Inhalable cardiac targeting peptide modified nanomedicine prevents pressure overload heart failure in male mice.

Heart failure causes considerable morbidity and mortality worldwide. Clinically applied drugs for the treatment of heart failure are still severely limited by poor delivery efficiency to the heart and off-target consumption. Inspired by the high heart delivery efficiency of inhaled drugs, we present an inhalable cardiac-targeting peptide (CTP)-modified calcium phosphate (CaP) nanoparticle for the delivery of TP-10, a selective inhibitor of PDE10A. The CTP modification significantly promotes cardiomyocyte and fibroblast targeting during the pathological state of heart failure in male mice. TP-10 is subsequently released from TP-10@CaP-CTP and effectively attenuates cardiac remodelling and improved cardiac function. In view of these results, a low dosage (2.5 mg/kg/2 days) of inhaled medication exerted good therapeutic effects without causing severe lung injury after long-term treatment. In addition, the mechanism underlying the amelioration of heart failure is investigated, and the results reveal that the therapeutic effects of this system on cardiomyocytes and cardiac fibroblasts are mainly mediated through the cAMP/AMPK and cGMP/PKG signalling pathways. By demonstrating the targeting capacity of CTP and verifying the biosafety of inhalable CaP nanoparticles in the lung, this work provides a perspective for exploring myocardium-targeted therapy and presents a promising clinical strategy for the long-term management of heart failure.

Three-dimensional echocardiography reveals early mitral valve alterations in hypertrophic cardiomyopathy genetic mutation carriers.

BACKGROUND: The mitral valve undergoes structural modifications in response to cardiac functional changes, often predating cardiac decompensation and overt clinical signs. Our study assessed the potential of mitral valve morphological changes as early indicators for detecting carriers of hypertrophic cardiomyopathy (HCM)-associated gene mutations. METHODS: We studied 505 participants: 189 without the pathogenic gene mutations and left ventricular hypertrophy (G-/LVH-), 149 carriers without LV hypertrophy (G+/LVH-), and 167 manifest HCM patients (G+/LVH+). We juxtaposed the mitral valve morphology and associated metrics across these groups, emphasizing those carrying MYH7 and MYBPC3 mutations. RESULTS: We discerned pronounced disparities in the mitral annulus and leaflet structures across the groups. The mitral valve apparatus in mutation carriers exhibited a tendency towards a flattened profile. Detailed analysis spotlighted MYBPC3 mutation carriers, whose mitral valves were notably flatter (with notably lower AHCWR values than non-carriers); this contrast was not evident in MYH7 mutation carriers. This mitral valve flattening, manifest in the mutation carriers, suggests it might be an adaptive response to incipient cardiac dysfunction in HCM's nascent stages. CONCLUSIONS: Three-dimensional echocardiography illuminates the initial mitral valve structural changes in HCM patients bearing pathogenic gene mutations. These morphological signatures hold promise as sensitive imaging markers, especially for asymptomatic carriers of the MYBPC3 mutation.

Effect of left bundle branch pacing on right ventricular function: A 3-dimensional echocardiography study.

BACKGROUND: The effect of left bundle branch pacing (LBBP) on right ventricular (RV) function is not well known, and there is conflicting evidence regarding whether cardiac resynchronization therapy improves RV function. OBJECTIVES: The study aimed to investigate the effect of LBBP on RV function and to evaluate the response of RV dysfunction (RVD) to LBBP. METHODS: Sixty-five LBBP candidates were prospectively included in the study and underwent echocardiography at baseline and 6-month follow-up. LBBP response was left ventricular (LV) reverse remodeling, defined as a reduction in LV end-systolic volume of ≥15% at follow-up. RESULTS: Patients were assigned to 2 subgroups on the basis of 3-dimensional echocardiography-derived RV ejection fraction (EF) before LBBP implantation: 30 patients (46%) in the no RVD group and 35 patients (54%) in the RVD group. The RVD group was characterized by higher N-terminal pro-brain natriuretic peptide levels, New York Heart Association functional class, and larger LV/RV size. LBBP induced a significant reduction in QRS duration, LV size, and improvement in LVEF and mechanical dyssynchrony in both the no RVD and RVD groups, and a significant improvement in RV volumes and RVEF in the RVD group (all P<.01). LBBP resulted in a similar percentage reduction in QRS duration, LV dimensions, LV volumes, and percentage improvement in LVEF in RVD and no RVD groups (all P＞.05). LV reverse remodeling (29 of 35 patients vs 27 of 30 patients; P = .323) in the RVD group was similar to that in the no RVD group after LBBP. CONCLUSION: LBBP induces excellent electrical and mechanical resynchronization, with a significant improvement in RV volumes and function. RVD did not diminish the beneficial effects on LV reverse remodeling after LBBP.

ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR.

BACKGROUND: Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated degradation of membrane proteins, is associated with cardiac hypertrophy progression. CHMP4C (charged multivesicular body protein 4C), a critical constituent of multivesicular bodies, is involved in cellular trafficking and signaling. However, the specific role of CHMP4C in the progression of cardiac hypertrophy remains largely unknown. METHODS: Mouse models with CHMP4C knockout or cardiadc-specific overexpression were subjected to transverse aortic constriction surgery for 4 weeks. Cardiac morphology and function were assessed through histological staining and echocardiography. Confocal imaging and coimmunoprecipitation assays were performed to identify the direct target of CHMP4C. An EGFR (epidermal growth factor receptor) inhibitor was administrated to determine whether effects of CHMP4C on cardiac hypertrophy were EGFR dependent. RESULTS: CHMP4C was significantly upregulated in both pressure-overloaded mice and spontaneously hypertensive rats. Compared with wild-type mice, CHMP4C deficiency exacerbated transverse aortic constriction-induced cardiac hypertrophy, whereas CHMP4C overexpression in cardiomyocytes attenuated cardiac dysfunction. Mechanistically, the effect of CHMP4C on cardiac hypertrophy relied on the EGFR signaling pathway. Fluorescent staining and coimmunoprecipitation assays confirmed that CHMP4C interacts directly with EGFR and promotes lysosome-mediated degradation of activated EGFR, thus attenuating cardiac hypertrophy. Notably, an EGFR inhibitor canertinib counteracted the exacerbation of cardiac hypertrophy induced by CHMP4C knockdown in vitro and in vivo. CONCLUSIONS: CHMP4C represses cardiac hypertrophy by modulating lysosomal degradation of EGFR and is a potential therapeutic candidate for cardiac hypertrophy.

Gene-echocardiography: refining genotype-phenotype correlations in hypertrophic cardiomyopathy.

AIMS: This study aims to clarify the association between hypertrophic patterns and genetic variants in hypertrophic cardiomyopathy (HCM) patients, contributing to the advancement of personalized management strategies for HCM. METHODS AND RESULTS: A comprehensive evaluation of genetic mutations was conducted in 392 HCM-affected families using Whole Exome Sequencing. Concurrently, relevant echocardiographic data from these individuals were collected. Our study revealed an increased susceptibility to enhanced septal and interventricular septal thickness in HCM patients harbouring gene mutations compared with those without. Mid-septal hypertrophy was found to be associated predominantly with myosin binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior wall ratio correlated with myosin heavy chain 7 (MYH7) variants. Mutations in MYH7, MYBPC3, and other sarcomeric or myofilament genes (troponin I3 [TNNI3], tropomyosin 1 [TPM1], and troponin T2 [TNNT2]) showed a relationship with increased hypertrophy in the anterior wall, interventricular septum, and lateral wall of the left ventricle. In contrast, alpha kinase 3 (ALPK3)-associated hypertrophy chiefly presented in the apical region, while hypertrophy related to titin (TTN) and obscurin (OBSCN) mutations exhibited a uniform distribution across the myocardium. Hypertrophic patterns varied with the type and category of gene mutations, offering valuable diagnostic insights. CONCLUSION: Our findings underscore a strong link between hypertrophic patterns and genetic variants in HCM, providing a foundation for more accurate genetic testing and personalized management of HCM patients. The novel concept of 'gene-echocardiography' may enhance the precision and efficiency of genetic counselling and testing in HCM.

The Relationship Between Lipoprotein-Associated Phospholipase-A2 and Coronary Artery Aneurysm in Children With Kawasaki Disease.

Background: Coronary artery lesions including aneurysm, as the most severe complications of Kawasaki disease (KD), remain of great concern. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is implicated in the regulation of inflammatory response and lipid metabolism. Since excessive inflammatory response and aberrant lipid metabolism have involved in the development of KD, we in this study sought to investigate the relationship between coronary artery aneurysm (CAA) and Lp-PLA2 and other blood parameters in children with KD. Methods: The participants included 71 KD patients, 63 healthy controls (HCs) and 51 febrile controls (FCs). KD patients were divided into KD-CAA (KD with CAA) group and KD-NCAA (KD without CAA) group. Serum Lp-PLA2 levels were measured using enzyme-linked immunosorbent assays. Other routine clinical parameters were also detected. Results: Serum Lp-PLA2 levels in KD group [4.83 µg/mL (3.95-6.77)] were significantly higher than those in HC [1.29 µg/mL (0.95-2.05)] and FC [1.74 µg/mL (1.18-2.74)] groups. KD-CAA group [5.56 µg/mL (4.55-22.01)] presented substantially higher serum Lp-PLA2 levels as compared with KD-NCAA group [4.64 µg/mL (2.60-5.55)]. In KD group, serum Lp-PLA2 level was positively related with erythrocyte sedimentation rate, the levels of leukocytes, platelets, albumin, creatine kinase-MB, and D-dimer, and the Z-scores of left main CA, right CA, left anterior descending CA, and left circumflex CA; and negatively related with mean corpuscular hemoglobin concentration and mean platelet volume. Moreover, receiver operating characteristic curves showed that Lp-PLA2 exhibited superior and moderate diagnostic performance for distinguishing KD patients from HC and FC ones, respectively, and possessed the potential ability to predict the occurrence of CAAs in KD. Conclusion: Lp-PLA2 may be related to KD and the formation of CAAs, and thus may serve as a potential diagnostic biomarker for KD.

Association between serum miR-221-3p and intravenous immunoglobulin resistance in children with Kawasaki disease.

OBJECTIVES: Intravenous immunoglobulin (IVIG) resistance was a major cause of coronary artery lesions in children with Kawasaki disease (KD). However, the cause of IVIG resistance in KD remains unknown. miR-221-3p has been confirmed involved in cardiovascular diseases and rheumatoid arthritis. The purpose of this study was to investigate the association between miR-221-3p and IVIG resistance in children with KD. METHODS: Fifty-five KD patients and 29 healthy controls (HCs) were enrolled in this study. KD patients were divided into group of sensitive to IVIG (IVIG-response, n = 42) and group of resistant to IVIG (IVIG-resistance, n = 13), group of 10 KD patients with coronary artery lesions (CALs, KD-CALs) and group of 10 sex- and age-matched KD patients without CALs (KD-NCALs). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of miR-221-3p. RESULTS: Compared with the HCs group, miR-221-3p were significantly increased in the KD group (p < 0.05), and the IVIG-resistance group had higher levels of miR-221-3p than those in the IVIG-response group (p < 0.05). CRP (C-reactive protein), PCT (procalcitonin), NLR (neutrophil-lymphocyte ratio) were positively correlated with miR-221-3p in KD patients. In addition, the group of IVIG resistance had a higher level of Kobayashi Score (p < 0.001). The receiver operating characteristic curve showed that miR-221-3p had a better value for diagnosis IVIG resistance in children with KD than Kobayashi Score with the AUC of 0.811 (95% CI, 0.672-0.951), 0.793 (95% CI, 0.618-0.968), respectively. Additionally, miR-221-3p was elevated (p < 0.05) and showed an AUC value of 0.83 (95% CI, 0.648-1.000, p < 0.05) for the prediction of the complication of coronary artery abnormalities in the group of KD with CALs. CONCLUSIONS: miR-221-3p might be involved in the pathogenesis of KD and IVIG resistance and miR-221-3p can be used as a new potential biomarker to predict IVIG resistance in children with KD.

The relationship between TNF-like protein 1A and coronary artery aneurysms in children with Kawasaki disease.

Kawasaki disease (KD) is an acute, systemic vasculitis of unknown etiology that occurs predominantly in infants and children, and the most crucial complication of KD is coronary artery aneurysm (CAA). Tumor necrosis factor (TNF)-like protein 1A (TL1A) is a member of the TNF superfamily, which possesses the ability of maintaining vascular homeostasis and regulating immune responses. This study aimed to examine serum TL1A levels in KD patients, and to investigate the relationship between TL1A and CAAs in children with KD. Blood samples were recruited from 119 KD patients, 35 febrile controls (FCs), and 37 healthy controls (HCs). The KD group was further divided into KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs) groups. Serum TL1A levels were measured using enzyme-linked immunosorbent assays, and clinical parameters were collected from KD patients. Serum TL1A levels of KD patients in the acute phase of KD were significantly higher than in the FC and HC groups. In particular, serum TL1A levels were substantially increased in the KD-CAA group compared with the KD-NCAA group. Furthermore, TL1A levels in the KD group were positively correlated with the duration of fever and the time point of IVIG and WBC levels, but negatively correlated with levels of RBC, Hb and albumin. TL1A might be involved in KD-associated vasculitis and in the development of CAAs.

Association between adropin and coronary artery lesions in children with Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis in children. Coronary artery lesions (CALs) are the most serious complications in KD, but the pathogenesis is still unclear so far. Adropin, a new biopeptide, plays an important role in metabolism and cardiovascular function. The aim of this study was to explore the relationship between adropin and KD. 66 KD patients and 22 healthy controls (HCs) were included in the study. KD patients were divided into KD with coronary artery lesions (KD-CALs) group and KD without CALs (KD-NCALs) group. The levels of serum adropin were determined by enzyme-linked immunosorbent assay (ELISA). Compared with the HC group, adropin concentrations were significantly increased in the KD group (p < 0.05), and the KD-CAL group had higher levels of adropin than those in the KD-NCAL group (p < 0.05). Pct (Procalcitonin) and DD (D-dimer) were positively correlated with adropin in the KD group (p < 0.05). Moreover, adropin had positive correlations with CRP (C-reactive protein) and DD in the KD-NCAL group and positive correlations with Pct, PLR (platelet-to-lymphocyte ratio), and DD in the KD-CAL group (p < 0.05). The receiver operating characteristic (ROC) curve showed that the best threshold value of serum adropin level was more than 2.8 ng/mL, with 72.2% sensitivity and 71.4% specificity for predicting CALs in children with KD.Conclusion: Adropin might be involved in the pathogenesis of KD and CALs and can be used as an auxiliary diagnostic biomarker of KD. What is Known: • CALs in KD were mainly caused by inflammation, immune imbalance, and vascular endothelial dysfunction, and adropin is involved in metabolic diseases and cardiovascular diseases. What is New: • In this study, we have found the relationship between adropin and KD, and serum adropin level can be used as an auxiliary diagnostic biomarker to predict CALs in KD.

The Relationship between Retinol-Binding Protein 4 and Markers of Inflammation and Thrombogenesis in Children with Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is a self-limited vasculitis with unknown etiologies, and coronary artery lesions (CALs) are the most common and serious complications. Retinol-binding protein 4 (RBP4) has been confirmed effects on vasodilation, platelet activation inhibition, and cardiovascular diseases by researches. Therefore, this study was aimed at investigating the relationship between RBP4 and inflammation as well as thrombogenesis in children with KD. METHODS: 79 subjects were from 62 children with KD and 17 healthy controls (HCs). The KD group was divided into KD with CALs (KD-CALs) and KD without CALs (KD-NCALs), and the serum RBP4 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the HC group, serum RBP4 levels in the KD group were significantly decreased (p < 0.05). RBP4, hemoglobin (Hb), and mean platelet volume (MPV) levels were higher, while platelet counts (Plt) and thrombin time (TT) levels were lower in the KD-NCALs group than in the KD-CALs group (p < 0.05). RBP4 had positive correlation with time point of intravenous immunoglobulin (IVIG), Hb, and percentage of leukomonocytes (L%) and negative correlation with the percentage of neutrophils (N%), MPV, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), prothrombin time (PT), fibrinogen (Fbg), and D-dimer (DD) in the KD group; RBP4 had positive correlation with the time point of IVIG and L% and negative correlation with N%, MPV, and NLR in the KD-NCALs group; and RBP4 had positive correlation with Hb and L% and negative correlation with N%, CRP, NLR, and PT in the KD-CALs group (p < 0.05). Multiple linear regression analysis confirmed that Hb and CRP in the KD group, MPV and N% in the KD-NCALs group, and PT and CRP in the KD-CALs group were independent predictors of RBP4 (p < 0.05). CONCLUSION: Lower RBP4 was observed in the KD group than in the HC group, and RBP4 had associations with markers of inflammation and thrombogenesis in children with KD.

Decreased serum Annexin A1 levels in Kawasaki disease with coronary artery aneurysm.

BACKGROUND: Kawasaki disease (KD) is an acute and systemic vasculitis whose etiology remains unclear. The most crucial complication is the formation of coronary artery aneurysm (CAA). Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases. This study sought to investigate the serum ANXA1 levels in KD patients and further explore the relationship between ANXA1 and CAA, as well as additional clinical parameters. METHODS: Serum samples were collected from 95 KD patients and 39 healthy controls (HCs). KD patients were further divided into two groups: KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs). Serum levels of ANXA1 and interleukin-6 (IL-6) were determined using enzyme-linked immunosorbent assays. RESULTS: Serum ANXA1 levels in the KD group were significantly lower than in the HC group. In particular, serum ANXA1 levels were substantially lower in the KD-CAA groups. Moreover, serum ANXA1 levels were positively correlated with N%, C-reactive protein (CRP), and IL-6 but negatively correlated with L% in the KD group. Positive correlations between serum ANXA1 levels and erythrocyte sedimentation rate (ESR), IL-6, and D-dimer (DD) were observed in the KD-CAA group. CONCLUSIONS: ANXA1 may be involved in the development of KD, and downregulation of ANXA1 may lead to the hypercoagulability seen in KD. IMPACT: For the first time, it was demonstrated that serum ANXA1 levels were significantly decreased in Kawasaki disease with coronary artery aneurysms. ANXA1 might be involved in the acute phase of Kawasaki disease. Low serum concentrations of ANXA1 might lead to the hypercoagulability stage in Kawasaki disease. ANXA1 might be a potential therapeutic target for patients with Kawasaki disease.

Hypomethylation of C1q/tumor necrosis factor-related protein-1 promoter region in whole blood and risks for coronary artery aneurysms in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is characterized as a self-limited systemic vasculitis. C1q/tumor necrosis factor-related protein-1 (CTRP1) had been associated with the occurrence of vasculitis in KD. Methylation at the promoter region of certain genes was reported to be involved in the development process of KD. This study aims to investigate the methylation levels of CTRP1 in KD, as well as, its potential to predict coronary artery aneurysms (CAAs). METHODS: 31 patients with KD and 14 healthy controls (HCs) were recruited into this study. The KD group was further divided into KD with CAA (KD-CAAs) group and KD without NCAAs (KD-NCAAs) group. Methylation levels of CpG sites were determined by MethylTarget sequencing, a method that uses multiple targeted CpG methylation analysis. RESULTS: The methylation levels of CTRP1 promoter region in the KD group were lower than that in the HC group at all predicted CpG sites, especially at sites 34, 51, 69, 79, 176 and 206. Compared with KD-CAAs group, the methylation levels of almost every CpG sites of CTRP1 were increased in the KD-NCAAs group, with site 69 and 154 found to be strongly related to the occurrence of CAAs. CONCLUSIONS: The difference in methylation levels of CTRP1 promoter may be involved in the development process of KD, and may be a potential predictive marker for the occurrence of CAAs.