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.

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.

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.