Evaluation of Advanced Echocardiographic Parameters of Right Ventricular in Patients with Pulmonary Hypertension

Right Heart Catheterization—To Do or Not To Do? Introducing a New Diagnostic Algorithm for Pulmonary Hypertension

<i>Circulation: Heart Failure</i> Editors’ Picks

Funding Acknowledgements Type of funding sources: None. Background Until now, right heart catheterization is still the gold standard for pulmonary hypertension examination, but this examination is invasive, has a risk of action, and is limited. Echocardiography provides an alternative examination that is easier, safer, cheaper, and more effective in evaluating pulmonary hypertension. Various echocardiographic parameters have been used to assess pulmonary hypertension but no parameter can distinguish the hemodynamics of pulmonary hypertension. Echocardiography pulmonary to left atrial ratio (ePLAR) is a new echocardiographic parameter that is formulated by the maximal tricuspid regurgitation velocity (TR Vmax) divided by the mitral E/e'. This simple parameter can determine precapillary pulmonary hypertension Purpose The aim of this study is to determine the correlation of ePLAR with right heart catheterization parameters in pulmonary arterial hypertension patients. Methods This is a cross-sectional study in the pulmonary arterial hypertension group conducted at M. Djamil Hospital from August 2021 to May 2022. Respondents underwent an echocardiography and right heart catheterization prosedure. The correlation of ePLAR with right heart catheterization parameters was assessed using the Spearman correlation test. Result The research subjects were 32 patients with pulmonary arterial hypertension, 20 women and 12 men, the median age was 21.50 (8-54) years and the most common cause of pulmonary arterial hypertension was congenital heart disease. The median value of ePLAR was 0.44(0.30-0.77) m/s, while the mean value of mPAP was 54.40 ± 16.24 mmHg and the median value of PVR was 8.39 (3.21-29.50) WU. Based on the Spearman correlation test, it was found that the ePLAR had a moderate positive correlation (r=0.554) with the mPAP and was statistically significant (p=0.001). The ePLAR had a strong positive correlation (r=0.779) with the PVR and was statistically significant (p&amp;lt;0.001) Conclusion There was a moderate and significant positive correlation between ePLAR and mPAP, there was a strong and significant positive correlation between ePLAR and PVR in patients with pulmonary arterial hypertension.

Although routine use of Doppler echocardiography has led to an increased recognition of pulmonary hypertension, the role of Doppler echocardiography has largely remained as a screening tool with the primary emphasis on the presence or absence of an increased Doppler-estimated pulmonary artery systolic pressure (PASP). However, the utility of Doppler echocardiography in the workup of pulmonary hypertension extends far beyond that of a screening tool, with the integration of relevant Doppler echocardiography parameters providing a wealth of hemodynamic insight into not only if a patient has pulmonary hypertension, but why they have pulmonary hypertension. This review summarizes some of the recent advances in the use of Doppler echocardiography in evaluating the pathophysiology of pulmonary hypertension. Distinguishing pulmonary hypertension related to pulmonary vascular disease (i.e. pulmonary arterial hypertension, pulmonary hypertension due to lung disease, or chronic thromboembolic pulmonary hypertension; PHPVD), from those with left heart disease associated pulmonary hypertension (pulmonary venous hypertension; PVH) is crucial as workup and treatment options differ dramatically. Recent studies have identified easily obtainable Doppler echocardiography parameters that can reliably distinguish between PHPVD and PVH, allowing for rapid triage of patients with evidence of PHPVD to invasive right heart catheterization whiles avoiding invasive investigation and the inappropriate use of pulmonary hypertension specific therapy in patients with PVH. This review highlights the importance of integrating two-dimensional and Doppler parameters in order to inform the clinician as to the hemodynamic cause of pulmonary hypertension, thus enhancing the diagnostic accuracy of Doppler echocardiography, rapidly identifying those with PHPVD and right heart dysfunction and assisting in triage of patients to further invasive hemodynamic assessment.

Introduction The association of pulmonary and systemic arterial hypertension is believed to be mediated through hypertensive left heart disease. The purpose of the current study was to investigate whether pulmonary arterial hypertension (PAH) is associated with systemic arterial hypertension among patients with apparently normal left heart diastolic function. Methods Consecutive patients who had echocardiographic evaluation between 2007 and 2019. Patients with disease states that are known to be associated with PAH including diastolic dysfunction were excluded from the analysis. Estimated right ventricular systolic pressure (RVSP) was extracted for all patients from the echocardiographic reports. PAH was defined as estimated RVSP &amp;gt;40 mmHg. Multivariate logistic regression models were applied. Results Final study population included 25,916 patients with a median age of 59 (IQR 44–69), of whom 12,501 (48%) were male and 13,265 (51%) had systemic arterial hypertension. Compared with normotensive patients, hypertensive patients were 3.2 times more likely to have PAH (95% CI; 2.91–3.53, p&amp;lt;0.001). A multivariate model adjusted for clinical and echocardiographic parameters that are known to be associated with PAH demonstrated that hypertensive patients are almost 3 times more likely to have PAH (95% CI 2.45–3.15, p&amp;lt;0.001). The association was significant in multiple subgroups but was more significant among women compared with men (OR 3.1 vs. 2.4, p for interaction &amp;lt;0.001). Conclusions PAH is associated with systemic arterial hypertension irrespective of left heart disease. The association is more pronounced among women. Funding Acknowledgement Type of funding sources: None. Estimated RVSP &amp;gt;40 by Systolic BP

Pulmonary arterial hypertension and left ventricular diastolic dysfunction are associated with significant morbidity and mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide has been proposed as part of composite screening algorithms for pulmonary arterial hypertension. Our aim was to assess the prevalence of pulmonary hypertension and diastolic dysfunction, and evaluate their association with serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients. Patients with systemic sclerosis were prospectively enrolled to undergo N-terminal pro-brain natriuretic peptide testing and transthoracic echocardiography at a tertiary Australian centre from January to October 2022. We collected demographic and transthoracic echocardiography variables including pulmonary hypertension estimated by tricuspid regurgitant velocity and diastolic dysfunction assessed by the ASE/EACVI 2016 guidelines. Pearson's correlation coefficient was used to evaluate association between N-terminal pro-brain natriuretic peptide and echocardiographic parameters. Sixty-one patients were enrolled (median age = 62 years (interquartile range = 55-69 years); 84% female). Two-thirds of patients had limited systemic sclerosis (40/61). Five patients (8%) had high likelihood of pulmonary hypertension by transthoracic echocardiography. Seven patients (11%) had diastolic dysfunction; however, seven patients (11%) had indeterminate diastology. Six patients underwent right heart catheterisation, with five patients diagnosed with pulmonary hypertension. N-terminal pro-brain natriuretic peptide in patients with pulmonary hypertension or diastolic dysfunction was significantly higher (median = 207 and 226 pg/mL, respectively) compared to patients without either condition (median = 69 pg/mL, p = 0.01). N-terminal pro-brain natriuretic peptide showed a statistically significant although limited correlation with estimated pulmonary pressures measured by tricuspid regurgitant velocity (r = 0.44, p = 0.002) and left ventricular filling pressures (r = 0.27, p = 0.04). Pulmonary hypertension and diastolic dysfunction are both observed in systemic sclerosis. N-terminal pro-brain natriuretic peptide is associated with both conditions; however, it cannot distinguish between the two disease processes. Right heart catheterisation may be required to make this distinction.

Protecting the Right Ventricle Network (PRORVNet): Time to Defend the “Forgotten Ventricle”?

Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension

Background: Patients with pulmonary venous hypertension (PVH) secondary to left heart disease can be further classified according to their hemodynamic profile: pulmonary hypertension (PH) in proportion to the pulmonary capillary wedge pressure (PCWP) and PH out of proportion to the PCWP or reactive PH. Currently, there are no measures that enable prediction of the development of reactive PH in patients with left heart disease. Objectives: In this study, we aim to characterize PVH patients with reactive PH as compared to proportional PH in an attempt to create a distinct profile for patients with left heart disease carrying a high risk for the development of reactive PH. Methods: Thirty-three PVH patients with reactive PH and 29 PVH patients with proportional PH were analyzed retrospectively over a 6-year period. Clinical, laboratory, echocardiographic and hemodynamic parameters were noted and compared between subgroups. Results: There was no significant difference between PVH patients with reactive and proportional PH with regard to gender, age (65.91 ± 11.9 vs. 66.69 ± 10.5 years) and body surface area (1.89 ± 0.24 vs. 1.9 ± 0.23 m²). Prevalence of the metabolic syndrome components was similar in both groups. Interestingly, PCWP was similar in both groups, as were the structural and functional parameters of the left heart. Conclusions: PVH patients with reactive PH have a similar profile as patients with proportional PH; consequently, the evolution of reactive PH is unpredictable. Therefore, it is imperative that physicians maintain a high index of suspicion for the development of reactive PH even in the early stage of heart disease.

Background : Secondary pulmonary hypertension is an important final endpoint in patients with chronic hypoxic lung disease, accompanied by deterioration of pulmonary hemodynamics. The clinical diagnosis of pulmonary hypertension and/or cor pulmonale could be difficult, and simple noninvasive evaluation of pulmonary artery pressures has been an relevant clinical challenge for many years. Doppler echocardiography might to be a more reliable method for evaluating pulmonary hemodynamics in such patients in terms of the accuracy, reproducibility and easiness for obtaining an appropriate echocardiographic window than M-mode echocardiography. The aim of this study was to assess echocardiographic parameters associated with pulmonary arterial hypertension, defined by increasing right ventricular systolic pressure(RVSP), calculated from trans-tricuspid gradient in patients with chronic hypoxic lungs. Method : We examined 19 patients with chronic hypoxic lung disease, suspected pulmonary hypertension under the clinical guidelines by two dimensional echocardiography via the left parasternal and subcostal approach in a supine position. Doppler echocardiography measured RVSP from tricuspid regurgitant velocity in continuous wave with 2.5MHz transducer and acceleration time(AT) on right ventricular outflow tract in pulsed wave for the estimation of pulmonary arterial pressure. Results : On echocardiography, moderate to severe degree of pulmonary arterial hypertension was defined as RVSP more than 40mmHg, presenting tricuspid regurgitation. Increased right ventricular endsystolic diameter and shortened AT were noted in the increased RVSP group. Increased RVSP was correlated negatively with the shortening of AT. Other clinical data, including pulmonary functional parameters, arterial blood gas analysis and M mode echocardiographic parameters were not changed significantly with the increased RVSP. Conclusion : These findings suggest that shortened AT on pulsed doppler can be useful when quantifying pulmonary arterial pressure with increased RVSP in patients with chronic lung disease with hypoxemia. Doppler echocardiography in pulmonary hypertension of chronic hypoxic lungs is an useful option, based on noninvasiveness under routine clinical practice.

Validation Study on the Accuracy of Echocardiographic Measurements of Right Ventricular Systolic Function in Pulmonary Hypertension

Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K+ channel, have been identified in pulmonary arterial hypertension patients. We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3-mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3-mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3-mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3-mutated rats were characterized by overactivation of ERK1/2 (extracellular signal-regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3-mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3-mutated rats developed age-dependent PH associated with low serum-albumin concentration. We established the first Kcnk3-mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease associated with significant morbidity and mortality. Pediatric patients often present with mixted aetiologies. Objectives: To characterize the epidemiology, management and outcome of pediatric PAH. Methods: Children with PAH were included and followed prospectively for six months. WHO functional class, 6-minute walk test, biomarkers, electrocardiogram, spirometers and echocardiographic parameters were evaluated in progressive PAH group. Results: Two hundred and four children were included in the study from July 2012 until July 2013, with a mean age of 6.13 years. Transient PAH patients (n=170, 83.33%) included newborns with persistent pulmonary hypertension (n=8, 3.92%) and children with congenital heart defects with systemic-to-pulmonary shuntflow PAH (n=162, 79.41%) in whom PAH resolved after successful surgery correction. Progressive PAH (n=34, 16.66%) included patients with idiopathic PAH (n=5, 2.45%), Eisenmenger syndrome (n=17, 8.33%) and post-operative PAH (n= 6, 2.94%). Patients with progressive PAH remained stable in regards to clinical status, WHO functional class, 6-minute walk distance, biomarkers, spirometers parameters and echocardiographic parameters with prognostic value. Conclusions: Pediatric PAH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Pediatric PAH associated with congenital heart defects represents a heterogeneous group with highly variable clinical courses. PAH specific therapies may have contributed to disease stability and favorable outcomes.

Background: Cardiac involvement is a major contributor to morbidity and mortality in systemic sclerosis (SSc), yet valvular heart disease remains underrecognized. Fibrotic and vascular remodeling in SSc may predispose to valve lesions, which can exacerbate right or left heart failure, particularly in the presence of pulmonary hypertension (PH). Emerging data suggest that valvular dysfunction, especially regurgitant lesions, is associated with more advanced cardiopulmonary disease and may serve as a marker of increased mortality risk. We aimed to characterize the burden and distribution of valvular disease across SSc subtypes and PH phenotypes. Methods: We analyzed a cohort of SSc patients from Johns Hopkins Medicine who were referred for transthoracic echocardiogram for evaluation of pulmonary vascular disease between September 2003 and April 2025. Demographic and clinical metrics, invasive hemodynamics, and echocardiographic parameters were analyzed. Patients were classified into limited cutaneous SSc, diffuse cutaneous SSc, or SSc with overlap of another mixed connective tissue disease (MCTD). PH subtype was determined based on invasive hemodynamics and World Health Organization classification. Disease duration was calculated from date of Raynaud’s onset. Comparative analyses were conducted using ANOVA, Chi-Squared tests, and ordered logistic regression. Results: Our cohort consisted of 211 SSc patients, mean age 64 ± 13 years, 82% female, 71% white, 52% limited SSc subtype, 74% with PH, Table 1 . Patients with interstitial lung disease associated PH or pulmonary arterial hypertension displayed significantly higher odds for more severe tricuspid regurgitation (TR) compared to those without PH (p = 0.001), Table 2 . Additionally, individuals with diffuse SSc showed a higher prevalence of advanced TR compared to those with limited SSc (p = 0.037) and MCTD (p = 0.019). Among patients with MCTD, extensive aortic regurgitation was more prevalent than in limited SSc (p = 0.018), and the occurrence of higher-grade mitral regurgitation was significantly greater compared to both limited (p = 0.021) and diffuse SSc (p = 0.037). Conclusion: Valvular regurgitation is a prevalent and clinically relevant manifestation in SSc, particularly among patients with PH and diffuse SSc or MCTD. These findings underscore the importance of routine echocardiographic surveillance to detect and manage valvular disease early in the course of SSc-related cardiopulmonary involvement.

Clinical presentations associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) at rest are highly similar. Differentiating between CTEPH and PAH using non-invasive techniques remains challenging. Thus, we examined whether analysis of ventilatory gas in response to postural changes can be useful as a non-invasive screening method for pulmonary hypertension (PH), and help differentiate CTEPH from PAH. We prospectively enrolled 90 patients with suspected PH and performed right heart catheterization, ventilation/perfusion scan and ventilatory gas analysis. Various pulmonary function parameters were examined in the supine and sitting postures, and postural changes were calculated (Δ(supine - sitting)). In total, 25 patients with newly diagnosed PAH, 40 patients with newly diagnosed CTEPH and 25 non-PH patients were included. ΔEnd-tidal CO2 pressure (PET CO2 ) was significantly lower in patients with CTEPH and PAH than in non-PH patients (both P < 0.001). ΔPET CO2 < 0 mm Hg could effectively differentiate PH from non-PH (area under the curve (AUC) = 0.969, sensitivity = 89%, specificity = 100%). Postural change from sitting to supine significantly increased the ratio of ventilation to CO2 production (VE/VCO2 ) in the CTEPH group (P < 0.001). By contrast, VE/VCO2 significantly decreased in the PAH group (P = 0.001). Notably, CTEPH presented with higher ΔVE/VCO2 than PAH, although no differences were observed in haemodynamic and echocardiographic parameters between the two groups (P < 0.001). Furthermore, ΔVE/VCO2 > 0.8 could effectively differentiate CTEPH from PAH (AUC = 0.849, sensitivity = 78%, specificity = 88%). Postural changes in ventilatory gas analysis are useful as a non-invasive bedside evaluation to screen for the presence of PH and distinguish between CTEPH and PAH.