Right Ventricle-Pulmonary Artery Coupling in Patients Undergoing Cardiac Interventions.

PURPOSE OF REVIEW: This review aims to summarize the fundamentals of RV-PA coupling, its non-invasive means of measurement, and contemporary understanding of RV-PA coupling in cardiac surgery, cardiac interventions, and congenital heart disease. RECENT FINDINGS: The need for more accessible clinical means of evaluation of RV-PA coupling has driven researchers to investigate surrogates using cardiac MRI, echocardiography, and right-sided pressure measurements in patients undergoing cardiac surgery/interventions, as well as patients with congenital heart disease. Recent research has aimed to validate these alternative means against the gold standard, as well as establish cut-off values predictive of morbidity and/or mortality. This emerging evidence lays the groundwork for identifying appropriate RV-PA coupling surrogates and integrating them into perioperative clinical practice.

The Role of Recipient Thyroid Hormone Supplementation in Primary Graft Dysfunction After Heart Transplantation: A Propensity-Adjusted Analysis.

OBJECTIVES: To investigate whether recipient administration of thyroid hormone (liothyronine [T3]) is associated with reduced rates of primary graft dysfunction (PGD) after orthotopic heart transplantation. DESIGN: Retrospective cohort study. SETTING: Single-center, university hospital. PARTICIPANTS: Adult patients undergoing orthotopic heart transplantation. INTERVENTIONS: A total of 609 adult heart transplant recipients were divided into 2 cohorts: patients who did not receive T3 (no T3 group, from 2009 to 2014), and patients who received T3 (T3 group, from 2015 to 2019). Propensity-adjusted logistic regression was performed to assess the association between T3 supplementation and PGD. MEASUREMENTS AND MAIN RESULTS: After applying exclusion criteria and propensity-score analysis, the final cohort included 461 patients. The incidence of PGD was not significantly different between the groups (33.9% no T3 group v 40.8% T3 group; p = 0.32). Mortality at 30 days (3% no T3 group v 2% T3 group; p = 0.53) and 1 year (10% no T3 group v 12% T3 group; p = 0.26) were also not significantly different. When assessing the severity of PGD, there were no differences in the groups' rates of moderate PGD (not requiring mechanical circulatory support other than an intra-aortic balloon pump) or severe PGD (requiring mechanical circulatory support other than an intra-aortic balloon pump). However, segmented time regression analysis revealed that patients in the T3 group were less likely to develop severe PGD. CONCLUSIONS: These findings indicated that recipient single-dose thyroid hormone administration may not protect against the development of PGD, but may attenuate the severity of PGD.

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.

Intracellular radar: Understanding γδ T cell immune surveillance and implications for clinical strategies in oncology.

T cells play a key role in anticancer immunity, with responses mediated through a diversity of αß or γδ T cell receptors. Although αß and γδ T cells stem from common thymic precursors, the development and subsequent biological roles of these two subsets differ considerably. γδ T cells are an unconventional T cell subset, uniquely poised between the adaptive and innate immune systems, that possess the ability to recognize intracellular disturbances and non-peptide-based antigens to eliminate tumors. These distinctive features of γδ T cells have led to recent interest in developing γδ-inspired therapies for treating cancer patients. In this minireview, we explore the biology of γδ T cells, including how the γδ T cell immune surveillance system can detect intracellular disturbances, and propose a framework to understand the γδ T cell-inspired therapeutic strategies entering the clinic today.

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.

Rapid Ventilator Splitting During COVID-19 Pandemic Using 3D Printed Devices and Numerical Modeling of 200 Million Patient Specific Air Flow Scenarios.

There has been a pressing need for an expansion of the ventilator capacity in response to the recent COVID19 pandemic. To address this need, we present a system to enable rapid and efficacious splitting between two or more patients with varying lung compliances and tidal volume requirements. Reserved for dire situations, ventilator splitting is complex, and has been limited to patients with similar pulmonary compliances and tidal volume requirements. Here, we report a 3D printed ventilator splitter and resistor system (VSRS) that uses interchangeable airflow resistors to deliver optimal tidal volumes to patients with differing respiratory physiologies, thereby expanding the applicability of ventilator splitting to a larger patient pool. We demonstrate the capability of the VSRS using benchtop test lungs and standard-of-care ventilators, which produced data used to validate a complementary, patient-specific airflow computational model. The computational model allows clinicians to rapidly select optimal resistor sizes and predict delivered pressures and tidal volumes on-demand from different patient characteristics and ventilator settings. Due to the inherent need for rapid deployment, all simulations for the wide range of clinically-relevant patient characteristics and ventilator settings were pre-computed and compiled into an easy to use mobile app. As a result, over 200 million individual computational simulations were performed to maximize the number of scenarios for which the VSRS can provide assistance. The VSRS will help address the pressing need for increased ventilator capacity by allowing ventilator splitting to be used with patients with differing pulmonary physiologies and respiratory requirements, which will be particularly useful for developing countries and rural communities with a limited ventilator supply.

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.