Continuous monitoring of left ventricular function in postoperative intensive care patients using artificial intelligence and transesophageal echocardiography.

BACKGROUND: Continuous monitoring of mitral annular plane systolic excursion (MAPSE) using transesophageal echocardiography (TEE) may improve the evaluation of left ventricular (LV) function in postoperative intensive care patients. We aimed to assess the utility of continuous monitoring of LV function using TEE and artificial intelligence (autoMAPSE) in postoperative intensive care patients. METHODS: In this prospective observational study, we monitored 50 postoperative intensive care patients for 120 min immediately after cardiac surgery. We recorded a set of two-chamber and four-chamber TEE images every five minutes. We defined monitoring feasibility as how often the same wall from the same patient could be reassessed, and categorized monitoring feasibility as excellent if the same LV wall could be reassessed in ≥ 90% of the total recordings. To compare autoMAPSE with manual measurements, we rapidly recorded three sets of repeated images to assess precision (least significant change), bias, and limits of agreement (LOA). To assess the ability to identify changes (trending ability), we compared changes in autoMAPSE with the changes in manual measurements in images obtained during the initiation of cardiopulmonary bypass as well as before and after surgery. RESULTS: Monitoring feasibility was excellent in most patients (88%). Compared with manual measurements, autoMAPSE was more precise (least significant change 2.2 vs 3.1 mm, P < 0.001), had low bias (0.4 mm), and acceptable agreement (LOA - 2.7 to 3.5 mm). AutoMAPSE had excellent trending ability, as its measurements changed in the same direction as manual measurements (concordance rate 96%). CONCLUSION: Continuous monitoring of LV function was feasible using autoMAPSE. Compared with manual measurements, autoMAPSE had excellent trending ability, low bias, acceptable agreement, and was more precise.

Cardiorespiratory fitness and the incidence of surgery for aortic valve stenosis-the HUNT study.

OBJECTIVES: Aortic valve stenosis (AVS) shares many risk factors with coronary disease, the latter being strongly and inversely associated with physical activity (PA) and cardiorespiratory fitness (CRF). However, the relationship between PA, CRF and AVS needs to be established. We explored whether PA habits and estimated CRF affect the risk of developing AVS demanding aortic valve replacement (AVR) and how these factors affect postoperative mortality. METHODS: Participants from the second and third waves of Trøndelag Health Study were cross-linked with a local heart surgery registry and the Norwegian Cause of Death Registry. Estimated CRF was calculated through a developed algorithm based on clinical and self-reported data. Fine-Gray competing risk analyses were used to investigate how PA habits and estimated CRF were associated with the risk of AVR across CRF quintiles, PA groups and per 1-metabolic equivalent task (MET) (3.5 ml/min/kg). RESULTS: In a study population of 57 214 participants, we found a 15% [95% confidence interval (CI) 1-27] reduced risk of AVR per 1-MET estimated CRF increment. Those in the highest CRF quintile had a 56% (95% CI 14-77) lower risk of surgery compared to the lowest quintile. Analyses on PA groups did not show significant results. Finally, we found a 37% (95% CI 17-53) lower risk of postoperative mortality per 1-MET increased estimated CRF. CONCLUSIONS: Our findings indicate a strong and inverse relationship between estimated CRF and incidence of AVR due to AVS. Higher estimated CRF was associated with lower mortality after surgery.

NF-κB Transcriptional Activity Indispensably Mediates Hypoxia-Reoxygenation Stress-Induced microRNA-210 Expression.

Ischemia-reperfusion (I-R) injury is a cardinal pathophysiological hallmark of ischemic heart disease (IHD). Despite significant advances in the understanding of what causes I-R injury and hypoxia-reoxygenation (H-R) stress, viable molecular strategies that could be targeted for the treatment of the deleterious biochemical pathways activated during I-R remain elusive. The master hypoxamiR, microRNA-210 (miR-210), is a major determinant of protective cellular adaptation to hypoxia stress but exacerbates apoptotic cell death during cellular reoxygenation. While the hypoxia-induced transcriptional up-regulation of miR-210 is well delineated, the cellular mechanisms and molecular entities that regulate the transcriptional induction of miR-210 during the cellular reoxygenation phase have not been elucidated yet. Herein, in immortalized AC-16 cardiomyocytes, we delineated the indispensable role of the ubiquitously expressed transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in H-R-induced miR-210 expression during cellular reoxygenation. Using dominant negative and dominant active expression vectors encoding kinases to competitively inhibit NF-κB activation, we elucidated NF-κB activation as a significant mediator of H-R-induced miR-210 expression. Ensuing molecular assays revealed a direct NF-κB-mediated transcriptional up-regulation of miR-210 expression in response to the H-R challenge that is characterized by the NF-κB-mediated reorchestration of the entire repertoire of histone modification changes that are a signatory of a permissive actively transcribed miR-210 promoter. Our study confers a novel insight identifying NF-κB as a potential novel molecular target to combat H-R-elicited miR-210 expression that fosters augmented cardiomyocyte cell death.

GSK3ß Inhibition Is the Molecular Pivot That Underlies the Mir-210-Induced Attenuation of Intrinsic Apoptosis Cascade during Hypoxia.

Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3ß) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3ß S9A mutant (ca-GSK3ß S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3ß kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3ß kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3ß kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death.

Cardiorespiratory fitness and the incidence of coronary surgery and postoperative mortality: the HUNT study.

OBJECTIVES: Low physical activity and cardiorespiratory fitness are known risk factors for coronary artery disease, but how they affect the risk of undergoing coronary artery bypass graft surgery is not established. We explored how physical activity and estimated cardiorespiratory fitness affect the risk of coronary surgery and postoperative outcome. METHODS: Participants with no history of coronary disease from the second wave of the Trøndelag Health Study (HUNT2) were cross-linked with the local heart surgery register and the Norwegian Cause of Death Registry. Cardiorespiratory fitness was estimated by a previously developed algorithm using clinical and self-reported information. Fine-Gray competing risk analyses were used to calculate the risk of undergoing isolated coronary surgery across physical activity groups and estimated cardiorespiratory fitness (mL/kg/min) as quintiles and per 1 metabolic equivalent of task (MET) (3.5 mL/kg/min). RESULTS: We included 45,491 participants. The mean population age was 46.0 [standard deviation (SD) 15.8] years, and the mean estimated fitness was 41.3 (SD 8.9) mL/kg/min. A total of 672 (1.5%) participants underwent coronary surgery during the follow-up period. The risk of undergoing isolated coronary surgery was 26% [95% confidence interval (CI) 3-44] lower for those classified as highly active compared to those classified as least active. Further, an 11% (95% CI 6-15) lower risk per 1-MET (3.5 mL/kg/min) of higher fitness. Finally, we observed a 15% (95% CI 5-23) lower mortality risk after surgery per 1-MET of higher fitness among those undergoing surgery. CONCLUSIONS: High levels of physical activity and high estimated fitness levels were inversely associated with the risk of developing coronary disease requiring surgery and overall mortality after surgery.

miR-210 Regulates Apoptotic Cell Death during Cellular Hypoxia and Reoxygenation in a Diametrically Opposite Manner.

Apoptotic cell death of cardiomyocytes is a characteristic hallmark of ischemia-reperfusion (I/R) injury. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxic stress. However, to date, no consensus has emerged with regards to the polarity of the miR-210-elicited cellular response, as miR-210 has been shown to exacerbate as well as attenuate hypoxia-driven apoptotic cell death. Herein, in AC-16 cardiomyocytes subjected to hypoxia-reoxygenation (H-R) stress, we unravel novel facets of miR-210 biology and resolve the biological response mediated by miR-210 into the hypoxia and reoxygenation temporal components. Using transient overexpression and decoy/inhibition vectors to modulate miR-210 expression, we elucidated a Janus role miR-210 in the cellular response to H-R stress, wherein miR-210 mitigated the hypoxia-induced apoptotic cell death but exacerbated apoptotic cell death during cellular reoxygenation. We further delineated the underlying cellular mechanisms that confer this diametrically opposite effect of miR-210 on apoptotic cell death. Our exhaustive biochemical assays cogently demonstrate that miR-210 attenuates the hypoxia-driven intrinsic apoptosis pathway, while significantly augmenting the reoxygenation-induced caspase-8-mediated extrinsic apoptosis pathway. Our study is the first to unveil this Janus role of miR-210 and to substantiate the cellular mechanisms that underlie this functional duality.

Remote ischemic preconditioning and incidence of postoperative atrial fibrillation.

OBJECTIVES: Although remote ischemic preconditioning (RIPC) has shown favorable effects on ischemia-reperfusion injury, much remains unknown of its mechanisms and clinical significance. We hypothesized that RIPC would reduce the incidence of postoperative atrial fibrillation (POAF) following coronary artery bypass graft (CABG) surgery. In addition, we investigated whether RIPC could induce alterations of circulating microRNA in blood plasma. DESIGN: This is a single-center, double-blind, randomized controlled trial. 92 adult patients referred for first-time isolated CABG surgery were randomly assigned to either RIPC (n = 45) or control (n = 47). The RIPC-stimulus comprised three 5-min cycles of upper arm ischemia, induced by inflating a blood pressure cuff to 200 mmHg, with an intervening 5 min reperfusion. Heart rhythm was assessed by telemetry. MicroRNA expression was assessed in plasma by real-time polymerase chain reaction. RESULTS: Of the 92 patients included in the study, 27 patients developed POAF (29%). 17 of these patients belonged to the RIPC group (38%), and 10 to the control group (21%). There were no significant alterations of microRNA expression. CONCLUSIONS: We did not observe a reduced incidence of POAF by RIPC before CABG surgery. Larger multi-center studies may be necessary to further clarify this issue.

Comparison of left versus right atrial myocardium in patients with sinus rhythm or atrial fibrillation - an assessment of mitochondrial function and microRNA expression.

Several of the cellular alterations involved in atrial fibrillation (AF) may be linked to mitochondrial function and altered microRNA (miR) expression. A majority of studies on human myocardium involve right atrial (RA) tissue only. There are indications that AF may affect the two atria differentially. This study aimed to compare interatrial differences in mitochondrial respiration and miR expression in the RA versus left atrium (LA) within patients with sinus rhythm (SR) and AF. Thirty-seven patients with AF (n = 21) or SR (n = 16), undergoing coronary artery bypass surgery and/or heart valve surgery, were included. Myocardial biopsies were obtained from RA and LA appendages. Mitochondrial respiration was assessed in situ in permeabilized myocardium. MiR array and real-time quantitative polymerase chain reaction were performed to evaluate miR expression. Mitochondrial respiratory rates were similar in RA versus LA. Expression of miR-100, -10b, -133a, -133b, -146a, -155, -199a-5p, -208b, and -30b were different between the atria in both SR and AF patients. In contrast, differential expression was observed between RA versus LA for miR-93 in patients with SR only, and for miR-1, -125b, -142-5p, -208a, and -92b within AF patients only. These results indicate that mitochondrial respiratory capacity is similar in the RA and LA of patients with SR and AF. Differences in miR expressional profiles are observed between the RA versus LA in both SR and AF, and several interatrial differences in miR expression diverge between SR and AF. These findings may contribute to the understanding of how AF pathophysiology may affect the two atria differently.

Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a potential to cause serious complications. Mitochondria play central roles in cardiomyocyte function and have been implicated in AF pathophysiology. MicroRNA (miR) are suggested to influence both mitochondrial function and the development of AF. Yet mitochondrial function and miR expression remain largely unexplored in human atrial tissue. This study aims to investigate mitochondrial function and miR expression in the right (RA) and left atria (LA) of patients with AF and sinus rhythm (SR). Myocardial tissue from the RA and LA appendages was investigated in 37 patients with AF (n = 21) or SR (n = 16) undergoing coronary artery bypass surgery and/or heart valve surgery. Mitochondrial respiration was measured in situ after tissue permeabilization by saponin. MiR expression was assessed by miR array and real-time quantitative reverse-transcription polymerase chain reaction. Maximal mitochondrial respiratory rate was increased in both RA and LA tissue of patients with AF vs. SR. Biatrial downregulation of miR-208a and upregulation of miR-106b, -144, and -451 were observed in AF vs. SR. In addition, miR-15b was upregulated in AF within RA only, and miR-106a, -18a, -18b, -19a, -19b, -23a, -25, -30a, -363, -486-5p, -590-5p, and -93 were upregulated in AF within LA only. These findings suggest that mitochondrial function and miR are involved in AF pathophysiology and should be areas of focus in the exploration for potential novel therapeutic targets.

Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery.

RATIONALE: Remote ischemic preconditioning (RIPC) has been suggested to induce cardioprotection during cardiac surgery. Maintaining proper atrial function is imperative in preventing arrhythmia and thrombus formation. Mitochondria have been proposed as key targets in conveying RIPC mechanisms and effects. MicroRNA (miR) is emerging as an important regulator of mitochondrial function, arrhythmia, and protection from ischemia and reperfusion. OBJECTIVE: This study aimed to evaluate the effect of RIPC on mitochondrial respiration and miR expression in human atrial tissue. METHODS AND RESULTS: Sixty patients undergoing coronary artery bypass graft surgery were randomized to RIPC (n=30) or control (n=30). RIPC was performed preoperatively by inflating a blood pressure cuff on the upper arm to 200 mm Hg for 3×5 minutes, with 5 minutes reperfusion intervals. Biopsies were obtained from the right atrial appendage before and after aortic cross-clamping. Mitochondrial respiration was measured in situ and miR assessed by commercial miR array and quantitative reverse transcription polymerase chain reaction. Postoperative atrial fibrillation occurrence was monitored by biotelemetry. Maximal mitochondrial respiration was preserved throughout surgery after RIPC but significantly reduced (-28%; P<0.05) after aortic cross-clamping in control. Incidence of postoperative atrial fibrillation was lower after RIPC versus control (14% versus 50%; P<0.01). Myocardial expression of miR-133a and miR-133b increased after aortic cross-clamping in both RIPC and control, whereas miR-1 was upregulated in control only. MiR-338-3p expression was higher in RIPC versus control after aortic cross-clamping. CONCLUSIONS: RIPC preserves mitochondrial respiration and prevents upregulation of miR-1 in the right atrium during coronary artery bypass graft. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01308138.