David J. Kaczorowski

Mammalian DNA Is an Endogenous Danger Signal That Stimulates Local Synthesis and Release of Complement Factor B

Complement factor B plays a critical role in ischemic tissue injury and autoimmunity. Factor B is dynamically synthesized and released by cells outside of the liver, but the molecules that trigger local factor B synthesis and release during endogenous tissue injury have not been identified. We determined that factor B is upregulated early after cold ischemia-reperfusion in mice, using a heterotopic heart transplant model. These data suggested upregulation of factor B by damage-associated molecular patterns (DAMPs), but multiple common DAMPs did not induce factor B in RAW264.7 mouse macrophages. However, exogenous DNA induced factor B mRNA and protein expression in RAW cells in vitro, as well as in peritoneal and alveolar macrophages in vivo. To determine the cellular mechanisms involved in DNA-induced factor B upregulation we then investigated the role of multiple known DNA receptors or binding partners. We stimulated peritoneal macrophages from wild-type (WT), toll-like receptor 9 (TLR9)-deficient, receptor for advanced glycation end products (RAGE)-/- and myeloid differentiation factor 88 (MyD88)-/- mice, or mouse macrophages deficient in high-mobility group box proteins (HMGBs), DNA-dependent activator of interferon-regulatory factors (DAI) or absent in melanoma 2 (AIM2), with DNA in the presence or absence of lipofection reagent. Reverse transcription-polymerase chain reaction, Western blotting and immunocytochemical analysis were employed for analysis. Synthesis of factor B was independent of TLR9, RAGE, DAI and AIM2, but was dependent on HMGBs, MyD88, p38 and NF-κB. Our data therefore show that mammalian DNA is an endogenous molecule that stimulates factor B synthesis and release from macrophages via HMGBs, MyD88, p38 and NF-κB signaling. This activation of the immune system likely contributes to damage following sterile injury such as hemorrhagic shock and ischemia-reperfusion.

Who Needs an RVAD in Addition to an LVAD

Mechanical circulatory support using left ventricular assist devices (LVAD) has become an accepted mode of therapy for both bridging patients with end-stage heart failure to transplant and as a destination therapy. Right ventricular (RV) dysfunction is common after LVAD insertion and is a significant source of morbidity and mortality in patients undergoing LVAD placement. Several studies have identified clinical, laboratory, hemodynamic, and echocardiographic parameters that may serve as risk factors for RV dysfunction after LVAD placement. Furthermore, scoring systems have been established to help quantitatively predict the potential need for RV support after LVAD placement.

Quantitative evaluation of change in coexistent mitral regurgitation after aortic valve replacement

OBJECTIVES Management of intermediate degrees of mitral regurgitation during aortic valve replacement for aortic stenosis remains controversial. We sought to evaluate the degree of reduction of mitral regurgitation in patients undergoing aortic valve replacement, as well as a mathematical relationship between aortic valve gradient reduction and the degree of mitral regurgitation decrement. METHODS We retrospectively analyzed demographic, intraoperative, and echocardiographic data on 802 patients who underwent aortic valve replacement or aortic root replacement between January 2010 and March 2011. A total of 578 patients underwent aortic valve replacement or aortic root replacement without intervention on the mitral valve. We excluded 88 patients with severe aortic insufficiency, 3 patients who underwent ventricular assist device placement, 4 patients who underwent prior mitral valve replacement, and 21 patients with incomplete data, yielding 462 patients for analysis. For each patient, the degree of pre- and postoperative mitral regurgitation was graded on a standard 0 to 4+ scale. RESULTS Of the 462 patients, 289 patients had at least mild mitral regurgitation. On average, mitral regurgitation decreased 0.24 degrees per patient for this cohort of 289 patients. Of the 56 patients with at least moderate mitral regurgitation, mitral regurgitation decreased 0.54 degrees per patient. Of 62 patients who underwent isolated aortic valve replacements, who had at least mild mitral regurgitation, and who had no evidence of structural mitral valve disease, mitral regurgitation decreased 0.24 degrees per patient. Linear regression analysis revealed no relationship between reduction in mitral regurgitation and gradient reduction across the aortic valve. CONCLUSIONS Reduction in mitral regurgitation after relief of aortic outflow tract obstruction is modest at best. Further, the magnitude of gradient change across the aortic valve has little influence on the degree of reduction in mitral regurgitation. These observations argue at minimum for performing a prospective evaluation of the clinical benefits of addressing moderate mitral regurgitation at the time of aortic valve intervention and may support a more aggressive approach to concomitant mitral surgery.

Profound hyperacute cardiac allograft rejection rescue with biventricular mechanical circulatory support and plasmapheresis, intravenous immunoglobulin, and rituximab therapy

Hyperacute rejection is a rare but potentially catastrophic complication after cardiac transplantation. We describe an unusual case of hyperacute rejection due to preformed anti-donor antibodies despite a negative preoperative panel-reactive antibody (PRA) screen. An excellent outcome was achieved in this case and our strategy involving the use of CentriMag ventricular assist devices (VADs) for biventricular support during treatment with rituximab, intravenous immunoglobulin (IVIG), and plasmapheresis is illustrated.

Successful Management of Cardiac Arrest Due to Pulmonary Embolus Using Extracorporeal Membrane Oxygenation and Ultrasound-Accelerated Catheter-Directed Thrombolysis.

Here we present the case of a patient that suffered a cardiac arrest due to pulmonary embolus. The patient was resuscitated using extracorporeal membrane oxygenation and treated with ultrasound-accelerated catheter-directed thrombolysis during support on extracorporeal membrane oxygenation, with an excellent outcome. This case demonstrates that the use of extracorporeal membrane oxygenation and ultrasound-accelerated catheter-directed thrombolysis can be highly effective for managing select patients with pulmonary embolus and cardiac arrest.

Aortic valve repair by sinotubular junctional remodeling to eliminate aortic regurgitation in donor cardiac allograft

Donor hearts for cardiac transplantation are scarce resources and their availability limits the number of heart transplants performed annually. When feasible, repairing donor hearts allows maximal use of these resources. Valvular heart disease has previously been considered a contraindication to use of a donor heart. However, several centers have reported use of donor hearts with aortic valve disease. Back bench aortic valve replacement has been used in donor hearts with a bicuspid aortic valve and aortic stenosis. Subcommissural annular plication has been used to correct aortic insufficiency (AI) in a heart with an aortic

Intracardiac exposure for transventricular mitral valve ring annuloplasty repair during Dor ventriculoplasty

Mitral valve pathology is common in patients with ischemic cardiomyopathy and often mandates intervention during surgical ventricular restoration (SVR). Although the ventricular side of the mitral valve is exposed during SVR, mitral interventions are most commonly performed through the left atrium or transeptally. Few cases of transventricular mitral valve intervention have been reported. We have previously reported cases of transventricular mitral valve replacement in the setting of contained left ventricular (LV) rupture after an acute myocardial infarction, and transventricular mitral valve repair in the setting of a large LV pseudoaneurysm repair. Here we report a case of transventricular mitral valve ring annuloplasty in the setting of an elective Dor ventriculoplasty with particular focus on the use of the off-pump coronary bypass stabilizer as an intracardiac exposure tool. A 63-year-old man presented to our clinic with an extensive medical history, which included a previous large myocardial infarction. He had developed a large, thrombus-filled, dyskinetic ventricular aneurysm and ejection fraction of 15% (Figure 1A). He was referred for surgical management. Coronary angiography revealed that there were no lesions requiring a coronary artery bypass graft. In addition, echocardiography revealed moderate, centrally directed mitral regurgitation (MR). SVR was planned. Moderate MR and the possibility of geometric distortion of the papillary muscle geometry after SVR prompted mitral valvuloplasty at the time of Dor ventriculoplasty. A median sternotomy was performed. The pericardium was opened. Adhesions were encountered and lysed. Systemic heparin was administered and cannulation was performed via the aorta and right atrium. A left atrial vent was placed through the right superior pulmonary vein. The aneurysm was densely adherent to the pericardium and diaphragm. Cardiopulmonary bypass was instituted and the aneurysm was dissected away from these structures (Figure 1B).