T. Brett Reece

2012 Update to The Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients Having Cardiac and Noncardiac Operations

Division of Cardiovascular and Thoracic Surgery, University of Kentucky, Lexington, Kentucky (VAF and SPS); Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (JHO); Division of Cardiothoracic Surgery, Oregon Health and Science University Medical Center, Portland, Oregon (HKS); State University of New York, Stony Brook School of Medicine, Stony Brook, New York (TR); Department of Cardiothoracic Surgery, University of Colorado Health Sciences Center, Aurora, Colorado (TBR); Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario (CDM); Division of Cardiovascular Surgery, Sanger Clinic, Charlotte, North Carolina (CRB); Departments of Anesthesiology, Immunology, and Pathology, Washington University School of Medicine, St. Louis, Missouri (GJD); and The Society of Thoracic Surgeons, Chicago, Illinois (KJ and ERC)

The Evolution of Chemokine Release Supports a Bimodal Mechanism of Spinal Cord Ischemia and Reperfusion Injury

Background— Paraplegia remains a devastating complication of thoracic aortic surgery. The mechanism of the antecedent spinal cord ischemia and reperfusion injury (IR) remains poorly described. IR involves 2 injuries, an initial ischemic insult and subsequent inflammatory amplification of the injury. This mechanism is consistent with the clinical phenomenon of delayed onset paraplegia. This study sought to characterize the inflammatory response in the spinal cord after IR and hypothesized that this would support a bimodal mechanism of injury. Methods and Results— Male C57Bl/6 mice were subjected to 5 minutes of aortic arch and left subclavian occlusion with subsequent reperfusion to generate spinal cord ischemia. Functional outcomes were scored at 12-hour intervals. Spinal cords were harvested after 0, 6, 12, 18, 24, 36, and 48 hours of reperfusion. Cytokine levels were analyzed using a mouse magnetic bead–based multiplex immunoassay. Inflammatory chemokine concentrations (interleukin [IL]-1&bgr;, IL-6, keratinocyte-derived cytokine, macrophage inflammatory protein-1&agr;, monocyte chemotactic protein-1, RANTES, and tumor necrosis factor-&agr;) peaked at 6 hours and 36 to 48 hours after reperfusion. Functional scores reflected initial gain in function with subsequent decline, inversely proportional to cytokine levels. Immunofluorescent staining demonstrated microglia activation at 12 and 48 hours. Conclusions— Spinal cord ischemia and reperfusion injury occurs in 2 phases, correlating to increases in inflammatory chemokines release and microglial activation. These observations chronologically parallel the too-common clinical syndrome of delayed-onset paraplegia. Understanding the molecular pathogenesis of this injury may allow future intervention to prevent this devastating complication.

Late Surgical Mitral Valve Repair after Percutaneous Repair with the MitraClip® System

Abstract  Percutaneous approaches for treating mitral regurgitation are under investigation, including repair with the MitraClip® percutaneous mitral repair system (Evalve, Inc., Menlo Park, CA, USA), which has undergone extensive preclinical and clinical evaluation in the EVEREST I and II trials. The procedure involves the transcatheter placement of one or two MitraClip devices under echocardiographic and fluoroscopic guidance to restore leaflet coaptation. A desirable feature of any percutaneous mitral valve (MV) repair system is that the device should not impede subsequent surgical repair if needed. To date, the majority of reported MV surgeries after MitraClip device implantation have occurred earlier, within one year of treatment. We herein describe four previously unreported cases of successful surgical MV repair up to five years after MitraClip device implantation, demonstrating that late MV repair remains possible, including after implantation of two clips.

Preservation of Motor Function After Spinal Cord Ischemia and Reperfusion Injury Through Microglial Inhibition

BACKGROUND Paraplegia remains a devastating complication of thoracoabdominal aortic procedures resulting from spinal cord ischemia and reperfusion injury (SCIR). Pharmacologic interventions have not proven efficacious in attenuating this injury, with poor understanding of the underlying mechanisms. The resident macrophages, or microglia in the spinal cord, may play a significant role in SCIR. The macrolide antibiotic, minocycline, has been shown in stroke models to inhibit microglial activation. This study hypothesized that microglial inhibition by minocycline after SCIR will attenuate injury with preservation of motor function. METHODS Mature male C57Bl/6 mice underwent 4 minutes of thoracic aortic occlusion with reperfusion. Mice receiving minocycline 30 minutes before ischemia and daily thereafter (90 mg/kg and 45 mg/kg, respectively) were compared with mice receiving vehicle controls. Hind-limb motor function was measured at 12-hour intervals, with spinal cord harvest for histologic and immunologic comparison at 60 hours. RESULTS Minocycline treatment significantly preserved hind limb motor function in all mice (n = 7) compared with complete paralysis in all untreated mice (n = 8), reaching significance from 24 hours of reperfusion through 60 hours. Immunofluorescent staining for Iba-1 revealed significant inhibition of microglial activation by minocycline treatment. Vehicle control sections demonstrated a greater degree of apoptosis compared with minocycline-treated spinal cord sections. CONCLUSIONS Minocycline limits microglial activation, paralleling functional preservation after aortic cross-clamping. These data suggest functional microglia contribute to reperfusion injury after spinal cord ischemia. The effects of minocycline demonstrate a potential pharmacological therapy as well as demonstrating a potential cellular target in preventing paraplegia after aortic intervention.

Native lung volume reduction surgery relieves functional graft compression after single-lung transplantation for chronic obstructive pulmonary disease

OBJECTIVE Single-lung transplantation is an accepted treatment for end-stage lung disease caused by chronic obstructive pulmonary disease. A complication unique to single-lung transplantation for chronic obstructive pulmonary disease is graft dysfunction due to compression caused by native lung hyperinflation. We hypothesized that patients with functional compromise from native lung hyperinflation would benefit from native lung volume reduction surgery. METHODS The charts of all patients undergoing single-lung transplantation for chronic obstructive pulmonary disease were reviewed for lung volume reduction surgery of their native lung. Data regarding length of stay, surgical morbidity and mortality, overall survival, type of lung volume reduction surgery, and pulmonary function were recorded to evaluate the effect of lung volume reduction surgery. RESULTS Between February 1992 and May 2007, 206 single-lung transplantations were performed for chronic obstructive pulmonary disease. Ten (5%) patients had clinically significant graft compression from native lung hyperinflation. After excluding other causes for functional decline, these patients underwent a modified lung volume reduction surgery between 12 and 142 months after single-lung transplantation (mean, 50 months). Lung volume reduction surgery consisted of anatomic resection. Two (20%) of 10 patients died during their hospitalization. Of the remaining 8 patients, 7 (87.5%) have demonstrated functional improvement on the basis of forced expiratory volume in 1 second improving from 12% to 200% (mean improvement, 57%). Within 6 months of lung volume reduction surgery, mean 6-minute walk values improved significantly (866 to 1055 feet), whereas desaturation with exertion decreased significantly. CONCLUSIONS Lung volume reduction surgery by means of formal lobectomy in patients with native lung hyperinflation undergoing single-lung transplantation and significant graft compression appears feasible. Additionally, improvements in forced expiratory volume in 1 second can be accomplished in nearly all properly selected patients. Lung volume reduction surgery should be considered in patients with decreasing graft function caused by graft compression from native lung hyperinflation.

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

The histone deacetylase inhibitor ITF2357 (givinostat) prevents diastolic dysfunction by enhancing cardiac myofibril relaxation. Deacetylation and diastolic dysfunction Systolic heart failure (heart failure with reduced ejection fraction) manifests as insufficient blood pumping due to contractile dysfunction. Impaired cardiac relaxation also contributes to a form of heart failure termed heart failure with preserved ejection fraction. Jeong et al. tested whether histone deacetylase inhibition, which has shown efficacy in some models of systolic heart failure, could prevent diastolic dysfunction. Inhibitor treatment improved cardiac relaxation without altering blood pressure or fibrosis in rodent models of hypertension- and aging-induced diastolic dysfunction with preserved ejection fraction. The authors determined that acetylation/deacetylation of myofibrils directly altered relaxation but not contraction, suggesting a mechanism for the development of diastolic dysfunction and a potential therapeutic target. There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor–mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.