Shengmai Powder is a classic Traditional Chinese Medicine formula that has been used for centuries to manage cardiovascular diseases characterized by "Qi-Yin deficiency with blood stasis." Optimized New Shengmai Powder (ONSMP), a modern refinement of this formula, has shown clinical efficacy in improving cardiac function in patients with ischemic heart failure. Although our previous studies have demonstrated pronounced cardioprotective effects of ONSMP in preclinical models, the underlying molecular mechanisms-particularly those regulating cardiomyocyte death-remain incompletely understood at the cellular level. Clarifying these mechanisms is essential to bridge traditional therapeutic practice with contemporary scientific validation and to substantiate the clinical utility of ONSMP with modern mechanistic evidence.

This study elucidates the molecular mechanisms by which ONSMP inhibits ferroptosis in cardiomyocytes.

LC-MS/MS was used to identify active constituents absorbed into the systemic circulation following ONSMP administration in a rat model of ischemic heart failure. A network pharmacology approach was then applied to predict potential therapeutic targets and signaling pathways through which ONSMP may treat ischemic heart failure and inhibit cardiomyocyte ferroptosis, followed by molecular docking and molecular dynamics simulations to evaluate the binding stability between representative compounds and core targets. An oxygen-glucose deprivation (OGD) injury model was established in H9C2 cardiomyocytes to mimic the pathological microenvironment of ischemic heart failure, and cells were treated with ONSMP-containing serum in the presence or absence of core-target inhibitors. Cell viability, iron homeostasis, lipid peroxidation, mitochondrial morphology and function, and the expression of ferroptosis-related genes and proteins were assessed. Finally, the functional contributions of key active constituents to the amelioration of ischemic myocardial injury were further validated.

A total of 44 absorbed constituents of ONSMP were detected in rat serum. Network pharmacology analysis indicated that ONSMP targets were significantly enriched in pathways related to oxidative stress responses and lipid peroxidation, with the cGMP-PKG signaling pathway emerging as a central hub. Molecular simulations confirmed stable interactions among AKT1, eNOS, PKG1, STAT3, and GPX4. In OGD-injured H9C2 cardiomyocytes, ONSMP-containing serum significantly improved cell viability, reduced intracellular iron accumulation and malondialdehyde levels, preserved mitochondrial integrity, and upregulated GPX4 expression. These effects were associated with activation of the AKT1/cGMP-PKG axis and were partially abrogated by AKT1 inhibition. Baicalin and Kaempferide were identified as representative bioactive constituents that may contribute to these anti-ferroptotic effects.

ONSMP exerts cardioprotective effects through multiple constituents acting on multiple targets. These effects are mediated, at least in part, by modulation of the cGMP-PKG signaling pathway, which enhances antioxidant defenses and suppresses ferroptosis in cardiomyocytes. Active constituents such as Baicalin and Kaempferide together provide a modern biological basis for the traditional therapeutic efficacy of ONSMP in ischemic heart failure.

We investigated the associations of genetic risk score for Alzheimer's disease (GRS-AD) with cardiometabolic risk from early childhood over a 20-year follow-up.

The STRIP study included 1062 children at baseline. GRS-AD was calculated for 631 participants using 22 independent genetic risk variants, including APOE ε2 and ε4 alleles, and excluding them (non-APOE-GRS-AD). We repeatedly measured waist circumference, high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, triglycerides, glucose, insulin, and blood pressure. The data were analysed with generalised additive mixed models.

GRS-AD was directly associated with serum LDL-C (unstandardised β = 0.140, 95% CI = 0.084 to 0.195) and inversely with HDL-C (β = -0.026, 95% CI = -0.044 to -0.009). GRS-AD was inversely associated with serum HDL-C in males (β = -0.044, 95% CI = -0.070 to -0.018) but not in females (β = -0.010, 95% CI = -0.032 to 0.012). The associations were diluted when the non-APOE-GRS-AD was applied.

A genetic predisposition to AD may alter lipid metabolism from early childhood.

While Alzheimer's disease and cardiometabolic diseases may have shared genetic determinants, the associations between genetic susceptibility for Alzheimer's disease and increased cardiometabolic risk from childhood to young adulthood are poorly understood. We investigated the associations of genetic risk score for Alzheimer's disease with cardiometabolic risk from early childhood over a 20-year follow-up. We found that a higher genetic risk score for Alzheimer's disease was associated with higher LDL cholesterol, non-HDL cholesterol, and ApoB, and with lower serum HDL cholesterol and ApoA1. These findings suggest that a genetic predisposition to Alzheimer's disease may alter lipid metabolism from early childhood.

Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), and ultimately promoted ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM. A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes ferroptosis. Created with Figdraw.com.

Pulmonary Arterial Hypertension (PAH) is a rare, progressive disorder characterized by pathological vascular remodeling of the pulmonary arteries, ultimately leading to right heart failure. Early diagnosis remains challenging, as clinical manifestations are often nonspecific, and definitive confirmation still requires invasive right heart catheterization. Circulating microRNAs (miRNAs) have emerged as promising biomarkers for cardiovascular diseases due to their plasma stability and direct involvement in disease pathophysiology. We performed small RNA sequencing on plasma samples from 25 IPAH patients and 10 healthy controls to identify differentially expressed miRNAs. Seven candidate miRNAs were selected for further validation by quantitative PCR in a multicenter cohort of 110 IPAH patients and controls. Logistic regression models were built to evaluate diagnostic performance. Functional studies for miR-3168 were performed using western blot and flow cytometry in Pulmonary Artery Endothelial Cells (PAECs), and tube formation assay in human umbilical vein endothelial cells (HUVECs). Our initial screen identified 29 differentially expressed miRNAs. Seven of these candidates, including members of the let-7 family and miR-3168, were successfully validated in the larger cohort. A diagnostic panel incorporating three miRNAs (let-7a-5p, miR-9-5p, and miR-31-5p) was developed, which achieved an area under the curve (AUC) of 0.862 (95% CI = 0.7481-1) for discriminating PAH patients from controls. Separately, we investigated the functional role of miR-3168, which was upregulated in PAH patients. In PAECs, overexpression of miR-3168 led to a reduction of BMPR2 protein levels. Moreover, miR-3168 overexpression impaired tube formation in HUVECs. Our study identifies a plasma-derived three-miRNA signature with strong potential for the non-invasive diagnosis of PAH. Furthermore, we implicate miR-3168 as a potential contributor to endothelial dysfunction through its regulation of BMPR2 and its anti-angiogenic effects in vitro. These findings reinforce the dual utility of circulating miRNAs as both clinically relevant non-invasive biomarkers and as tools to discover novel disease biology.

Cardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD.

The impact of obstructive sleep apnea (OSA) on subsequent cardiovascular events in patients with acute coronary syndrome (ACS) remains debated. This study aims to investigate whether the association of OSA with cardiovascular events is affected by lipoprotein (a) [Lp(a)] levels.

This is a sub-analysis of prospective cohort study (OSA-ACS, NCT03362385) enrolled ACS patients. OSA defined as an apnea-hypopnea index ≥15 events/h. The effects of OSA on subsequent cardiovascular outcomes were evaluated across varying Lp(a) thresholds. Coronary plaque features by coronary computed tomography angiography were also analyzed.

A total of 1137 patients were enrolled, 608 patients (53.5%) were diagnosed with OSA. At a median follow-up of 3.6 years, OSA was associated with a higher risk of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with Lp(a) level > median (HR 1.59, 95% CI 1.12-2.26, p=.009), but not in patients with Lp(a) level ≤ median (HR 1.09, 95% CI 0.80-1.49, p=.60). There were consistent increases in HRs for MACCE in the OSA group with Lp(a) levels rising, as stratified by tertiles or quartiles of Lp(a). In patients with Lp(a) level > median, OSA demonstrated a higher prevalence of ≥1 high-risk plaque (HRP) feature (51.4% vs. 33.3%, p=.03) and low-attenuation plaque (50.0% vs. 32.8, p=.04) per vessel than non-OSA.

OSA was associated with a continuously increased cardiovascular risk and a higher prevalence of HRP features as Lp(a) levels rose. Lp(a) may help identify ACS patients at higher cardiovascular risk, in whom the efficacy of OSA treatment should be further investigated.

Older patients hospitalized for cardiovascular disease (CVD) are at risk of physical function decline and adverse health outcomes. Cardiac rehabilitation (CR) improves physical functioning but is underutilized by older patients. Home-based CR potentially improves utilization, yet its effectiveness in older patients who are frail remains understudied.

The objective of this study was to investigate the effects of a transitional-care integrated home-based CR program on physical functioning in older patients who are frail after CVD hospitalization.

This was a prespecified secondary analysis of physical functioning at the 6-month follow-up in the Cardiac Care Bridge multicenter randomized trial.

A home-based setting was used.

The study participants were patients who were frail and ≥ 70 years old after CVD hospitalization.

The intervention was transitional care followed by physical therapist led home-based CR and community nurse visits.

The primary physical function outcome was the Short Physical Performance Battery (SPPB) in cases with complete follow-up data. Secondary outcomes included the 2-minute step test, grip strength, and Amsterdam Linear Disability Scale. Sensitivity analyses included an intention-to-treat analysis by multiple imputation of the full cohort.

In total, 85 of 153 participants in the intervention group and 85 of 153 participants in the control group were analyzed (mean age = 82.6 [SD = 6.3] years; 46% men; median of 2 [interquartile range = 1-4] comorbidities). At the 6-month follow-up, more participants in the intervention group than in the control group demonstrated SPPB improvement (61% vs 51%) or maintenance (29% vs 12%), and fewer deteriorated (11% vs 37%). The mean SPPB values at 6 months were 6.3 (SD = 0.3) and 5.5 (SD = 0.2), respectively, with a mean difference of 0.8 (95% CI = 0.0 to 1.6), favoring the intervention group. No between-group differences were observed in the 2-minute step test, grip strength, or Amsterdam Linear Disability Scale.

Among older patients who were frail and had CVD, a comprehensive transitional-care program with integrated home-based CR resulted in clinically relevant improvements in physical functioning.

The results substantiate the effectiveness of home-based CR in older patients who are frail and have CVD.