Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR.

Background: Measures that can detect large treatment effects are important for monitoring therapeutic effectiveness. The 2022 European Society of Cardiology/European Respiratory Society guidelines highlight the importance of imaging in monitoring disease status and treatment response in pulmonary arterial hypertension (PAH). Are the standardised treatment effect sizes (STES) of cardiac magnetic resonance imaging (cMRI) comparable with functional and haemodynamic variables? Methods: REPAIR (ClinicalTrials.gov: NCT02310672) was a prospective, multicentre, single-arm, open-label, 52-week phase 4 study evaluating the effect of macitentan 10 mg, with or without a phosphodiesterase 5 inhibitor (PDE5i), on right ventricular (RV) remodelling, cardiac function and cardiopulmonary haemodynamics. Both cMRI and functional assessments were performed at screening and at weeks 26 and 52; haemodynamic measurements were conducted at screening and week 26. In this post hoc analysis, STES were estimated using the parametric Cohen's d and non-parametric Cliff's delta tests. Results: At week 26, large STES (Cohen's d) were observed for 10 of the 20 cMRI variables assessed, including the prognostic measures of RV and left ventricular stroke volume and RV ejection fraction and the haemodynamic trial end-point, pulmonary vascular resistance; medium STES were observed for 6-min walk distance (6MWD). The STES were consistent in treatment-naïve patients and those escalating therapy and maintained at week 52. Similar results were obtained using the non-parametric Cliff's delta method. Conclusions: The treatment effect of macitentan, alone or in combination with a PDE5i, was comparable for several cMRI and haemodynamic variables with prognostic value in PAH, and greater than that of 6MWD in patients with PAH, highlighting the emerging relevance of cMRI in PAH.

Toward the Implementation of Optimal Cardiac Magnetic Resonance Risk Stratification in Pulmonary Arterial Hypertension.

BACKGROUND: The 2022 European Society of Cardiology/European Respiratory Society pulmonary hypertension (PH) guidelines incorporate cardiac magnetic resonance (CMR) imaging metrics in the risk stratification of patients with pulmonary arterial hypertension (PAH). Thresholds to identify patients at estimated 1-year mortality risks of < 5%, 5% to 20%, and > 20% are introduced. However, these cutoff values are mostly single center-based and require external validation. RESEARCH QUESTION: What are the discriminative prognostic properties of the current CMR risk thresholds stratifying patients with PAH? STUDY DESIGN AND METHODS: We analyzed data from incident, treatment-naïve patients with PAH from the Amsterdam University Medical Centres, Vrije Universiteit, The Netherlands. The discriminative properties of the proposed CMR three risk strata were tested at baseline and first reassessment, using the following PH guideline variables: right ventricular ejection fraction, indexed right ventricular end-systolic volume, and indexed left ventricular stroke volume. RESULTS: A total of 258 patients with PAH diagnosed between 2001 and 2022 fulfilled the study criteria and were included in this study. Of these, 172 had follow-up CMR imaging after 3 months to 1.5 years. According to the CMR three risk strata, most patients were classified at intermediate risk (n = 115 [45%]) upon diagnosis. Only 29 (11%) of patients with PAH were classified at low risk, and 114 (44%) were classified at high risk. Poor survival discrimination was seen between risk groups. Appropriate survival discrimination was seen at first reassessment. INTERPRETATION: Risk stratifying patients with PAH with the recent proposed CMR cutoffs from the European Society of Cardiology/European Respiratory Society 2022 PH guidelines requires adjustment because post-processing consensus is lacking and general applicability is limited. Risk assessment at follow-up yielded better survival discrimination, emphasizing the importance of the individual treatment response.

Long-Term Effects of Pulmonary Endarterectomy on Right Ventricular Stiffness and Fibrosis in Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function. METHODS: We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV-arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism. RESULTS: RV mass significantly decreased from 43±15 to 27±11g/m2 (-15.9 g/m2 [95% CI, -21.4 to -10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 in healthy controls [95% CI, 2.1 to 9.8]; P<0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2-6.1]; P=0.013) as a result of a larger reduction in cellular volume than in matrix volume (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-ß (transforming growth factor-ß) were elevated at baseline and remained elevated post-PEA. CONCLUSIONS: Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover.

Restoration of right ventricular function in the treatment of pulmonary arterial hypertension.

OBJECTIVE: A 45% threshold of right ventricular ejection fraction (RVEF) is proposed clinically relevant in patients with pulmonary arterial hypertension (PAH). We aim to determine treatment response, long-term right ventricular (RV) functional stability and prognosis of patients with PAH reaching or maintaining the RVEF 45% threshold. METHODS: Incident, treatment-naive, adult PAH patients with cardiac magnetic resonance imaging at baseline and first follow-up were included (total N=127) and followed until date of censoring or death/lung transplantation. Patients were categorised into two groups based on 45% RVEF. Baseline predictors, treatment response and prognosis were assessed with logistic regression analyses, two-way analysis of variance and log-rank tests. RESULTS: Patients were 50±17 years old, 73% female, of which N=75 reached or maintained the 45% RVEF threshold at follow-up (RVEF≥45%@FU), while N=52 patients did not (RVEF<45%@FU). RV end-diastolic volume and N-terminal pro-B-type natriuretic peptide at baseline were multivariable predictors of an RVEF ≥45% at follow-up. A 40% pulmonary vascular resistance (PVR) reduction resulted in greater improvement in RV function (ΔRVEF 17±11 vs. 5±8; pinteraction<0.001) compared to a PVR reduction <40%, but did not guarantee an RVEF ≥45%. Finally, the 45% RVEF threshold was associated with stable RV function during long-term follow-up and better survival (HR: 1.91 (95% CI: 1.11 to 3.27)). Patients failing to reach or maintain the 45% RVEF threshold at first follow-up mostly stayed below this threshold over the next consecutive visits. CONCLUSION: After treatment initiation, 60% of patients with PAH reach or maintain the 45% RVEF threshold, which is associated with a long-term stable RV function and favourable prognosis.

Right Atrial Adaptation to Precapillary Pulmonary Hypertension: Pressure-Volume, Cardiomyocyte, and Histological Analysis.

BACKGROUND: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. OBJECTIVES: This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses. METHODS: RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis. RESULTS: RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2- to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm2 accompanied by interstitial and perivascular fibrosis. CONCLUSIONS: RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis.

Characterizing the Bone Marrow Environment in Advanced-Stage Myelofibrosis during Ruxolitinib Treatment Using PET/CT and MRI: A Pilot Study.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

When right ventricular pressure meets volume: The impact of arrival time of reflected waves on right ventricle load in pulmonary arterial hypertension.

Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. A larger volume at a given pressure generates more wall tension. Return of reflected waves early after the onset of contraction, when RV volume is larger, may augment RV load. We aimed to elucidate: (1) the distribution of arrival times of peak reflected waves in treatment-naïve PAH patients; (2) the relationship between time of arrival of reflected waves and RV morphology; and (3) the effect of PAH treatment on the arrival time of reflected waves. Wave separation analysis was conducted in 68 treatment-naïve PAH patients. In the treatment-naïve condition, 54% of patients had mid-systolic return of reflected waves (defined as 34-66% of systole). Despite similar pulmonary vascular resistance (PVR), patients with mid-systolic return had more pronounced RV hypertrophy compared to those with late-systolic or diastolic return (RV mass/body surface area; mid-systolic return 54.6 ± 12.6 g m-2 , late-systolic return 44.4 ± 10.1 g m-2 , diastolic return 42.8 ± 13.1 g m-2 ). Out of 68 patients, 43 patients were further examined after initial treatment. At follow-up, the stiffness of the proximal arteries, given as characteristic impedance, decreased from 0.12 to 0.08 mmHg s mL-1 . Wave speed was attenuated from 13.3 to 9.1 m s-1 , and the return of reflected waves was delayed from 64% to 71% of systole. In conclusion, reflected waves arrive at variable times in PAH. Early return of reflected waves was associated with more RV hypertrophy. PAH treatment not only decreased PVR, but also delayed the timing of reflected waves. KEY POINTS: Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. Larger volume at a given pressure causes larger RV wall tension. Early return of reflected waves adds RV pressure in early systole, when RV volume is relatively large. Thus, early return of reflected waves may increase RV wall tension. Wave reflection can provide a description of RV load. In PAH, reflected waves arrive back at variable times. In over half of PAH patients, the RV is exposed to mid-systolic return of reflected waves. Mid-systolic return of reflected waves is related to RV hypertrophy. PAH treatment acts favourably on the RV not only by reducing resistance, but also by delaying the return of reflected waves. Arrival timing of reflected waves is an important parameter for understanding the relationship between RV load and its function in PAH.

Early Response Prediction of Multiparametric Functional MRI and 18F-FDG-PET in Patients with Head and Neck Squamous Cell Carcinoma Treated with (Chemo)Radiation.

BACKGROUND: Patients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring. METHODS: Fifty-seven histopathologically-proven HNSCC patients with curative (chemo)radiotherapy were prospectively included. All patients had an MRI (DW,-IVIM, DCE-MRI) and 18F-FDG-PET/CT before and 10 days after start-treatment (intratreatment). Primary tumor functional imaging parameters were extracted. Univariate and multivariate analysis were performed to construct prognostic models and risk stratification for 2 year locoregional recurrence-free survival (LRFFS), distant metastasis-free survival (DMFS) and overall survival (OS). Model performance was measured by the cross-validated area under the receiver operating characteristic curve (AUC). RESULTS: The best LRFFS model contained the pretreatment imaging parameters ADC_kurtosis, Kep and SUV_peak, and intratreatment imaging parameters change (Δ) Δ-ADC_skewness, Δ-f, Δ-SUV_peak and Δ-total lesion glycolysis (TLG) (AUC = 0.81). Clinical parameters did not enhance LRFFS prediction. The best DMFS model contained pretreatment ADC_kurtosis and SUV_peak (AUC = 0.88). The best OS model contained gender, HPV-status, N-stage, pretreatment ADC_skewness, D, f, metabolic-active tumor volume (MATV), SUV_mean and SUV_peak (AUC = 0.82). Risk stratification in high/medium/low risk was significantly prognostic for LRFFS (p = 0.002), DMFS (p < 0.001) and OS (p = 0.003). CONCLUSIONS: Intratreatment functional imaging parameters capture early tumoral changes that only provide prognostic information regarding LRFFS. The best LRFFS model consisted of pretreatment, intratreatment and Δ functional imaging parameters; the DMFS model consisted of only pretreatment functional imaging parameters, and the OS model consisted ofHPV-status, gender and only pretreatment functional imaging parameters. Accurate clinically applicable risk stratification calculators can enable personalized treatment (adaptation) management, early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring.

Interplay of sex hormones and long-term right ventricular adaptation in a Dutch PAH-cohort.

BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAH-patients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females ≤45years had best prognosis in comparison to females ≥55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females ≤45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females ≤45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAH-patients. DHEA-S appeared to be lower in male and female PAH-patients. Females ≤45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.

Right atrial function is associated with right venticular diastolic stiffness: RA-RV interaction in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA-RV interaction. METHODS: PAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying-RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure. RESULTS: With increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high. CONCLUSIONS: In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

Right Ventricular and Right Atrial Function Are Less Compromised in Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction: A Comparison With Pulmonary Arterial Hypertension With Similar Pressure Overload.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity. METHODS: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP ≥30 and ≤50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging. RESULTS: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52±11 versus PAH: 36±12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3±0.2 versus PAH: 1.2±0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg). CONCLUSIONS: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity.

The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension.

OBJECTIVES: The REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patients with pulmonary arterial hypertension (PAH), using cardiac magnetic resonance (CMR) and right heart catheterization (RHC). BACKGROUND: RV failure is the primary cause of death in PAH. CMR is regarded as the most accurate noninvasive method for assessing RV function and remodeling and CMR measures of RV function and structure are strongly prognostic for survival in patients with PAH. Despite this, CMR is not routinely used in PAH clinical trials. METHODS: REPAIR was a 52-week, open-label, single-arm, multicenter, phase 4 study evaluating the effect of macitentan 10 mg, with or without phosphodiesterase type-5 inhibition, on RV remodeling and function and cardiopulmonary hemodynamics. Primary endpoints were change from baseline to week 26 in RV stroke volume, determined by CMR; and pulmonary vascular resistance, determined by RHC. Efficacy measures were assessed for all patients with baseline and week 26 data for both primary endpoints. RESULTS: At a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive. At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level: 8.4-15.6 mL; P < 0.0001) and pulmonary vascular resistance decreased by 38% (99% confidence level: 31%-44%; P < 0.0001) at week 26. Significant positive changes were also observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional endpoints at week 26. Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52. Safety (n = 87) was consistent with previous clinical trials. CONCLUSIONS: In the context of this study, macitentan treatment in patients with PAH resulted in significant and clinically-relevant improvements in RV function and structure and cardiopulmonary hemodynamics. At 52 weeks, improvements in RV function and structure were sustained. (REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension [REPAIR]; NCT02310672).

Positive end-expiratory pressure affects geometry and function of the human diaphragm.

Positive end-expiratory pressure (PEEP) is routinely applied in mechanically ventilated patients to improve gas exchange and respiratory mechanics by increasing end-expiratory lung volume (EELV). In a recent experimental study in rats, we demonstrated that prolonged application of PEEP causes diaphragm remodeling, especially longitudinal muscle fiber atrophy. This is of potential clinical importance, as the acute withdrawal of PEEP during ventilator weaning decreases EELV and thereby stretches the adapted, longitudinally atrophied diaphragm fibers to excessive sarcomere lengths, having a detrimental effect on force generation. Whether this series of events occurs in the human diaphragm is unknown. In the current study, we investigated if short-term application of PEEP affects diaphragm geometry and function, which are prerequisites for the development of longitudinal atrophy with prolonged PEEP application. Nineteen healthy volunteers were noninvasively ventilated with PEEP levels of 2, 5, 10, and 15 cmH2O. Magnetic resonance imaging was performed to investigate PEEP-induced changes in diaphragm geometry. Subjects were instrumented with nasogastric catheters to measure diaphragm neuromechanical efficiency (i.e., diaphragm pressure normalized to its electrical activity) during tidal breathing with different PEEP levels. We found that increasing PEEP from 2 to 15 cmH2O resulted in a caudal diaphragm displacement (19 [14-26] mm, P < 0.001), muscle shortening in the zones of apposition (20.6% anterior and 32.7% posterior, P < 0.001), increase in diaphragm thickness (36.4% [0.9%-44.1%], P < 0.001) and reduction in neuromechanical efficiency (48% [37.6%-56.6%], P < 0.001). These findings demonstrate that conditions required to develop longitudinal atrophy in the human diaphragm are present with the application of PEEP.NEW & NOTEWORTHY We demonstrate that PEEP causes changes in diaphragm geometry, especially muscle shortening, and decreases in vivo diaphragm contractile function. Thus, prerequisites for the development of diaphragm longitudinal muscle atrophy are present with the acute application of PEEP. Once confirmed in ventilated critically ill patients, this could provide a new mechanism for ventilator-induced diaphragm dysfunction and ventilator weaning failure in the intensive care unit (ICU).

Right ventricular adaptation to pressure-overload: Differences between chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH. METHODS: We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders. RESULTS: We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p < .01), and a lower RV relative wall thickness (0.6 ± 0,1 g/ml vs 0.7 ± 0,2 g/ml; p < .01). The correlation coefficient of RV diastolic stiffness to afterload was higher in CTEPH compared to iPAH (p < .05; independent of age and gender). CONCLUSIONS: Despite differences in patient characteristics, disease etiology and physiology, RV functional parameters in CTEPH and iPAH are mostly similar. The right ventricle in CTEPH is marginally more dilated, stiffer and less hypertrophic than in iPAH.

Repeatability of IVIM biomarkers from diffusion-weighted MRI in head and neck: Bayesian probability versus neural network.

PURPOSE: The intravoxel incoherent motion (IVIM) model for DWI might provide useful biomarkers for disease management in head and neck cancer. This study compared the repeatability of three IVIM fitting methods to the conventional nonlinear least-squares regression: Bayesian probability estimation, a recently introduced neural network approach, IVIM-NET, and a version of the neural network modified to increase consistency, IVIM-NETmod . METHODS: Ten healthy volunteers underwent two imaging sessions of the neck, two weeks apart, with two DWI acquisitions per session. Model parameters (ADC, diffusion coefficient Dt , perfusion fraction fp , and pseudo-diffusion coefficient Dp ) from each fit method were determined in the tonsils and in the pterygoid muscles. Within-subject coefficients of variation (wCV) were calculated to assess repeatability. Training of the neural network was repeated 100 times with random initialization to investigate consistency, quantified by the coefficient of variance. RESULTS: The Bayesian and neural network approaches outperformed nonlinear regression in terms of wCV. Intersession wCV of Dt in the tonsils was 23.4% for nonlinear regression, 9.7% for Bayesian estimation, 9.4% for IVIM-NET, and 11.2% for IVIM-NETmod . However, results from repeated training of the neural network on the same data set showed differences in parameter estimates: The coefficient of variances over the 100 repetitions for IVIM-NET were 15% for both Dt and fp , and 94% for Dp ; for IVIM-NETmod , these values improved to 5%, 9%, and 62%, respectively. CONCLUSION: Repeatabilities from the Bayesian and neural network approaches are superior to that of nonlinear regression for estimating IVIM parameters in the head and neck.

Multiparametric functional MRI and 18F-FDG-PET for survival prediction in patients with head and neck squamous cell carcinoma treated with (chemo)radiation.

OBJECTIVES: To assess (I) correlations between diffusion-weighted (DWI), intravoxel incoherent motion (IVIM), dynamic contrast-enhanced (DCE) MRI, and 18F-FDG-PET/CT imaging parameters capturing tumor characteristics and (II) their predictive value of locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy. METHODS: Between 2014 and 2018, patients with histopathologically proven HNSCC, planned for curative (chemo) radiotherapy, were prospectively included. Pretreatment clinical, anatomical, and functional imaging parameters (obtained by DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT) were extracted for primary tumors (PT) and lymph node metastases. Correlations and differences between parameters were assessed. The predictive value of LRFS and OS was assessed, performing univariable, multivariable Cox and CoxBoost regression analyses. RESULTS: In total, 70 patients were included. Significant correlations between 18F-FDG-PET parameters and DWI-/DCE volume parameters were found (r > 0.442, p < 0.002). The combination of HPV (HR = 0.903), intoxications (HR = 1.065), PT ADCGTV (HR = 1.252), Ktrans (HR = 1.223), and Ve (HR = 1.215) was predictive for LRFS (C-index = 0.546; p = 0.023). N-stage (HR = 1.058), HPV positivity (HR = 0.886), hypopharyngeal tumor location (HR = 1.111), ADCGTV (HR = 1.102), ADCmean (HR = 1.137), D* (HR = 0.862), Ktrans (HR = 1.106), Ve (HR = 1.195), SUVmax (HR = 1.094), and TLG (HR = 1.433) were predictive for OS (C-index = 0.664; p = 0.046). CONCLUSIONS: Functional imaging parameters, performing DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT, yielded complementary value in capturing tumor characteristics. More specific, intoxications, HPV-negative status, large tumor volume-related parameters, high permeability (Ktrans), and high extravascular extracellular space (Ve) parameters were predictive for adverse locoregional recurrence-free survival and adverse overall survival. Low cellularity (high ADC) and high metabolism (high SUV) were additionally predictive for decreased overall survival. These different predictive factors added to estimated locoregional and overall survival. KEY POINTS: • Parameters of DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT were able to capture complementary tumor characteristics. • Multivariable analysis revealed that intoxications, HPV negativity, large tumor volume and high vascular permeability (Ktrans), and extravascular extracellular space (Ve) were complementary predictive for locoregional recurrence. • In addition to predictive parameters for locoregional recurrence, also high cellularity (low ADC) and high metabolism (high SUV) were complementary predictive for overall survival.

Early return of reflected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension.

Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are as follows: 1) to investigate whether reflected pressure returns sooner in proximal than in distal CTEPH and 2) to elucidate whether the timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy, and wall stress. Right heart catheterization and cardiac MRI were performed in 17 patients with proximal CTEPH and 17 patients with distal CTEPH. In addition to the determination of PVR, compliance, and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as %systole). Findings were related to RV dimensions and time-resolved RV wall stress. Proximal CTEPH was characterized by higher RV volumes, mass, and wall stress, and lower RVEF. While PVR, compliance, and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53 ± 8% vs. distal 63 ± 15%, P < 0.05). The magnitude of the reflected pressure waves did not differ. RV volumes, RVEF, RV mass, and wall stress were all related to the timing of peak reflected pressure. Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance, and characteristic impedance do not explain the differences in RV function between proximal and distal CTEPH.NEW & NOTEWORTHY In chronic thromboembolic pulmonary hypertension (CTEPH), proximal localization of vessel obstructions is associated with poor right ventricular (RV) function compared with distal localization, though pulmonary vascular resistance, vascular compliance, characteristic impedance, and the magnitude of wave reflection are similar. In proximal CTEPH, the RV is exposed to an earlier return of the reflected wave. Early wave reflection may increase RV wall stress and compromise RV function.

Persistent exercise intolerance after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

AIM: Haemodynamic normalisation is the ultimate goal of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). However, whether normalisation of haemodynamics translates into normalisation of exercise capacity is unknown. The incidence, determinants and clinical implications of exercise intolerance after PEA are unknown. We performed a prospective analysis to determine the incidence of exercise intolerance after PEA, assess the relationship between exercise capacity and (resting) haemodynamics and search for preoperative predictors of exercise intolerance after PEA. METHODS: According to clinical protocol all patients underwent cardiopulmonary exercise testing (CPET), right heart catheterisation and cardiac magnetic resonance (CMR) imaging before and 6 months after PEA. Exercise intolerance was defined as a peak oxygen consumption (V'O2 ) <80% predicted. CPET parameters were judged to determine the cause of exercise limitation. Relationships were analysed between exercise intolerance and resting haemodynamics and CMR-derived right ventricular function. Potential preoperative predictors of exercise intolerance were analysed using logistic regression analysis. RESULTS: 68 patients were included in the final analysis. 45 (66%) patients had exercise intolerance 6 months after PEA; in 20 patients this was primarily caused by a cardiovascular limitation. The incidence of residual pulmonary hypertension was significantly higher in patients with persistent exercise intolerance (p=0.001). However, 27 out of 45 patients with persistent exercise intolerance had no residual pulmonary hypertension. In the multivariate analysis, preoperative transfer factor of the lung for carbon monoxide (T LCO) was the only predictor of exercise intolerance after PEA. CONCLUSIONS: The majority of CTEPH patients have exercise intolerance after PEA, often despite normalisation of resting haemodynamics. Not all exercise intolerance after PEA is explained by the presence of residual pulmonary hypertension, and lower preoperative T LCO was a strong predictor of exercise intolerance 6 months after PEA.

Repeatability of arterial input functions and kinetic parameters in muscle obtained by dynamic contrast enhanced MR imaging of the head and neck.

BACKGROUND: Quantification of pharmacokinetic parameters in dynamic contrast enhanced (DCE) MRI is heavily dependent on the arterial input function (AIF). In the present patient study on advanced stage head and neck squamous cell carcinoma (HNSCC) we have acquired DCE-MR images before and during chemo radiotherapy. We determined the repeatability of image-derived AIFs and of the obtained kinetic parameters in muscle and compared the repeatability of muscle kinetic parameters obtained with image-derived AIF's versus a population-based AIF. MATERIALS AND METHODS: We compared image-derived AIFs obtained from the internal carotid, external carotid and vertebral arteries. Pharmacokinetic parameters (ve, Ktrans, kep) in muscle-located outside the radiation area-were obtained using the Tofts model with the image-derived AIFs and a population averaged AIF. Parameter values and repeatability were compared. Repeatability was calculated with the pre- and post-treatment data with the assumption of no DCE-MRI measurable biological changes between the scans. RESULTS: Several parameters describing magnitude and shape of the image-derived AIFs from the different arteries in the head and neck were significantly different. Use of image-derived AIFs led to higher pharmacokinetic parameters compared to use of a population averaged AIF. Median muscle pharmacokinetic parameters values obtained with AIFs in external carotids, internal carotids, vertebral arteries and with a population averaged AIF were respectively: ve (0.65, 0.74, 0.58, 0.32), Ktrans (0.30, 0.21, 0.13, 0.06), kep (0.41, 0.32, 0.24, 0.18). Repeatability of pharmacokinetic parameters was highest when a population averaged AIF was used; however, this repeatability was not significantly different from image-derived AIFs. CONCLUSION: Image-derived AIFs in the neck region showed significant variations in the AIFs obtained from different arteries, and did not improve repeatability of the resulting pharmacokinetic parameters compared with the use of a population averaged AIF. Therefore, use of a population averaged AIF seems to be preferable for pharmacokinetic analysis using DCE-MRI in the head and neck area.

Hemodynamic Effects of Pulmonary Arterial Hypertension-Specific Therapy in Patients With Heart Failure With Preserved Ejection Fraction and With Combined Post- and Precapillay Pulmonary Hypertension.

BACKGROUND: Drugs approved for pulmonary arterial hypertension have been considered for patients with heart failure with preserved ejection fraction and combined post- and precapillary pulmonary hypertension (Cpc-PH). We aimed to study changes in cardiac volumes, cardiac load and left ventricular (LV) filling pressures in patients with heart failure with preserved ejection fraction and Cpc-PH in response to pulmonary arterial hypertension-specific treatment. METHODS AND RESULTS: In this prospective study, 23 patients with heart failure with preserved ejection fraction and Cpc-PH underwent right-heart catheterization, including acute provocation testing (fluid loading and inhaled nitric oxide) and cardiac MRI at baseline. Right-heart catheterization and cardiac MRI were repeated after 4 months of treatment. At baseline, acutely increasing preload by fluid loading resulted in a significant increase in pulmonary arterial wedge pressure (PAWP), whereas reducing right ventricular (RV) afterload and increasing LV distensability by acute administration of inhaled nitric oxide had no effect on PAWP. After 4 months of treatment, we observed a significant reduction in RV and LV afterload and increased RV and LV stroke volume, but PAWP significantly increased. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and Cpc-PH, 4 months of pulmonary arterial hypertension-specific treatment increased RV and LV stroke volume at the expense of increased PAWP. This increase in PAWP was similarly observed acutely after fluid loading.