Bruce R Ito

Activation of the homeostatic intracellular repair response during cardiac surgery.

BACKGROUND The homeostatic intracellular repair response (HIR2) is an endogenous beneficial pathway that eliminates damaged mitochondria and dysfunctional proteins in response to stress. The underlying mechanism is adaptive autophagy. The purpose of this study was to determine whether the HIR2 response is activated in the heart in patients undergoing cardiac surgery and to assess whether it is associated with the duration of ischemic arrest and predicted surgical outcomes. STUDY DESIGN Autophagy was assessed in 19 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass. Biopsies of the right atrial appendage obtained before initiation of cardiopulmonary bypass and after weaning from cardiopulmonary bypass were analyzed for autophagy by immunoblotting for LC3, Beclin-1, autophagy 5-12, and p62. Changes in p62, a marker of autophagic flux, were correlated with duration of ischemia and with the mortality/morbidity risk scores obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (version 2.73). RESULTS Heart surgery was associated with a robust increase in autophagic flux indicated by depletion of LC3-I, LC3-II, Beclin-1, and autophagy 5-12; the magnitude of change for each of these factors correlated significantly with changes in the flux marker p62. In addition, changes in p62 correlated directly with cross-clamp time and inversely with the mortality and morbidity risk scores. CONCLUSIONS These findings are consistent with preclinical studies indicating that HIR2 is cardioprotective and reveal that it is activated in patients in response to myocardial ischemic stress. Strategies designed to amplify HIR2 during conditions of cardiac stress might have a therapeutic use and represent an entirely new approach to myocardial protection in patients undergoing heart surgery.

Discordant signaling and autophagy response to fasting in hearts of obese mice: Implications for ischemia tolerance

Autophagy is regulated by nutrient and energy status and plays an adaptive role during nutrient deprivation and ischemic stress. Metabolic syndrome (MetS) is a hypernutritive state characterized by obesity, dyslipidemia, elevated fasting blood glucose levels, and insulin resistance. It has also been associated with impaired autophagic flux and larger-sized infarcts. We hypothesized that diet-induced obesity (DIO) affects nutrient sensing, explaining the observed cardiac impaired autophagy. We subjected male friend virus B NIH (FVBN) mice to a high-fat diet, which resulted in increased weight gain, fat deposition, hyperglycemia, insulin resistance, and larger infarcts after myocardial ischemia-reperfusion. Autophagic flux was impaired after 4 wk on a high-fat diet. To interrogate nutrient-sensing pathways, DIO mice were subjected to overnight fasting, and hearts were processed for biochemical and proteomic analysis. Obese mice failed to upregulate LC3-II or to clear p62/SQSTM1 after fasting, although mRNA for LC3B and p62/SQSTM1 were appropriately upregulated in both groups, demonstrating an intact transcriptional response to fasting. Energy- and nutrient-sensing signal transduction pathways [AMPK and mammalian target of rapamycin (mTOR)] also responded appropriately to fasting, although mTOR was more profoundly suppressed in obese mice. Proteomic quantitative analysis of the hearts under fed and fasted conditions revealed broad changes in protein networks involved in oxidative phosphorylation, autophagy, oxidative stress, protein homeostasis, and contractile machinery. In many instances, the fasting response was quite discordant between lean and DIO mice. Network analysis implicated the peroxisome proliferator-activated receptor and mTOR regulatory nodes. Hearts of obese mice exhibited impaired autophagy, altered proteome, and discordant response to nutrient deprivation.

Autophagy and the human heart.

AF. Unfortunately, alternative energy sources used for the Cox maze IV have not shown consistent results. We had the opportunity to compare 2 groups of patients who underwent MV surgery and surgery for AF. With regard to the AF, all the cases were performed exclusively by the cut-and-sew method to guarantee total transmural lesions. One hundred patients underwent only isolation of the pulmonary veins; 20 underwent a Cox maze III procedure. All patients were operated on by the same surgeon (O.A.G.-V.). Sinus rhythm conversion rate was immensely superior for the Cox maze III group (19/20; 95%), than for the pulmonary vein isolation group (76/100; 76%) at 3 months’ follow-up. The prevalence of normal sinus rhythm was higher in the Cox maze III group at 6 months’ followup (95% vs 54%). Although our data have not yet been published, a brief analysis of them shows that the sole isolation of the pulmonary veins is not enough to eliminate longstanding persistent AF in the setting of concomitant MV disease. In addition, the Cox maze III procedure must be performed by the cut-andsew method, because this is the only measure that will ensure transmural lesions. Moreover, a biatrial lesion set pattern is highly mandatory in the Cox maze III procedure to eliminate long-standing persistent AF. Definitely, the standard cut-andsew Cox-maze III procedure remains the best choice in surgery for AF, especially for patients with MV disease.

Low Intensity Epicardial Pacing During the Absolute Refractory Period Augments Left Ventricular Function Mediated by Local Catecholamine Release.

Biventricular epicardial (Epi) pacing can augment left ventricular (LV) function in heart failure. We postulated that these effects might involve catecholamine release from local autonomic nerve activation. To evaluate this hypothesis we applied low intensity Epi electrical stimuli during the absolute refractory period (ARP), thus avoiding altered activation sequence.