Therapy For Ischemic Heart Disease Research Articles

Ginsenoside Rb1 promotes angiogenesis potentially by activating the JAK-STAT3 signalling pathway

Conventional revascularization strategies for ischemic heart disease (IHD) are designed to prompt reperfusion of the coronary artery to the salvaged cardiomyocytes. However, these strategies may cause myocardial reperfusion injuries. Therefore, a safe and effective strategy needs to be developed to improve the conventional strategies. Here, we investigated the pro-angiogenic effect of Ginsenoside Rb1 (Rb1) to provide the experimental basis for angiogenesis-mediated drug therapy of IHD. Thus, Human umbilical vein endothelial cells (HUVECs) were treated with either a vehicle or Rb1 at 4, 8, 12 or 16 μM for 24 h. A model of hindlimb ischemia was established using C57BL/6J mice. In sham-operated mice, only the femoral artery was isolated without ligation whereas the other operations and supplementation control group were consistent. The mice in the supplementation group were injected with Rb1 (50 mg/kg body wt./day) for 7 days. The results indicated that Rb1 promotes cell proliferation, adhesion, migration and tube formation in the HUVECs in a dose-dependent manner. The ED50 of Rb1 to improve cell adhesion is 8 μM. In mice, Rb1 promoted angiogenesis after the ligation of the femoral artery and ameliorated the ischemic conditions. Intriguingly, more blood flow recovery was observed in the Rb1 supplemented mice than in the vehicle-treated mice (0.85 ± 0.05 vs. 0.71±0.10 on day 3; 0.94±0.10 vs. 0.75±0.08 on day 7). In HUVECs, Rb1 increased the phosphorylation of STAT3 and JAK, which may be the mechanism through which Rb1 mitigates IHD. Moreover, our results confirmed that Rb1mitigates IHD potentially by activating the JAK-STAT3 pathway. Further clinical trials are warranted to verify the clinical implications of Rb1.

Pioglitazone-incorporated microspheres alleviates cardiac dysfunction through macrophage polarization in a rat myocardial infarction model

Abstract Inflammatory processes are essential for the repair processes after myocardial infarction. Among inflammatory cells involved in this process, macrophages play a critical role through polarization in pro-inflammatory M1 or reparative M2 subtype. Pioglitazone, known as a treatment drug for diabetes mellitus, is reported to regulate macrophage polarization toward reparative M2 subtype. Poly L-lactic-co-glycolic acid (PLGA) has been widely accepted as the delivery carrier in drug delivery system (DDS). Here, we aimed to validate the therapeutic effects and investigate the mechanisms of DDS-based treatment using pioglitazone to left ventricular remodeling after myocardial infarction. Pioglitazone-incorporated PLGA microspheres (PGZ-MS) were prepared and the drug release profile was evaluated. The concentration of interleukin-10 secreted from murine bone marrow derived macrophages incubated with PGZ-MS was quantified in the culture supernatant. To validate the therapeutic potential of PGZ-MS in vivo, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce myocardial infarction. Mock-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction (n=9–11/group). Cardiac function and left ventricular size were assessed by echocardiography. At 28-day after surgery, rats were sacrificed, and excised hearts were evaluated histologically. PGZ-MS released 1.8±0.3% of incorporated PGZ within 24 hours and 29.5±1.2% within 14 days indicating sustained release of PGZ in vitro. PGZ-MS augmented Interleukin-10 release from bone marrow derived macrophages, indicating polarization toward reparative M2 subtype. PGZ-MS significantly ameliorated cardiac function after myocardial infarction (fractional shortening: MI vs MI+Mock-MS vs MI+PGZ-MS, 24.4±1.1 vs 24.3±1.6 vs 32.2±1.4%; P=0.0035) with reverse remodeling (wall thickness: MI vs MI+Mock-MS vs MI+PGZ-MS, 0.69±0.12 vs 0.71±0.13 vs 1.06±0.09; P=0.03). Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization toward reparative M2 subtype (ratio of reparative M2 macrophages: 0.39±0.03 vs 0.42±0.02 vs 0.54±0.02; P=0.0004) and attenuated apoptosis of cardiomyocytes in the ischemic border zone (MI vs MI+Mock-MS vs MI+PGZ-MS, 2.6±0.2 vs 1.9±0.2 vs 1.2±0.2 cells/field; P=0.002). In the present study, we confirmed that PGZ-MS could realize sustained release of pioglitazone which resulted in sustained effect of macrophage polarization and attenuated left ventricular remodeling accompanied with the amelioration of cardiac dysfunction and cardiomyocytes apoptosis. The strategy of DDS-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischemic heart disease in the future. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan

Cross talk of vasopressin conditioned cell therapy in ischemic heart disease: Role of oxidative stress markers.

Objective(s):Background: Impaired coronary blood flow causes cardiac ischemia. Cellular therapy is a new approach to the treatment of myocardial ischemia. This study aimed to investigate the effect of adipose tissue-derived mesenchymal stem cells (AD-MSCs) conditioned with vasopressin on oxidative stress, perivascular collagen, and angiogenesis caused by myocardial infarction (MI) in rats. Materials and Methods:We divided 40 male albino Wistar rats into 4 groups; Control group; No intervention; in experimental groups, after it generated induced MI on models, it divided into three groups: Vehicle group (150 μl of cell-free culture medium received); ASC-MI group (6× 106 AD-MSC received) and AVP-ASC-MI group (received 6 × 106 AD-MSC conditioned with 10 nM vasopressin). Then, histologic parameters and anti-oxidant enzymes were evaluated 7 days post-MI cell injection. Results:Arterial muscle diameter improved and collagen deposition around the coronary arteries decreased in cell-received groups compared with the vehicle group. Malondialdehyde (MDA), catalase (CAT), (GSH) Glutathione, and Total Anti-oxidant Capacity (TAC) parameters were not significantly different between the cells received groups compared with the vehicle group. But the Catalase (CAT) parameter in the ASC-MI group had a significant increase from the control group. Conclusion:We prepared direct evidence that intramyocardial injection of AD-MSCs reveals the positive cardiac remodeling post-MI in rats, and these useful effects can be more enhanced by administrating injection of conditioned ADSCs with vasopressin.

Pioglitazone-incorporated microspheres targeting macrophage polarization alleviates cardiac dysfunction after myocardial infarction.

Excessive and chronic inflammation after a myocardial infarction (MI) is associated with left ventricular remodelling and impaired cardiac function. Among inflammatory cells, macrophages play a critical role in polarizing proinflammatory M1 or the reparative M2 subtype. Pioglitazone (PGZ) is reported to regulate macrophage polarization to the M2 subtype. Our goal was to validate the therapeutic effects and the mechanisms of PGZ utilizing a drug delivery system. Poly L-lactic-co-glycolic acid microspheres (MS) incorporating PGZ were prepared. To validate the therapeutic potential of PGZ-MS, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce an MI. Placebo-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction. Cardiac function and size were assessed by echocardiography. At 28 days after surgery, the rats were sacrificed, and the excised hearts were evaluated histologically. Sustained release of PGZ from the PGZ-MS was confirmed in vitro. PGZ-MS significantly rehabilitated cardiac dysfunction after an MI (fractional shortening: MI vs MI+placebo-MS vs MI+PGZ-MS, 24.4 ± 1.1 vs 24.3 ± 1.6 vs 32.2 ± 1.4%; P = 0.0035) with reverse remodelling. Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization (ratio of M2 subtype: 0.39 ± 0.03 vs 0.42 ± 0.02 vs 0.54 ± 0.02; P = 0.0004) and attenuated apoptosis of cardiomyocytes in the ischaemic border zone. We confirmed macrophage polarization by sustained release of PGZ, which resulted in amelioration of adverse left ventricular remodelling and cardiac dysfunction. Drug delivery system-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischaemic heart disease. (241 words).

Clinical and electrophysiological characteristics of psychovegetative syndrome during rehabilitation after coronary bypass graft

Objective. To investigate the impact of anxiety in development of psychovegetative syndrome in patients after operative myocardial revascularization, to describe the nature and direction of resulting autonomic dysfunction and to study the effect of treatment with anti-anxiety therapy for this condition.
 Materials and methods. 54 patients aged 4575 (36 the main group, 18 the comparison group), on average 1112 days after the coronary artery bypass graft (CABG) and during the process of early and late postoperative rehabilitation were investigated. A score assessment of the psychological and autonomic spheres, and sleep quality was analyzed. Indicators of vegetative tone and vegetative regulation were assessed, in particular, temporal and spectral indicators of heart rate variability. In addition to basic therapy for ischemic heart disease (IHD), the patients of the main group received therapy with vegetative corrector.
 Results. In most cases, in the early postoperative period after CABG, moderate anxiety disorders and sleep disturbance were registered in combination with autonomic dysregulation with sympathetic influences prevailing. Addition of psychotropic therapy to the basic therapy of IHD patients in the main group allowed for 1014 days to significantly reduce the level of anxiety, improve sleep quality and correct the existing autonomic disorders with a tendency to further regression in the late postoperative period.
 Conclusions. This study found that patients with an increased level of anxiety after CABG are characterized by the formation of a psychovegetative syndrome with predominance of sympathetic activity. The use of anxiolytic therapy can reduce the severity of anxiety and autonomic dysfunction, which can probably become an additional factor contributing to successful rehabilitation of patients after CABG in the early and late postoperative periods and prevention of IHD progression.

Mitochondrial Membrane Potential Identifies a Subpopulation of Mesenchymal Progenitor Cells to Promote Angiogenesis and Myocardial Repair.

Identifying effective donor cells is one of obstacles that limits cell therapy for heart disease. In this study, we sorted a subpopulation of human mesenchymal progenitor cells (hMPCs) from the right atrial appendage using the low mitochondrial membrane potential. Compared to the non-sorted cells, hMPCs hold the capacity for stemness and enrich mesenchymal stem cell markers. The hMPCs display better ability for survival, faster proliferation, less production of reactive oxygen species (ROS), and greater release of cytoprotective cytokines. The hMPCs exhibit decreased expression of senescence genes and increased expression of anti-apoptotic and antioxidant genes. Intramyocardial injection of hMPCs into the infarcted heart resulted in increased left ventricular ejection fraction and reduced cardiac remodeling and infarct size in the group of animals receiving hMPCs. Both in vitro and in vivo studies indicated hMPCs have the potential to differentiate into endothelial cells and smooth muscle cells. Immunohistochemistry staining showed that cell therapy with hMPCs enhances cardiac vascular regeneration and cardiac proliferation, and decreases cardiac cell apoptosis, which is associated with the increased secretion of cytoprotective and pro-angiogenic cytokines. Overall, we discovered a subpopulation of human mesenchymal progenitor cells via their low mitochondrial membrane potential, which might provide an alternative donor cell source for cellular therapy for ischemic heart disease.

Reduction in shock burden with catheter ablation versus escalated antiarrhythmic drug therapy: Insights from the VANISH trial

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1. Canadian Institutes of Health Research (CIHR) 2. Additional financial support from St. Jude Medical and Biosense Webster Background Recurrent shocks for ventricular tachycardia (VT) are associated with an increased risk of heart failure and mortality and have a negative influence on quality of life. Catheter ablation has been shown to improve VT event-free survival in patients with antiarrhythmic drug (AAD)-refractory VT and prior myocardial infarction (MI); however, the effects of ablation on shock burden has yet to be investigated. Purpose Our primary objectives were to compare the shock-treated VT event burden and appropriate shock burden following randomization to treatment with either catheter ablation or escalated AAD therapy among VT patients with prior MI in the Ventricular tachycardia AblatioN versus escalated antiarrhythmic drug therapy in Ischemic Heart disease (VANISH) randomized trial. Methods Recurrent event analyses were performed using the intention-to-treat population of the VANISH trial. Shock-treated VT event burden was defined as the total number of VT events treated with ≥1 appropriate internal or external shocks. Appropriate shock burden was defined as the total number of appropriate internal and external shocks delivered, regardless of the number of VT events. All VT events and implantable cardioverter defibrillator (ICD) therapies were adjudicated by reviewers blinded to the treatment allocation. Three recurrent event models were used to compare the shock burden between treatment arms (Anderson-Gill (AG), Frailty, and Prentice, Williams, and Peterson Total Time (PWP-TT). Each model clustered by patient and accounted for competing risk of death with the Fine and Gray sub-distributions hazards model. Results Of the 259 patients enrolled in the VANISH trial [median age 69.8 (IQR 63.0-74.2) years, 7.0% women], 132 patients were randomized to ablation and 129 patients to escalated AAD therapy. Over a median follow-up of 23.4 (IQR 14.7-40.4) months, there were 138 shock-treated VT events [39.07 (95% CI 33.14-46.07) shock-treated VT events per 100 person-years] in the ablation arm and 218 shock-treated VT events [64.60 (95% CI 56.49–73.84) shock-treated VT events per 100 person-years] in the escalated AAD therapy arm (Figure 1). Ablation patients had a 40% lower shock-treated VT event burden (ie. number of shock-treated VT events) compared to patients randomized to escalated AAD therapy [Figure 1; AG HR 0.60 (95% 0.38-0.95)]. Further, there was also a statistically significant reduction in the appropriate shock burden (i.e. number of appropriate shocks) among ablation patients (169 appropriate shocks) compared to escalated AAD therapy patients (266 appropriate shocks) [Figure 1; AG HR 0.61 (95% CI 0.37-0.96)]. All results were consistent between the 3 recurrent event models. Conclusion Among patients with AAD-refractory VT and a prior MI, catheter ablation reduced shock-treated VT event burden and appropriate shock burden compared to escalated AAD therapy.

Modified Exosomes: a Good Transporter for miRNAs within Stem Cells to Treat Ischemic Heart Disease.

Stem cell-based therapy for ischemic heart disease (IHD) has become a promising but controversial strategy during the past two decades. The fate and effects of stem cells engrafted into ischemia myocardium are still not fully understood. Stem cell-derived exosomes, a subcategory of extracellular vesicles with nano size, have been considered as an efficient and safe transporter for microRNAs (miRNAs) and a central mediator of the cardioprotective potentials of the parental cells. Hypoxia, pharmacological intervention, and gene manipulation could alter the exosomal miRNAs cargos from stem cells and promote therapeutic potential. Furthermore, several bioengineering methods were also successfully applied to modify miRNAs content and components of exosomal membrane proteins recently. In this review, we outline relevant results about exosomal miRNAs from stem cells and focus on the current strategies to promote their therapeutic efficiency in IHD.

Urolithin B, a Gut Microbiota Metabolite, Reduced Susceptibility to Myocardial Arrhythmic Predisposition after Hypoxia.

Cardiomyocyte apoptosis, neural remodeling, and gap junction channel change play critical roles in ventricular arrhythmia (VA) after acute myocardial infarction (AMI). Urolithin B (UB), one of the gut metabolites of ellagitannins, a class of antioxidant polyphenols, has various biological activities, but its direct role in cardiomyocyte apoptosis, neural remodeling, and gap junction channel change after AMI remains elusive. We investigated whether urolithin B reduced susceptibility of myocardial arrhythmic after myocardial infarction (MI). In vitro, the cardiomyocytes were subjected to hypoxia (94% N2/5% CO2/1% O2) for 3 hours. Cardiomyocyte apoptosis was assessed by TUNEL staining and western blotting. Urolithin B was found to decrease the number of apoptotic cells after hypoxia. Moreover, there was a substantial decrease in the expression of neural remodeling markers in the urolithin B treatment group. Urolithin B significantly increased the expression level of gap junction channel protein. Mechanistically, urolithin B inhibited cardiomyocyte apoptosis by activating Akt/the mammalian target of rapamycin (mTOR) pathway, and the protection of urolithin B against cardiomyocyte apoptosis was compromised with Akt gene silencing. Furthermore, urolithin B suppressed nuclear translocation of nuclear factor-kB (NF-κB) to facilitate nerve remodeling. Taken together, our findings suggested that UB reduced the occurrence of myocardial arrhythmias after hypoxia via regulation of the Akt/mTOR pathway and NF-κB nuclear translocation, which highlights the potential of UB as a novel therapy for ischemic heart disease.

Dynamics of psychovegetative syndrome in patients during the period of rehabilitation after coronary bypass

The study was to investigate the role of moderate and severe anxiety in development of psychovegetative syndrome after coronary artery bypass graft (CABG), to describe the nature and direction of resulting autonomic dysfunction and to study possibilities of anti-ancient therapy. We studied 33 patients (19 - in the main group, 14 - in the comparison group) on average 13 days after CABG and in dynamics in the process of early postoperative rehabilitation. A point assessment of the psychological and autonomic spheres, and sleep quality was made. Indicators of vegetative tone and vegetative regulation were studied, in particular, temporal and spectral indicators of heart rate variability. In addition to basic therapy for ischemic heart disease (IHD), the patients in main group were received therapy with alimemazine. In most cases, after CABG, moderate situational and personal anxiety and sleep disturbances were recorded in combination with autonomic dysregulation with a predominance of sympathetic influences from the autonomic nervous system (ANS). Adding to the basic therapy of IHD among patients of the main group of the drug with a mild anti-anxiety effect, allowed for 2 weeks to significantly reduce the level of anxiety and correct the existing autonomic disorders. This study found that patients with an increased level of anxiety after CABG are characterized by the formation of a psychovegetative syndrome with a predominance of sympathetic activity. The using anti-anxiety drugs can reduce the severity of anxiety and autonomic dysfunction, which can probably become a factor contributing to the successful rehabilitation of patients after CABG in the early and late postoperative periods, and the prevention of progression of IHD.

Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction.

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

Ефективність та безпечність триметазидину (Карметадину) в комплексному лікуванні хворих на ішемічну хворобу серця та хронічну серцеву недостатність

Метою дослідження було вивчення ефективності та безпечності триметазидину (Карметадин, компанія World Medicine) в комплексному лікуванні пацієнтів з ішемічною хворобою серця та хронічною серцевою недостатністю. 80 включеним у дослідження хворим з ішемічною хворобою серця (стабільна стенокардія напруження II–III функціонального класу) та хронічною серцевою недостатністю (II–III функціональний клас за класифікацією NYHA) проводили стандартне загальноклінічне обстеження, лабораторні (загальні аналізи крові та сечі, ліпідний, печінковий, нирковий комплекси, коагулограма, глюкоза крові) та інструментальні (електрокардіографія, ехокардіографія, добове моніторування електрокардіограми) дослідження. Пацієнти були розділені на дві групи. У контрольну групу увійшли 40 хворих, яким було призначено комплексне лікування: антитромботична терапія (аспірин 100 мг на добу), бета-адреноблокатор (бісопролол 5–10 мг на добу залежно від початкової частоти серцевих скорочень та рівня артеріального тиску за умови попередньої титрації дози), інгібітор ангіотензинперетворюючого ферменту (раміприл 5–10 мг на добу залежно від початкового рівня артеріального тиску за умови попередньої титрації дози), статин (розувастатин 20 мг на добу), при необхідності були рекомендовані нітрати та діуретики. 40 пацієнтів основної групи на фоні вищезазначеної базисної терапії приймали Карметадин (35 мг 2 рази на добу, таблетки з модифікованим вивільненням препарату). Період спостереження становив 6 місяців. Застосування Карметадину в складі комплексного лікування хворих на ішемічну хворобу серця та хронічну серцеву недостатність асоціювалося з поліпшенням якості життя пацієнтів, суттєвим зменшенням кількості та тривалості ангінозних атак, зниженням потреби в короткодіючих нітратах, поліпшенням функціонального класу серцевої недостатності, збільшенням фракції викиду лівого шлуночка; не призводило до розвитку побічних ефектів, що потребували би відміни препарату.

Modern aspects of the application of antiplatelet and hypolipidemic therapy in ischemic heart disease after coronary artery stenting

In this article it will be discussed actual issues and modern problems of the ischemic disease of the heart, antiplatelet therapy, its effects, hypolipidemic therapy, indications, counter indications, potential side effects as well as, successful management strategies after percutaneous coronary intervention following with drug eluted stents.

Modern aspects of the application of antiplatelet and hypolipidemic therapy in ischemic heart disease after coronary artery stenting

Modern aspects of the application of antiplatelet and hypolipidemic therapy in ischemic heart disease after coronary artery stenting

Gene therapy for ischaemic heart disease and heart failure.

Gene therapy has been expected to become a novel treatment method since the structure of DNA was discovered in 1953. The morbidity from cardiovascular diseases remains remarkable despite the improvement of percutaneous interventions and pharmacological treatment, underlining the need for novel therapeutics. Gene therapy-mediated therapeutic angiogenesis could help those who have not gained sufficient symptom relief with traditional treatment methods. Especially patients with severe coronary artery disease and heart failure could benefit from gene therapy. Some clinical trials have reported improved myocardial perfusion and symptom relief in CAD patients, but few trials have come up with disappointing negative results. Translating preclinical success into clinical applications has encountered difficulties in successful transduction, study design, endpoint selection, and patient selection and recruitment. However, promising new methods for transducing the cells, such as retrograde delivery and cardiac-specific AAV vectors, hold great promise for myocardial gene therapy. This review introduces gene therapy for ischaemic heart disease and heart failure and discusses the current status and future developments in this field.

Nicorandil inhibits TLR4/MyD88/NF-κB/NLRP3 signaling pathway to reduce pyroptosis in rats with myocardial infarction.

Pyroptosis is an inflammatory cell death that regulates cardiomyocyte loss after myocardial infarction. Reports indicate that nicorandil has a strong anti-inflammatory effect and protects the myocardium from myocardial infarction. However, its relationship with pyroptosis is largely unreported. Here, we investigated to influence and mechanism of action of nicorandil on cardiomyocyte pyroptosis. Forty Sprague Dawley rats were randomly assigned to sham, MI, MI + nicorandil, and MI + nicorandil + TAK242 groups (10 per group). Myocardial infarction modeling was performed through ligation of the anterior descending branch of the left coronary artery. The function of cardiac was evaluated through echocardiography, detection of myocardial adenine nucleotides, cTnI, LDH, TTC, and HE staining. Moreover, we used qRT-PCR, immunohistochemistry, and Western blotting to examine the expression of pyroptosis-related molecules and the inflammasome pathway of TLR4/MyD88/NF-κB/NLRP3. Myocardial infarction caused the activation of GSDMD, aggravated myocardial injury, and triggered cardiac dysfunction. Myocardial infarction induced pyroptotic cell death, manifested as upregulation in mRNA and protein levels associated with pyroptosis, including caspase-1 cleavage and increased expression of IL-1β and IL-18. These changes were mitigated by nicorandil. The achieved data implicate that myocardial infarction induces pyroptosis via the TLR4/MyD88/NF-κB/NLRP3 pathway, which can be inhibited by nicorandil pretreatment. Therefore, nicorandil exerts cardioprotective effects by activating KATP channels, and at least in part through inhibition of the TLR4/MyD88/NF-κB/NLRP3 pathway to reduce myocardial infarction-induced pyroptosis. As such, it is a potential therapy for ischemic heart disease.

Comparative effectiveness of ventricular tachycardia ablation versus escalated antiarrhythmic drug therapy by location of myocardial infarction: A sub-study of the VANISH trial

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Fonds de recherché du Québec-Santé (FRQS) [post doctoral award for Dr. Samuel) BACKGROUND Complexity of ventricular tachycardia (VT) substrate, efficiency of lesion formation, and the size and thickness of infarction area border zones differ based on location of myocardial infarctions (MI). These differences may translate into heterogeneity in risk of events and effectiveness of treatments for VT. Small observational studies suggest that VT from inferior infarctions have higher risk of early recurrence despite smaller infarct areas. However, differential effectiveness of VT treatments based on location of MI not been definitively established. PURPOSE The objective of this sub-study of the Ventricular tachycardia AblatioN versus escalated antiarrhythmic drug therapy in ISchemic Heart disease (VANISH) randomized trial was to compare the effectiveness of VT ablation by location of MI in reducing the composite endpoint of all-cause mortality, VT storm, or appropriate ICD therapy when compared to escalated pharmacological therapy in VT patients with a prior MI. METHODS VANISH participants were categorized into 3 subgroups based on MI location: 1. Inferior (may also have MI in other locations); 2. Non-inferior (no inferior MI, all patients not in group 1); and 3. Anterior (may also have MI in other locations). Inverse probability of treatment weighting was used to balance baseline characteristics (ie. age, sex, comorbidities, medications, and the location of additional infarctions) between patients randomized to ablation or escalated therapy within each subgroup. Weighted Cox proportional hazards models were calculated separately for each subgroup. RESULTS Of 259 patients enrolled in the VANISH trial [median age 69.8 (IQR 63.0-74.2) years, 7.0% women], 135 had an inferior MI, 124 a non-inferior MI, and 83 an anterior MI. Among patients with an inferior MI, no statistically significant difference in the primary outcome was detected between patients randomized to ablation or escalated therapy [aHR 0.78 (95% CI 0.51-1.20)]. In contrast, patients with non-inferior MIs had a statistically significant reduction in the incidence of the primary outcome with ablation [aHR 0.48 (95% CI 0.27-0.86)]; which was of greater magnitude than the reduction observed in the overall results of the VANISH trial [HR 0.72 (95% CI 0.53-0.98)]. In addition, a trend towards a reduction in the primary outcome with ablation was detected in patients with anterior MIs [aHR 0.50 (95% CI 0.23-1.09)]. CONCLUSION The effectiveness of VT ablation versus escalated pharmacological therapy varies based on the location of the MI. Patients with MI scars located only in non-inferior regions of the ventricles derive greater benefit from VT ablation in reducing VT-related events. Further studies are required to explore reasons for this finding and to assess the impact of VT treatment strategies based on MI location in optimizing outcomes.

Acupuncture as Adjuvant Therapy for Treating Stable Angina Pectoris with Moderate Coronary Artery Lesions and the Mechanism of Heart-Brain Interactions: A Randomized Controlled Trial Protocol.

Background. Stable angina pectoris with moderate coronary artery lesions is a syndrome caused by coronary artery stenosis, which endangers the quality of life. Previous acupuncture studies have shown effectiveness as a complementary therapy for ischaemic heart disease. However, more clinical evidence is needed for verification, and the mechanism should be investigated, especially involving the functional interactions between the heart and brain. Therefore, we designed a clinical trial to provide more evidence for acupuncture efficacy and its mechanism in ischaemic heart disease. Methods/Design. A total of 80 participants will be randomized to the electroacupuncture group and sham-electroacupuncture group at a ratio of 1 : 1. This trial will be conducted over 8 weeks, including a 2-week screening, 2-week treatment, and 4-week follow-up. All participants will continue to receive similar basic disease treatment procedures before the trial (including lifestyle changes and treatment for standard supportive medications, hypertension, and hyperlipidaemia, such as aspirin, metoprolol succinate, atorvastatin, and sodium fosinopril). Additionally, 12 sessions of acupuncture will be administered during the treatment period. The main outcome is Seattle Angina Questionnaire scores. The other observation indices are the heart rate variability and self-rating anxiety scale and self-rating depression scale scores. To explore mechanisms based on the hypothesis of a correlation between heart and brain function, fMRI scans will be used to detect functional brain changes in 15 patients from each group at baseline and at the end of treatment. Finally, the efficacy of acupuncture will be evaluated, and the HRV and imaging data will be correlated with clinical data to investigate the possible relationships between the brain and heart activity. Discussion. This trial will provide evidence for acupuncture as adjuvant therapy for the treatment of stable angina pectoris with moderate coronary artery lesions. The results will shed light on potential mechanisms of heart-brain interactions underlying acupuncture as an adjuvant therapy for treating ischaemic heart disease. Trials registration: Clinical Trial, https://clinicaltrials.gov/ct2/show/ChiCTR1900024937. Registered 4 August 2019, http://www.chictr.org.cn/.

The Current Dilemma and Breakthrough of Stem Cell Therapy in Ischemic Heart Disease.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide. Stem cell transplantation has become a promising approach for the treatment of IHD in recent decades. It is generally recognized that preclinical cell-based therapy is effective and have yielded encouraging results, which involves preventing or reducing myocardial cell death, inhibiting scar formation, promoting angiogenesis, and improving cardiac function. However, clinical studies have not yet achieved a desired outcome, even multiple clinical studies showing paradoxical results. Besides, many fundamental puzzles remain to be resolved, for example, what is the optimal delivery timing and approach? Additionally, limited cell engraftment and survival, challenging cell fate monitoring, and not fully understood functional mechanisms are defined hurdles to clinical translation. Here we review some of the current dilemmas in stem cell-based therapy for IHD, along with our efforts and opinions on these key issues.

FUNCTIONAL STATE OF KIDNEYS IN PATIENTS WITH IHD

The aim of the study: to study the functional state of the kidneys in patients with ischemic heart disease (IHD) in the long-term period after myocardial revascularization. Material and research methods. The study included 160 patients with ischemic heart disease (IHD), hospitalized for coronary angiography and decisions on the appropriateness and choice of revascularization technique. The study did not include patients with eGFR less than 60 ml/min. All patients were prescribed standard IHD therapy. On the second day after the endovascular procedure, coronary angiography/percutaneous coronary intervention (CAG/PCI), all patients underwent determination of the blood creatinine concentration to identify patients who developed contrast-induced nephropathy (CIN). In dynamics, three months later, at the end of the first and second years of observation after revascularization, all patients underwent determination of the functional state of the kidneys: the concentration of blood creatinine, with the calculation of GFR, the concentration of parathyroid hormone, phosphorus, uric acid in the peripheral blood. According to the results of coronary angiography, 21 patients underwent surgical revascularization (coronary artery bypass grafting CABG) within a month after CAG. Endovascular revascularization (stenting of the coronary arteries) was performed in 139 patients. CIN in the early period after endovascular intervention was observed in 37 patients. The study showed that during 2 years of follow-up after coronary revascularization, there was a progressive decrease in eGFR: by the 3rd month, eGFR decreased by -17.39 ± 1.17%, by the end of the 1st year - by -43.62 ± 1.28%, by the end of the second year of follow-up - by -46.50 ± 1.79% The decrease in eGFR was significantly more pronounced in the group of patients who had CIN in the early period after endovascular intervention (37 patients): (-39 , 82 ± 2.02% by the end of the 3rd month, -54.61 ± 2.94% by the end of the 1st year and -60.10 ± 3.99% by the end of the 2nd year of follow-up versus -10, 65 ± 0.57%, -40.32 ± 1.27% and -42.41 ± 1.85% in patients with CIN, respectively, p <0.001). By the third month of follow-up, the dynamics of eGFR in the groups, depending on the revascularization method, did not differ (-16.36 ± 3.30% and -17.55 ± 1.25%, respectively). By the end of the 1st year of follow-up, in patients who underwent surgical revascularization, the decrease in eGFR was significantly more pronounced than in patients who underwent coronary artery stenting (-51.80 ± 3.51% versus -42.39 ± 1.35%, p <0.05), and the differences increased even more during the second year of observation (-57.99 ± 4.75% versus -44.76 ± 1.89%, p <0.05). Violation of the functional state of the kidneys was manifested by an increase in the concentration of blood phosphorus, parathyroid hormone and uric acid. The concentration of these markers increased during observation in parallel with a decrease in eGFR. The concentration of these substances was higher in patients after CIN. compared with patients with an uncomplicated postprocedural period. The concentration of uric acid was initially higher in the group of patients who underwent CABG compared with patients who underwent percutaneous coronary intervention PTCI. Conclusion. In patients with IHD after revascularization, there is a significant decrease in the glomerular filtration function of the kidneys by the 3rd month after the endovascular procedure and lasts at least 2 years. The most significant decrease was observed in patients with diabetes mellitus, as well as in patients who underwent CIN in the early period after endovascular intervention. The progression of CKD continues to be accompanied by an increase in the concentration of parathyroid hormone, uric acid and blood phosphates.