surgical-porcine-model-chronic-myocardial-ischemia-treated-exosome

Surgical Porcine Model of Chronic Myocardial Ischemia Treated by Exosome-laden Collagen Patch and Off-pump Coronary Artery Bypass Graft

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts ...

University of Minnesota

Prior coronary artery bypass grafting (CABG) has been considered a relative contraindication to lung transplantation due to the atherosclerotic disease burden and technical challenges. We hypothesized that lung transplant recipients with prior CABG have increased mortality compared to recipients without prior CABG. Further, the causes of death are different for lung transplant recipients with prior CABG vs without CABG. The Scientific Registry of Transplant Recipients database was queried to define the survival and causes of death of lung transplant recipients with or without CABG during the Lung Allocation Score era from May 5, 2005 to December 31, 2015. The primary end-points were all-cause mortality at 1 year and 5 years, as well as mortality due to major causes of death. This retrospective study cohort included a total of 13,064 lung transplant recipients, of whom 319 patients had previously undergone CABG, representing 2.4% of all transplants. Patients without prior CABG were more likely to have undergone bilateral lung transplantation compared to those with prior CABG (61.2 % vs 15.7%, P < 0.001). Among patients with prior CABG, single right lung transplant was most common. Overall patient survival at 1 year was 76.8% for lung transplant recipients with prior CABG and 85.4% for patients without prior CABG. Freedom from death due to graft failure at 1 and 5 years in patients with a prior CABG was 93.1% and 76.2% respectively, cardiac and/or cerebrovascular disease 96.2% and 88.5% respectively, and hemorrhage 97.9% and 97.5% respectively. In a multivariate Cox regression model utilizing time-dependent coefficients for recipient age, prior CABG, among several other risk factors, was associated with increased mortality within 1 year. Prior CABG is associated with short- and long-term mortality in lung transplant recipients with history of CABG despite the majority of these patients undergoing single lung transplantation vs bilateral lung transplantation. Graft failure and/or pulmonary causes are the most common cause of death regardless of whether or not the lung transplant recipient had prior CABG, but patients with prior CABG are at increased risk of death due to graft failure, cardiac or cerebrovascular disease, and hemorrhage.

Lung Transplant Recipients With Prior Coronary Artery Bypass Grafting Are at Increased Risk of Death and Early Perioperative Hemorrhage.

Program directors are tasked with selecting whom they think will be the best fit for residency and the next leaders of the field. While numerical metrics have played a vital role in this process, recent changes to student evaluation are reducing the availability of these metrics. This poses unique challenges for both applicants and program directors. Here we discuss how this will likely shift the focus on other parts of the application and the consequences (good and bad) of doing so.

Considerations for a Holistic Model in Evaluating Medical Students for Cardiothoracic Surgical Residency.

A porcine model was used to study diastolic dysfunction in hibernating myocardium (HM) and recovery with coronary artery bypass surgery (CABG).

Persistent diastolic dysfunction in chronically ischemic hearts following coronary artery bypass graft.

Sternal infection after cardiac surgery is an infrequent post-operative complication.  sternal osteomyelitis is a rarity. We review the case of a 77-year-old man with invasive aspergillosis of the sternum and left costal cartilage 23 years after undergoing cardiac surgery. The patient promptly underwent surgical irrigation and debridement, followed by antifungal therapy. Clinical suspicion of sternal fungal infection should be high in patients with mediastinitis with a history of cardiac surgery. Treatment should be prompt.

Sternal osteomyelitis caused by  years after coronary artery bypass grafting: A case report.

Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.

Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium.

In previous studies, lower functional status measured by Karnofsky Performance Status (KPS) correlated with worse survival after redo lung transplant. We hypothesize that combining reduced functional status and time from primary lung transplant will correlate with the etiology of lung allograft failure after primary lung transplant and more accurately predict survival after redo lung transplant.

Time since primary transplant and poor functional status predict survival after redo lung transplant.

Urgent abdominal colectomy is indicated for patients with fulminant  infection (CDI) when other medical therapies fail, yet mortality remains high. Fecal microbiota transplant is a less invasive alternative approach for patients with fulminant CDI. We report the 30-day complications of patients with fulminant CDI who underwent either abdominal colectomy, fecal microbiota transplantation (FMT), or FMT followed by abdominal colectomy (FMT-CO). Methods We performed a single-center, retrospective case review of combined medical and surgical patients with CDI at a large academic medical center between 2008 and 2016. Cohorts were identified as patients with fulminant CDI who underwent total abdominal colectomy alone (CO), FMT alone (FMT), or FMT-CO. We analyzed patient demographics, history, comorbidities, clinical and laboratory variables, CDI severity scores, and mortality outcomes at 30 days. Results We identified 5,150 patients with CDI at our center during the review period; 16 patients met the criteria for fulminant CDI and were included in this study, with four patients in the CO cohort, eight patients in the FMT cohort, and four patients in the FMT-CO cohort. Demographics and CDI severity scores were similar for all three groups, although the selected comorbidity profiles differed significantly among the three cohorts. The 30-day mortality rates for patients in the CO, FMT, and FMT-CO groups were 25%, 12.5%, and 25%, respectively.  FMT is an alternative or adjunctive therapy to colectomy for patients with fulminant CDI that is not associated with increased mortality. Implementation of FMT protocols in clinical practice would be dependent on the availability of qualified transplant material and successful early identification of patients likely to benefit from FMT.

Fecal Microbiota Transplantation for Fulminant Clostridioides Difficile Infection: A Combined Medical and Surgical Case Series.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.

This study aimed to investigate whether or not the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB), which is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve.

Stem cell-derived exosome patch with coronary artery bypass graft restores cardiac function in chronically ischemic porcine myocardium.

Left ventricular assist device (LVAD) is an option for bridge-to-transplant or destination therapy for patients with end-stage heart failure. Right heart failure (RHF) remains a complication after LVAD implantation that portends high morbidity and mortality, despite advances in LVAD technology. Definitions of RHF vary, but generally include the need for inotropic or pulmonary vasodilator support, or potential right ventricular (RV) mechanical circulatory support. This review covers the complex pathophysiology of RHF related to underlying myocardial dysfunction, interventricular dependence, and RV afterload, as well as treatment strategies to curtail this challenging problem.

Article	Year
Lung Transplant Recipients With Prior Coronary Artery Bypass Grafting Are at Increased Risk of Death and Early Perioperative Hemorrhage. Seminars in thoracic and cardiovascular surgery\| PubMed ID: 34023526	2022
Considerations for a Holistic Model in Evaluating Medical Students for Cardiothoracic Surgical Residency. Seminars in thoracic and cardiovascular surgery\| PubMed ID: 35714822	2022
Persistent diastolic dysfunction in chronically ischemic hearts following coronary artery bypass graft. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 36154976	2023
Sternal osteomyelitis caused by years after coronary artery bypass grafting: A case report. IDCases\| PubMed ID: 36353703	2022
Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium. Antioxidants (Basel, Switzerland)\| PubMed ID: 36358527	2022
Time since primary transplant and poor functional status predict survival after redo lung transplant. Journal of thoracic disease\| PubMed ID: 36389317	2022
Fecal Microbiota Transplantation for Fulminant Clostridioides Difficile Infection: A Combined Medical and Surgical Case Series. Cureus\| PubMed ID: 36938160	2023
An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium. International journal of molecular sciences\| PubMed ID: 36982547	2023
Stem cell-derived exosome patch with coronary artery bypass graft restores cardiac function in chronically ischemic porcine myocardium. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 37482241	2023
Right heart failure after left ventricular assist device implantation: a persistent problem. Indian journal of thoracic and cardiovascular surgery\| PubMed ID: 37525713	2023

Rishav Aggarwal

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