A. Böning

Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III

BACKGROUND Occlusion of the left atrial appendage (LAA) is a promising approach to stroke prevention in atrial fibrillation (AF). However, evidence of its efficacy and safety to date is lacking. We herein describe the rationale and design of a definitive LAA occlusion trial in cardiac surgical patients with AF. METHODS We plan to randomize 4,700 patients with AF in whom on-pump cardiac surgical procedure is planned to undergo LAA occlusion or no LAA occlusion. The primary outcome is the first occurrence of stroke or systemic arterial embolism over a mean follow-up of four years. Other outcomes include total mortality, operative safety outcomes (chest tube output in the first post-operative 24 hours, rate of post-operative re-exploration for bleeding in the first 48 hours post-surgery and 30-day mortality), re-hospitalization for heart failure, major bleed, and myocardial infarction. RESULTS Left Atrial Appendage Occlusion Study (LAAOS) III is funded in a vanguard phase by the Canadian Institutes for Health Research (CIHR), the Canadian Network and Centre for Trials Internationally, and the McMaster University Surgical Associates. As of September 9, 2013, 162 patients have been recruited into the study. CONCLUSIONS LAAOS III will be the largest trial to explore the efficacy of LAA occlusion for stroke prevention. Its results will lead to a better understanding of stroke in AF and the safety and efficacy of surgical LAA occlusion.

Acute Kidney Injury After On-Pump or Off-Pump Coronary Artery Bypass Grafting in Elderly Patients

BACKGROUND An exploratory analysis of the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial was performed to investigate the effect of off-pump coronary artery bypass grafting (CABG) on kidney function after the operation. METHODS Data on kidney function were available from 1,612 patients, representing 67% of the study population. Preoperative kidney function was graded according to the glomerular filtration rate. Acute kidney injury (AKI) within the first week after the operation was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. The incidence and severity of AKI was compared between patients operated on on-pump or off-pump. RESULTS Impaired kidney function was seen in 642 patients (40%), and 19 patients had preexisting end-stage kidney disease. AKI of any severity occurred in half of all patients undergoing CABG, with AKIN stage 1 accounting for most of the cases. The incidence and severity of AKI in patients undergoing on-pump vs off-pump CABG was AKIN stage 1: 298 (37%) vs 329 (42%); AKIN stage 2: 38 (5%) vs 43 (5%); and AKIN stage 3: 44 (6%) vs 44 (6%), which did not differ significantly (p=0.174). New renal replacement therapy was necessary in 3.2% (on-pump) and in 2.7% (off-pump) of all patients. Stratification according to preoperative kidney function yielded comparable frequencies of AKI for on-pump and off-pump CABG. CONCLUSIONS AKI was common in elderly patients undergoing CABG, but deterioration of kidney function requiring renal replacement therapy was a rare event. Off-pump CABG was not associated with decreased rates or reduced severity of AKI in elderly patients.

RNase1 as a potential mediator of remote ischaemic preconditioning for cardioprotection

OBJECTIVES Remote ischaemic preconditioning (RIPC) is a non-invasive and virtually cost-free strategy for protecting the heart against acute ischaemia-reperfusion injury (IRI). We have recently shown that the inhibition of extracellular RNA (eRNA) using non-toxic RNase1 protected the heart against acute IRI, reduced myocardial infarct (MI) size and preserved left ventricular systolic function in rodent animal MI models. Based on this previous work in animals, the role of the eRNA/RNase1 system in cardiac RIPC in humans should be defined. METHODS Fourteen patients underwent cardiac surgery without RIPC; from each patient, six separate 5 ml blood specimens from radial artery and two blood specimens from coronary sinus at different time points during heart surgery were taken. Six healthy donors received RIPC (4 × 5 min upper limb ischaemia); blood parameters were quantified before and after RIPC. Twelve patients underwent cardiac surgery of which 6 received RIPC, whereas the remaining 6 were exposed to sham procedure. Circulating eRNA was quantified in plasma from arterial and coronary sinus blood obtained from patients undergoing cardiac by standard procedures. Tumour necrosis factor-α (TNF-α) production by heart tissue was assessed by enzyme-linked immuno-sorbent assay; RNase activity was quantified by an enzymatic assay. RESULTS Before surgery, eRNA levels were similar in both groups (14 ± 6 vs 13 ± 5 ng/ml; P = 0.9967). In patients without RIPC, arterial eRNA levels rose during surgery (87 ± 12 ng/ml) and peaked after (127 ± 11 ng/ml) aortic declamping; accordingly, eRNA levels in coronary sinus blood were significantly higher (206 ± 32 ng/ml; P = 0.0129) than that in radial artery. Moreover, significant elevation of TNF-α (36 ± 6 ng/ml; P = 0.0059) particularly in coronary sinus blood after opening of the aortic clamping was observed. Interestingly, applying a RIPC protocol significantly increased levels of plasma endogenous vascular RNase1 by >7-fold, and the levels of arterial (31 ± 7 ng/ml; P = 0.0024) and coronary sinus (37 ± 9 ng/ml; P < 0.0001) circulating eRNA, as well as circulating TNF-α (20 ± 4 ng/ml; P = 0.0050) levels were significantly reduced. CONCLUSIONS Upon RIPC, the level of cardioprotective RNase1 increased, while the concentration of damaging eRNA and TNF-α decreased. The present findings imply a significant contribution of the RIPC-dependent (endothelial) RNase1 for improving the outcome of cardiac surgery. However, the exact mechanism of RNase1-induced cardioprotection still remains to be explored.

Interleukin-6 Contributes to the Paracrine Effects of Cardiospheres Cultured from Human, Murine and Rat Hearts

Cardiosphere‐derived cells (CDCs) were cultured from human, murine, and rat hearts. Diluted supernatant (conditioned‐medium) of the cultures improved the contractile behavior of isolated rat cardiomyocytes (CMCs). This effect is mediated by the paracrine release of cytokines. The present study tested the hypothesis, that the cardiovascular state of the donor’s heart influences this effect on CMCs and tries to identify the responsible factors. CDCs were cultured from human tissue samples of cardiac surgery and from murine and rat hearts. The supernatants of cultured CDCs from hypertensive humans and rats showed a higher improvement of the contractile behavior of CMCs compared to CDCs of normotensive origin. Subsequently, the cytokine profile of the supernatants was analyzed. Among the cytokines elevated in supernatants originating from hypertensive humans or rats was Interleukin‑6. CDCs were also generated from Interleukin‑6−/−‐mice and their wildtype littermates. The supernatant of the cultured Interleukin‑6−/−‐CDCs had no effect on the contractile behavior, whereas the supernatant of the Interleukin‑6+/+‐CDCs showed a positive effect. To confirm the hypothesis that Interleukin‑6 contributes to the paracrine effects, CMCs were incubated with Interleukin‑6. It improved the contractile function in a concentration dependent way. Finally, the effect of the supernatant of cultured CDCs derived from a hypertensive human sample could be abolished by simultaneous incubation with a specific Interleukin‑6 antibody. CDCs release cytokines that improve the contractile behavior of CMCs. This effect is more intense in CDCs from hypertensive donors. Interleukin‑6 is involved in this phenomenon. J. Cell. Physiol. 229: 1681–1689, 2014.

Differences in ischemic damage between young and old hearts — Effects of blood cardioplegia

OBJECTIVE Senescent patients exhibit an elevated perioperative risk for cardiac dysfunction, hemodynamic depression and subsequent cardiac death compared to young patients. Despite the fact that a growing proportion of cardiac surgery patients are octogenarians, cardioplegic regimes remain comparable across patients of all ages. We compared the hemodynamic performance, metabolic parameters and ultrastructural changes in adult and senescent rat hearts after application of Buckbergs blood cardioplegia (BCP) to evaluate differences between the age groups regarding postischemic myocardial function and cellular ultrastructure. METHODS Hearts of adult (young adult group, 3-4 months) and senescent (old group, 24 months) male Wistar rats were excised and inserted into a blood perfused isolated heart apparatus (Langendorff perfusion). After a stabilization period of 30 min, in 16 adult and 16 senescent hearts, Buckberg BCP was administered antegradely and repeated every 20 min. Six young adult and 3 senescent hearts served as ischemia control. After an aortic clamping time of 90 min an antegrade hot shot was administered. During reperfusion ex vivo cardiac functional parameters were recorded, including coronary blood flow, left ventricular developed pressure (LVDP) and velocity of myocardial contraction or relaxation (+/-dp/dt). Oxygen consumption and lactate production of the hearts were calculated. After perfusion fixation, the hearts of five rats in each BCP group and 3 rats in each ischemia group were investigated for cellular edema and mitochondrial damage by morphometry using transmission electron microscopy. RESULTS While recovery of cardiac function after 90 min of unprotected ischemia was significantly impaired in senescent hearts, functional recovery after ischemia protected by BCP was similar in adult and senescent hearts. Mitochondrial ultrastructure was severely damaged in both age groups after 90 min ischemia, but well preserved in both BCP groups. The qualitative analysis was confirmed by the morphometric cellular edema index and the volume-to-surface ratio of the mitochondria. Myocardial oxygen consumption was highest and lactate production was lowest in senescent hearts. CONCLUSION Senescent rat hearts were more susceptible to unprotected ischemia/reperfusion injury than young adult hearts. When protected by BCP, we found no difference in hemodynamic performance between adult and senescent hearts indicating preserved myocardial protection even in senescent individuals.

Is Warm or Cold Calafiore Blood Cardioplegia Better? Hemodynamic, Metabolic, and Electron Microscopic Differences

BACKGROUND Controversy exists as to whether warm or cold Calafiore blood cardioplegia (BCP) is better for cardiac preservation. Therefore, we compared hemodynamic performance, myocardial metabolism, and ultrastructural preservation in rat hearts after application of cold or warm BCP. MATERIALS AND METHODS The hearts of 24 male Wistar rats were excised and inserted into a blood perfused isolated heart apparatus, and after a stabilization period of 30 minutes, either cold (4°C) or warm (36°C) Calafiore BCP was administered during an aortic clamping time of 90 minutes (12 rats each). Hearts clamped without BCP and hearts immediately excised in anesthesia served as worst case and no damage controls, respectively (n=3 each). During reperfusion, functional hemodynamic parameters were recorded in BCP groups, and myocardial oxygen consumption and lactate production were calculated. After perfusion fixation, the hearts of three rats in each group were investigated for cellular edema and mitochondrial damage by morphometry using transmission electron microscopy. RESULTS Cardiac function after BCP application during aortic clamping showed a slightly better recovery with warm than with cold Calafiore BCP as indicated by higher left ventricular developed pressure (warm 97% of baseline, cold 68% of baseline) after warm BCP. Other hemodynamic parameters and coronary flow were not different between warm and cold BCP. Myocardial oxygen consumption and lactate production were similar under warm and cold conditions. Electron microscopy showed typical signs of ischemia in the ischemia group without BCP. Mitochondrial ultrastructure was well preserved in both BCP groups, but cellular edema was more pronounced with cold than with warm BCP. The qualitative analysis was confirmed by the morphometric cellular edema index and the volume-to-surface ratio of the mitochondria. CONCLUSION Only mild differences were observed between warm and cold BCP in rats with respect to cardiac function, metabolism, and tissue preservation after aortic clamping. However, a small tendency toward better postischemic recovery was observed with warm BCP.

Prophylactic intra-aortic balloon counterpulsation in cardiac surgery: challenges in planning the "right" trial.

e246 www.ccmjournal.org March 2014 • Volume 42 • Number 3 Prophylactic Intra-Aortic Balloon Counterpulsation in Cardiac Surgery: Challenges in Planning the “Right” Trial To the Editor: In a recent issue of Critical Care Medicine, we read with great interest the article by Ranucci et al (1) evaluating the impact of prophylactic intra-aortic balloon counterpulsation (IABC) on the postoperative outcome of patients with reduced left-ventricular ejection fraction (LVEF) undergoing elective coronary artery bypass grafting surgery (CABG). The authors report in this single-center randomized controlled trial that prophylactic IABC has no positive effects on postoperative major morbidity as defined by the Society of Thoracic Surgeons. However, the present trial raises some concerns that we would like to address in this letter. As the authors state in their discussion, the inclusion criteria were mostly based on the poor LVEF. However, in all previous trials concerning prophylactic IABC, including the trials of Christenson et al (2–4) in the late 1990s, heterogeneous inclusion criteria with questionable implication on perioperative risk have been a major drawback. Inclusion criteria based on a modern and valid risk estimation instrument (e.g., European System for Cardiac Operative Risk Evaluation II) to really include high-risk patients would have been advantageous. The single-center trial was powered to detect a 50% relative risk reduction of the composite endpoint “major morbidity” (absolute risk reduction 40% to 20%). In our opinion, some of its components do not relate to IABC (e.g., sternal wound infection, need of reoperation, which is mostly due to bleeding). Prolonged mechanical ventilation and acute renal failure are perioperative surrogate variables. Their persistence after a certain time after operation (e.g., 30 d, 6 mo) would have been of interest. Operative mortality is the most relevant component of the primary endpoint. A primary endpoint that is more focused on patient-relevant criteria (30-d mortality, survival, and New York Heart Association stadium at 6 mo, 1 yr) would have been preferable. The authors have disclosed that they do not have any potential conflicts of interest.

Reduction of groin wound complications in vascular surgery patients using closed incision negative pressure therapy (ciNPT): a prospective, randomised, single‐institution study

Groin wound infections in patients undergoing vascular procedures often cause a lengthy process of wound healing. Several clinical studies and case reports show a reduction of surgical site infections (SSIs) in various wound types after using closed incision negative pressure therapy (ciNPT). The aim of this prospective, randomised, single‐institution study was to investigate the effectiveness of ciNPT (PREVENA™ Therapy) compared to conventional therapy on groin incisions after vascular surgery. From 1 February to 30 October 2015, 100 patients with 129 groin incisions were analysed. Patients were randomised and treated with either ciNPT (n = 58 groins) or the control dressing (n = 71 groins). ciNPT was applied intraoperatively and removed on days 5–7 postoperatively. The control group received a conventional adhesive plaster. Wound evaluation based on the Szilagyi classification took place postoperatively on days 5–7 and 30. Compared to the control group, the ciNPT group showed a significant reduction in wound complications (P < 0·0005) after both wound evaluation periods and in revision surgeries (P = 0·022) until 30 days postoperatively. Subgroup analysis revealed that ciNPT had a significant effect on almost all examined risk factors for wound healing. ciNPT significantly reduced the incidence of incision complications and revision procedures after vascular surgery.

Combined aortic valve replacement and coronary artery bypass grafting in octogenarians: results not as excellent as reported

group. As A. Boning suggested, our results might not be relevant to the full clinical picture for European countries. However, we added a comparison of the survival curves between our cohort and the age- and sex-matched normal Japanese population as a figure in the supplementary material. There were no differences in survival between them. The main goal of the study was not to compare our results with other studies, but to compare elderly patients with non-elderly patients in our country. We speculated that improvements in surgical techniques, critical care and rehabilitation, might result in equivalent outcomes in both elderly and non-elderly patients. However, we should further extend the investigation, because the major limitations of our study included a single institutional study based on the relatively small number of patients and postoperative events.

Citrulline Improves Early Post-Ischemic Recovery or Rat Hearts In Vitro by Shifting Arginine Metabolism From Polyamine to Nitric Oxide Formation:

Background: Reperfusion or reopening of occluded vessels is the gold standard to terminate ischemia. However, early functional recovery after reperfusion is often low requiring inotropic intervention. Although catecholamines increase inotropy and chronotropy, they are not the best choice because they increase myocardial oxygen and substrate demand. As nitric oxide (NO) contributes to cardiac function, we tested the hypothesis that addition of citrulline during the onset of reperfusion improves post-ischemic recovery because citrulline can reenter arginine consumption of NO synthases (NOS) but not of arginases. Methods: Hearts from adult rats were used in this study, exposed to 45-minute global ischemia and subsequently reperfused for 180 minutes. Citrulline (100 µM) or arginine (100 µM) was added with reperfusion and remained in the perfusion buffer for 180 minutes. Nω-nitro-l-arginine methyl ester (l-NAME) was used to antagonize NOS activity. Results: Citrulline increased load-free cell shortening of isolated adult rat cardiomyocytes and improved left ventricular developed pressure (LVDP) under normoxic conditions, indicating that citrulline can affect heart function. Ischemia/reperfusion caused a constitutive loss of function during 3 hours of reperfusion, whereas citrulline, but not arginine, improved the functional recovery during reperfusion. This effect was attenuated by co-administration of l-NAME. Although citrulline increased the formation of nitrite, l-NAME attenuated this effect indicating again a positive effect of citrulline on NO formation. Citrulline, but not arginine, increased the expression of arginase-1 (protein and mRNA) but l-NAME attenuated this effect again. Collectively, citrulline improved the post-ischemic recovery in an NO-dependent way. Conclusions: Citrulline, known to block arginase and to support NO formation, improves the early functional recovery of post-ischemic hearts and may be an alternative to catecholamines to improve early post-ischemic recovery.