Timo Rinne

Novel pharmacological preconditioning with diazoxide attenuates myocardial stunning in coronary artery bypass grafting

OBJECTIVE To investigate whether novel pharmacological preconditioning with diazoxide could protect the myocardial function and decrease myocardial injury in patients undergoing coronary artery bypass grafting (CABG). METHODS Forty patients with stable angina who were scheduled for isolated elective CABG operations were randomized into control group (n=20) and diazoxide (DZX) group (n=20). In the DZX group, 1.5 mg/kg diazoxide was infused intravenously within 5 min followed by a 5-min washout before commencing the cardiopulmonary bypass (CPB). In the control group, a time-matched period of placebo infusion was given. Hemodynamic data and biochemical markers of myocardial injury were measured perioperatively. RESULTS There were no adverse effects related to diazoxide. Cardiac index (CI) increased postoperatively as compared with baseline. In the DZX group, the improvement of CI was better than that in the control group (p=0.001). Left and right ventricular stroke work indexes decreased postoperatively, and recovered much faster in the DZX group (p=0.027 and p=0.049, respectively). There were no statistically significant differences in the other hemodynamic parameters. The creatine kinase cardiac isoenzyme (CK-MB) was highest in both groups on the first postoperative day (control 28.8+/-23.8 and DZX 27.3+/-19.4, N.S.). The cumulative release of CK-MB postoperatively was lower in the DZX patients as compared with the controls, but the difference remained not significant (p=0.09). CONCLUSIONS Pharmacological preconditioning of the human heart with diazoxide is feasible; it confers additional myocardial protection beyond that provided by the cardioplegia alone by attenuating myocardial stunning after CABG operations.

Isoflurane produces only minor preconditioning in coronary artery bypass grafting.

Objective—To investigate whether administration of isoflurane prior to cardiopulmonary bypass (CPB) could partly account for the observed protection of the myocardial function and to decrease myocardial injury in patients undergoing coronary artery bypass grafting (CABG). Methods—Thirty‐four patients with stable angina who were scheduled for isolated elective CABG operations were randomized into the control group or isoflurane (ISO) group. In the ISO group, isoflurane was inhaled for 5 min followed by another 5‐min washout period before commencing CPB. The control group did not receive isoflurane. Hemodynamic data and biochemical markers of myocardial injury were measured perioperatively. Results—There were no adverse effects related to isoflurane. Cardiac index (CI) increased postoperatively as compared with the baseline. In the ISO group, there was a tendency for a greater increase of CI than that in the control group (p = 0.054, ANOVA for repeated measurements). At 1 h after CPB, the change of CI was much higher in the ISO group than that in the controls (p = 0.001). Both the creatine kinase cardiac isoenzyme (CK‐MB) and troponin I (TnI) reached peak value at 6 h after CPB. Isoflurane patients released slightly less CK‐MB than the controls postoperatively, but the difference was not significant (p = 0.16, ANOVA for repeated measurements). The release of TnI was similar in both groups (p = 0.65, ANOVA for repeated measurements). Conclusions—Administration of isoflurane prior to commencing CPB may bring an improvement in early hemodynamic performance after CABG operations.

The anti-inflammatory effect of diazoxide in coronary artery bypass grafting.

Many therapeutic strategies have been designed to suppress the inflammatory response in patients undergoing coronary artery bypass grafting (CABG). Pharmacological preconditioning with diazoxide is an alternative in effective cardioprotective strategies, but more evidence is required to show its effect on the inflammatory response. Forty patients with stable angina who were scheduled for isolated elective CABG operations were randomized into control and diazoxide (DZX) groups. In the DZX group, 1.5 mg/kg diazoxide was infused intravenously in 5 min followed by a 5-min washout before commencing the cardiopulmonary bypass. In the control group, placebo infusion was given similarly. Blood samples for cytokine measurement were collected from the radial artery and coronary sinus perioperatively, and hemodynamic data were recorded. Thirty-six patients fulfilled the data collection. Cardiac index (CI) increased in both groups over time as compared with baseline. In the DZX group, the increase of CI was greater than that in the control group (P = 0.002). Systemic and coronary sinus plasma levels of IL-6, IL-8, and IL-10 increased significantly after reperfusion in both groups as compared with baseline (P < 0.05). IL-6 and IL-8 both reached the peak value at 6 h after cardiopulmonary bypass. IL-10 reached peak level at 20 min after reperfusion in both groups. There was significantly higher IL-10 in DZX groups (P = 0.015). The ratios of IL-6 to IL-10 and IL-8 to IL-10 were significantly lower in DZX groups than in controls (P = 0.025 and P = 0.041 for each, respectively). Pharmacological preconditioning with DZX in CABG patients shifts the circulating inflammatory cytokine balance toward the anti-inflammatory direction.

Comparison of cardioprotection with crystalloid and blood cardioplegia in CABG patients

One hundred patients scheduled for elective coronary artery bypass grafting (CABG) were randomly allocated to two groups for myocardial preservation:blood cardioplegia (BCP) or crystalloid cardioplegia (CCP). The study protocol comprised recording of the following parameters: mode of resumption of cardiac rhythm, CK-MB analysis, ECG recording, cardiac output measurement, cross-clamping and perfusion times, and clinical outcome. The study period covered the time from commencement of anesthesia to the first postoperative morning. Spontaneous resumption of sinus rhythm was recorded only in the BCP group (22/51 v 0/49, P < 0.001). CK-MB values were similar in both groups, but 1 hour postoperatively the BCP group had lower values (58.8 +/- 26.7 v 74.5 +/- 31.5 U/L, P = 0.0098 by t test). Fifteen patients in the BCP group did not receive any electric countershock; this subgroup had very low CK-MB values. There were four intraoperative myocardial infarctions in the BCP group and two in the CCP group (BCP: 3/51 v CCP: 3/49, P = 0.68). The results suggest better cardioprotection with blood cardioplegia in this subgroup of patients. Spontaneous resumption of normal cardiac rhythm seems to indicate good myocardial preservation, as reflected in markedly lower CK-MB values in this subgroup.

The anti-inflammatory effect of bradykinin preconditioning in coronary artery bypass grafting (bradykinin and preconditioning)

Objective. The present study was designed to investigate the cardioprotective effect of exogenous administration of bradykinin (BK) in cardiac surgery. Methods. Forty-one patients who were scheduled for isolated coronary artery bypass grafting (CABG) were randomized into Control group and BK group. BK patients received 25 µg bradykinin infusion for 7 minutes before the cardiopulmonary bypass (CPB). Release of cardiac specific troponin I (TnI) and creatine kinase cardiac isoenzyme (CK-MB) was recorded. Perioperative circulating cytokine interleukin (IL)-6, 8 and 10 were measured. Results. There was no significant difference in TnI between groups. However, BK patients released significantly less CK-MB than the controls (p =0.043). Systemic plasma levels of IL-6, IL-8 and IL-10 increased significantly after reperfusion in both groups as compared with baseline (p <0.05). The ratio of IL-8 to IL-10 was significantly lower in BK groups than in controls (p =0.03). Conclusions. We conclude that exogenous administration of BK prior to CPB in CABG patients attenuates ischemic myocardial injury. It also shifts the circulating inflammatory cytokine balance towards the anti-inflammatory direction.

Initial results of a clinical study: adenosine enhanced cardioprotection and its effect on cardiomyocytes apoptosis during coronary artery bypass grafting

OBJECTIVE Apoptosis has been considered as one of the mechanisms of cardiomyocyte loss during open heart surgery. Adenosine is cardioprotective against ischemia-reperfusion injury in experimental models. The aim of this study was to find out whether the administration of single dose adenosine added to blood cardioplegia is effective in decreasing the apoptosis process. METHODS In a double-blinded randomized control intervention study, 40 patients were enrolled for elective coronary artery bypass grafting. In the adenosine group (n=20) patients received 250 microg/kg adenosine in the aortic root after cross-clamping followed by cold blood cardioplegia. In the control group (n=20) patients had only antegrade cardioplegia. Left ventricular tissue samples (from apex) were taken before and after the bypass. The apoptotic cells were identified by dUTP nick-end labeling (TUNEL) using an apoptosis detection kit. The number of TUNEL-positive cardiomyocytes was expressed as percentage of the total number of cardiomyocytes in histological tissue sections. RESULTS The groups were closely identical in demographic data, cross-clamp time, cardiopulmonary bypass time and weaning time. The postoperative cardiac index and other hemodynamic parameters, including the patterns of CK-MB, did not show statistically significant differences. In the tissue samples there were an equal number of patients who developed apoptosis after the cross-clamp. Although the frequency of apoptosis in the control group was two times higher than in the adenosine group, this was statistically not significant. CONCLUSIONS Adenosine enhanced blood cardioplegia could not prevent myocardial apoptosis completely. However, it seems to be that adenosine might influence the frequency of apoptosis and this needs to be considered in future investigations.

Adipocytokine resistin correlates with oxidative stress and myocardial injury in patients undergoing cardiac surgery

OBJECTIVES Adipocytokines are hormones regulating energy metabolism and appetite and according to recent reports also inflammatory responses including ischaemia-reperfusion injury. Based on experimental data, we hypothesized that the levels of adipocytokines adiponectin, adipsin, leptin and/or resistin would correlate with myocardial injury, inflammation and oxidative stress during cardiac surgery. METHODS Thirty-two patients undergoing an elective on-pump coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB) were recruited into the study. Blood samples were collected after the induction of anaesthesia, and at the onset of CPB, 1 and 15 min after the removal of aortic cross-clamp and 4 and 24 h after the onset of CPB. Samples were analysed for levels of four adipocytokines (adiponectin, adipsin, leptin and resistin) and markers of oxidative stress [myeloperoxidase (MPO) and 8-isoprostane], inflammation [interleukin-6 (IL-6)] and myocardial injury [troponin T (TnT)]. RESULTS Adiponectin and adipsin concentrations declined, while leptin and resistin levels increased significantly by 24 h after the onset of the operation. Interestingly, basal levels of resistin (r = 0.41, P = 0.020) as well as the maximal increase occurring in resistin levels during the 24-h follow-up (r = 0.49, P = 0.005) correlated positively with TnT release. In addition, the reperfusion-induced elevation in resistin levels correlated positively with oxidative stress measured as increases in MPO concentrations. CONCLUSIONS As an original finding, we report here that resistin levels correlate with oxidative stress and myocardial injury in patients undergoing cardiac surgery. In addition, leptin levels were increased on the first postoperative day, but only minor declines were found in adiponectin and adipsin levels. Resistin has been implicated in unfavourable metabolic, cardiovascular and inflammatory responses: it may thus serve as a useful biomarker or a drug target in conditions complicated by ischaemia-reperfusion injury.

Adenosine With Cold Blood Cardioplegia During Coronary Revascularization

OBJECTIVE To investigate whether adenosine in association with blood cardioplegia results in more rapid cardiac arrest or improved myocardial protection. DESIGN A prospective, randomized, placebo-controlled double-blind clinical study. SETTING Operative and intensive care units in a university hospital, Finland. PARTICIPANTS Forty patients undergoing primary, elective coronary revascularization. INTERVENTION Adenosine as a bolus dose, 12 mg intravenously, was given immediately before the induction of blood cardioplegia. MEASUREMENTS AND MAIN RESULTS There were nonsignificantly higher serial serum values of CK (MB) (p = 0.33), troponin-T (p = 0.23), and troponin-I (p = 0.10) in the adenosine group. There were no differences between the groups in arrest time, blood pressure decrease, or lactate extraction. CONCLUSIONS The adenosine regimen used in this study did not cause more rapid arrest with blood cardioplegia. The effect on cardioprotection was insignificant.

Conduction Disturbances After Blood and Crystalloid Cardioplegia in Coronary Bypass Surgery

Postoperative conduction disturbances after coronary artery bypass grafting were analyzed in 100 patients who randomly received either blood or crystalloid cardioplegia. Conduction disturbances, mostly transient, developed after termination of cardiopulmonary bypass in 30 of the 100 patients--15 in either group. Ischaemia appeared to be a major determinant for conduction disturbances. Previous inferior myocardial infarction and stenosis of the right coronary artery both exposed the patient to risk of right bundle branch block.

Cardiopulmonary bypass decreases pulmonary vascular resistance index after coronary artery bypass surgery

Abstract Background. Decreased pulmonary vascular resistance index (PVRI) reflects favorable postoperative pulmonary circulation after coronary artery bypass grafting. This randomized study investigated whether cardiopulmonary bypass (CPB) impacts PVRI after coronary artery bypass grafting. Material and methods. A total of 47 patients undergoing coronary artery bypass grafting were randomized into four groups according to the ventilation and surgical technique: (1) No ventilation group, with intubation tube detached from the ventilator, (2) low tidal volume group, with continuous low tidal volume ventilation, (3) continuous 10 cm H2O positive airway pressure (CPAP) group, and (4) randomly selected patients undergoing surgery without CPB. Oxygenation index, pulmonary shunt, alveolar-arterial oxygen gradient and PVRI were determined. PVRI was calculated as the transpulmonary pressure gradient divided by cardiac index multiplied by 80. Results. During the first postoperative morning there were no statistical differences in oxygenation index, pulmonary shunt or alveolar-arterial oxygen gradient between the groups, while PVRI remained elevated in patients without CPB as compared with patients with CPB (263 ± 98 vs. 122 ± 84, dyne-s-cm−5, respectively, p < 0.001). PVRI decreased in all patients with CPB regardless of ventilation technique. In contrast, elevated postoperative PVRI values were predictive for patients without CPB (AUC 0.786; SE 0.043; p < 0.001; 95% CI. 0.701–0.870). Conclusions. Modified ventilation does not affect PVRI in elective patients with healthy lungs during CPB. Instead, CPB per se may have an important role on diminished PVRI. We suggest that CPB preserves pulmonary arterial endothelial integrity.