Occlusion Of Left Coronary Artery Research Articles

5-Aminolevulinic acid combined with ferrous iron ameliorates myocardial ischemia/reperfusion injury by increasing heme oxygenase-1.

5-Aminolevulinic acid (5-ALA) is a naturally occurring metabolic precursor of heme, and 5-ALA combined with ferrous iron can induce heme oxygenase-1 (HO-1) in various cells. In this study, we investigated the cardioprotective effect of 5-ALA after myocardial ischemia/reperfusion (I/R) injury using a murine model. Male C57BL/6J mice (10-12weeks of age and weighing 21-26g) were pretreated with 100mg/kg of 5-ALA hydrochloride and 157mg/kg of sodium ferrous citrate (SFC) or vehicle 48h, 24h, and 1h before I/R, and underwent 50min of left coronary artery occlusion followed by reperfusion. Infarct area (IA) and area at risk (AAR) were determined by Evans blue and triphenyltetrazolium chloride double staining after reocclusion. Pre-administration with 5-ALA/SFC significantly reduced IA/AAR compared with placebo (34.0% vs. 51.7%, respectively; p = 0.001). Real-time PCR assay after reperfusion showed that mRNA expressions of TNF-α, IL-1β, and BNP were significantly lower, and that of HO-1 was significantly higher in the 5-ALA/SFC group than in the vehicle group in ischemic sites. An inhibition experiment revealed that zinc protoporphyrin IX, an inhibitor of HO-1, inhibited the cardioprotective effects of 5-ALA/SFC. These results suggest that 5-ALA/SFC might play a cardioprotective role in myocardial I/R injury by attenuating the inflammatory reaction by increasing the expression of HO-1.

Borneol promotes berberine-induced cardioprotection in a rat model of myocardial ischemia/reperfusion injury via inhibiting P-glycoprotein expression

Berberine is reported to protect the heart against ischemia/reperfusion (I/R) injury, although efficacy is limited by low bioavailability. This study aims to determine whether borneol, a classic guiding drug, can enhance the cardioprotection induced by berberine and to clarify the underlying mechanisms involving P-glycoprotein (P-gp) in the heart. Adult male Sprague Dawley rats were gavaged with berberine (200 mg/kg) with or without borneol (100 mg/kg) for 7 consecutive days. A rat model of myocardial I/R injury was established by 30 min left coronary artery occlusion followed with 120 min reperfusion. The arrhythmia score, cardiac enzyme content, and myocardial infarct size were determined following reperfusion. Heart tissues were collected for Western blot and immunofluorescence analyses to measure the protein expression levels of Bcl-2, Bax, and P-gp. The results showed that administration of berberine protected the heart against I/R injury, as demonstrated by lower arrhythmia scores, serum cTnI contents, myocardial infarct size, and cardiomyocytes apoptosis. Moreover, borneol substantially enhanced the cardioprotective effects of berberine. Western blot and immunofluorescence analyses showed that both berberine and I/R injury did not alter P-gp expression in heart. In contrast, borneol combined with berberine significantly reduced P-gp levels by 43.4% (P = 0.0240). Interestingly, treatment with borneol alone decreased P-gp levels, but did not protect against myocardial I/R injury. These findings suggest that borneol, as an adjuvant drug, improved the cardioprotective effects of berberine by inhibiting P-gp expression in heart. Borneol combined with berberine administration provides a new strategy to protect the heart against I/R injury.

P226 EMPAGLIFLOZIN IS ABLE TO REDUCE COLLAGEN DEPOSITION IMPROVING HEART FUNCTION IN MYOCARDIAL INFARCTED RATS

Cardiovascular diseases, particularly Acute Myocardial Infarction (AMI), are the leading cause of death worldwide. Studies show that empagliflozin improves cardiac function and outcomes in patients with heart failure. This study hypothesizes that different doses of empagliflozin (3 mg/kg and 10 mg/kg) affect collagen deposition and cardiac function differently. Male Wistar rats were divided into four groups: control (Ctrl), infarcted (AMI), infarcted treated with empagliflozin 3 mg/kg (AMI+EMPA3), and infarcted treated with empagliflozin 10 mg/kg (AMI+EMPA10). Infarcted groups underwent left coronary artery occlusion. Treated groups received empagliflozin for 14 days via oral gavage. Echocardiographic evaluation was followed by euthanasia and tissue collection. Collagen deposition was assessed histologically and stained with picrosirius red, with area calculations done. Data were analyzed using the 1-way ANOVA test. Echocardiographic results showed an improvement in diastolic function index (E’/A’) in the AMI+EMPA10 group (1.654 ± 0.3) in relation to the Ctrl (0.98 ± 0.5), AMI (0.58 ± 0.1) and AMI+EMPA3 (1.02 ± 0.4). Systolic function, measured by ejection fraction, was reduced in AMI (30.14 ± 9.7%) and AMI+EMPA3 (33.68 ± 13.2%) compared to Ctrl (77.09 ± 8.1%). The AMI+EMPA10 group showed improved ejection fraction (50.69 ± 14.5%). Fractional area change showed similar patterns (Ctrl: 61.18 ± 5.7; AMI: 23.94 ± 5.7%; AMI+EMPA3: 27.39 ± 7.2%; AMI+EMPA10: 38.46 ± 7.1%). Histology revealed no difference in total left ventricle area among groups, but collagen area was increased in AMI (81.30 ± 16.2 mm2) and AMI+EMPA3 (86.64 ± 15.3 mm2) compared to Ctrl (62.89 ± 16.2 mm2), but not in AMI+EMPA10 (77.68 ± 8.5 mm2). In conclusion, empagliflozin treatment improved left ventricular diastolic and systolic function dose-dependently and reduced collagen deposition in infarcted rats. Supported by: CNPq 312962/2020-7

Targeted Antioxidant Therapy Reduces Hyperglycemic Exacerbation of Myocardial Ischemia/Reperfusion Injury

IntroductionAcute hyperglycemia (HG) enhances inflammatory and oxidative stress and exacerbates myocardial infarct size during ischemia-reperfusion injury by activating splenic leukocytes. Formyl peptide receptor 1 (FPR1) on leukocytes is activated by and mediates myocardial ischemia-reperfusion injury. We hypothesize that selective FPR1 antagonist cinnamoyl-F-(D)L-F-(D)L-F (CF) or potent reducing agent tris (2-carboxyethyl) phosphine hydrochloride (TCEP) could abrogate hyperglycemic infarct exacerbation, both alone and synergistically via a novel CF-TCEP compound that would target leukocytes for antioxidative effect. MethodsAcute HG was induced in wild type mice with an intraperitoneal dextrose injection followed by left coronary artery occlusion (30 min) and reperfusion (60 min). In treatment groups, CF (0.1 mg/kg or 1 mg/kg), TCEP (1 mg/kg or 20 mg/kg), or the CF-TCEP conjugate (0.1 mg/kg) was administered intravenously before reperfusion. The hearts were harvested to measure infarct size (IF). ResultsHG resulted in >50% increase in IF compared to euglycemic mice (52.1 ± 3.0 versus 34.0 ± 3.2%, P < 0.05). Neither CF nor TCEP independently exerted an infarct-sparing effect at lower doses (46.2 ± 2.1% or 50.9 ± 4.1%, P > 0.05 versus HG control) but at high doses, significantly attenuated IF exacerbation (23.2 ± 5.2% or 33.9 ± 3.6%, P < 0.05 versus HG control). However, the low-dose CF-TCEP conjugate significantly reduced IF (39.1 ± 1.7%, P < 0.05 versus HG control). IF was decreased to near euglycemic control levels (P > 0.05). ConclusionsThe CF-TECP conjugate synergistically attenuated HG infarct exacerbation at significantly lower respective doses of CF and TCEP. In addition to the intrinsic anti-inflammatory effect of blocking FPR1, CF is also a feasible tool for leukocyte-targeted therapy to treat IRI.

Effect of live and inactivated probiotic strains of &lt;i&gt;Lactobacillus acidophilus&lt;/i&gt; and &lt;i&gt;Bifidobacterium animalis&lt;/i&gt; subsp. &lt;i&gt;lactis&lt;/i&gt; on myocardial infarction size in rats with systemic inflammatory response syndrome

Within the concept of a heart-gut axis, new works are emerging to support the efficacy of probiotic strains to increase myocardial resistance to ischemia-reperfusion injury (IRI) in comorbidity. The question remains open whether the presence of live probiotic bacteria is a necessary condition for the realization of their cardioprotective effect. The aim of this work was to determine the manifestation of cardio-protective effect of living and pasteurized probiotic strains Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12) in rats with systemic inflammatory response syndrome (SIRS). Myocardial resistance to IRI was assessed using an in vivo model of left coronary artery occlusion-reperfusion. Experiments were performed on male Wistar rats with improved conventional status with visceral obesity, chemically induced colitis and antibiotic-induced dysbiosis, which together provided the formation of (SIRS) against the background of oral administration of live and inactivated probiotic bacteria. Myocardial resistance to ischemia-reperfusion injury was assessed using the technique of left coronary artery occlusion in vivo. The infarct size in the group with simulated SIRS was significantly higher than in the control group 43% (39; 44) and 31% (28; 35), (p 0.05). In the SIRS group with the introduction of inactivated probiotic bacteria, the infarct size 45% (37; 48) did not differ from the SIRS group and was significantly higher than in the control (p 0.05). At the same time, the size of the infarction in the group with the introduction of live probiotics did not differ from that in the control group and amounted to 32% (28; 37). There are specific features of the action of live and inactivated probiotic microorganisms with preservation of cardioprotective effect when using live lacto- and bifidobacteria in animals with SIRS.

New advances in the protective mechanisms of acidic pH after ischemia: Participation of NO

BackgroundIt has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. ObjectiveTo examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. MethodsIsolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. ResultsAR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. ConclusionsOur data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.

Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Role of NOD1 in atrial myopathy associated with heart failure

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funding: Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (ISCIII [PI17/01344 and PI20/01482]), Ministry of Education (FPU19/01973), SEC, Proyecto Traslacional 2019, FEDER, FSE, CIBER-CV, a network funded by ISCIII Introduction Heart failure (HF) is a complex syndrome that constitutes one of the leading causes of cardiovascular death worldwide. Although multifactorial mechanisms appear to be responsible of atrial and ventricular HF-myopathy, the innate immune system and the derived inflammatory response have gained much attention in the last years. Previous studies from our group have demonstrated that the nucleotide-binding oligomerization domain 1 (NOD1), a receptor of the innate immune system, plays a role in HF left ventricular (LV) dysfunction. However, its role in HF-atrial myopathy remains completely unknown. The main purpose of our study is to determine the role of NOD1 in human and experimental HF-atrial myopathy. Methods and Results The study was performed in two cohorts of individuals who underwent heart valve repair surgery, 51 non-failing individuals (NF) with LV ejection fraction (LVEF)&amp;gt;50% and NT-ProBNP levels&amp;lt;200pg/mL and 41 subjects with medium to severe reduced EF (HF)&amp;lt;50% and NT-ProBNP levels&amp;gt;200pg/mL. An informed consent was signed by all patients. Atrial myocardial tissue was excised from the atrial appendage and prepared for biochemical and histological studies. Echocardiography analysis showed that left and right atrial areas (LA and RA) were significantly increased in the HF group compared to NF, while LA and RA reservoir functions were significantly decreased in HF. Immunostaining demonstrated NOD1 location in atrial cardiomyocytes, being the protein levels of NOD1 and its specific adaptor RIP2 significantly increased in atrial tissue obtained from HF vs. NF. Although the prevalence of atrial fibrillation (AF) was significantly higher in the HF group compared to NF, the upregulation of NOD1 was not conditioned by the presence of AF. Similarly, pigs that underwent transverse aortic constriction (TAC) or proximal left circumflex coronary artery occlusion involving the LA branch (LAI), showed an upregulation of NOD1 pathway in atrial tissue, compared with the sham operated animals. Interestingly, an atrial upregulation of NOD1 axis was also observed in wild-type TAC mice, whereas Nod1-/- knockout mice showed a prevention in both structural and functional atrial remodelling induced by TAC, mainly by a prevention of intracellular calcium mishandling in isolated atrial cardiomyocytes. Finally, wild-type mice injected i.p. for 3 days with 3.3 mg/kg with a selective activator of NOD1, showed increased structural atrial remodelling and intracellular calcium mishandling compared to the vehicle-treated group. Conclusions Our results demonstrate that NOD1 axis is upregulated in human, swine and murine atrial failing myocardium. Genetic deletion of NOD1 prevented HF-atrial structural and functional remodelling, mainly by avoiding intracellular calcium mishandling, whereas its pharmacological activation induced atrial dilation and intracellular Ca2+ mishandling. All these data uncover NOD1 as a new player in atrial HF-remodelling.

Attempted retrieval of guidewire fragment using the twisting wire technique causes coronary perfusion: Case report.

Guidewire fracture is one of the biggest risks of percutaneous coronary intervention, twisting wire technique is very useful for retrieving the fractured wire, but the potential risks have been inadequately reported. Herein, we present a case of retrieval of guidewire fragments using the twisting wire technique that causes coronary perfusion. A 37-year-old male patient was admitted to our hospital for elective percutaneous coronary intervention of the left circumflex coronary artery. For chronic total occlusion of the distal left circumflex coronary artery, antegrade recanalization by wire escalation, and parallel wire techniques were attempted. However, we shockingly found that the BMW guidewire, anchored in the right coronary artery, spontaneously fractured from the proximal right coronary artery, and a lengthy fragment of the guidewire remained in the coronary. Many attempts were made to retrieve the remnant guidewire including the twisting wire technique, which leads to the perforation of the coronary. Finally, percutaneous retrieving procedures were stopped in favor of surgical extraction via a small coronary arteriotomy. This procedure was successful. To the best of our knowledge, the present case is the first reported spontaneous fracture of the guidewire. Leaving such a lengthy remnant guidewire in the artery, or leaving stenting over the wire, would impose a high risk of coronary thrombosis, perforation, and embolization. Yet, the perforation of the artery that occurred in this case, which could have had life-threatening consequences, resulted from our attempts to retrieve the guidewire using the twisting wire technique.

Twelve-year trends in unprotected left main coronary artery occlusion: insights from a real-world multicentre study.

Acute myocardial infarction (AMI) resulting from unprotected left main coronary artery (LMCA) occlusion and subtotal occlusion is a life-threatening condition. Although AMI management has improved in the past two decades, there is limited information on recent trends in patient characteristics, management, and outcomes for acute unprotected LMCA-related AMI. This study aims to assess such trends over a 12year period. This retrospective multicentre study includes patients with unprotected LMCA occlusion/subtotal occlusion admitted to three tertiary hospitals between 2008 and 2020. The patients were divided into two groups based on the chronology of presentation: a 'past group' (January 2008 to December 2014) and a 'contemporary group' (January 2015 to December 2020). The study compares clinical characteristics, management approaches, and outcomes between the two groups. The study includes 128 patients, with 51 (40%) in the 'past group' and 77 (60%) in the 'contemporary group'. Baseline risk factors did not show statistically significant differences between the two groups, except for hypertension (49% vs. 74%; P=0.005). Chest pain was more frequent in the 'past group' (98% vs. 89%; P=0.014), and a trend towards more cardiac arrests was observed in the 'contemporary group' (18% vs. 31%; P=0.087). Revascularization type did not differ significantly (P=0.419), but manual thrombectomy was less frequently used (41% vs. 23%; P=0.032) and stent implantation showed a trend towards higher rates (66% vs. 78%; P=0.150) in the 'contemporary cohort'. There was a gradual shift from bare-metal to drug-eluting stents, with a significantly higher percentage of ticagrelor/prasugrel loading in the 'contemporary cohort' (5% vs. 79%; P<0.001). The use of mechanical circulatory support (MCS), although not statistically significant, was higher among patients in the 'past group' (67% vs. 51%; P=0.073). The type of MCS differed significantly between groups, with a decrease in intra-aortic balloon pump use (67% vs. 42%; P=0.005) and an increase in veno-arterial extracorporeal membrane oxygenation (4% vs. 22%; P=0.005) and Impella system (0% vs. 3%) over time. Survival analysis showed no significant differences (P=0.599; log-rank test) in all-cause mortality between the different time groups, with the long-term survival rate being approximately 30%. In our real-world population, despite the progressive use of newer drugs and more advanced devices over time, patients with unprotected LMCA occlusion/subtotal occlusion remain a subpopulation with poor prognosis.

Single stent versus two stent strategy in primary PCI for unprotected LM occlusion

Abstract Background Acute MI due to left main coronary artery (LMCA) occlusion carry the highest anatomical risk for morbidity and mortality during primary PCI. Although several clinical trials compared different PCI techniques and strategies for LMCA, still special populations and different clinical scenarios have lack of evidence about ideal approaches. Purpose We aim to compare provisional stenting versus two stent upfront technique in acute MI due to LMCA occlusion regarding short term clinical outcomes. Methods This was a prospective observational study from three large centers within the period from February 2019 to Feb 2023. Patients with acute STEMI due to LMCA occlusion who are candidates for primary PCI were included and was assigned to two groups according to operator discretion. Group I (provisional stenting) versus group II (upfront two stent strategy). Our primary outcome was MACE within 30 days and secondary Outcomes were angiographic outcomes after intervention including TIMI flow, CTFC and myocardial blush. Results A total of 62 patients met our inclusion criteria, mean age (62.64±8.61), 24.6% women. Thirty-eight patients in group I undergone provisional stenting and twenty-four patients in group II undergone two stent strategy. MACE was significantly higher in the two-stent strategy group (61.62% vs 40.34%, P&amp;lt;0.001] compared with provisional stenting group. the IV epinephrine group. Angiographic outcomes were significantly better in provisional stenting group by the end of the procedure. There was marked increase in patients who achieved postprocedural TIMI III and TMPG III in group I by 22% and 18% respectively in comparison with two stent strategy group. Conclusion Our observational study concluded that provisional stenting carries better short-term outcomes in acute MI intervention due to unprotected LMCA occlusion. Clinical studies are needy in this specific population.Study flow chartFigure I

Cardiomyocyte-specific beta3-adrenergic receptor expression reduces infarct size inhibiting the autophagic flux in mice

Abstract Background Since the discovery of β3-adrenergic receptor (β3AR), the third class of β-adrenergic receptors, expression in in both cardiomyocytes and endothelial cells of the cardiovascular system, it has come to the focus due to it´s possible implication in cardiovascular diseases. Although it´s expression is low compared to β1 and β2 subtypes (1), its been demonstrated that β3AR agonists have a cardioprotective effect in ischemia/reperfusion (IR) injury though inhibition of mitochondrial pore opening (2). Purpose In this project we determined the cellular origin of the β3AR cardioprotection and its role on cellular autophagic machinery. Methods Mice with overexpression of the β3AR in cardiomyocytes or endothelial cells and their control littermates were subjected to left coronary artery occlusion for 45 min followed reperfusion after 24h and 7days. Left ventricular function was assessed by echocardiography at day 7. Then, heart samples were collected at baseline and 24h and 7 days after IRI. Mitochondrial number were analyzed by transmission electron microscopy. Proteins related to autophagy signaling pathways were measured by western blot and RT-qPCR. Results Cardiomyocyte-specific β3AR overexpression protects the heart upon IR injury, reduced cardiac fibrosis which improved cardiac function and maintained heart mass. Studying the effects at baseline to understand the molecular mechanisms of cardioprotection, we found that β3AR overexpression in cardiomyocytes showed a reduction in autophagy markers such as LC3B and Parkin, meaning there is an alteration in the autophagic flux. Conclusions Cardiomyocyte-specific overexpression of β3-adrenergic receptor reduces infarct size and protects the heart affecting the autophagy machinery. Our results shed light on the role of the β3AR in the mitochondrial quality control system, offering evidence of its potential use as a target to decrease IR injury in patients with acute myocardial infarction.

Abstract 14730: The Effect of Electronic Cigarette Exposure With Nicotine on Expression of Inflammatory Genes and Blood Parameters in a Chronic Myocardial Infarction Model

Background: There are no data available regarding the effects of chronic electronic cigarette (eC) exposure on inflammatory gene expressions after myocardial infarction (MI) and whether eC could alter blood counts and chemistries in this setting. We determined the effect of eC on expression of genes for inflammatory cytokines and receptors and blood parameters during the healing phase of MI. Methods and Results: Sprague Dawley rats of either sex were subjected to a proximal left coronary artery occlusion to induce a large anterior wall MI. At 1 week, rats were randomized to exposure to air or E-cig with nicotine (eC Nic + ) for 12 weeks. After 12 weeks of exposure, rat inflammatory cytokine and receptor PCR array was performed (n=4 in each group). The data showed 70 out of 84 inflammatory-related genes were downregulated in the eC Nic+ group versus the air group and 11 downregulated genes reached a significant difference. Interleukin 6 (IL6), Tumor necrosis factor superfamily (TNF), Chemokine (C-C motif) ligand 12 (Ccl12), and C-X-C Motif Chemokine Receptor 3 (Cxcr3) gene expressions were significantly decreased by -6.49 fold, p=0.0048, -2.63 fold, p=0.0227, -2.71 fold, p=0.0146, and -2.28 fold, p=0.0067, respectively, in the eC Nic+ group vs air group. The rats in eC Nic+ group had significantly decreased white blood cell (WBC), lymphocyte and platelet count compared to the air group (Figure). Conclusions: Exposure to eC Nic+ alters the expression of inflammatory genes and decreases blood immune cells during the healing phase of MI. Our findings suggest that chronic inhalation of e-cigarette aerosols can suppress the immune and inflammatory response in the already compromised setting of MI.

Abstract 13361: The Effect of Electronic Cigarette Exposure on Flow Mediated Vasodilation and LV Remodeling in a Chronic Myocardial Infarction Model

Introduction: There is little information about the effect of electronic cigarette (e-C) exposure on the cardiovascular system in the setting of myocardial infarction (MI) and whether e-C’s could alter vascular or cardiac function during the healing phase of MI. We determine the effect of e-C on endothelial function, cardiac remodeling and function during the healing phase of MI. Methods: Sprague Dawley rats (both sexes) were anesthetized and subjected to a proximal left coronary artery occlusion to induce a large anterior wall MI. At one week, rats were randomized to receive either 12 weeks of exposure to purified air (n=37) or e-cig vapor plus 15 mg/ml of nicotine (e-Cn=32). At 12 weeks endothelial function was tested by assessing femoral artery diameter and blood flow following a 5- minute femoral artery occlusion and reperfusion (ultrasound and flow probe). Cardiac function was assessed by echocardiography; remodeling was also assessed by quantitative histologic analysis. Results: Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the e-Cn group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p=0.034). Femoral artery diameter after reperfusion was narrower in the e-Cn group (0.54 ± 0.02mm) compared to the air group (0.60 ± 0.02mm; p=0.023). Postmortem left ventricular (LV) volumes were similar in the e-Cn (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p=NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in e-Cn group versus 1.3 ± 0.1 in air group; p=NS). Gross pathology LV wall thickness was greater in the e-Cn group (1.38 ± 0.12 mm) versus the air group (1.04 ± 0.10 mm) despite no increase in blood pressure at 12 weeks in the e-CN group. LV fractional shortening by echo did not differ between groups at 12 weeks (e-Cn at 29 ± 2% and air at 27 ± 1%; p=NS). Conclusion: Exposure to e-Cn during the healing phase of MI was associated with altered endothelial function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function. E-Cn did increase gross pathologic LV wall thickness. E-Cn exposure during the healing phase of MI has deleterious effects on the CV system but does not dilate the LV.

Angiographic Coronary Revascularization in Patient with Chronic Total Occlusion of Left Coronary Artery Originating from Right Coronary Cusp: A Retrograde Approach

A 51-years-old man with left main coronary artery originating from right Valsalva sinus presented with unstable angina and multi-vessel coronary disease and chronic total occlusion of anterior descending artery. Percutaneous coronary intervention using retrograde approach achieved complete revascularization and symptom relief.

Splenic monocytes mediate inflammatory response and exacerbate myocardial ischemia/reperfusion injury in a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion.

The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) recruits inflammasomes, initiating inflammatory responses and mediating tissue injury. We hypothesize that myocardial cell-free DNA (cfDNA) activates the splenic NLRP3 inflammasome during early reperfusion, increases systemic inflammatory response, and exacerbates myocardial infarct. Mice were subjected to 40min of ischemia followed by 0, 1, 5, or 15min, or 24h of reperfusion. Splenic leukocyte adoptive transfer was performed by injecting isolated splenocytes to mice with splenectomy performed prior to left coronary artery occlusion. CY-09 (4mg/kg) was administered 5min before reperfusion. During post-ischemic reperfusion, splenic protein levels of NLRP3, cleaved caspase-1, and interleukin-1β (IL-1β) were significantly elevated and peaked (2.1 ± 0.2-, 3.4 ± 0.4-, and 3.2 ± 0.2-fold increase respectively, p < 0.05) within 5min of reperfusion. In myocardial tissue, NLRP3 was not upregulated until 24h after reperfusion. Suppression by CY09, a specific NLRP3 inflammasome inhibitor, or deficiency of NLRP3 significantly reduced myocardial infarct size (17.3% ± 4.2% and 33.2% ± 1.8% decrease respectively, p < 0.01). Adoptive transfer of NLRP3-/- splenocytes to WT mice significantly decreased infarct size compared to transfer of WT splenocytes (19.1% ± 2.8% decrease, p < 0.0001). NLRP3 was mainly activated at 5min after reperfusion in CD11b+ and LY6G- splenocytes, which significantly increased during reperfusion (24.8% ± 0.7% vs.14.3% ± 0.6%, p < 0.0001). The circulating cfDNA level significantly increased in patients undergoing cardiopulmonary bypass (CPB) (43.3 ± 5.3ng/mL, compared to pre-CPB 23.8 ± 3.5ng/mL, p < 0.01). Mitochondrial cfDNA (mt-cfDNA) contributed to NLRP3 activation in macrophages (2.1 ± 0.2-fold increase, p < 0.01), which was inhibited by a Toll-like receptor 9(TLR9) inhibitor. The NLRP3 inflammasome in splenic monocytes is activated and mediates the inflammatory response shortly after reperfusion onset, exacerbating MI/R injury in mt-cfDNA/TLR9-dependent fashion. The schema reveals splenic NLRP3 mediates the inflammatory response in macrophages and exacerbates MI/R in a mitochondrial cfDNA/ TLR9-dependent fashion.

THU583 Cardioprotection By Nitric Oxide Is Mediated Via Mitochondrial Function In Rodents

Abstract Disclosure: K. Islam: None. R. Islam: None. A. Draper: None. Background: Reduced nitric oxide (NO)bioavailability and decreased expression of mitochondrial transcription factor A (TFAM) occurs in the setting of heart failure (HF). TFAM promotes transcription of mitochondrial DNA, mitochondrial biogenesis, respiratory chain activity, and ATP synthesis. We investigated the effects of oral NaNO2therapy to increase NO in chronic HF following acute myocardial infarction and examined the effects of NaNO2 on the activation of TFAM, mitophagy, and antioxidant signaling pathways. Methods: Male C57/BL6J mice underwent 60 minutes of myocardial ischemia (MI) induced by left coronary artery (LCA) occlusion followed by 4 weeks of reperfusion. NaNO2 or saline vehicle (VEH)was administered at a dose of 165 µg/kg at reperfusion and then daily for 4weeks in the drinking water (100 mg/L). Left ventricular ejection fraction (LVEF) was determined at baseline and at 4 weeks of reperfusion. At 4 weeks of reperfusion myocardial tissue samples were collected and analyzed by RT-qPCR, immunoblot, oxidative stress assay, and protein sulfhydration assay. Results: NaNO2 administration markedly preserved left ventricular ejection fraction (LVEF) and improved left ventricular diastolic and systolic dimensions at 4 weeks as compared to VEH. Mitochondrial antioxidant proteins, SOD2 (MnSOD), peroxiredoxin-3 (Prx-3) and thioredoxin 2 (TXN2) (p &amp;lt; 0.05) were markedly increased in NaNO2treated mice compared to VEH. Expression of mitophagic markers, p62 (p &amp;lt;0.05) and Map1lc3 (p &amp;lt; 0.05) were significantly increased in NaNO2treated HF mice as compared to VEH. Expression of mitochondrial quality control such as PINK1 and PARKIN2 were also markedly increased HF mice after treated with nitrite therapy as compared with VEH. Marked induction of sulfhydration of interferon regulator factor 1 (IRF-1) as well as upregulation of mitochondrial transcription factor A (TFAM) (p &amp;lt; 0.05) and suppression of DNA methyltransferase3a (Dnmt-3a) (p &amp;lt; 0.05) were observed in NaNO2 treated ischemic HF mice as compared with VEH. Conclusions: Our results clearly demonstrate thatNaNO2 therapy improves left ventricular function during ischemic HF through induction of antioxidant signaling, mitophagy, sulfhydration of IRF-1and TFAM resulting in increased mitochondrial biogenesis. Presentation: Thursday, June 15, 2023

Panax quinquefolius saponins combined with dual antiplatelet therapy enhanced platelet inhibition with alleviated gastric injury via regulating eicosanoids metabolism

BackgroundPanax quinquefolius saponin (PQS) was shown beneficial against platelet adhesion and for gastroprotection. This study aimed to investigate the integrated efficacy of PQS with dual antiplatelet therapy (DAPT) on platelet aggregation, myocardial infarction (MI) expansion and gastric injury in a rat model of acute MI (AMI) and to explore the mechanism regarding arachidonic acid (AA)-derived eicosanoids metabolism.MethodsWistar rats were subjected to left coronary artery occlusion to induce AMI model followed by treatment with DAPT, PQS or the combined therapy. Platelet aggregation was measured by light transmission aggregometry. Infarct size, myocardial histopathology was evaluated by TTC and H&E staining, respectively. Gastric mucosal injury was examined by scanning electron microscope (SEM). A comprehensive eicosanoids profile in plasma and gastric mucosa was characterized by liquid chromatography-mass spectrometer-based lipidomic analysis.ResultsPQS+DAPT further decreased platelet aggregation, lessened infarction and attenuated cardiac injury compared with DAPT. Plasma lipidomic analysis revealed significantly increased synthesis of epoxyeicosatrienoic acid (EET) and prostaglandin (PG) I2 (potent inhibitors for platelet adhesion and aggregation) while markedly decreased thromboxane (TX) A2 (an agonist for platelet activation and thrombosis) by PQS+DAPT, relative to DAPT. DAPT induced overt gastric mucosal damage, which was attenuated by PQS co-administration. Mucosal gastroprotective PGs (PGE2, PGD2 and PGI2) were consistently increased after supplementation of PQS+DAPT.ConclusionsCollectively, PQS+DAPT showed synergistic effect in platelet inhibition with ameliorated MI expansion partially through upregulation of AA/EET and AA/PGI2 synthesis while suppression of AA/TXA2 metabolism. PQS attenuated DAPT-induced gastric injury, which was mechanistically linked to increased mucosal PG production.

Tolerability and efficacy of a reduced dose adenosine stress cardiac magnetic resonance protocol under general anesthesia in infants and children.

Intravenous adenosine induces pharmacological stress by causing vasodilatation and thus carries the risk of severe hypotension when combined with vasodilatory effects of anesthetic agents. This study describes our experience with a reduced dose adenosine cardiac magnetic resonance imaging (MRI) protocol in young children under general anesthesia (GA). This is a retrospective report of all patients from birth to 18years who underwent adenosine stress cardiac MRI under GA between August 2018 and November 2022. Based on our anecdotal experience of severe adverse effects in patients receiving adenosine infusion under GA and in discussion with the pediatric anesthesia team, we developed a modified protocol starting at a dose of 110 mcg/kg/min with incremental escalation to a full dose of 140 mcg/kg/min to achieve desired hemodynamic effect. Twenty-two children (mean age 6.5years, mean weight 28kg) satisfied the inclusion criteria. The diagnoses included Kawasaki disease (7), anomalous aortic origin of left coronary artery (3), anomalous aortic origin of right coronary artery (2), coronary fistula (3), repaired d-transposition of great arteries (2), repaired anomalous left coronary artery from pulmonary artery (2), repaired truncus arteriosus with left coronary artery occlusion (1), extracardiac-Fontan with left coronary artery myocardial bridge (1), and post heart transplantation (1). Nine patients needed dose escalation beyond 110 mcg/kg/min. Two patients had transient hypotension during testing (systemic blood pressure drop > 25mmHg). No patient developed significant heart block or bronchospasm. Six patients (repeat study in one) demonstrated inducible perfusion defects (27%) on stress perfusion sequences-5 of whom had confirmed significant coronary abnormalities on angiography or direct surgical inspection. A reduced/incremental dose adenosine stress cardiac MRI protocol under GA in children is safe and feasible. This avoids severe hypotension which is both unsafe and may result in inaccurate data.

Short-term toll-like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction.

Ischaemia-reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long-term consequence. The extent of neutrophil infiltration and neutrophil-mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll-like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor. Forty-nine male adult Sprague-Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30min. Oligonucleotide (ODN) 2088, a toll-like receptor 9 (TLR9) antagonist, control-ODN, or DNase, were administered at the time of reperfusion and over 24h via a mini-osmotic pump. The hearts were harvested 24h or 4weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P=0.003) in association with drastically enhanced neutrophil infiltration (P=0.005) and increased markers of tissue damage. Additionally, an up-regulation of the chemotactic receptor CXCR2 (P=0.046) was found after TLR9 inhibition. No such effects were observed in control-ODN or DNase-treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury. Our data indicate a TLR9-dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down-regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR-/- mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24h following IRI.