[The role of inflammation in heart failure with preserved ejection fraction].

Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterized by left ventricular diastolic dysfunction with preserved ejection fraction. With the aging of the population and the increasing prevalence of metabolic diseases, such as hypertension, obesity and diabetes, the prevalence of HFpEF is increasing. Compared with heart failure with reduced ejection fraction (HFrEF), conventional anti-heart failure drugs failed to reduce the mortality in HFpEF due to the complex pathophysiological mechanism and multiple comorbidities of HFpEF. It is known that the main changes of cardiac structure of in HFpEF are cardiac hypertrophy, myocardial fibrosis and left ventricular hypertrophy, and HFpEF is commonly associated with obesity, diabetes, hypertension, renal dysfunction and other diseases, but how these comorbidities cause structural and functional damage to the heart is not completely clear. Recent studies have shown that immune inflammatory response plays a vital role in the progression of HFpEF. This review focuses on the latest research progress in the role of inflammation in the process of HFpEF and the potential application of anti-inflammatory therapy in HFpEF, hoping to provide new research ideas and theoretical basis for the clinical prevention and treatment in HFpEF.

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (PparaΔCM) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible PparaΔCM mouse model. PparaΔCM and Pparafl/fl mice were randomly subjected to sham or TAC for 2 weeks. Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis. Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated, but genes critical for glycolysis were markedly upregulated in PparaΔCM hearts. Moreover, the hypertrophy-related genes, including genes involved in extracellular matrix (ECM) remodeling, cell adhesion, and cell migration, were upregulated in hypertrophic PparaΔCM hearts. Western blot analyses demonstrated an increased HIF1α protein level in hypertrophic PparaΔCM hearts. PET/CT analyses showed an enhanced glucose uptake in hypertrophic PparaΔCM hearts. Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Pparafl/fl hearts; however, these increases were markedly blunted in PparaΔCM hearts. In contrast, hypertrophic PparaΔCM hearts exhibited enhanced extracellular acidification rate (ECAR) capacity, as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve. These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling, thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.

Level of Pregnancy-associated Plasma Protein-A Correlates With Coronary Thin-cap Fibroatheroma Burden in Patients With Coronary Artery Disease: Novel Findings From 3-Vessel Virtual Histology Intravascular Ultrasound Assessment.

Pregnancy-associated plasma protein-A (PAPP-A) level is an independent predictor of acute cardiovascular event occurrence. To test the hypothesis that increased PAPP-A levels would be associated with a higher burden of coronary thin-cap fibroatheroma (TCFA) thereby underlying the heightened risk for cardiovascular events in patients with coronary artery disease; 154 patients (462 vessels and 975 plaques) with stable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS) referred for percutaneous coronary intervention were assessed using 3-vessel virtual histology (VH)-intravascular ultrasound (IVUS). Thin-cap fibroatheroma virtual histology was defined as focal, necrotic core (NC)-rich (≥10% of cross-sectional area) plaques in contact with the lumen, and plaque burden ≥40%. Pregnancy-associated plasma protein-A levels were determined by sandwich enzyme-linked immunosorbent assay, and patients were divided into 3 groups based on PAPP-A level tertiles. Although the highest PAPP-A level tertile was not associated with 3-vessel plaque number, it was associated with 3-vessel VH-TCFA number and necrotic core volume. Patients with ≥3 VH-TCFAs had a higher PAPP-A level than patients with 1 to 3 VH-TCFAs or without any VH-TCFA (13.3 ±â€Š11.8 versus 7.8 ±â€Š4.7 versus 7.4 ±â€Š4.7 mIU/L, P < 0.001, respectively). Moreover, PAPP-A level was an independent predictor of higher total number of VH-TCFAs (OR 1.18; 95% CI 1.07-1.29, P = 0.001). This VH-IVUS study demonstrated, for the first time to our knowledge, that higher PAPP-A levels are associated with higher 3-vessel TCFA burden in patients with coronary artery disease. Pregnancy-associated plasma protein-A, therefore, might be a useful serum biomarker to predict increased coronary TCFA burden and plaque instability.

Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells.

Hyperglycemia, advanced glycation end products (AGEs), hyperinsulinemia and dyslipidemia may play roles in the development of diabetes-associated atherosclerosis and post-angioplasty restenosis. Clinically, their effects seem to be synergic. However, few studies have focused on the synergistic action of these factors. In the present study, we investigated whether glycated serum albumin (GSA) has a synergistic effect with insulin on the proliferation of vascular smooth muscle cells (VSMCs). VSMCs were isolated from rat thoracic aortas and cultured in fetal bovine serum (FBS)-free medium for 24 h, then exposed to GSA, insulin or GSA + insulin for 48 h with or without pretreatment of mitogen-activated protein kinase (MAPK) inhibitors or the antioxidant N-acetylcysteine (NAC). Cell growth rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or cell counting. The changes of phosphorylated-p38 MAPK and phosphorylated-C-Jun N-terminal kinase 1/2 (JNK1/2) were measured by Western blot analysis. The results showed that only p38 MAPK, but not JNK was activated by GSA and insulin co-incubation. VSMC proliferation was increased by insulin (10-1000 nmol/L) or GSA (10, 100 microg/mL). Co-incubation of insulin (100 nmol/L) and GSA (100 mug/mL) caused a more potent increase in VSMC proliferation than insulin or GSA incubation alone. p38 MAPK inhibitor, SB203580, as well as NAC, could inhibit the VSMC proliferation induced by co-incubation of GSA and insulin. The results show that insulin enhances GSA-induced VSMC proliferation, which may be mediated through a reactive oxygen species (ROS)-p38 MAPK pathway. The synergism of AGEs and insulin may play a detrimental role in the pathogenesis of diabetic atherosclerosis and post-angioplasty restenosis.