Preoperative Anemia and Postoperative Outcomes in Cardiac Surgery: A Mediation Analysis Evaluating Intraoperative Transfusion Exposures.

BACKGROUND: Preoperative anemia is associated with adverse outcomes in cardiac surgery, yet it remains unclear what proportion of this association is mediated through red blood cell (RBC) transfusions. METHODS: This is a historical observational cohort study of adults undergoing coronary artery bypass grafting or valve surgery on cardiopulmonary bypass at an academic medical center between May 1, 2008, and May 1, 2018. A mediation analysis framework was used to evaluate the associations between preoperative anemia and postoperative outcomes, including a primary outcome of acute kidney injury (AKI). Intraoperative RBC transfusions were evaluated as mediators of preoperative anemia and outcome relationships. The estimated total effect, average direct effect of preoperative anemia, and percent of the total effect mediated through transfusions are presented with 95% confidence intervals and P -values. RESULTS: A total of 4117 patients were included, including 1234 (30%) with preoperative anemia. Overall, 437 of 4117 (11%) patients went on to develop AKI, with a greater proportion of patients having preoperative anemia (219 of 1234 [18%] vs 218 of 2883 [8%]). In multivariable analyses, the presence of preoperative anemia was associated with increased postoperative AKI (6.4% [4.2%-8.7%] absolute difference in percent with AKI, P < .001), with incremental decreases in preoperative hemoglobin concentrations displaying greater AKI risk (eg, 11.9% [6.9%-17.5%] absolute increase in probability of AKI for preoperative hemoglobin of 9 g/dL compared to a reference of 14 g/dL, P < .001). The association between preoperative anemia and postoperative AKI was primarily due to direct effects of preoperative anemia (5.9% [3.6%-8.3%] absolute difference, P < .001) rather than mediated through intraoperative RBC transfusions (7.5% [-4.3% to 21.1%] of the total effect mediated by transfusions, P = .220). Preoperative anemia was also associated with longer hospital durations (1.07 [1.05-1.10] ratio of geometric mean length of stay, P < .001). Of this total effect, 38% (22%, 62%; P < .001) was estimated to be mediated through subsequent intraoperative RBC transfusion. Preoperative anemia was not associated with reoperation or vascular complications. CONCLUSIONS: Preoperative anemia was associated with higher odds of AKI and longer hospitalizations in cardiac surgery. The attributable effects of anemia and transfusion on postoperative complications are likely to differ across outcomes. Future studies are necessary to further evaluate mechanisms of anemia-associated postoperative organ injury and treatment strategies.

Obesity and vascular complication in percutaneous transfemoral transcatheter aortic valve insertion.

BACKGROUND: Obesity has been associated with an increased risk of vascular complication during percutaneous coronary intervention, but there are no data on the risk of vascular complication during percutaneous transfemoral transcatheter aortic valve insertion (TAVI). OBJECTIVES: We hypothesized there would be a similar increased risk associated with TAVI. METHODS: We reviewed the records of 1176 patients who received percutaneous transfemoral transcatheter aortic valve insertion from September 2015 to September 2020. All patients received 1) preoperative computed tomoraphy angiography assessment of the abdomen and pelvis to delineate iliofemoral artery anatomy, 2) ultrasound-guided percutaneous femoral arterial access, and 3) pre-closure of the delivery sheath femoral access site. Vascular complication was recorded based on definitions set forth by Valve Academic Research Consortium 3. RESULTS: The median age of patients was 81 years, and 60% were men. The median body mass index (BMI) was 29 kg/m2 (range, 11-67), and 91 (8%) patients had a value ≥40 kg/m2 (i.e., morbid obesity). Delivery sheath size was 14-French in 859 (73%) patients, 16-French in 311 (26%), and 18-French in 6 (1%). Vascular complication occurred in 53 (5%) patients, including 39 (7%) among the first half of procedures and 14 (2%) among the second half (p < 0.001). When stratified by obesity status (BMI < or ≥30 kg/m2 , p < 0.001), the complication rate was 4% in nonobese patients and 5% in obese patients. Multivariable analysis showed no overall association between risk of vascular complication and BMI categories (p = 0.583)BMI continuous values (p = 0.529), or sheath size (p = 0.217). CONCLUSIONS: Obesity is not associated with a vascular complication during percutaneous transfemoral transcatheter aortic valve insertion. The operation should not be denied in obese patients.

Rationale and design of a randomized trial evaluating an external support device for saphenous vein coronary grafts.

BACKGROUND: Coronary artery bypass grafting (CABG) is the most common revascularization approach for the treatment of multi-vessel coronary artery disease. While the internal mammary artery is nearly universally used to bypass the left anterior descending coronary artery, autologous saphenous vein grafts (SVGs) are still the most frequently used conduits to grafts the remaining coronary artery targets. Long-term failure of these grafts, however, continues to limit the benefits of surgery. METHODS: The Cardiothoracic Surgical Trials Network trial of the safety and effectiveness of a Venous External Support (VEST) device is a randomized, multicenter, within-patient trial comparing VEST-supported versus unsupported saphenous vein grafts in patients undergoing CABG. Key inclusion criteria are the need for CABG with a planned internal mammary artery to the left anterior descending and two or more saphenous vein grafts to other coronary arteries. The primary efficacy endpoint of the trial is SVG intimal hyperplasia (plaque + media) area assessed by intravascular ultrasound at 12 months post randomization. Occluded grafts are accounted for in the analysis of the primary endpoint. Secondary confirmatory endpoints are lumen diameter uniformity and graft failure (>50% stenosis) assessed by coronary angiography at 12 months. The safety endpoints are the occurrence of major adverse cardiac and cerebrovascular events and hospitalization within 5 years from randomization. CONCLUSIONS: The results of the VEST trial will determine whether the VEST device can safely limit SVG intimal hyperplasia in patients undergoing CABG as treatment for coronary atherosclerotic disease.

Impact of mitral intervention on outcomes of patients with mitral valve dysfunction and annulus calcification.

OBJECTIVES: To compare all-cause mortality in patients with mitral annulus calcification (MAC) and severe mitral valve dysfunction (MVD) who received standard mitral intervention versus no intervention. BACKGROUND: Patients with MAC often have high surgical risk due to advanced age, comorbidities, and technical challenges related to calcium. The impact of a mitral intervention on outcomes of patients with MAC and severe MVD is not well known. METHODS: Retrospective review of patients with MAC by transthoracic echocardiography (TTE) in 2015 at a single institution. Patients with severe mitral stenosis (MS) or regurgitation (MR) were analyzed and stratified into two groups: surgical or transcatheter intervention performed <1 year after the index TTE, and no or later intervention. The primary endpoint was all-cause mortality. RESULTS: Of 5502 patients with MAC, 357 had severe MVD (MS = 27%, MR = 73%). Of those, 108 underwent mitral intervention (surgery = 87; transcatheter = 21). They were younger (73 ± 11 vs. 76 ± 11 years, p < 0.01) and less frequently had cardiovascular diseases compared with no-intervention. Frequency in women was similar (45% vs. 50%, p = 0.44). During median follow-up of 3.2 years, the intervention group had higher estimated survival than those without intervention (80% vs. 72% at 1 year and 55% vs. 35% at 4 year, p < 0.01). Adjusted for age, eGFR, LVEF < 50%, and pulmonary hypertension, mitral intervention was an independent predictor of lower mortality (hazard ratio = 0.66, 95% confidence interval 0.43-0.99, p = 0.046). CONCLUSION: Patients with MAC and severe MVD who underwent mitral intervention <1 year from index TTE had lower mortality than those without intervention. Mitral intervention was independently associated with lower mortality.

Effect of eliminating pre-discharge transthoracic echocardiogram on outcomes after TAVR.

OBJECTIVES: The aim of this study was to determine the safety of eliminating the pre-discharge transthoracic echocardiogram (TTE) on 30-day outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: TTE is utilized before, during, and after TAVR. Post-procedural, pre-discharge TTE assists in assessment of prosthesis function and detection of clinically significant paravalvular leak (PVL) after TAVR. METHODS: Patients who underwent TAVR at Mayo Clinic from July 2018 to July 2019 were included in a prospective institutional registry. Patients undergoing TAVR prior to February 2019 received a pre-discharge TTE, while those undergoing TAVR after February 2019 did not. Both cohorts were evaluated with TTE at 30 days post-TAVR. RESULTS: A total of 330 consecutive patients were included. Of these, 160 patients (age 81.1 ± 7.6) had routine pre-discharge TTE, while 170 patients (age 78.9 ± 7.5) were dismissed without routine pre-discharge TTE. Mortality at 30 days was similar between the two groups (0% and 1.2%, respectively). One episode of PVL requiring intervention (0.6%) occurred in the pre-discharge TTE group and none in the group without pre-discharge TTE at 30-day follow-up. There was a similar incidence of total composite primary and secondary adverse events between the cohort receiving a pre-discharge TTE and those without (28.1% vs. 25.3%, P = 0.56) at 30 days. The most common event was need for permanent pacemaker or ICD implantation in both groups (13.1% vs. 11.8%, P = 0.71). CONCLUSIONS: Elimination of the pre-discharge TTE is safe and associated with comparable 30-day outcomes to routine pre-discharge TTE. These findings have implication for TAVR practice cost-efficiency and health care utilization.

Transcarotid Versus Transaxillary/Subclavian Transcatheter Aortic Valve Replacement (TAVR): Analysis of Outcomes.

Transcatheter aortic valve replacement (TAVR) has revolutionized the percutaneous management of valvular heart disease and has evolved to progressively minimalist techniques over the past decade. This review discusses the impact of minimalist TAVR, explores the alternative approaches when transfemoral (TF) TAVR is not possible, and analyzes the current outcomes of transcarotid (TC) versus transaxillary/subclavian (TAx) TAVR, which are the two leading nonfemoral (NF) approaches emerging as the preferred alternatives to TF TAVR.

Outcomes of cardiac surgery in nonagenarians.

BACKGROUND: While advanced age can be considered by some a contraindication to open-heart surgery, there is a paucity of data regarding outcomes of cardiac surgery in nonagenarians. We, therefore, sought to investigate the outcomes of nonagenarians undergoing cardiac surgery. METHODS: A retrospective review of our institutional Society of Thoracic Surgeons database between 1993 and 2019 was performed. Among a total of 32,421 patients who underwent open-heart surgery, 134 patients (0.4%) were nonagenarians (50.7% females, median age 91.6 [interquartile range: 90.7-92.9]). A comparison was performed between nonagenarians and patients aged 80-89 years. A regression analysis was performed to evaluate factors associated with midterm mortality in nonagenarians. RESULTS: The incidence of cardiac surgery in nonagenarians has been stable over time, from 0.4% in (1993-2000), 0.5% in (2001-2010) to 0.4% in (2011-2019). Valve surgery and CABG+valve were higher in nonagenarians compared to octogenarians (44.8% vs. 25.6%, 39.6% vs. 30.7%, respectively), but CABG was lower (15.7% vs. 33.8%); p < .01. Urgent/emergent surgery status was similar between groups (p = .7). Operative mortality was similar in the two groups (6% vs. 4.6%, p = .5). Hospital complications were comparable between groups. CONCLUSION: Cardiac surgery in nonagenarians can be achieved with acceptable morbidity and mortality. This study can be a benchmark for risk stratification for cardiac surgery in this high-risk population.

Robotic vs. minimally invasive mitral valve repair: A 5-year comparison of surgical outcomes.

BACKGROUND: Minimally invasive mitral valve repair (MVr) is commonly performed. Data on the outcomes of robotic MVr versus nonrobotic minimally invasive MVr are lacking. We sought to compare the short-term and mid-term outcomes of robotic and nonrobotic MVr. METHODS: We reviewed all patients who underwent robotic MVr (n = 424) or nonrobotic MVr via right mini-thoracotomy (n = 86) at Mayo Clinic, Rochester, MN, from January 2015 to February 2020. Data on baseline and operative characteristics, operative and long-term outcomes were analyzed. Patients were matched 1:1 using propensity scores. RESULTS: Sixty-nine matched pairs were included in the study. The median age was 59 years (interquartile range [IQR]: 54-69) and 75% (n = 103) were male. Baseline characteristics were similar after matching. Robotic and nonrobotic MVr had similar operative characteristics, except that robotic had longer cross-clamp times (57 [48-67] vs. 47 [37-58] min, p < .001) and more P2 resections (83% vs. 68%, p = .05) compared to nonrobotic MVr. There was no difference in operative outcomes between groups. Hospital stay was shorter after robotic MVr (4 [3-4] vs. 4 [4-6] days, p = .003). After a median follow-up of 3.3 years (IQR, 2.1-4.5), there was no mortality in either group, and there was no difference in freedom from mitral valve reoperations between robotic and nonrobotic MVr (5 years: 97.1% vs. 95.7%, p = .63). Follow-up echocardiogram analysis predicted excellent freedom from recurrent moderate-or-severe mitral regurgitation at 3 years after robotic and nonrobotic MVr (90% vs. 92%, p = .18, respectively). CONCLUSIONS: Both short-term and mid-term outcomes of robotic and nonrobotic minimally invasive mitral repair surgery are comparable.

Immobile Leaflets at Time of Bioprosthetic Valve Implantation: A Novel Risk Factor for Early Bioprosthetic Failure: A Novel Risk Factor for Early Bioprosthetic Failure.

OBJECTIVES: The clinical implications of finding immobile leaflet(s) at the time of bioprosthetic valve implantation but with acceptable prosthetic haemodynamics are uncertain. We sought to determine the characteristics of such patients and their impact on outcome. METHODS: Patients with immobile leaflet at the time of surgical bioprosthetic valve implantation were identified retrospectively by a systematic search of an institutional echocardiography database (2010-2020). Intraoperative echocardiograms were reviewed de-novo to confirm immobile leaflet(s) at the time of implantation. Cases were matched 1:2 to controls with normal bioprosthetic leaflets motion for age, sex, prosthesis position, prosthesis model, size, year of implantation, and pre-implantation left ventricular ejection fraction. Proportional hazards method was used to analyse the composite endpoint of stroke, valve thrombosis or re-intervention. RESULTS: Immobile leaflet at the time of bioprosthetic valve implantation were found in 26 patients (median age 71 ys 39% males) following tricuspid (n=13), mitral (n=11) and aortic (n=2) valve replacements; 96% received porcine prostheses; prosthesis size was 27 mm or larger in 92%. Immobile leaflet were recorded on intraoperative reports in 16 (62%) cases. It resulted in elevated gradient or mild-moderate prosthetic regurgitation in three (12%), but none led to immediate corrective action intraoperatively. At median follow-up of 21 (4-50) months, presence of immobile leaflet was associated with composite clinical endpoint of stroke, valve thrombosis or re-intervention (hazard ratio 6.8, 95% CI 1.8-25.2, p<0.01) compared to controls. CONCLUSION: Immobile leaflet immediately post-bioprosthetic valve implantation is frequently under-recognised intraoperatively and appears to be associated with early bioprosthetic dysfunction and worse clinical outcome.

Effect of a fourth-generation transcatheter valve enhanced skirt on paravalvular leak.

OBJECTIVES: The aim of this study was to assess the 30 day incidence of paravalvular leak (PVL) and need for aortic valve reintervention of a fourth generation balloon expandable transcatheter valve with enhanced skirt (4G-BEV) (SAPIEN 3 Ultra) compared with a third generation balloon expandable transcatheter valve (3G-BEV) (SAPIEN 3). BACKGROUND: The incidence of PVL has steadily declined with iterative improvements in transcatheter aortic valve replacement (TAVR) technology and implantation strategies. METHODS: Patients who underwent TAVR at Mayo Clinic from 7/2018 to 7/2019 were included in a prospective institutional registry. 4G-BEV has been utilized since 2/2019, and, after this date, 3G-BEV and 4G-BEV were simultaneously used. 4G-BEV had three sizes (20, 23, and 26 mm) while 3G-BEV included four sizes (20, 23, 26, and 29 mm). Both cohorts were evaluated at 30 days post-TAVR with a transthoracic echocardiogram to assess for PVL. RESULTS: A total of 260 consecutive patients were included. Of these, 101 patients received a 4G-BEV and 159 patients received a 3G-BEV. There were more females (p = .0005) and a lower aortic valve calcium score (p = .02) in the 4G-BEV cohort at baseline. Age, STS risk score, NYHA Class, and aortic valve mean gradient did not differ between groups. 4G-BEV was associated with a lower incidence of mild PVL (10.8 vs. 36.5%; p < .0001) and moderate PVL (0 vs. 5.8%) compared to the 3G-BEV at 30 days. There was no association between PVL and valve size in either cohort. CONCLUSIONS: Utilization of 4G-BEV is associated with reduced PVL at 30 days post-TAVR compared with 3G-BEV.

Functional tricuspid regurgitation of degenerative mitral valve disease: a crucial determinant of survival.

AIMS: To assess functional tricuspid regurgitation (FTR) determinants, consequences, and independent impact on outcome in degenerative mitral regurgitation (DMR). METHODS AND RESULTS: All patients diagnosed with isolated DMR 2003-2011, with structurally normal tricuspid leaflets, prospective FTR grading and systolic pulmonary artery pressure (sPAP) estimation by Doppler echocardiography at diagnosis were identified and long-term outcome analysed. The 5083 DMR eligible patients [63 ± 16 years, 47% female, ejection fraction (EF) 63 ± 7%, and sPAP 35 ± 13 mmHg] presented with FTR graded trivial in 45%, mild in 37%, moderate in 15%, and severe in 3%. While pulmonary hypertension (PHTN-sPAP ≥ 50 mmHg) was the most powerful FTR severity determinant, other strong FTR determinants were older age, female sex, lower left ventricle EF, DMR, and particularly atrial fibrillation (AFib) (all P ≤ 0.002). Functional tricuspid regurgitation moderate/severe was independently linked to more severe clinical presentation, more oedema, lower stroke volume, and impaired renal function (P ≤ 0.01). Survival (95% confidence interval) throughout follow-up [70% (69-72%) at 10 years] was strongly associated with FTR severity [82% (80-84%) for trivial, 69% (66-71%) for mild, 51% (47-57%) for moderate, and 26% (19-35%) for severe, P < 0.0001]. Excess mortality persisted after comprehensive adjustment [adjusted hazard ratio 1.40 (1.18-1.67) for moderate FTR and 2.10 (1.63-2.70) for severe FTR, P ≤ 0.01]. Excess mortality persisted adjusting for sPAP/right ventricular function (P < 0.0001), by matching [adjusted hazard ratios 2.08 (1.50-2.89), P < 0.0001] and vs. expected survival [risk ratio 1.79 (1.48-2.16), P < 0.0001]. Within 5-year of diagnosis valve surgery was performed in 73% (70-75%) and 15% (13-17%) of severe and moderate DMR and in only 26% (19-34%) and 6% (4-8%) of severe and moderate FTR. Valvular surgery improved outcome without alleviating completely higher mortality associated with FTR (P < 0.0001). CONCLUSION: In this large DMR cohort, FTR was frequent and causally, not only linked to PHTN but also to other factors, particularly AFib. Higher FTR severity is associated at diagnosis with more severe clinical presentation. Long term, FTR is independently of all confounders, associated with considerably worse mortality. Functional tricuspid regurgitation moderate and even severe is profoundly undertreated. Thus careful assessment, consideration for tricuspid surgery, and testing of new transcatheter therapy is warranted.

Causes and mechanisms of isolated mitral regurgitation in the community: clinical context and outcome.

AIMS: To define the hitherto unknown aetiology/mechanism distributions of mitral regurgitation (MR) in the community and the linked clinical characteristics/outcomes. METHODS AND RESULTS: We identified all isolated, moderate/severe MR diagnosed in our community (Olmsted County, MN, USA) between 2000 and 2010 and classified MR aetiology/mechanisms. Eligible patients (n = 727) were 73 ± 18 years, 51% females, with ejection fraction (EF) 49 ± 17%. MR was functional (FMR) in 65%, organic (OMR) in 32% and 2% mixed. Functional MR was linked to left ventricular remodelling (FMR-v) 38% and isolated atrial dilatation (FMR-a) 27%. At diagnosis FMR-v vs. FMR-a, vs. OMR displayed profound differences (all P < 0.0001) in age (73 ± 14, 80 ± 10, 68 ± 21years), male-sex (59, 33, 51%), atrial-fibrillation (28, 54, 13%), EF (33 ± 14, 57 ± 11, 61 ± 10%), and regurgitant-volume (38 ± 13, 37 ± 11, 51 ± 24 mL/beat). Dominant MR mechanism was Type I (normal valve-movement) 38%, Type II (excessive valve-movement) 25%, Type IIIa (diastolic movement-restriction) 3%, and Type IIIb (systolic movement-restriction) 34%. Outcomes were mediocre with excess-mortality vs. general-population in FMR-v [risk ratio 3.45 (2.98-3.99), P < 0.0001] but also FMR-a [risk ratio 1.88 (1.52-2.25), P < 0.0001] and OMR [risk ratio 1.83 (1.50-2.22), P < 0.0001]. Heart failure was frequent, particularly in FMR-v (5-year 83 ± 3% vs. 59 ± 4% FMR-a, 40 ± 3% OMR, P < 0.0001). Mitral surgery during patients' lifetime was performed in 4% of FMR-v, 3% of FMR-a, and 37% of OMR. CONCLUSION: Moderate/severe isolated MR in the community displays considerable aetiology/mechanism heterogeneity. Functional MR dominates, mostly FMR-v but FMR-a is frequent and degenerative MR dominates OMR. Outcomes are mediocre with excess-mortality particularly with FMR-v but FMR-a, despite normal EF incurs notable excess-mortality and frequent heart failure. Pervasive undertreatment warrants clinical trials of therapies tailored to specific MR cause/mechanisms.

RIsk Stratification prior to lead Extraction and impact on major intraprocedural complications (RISE protocol).

BACKGROUND: An internal risk stratification algorithm was developed to decrease the risk of major adverse cardiac events (MACEs) during lead extractions (LEs). OBJECTIVE: To report upon the impact of a risk stratification algorithm (RISE [RIsk Stratification prior to lead Extraction] protocol) on outcomes of LEs in a high-volume center. METHODS: A retrospective review of a prospectively maintained LEs database was performed to identify features associated with MACEs. On the basis of the retrospective data, the RISE protocol differentiated LEs procedures into "High" and "Low" risk for occurrence of MACEs. High-risk LEs included dual-coil defibrillator lead (≥3 years), pacemaker and single-coil lead (≥5 years), and any StarFix coronary sinus lead. During the prospective evaluation of the RISE protocol, "High-risk" LEs were performed in an operating room (OR) or hybrid laboratory with the cardiac anesthesiologist, OR nursing team, perfusionist in the room, and a cardiac surgeon on the premises. "Low-risk" LEs were performed in the electrophysiology (EP) laboratory with anesthesia provided by EP nursing team. The preintervention (pre-RISE) and postintervention (post-RISE) group spanned 19 and 40 months and consisted of 449 (632 leads) and 751 patients (1055 leads), respectively. The primary outcome of MACEs in the two groups was compared. RESULTS: Protocol compliance was 100%. The primary outcome of MACEs occurred in 15 patients (3.34%) before and 12 (1.6%) after implementation of the RISE protocol (P = .04). CONCLUSION: RISE identified a low-risk group where minimal resources are needed and allowed for rapid intervention in the high-risk group that reduced the consequences of MACEs.

Mitral Valve Surgery for Congestive Heart Failure.

Mitral valve diseases are common causes of congestive heart failure. Chronic primary and secondary (functional) mitral valve regurgitation are the most common reasons. Valve repair for primary mitral regurgitation cures mitral valve disease, whereas in functional regurgitation, mitral valve repair is associated with high failure rates secondary to persistent/progressive ventricular dysfunction and remodeling. Most patients are managed with strict adherence to the valve guidelines. Mitral valve replacement has an increased role in management of functional mitral regurgitation. Surgery for mitral valve disease is indicated in symptomatic patients with severe valve disease and in asymptotic before irreversible ventricular damage occurs.

Mitochondrial uncoupling does not decrease reactive oxygen species production after ischemia-reperfusion.

Cardiac ischemia-reperfusion (IR) leads to myocardial dysfunction by increasing production of reactive oxygen species (ROS). Mitochondrial H(+) leak decreases ROS formation; it has been postulated that increasing H(+) leak may be a mechanism of decreasing ROS production after IR. Ischemic preconditioning (IPC) decreases ROS formation after IR, but the mechanism is unknown. We hypothesize that pharmacologically increasing mitochondrial H(+) leak would decrease ROS production after IR. We further hypothesize that IPC would be associated with an increase in the rate of H(+) leak. Isolated male Sprague-Dawley rat hearts were subjected to either control or IPC. Mitochondria were isolated at end equilibration, end ischemia, and end reperfusion. Mitochondrial membrane potential (mΔΨ) was measured using a tetraphenylphosphonium electrode. Mitochondrial uncoupling was achieved by adding increasing concentrations of FCCP. Mitochondrial ROS production was measured by fluorometry using Amplex-Red. Pyridine dinucleotide levels were measured using HPLC. Before IR, increasing H(+) leak decreased mitochondrial ROS production. After IR, ROS production was not affected by increasing H(+) leak. H(+) leak increased at end ischemia in control mitochondria. IPC mitochondria showed no change in the rate of H(+) leak throughout IR. NADPH levels decreased after IR in both IPC and control mitochondria while NADH increased. Pharmacologically, increasing H(+) leak is not a method of decreasing ROS production after IR. Replenishing the NADPH pool may be a means of scavenging the excess ROS thereby attenuating oxidative damage after IR.