Stephen K. Ball

Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response

Acute kidney injury (AKI) frequently afflicts patients undergoing cardiopulmonary bypass and independently predicts death. Both hemoglobinemia and myoglobinemia are independent predictors of postoperative AKI. Release of free hemeproteins into the circulation is known to cause oxidative injury to the kidneys. This study tested the hypothesis that postoperative AKI is associated with both enhanced intraoperative hemeprotein release and increased lipid peroxidation assessed by measuring F₂-isoprostanes and isofurans. In a case-control study nested within an ongoing randomized trial of perioperative statin treatment and AKI, we compared levels of F₂-isoprostanes and isofurans with plasma levels of free hemoglobin and myoglobin in 10 cardiac surgery AKI patients to those of 10 risk-matched controls. Peak plasma free hemoglobin concentrations were significantly higher in AKI subjects (289.0 ± 37.8 versus 104.4 ± 36.5mg/dl, P = 0.01), whereas plasma myoglobin concentrations were similar between groups. The change in plasma F₂-isoprostane and isofuran levels (repeated-measures ANOVA, P = 0.02 and P = 0.001, respectively) as well as the change in urine isofuran levels (P = 0.04) was significantly greater in AKI subjects. In addition, change in peak plasma isofuran levels correlated not only with peak free plasma hemoglobin concentrations (r² = 0.39, P = 0.001) but also with peak change in serum creatinine (r² = 0.20, P = 0.01). Postoperative AKI is associated with both enhanced intraoperative hemeprotein release and enhanced lipid peroxidation. The correlations among hemoglobinemia, lipid peroxidation, and AKI indicate a potential role for hemeprotein-induced oxidative damage in the pathogenesis of postoperative AKI.

Milrinone Use Is Associated With Postoperative Atrial Fibrillation After Cardiac Surgery

Background— Postoperative atrial fibrillation (AF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. Methods and Results— We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven patients (28.9%) developed AF a mean of 2.9±2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in nonusers; P<0.001). Older age (63.4±10.7 versus 56.7±12.3 years; P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (27.1±9.3 versus 21.8±7.5 mm Hg; P=0.001) also were associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio, 4.86; 95% confidence interval, 2.31 to 10.25; P<0.001) independently predicted postoperative AF. When only data from patients with pulmonary artery catheters were analyzed and pulmonary artery pressure was included in the model, age, milrinone use (odds ratio, 4.45; 95% confidence interval, 2.01 to 9.84; P<0.001), and higher pulmonary artery pressure (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. Conclusion— Milrinone use is an independent risk factor for postoperative AF after elective cardiac surgery.

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery.

Objective: This study tested the hypothesis that interruption of the renin–angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the prevalence of atrial fibrillation after cardiac surgery. Design: Randomized double-blind placebo-controlled study. Setting: University-affiliated hospitals. Patients: Four hundred forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. Interventions: One week to 4 days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5mg the first 3 days followed by 5mg/day, with the dose reduced to 2.5mg/day on the first postoperative day only), or spironolactone (25mg/day). Measurements: The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the prevalence of hypotension, length of hospital stay, stroke, and death. Main Results: The prevalence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (p = .95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, p = .006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days vs. 5.7±3.2 days and 5.8±3.4 days, respectively, p = .08 for the comparison of placebo vs. the active treatment groups using log-rank test). Compared with patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 mins vs. 1091.3±3067.3 mins, p = .04). Conclusions: Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.

Minimally invasive mitral valve surgery expands the surgical options for high-risks patients.

Background:A simplified minimally invasive mitral valve surgery (MIMVS) approach avoiding cross-clamping and cardioplegic myocardial arrest using a small (5 cm) right antero-lateral incision was developed. We hypothesized that, in high-risk patients and in patients with prior sternotomy, this approach would yield superior results compared to those predicted by the Society of Thoracic Surgeons (STS) algorithm for standard median sternotomy mitral valve surgery. Methods:Five hundred and four consecutive patients (249 males/255 females), median age 65 years (range 20–92 years) underwent MIMVS between 1/06 and 8/09. Median preoperative New York Heart Association function class was 3 (range 1–4). Eighty-two (16%) patients had an ejection fraction ⩽35%. Forty-seven (9%) had a STS predicted mortality ≥10%. Under cold fibrillatory arrest (median temperature 28°C) without aortic cross-clamp, mitral valve repair (224/504, 44%) or replacement (280/504, 56%) was performed. Results:Thirty-day mortality for the entire cohort was 2.2% (11/504). In patients with a STS predicted mortality ≥ 10% (range 10%–67%), the observed 30-day mortality was 4% (2/47), lower than the mean STS predicted mortality of 20%. Morbidity in this high-risk group was equally low: 1 of 47 (2%) patients underwent reexploration for bleeding, 1 of 47 (2%) patients suffered a permanent neurologic deficit, none had wound infection. The median length of stay was 8 days (range 1–68 days). Conclusions:This study demonstrates that MIMVS without aortic cross-clamp is reproducible with low mortality and morbidity rates. This approach expands the surgical options for high-risk patients and yields to superior results than the conventional median sternotomy approach.

Results of Completion Arteriography After Minimally Invasive Off-Pump Coronary Artery Bypass

BACKGROUND The benefits of a minimally invasive approach to off-pump coronary artery bypass remain controversial. The value of completion arteriography in validating this technique has not been investigated. METHODS From April 2007 to October 2009, fifty-six patients underwent isolated minimally invasive coronary artery bypass grafting through a left thoracotomy without cardiopulmonary bypass. Forty-three of these patients underwent completion arteriography. RESULTS Sixty-five grafts were performed in these 56 patients, (average, 1.2 grafts per patient; range, 1 to 3). Forty-eight grafts were studied in the 43 patients undergoing completion arteriography. There were 4 findings on arteriogram leading to further immediate intervention (8.3%). These included 3 grafts with anastomotic stenoses or spasm requiring stent placement, and 1 patient who had limited dissection in the left internal mammary artery graft and underwent placement of an additional vein graft. These findings were independent of electrocardiographic changes or hemodynamic instability. The remainder of the studies showed no significant abnormalities. There were no deaths. One patient who did not have a completion arteriogram suffered a postoperative myocardial infarction requiring stent placement for anastomotic stenosis. Patients were discharged home an average of 6.8 days postoperatively. There were no instances of renal dysfunction postoperatively attributable to catheterization. CONCLUSIONS Minimally invasive coronary artery bypass is safe and effective. Findings of completion arteriography occasionally reveal previously under-recognized findings that, if corrected in a timely fashion, could potentially impact graft patency and clinical outcomes. Our experience validates this minimally invasive technique.

Quantitative Imaging of Preamyloid Oligomers, a Novel Structural Abnormality, in Human Atrial Samples

Abnormalities in atrial myocardium increase the likelihood of arrhythmias, including atrial fibrillation (AF). The deposition of misfolded protein, or amyloidosis, plays an important role in the pathophysiology of many diseases, including human cardiomyopathies. We have shown that genes implicated in amyloidosis are activated in a cellular model of AF, with the development of preamyloid oligomers (PAOs). PAOs are intermediates in the formation of amyloid fibrils, and they are now recognized to be the cytotoxic species during amyloidosis. To investigate the presence of PAOs in human atrium, we developed a microscopic imaging-based protocol to enable robust and reproducible quantitative analysis of PAO burden in atrial samples harvested at the time of elective cardiac surgery. Using PAO- and myocardial-specific antibodies, we found that PAO distribution was typically heterogeneous within a myocardial sample. Rigorous imaging and analysis protocols were developed to quantify the relative area of myocardium containing PAOs, termed the Green/Red ratio (G/R), for a given sample. Using these methods, reproducible G/R values were obtained when different sections of a sample were independently processed, imaged, and analyzed by different investigators. This robust technique will enable studies to investigate the role of this novel structural abnormality in the pathophysiology of and arrhythmia generation in human atrial tissue.

Current status of hybrid coronary revascularization.

Hybrid coronary revascularization combines coronary artery bypass surgery with percutaneous coronary intervention techniques to treat coronary artery disease. The potential benefits of such a technique are to offer the patients the best available treatments for coronary artery disease while minimizing the risks of the surgery. Hybrid coronary revascularization has resulted in the establishment of new ‘hybrid operating suites’, which incorporate and integrate the capabilities of a cardiac surgery operating room with that of an interventional cardiology laboratory. Hybrid coronary revascularization has greatly augmented teamwork and cooperation between both fields and has demonstrated encouraging as well as good initial outcomes.

Contribution of Endogenous Bradykinin to Fibrinolysis, Inflammation, and Blood Product Transfusion Following Cardiac Surgery: A Randomized Clinical Trial

Bradykinin increases during cardiopulmonary bypass (CPB) and stimulates the release of nitric oxide, inflammatory cytokines, and tissue‐type plasminogen activator (t‐PA), acting through its B2 receptor. This study tested the hypothesis that endogenous bradykinin contributes to the fibrinolytic and inflammatory response to CPB and that bradykinin B2 receptor antagonism reduces fibrinolysis, inflammation, and subsequent transfusion requirements. Patients (N = 115) were prospectively randomized to placebo, ε‐aminocaproic acid (EACA), or HOE 140, a bradykinin B2 receptor antagonist. Bradykinin B2 receptor antagonism decreased intraoperative fibrinolytic capacity as much as EACA, but only EACA decreased D‐dimer formation and tended to decrease postoperative bleeding. Although EACA and HOE 140 decreased fibrinolysis and EACA attenuated blood loss, these treatments did not reduce the proportion of patients transfused. These data suggest that endogenous bradykinin contributes to t‐PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D‐dimer concentrations during EACA treatment.

Hypertension Is Associated With Preamyloid Oligomers in Human Atrium: A Missing Link in Atrial Pathophysiology?

Background Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ‐specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated. Methods and Results Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation‐specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium‐specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension. Conclusion PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.