Association Between Admission Systolic Blood Pressure and Cardiovascular Events in Acute Myocardial Infarction Patients with Different Left Ventricular Ejection Fractions.

BACKGROUND: Among patients with acute heart failure, left ventricular ejection fraction (LVEF) is closely related with admission blood pressure. However, it is unclear whether the systolic blood pressure is associated with the LVEF in acute myocardial infarction (AMI) patients. we evaluated the predictive value of admission SBP in AMI patients with different LVEF status. METHODS: Data were from our hospital database bank. 4114 patients were included in this analysis. Patients were divided into 2 groups according to their LVEF in the first echocardiography record after admission. Patients were categorized into 4 groups (SBP 90-99 mm Hg, SBP 100-119 mm Hg, SBP 120-139 mm Hg, and SBP ≥140 mm Hg) based on SBP level at admission. RESULTS: The mean age was 64.9 ± 12.5 years and 28% were female. For patients of LVEF < 50% in the lowest SBP group (SBP 90-99 mm Hg), the incidence of in-hospital cardiovascular death was significantly higher than other SBP groups (reference: SBP 90-99 mm Hg) (adjusted OR = 0.267, 95% CI: 0.113-0.728 for SBP 120-139 mm Hg, P =.004 and OR = 0.241, 95% CI: 0.089-0.651 for SBP ≥ 140 mm Hg, P =.005). Patients of LVEF ≥50% in the highest SBP group (SBP ≥ 140 mm Hg) were at higher risk of cardiogenic mortality during long-term follow-up (reference: SBP ≥140 mm Hg) (adjusted HR = 0.313, 95% CI: 0.489-0.962 for SBP 100-119 mm Hg, P <.001, HR = 0.701, 95% CI: 0.488-0.987 for SBP 120-139 mm Hg, P =.003, and HR = 0.554, 95% CI: 0.198-0.837 for SBP 90-99 mm Hg, P =.001). CONCLUSION: SBP 90-99 mm Hg were associated with increased in-hospital cardiovascular death in AMI population with LVEF < 50%, and SBP > 140 mm Hg were associated with increased long-term cardiovascular death in AMI subjects with LVEF >50%.

Voltage-dependent anion channel 1 (VDAC1) overexpression alleviates cardiac fibroblast activation in cardiac fibrosis via regulating fatty acid metabolism.

Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix in the myocardium with cardiac fibroblast activation, leading to chronic cardiac remodeling and dysfunction. However, little is known about metabolic alterations in fibroblasts during cardiac fibrosis, and there is a lack of pharmaceutical treatments that target metabolic dysregulation. Here, we provided evidence that fatty acid ß-oxidation (FAO) dysregulation contributes to fibroblast activation and cardiac fibrosis. With transcriptome, metabolome, and functional assays, we demonstrated that FAO was downregulated during fibroblast activation and cardiac fibrosis, and that perturbation of FAO reversely affected the fibroblast-to-myofibroblast transition. The decrease in FAO may be attributed to reduced long-chain fatty acid (LCFA) uptake. Voltage-dependent anion channel 1 (VDAC1), the main gatekeeper of the outer mitochondrial membrane (OMM), serves as the transporter of LCFA into the mitochondria for further utilization and has been shown to be decreased in myofibroblasts. In vitro, the addition of exogenous VDAC1 was shown to ameliorate cardiac fibroblast activation initiated by transforming growth factor beta 1 (TGF-ß1) stimuli, and silencing of VDAC1 displayed the opposite effect. A mechanistic study revealed that VDAC1 exerts a protective effect by regulating LCFA uptake into the mitochondria, which is impaired by an inhibitor of carnitine palmitoyltransferase 1A. In vivo, AAV9-mediated overexpression of VDAC1 in myofibroblasts significantly alleviated transverse aortic constriction (TAC)-induced cardiac fibrosis and rescued cardiac function in mice. Finally, we treated mice with the VDAC1-derived R-Tf-D-LP4 peptide, and the results showed that R-Tf-D-LP4 prevented TAC-induced cardiac fibrosis and dysfunction in mice. In conclusion, this study provides evidence that VDAC1 maintains FAO metabolism in cardiac fibroblasts to repress fibroblast activation and cardiac fibrosis and suggests that the VDAC1 peptide is a promising drug for rescuing fibroblast metabolism and repressing cardiac fibrosis.

The role of cardiac resident macrophage in cardiac aging.

Advancements in longevity research have provided insights into the impact of cardiac aging on the structural and functional aspects of the heart. Notable changes include the gradual remodeling of the myocardium, the occurrence of left ventricular hypertrophy, and the decline in both systolic and diastolic functions. Macrophages, a type of immune cell, play a pivotal role in innate immunity by serving as vigilant agents against pathogens, facilitating wound healing, and orchestrating the development of targeted acquired immune responses. Distinct subsets of macrophages are present within the cardiac tissue and demonstrate varied functions in response to myocardial injury. The differentiation of cardiac macrophages according to their developmental origin has proven to be a valuable strategy in identifying reparative macrophage populations, which originate from embryonic cells and reside within the tissue, as well as inflammatory macrophages, which are derived from monocytes and recruited to the heart. These subsets of macrophages possess unique characteristics and perform distinct functions. This review aims to summarize the current understanding of the roles and phenotypes of cardiac macrophages in various conditions, including the steady state, aging, and other pathological conditions. Additionally, it will highlight areas that require further investigation to expand our knowledge in this field.

COVID-19 and Acute Cardiac Injury: Clinical Manifestations, Biomarkers, Mechanisms, Diagnosis, and Treatment.

PURPOSE OF REVIEW: This review aims to comprehensively explore the clinical characteristics of COVID-19-related cardiac injury and examine the potential mechanisms underlying cardiac injury in patients affected by COVID-19. RECENT FINDINGS: The COVID-19 pandemic has primarily been associated with severe respiratory symptoms. However, emerging evidence has indicated that a significant number of COVID-19 patients also experience myocardial injury, leading to conditions such as acute myocarditis, heart failure, acute coronary syndrome, and arrhythmias. The incidence of myocardial injury is notably higher in patients with preexisting cardiovascular diseases. Myocardial injury often manifests with elevated levels of inflammation biomarkers, as well as abnormalities observed on electrocardiograms and echocardiograms. COVID-19 infection has been found to be associated with myocardial injury, which can be attributed to several pathophysiological mechanisms. These mechanisms include injury caused by hypoxia, resulting from respiratory compromise, a systemic inflammatory response triggered by the infection, and direct attack on the myocardium by the virus itself. Furthermore, the angiotensin-converting enzyme 2 (ACE2) receptor plays a crucial role in this process. Early recognition, prompt diagnosis, and a comprehensive understanding of the underlying mechanisms are essential for effectively managing and reducing the mortality associated with myocardial injury in COVID-19 patients.

Phosphatidylethanolamine N-methyltransferase: from Functions to Diseases.

Locating on endoplasmic reticulum and mitochondria associated membrane, Phosphatidylethanolamine N-methyltransferase (PEMT), catalyzes phosphatidylethanolamine methylation to phosphatidylcholine. As the only endogenous pathway for choline biosynthesis in mammals, the dysregulation of PEMT can lead to imbalance of phospholipid metabolism. Dysregulation of phospholipid metabolism in the liver or heart can lead to deposition of toxic lipid species that adversely result in dysfunction of hepatocyte/cardiomyocyte. Studies have shown that PEMT-/- mice increased susceptibility of diet-induced fatty liver and steatohepatitis. However, knockout of PEMT protects against diet-induced atherosclerosis, diet-induced obesity, and insulin resistance. Thus, novel insights to the function of PEMT in various organs should be summarized. Here, we reviewed the structural and functional properties of PEMT, highlighting its role in the pathogenesis of obesity, liver diseases, cardiovascular diseases, and other conditions.

The predictive effect of direct-indirect bilirubin ratio on clinical events in acute coronary syndrome: results from an observational cohort study in north China.

BACKGROUND: Patients with extremely high-risk ASCVD usually suffered poor prognosis, bilirubin is considered closely related to cardiovascular outcomes. However, there is controversy over the relationship between bilirubin and coronary artery disease. This study aimed to evaluate the predictive value of the DIBIL ratio in patients with extremely high-risk ASCVD. METHODS: 10,260 consecutive patients with extremely high-risk ASCVD were enrolled in this study. All patients were divided into three groups according to their DIBIL ratio. The incidence of MACCEs was recorded, and in a competing risk regression, the incidence of MACCEs and their subgroups were recorded. The direct-indirect bilirubin ratio (DIBIL ratio) was calculated by the direct bilirubin (umol/L)/indirect bilirubin (umol/L) ratio, all laboratory values were obtained from the first fasting blood samples during hospitalization. RESULTS: The area under the ROC curve of the DIBIL ratio to predict the occurrence of all-cause death was 0.668, the cut-off value of which is 0.275. Competing risk regression indicated that DIBIL ratio was positively correlated with all-cause death [1.829 (1.405-2.381), p < 0.001], CV death [1.600 (1.103, 2.321), p = 0.013]. The addition of DIBIL ratio to a baseline risk model had an incremental effect on the predictive value for all-cause death [IDI 0.004(0, 0.010), p < 0.001; C-index 0.805(0.783-0.827), p < 0.001]. CONCLUSION: The DIBIL ratio was an excellent tool to predict poor prognosis, suggesting that this index may be developed as a biomarker for risk stratification and prognosis in extremely ASCVD patients.

Association of haemoglobin glycation index with outcomes in patients with acute coronary syndrome: results from an observational cohort study in China.

BACKGROUND: The hemoglobin glycation index (HGI) is the difference between measured and estimated glycation of hemoglobin. However, there is limited evidence to investigate the HGI and the clinical outcomes of acute coronary syndrome patients. This study aimed to evaluate the association between HGI and the clinical outcomes of acute coronary syndrome (ACS) in a China cohort. METHOD: This single-center retrospective study was carried out in the Cardiovascular Center of Beijing Friendship Hospital, a total of 11004 consecutive patients with ACS from Dec 2012-Dec 2020 were enrolled in this study. Patients were divided into quintiles according to their HGI levels. The incidence of major adverse cardiac and cerebrovascular events (MACCEs) was recorded. RESULT: HGI were divided into five quintiles quintiles: -0.906 (-7.188, -0.663), -0.491 (-0.663, -0.343), -0.196 (-0.342, -0.039), 0.170 (-0.039, 0.485), and 1.156 (0.485, 7.875), respectively. Competing risk regression revealed that HGI was positively related to all-cause death, CV death, and composite MACCEs. Multivariate Cox proportional hazards regression analysis indicated that hypertension (HR:1.109, P = 0.013), previous stroke (HR:1.208, P < 0.001), past PCI (HR: 1.268, P < 0.001), age (HR: 1.011, P < 0.001), BMI (HR: 0.987, P = 0.012), heart rate (HR: 1.004, P = 0.001), NSTEMI (HR: 1.205, P < 0.001), WBC (HR: 1.020, P = 0.008), eGFR (HR: 0.993, P < 0.001), HDL-C (HR: 0.809, P = 0.002), LVEF (HR:0.240, P < 0.001), LM/three-vessel or proximal LAD involved (HR: 1.208 P < 0.001; HR:0.914, P = 0.019, respectively), and antiplatelet agents during hospitalization (HR:0.806, P = 0.020) independently predicted the incidence of MACCEs in ACS patients. Restricted cubic spline indicated a U-shaped association between the HGI and risk of MACCEs. CONCLUSION: Both low HGI and high HGI was associated with an increased risk of adverse outcomes in patients with acute coronary syndrome, compared with moderate HGI.

The Role of Mitochondria in Metabolic Syndrome-Associated Cardiomyopathy.

With the rapid development of society, the incidence of metabolic syndrome (MS) is increasing rapidly. Evidence indicated that patients diagnosed with MS usually suffered from cardiomyopathy, called metabolic syndrome-associated cardiomyopathy (MSC). The clinical characteristics of MSC included cardiac hypertrophy and diastolic dysfunction, followed by heart failure. Despite many studies on this topic, the detailed mechanisms are not clear yet. As the center of cellular metabolism, mitochondria are crucial for maintaining heart function, while mitochondria dysfunction plays a vital role through mechanisms such as mitochondrial energy deprivation, calcium disorder, and ROS (reactive oxygen species) imbalance during the development of MSC. Accordingly, in this review, we will summarize the characteristics of MSC and especially focus on the mechanisms related to mitochondria. In addition, we will update new therapeutic strategies in this field.

Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM), as a serious complication of diabetes, causes structural and functional abnormalities of the heart and eventually progresses to heart failure. Currently, there is no specific treatment for DCM. Studies have proved that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors for the development and progression of DCM. The mitochondria-associated ER membranes (MAMs) are a unique domain formed by physical contacts between mitochondria and ER and mediate organelle communication. Under high glucose conditions, changes in the distance and composition of MAMs lead to abnormal intracellular signal transduction, which will affect the physiological function of MAMs, such as alter the Ca2+ homeostasis in cardiomyocytes, and lead to mitochondrial dysfunction and abnormal apoptosis. Therefore, the dysfunction of MAMs is closely related to the pathogenesis of DCM. In this review, we summarized the evidence for the role of MAMs in DCM and described that MAMs participated directly or indirectly in the regulation of the pathophysiological process of DCM via the regulation of Ca2+ signaling, mitochondrial dynamics, ER stress, autophagy, and inflammation. Finally, we discussed the clinical transformation prospects and technical limitations of MAMs-associated proteins (such as MFN2, FUNDC1, and GSK3ß) as potential therapeutic targets for DCM.

Evaluation of Sampson equation for LDL-C in acute coronary syndrome patients: a Chinese population-based cohort study.

OBJECTIVE: Low-density lipoprotein cholesterol (LDL-C) is an important cardiovascular disease marker that is used to estimate the risk of acute coronary syndrome in patients. The Sampson equation is an accurate LDL-C equation, but its application in Chinese patients is unclear. METHODS: This study enrolled 12,989 consecutive Chinese patients with the acute coronary syndrome (ACS), LDL-C levels were determined by direct standard method and two indirect equations (Friedewald and Sampson). The detection accuracy and consistency of these two equations were compared in patients classified by triglyceride (TG). In addition, the efficiency of the Sampson equation was also evaluated in patients with different comorbidities. RESULTS: Patients were divided into six groups according to TG level, and indicated that the Sampson formula was more accurate than the Friedewald formula in all TG spectrums (P < 0.001). The Friedewald formula may underestimate the risk in patients with TG > 400 mg/dL, especially in TG > 800 mg/dL group (r: 0.931 vs. 0.948, 0.666 vs. 0.898, respectively). Compared with the Friedewald equation, the Sampson equation showed more advantages in female, age ≥ 65, body index mass (BMI) < 25, non-smoker, and non-diabetes (0.954 vs. 0.937, 0.956 vs. 0.934, 0.951 vs. 0.939, 0.951 vs. 0.936, and 0.947 vs. 0.938, respectively) than those in male, age < 65, BMI ≥ 25, smoker, and diabetes. CONCLUSIONS: Compared with the Friedewald equation, the Sampson equation is more accurate for LDL-C evaluation in Chinese patients diagnosed with ACS, especially in patients with hypertriglyceridemia even in those with TG > 800 mg/dL. Additionally, the Sampson equation demonstrates greater accuracy even in subgroups of various baseline characteristics and comorbidities.

Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.

BACKGROUND: Calcium (Ca2+) is a key regulator of energy metabolism. Impaired Ca2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. METHODS: MCU knockout or transgenic mice were infused with isoproterenol (ISO; 10 mg/kg per day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nmol/L, 48 hours). Intracellular Ca2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. RESULTS: Chronic administration of the ß-adrenergic receptor agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. It is interesting that ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout mice. Cardiomyocytes from knockout mice or overexpressing a dominant negative MCU exhibited defective intracellular Ca2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca2+/calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated CREB (cAMP-response element binding protein), which bound the Mcu promoter to enhance Mcu gene transcription. CONCLUSIONS: The ß-adrenergic receptor/CaMKIIδB/CREB pathway upregulates Mcu gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability.

New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease.

IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria (such as mitophagy, mtROS, and mitochondria-related inflammation) on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field.

Mitofusin-2: A New Mediator of Pathological Cell Proliferation.

Cell proliferation is an important cellular process for physiological tissue homeostasis and remodeling. The mechanisms of cell proliferation in response to pathological stresses are not fully understood. Mitochondria are highly dynamic organelles whose shape, number, and biological functions are modulated by mitochondrial dynamics, including fusion and fission. Mitofusin-2 (Mfn-2) is an essential GTPase-related mitochondrial dynamics protein for maintaining mitochondrial network and bioenergetics. A growing body of evidence indicates that Mfn-2 has a potential role in regulating cell proliferation in various cell types. Here we review these new functions of Mfn-2, highlighting its crucial role in several signaling pathways during the process of pathological cell proliferation. We conclude that Mfn-2 could be a new mediator of pathological cell proliferation and a potential therapeutic target.

Stimulation of Sigma-1 Receptor Protects against Cardiac Fibrosis by Alleviating IRE1 Pathway and Autophagy Impairment.

Sigma-1 receptor (Sig1R), a chaperone in the endoplasmic reticulum (ER) membrane, has been implicated in cardiac hypertrophy; however, its role in cardiac fibroblast activation has not been established. This study investigated the possible association between Sig1R and this activation by subjecting mice to sham, transverse aortic constriction (TAC), and TAC plus fluvoxamine (an agonist of Sig1R) treatments. Cardiac function and fibrosis were evaluated four weeks later by echocardiography and histological staining. In an in vitro study, neonatal rat cardiac fibroblasts were treated with fluvoxamine or NE-100 (an antagonist of Sig1R) in the presence or absence of transforming growth factor beta1 (TGF-ß1). Fibrotic markers, ER stress pathways, and autophagy were then investigated by qPCR, western blotting, immunofluorescence, confocal microscopy, and transmission electron microscopy. Fluvoxamine treatment reduced cardiac fibrosis, preserved cardiac function, and attenuated cardiac fibroblast activation. Inhibition of the IRE1/XBP1 pathway, a branch of ER stress, by a specific inhibitor of IRE1 endonuclease activity, attenuated the pathological process. Fluvoxamine stimulation of Sig1R restored autophagic flux in cardiac fibroblasts, indicating that Sig1R appears to play a protective role in the activation of cardiac fibroblasts by inhibiting the IRE1 pathway and restoring autophagic flux. Sig1R may therefore represent a therapeutic target for cardiac fibrosis.

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging.

Mitochondrial DNA (mtDNA) damage is associated with the development of cardiovascular diseases. Cardiac aging plays a central role in cardiovascular diseases. There is accumulating evidence linking cardiac aging to mtDNA damage, including mtDNA mutation and decreased mtDNA copy number. Current wisdom indicates that mtDNA is susceptible to damage by mitochondrial reactive oxygen species (mtROS). This review presents the cellular and molecular mechanisms of cardiac aging, including autophagy, chronic inflammation, mtROS, and mtDNA damage, and the effects of mitochondrial biogenesis and oxidative stress on mtDNA. The importance of nucleoid-associated proteins (Pol γ), nuclear respiratory factors (NRF1 and NRF2), the cGAS-STING pathway, and the mitochondrial biogenesis pathway concerning the development of mtDNA damage during cardiac aging is discussed. Thus, the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.