Regional Myocardial Ischemia Research Articles

Abstract 4113997: Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 rd with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD are lacking. Methods: Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. Results: SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing to 150 bpm (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). Conclusions: This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Prognostic value of quantitative anatomical and functional measures of coronary artery disease in diabetic and non-diabetic patients

Abstract Background Diabetes is associated with increased risk of coronary artery disease (CAD). However, the relative prognostic importance of anatomical and functional findings of CAD in the presence vs. absence of diabetes is incompletely understood. Technological advances have made quantitative analysis of coronary artery plaques and stenosis feasible by coronary computed tomography angiography (CTA). In turn, positron emission tomography (PET) enables absolute quantification of myocardial blood flow (MBF). Purpose To study long-term prognostic value of quantified severity of coronary atherosclerosis and myocardial perfusion in non-diabetic vs. diabetic patients with suspected CAD. Methods From two academic medical centres, we identified symptomatic patients with suspected CAD who had undergone coronary CTA and [15O]H2O PET myocardial perfusion imaging during adenosine stress. Based on artificial intelligence -guided quantitative analysis of coronary CTA scans, the anatomical severity of CAD was measured as the presence of obstructive CAD (≥50% diameter stenosis) and percent atheroma volume (PAV; higher vs. lower than median). The functional severity of CAD was measured as the presence of regional myocardial ischemia (≥2 adjacent segments with stress MBF <2.3 ml/g/min) and global stress MBF (<2.2 ml/g/min vs. ≥ 2.2 ml/g/min) by PET. Annual rates of adverse events (AER) including all-cause mortality, myocardial infarction (MI), and unstable angina pectoris (UAP) were evaluated. Results Among 1311 patients, 251 (19%) had diabetes. Patients with diabetes had more frequently obstructive CAD (55% vs. 43%, p<0.001) and regional myocardial ischemia (51% vs. 43%, p=0.015), higher plaque burden by PAV (12% vs. 7%, p<0.001), and lower global stress MBF (2.78 ml/g/min vs. 3.05 ml/g/min, p<0.001). During median follow-up of 7.1 years, 171 (13.0%) patients experienced AE (85 deaths, 56 MIs, and 30 UAPs). Patients with diabetes had higher AER than non-diabetic patients (3.1% vs. 1.6%, p<0.001). The presence of obstructive stenosis was associated with increased AER in non-diabetic (2.6% vs. 1.0%, p<0.001) and diabetic patients (4.2% vs. 1.9%, p<0.001). High plaque burden by PAV was associated with increased AER in non-diabetic (2.8% vs. 0.7%, p<0.001) and diabetic patients (3.9% vs. 1.7%, p<0.001). The presence of regional myocardial ischemia was associated with increased AER in non-diabetic (2.5% vs. 1.1%, p<0.001), but not in diabetic patients (3.4% vs. 2.7%, p=0.238). Low global stress MBF was associated with increased AER in non-diabetic (2.9% vs. 1.3%, p<0.001), but not among diabetic patients (3.2% vs. 3.0%, p=0.286). Conclusions Diabetes was associated with more advanced CAD. Quantified severity of anatomical findings predicted long-term adverse outcome in non-diabetic and diabetic patients. In contrast, functional imaging risk stratified non-diabetic patients, whereas diabetic patients had impaired long-term outcome irrespective of perfusion findings.

Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease.

To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS. Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups. Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis. MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS.

Sulforaphane improves post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the Nrf2/IRF1/GPX4 pathway

BackgroundFerroptosis is an important type of cell death contributing to myocardial dysfunction induced by whole body ischemia reperfusion following cardiac arrest (CA) and resuscitation. Sulforaphane (SFN), known as the activator of the nuclear factor E2-related factor 2 (Nrf2), has been proven to effectively alleviate regional myocardial ischemia reperfusion injury. The present study was designed to investigate whether SFN could improve post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis and its potential regulatory mechanism. Methods and resultsAn in vivo pig model of CA and resuscitation was established. Hypoxia/reoxygenation (H/R)-stimulated AC16 cardiomyocytes was constructed as an in vitro model to simulate the process of CA and resuscitation. In vitro experiment, SFN reduced ferroptosis-related ferrous iron, lipid reactive oxygen species, and malondialdehyde, increased glutathione, and further promoted cell survival after H/R stimulation in AC16 cardiomyocytes. Mechanistically, the activation of Nrf2 with the SFN decreased interferon regulatory factor 1 (IRF1) expression, then reduced its binding to the promoter of glutathione peroxidase 4 (GPX4), and finally recovered the latter’s transcription after H/R stimulation in AC16 cardiomyocytes. In vivo experiment, SFN reversed abnormal expression of IRF1 and GPX4, inhibited cardiac ferroptosis, and improved myocardial dysfunction after CA and resuscitation in pigs. ConclusionsSFN could effectively improve myocardial dysfunction after CA and resuscitation, in which the mechanism was potentially related to the inhibition of cardiomyocytes ferroptosis through the regulation of Nrf2/IRF1/GPX4 pathway.

Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking. Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Is ischemic stimulus involved for J wave augmentation during coronary angiography and intracoronary administration of normal saline?

J waves may be augmented by coronary angiography (CAG) or intracoronary drug administration but the underlying mechanism is unknown. The effect of intracoronary normal saline (NS) on J waves were investigated. After the standard CAG using iopamidol (IopamiroR Inj), NS was injected into the right coronary artery in 10 patients with and eight patients without J waves at the baseline. The 12-lead ECG was monitored, stored on a computer and retrieved later for measurement of the J wave amplitude before or during the coronary interventions. J waves in leads II, III and aVF at baseline increased significantly in each lead during the right CAG and NS injection into the right coronary artery. The J wave changes were similar between the two interventions and distinct similar alterations were observed in the QRS complex. We postulated that the ischemic myocardium that was induced during CAG or intracoronary NS administration slowed the conduction velocity of depolarization in the perfusion territory and delayed the timing of J waves to appear. Then, the delayed appearance of J waves would be less opposed by electromotive force from other areas resulting in augmentation. J wave augmentation was observed during CAG and intracoronary NS administration. As a mechanism of augmentation, we postulated that contrast media and NS induce myocardial ischemia and delay the timing of J waves to a point of less opposition by electromotive force from other areas. J wave augmentation has been reported during intracoronary injection of contrast media or drugs. The present study confirmed that normal saline alone was able to augment J waves. Mechanistically, coronary interventions using anoxic solutions can cause regional myocardial ischemia and reduce the conduction velocity of depolarization. Then, delayed J waves are less opposed by the electromotive force from remote areas which leads to augmentation. When a drug is diluted in normal saline and given intracoronarily, changes in J waves can be due to normal saline. The pathophysiological and clinical significance of J waves augmented during coronary interventions need to be established.

Cardio- and Vasoprotective Effects of Quinacrine in an In Vivo Rat Model of Myocardial Ischemia/Reperfusion Injury.

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.

Arrhythmogenic right ventricular cardiomyopathy with sustained ventricular tachycardia: a case report

IntroductionArrhythmogenic right ventricular cardiomyopathy (ARVC) is an infrequent hereditary disorder distinguished by fibrofatty replacement of the myocardium in the right ventricular, which predisposes individuals to life-threatening arrhythmias. This case delineates an ARVC patient who suffered recurrent bouts of sustained ventricular tachycardia (VT). In this case, we mainly discuss the application of myocardial contrast echocardiography (MCE) in displaying myocardial fibrosis in patients with ARVC.Case presentationA 43-year-old male experienced three episodes of unexplained VT over an eight-year period, accompanied by symptoms of chest discomfort, palpitations and dizziness. Coronary angiography revealed no significant coronary stenosis. The electrocardiogram (ECG) results indicated characteristic epsilon waves in right precordial leads, and subsequent echocardiography identified right ventricular enlargement and right ventricular systolic dysfunction. MCE further disclosed regional myocardial ischemia at the epicardium of the left ventricular apex. Ultimately, cardiovascular magnetic resonance imaging (CMR) corroborated the ARVC diagnosis, highlighting linear intensification in the right ventricle during the delayed enhancement.ConclusionPrompt identification of ARVC is crucial for timely intervention and management. MCE may offer an effective and valuable technique for the detection of myocardial involvement in ARVC patient.

Investigation of the effects of cilostazol on the myocardial ischemia-reperfusion injury of rats.

&lt;b&gt;&lt;i&gt;Background&lt;/i&gt;&lt;/b&gt;. Myocardial ischemia, occurring as a consequence of imbalance between oxygen supply and demand, causes a rapid metabolic and structural&lt;br /&gt; impairment within the tissue. After a period of ischemia, sudden onset of reperfusion causes a transition to aerobic metabolism within living cells. Afterwards, emerging substrates initiate a chain of reactions leading to tissue injury. This situation is called “ischemia reperfusion injury”. Despite all technical advancements in anesthesia, myocardial protection and cardiac surgical techniques, we still face the clinical reflections of ischemia reperfusion (IR) injury.&lt;br /&gt; &lt;b&gt;&lt;i&gt;Materials and methods&lt;/i&gt;&lt;/b&gt;. The protective effect of cilostasole on IR injury in an animal model of experimental myocardial ischemia and reperfusion was investigated. In this regional myocardial ischemia model, male Wistar-Albino rats were used as subjects and they were allocated into three groups; ischemia (n=8), sham (n=8), and cilostazole (n=8). LAD was occluded for 45 minutes, and then reperfused for three hours. Rats received Cilostazole 20 mg/kg/d by gastric gavage once daily. During IR hemodynamic parameters were recorded. Serum analysis for CK-MB and Troponin T were analysed at 180th minute of ischemia. Ischemic zone was measured by dying with Evans Blue and infarct area was measured by dying with triphenyltetrazolium chloride.&lt;br /&gt; &lt;b&gt;&lt;i&gt;Results.&lt;/i&gt;&lt;/b&gt; Before the onset of LAD occlusion, as well as at 25th, 60th and 120th minutes of occlusion, all groups were similar in terms of blood pressure and pulse rate.&lt;br /&gt; The total area, affected area and necrotic area were calculated by using formulas; affected area ratio= affected area/total area X 100, necrotic area ratio = necrotic area/total affected area X 100, necrotic area and affected area ratio = necrotic area /affected area X 100.&amp;nbsp; Affected area and total area ratio was significantly higher in IR group, compared with cilostazole group (t=8.965; p&amp;lt;0.001). Similarly, necrotic area and total area ratio was higher in IR group, compared with cilostazole group (t=8.965; p&amp;lt;0.001). The necrotic area and affected area ratios were similar in IR and cilostazole groups (t=0.245; p=0.810). CK-MB level differences were not statistically significant between two groups (Z=0.382; p=0.721).&lt;br /&gt; Troponin levels were similar between IR and cilostazole groups and the difference was not statistically significant (Z=0.630; p=0.574). Pathological specimens of the heart were scanned for myocytolysis, PMNL and hemorrhage.&amp;nbsp; The difference between mean value of MDA enzyme levels were statistically significant (p&amp;lt;0.001) between all groups.&amp;nbsp; MDA enzyme levels, from higher to lower was IR, cilostazole and Sham group.&amp;nbsp; SOD levels (F=5.910; p=0.009) were significantly lower in Sham group when compared with IR group (p=0.008). The differences between Sham and cilostazole groups and IR and cilostazole gropus were not statistically significant (p=0.008). According to planimetric values and enzyme levels, cilostazole was found to be effective in reducing the ischemic zone, without effecting the necrotic zone in cardiac ischemia reperfusion damage. Therefore cilostazole has protective effects agains ischemia reperfusion damage.&lt;br /&gt; &lt;br /&gt; &lt;b&gt;Conclusion&lt;/b&gt;.&amp;nbsp;This study explored how cilostazol affects myocardial ischemia-reperfusion injury in rats, finding that cilostazol administration during reperfusion may protect against such injury. Through various analyses, we observed positive outcomes associated with cilostazol treatment, suggesting its potential in reducing myocardial damage. Further research is needed to understand the underlying mechanisms and optimize therapeutic strategies, but our findings highlight cilostazol's promise in improving clinical outcomes in cardiac interventions.

Validation of resting full-cycle ratio and diastolic pressure ratio with [15O]H2O positron emission tomography myocardial perfusion

Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are invasive techniques used to evaluate the hemodynamic significance of coronary artery stenosis. These methods have been validated through perfusion imaging and clinical trials. New invasive pressure ratios that do not require hyperemia have recently emerged, and it is essential to confirm their diagnostic efficacy. The aim of this study was to validate the resting full-cycle ratio (RFR) and the diastolic pressure ratio (dPR), against [15O]H2O positron emission tomography (PET) imaging. A total of 129 symptomatic patients with an intermediate risk of coronary artery disease (CAD) were included. All patients underwent cardiac [15O]H2O PET with quantitative assessment of resting and hyperemic myocardial perfusion. Within a 2 week period, coronary angiography was performed. Intracoronary pressure measurements were obtained in 320 vessels and RFR, dPR, and FFR were computed. PET derived regional hyperemic myocardial blood flow (hMBF) and myocardial perfusion reserve (MPR) served as reference standards. In coronary arteries with stenoses (43%, 136 of 320), the overall diagnostic accuracies of RFR, dPR, and FFR did not differ when PET hyperemic MBF < 2.3 ml min−1 (69.9%, 70.6%, and 77.1%, respectively) and PET MPR < 2.5 (70.6%, 71.3%, and 66.9%, respectively) were considered as the reference for myocardial ischemia. Non-significant differences between the areas under the receiver operating characteristic (ROC) curve were found between the different indices. Furthermore, the integration of FFR with RFR (or dPR) does not enhance the diagnostic information already achieved by FFR in the characterization of ischemia via PET perfusion. In conclusion, the novel non-hyperemic pressure ratios, RFR and dPR, have a diagnostic performance comparable to FFR in assessing regional myocardial ischemia. These findings suggest that RFR and dPR may be considered as an FFR alternative for invasively guiding revascularization treatment in symptomatic patients with CAD.

The Infarct-Limiting Effect of Remote Ischemic Conditioning in Rats Is Not Affected by Aspirin.

Remote ischemic conditioning (RIC)has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.

Supramolecular self-assembled nanoparticles camouflaged with neutrophil membrane to mitigate myocardial ischemia/reperfusion (I/R) injury

The clinically restored blood supply post myocardial infarction (MI) will break the physiological and metabolic balance of the ischemic myocardial region, leading to a new injury known as myocardial ischemia/reperfusion (I/R) injury. Abundant oxygen brought by the fresh blood would trigger the damaged myocardium to produce excessive reactive oxygen species (ROS) and thereby inflammation along with the recruitment and infiltration of activated neutrophils and macrophages. Inspired by the active targeting process of inflammatory cells, a novel “neutrophil-like” nanoassembly (At@NQA) was prepared by modifying neutrophil membrane fragments onto At@QA NPs containing 1:1 (molar ratio) calixarene molecule (QA) and anti-inflammatory and anti-fibrotic atorvastatin calcium (At). Tail vein injection of the At@NQA could efficiently target the damaged myocardium, inhibit oxidative damage and inflammation, reduce myocardial fibrosis, increase myocardial troponin T (cTnT) and connexin 43 (Cx43) expression, and thus improve cardiac functions effectively.

A deep learning-based fully automatic and clinical-ready framework for regional myocardial segmentation and myocardial ischemia evaluation.

Myocardial ischemia diagnosis with CT perfusion imaging (CTP) is important in coronary artery disease management. Traditional analysis procedure is time-consuming and error-prone due to the semi-manual and operator-dependent nature. To improve the diagnostic performance, a deep learning-based, fully automatic, and clinical-ready framework was developed. Two collaborating deep learning networks including a 3D U-Net for left ventricle segmentation and a CNN for anatomical landmarks detection were trained on 276 subjects. With our processing framework, the 17-segment left ventricular model was automatically generated conformed to the clinical standard. Myocardial blood flow computed by commercial software was extracted within each segment and visualized against the bull's eye plot. The performance was validated on another 45 subjects. Coronary angiography and invasive fractional flow reserve measurements were also performed in these patients to serve as the gold standard for myocardial ischemia diagnosis. As a result, the diagnostic accuracy for our method was 81.08%, much higher than that for commercially available CTP analysis software (56.75%), and our method demonstrated a higher consistency (Kappa coefficient 0.759 vs. 0.585). Besides, the average processing time of our method was much lower (30 ± 10.5s/subject vs. over 30min/subject). In conclusion, the proposed deep learning-based framework could be a promising tool for assisting CTP analysis.

Additional improvement in regional myocardial ischemia after intracardiac injection of bone marrow cells during CABG surgery.

Post-procedure residual ischemia is associated with worse prognosis in patients with coronary artery diasease (CAD). We evaluated whether autologous bone marrow-derived cells (BMC) contribute to additional reduction in regional stress-induced myocardial ischemia (SIMI) in patients undergoing incomplete coronary artery bypass graft surgery (CABG). In a double-blind, randomized, placebo-controlled trial, we enrolled 143 patients (82% men, 58 ± 11 years) with stable CAD and not candidates for complete CABG. They received 100 million BMC (n = 77) or placebo (n = 66) injected into ischemic non-revascularized segments during CABG. The primary outcome was improvement on SIMI quantified as the area at risk in injected segments assessed by cardiovascular magnetic resonance (CMR) 1, 6, and 12 months after CABG. The reduction in global SIMI after CABG was comparable (p = 0.491) in both groups indicating sustained beneficial effects of the surgical procedure over 12 month period. In contrast, we observed additional improvement in regional SIMI in BMC treated group (p = 0.047). Baseline regional SIMI values were comparable [18.5 (16.2-21.0) vs. 18.5 (16.5-20.7)] and reached the lowest values at 1 month [9.74 (8.25; 11.49) vs. 12.69 (10.84; 14.85)] for BMC and placebo groups, respectively. The ischemia's improvement from baseline represented a 50% difference in regional SIMI in favor of the BMC transplanted group at 30 days. We found no differences in clinical and LVEF% between groups during the 12 month follow-up period. The 1 month rate of major adverse cerebral and cardiovascular events (MACCE) (p = 0.34) and all-cause mortality (p = 0.08) did not differ between groups 1 month post intervention. We provided evidence that BMC leads to additional reduction in regional SIMI in chronic ischemic patients when injected in segments not subjected to direct surgical revascularization. This adjuvant therapy deserves further assessment in patients with advanced CAD especially in those with microcirculation dysfunction. https://clinicaltrials.gov/, identifier NCT01727063.

Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injectedinto the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction(LVEF) 30%-50% who were undergoing elective coronaryartery bypass surgery. Thirty epicardial injections of AZD8601 (total 3mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6months. There were nodeaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions,orarrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-typenatriuretic peptide levels, but the study is limited insize, and significant efficacy conclusions are not possiblefrom the dataset. Naked mRNA without lipid encapsulationmay provide a safe delivery platform for introducinggenetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool.

Median nerve stimulation elevates ventricular fibrillation threshold via the cholinergic anti-inflammatory pathway in myocardial infarction canine model.

Median nerve stimulation (MNS) diminishes regional myocardial ischemia and ventricular arrhythmia; however, the underlying mechanism has not been elucidated. In this study, we randomly categorized 22 adult mongrel dogs into a control group, MNS group 1, and MNS group 2. After a 4-week experimental myocardial infarction (MI), ventricular electrophysiology was measured in the MNS group 1 before and after 30 min of MNS. The same measurements were performed in the MNS group 2 dogs via bilateral vagotomy. Venous blood and ventricular tissue were collected to detect molecular indicators related to inflammation and cholinergic pathways by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and Western blot (WB). No significant changes were reported in the ventricular effective refractory period (ERP) in the MNS group 1 and MNS group 2 dogs before and after MNS. The ventricular fibrillation threshold (VFT) in the MNS group 1 was significantly higher than that in the MNS group 2 (20.3 ± 3.7 V vs. 8.7 ± 2.9 V, P < 0.01). The levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear transcription factor-κB (NF-κB) were lower (P < 0.01), whereas the levels of Ach were higher in the peri-infarct zone tissues in the MNS group 1 dogs than those in the MNS group 2 dogs (P < 0.01). This study demonstrated that MNS increases VFT in a canine model with MI. The effects of MNS on VFT are potentially associated with the cholinergic anti-inflammatory pathway.

Fractional myocardial blood volume by ferumoxytol-enhanced MRI: Estimation of ischemic burden.

To investigate model-fitted fractional myocardial blood volume (fMBV) derived from ferumoxytol-enhanced MRI as a measure of myocardial tissue hypoperfusion at rest. We artificially induced moderate to severe focal coronary stenosis in the left anterior descending artery of 19 swine by percutaneous delivery of a 3D-printed coronary implant. Using the MOLLI pulse sequence, we acquired T1 maps at 3 T after multiple incremental ferumoxytol doses (0.0-4.0mg/kg). We computed pixel-wise fMBV using a multi-compartmental modeling approach in 19 ischemic swine and 4 healthy swine. Ischemic myocardial segments showed a mean MRI-fMBV of 11.72 ± 3.00%, compared with 8.23 ± 2.12% in remote segments and 8.38 ± 2.23% in normal segments. Ischemic segments showed a restricted transvascular water-exchange rate (ki =15.32 ± 8.69 s-1 ) relative to remote segments (ki =17.78 [11.60, 26.36] s-1 ). A mixed-effects model found significant difference in fMBV (p=0.002) and water-exchange rate (p < 0.001) between ischemic and remote myocardial regions after adjusting for biological sex and slice location. Analysis of fMBV as a predictor of impaired myocardial contractility using receiver operating characteristics showed an area under the curve of 0.89 (95% confidence interval [CI] 0.80, 0.95). An MRI-fMBV threshold of 9.60% has a specificity of 90.0% (95% CI 76.3, 97.2) and a sensitivity of 72.5% (95% CI 56.1, 83.4) for prediction of impaired myocardial contractility. Model-fitted fMBV derived from ferumoxytol-enhanced MRI can distinguish regions of ischemia from remote myocardium in a swine model of myocardial hypoperfusion.

Repetitive Preload Elevation in Swine with Chronic Coronary Artery Disease Promotes Pro‐Fibrotic Gene Expression and Transmural Fibrosis in Remote Non‐Ischemic Myocardium

ObjectiveUsing implantable telemetry, we recently found that transient elevations in preload are common in swine with multi‐vessel coronary artery disease (CAD), presumably as a result of intermittent demand‐induced regional myocardial ischemia. Based on prior evidence that repetitive preload elevation can lead to interstitial fibrosis and myocardial stiffening in the absence of ischemia, the present study was designed to compare temporal changes in pro‐fibrotic gene expression and transmural variability in interstitial fibrosis in ischemic vs. non‐ischemic areas of the left ventricle (LV) in a porcine model of chronic CAD.MethodsA total of 20 juvenile swine were instrumented with fixed 1.5 mm constrictors on the proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries and followed for up to 3‐months, during which coronary stenosis severity progressed to &gt;90 % (LAD: 93±2 %; LCx: 91±3 %). Expression of fibronectin (FN1) and lysyl oxidase like‐2 (LOXL‐2) was assessed in ischemic (LAD) and non‐ischemic (RCA) regions of the LV via quantitative PCR 1‐month (n=4) or 3‐months (n=8) after instrumentation and compared to normal controls (n=8). Post‐mortem quantification of interstitial fibrosis was performed on picrosirius red‐stained tissue samples from ischemic and non‐ischemic regions (n=16), with an automated classifier‐based approach to compare regional transmural variability in collagen content to that of normal controls (n=11). Flash‐frozen tissue samples from a sub‐set of animals with CAD (n=4) and normal controls (n=4) were subjected to uniaxial tensile testing to assess passive subendocardial stiffness.ResultsOne month after instrumentation, FN1 expression was 2.5±0.9‐fold higher than control in the ischemic region and 2.7±0.7‐fold higher than control in the non‐ischemic region of the LV (both p&lt;0.05). LOXL2 expression was also significantly higher in the ischemic (2.2 ± 0.6‐fold higher than control) and non‐ischemic (2.4 ± 0.3‐fold higher than control) regions of the LV at this timepoint. Two months later, pro‐fibrotic gene expression had normalized but a significant elevation in interstitial collagen content was observed throughout the LV of animals with CAD (Figure; left panel). Interestingly, subendocardial fibrosis was particularly prominent in the non‐ischemic RCA territory, which coincided with a significant increase in subendocardial passive stiffness in this region (Figure; right panel).ConclusionsIn a porcine model of chronic CAD, repetitive preload elevation is associated with transient changes in pro‐fibrotic gene expression that ultimately lead to transmural fibrosis that is particularly prominent in non‐ischemic areas of the LV. Regional transmural variability in collagen content coincides with changes in the passive stiffness of non‐ischemic myocardium, suggesting that repetitive preload elevation may contribute to fibrosis‐mediated diastolic dysfunction in patients with chronic CAD.

Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium: A MiHeart/IHD Quantitative Perfusion CMR Substudy

ObjectivesThis study investigated whether intramyocardial bone marrow–derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BackgroundPatients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. MethodsThe MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. ResultsOf 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 ± 0.79 vs 1.64 ± 0.89 in adjacent and 1.79 ± 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). ConclusionsBMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments.

The Coronary Collateral Artery: The Prognostic Importance and Functional Relevance

Coronary collateral artery (CCA) is an alternative source of blood supply to an ischemic myocardial region. It is generally believed that there is a beneficial effect of collaterals in patients with coronary artery disease (CAD). Recently, reliable methods have become available for the assessment of the adequacy of collateral flow. However, the debate regarding the importance of CCA in the different clinical settings continues. In this review article, we discuss about the functional relevance of CCA to provide an overview of its impact on the prognosis of patients with CAD.