Reduced anticoagulation is safe in high-risk patients with the On-X mechanical aortic valve.

PURPOSE OF REVIEW: The goal of anticoagulation in patients with mechanical aortic valve replacement (AVR) is to maintain an optimal international normalized ratio (INR) that minimizes both the risk of bleeding and thromboembolic events. Here, we review the published data on anticoagulation with bileaflet mechanical prostheses, with a focus on the On-X valve (On-X Life Technologies, Austin, TX), which was designed to function with less anticoagulation or, in some cases, antiplatelet therapy only. RECENT FINDINGS: Several long-term follow-up studies with the On-X valve demonstrate low rates of bleeding and thromboembolism with standard and low-dose anticoagulation. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) compared the safety of less aggressive anticoagulation (INR 1.5-2.0) with standard anticoagulation (INR 2.0-3.0) after implantation of On-X aortic prostheses for patients at high risk of thromboembolic events. The updated 5-year data confirm that low-dose warfarin is associated with lower major bleeding (1.6 vs. 3.9%/patient-year; P = 0.007) with no difference in thromboembolic events (0.11 vs. 0.52%/patient-year; P = 0.2). SUMMARY: Nonrandomized studies and the PROACT data support the safety and efficacy of maintaining the On-X bileaflet mechanical aortic valve prosthesis at a lower target INR than current guideline recommendations for patients at high risk of thromboembolic events. These results offer the promise of a valve prosthesis with excellent durability combined with reduced anticoagulation-related complications.

Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury.

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium.

Right ventricular (RV) and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n = 6]. RV-PAB was achieved by banding the pulmonary artery (n = 6). Controls (n = 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex assembly and oxidative phosphorylation. In RV-PAB there is also an increased transcript expression levels for cardiac oxidative phosphorylation but increased protein expression levels for structural constituents of muscle, cardiac muscle tissue development, and calcium handling. These results identify divergent transcript and protein expression profiles in LV-AOB and RV-PAB and provide new insight into the biological basis of ventricular specific hypertrophy. The identification of these pathways should allow for the development of specific therapeutic interventions for targeted treatment and amelioration of LV-AOB and RV-PAB to ameliorate morbidity and mortality.

Microarray and proteomic analysis of the cardioprotective effects of cold blood cardioplegia in the mature and aged male and female.

Recently we have shown that the cardioprotection afforded by cardioplegia is modulated by age and gender and is significantly decreased in the aged female. In this report we use microarray and proteomic analyses to identify transcriptomic and proteomic alterations affecting cardioprotection using cold blood cardioplegia in the mature and aged male and female heart. Mature and aged male and female New Zealand White rabbits were used for in situ blood perfused cardiopulmonary bypass. Control hearts received 30 min sham ischemia and 120 min sham reperfusion. Global ischemia (GI) hearts received 30 min of GI achieved by cross-clamping of the aorta. Cardioplegia (CP) hearts received cold blood cardioplegia prior to GI. Following 30 min of GI the hearts were reperfused for 120 min and then used for RNA and protein isolation. Microarray and proteomic analyses were performed. Functional enrichment analysis showed that mitochondrial dysfunction, oxidative phosphorylation and calcium signaling pathways were significantly enriched in all experimental groups. Glycolysis/gluconeogenesis and the pentose phosphate pathway were significantly changed in the aged male only (P < 0.05), while glyoxylate/dicarboxylate metabolism was significant in the aged female only (P < 0.05). Our data show that specific pathways associated with the mitochondrion modulate cardioprotection with CP in the aged and specifically in the aged female. The alteration of these pathways significantly contributes to decreased myocardial functional recovery and myonecrosis following ischemia and may be modulated to allow for enhanced cardioprotection in the aged and specifically in the aged female.

Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery.

BACKGROUND: Delirium is a common outcome after cardiac surgery. Delirium prediction rules identify patients at risk for delirium who may benefit from targeted prevention strategies, early identification, and treatment of underlying causes. The purpose of the present prospective study was to develop a prediction rule for delirium in a cardiac surgery cohort and to validate it in an independent cohort. METHODS AND RESULTS: Prospectively, cardiac surgery patients > or =60 years of age were enrolled in a derivation sample (n=122) and then a validation sample (n=109). Beginning on the second postoperative day, patients underwent a standardized daily delirium assessment, and delirium was diagnosed according to the confusion assessment method. Delirium occurred in 63 (52%) of the derivation cohort patients. Multivariable analysis identified 4 variables independently associated with delirium: prior stroke or transient ischemic attack, Mini Mental State Examination score, abnormal serum albumin, and the Geriatric Depression Scale. Points were assigned to each variable: Mini Mental State Examination < or =23 received 2 points, and Mini Mental State Examination score of 24 to 27 received 1 point; Geriatric Depression Scale >4, prior stroke/transient ischemic attack, and abnormal albumin received 1 point each. In the derivation sample, the cumulative incidence of delirium for point levels of 0, 1, 2, and > or =3 was 19%, 47%, 63%, and 86%, respectively (C statistic, 0.74). The corresponding incidence of delirium in the validation sample was 18%, 43%, 60%, and 87%, respectively (C statistic, 0.75). CONCLUSIONS: Delirium occurs frequently after cardiac surgery. Using 4 preoperative characteristics, clinicians can determine cardiac surgery patients' risk for delirium. Patients at higher delirium risk could be candidates for close postoperative monitoring and interventions to prevent delirium.

Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart.

Cardioplegia is used to partially alleviate the effects of surgically induced global ischemia injury; however, the molecular mechanisms involved in this cardioprotection remain to be elucidated. To improve the understanding of the molecular processes modulating the effects of global ischemia and the cardioprotection afforded by cardioplegia, we constructed rabbit heart cDNA libraries and isolated, sequenced, and identified a compendium of nonredundant cDNAs for use in transcriptomic and proteomic analyses. New Zealand White rabbits were used to compare the effects of global ischemia and cardioplegia compared with control (nonischemic) hearts. The effects of RNA and protein synthesis on the cardioprotection afforded by cardioplegia were investigated separately by preperfusion with either alpha-amanitin or cycloheximide. Our results demonstrate that cardioplegia partially ameliorates the effects of global ischemia and that the cardioprotection is modulated by RNA- and protein-dependent mechanisms. Transcriptomic and proteomic enrichment analyses indicated that global ischemia downregulated genes/proteins associated with mitochondrial function and energy production, cofactor catabolism, and the generation of precursor metabolites of energy. In contrast, cardioplegia significantly increased differentially expressed genes/proteins associated with the mitochondrion and mitochondrial function and significantly upregulated the biological processes of muscle contraction, involuntary muscle contraction, carboxylic acid and fatty acid catabolic processes, fatty acid beta-oxidation, and fatty acid metabolic processes.

Protecting the myocardial cell during coronary revascularization. The William W. L. Glenn Lecture.

BACKGROUND: Using the ischemic myocardial cell as a paradigm, competitive coronary revascularization technologies will be analyzed for their potential in causing additional myocardial cell damage during the course of therapeutic procedures. METHODS AND RESULTS: Percutaneous coronary intervention (PCI) using balloon and/or stent (bare metal or coated) approaches may be associated with myonecrosis related to atherosclerotic debris plugging the downstream coronary microcirculation as well as ischemia/reperfusion injury associated with revascularization of occluded coronary vessels. The placement of distal mechanical devices and filters during the course of PCI has not been successful in ameliorating this problem. Coronary revascularization using coronary artery bypass grafting (CABG) similarly may be associated with myocardial stunning and cell necrosis associated with ischemia/reperfusion injury. Surgically induced myocardial ischemia secondary to aortic cross clamping, results from the attenuation or cessation of coronary blood flow such that oxygen delivery to the myocardium is insufficient to meet basal myocardial requirements to preserve cellular membrane stability and viability. Recovery involves: (1) resumption of normal oxidative metabolism and the restoration of myocardial energy reserves; (2) reversal of ischemia induced cell swelling and loss of membrane ion gradients and the adenine nucleotide pool; (3) repair of damaged cell organelles such as the mitochondria and the sarcoplasmic reticulum. Despite meticulous adherence to presently known principles of surgical myocardial protection using advanced cardioplegic technologies, some patients require inotropic support and/or mechanical assist devices postoperatively, when none was required preoperatively. CONCLUSIONS: Which method of coronary revascularization causes the least amount of myocardial cell injury and is associated with superior long-term outcomes remains an area of increasing controversy.

Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion.

OBJECTIVE: To demonstrate the clinical efficacy of autologous mitochondrial transplantation in preparation for translation to human application using an in vivo swine model. METHODS: A left mini-thoracotomy was performed on Yorkshire pigs. The pectoralis major was dissected, and skeletal muscle tissue was removed and used for the isolation of autologous mitochondria. The heart was subjected to regional ischemia (RI) by temporarily snaring the circumflex artery. After 24 minutes of RI, hearts received 8 × 0.1 mL injections of vehicle (vehicle-only group; n = 6) or vehicle containing mitochondria (mitochondria group; n = 6) into the area at risk (AAR), and the snare was released. The thoracotomy was closed, and the pigs were allowed to recover for 4 weeks. RESULTS: Levels of creatine kinase-MB isoenzyme and cardiac troponin I were significantly increased (P = .006) in the vehicle-only group compared with the mitochondria group. Immune, inflammatory, and cytokine activation markers showed no significant difference between groups. There was no significant between-group difference in the AAR (P = .48), but infarct size was significantly greater in the vehicle group (P = .004). Echocardiography showed no significant differences in global function. Histochemistry and transmission electron microscopy revealed damaged heart tissue in the vehicle group that was not apparent in the mitochondria group. T2-weighted magnetic resonance imaging and histology demonstrated that the injected mitochondria were present for 4 weeks. CONCLUSIONS: Autologous mitochondrial transplantation provides a novel technique to significantly enhance myocardial cell viability following ischemia and reperfusion in the clinically relevant swine model.

Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer.

BACKGROUND: Intercessory prayer is widely believed to influence recovery from illness, but claims of benefits are not supported by well-controlled clinical trials. Prior studies have not addressed whether prayer itself or knowledge/certainty that prayer is being provided may influence outcome. We evaluated whether (1) receiving intercessory prayer or (2) being certain of receiving intercessory prayer was associated with uncomplicated recovery after coronary artery bypass graft (CABG) surgery. METHODS: Patients at 6 US hospitals were randomly assigned to 1 of 3 groups: 604 received intercessory prayer after being informed that they may or may not receive prayer; 597 did not receive intercessory prayer also after being informed that they may or may not receive prayer; and 601 received intercessory prayer after being informed they would receive prayer. Intercessory prayer was provided for 14 days, starting the night before CABG. The primary outcome was presence of any complication within 30 days of CABG. Secondary outcomes were any major event and mortality. RESULTS: In the 2 groups uncertain about receiving intercessory prayer, complications occurred in 52% (315/604) of patients who received intercessory prayer versus 51% (304/597) of those who did not (relative risk 1.02, 95% CI 0.92-1.15). Complications occurred in 59% (352/601) of patients certain of receiving intercessory prayer compared with the 52% (315/604) of those uncertain of receiving intercessory prayer (relative risk 1.14, 95% CI 1.02-1.28). Major events and 30-day mortality were similar across the 3 groups. CONCLUSIONS: Intercessory prayer itself had no effect on complication-free recovery from CABG, but certainty of receiving intercessory prayer was associated with a higher incidence of complications.

Mitochondrial transplantation for therapeutic use.

Mitochondria play a key role in the homeostasis of the vast majority of the body's cells. In the myocardium where mitochondria constitute 30 % of the total myocardial cell volume, temporary attenuation or obstruction of blood flow and as a result oxygen delivery to myocardial cells (ischemia) severely alters mitochondrial structure and function. These alterations in mitochondrial structure and function occur during ischemia and continue after blood flow and oxygen delivery to the myocardium is restored, and significantly decrease myocardial contractile function and myocardial cell survival. We hypothesized that the augmentation or replacement of mitochondria damaged by ischemia would provide a mechanism to enhance cellular function and cellular rescue following the restoration of blood flow. To test this hypothesis we have used a model of myocardial ischemia and reperfusion. Our studies demonstrate that the transplantation of autologous mitochondria, isolated from the patient's own body, and then directly injected into the myocardial during early reperfusion augment the function of native mitochondria damaged during ischemia and enhances myocardial post-ischemic functional recovery and cellular viability. The transplanted mitochondria act both extracellularly and intracellularly. Extracellularly, the transplanted mitochondria enhance high energy synthesis and cellular adenosine triphosphate stores and alter the myocardial proteome. Once internalized the transplanted mitochondria rescue cellular function and replace damaged mitochondrial DNA. There is no immune or auto-immune reaction and there is no pro-arrhythmia as a result of the transplanted mitochondria. Our studies and those of others demonstrate that mitochondrial transplantation can be effective in a number of cell types and diseases. These include cardiac and skeletal muscle, pulmonary and hepatic tissue and cells and in neuronal tissue. In this review we discuss the mechanisms leading to mitochondrial dysfunction and the effects on cellular function. We provide a methodology for the isolation of mitochondria to allow for clinical relevance and we discuss the methods we and others have used for the uptake and internalization of mitochondria. We foresee that mitochondrial transplantation will be a valued treatment in the armamentarium of all clinicians and surgeons for the treatment of varied ischemic disorders, mitochondrial diseases and related disorders.

Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.

We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.

Interactive biomaterials: taking surgery to the next level.

Medicine has been advanced greatly by implantable biomaterials, but today's standard materials are not without problems. Infection, erosion, adhesions, persistent pain, and other complications suggest that something better is possible. Just as normal tissues self-renew, it is desirable to have an implant recapitulate original anatomy for both structure and function. Short of complete tissue regeneration, perhaps an implant material could transition from an inanimate bridge to a living tissue with strong similarity to the original host architecture-to optimize the biology and not simply the mechanics of tissue repair. Such remodelable or tissue-inductive materials exist today and are in use in a wide variety of surgical applications. Changing the idea that implants must be rigid, inert, and permanent to an understanding that implants can provide short-term mechanics and long-term repair by harnessing the host's healing abilities represents a paradigm shift that will ultimately benefit patients and the practice of surgery.

Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function.

Previously, we have demonstrated that the transplantation of viable, structurally intact, respiration competent mitochondria into the ischemic myocardium during early reperfusion significantly enhanced cardioprotection by decreasing myocellular damage and enhancing functional recovery. Our in vitro and in vivo studies established that autologous mitochondria are internalized into cardiomyocytes following transplantation; however, the mechanism(s) modulating internalization of these organelles were unknown. Here, we show that internalization of mitochondria occurs through actin-dependent endocytosis and rescues cell function by increasing ATP content and oxygen consumption rates. We also show that internalized mitochondria replace depleted mitochondrial (mt)DNA. These results describe the mechanism for internalization of mitochondria within host cells and provide a basis for novel therapeutic interventions allowing for the rescue and replacement of damaged or impaired mitochondria.

Study of the Therapeutic Effects of Intercessory Prayer (STEP): study design and research methods.

BACKGROUND: The effect of intercessory prayer (IP) on outcome in cardiac cases has been evaluated previously, but results are controversial. The goals of the Study of the Therapeutic Effects of Intercessory Prayer (STEP) are to evaluate the effects of receipt of additional study IP and awareness of receipt of additional study IP on outcomes in patients undergoing coronary artery bypass graft surgery. STEP is not designed to determine whether God exists or whether God does or does not respond to IP. METHODS: STEP is a multicenter, controlled trial of 1802 patients in 6 US hospitals, randomized to 1 of 3 groups. Two groups were informed that they may or may not receive 14 consecutive days of additional IP starting the night before coronary artery bypass graft surgery; Group 1 received IP, Group 2 did not. A third group (Group 3) was informed that they would receive additional IP and did so. Three mainstream religious sites provided daily IP for patients assigned to receive IP. At each hospital, research nurses blinded to patient group assignment reviewed medical records to determine whether complications occurred, on the basis of the Society for Thoracic Surgeons definitions. A blinded nurse auditor from the Coordinating Center reviewed every study patient's data against the medical record before release of study forms. RESULTS: The STEP Data and Safety Monitoring Board reviewed patient safety and outcomes in the first 900 study patients. Patients were enrolled in STEP from January 1998 to November 2000.

The mitochondrial K(ATP) channel and cardioprotection.

Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels allow coupling of membrane potential to cellular metabolic status. Two K(ATP) channel subtypes coexist in the myocardium, with one subtype located in the sarcolemma (sarcK(ATP)) membrane and the other in the inner membrane of the mitochondria (mitoK(ATP)). The K(ATP) channels can be pharmacologically modulated by a family of structurally diverse agents of varied potency and selectivity, collectively known as potassium channel openers and blockers. Sufficient evidence exists to indicate that the K(ATP) channels and, in particular, the mitoK(ATP) channels play an important role both as a trigger and an effector in surgical cardioprotection. In this review, the biochemistry and surgical specificity of the K(ATP) channels are examined.

Diazoxide amelioration of myocardial injury and mitochondrial damage during cardiac surgery.

BACKGROUND: Recently, we have shown that the selective opening of mitochondrial ATP-sensitive potassium channels with diazoxide significantly decreases myocardial injury. The purpose of this study was to determine the effects of diazoxide on apoptosis and the mechanisms modulating apoptosis and myocardial injury in a blood-perfused model of acute myocardial infarction. METHODS: Pigs (32 to 42 kg) undergoing total cardiopulmonary bypass underwent left anterior descending coronary artery occlusion for 30 minutes. The aorta was cross-clamped and magnesium-supplemented potassium cold-blood cardioplegia (DSA; n = 6) or magnesium-supplemented potassium cardioplegia containing 50 micromol/L diazoxide (DZX; n = 6) was administered, followed by 30 minutes of global ischemia and 120 minutes of reperfusion. Left ventricular tissue samples from DSA and DZX hearts were obtained after reperfusion. Apoptosis was determined by TUNEL, caspase-3 and PARP cleavage, and caspase-3 activity. Bax and bcl-2 levels were determined and tissue morphology was examined by light and transmission electron microscopy. RESULTS: Apoptosis, as estimated by TUNEL-positive nuclei/3,000 myocardial cells, was 120.3 +/- 48.8 in DSA hearts and was significantly decreased to 21.4 +/- 5.3 in DZX hearts (p < 0.05 vs control). Caspase-3 and poly-ADP-ribose polymerase cleavage and pro-apoptotic bax protein levels were significantly decreased with diazoxide (p < 0.05 vs DSA). Light and transmission electron microscopy indicated severe disruption of tissue with capillary dilatation, mitochondrial cristae damage, and evidence of increased presence of mitochondrial granules in DSA as compared with DZX hearts. CONCLUSIONS: The addition of diazoxide (50 micromol/L) to cardioplegia significantly decreases regional myocardial apoptosis and mitochondrial damage, and provides an additional modality for achieving myocardial protection.

A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs.

BACKGROUND: Reactive oxygen and nitrogen species generated after reperfusion injury result in organ dysfunction. Peroxynitrite, a reactive nitrogen molecule produced from the reaction of superoxide anions and nitric oxide, is thought to be a causative agent in oxidative reperfusion injury. The aim of this study was to investigate the effects of a novel peroxynitrite decomposition catalyst (FP-15) in an acute myocardial ischemia/reperfusion model. METHODS: Pigs were subjected to 60 minutes of regional ischemia by reversibly ligating the left anterior descending coronary artery followed by 180 minutes of reperfusion. In the treatment group (n = 6), an FP-15 (1 mg/kg) bolus was infused through the jugular vein after 30 minutes of ischemia followed by a continuous infusion (1 mg x kg(-1) x h(-1)) during reperfusion. Vehicle was infused in the control group (n = 6). Coronary flow was recorded by an ultrasonic flow probe and infarct size determined by tetrazolium staining. Arterial and left ventricular pressures were monitored continuously and regional myocardial function determined by sonomicrometry. RESULTS: No significant differences were observed in either hemodynamics or ischemic area at risk. However, the infarct size was significantly reduced (35.3% +/- 3.5% versus 21.6% +/- 2.6% of the ischemic area, control versus FP-15-treated groups, respectively, p < 0.05). +dP/dt was transiently improved in the FP-15-treated groups while during most of the reperfusion period coronary flow, and was significantly lower in the FP-15-treated group as compared to the control group (p < 0.01). CONCLUSIONS: FP-15 administration reduces myocardial infarct size and reactive hyperemia. These data support the pathogenic role of endogenously produced peroxynitrite and that FP-15 is effective in preventing myocardial reperfusion injury.

Myocardial protection by PJ34, a novel potent poly (ADP-ribose) synthetase inhibitor.

BACKGROUND: The activation of poly (ADP-ribose) synthetase plays an important role in the pathogenesis leading to myocardial ischemia-reperfusion injury. The aim of this study was to determine if a novel potent inhibitor of poly (ADP-ribose) synthetase, PJ34, provides myocardial protection. METHODS: Pigs were subjected to 60 minutes of regional ischemia followed by 180 minutes of reperfusion. Ten mg/kg of PJ34 (PJ34; n = 6) was administrated intravenously (treated group) from 15 to 5 minutes before reperfusion followed by 3 mg/kg/hour of PJ34 from 5 minutes before reperfusion to the end of 180 minutes reperfusion. Control pigs (n = 7) received vehicle only. Arterial and left ventricular pressure and coronary flow were monitored. RESULTS: The PJ34 showed significant reduction on infarct size (37.5%+/-4.5% and 50.5%+/-4.8% of the area at risk) for PJ34 and control pigs groups, respectively, (p < 0.05). Significant reduction in postsystolic shortening, as well as improvement on segment shortening, and positive first derivative of pressure over time (+dP/dt) maximum were also observed in PJ34 versus control pigs (p < 0.05). CONCLUSIONS: Our results suggest that PJ34 provides cardioprotection by decreasing myocardial infarct size and enhancing postischemic regional and global functional recovery.

Mitochondrial DNA deletions in coronary artery bypass grafting patients.

OBJECTIVE: Mitochondrial DNA (mitoDNA) deletions have been shown to increase with aging and ischemia and have been suggested to contribute to myocardial dysfunction. The purpose of this study was to determine the prevalence and specificity of mitoDNA deletions in coronary artery bypass patients. METHODS: Right atrial appendix tissue from 51 cardiac surgical patients (30-93 years; mean 64+/-14 years) was obtained during cardiopulmonary bypass cannulation (Control), just prior to the removal of the venous cannula (Ischemia, 169+/-38 min) and following removal of the cannula (Reperfusion) and used for polymerase chain reaction (PCR) and sequence analysis. RESULTS: A novel mitoDNA deletion (approximately 7.3 kb, mitoDNA(7.3)) was found in three unrelated, male patients (53, 67, 75 years old). All mitoDNA(7.3) deletion breakpoints were found downstream of the ATP synthase 8 genes and at the 3' end of the cytochrome b genes. The prevalence of the mitoDNA(7.3) deletion was significantly increased (P<0.05) following ischemia and reperfusion. Clinical data indicated that postoperative left ventricular ejection fraction was lower (38.3 vs. 46.4%), and the incidence of previous myocardial infarction higher (1.7 vs. 0.6) in patients exhibiting mitoDNA deletions. CONCLUSION: Our results reveal a novel mitochondrial DNA deletion occurring within the genome region coding for the mitochondrial genes of oxidative phosphorylation that is significantly increased during ischemia and reperfusion. The incidence and prevalence of mitoDNA(7.3) deletions in patients with clinical indications of poor recovery suggests that mitoDNA(7.3) deletions may provide an important indicator to surgical outcome in the cardiac surgical patient.

Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis.

OBJECTIVE: Mitochondrial ATP-sensitive potassium channels have been proposed to be myoprotective. The relevance and specificity of this mechanism in cardiac surgery was unknown. The purpose of this study was to examine the effects of the mitochondrial potassium ATP-sensitive channel opener diazoxide on regional and global myocardial protection using a model of acute myocardial infarction. METHODS: Pigs (n=19) were placed on total cardiopulmonary bypass and then subjected to 30 min normothermic regional ischemia by snaring the left anterior descending coronary artery (LAD). The aorta was then crossclamped and cold blood Deaconess Surgical Associates cardioplegia (DSA; n=6) or DSA containing 50 microM diazoxide (DZX; n=6) was delivered via the aortic root and the hearts subjected to 30 min hypothermic global ischemia. The crossclamp and snare were removed and the hearts reperfused for 120 min. RESULTS: No significant differences in preload recruitable stroke work relationship, Tau, proximal, distal or proximal/distal coronary flow, regional or global segmental shortening, systolic bulging or post-systolic shortening were observed within or between DSA and DZX hearts during reperfusion. Infarct was present only in the region of LAD occlusion in both DSA and DZX hearts. Infarct size (% of area at risk) was 33.6+/-2.9% in DSA and was 16.8+/-2.4% in DZX hearts (P<0.01 versus DSA). Apoptosis as estimated by TUNEL positive nuclei was 120.3+/-48.8 in DSA and was significantly decreased to 21.4+/-5.3 in DZX hearts. Myocardial infarct was located centrally within the area at risk in both DSA and DZX hearts but was significantly increased at borderline zones within the area at risk in DSA hearts. CONCLUSIONS: The addition of diazoxide to cardioplegia significantly decreases regional myocardial cell necrosis and apoptosis in a model of acute myocardial infarction and represents an additional modality for achieving myocardial protection.