Potential Targets of Natural Products for Improving Cardiac Ischemic Injury: The Role of Nrf2 Signaling Transduction.

Myocardial ischemia is the leading cause of health loss from cardiovascular disease worldwide. Myocardial ischemia and hypoxia during exercise trigger the risk of sudden exercise death which, in severe cases, will further lead to myocardial infarction. The Nrf2 transcription factor is an important antioxidant regulator that is extensively engaged in biological processes such as oxidative stress, inflammatory response, apoptosis, and mitochondrial malfunction. It has a significant role in the prevention and treatment of several cardiovascular illnesses, since it can control not only the expression of several antioxidant genes, but also the target genes of associated pathological processes. Therefore, targeting Nrf2 will have great potential in the treatment of myocardial ischemic injury. Natural products are widely used to treat myocardial ischemic diseases because of their few side effects. A large number of studies have shown that the Nrf2 transcription factor can be used as an important way for natural products to alleviate myocardial ischemia. However, the specific role and related mechanism of Nrf2 in mediating natural products in the treatment of myocardial ischemia is still unclear. Therefore, this review combs the key role and possible mechanism of Nrf2 in myocardial ischemic injury, and emphatically summarizes the significant role of natural products in treating myocardial ischemic symptoms, thus providing a broad foundation for clinical transformation.

Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.

OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.

Hospital admission and mortality rates for ischemic heart disease in Thailand: 2012-2021.

OBJECTIVE: To provide an update on the epidemiology of ischemic heart disease (IHD), including the age-standardized rates of hospital admission and mortality for IHD in Thailand from 2012 to 2021, using the Ministry of Public Health National database. RESULTS: The overall age-standardized hospital admission rate for IHD decreased from 427.5 per 100,000 people in 2012 to 390.5 per 100,000 in 2021. In men, the age-standardized hospital admission rate was 462.7 per 100,000 people in 2012, reaching 485.8 per 100,000 in 2021, p for trend = 0.141. In women, the age-standardization hospital admission rate for IHD dropped by 24.1% over the decade (p for trend = 0.008). The overall age-standardized IHD mortality rate in 2012 was 23.4 per 100,000 people, peaked at 28.6 per 100,000 in 2016, and reached 26.9 per 100,000 in 2021, p for trend = 0.181. In men, the age-standardized IHD mortality rate rose by 26.6% over a decade, p for trend = 0.004. The age-standardized IHD mortality rate among women was consistent from 2012 to 2021, p for trend = 0.130. However, for people aged < 60, rising trends in IHD mortality rates over a decade were observed; it rose by 59.6% in men and 36.1% in women.

Computed tomography myocardial perfusion imaging to detect myocardial ischemia in patients with anxiety and obstructive coronary heart disease post-exposure to mental stressors.

This study aims to measure myocardial blood flow (MBF) using dynamic CT- myocardial perfusion imaging (CT-MPI) combined with mental stressors in patients with obstructive coronary artery disease (OCAD) and in patients with anxiety and no obstructive coronary artery disease (ANOCAD). A total of 30 patients with OCAD with 30 patients with ANOCAD were included in this analysis. Using the 17-segment model, the rest and stress phase MBF of major coronary arteries in participants were recorded respectively. Compared with ANOCAD patients, OCAD patients were more likely to have localized reduction of MBF (p < 0.05). For patients with ANOCAD, both global MBF and MBF of the main coronary arteries in the stress phase were lower than those in the rest phase (all p < 0.05), but there was no significant difference in MBF among the main coronary arteries in the rest or stress phase (p = 0.25, p = 0.15). For patients with OCAD, the MBF of the target area was lower than that of the non-target area in both the rest and stress phase, and the MBF of the target area in the stress phase was lower than that in the rest phase (all p < 0.05). However, there was no significant difference in MBF between the rest or stress phase in the non-target area (p = 0.73). Under mental stress, the decrease in MBF in ANOCAD patients was diffuse, while the decrease in MBF in OCAD patients was localized. Dynamic CT-MPI combined with mental stressors can be used to detect MBF changes in anxiety patients.

Regulation of optimized new Shengmai powder on cardiomyocyte apoptosis and ferroptosis in ischemic heart failure rats: The mediating role of phosphatidylinositol-3-kinase/protein kinase B/tumor protein 53 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration. AIM OF THE STUDY: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF). MATERIALS AND METHODS: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction. RESULTS: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models. CONCLUSION: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF.

Widespread use of proton pump inhibitors or potassium-competitive acid blocker has changed the status of gastrointestinal bleeding in patients with ischemic heart disease: real-world data from high volume centers.

BACKGROUND: Although proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) are useful in peptic ulcer prevention, their efficacy in preventing other gastrointestinal bleeding remains unclear. This study aimed to identify the status of gastrointestinal bleeding in the modern era when PPIs are widely used. METHODS: This study included patients who underwent percutaneous coronary intervention (PCI) between 2018 and 2019 at two high-volume centers. Patients were categorized based on whether they experienced gastrointestinal bleeding within 2 years of PCI into groups A (patients who experienced gastrointestinal bleeding within 2 years after PCI) and B (patients who did not experience gastrointestinal bleeding). RESULTS: Groups A and B included 21 (4.1%) and 494 (95.9%) patients, respectively (a total of 515 patients). Age at the initial PCI (77.8±2.4 and 72.0±0.5 years in groups A and B, respectively; p = 0.02), weight (53.8±3.2 and 61.8±0.7 kg in groups A and B, respectively; p = 0.01), and concomitant warfarin use (14.3% and 2.0% in groups A and B, respectively; p = 0.0005) were significantly different between the groups. The high bleeding risk rate (90.5% and 47.6% in groups A and B, respectively; p = 0.0001) was significantly different between the groups. A total of 95.9% of patients were taking PPIs or PCAB without significant differences between the groups. However, only one patient, who was taking steroids, had a gastric ulcer during PCAB treatment. CONCLUSIONS: Acid-related upper gastrointestinal bleeding is largely controlled by PPIs in post-PCI patients. Furthermore, the risk factors for non-acid-related bleeding include older age, lower weight, and concomitant warfarin use.

Meta-analysis of the association between interleukin-17 and ischemic cardiovascular disease.

BACKGROUND: Interleukin-17 (IL-17) has been hypothesized to be involved in ischemic cardiovascular disease (ICVD). However, the association of IL-17 with ICVD remained unclear. The aim of this study was to systematically analyze the available evidence regarding the association between IL-17 and ICVD. METHODS: We searched the PubMed, Web of Science, Cochrane Library, and Embase databases up to October 2023 to identify publications on the association between IL-17 and ICVD. The merged results were analyzed using a random effects model for meta-analysis and subgroup analysis. RESULTS: A total of 955 publications were initially identified in our search and screened; six studies were eventually included in the analysis. The average age of study participants was 60.3 ± 12.6 years and 65.5% were men. There was a high degree of heterogeneity among studies. The results showed that IL-17 level were higher in the case group than those in the control group (standardized mean difference, SMD = 1.60, 95% confidence interval (95% CI): 0.53-2.66, P = 0.003). In sensitivity analysis, the merged results showed good robustness. Additionally, subgroup analysis showed that race and ethnicity, sample size, and detection methods were significant factors influencing heterogeneity in the published studies. CONCLUSION: Our finding revealed that increased IL-17 level contributed to the development of ICVD, suggesting IL-17 as a potential risk marker. Further research is needed to establish IL-17 as a therapeutic biomarker of ICVD.

Role of myocardial strain imaging in diagnosing inducible myocardial ischemia with treadmill contrast-enhanced stress echocardiography.

INTRODUCTION: The aim of this study is to analyze the diagnostic value of global longitudinal strain (GLS) in detecting inducible myocardial ischemia in patients with chest pain undergoing treadmill contrast-enhanced stress echocardiography (SE). METHODS: We retrospectively enrolled all patients who underwent invasive coronary angiography after treadmill contrast-enhanced SE. Rest and peak-stress myocardial GLS, segmental LS, and LS of 4-chamber (CH), 2-CH, and 3-CH views were reported. Luminal stenosis of more than 70% or fractional flow reserve (FFR) of < 0.8 was considered significant. RESULTS: In total 33 patients were included in the final analysis, among whom sixteen patients (48.4%) had significant coronary artery stenosis. Averaged GLS, 3-CH, and 4-CH LS were significantly lower in patients with critical coronary artery stenosis compared to those without significant stenosis (-17.1 ± 7.1 vs. -24.2 ± 7.2, p = 0.041), (-18.2 ± 8.9 vs. -24.6 ± 8.2, p = 0.045) and (-14.8 ± 6.2 vs. -22.8 ± 7.8, p = 0.009), respectively. Receiver operating characteristic (ROC) analysis of ischemic and non-ischemic segments demonstrated that a cut-off value of -20% of stress LS had 71% sensitivity and 60% specificity for ruling out inducible myocardial ischemia (Area under the curve was AUC = 0.72, P < 0.0001). CONCLUSION: Myocardial LS measured with treadmill contrast-enhanced stress echocardiography demonstrates potential value in identifying patients with inducible myocardial ischemia.

Cardiac evaluation in amiodarone-induced thyroid dysfunction with suspected cardiac ischemia?: a case report and review of the literature.

BACKGROUND: Amiodarone-induced thyroid dysfunction (AIT) is a side-effect associated with the use of Amiodarone for the treatment of refractory arrythmias. Resulting hyperthyroidism can precipitate cardiac complications, including cardiac ischemia and myocardial infarction, although this has only been described in a few case reports. CASE PRESENTATION: We present here a clinical scenario involving a 66-year-old male Caucasian patient under Amiodarone for atrial fibrillation, who developed AIT. In the presence of dyspnea, multiple cardiovascular risk factors and ECG abnormalities, a transthoracic echocardiogram was performed, showing inferobasal hypokinesia. This led to further investigations through a cardiac PET-CT, where cardiac ischemia was suspected. Ultimately, the coronary angiography revealed no abnormalities. Nonetheless, these extensive cardiologic investigations led to a delay in initiating an emergency endovascular revascularization for acute-on-chronic left limb ischemia. Although initial treatment using Carbimazole was not successful after three weeks, the patient reached euthyroidism after completion of the treatment with Prednisone so that eventually thyroidectomy was not performed. Endovascular revascularization was finally performed after more than one month. CONCLUSIONS: We discuss here cardiac abnormalities in patients with AIT, which may be due to relative ischemia secondary to increased metabolic demand during hyperthyroidism. Improvement of cardiac complications is expected through an optimal AIT therapy including medical therapy as the primary approach and, when necessary, thyroidectomy. Cardiac investigations in the context of AIT should be carefully considered and may not justify delaying other crucial interventions. If considered mandatory, diagnostic procedures such as coronary angiography should be preferred to functional testing.

Effects of nordic walking training on gait and exercise tolerance in male ischemic heart disease patients.

This technique-focused observational study explores the impact of a 6-week Nordic Walking (NW) program on physiological and biomechanical aspects in ischemic heart disease (IHD) patients. Twelve male IHD patients (66.2 ± 5.2 years, 12.2 ± 7.5 years of disease duration) were evaluated pre- and post-training for (i) gait parameters, (ii) exercise tolerance using electrocardiographic (ECG) stress test, (iii) a 6-min walk test (6MWT). The NW training, adhering to IHD patient guidelines, involved a 100-m walk at a self-selected, preferred speed without sticks, with classic NW sticks and mechatronic sticks. A mechatronic measuring system, specifically engineered for measuring, diagnosing and monitoring the patient's gait, was integrated into mechatronic sticks. Post-training, significant enhancements were observed in ECG stress test duration, metabolic equivalency, and 6MWT distance, irrespective of the stick type. However, no significant changes were noted in spatiotemporal parameters concerning the measured side, stick utilisation, or type. The results suggest that NW training boosts exercise capacity and refines gait mechanics in male IHD patients. However, the improvement in exercise capacity was not linked to changes in gait mechanics from NW training but rather to the movement during NW gait. Hence, the key to enhancing exercise capacity in IHD patients is the movement during NW gait, not the quality of gait mechanics.

A burden of proof study on alcohol consumption and ischemic heart disease.

Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk - specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males - while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

Association between uterine leiomyoma and fragmented QRS waves: a prospective case-control study.

OBJECTIVE: The aim of this study was to evaluate the relationship between uterine leiomyoma and fragmented QRS, a non-invasive indicator of cardiovascular risk and myocardial ischemia, in women with uterine leiomyoma. METHODS: In this prospective case-control study, a total of 47 patients diagnosed with uterine leiomyoma (case group) and 47 healthy individuals without uterine leiomyoma (control group) who had undergone bilateral tubal ligation surgery were included. Various demographic, clinical, and laboratory parameters and the presence of fragmented QRS were recorded. RESULTS: The leiomyoma group showed significantly higher body mass index (27.46±2.18 vs. 25.9±2.87 kg/m2, p=0.005) and waist circumference (91.34±9.30 vs. 84.97±9.3 cm, p=0.001) compared with the control group. Uterine volumes were also significantly higher in the leiomyoma group (235.75±323.48 vs. 53.24±12.81 mm3, p<0.001). The presence of fragmented QRS was detected in 18.1% of the patients. Multiple regression analysis identified age, fasting blood glucose value, and the presence of fragmented QRS as independent risk factors for the presence of leiomyoma. CONCLUSION: This study provides valuable insights into the relationship between uterine leiomyoma and fragmented QRS. The presence of fragmented QRS was identified as an independent risk factor for the presence of leiomyoma. Further research is needed to better understand the underlying mechanisms connecting uterine leiomyoma and cardiovascular health.

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia.

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

Extension of interval between adjacent pulse delivery cycles to deal with myocardial ischemia by intravascular lithotripsy: case report.

BACKGROUND: Intravascular lithotripsy (IVL) represents a novel approach in the management of coronary calcification. This technique employs acoustic pressure waves, generated by a shockwave balloon, to effectively fracture both superficial and deep calcification in situ. The efficacy and safety of IVL have been convincingly demonstrated through the Disrupt CAD I-IV studies. While IVL is associated with the occurrence of atrial and ventricular arrhythmias, there is no evidence to indicate it causes myocardial ischemia. CASE DESCRIPTION: A 71-year-old man was admitted presenting with chest pain. His previous coronary angiography revealed stenosis and calcification in the left anterior descending branch. An attempt to predilate the lesion using two Lacrosse non-slip element balloons was unsuccessful. Ventricular premature beats and transient ST-segment depression were captured during the utilization of IVL. The operator gradually extended the pulse emission interval across two consecutive cycles to mitigate myocardial ischemia. Notably, when the interval reached 30s, the patient had no chest pain or ST-segment changes. Subsequent images of intravascular ultrasound confirmed calcification ruptures. Therapeutic intervention included the placement of a stent and the application of a drug-coated balloon in the left anterior descending branch. A telephonic follow-up six months later indicated the patient had no discomfort. CONCLUSIONS: This case underscores the effectiveness of gradually extending the pulse emission interval as a strategic complement to the clinical application of IVL. In certain clinical scenarios, it may become imperative to suspend the pulse delivery to improve myocardial blood supply.

Remotely Triggered LAD Occlusion Using a Balloon Catheter in Spontaneously Breathing Mice.

Acute myocardial infarction (AMI) is a prevalent and high-mortality cardiovascular condition. Despite advancements in revascularization strategies for AMI, it frequently leads to myocardial ischemia-reperfusion injury (IRI), amplifying cardiac damage. Murine models serve as vital tools for investigating both acute injury and chronic myocardial remodeling in vivo. This study presents a unique closed-chest technique for remotely inducing myocardial IRI in mice, enabling the investigation of the very early phase of occlusion and reperfusion using in-vivo imaging such as MRI or PET. The protocol utilizes a remote occlusion method, allowing precise control over ischemia initiation after chest closure. It reduces surgical trauma, enables spontaneous breathing, and enhances experimental consistency. What sets this technique apart is its potential for simultaneous noninvasive imaging, including ultrasound and magnetic resonance imaging (MRI), during occlusion and reperfusion events. It offers a unique opportunity to analyze tissue responses in almost real-time, providing critical insights into processes during ischemia and reperfusion. Extensive systematic testing of this innovative approach was conducted, measuring cardiac necrosis markers for infarction, assessing the area at risk using contrast-enhanced MRI, and staining infarcts at the scar maturation stage. Through these investigations, emphasis was placed on the value of the proposed tool in advancing research approaches to myocardial ischemia-reperfusion injury and accelerating the development of targeted interventions. Preliminary findings demonstrating the feasibility of combining the proposed innovative experimental protocol with noninvasive imaging techniques are presented herein. These initial results highlight the benefit of utilizing the purpose-built animal cradle to remotely induce myocardial ischemia while simultaneously conducting MRI scans.