Myocardial function may improve equally in diabetic patients following both multivessel percutaneous coronary intervention and coronary artery bypass grafting: results from a CARDia trial substudy.

AIMS: The CARDia (Coronary Artery Revascularization in Diabetes) trial compared coronary artery bypass grafting (CABG) and optimal percutaneous coronary intervention (PCI) in diabetic patients with multivessel coronary disease. Patients enrolled had symptoms of myocardial ischaemia. As symptom assessment is flawed in diabetic patients, a substudy was undertaken to compare the extent to which these revascularization strategies alter reversible ischaemia. METHODS AND RESULTS: Seventy-one patients underwent stress echo at baseline and at 6 months. A 17-segment echocardiographic wall motion score index (WMSI) was assigned at baseline [WMSI(pre)] and at 6 months [WMSI(post)]. An overall score defined the difference: WMSI(∂) = WMSI(pre)--WMSI(post). Of 71 patients recruited, 42 underwent PCI and 29 CABG. Mean WMSI(pre) in the PCI group was 1.63 and mean WMSI(post) was 1.32. Mean WMSI(pre) in the CABG group was 1.69 and mean WMSI(post) was 1.46. The PCI WMSI(∂) was 0.31 and CABG WMSI(∂) was 0.23 (P = 0.8). Of 42 PCI patients, 39 demonstrated ischaemia at baseline. At 6 months 31 had improvements in ischaemia (79%), 5 showed no improvement, and 3 ischaemia worsened. Of 29 CABG patients, 23 demonstrated ischaemia at baseline. At 6 months, 20 had improvements in ischaemia (87%), 2 had no improvement, and in 1 ischaemia worsened. No difference was seen in the number of patients with improvements in reversible ischaemia between PCI and CABG [79 vs. 87%, (P = 0.9)]. CONCLUSION: Optimal revascularization in diabetic patients with multivessel disease remains controversial. This subset analysis of the CARDia trial suggests both PCI and CABG achieve similar improvement in reversible ischaemia.

Myocardial stunning is associated with impaired calcium uptake by sarcoplasmic reticulum.

Myocardial stunning (temporary post-ischaemic contractile dysfunction) may be caused by oxidative stress and/or impaired myocyte calcium homeostasis. Regional myocardial stunning was induced in open-chest pigs (segment shortening reduced to 68.3+/-4.7% of baseline) by repetitive brief circumflex coronary occlusion (I/R). Reduced glutathione was depleted in stunned myocardium (1.34+/-0.06 vs. 1.77+/-0.11 nmol/mg, p=0.02 vs. remote myocardium) indicating regional oxidant stress, but no regional differences were observed in protein-bound 3-nitrotyrosine or S-nitrosothiol content. Repetitive I/R did not affect myocardial quantities of the sarcolemmal sodium-calcium exchanger, L-type channel, SR calcium ATPase and phospholamban, or the kinetics of ligand binding to L-type channels and SR calcium release channels. However, initial rates of oxalate-supported (45)Ca uptake by SR were impaired in stunned myocardium (41.3+/-13.5 vs. 73.0+/-15.6 nmol/min/mg protein, p=0.03). The ability of SR calcium ATPase to sequester cytosolic calcium is impaired in stunned myocardium. This is a potential mechanism underlying contractile dysfunction.

Absolute blood flow and oxygen consumption in stunned myocardium in patients with coronary artery disease.

OBJECTIVES: In patients with coronary artery disease (CAD), we sought to demonstrate normal myocardial blood flow (MBF) and myocardial oxygen consumption (MMRO(2)) to post-ischemic myocardium that exhibited reversible dysfunction and the relation between the severity of the dysfunction and the preceding ischemia. BACKGROUND: In animal models of stunning, MBF and MMRO(2) are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia. METHODS: Myocardial blood flow and MMRO(2) were measured using positron emission tomography and oxygen 15-labelled water (H(2)(15)O) and oxygen 15-labelled oxygen ((15)O(2)), respectively, in 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia. RESULTS: Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO(2) (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of <50%, 50% to 80% and >80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with <50%) and 1.47 (1.33 to 1.60) (p = 0.03 compared with 50% to 80% and p = 0.002 compared with <50%), respectively. CONCLUSIONS: In patients with CAD, dobutamine produces prolonged, but reversible, LV dysfunction when MBF is normal, confirming stunning. This stunning is related to the severity of the coronary stenosis and the reduction in peak MBF. Myocardial oxygen consumption to stunned myocardium is normal.

Effect of enhanced external counterpulsation on dobutamine-induced left ventricular wall motion abnormalities in severe chronic angina pectoris.

We studied the effect of enhanced external counterpulsation (EECP) in 23 consecutive patients with stable angina pectoris who had a positive dobutamine stress echocardiogram. After EECP, stress-induced wall motion score (WMS) improved by > or =2 grades in 43% of the patients (n = 10); the average improvement was 5.3 +/- 3.8 compared with -0.6 +/- 3.0 in the remaining 13 patients (p = 0.007). The diastolic/systolic augmentation ratio increased by 217% in response to the full course of EECP (p = 0.0002) among patients with improved WMS, and by 71% (p = 0.004) among the other patients; the increase was greater among patients with improved WMS than among patients with no improvement (p = 0.01). After EECP, Canadian Cardiovascular Society angina class improved from 3.1 +/- 0.6 to 2.2 +/- 0.7 (p <0.0001) in the entire group and exercise capacity increased by 73 seconds (p = 0.0002) in patients who were able to exercise (n = 18).

Drug treatment of stable angina pectoris in the elderly: defining the place of calcium channel antagonists.

Chronic stable angina pectoris (CSAP) resulting from coronary artery disease (CAD) is common in elderly patients, and significantly reduces their quality of life. Myocardial revascularisation procedures in this age group entail significant risks, largely related to comorbidities rather than advanced age itself. Coronary artery anatomy is more likely to be technically unsuitable for revascularisation and angina more resistant to drug treatment. Therefore, elderly patients often take combinations of antianginal drugs. Calcium channel antagonists (CCAs) are effective antianginal drugs first introduced for clinical use in the late 1970's. They reduce myocardial ischaemia by both causing vasodilatation of coronary resistance vessels and reducing cardiac workload (negative inotropic effect). However, adverse effects related to abrupt arterial vasodilatation limited the tolerability of these short acting 'first generation' drugs (nifedipine, verapamil and diltiazem). Furthermore, short acting nifedipine may occasionally increase both the frequency of angina pectoris and mortality in patients with CAD. Since then, long acting formulations of first generation agents and new chemical entities (second and third generation drugs) have been developed. These are well tolerated and effective at attenuating both myocardial ischaemia and the frequency and severity of angina pectoris in most patients with stable CAD. Current guidelines on the drug treatment of CSAP propose that beta-adrenoceptor antagonists (beta-blockers) should be used as first line medication primarily for their prognostic benefits, and that CCAs need only be introduced if beta-blockers are not tolerated, contraindicated or ineffective. Despite this, there is a wealth of evidence from clinical trials that demonstrate equal antianginal efficacy for CCAs and beta-blockers. The presence of chronic heart failure and prior myocardial infarction are clear indications for the use of beta-blockers in preference to CCAs for the treatment of CSAP. However, in patients with both CSAP and hypertension, second and third generation CCAs may offer prognostic benefits of similar magnitude to those provided by beta-blockers. Therefore, antianginal drug therapy must be tailored to the individual needs and comorbidities of each elderly patient.

Enhanced external counterpulsation does not alter arterial stiffness in patients with angina.

BACKGROUND: Enhanced external counterpulsation (EECP) is a noninvasive treatment for angina that acutely augments diastolic pressure and reduces cardiac afterload. However, the mechanism of the sustained clinical benefit seen with this therapy is not known. HYPOTHESIS: The study aimed to determine whether EECP leads to an improvement in arterial stiffness. METHODS: In all, 22 men and 1 woman with angina (age 63.6 +/- 6.7 years, mean +/- SD) were studied prior to and after 35 h of EECP therapy over 7 weeks. We measured carotid-radial (C-R) pulse wave velocity (PWV), and aortic augmentation index (AI) was derived from radial and carotid artery waveforms using applanation tonometry. Seventeen patients underwent treadmill exercise testing before and after the 7 weeks of EECP. RESULTS: After EECP therapy, despite a significant improvement in treadmill exercise time and a reduction in systolic and diastolic blood pressures, there was no significant change in any arterial stiffness parameters: Mean C-R PWV was 8.4 +/- 0.8 m/s at baseline and 8.0 +/- 1.2 m/s after 7 weeks of EECP, mean change: -0.4, 95% confidence interval (CI): -1.0, + 0.2, p = 0.17. Mean radial-derived AI was 25.7 +/- 10.4% before and 24.6 +/- 10.8% after, mean change: +1.1%, 95% CI: -2.3, +4.5, p = 0.53. Median AI-carotid was 31.5% before and 28.7% after; median change: -0.5, interquartile range: -9.5, +3.5, p = 0.32. Nineteen patients returned for 6-month recordings; neither blood pressure nor arterial stiffness readings were significantly different from baseline. CONCLUSION: Enhanced external counterpulsation therapy does not significantly alter arterial stiffness. Other than an initial reduction in blood pressure, the sustained clinical benefit seen with this therapy is unlikely to be effected through alterations in arterial wall mechanical properties.

The Bypass Angioplasty Revascularization in Type 1 and Type 2 Diabetes Study: 5-year follow-up of revascularization with percutaneous coronary intervention versus coronary artery bypass grafting in diabetic patients with multivessel disease.

OBJECTIVES: The aim of the Bypass Angioplasty Revascularization in Type 1 and Type 2 Diabetes study was to assess percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) as treatments for multivessel coronary artery disease in diabetic patients. BACKGROUND: CABG is generally regarded as the treatment of choice for multivessel coronary artery disease in diabetes. PCI is an alternative therapy. The Bypass Angioplasty Revascularization in Type 1 and 2 Diabetes study compared long-term outcomes of CABG with PCI in diabetic patients treated during the bare-metal stent era. METHODS: We collected data prospectively on consecutive diabetic patients undergoing index angiography in a single tertiary centre from January 1998 to December 2001. Multivessel coronary artery disease was defined as more than 50% luminal stenosis in two or more vessels. Exclusion criteria included left main stem disease and previous revascularization. RESULTS: Two hundred and thirty-five eligible patients underwent CABG and 237 PCI. Median follow-up was 5.4 years. There were 46 (19%) deaths in the CABG group and 43 (18%) deaths in the PCI group (P = 0.64). Cox regression analysis revealed baseline glomerular filtration rate (hazard ratio 0.979, P = 0.001), age (hazard ratio 1.034, P = 0.033), urgent procedure (hazard ratio 1.97, P = 0.008) and myocardial infarction within 4 weeks (hazard ratio 2.494, P = 0.041) to be important predictors of outcome. At 5 years, there was no mortality difference (hazard ratio 1.0) following adjustment for baseline characteristics, and the Kaplan-Meier survival curves were similar. A subanalysis of patients with three-vessel disease revealed similar outcomes with both PCI and CABG. CONCLUSION: In the Bypass Angioplasty Revascularization in Type 1 and Type 2 Diabetes study, diabetic patients with multivessel coronary artery disease had similar long-term mortality whether treated with CABG or PCI, the revascularization determined by the physician's choice. This was despite the frequent use of a strategy of selective revascularization in the PCI arm. Randomized trials comparing PCI and CABG specifically in diabetes, that is, Coronary Artery Revascularization in Diabetes and Future Revascularization Evaluation in Diabetes Mellitus: Optimal Management, will show whether drug-eluting stents further enhance PCI outcomes over the long term.

Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial.

OBJECTIVES: The purpose of this study was to compare the safety and efficacy of percutaneous coronary intervention (PCI) with stenting against coronary artery bypass grafting (CABG) in patients with diabetes and symptomatic multivessel coronary artery disease. BACKGROUND: CABG is the established method of revascularization in patients with diabetes and multivessel coronary disease, but with advances in PCI, there is uncertainty whether CABG remains the preferred method of revascularization. METHODS: The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), and stroke, and the main secondary outcome included the addition of repeat revascularization to the primary outcome events. A total of 510 diabetic patients with multivessel or complex single-vessel coronary disease from 24 centers were randomized to PCI plus stenting (and routine abciximab) or CABG. The primary comparison used a noninferiority method with the upper boundary of the 95% confidence interval (CI) not to exceed 1.3 to declare PCI noninferior. Bare-metal stents were used initially, but a switch to Cypher (sirolimus drug-eluting) stents (Cordis, Johnson & Johnson, Bridgewater, New Jersey) was made when these became available. RESULTS: At 1 year of follow-up, the composite rate of death, MI, and stroke was 10.5% in the CABG group and 13.0% in the PCI group (hazard ratio [HR]: 1.25, 95% CI: 0.75 to 2.09; p=0.39), all-cause mortality rates were 3.2% and 3.2%, and the rates of death, MI, stroke, or repeat revascularization were 11.3% and 19.3% (HR: 1.77, 95% CI: 1.11 to 2.82; p=0.02), respectively. When the patients who underwent CABG were compared with the subset of patients who received drug-eluting stents (69% of patients), the primary outcome rates were 12.4% and 11.6% (HR: 0.93, 95% CI: 0.51 to 1.71; p=0.82), respectively. CONCLUSIONS: The CARDia (Coronary Artery Revascularization in Diabetes) trial is the first randomized trial of coronary revascularization in diabetic patients, but the 1-year results did not show that PCI is noninferior to CABG. However, the CARDia trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these 2 revascularization strategies. (The Coronary Artery Revascularisation in Diabetes trial; ISRCTN19872154).

Recommendations for the management of patients after heart valve surgery.

Approximately 50,000 valve replacement operations take place in Europe annually and almost as many valve repair procedures. Previous European guidelines on management of patients after valve surgery were last published in 1995 and were limited to recommendations about antithrombotic prophylaxis. American guidelines covering the broader topic of the investigation and treatment of patients with valve disease were published in 1998 but devoted relatively little space to post-surgical management. This document represents the consensus view of a committee drawn from three European Society of Cardiology (ESC) Working Groups (WG): the WG on Valvular Heart Disease, the WG on Thrombosis, and the WG on Rehabilitation and Exercise Physiology. In almost all areas of patient management after valve surgery, randomized trials and meta-analyses do not exist. Such randomized trials as do exist are very few in number, are narrowly focused with small numbers, have limited general applicability, and do not lend themselves to meta-analysis because of widely divergent methodologies and different patient characteristics. Recommendations are therefore almost entirely based on non-randomized studies and relevant basic science.

Evidence that stunning can be cumulative in man.

Myocardial stunning and hibernation are two entities that have become increasingly recognised as clinically important causes of reversible left ventricular (LV) dysfunction. Their occurrence is important as resting myocardial dysfunction, which was once thought to be irreversible, may recover if ischaemia is lessened or abolished. Recent evidence has suggested that cumulative stunning can occur in man and may in fact be responsible for the phenomenon of hibernation. In this chapter we will review the evidence supporting the occurrence of cumulative stunning in man.

Effect of repeated episodes of reversible myocardial ischemia on myocardial blood flow and function in humans.

Nine patients with coronary artery disease and normal left ventricular (LV) function underwent two episodes of dobutamine-induced ischemia to determine whether repeated episodes of ischemia lead to cumulative stunning. Positron emission tomography (PET) and oxygen 15-labeled H(2)O was used to assess myocardial blood flow (MBF) at baseline, peak stress, and after stress for each ischemic episode. Quantitative echocardiographic assessment of global ejection fraction (EF) and regional systolic function (SF) was performed at rest and regular intervals after dobutamine. SF was assessed for regions subtended by a coronary artery with a >70% diameter stenosis. Both EF and SF were more severely impaired 45 min after the second episode of stress compared with 45 min after the first (both P < 0.01), despite no difference in duration of the two dobutamine infusions or MBF at peak stress (1.72 vs. 1.69). After both episodes of ischemia, when LV function was impaired but subsequently recovered, MBF (1.15 +/- 0.39 and 1.20 +/- 0.43, respectively) was no different to baseline MBF (1.02 +/- 0.35), confirming that repeated episodes of dobutamine-induced ischemia lead to cumulative myocardial stunning.

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.