Search

Cardiac and cerebrovascular diseases are currently the leading causes of mortality and disability worldwide. Both the heart and brain display similar vascular anatomy, with large conduit arteries running on the surface of the organ providing tissue perfusion through an intricate network of penetrating small vessels. Both organs rely on fine tuning of local blood flow to match metabolic demand. Blood flow regulation requires adequate functioning of the microcirculation in both organs, with loss of microvascular function, termed small vessel disease (SVD) underlying different potential clinical manifestations. SVD in the heart, known as coronary microvascular dysfunction, can cause chronic or acute myocardial ischemia and may lead to development of heart failure. In the brain, cerebral SVD can cause an acute stroke syndrome known as lacunar stroke or more subtle pathological alterations of the brain parenchyma, which may eventually lead to neurological deficits or cognitive decline in the long term. Coronary microcirculation cannot be visualized in vivo in humans, and functional information can be deduced by measuring the coronary flow reserve. The diagnosis of cerebral SVD is largely based on brain magnetic resonance imaging, with white matter hyperintensities, microbleeds, and brain atrophy reflecting key structural changes. There is evidence that such structural changes reflect underlying cerebral SVD. Here, we review interactions between SVD and cardiovascular risk factors, and we discuss the evidence linking cerebral SVD with large vessel atheroma, atrial fibrillation, heart failure, and heart valve disease.

In recent years, it has become apparent that coronary microvascular dysfunction plays a pivotal pathogenic role in angina pectoris. Functional and structural mechanisms can affect the physiological function of the coronary microvasculature and lead to myocardial ischemia in people without coronary atheromatous disease and also in individuals with obstructive coronary artery disease. Abnormal dilatory responses of the coronary microvessels, coronary microvascular spasm, and extravascular compressive forces have been identified as pathogenic mechanisms in both chronic and acute forms of ischemic heart disease. The condition characterized by anginal symptoms and evidence of myocardial ischemia triggered by coronary microvascular dysfunction, in the absence of obstructive coronary disease, is known as microvascular angina. The concept of microvascular angina, however, may extend further to include patients with obstructive coronary artery disease and individuals with angina after coronary revascularization or heart transplantation because coronary microvascular dysfunction contributes to myocardial ischemia in many such patients. Patients with microvascular angina constitute a sizeable proportion of all cases of stable angina undergoing diagnostic coronary angiography and of those with persisting angina after successful coronary revascularization. Coronary microvascular dysfunction is also often responsible for angina in individuals with cardiomyopathy and heart valve disease as well as acute coronary syndrome cases such as Takotsubo syndrome and myocardial infarction with no obstructive coronary artery disease. Patients with stable microvascular angina present typically with effort or rest chest pain and a reduced coronary flow reserve or microvascular spasm. This condition, which affects women and men, can markedly impair quality of life and prognosis and represents a substantial cost burden to healthcare systems and individuals alike. In recent years, progress in the diagnosis of myocardial ischemia and the use of tests to investigate functional and structural causes for a reduced coronary flow reserve and microvascular spasm have allowed the identification of an increased number of cases of microvascular angina in everyday clinical practice. Although some of the available anti-anginal drugs may be helpful, treatment of coronary microvascular dysfunction remains a major challenge. The present article discusses the fundamental role that coronary microvascular dysfunction plays in the pathogenesis of ischemic heart disease, the clinical characteristics of patients presenting with microvascular angina, and possible diagnostic and therapeutic strategies.

The Cardiovascular Disease in Women Committee of the American College of Cardiology, in conjunction with interested parties (from the National Heart, Lung, and Blood Institute, American Heart Association, and European Society of Cardiology), convened a working group to develop a consensus on the syndrome of myocardial ischemia with no obstructive coronary arteries. In general, these patients have elevated risk for a cardiovascular event (including acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures) compared with reference subjects and appear to be at higher risk for development of heart failure with preserved ejection fraction. A subgroup of these patients also has coronary microvascular dysfunction and evidence of inflammation. This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area. Working group members critically reviewed available literature and current practices for risk assessment and state-of-the-science techniques in multiple areas, with a focus on next steps needed to develop evidence-based therapies. This report presents highlights of this working group review and a summary of suggested research directions to advance this field in the next decade.

We wish to thank Drs Mewton and Croisille for their interest in our study1 and for their proactive comments. In our study, among the 31 patients with angiographic no reflow that represented 36% of the overall population, 18 had impaired thrombolysis in myocardial infarction flow …

Patients and animal models of arterial hypertension are characterized by structural and functional abnormalities of the coronary microcirculation. Using a translational approach, we ascertained whether antihypertensive treatment can reverse microvascular remodelling and improve myocardial perfusion.In 20 hypertensive patients with left ventricular hypertrophy, blood pressure, left ventricular mass index and myocardial blood flow were measured at baseline and after 6 months of treatment with perindopril + indapamide. In spontaneously hypertensive rats, blood pressure, coronary flow and histomorphometry of intramural coronary arterioles were measured after 8 weeks of treatment with placebo or perindopril + indapamide.In patients, treatment decreased blood pressure (161 ± 10/96 ± 5 to 136 ± 12/81 ± 6 mmHg; P0.0001) and left ventricular mass index (93 ± 16 to 85 ± 17 g/m; P0.01) while increasing baseline (0.69 ± 0.13 to 0.88 ± 0.36 ml/min per g; P0.05) and hyperaemic myocardial blood flow (1.42 ± 0.32 to 1.94 ± 0.99 ml/min per g; P0.05). In rats treated with perindopril + indapamide (n = 11), blood pressure was 93 ± 18/55 ± 18 mmHg compared to 215 ± 18/161 ± 17 mmHg in placebo (n = 6; P0.001), baseline flow was unchanged whilst hyperaemic coronary flow was 19.89 ± 3.50 vs. 12.15 ± 0.99 ml/min per g, respectively (P0.01). The medial area of intramural arterioles was 1613 ± 409 with perindopril + indapamide and 8118 ± 901 μm with placebo (P0.001).In patients with arterial hypertension and left ventricular hypertrophy, perindopril + indapamide reduced blood pressure and left ventricular mass index and improved resting and hyperaemic myocardial blood flow. Data in rats provide evidence that the improvement in coronary flow observed after treatment is due to reverse remodelling of intramural coronary arterioles and improved microvascular function.

With the widespread clinical use of angiography in the 70s of the last century, it became apparent that a sizeable proportion of patients referred for anginal symptoms had angiographically normal coronary arteries. These findings stimulated a hot debate among clinicians and scientists on the mechanisms and significance of this condition that seemed to be by far more frequent in women. For many years, there was uncertainty on the real significance of this condition that was often accompanied by electrocardiographic evidence of ischemia during stress.1 The situation began to unravel when myocardial perfusion studies demonstrated that many of these patients had evidence of abnormal perfusion. Cannon and Epstein2 introduced the term microvascular angina (MVA) for this patient population, in view of what appeared to be heightened sensitivity of the coronary microcirculation to vasoconstrictor stimuli associated with a limited microvascular vasodilator capacity. They proposed that dysfunction of small intramural prearteriolar coronary arteries might be the pathogenetic cause of this syndrome. See Article by Thomson et al In the past 20 years, it has become apparent that symptoms and signs of myocardial ischemia, despite normal coronary angiography, could be demonstrated in several clinical conditions, from subjects with risk factors for coronary artery disease to patients with different types of myocardial diseases. The term coronary microvascular dysfunction (CMD) was coined to provide an overarching definition that would encompass a large number of clinical scenarios characterized by evidence of a reduced coronary flow reserve (CFR) that could not be explained by an …

A meta-analysis of 13 randomized placebo-controlled trials demonstrated a benefit for dipyridamole therapy, particularly with longer duration of treatment. Although the mechanism of this effect is not well understood, dipyridamole increases endogenous tissue adenosine, which may have a beneficial effect on myocardial perfusion. Therefore, we measured the effects of dipyridamole on myocardial blood flow (MBF) and coronary flow reserve (CFR) by using positron emission tomography and H2O in patients with coronary artery disease.Forty-four patients with angiographically documented coronary artery disease were double-blind randomized to either oral dipyridamole [200 milligrams (mg) twice daily (bd)] or placebo as add-on to conventional antianginal treatment for 24 weeks. MBF was measured at rest and during dobutamine stress at baseline and study completion for the region subtended by the most severe coronary artery stenosis (Isc) and remote myocardium subtended by arteries with minimal or no disease (Rem). CFR was calculated as MBF-peak/MBF-rest.Thirty-five patients completed the study. Isc MBF-rest decreased in patients receiving dipyridamole (0.10 mL/minute/g; P = 0.03) and increased in the placebo group (0.16 mL/minute/g; P = 0.01) during the 24-week study. No significant change in MBF-peak was demonstrated in either group. Consequently, Isc-CFR increased significantly in patients receiving dipyridamole (1.65 +/- 0.47 vs 1.83 +/- 0.67; P0.05). By contrast, Isc-CFR decreased significantly in those receiving placebo (1.74 +/- 0.44 versus 1.38 +/- 0.46; P0.03). No change was seen in Rem-CFR territories.At the end of treatment, a reduction in baseline MBF but no significant changes in hyperemic MBF were observed in ischemic myocardial territories, and therefore the significance of the observed improvement in CFR remains unclear.

Background— Life-threatening ventricular tachyarrhythmias can occur in young patients without structural heart disease (idiopathic forms). In many patients, these are typically triggered by an increased sympathetic tone, eg, by physical or mental stress. In contrast, in Brugada syndrome, ventricular tachyarrhythmias more often occur during rest or sleep when the vagal tone is predominant. Furthermore, adrenergic agonists can reduce the level of ST-segment elevation, whereas it is increased by parasympathetic agonists or adrenergic antagonists. The aim of this study was to investigate presynaptic and postsynaptic myocardial sympathetic function in patients with Brugada syndrome. Methods and Results— Nine patients with Brugada syndrome (6 male, 3 female; age, 41±13 years) were enrolled in this study. The cardiac autonomic nervous system was assessed noninvasively, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analogue 11 C-Hydroxyephedrine ( 11 C-HED) and the nonselective β-blocker 11 C-CGP 12177 ( 11 C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11 C-HED, was globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects (92.9±16.2 mL/g versus 69.1±14.2 mL/g; P 11 C-CGP, was similar in patients and control subjects (10.4±6.7 pmol/g versus 10.2±2.9 pmol/g; P =NS). Conclusions— The present study on autonomic innervation in Brugada syndrome describes an enhanced presynaptic norepinephrine recycling with preserved β-adrenoceptor density, further supporting the hypothesis of an autonomic dysfunction in Brugada syndrome. This is a further step toward the understanding of the pathophysiology of the disease with potential future impact on therapeutic strategies.

Background— Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients. Methods and Results— MBF (mL · min −1 · g −1 ) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and 15 O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N G -monomethyl- l -arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P P Conclusions— The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA.

Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death. Accordingly, we measured the expression of survival genes in hibernating myocardium, both in patients surgically treated for hibernation and in a chronic swine model of repetitive ischemia reproducing the features of hibernation. Human hibernating myocardium was characterized by an upregulation of genes and corresponding proteins involved in anti-apoptosis (IAP), growth (VEGF, H11 kinase), and cytoprotection (HSP70, HIF-1α, GLUT1). In the swine model, the same genes and proteins were upregulated after repetitive ischemia, which was accompanied by a concomitant decrease in myocyte apoptosis. These changes characterize viable tissue, because they were not found in irreversibly injured myocardium. Our report demonstrates a novel mechanism by which the activation of an endogenous gene program of cell survival underlies the sustained viability of the hibernating heart. Potentially, promoting such a program offers a novel opportunity to salvage postmitotic tissues in conditions of ischemia.

Background— Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT. Methods and Results— Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129±30 to 94±24 g/m 2 ; P r =0.44; P =0.04). Conclusions— Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.

Coronary vasoconstriction that occurs after percutaneous transluminal coronary angioplasty (PTCA) is abolished by intracoronary phentolamine. An impairment of coronary vasodilator reserve (CVR) has been observed less than or equal to 7 days after successful PTCA. To ascertain whether pretreatment with the or, adrenergic receptor blocker doxazosin could prevent the limitation of CVR after PTCA, we carried out a randomised, double-blind, controlled study on 26 patients with significant (>75%) single vessel disease undergoing PTCA. Twelve patients received doxazosin 4 mg daily in addition to their standard treatment, while 14 patients received matching placebo, starting 11 days before PTCA. Myocardial blood flow (MBF) at, baseline and after i.v. dipyridamole (0.56 mg/kg) was measured within 5 days after PTCA using positron emission tomography (PET) with oxygen-15-labelled water. Angioplasty was successful in all patients with a residual stenosis less than or equal to 35%. At PET scanning, hemodynamic parameters were comparable in the two groups. In the territory subtended by the dilated artery, CVR was significantly higher in patients treated with doxazosin compared with those receiving placebo (2.78 +/- 0.1.21 vs. 1.95 +/- 0.68; p < 0.01). Conversely, CVR in the remote territories subtended by angiographically normal arteries was similar in the two groups (2.53 +/- 0.92 and 2.48 +/- 0.80, respectively; p = NS). Treatment with oral doxazosin in addition to standard antianginal therapy can prevent the impairment of CVR frequently observed despite successful PTCA.

Abstract —The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of α-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of α-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to α-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both α 1 - and α 2 -adrenoceptors in epicardial conduit arteries and microvessels. Such augmented α-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of α 2 -adrenergic coronary constriction.

We sought to test the response of the coronary microcirculation to alpha-adrenoceptor blockade in patients with syndrome X (angina, ischemia-like stress electrocardiogram, and a normal coronary arteriogram). The response of the microcirculation was assessed by quantification of coronary vasodilator reserve (the ratio of hyperemic to resting myocardial blood flow). We investigated 28 patients with syndrome X [18 women, age 54.4 (7.6) years]. Myocardial blood flow was measured at rest and after dipyridamole by using positron emission tomography with H(2)15O. The measurements were made before and after treatment for 10 days with doxazosin (1 mg o.d. for 3 days, followed by 2 mg o.d. for 7 days) or a matched placebo, similarly administered. Patients were randomized to alpha1-blockade or to placebo in double-blind fashion. No significant differences were demonstrable between syndrome X patients treated with doxazosin and those receiving placebo, with respect to resting myocardial blood flow, myocardial blood flow after dipyridamole, or coronary vasodilator reserve (the ratio of the latter two). In addition, no relations were demonstrable among myocardial blood flow, coronary vasodilator reserve, development of chest pain after dipyridamole, or development of ischemia-like ECG changes. Doxazosin had no effect on the perception of chest pain after dipyridamole. No differences were found between the effects of alpha1-blockade with doxazosin or those of placebo with respect to myocardial blood flow in syndrome X. The values obtained for myocardial blood flow and coronary vasodilator reserve for the patients were within the normal range. The data do not support the case for alpha1-mediated vasoconstriction having an etiologic role in the chest pain of syndrome X.

Anginal symptoms and electrocardiographic changes suggestive of myocardial ischemia, despite angiographically normal coronary arteries, are common in patients with cardiomyopathies and those with left ventricular hypertrophy secondary to pressure overload. Studies using positron-emission tomography (PET) to measure regional myocardial blood flow have demonstrated that maximum myocardial blood flow and coronary flow reserve are severely blunted in patients with hypertrophic as well as dilated cardiomyopathy.1,2 In the absence of epicardial stenoses, blunted maximum myocardial blood flow and coronary flow reserve are suggestive of coronary microvascular dysfunction.3,4 Furthermore, it has been demonstrated that in both hypertrophic and dilated cardiomyopathy, the severity of coronary microvascular dysfunction, assessed by measuring myocardial blood flow with PET, is an independent predictor of prognosis.2,5 In patients with cardiomyopathies, coronary microvascular dysfunction can be sustained by a number of different pathogenetic mechanisms. These include structural and functional abnormalities of the intramural arterioles as well as extravascular mechanisms (eg, increased extramural compression).4 Article 161 Anderson-Fabry disease (AFD) is an X-linked deficiency of lysosomal α-galactosidase A.6 This deficiency results in multiorgan damage from glycosphingolipid deposition, leading to renal, cardiac, and cerebrovascular disease and premature death. Patients with AFD complain of angina despite angiographically normal coronary arteries. Recent studies have also shown that there is progressive deterioration in left ventricular systolic function and myocardial scarring in patients with AFD cardiomyopathy. A number of mechanisms may contribute to microvascular dysfunction in these patients. AFD cardiomyopathy is characterized by globotriaosyl-ceramide (Gb3) and related glycosphingolipid deposition in myocytes, conduction tissue, vascular endothelium, and valvular tissue. This is accompanied by secondary changes, such as myocyte hypertrophy and fibrosis, often mimicking hypertrophic cardiomyopathy.7 In the vasculature, Gb3 accumulates in endothelial and smooth muscle cells, possibly causing structural abnormalities that may be responsible for vascular dysfunction. In addition, it …

Background —Postprandial angina pectoris has been recognized for more than two centuries and can be identified in up to 10% of patients with chronic ischemic heart disease. Redistribution of myocardial blood flow, from a region supplied by a severely stenotic coronary artery to those supplied by less diseased or normal vessels, is a potential mechanism of postprandial angina. Methods and Results —To test this hypothesis, we have determined the effects of a standard liquid meal on whole heart and regional myocardial blood flow, measured by means of dynamic positron emission tomography (PET) with 15 O-labeled water in 14 patients with a reproducible history of postprandial angina and 7 matched control subjects. The standard liquid meal precipitated angina pectoris in all patients. Baseline whole heart blood flow was similar and increased normally after the meal in patients (0.97±0.14 to 1.14±0.25 mL · min −1 · g −1 , P −1 · g −1 , P P P =NS versus baseline). In patients, analysis of regional myocardial blood flow demonstrated decreased myocardial blood flow in territories supplied by stenotic arteries (1.01±0.35 to 0.76±0.27 mL · min −1 · g −1 , P −1 · g −1 , P Conclusions —The standard liquid meal induced angina pectoris in patients with coronary artery disease. Although whole heart blood flow increased appropriately for the greater cardiac work, there was a redistribution of regional blood flow from territories supplied by severely stenosed coronary arteries to those supplied by less diseased or normal arteries. This redistribution may be the cause of myocardial ischemia in postprandial angina.

The long-term consequences of CAD remain a prominent clinical problem. Particularly with new therapeutic strategies that reduce the mortality associated with acute coronary syndromes, more patients suffer from the long-term sequelae of this condition. In this setting, the identification of those segments of myocardium that appear dysfunctional distal to coronary stenoses and that can improve after coronary revascularization is of considerable clinical importance. Although the diagnostic and therapeutic aspects of this problem are clearly defined, the pathophysiological mechanisms underlying the dysfunctional myocardium are controversial. It was demonstrated more than 20 years ago1 2 that resting wall-motion abnormalities in patients with CAD can improve after administration of an inotropic agent or after coronary bypass. An article published in 1978 by Diamond et al3 presaged the concept of hibernating myocardium: “Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic non-infarcted myocardium can exist in a state of function hibernation.” Rahimtoola, in an article published in 1985,4 popularized this concept and later suggested that “hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand.”5 Since the introduction of the term “hibernation,”3 4 5 6 the clinical importance of reversible left ventricular dysfunction has been widely accepted. The concept of an adaptive process that decreases myocardial oxygen consumption in the presence of either chronically or intermittently reduced oxygen delivery has generated considerable clinical and experimental interest. Accordingly, our aims were to (1) review the current criteria of the definition of hibernating myocardium, (2) summarize recent clinical as well as experimental data pertaining to this subject, …

Background Chronically dysfunctional myocardium may improve after coronary revascularization. This condition was thought to be due to a chronically reduced myocardial blood flow (MBF). Recently, however, it has been shown that in patients without previous infarction but with chronic left ventricular dysfunction, baseline MBF was normal. Methods and Results To study the pathophysiology of chronic left ventricular dysfunction in patients with previous infarction, regional MBF (milliliter per minute per gram of water-perfusable tissue) and glucose utilization (MRG; micromoles per minute per gram) during hyperinsulinemic euglycemic clamp were measured with positron emission tomography in 30 patients before bypass. At baseline, 133 myocardial segments were normal, and 107 were dysfunctional. After revascularization, 59 of 107 segments improved, while 48 of 107 were unchanged. MBF was 0.92±0.25 mL · min −1 · g −1 in normal segments, 0.87±0.31 mL · min −1 · g −1 in improved segments ( P =NS versus normal), and 0.82±0.40 mL · min −1 · g −1 in unchanged segments ( P 0.42 mL · min −1 · g −1 , a cutoff value corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71±0.14 μmol · min −1 · g −1 in 9 age-matched normal subjects, 0.45±0.19 μmol · min −1 · g −1 ( P −1 · g −1 in improved segments ( P =NS versus normal), and 0.34±0.17 μmol · min −1 · g −1 in unchanged segments ( P Conclusions The results suggest that resting MBF measured with 15 O-labeled water in chronically dysfunctional segments is not reduced and that the myocardium of these patients is less sensitive to insulin than that of normal subjects.

Premature coronary atherosclerosis, which is actually seen as an active inflammatory process, is an established complication of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We hypothesized that exposure to chronic inflammation, even in the absence of classical cardiovascular risk factors (CVRF), could result in coronary microvascular dysfunction (CMD), an early marker of coronary atherosclerosis. By means of positron emission tomography in combination with oxygen-15 labeled water, myocardial blood flow (MBF) was measured at rest and during iv adenosine infusion (140 μg/kg/min) in 13 SLE and 12 RA patients (mean [±SD] age 44±10 years) without CVRF. All patients underwent coronary angiography using multi-slice (64 slices) computed tomography and only those with none or trivial coronary artery disease (

Blood oxygenation level-dependent (BOLD) MRI clinical studies at 1.5 Tesla (T) have been principally limited by low signal to noise. We sought to apply this method at 3T in patients with coronary artery disease (CAD) and normal volunteers, and validated it against perfusion measurements by PET. Twenty-two patients (age 62±8 yrs, 16 men) with CAD (at least 1 stenosis > 50% on quantitative coronary angiography-QCA) and 10 normal volunteers (age 52±7 yrs, 7 men) underwent 3T BOLD MRI and PET. For BOLD MRI a mid-ventricular slice was acquired every 30sec at rest and during adenosine stress (140 μg/kg/min). A set of 6 images was acquired at rest and at peak stress. Using PET with oxygen-15 labelled water, myocardial blood flow (MBF) was measured at baseline and during adenosine hyperemia. The BOLD short-axis view was divided into 6 segments, according to the mid-ventricular segments of the 17-AHA segment model, and mean signal intensities (SI) were calculated using QMass (Medis) software. PET images were analyzed with MATLAB software (MathWorks Inc.) and registered with the BOLD short-axis image using anatomical landmarks. Taking QCA as the gold standard, cut-off values for stress MBF (< 2.57ml/min/g - AUC 0.79) and BOLD SI change (< 4.75% -AUC 0.78) were determined to define ischemic segments. Rest MBF, stress MBF, coronary flow reserve and BOLD-SI change of ischemic (n=69), remote to ischemia (n=73) and normal segments (n=60) are shown in table . BOLD MRI and PET agreed on the presence or absence of ischemia in 18 of the 22 patients (82%), and in all normals. With regards to per segment analysis: taking PET as the gold standard and by applying the cut-off values for stress MBF and BOLD SI, BOLD MRI had only moderate sensitivity (61%) but good specificity (88%) for the identification of ischemia. T2-prepared SSFP 3T BOLD imaging is feasible in the clinical setting and has good agreement with PET perfusion measurements for the detection of myocardial ischemia.

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 …

To the Editor: The recent publication of findings on the utilization rate for glucose (MRglu) in the ischemic and reperfused isolated rat heart1 concludes that the lumped constant (LC) for [18F]2-deoxy-2-fluoroglucose (FDG) is variable under conditions in which free fatty acids (FFAs) are the main metabolic substrate. The article thus signals a cautionary message to those workers using FDG in the fasted state. However, what is not stated in the take-home message is the important finding that the LC is unaffected by ischemia and reperfusion when circulating FFAs are low. The authors assert that the coadministration of glucose and FFAs results in a far more physiological condition than glucose alone, and thus they pay scant attention to the equally physiological condition in which insulin levels are increased and FFA concentrations greatly diminished. This is unfortunate, …

Background. We assessed the relation between the severity of stenosis in a coronary artery and the degree of impairment of myocardial blood flow. Studies in laboratory animals have shown that as the degree of coronary-artery stenosis increases, the maximal coronary flow measured after maximal vasodilatation progressively decreases, with a concomitant decrease in basal flow. However, this relation has not been carefully documented in humans through measurement of myocardial blood flow. Methods, We studied 35 patients with single-vessel coronary artery disease and normal left ventricular function and 21 age-matched controls. Regional myocardial blood flow in the area supplied by the stenosed artery was measured by positron-emission tomography with oxygen-15-labeled water while the subject was at rest (basal flow) and during hyperemia induced by the intravenous administration of the vasodilator adenosine (140 mu g per kilogram of body weight per minute) or dipyridamole (0.56 mg per kilogram). Results. The mean (+/-SD) basal myocardial blood flow was 1.14+/-0.42 ml per minute per gram of tissue in the patients and 1.13+/-0.26 ml per minute per gram in the controls; during hyperemia, myocardial flow was 2.10+/-1.16 and 3.37+/-1.25 ml per minute per gram (P