Philippe Grieshaber

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.

Platelet-activating protamine-heparin-antibodies lead to higher protamine demand in patients undergoing cardiac surgery.

OBJECTIVES Platelet-activating antibodies against protamine-heparin-complexes were described in patients undergoing cardiac surgery, but their clinical consequences remain unclear. This prospective single-center observational study aimed to describe the prevalence and clinical consequences of protamine-heparin-complex antibodies in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS A total of 200 patients undergoing cardiac surgery with cardiopulmonary bypass were included. Blood samples were collected preoperatively and 1 hour, 24 hours, and 7 days after weaning from cardiopulmonary bypass. All sera were tested for the presence of protamine-heparin-complex antibodies using a modified heparin-induced platelet-activation assay. Specific Fcγ receptor IIa-dependent platelet activation was confirmed by repeated testing in the presence of the Fcγ receptor IIa-blocking antibody IV.3. RESULTS Samples from 185 patients were obtained, of whom 24 patients (13%) were positive for protamine-heparin-complex antibodies preoperatively. In all positive samples, functional reactivity was reversible in the presence of IV.3. Although patients with a preoperative presence of protamine-heparin-complex antibodies were significantly older compared with patients negative for protamine-heparin-complex antibodies (73 ± 9.8 years vs 68 ± 10 years, P = .037), no other potential risk factors were identified at 1 day before operation. Patients with protamine-heparin-complex antibodies required significantly more protamine to neutralize heparin (47.66 mg vs 41.67 mg, P = .027). Protamine-heparin-complex antibodies have no significant influence on perioperative platelet numbers, bleeding complications, transfusion requirement, thromboembolic events, major cardiovascular and cerebrovascular events, inflammation parameters, or kidney function. CONCLUSIONS Protamine-heparin-complex antibodies occur frequently in patients undergoing cardiac surgery on cardiopulmonary bypass, resulting in specific platelet activation in vitro. Protamine-heparin-complex antibodies are associated with increased protamine requirement after cardiopulmonary bypass and possibly slower recovery of platelet numbers.

Impact of prophylactic administration of Levosimendan on short-term and long-term outcome in high-risk patients with severely reduced left-ventricular ejection fraction undergoing cardiac surgery – a retrospective analysis

BackgroundPatients with severely reduced left-ventricular ejection fraction carry a high risk of morbidity and mortality after cardiac surgery. Levosimendan can be used prophylactically in these patients having shown positive effects on short-term outcome. However, effects on long-term outcome and patient subgroups benefiting the most are unknown. We aim to address these topics with real-life data from our clinical practice.MethodsTwo hundred eigthy eight patients with preoperative LVEF ≤ 35% underwent cardiac surgery with cardiopulmonary bypass between 2009 and 2013. Thereof, 246 were included in the matched analysis. Eigthy two patients received 12.5mg Levosimendan starting at induction of anesthesia. Outcomes of patients undergoing coronary artery bypass grafting surgery (n = 103), isolated valve surgery/ascending aortic surgery (n = 45) and those undergoing combination procedures (n = 98) were analyzed separately. Additionally, multivariate regression analysis was conducted in order to identify predictors of short-term outcome parameters for different subgroups of patients.ResultsThirty days mortality rates of 16% in the Levosimendan group and 21% in the control group (OR 0.7; 95%–CI 0.36–1.5; p = 0.37) were observed. Levosimendan showed a positive effect on postoperative renal function. A higher rate of new-onset atrial fibrillation (OR 4.0; 95%–CI 2.2–7-2; p < 0.0001) was observed in the Levosimendan group. Follow-up until three years postoperatively showed no differences in long-term survival between the groups.ConclusionProphylactic administration of Levosimendan did not affect overall short- and long-term outcomes. The value of prophylactic use of Levosimendan remains questionable and more data is needed to confirm subgroups that might benefit most.

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.

Prophylactic intra-aortic balloon counterpulsation in cardiac surgery: it is time for clear evidence

In the previous issue of Critical Care, Yu and colleagues report increased morbidity and mortality in patients after myocardial infarction undergoing prophylactic intra-aortic balloon pump support before coronary artery bypass graft surgery. The impact of prophylactic intra-aortic balloon pump implantation before coronary artery bypass graft therapy still is controversially debated. However, Yu and colleagues emphasize further discussion and substantiate the need for a prospective randomized controlled trial on this subject.

Myocardial Ischemia Caused by Subepicardial Hematoma

Background Bleeding from bypass anastomosis leakage occurs early after coronary artery bypass grafting. Later, once the anastomosis is covered by intima, spontaneous bleeding is unlikely. Case Description A 63-year-old male patient developed a pseudoaneurysm-like, subepicardial late-term bleeding resulting in a hematoma that compromised coronary artery flow by increasing extracoronary pressure. This resulted in severe angina pectoris (Canadian Cardiovascular Society IV) and myocardial ischemia within the affected area. After surgical removal of the hematoma and repair of the anastomosis, the patients symptoms disappeared and no signs of myocardial ischemia were present. Conclusion Surgical removal is an efficient therapy for subepicardial hematoma inducing myocardial ischemia.

Is delayed surgical revascularization in acute myocardial infarction useful or dangerous? New insights into an old problem

OBJECTIVES Haemodynamically stable patients admitted for coronary artery bypass grafting in acute myocardial infarction often undergo delayed surgery in order to avoid the risks of emergency surgery. However, initially stable patients undergoing delayed surgery may develop low cardiac output syndrome (LCOS) during the waiting period, which might be a major drawback of this strategy. We aim to define risk factors and clinical consequences of LCOS during the waiting period. METHODS A total of 530 consecutive patients with acute myocardial infarction (33% non-ST-segment elevation myocardial infarction and 67% ST-segment-elevation myocardial infarction) underwent isolated coronary artery bypass grafting between 2008 and 2013. Outcomes after either immediate (<48 h after onset of symptoms) or delayed (>48 h after onset of symptoms) therapy were compared. Predictors of preoperative development of LCOS were identified using multivariate regression analysis. RESULTS Of the 327 patients undergoing delayed therapy, 39 (12%) developed preoperative LCOS, resulting in increased mortality compared with patients who remained stable (21 vs 7.6%, P < 0.001). Immediate therapy resulted in similar mortality compared with delayed therapy (6.4 vs 7.6%; P = 0.68) and better 7-year survival (70 vs 55%; P < 0.001). Predictors of developing LCOS were reduced left ventricular function (odds ratio 4.4), renal impairment (odds ratio 3.0), acute pulmonary infection (odds ratio 3.4) and the extent of troponin elevation at admission (odds ratio 1.01 per increase by 1 µg/l). CONCLUSIONS In patients with acute myocardial infarction undergoing delayed coronary artery bypass grafting, preoperative LCOS is a relevant and dangerous condition that can be avoided by operating immediately or by carefully selecting patients to be delayed according to the risk parameters identified preoperatively.

Freestyle stentless bioprosthesis for aortic valve therapy: 17-year clinical results

Background Aortic valve replacement with stentless bioprostheses has been shown to produce lower aortic gradients than stented bioprostheses, thus facilitating left ventricular mass regression and preventing heart failure. We sought to determine the long-term results of stentless biological aortic valve replacement over a 17-year follow-up. Methods Between 1996 and 2012, 2551 patients underwent isolated aortic valve replacement with a stentless prosthesis (Medtronic Freestyle) at a single center. The mean patient age was 72 ± 10 years, 55% were male, 24.1% were in New York Heart Association class I and II, 9.6% had undergone previous surgery, 18.1% had coronary artery disease, and 23.1% had diabetes. For the long-term follow-up, patients were contacted in writing and by telephone; follow-up was 96.3% complete, resulting in 11,546 patient-years. Results At 30 days, mortality (5.4%), renal failure (3.9%), myocardial infarction (0.7%), and stroke (1.4%) rates were acceptable. During long-term follow-up of 1–17 years, the bleeding rate (2.9%) was higher than the thromboembolic event rate (0.7%) despite 18.1% of patients being on oral anticoagulants. New pacemaker implantation (4.5%; 0.87 events/100 patient-years), neurological disorders (5%; 0.52 events/100 patient-years), valve insufficiency (0.7%; 0.16 events/100 patient-years), paravalvular leakage (0.4%; 0.09 events/100 patient-years) and reoperation due to valvular complications (0.7%; 0.38 events/100 patient-years) were rare. Long-term survival was 41.8% ± 1.6 after 10 years, 21.3% ± 2.3 after 15 years, and 12.1% ± 3.9 after 17 years. Conclusion Long-term results after aortic valve replacement with stentless biological prostheses compare favorably with those obtained with stented bioprostheses.

Fibrin-Coated Collagen Fleece Seems to Prevent Sternal Instability after Cardiac Surgery: A Matched Pair Data Analysis

BACKGROUND  To examine if fibrin-coated collagen fleece (Tachosil) interferes with bone and wound healing when it is used on the cut surface of the sternum after median sternotomy. METHODS  A total of 25 patients with osteoporotic sternal disorders were treated with fibrin-coated collagen fleece at the cut surface of the sternum after median sternotomy (therapy group). We compared the occurrence of impaired wound healing and sternal instability, reoperation rate, and 30-day mortality with a control group of 25 case-matched patients. After matching for age, gender, and risk factors for sternal instability (diabetes mellitus, osteoporosis, body mass index, nicotine consumption), both groups were comparable. RESULTS  Sternal instability occurred in one (4%) patient in the study group and in five (20%) patients in the control group. Impaired wound healing occurred in one (4%) patient in the therapy group and two (8%) patients in the control group. Reoperation was necessary in four (16%) patients in the therapy group and 6 (24%) patients in the control group. The 30-day mortality occurred in six (24%) patients in the therapy group and four (16%) patients in the control group. CONCLUSIONS  The use of fibrin-coated collagen fleece on the cut surface of the sternum in patients with osteoporosis does not impair bone and wound healing. Furthermore, it seems to result in less sternal instability. A larger prospective study is necessary to verify the results of this explorative study.

Prophylactic intra-aortic balloon counterpulsation before surgical myocardial revascularization in patients with acute myocardial infarction

Introduction: Prophylactic intra-aortic balloon counterpulsation (pIABC) is recommended for high-risk patients undergoing coronary artery bypass grafting (CABG) surgery. Criteria for high-risk patients benefiting from pIABC are unclear. This study aimed to specifically describe the effect of pIABC on outcomes of patients with acute myocardial infarction (AMI) undergoing CABG. Methods: In 178 of 484 AMI patients (non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI] ≤5 days before surgery) without cardiogenic shock who underwent CABG between 2008 and 2013, pIABC was initiated preoperatively. After propensity score matching, the outcomes of 400 patients were analyzed (pIABC: 150; Control: 250). Results: After propensity score matching, baseline and operative characteristics were balanced between the groups except for a higher rate of patients with a left ventricular ejection fraction (LVEF)≤30% in the pIABC group (26% vs. Control: 13%; p=0.032). Seven point two percent (7.2%) of the control patients received an IABP intraoperatively or postoperatively. Postoperative extracorporeal life support (ECLS) was only needed in the control group (1.2% vs. 0%; p=0.01). Postoperative plasma curves of troponin I, creatine kinase (CK) and creatine kinase isoform MB (CK-MB) levels were reduced in the pIABC group compared with the control group. In-hospital mortality was reduced in the pIABC group (3.3% vs. control: 6.4%; p=0.18). After multivariate adjustment for other preoperative risk factors, pIABC was significantly protective concerning in-hospital mortality (HR 0.56; 95%-CI 0.023-0.74; p=0.021). Mortality (pIABC vs. control) was more affected in patients with preoperative LVEF≤30% (2/36 (5.6%) vs. 6/31 (19%); heart rate (HR) 0.25; 95%-CI 0.046-1.3; p=0.13) compared with LVEF>30% (3/114 (2.6%) vs. 10/219 (4.6%); HR 0.56; 95%-CI 0.15-2.1; p=0.55). Long-term survival did not differ between the groups. Conclusions: pIABC in CABG for AMI is associated with reduced perioperative cardiac injury and in-hospital mortality. Long-term survival is not affected.