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People living with HIV are at higher risk of heart failure and associated left atrial remodeling compared to people without HIV. Mechanisms are unclear but have been linked to inflammation and premature aging. Here we obtain plasma proteomics concurrently with cardiac magnetic resonance imaging in two independent study populations to identify parallels between HIV-related and aging-related immune dysfunction that could contribute to atrial remodeling and clinical heart failure. We discover a plasma proteomic signature that may in part reflect or contribute to HIV-associated atrial remodeling, many features of which are associated with older age and time to incident heart failure among an independent community-based cohort without HIV. This proteomic profile was statistically enriched for immune checkpoint proteins, tumor necrosis factor signaling, ephrin signaling, and extracellular matrix organization, identifying possible shared pathways in HIV and aging that may contribute to risk of heart failure. Mechanisms underlying excess risk of heart failure among people with HIV are unclear. Here, the authors identify a proteomic signature enriched in immune activation and extracellular matrix remodeling that may reflect shared pathways in HIV and aging that contribute to risk of heart failure.

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice—elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using N ω -nitro- l -arginine methyl ester ( l -NAME)—recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S -nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α–XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF. iNOS-driven dysregulation of the IRE1α–XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction.

Over half of patients with heart failure have a preserved ejection fraction (>50%, called HFpEF), a syndrome with substantial morbidity/mortality and few effective therapies . Its dominant comorbidity is now obesity, which worsens disease and prognosis . Myocardial data from patients with morbid obesity and HFpEF show depressed myocyte calcium-stimulated tension and disrupted gene expression of mitochondrial and lipid metabolic pathways , abnormalities shared by human HF with a reduced EF but less so in HFpEF without severe obesity. The impact of severe obesity on human HFpEF myocardial ultrastructure remains unexplored. Here we assessed the myocardial ultrastructure in septal biopsies from patients with HFpEF using transmission electron microscopy. We observed sarcomere disruption and sarcolysis, mitochondrial swelling with cristae separation and dissolution and lipid droplet accumulation that was more prominent in the most obese patients with HFpEF and not dependent on comorbid diabetes. Myocardial proteomics revealed associated reduction in fatty acid uptake, processing and oxidation and mitochondrial respiration proteins, particularly in very obese patients with HFpEF.

Statins are widely used for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), and, under the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol treatment guidelines, more individuals are eligible for statin therapy. In this review, we summarize evidence for a mild increase in serum glucose and increased incidence of diabetes associated with statins, the hypothesized mechanisms by which statins may impair glucose homeostasis, the risk of diabetes associated with particular statins, and the net effect on ASCVD risk. As emphasized by the ACC/AHA guideline group and other experts, the risk-reducing benefits of statin therapy generally outweigh the mild rise in glucose levels or new diagnoses of diabetes. As such, an appropriate balancing of benefits and risks is critical in clinical practice as clinicians engage patients in shared decision making. Moreover, when discussing statins and risk of diabetes, this is a prime opportunity for clinicians to provide further counseling on the central importance of weight loss and adhering to a healthy lifestyle in glucose homeostasis and diabetes prevention.

ABSTRACT Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced obesity and CMS in ovariectomized female and male mice. PDE9-I reduces abdominal, hepatic, and myocardial fat accumulation, stimulates mitochondrial activity in brown and white fat, and improves CMS, without altering activity or food intake. PDE9 localizes to mitochondria, and its inhibition stimulates lipolysis and mitochondrial respiration coupled to PPARα-dependent gene regulation. PPARα upregulation is required for PDE9-I metabolic efficacy and is absent in non-ovariectomized females that also display no metabolic benefits from PDE9-I. The latter is compatible with estrogen receptor-α altering PPARα chromatin binding identified by ChIPSeq. In humans with heart failure and preserved ejection fraction, myocardial expression of PPARA and its regulated genes is reduced versus control. These findings support testing PDE9-I to treat obesity/CMS in men and postmenopausal women. Summary Oral inhibition of phosphodiesterase type 9 stimulates mitochondrial fat metabolism and lipolysis, reducing central obesity without changing appetite Competing Interest Statement Drs. Kass and Mishra are co-inventors on a pending PCT submitted by Johns Hopkins on PDE9 inhibitors for the treatment of cardiometabolic disorders and obesity.

Heart failure with preserved ejection fraction (HFpEF) continues to be poorly understood at the molecular level. While previous studies have identified gene expression signatures unique to HFpEF, genes associated with clinical decompensation have not been determined. Here, we performed exploratory analysis of myocardial RNA-seq data to identify genes associated with event-free survival in HFpEF. We analyzed previously published RNA sequencing data of right ventricular septal endomyocardial biopsies from HFpEF patients (n=41) with paired clinical, echocardiographic, and outcome data (including mortality and heart failure hospitalizations). We constructed random survival forests with forward stepwise regularization (the “variable hunting” method) to determine genes associated with time to first event using a combined end-point of heart failure hospitalization or all-cause death. Selection of candidate forest variables was tested with both random and weighted sampling methods. We identified 33 genes that are predictive of survival in HFpEF. This set includes genes previously implicated in heart failure, including ADAMTSL2, ADRB1, BMP6, and METRNL. Survival forests constructed using these genes outperform those constructed from clinical and hemodynamic parameters alone (out-of-bag C-index 0.894 vs 0.545). Moreover, in survival forests constructed from both gene data and hemodynamic measurements, individual survival genes consistently showed higher variable importance than clinical/hemodynamic parameters. Our study shows that random survival forests identify myocardial gene signatures that may better model HFpEF prognosis than clinical measurements. Further studies are warranted to validate findings in independent cohorts.

Significant variations have been observed in viral copies generated during SARS-CoV-2 infections. However, the factors that impact viral copies and infection dynamics are not fully understood, and may be inherently dependent upon different viral and host factors. Here, we conducted virus whole genome sequencing and measured viral copies using RT-qPCR from 9,902 SARS-CoV-2 infections over a 2-year period to examine the impact of virus genetic variation on changes in viral copies adjusted for host age and vaccination status. Using a genome-wide association study (GWAS) approach, we identified multiple single-nucleotide polymorphisms (SNPs) corresponding to amino acid changes in the SARS-CoV-2 genome associated with variations in viral copies. We further applied a marginal epistasis test to detect interactions among SNPs and identified multiple pairs of substitutions located in the spike gene that have non-linear effects on viral copies. We also analyzed the temporal patterns and found that SNPs associated with increased viral copies were predominantly observed in Delta and Omicron BA.2/BA.4/BA.5/XBB infections, whereas those associated with decreased viral copies were only observed in infections with Omicron BA.1 variants. Our work showcases how GWAS can be a useful tool for probing phenotypes related to SNPs in viral genomes that are worth further exploration. We argue that this approach can be used more broadly across pathogens to characterize emerging variants and monitor therapeutic interventions.

Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC ₅₀, 3–21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.

Cotton fiber is an important natural textile fiber due to its exceptional length and thickness. These properties arise largely through primary and secondary cell wall synthesis. The cotton fiber of commerce is a cellulosic secondary wall surrounded by a thin cuticulated primary wall, but there were only sparse details available about the polysaccharides in the fiber cell wall of any cotton species. In addition, Gossypium hirsutum (Gh) fiber was known to have an adhesive cotton fiber middle lamella (CFML) that joins adjacent fibers into tissue-like bundles, but it was unknown whether a CFML existed in other commercially important cotton fibers. We compared the cell wall chemistry over the time course of fiber development in Gh and Gossypium barbadense (Gb), the two most important commercial cotton species, when plants were grown in parallel in a highly controlled greenhouse. Under these growing conditions, the rate of early fiber elongation and the time of onset of secondary wall deposition were similar in fibers of the two species, but as expected the Gb fiber had a prolonged elongation period and developed higher quality compared to Gh fiber. The Gb fibers had a CFML, but it was not directly required for fiber elongation because Gb fiber continued to elongate rapidly after CFML hydrolysis. For both species, fiber at seven ages was extracted with four increasingly strong solvents, followed by analysis of cell wall matrix polysaccharide epitopes using antibody-based Glycome Profiling. Together with immunohistochemistry of fiber cross-sections, the data show that the CFML of Gb fiber contained lower levels of xyloglucan compared to Gh fiber. Xyloglucan endo-hydrolase activity was also higher in Gb fiber. In general, the data provide a rich picture of the similarities and differences in the cell wall structure of the two most important commercial cotton species.

Repeated exposure to cocaine increases dendritic spine density on nucleus accumbens (NAc) neurons. Here the authors show that the small GTPase Rac1 is necessary and sufficient for cocaine-induced behavior and spine changes in NAc neurons, adding support for a causal role for structural plasticity in cocaine-induced behavior. Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.