A systematic review and meta-analysis of Murray's Law in the Coronary Arterial Circulation.

Murray's law has been viewed as a fundamental law of physiology. Relating blood flow (Q) to vessel diameter (D) (Q µD3), it dictates minimum lumen area (MLA) targets for coronary bifurcation percutaneous coronary intervention (PCI). The cubic exponent (3.0) however, has long been disputed, with alternative theoretical derivations arguing this should be closer to 2.33 (7/3). The aim of this meta-analysis was to quantify the optimum flow-diameter exponent in human and mammalian coronary arteries. We conducted a systematic review and meta-analysis of all articles quantifying an optimum flow-diameter exponent for mammalian coronary arteries within the Cochrane library, PubMed Medline, Scopus, and Embase databases on 20/3/2023. A random-effects meta-analysis was used to determine a pooled flow-diameter exponent. Risk of bias was assessed with the National Institutes of Health (NIH) quality assessment tool, funnel plots and Egger regression. From a total of 4,524 articles, 18 were suitable for meta-analysis. Studies included data from 1,070 unique coronary trees, taken from 372 humans and 112 animals. The pooled flow diameter exponent across both epicardial and transmural arteries was 2.39 (95% CI 2.24 - 2.54, I2 = 99%). The pooled exponent of 2.39 showed very close agreement with the theoretical exponent of 2.33 (7/3) reported by Kassab and colleagues. This exponent may provide a more accurate description of coronary morphometric scaling in human and mammalian coronary arteries, as compared with Murray's original law. This has important implications for the assessment, diagnosis, and interventional treatment of coronary artery disease.

Preconditioning with selective autoretroperfusion: In vivo and in silico evidence of washout hypothesis.

Introduction: Prompt reperfusion of coronary artery after acute myocardial infarction (AMI) is crucial for minimizing heart injury. The myocardium, however, may experience additional injury due to the flow restoration itself (reperfusion injury, RI). The purpose of this study was to demonstrate that short preconditioning (10 min) with selective autoretroperfusion (SARP) ameliorates RI, based on a washout hypothesis. Methods: AMI was induced in 23 pigs (3 groups) by occluding the left anterior descending (LAD) artery. In SARP-b (SARP balloon inflated) and SARP-nb (SARP balloon deflated) groups, arterial blood was retroperfused for 10 min via the great cardiac vein before releasing the arterial occlusion. A mathematical model of coronary circulation was used to simulate the SARP process and evaluate the potential washout effect. Results: SARP restored left ventricular function during LAD occlusion. Ejection fraction in the SARP-b group returned to baseline levels, compared to SARP-nb and control groups. Infarct area was significantly larger in the control group than in the SARP-b and SARP-nb groups. End-systolic wall thickness was preserved in the SARP-b compared to the SARP-nb and control groups. Analyte values (pH, lactate, glucose, and others), measured every 2 min during retroperfusion, suggest a "washout" effect as one important mechanism of action of SARP in reducing infarct size. With SARP, the values progressively approached baseline levels. The mathematical model also confirmed a possible washout effect of tracers. Discussion: RI can be ameliorated by delaying restoration of arterial flow for a brief period of time while pretreating the infarction with SARP to restore homeostasis via a washout mechanism.

Venous thromboembolism swine model with reflux-induced venous hypertension.

Objective: This study describes a novel swine model of venous thromboembolism (VTE) with reflux-induced venous hypertension. Methods: Six pigs underwent disruption of the tricuspid chordae tendineae to create reflux and venous hypertension in the femoral vein. The vein was traumatized 2 to 3 weeks later by repeated withdrawal of a slightly overinflated occlusion balloon across the lumen, followed by balloon occlusion of the outflow. A small amount of thrombin was injected into the traumatized vein segment immediately after outflow occlusion. Thrombosis of the traumatized vein evolved into an organized thrombus seven weeks later. The histological features of the harvested post-thrombotic femoral vein were studied with hematoxylin and eosin and Trichrome stains. Results: In all six pigs, initial disruption of the chordae tendineae was successfully performed to create tricuspid reflux and venous hypertension. After two-stage sequential procedures, a thrombus formed in the target femoral vein segment. Histology of the harvested thrombotic vein showed features of an organizing thrombus with collagen formation and fibrosis. Conclusions: The novel swine VTE model may serve as a platform for developing and testing human-sized therapeutic procedures and devices in translational venous research. Clinical Relevance: This study describes a swine model of VTE created by incorporating all three elements of Virchow's triad. The model uniquely incorporates reflux-induced venous hypertension, which may be used in studying venous insufficiency and VTE in those with systemic venous hypertension. Likewise, this model may serve as a platform for development and evaluation of diagnostic imaging or therapeutic procedures and devices in subjects with systemic venous hypertension.

Mechanisms of coronary sinus reducer for treatment of myocardial ischemia: in silico study.

The coronary sinus reducer (CSR) is an emerging medical device for treating patients with refractory angina, often associated with myocardial ischemia. Patients implanted with CSR have shown positive outcomes, but the underlying mechanisms are unclear. This study sought to understand the mechanisms of CSR by investigating its effects on coronary microcirculation hemodynamics that may help explain the therapy's efficacy. We applied a validated computer model of the coronary microcirculation to investigate how CSR affects hemodynamics under different degrees of coronary artery stenosis. With moderate coronary stenosis, an increase in capillary transit time (CTT) [up to 69% with near-complete coronary sinus (CS) occlusion] is the key change associated with CSR. Because capillaries in the microcirculation can still receive oxygenated blood from the upstream artery with moderate stenosis, the increase in CTT allows more time for the exchange of gases and nutrients, aiding tissue oxygenation. With severe coronary stenosis; however, the redistribution of blood draining from the nonischemic region to the ischemic region (up to 96% with near-complete CS occlusion) and the reduction in capillary flow heterogeneity are the key changes associated with CSR. Because blood draining from the nonischemic region is not completely devoid of O2, the redistribution of blood to the capillaries in the ischemic region by CSR is beneficial especially when little or no oxygenated blood reaches these capillaries. This simulation study provides insights into the mechanisms of CSR in improving clinical symptoms. The mechanisms differ with the severity of the upstream stenosis.NEW & NOTEWORTHY Emerging coronary venous retroperfusion treatments, particularly coronary sinus reducer (CSR) for refractory angina linked to myocardial ischemia, show promise; however, their mechanisms of action are not well understood. We find that CSR's effectiveness varies with the severity of coronary stenosis. In moderate stenosis, CSR improves tissue oxygenation by increasing capillary transit time, whereas in severe stenosis, it redistributes blood from nonischemic to ischemic regions and reduces capillary flow heterogeneity.

Review of cardiac-coronary interaction and insights from mathematical modeling.

Cardiac-coronary interaction is fundamental to the function of the heart. As one of the highest metabolic organs in the body, the cardiac oxygen demand is met by blood perfusion through the coronary vasculature. The coronary vasculature is largely embedded within the myocardial tissue which is continually contracting and hence squeezing the blood vessels. The myocardium-coronary vessel interaction is two-ways and complex. Here, we review the different types of cardiac-coronary interactions with a focus on insights gained from mathematical models. Specifically, we will consider the following: (1) myocardial-vessel mechanical interaction; (2) metabolic-flow interaction and regulation; (3) perfusion-contraction matching, and (4) chronic interactions between the myocardium and coronary vasculature. We also provide a discussion of the relevant experimental and clinical studies of different types of cardiac-coronary interactions. Finally, we highlight knowledge gaps, key challenges, and limitations of existing mathematical models along with future research directions to understand the unique myocardium-coronary coupling in the heart. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Cardiovascular Diseases > Molecular and Cellular Physiology.

Rapid automated lumen segmentation of coronary optical coherence tomography images followed by 3D reconstruction of coronary arteries.

Purpose: Optical coherence tomography has emerged as an important intracoronary imaging technique for coronary artery disease diagnosis as it produces high-resolution cross-sectional images of luminal and plaque morphology. Precise and fast lumen segmentation is essential for efficient OCT morphometric analysis. However, due to the presence of various image artifacts, including side branches, luminal blood artifacts, and complicated lesions, this remains a challenging task. Approach: Our research study proposes a rapid automatic segmentation method that utilizes nonuniform rational B-spline to connect limited pixel points and identify the edges of the OCT lumen. The proposed method suppresses image noise and accurately extracts the lumen border with a high correlation to ground truth images based on the area, minimal diameter, and maximal diameter. Results: We evaluated the method using 3300 OCT frames from 10 patients and found that it achieved favorable results. The average time taken for automatic segmentation by the proposed method is 0.17 s per frame. Additionally, the proposed method includes seamless vessel reconstruction following the lumen segmentation. Conclusions: The developed automated system provides an accurate, efficient, robust, and user-friendly platform for coronary lumen segmentation and reconstruction, which can pave the way for improved assessment of the coronary artery lumen morphology.

Simulation of coronary capillary transit time based on full vascular model of the heart.

Capillary transit time (CTT) is a fundamental determinant of gas exchange between blood and tissues in the heart and other organs. Despite advances in experimental techniques, it remains difficult to measure coronary CTT in vivo. Here, we developed a novel computational framework that couples coronary microcirculation with cardiac mechanics in a closed-loop system that enables prediction of hemodynamics in the entire coronary network, including arteries, veins, and capillaries. We also developed a novel "particle-tracking" approach for computing CTT where "virtual tracers" are individually tracked as they traverse the capillary network. Model predictions compare well with blood pressure and flow rate distributions in the arterial network reported in previous studies. Model predictions of transit times in the capillaries (1.21 ± 1.5 s) and entire coronary network (11.8 ± 1.8 s) also agree with measurements. We show that, with increasing coronary artery stenosis (as quantified by fractional flow reserve, FFR), intravascular pressure and flow rate downstream are reduced but remain non-stationary even at 100 % stenosis because some flow (∼3 %) is redistributed from the non-occluded to the occluded territories. Importantly, the model predicts that occlusion of a large artery results in higher CTT. For moderate stenosis (FFR > 0.6), the increase in CTT (from 1.21 s without stenosis to 2.23 s at FFR=0.6) is caused by a decrease in capillary flow rate. In severe stenosis (FFR = 0.1), the increase in CTT to 14.2 s is due to both a decrease in flow rate and an increase in path length taken by "virtual tracers" in the capillary network.

Novel venous balloon for compliance measurement and stent sizing in a post-thrombotic swine model.

Objective: Real-time accurate venous lesion characterization is needed during endovenous interventions for stent deployment. The goal of this study is to validate a novel device for venoplasty sizing and compliance measurements. Methods: A compliance measuring sizing balloon (CMSB) uses real-time electrical conductance measurements based on Ohm's Law to measure the venous size and compliance in conjunction with pressure measurement. The sizing accuracy and repeatability of the CMSB system were performed with phantoms on the bench and in a swine model with an induced post thrombotic (PT) stenosis in the common femoral vein of swine. Results: The accuracy and repeatability of the CMSB system were validated with phantom bench studies of known dimensions in the range of venous diameters. In 9 swine (6 experimental and 3 control animals), the luminal cross-sectional areas (CSA) increased heterogeneously along the PT stenosis when the CMSB system was inflated by stepwise pressures. The PT stenosis showed lower compliance compared to the non-PT vein segments (5 mm2 vs. 10 mm2 and 13 mm2 at a pressure change of 40 cm H2O). Compliance had no statistical difference between venous hypertension (VHT) and Control. Compliance at PT stenosis, however, was significantly smaller than that at Control and VHT (p < 0.05, ANOVA). Conclusion: The CMSB system provides accurate, repeatable, real-time measurements of CSA and compliance for assessment of venous lesions to guide interventions. These findings provide the impetus for future first-in-human studies.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Background: Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. Methods and results: In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. Conclusions: These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.

Artificial Intelligence, Computational Simulations, and Extended Reality in Cardiovascular Interventions.

Artificial intelligence, computational simulations, and extended reality, among other 21st century computational technologies, are changing the health care system. To collectively highlight the most recent advances and benefits of artificial intelligence, computational simulations, and extended reality in cardiovascular therapies, we coined the abbreviation AISER. The review particularly focuses on the following applications of AISER: 1) preprocedural planning and clinical decision making; 2) virtual clinical trials, and cardiovascular device research, development, and regulatory approval; and 3) education and training of interventional health care professionals and medical technology innovators. We also discuss the obstacles and constraints associated with the application of AISER technologies, as well as the proposed solutions. Interventional health care professionals, computer scientists, biomedical engineers, experts in bioinformatics and visualization, the device industry, ethics committees, and regulatory agencies are expected to streamline the use of AISER technologies in cardiovascular interventions and medicine in general.

An in silico study of the effects of left ventricular assist device on right ventricular function and inter-ventricular interaction.

BACKGROUND: Left ventricular assist device (LVAD) is associated with a high incidence of right ventricular (RV) failure, which is hypothesized to be caused by the occurring inter-ventricular interactions when the LV is unloaded. Factors contributing to these interactions are unknown. METHODS: We used computer modeling to investigate the impact of the HeartMate 3 LVAD on RV functions. The model was first calibrated against pressure-volume (PV) loops associated with a heart failure (HF) patient and validated against measurements of inter-ventricular interactions in animal experiments. The model was then applied to investigate the effects of LVAD on (1) RV chamber contractility indexed by V 60 derived from its end-systolic PV relationship, and (2) RV diastolic function indexed by V 20 derived from its end-diastolic PV relationship. We also investigated how septal wall thickness and regional contractility affect the impact of LVAD on RV function. RESULTS: The impact of LVAD on RV chamber contractility is small at a pump speed lower than 4k rpm. At a higher pump speed between 4k and 9k rpm, however, RV chamber contractility is reduced (by ~3% at 6k rpm and ~10% at 9k rpm). The reduction of RV chamber contractility is greater with a thinner septal wall or with a lower myocardial contractility at the LV free wall, septum, or RV free wall. CONCLUSION: RV chamber contractility is reduced at a pump speed higher than 4k rpm, and this reduction is greater with a thinner septal wall or lower regional myocardial contractility. Findings here may have clinical implications in identifying LVAD patients who may suffer from RV failure.

Performance of xenogeneic pulmonary visceral pleura as bioprosthetic heart valve cusps in swine.

Objective: Bovine pericardium is common biological material for bioprosthetic heart valve. There remains a significant need, however, to improve bioprosthetic valves for longer-term outcomes. This study aims to evaluate the chronic performance of bovine pulmonary visceral pleura (PVP) as bioprosthetic valve cusps. Methods: The PVP was extracted from the bovine lung and fixed in 0.625% glutaraldehyde overnight at room temperature. The PVP valve cusps for the bioprosthetic valve were tailored using a laser cutter. Three leaflets were sewn onto a nitinol stent. Six PVP bioprosthetic valves were loaded into the test chamber of the heart valve tester to complete 100 million cycles. Six other PVP bioprosthetic valves were transcardially implanted to replace pulmonary artery valve of six pigs. Fluoroscopy and intracardiac echocardiography were used for in vivo assessments. Thrombosis, calcification, inflammation, and fibrosis were evaluated in the terminal study. Histologic analyses were used for evaluations of any degradation or calcification. Results: All PVP bioprosthetic valves completed 100 million cycles without significant damage or tears. In vivo assessments showed bioprosthetic valve cusps open and coaptation at four months post-implant. No calcification and thrombotic deposits, inflammation, and fibrosis were observed in the heart or pulmonary artery. The histologic analyses showed complete and compact elastin and collagen fibers in the PVP valve cusps. Calcification-specific stains showed no calcific deposit in the PVP valve cusps. Conclusions: The accelerated wear test demonstrates suitable mechanical strength of PVP cusps for heart valve. The swine model demonstrates that the PVP valve cusps are promising for valve replacement.

Novel patch biomaterial treatment for colon diverticulosis in swine model.

Current leading managements for diverticular disease cannot prevent the recurrence of diverticulitis, bleeding and/or other complications. There is an immediate need for developing new minimal invasive therapeutic strategies to prevent and treat this disease. Through a biomechanical analysis of porcine colon with diverticular lesions, we proposed a novel adhesive patch concept aiming at mechanical reconstruction of the diseased colon wall. This study aims to evaluate the surgical feasibility (safety and efficacy) of pulmonary visceral pleura (PVP) patch therapy using a pig model of diverticulosis. Six female Yucatan miniature pigs underwent collagenase injection (CI) for the development of diverticular lesions. The lesions in each animal either received patch implantation (treated group, n = 40 for 6 pigs) or left intact (untreated group, n = 44 for 6 pigs). The normal colonic wall in each animal received patch implantation at two spots to serve as control (n = 12 for 6 pigs). After 3 months of observation, the performance and safety of the patch treatment were evaluated through macroscopic and histological examination. We found that 95% of pouch-like herniation of the mucosa was prevented from the colon wall with the treatment. The pouch diameter was significantly reduced in the treated group as compared to the untreated group (p < 0.001). The patch application caused a significant increase in the levels of collagen of the colon tissue as compared to the untreated and control groups (p < 0.001). No difference was found in the lymphocyte and macrophage inflammatory infiltrate between the groups. Our results suggest that patch treatment efficiently inhibits the diverticular pouch deformation and promotes the healing of the colon wall with a normal inflammatory response, which may minimize the risk of diverticulosis reoccurrence and complications over time.

Conduit design with expanding diameter for enhanced flow.

Conduits are commonly used for treating lesions in arteries and veins. The conventional stents are cylindrical in shape, which increases flow resistance with length. This study presents a design of stents and conduits where the conduit caliber expands gradually to reduce resistance while avoiding flow separation. Inflow was provided from a header tank at two different pressures (i.e., 10 and 25 mm Hg pressure) into a cylindrical or expanding conduit. The initial conduit calibers were 2-, 3-, 4-, and 5-mm and 160-, 310-, and 620-mm lengths in each case. The flow rates of expanding caliber conduits (at a rate of r4-6/cm where r is the initial conduit radius) were compared to traditional cylindrical conduits of constant radius. The expanded caliber yields a significantly increased flow of 16-55% for R4/L expansion, 9-44% for R5/L expansion, and 1-28% for R6/L expansion. Simulated flow models using computational fluid dynamics (CFD) were used to validate and expand the experimental findings. Flow separation was detected for certain simulations by flow pathlines and wall shear stress (WSS) calculations. The results showed that a caliber expansion rate of r6/cm is the optimal rate of expansion for most potential applications with minimum flow separation, lower resistance, and increased flow.

Patient-specific computational simulation of coronary artery bypass grafting.

INTRODUCTION: Coronary artery bypass graft surgery (CABG) is an intervention in patients with extensive obstructive coronary artery disease diagnosed with invasive coronary angiography. Here we present and test a novel application of non-invasive computational assessment of coronary hemodynamics before and after bypass grafting. METHODS AND RESULTS: We tested the computational CABG platform in n = 2 post-CABG patients. The computationally calculated fractional flow reserve showed high agreement with the angiography-based fractional flow reserve. Furthermore, we performed multiscale computational fluid dynamics simulations of pre- and post-CABG under simulated resting and hyperemic conditions in n = 2 patient-specific anatomies 3D reconstructed from coronary computed tomography angiography. We computationally created different degrees of stenosis in the left anterior descending artery, and we showed that increasing severity of native artery stenosis resulted in augmented flow through the graft and improvement of resting and hyperemic flow in the distal part of the grafted native artery. CONCLUSIONS: We presented a comprehensive patient-specific computational platform that can simulate the hemodynamic conditions before and after CABG and faithfully reproduce the hemodynamic effects of bypass grafting on the native coronary artery flow. Further clinical studies are warranted to validate this preliminary data.

Machine learning used for simulation of MitraClip intervention: A proof-of-concept study.

Introduction: Severe mitral regurgitation (MR) is a mitral valve disease that can lead to lifethreatening complications. MitraClip (MC) therapy is a percutaneous solution for patients who cannot tolerate surgical solutions. In MC therapy, a clip is implanted in the heart to reduce MR. To achieve optimal MC therapy, the cardiologist needs to foresee the outcomes of different scenarios for MC implantation, including the location of the MC. Although finite element (FE) modeling can simulate the outcomes of different MC scenarios, it is not suitable for clinical usage because it requires several hours to complete. Methods: In this paper, we used machine learning (ML) to predict the outcomes of MC therapy in less than 1 s. Two ML algorithms were used: XGBoost, which is a decision tree model, and a feed-forward deep learning (DL) model. The MC location, the geometrical attributes of the models and baseline stress and MR were the features of the ML models, and the predictions were performed for MR and maximum von Mises stress in the leaflets. The parameters of the ML models were determined to achieve the minimum errors obtained by applying the ML models on the validation set. Results: The results for the test set (not used during training) showed relative agreement between ML predictions and ground truth FE predictions. The accuracy of the XGBoost models were better than DL models. Mean absolute percentage error (MAPE) for the XGBoost predictions were 0.115 and 0.231, and the MAPE for DL predictions were 0.154 and 0.310, for MR and stress, respectively. Discussion: The ML models reduced the FE runtime from 6 hours (on average) to less than 1 s. The accuracy of ML models can be increased by increasing the dataset size. The results of this study have important implications for improving the outcomes of MC therapy by providing information about the outcomes of MC implantation in real-time.

Coupled thermal-hemodynamics computational modeling of cryoballoon ablation for pulmonary vein isolation.

Cryoballoon ablation (CBA) is a cryo-energy based minimally invasive treatment procedure for patients suffering from left atrial (LA) fibrillation. Although this technique has proved to be effective, it is prone to reoccurrences and some serious thermal complications. Also, the factors affecting thermal distribution at the pulmonary vein-antrum junction that are critical to the treatment success is poorly understood. Computer modeling of CBA can resolve this issue and help understand the factors affecting this treatment. To do so, however, numerical challenges associated with the simulation of advection-dominant transport process must be resolved. Here, we describe the development of a thermal-hemodynamics computational framework to simulate incomplete occlusion in a patient-specific LA geometry during CBA. The modeling framework uses the finite element method to predict hemodynamics, thermal distribution, and lesion formation during CBA. An incremental pressure correction scheme is used to decouple velocity and pressure in the Navier-Stokes equation, whereas several stabilization techniques are also applied to overcome numerical instabilities. The framework was implemented using an open-source FE library (FEniCS). We show that model predictions of the hemodynamics in a realistic human LA geometry match well with measurements. The effects of cryoballoon position, pulmonary vein blood velocity and mitral regurgitation on lesion formation during CBA was investigated. For a -700C cryoballoon temperature, the model predicts lesion formation for gaps less than 2.5 mm and increasing efficiency of CBA for higher balloon tissue contact areas. The simulations also predict that lesion formation is not sensitive to variation in pulmonary vein blood velocity and mitral regurgitation. The framework can be applied to optimize CBA in patients for future clinical studies.

Definitions and Standardized Endpoints for Treatment of Coronary Bifurcations.

The Bifurcation Academic Research Consortium (Bif-ARC) project originated from the need to overcome the paucity of standardization and comparability between studies involving bifurcation coronary lesions. This document is the result of a collaborative effort between academic research organizations and the most renowned interventional cardiology societies focused on bifurcation lesions in Europe, the United States, and Asia. This consensus provides standardized definitions for bifurcation lesions; the criteria to judge the side branch relevance; the procedural, mechanistic, and clinical endpoints for every type of bifurcation study; and the follow-up methods. Considering the complexity of bifurcation lesions and their evaluation, detailed instructions and technical aspects for site and core laboratory analysis of bifurcation lesions are also reported. The recommendations included within this consensus will facilitate pooled analyses and the effective comparison of data in the future, improving the clinical relevance of trials in bifurcation lesions, and the quality of care in this subset of patients.

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand-supply feedback system.

BACKGROUND AND OBJECTIVE: The myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. METHODS: To investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. RESULTS: We found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. CONCLUSIONS: Model predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation.

Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1-10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.