Markus Malmberg

Cardiomyocyte apoptosis after cardioplegic ischemia: comparison to unprotected regional ischemia-reperfusion.

Background: Cardiomyocyte apoptosis might contribute to left ventricular (LV) dysfunction following cardiac surgery. Magnetic resonance imaging is considered the most accurate method of determining LV function. We compared apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, TUNEL, staining and detection of caspase 3 activation) and LV function after regional ischemia-reperfusion (I-R) and global cardioplegic ischemia. Methods: Pigs were randomized to undergo regional myocardial I-R for 20 + 20 min, global myocardial ischemia with cardiopulmonary bypass (CPB) for 40 min or CPB without ischemia (control), followed by 274 min of reperfusion. Results: Compared with the control group, the number of TUNEL-positive cardiomyocytes was higher in the global ischemia group with CPB (0.024 ± 0.014%; p = 0.02) and further increased in areas of unprotected regional I-R (0.444 ± 0.562%; p = 0.003, vs. control). Myocytes with active caspase 3 were detected after global and regional ischemia. The global ejection fraction did not differ between CPB and regional I-R groups. Conclusions: The use of cardioplegia and CPB efficiently protects the heart from global I-R-induced cardiomyocyte apoptosis during open heart surgery.

Cardiomyocyte Apoptosis After Antegrade and Retrograde Cardioplegia During Aortic Valve Surgery

BACKGROUND Retrograde delivery is associated with inadequate perfusion of cardioplegia to all regions of the heart, but the effects on cardiomyocyte death and functional outcome remain unknown. We compared antegrade and retrograde cardioplegia in a randomized clinical trial to see whether it has effect on cardiomyocyte apoptosis and left ventricular function. METHODS Patients underwent elective aortic valve replacement surgery due to aortic valve stenosis. They were randomly allocated to receive antegrade (n = 10) or retrograde (n = 10) cardioplegia. Apoptotic cardiomyocytes (terminal transferase-mediated dUTP nick end labeling, caspase activation) and RNA levels of apoptosis-regulating proteins were studied in transmyocardial biopsies obtained before and after the operation. Magnetic resonance imaging and transesophageal echocardiography were performed, and cardiac enzymes were measured. RESULTS Clinical outcome and cardiac enzyme release were comparable between the groups. Cardiomyocyte apoptosis was significantly increased (terminal transferase-mediated dUTP nick end labeling) in the left ventricle after the operation in the retrograde, but not in the antegrade group (respectively, 0.00% [0.039%] versus 0.092% [0.205%], p = 0.01; and 0.00% [0.00%] versus 0.023% [0.054%], p = 0.14). Expression of apoptosis-regulating proteins BAX, BAD, and BCL-2 were comparable between groups. By transesophageal echocardiography, the systolic mitral annulus movement was decreased immediately after the operation in the retrograde group. By magnetic resonance imaging, the left ventricle mass index was reduced preoperatively to 9 months postoperatively in the antegrade group. CONCLUSIONS In contrast to antegrade cardioplegia, retrograde cardioplegia is associated with increased cardiomyocyte apoptosis, impaired immediate postoperative systolic function, and lack of long-term favorable left ventricle remodeling after aortic valve replacement, suggesting inadequate myocardial protection.

Is emergency and salvage coronary artery bypass grafting justified? The Nordic Emergency/Salvage coronary artery bypass grafting study.

OBJECTIVES According to the EuroSCORE-II criteria, patients undergoing emergency coronary artery bypass grafting (CABG) are operated on before the beginning of the next working day after decision to operate while salvage CABG patients require cardiopulmonary resuscitation en route to the operating theatre. The objective of this multicentre study was to investigate the efficacy of emergency and salvage CABG. METHODS A retrospective analysis of all patients that underwent emergency or salvage CAGB at four North-European university hospitals from 2006 to 2014. RESULTS A total of 614 patients; 580 emergency and 34 salvage CABG patients (mean age 67 ± 10 years, 56% males) were included. All patients had an acute coronary syndrome: 234 (38%) had an ST segment elevation myocardial infarction (STEMI) and 289 (47%) had a non-STEMI. Haemodynamic instability requiring inotropic drugs and/or intra-aortic balloon pump preoperatively occurred in 87 (14%) and 82 (13%) of the patients, respectively. Three hundred and thirty-one patient (54%) were transferred to the operating room immediately after angiography and 205 (33%) had a failure of an attempted percutaneous coronary intervention. Cardiopulmonary resuscitation within 1 h before the operation was performed in 49 patients (8%), and 9 patients (1%) received cardiac massage during sternotomy. Hospital mortality for emergency and salvage operations was 13 and 41%, respectively. Early complications included reoperation for bleeding (15%), postoperative stroke (6%) and de novo dialysis for acute kidney injury (6%). Overall 5-year survival rate was 79% for emergency operations and 46% for salvage operations. Only one out of 9 patients receiving cardiac massage during sternotomy survived. CONCLUSIONS Early mortality in patients undergoing emergent and salvage CABG is substantial, especially in salvage patients. Long-term survival is acceptable in both emergent and salvage patients. Life-saving emergency and salvage CABG is justified in most patients but salvage patients have dismal prognosis if cardiac massage is needed during sternotomy.

Intracoronary Levosimendan during Ischemia Prevents Myocardial Apoptosis

Background: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia–reperfusion model. Methods: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 μg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. Results: Pigs after ischemia–reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). Conclusion: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I–R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.

Thirty-year results after implantation of the Björk-Shiley Convexo-Concave Heart valve prosthesis.

BACKGROUND Modifications of the Björk-Shiley valve prosthesis have shown good long-term results. The convexo-concave model, however, was recalled 27 years ago because of a propensity for breakage due to outlet strut fracture. The objective of this study is to describe the 30-year outcome after implantation of the Björk-Shiley convexo-concave mechanical heart valve prosthesis (Pfizer, Rye Brook, NY). METHODS The study included 279 patients who were operated between 1979 and 1983 at Turku University Hospital. A total of 305 valves were implanted; 205 in the aortic position and 100 in the mitral position. Patient records were reviewed for baseline characteristics and late events, data on mortality were acquired from registries. RESULTS Mean actuarial survival was 19.8 years and mean follow-up was 19.2 years (maximum 34 years). Freedom from reoperation was 91.3% at 30 years. There were 3 outlet strut fractures (2 fatal) during follow-up. Statistically significant predictors of mortality were age and concomitant coronary artery bypass grafting. CONCLUSIONS Despite the possibility of structural valve failure the Björk-Shiley convexo-concave valve confers excellent 30-year survival.

Performance of CHA2DS2-VASc score for stroke prediction after surgical aortic valve replacement

Objective: Stroke is a frequent complication occurring early and late after surgical aortic valve replacement. There is an unmet clinical need for simple tools to assess postoperative stroke risk. We sought to assess the predictive performance of Congestive heart failure; Hypertension; Age ≥75 (doubled); Diabetes mellitus; prior Stroke, transient ischemic attack or thromboembolism (doubled); Vascular disease; Age 65 to 74; Sex category (female) (CHA2DS2‐VASc) score in patients undergoing surgical aortic valve replacement with a bioprosthesis. Methods: Seven hundred fourteen patients undergoing isolated surgical aortic valve replacement with a bioprosthesis at 4 university hospitals were included. Data were collected retrospectively from patient records and monitored by an independent party. Results: Median follow‐up time was 4.8 years. Mean CHA2DS2‐VASc score was 4.1 ± 1.6. Low (scores, 0‐1), high (scores, 2‐4), and very high (scores, 5‐9) CHA2DS2‐VASc scores were observed in 39 (5.5%), 400 (56.0%), and 262 (38.5%) patients, respectively. Incidences of stroke or transient ischemic attack at 1 year were 2.6%, 4.8%, and 10.7%; at 5 years incidences were 5.2%, 14.0%, and 21.9%; and at 10 years incidence were 5.2%, 20.7%, and 37.9% for patients in low, high, and very high scores, respectively. Incidences of major bleeds at 1 year were 0%, 1.8%, and 2.7%; at 5 years incidences were 0%, 5.4%, and 8.7%; and at 10 years incidences were 0%, 9.0%, and 27.1%, respectively. Competing risk analysis showed that patients with CHA2DS2‐VASc score of 5 through 9 had a significantly increased risk of stroke or transient ischemic attack (hazard ratio, 4.75; 95% confidence interval, 1.09‐20.6; P = .037) irrespective of preoperative or new‐onset in‐hospital atrial fibrillation compared with low‐risk patients. Conclusions: CHA2DS2‐VASc is a valuable tool to identify patients with increased risk of stroke and major bleeding, and for whom alternative strategies for prevention of late neurologic complications should be adopted.

Occurrence and Classification of Cerebrovascular Events after Isolated Bioprosthetic Surgical Aortic Valve Replacement: A Competing Risk Analysis of the CAREAVR Study

ABSTRACT Background: The long-term incidence of stroke and the proportion of cardioembolic events after bioprosthetic surgical aortic valve replacement (SAVR) remain largely unknown. Methods: The CAREAVR study sought to assess the rate of stroke and transient ischemic attack (TIA) in patients who underwent isolated surgical aortic valve replacement with a bioprosthesis at four Finnish university hospitals between 2002 and 2014. Data was collected retrospectively and included 721 patients. Median follow-up time was 4.8 [3.0–7.0] years. Results: At 5 years, freedom from stroke was 89.0%, from TIA 94.1%, and from stroke and TIA 83.7%. The median time between index procedure and stroke or TIA was 1.7 years [29 days–3.9 years]. Stroke was of cardioembolic origin in 44.4% of patients. In multivariable competing risk analysis, increased age (HR 1.03, 95%CI 1.00–1.06, p = 0.022), previous stroke or TIA (HR 1.75, 95%CI 1.14–2.70, p = 0.010), New York Heart Association (NYHA) class III or more (HR 1.51, 95%CI 1.01–2.24, p = 0.044) and insulin treatment at discharge (HR 1.20, 95%CI 1.09–3.64, p = 0.024) were independent predictors of stroke or TIA. Cerebrovascular events occurred in 47.2% of patients with ongoing anticoagulation therapy. Conclusion: In this study, the incidence of stroke in the early postoperative period after bioprosthetic SAVR was higher than previously documented. Almost half of strokes were of cardioembolic etiology. These findings highlight the need for the better prevention strategies for cardioembolic events after bioprosthetic SAVR.

Thromboembolisms related to post-operative electrical cardioversions for atrial fibrillation in patients with surgical aortic valve replacement

Aims Post-operative atrial fibrillation (POAF) is a frequent complication after open-heart surgery, and cardioversions (CV) are commonly performed to restore sinus rhythm. However, little data exists on thrombo-embolic risk related to early post-operative CV and on the recurrence of POAF after CV. CAREAVR study sought to assess the rate of strokes, transient ischaemic attacks (TIA), and mortality shortly after POAF-triggered CV in patients who underwent isolated surgical aortic valve replacement (SAVR) with a bioprosthesis. Methods and results Altogether 721 patients underwent isolated SAVR with a bioprosthesis at four Finnish university hospitals. During post-operative hospitalization, after patients with prior chronic AF were excluded, 309/634 (48.7%) of patients had at least one episode of POAF [median time (interquartile range) 3 (3) days], and an electrical CV was performed in 113/309 (36.6%) of them. The length of hospital stay was not affected by CV. At 30 days follow-up, the rate of stroke, TIA or mortality was higher in those AF patients who underwent CV vs. those who did not (9.7% vs. 3.6%, P = 0.04, respectively; adjusted hazard ratio 2.63, 95% confidence interval 1.00-6.92, P = 0.05). Similar proportion of patients in both groups were in AF rhythm at discharge (32.7% vs. 35.7%, P = 0.18); and at 3 months (25.0% vs. 23.6%, P = 0.40), respectively. Conclusion In this real-world population of patients undergoing isolated SAVR, the rate of POAF was nearly 50%. One-third of these patients underwent an electrical CV, and they exhibited over two-fold risk for thromboembolisms and mortality. Cardioversion did not affect the short-term prevalence of AF.