Native hepatic T1-time as a non-invasive predictor of diastolic dysfunction and a monitoring tool for disease progression and treatment response in patients with pulmonary hypertension.

AIMS: Hepatic T1-time derived from cardiac magnetic resonance imaging (cMRI) reflects venous congestion and may provide a simple alternative to invasive end-diastolic elastance (Eed) for assessment of right ventricular (RV) diastolic function. We investigated the association of native hepatic T1-time with single-beat Eed and the value of hepatic T1-time for longitudinal monitoring in pulmonary hypertension (PH). METHODS AND RESULTS: We retrospectively enrolled 85 patients with suspected PH (59% female; 78 with PH diagnosed; 7 with PH excluded) who underwent standard right heart catheterization and cMRI within 24 h between 2015 and 2020. Hepatic T1-time showed moderate to strong correlations (rho >0.3, P ≤ 0.002) with pulmonary vascular resistance, native myocardial T1-time, Eed, RV size and function, brain natriuretic peptide (BNP) level, and 6-min walk distance, and a significant association with functional class (Kruskal-Wallis P < 0.001). Eed, myocardial T1-time, and BNP were independently linked to hepatic T1-time in multivariable regression. Hepatic T1-time > 598 ms predicted elevated Eed with 72.9% sensitivity and 82.1% specificity. Hepatic T1-time was superior to Eed in predicting clinical worsening. In 16 patients with follow-up assessments, those with decreasing hepatic T1-time (7 patients) showed significant hemodynamic improvements, whereas those with increasing hepatic T1-time (9 patients) did not. In a second retrospective cohort of 27 patients with chronic thromboembolic PH undergoing balloon pulmonary angioplasty, hepatic T1-time decreased significantly and hemodynamics improved after the procedure. CONCLUSIONS: Hepatic T1-time predicts RV diastolic dysfunction and prognosis, and may be useful for monitoring disease progression and treatment response in PH.

Physiological mechanisms behind respiratory variations in right atrial pressure in pulmonary hypertension.

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP - end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH.Trial registration. NCT04663217.

Liver stiffness is associated with right heart dysfunction, cardiohepatic syndrome, and prognosis in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can lead to congestive hepatopathy, known as cardiohepatic syndrome (CHS). Hepatic congestion is associated with increased liver stiffness, which can be quantified using shear wave elastography. We aimed to investigate whether hepatic shear wave elastography detects patients at risk in the early stages of PH. METHODS: Sixty-three prospectively enrolled patients undergoing right heart catheterization (52 diagnosed with PH and 11 with invasive exclusion of PH) and 52 healthy volunteers underwent assessments including echocardiography and hepatic shear wave elastography. CHS was defined as increased levels of ≥2 of the following: gamma-glutamyl transferase, alkaline phosphatase, and bilirubin. Liver stiffness was defined as normal (≤5.0 kPa) or high (>5.0 kPa). RESULTS: Compared with normal liver stiffness, high liver stiffness was associated with impaired right ventricular (RV) and right atrial (RA) function (median [interquartile range] RV ejection fraction: 54 [49; 57]% vs 45 [34; 51]%, p < 0.001; RA reservoir strain: 49 [41; 54]% vs 33 [22; 41]%, p < 0.001), more severe tricuspid insufficiency (p < 0.001), and higher prevalence of hepatovenous backflow (2% vs 29%, p < 0.001) and CHS (2% vs 10%, p = 0.038). In the patient subgroup with precapillary PH (n = 48), CHS and high liver stiffness were associated with increased European Society of Cardiology/European Respiratory Society 2022 risk scores (p = 0.003). CONCLUSIONS: Shear wave liver elastography yields important information regarding right heart function and may complement risk assessment in patients with (suspected) PH.

Echocardiographic evaluation of right ventricular diastolic function in pulmonary hypertension.

Background: Right ventricular (RV) diastolic dysfunction may be prognostic in pulmonary hypertension (PH). However, its assessment is complex and relies on conductance catheterisation. We aimed to evaluate echocardiography-based parameters as surrogates of RV diastolic function, provide validation against the gold standard, end-diastolic elastance (Eed), and define the prognostic impact of echocardiography-derived RV diastolic dysfunction. Methods: Patients with suspected PH who underwent right heart catheterisation including conductance catheterisation were prospectively recruited. In this study population, an echocardiography-based RV diastolic function surrogate was derived. Survival analyses were performed in patients with precapillary PH in the Giessen PH Registry, with external validation in patients with pulmonary arterial hypertension at Sapienza University (Rome). Results: In the derivation cohort (n=61), the early/late diastolic tricuspid inflow velocity ratio (E/A) and early tricuspid inflow velocity/early diastolic tricuspid annular velocity ratio (E/e') did not correlate with Eed (p>0.05). Receiver operating characteristic analysis revealed a large area under the curve (AUC) for the peak lateral tricuspid annulus systolic velocity/right atrial area index ratio (S'/RAAi) to detect elevated Eed (AUC 0.913, 95% confidence interval (CI) 0.839-0.986) and elevated end-diastolic pressure (AUC 0.848, 95% CI 0.699-0.998) with an optimal threshold of 0.81 m2·s-1·cm-1. Subgroup analyses demonstrated a large AUC in patients with preserved RV systolic function (AUC 0.963, 95% CI 0.882-1.000). Survival analyses confirmed the prognostic relevance of S'/RAAi in the Giessen PH Registry (n=225) and the external validation cohort (n=106). Conclusions: Our study demonstrates the usefulness of echocardiography-derived S'/RAAi for noninvasive assessment of RV diastolic function and prognosis in PH.

Hepatorenal dysfunction in patients with chronic thromboembolic pulmonary hypertension.

Background: Cardiac interactions with organs such as the liver or kidneys have been described in different cardiovascular diseases. However, the clinical relevance of hepatorenal dysfunction in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We determined the association of hepatorenal dysfunction (measured using the Model for End-stage Liver Disease Sodium [MELDNa] score) with right heart function and survival in patients with CTEPH. Methods: We analyzed all patients with CTEPH in the Giessen Pulmonary Hypertension Registry who had available MELDNa scores and were not taking vitamin K antagonists. The MELDNa score was calculated as MELD score - serum Na - (0.025 * MELD score * (140 - serum Na)) + 140; the MELD score was calculated as 10*(0.957*ln(creatinine)+0.378*ln(bilirubin)+1.12*ln(International Normalized Ratio))+6.43. Results: Seventy-two patients were included (74% female; median [Q1, Q3] MELDNa: 9 [6, 11]). MELDNa correlated well with right atrial and ventricular function and pulmonary hemodynamics. Forward regression analysis revealed that hepatorenal dysfunction mainly depends on right atrial strain and tricuspid regurgitation, but not right ventricular systolic dysfunction. Hepatorenal dysfunction predicted mortality at baseline and follow-up (adjusted hazard ratios [95% confidence intervals] per unit increase of MELDNa: 1.6 [1.1, 2.4] and 1.8 [1.1, 2.9], respectively). Changes in hepatorenal function also predicted mortality. Conclusion: Hepatorenal dysfunction in CTEPH is primarily associated with venous congestion rather than cardiac forward failure. As a surrogate parameter for hepatorenal dysfunction, MELDNa is a simple method to identify at-risk patients at baseline and follow-up.

Intermittent body composition analysis as monitoring tool for muscle wasting in critically ill COVID-19 patients.

OBJECTIVES: SARS-CoV-2 virus infection can lead to acute respiratory distress syndrome (ARDS), which can be complicated by severe muscle wasting. Until now, data on muscle loss of critically ill COVID-19 patients are limited, while computed tomography (CT) scans for clinical follow-up are available. We sought to investigate the parameters of muscle wasting in these patients by being the first to test the clinical application of body composition analysis (BCA) as an intermittent monitoring tool. MATERIALS: BCA was conducted on 54 patients, with a minimum of three measurements taken during hospitalization, totaling 239 assessments. Changes in psoas- (PMA) and total abdominal muscle area (TAMA) were assessed by linear mixed model analysis. PMA was calculated as relative muscle loss per day for the entire monitoring period, as well as for the interval between each consecutive scan. Cox regression was applied to analyze associations with survival. Receiver operating characteristic (ROC) analysis and Youden index were used to define a decay cut-off. RESULTS: Intermittent BCA revealed significantly higher long-term PMA loss rates of 2.62% (vs. 1.16%, p < 0.001) and maximum muscle decay of 5.48% (vs. 3.66%, p = 0.039) per day in non-survivors. The first available decay rate did not significantly differ between survival groups but showed significant associations with survival in Cox regression (p = 0.011). In ROC analysis, PMA loss averaged over the stay had the greatest discriminatory power (AUC = 0.777) for survival. A long-term PMA decline per day of 1.84% was defined as a threshold; muscle loss beyond this cut-off proved to be a significant BCA-derived predictor of mortality. CONCLUSION: Muscle wasting in critically ill COVID-19 patients is severe and correlates with survival. Intermittent BCA derived from clinically indicated CT scans proved to be a valuable monitoring tool, which allows identification of individuals at risk for adverse outcomes and has great potential to support critical care decision-making.

Clinical and functional relevance of right ventricular contraction patterns in pulmonary hypertension.

BACKGROUND: The right ventricle has a complex contraction pattern of uncertain clinical relevance. We aimed to assess the relationship between right ventricular (RV) contraction pattern and RV-pulmonary arterial (PA) coupling defined by the gold-standard pressure-volume loop-derived ratio of end-systolic/arterial elastance (Ees/Ea). METHODS: Prospectively enrolled patients with suspected or confirmed pulmonary hypertension underwent three-dimensional echocardiography, standard right heart catheterization, and RV conductance catheterization. RV-PA uncoupling was categorized as severe (Ees/Ea < 0.8), moderate (Ees/Ea 0.8-1.29), and none/mild (Ees/Ea ≥ 1.3). Clinical severity was determined from hemodynamics using a truncated version of the 2022 European Society of Cardiology/European Respiratory Society risk stratification scheme. RESULTS: Fifty-three patients were included, 23 with no/mild, 24 with moderate, and 6 with severe uncoupling. Longitudinal shortening was decreased in patients with moderate vs no/mild uncoupling (p <0.001) and intermediate vs low hemodynamic risk (p < 0.001), discriminating low risk from intermediate/high risk with an optimal threshold of 18% (sensitivity 80%, specificity 87%). Anteroposterior shortening was impaired in patients with severe vs moderate uncoupling (p = 0.033), low vs intermediate risk (p = 0.018), and high vs intermediate risk (p = 0.010), discriminating high risk from intermediate/low risk with an optimal threshold of 15% (sensitivity 100%, specificity 83%). Left ventricular (LV) end-diastolic volume was decreased in patients with severe uncoupling (p = 0.035 vs no/mild uncoupling). CONCLUSIONS: Early RV-PA uncoupling is associated with reduced longitudinal function, whereas advanced RV-PA uncoupling is associated with reduced anteroposterior movement and LV preload, all in a risk-related fashion. CLINICALTRIALS: GOV: NCT04663217.

Echocardiographic pressure-strain loop-derived stroke work of the right ventricle: validation against the gold standard.

AIMS: Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo-based myocardial work (MW) module] vs. gold-standard invasive right ventricular (RV) pressure-volume (PV) loops. METHODS AND RESULTS: From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure-strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop-derived RV SW in the overall cohort [rho = 0.546 (P < 0.001)] and the PAH/CTEPH subgroup [rho = 0.568 (P < 0.001)]. Overall, RVGWW correlated with invasive measures of arterial elastance (Ea), the ratio of end-systolic elastance (Ees)/Ea, and end-diastolic elastance (Eed) significantly. CONCLUSIONS: Integrated echo measurement of pressure-strain loop-derived SW correlates with PV loop-based assessment of RV SW. Wasted work correlates with invasive measures of load-independent RV function. Given the methodological and anatomical challenges of RV work assessment, evolution of this approach by incorporating more elaborated echo analysis data and an RV reference curve might improve its reliability to mirror invasively assessed RV SW.

Adaptive versus maladaptive right ventricular remodelling.

Right ventricular (RV) function and its adaptation to increased afterload [RV-pulmonary arterial (PA) coupling] are crucial in various types of pulmonary hypertension, determining symptomatology and outcome. In the course of disease progression and increasing afterload, the right ventricle undergoes adaptive remodelling to maintain right-sided cardiac output by increasing contractility. Exhaustion of compensatory RV remodelling (RV-PA uncoupling) finally leads to maladaptation and increase of cardiac volumes, resulting in heart failure. The gold-standard measurement of RV-PA coupling is the ratio of contractility [end-systolic elastance (Ees)] to afterload [arterial elastance (Ea)] derived from RV pressure-volume loops obtained by conductance catheterization. The optimal Ees/Ea ratio is between 1.5 and 2.0. RV-PA coupling in pulmonary hypertension has considerable reserve; the Ees/Ea threshold at which uncoupling occurs is estimated to be ~0.7. As RV conductance catheterization is invasive, complex, and not widely available, multiple non-invasive echocardiographic surrogates for Ees/Ea have been investigated. One of the first described and best validated surrogates is the ratio of tricuspid annular plane systolic excursion to estimated pulmonary arterial systolic pressure (TAPSE/PASP), which has shown prognostic relevance in left-sided heart failure and precapillary pulmonary hypertension. Other RV-PA coupling surrogates have been formed by replacing TAPSE with different echocardiographic measures of RV contractility, such as peak systolic tissue velocity of the lateral tricuspid annulus (S'), RV fractional area change, speckle tracking-based RV free wall longitudinal strain and global longitudinal strain, and three-dimensional RV ejection fraction. PASP-independent surrogates have also been studied, including the ratios S'/RV end-systolic area index, RV area change/RV end-systolic area, and stroke volume/end-systolic volume. Limitations of these non-invasive surrogates include the influence of severe tricuspid regurgitation (which can cause distortion of longitudinal measurements and underestimation of PASP) and the angle dependence of TAPSE and PASP. Detection of early RV remodelling may require isolated analysis of single components of RV shortening along the radial and anteroposterior axes as well as the longitudinal axis. Multiple non-invasive methods may need to be applied depending on the level of RV dysfunction. This review explains the mechanisms of RV (mal)adaptation to its load, describes the invasive assessment of RV-PA coupling, and provides an overview of studies of non-invasive surrogate parameters, highlighting recently published works in this field. Further large-scale prospective studies including gold-standard validation are needed, as most studies to date had a retrospective, single-centre design with a small number of participants, and validation against gold-standard Ees/Ea was rarely performed.

Long-term comprehensive cardiopulmonary phenotyping of COVID-19.

BACKGROUND: Persistent symptoms after initial COVID-19 infection are common and are frequently referred to by the umbrella terms "post-COVID syndrome" and "long COVID". The sheer number of affected patients pose an increasing challenge to healthcare systems worldwide. To date, our understanding of the pathophysiology of the post-COVID syndrome remains poor and the extent to which persistent cardiopulmonary abnormalities contribute to the symptom complex is unclear. We sought to determine the presence and impact of cardiopulmonary sequelae after COVID-19 in longitudinal assessment. METHODS: We report on 71 patients who underwent comprehensive, longitudinal testing in regular intervals for up to 12 months after their initial COVID-19 diagnosis. Testing included pulmonary function testing, cardiopulmonary exercise testing, dedicated left and right heart echocardiography, lung ultrasonography, and cardiac MRI. RESULTS: Our results demonstrate that subjective quality of life after COVID-19 (EQ-5D visual acuity scale, VAS, 67.4 for patients treated as outpatient, 79.2 for patients admitted to the general floor, 71.8 for patients treated in an ICU) is not related to the severity of the initial infection. Maximal exercise capacity is also reduced (VO2max 79% predicted, SD ± 19%); however, this is driven in large parts by patients who had initially required ICU-level of care. The degree of objective reduction in exertion did not correlate with quality of life scores. Pulmonary function testing revealed mild and persistent reduction in DLCO over the first 12 months without significant restrictive or obstructive lung disease. Left and right heart function was intact with good RV function and intact RV/PA coupling, imaging findings suggestive of myocarditis were uncommon (7% of patients). CONCLUSION: A reduction in exercise capacity after COVID-19 is common, but is most prominent in patients previously treated in the ICU and more likely related to deconditioning or fatigue than to cardiopulmonary impairment. Subjective quality of life scores are independent of the severity of initial infection and do not correlate with objective measures of cardiopulmonary function. In our cohort, persistent cardiopulmonary impairment after COVID-19 was uncommon. The post-COVID syndrome is unlikely to be the result of cardiopulmonary sequalae and may reflect a post-ICU syndrome in some. Trial registration Registered on clinicaltrials.gov (NCT04442789), Date: June 23, 2020.

Relevance of Cor Pulmonale in COPD With and Without Pulmonary Hypertension: A Retrospective Cohort Study.

BACKGROUND: The relevance of cor pulmonale in COPD and pulmonary hypertension due to COPD (PH-COPD) is incompletely understood. We aimed to investigate the relationship of right ventricular-pulmonary arterial (RV-PA) uncoupling with disease severity in COPD, and the relationship of RV-PA uncoupling and use of targeted PH therapies with mortality in PH-COPD. METHODS: We retrospectively analyzed 231 patients with COPD without PH and 274 patients with PH-COPD. COPD was classified according to GOLD stages and the modified Medical Research Council dyspnoea scale. PH was categorized as mild-to-moderate or severe. RV-PA uncoupling was assessed as the echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. RESULTS: Of the cohort with COPD without PH, 21, 58, 54 and 92 were classified as GOLD I, II, III and IV, respectively. Patients in advanced GOLD stages and those with severe dyspnoea showed significantly decreased TAPSE/PASP.Of the PH-COPD cohort, 144 had mild-to-moderate PH and 130 had severe PH. During follow-up, 126 patients died. In univariate Cox regression, TAPSE/PASP and 6-min walk distance (6MWD; 10 m increments) predicted survival [hazard ratios (95% CI): 0.12 (0.03-0.57) and 0.95 (0.93-0.97), respectively]; notably, PH severity and simplified European Society of Cardiology/European Respiratory Society risk stratification did not. Among patients in the lowest or intermediate tertiles of TAPSE/PASP and 6MWD, those with targeted PH therapy had higher survival than those without (53 vs. 17% at 3 years). CONCLUSION: Cor pulmonale (decreased TAPSE/PASP and 6MWD) is associated with disease severity in COPD and predicts outcome in PH-COPD.

Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-ß Signaling Similar to those Induced by Exposure to Hyperoxia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. RESULTS: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. CONCLUSION: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.