functions as well as having functional and symptomatic benefits in HFrEF patients. In this study, we aimed to evaluate the effects of SGLT2 inhibitor treatment on RV function and PAS in HFrEF patients. Materials and Methods: 168 HFrEF patients with New York Heart Association (NYHA) class ≥2 symptoms despite optimal medical treatment and who were started on SGLT2 inhibitor therapy were included in this retrospective study. NYHA classification, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores, laboratory tests, and transthoracic echocardiography (TTE) measurements were recorded before treatment and at the end of the 6-month follow-up. Results: The mean age of the patients was 62.7 ± 11.4 years, and 38 (22.6%) were women. RV function (RV fractional area change (FAC) (33.8 ± 6.4% vs. 39.2 ± 7.3%, p < 0.001); tricuspid annular plane systolic excursion (TAPSE) (18.4 ± 3.8 mm vs. 19.6 ± 3.6 mm, p < 0.001); RV S’ (10 (8 − 13) cm/s vs. 13 (10 − 16) cm/s, p < 0.001); RV myocardial performance index (RV MPI) (0.68 ± 0.12 vs. 0.59 ± 0.11, p < 0.001); mean pulmonary artery pressure (mPAP) (39.6 ± 7.8 mmHg vs. 32 ± 6.8 mmHg, p = 0.003)) and PAS (24.2 ± 4.6 kHz/ms vs. 18.6 ± 3.1 kHz/ms, p < 0.001) values at the 6-month follow-up after SGLT2 inhibitor therapy significantly improved. It was found that SGLT2 inhibitor treatment provided significant improvement in NYHA classification, MLWHFQ scores, and NT-proBNP levels (2876 ± 401 vs. 1034 ± 361, p < 0.001), and these functional and symptomatic positive changes in HFrEF patients were significantly correlated with positive changes in LVEF, PAS, and RV functional status. Conclusions: SGLT2 inhibitor treatment results in symptomatic and functional well-being in HFrEF patients, as well as positive changes in RV function and PAS.

Possible use of pulmonary artery stiffness in screening for portopulmonary hypertension.

Possible use of pulmonary artery stiffness in screening for portopulmonary hypertension.

Evaluation of pulmonary arterial stiffness and comparison with right ventricular functions in patients with cirrhosis preparing for liver transplantation.

Pulmonary complications are common in patients with liver cirrhosis. Devolopment of pulmonary hypertension (PH) is associated with a poor prognosis in these patients. Pulmonary arterial stiffness (PAS) is considered an early sign of pulmonary vascular remodeling. The aim of this study is to investigate PAS and compare it with right ventricular (RV) functions in patients with cirrhosis who are scheduled for liver transplantation. The study included 52 cirrhosis patients (mean age 51.01 ± 12.18 years, male gender 76.9%) who were prepared for liver transplantation and 59 age and sex matched (mean age 51.28 ± 13.63 years, male gender 62.7%) healthy individuals. Patients with left ventricular ejection fraction (LVEF) less than 55%, ischemic heart disease, more than mild valvular heart disease, chronic pulmonary disease, congenital heart disease, rheumatic disease, moderate to high echocardiographic PH probability, rhythm or conduction disorders on electrocardiography were excluded from the study. In addition to conventional echocardiographic parameters, PAS value, pulmonary vascular resistance (PVR) and RV ejection efficiency was calculated by the related formulas with transthoracic echocardiography (TTE). Demographic characteristics and cardiovascular risk factors of the groups were similar. PAS, PVR, and sPAP values were found to be significantly higher in the patient group (20.52 ± 6.52 and 13.73 ± 2.05; 1.43 ± 0.15 and 1.27 ± 0.14; 27.69 ± 3.91 and 23.37 ± 3.81 p < 0.001, respectively). RV FAC and RV Ee were significantly lower and RV MPI was significantly higher in the patient group (45.31 ± 3.85 and 49.66 ± 3.62, p < 0.001; 1.69 ± 0.35 and 1.85 ± 0.23, p=0.005; 0.39 ± 0.07 and 0.33 ± 0.09, p=0.001, respectively). PAS was significantly correlated with RV FAC and MPI (r=-0.423, p < 0.001; r=0.301, p=0.001, respectively). Increased PAS in cirrhosis patients may be associated with early pulmonary vascular involvement. Evaluation of RV functions is important to determine the prognosis in these patients. FAC, MPI, and RV Ee measurements instead of TAPSE or RV S' may be more useful in demonstrating subclinical dysfunction. The correlation of PAS with RV FAC and MPI may indicate that RV subclinical dysfunction is associated with early pulmonary vascular remodeling in patients with liver cirrhosis.

Right ventricular-pulmonary arterial uncoupling in mild-to-moderate asthma

Objective Persistent pulmonary hypertension and resulting right ventricular (RV) failure are highly encountered phenomenon in severe pulmonary diseases. However, in this study, we aimed to examine the effects of mild-to-moderate asthma on RV functions, pulmonary arterial stiffness (PAS), and coupling of RV to the pulmonary artery (PA) in the absence of overt pulmonary hypertension. Methods We enrolled 53 patients with mild-to-moderate asthma, and 50 healthy control subjects. A comprehensive two dimensional transthoracic echocardiography was performed on each individual. The parameters measuring RV function were all examined. PAS was calculated by dividing maximal frequency shift of pulmonary flow by pulmonary acceleration time. RV-PA coupling was estimated by the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) ratio (TAPSE/PASP). Results Baseline demographics, clinical and laboratory parameters of both groups were similar (p > 0.05). Most of conventional echocardiographic parameters measuring RV function were impaired in patients with asthma compared to control subjects. PAS values were significantly higher in the asthma group [24 (21–26) vs. 20 (18–22), p < 0.001], and TAPSE/PASP ratio was significantly lower in the asthma group versus the control group [0.81 ± 0.08 vs. 0.96 ± 0.11, p < 0.001]. Multilinear regression analysis revealed PAS, TAPSE, and PASP as independent predictors of TAPSE/PASP ratio. Conclusion Mild-to-moderate asthma was shown to be associated with both subclinical RV dysfunction and increased PAS values. TAPSE/PASP ratio was also markedly decreased, suggesting RV-PA uncoupling even in the absence of overt pulmonary hypertension. PAS referring RV afterload was shown to be an independent predictor of TAPSE/PASP ratio.

Feasibility of Echocardiographic Estimation of Pulmonary Artery Stiffness in Horses

Pulmonary artery stiffness (PAS) is an index of pulmonary artery elasticity that permits to evaluate the pulmonary vascular bed in humans. It can early detect an increase in pulmonary artery stiffness as a consequence of remodeling of the vessel wall caused by chronic pulmonary and congenital heart diseases. This remodeling can occur also in horses with chronic respiratory diseases. Thus, PAS could be a useful echocardiographic parameter also in horses. However, in literature, there are no studies regarding PAS in horses. The aim of this study is to evaluate the feasibility of PAS in horses. Fifteen healthy horses were included in this prospective study. Maximal frequency shift and acceleration time were measured from the pulsed-wave Doppler trace of the pulmonary artery flow, obtained from the right parasternal short-axis view at the level of the pulmonary artery, and then PAS was calculated as the ratio of Maximal frequency shift to acceleration time. The low variability assessed for intra- and inter-observer variability, day-to-day variability and image acquisition variability suggests that PAS can be measured consistently in horses. Further studies could be useful to assess the clinical usefulness of PAS in unhealthy horses, such as those affected by chronic respiratory diseases.

The relationship between bioelectrical impedance parameters and pulmonary artery stiffness in obese subjects.

Obesity is a public health problem that needs to be treated and it occurs as a result of excessive fat accumulation in the body. The relationship between obesity and pulmonary hypertension is well known. The aim of this study is to evaluate the relationship between pulmonary artery stiffness, right ventricular functions and bioelectrical impedance parameters in obese, overweight, and healthy individuals. In this study, 41 obese (17 female and 24 male, mean age 43.5±10.3), 39 overweight (20 female and 19 male, mean age 38.6±10.4), 34 healthy control group (19 female and 15 male, mean age 40.5±8.6) were included. Anthropometric measurements and bioelectrical impedance parameters of all participants were performed. Right ventricular functions and pulmonary artery stiffness were evaluated by using conventional echocardiography. Right ventricle myocardial performance index, pulmonary artery stiffness values were statistically different between groups. Positive correlation was observed between pulmonary artery stiffness and Body Mass Index, Waist and Hip circumferences. Significant negative correlation was observed between muscle to fat ratio and pulmonary artery stiffness. In the linear regression analysis, it was observed that the muscle to fat ratio was independent predictor of pulmonary artery stiffness (β=-1.835; 95%CI(-2.434 - - .784); p<0.001). This study showed that right ventricular function was impaired and pulmonary artery stiffness increased in obese individuals. These findings could be considered as early markers of pulmonary hypertension in obese patients who do not yet have clinical evidence of cardiovascular disease.

Right heart response to different loading conditions - a comparison of chronic volume versus pressure overload using an integrated echocardiographic and invasive approach

Abstract Funding Acknowledgements Type of funding sources: None. Background. It is widely believed that right ventricular (RV) volume overload is better tolerated than RV pressure overload and this is mainly due to the preservation of or even an increase in RV longitudinal function in patients (pts) with RV volume overload. Conversely, patients with RV pressure overload experience an early decrease in radial shortening and the global RV performance is maintained due to a normal longitudinal function. The multiparametric assessment of RV function and RV-pulmonary artery (PA) coupling could offer a better understanding of the RV adaptive mechanisms in response to volume versus pressure overload. Purpose. To assess the right heart remodelling and function in different chronic loading conditions using an integrated echocardiographic and invasive approach. Methods. Thirty-nine patients with atrial septal defect (ASD) and 41 pts with pulmonary hypertension (PH) age and gender-matched were enrolled. The etiology of PH was idiopathic (14 pts), operated congenital heart disease (3), connective tissue disease (9), chronic thromboembolic PH (8) and other forms of arterial PH (7). Clinical parameters, B-type natriuretic peptide (BNP), RV function and pulmonary artery stiffness (PAS) echocardiographic parameters were assessed. RV-PA coupling was assessed using the TAPSE to systolic PA pressure ratio. A right heart catheterization was also performed and ASD pts with pulmonary vascular resistance &amp;gt;3 Wu and/or Qp/Qs ratio &amp;lt;1.5 were excluded. Results. PH pts were more symptomatic than pts with ASD (32 PH pts vs 6 ASD pts were in NYHA class III and IV, p &amp;lt; 0.001). ASD pts had lower BNP levels (lnBNP 4.24 ± 1.11 vs 5.49 ± 1.29, p &amp;lt; 0.001), similar right atrial (RA) area (26.6 ± 7.7 vs 27.8 ± 11.9 cm2, p = 0.61) and pressure (7.5 ± 4.2 vs 8.2 ± 5.9 mmHg), lower systolic (1.11 ± 0.13 vs 1.55 ± 0.50) and diastolic (1.21 ± 0.16 vs 1.50 ± 0.32) eccentricity index (p &amp;lt; 0.001) and better RV function parameters than PH pts (all p &amp;lt; 0.001): TAPSE (26 ± 5 vs 16 ± 3 mm), RV-free wall S wave (14.4 ± 2.5 vs 9.9 ± 2.1 cm/s), RV fractional area change (46 ± 8 vs 32 ± 8%), RV global longitudinal strain on 3 segments (-27.6 ± 5.0 vs -14.4 ± 6.0%) or 6 segments (-24.2 ± 4.3 vs -12.5 ± 4.9%). Also, ASD pts had less impaired PAS parameters (pulmonary compliance 4.03 ± 5.54 vs 1.53 ± 3.01 mm2/mmHg, p = 0.016; elastic modulus 167 ± 131 vs 594 ± 369 mmHg, p &amp;lt; 0.001; beta index 5.36 ± 3.77 vs 11.00 ± 6.39, p &amp;lt; 0.001) and better RV-PA coupling (0.60 ± 0.20 vs 0.19 ± 0.06 mm/mmHg, p &amp;lt; 0.001) than PH pts. The BNP levels significantly correlated with RA area, parameters of RV size and systolic function and RV-PA coupling in both groups, but invasively assessed PA pressure correlated with BNP levels only in ASD pts. Conclusions Patients with ASD as a model of chronic RV volume overload have not only preserved RV longitudinal function but also better global RV function, PAS and RV-PA coupling compared to pts with chronic RV pressure overload. The BNP levels are significantly more impaired in pts with chronic RV pressure overload.

PULMONARY TO SYSTEMIC PULSATILE AND RESISTIVE VASCULAR RESPONSES TO EXERCISE IN PATIENTS WITH PULMONARY HYPERTENSION SECONDARY TO LEFT HEART DISEASE (HFPEF)

<h3>BACKGROUND</h3> Systemic and pulmonary arterial stiffening with age are said to be linked, and contribute towards the development of pulmonary hypertension (PH) with age. Systemic arterial stiffening may contribute to the development of PH due to left heart disease (PH-LHD). However, the relationships between the systemic and pulmonary circuit have not been as well described in populations with pulmonary hypertension. Exercise during right heart catheterization (RHC) is used to discriminate between PH-LHD and pulmonary arterial hypertension (PAH). In this study we aimed to describe the relationships between pulmonary and systemic compliance (a measure of vascular stiffening, also referred to as pulsatile loading) and vascular resistance (a measure of resistive loading) at rest and during exercise RHC, in patients with normal hemodynamics, PH-LHD and PAH. We hypothesized that systemic and pulmonary arterial stiffening would be linked in PH-LHD but not PAH. <h3>METHODS AND RESULTS</h3> A retrospective hemodynamic analysis was conducted using data from 80 individuals (50% female, 59±15 years) with dyspnea and/or suspected pulmonary hypertension who underwent RHC and a bout of semi-upright submaximal cycling. Exercise hemodynamic classifications were as follows: Normal – change in mean pulmonary artery pressure (mPAP) over cardiac output (CO)(ΔmPAP/ΔCO ≥3.2 woods units (WU)), Exercise PAH - ΔmPAP/ΔCO >3.2WU and exercise pulmonary arterial wedge pressure (PAWP) < 20mmHg, and Exercise PH-LHD - ΔmPAP/ΔCO >3.2WU and PAWP >20mmHg with exercise. Proportional relationships between pulsatile load in the pulmonary vs. systemic circuit are displayed in Table 1. There was a significantly greater increase in the pulmonary pulse pressure (PPP) to systemic pulse pressure (SPP) (73±40% to 93±51% vs. 51±29% to 63±36%, p < 0.001) and pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR) (26±16% to 39±27% vs. 14±11% to 25±18%, p < 0.01) from rest to exercise in the PAH group when compared to PH-LHD. Otherwise, there were no differences in the total pulmonary resistance (TPulmR) to total peripheral resistance (TPR) ratio. There was a significant correlation between pulmonary (PulmCp) and systemic compliance (SysCp), both at rest (r2=0.33, p < 0.01) and during exercise (r2=0.16, p=0.05), in the PH-LHD group (Figure 1). <h3>CONCLUSION</h3> The proportional vascular loads between the pulmonary and systemic circulations differ as expected between PAH and PH-LHD. However, the net proportional resistive load (TPulmR/TPR) was very similar. There was a significant relationship between systemic and pulmonary stiffening (pulsatile load) at rest and exercise only in the PH-LHD group, which provides support for the hypothesis that systemic arterial stiffening is a mechanism that promotes the development of PH-LHD.

Mechanisms of Hypoxia-Induced Pulmonary Arterial Stiffening in Mice Revealed by a Functional Genetics Assay of Structural, Functional, and Transcriptomic Data.

Hypoxia adversely affects the pulmonary circulation of mammals, including vasoconstriction leading to elevated pulmonary arterial pressures. The clinical importance of changes in the structure and function of the large, elastic pulmonary arteries is gaining increased attention, particularly regarding impact in multiple chronic cardiopulmonary conditions. We establish a multi-disciplinary workflow to understand better transcriptional, microstructural, and functional changes of the pulmonary artery in response to sustained hypoxia and how these changes inter-relate. We exposed adult male C57BL/6J mice to normoxic or hypoxic (FiO2 10%) conditions. Excised pulmonary arteries were profiled transcriptionally using single cell RNA sequencing, imaged with multiphoton microscopy to determine microstructural features under in vivo relevant multiaxial loading, and phenotyped biomechanically to quantify associated changes in material stiffness and vasoactive capacity. Pulmonary arteries of hypoxic mice exhibited an increased material stiffness that was likely due to collagen remodeling rather than excessive deposition (fibrosis), a change in smooth muscle cell phenotype reflected by decreased contractility and altered orientation aligning these cells in the same direction as the remodeled collagen fibers, endothelial proliferation likely representing endothelial-to-mesenchymal transitioning, and a network of cell-type specific transcriptomic changes that drove these changes. These many changes resulted in a system-level increase in pulmonary arterial pulse wave velocity, which may drive a positive feedback loop exacerbating all changes. These findings demonstrate the power of a multi-scale genetic-functional assay. They also highlight the need for systems-level analyses to determine which of the many changes are clinically significant and may be potential therapeutic targets.

Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = -0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = -0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices.NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.

Abnormal pulmonary flow is associated with impaired right ventricular coupling in patients with COPD.

Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting primarily from increased afterload mediated by chronic alveolar hypoxemia and resulting hypoxic pulmonary vasoconstriction. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior analysis of helicity in the pulmonary arteries in pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. However, these flow hemodynamics have yet to be fully explored in patients with COPD. We hypothesized that patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Patients with COPD (n = 15) (65 years ± 6) and controls (n = 10) (58 years ± 9) underwent 4D-Flow MRI to calculate helicity. The helicity was calculated in the main pulmonary artery (MPA) and along the RV outflow tract (RVOT)-MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). We found COPD patients had decreased helicity relative to healthy controls in the MPA (19.4 ± 7.8vs 32.8 ± 15.9, P = 0.007) and reduced helicity along the RVOT-MPA axis (33.2 ± 9.0 vs 43.5 ± 8.3, P = 0.010). Our investigation indicates a strong association between helicity along the MPA-RV outflow tract axis and RV function and suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV-pulmonary arterial coupling in COPD.