Biomedical subjects

Domenico Pagano

Publications and source records attributed to Domenico Pagano.

12 recordsLinked to original sources

PubMed2006

Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease.

OBJECTIVES: This research was designed to assess the effect of type 2 diabetes mellitus (T2DM) on myocardial glucose utilization in patients with heart failure secondary to coronary artery disease. BACKGROUND: Patients with T2DM and coronary artery disease have an increased morbidity and mortality compared with patients with coronary artery disease without diabetes that may relate to a reduction in the ability of the myocardium to utilize glucose. METHODS: Myocardial blood flow and glucose utilization were assessed during a hyperinsulinemic clamp by 18F-flurodeoxyglucose and positron emission tomography in 54 patients (19 with T2DM) with multivessel coronary artery disease and heart failure. In a subgroup of 18 patients, myocardial biopsies were obtained during coronary bypass surgery to assess glucose transporter (GLUT4) distribution and protein concentration, and compared with myocardium from transplant donor hearts. RESULTS: Myocardial blood flow was similar in patients without diabetes and those with T2DM. Myocardial glucose utilization was lower in patients with T2DM (0.34 +/- 0.16 vs. 0.47 +/- 0.24 micromol x min(-1) x g(-1), p = 0.0002) despite comparable plasma insulin concentrations and a higher blood glucose concentration. Extraction of glucose by the myocardium was reduced in patients with T2DM (7.1 +/- 3.1% vs. 13.5 +/- 5.2%, p < 0.01). Myocardial GLUT4 protein was similar in patients with and without T2DM (p = 0.75). CONCLUSIONS: Patients with coronary artery disease and heart failure exhibit myocardial insulin resistance, and this is greater in those with T2DM. This may limit the ability of the myocardium in patients with T2DM to withstand ischemia and may contribute to the increased cardiovascular morbidity and mortality in such patients.

Aged↗

PubMed2006

How does glucose insulin potassium improve hemodynamic performance? Evidence for altered expression of beta-adrenoreceptor and calcium handling genes.

BACKGROUND: Glucose insulin potassium (GIK) improves hemodynamic performance after coronary artery surgery (CABG). We investigated whether this is associated with changes in gene expression of beta1-adrenergic receptor (ADRB1) or other calcium handling proteins. METHODS AND RESULTS: During a randomized double-blind placebo-controlled trial, 48 patients undergoing on-pump CABG, allocated to receive pre-ischemic placebo (5% dextrose) or GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1); 0.75 mL.kg(-1).h(-1)) continued for 6 hours after the removal of the aortic cross-clamp (AXC), underwent left ventricular biopsy for analysis of specific mRNAs immediately before AXC, before release of AXC, and 10 minutes after reperfusion (placebo n=24, GIK n=24). GIK or placebo was infused for a mean of 79+/-21 minutes or 79+/-18 minutes pre-ischemia respectively. Serial hemodynamic measurements were performed. Biopsy samples were snap-frozen and stored at -80 degrees C, mRNA was extracted and TaqMan real-time polymerase chain reaction was performed to investigate expression of ADRB1, sarcoplasmic reticulum Ca-ATPase (SERCA2a), and phospholamban (PLB). GIK significantly increased cardiac index versus placebo (P=0.037). TaqMan reverse-transcriptase polymerase chain reaction showed significantly greater ADRB1 mRNA expression at all time points (4.9-fold, 7.4-fold, and 15.6-fold increase, respectively; P<0.001), significantly greater SERCA2a mRNA expression after reperfusion (13.2-fold; P<0.001), and increased PLB mRNA expression at pre-ischemia and reperfusion (P<0.001 for both time-points) in GIK groups versus placebo. CONCLUSIONS: The beneficial hemodynamic effects of GIK therapy are associated with increased ADRB1 and SERCA2a mRNA expression. Further work is therefore warranted to investigate these mRNA effects at the protein level.

Aged↗

PubMed2006

Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.

BACKGROUND: Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may improve cardiovascular performance after coronary artery surgery (CABG) but their effects have not been directly compared and the effects of combined treatment are unknown. METHODS AND RESULTS: In 2 consecutive randomized double-blind placebo-controlled trials, in patients undergoing first time isolated on-pump CABG between January 2000 and September 2004, 440 patients were recruited and randomized to either placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1)) (0.75 mL.kg(-1) h(-1)) (n=157), T3 (0.8 microg.kg(-1) followed by 0.113 microg.kg(-1) h(-1)) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was administered from start of operation until 6 hours after removal of aortic cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac index (CI) was significantly increased in both the GIK and GIK/T3 group in the first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009 and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and 12 hours after AXC removal (P=0.01) but combination therapy did not. Release of cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC. CONCLUSIONS: Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Combination therapy does not provide added hemodynamic effect.

Aged↗

PubMed2006

Patient-prosthesis mismatch does not affect survival following aortic valve replacement.

OBJECTIVE: Patient-prosthesis mismatch (PPM) has been reported to increase perioperative mortality and reduce postoperative survival in patients undergoing aortic valve replacement (AVR). We analysed the effect of PPM at values predicting severe mismatch on survival following AVR in our unit. METHODS: Prospectively collected data on 1481 consecutive patients who had undergone AVR with or without coronary artery revascularisation between 1997 and 2005 were analysed. Projected in vitro valve effective orifice area (EOA) and geometric prosthesis internal orifice area (GOA) were evaluated and values were indexed to body surface area (cm(2)m(-2)). PPM was defined as EOAi<0.6 and/or GOAi<1.1. Long-term survival data were obtained from the National Institute of Statistics. RESULTS: One thousand four hundred and eighteen patients were identified. 67/1418 (4.7%) patients had GOAi<1.1; 122/1418 (8.6%) had EOAi<0.6 and 38 (2.6%) patients exhibited both forms of mismatch. One thousand two hundred and sixty-seven patients (89%) demonstrated no mismatch (reference group). There were 75 in-hospital deaths (overall mortality 5.3%) with no significant difference between the mismatch and the reference groups. Survival data were available for up to 8 years (median 36 months, IQR 6-60 months). There were 160 late deaths (13/143 PPM group vs 147/1198 reference group). The 5-year survival estimate was similar for both groups (83% PPM group; 81% reference group; p=0.47). Cox-hazard analysis identified advanced age as the only predictor of reduced survival (age>80, RR 2.13, 95% CI 1.38-4.586, p=0.004). CONCLUSIONS: Severe patient-prosthesis mismatch was predicted in 4-10% of patients undergoing AVR but this did not affect in-hospital mortality or mid-term survival.

Adult↗

PubMed2006

MADCAP: a graphical method for assessing risk scoring systems.

OBJECTIVE: We set out to develop a method for assessing the performance of clinical risk models over the spectrum of risks and to assess the performance of the EuroSCORE risk model used in cardiac surgery. METHODS: We developed a graphical method for assessing the performance of clinical risk models over the spectrum of risks. To illustrate the technique, we analysed retrospective data concerning 9268 patients that underwent cardiac surgery and for whom both the additive EuroSCORE prediction of risk of morality and vital status at 30 days were available. RESULTS: The graphical tool developed, called MADCAP (Mean Adjusted Deaths Compared Against Predictions), can be used to highlight systematic features of the performance of a clinical risk model. Its use in the current study indicates that the additive version of the EuroSCORE model seems to underestimate risk amongst low-risk cases (0% and 1%). Otherwise the score systematically favours risk avoiding behaviour as the risk model underestimates mortality for 2--6% prediction but not at 7% and above. CONCLUSION: The robustness of case-mix adjusted audit is dependent on the performance of the risk scoring system over the entire spectrum of risk. If we are to use risk adjustment of mortality rates when comparing outcomes obtained by different units or individual surgeons, it is essential that we continually review the performance of the risk adjustment method. The MADCAP method presented here provides a useful tool to this end.

Cardiac Surgical Procedures↗

PubMed2006

Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease.

INTRODUCTION: Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood. METHODS: For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation. RESULTS: The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 +/- 1.57 microg/mL vs CABG: 9.11 +/- 15.7 microg/mL; p < 0.001) and resistin (control: 10.53 +/- 0.81 ng/mL vs CABG: 16.8 +/- 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 +/- 14.8 microg/mL vs CABG: 11.9 +/- 6.0 microg/mL; p < 0.05) when compared to BMI matched controls. CONCLUSION: Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.

Adiponectin↗

PubMed2006

Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: a randomized controlled trial.

OBJECTIVE: We sought to assess the role of glucose-insulin-potassium in providing myocardial protection in nondiabetic patients undergoing coronary artery surgery with cardiopulmonary bypass. METHODS: A prospective, randomized, double-blind, placebo-controlled trial was conducted at a single-center university hospital performing adult cardiac surgery. Two hundred eighty nondiabetic adult patients undergoing first-time elective or urgent isolated multivessel coronary artery bypass grafting were prospectively randomized to receive glucose-insulin-potassium infusion or placebo (dextrose 5%) before, during, and for 6 hours after surgical intervention. Anesthetic, cardiopulmonary bypass, myocardial protection, and surgical techniques were standardized. The primary end point was postreperfusion cardiac index. Secondary end points were systemic vascular resistance index, the incidence of low cardiac output episodes, inotrope and vasoconstrictor use, and biochemical-electrocardiographic evidence of myocardial injury. The incidence of dysrhythmias and infections requiring treatment was recorded prospectively. RESULTS: The glucose-insulin-potassium group experienced higher cardiac indices (P < .001) throughout infusion and reduced vascular resistance (P < .001). The incidence of low cardiac output episodes was 15.9% (22/138) in the glucose-insulin-potassium group and 27.5% (39/142) in the placebo group (P = .021). Inotropes were required in 18.8% (26/138) of the glucose-insulin-potassium group and 40.8% (58/142) of the placebo group (P < .001). Fewer patients in the glucose-insulin-potassium group (12.3% [16/133]) versus those in the placebo group (23.4% [32/137]) had significant myocardial injury (P = .017). Noncardiac morbidity was not different. CONCLUSION: Glucose-insulin-potassium therapy improves early postoperative cardiovascular performance, reduces inotrope requirement, and might reduce myocardial injury. These potential benefits are not at the expense of increased noncardiac morbidity.

Cardiomyopathies↗

PubMed2005

Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting.

BACKGROUND: Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 micromol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. METHODS AND RESULTS: We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine <200 micromol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 micromol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine <130 micromol/L (<1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P<0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P<0.001) and postoperative stroke (2.2% versus 5.0%; P<0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 micromol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P=0.007) or glomerular filtration rate estimates <60 mL/min per 1.73 m2, derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P=0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P<0.001). CONCLUSIONS: Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

Aged↗

PubMed2005

Glucose and insulin influences on heart and brain in cardiac surgery.

The elective global ischemia of on-pump coronary artery bypass surgery contributes to the incidence of postoperative mortality, complications, and use of resources. In addition to cardiopulmonary bypass and techniques for myocardial protection such as aortic cross clamp, ventricular fibrillation, and cardioplegia, the administration of systemic glucose-insulin-potassium (GIK) in the perioperative period may act as both a metabolic modulator and potential inodilator. GIK may therefore serve to protect the myocardium and promote adequate cardiac and hemodynamic performance that would improve patient recovery. Cell, tissue, and animal experiments have determined a number of mechanisms of action by which this may be achieved, with increasing focus on insulin as the key component. The original concepts centered on GIK during or after ischemia switching metabolism away from that based on non-esterified fatty acids toward a more favorable glucose-based metabolism and thus improving the efficiency of adenosine triphosphate production and glycogen preservation. Insulin's ability to reduce intracellular fatty acid metabolism may also reduce cellular membrane damage. More recently other mechanisms have also been suggested, including osmotic, oxygen free radical scavenging, and antiapoptotic and anti-inflammatory effects. However, trials that have examined the role of GIK in cardiac surgery have been small, open label, and involved a wide variety of regimens. They have demonstrated improved glycogen preservation, reduced infarct size, reduced incidences of dysrhythmias, need for inotropic agents, and low cardiac output state, and overall reduced lengths of stay. The perceived need to achieve strict blood glucose control to reduce neurologic injury and improve overall mortality have conflicted with its practical difficulties, particularly during cold cardiopulmonary bypass, and the exact role of supplemental glucose administration and resulting hyperglycemia require re-examination.

Apoptosis↗

PubMed2004

The natural history of myocardium awaiting revascularisation in patients with impaired left ventricular function.

AIMS: Our aim was to follow changes in myocardial function and physiology in patients awaiting coronary artery bypass surgery (CABG) and relate changes to post-revascularisation functional response. METHODS AND RESULTS: In 21 patients with CAD and LV dysfunction, myocardial glucose utilisation (MGU) and blood flow (MBF) were measured with positron emission tomography using F-18-fluorodeoxyglucose and oxygen-15-labelled water. Left ventricular function, MGU, and MBF were re-assessed after one year, immediately prior to CABG. At baseline, dysfunctional myocardium displayed a reduction in MGU, hyperaemic MBF, and coronary vasodilator reserve (CVR) compared to normally functioning muscle. In the year preceding CABG, the overall wall motion score index increased (2.09 +/- 0.65 vs. 2.3 +/- 0.7, p=0.0001) and the LV ejection fraction decreased (30.6 +/- 11.1% vs. 27.3 +/- 11.5%, p<0.001). LVEF fell in 14 patients (28.7 +/- 9.4 vs. 23.8, p<0.0001). Aggregate regional wall motion worsened in 15 patients. In contrast to myocardium displaying stable function at echocardiography, myocardium with evidence of deterioration showed a parallel decrease in hyperaemic MBF and CVR (1.57 +/- 0.67 vs. 1.19 +/- 0.7 ml/min/g, [p=0.004] and 1.9 +/- 0.75 vs. 1.33 +/- 0.6, [p=0.005], respectively). Such myocardium displayed attenuated recovery postoperatively (21/68 [31%] LV segments) versus 'waiting-time' stable myocardium (98/169 [58%], p=0.0002). CONCLUSION: Delayed revascularisation in ischaemic left ventricular impairment results in declining function and a reduced likelihood of contractile improvement.

Coronary Artery Bypass↗

PubMed2003

Coronary artery surgery for ischaemic heart failure: the surgeon's view.

Recent advances in medical therapy have improved outcomes for patients with severe heart failure. However, overall survival remains poor. Transplantation is an established therapy for these patients but is limited by the large mismatch between demand and donor organ availability. Recently it has been recognised that not all ventricular dysfunction secondary to coronary artery disease is irreversible. Revascularisation in certain patients would appear to improve ventricular function. These patients are said to demonstrate myocardial "hibernation". Revascularisation in these patients may provide a further treatment option in the treatment of heart failure.

Coronary Artery Bypass↗

PubMed2002

Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium.

BACKGROUND: Myocardial hibernation may result from repetitive episodes of transient ischaemia leading to prolonged dysfunction. Inducible nitric oxide synthase (iNOS) expression has been demonstrated in animals following brief, non-lethal ischaemia-reperfusion injury. We therefore, hypothesised that in human hibernating myocardium: 1). iNOS would be present; 2). the reaction of nitric oxide and superoxide would form the strong oxidant peroxynitrite; 3) that this process would be accompanied by the expression of cyclooxygenase-2 (Cox-2) which interacts with NOS and whose products could further affect myocardial function. METHOD AND RESULTS: In sixteen patients with coronary artery disease (CAD), left ventricular biopsies were obtained from chronically dysfunctional segments subtended by a stenotic artery (> 75 %) and shown to be viable by (18)F-fluorodeoxyglucose positron emission tomography. Comparison was made with myocardial biopsies (n = 8) from normally contracting myocardium in patients undergoing coronary surgery, from unused transplant donors and at post-mortem. Regional wall motion score improved in all patients 6 months post-revascularisation (from 2.7 +/- 0.7 to 1.5 +/- 0.5; p < 0.001), confirming hibernation. Immunocytochemistry localized reactivity to iNOS, Cox-2 and nitrotyrosine (a marker of peroxynitrite formation) to cardiomyocytes from hibernating segments. No difference in reactivity to endothelial NOS was seen between hibernating and control cardiomyocytes. CONCLUSION: Cox-2 and iNOS are co-expressed in hibernating myocardium with nitrotyrosine suggesting nitric oxide production and peroxynitrite formation. We propose that this is secondary to ischaemia-reperfusion and that the products of these enzymes may have consequences for myocardial contractile function and survival.

Angiotensin-Converting Enzyme Inhibitors↗