Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells

Purpose Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Methods Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. Results PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. Conclusion PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Graphical abstract Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

Association of myocardial fibrosis detected by late gadolinium-enhanced MRI with clinical outcomes in patients with diabetes: a systematic review and meta-analysis

ObjectiveThis meta-analysis assessed the associations of myocardial fibrosis detected by late gadolinium-enhanced (LGE)-MRI with the risk of major adverse cardiac and cerebrovascular events (MACCEs) and major adverse cardiac events (MACEs) in patients with diabetes.DesignSystematic review and meta-analysis reported in accordance with the guidelines of the Meta-analysis of Observational Studies in Epidemiology statement.Data sourcesWe searched the Medline, Embase and Cochrane by Ovid databases for studies published up to 27 August 2021.Eligibility criteriaProspective or respective cohort studies were included if they reported the HR and 95% CIs for MACCEs/MACEs in patients with either type 1 or 2 diabetes and LGE-MRI-detected myocardial fibrosis compared with patients without LGE-MRI-detected myocardial fibrosis and if the articles were published in the English language.Data extraction and synthesisTwo review authors independently extracted data and assessed the quality of the included studies. Pooled HRs and 95% CIs were analysed using a random effects model. Heterogeneity was assessed using forest plots and I2 statistics.ResultsEight studies with 1121 patients with type 1 or type 2 diabetes were included in this meta-analysis, and the follow-up ranged from 17 to 70 months. The presence of myocardial fibrosis detected by LGE-MRI was associated with an increased risk for MACCEs (HR: 2.58; 95% CI 1.42 to 4.71; p=0.002) and MACEs (HR: 5.28; 95% CI 3.20 to 8.70; p<0.001) in patients with diabetes. Subgroup analysis revealed that ischaemic fibrosis detected by LGE was associated with MACCEs (HR 3.80, 95% CI 2.38 to 6.07; p<0.001) in patients with diabetes.ConclusionsThis study demonstrated that ischaemic myocardial fibrosis detected by LGE-MRI was associated with an increased risk of MACCEs/MACEs in patients with diabetes and may be an imaging biomarker for risk stratification. Whether LGE-MRI provides incremental prognostic information with respect to MACCEs/MACEs over risk stratification by conventional cardiovascular risk factors requires further study.

Impact of Homoarginine on Myocardial Function and Remodeling in a Rat Model of Chronic Renal Failure

Purpose: Low plasma concentrations of the amino acid homoarginine (HA) have been shown to correlate with adverse cardiovascular outcome, particularly in patients with chronic kidney disease. The present study sought to investigate the effect of HA treatment on cardiac remodeling in rats undergoing artificially induced renal insufficiency by 5/6 nephrectomy (5/6 Nx). Methods: A total of 33 male Wistar rats were randomly divided into sham and 5/6 Nx groups, receiving either placebo treatment or 400 mg·kg−1·day−1 HA over a 4-week period. Results: 5/6 Nx per se resulted in adverse myocardial remodeling with aggravated cardiac function and associated cardiac overload as the most obvious alteration (−23% ejection fraction, P < 0.0001), as well as increased myocardial fibrosis (+80%, P = 0.0005) compared to placebo treated sham animals. HA treatment of 5/6 Nx rats has led to an improvement of ejection fraction (+24%, P = 0.0003) and fractional shortening (+21%, P = 0.0126), as well as a decrease of collagen deposition (−32%, P = 0.0041), left ventricular weight (−14%, P = 0.0468), and myocyte cross-sectional area (−12%, P < 0.0001). These changes were accompanied by a downregulation of atrial natriuretic factor (−65% P < 0.0001) and collagen type V alpha 1 chain (−44%, P = 0.0006). Sham animals revealed no significant changes in cardiac function, myocardial fibrosis, or any of the aforementioned molecular changes after drug treatment. Conclusion: Dietary HA supplementation appears to have the potential of preventing cardiac remodeling and improving heart function in the setting of chronic kidney disease. Our findings shed new light on HA as a possible new therapeutic agent for patients at high cardiovascular risk.

Identifying Mitral Valve Prolapse at Risk for Ventricular Arrhythmias and Myocardial Fibrosis from 12-lead Electrocardiograms using Deep Learning

Background: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset of MVP patients developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) represents a marker of arrhythmic risk that is associated with myocardial fibrosis and increased mortality in MVP. We hypothesize that an ECG-based machine-learning model can identify MVP with ComVE and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. Methods: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients evaluated at the University of California San Francisco (UCSF) between 2012 and 2020. A separate CNN was also trained to detect late gadolinium enhancement (LGE) using 87 ECGs from MVP patients with contrast CMR. Results: The prevalence of ComVE was 160/569 or 28% (20 patients or 3% had cardiac arrest or sudden cardiac death). The area under the curve (AUC) of the CNN to detect ComVE was 0.81 (95% CI, 0.78-0.84). AUC remained high even after excluding patients with moderate-severe mitral regurgitation (MR) [0.80 (95% CI, 0.77-0.83)], or with bileaflet MVP [0.81 (95% CI, 0.76-0.85)]. The top ECG segments able to discriminate ComVE vs no ComVE were related to ventricular depolarization and repolarization (early-mid ST and QRS fromV1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 21 (24%) of 87 patients with available CMR. The AUC for detection of LGE was 0.75 (95% CI, 0.68-0.82). Conclusions: Standard 12-lead ECGs analyzed with machine learning can detect MVP at risk for ventricular arrhythmias and fibrosis and can identify novel ECG correlates of arrhythmic risk regardless of leaflet involvement or mitral regurgitation severity. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.