The landscape of liver transplantation for patients with alcohol-associated liver disease in the United States.

Indications for liver transplants have expanded to include patients with alcohol-associated liver disease (ALD) over the last decade. Concurrently, the liver allocation policy was updated in February 2020 replacing the Donor Service Area with Acuity Circles (ACs). The aim is to compare the transplantation rate, waitlist outcomes, and posttransplant survival of candidates with ALD to non-ALD and assess differences in that effect after the implementation of the AC policy. Scientific Registry for Transplant Recipients data for adult candidates for liver transplant were reviewed from the post-AC era (February 4, 2020-March 1, 2022) and compared with an equivalent length of time before ACs were implemented. The adjusted transplant rates were significantly higher for those with ALD before AC, and this difference increased after AC implementation (transplant rate ratio comparing ALD to non-ALD = 1.20, 1.13, 1.61, and 1.32 for the Model for End-Stage Liver Disease categories 37-40, 33-36, 29-32, and 25-28, respectively, in the post-AC era, p < 0.05 for all). The adjusted likelihood of death/removal from the waitlist was lower for patients with ALD across all lower Model for End-Stage Liver Disease categories (adjusted subdistribution hazard ratio = 0.70, 0.81, 0.84, and 0.70 for the Model for End-Stage Liver Disease categories 25-28, 20-24, 15-19, 6-14, respectively, p < 0.05). Adjusted posttransplant survival was better for those with ALD (adjusted hazard ratio = 0.81, p < 0.05). Waiting list and posttransplant mortality tended to improve more for those with ALD since the implementation of AC but not significantly. ALD is a growing indication for liver transplantation. Although patients with ALD continue to have excellent posttransplant outcomes and lower waitlist mortality, candidates with ALD have higher adjusted transplant rates, and these differences have increased after AC implementation.

Extracorporeal Membrane Oxygenation Patient Outcomes Following Restrictive Blood Transfusion Protocol.

OBJECTIVES: To investigate the effect of a restrictive blood product utilization protocol on blood product utilization and clinical outcomes. DESIGN: We retrospectively reviewed all adult extracorporeal membrane oxygenation (ECMO) patients from January 2019 to December 2021. The restrictive protocol, implemented in March 2020, was defined as transfusion of blood products for a hemoglobin level less than 7, platelet levels less than 50, and/or fibrinogen levels less than 100. Subgroup analysis was performed based on the mode of ECMO received: venoarterial ECMO, venovenous ECMO, and ECMO support following extracorporeal cardiopulmonary resuscitation (ECPR). SETTING: M Health Fairview University of Minnesota Medical Center. PATIENTS: The study included 507 patients. INTERVENTIONS: One hundred fifty-one patients (29.9%) were placed on venoarterial ECMO, 70 (13.8%) on venovenous ECMO, and 286 (56.4%) on ECPR. MEASUREMENTS AND MAIN RESULTS: For patients on venoarterial ECMO (48 [71.6%] vs. 52 [63.4%]; p = 0.374), venovenous ECMO (23 [63.9%] vs. 15 [45.5%]; p = 0.195), and ECPR (54 [50.0%] vs. 69 [39.2%]; p = 0.097), there were no significant differences in survival on ECMO. The last recorded mean hemoglobin value was also significantly decreased for venoarterial ECMO (8.10 [7.80-8.50] vs. 7.50 [7.15-8.25]; p = 0.001) and ECPR (8.20 [7.90-8.60] vs. 7.55 [7.10-8.88]; p < 0.001) following implementation of the restrictive transfusion protocol. CONCLUSIONS: These data suggest that a restrictive transfusion protocol is noninferior to ECMO patient survival. Additional, prospective randomized trials are required for further investigation of the safety of a restrictive transfusion protocol.

Academic and Wellness Outcomes Associated with use of Anki Spaced Repetition Software in Medical School.

OBJECTIVES: Medical students are increasingly using a spaced repetition software called Anki to study. There are limited studies evaluating the relationship between Anki and learner outcomes. In this study, we describe the history of Anki use in medical school and assess the potential relationships between use of Anki and medical student academic, extracurricular, and wellness outcomes. METHODS: We used cross-sectional data from a 50-item online survey and retrospective academic performance data from our institution's outcomes database. Participants were medical students. The survey assessed the frequency and timing of Anki use, student perceived stress, sleep quality, burnout risk, and involvement in extracurricular activities. Academic success was measured by USMLE Step 1 and Step 2 scores. RESULTS: 165 students responded survey. 92 (56%) identified as daily Anki users. Daily Anki use was correlated with increased Step 1 score (P = .039), but not Step 2 scores. There was an association between Anki use and increased sleep quality (P = .01), but no difference for other measurements of wellness or extracurricular involvement. CONCLUSION: The study demonstrates potential benefits of daily use of Anki but also confirms that a variety of study methods can be used to achieve similar medical school outcomes.

Attitudes Among General Surgery Program Directors and Faculty Toward Openly Nonheterosexual Applicants.

OBJECTIVE: Historically, nonheterosexual physicians have experienced bias in medical training. While resident-focused studies have been conducted in general surgery, the views of program directors and faculty are less evident. In this study, we surveyed program directors and faculty in general surgery to assess their attitudes toward openly nonheterosexual residency applicants. DESIGN: A national, cross-sectional online survey. PARTICIPANTS: Program directors and faculty in general surgery listed on the Association of Program Directors in Surgery listserv. RESULTS: Of the 123 participants who returned the survey; 33% were faculty and 58% were program directors. The response rate was 28% for program directors and 13% for faculty. Of respondents, 68% reported having openly nonheterosexual residents in their program and 38% were aware the candidates were nonheterosexual when they ranked them. Most respondents (76%) would advise a nonheterosexual mentee to be honest about their sexuality if asked during the interview and application process for general surgery (Figure 1). Of respondents, 84% reported that knowing an applicant was nonheterosexual would not affect how they ranked them while 76% reported that their program's faculty would always feel comfortable if a nonheterosexual resident brought their partner to a residency social event. CONCLUSIONS: To our knowledge, this is the first survey of general surgery program directors regarding their attitudes toward nonheterosexual residency applicants. While a few individuals continue to hold biased beliefs, there appears to be substantial acceptance of nonheterosexual general surgery residency candidates amongst program directors and faculty who responded to our survey.

Massive blood transfusion following older adult trauma: The effect of blood ratios on mortality.

BACKGROUND: Massive blood transfusion (MBT) following older adult trauma poses unique challenges. Despite extensive evidence on optimal resuscitative strategies in the younger adult patients, there is limited research in the older adult population. METHODS: We used the Trauma Quality Improvement Program (TQIP) database from 2013 to 2017 to identify all patients over 65 years old who received a MBT. We stratified our population into six fresh-frozen plasma:packed red blood cell (FFP:pRBC) ratio cohorts (1:1, 1:2, 1:3, 1:4, 1:5, 1:6+). Our primary outcomes were 24-h and 30-day mortality. We constructed multivariable regression models with 1:1 group as the baseline and adjusted for confounders to estimate the independent effect of blood ratios on mortality. RESULTS: A total of 3134 patients met our inclusion criteria (median age 73 ± 7.6 years, 65% male). On risk-adjusted multivariable analysis, 1:1 FFP:pRBC ratio was independently associated with lowest 24-h mortality (1:2 odds ratio [OR] 1.60, 95% confidence interval [CI] 1.25-2.06, p < 0.001) and 30-day mortality (1:2 OR 1.44, 95% CI 1.15-1.80, p = 0.002). CONCLUSIONS: Compared to all other ratios, the 1:1 FFP:pRBC ratio had the lowest 24-h and 30-day mortality following older adult trauma consistent with findings in the younger adult population.

Rotational Thromboelastometry-Guided Venoarterial Extracorporeal Membrane Oxygenation in the Treatment of Amniotic Fluid Embolism.

Amniotic fluid embolism (AFE) is a rare and often fatal complication of pregnancy that occurs during the puerperium. The low incidence of AFE has resulted in few large studies, which makes evidence-based management of AFE challenging. The use of extracorporeal membrane oxygenation (ECMO) has been reported but is limited by availability and challenges managing anticoagulation. In this report, we detail the case of a 29-year-old female who suffered from an AFE leading to cardiac arrest and disseminated intravascular coagulopathy. She was treated with protocolized A-OK (adenosine, ondansetron, and ketorolac), emergency c-section, cardiopulmonary resuscitation, massive blood transfusion, and rotational thromboelastometry-guided ECMO, allowing her to forgo initial anticoagulation. After a prolonged rehabilitation with initial poor neurological status, she made a complete recovery. In this report, we describe the protocols that contributed to her recovery and detail management of complicated AFE for other clinicians.

Splenectomy versus Imaging-Guided Percutaneous Drainage for Splenic Abscess: A Systematic Review and Meta-Analysis.

Background: Splenic abscess (SA) is a rare, life-threatening illness that is generally treated with splenectomy. However, this is associated with high mortality and morbidity. Recently, percutaneous drainage (PD) has emerged as an alternative therapy in select patients. In this study, we compare mortality and complications in patients with SA treated with splenectomy versus PD. Patients and Methods: A systematic literature search of 13 databases and online search engines was conducted from 2019 to 2020. A bivariate generalized linear mixed model (BGLMM) was used to conduct a separate meta-analysis for both mortality and complications. We used the risk of bias in non-randomized studies of interventions (ROBINS-I) tool to evaluate risk of bias in non-randomized studies, and the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach for assessing quality of evidence and strength of recommendations. Results were presented according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Results: The review included 46 retrospective studies from 21 countries. For mortality rate, 27 studies compared splenectomy and PD whereas 10 used PD only and nine used splenectomy only. Data for major complications were available in 18 two-arm studies, seven single-arm studies with PD, and seven single-arm studies with splenectomy. Of a total of 589 patients, 288 were treated with splenectomy and 301 underwent PD. Mortality rate was 12% (95% confidence interval [CI], 8%-17%) in patients undergoing splenectomy compared with 8% (95% CI, 4%-13%) with PD. Complication rates were 26% (95% CI, 16%-37%) in the splenectomy group compared with 10% (95% CI, 4%-17%) in the PD group. Conclusions: Percutaneous drainage s associated with a trend toward lower complications and mortality rates compared with splenectomy in the treatment of SA, however, these findings were not statistically significant. Because of the heterogeneity of the data, further prospective studies are needed to draw definitive conclusions.

Outcomes of Patients Undergoing Interfacility Extracorporeal Membrane Oxygenation Transfer Based on Cannulation Location and Mode of Transport.

As the use of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers has not been fully studied. This study evaluates complications and inhospital mortality in adult patients treated with venovenous (V-V) ECMO based on institutional location of cannulation and mode of transport. DESIGN: Retrospective cohort study. SETTING: Large midwestern ECMO center. PATIENTS: Adult patients receiving VV-ECMO. INTERVENTIONS: Need for transfer to ECMO center following VV-ECMO cannulation. MEASUREMENTS AND MAIN RESULTS: The study included 102 adult patients, 57% of which were cannulated at an outside institution prior to transfer. Of these, 60% were transported by ground, and the remainder were transported by air. Risk-adjusted logistic regression did not reveal any significant increase in odds for any complication or inhospital mortality between the groups based on location of cannulation or mode of transport. CONCLUSIONS: This study supports the practice of interfacility ECMO transfer with no difference in outcomes or inhospital mortality based on institutional location of cannulation or mode of transport.

Evaluation of Minnesota Score in the Allocation of Venovenous Extracorporeal Membrane Oxygenation During Resource Scarcity.

Background: In this study, we evaluate the previously reported novel Minnesota Score for association with in-hospital mortality and allocation of venovenous extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome with or without SARS-CoV-2 pneumonia. Methods: This was a retrospective cohort study across four extracorporeal membrane oxygenation centers in Minnesota. Logistic regression was used to assess the relationship between the scores and in-hospital mortality, duration of ECMO cannulation, and discharge disposition. Priority groups were established statistically by maximizing the sum of sensitivity and specificity and compared to the previous qualitatively established priority groups. Results: Of 124 patients included in the study, 38% were treated for COVID-19 acute respiratory distress syndrome. The median age was 48 years, and 73% were male. The in-hospital mortality rate was 38%. The Minnesota Score was significantly associated with in-hospital mortality only (OR 1.13, p=0.02). Statistically determined cut points were similar to qualitative cut points. SARS-CoV-2 status did not change the findings. Conclusions: In our patient cohort, the Minnesota Score is associated with increased mortality. With further validation, proposed priority groups could be utilized for allocation of ECMO in times of increasing scarcity.

Increasing Mortality in Venovenous Extracorporeal Membrane Oxygenation for COVID-19-Associated Acute Respiratory Distress Syndrome.

OBJECTIVES: Determine the factors associated with mortality in venovenous extracorporeal membrane oxygenation (V-V ECMO) patients with COVID-19 infection and provide an updated report of clinical outcomes for patients treated with V-V ECMO for COVID-19 in Minnesota. DESIGN: Multicenter prospective observational study. SETTING: The four adult Extracorporeal Life Support Organization-certified Centers of Excellence in Minnesota. PATIENTS: A total of 100 patients treated with V-V ECMO for COVID-19-associated acute respiratory distress syndrome (ARDS) from March 2020 to May 2021. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 60-day survival for patients treated with V-V ECMO for COVID-19. Outcomes of patients treated from November 2020 to May 2021(cohort 2) were compared with data from a previous cohort of patients, collected from March 2020 to October 2020 (cohort 1). The data from both cohorts were merged into a single dataset (Combined Cohort). Survival on V-V ECMO due to COVID-19-associated ARDS significantly decreased after October 2020 (63% vs 41%; p = 0.026). The median interval from hospital admission to V-V ECMO cannulation was significantly associated with 60-day mortality (10 d [6-14 d] in nonsurvivors vs 7 d [4-9 d] in survivors; p = 0.001) in the Combined Cohort and was also significantly longer in cohort 2 than cohort 1 (10 d [7-14 d] vs 6 d [4-10 d]; p < 0.001). In the Combined Cohort, the 60-day survival for patients who did not receive steroids was 86% (n = 12) versus 45% (n = 39) for patients who received at least one dose of steroids (p = 0.005). CONCLUSIONS: There was a significant increase in mortality for patients treated with V-V ECMO for COVID-19-associated ARDS in cohort 2 compared with cohort 1. Further research is required to determine the cause of the worsening trend in mortality.

Reduced bone mineral density in the first year after total pancreatectomy with islet autotransplantation (TPIAT).

BACKGROUND/OBJECTIVES: The effect of total pancreatectomy with islet autotransplantation (TPIAT) on bone mineral density (BMD) in patients with CP is unknown. We aimed to assess bone health in patients with CP after TPIAT. METHODS: We measured BMD, BMD Z-score, and bone mineral content (BMC) for total body, lumbar spine, right and left hip in 78 patients before and after TPIAT using dual-energy X-ray absorptiometry (DXA, n = 78 pre-TPIAT, n = 65 paired pre- and 12 months post-TPIAT, n = 33 paired 12 and 18 months post-TPIAT), and tested for association with clinical history including age, smoking status, and medications using paired and two-sample t-tests, linear regression, and Fisher's exact test. Laboratory measures related to bone health were also assessed. RESULTS: In the patients with pre-TPIAT DXA, 12% had low BMD (Z-score ≤ -2). BMD, BMD Z-score, and BMC all decreased from pre-to 12 months post-TPIAT. BMD declined by 1.7%-4.1% with the greatest change at the hips. Adjusted for change in lean and fat body mass, DXA changes remained significant for total body and hip. Serum carboxy-terminal collagen crosslinks telopeptide and alkaline phosphatase increased at 12 months post-TPIAT, suggesting possible increased bone remodeling. BMD, BMD Z-score, and BMC did not change between 12 months and 18 months in any of the four regions (p > 0.6). CONCLUSIONS: TPIAT is associated with decreases in BMD in the body, lumbar, and hip regions of patients with CP in the first year after TPIAT but these appear to stabilize between 12 and 18 months after TPIAT.

Risk Factors of Mortality for Patients Receiving Venovenous Extracorporeal Membrane Oxygenation for COVID-19 Acute Respiratory Distress Syndrome.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO. Patients and Methods: This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO. Results: There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis. Conclusions: Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.

Operationalizing Ethical Guidance for Ventilator Allocation in Minnesota: Saving the Most Lives or Exacerbating Health Disparities?

A statewide working group in Minnesota created a ventilator allocation scoring system in anticipation of functioning under a Crisis Standards of Care declaration. The scoring system was intended for patients with and without coronavirus disease 2019. There was disagreement about whether the scoring system might exacerbate health disparities and about whether the score should include age. We measured the relationship of ventilator scores to in-hospital and 3-month mortality. We analyzed our findings in the context of ethical and legal guidance for the triage of scarce resources. DESIGN: Retrospective cohort study. SETTING: Multihospital within a single healthcare system. PATIENTS: Five-hundred four patients emergently intubated and admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Ventilator Allocation Score was positively associated with higher mortality (p < 0.0001). The 3-month mortality rate for patients with a score of 6 or higher was 96% (42/44 patients). Age was positively associated with mortality. The 3-month mortality rate for patients 80 and older with scores of 4 or greater was 93% (40/43 patients). Of patients assigned a score of 5, those with end stage renal disease had lower mortality than patients without end stage renal disease although the difference did not achieve statistical significance (n = 27; 25% vs 58%; p = 0.2). CONCLUSIONS: The Ventilator Allocation Score can accurately identify patients with high rates of short-term mortality. However, these high mortality patients only represent 27% of all the patients who died, limiting the utility of the score for allocation of scarce resources. The score may unfairly prioritize older patients and inadvertently exacerbate racial health disparities through the inclusion of specific comorbidities such as end stage renal disease. Triage frameworks that include age should be considered. Purposeful efforts must be taken to ensure that triage protocols do not perpetuate or exacerbate prevailing inequities. Further work on the allocation of scarce resources in critical care settings would benefit from consensus on the primary ethical objective.

The Use of Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Infection: One Region's Comprehensive Experience.

Severe acute respiratory distress syndrome (ARDS) unresponsive to conventional intensive care unit (ICU) management is an accepted indication for venovenous extracorporeal membrane oxygenation (V-V ECMO) support. The frequency with which patients with coronavirus disease 2019 (COVID-19) pneumonia are selected for V-V ECMO has not been described. This was a cohort study including all patients placed on either V-V ECMO or venoarteriovenous ECMO at the four adult ECMO Centers of Excellence. Primary outcomes evaluated were survival to decannulation from the ECMO circuit, survival to discharge, and 60-day survival. Secondary outcomes were hospital length of stay (LOS), ICU LOS, length of ECMO cannulation, and length of intubation. During the study period, which corresponded to the first surge in COVID-19 hospitalizations in Minnesota, 35 patients with ARDS were selected for V-V ECMO support out of 1,849 adult ICU patients with COVID-19 infection in the state (1.9% incidence; 95% CI, 1.3-2.6%). This represents 46 (95% CI, 34-61) expected V-V ECMO patients per 100,000 confirmed positive cases of COVID-19. Twenty-six of the 35 patients (74.3%) supported with V-V ECMO survived to 60-day post-ECMO decannulation. Recent studies have demonstrated ongoing success rescuing patients with severe ARDS in COVID-19 infection. Our data add to the support of ECMO and the consideration for encouraging cooperation among regional ECMO centers to ensure access to this highest level of care. Finally, by evaluating all the patients of a single region, we estimate overall need for this resource intensive intervention based on the overall number of COVID-19 cases and ICU admissions.

Surgical microwave ablation for multifocal non-resectable liver metastases: a single institution experience treating five or more liver lesions.

BACKGROUND: Thermal ablation is an effective treatment for patients with metastatic colon and rectal cancer and allows surgeons to offer curative intent therapy to patients who are otherwise not candidates for resection. We aimed to report outcomes of a single institution experience using microwave ablation (MWA) with or without resection to treat five or more liver metastases. METHODS: In this retrospective cohort study, the University of Minnesota Division of Surgical Oncology liver surgery database was queried to identify all patients who underwent thermal ablation of five or more colorectal liver metastases (CRLM) between 2012-2018. We reviewed patient, disease, and tumor characteristics and measured local, intrahepatic, and extrahepatic recurrence (EHR) rates. We also calculated median overall survival (OS) and disease-free survival (DFS). RESULTS: Ten patients identified had five or more (range, 5-18) tumors ablated with or without combined liver and bowel resection. Median age was 50, and most patients were male (70%) and Caucasian (90%). Four patients received ablation alone (5-12 lesions), while six had combined resection and ablation (5-18 lesions). Ablation was performed laparoscopically in six patients, and four had ablations without resection. All patients received pre- and post-operative chemotherapy. A median of 7 tumors were ablated per patient. Median follow-up was 2.3 years. Among 75 tumors ablated, ablation site recurrence (ASR) (within 1 cm of ablation site) was seen in three with a per-lesion recurrence rate of 4%. Intrahepatic recurrence (IHR) occurred in 6 (60%) patients and EHR in 1 (10%). Five patients underwent retreatment of IHR during follow-up. Median OS was 3 years and DFS was 7.1 months. At the time of last follow up, 6 patients were disease-free. CONCLUSIONS: Thermal ablation can provide acceptable DFS and OS, even with high volume metastatic colorectal cancers. Future efforts should be focused on defining selection criteria for those most likely to benefit from this aggressive approach.

Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart.

Alternans of action potential duration (APD) and intracellular calcium ([Ca²âº]i) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia-reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled, which may affect alternans formation in the heart. The aim of our study was to investigate the role of mitochondria on the formation of APD and [Ca²âº]i alternans in the isolated rabbit heart. We performed dual voltage and [Ca²âº]i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia (n = 6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n = 6). We investigated the formation of alternans of APD, [Ca²âº]i amplitude (CaA), and [Ca²âº]i duration (CaD) under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD, CaD, and CaA alternans; an increase of intraventricular APD but not CaD heterogeneity; and significant reduction in conduction velocity compared with that of control. Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca²âº]i transients, whereas ischemia induces a significantly larger reduction of APD compared with that in FCCP treatment. In conclusion, our results demonstrate that uncoupling of mitochondria leads to an earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca²âº]i alternans in the heart, which in turn creates a substrate for ventricular arrhythmias.