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Symptoms and signs of myocardial ischemia are often found in patients with hypertrophic cardiomyopathy (HCM) despite angiographically normal coronary arteries. Myocardial ischemia is deemed responsible for some of the lethal complications of HCM including ventricular arrhythmias, sudden death, progressive left ventricular remodeling, and systolic dysfunction. In the past decade, a number of studies using positron emission tomography have demonstrated severe impairment of the vasodilator response to dipyridamole in the majority of HCM patients, not only in the hypertrophied septum but also in the non-hypertrophied left ventricular free wall. In the absence of coronary stenoses, this finding is indicative of diffuse microvascular dysfunction, in line with the autoptic evidence of widespread abnormalities of the intramural coronary arterioles. In turn, microvascular dysfunction represents a very likely substrate for recurrent ischemia. This may account for the fact that microvascular dysfunction has recently been shown to represent an early and powerful predictor of an unfavorable outcome in HCM. The aim of this article is to provide a concise overview of the available evidence of microvascular dysfunction and ischemia in HCM, and to speculate on the potential implications for management.

Purpose: Tetrahydrobiopterin (BH4) is an essential co-factor for the synthesis of nitric oxide (NO), and BH4 deficiency may cause impaired NO synthase (NOS) activity. We studied whether BH4 deficiency contributes to the coronary microcirculatory dysfunction observed in patients with hypercholesterolaemia. Methods: Myocardial blood flow (MBF; ml min(-1) g(-1)) was measured at rest, during adenosine-induced (140 mug kg(-1) min(-1) over 7 min) hyperaemia (mainly non-endothelium dependent) and immediately after supine bicycle exercise (endothelium-dependent) stress in ten healthy volunteers and in nine hypercholesterolaemic subjects using O-15-labelled water and positron emission tomography. Measurements were repeated 60 min later, after intravenous infusion of BH4 (10 mg k(g)-(1) body weight over 30 min). Adenosine-induced hyperaemic MBF is considered to represent (near) maximal flow. Flow reserve utilisation was calculated as the ratio of exercise-induced to adenosine-induced hyperaemic MBF and expressed as percent to indicate how much of the maximal (adenosine-induced) hyperaemia can be achieved by bicycle stress. Results: BH4 increased exercise-induced hyperaemia in controls (2.96 +/- 0.58 vs 3.41 +/- 0.73 ml min(-1) g(-1), p

Heart failure accounts for approximately 20% of all hospital admissions among people over 65, and in the past 10 years the hospitalisation rate has increased by almost 160%.1 Although different large randomised trials carried out during the past two decades have demonstrated a significant reduction in mortality for heart failure patients treated medically, symptomatic heart failure continues to have a one year mortality close to 45%.23 In an effort to improve the early recognition of heart failure, the American College of Cardiology and the American Heart Association have recently proposed a new approach to the classification of heart failure based on four progressive stages.4 This new categorisation emphasises the evolution and progression of heart failure and is quite different from the traditional New York Heart Association (NYHA) classification whose primary objective was to describe functional limitations. Although this recent classification underscores the risk factors and structural abnormalities, which are necessary for the development of heart failure, patients are considered independent of the origin of their condition and no major emphasis is placed on the aetiology. In over two thirds of cases heart failure is secondary to coronary artery disease. The increasingly successful treatment and reduced mortality of acute coronary syndromes has increased the prevalence of chronic heart failure in patients with coronary artery disease.5 Evidence from non-randomised studies suggests that in patients with post-ischaemic heart failure, coronary revascularisation can lead to symptomatic and prognostic benefits.5 To understand the reasons for the beneficial effects of revascularisation, it is necessary to review the underlying mechanisms of heart failure in patients with coronary artery disease. This is generally the result of three factors

For many years the functional sequelae of chronic coronary artery disease (CAD) were considered essentially irreversible and amenable only to palliative treatment. For example, asynergy on the left ventriculogram implied infarcted myocardium or scar. Evidence accrued over the past three decades, however, indicates that chronic left ventricular dysfunction in patients with CAD is not necessarily irreversible.1 Two pieces of evidence led to a new concept of reversible myocardial …

For many years the functional sequelae of chronic coronary artery disease (CAD) were considered irreversible. Evidence accrued over the past three decades proves that this concept is not necessarily true. Non-randomised studies demonstrated that coronary revascularisation (CR) confers symptomatic and prognostic benefits to patients with CAD and heart failure. Based on available studies, one can assume that the beneficial effect of CR in heart failure derives primarily from recovery of contractile function in 'hibernating myocardium' (HM), i.e., chronically dysfunctional, but viable, myocardium subtended by stenosed coronary arteries which recovers after CR. Cardiac imaging with echocardiography, single photon and positron emission tomography (PET) and magnetic resonance allows the identification of HM. These techniques have comparable predictive values in patients with moderate left ventricular impairment. PET studies have shown that resting myocardial blood flow is preserved in most cases of HM while its main feature is a severe impairment of coronary flow reserve. Thus, the pathophysiology of HM is more complex than initially postulated. Recent evidence that repetitive ischaemia in patients can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and HM are two facets of the same coin.

Hibernating myocardium can be defined as a chronic, but reversible left ventricular dysfunction that may contribute to congestive heart failure in patients with coronary artery disease. The dysfunction can improve after coronary revascularization and therefore its identification and treatment become central in the management of patients with heart failure secondary to coronary artery disease. Hibernating myocardium can be detected by several techniques (echocardiography performed during the infusion of dobutamine, single photon and positron emission tomography-PET, and magnetic resonance imaging), but none of these techniques can be considered unequivocally superior to the others for the identification of hibernating myocardium. As PET technology has advanced, the noninvasive quantification of absolute regional myocardial blood flow has become possible. The measurement of myocardial blood flow by PET has contributed to the demonstration that transmural blood flow in hibernating muscle is generally within the normal range while the coronary flow reserve is invariably and severely impaired. These findings have contributed to a new pathophysiological theory of hibernation where repetitive ischemia and stunning are considered as the initial mechanisms that might start the process of myocardial hibernation.

Background: Most patients with heart failure due to left ventricular systolic dysfunction (LVSD) secondary to coronary artery disease (CAD) have evidence of myocardium in jeopardy (reversible ischaemia and/or stunning hibernation). It is not known whether revascularisation in such cases is safe or beneficial. Aims: To determine whether revascularisation will improve the survival of patients with LVSD and heart failure secondary to CAD and myocardium in jeopardy. Methods: This is a randomised controlled trial comparing revascularisation or not, in addition to optimal medical therapy with ACE inhibitors, beta-blockers, aldosterone antagonists and an anti-thrombotic agent. Patients must have heart failure requiring treatment with diuretics, a left ventricular ejection fraction

The most common cause of heart failure is coronary artery disease, and whilst intensive treatment of acute coronary syndromes and myocardial infarction continue to reduce the mortality associated with these conditions, many survivors develop heart failure. In general, heart failure secondary to ischaemic heart disease results from: (i) irreversible myocyte loss due to infarction with scar formation; (ii) chronic left ventricular dysfunction which may recover after revascularisation (hibernating myocardium); (iii) changes in remote myocardium (adverse remodelling). A number of studies suggest that patients with post-ischaemic heart failure may derive symptomatic and prognostic benefit from coronary revascularisation and most of this benefit is thought to derive from functional improvement of hibernating myocardium. Although the mechanisms of hibernation remain poorly understood, studies with positron emission tomography have shown that blood flow to hibernating myocardium is usually within or only slightly below the normal range whilst the coronary vasodilator reserve is always severely reduced and the concept that stunning and hibernation may be causally related has gained support in recent years. There is increasing consensus amongst clinicians regarding the importance of identifying and treating hibernating myocardium in patients with coronary artery disease and heart failure, and a randomised study comparing optimum medical treatment to optimum medical treatment with complete revascularisation has just commenced in the United Kingdom (HEART-UK) and will provide guidance regarding diagnosis and treatment of these patients.

Background Changes in myocardial blood flow (MBF) and coronary flow reserve (CFR) are independent prognostic risk factors in idiopathic dilated cardiomyopathy (DCM). The aim of this study was to assess the impact of left ventricular unloading using left ventricular assist device (LVAD) combination therapy on resting MBF and CFR in patients with end-stage heart disease. Methods We studied 11 patients with deteriorating end-stage DCM (New York Heart Association Class 4) treated with LVAD support combined with pharmacologic therapy in a recovery program. Absolute MBF was measured using oxygen-15-labeled water (H 2 15 O) positron emission tomography (PET) at rest during LVAD support and 15 minutes after the LVAD was switched off. Data were corrected for rate pressure product (RPP) when appropriate. Hyperemic MBF (intravenous adenosine, 140 μg/kg · min) was also measured in 6 patients with the LVAD switched off. CFR was calculated as the ratio MBF adenosine/MBF LVAD off (corrected). Data are expressed as mean ± SD. Results At 317 ± 193 days after device implantation, resting MBF was 0.95 ± 0.29 (LVAD on) and 1.46 ± 0.62 (LVAD off, corrected) ml/min · g ( p = 0.01). MBF (LVAD on) was comparable with that of 11 age- and gender-matched normal controls (1.09 ± 0.22 ml/min · g). CFR in the LVAD group was 1.49 ± 0.99 compared with 3.56 ± 1.42 in normal controls ( p Conclusions During LVAD support, resting MBF (LVAD on) was comparable to MBF in normal controls and increased when the LVAD was switched off. However, CFR was significantly impaired, even though all patients studied showed varying degrees of myocardial recovery. The implications of these findings, particularly in the long term, require further study.

Respiratory motion is a source of artefacts and quantification errors in cardiac imaging. Preliminary studies with retrospective respiratory gating in PET support the observation of other imaging modalities of a rigid-body motion of the heart during respiration. However, the use of gating techniques to eliminate motion may result in poor count statistics per reconstructed image. We have implemented a motion correction technique which applies rigid-body transformations on list-mode data event-by-event on the basis of a geometric model of intersection of the lines-of-response with the scanner. Pre-correction for detector efficiencies and photon attenuation before transformation are included in the process. Projection data are acquired together with physiological signal (every ms) from an inductive respiration monitor with an elasticised belt at chest level. Data are retrospectively sorted into separate respiratory gates on an off-line workstation. Transformation parameters relating the gated images, estimated by means of image registration, can be applied on the original list-mode data to obtain a single motion-corrected dataset. The accuracy of the technique was assessed with point source data and a good correlation between applied and measured transformations, estimated from the centroid of the source, was observed. The technique was applied on phantom data with simulated respiratory motion and on patient data with C/sup 15/O and /sup 18/FDG. Quantitative assessment of preliminary C/sup 15/O patient datasets showed at least 4.5% improvement in the recovery coefficient at the centre of the left ventricle.

Identification and treatment of hibernating myocardium (HM) lead to improvement in LV function and prognosis in patients with post-ischemic heart failure. Different techniques are used to diagnose HM: echocardiography, MRI, SPECT and PET and, in patients with moderate LV impairment, their predictive values are similar. There are few data on patients with severe LV dysfunction and heart failure in whom the greatest benefits are apparent after revascularization. Quantification of FDG uptake with PET during hyperinsulinemic euglycemic clamp is accurate in these patients with the greatest mortality risk in whom other techniques may give high false negative rates. The debate on whether resting myocardial blood flow to HM is reduced or not has stimulated new research on heart failure in patients with coronary artery disease. PET with (H2O)-O-15 or (NH3)-N-13 has been used for the absolute quantification of regional blood flow in human HM. When HM is properly identified, resting blood flow is not different from that in healthy volunteers although a reduction of similar to20% can be demonstrated in a minority of cases. PET studies have shown that the main feature of HM is a severe impairment of coronary vasodilator reserve that improves after revascularization in parallel with LV function. Thus, the pathophysiology of HM is more complex than initially postulated. The recent evidence that repetitive ischemia in patients can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and HM are two facets of the same coin.

JRAAS 2003;4:94-5 The importance of microvascular abnormalities associated with hypertension is increasingly recognised, and these may be central to the development of hypertensive end-organ damage in the heart, as well as in the kidney and elsewhere. Clinical and experimental studies suggest that different classes of antihypertensive agents differ in their ability to reduce or reverse microvascular abnormalities. Positron emission tomography (PET) allows reproducible, non-invasive measurements of absolute myocardial blood flow (MBF) in man. The ratio of MBF measured during near maximal vasodilatation (with drugs such as adenosine or dipyridamole) to resting MBF gives the coronary vasodilator reserve (CVR), which is an integrated index of the function of the coronary circulation. In patients with coronary artery disease, CVR gives information on the functional significance of coronary stenoses; in the absence of coronary artery stenosis, CVR is primarily an indicator of the status of the coronary microcirculation. In this study, we used PET to investigate the effects on the coronary microcirculation of six months of antihypertensive treatment with a very low-dose combination of the angiotensin-converting enzyme (ACE) inhibitor, perindopril, and the diuretic, indapamide (Preterax, Servier). Six newly-diagnosed, never-treated patients (mean [SD] age 57.2 [10.0] years; five male), with uncomplicated moderate essential hypertension (systolic blood pressure [SBP] 160–179 mmHg and/or diastolic blood pressure [DBP] 95–109 mmHg),and without clinical history or symptoms of coronary artery disease (confirmed by negative ECG during maximal exercise test at selection visit),were included.All patients gave informed written consent, and the protocol was approved by the local Consultative Committee for the Protection of Persons Engaged in Biomedical Research. Patients underwent 2-D echocardiography and PET at baseline (M0), and after six months of therapy (M6) with perindopril 2.0 mg/indapamide 0.625 mg once-daily (o.d.). Resting MBF and maximal MBF after vasodilatation with dipyridamole (0.80 mg/kg i.v.) were measured by PET with H2O as tracer, as previously described. The short-term reproducibility of this method has been established by repeated measurements in healthy volunteers. Reproducibility coefficients (accounting for methodological and physiological variability) for resting MBF, maximal MBF and CVR were 0.17 ml/minute/g, 0.90 ml/minute/g, and 1.32, respectively. PET data analyses for MBF quantifications were performed at the end of the study, in random order, by a ‘blinded’ investigator. One patient was not evaluable for changes in blood pressure (BP) (because of instability in BP between selection and M0), and one other patient was not evaluable for PET (because of movement during scanning). Thus, four patients completed the study ‘per-protocol’ (PP).Values are quoted as mean (+SD), and significance was assessed by paired Student t-test. No treatment-related adverse events were reported during the study. After six months of therapy,BP had normalised to SBP < 140 and/or DBP < 80 mmHg in all six patients. For the PP patients, SBP decreased from 160.3 (+12.0) mmHg at M0 to 133.8 (+3.8) mmHg at M6 (p=0.040), and DBP from 100.3 (+9.5) to 83.5 (+3.7) mmHg (p=0.053).One patient had left ventricular (LV) hypertrophy at baseline (LV mass index by echocardiography 131 g/m), which normalised after treatment (118 g/m). CVR in normal subjects,measured by this technique, is 4.0 (+0.67). As in a previous study, CVR in our hypertensive patients was impaired at baseline, with a mean of 2.05 (+0.41) for the PP patients (Table 1). After six months of therapy, CVR increased to 5.49 (+2.55) (p=0.0498); the corresponding change for the five evaluable patients was 2.09 (+0.36) at M0 to 4.89 (+2.58) at M6 (p=0.0562).Every patient showed an improvement in CVR after treatment; however, inspection of absolute MBF values revealed clear differences between patients. In some patients, the improvement in CVR was primarily due to an increase in maximal MBF (patients one, two, and five; see Table 1), while in others the main change was a reduction of initially high resting MBF values (patients three and four). There are several plausible mechanisms by which perindopril/indapamide might improve CVR in hypertensive patients. Long-term ACE inhibition can reverse changes in small vessel structure and microvascular rarefaction, and improve endothelial function. Perindopril treatment also reduces periarteriolar fibrosis in hypertensive patients. Recent Research letter

Myocardial infarction in persons aged below 45 years is a rareevent, usually not related to coronary atherosclerosis, but mostly oc-curs as a consequence of cocaine abuse, congenital coronary abnor-malities, or spasm. We present the case of a young man with anacute anterior myocardial infarction caused by a rare protein defi-ciency in the coagulation system.A29‐year-oldman,of Africandescent,withnopriorhistoryof car-diac event, presented at our emergency department complaining ofsevere acute chest pain radiating to the left arm. Electrocardiographyshowed 2 mm ST elevation in V1 to V4. Transthoracic echocardiogra-phy revealed akinesia of the anterior wall and apex with mild globaldysfunction (ejection fraction 50%). Loading doses of ASA andclopidogrel were administered before coronary angiography thatshowed a large proximal thrombus in the left anterior descending cor-onary artery (LAD) causing total occlusion. Intracoronary abciximabwas administered, and, given large clot burden, thrombus aspirationwas performed before deploying two bare metal stents. At the endof the procedure the patient developed cardiogenic shock requiringadrenaline administration and IABP. Despite arterial patency beingrestored, TIMI flow 1 persisted in the LAD (Fig. 1A).Afterwards,contrast-enhancedcardiacmagneticresonance(CMR)showed transmural infarct of left ventricular apex that appeared thinand akinetic and multiple necrosis foci on interventricular septum(Fig. 1B). A complete thrombophilic screening was carried out, finallyrevealing a combined deficiency of proteins S and C: plasma protein Cand S concentration were respectively 39% and 43% of normal. A ther-apy with low molecular weight heparin was started at a dosage of6000 IU once daily, and 12 months dual antiplatelet therapy was rec-ommended. Two months later therapy was converted to oral antico-agulant with dabigatran 220 mg once daily. At 6 months follow up,the patient remained asymptomatic. Family history revealed recur-rence of severe thromboembolism among his relatives.Protein C is a vitamin K-dependentprotein, synthesized in theliver,that inactivates coagulation factors Va and VIIIa, which are required tothrombin generation and factor X activation. This process is stronglysupported by protein S activity as cofactor. Moreover Protein C hasestablished antin flammatory activity and seems to harbor cyto-protectivepropertiesonendothelialcells.Itisestimatedthatcongenitalprotein C deficiency is present in 2 to 5% of patients with thromboem-bolism [1]. Prevalence of clinically symptomatic deficiencies of proteinC in the general population lies between 1:16,000 and 1:36,000 whilethat of symptomatic protein S deficiency is 1:20,000. Both protein Cand S deficiencies are associated with increased risk of developingdeep venous thrombosis (risk ratio 8.1 for protein S deficiency and 7.3for protein C deficiency) [2] and higher risk of recurrent thrombosis,with typically young age of onset and family cluster occurrence. Thefew available reports of families with combined protein C and S defi-ciency suggest that both genes segregate independently as an autoso-mal dominant trait. Although venous district is typically involved(deep veins, pulmonary artery, jugular vein), arterial thrombosis hasbeen reported. Aorta, mesenteric and cerebral arteries can be affected[3]. Patients with C protein deficiency are at potential risk of warfarininduced skin necrosis, and for that we preferred LMWE and dabigatranto vitamin K antagonist.After acute myocardial infarction inadequate tissue perfusion mayoccur despite early and successful reopening of the infarct-related ar-tery with primary percutaneous coronary intervention. This situation,known as “No Reflow” (NR), significantly affects outcome [4]. NR canbe related to ischemia-reperfusion injury or to downstream emboli-zation of atherosclerotic material into the microvasculature. CMR al-lows the detection of myocardial injury with high accuracy: theintensity of myocardial enhancement is related to expansion of theinterstitial volume secondary to cell necrosis; persistent hypo-perfusion on first pass contrast-enhanced images suggests microvas-cular obstruction (Fig. 2A), which impedes delivery of contrastmedium, or dysfunction of coronary microvasculature that can be re-liably assessed by positron emission tomography (Fig. 2B).Current approaches for prevention and treatment of NR includevasodilators, glycoprotein IIb/IIIa inhibitors and thrombus aspiration.Although we used all of the above, the patient did not achievesuccessful reperfusion. Thrombophilia may have contributed to ex-tensive myocardial damage through a greater and diffuse pro

Development of left ventricular hypertrophy (LVH) in aortic stenosis (AS) is accompanied by dysfunction of the coronary microcirculation, demonstrated by an impaired coronary vasodilator reserve (CVR), but the relative contribution of LVH and changes in haemodynamics remains unclear. In twenty patients with AS, an increase in resting myocardial blood flow (MBF), assessed with positron emission tomography, was demonstrated, proportional to hypertrophy measured with cardiac magnetic resonance, presumably as a result of coronary autoregulation. However, an inverse relationship between CVR and echocardiographic peak transvalvular pressure gradient and left ventricular pressure multiplied by heart rate (LVRPP) suggests that the effect of haemodynamic and intramural forces may be to counteract autoregulation, maintaining transmural MBF at rest, but impairing the coronary microcirculation stress response, particularly within the subendocardium.

OBJECTIVES To investigate whether myocardial beta-adrenoceptor (beta-AR) downregulation precedes and predicts left ventricular (LV) dilation after acute myocardial infarction (AMI), we measured beta-AR density within four weeks of AMI and correlated it with serial measurements of LV volumes. BACKGROUND Patients who develop heart failure following AMI have an increased sympathetic drive to the heart within the first four weeks after infarction. METHODS We prospectively studied 61 patients in whom AMI was the first presentation of coronary artery disease (CAD) and with no signs of heart failure. The LV volumes were measured one, three, and six months after AMI by echocardiography. Beta-AR density was measured using positron emission tomography with S-[C-11]CGP 12177. Seventeen matched healthy volunteers served as controls. RESULTS Whole heart beta-AR density was lower in patients than in controls (6.25 +/- 0.98 pmol/g vs. 8.32 +/- 2.14 pmol/g, p < 0.0001). In patients, beta-AR density was inversely correlated with end-systolic and end-diastolic volumes six months after AMI. Patients whose LV was dilated at six months had a lower beta-AR density in noninfarcted myocardium than patients without dilation (6.15 pmol/g vs. 6.98 pmol/g, p = 0.008). In addition, beta-AR density in noninfarcted myocardium, was higher when the infarct-related artery was patent (6.87 +/- 1.14 pmol/g vs. 5.76 +/- 0.86 pmol/g occluded, p < 0.01). CONCLUSIONS Myocardial beta-AR density is reduced after AMI in the absence of heart failure, and the reduction predicts later LV dilation. These data are suggestive of an enhanced sympathetic drive to the heart, having an important etiologic role in LV remodeling after AMI. (C) 2002 by the American College of Cardiology Foundation.

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 18F-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.

The aim of this study was to compare cardiac volume and function assessment using PET with the reference technique of cardiovascular magnetic resonance (CMR).Left ventricular (LV) and right ventricular (RV) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fractions (EF) were measured in 9 patients using both CMR and PET with inhaled C(15)O.Correlation between the techniques was generally reasonable (r values ranged from 0.63 to 0.99). Best agreement was seen for ESV (LV and RV). With PET, there was a tendency to underestimate LV EF and EDV, and RV EDV and SV. Agreement was worst for LV SV. Percentage difference between CMR and PET measurements ranged from -2% to 15%; Bland-Altman limits of agreement ranged from 24% to 75%.Although small systematic differences exist, the agreement between PET and CMR suggests useful information regarding function, and volumes may be obtained from a standard PET protocol.

Objective: To investigate the central neural contribution to chest pain perception in cardiac syndrome X (angina-like pain, ECG changes during stress, angiographically normal coronary arteriogram). Subjects: Eight syndrome X patients and eight healthy volunteers. Methods: Dobutamine stress using echocardiography to assess myocardial function, and positron emission tomography to measure changes in regional cerebral blood flow, as an index of neuronal activity. Results: During similar doses of dobutamine, syndrome X patients and controls showed comparable regional cerebral blood flow changes in the hypothalamus, thalami, right orbito-frontal cortex, and anterior temporal poles, associated with the sensation of a fast or powerful heart beat. In patients, but not controls, the stress also generated severe chest pain associated with increased activity in the right anterior insula/frontal operculum junction. There were ischaemia-like ECG changes in the syndrome X patients, but no left ventricular dysfunction on echocardiography. Activation of the right insula during chest pain clearly distinguished the syndrome X patients from a group of patients with known coronary disease. Conclusions: Chest pain and ECG changes were not accompanied by demonstrable myocardial dysfunction in syndrome X patients, but altered central neural handling of afferent signals may contribute to the abnormal pain perception in these patients.

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 H2O 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.

Along with hibernating myocardium, infarct size is a critical term in the progression of left ventricular remodelling and congestive heart failure. Both infarcted and hibernating myocardium determine changes in remote non-ischaemic tissue. This study was designed to test the accuracy of a new technique to quantify infarct size using positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG). Studies were carried out in (a) nine pigs with acute myocardial infarction (two sham-operated), produced by a 90-min occlusion of the circumflex coronary artery followed by a 4-h reperfusion, and (b) humans (six patients with ischaemic cardiomyopathy awaiting cardiac transplantation and five normal volunteers). In both animals and patients, myocardial FDG uptake was measured by PET during hyperinsulinaemic-euglycaemic clamp. Infarct size was quantified by an absolute threshold of tracer uptake obtained from the parametric (voxel-by-voxel) image of the metabolic rate of FDG. PET infarct size estimates were compared with independent ex vivo planimetric measurements of the explanted swine and patient hearts (at transplantation) after staining with triphenyltetrazolium chloride. There was good agreement between the planimetric and PET infarct size estimates both in pigs (n=9; r=0.96, y=0.94x +0.64, SEE=0.10, P

It has been recognized that there is a group of patients with severe disabling angina and coronary artery disease who are refractory to conventional forms of treatment. Although this issue has already been debated at the level of the National Societies, we felt that it was appropriate to also tackle it at the European level. This is particularly important in view of the rapid pace of growth of this problem and the lack of a standardized approach. This has encouraged the development of a variety of treatments that vary considerably in terms of cost-effectiveness and safety and require proper validation procedures. The aim of this paper is to draw attention to the problem and start a process that will lead to improvement and harmonization of the care of patients with refractory angina.

Accurate prediction of improvement in left ventricular ejection fraction (LVEF) after revascularisation is critical in the therapeutic decision-making process in patients with chronic ischaemic dysfunction. Positron emission tomography (PET) allows non-invasive evaluation of myocardial blood flow (MBF), metabolic rate of glucose (MRG, absolute and relative) and the water-perfusable tissue fraction (PTF). Each of these indices has been proposed for the prediction of functional recovery. Their relative merits, however, are unknown, because a direct head-to-head comparison of their predictive accuracy in the same patients has not been performed. In this study, MBF, MRG (absolute and relative) and PTF were evaluated in 34 patients with severe ischaemic LV dysfunction (LVEF 32% +/- 9%). MBF and PTF were determined by oxygen-15 labelled water PET, and MRG (absolute and relative) was determined by fluorine-18 fluorodeoxyglucose (FDG) PET during hyperinsulinaemic euglycaemic clamp. LVEF was measured by radionuclide ventriculography before and 4-6 months after surgery. Sensitivities of MBF, PTF, absolute MRG and relative MRG in predicting improvement in LVEF were 80%, 80%, 90% and 100%, respectively. Their specificities were 54%, 67%, 71% and 71%, respectively. The lowest specificity was obtained for MBF, an intermediate specificity was obtained for PTF and the highest specificities were obtained with FDG PET using absolute and relative MRG. It is concluded that metabolic imaging is superior to perfusion-based indexes for assessment of the potential for functional recovery after revascularisation.

Aims/hypothesis. We investigated the effect of physiological hyperinsulinaemia on global and regional myocardial blood flow and glucose uptake in five patients with Type II (non-insulin-dependent) diabetes mellitus and seven healthy control subjects. Methods. Myocardial blood flow was assessed by positron emission tomography with oxygen-15 labelled water (H2 15O) either before or after 1 h of euglycaemic hyperinsulinaemia. Myocardial glucose uptake was assessed by positron emission tomography and fluorine-18 labelled fluorodeoxyglucose (18FDG). Results. During hyperinsulinaemia, myocardial blood flow increased from 0.91±0.03 to 1.00±0.03 ml.min–1.g–1 in control subjects (p

Development of radioactive tracers to probe both pre- and postsynaptic sympathetic function has made possible a more widespread non-invasive assessment of the sympathetic nervous system Cardiac myocytes and the coronary circulation are innervated by both sympathetic and parasympathetic fibres which constitute the autonomic nervous system.1,2 The autonomic outflow is controlled by regulatory centres in the midbrain, hypothalamus, pons, and medulla which integrate inputs from other brain areas as well as afferent stimuli from the periphery. The efferent signals follow descending pathways in the lateral funiculus of the spinal cord that terminate on cell bodies in the intermediolateral and intermediomedial columns. Sympathetic fibres leave the spinal cord at T1–L2-3. These myelinated preganglionic fibres synapse in the paravertebral ganglia while small unmyelinated postganglionic fibres connect with body organs.3 Sympathetic innervation to the heart is provided by fibres originating from a series of ganglia which constitute the cardiac plexus. These fibres branch and terminate as sympathetic nerve endings in atrial and ventricular tissue. The main neurotransmitter of the sympathetic system is noradrenaline (norepinephrine) that, after its release by sympathetic nerve terminals, can bind to a series of different postsynaptic receptors (α and β) whose activation determine the …

The “oxyradical hypothesis” of myocardial stunning proposes that superoxide, released on reperfusion, leads to contractile dysfunction via the production of the more reactive hydroxyl free radical from the iron catalysed Haber-Weiss reaction. However, superoxide reacts many times faster with nitric oxide (NO), than with ferric iron, leading to the formation of peroxynitrite (ONOO−), which is a potent oxidising and nitrating agent with properties and reactivity similar to hydroxyl radicals. Consequently ONOO− is a candidate for the initiation of oxidation reactions following brief ischaemia–reperfusion injury . The production of reactive nitrogen intermediates such as ONOO− is reflected in vivo by the formation of the amino acid derivative 3-nitrotyrosine. Recently, we have developed a sensitive method for the quantitative analysis of tissue nitrotyrosine which avoids the artefactual formation of nitrotyrosine that can occur with more conventional protein preparative steps.1 The present study sought to test the hypothesis that myocardial stunning causes increased formation of tissue nitrotyrosine. Large White pigs (mean (SD) weight 38 (4) kg) were anaesthetised and prepared as previously described2 to allow temporary occlusion of the circumflex coronary artery with simultaneous recording of haemodynamic parameters, circumflex coronary blood flow (group A only) and regional and distal myocardial contractile function by sonomicrometric segment shortening. Following 30 minutes of stabilisation, regional ischaemia–reperfusion was induced by 10 cycles …

[A(14)-*i]iodoinsulin was prepared for studies to assess the suitability of labeled iodoinsulin for positron emission tomography (PET). Iodine-125 was used to establish the methods and for preliminary studies in rats. Further studies and PET scanning in rats were carried out using iodino-124. Tissue and plasma radioactivity was measured as the uptake index (UI = {cpm.(g tissue)(-1)}/{cpm injected.(g body weight)(-1)}) at 1 to 40 min after intravenous injection of either [A(14)-I-125]iodoinsulin or [A(14)-I-124]iodoinsulin. For both radiotracers, initial clearance of radioactivity from plasma was rapid (T-1/2 similar to 1 min), reaching a plateau (UI = 2.8) at similar to 5 min which was maintained tot, 35 min. Tissue biodistributions of the two radiotracers were comparable; at 10 min after injection, UI for myocardium was 2.4, liver, 4.0, pancreas, 5.4, brain, 0.17, kidney, 22, lung, 2.3, muscle, 0.54 and fat, 0.28. Predosing rats with unlabelled insulin reduced the UI for myocardium (0.95), liver (1.8), pancreas (1.2) and brain (0.08), increased that for kidney (61) but had no effect on that for lung (2.5), muscle (0.50) or fat (0.34). Analysis of radioactivity in plasma demonstrated a decrease of [I-125]iodoinsulin associated with the appearance of labeled metabolites; the Percentage of plasma radioactivity due to [I-125]iodoinsulin was 40% at 5 min and 10% at 10 min. The heart, liver and kidneys were visualized using [I-124]iodoinsulin with PET. (C) 2002 Elsevier Science Inc. All rights reserved.

We investigated the effect of insulin on total and regional myocardial blood flow (MBF) and glucose uptake (MGU) in healthy subjects (50 ± 5 yr) by means of positron emission tomography (PET) with oxygen-15-labeled water (H2 15O) and fluorine-18 labeled fluorodeoxyglucose (18FDG) before and during physiological hyperinsulinemia (40 mU · min−1 · m−2). Twelve male subjects were included in the study. During hyperinsulinemia, MBF increased from 0.91 ± 0.28 to 1.01 ± 0.31 ml · min−1 · g−1 ( n= 7 patients, P = 0.05; n = 112 regions, P < 0.005). Intersubject variability ranged from −3.0 to +41%. MGU increased from 0.11 ± 0.08 ( n = 5) to 0.56 ± 0.08 μmol · min−1 · g−1( P < 0.0001, n = 7). MBF and insulin-mediated MGU were higher in the septum and anterior and lateral wall along short-axis regions of the heart. During hyperinsulinemia, MBF was also higher in the apex and midventricle compared with the base. MBF and MGU were positively correlated before ( r = 0.66, P < 0.0001) and during hyperinsulinemia ( r= 0.24, P < 0.05). These results provide evidence that insulin stimulates MBF in normal human hearts and appears to involve mainly those regions of the heart where insulin-mediated MGU is higher. Furthermore, regional distribution of insulin-stimulated MBF and MGU does not appear to be uniform across the left ventricular wall of healthy subjects.

Background — Development of left ventricular hypertrophy in aortic stenosis (AS) is accompanied by coronary microcirculatory dysfunction, demonstrated by an impaired coronary vasodilator reserve (CVR). However, evidence for regional abnormalities in myocardial blood flow (MBF) and the potential mechanisms is limited. The aims of this study were to quantitatively demonstrate differences in subendocardial and subepicardial microcirculation and to investigate the relative contribution of myocyte hypertrophy, hemodynamic load, severity of AS, and coronary perfusion to impairment in microcirculatory function. Methods and Results — Twenty patients with isolated moderate to severe AS were studied using echocardiography to assess severity of AS, cardiovascular magnetic resonance to measure left ventricular mass (LVM), and PET to quantify resting and hyperemic (dipyridamole 0.56 mg/kg) MBF and CVR in both the subendocardium and subepicardium. In the patients with most severe AS (n=15), the subendocardial to subepicardial MBF ratio decreased from 1.14±0.17 at rest to 0.92±0.17 during hyperemia ( P P =0.01). Resting total LV blood flow was linearly related to LVM, whereas CVR was not. Increase of total LV blood flow during hyperemia (mean value, 89.6±59.6%; range, 17% to 233%) was linearly related to aortic valve area. The decrease in CVR was related to severity of AS, increase in hemodynamic load, and reduction in diastolic perfusion time, particularly in the subendocardium. Conclusions — CVR was more severely impaired in the subendocardium in patients with LVH attributable to severe AS. Severity of impairment was related to aortic valve area, hemodynamic load imposed, and diastolic perfusion rather than to LVM.

In a recent issue of the Journal , Arshad et al. ([1][1]) reported a significantly greater reduction in death and heart failure with cardiac resynchronization therapy defibrillators (CRT-D) in women than in men. In their discussion, they described the characteristics of the patients. We wish to

Objective: Absolute myocardial blood flow (MBF) is not well-defined in large normal populations, and appears to be heterogeneous in both humans and animals. These factors contribute to the difficulties in defining resting MBF to hibernating myocardium. We therefore assessed absolute baseline and hyperemic MBF in a large population of normal humans. Methods: MBF was quantified by positron emission tomography with oxygen-15-labeled water at baseline and during hyperemia induced by either adenosine or dipyridamole in 131 men and 38 women, aged 21-86 (mean 46+/-12) years. MBF was corrected for workload using the rate-pressure product (RPP). Results: Uncorrected baseline MBF ranged from 0.590 to 2.050 (mean 0.985+/-0.230) ml/min/g (coefficient of variation=27%), and corrected MBF from 0.736 to 2.428 (mean 1.330+/-0.316) ml/min/g (coefficient of variation=24%). MBF in the inferior region was significantly (P

Aims To assess the accuracy of positron emission tomography to predict recovery of global cardiac function after revascularization in patients with coronary artery disease.Methods and Results One hundred and seventy-eight patients (157 male, 58 +/- 10 years) with coronary artery disease and left ventricular dysfunction (mean ejection fraction 39 +/- 14%) were enrolled in six European centres. They underwent a common protocol for the assessment of viability using F-18-fluoro-2-deoxyglucose (FDG) positron emission tomography during a standardized euglycaemic hyperinsulinaemic glucose clamp before revascularization by either surgery (n = 140) or angioplasty (n = 38). Seven patients were excluded because of incomplete revascularization of a dysfunctional region. Based on the recovery of global ejection fraction 2-6 months after revascularization, patients were classified into two groups: 82 patients who had a >5% improvement in ejection fraction postoperatively, and 89 patients without postoperative ejection fraction improvement. Optimal cut-off points for postoperative improvement of global cardiac function were computed, using receiver operating curve analysis. The highest sensitivity (79%) and specificity (55%) for predicting postoperative ejection fraction improvement by positron emission tomography was found when three or more dysfunctional segments had a relative FDG uptake >45% of normal remote myocardium (overall accuracy 67%).Conclusions In a large cohort of coronary patients with impaired ejection fraction, FDG positron emission tomography demonstrated high sensitivity and moderate specificity to predict improvement of cardiac function after coronary revascularization.

The effect of coronary artery bypass grafting (CABG) on absolute myocardial blood flow (MBF) has not been investigated previously. MBF (ml · min−1· g−1) was measured at rest and during hyperemia (0.56 mg/kg iv dipyridamole) using H215O and positron emission tomography in eight patients with three-vessel disease before surgery and 1 and 6 mo after full revascularization. Baseline MBF was 0.87 ± 0.12 preoperatively and 1.04 ± 0.14 and 0.95 ± 0.13 at 1 and 6 mo after CABG, respectively ( P < 0.05, 6 mo vs. preoperatively). Hyperemic MBF was 1.36 ± 0.28 preoperatively and increased to 1.98 ± 0.50 and 2.45 ± 0.64 at 1 and 6 mo after CABG, respectively ( P < 0.01, 6 mo vs. preoperatively). Coronary vasodilator reserve (hyperemic/baseline MBF) increased from 1.59 ± 0.40 preoperatively to 1.93 ± 0.13 and 2.57 ± 0.49 at 1 and 6 mo, respectively ( P < 0.05, 6 mo vs. preoperatively). Minimal (dipyridamole) coronary resistance (mmHg · min · g−1· ml−1) fell progressively from 59.37 ± 14.56 before surgery to a nadir of 35.76 ± 10.12 at 6 mo after CABG ( P < 0.01 vs. preoperatively). The results of the present study confirm that CABG improves coronary vasodilator reserve progressively as a result of reduction in minimal coronary resistance. These data suggest persistent microvascular dysfunction that recovers slowly after surgery.

Angina pectoris is a common symptom and one that can have profound implications for the patient. However, it correlates poorly with the extent of myocardial ischaemia and with prognosis. In order to understand more fully the heterogeneity of the experience of chest pain, we have adopted the technique of functional neuroimaging, where positron emission tomography is used to measure regional cerebral blood flow as an index of regional neuronal activation, during myocardial ischaemia in patients with coronary artery disease. Fire have been able to delineate those brain areas that are involved in the perception of angina: the hypothalamus, periaquaductal grey, thalami and bilaterally the prefrontal cortex and in the left the inferior anterocaudal cingulate cortex. By studying patients with silent myocardial ischaemia, we have established that the silence is not merely a matter of impaired afferent signalling resulting from autonomic neuropathy, but that it is associated with a failure of transmission of signals from the thalamus to the frontal cortex. At the other end of the spectrum, we have studied patients with syndrome X, a condition of chest pain with ischaemic-like stress electrocardiography (ECG) but entirely normal coronary angiogram; ton the basis of our own and other data we consider an ischaemic aetiology to be most unlikely in this condition). In syndrome X, distinct patterns of cerebral activation were found with characteristic activation of the right anterior insula at its junction with the frontal operculum. In conclusion, we present a unified view of the cerebral handling of afferent signals from the heart throughout this spectrum of experience of chest pain, a view that accounts for the clinical features of the patients studied.

OBJECTIVES The present study evaluates the impact of total cholesterol (TC) and its subfractions on coronary flow reserve (CFR), an index of the integrated function of the coronary circulation, in asymptomatic subjects. BACKGROUND Endothelial dysfunction of the coronary microcirculation has been reported in asymptomatic subjects with hypercholesterolemia. METHODS Using oxygen-15-labeled water and positron emission tomography, myocardial blood flow (MBF, in ml/min per g) was measured at rest and during intravenous adenosine (140 mu g/kg body weight per min) in 80 asymptomatic nonsmoking men: group 1 (n = 61; age 45 +/- 7 years) had normal TC (less than or equal to 6.5 mmol/liter or less than or equal to 250 mg/dl) and group 2 (n = 19; age 48 +/- 10 years) had elevated TC. RESULTS Total cholesterol were 5.1 +/- 0.8 and 7.2 +/- 0.7 mmol/liter in groups 1 and 2 (p < 0.0005), respectively; low density lipoprotein (LDL) cholesterol levels were 3.2 +/- 0.8 and 4.9 +/- 0.7 mmol/liter (p < 0.0005); high density lipoprotein (HDL) cholesterol levels were 1.1 +/- 0.3 and 1.0 +/- 0.4 mmol/liter (p = NS); and triglyceride levels were 1.8 +/- 1.3 and 3.0 +/- 1.8 mmol/liter (p < 0.005). Groups 1 and 2 did not differ with regard to MBF at rest (0.87 +/- 0.14 vs. 0.84 +/- 0.14), MBF during adenosine (3.63 +/- 1.02 vs. 3.30 +/- 0.86) or CFR (4.23 +/- 1.29 vs. 3.95 +/- 0.93). A significant but weak correlation was found between CFR and HDL in group 1 (r = 0.29, p < 0.05), but not in group 2. In contrast, a significant inverse correlation between LDL and CFR was found in group 2 (r = -0.61, p < 0.05), but not in group 1. CONCLUSION Low density lipoprotein cholesterol but not TC correlated inversely with CFR in hypercholesterolemic subjects. Thus, LDL-induced coronary microvascular dysfunction could play an important role in the pathogenesis of coronary artery disease and its complications. (J Am Coil Cardiol 2000;36:103-9) (C) 2000 by the American College of Cardiology.

Background: Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors.Methods: The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack.Results: Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (−13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo.Conclusions: These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

To the Editor: We read the recent article by Bottcher et al1 with interest. Unfortunately, the authors do not discuss their findings in the light of a previous study by our group.2 This study is quite relevant to their work and was published in Circulation 5 years ago. In our experiment, we also used positron emission tomography to measure myocardial blood flow (MBF) at rest and after the administration of intravenous dipyridamole in patients with syndrome X (n=29) and in a substantial control group (n=20). Our principal finding was that no significant differences existed between patients and controls with respect to myocardial blood flow (Figure 1⇓). With a broader range of controls, Bottcher et al’s corresponding figure (Figure 2⇓) would probably not be distinguishable from ours. Although Bottcher et al’s data are quite consistent with ours in a number of respects, their interpretation of the data is perplexing. For example, on …

Background —The frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergic properties suggest an involvement of the cardiac adrenergic system in arrhythmogenesis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by 123 I-MIBG–single-photon emission computed tomography. Methods and Results —This study investigated neuronal reuptake of norepinephrine (uptake-1) and β-adrenergic receptor density in 8 patients with ARVC and 29 age-matched control subjects. All subjects underwent positron emission tomography with the volume of distribution (V d ) of [ 11 C]hydroxyephedrine ( 11 C-HED) used to assess presynaptic norepinephrine reuptake, the maximum binding capacity (B max ) of [ 11 C]CGP-12177 ( 11 C-CGP-12177) to assess postsynaptic β-adrenergic receptor density, and [ 15 O]H 2 O for quantification of myocardial blood flow. Patients with ARVC demonstrated a highly significant global reduction in postsynaptic β-adrenergic receptor density compared with that in control subjects (B max of 11 C-CGP-12177: 5.9±1.3 vs 10.2±2.9 pmol/g tissue, P d of 11 C-HED: 59.1±25.2 vs 71.0±18.8 mL/g tissue, NS). There were no differences in myocardial blood flow between the groups, and plasma norepinephrine was within normal limits in patients and control subjects. Conclusions —The findings demonstrate a significant reduction of myocardial β-adrenergic receptor density in patients with ARVC. This may result from a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the result of impaired presynaptic catecholamine reuptake. These findings give new insights into the pathophysiology of arrhythmogenesis in ARVC, with potential impact on diagnostic evaluation and therapeutic management.

BACKGROUND—In patients with postischaemic left ventricular dysfunction, segments recovering function after revascularisation (hibernating myocardium) may not respond during dobutamine echocardiography, despite preserved [18F] 2-fluoro-2-deoxy-D-glucose (FDG) uptake at positron emission tomography. OBJECTIVE—To investigate whether this lack of response might reflect the degree of ultrastructural change in hibernating myocardium. METHODS—Transmural biopsies were obtained from 22 dysfunctional segments in 22 patients during coronary artery bypass grafting and examined by light and electron microscopy. Wall motion scores and coronary vasodilator reserve were assessed before and after coronary artery bypass grafting (CABG). RESULTS—Mean (SD) wall motion score improved in all segments following CABG (from 2.24 (0.4) to 1.55 (0.4); p

OBJECTIVE—To determine whether pharmacological stress leads to prolonged but reversible left ventricular dysfunction in patients with coronary artery disease, similar to that seen after exercise. DESIGN—A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and dobutamine induced ischaemia. SUBJECTS—10 patients with stable angina, angiographically proven coronary artery disease, and normal left ventricular function. INTERVENTIONS—Treadmill exercise and dobutamine stress were performed on different days. Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test. RESULTS—Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction. There was no difference in the maximum double product (p = 0.53) or ST depression (p = 0.63) with either form of stress. After exercise, ejection fraction was reduced at 15 and 30 minutes compared with baseline (mean (SEM), −5.6 (1.5)%, p

Changes in the numbers of human cardiac adrenoceptors (ARs) are associated with various diseases, such as myocardial ischemia, congestive heart failure, cardiomyopathy and hypertension. There is a clear need for capability to assess human cardiac ARs directly in vivo. Positron emission tomography (PET) is an imaging technique that provides this possibility, if effective radioligands can be developed for the targeted ARs. Here, the status of myocardial AR radioligand development for PET is described. Currently, there exist effective radioligands for imaging beta-ARs in human myocardium. One of these, [11C](S)-CGP 12177, is applied extensively to clinical research with PET, sometimes with other tracers of other aspects of the noradrenalin system. Alternative radioligands are in development for beta-ARs, including beta 1-selective radioligands. A promising radioligand for imaging myocardial alpha 1-ARs, [11C]GB67, is now being evaluated in human PET experiments.

Background —Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. Methods and Results —We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects ( P Conclusions —The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Atherosclerotic disease of the vascular system is a continuum. Disease may begin early in life, but it does not become clinically overt until atherosclerotic plaques reach a critical stage. The clinical manifestations of the disease are related to the impairment of tissue perfusion caused by the

This review article discusses some of the potentially beneficial effects of calcium antagonists on the coronary microcirculation. These include their vasodilating action on coronary resistance vessels as well as their effects on extravascular resistance (i.e. intramyocardial pressure). Examples are presented of how the non-invasive measurement of myocardial blood flow and flow reserve by means of positron emission tomography (PET) can contribute to the understanding of the effects of drug treatment on the coronary microcirculation. The action of calcium antagonists on the coronary microcirculation can contribute to explain the efficacy, of these drugs against ischemia and ischemia-reperfusion damage.

OBJECTIVE—To assess the impact of revascularisation of viable myocardium on survival in patients with postischaemic heart failure. METHODS—35 patients (mean (SD) age 58 (7) years) with severe heart failure (New York Heart Association (NYHA) functional class ⩾ III), mean left ventricular ejection fraction (LVEF) 24 (7)% (range 10-35%), and limited exercise capacity (peak oxygen consumption (VO2) 15 (4) ml/kg/min) were studied. 21/35 patients had no angina. Myocardial viability was assessed with quantitative positron emission tomography and the glucose analogue 18F-fluorodeoxyglucose (FDG) (viable segment = FDG uptake ⩾ 0.25 µmol/min/g) in all patients before coronary artery bypass grafting. Patients were divided into two groups: group 1, ⩾ 8 viable dysfunctional segments (mean 12 (2), range 8-15); and group 2