The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies.

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous condition that accounts for more than half of all HF cases. It is a major cause of morbidity and mortality worldwide; however, preclinical models often do not capture the heterogeneity and sex-specific and cardiometabolic features observed in patients. We hypothesised that biological sex and the degree of nitric oxide synthase (NOS) inhibition would influence development of HFpEF-like versus HFrEF-like phenotypes. Methods and Results: Male and female C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; male and female) NOS inhibition using N(ω)-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving low-dose L-NAME+HFD developed a HFpEF-like phenotype characterised by impaired diastolic function, exercise intolerance and preserved systolic function. Increasing NOS inhibition did not worsen diastolic dysfunction but induced inflammatory and stress-associated transcriptional pathways in female hearts. In contrast, male mice administered high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and impaired systolic function, consistent with a HFrEF-like phenotype. Despite different cardiac phenotypes, circulating lipidomic profiling revealed broadly conserved sphingolipid and phospholipid remodelling, with sex-specific regulation of phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses identified shared regulation of extracellular matrix, calcium-handling and metabolic pathways, whereas greater NOS inhibition was associated with transcriptional signatures related to inflammatory signalling, cellular stress responses and mitochondrial homeostasis. Conclusions: Cardiometabolic stress does not produce a uniform HF phenotype. Instead, biological sex and the degree of NOS inhibition direct distinct functional and molecular remodelling trajectories, identifying HFpEF-like dysfunction as one of several potential cardiac responses to cardiometabolic injury in male and female mice.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases and is a major cause of morbidity and mortality worldwide. However, existing preclinical models often do not capture the heterogeneity, sex-specific and cardiometabolic features that characterise the clinical syndrome. Our goal was to develop an model of HFpEF in mature female mice. Methods and Results: Female and male C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; female and male) nitric oxide synthase (NOS) inhibition using N(ω)-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving 0.3 g/L L-NAME+HFD developed an HFpEF-like phenotype with glucose intolerance, reduced exercise capacity and impaired ventricular filling, including reduced E-wave velocity, E/A ratio and E-wave deceleration rate; ejection fraction (EF) and global longitudinal strain (GLS) remained unchanged versus female controls. Increasing NOS inhibition did not enhance the HFpEF-like phenotype but was associated with a transcriptional profile enriched for inflammatory, cellular-stress and mitochondrial homeostasis pathways. In contrast, male mice receiving 0.5 g/L L-NAME+HFD developed hypertension, elevated ventricular pressures and systolic dysfunction. Circulating lipidomic profiling demonstrated conserved sphingolipid and phospholipid remodelling across treatment groups despite different cardiac phenotypes. Conclusions: Combining HFD-induced metabolic stress with modest NOS inhibition established an early HFpEF-like phenotype in mature female mice characterised by glucose intolerance, reduced exercise capacity and impaired ventricular filling. This model may serve as a platform for evaluating therapeutic interventions for HFpEF before advanced fibrosis develops.