Mitochondrial transplantation in cardiac surgical patients: optimism, caveats, and outstanding questions.

PURPOSE OF REVIEW: Mitochondria satisfy the high metabolic demand of the heart, and also play major roles in reactive oxygen species signaling, calcium buffering, and regulation of cell death. Mitochondrial damage or dysfunction can drive diseases seen in cardiac surgical patients, including heart failure and ischemia/reperfusion injury. Exogenous transplantation of isolated mitochondria has been proposed as one way to augment mitochondrial function and mitigate a number of pathologic processes, with a heavy focus on ischemia/reperfusion injury. RECENT FINDINGS: Animal models of cardiac ischemia/reperfusion injury have shown functional benefits after mitochondrial transplantation. Many of the mechanisms underlying this therapy's effect; optimal dosing, delivery, and timing; and how it will translate to cardiac surgical patients are yet unknown. SUMMARY: Mitochondrial transplantation is a potential therapeutic strategy for cardiac ischemia/reperfusion injury. Effective application to selected cardiac surgical patients can be informed by further mechanistic investigations.

Predictive capabilities of the European registry for patients with mechanical circulatory support right-sided heart failure risk score after left ventricular assist device implantation.

OBJECTIVES: The prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implantation remains a challenge. Recently, risk scores were derived from analysis of the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) data, the EUROMACS-RHF, and the modified postoperative EUROMACS-RHF. The authors assessed the performance characteristics of these 2 risk score formulations in a continuous-flow LVAD cohort at their institution. DESIGN: A retrospective, observational study. SETTING: At a tertiary-care academic medical center. PARTICIPANTS: Adult patients who underwent durable LVAD implantation between 2015 and 2018. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Early post-LVAD RHF was defined as follows: (1) need for right ventricular assist device, or (2) inotropic or inhaled pulmonary vasodilator support for ≥14 postoperative days. The authors used logistic regression and examined receiver operating characteristic (ROC) curves to evaluate the ability of the 2 risk scores to distinguish between outcome groups. A total of 207 patients met the inclusion criteria. Of the patients, 16% developed RHF (33/207). The EUROMACS-RHF score was not predictive of RHF in the authors' cohort (odds ratio [OR] 1.25; 95% CI [0.99-1.60]; p = 0.06), but the postoperative EUROMACS-RHF CPB score was significantly associated (OR 1.38; 95% CI [1.03-1.89]; p = 0.03). The scores had similar ROC curves, with weak discriminatory performance: 0.601 (95% CI [0.509-0.692]) and 0.599 (95% CI [0.505-0.693]) for EUROMACS-RHF and postoperative EUROMACS-RHF, respectively. CONCLUSIONS: In the authors' single-center retrospective analysis, the EUROMACS-RHF risk score did not predict early RHF. An optimized risk score for the prediction of RHF after LVAD implantation remains an urgent unmet need.

Identification of Trajectory-Based Acute Kidney Injury Phenotypes Among Cardiac Surgery Patients.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of cardiac surgical procedures for which unrecognized heterogeneity may underpin poor success in identifying effective therapies. We aimed to identify phenotypically similar groups of patients as defined by their postoperative creatinine trajectories. METHODS: This was a retrospective, single-center cohort study in an academic tertiary care center including patients undergoing coronary artery bypass graft procedures. AKI phenotypes were evaluated through latent class mixed modeling of serum creatinine patterns (trajectories). To identify trajectory phenotypes, modeling was performed using postoperative creatinine values from 50% of patients (development cohort) and for comparison similarly conducted for the remaining sample (validation cohort). Subsequent assessments included comparisons of classes between development and validation cohorts for consistency and stability, and among classes for patient and procedural characteristics, complications, and long-term survival. RESULTS: We identified 12 AKI trajectories in both the development (n = 2647) and validation cohorts (n = 2647). Discrimination among classes was good (mean posterior class membership probability, 66%-88%), with differences in rate, timing, and degree of serum creatinine rise/fall, and recovery. In matched class comparisons between cohorts, many other phenotypic similarities were present. Notably, 4 high-risk phenotypes had greater long-term risk for death relative to lower risk classes. CONCLUSIONS: Latent class mixed modeling identified 12 reproducible AKI classes (serum creatinine trajectory phenotypes), including 4 with higher risk of poor outcome, in patients following coronary artery bypass graft procedures. Such hidden structure offers a novel approach to grouping patients for renoprotection investigations in addition to reanalysis of previously conducted trials.

Renal-Resistive Index for Prediction of Acute Kidney Injury in the Setting of Aortic Insufficiency.

Acute kidney injury (AKI) is a common postoperative complication after cardiac surgery with cardiopulmonary bypass (CPB), and leads to significant morbidity, mortality, and cost. Although early recognition and management of AKI may reduce the burden of renal disease, reliance on serum creatinine accumulation to confidently diagnose it leads to a significant and important delay (up to 48 hours). Hence, a search for earlier AKI biomarkers is warranted. The renal-resistive index (RRI) is a promising early AKI biomarker that reflects intrarenal arterial pulsatility as reflected by the peak systolic and end-diastolic blood velocities divided by the peak systolic velocity. During cardiac surgery, post-CPB elevation of RRI is correlated with renal injury. The RRI is influenced by intrarenal and extrarenal factors, as well as different hemodynamic states. Understanding its limitations may increase its usefulness as an early AKI biomarker. For example, tachycardia or aortic stenosis typically results in a lower RRI, whereas bradycardia or increased systemic pulse pressure (as seen with aortic insufficiency) are associated with a higher RRI, unrelated to any intrarenal effects. In this E-Challenge, the authors present two cases in which the RRI was used to evaluate a patient's risk of developing AKI.

Sirtuin-1 expression and activity is diminished in aged liver grafts.

The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory. Sirtuin1 has been identified as a key mediator of mitochondrial recovery following ischemia-reperfusion injury. The purpose of this study was to determine whether differences exist in sirtuin-1 expression/activity in old vs. young liver grafts and to determine correlations with mitochondrial function, graft metabolic function, and graft injury. Old and young rat liver grafts (N = 7 per group) were exposed to 12 h of static cold storage (SCS), followed by a 2 h period of graft reperfusion ex vivo. Sirtuin1 expression and activity, mitochondrial function, graft metabolic function, and graft injury were compared. Sirtuin1 expression is upregulated in young, but not old, liver grafts in response to cold storage and reperfusion. This is associated with diminished tissue ATP, antioxidant defense, and graft metabolic function in old liver grafts. There was no evidence of increased inflammation or histologic injury in old grafts. Sirtuin1 expression is diminished in old liver grafts and correlates with mitochondrial and metabolic function. The sirtuin pathway may represent a target for intervention to enhance the function of aged liver grafts.

Intraoperative renal resistive index threshold as an acute kidney injury biomarker.

STUDY OBJECTIVE: The lag in creatinine-mediated diagnosis of cardiac surgery-associated acute kidney injury (AKI) may be impeding the development of renoprotection therapies. Postoperative renal resistive index (RRI) measured by transabdominal Doppler ultrasound is a promising early AKI biomarker. RRI measured intraoperatively by transesophageal echocardiography (TEE) is available even earlier but is less evaluated. Therefore, we conducted an assessment of intraoperative RRI as an AKI biomarker using previously reported post-renal insult thresholds. DESIGN: Retrospective convenience sample. SETTING: Intraoperative. PATIENTS: 180 adult cardiac surgical patients between July 2013 and July 2014. INTERVENTION: None. MEASUREMENTS: Pre- and post-cardiopulmonary bypass (CPB) RRI thresholds, measured using intraoperative TEE, exceeding 0.74 or 0.79 were used to evaluate for an association with KDIGO AKI risk using the Chi-square test. Other consensus AKI criteria (AKIN, RIFLE) were similarly evaluated. Additional t-test analyses examined the relationship of pre- and pre-to-post (delta) CPB RRI with AKI. MAIN RESULTS: Post-CPB RRI for 99 patients included 36 and 23 with values exceeding 0.74 and 0.79, respectively. Analyses confirmed associations of both RRI thresholds with all consensus AKI definitions (0.74; KDIGO: p = 0.05, AKIN: p = 0.03, RIFLE: p = 0.03, 0.79; KDIGO: p = 0.002, AKIN: p = 0.001, RIFLE: p = 0.004). In contrast, pre-CPB and pre-to post-CPB RRI were not associated with AKI. CONCLUSIONS: RRI obtained intraoperatively in cardiac surgery patients, assessed using previously reported thresholds, is highly associated with AKI and warrants further evaluation as a promising "earliest" AKI biomarker. These significant findings suggest that RRI assessment should be included in the standard intraoperative TEE exam.

Mitochondrial Dysfunction in Cardiac Surgery.

Mitochondria are key to the cellular response to energetic demand, but are also vital to reactive oxygen species signaling, calcium hemostasis, and regulation of cell death. Cardiac surgical patients with diabetes, heart failure, advanced age, or cardiomyopathies may have underlying mitochondrial dysfunction or be more sensitive to perioperative mitochondrial injury. Mitochondrial dysfunction, due to ischemia/reperfusion injury and an increased systemic inflammatory response due to exposure to cardiopulmonary bypass and surgical tissue trauma, impacts myocardial contractility and predisposes to arrhythmias. Strategies for perioperative mitochondrial protection and recovery include both well-established cardioprotective protocols and targeted therapies that remain under investigation.

Intraoperative Renal Resistive Index as an Acute Kidney Injury Biomarker: Development and Validation of an Automated Analysis Algorithm.

OBJECTIVE: Intraoperative Doppler-determined renal resistive index (RRI) is a promising early acute kidney injury (AKI) biomarker. As RRI continues to be studied, its clinical usefulness and robustness in research settings will be linked to the ease, efficiency, and precision with which it can be interpreted. Therefore, the authors assessed the usefulness of computer vision technology as an approach to developing an automated RRI-estimating algorithm with equivalent reliability and reproducibility to human experts. DESIGN: Retrospective. SETTING: Single-center, university hospital. PARTICIPANTS: Adult cardiac surgery patients from 7/1/2013 to 7/10/2014 with intraoperative transesophageal echocardiography-determined renal blood flow measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Renal Doppler waveforms were obtained retrospectively and assessed by blinded human expert raters. Images (430) were divided evenly into development and validation cohorts. An algorithm for automated RRI analysis was built using computer vision techniques and tuned for alignment with experts using bootstrap resampling in the development cohort. This algorithm then was applied to the validation cohort for an unbiased assessment of agreement with human experts. Waveform analysis time per image averaged 0.144 seconds. Agreement was excellent by intraclass correlation coefficient (0.939; 95% confidence interval [CI] 0.921 to 0.953) and in Bland-Altman analysis (mean difference [human-algorithm] -0.0015; 95% CI -0.0054 to 0.0024), without evidence of systematic bias. CONCLUSION: The authors confirmed the value of computer vision technology to develop an algorithm for RRI estimation from automatically processed intraoperative renal Doppler waveforms. This simple-to-use and efficient tool further adds to the clinical and research value of RRI, already the "earliest" among several early AKI biomarkers being assessed.

The Association of Aortic Valve Pathology With Renal Resistive Index as a Kidney Injury Biomarker.

BACKGROUND: Acute kidney injury (AKI) is a common serious complication after cardiac surgery. Doppler-determined renal resistive index (RRI) is a promising early AKI biomarker in this population. However, the relationship between aortic valve pathology (insufficiency and/or stenosis) and RRI is unknown. This study aimed to investigate RRI variability related to aortic valve pathology. METHODS: In a retrospective review of cardiac surgery patients, RRI and aortic valve pathology were assessed prior to cardiopulmonary bypass using transesophageal echocardiography. Aortic valve status was categorized into four subgroups: normal (insufficiency and stenosis, none/trace/mild), insufficiency (insufficiency, moderate/severe; stenosis, none/trace/mild), combined insufficiency/stenosis (insufficiency and stenosis, moderate/severe), or stenosis (insufficiency, none/trace/mild; stenosis, moderate/severe). RRI and time-matched hemodynamic and Doppler measurements were compared among subgroups. RESULTS: Of 175 patients, 60 had aortic valve pathology (16 insufficiency, 18 insufficiency/stenosis, 26 stenosis). Compared with the normal subgroup, patients with aortic insufficiency had lower diastolic blood pressure and trough renal Doppler velocities, and higher RRI (0.77 versus 0.69; p < 0.001); patients with combined insufficiency/stenosis also had higher RRI (0.72 versus 0.69, p = 0.042). CONCLUSIONS: Patients with aortic insufficiency and combined insufficiency/stenosis had higher median RRI values compared with normal patients. For these individuals, diastolic flow differences related to aortic insufficiency may explain why their presurgery RRI values often exceeded postoperative thresholds typically associated with AKI. Strategies to account for the potentially confounding effects of aortic insufficiency on renal flow patterns, independent of renal injury, may add to the value of RRI as an early AKI biomarker.

Hypercapnia in diving: a review of CO2 retention in submersed exercise at depth.

Carbon dioxide (CO2) retention, or hypercapnia, is a known risk of diving that can cause mental and physical impairments leading to life-threatening accidents. Often, such accidents occur due to elevated inspired carbon dioxide. For instance, in cases of CO2 elimination system failures during rebreather dives, elevated inspired partial pressure of carbon dioxide (PCO2) can rapidly lead to dangerous levels of hypercapnia. Elevations in PaCO2 (arterial pressure of PCO2) can also occur in divers without a change in inspired PCO2. In such cases, hypercapnia occurs due to alveolar hypoventilation. Several factors of the dive environment contribute to this effect through changes in minute ventilation and dead space. Predominantly, minute ventilation is reduced in diving due to changes in respiratory load and associated changes in respiratory control. Minute ventilation is further reduced by hyperoxic attenuation of chemosensitivity. Physiologic dead space is also increased due to elevated breathing gas density and to hyperoxia. The Haldane effect, a reduction in CO2 solubility in blood due to hyperoxia, may contribute indirectly to hypercapnia through an increase in mixed venous PCO2. In some individuals, low ventilatory response to hypercapnia may also contribute to carbon dioxide retention. This review outlines what is currently known about hypercapnia in diving, including its measurement, cause, mental and physical effects, and areas for future study.

Swimming-Induced Pulmonary Edema: Pathophysiology and Risk Reduction With Sildenafil.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) occurs during swimming or scuba diving, often in young individuals with no predisposing conditions, and its pathophysiology is poorly understood. This study tested the hypothesis that pulmonary artery and pulmonary artery wedge pressures are higher in SIPE-susceptible individuals during submerged exercise than in the general population and are reduced by sildenafil. METHODS AND RESULTS: Ten study subjects with a history of SIPE (mean age, 41.6 years) and 20 control subjects (mean age, 36.2 years) were instrumented with radial artery and pulmonary artery catheters and performed moderate cycle ergometer exercise for 6 to 7 minutes while submersed in 20°C water. SIPE-susceptible subjects repeated the exercise 150 minutes after oral administration of 50 mg sildenafil. Work rate and mean arterial pressure during exercise were similar in controls and SIPE-susceptible subjects. Average o2 and cardiac output in controls and SIPE-susceptible subjects were: o2 2.42 L·min(-1) versus 1.95 L·min(-1), P=0.2; and cardiac output 17.9 L·min(-1) versus 13.8 L·min(-1), P=0.01. Accounting for differences in cardiac output between groups, mean pulmonary artery pressure at cardiac output=13.8 L·min(-1) was 22.5 mm Hg in controls versus 34.0 mm Hg in SIPE-susceptible subjects (P=0.004), and the corresponding pulmonary artery wedge pressure was 11.0 mm Hg versus 18.8 mm Hg (P=0.028). After sildenafil, there were no statistically significant differences in mean pulmonary artery pressure or pulmonary artery wedge pressure between SIPE-susceptible subjects and controls. CONCLUSIONS: These observations confirm that SIPE is a form of hemodynamic pulmonary edema. The reduction in pulmonary vascular pressures after sildenafil with no adverse effect on exercise hemodynamics suggests that it may be useful in SIPE prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00815646.

The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle.

The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

SIGNIFICANCE: Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. RECENT ADVANCES: Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. CRITICAL ISSUES: Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. FUTURE DIRECTIONS: Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Peroxisome proliferator-activated receptor γ co-activator 1-α as a critical co-activator of the murine hepatic oxidative stress response and mitochondrial biogenesis in Staphylococcus aureus sepsis.

A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor γ co-activator 1-α (PPARGC-1-α or PGC-1α), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of PGC-1α modulates gene expression for the mitochondrial antioxidant enzyme SOD-2 during hepatic inflammatory stress. Using Staphylococcus aureus peritonitis in mice, we found significant Sod2 gene induction in WT mice, whereas PGC-1α heterozygotes (PGC-1α(+/-)) failed to augment Sod2 mRNA and protein levels. Impaired Sod2 regulation in PGC-1α(+/-) mice was accompanied by oxidative stress shown by elevated mitochondrial GSSG/GSH and protein carbonyls. In silico analysis of the mouse proximal Sod2 promoter region revealed consensus binding sites for the Nfe2l2 (Nrf2) transcription factor. Chromatin immunoprecipitation demonstrated diminished Nfe2l2 protein binding to the antioxidant response element promoter site proximal to the Sod2 start site in PGC-1α heterozygous mice, implicating PGC-1α in facilitation of Nfe2l2 DNA binding. Nuclear protein co-immunoprecipitation demonstrated an interaction between hepatic Nfe2l2 and PGC-1α in WT mice that was greatly reduced in PGC-1α(+/-) mice. The data indicate that PGC-1α promotes mitochondrial antioxidant enzyme expression through Nfe2l2-mediated SOD-2 expression in sepsis. The presence of this new PGC-1α-dependent signaling axis indicates that PGC-1α opposes mitochondrial oxidative stress by means of selective induction of one or more antioxidant response element-driven genes. By implication, exploitation of this axis could lead to new pharmacological interventions to improve the antioxidant defenses during oxidative stress-induced mitochondrial damage.

Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans.

Given that the physiology of heme oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake (Vo(2max)) in humans. In 10 healthy subjects, we biopsied the vastus lateralis and performed Vo(2max) tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat Vo(2max) testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After Vo(2max) testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, mitochondrial transcription factor-A (Tfam), and DNA polymerase gamma (Polgamma) with no change in mitochondrial DNA (mtDNA) copy number or Vo(2max). Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by Vo(2max) testing alone, whereas CO alone increased Tfam and Polgamma mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity.