OsCYP706C2 diverts rice strigolactone biosynthesis to a noncanonical pathway branch.

Strigolactones exhibit dual functionality as regulators of plant architecture and signaling molecules in the rhizosphere. The important model crop rice exudes a blend of different strigolactones from its roots. Here, we identify the inaugural noncanonical strigolactone, 4-oxo-methyl carlactonoate (4-oxo-MeCLA), in rice root exudate. Comprehensive, cross-species coexpression analysis allowed us to identify a cytochrome P450, OsCYP706C2, and two methyl transferases as candidate enzymes for this noncanonical rice strigolactone biosynthetic pathway. Heterologous expression in yeast and Nicotiana benthamiana indeed demonstrated the role of these enzymes in the biosynthesis of 4-oxo-MeCLA, which, expectedly, is derived from carlactone as substrate. The oscyp706c2 mutants do not exhibit a tillering phenotype but do have delayed mycorrhizal colonization and altered root phenotype. This work sheds light onto the intricate complexity of strigolactone biosynthesis in rice and delineates its role in symbiosis and development.

Confirmation that Monochamol is a Male Produced Aggregation-Sex Pheromone for Monochamus maculosus Haldeman (Coleoptera: Cerambycidae).

The recognition of cerambycids as frequent and damaging invaders led to an increase in the interest in the chemical ecology of the group with the identification of pheromones and pheromone-like attractants for well over 100 species. Pheromone components of the Cerambycidae are often phylogenetically conserved, with a single compound serving as a pheromone component for several related species. In the subfamily Lamiinae, the compound 2-(undecyloxy)ethanol (monochamol) has been identified as an aggregation-sex pheromone for several species of the genus Monochamus. In other species, including Monochamus maculosus Haldeman, field trials have demonstrated that monochamol is a pheromone attractant, but at that point it was still unknown as to whether it was a pheromone for this species. Here we report the identification, and laboratory and field trials of a pheromone component produced by adult male M. maculosus. Chemical analyses of headspace volatile collections sampled from field collected beetles of both sexes revealed the presence of one male-specific compound that was identified as 2-(undecyloxy)ethanol. Electroantennography analyses showed that monochamol elicited responses from the antennae of female beetles. Traps baited with monochamol in the field captured M. maculosus adults of both sexes corroborating the identification of monochamol as the sex-aggregation pheromone of this species. The attractivity of monochamol to adult M. maculosus in our field trapping experiment was synergized by the addition of the host volatile α-pinene.

Navigating the Transition to Adulthood: Insights from Caregivers of Autistic Individuals.

With many teens having to transition from a mainly educational system of support to a set of health and social service systems (Shattuck et al. in Autism Res Treat https://doi.org/10.1155/2014/924182 , 2017), there is a critical need to advance research and support services in the area of autism and transition to aid autistic* individuals and their families. This study aims to learn more about the experiences of caregivers of autistic young adults, their experiences navigating the transition process post-graduation, and what realistic steps could be undertaken by high schools, vocational schools, colleges, Regional Centers, and places of employment to ease this transition. Ten semi-structured interviews were conducted with caregivers of autistic young adults over the age of 18 focused on their experiences helping their children navigate the transition to adulthood. Using an iterative and inductive coding approach, three overarching themes were uncovered with twelve subthemes. The three major themes recurring in caregiver interviews were their experiences with navigating service receipt, exploring the landscape of opportunities available for their children, and the parent experiences specific to their role in their child's transition into adulthood. Findings from this study provide a chance for stakeholders to learn from the lived experiences of caregivers navigating the frustration and confusion pertaining to transition for their autistic adult child due to the highly prohibitive access to service receipt, experiencing significant financial burdens, finding a niche for their children that fits their needs, desires, and talents, and managing their well-being.

Assessing variation in faecal glucocorticoid concentrations in gray whales exposed to anthropogenic stressors.

Understanding how individual animals respond to stressors behaviourally and physiologically is a critical step towards quantifying long-term population consequences and informing management efforts. Glucocorticoid (GC) metabolite accumulation in various matrices provides an integrated measure of adrenal activation in baleen whales and could thus be used to investigate physiological changes following exposure to stressors. In this study, we measured GC concentrations in faecal samples of Pacific Coast Feeding Group (PCFG) gray whales (Eschrichtius robustus) collected over seven consecutive years to assess the association between GC content and metrics of exposure to sound levels and vessel traffic at different temporal scales, while controlling for contextual variables such as sex, reproductive status, age, body condition, year, time of year and location. We develop a Bayesian Generalized Additive Modelling approach that accommodates the many complexities of these data, including non-linear variation in hormone concentrations, missing covariate values, repeated samples, sampling variability and some hormone concentrations below the limit of detection. Estimated relationships showed large variability, but emerging patterns indicate a strong context-dependency of physiological variation, depending on sex, body condition and proximity to a port. Our results highlight the need to control for baseline hormone variation related to context, which otherwise can obscure the functional relationship between faecal GCs and stressor exposure. Therefore, extensive data collection to determine sources of baseline variation in well-studied populations, such as PCFG gray whales, could shed light on cetacean stress physiology and be used to extend applicability to less-well-studied taxa. GC analyses may offer greatest utility when employed as part of a suite of markers that, in aggregate, provide a multivariate measure of physiological status, better informing estimates of individuals' health and ultimately the consequences of anthropogenic stressors on populations.

Can Pheromones Contribute to Phylogenetic Hypotheses? A Case Study of Chrysomelidae.

Pheromones mediate species-level communication in the search for mates, nesting, and feeding sites. Although the role of pheromones has long been discussed by various authors, their existence was not proven until the mid-twentieth century when the first sex pheromone was identified. From this finding, much has been speculated about whether this communication mechanism has acted as a regulatory agent in the process of speciation, competition, and sexual selection since it acts as an intraspecific barrier. Chrysomelidae is one of the major Phytophaga lineages, with approximately 40,000 species. Due to this immense diversity the internal relationships remain unstable when analyzed only with morphological data, consequently recent efforts have been directed to molecular analyses to establish clarity for the relationships and found their respective monophyly. Therefore, our goals are twofold 1) to synthesize the current literature on Chrysomelidae sex pheromones and 2) to test whether Chrysomelidae sex pheromones and their chemical structures could be used in phylogenetic analysis for the group. The results show that, although this is the first analysis in Chrysomelidae to use pheromones as a phylogenetic character, much can be observed in agreement with previous analyses, thus confirming that pheromones, when known in their entirety within lineages, can be used as characters in phylogenetic analyses, bringing elucidation to the relationships and evolution of organisms.

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.

The variable influence of anthropogenic noise on summer season coastal underwater soundscapes near a port and marine reserve.

Monitoring soundscapes is essential for assessing environmental conditions for soniferous species, yet little is known about sound levels and contributors in Oregon coastal regions. From 2017 to 2021, during June-September, two hydrophones were deployed near Newport, Oregon to sample 10-13,000 Hz underwater sound. One hydrophone was deployed near the Port of Newport in a high vessel activity area, and another 17 km north within a protected Marine Reserve. Vessel noise and whale vocalizations were detected at both sites, but whales were recorded on more days at the Marine Reserve. Median sound levels in frequencies related to noise from various vessel types and sizes (50 - 4,000 Hz) were up to 6 dB higher at the Port of Newport, with greater diel variability compared to the Marine Reserve. In addition to documenting summer season conditions in Oregon waters, these results exemplify how underwater soundscapes can differ over short distances depending on anthropogenic activity.

Effect of a probiotic fermented milk supplementation on behavior and sleep.

This study attempted to analyze the effect of supplementing Wistar-Kyoto rats with fermented milk containing the probiotic Bifidobacterium animalis BB-12 and pomegranate juice on the microbiota-gut-brain axis of rats, with special focus on their behavior, sleep patterns, and response to stress. This study was divided into two experiments: (1) For the behavioral analysis the animals were divided into two groups: Fermented probiotic milk (BB + 1) and control (BB-). (2) For the sleep analysis the animals were divided into two groups: Fermented probiotic milk (BB + 2) and control (H2O). For the behavioral analysis, the open field method was used, which evaluates the behavior after ten, twenty, and thirty days of supplementation. For sleep analysis, the animals were submitted to implantation of electrodes and 24 h polysomnography, followed by 48 h sleep deprivation (REM) and 48 h polysomnography, then euthanized 100 days after the beginning of the experiment. In addition, animal feces were collected before and after sleep deprivation to assess its effects on the microbiota. A decrease in anxiety-related behaviors was observed in the supplemented animals and an increase in sleep efficiency and a reduction in the number of awakenings of the animals before deprivation. It has also been observed that sleep deprivation decreased the amount of total bacterial DNA. The number of copies of genomes of the genus Bifidobacterium did not differ in both groups.

Patient Experience of Systemic Sclerosis-Related Calcinosis: An International Study Informing Clinical Trials, Practice, and the Development of the Mawdsley Calcinosis Questionnaire.

Systemic sclerosis (SSc) -related calcinosis can be a debilitating, constantly painful, poorly understood vascular complication of calcium hydroxyapatite deposition in soft tissue structures that affects approximately 40% of both limited and diffuse cutaneous SSc subtypes. This publication describes the iterative and multitiered international qualitative investigations that yielded remarkable insights into natural history, daily experience, and complications of SSc-calcinosis providing pivotal information for health management. Patient-driven question development and field testing, according to Food and Drug Administration guidance, propelled the development of a patient-reported outcome measure for SSc-calcinosis, the Mawdsley Calcinosis Questionnaire.

Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension.

Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families. Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis. Results: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH. Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.

Clinical Characteristics of Patients Undergoing Right Heart Catheterizations in Community Hospitals.

Background Recognition of precapillary pulmonary hypertension (PH) has significant implications for patient management. However, the low a priori chance to find this rare condition in community hospitals may create a barrier against performing a right heart catheterization (RHC). This could result in misclassification of PH and delayed diagnosis/treatment of precapillary PH. Therefore, we investigated patient characteristics and echocardiographic parameters associated with the decision whether to perform an RHC in patients with incident PH in 12 Dutch community hospitals. Methods and Results In total, 275 patients were included from the OPTICS (Optimizing PH Diagnostic Network in Community Hospitals) registry, a prospective cohort study with patients with incident PH; 157 patients were diagnosed with RHC (34 chronic thromboembolic PH, 38 pulmonary arterial hypertension, 81 postcapillary PH, 4 miscellaneous PH), while 118 patients were labeled as probable postcapillary PH without hemodynamic confirmation. Multivariable analysis showed that older age (>60 years), left ventricular diastolic dysfunction grade 2-3, left atrial dilatation were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilatation, and tricuspid regurgitation velocity ≥3.7 m/s favor an RHC performance. Conclusions Older age and echocardiographic parameters of left heart disease were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilation, and severe PH on echocardiography favored an RHC performance. As such, especially elderly patients may be at an increased risk of diagnostic delays and missed diagnoses of treatable precapillary PH, which could lead to a worse prognosis.

Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4.

Targeted protein degradation (TPD) strategies exploit bivalent small molecules to bridge substrate proteins to an E3 ubiquitin ligase to induce substrate degradation. Few E3s have been explored as degradation effectors due to a dearth of E3-binding small molecules. We show that genetically induced recruitment to the GID4 subunit of the CTLH E3 complex induces protein degradation. An NMR-based fragment screen followed by structure-guided analog elaboration identified two binders of GID4, 16 and 67, with Kd values of 110 and 17 µM in vitro. A parallel DNA-encoded library (DEL) screen identified five binders of GID4, the best of which, 88, had a Kd of 5.6 µM in vitro and an EC50 of 558 nM in cells with strong selectivity for GID4. X-ray co-structure determination revealed the basis for GID4-small molecule interactions. These results position GID4-CTLH as an E3 for TPD and provide candidate scaffolds for high-affinity moieties that bind GID4.

First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

Data on Cu- and Ni-Si-Mn-rich solute clustering in a neutron irradiated austenitic stainless steel.

The data presented in this article is supplementary to the research article "Phase instabilities in austenitic steels during particle bombardment at high and low dose rates" (Levine et al.) [5]. Needle-shaped samples were prepared with focused ion beam milling from a 304L stainless steel that was irradiated with fast neutrons (E > 0.1 MeV) in the BOR-60 reactor at 318 °C to 47.5 dpa. Atom probe tomography (APT) experiments in voltage mode were then conducted on a Cameca LEAP 5000X HR. Atom position, range, and mass spectrum files after reconstruction with Cameca's IVAS software are included. Cu- and Ni-Si-Mn-rich solute nanoclusters were identified and analyzed using the Open Source Characterization of APT Reconstructions (OSCAR) program. Python code for OSCAR [4], information on the program's underlying algorithm, and sample output files are provided. A proximity histogram of a Ni-Si-Mn-rich cluster and a 1D density/solute concentration profile of a Cu-rich cluster are given to demonstrate OSCAR's analytical functionalities. The provided APT dataset is valuable for benchmarking phase instabilities in neutron-irradiated austenitic stainless steels that occur at high doses. The OSCAR program can be reused to process other APT data sets where solute nanoclustering is of interest.

A Bioinformatics Tool for Efficient Retrieval of High-Confidence Terpene Synthases (TPS) and Application to the Identification of TPS in Coffea and Quillaja.

Terpenoids are a class of compounds that are found in all living organisms. In plants, some terpenoids are part of primary metabolism, but most terpenes found in plants are classified as specialized metabolites, encoded by terpene synthases (TPS). It is not obvious how to assign the putative product of a given TPS using bioinformatics tools. Phylogenetic analyses easily assign TPS into families; however members of the same TPS family can synthetize more than one terpenoid-and, in many biotechnological applications, researchers are more interested in the product of a given TPS rather than its phylogenetic profile. Automated protein annotation can be used to classify TPS based on their products, despite the family they belong to. Here, we implement an automated bioinformatics method, search_TPS, to identify TPS proteins that synthesize mono, sesqui and diterpenes in Angiosperms. We verified the applicability of the method by classifying wet lab validated TPS and applying it to find TPS proteins in Coffea arabica, C. canephora, C. eugenioides, and Quillaja saponaria. Search_TPS is a computational tool based on PERL scripts that carries out a series of HMMER searches against a curated database of TPS profile hidden Markov models. The tool is freely available at https://github.com/liliane-sntn/TPS .

Distinct Platelet Ribonucleic Acid Signatures in Patients with Pulmonary Hypertension.

Rationale: Pulmonary hypertension encompasses progressive disorders leading to right ventricular dysfunction and early death. Late detection is an important cause of poor clinical outcomes. However, biomarkers that accurately predict the presence of pulmonary hypertension are currently lacking. Objectives: In this study, we provide evidence that blood platelets contain a distinctive ribonucleic acid (RNA) profile that may be exploited for the detection of pulmonary hypertension. Methods: Blood platelet RNA was isolated prospectively from 177 prevalent patients with different subtypes of pulmonary hypertension as well as 195 control subjects clinically not suspected of pulmonary hypertension. Sequencing libraries were created using SMARTer (Switching Mechanism at 5' end of RNA Template) copy desoxyribonucleic acid amplification and sequenced on the Illumina High Throughput Sequencing platform. RNA-sequencing reads were mapped to the human reference genome, and intron-spanning spliced RNA reads were selected. Differential spliced RNA panels were calculated by analysis of variance statistics. A particle swarm optimization-enhanced classification algorithm was built employing a development (n = 213 samples) and independent validation series (n = 159 samples). Results: We detected a total of 4,014 different RNAs in blood platelets from patients with pulmonary hypertension (n = 177) and asymptomatic control subjects (n = 195). Gene ontology analysis revealed enhanced RNA concentrations for genes related to RNA processing, translation, and mitochondrial function. A particle swarm optimization-selected RNA panel of 408 distinctive differentially spliced RNAs mediated detection of pulmonary hypertension with 93% sensitivity, 62% specificity, 77% accuracy, 0.89 (95% confidence interval, 0.83-0.93) area under the curve, and a negative predictive value of 91% in the independent validation series. The prediction score was independent of age, sex, smoking, pulmonary hypertension subtype, and the use of pulmonary hypertension-specific medication or anticoagulants. Conclusions: A platelet RNA panel may accurately discriminate patients with pulmonary hypertension from asymptomatic control subjects. In the light of current diagnostic delays, this study is the starting point for further development and evaluation of a platelet RNA-based blood test to ultimately improve early diagnosis and clinical outcomes in patients with pulmonary hypertension.

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.

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia.

Allelic variations affecting the activity of the maternal renin-angiotensin system may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form, and intrauterine growth restriction. We examined the association of common allelic variants of angiotensin II type 1 and type 2 receptor genes (AT1R and AT2R) sorted in five AT1R/AT2R receptor combination genotype groups with susceptibility to early-onset preeclampsia (EOP). The occurrence of AT1R (A1166C) and A2TR (C3123A) alleles in wild type (AA, CC), heterozygous (A/C, C/A), and homozygous (C/C, A/A) states was recorded in 84 women with a history of EOP and 84 age-matched controls sorted in five AT1R/AT2R receptor combination genotype (wild type: AA/CC, one mutant: AA/CA, AC/CC, two mutant: AC/CA, AA/AA, CC/CC, three mutants: AC/AA, CC/CA and four mutant: CC/AA) groups, by polymerase chain reaction-RFLP analysis. Three mutant receptor combination genotype carriers were more common in women with a history of EOP than in controls (26.18% vs. 4.76%, p = 0.003, OR = 8.25). Receptor combination genotyping may be of clinical value in: (a) maternal prediction of susceptibility to EOP, (b) disease subtyping for directed studies with receptor signaling antagonists, (c) the broader study of hypertension.

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.