Baker IDI Heart and Diabetes Institute

Background: The one-year SINEMA trial demonstrated improved blood pressure (BP) control and reduced mortality up to 72 months after the intervention. This article aims to assess between-arm differences in mean annual cumulative BP and to explore whether the associations between cumulative BP and biofunctional outcomes differed by trial arm. Methods: Post-hoc secondary analysis of the SINEMA cluster-randomized trial, which recruited 1299 adults with stroke from 50 rural villages in Hebei, China, between 2017 and 2018. The 12-month intervention was followed by observational assessments at 72 and 84 months post-baseline. BP was measured during each face-to-face follow-up, assessed by blinded assessors at baseline, 12, 72, and 84 months. Mean annual cumulative systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) were calculated. Biofunctional outcomes included health-related quality of life, modified Rankin Scale, activities of daily living, physical function, and cognition function. Results: Among 897 participants (mean age 62.7 years; 40.8% female) with complete data across all assessment, the intervention arm demonstrated significantly lower mean annual cumulative SBP (?2.2 mm Hg; 95% CI, ?3.9 to ?0.6), DBP (?1.6 mm Hg; 95% CI, ?2.4 to ?0.7), and MAP (?1.8 mm Hg; 95% CI, ?2.8 to ?0.8), not PP, compared with usual care. Significant associations between cumulative BP and biofunctional outcomes were observed in the control arm while not in the intervention arm. Interaction effects between trial arm and cumulative BP were significant for multiple outcomes, most prominently for cumulative SBP. Conclusions: The one-year SINEMA intervention was associated with lower cumulative BP burden over 72-84 months but did not improve overall biofunctional outcomes. Secondary analyses revealed that the association between cumulative BP burden and biofunctional decline differed by intervention arm, suggesting cumulative BP exposure may be an important long-term risk indicator and the intervention may modify BP-outcome relationships through mechanisms requiring further investigation.

Abstract Preclinical models have been instrumental in defining the immunological mechanisms underlying hypertension, yet human studies remain comparatively limited, leaving a major gap in translational understanding. To address this, we investigated immune cell dynamics in human hypertension by profiling peripheral blood mononuclear cells from 48 normotensive and hypertensive participants, characterised using ambulatory blood pressure (BP) monitoring. High□dimensional spectral flow cytometry revealed strong positive correlations between night□time systolic BP and multiple CD8□T□cell subsets. Hypertensive participants also exhibited significantly elevated CD8□T cell subsets, a pattern that persisted even among those receiving anti□hypertensive medication with subsequently controlled BP. These findings suggest that BP control does not necessarily equate to biological control of hypertension and highlight a distinct CD8□T cell–driven signature that differentiates individuals with normal BP and hypertension.

Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer’s disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer’s disease.

We know that ischaemic cardiomyopathy leads to compensatory changes in the cardiovascular system to offset the reduction in cardiac output; there is a marked increase in cardiac sympathetic drive, as measured by noradrenaline spillover, and a marked increase in sympathetic vasoconstrictor drive to the skeletal muscle vascular bed, as measured by recording muscle sympathetic nerve activity from a peripheral nerve. Conversely based on assessment of heart rate variability there is believed to be a decrease in cardiac parasympathetic drive. Accordingly we might expect a decrease in ongoing neural activity in the vagus nerve. To test this we performed microelectrode recordings from the right vagus nerve in 14 patients with ischaemic cardiomyopathy and left ventricular ejection fractions ranging from 30%-48%. Multiple intrafascicular sites were analysed in each participant, with 57 multiunit sites being identified in which ongoing neural activity exhibited cardiac rhythmicity. Construction of cross-correlation histograms between the neural activity and the ECG demonstrated that there was no reduction in cardiac-modulated neural activity when compared to a group of healthy controls. Rather the magnitude of cardiac modulation of vagal activity was significantly elevated in ischaemic cardiomyopathy: 30.8%±13.7% (mean±SD) vs. 18.1%±18.0% (P<0.0001). Conversely there was no significant difference in the magnitude of respiratory modulation of vagal activity (48.0±24.6% vs. 40.7%±22.7%, P=0.1122). We conclude that ongoing cardiac-modulated activity in the right vagus nerve is elevated in ischaemic cardiomyopathy. Given that most of the vagus nerve is sensory we interpret this as reflecting an increase in afferent activity from the failing heart. KEY POINTS: Intraneural recordings from the cervical vagus were obtained in awake patients with ischaemic cardiomyopathy via tungsten microelectrodes inserted into the nerve through ultrasound guidance. Cross-correlation analysis of multiunit vagal activity revealed cardiac and respiratory modulation, from which the amplitude of modulation could be computed. We expected cardiac-locked vagal activity to be reduced, given the evidence for an overall reduction in heart rate variability in heart failure and the interpretation that this largely reflects an increase in cardiac sympathetic drive and a decrease in parasympathetic drive. However compared to data obtained in healthy participants the magnitude of cardiac modulation of vagal activity was significantly elevated in ischaemic cardiomyopathy (31% vs. 18%), but there was no significant difference in the magnitude of respiratory modulation of vagal activity (48% vs. 41%). We interpret this as reflecting an increase in afferent activity from the failing heart.

BackgroundLipid biology is profoundly disrupted in AD, as evidenced by abundant genetic studies highlighting the roles of lipid metabolism, endosomal/lysosomal trafficking, bioenergetics, and other cellular and molecular alterations. Despite these observations, there is currently no unified hypothesis to explain the etiology of AD that reconciles lipid disruption with neuronal loss.MethodUsing baseline measurements from ADNI plasma lipidomics and CSF proteomics, extensive reconciliation of the literature, and methods related to systems engineering and QSP, we built a model of brain homeostasis centered around feedback loops and mass balance. We then apply our model to several large multiomic datasets, including those in ADNI and GNPC for validation.ResultWe identified multiomic/proteomic evidence of two convergent feedback loops driving AD pathophysiology: 1) Saturated Microglial Flux Capacity: Microglia become overwhelmed by neuronal and myelin debris, leading to impaired processing. 2) Impaired ANLS Signaling: Elevated astrocyte membrane cholesterol disrupts ANLS, compromising neuronal metabolic support.ConclusionNeurodegeneration in AD is driven by the brain's failure to process excess cholesterol from neuronal debris, resulting in widespread lipidomic, metabolic, and proteomic disruptions. Disruptions in lipid homeostasis occur upstream of both amyloid and tau pathology, as excess cholesterol accumulation enhances APP translocation to γ‐secretase, accelerating amyloid production, while also impairing astrocytic metabolic support, leading to ATP deficits, elevated intracellular Ca²⁺, and aberrant tau phosphorylation. This breakdown in cholesterol homeostasis offers a comprehensive explanation for the observed multi‐omic alterations in AD, positioning lipid dysregulation as a primary driver of disease progression. Our unified hypothesis enables us to leverage large omics data to learn new biology, and identify and evaluate novel therapeutic targets for both the prevention and treatment of AD.

Some types of dietary fibre undergo fermentation by the gut microbiome, producing microbial metabolites called short-chain fatty acids (SCFAs) – these are protective against cardiovascular disease (CVD). Emerging evidence suggests that maternal fibre intake also protects the offspring. Here, we aimed to determine whether delivery of SCFAs during pregnancy results in sex- and cell-specific molecular changes to the offspring’s heart. Female mice were subjected to high or low-fibre diets during pregnancy and lactation, while all offspring received a standard-fibre diet. We then studied the single-cell transcriptome (scRNA-seq, n = 16) and immune composition (fluorescence-activated cell sorting, n = 27) of the hearts and gut microbiome profiles (16S rRNA, n = 28) of six-week-old male and female offspring. Maternal fibre intake induced significant changes in the cardiac cellular and immunological landscapes, revealing sex-specific signatures at the single-cell level. High-fibre intake reduced the number of monocytes in the hearts of male offspring and the number of B cells in both female and male offspring. Cardiac fibroblasts in both male and female offspring of high-fibre intake dams showed an anti-fibrotic transcriptome. In contrast, only male offspring showed an anti-inflammatory transcriptome in macrophages and endothelial cells. Our findings suggest that high-fibre intake during pregnancy may induce a CVD-protective transcriptome (i.e., anti-fibrotic and anti-inflammatory), especially in male offspring. These findings underscore the relevance of maternal dietary choices during pregnancy influencing cardiovascular health outcomes in the offspring.

We aimed to evaluate sensor accuracy and insulin delivery integrity of a novel device combining continuous glucose monitoring (CGM) with an insulin delivering cannula (CGM-IS) (Pacific Diabetes Technologies, Portland, Oregon, USA) during 7-day wear, in adults with type 1 diabetes (T1D). This single centre, single arm, non-randomised study involves 40 T1D adults who were using insulin pumps and CGM for 7 days, with three meal test days and four free living days. The main endpoints were sensor accuracy according to mean average relative difference (MARD) and infusion set function reflected by time in range (TIR), mean sensor glucose and total daily dose (TDD) of insulin. Sensor MARD was 16.4%, 14.8% and 17.7% on Days 1, 4 and 7, respectively. 60.0% of readings met the 15/15 criterion for blood glucose (BG) readings <70.2 mg/dL. Insulin delivery integrity was maintained to Day 3. At Days 5-6 TDD increased by 7.3 units/day (16%), mean BG increased by 16.2 mg/dL (10.2%), and TIR fell by -7.8% (11.2%). 92.1% of devices lasted >4 days. Mean wear time was 6.3 ± 1.4 days. The device was well tolerated. This human feasibility study supports the potential of CGM-IS use for up to 7 days with a mean survival of over 6 days. However, our data indicate that the durability of insulin delivery and sensor refinement are required prior to commercialisation.

Metabolic dysregulation is a hallmark of Alzheimer’s disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A significant limitation of these studies has been a predominant focus on non-Hispanic white participants. Despite evidence that AD prevalence, progression, and biomarkers differ across ethnoracial groups, it remains unclear whether previously identified metabolic dysregulation in AD brains generalizes across populations. We addressed this gap by analyzing large-scale metabolomics data from 547 postmortem dorsolateral prefrontal cortex brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort analyzed to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group. Sixty metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates, dipeptides, and sphingolipid-ceramide pathway lipids. These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.

Abstract Introduction Cancer survivors face an elevated risk of heart failure due to shared risk factors and cardiotoxic cancer treatments. While current guidelines recommend cardiac surveillance in this population, the optimal timing and intensity of monitoring remain poorly defined. Furthermore, the prevalence of subclinical cardiac dysfunction in asymptomatic cancer survivors are not well characterized, particularly in relation to time since cancer treatment. Purpose This study investigated the association between cancer history and cardiac function in asymptomatic individuals. Methods This cross-sectional study included participants with documented cancer history from cancer registries and matched with non-cancer controls using propensity scoring based on age, sex, diabetes and blood pressure. Cardiac function, primarily left ventricular ejection fraction (LVEF), was assessed using cardiac magnetic resonance (CMR). Results Of 23,854 cancer survivors (age 61.0±6.8 years, 60.9% female) and an equal number of matched controls, 1,051 survivors and 1,538 controls underwent CMR. Survivors from breast or haematological malignancies demonstrated minor differences in LVEF (59.5±6.4 vs 60.1±6.4, p&amp;lt;0.001) and global circumferential strain (-22.4±3.5 vs -22.6±3.5, p&amp;lt;0.001) compared to controls. Analysis stratified by time since cancer diagnosis revealed that both LVEF (p=0.014) and global circumferential strain (p=0.045) were less likely to be impaired with increasing time from diagnosis. More participants with a history of cancer (OR=1.29 [1.09-1.53], p=0.004), particularly breast cancer (OR=1.49 [1.22-1.81], p&amp;lt;0.001), were associated with low LVEF (&amp;lt;=55%) after adjusting for age, sex, years since cancer diagnoses and blood pressure medication. Conclusion This study identifies a critical window for cardiac surveillance in cancer survivors, with the highest risk of subclinical dysfunction occurring in the early post-treatment period. The findings support implementing targeted cardiac monitoring strategies, particularly for breast cancer survivors, with potential for reducing monitoring intensity over time in those without early dysfunction. These results can inform the development of more cost-effective, risk-stratified cardiac surveillance protocols in cancer survivorship care, potentially enabling earlier intervention in high-risk periods while avoiding unnecessary testing in long-term survivors with stable cardiac function.Flowchart of included participants Violin plot of participants' lvef