Outcomes of Surgical Ablation for Atrial Fibrillation in On- versus Off-pump Coronary Artery Bypass Grafting.

OBJECTIVES: A considerable number of patients undergoing coronary artery bypass grafting surgery suffer from atrial fibrillation and should be treated concomitantly. This manuscript evaluates the impact of on-pump versus off-pump bypass grafting on the applied lesion-set and rhythm outcome. METHODS: Between January 2017 and April 2020 patients who underwent combined bypass grafting and surgical ablation for atrial fibrillation were consecutively enrolled in the German CArdioSurgEry Atrial Fibrillation registry (CASE-AF, 17 centers). Data were prospectively collected. Follow-up was planned after one year. RESULTS: 224 Patients were enrolled. No differences in baseline characteristics were seen between on- and off-pump bypass grafting, especially not in type of atrial fibrillation and left atrial size. In the on-pump group (n = 171, 76%), pulmonary vein isolation and an extended left atrial lesion-set were performed more often compared to off-pump bypass grafting. (58% vs 26%, 33 vs 9%, respectively, p < 0.001). In off-pump bypass grafting a box isolating the atrial posterior wall was the dominant lesion (72% off-pump vs 42% on-pump, p < 0.001). Left-atrial appendage management was comparable in on-pump vs off-pump bypass grafting (94% vs 91%, p = 0.37). Sinus rhythm at follow-up was confirmed in 61% in the on-pump group and in 65% in the off-pump group (p = 0.66). No differences were seen in in-hospital or follow-up complication-rates between the two groups. CONCLUSIONS: In coronary artery bypass grafting patients undergoing concomitant atrial fibrillation ablation, our data suggests that the technique applied for myocardial revascularization (off-pump vs on-pump) leads to differences in the ablation lesion set, but not in safety and effectiveness.

CTRP13-Mediated Effects on Endothelial Cell Function and Their Potential Role in Obesity.

BACKGROUND: Obesity, a major component of cardiometabolic syndrome, contributes to the imbalance between pro- and anti-atherosclerotic factors via dysregulation of adipocytokine secretion. Among these adipocytokines, the C1q/TNF-related proteins (CTRPs) play a role in the modulation of atherosclerosis development and progression. Here, we investigated the vascular effects of CTRP13. RESULTS: CTRP13 is not only expressed in adipose tissue but also in vessels/endothelial cells (ECs) of mice, rats, and humans. Obese individuals (mice, rats, and humans) showed higher vascular CTRP13 expression. Human Umbilical Vein Endothelial Cells (HUVECs), cultured in the presence of serum from obese mice, mimicked this obesity-associated effect on CTRP13 protein expression. Similarly, high glucose conditions and TNF-alpha, but not insulin, resulted in a strong increase in CTRP13 in these cells. Recombinant CTRP13 induced a reduction in EC proliferation via AMPK. In addition, CTRP13 reduced cell cycle progression and increased p53 phosphorylation and p21 protein expression, but reduced Rb phosphorylation, with the effects largely depending on alpha-2 AMPK as suggested by adenoviral overexpression of dominant-negative (DN) or wild-type (WT) alpha 1/alpha 2 AMPK. CONCLUSION: The present study demonstrates that CTRP13 expression is induced in ECs under diabetic conditions and that CTRP13 possesses significant vaso-modulatory properties which may have an impact on vascular disease progression in patients.

Surgical Ablation of Atrial Fibrillation in High-Risk Patients: Success versus Risk.

BACKGROUND: Surgical atrial ablation is evaluated by surgeons in relation to the estimated surgical risk. We analyze whether high-risk patients (HRPs) experience risk escalation by ablation procedures. METHODS: The CASE-Atrial Fibrillation (AF) registry is a prospective, multicenter, all-comers registry of atrial ablation in cardiac surgery. We analyzed the 1-year outcome regarding survival and rhythm endpoints of 1,000 consecutive patients according to the operative risk classification (EuroSCORE II ≤ 2 vs. >2). RESULTS: Higher NYHA (New York Heart Association) score, ischemic heart failure, status poststroke, renal insufficiency, chronic obstructive pulmonary disease, and diabetes mellitus were strongly represented in HRPs. HRPs exhibit more left ventricular ejection fraction < 40% (19.2 vs. 8.8%; p < 0.001) but identical left atrial diameter and left ventricular end-diastolic diameter compared with low-risk patients (LRPs). CHA2DS-Vasc-score (2.4 ± 1 vs. 3.6 ± 1.5; p < 0.001), sternotomies, combination surgeries, coronary artery bypass graft, and mitral valve procedures were increased in HRPs. LRPs underwent stand-alone ablations as well. Ablation energy did not differ. Left atrial appendage closure was performed in up to 86.1% (mainly cut-and-sew procedures). Mortality corresponded to the original risk class without an escalation that may be related to ablation, stroke rate, or myocardial infarction. A total of 60.6% of HRPs versus 75.1% of LRPs were discharged in sinus rhythm. Long-term EHRA (European Heart Rhythm Association) score symptoms were lower in HRPs. Repeated rhythm therapies were rare. Additional antiarrhythmics received a minority without group dependency. A total of 1.6 versus 4.1% of HRPs (p = 0.042) underwent long-term stroke; excess mortality was not observed. Anticoagulation remained common in HRPs. CONCLUSION: Surgical risk and long-term mortality are determined by the underlying disease. In HRPs, freedom from AF and symptom relief can be achieved. Preoperative risk scores should not lead to withholding an ablation procedure.

Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.

AIMS: The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia. METHODS AND RESULTS: In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n = 31) and AF (n = 11), respectively. RT- PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same. CONCLUSIONS: This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF.

Surgical ablation of long-standing persistent atrial fibrillation: 1-year outcomes from the CArdioSurgEry Atrial Fibrillation (CASE-AF) registry.

OBJECTIVES: The CArdioSurgEry Atrial Fibrillation (CASE-AF) registry is a prospective, multicentre study for collecting and analysing real-world data of surgical atrial fibrillation (AF) treatment. This study aimed to evaluate outcomes of surgery for long-standing persistent AF at 1 year. METHODS: In total, 17 centres consecutively include all eligible patients with continuous AF lasting for ≥1 year. Exclusion criteria are missing informed consent or age <18 years. For patient-reported outcomes measures, the European Heart Rhythm Association score was used. No presence of AF (based on ECG findings including Holter ECG and/or implanted devices), no re-ablation, no further cardioversion and no rehospitalization due to AF after a 3-month blanking period defined no AF recurrence at 1 year. RESULTS: From January 2017 to January 2020, a total of 1115 patients were enrolled in CASE-AF. Of them, 202 patients (mean age 69.7 ± 7.8 years, 27.2% female) underwent surgical ablation of long-standing persistent AF (study cohort), mostly accompanied by left atrial appendage closure (n = 180 [89%], resection n = 75 [42%]) and predominantly performed as concomitant (n = 174 [86%]) and left atrial only procedure (n = 144 [71%]). Early mortality (30 days) was 2.0% and morbidity was low. At follow-up (median 14.4 months, interquartile range, 12.7-17.6 months, 100% complete), 106 patients (56%) had no AF recurrence and 93% of them were asymptomatic. AF recurrence was accompanied by AF-related rehospitalization (n = 12, P = 0.003), direct current shock cardioversion (n = 23, P < 0.001), AF ablation (n = 7, P = 0.003) and stroke (n = 3, P = 0.059). Multivariable analysis identified cryoablation, predominantly performed endocardially including additional left atrial (74%) and biatrial (42%) lesions, as a significant factor for freedom from AF recurrence (odds ratio 2.7, 95% confidence interval 1.07-6.79, P = 0.035). CONCLUSIONS: According to CASE-AF, surgical ablation of long-standing persistent AF is most effective when concomitantly performed using endocardial cryoablation. Ongoing follow-up allows further elucidation of efficacious treatment strategies.

Living Longer or Better-Patient's Choice in Cardiac Surgery Is Gender-Dependent-A Multicenter Study.

In view of the increasing age of cardiac surgery patients, questions arise about the expected postoperative quality of life and the hoped-for prolonged life expectancy. Little is known so far about how these, respectively, are weighted by the patients concerned. This study aims to obtain information on the patients' preferences. Between 2015 and 2017, data were analyzed from 1349 consecutive patients undergoing cardiac surgery at seven heart centers in Germany. Baseline data regarding the patient's situation as well as a questionnaire regarding quality of life versus lifespan were taken preoperatively. Patients were divided by age into four groups: below 60, 60-70, 70-80, and above 80 years. As a result, when asked to decide between quality of life and length of life, about 60% of the male patients opted for quality of life, independent of their age. On the other hand, female patients' preference for quality of life increased significantly with age, from 51% in the group below sixty to 76% in the group above eighty years. This finding suggests that female patients adapt their preferences with age, whereas male patients do not. This should impact further the treatment decisions of elderly patients in cardiac surgery within a shared decision-making process.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Remote ischemic preconditioning in patients undergoing cardiac surgery with six ischemic cycles.

BACKGROUND: We have previously shown that remote ischemic preconditioning (RIP), which utilizes in part the extracellular RNA (eRNA)/RNase1 pathway, can induce ischemic tolerance in humans. Because RIP has thus far been tested only with four cycles of extremity ischemia/reperfusion, we investigated the influence of six cycles of ischemia on the eRNA/RNase1 pathway in cardiac patients. METHODS: Six cycles of RIP were carried out in 14 patients undergoing cardiac surgery. Blood samples were taken at 13 timepoints during surgery and at three timepoints after surgery for determining serum levels of RNase1, eRNA, and TNF-α. Trans-cardiac gradients between the myocardial blood inflow and outflow were calculated. RESULTS: Between the fourth and the sixth RIP cycles, a noticeable increase in the levels of eRNA (fourth: 151.6 (SD: 44.2) ng/ml vs sixth: 181.8 (SD: 87.5) ng/ml, p = .071), and a significant increase in RNase1 (fourth: 151.1 (SD: 42.6) U/ml vs sixth: 175.3 (SD: 41.2) U/ml, p = .001), were noted. The trans-cardiac gradients of RNase1 and eRNA before and after ischemia were not significantly different (p = .158 and p = .221; p = .397 and p = .683, respectively). Likewise, the trans-cardiac gradient of TNF-α was similar before and after ischemia. During the first 48 h after the surgery, RNase1 activity rose significantly and exceeded baseline values (135.7 (SD: 40.6) U/ml before and 279.2 (SD: 85.6) U/ml after surgery, p = .001) as did eRNA levels (148,6 (SD: 35.4) ng/ml before and 396.5 (SD: 154.5) ng/ml after surgery, p = .005), whereas TNF-α levels decreased significantly (91.7 (SD: 47.7) pg/ml before and 35.7 (SD: 36.9) pg/ml after surgery, p = .001). CONCLUSION: Six RIP cycles increased the RNase1 levels significantly above those observed with four cycles. More clinical data are required to show whether this translates into a benefit for patients.

Surgical Ablation of Permanent Atrial Fibrillation: Age, LV Dilatation, Obesity.

OBJECTIVES: Although concomitant surgical ablation can help to reach freedom from atrial fibrillation (FREEAF) even in patients with permanent atrial fibrillation (AF), some cardiac surgeons hesitate to perform concomitant ablation to avoid perioperative risk escalation. Here, we investigated outcome and predicators of therapeutic success of concomitant surgical ablation in an all-comers study. METHODS: Ablation-naïve patients with formerly accepted permanent AF (FAP, n = 41) or paroxysmal AF (parAF, n = 24) underwent concomitant epicardial bipolar radio frequency ablation and implantable loop recorder (ILR) at two surgical departments. Follow-up examination for 24 months included electrocardiogram, ILR readout, 24h Holter monitoring, echocardiography, and blood sampling. RESULTS: Eighty-six percent of parAF and 70% of FAP patients reached FREEAF (month 24). Mortality was low (parAF/FAP: 5.3 ± 0.2%/4.1 ± 0.3%; p < 0.05; EuroScoreII; 6.1 ± 0.7%/6.4 ± 0.4%, p = ns) and no strokes occurred. FREEAF induced atrial reverse remodeling (left atrial [LA] diameter: -6.7 ± 2.2 mm) and improved cardiac function (left ventricular ejection fraction [LVEF]: +7.3 ± 2.8%), while AF resulted in further atrial dilation (+8.0 ± 1.0 mm, p < 0.05) and LVEF reduction (-7.0 ± 1.3%, p < 0.05). Higher LV (odds ratio [OR]: 1.164) and LA diameter (OR: 1.218), age (OR: 1.180) and body mass index (BMI) (OR: 1.503) increased the risk factors of AF recurrence. Patients remaining in sinus rhythm (SR) demonstrated a decrease in BMI, while AF recurrence was associated with stable overweight. Further aging did not reduce FREEAF. CONCLUSIONS: Long-term SR is achievable by concomitant surgical ablation even in FAP patients. Therefore, it should be offered routinely. Obesity influences therapeutic long-term success but may also offer addressable therapeutic targets to reach higher FREEAF rates.

Rationale and Initiative of the Impella in Cardiac Surgery (ImCarS) Register Platform.

OBJECTIVES: Cardiac support systems are being used increasingly more due to the growing prevalence of heart failure and cardiogenic shock. Reducing cardiac afterload, intracardiac pressure, and flow support are important factors. Extracorporeal membrane oxygenation (ECMO) and intracardiac microaxial pump systems (Impella) as non-permanent MCS (mechanical circulatory support) are being used increasingly. METHODS: We reviewed the recent literature and developed an international European registry for non-permanent MCS. RESULTS: Life-threatening conditions that are observed preoperatively often include reduced left ventricular function, systemic hypoperfusion, myocardial infarction, acute and chronic heart failure, myocarditis, and valve vitia. Postoperative complications that are commonly observed include severe systemic inflammatory response, ischemia-reperfusion injury, trauma-related disorders, which ultimately may lead to low cardiac output (CO) syndrome and organ dysfunctions, which necessitates a prolonged ICU stay. Choosing the appropriate device for support is critical. The management strategies and complications differ by system. The "heart-team" approach is inevitably needed.However despite previous efforts to elucidate these topics, it remains largely unclear which patients benefit from certain systems, when is the right time to initiate (MCS), which support system is appropriate, what is the optimal level and type of support, which therapeutic additive and supportive strategies should be considered and ultimately, what are the future prospects and therapeutic developments. CONCLUSION: The European cardiac surgical register ImCarS has been established as an IIT with the overall aim to evaluate data received from the daily clinical practice in cardiac surgery. Interested colleagues are cordially invited to join the register. CLINICAL REGISTRATION NUMBER: DRKS00024560. POSITIVE ETHICS VOTE: AZ 246/20 Faculty of Medicine, Justus-Liebig-University-Gießen.

AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium.

BACKGROUND: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium. METHODS: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice. RESULTS: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes. CONCLUSIONS: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.

Oral application of levosimendan before ischaemia/reperfusion with or without cardioplegic arrest in rats.

OBJECTIVES: Clinical studies have indicated minor beneficial effects of the calcium sensitizer levosimendan on clinical outcomes in patients undergoing cardiac surgery. Here, the influence of levosimendan administered 24 h before cardiac arrest on myocardial function was examined in rat hearts perfused in a Langendorff model. METHODS: Levosimendan (Levo group) or NaCl (control group) was administered to 53 rats via drinking water 24 h prior to mounting excised hearts on a Langendorff apparatus. Cardiac arrest with or without cardioplegia was induced in both groups; another set of hearts was perfused continuously. During 90-min reperfusion at 36°C, functional parameters were measured and normalized to baseline values. Troponin I was quantified in coronary sinus effluent, and the functionality of isolated cardiomyocytes was studied. RESULTS: Oral application of levosimendan showed therapeutic efficacy. Baseline values were similar in the Levo and NaCl groups except for coronary flow. After ischaemia and reperfusion, Levo hearts did not recover better than NaCl hearts {left ventricular derived pressure: 63 [standard deviation (SD): 36.2] vs 46 (SD: 41.8)% baseline; P = 0.386}, In hearts exposed to cardioplegia, functional recovery only slightly differed in the Levo and NaCl groups [left ventricular derived pressure: 69.96 (SD: 12.7) vs 51.89 (SD: 28.1)% baseline; P = 0.09]. Cell shortening of cardiomyocytes isolated from hearts exposed to ischaemia or perfusion was better in Levo groups [cell shortening: 7.65 (SD: 1.95) %; 7.8 (SD: 1.79)% vs 6.28 (SD: 1.67)%; 6.5 (SD: 1.87)%, P < 0.001]; this benefit was absent in cardioplegia-treated hearts. CONCLUSIONS: Levosimendan applied orally before ischaemia/reperfusion improves functional recovery, but this effect is only moderate when cardioplegia is included. Differences between hearts exposed to cardioplegia or to global ischaemia may indicate why levosimendan-related beneficial effects do not directly translate into better clinical outcome.

[Coronary revascularization: Interventional therapy or coronary bypass surgery]. / Koronarrevaskularisation: Interventionelle Therapie versus Bypassoperation.

Coronary artery disease remains the leading cause of death and is responsible for myocardial infarction, heart failure and angina. Therapy combines optimal control of cardiovascular risk factors with coronary revascularization performed by interventional therapy or bypass surgery. While interventional therapy is preferred for single or two vessel disease, interdisciplinary heart team decision should be reached for complex lesion, three vessel or left main disease. Both revascularization strategies perform similar for low level complexity three vessel or left main disease while coronary bypass surgery proved superior for more complex coronary artery disease. Heart team decision should be based on vascular anatomy and expected revascularization success under consideration of operative risk and patient preference.

Comparative Analysis of CTRP-Mediated Effects on Cardiomyocyte Glucose Metabolism: Cross Talk between AMPK and Akt Signaling Pathway.

C1q/tumor necrosis factor -alpha-related proteins (CTRPs) have been shown to mediate protective cardiovascular effects, but no data exists on their effects on glucose and fatty acid (FA) metabolism in cardiomyocytes. In the present study, adult rat cardiomyocytes and H9C2 cardiomyoblasts were stimulated with various recombinant CTRPs. Glucose or FA uptake, expression of genes involved in glucose or FA metabolism and the role of the AMP-activated protein kinase (AMPK) and Akt were investigated. Although most CTRPs induced an increase in phosphorylation of AMPK and Akt in cardiomyocytes, mainly CTRP2, 7, 9 and 13 induced GLUT1 and GLUT4 translocation and glucose uptake in cardiomyocytes, despite high structural similarities among CTRPs. AMPK inhibition reduced the CTRPs-mediated activation of Akt, while Akt inhibition did not impair AMPK activation. In addition, CTRP2, 7, 9 and 13 mediated strong effects on the expression of enzymes involved in glucose or FA metabolism. Loss of adiponectin receptor 1, which has been suggested to be involved in CTRP-induced signal transduction, abolished the effects of some but not all CTRPs on glucose metabolism. Targeting the AMPK signaling pathway via CTRPs may offer a therapeutic principle to restore glucose homeostasis by acting on glucose uptake independent of the Akt pathway.

Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes.

The adipocytokine adiponectin and its structural homologs, the C1q/TNF-related proteins (CTRPs), increase insulin sensitivity, fatty acid oxidation and mitochondrial biogenesis. Adiponectin- and CTRP-induced signal transduction has been described to involve the adiponectin receptors and a number of co-receptors including the Low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is another target of the proprotein convertase subtilisin/kexin-9 (PCSK9) in addition to the LDL-receptor (LDL-R). Here, we investigated the influence of PCSK9 on the metabolic effects of CTRP9, the CTRP with the highest homology to adiponectin. Knockdown of LRP1 in H9C2 cardiomyoblasts blunts the effects of CTRP9 on signal transduction and mitochondrial biogenesis, suggesting its involvement in CTRP9-induced cellular effects. Treatment of adult rat cardiomyocytes with recombinant PCSK9 but not knockdown of endogenous PCSK9 by siRNA results in a strong reduction in LRP1 protein expression and subsequently reduces the mitochondrial biogenic effect of CTRP9. PCSK9 treatment (24 h) blunts the effects of CTRP9-induced signaling cascade activation (AMP-dependent protein kinase, protein kinase B). In addition, the stimulating effects of CTRP9 on cardiomyocyte mitochondrial biogenesis and glucose metabolism (GLUT-4 translocation, glucose uptake) are largely blunted. Basal fatty acid (FA) uptake is strongly reduced by exogenous PCSK9, although protein expression of the PCSK9 target CD36, the key regulator of FA transport in cardiomyocytes, is not altered. In addition, only minor effects of PCSK9 were observed on CTRP9-induced FA uptake or the expression of genes involved in FA metabolism or uptake. Finally, this CTRP9-induced increase in CD36 expression occurs independent from LRP1 and LDL-R. In conclusion, PCSK9 treatment influences LRP1-mediated signaling pathways in cardiomyocytes. Thus, therapeutic PCSK9 inhibition may provide an additional benefit through stimulation of glucose metabolism and mitochondrial biogenesis in addition to the known lipid-lowering effects. This could be an important beneficial side effect in situations with impaired mitochondrial function and reduced metabolic flexibility thereby influencing cardiac function.

Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts.

OBJECTIVES: Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS: Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS: In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 µmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS: In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.