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Pulmonary vascular resistance (PVR) is traditionally used to describe pulmonary hemodynamic characteristics. However, it does not take into account pulmonary artery compliance (Ca) or pulsatile flow. The product of PVR and Ca is known as RC time. Previous studies assert that the PVR‐Ca relationship is fixed and RC time is constant between health and disease states. We hypothesized that RC time was not constant in health and pulmonary vascular disease. Right heart catheterizations performed in Papworth Hospital over a 6 year period were analyzed. Subjects were divided into those with normal pulmonary hemodynamics (NPH group; n = 156) and pulmonary arterial hypertension (PAH group; n = 717). RC time and the right ventricle (RV) oscillatory power fraction were calculated. RC time for the NPH group (0.47 ± 0.13 sec) is significantly lower than the PAH group (0.56 ± 0.16 sec; P < 0.0001). The RV oscillatory power fraction is lower in the NPH group (P < 0.0001). RC time correlates inversely with the RV oscillatory power fraction in each group. We conclude, there is an inverse relationship between PVR and Ca, however, this relationship is not always fixed. Consequently, RC time is significantly lower in health compared to disease with elevated pulmonary artery pressures. PAH leads to a decrease in cardiac efficiency. RC time is not constant between health and diseases with elevated pulmonary artery pressures. Although there remains an inverse relationship between PVR and Ca, this relationship is not immutably fixed between health and disease states. This may have implications for right ventricular function in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2 , ATP13A3 , AQP1 and SOX17 .

BackgroundThe molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and resultsWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent–offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.ConclusionOur findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

IntroductionThere is growing interest in identifying cardiovascular magnetic resonance (CMR) signatures in ageing due to their relevance to cardiovascular health.1 It also remains uncertain whether patients with heart failure with preserved ejection fraction (HFpEF) have disruptions in their aortic flow. This study aimed to explore sophisticated indicators of aortic flow disturbances in ageing and in HFpEF.Materials and MethodsThis study used two-dimensional phase-contrast CMR data at an orthogonal plane just above the sino-tubular junction. We recruited 10 young healthy controls (HCs), 10 old HCs and 23 patients with HFpEF. We analysed average systolic aortic flow displacement (FDsavg), systolic flow reversal ratio (sFRR) and pulse wave velocity (PWV). In a sub-group analysis, we compared old HCs versus age-gender-matched HFpEF (N=10).ResultsDifferences were significant in mean age (P<0.001) among young HCs (22.9±3.5 years), old HCs (60.5±10.2 years) and HFpEF patients (73.7±9.7 years). FDsavg, sFRR and PWV varied significantly (P<0.001) in young HCs (8±4%, 2±2%, 4±2m/s), old HCs (16±5%, 7±6%, 11±8m/s), and HFpEF patients (23±10%, 11±10%, 8±3). No significant PWV differences existed between old HCs and HFpEF. (table 1, figure 1 and figure 2) HFpEF had significantly higher FDsavgversus old HCs (23±10% vs 16±5%, P<0.001). A FDsavg > 17.7% achieved 74% sensitivity, 70% specificity for differentiating them. sFRR was notably higher in HFpEF (11±10% vs 7±6%, P<0.001). A sFRR > 7.3% yielded 78% sensitivity, 70% specificity in differentiating these groups. (figure 2) In sub-group analysis, FDsavg remained distinctly elevated in HFpEF (22.4±9.7% vs 16±4.9%, P=0.029). FDsavg of >16% showed 100% sensitivity and 70% specificity (P=0.01). Similarly, sFRR remained significantly higher in HFpEF (11.3±9.5% vs 6.6±6.4%, P=0.007). A sFRR of >7.2% showed 100% sensitivity and 60% specificity (P<0.001). (figure 3) DiscussionThis study is one of the first to show a rise in sFRR and FDsavg in both ageing and HFpEF with distinct differences between the two groups even when matched for age and gender. CMR-derived FDsavg and sFRR can assist in early detection and sub phenotyping of HFpEF. Our recent work2 demonstrated that these aortic flow abnormalities, particularly, FDsavg, can led to reduced exercise capacity and identify high risk individuals. Abstract 31 Table 1Aortic flow indices trend across the three groups Young HCs (10) Old HCs (10) HFpEF (23) P Aortic flow parameters AO Forward Flow, ml 97±35 70±18* 70±19 0.02 AO Forward Flow indexed, ml/m2 48±14 38±15* 36±10 0.01 AO Backward Flow, ml 2±1 1±4 2±3 0.86 AO Backward Flow indexed, ml 1±1 1±2 1±1 0.93 AO Max Area, mm2 7±2 9±3 10±5 0.01 AO Min Area, mm2 5±1 7±2* 8±4 <0.001 Flow Displacement systolic average,% 8±4 16±5* 23±10# <0.001 Rotational Angle, ° 0±0 -3±16 16±48# 0.04 Systolic Forward Flow, ml 90±37 66±18 77±27 0.15 Systolic Retrograde Flow, ml 2±1 4±4* 7±6# <0.001 Systolic Flow Reversal Ratio,% 2±2 7±6* 11±10# <0.001 Pulse Wave Velocity, m/s 4±2 11±8* 8±3 0.03 Data were represented as median ± IQR (%). AO aorta, HCs healthy cohorts, HFpEF heart failure with preserved ejection fraction. *P<0.05 compared young HCs versus old HCs; #P<0.05 compared old HCs versus HFpEF.Abstract 31 Figure 1Circular bar plot illustrating a linear correlation of age with left ventricular and aortic flow parameters via the multiple regression method using all other CMR variables as covariates - highlighting the correlation with FDsavg and AOminAbstract 31 Figure 2A – Bar charts demonstrating flow displacement systolic average trends in young vs old healthy cohorts vs HFpEF patients. B – Bar charts demonstrating systolic flow reversal ratio trends in young and old healthy cohorts and HFpEF patientsAbstract 31 Figure 3A – Bar charts demonstrating average systolic flow displacement trends in age-gender-matched old healthy cohorts and HFpEF patients. B – Bar charts demonstrating systolic flow reversal ratio trends in age-gender-matched old healthy cohorts vs HFpEF patients. C and D – Receiver operating characteristic (ROC) with area under the curve demonstrating acceptable correlation in age-gender-matched old HCs vs patients with HFpEFConclusionAortic flow haemodynamics (FDsavg and sFRR) are significantly affected in ageing and HFpEF patients. Studies with larger and diverse cohort are required to draw definitive conclusions.AcknowledgementsReferencesShah M, et al. Environmental and genetic predictors of human cardiovascular ageing. Nature Communications 2023;14(1).Zhao X, et al. Aortic flow is associated with aging and exercise capacity. European Heart Journal Open 2023;3(4).

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. Significance Next-generation sequencing is identifying millions of novel gene variants, presenting challenges to researchers and clinicians. Variations in the genes ITGA2B and ITGB3 affect integrin αIIbβ3, leading to the bleeding disorder Glanzmann thrombasthenia. We analyzed novel missense variants on ∼32,000 alleles of ITGA2B and ITGB3 and found missense variants affecting ∼10% of the amino acids in each protein in ∼1.3% of the population. Almost all variants are rare, indicating recent entry into the population. Two novel variants we predicted would be deleterious profoundly affected recombinant protein expression. At cut-off values that correctly predicted at least 69% of the known Glanzmann thrombasthenia mutations as deleterious, three variant prediction algorithms predicted that at least 27% of the novel variants are deleterious.

Abstract Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.