Cardiovascular Therapeutics

Background. To date, immunotherapy for patients with malignant tumors has shown a significant association with myocarditis. However, the mechanism of metabolic reprogramming changes for immunotherapy-related cardiotoxicity is still not well understood. Methods. The CD45⁺ single-cell RNA sequencing (scRNA-seq) of the Pdcd1^-/-Ctla4^+/- and wild-type mouse heart in GSE213486 was downloaded to demonstrate the heterogeneity of immunocyte atlas in immunotherapy-related myocarditis. The liquid chromatography–tandem mass spectrometry (LC-MS/MS) spectrum metabolomics analysis detects the metabolic network differences. The drug prediction, organelle level interaction, mitochondrial level regulatory network, and phosphorylation site prediction for key regulators have also been screened via multibioinformatics analysis methods. Results. The scRNA analysis shows that the T cell is the main regulatory cell subpopulation in the pathological progress of immunotherapy-related myocarditis. Mitochondrial regulation pathway significantly participated in pseudotime trajectory- (PTT-) related differential expressed genes (DEGs) in the T cell subpopulation. Additionally, both the gene set enrichment analysis (GSEA) of PTT-related DEGs and LC-MS/MS metabolomics analysis showed that mitochondrial-regulated glycerolipid metabolism plays a central role in metabolic reprogramming changes for immunotherapy-related cardiotoxicity. Finally, the hub-regulated protease of diacylglycerol kinase zeta (Dgkz) was significantly identified and widely played various roles in glycerolipid metabolism, oxidative phosphorylation, and lipid kinase activation. Conclusion. Mitochondrial-regulated glycerolipid metabolism, especially the DGKZ protein, plays a key role in the metabolic reprogramming of immunotherapy-related myocarditis.

The objectives of this study were to evaluate statin eligibility among Middle Eastern patients admitted with acute myocardial infarction (AMI) who had no prior use of statin therapy, according to 2013 ACC/AHA and 2016 USPSTF guidelines, and to compare statin eligibility between men and women. This was a retrospective multicenter observational study of all adult patients admitted to five tertiary care centers in Jordan with a first-time AMI, no prior cardiovascular disease, and no prior statin use between April 2018 and June 2019. Ten-year atherosclerotic cardiovascular disease (ASCVD) risk score was estimated based on ACC/AHA risk score. A total of 774 patients met the inclusion criteria. The mean age was 55 years (), 120 (15.5%) were women, and 688 (88.9%) had at least one risk factor of cardiovascular disease. Compared to men, women were more likely to be older; had a history of diabetes, hypertension, and hypercholesterolemia; and had higher body mass index, systolic blood pressure, total cholesterol, and high-density lipoproteins. Compared to women, men were more likely to have a higher 10-year ASCVD risk score (14.0% vs. 17.8%, ), and more men had a 10-year ASCVD risk score of ≥7.5% and ≥10%. The proportion of patients eligible for statin therapy was 80.2% based on the 2013 ACC/AHA guidelines and 59.5% based on the USPSTF guidelines. A higher proportion of men were eligible for statin therapy compared to women, based on both the 2013 ACC/AHA (81.4% vs. 73.5%, ) and USPSTF guidelines (62.0% vs. 45.2%, ). Among Middle Easterners, over half of patients with AMI would have been eligible for statin therapy prior to admission based on the 2013 ACC/AHA and USPSTF guidelines, with the presence of gender gap. Adopting these guidelines in clinical practice might positively impact primary cardiovascular preventive strategies in this region.

The response to ischemia in peripheral artery disease (PAD) depends on compensatory neovascularization and coordination of tissue regeneration. Identifying novel mechanisms regulating these processes is critical to the development of nonsurgical treatments for PAD. E-selectin is an adhesion molecule that mediates cell recruitment during neovascularization. Therapeutic priming of ischemic limb tissues with intramuscular E-selectin gene therapy promotes angiogenesis and reduces tissue loss in a murine hindlimb gangrene model. In this study, we evaluated the effects of E-selectin gene therapy on skeletal muscle recovery, specifically focusing on exercise performance and myofiber regeneration. C57BL/6J mice were treated with intramuscular E-selectin/adeno-associated virus serotype 2/2 gene therapy (E-sel/AAV) or LacZ/AAV2/2 (LacZ/AAV) as control and then subjected to femoral artery coagulation. Recovery of hindlimb perfusion was assessed by laser Doppler perfusion imaging and muscle function by treadmill exhaustion and grip strength testing. After three postoperative weeks, hindlimb muscle was harvested for immunofluorescence analysis. At all postoperative time points, mice treated with E-sel/AAV had improved hindlimb perfusion and exercise capacity. E-sel/AAV gene therapy also increased the coexpression of MyoD and Ki-67 in skeletal muscle progenitors and the proportion of Myh7⁺ myofibers. Altogether, our findings demonstrate that in addition to improving reperfusion, intramuscular E-sel/AAV gene therapy enhances the regeneration of ischemic skeletal muscle with a corresponding benefit on exercise performance. These results suggest a potential role for E-sel/AAV gene therapy as a nonsurgical adjunct in patients with life-limiting PAD.

Background and Aims. The distal transradial access (dTRA) is a new puncture site for coronary catheterization. We sought to evaluate the feasibility, safety, and complication rates of using the dTRA for cardiac catheterization in Chinese patients. Methods. A total of 263 consecutive patients who underwent catheterization through the dTRA were enrolled. The primary endpoint of the study was the rate of conversion to another access site due to the impossibility of successful artery puncture or intubation. Secondary safety endpoints were the rates of bleeding-related complications and nerve disorders. Results. Among 263 patients, the puncture success rate was 96.2% (253/263). Eleven patients were successfully punctured, but the guide wire was difficult to advance. One patient had intubation failure, and the success rate of intubation was 91.6% (241/263). Two hundred thirty-three patients underwent puncture via the right dTRA, 5 patients underwent puncture via the left dTRA, and 3 patients underwent puncture via the bilateral dTRA. A total of 158 (65.6%) patients underwent coronary angiography, and 83 (34.4%) patients underwent percutaneous coronary intervention. After the procedure, only 2 (0.8%) patients had mild bleeding at the puncture site, 2 (0.8%) had a forearm hematoma, and no patient had a nerve disorder. Conclusions. DTRA has a low incidence of complications, making it a safe and effective technique for cardiac catheterization.

The current study was designed to determine pulegone’s antihypertensive and vasoprotective activity in L-NAME-induced hypertensive rats. Firstly, the hypotensive dose-response relationship of pulegone was evaluated in normotensive anesthetized rats using the invasive method. Secondly, the mechanism involved in hypotensive activity was determined in the presence of pharmacological drugs such as atropine/muscarinic receptor blocker (1 mg/kg), L-NAME/NOS inhibitor (20 mg/kg), and indomethacin/COX inhibitor (5 mg/kg) in anesthetized rats. Furthermore, studies were carried out to assess the preventive effect of pulegone in L-NAME-induced hypertensive rats. Hypertension was induced in rats by administering L-NAME (40 mg/kg) orally for 28 days. Rats were divided into six groups which were treated orally with tween 80 (placebo), captopril (10 mg/kg), and different doses of pulegone (20 mg/kg, 40 mg/kg, and 80 mg/kg). Blood pressure, urine volume, sodium, and body weight were monitored weekly. After 28 days, the effect of pulegone on lipid profile, hepatic markers, antioxidant enzymes, and nitric oxide was estimated from the serum of treated rats. Moreover, plasma mRNA expression of eNOS, ACE, ICAM1, and EDN1 was measured using real-time PCR. Results show that pulegone dose-dependently decreased blood pressure and heart rate in normotensive rats, with the highest effect at 30 mg/kg/i.v. The hypotensive effect of pulegone was reduced in the presence of atropine and indomethacin, whereas L-NAME did not change its hypotensive effect. Concurrent treatment with pulegone for four weeks in L-NAME-treated rats caused a reduction in both systolic blood pressure and heart rate, reversed the reduced levels of serum nitric oxide (NO), and ameliorated lipid profile and oxidative stress markers. Treatment with pulegone also improved the vascular response to acetylcholine. Plasma mRNA expression of eNOS was reduced, whereas ACE, ICAM1, and EDN1 levels were high in the L-NAME group, which was facilitated by pulegone treatment. To conclude, pulegone prevented L-NAME-induced hypertension by demonstrating a hypotensive effect through muscarinic receptors and cyclooxygenase pathway, indicating its use as a potential candidate in managing hypertension.

Background. Atrial fibrillation (AF) is the most common arrhythmia in clinical. Atrial fibrosis is a hallmark feature of atrial structural remodeling in AF, which is regulated by the TGF-β1/Smad3 pathway. Recent studies have implicated that miRNAs are involved in the process of AF. However, the regulatory mechanisms of miRNAs remain largely unknown. This study is aimed at investigating the function and regulatory network of miR-135a in AF. Methods. In vivo, the plasma was collected from patients with AF and non-AF subjects. Adult SD rats were induced by acetylcholine (ACh) (66 μg/ml)-CaCl₂ (10 mg/ml) to establish an AF rat model. In vitro, atrial fibroblasts (AFs), isolated from adult SD rats, were treated with high-frequency electrical stimulation (HES) (12 h) and hypoxia (24 h) to mimic the AF and atrial fibrosis, respectively. miR-135a expression was detected through quantitative real-time polymerase chain reaction (qRT-PCR). The association between miR-135a and Smad3 was speculated by the TargetScan database and confirmed by the luciferase reporter assay. Fibrosis-related genes, Smad3, and TRPM7 were all assessed. Results. The expression of miR-135a was markedly decreased in the plasma of AF patients and AF rats, which was consistent with that in HES-treated and hypoxia-treated AFs. Smad3 was identified as a target of miR-135a. the downregulation of miR-135a was associated with the enhancement of Smad3/TRPM7 expressions in AFs. Additionally, the knockdown of Smad3 significantly reduced the expression of TRPM7 and further inhibited atrial fibrosis. Conclusions. Our study demonstrates that miR-135a regulates AF via Smad3/TRPM7, which is a potential therapeutic target for AF.