Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.

Quantitative CT Evaluation of Small Pulmonary Vessels Has Functional and Prognostic Value in Pulmonary Hypertension.

Background The in vivo relationship between peel pulmonary vessels, small pulmonary vessels, and pulmonary hypertension (PH) is not fully understood. Purpose To quantitatively assess peel pulmonary vessel volumes (PPVVs) and small pulmonary vessel volumes (SPVVs) as estimated from CT pulmonary angiography (CTPA) in different subtypes of PH compared with controls, their relationship to pulmonary function and right heart catheter metrics, and their prognostic value. Materials and Methods In this retrospective single-center study performed from January 2008 to February 2018, quantitative CTPA analysis of total SPVV (TSPVV) (0.4- to 2-mm vessel diameter) and PPVV (within 15, 30, and 45 mm from the lung surface) was performed. Results A total of 1823 patients (mean age, 69 years ± 13 [SD]; 1192 women [65%]) were retrospectively analyzed; 1593 patients with PH (mean pulmonary arterial pressure [mPAP], 43 mmHg ± 13 [SD]) were compared with 230 patient controls (mPAP, 19 mm Hg ± 3). The mean vessel volumes in pulmonary peels at 15-, 30-, and 45-mm depths were higher in pulmonary arterial hypertension (PAH) and PH secondary to lung disease compared with chronic thromboembolic PH (45-mm peel, mean difference: 6.4 mL [95% CI: 1, 11] [P < .001] vs 6.8 mL [95% CI: 1, 12] [P = .01]). Mean small vessel volumes at a diameter of less than 2 mm were lower in PAH and PH associated with left heart disease compared with controls (1.6-mm vessels, mean difference: -4.3 mL [95% CI: -8, -0.1] [P = .03] vs -6.8 mL [95% CI: -11, -2] [P < .001]). In patients with PH, the most significant positive correlation was noted with forced vital capacity percentage predicted (r = 0.30-0.40 [all P < .001] for TSPVVs and r = 0.21-0.25 [all P < .001] for PPVVs). Conclusion The volume of pulmonary small vessels is reduced in pulmonary arterial hypertension and pulmonary hypertension (PH) associated with left heart disease, with similar volume of peel vessels compared with controls. For chronic thromboembolic PH, the volume of peel vessels is reduced. In PH, small pulmonary vessel volume is associated with pulmonary function tests. Clinical trial registration no. NCT02565030 Published under a CC BY 4.0 license Online supplemental material is available for this article.

MicroRNA in pulmonary vascular disease.

MicroRNA (miRNA) are short noncoding RNA that regulate gene expression by inhibiting translation or promoting degradation of target mRNA. miRNA are key regulators of a wide range of cellular processes and their discovery has revolutionized our understanding of gene regulatory networks. Pulmonary arterial hypertension (PAH) is a debilitating and fatal disease characterized by remodeling of pulmonary arteries and right heart failure. Factors including sustained pulmonary vasoconstriction, inflammation, and altered cellular signaling pathways drive disease through pulmonary artery endothelial dysfunction, smooth muscle cell proliferation, and the recruitment of circulating cells. miRNA have been shown to regulate many of the key drivers of pathology, yet the role of only a limited number of miRNA has been recognized in PAH. Investigation of the diverse regulatory functions of miRNA offers the potential to further understanding of the cellular pathology of PAH and to provide much needed diagnostic and therapeutic strategies. This review focuses on recent advances in the investigation of miRNA in PAH.

Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis.

X-linked retinoschisis results in visual loss in early life with splitting within the inner retinal layers. Many missense and protein truncating mutations of the causative gene RS1 (encoding retinoschisin) have been identified but disease severity is not mutation-dependent. Retinoschisin is a soluble secretory protein predicted to have a globular conformation. Missense mutations would be expected to interfere with protein folding leading to an abnormal conformation and intracellular retention and elimination. To test this hypothesis we have expressed seven pathological RS1 mutations (L12H, C59S, G70S, R102W, G109R, R141G and R213W) in COS-7 cells and investigated their intracellular processing and transport. Using immunoblotting and confocal fluorescent immunocytochemistry we show normal secretion of WT RS1, but either reduced (C59S and R141G) or absent (L12H, G70S, R102W, G109R and R213W) secretion of mutant RS1 and intracellular retention. In addition, we show that L12H RS1 is degraded by proteasomes and in vitro transcription/translation revealed the defects in both cleavage of its signal peptide and translocation into the endoplasmic reticulum. Our results indicate the pathological basis of RS1 is intracellular retention of the majority of mutant proteins, which may explain why disease severity is not mutation-specific. Furthermore, we have shown that in vitro expression of RS1 may be a useful functional assay to investigate the pathogenicity of sequence changes within the RS1 gene.