Molecular Imaging for Efficacy of Pharmacologic Intervention in Myocardial Remodeling

ObjectivesUsing molecular imaging techniques, we examined interstitial alterations during postmyocardial infarction (MI) remodeling and assessed the efficacy of antiangiotensin and antimineralocorticoid intervention, alone and in combination.BackgroundThe antagonists of the renin-angiotensin-aldosterone axis restrict myocardial fibrosis and cardiac remodeling after MI and contribute to improved survival. Radionuclide imaging with technetium-99m–labeled Cy5.5 RGD imaging peptide (CRIP) targets myofibroblasts and indirectly allows monitoring of the extent of collagen deposition post-MI.MethodsCRIP was intravenously administered for gamma imaging after 4 weeks of MI in 63 Swiss-Webster mice and in 6 unmanipulated mice. Of 63 animals, 50 were treated with captopril (C), losartan (L), spironolactone (S) alone, or in combination (CL, SC, SL, and SCL), 8 mice received no treatment. Echocardiography was performed for assessment of cardiac remodeling. Hearts were characterized histopathologically for the presence of myofibroblasts and thick and thin collagen fiber deposition.ResultsAcute MI size was similar in all groups. The quantitative CRIP percent injected dose per gram uptake was greatest in the infarct area of untreated control mice (2.30 ± 0.14%) and decreased significantly in animals treated with 1 agent (C, L, or S; 1.71 ± 0.35%; p = 0.0002). The addition of 2 (CL, SC, or SL 1.31 ± 0.40%; p < 0.0001) or 3 agents (SCL; 1.16 ± 0.26%; p < 0.0001) demonstrated further reduction in tracer uptake. The decrease in echocardiographic left ventricular function, strain and rotation parameters, as well as histologically verified deposition of thin collagen fibers, was significantly reduced in treatment groups and correlated with CRIP uptake.ConclusionsRadiolabeled CRIP allows for the evaluation of the efficacy of neurohumoral antagonists after MI and reconfirms superiority of combination therapy. If proven clinically, molecular imaging of the myocardial healing process may help plan an optimal treatment for patients susceptible to heart failure

Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer:A Randomized Clinical Trial

PURPOSE:Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking.METHODS:Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior &lt;.0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality.RESULTS:Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior =.0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior =.0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P =.4940).CONCLUSION:On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.</p

The Search for an Outcome Variable That Measures Both Quality and Processes in Cardiac Surgery: Comparing the Quality Process Index and Mortality

Background: The translation of a large quantity of data into valuable insights for daily clinical practice is underexplored. A considerable amount of information is overwhelming, making it difficult to distill and assess quality and processes at the hospital level. This study contributes to this necessary translation by developing a Quality Process Index that summarizes clinical data to measure quality and processes. Methods: The Quality Process Index was constructed to enable retrospective analyses of quality and process evolution from 2011 to 2021 for various surgery types in the Amsterdam Cardiosurgical Database (n = 5497). It is presented alongside mortality rates, which are the golden standard for quality measurement. The two outcome variables are compared as quality and process measurement options. Results: Results showed that the mean Quality Process Index appeared rather stable, even though analysis of variance found that the mean Quality Process Index differed significantly over the years (p < 0.001). The 30-day and 120-day mortality rates appeared to fluctuate more, but interestingly, we failed to reject the null hypothesis of equal means. The Quality Process Index and mortality rates were statistically negatively correlated, and the extent of correlation was more pronounced with the 120-day mortality rate, as computed using the Pearson correlation coefficient (Formula presented.) (30-day (Formula presented.) = −0.07, p < 0.001 and 120-day mortality rates (Formula presented.) = −0.12, p < 0.001). Conclusions: The Quality Process Index seeks to address the need to translate data for quality and process improvement in healthcare. While mortality remains the most impactful outcome measure, the Quality Process Index provides a more stable and comprehensive measurement of quality and process improvement or deterioration in healthcare. Therefore, the Quality Process Index as a quantification reinforces the understanding of the definition of quality and process improvement

Systematic Review of Interventions to Reduce Operating Time in Lung Cancer Surgery

Introduction: Operating rooms are a scarce resource but often used inefficiently. Operating room efficiency emerges as an important part of maximizing surgical capacity and productivity, minimizing delays, and optimizing lung cancer outcomes. The operative time (time between patient entering and leaving the operating room) is discrete and the one that the surgical team can most directly influence. We performed a systematic review to evaluate the literature and identify methods to improve the efficiency of the intraoperative phase of operations for lung cancer. Methods: A literature search (in PubMed, Embase, Cochrane, and Scopus) was performed from inception up to March 9, 2020, according to the methodology described in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Results: We identified 3 articles relevant to the intraoperative phase of lung cancer operating room efficiency. All 3 were consistent in showing clinically relevant time reductions in the intraoperative phase or procedures relevant to this phase. The authors demonstrated that the application of various improvement methodologies resulted in a substantial reduction in operative time, which was associated with a reduction in complications, and improved staff morale. Conclusions: Our systematic review found that various improvement methodologies have the potential to significantly reduce operative time for lung cancer surgery. This increases the value of lung cancer surgery. These findings are consistent with the wider literature on improving surgical efficiency

Quality and process improvement of the multidisciplinary Heart Team meeting using Lean Six Sigma

Introduction The Heart Team is a multidisciplinary meeting for shared decision-making in cardiology and cardiothoracic surgery. A quality improvement project to optimise the Heart Team was initiated after the merger of the cardiac centres of Amsterdam University Medical Centre. Methods Lean Six Sigma was applied with the purpose of improving efficiency and quality of care. Qualitative and quantitative analyses supported the multidisciplinary team during quality improvement sessions. Lean Six Sigma tools included process mapping, gemba walks, root cause analysis, line balancing, first time right, standardised work and poka-yoke. Interventions Seven areas of improvement were introduced. Key elements were the improvement of the patient referral process, introduction of a structured agenda, task division and balanced planning of patients, better exchange of information, improved availability of diagnostics and supportive tools and information technology. Work agreements were introduced to support a positive work culture and mutual respect. Results Lean Six Sigma designed an optimised Heart Team to improve efficiency by better resource utilisation, first time right decision-making, patient selection, complete and better access to information and elimination of waste. It leads to higher quality of decision-making by involving physicians in a more structured preparation, attendance of an imaging cardiologist, meeting duration within limits, installation of standard operating procedures, increased involvement of the referring cardiologists and a better engaged team. Conclusions Heart Teams are essential to make evidence-based, patient-centred treatment plans for optimal patient outcomes. However, clinical practice and experience showed that it is challenging to have an efficient and effective discussion with complete patient information and to bring together healthcare professionals. The application of Lean Six Sigma resulted in an optimised Heart Team and created a best practice design for patient-centred, evidence-based decision-making. After implementation and process stability, a postintervention analysis could clarify long-term success and sustainability

Transition of Macrophages to Fibroblast-Like Cells in Healing&nbsp;Myocardial Infarction.

BackgroundMacrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.ObjectivesThis study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.MethodsProlonged in&nbsp;vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in&nbsp;vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.ResultsExpression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI.ConclusionsThe data provide both in&nbsp;vitro and in&nbsp;vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes

Annexin A5 Uptake in Ischemic Myocardium: Demonstration of Reversible Phosphatidylserine Externalization and Feasibility of Radionuclide Imaging

Ischemic insult to the myocardium is associated with cardiomyocyte apoptosis. Because apoptotic cell death is characterized by phosphatidylserine externalization on cell membrane and annexin-A5 (AA5) avidly binds to phosphatidylserine, we hypothesized that radiolabeled AA5 should be able to identify the regions of myocardial ischemia. Methods: Models of brief myocardial ischemia by the occlusion of the coronary artery for 10 min (I-10) and reperfusion for 180 min (R-180) for the detection of phosphatidylserine exteriorization using Tc-99m-labeled AA5 and gamma-imaging were produced in rabbits. Tc-99m-AA5 uptake after brief ischemia was compared with an I-40/R-180 infarct model. Histologic characterization of both myocardial necrosis and apoptosis was performed in ischemia and infarct models. Phosphatidylserine exteriorization was also studied in a mouse model, and the dynamics and kinetics of phosphatidylserine exposure were assessed using unlabeled recombinant AA5 and AA5 labeled with biotin, Oregon Green, or Alexa 568. Appropriate controls were established. Results: Phosphatidylserine exposure after ischemia in the rabbit heart could be detected by radionuclide imaging with Tc-99m-AA5. Pathologic characterization of the explanted rabbit hearts did not show apoptosis or necrosis. Homogenization and ultracentrifugation of the ischemic myocardial tissue from rabbit hearts recovered two thirds of the radiolabeled AA5 from the cytoplasmic compartment. Murine experiments demonstrated that the cardiomyocytes expressed phosphatidylserine on their cell surface after an ischemic insult of 5 min. Phosphatidylserine exposure occurred continuously for at least 6 h after solitary ischemic insult. AA5 targeted the exposed phosphatidylserine on cardiomyocytes; AA5 was internalized into cytoplasmic vesicles within 10-30 min. Twenty-four hours after ischemia, cardiomyocytes with internalized AA5 had restored phosphatidylserine asymmetry of the sarcolemma, and no detectable phosphatidylserine remained on the cell surface. The preadministration of a pan-caspase inhibitor, zVAD-fmk, prevented phosphatidylserine exposure after ischemia. Conclusions: After a single episode of ischemia, cardiomyocytes express phosphatidylserine, which is amenable to targeting by AA5, for at least 6 h. Phosphatidylserine exposure is transient and internalized in cytoplasmic vesicles after AA5 binding, indicating the reversibility of the apoptotic process

Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction

[Background]: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. [Objectives]: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. [Methods]: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. [Results]: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI. [Conclusions]: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.This work was supported by grants SAF2017-82436R and RTC2017-6283 from MINEICO, S2017/BMD-3686 from Comunidad de Madrid, CIVP18A3864 from Fundación Ramón Areces and CIBERCV (funded by the Instituto de Salud Carlos III), Fondos FEDER, and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award IK2BX003922 (to Dr. DeLeon-Pennell)

Noninvasive Molecular Imaging of Cell Death in Myocardial Infarction using 111In-GSAO

Acute insult to the myocardium is associated with substantial loss of cardiomyocytes during the process of myocardial infarction. In this setting, apoptosis (programmed cell death) and necrosis may operate on a continuum. Because the latter is characterized by the loss of sarcolemmal integrity, we propose that an appropriately labeled tracer directed at a ubiquitously present intracellular moiety would allow non-invasive definition of cardiomyocyte necrosis. A trivalent arsenic peptide, GSAO (4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid), is capable of binding to intracellular dithiol molecules such as HSP90 and filamin-A. Since GSAO is membrane impermeable and dithiol molecules abundantly present intracellularly, we propose that myocardial localization would represent sarcolemmal disruption or necrotic cell death. In rabbit and mouse models of myocardial infarction and post-infarct heart failure, we employed In-111-labelled GSAO for noninvasive radionuclide molecular imaging. In-111-GSAO uptake was observed within the regions of apoptosis seeking agent-(99)mTc-Annexin A5 uptake, suggesting the colocalization of apoptotic and necrotic cell death processes