Myocardial blood flow measurement by PET: technical aspects and clinical applications.

The availability of plastic microspheres labeled with different -emitting isotopes has allowed the quantification of blood flow in different organs, including the heart (1). In the past 3 decades this has made it possible to study the changes in myocardial blood flow (MBF) under different physiologic and pathophysiologic conditions in experimental animals. In a similar fashion, the development of PET has allowed the noninvasive quantification of regional MBF in healthy humans and patients with different cardiovascular diseases. This article summarizes how PET measurement of MBF has contributed to advance our understanding of cardiac physiology and pathophysiology.

[1]  Y. Yonekura,et al.  Generator-produced copper-62-PTSM as a myocardial PET perfusion tracer compared with nitrogen-13-ammonia. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  R. Berne,et al.  Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta. , 1990, The American journal of physiology.

[3]  H. Schelbert,et al.  Noninvasive quantification of myocardial blood flow in humans. A direct comparison of the [13N]ammonia and the [15O]water techniques. , 1996, Circulation.

[4]  S. Kaul,et al.  Microvasculature in acute myocardial ischemia: part II: evolving concepts in pathophysiology, diagnosis, and treatment. , 2004, Circulation.

[5]  C. Hennekens,et al.  Statement on smoking and cardiovascular disease for health care professionals. American Heart Association. , 1992, Circulation.

[6]  M. Schwaiger,et al.  Gender differences in myocardial blood flow dynamics: lipid profile and hemodynamic effects. , 1999, Journal of the American College of Cardiology.

[7]  Adriaan A. Lammertsma,et al.  Noninvasive Quantification of Regional Myocardial Blood Flow in Coronary Artery Disease With Oxygen‐15–Labeled Carbon Dioxide Inhalation and Positron Emission Tomography , 1991, Circulation.

[8]  K. Yamada,et al.  Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. , 1999, Journal of the American College of Cardiology.

[9]  K. Kugiyama,et al.  Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation. , 1998, Circulation.

[10]  G. Hutchins,et al.  Heterogeneity of regional nitrogen 13-labeled ammonia tracer distribution in the normal human heart: Comparison with rubidium 82 and copper 62-labeled PTSM , 1994, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[11]  M. Phelps,et al.  Reproducibility of measurements of regional resting and hyperemic myocardial blood flow assessed with PET. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[12]  P. Kaufmann,et al.  Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. , 2000, Journal of the American College of Cardiology.

[13]  B. Strauer.  Ventricular function and coronary hemodynamics in hypertensive heart disease. , 1979, The American journal of cardiology.

[14]  P. Elliott,et al.  Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy , 2001, The Lancet.

[15]  M. Omata,et al.  Reduced myocardial flow reserve in non-insulin-dependent diabetes mellitus. , 1997, Journal of the American College of Cardiology.

[16]  D. Sackett,et al.  Relation between aortic atherosclerosis and the use of cigarettes and alcohol. An autopsy study. , 1968, The New England journal of medicine.

[17]  R. Wilson,et al.  Methods of measurement of myocardial blood flow in patients: a critical review. , 1987, Circulation.

[18]  K. Kugiyama,et al.  Does passive smoking impair endothelium-dependent coronary artery dilation in women? , 1998, Journal of the American College of Cardiology.

[19]  P. Kaufmann,et al.  Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. , 1996, Circulation.

[20]  M. Phelps,et al.  Effect of short-term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve. , 1995, Circulation.

[21]  F. Prinzen,et al.  Blood flow distributions by microsphere deposition methods. , 2000, Cardiovascular research.

[22]  E. Braunwald,et al.  Idiopathic Hypertrophic Subaortic Stenosis: Clinical Analysis of 126 Patients with Emphasis on the Natural History , 1968, Circulation.

[23]  K. Gould,et al.  Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilatation. I. Physiologic basis and experimental validation. , 1978, The American journal of cardiology.

[24]  P. McNamara,et al.  Morbidity and Mortality in Diabetics In the Framingham Population: Sixteen Year Follow-up Study , 1974, Diabetes.

[25]  R D Fish,et al.  Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. , 1990, Circulation.

[26]  R. Reneman,et al.  The importance of size and diameter distribution of the microspheres for accurate determination of regional myocardial blood flow (MBF). , 1977, Bibliotheca anatomica.

[27]  E. Bassenge,et al.  Coronary vasodilation to acetylcholine, adenosine and bradykinin in dogs: effects of inhibition of NO-synthesis and captopril. , 1993, European heart journal.

[28]  S. Bergmann,et al.  Noninvasive delineation of the effects of moderate aging on myocardial perfusion. , 1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[29]  C. Tracy,et al.  Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. , 1987, Journal of the American College of Cardiology.

[30]  M. Walsh,et al.  Augmented myocardial perfusion reserve after coronary angioplasty quantified by positron emission tomography with H2(15)O. , 1990, Journal of the American College of Cardiology.

[31]  O Muzik,et al.  Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. , 1999, Circulation.

[32]  G. Cheon,et al.  Quantification of Regional Myocardial Blood Flow Using Dynamic H 2 15 O Pet and Factor Analysis , 2001 .

[33]  Y. Yonekura,et al.  Measurement of regional cerebral blood flow with copper-62-PTSM and a three-compartment model. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[34]  B. Carabello.  The relationship of left ventricular geometry and hypertrophy to left ventricular function in valvular heart disease. , 1995, The Journal of heart valve disease.

[35]  M J Welch,et al.  Quantification of regional myocardial blood flow in vivo with H2150* , 2005 .

[36]  B. Maron,et al.  Implications of left ventricular remodeling in hypertrophic cardiomyopathy. , 1998, The American journal of cardiology.

[37]  G. Hutchins,et al.  A region of interest strategy for minimizing resolution distortions in quantitative myocardial PET studies. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[38]  J. Shepherd.  A call to action. , 1998, European heart journal.

[39]  B. Maron,et al.  Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. , 1995, Journal of the American College of Cardiology.

[40]  W. Kübler,et al.  Coronary dilatory capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients. , 1983, The American journal of cardiology.

[41]  M J Welch,et al.  Quantification of Regional Myocardial Perfusion With Generator‐Produced 62Cu‐PTSM and Positron Emission Tomography , 1993, Circulation.

[42]  S. Vatner,et al.  Spatial heterogeneity of myocardial blood flow presages salvage versus necrosis with coronary artery reperfusion in conscious baboons. , 1996, Circulation.

[43]  B. Strauer,et al.  Remodelling of intramyocardial arterioles and extracellular matrix in patients with arterial hypertension and impaired coronary reserve. , 1995, European heart journal.

[44]  G Thiene,et al.  Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. , 2000, Human pathology.

[45]  M. Marcus,et al.  Heterogeneous Microvascular Coronary α‐Adrenergic Vasoconstriction , 1989 .

[46]  H. Drexler,et al.  Endothelial Dysfunction of the Coronary Microvasculature Is Associated With Impaired Coronary Blood Flow Regulation in Patients With Early Atherosclerosis , 1991, Circulation.

[47]  I. Olivotto,et al.  Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. , 2003, The New England journal of medicine.

[48]  O. Hess,et al.  Regional myocardial ischemia in hypertrophic cardiomyopathy: impact of myectomy. , 2004, The Journal of thoracic and cardiovascular surgery.

[49]  F Bender,et al.  Identification of a rare congenital anomaly of the myocardium by two-dimensional echocardiography: persistence of isolated myocardial sinusoids. , 1984, The American journal of cardiology.

[50]  B. Maron,et al.  Impact of Atrial Fibrillation on the Clinical Course of Hypertrophic Cardiomyopathy , 2001, Circulation.

[51]  Cyrill Burger,et al.  CT attenuation correction for myocardial perfusion quantification using a PET/CT hybrid scanner. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[52]  G. Hutchins,et al.  Metabolic fate of [13N]ammonia in human and canine blood. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[53]  P. Kaufmann,et al.  High level of cholesterol increases coronary vasomotor tone during exercise , 2000, Coronary artery disease.

[54]  J. Ritchie,et al.  Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation. III. Clinical trial. , 1978, The American journal of cardiology.

[55]  B. Maron,et al.  Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. , 1999, JAMA.

[56]  P. Merlet,et al.  Assessment of coronary reserve in man: comparison between positron emission tomography with oxygen-15-labeled water and intracoronary Doppler technique. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[57]  M. Link,et al.  Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. , 2000, The New England journal of medicine.

[58]  A. Deussen,et al.  Blood flow heterogeneity in the heart , 1998, Basic Research in Cardiology.

[59]  A. L'Abbate,et al.  Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. , 1991, Journal of the American College of Cardiology.

[60]  B. Strauer,et al.  Morphometric investigation of human myocardium in arterial hypertension and valvular aortic stenosis. , 1992, European heart journal.

[61]  O Muzik,et al.  Early Detection of Abnormal Coronary Flow Reserve in Asymptomatic Men at High Risk for Coronary Artery Disease Using Positron Emission Tomography , 1994, Circulation.

[62]  H. Schelbert,et al.  L-Arginine normalizes coronary vasomotion in long-term smokers. , 1999, Circulation.

[63]  P. Kaufmann,et al.  Abnormal coronary vasomotion in hypertension: role of coronary artery disease. , 1996, Journal of the American College of Cardiology.

[64]  P. Kaufmann,et al.  Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. , 2000, Journal of the American College of Cardiology.

[65]  M E Phelps,et al.  13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography. , 1989, Circulation.

[66]  P. Herrero,et al.  Implementation and evaluation of a two-compartment model for quantification of myocardial perfusion with rubidium-82 and positron emission tomography. , 1992, Circulation research.

[67]  M. Omata,et al.  Reduced coronary flow reserve in familial hypercholesterolemia. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[68]  F. Cecchi,et al.  Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy. , 1994, The American journal of cardiology.

[69]  M J Welch,et al.  Regional myocardial perfusion assessed with generator-produced copper-62-PTSM and PET. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[70]  G. Osikowicz,et al.  Effects of chronic oral consumption of nicotine on the rabbit aortic endothelium. , 1981, The American journal of pathology.

[71]  F. Prinzen,et al.  Blood flow distribution in the left ventricular free wall in open-chest dogs , 1981, Basic Research in Cardiology.

[72]  H. Drexler,et al.  Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. , 1991, Circulation.

[73]  P. Herrero,et al.  Noninvasive quantification of regional myocardial perfusion with rubidium-82 and positron emission tomography. Exploration of a mathematical model. , 1990, Circulation.

[74]  A. Zeiher,et al.  Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. , 1995, Circulation.

[75]  T Takishima,et al.  Phasic Blood Flow Velocity Pattern in Epimyocardial Microvessels in the Beating Canine Left Ventricle , 1986, Circulation research.

[76]  H. Drexler,et al.  Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium. , 1989, Journal of the American College of Cardiology.

[77]  T. Imaizumi,et al.  Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. , 1997, Circulation.

[78]  A. Lammertsma,et al.  Measurement of regional myocardial blood flow using C15O2 and positron emission tomography: comparison of tracer models. , 1992, Clinical physics and physiological measurement : an official journal of the Hospital Physicists' Association, Deutsche Gesellschaft fur Medizinische Physik and the European Federation of Organisations for Medical Physics.

[79]  S. Bergmann,et al.  Enhancement of regional myocardial efficiency and persistence of perfusion, oxidative, and functional reserve with paired pacing of stunned myocardium. , 1994, Circulation.

[80]  M. Walsh,et al.  Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography. , 1989, Journal of the American College of Cardiology.

[81]  M. Le May,et al.  Evaluation of myocardial perfusion using rubidium-82 positron emission tomography after myocardial infarction in patients receiving primary stent implantation or thrombolytic therapy. , 2001, The American journal of cardiology.

[82]  M. Marcus,et al.  Understanding the Coronary Circulation Through Studies at the Microvascular Level , 1990, Circulation.

[83]  C. Henschke,et al.  Pathophysiology of Chest Pain in Patients with Cardiomyopathies and Normal Coronary Arteries , 1982, Circulation.

[84]  G. V. von Schulthess.  Cost considerations regarding an integrated CT-PET system , 2000, European radiology.

[85]  M. D. Di Carli,et al.  Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. , 2003, Journal of the American College of Cardiology.

[86]  P. Camici,et al.  Role of positron emission tomography in the investigation of human coronary circulatory function. , 1994, Cardiovascular research.

[87]  P. Elliott,et al.  Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. , 2000, Journal of the American College of Cardiology.

[88]  C. Honig,et al.  NONUNIFORM DISTRIBUTION OF BLOOD FLOW AND GRADIENTS OF OXYGEN TENSION WITHIN THE HEART. , 1964, The American journal of physiology.

[89]  J. Hoffman,et al.  Transmural myocardial perfusion. , 1987, Progress in cardiovascular diseases.

[90]  J. Greenfield,et al.  Regional myocardial blood flow during graded treadmill exercise in the dog. , 1975, The Journal of clinical investigation.

[91]  O Muzik,et al.  Validation of nitrogen-13-ammonia tracer kinetic model for quantification of myocardial blood flow using PET. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[92]  B. Maron.  Hypertrophic cardiomyopathy: a systematic review. , 2002, JAMA.

[93]  B. Maron,et al.  Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. , 2000, Circulation.

[94]  K. Kugiyama,et al.  Vitamin C attenuates abnormal vasomotor reactivity in spasm coronary arteries in patients with coronary spastic angina. , 1998, Journal of the American College of Cardiology.

[95]  O. Rimoldi,et al.  Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. , 2001, Cardiovascular research.

[96]  Stamatis Adamopoulos,et al.  17β-Estradiol Attenuates Acetylcholine-Induced Coronary Arterial Constriction in Women but Not Men With Coronary Heart Disease , 1995 .

[97]  P. Marzullo,et al.  Regional myocardial blood flow in stable angina pectoris associated with isolated significant narrowing of either the left anterior descending or left circumflex coronary artery. , 1993, The American journal of cardiology.

[98]  C. Wyss,et al.  Isolated ventricular noncompaction is associated with coronary microcirculatory dysfunction. , 2002, Journal of the American College of Cardiology.

[99]  D. Neglia,et al.  Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. , 1995, Circulation.

[100]  F Shishido,et al.  Measurement of absolute myocardial blood flow with H215O and dynamic positron-emission tomography. Strategy for quantification in relation to the partial-volume effect. , 1988, Circulation.

[101]  Adriaan A. Lammertsma,et al.  Measurement of myocardial blood flow with oxygen-15 labelled water: comparison of different administration protocols , 1998, European Journal of Nuclear Medicine.

[102]  Iacopo Olivotto,et al.  Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy. , 2003, Journal of the American College of Cardiology.

[103]  W. Kannel,et al.  Diabetes and cardiovascular disease. The Framingham study. , 1979, JAMA.

[104]  O. Raitakari,et al.  Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy. , 2004, The American journal of cardiology.

[105]  R. Hamlin,et al.  Intramyocardial pressure and distribution of coronary blood flow during systole and diastole in the horse. , 1982, Cardiovascular research.

[106]  B. Maron,et al.  Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. , 2003, The New England journal of medicine.

[107]  M. Matsuda,et al.  Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. , 1987, Circulation.

[108]  Valerie Treyer,et al.  CT vs 68Ge attenuation correction in a combined PET/CT system: evaluation of the effect of lowering the CT tube current , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[109]  W. Kübler,et al.  Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. , 1984, Circulation.

[110]  Myocardial kinetics of potassium-38 in humans and comparison with copper-62-PTSM. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[111]  Estimation of myocardial blood flow and myocardial flow reserve by 99mTc-sestamibi imaging: comparison with the results of [15O]H2O PET , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[112]  M. Schwaiger,et al.  Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. , 1999, Circulation.

[113]  William A. Pryor,et al.  The Tar Radical ( s ) in Cigarette Smoke : ESR Studies , 2006 .

[114]  Cyrill Burger,et al.  Bicycle exercise stress in PET for assessment of coronary flow reserve: repeatability and comparison with adenosine stress. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[115]  Gambling with cardiovascular risk: picking the winners and the losers , 1999, The Lancet.

[116]  P. Kaufmann,et al.  In vitro validation of volumetric blood flow measurement using Doppler flow wire. , 2000, Ultrasound in medicine & biology.

[117]  B. Maron,et al.  Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. , 2000, The New England journal of medicine.

[118]  P. Kaufmann,et al.  Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy , 2001, Heart.

[119]  E. Sonnenblick,et al.  Spatial heterogeneity of local blood flow and metabolite content in dog hearts. , 1988, The American journal of physiology.

[120]  J. Cooke,et al.  L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. , 1992, The Journal of clinical investigation.

[121]  O. Rimoldi,et al.  Myocardial blood flow in patients with hibernating myocardium. , 2003, Cardiovascular research.

[122]  M. Phelps,et al.  Dual spillover problem in the myocardial septum with nitrogen-13-ammonia flow quantitation. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[123]  K. Yoshida,et al.  Coronary flow reserve in angiographically normal coronary arteries with one-vessel coronary artery disease without traditional risk factors. , 2001, European heart journal.

[124]  J. Bassingthwaighte,et al.  Fractal Nature of Regional Myocardial Blood Flow Heterogeneity , 1989, Circulation research.

[125]  B. Strauer,et al.  Coronary haemodynamics in hypertensive heart disease. , 1992, European heart journal.

[126]  M. Marcus,et al.  Small vessel phenomena in the coronary microcirculation: phasic intramyocardial perfusion and coronary microvascular dynamics. , 1988, Progress in cardiovascular diseases.

[127]  Validation of myocardial blood flow estimation with nitrogen-13 ammonia PET by the argon inert gas technique in humans , 2001, European Journal of Nuclear Medicine.

[128]  J B Bassingthwaighte,et al.  Regional Distribution of Diffusible Tracers and Carbonized Microspheres in the Left Ventricle of Isolated Dog Hearts , 1973, Circulation research.

[129]  K. Kugiyama,et al.  Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. , 1999, Journal of the American College of Cardiology.

[130]  O. Rimoldi,et al.  Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment , 1999, Basic Research in Cardiology.

[131]  W. Williams,et al.  Hypertrophic cardiomyopathy. Clinical spectrum and treatment. , 1995, Circulation.

[132]  J. Deanfield,et al.  Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. , 1996, The New England journal of medicine.

[133]  J. Zell,et al.  Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. , 2003, The American journal of cardiology.

[134]  William Wijns,et al.  Relation Between Myocardial Blood Flow and the Severity of Coronary-Artery Stenosis , 1995 .

[135]  A. Maseri,et al.  Delayed recovery of coronary resistive vessel function after coronary angioplasty. , 1993, Journal of the American College of Cardiology.

[136]  N. Mullani,et al.  Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. , 1995, JAMA.

[137]  N. Buus,et al.  Peripheral Flow Response to Transient Arterial Forearm Occlusion Does Not Reflect Myocardial Perfusion Reserve , 2001, Circulation.

[138]  D. Kuhl,et al.  N‐13 Ammonia as an Indicator of Myocardial Blood Flow , 1981, Circulation.

[139]  T. Lüscher,et al.  Coronary Heart Disease in Smokers: Vitamin C Restores Coronary Microcirculatory Function , 2000, Circulation.

[140]  Dudley J Pennell,et al.  Functional Changes in Coronary Microcirculation After Valve Replacement in Patients With Aortic Stenosis , 2003, Circulation.

[141]  A. Buck,et al.  PET attenuation coefficients from CT images: experimental evaluation of the transformation of CT into PET 511-keV attenuation coefficients , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[142]  Felix Matthews,et al.  A novel in vivo procedure for volumetric flow measurements. , 2004, Ultrasound in medicine & biology.

[143]  Ornella Rimoldi,et al.  Absolute quantification of myocardial blood flow with H(2)(15)O and 3-dimensional PET: an experimental validation. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[144]  J. Hoffman,et al.  Profound spatial heterogeneity of coronary reserve. Discordance between patterns of resting and maximal myocardial blood flow. , 1990, Circulation research.

[145]  F. Cecchi,et al.  Dipyridamole-induced subendocardial underperfusion in hypertrophic cardiomyopathy assessed by positron-emission tomography , 1991 .

[146]  A. Yeung,et al.  The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. , 1995, The New England journal of medicine.

[147]  Z. Krajcer,et al.  Coronary artery disease in hypertrophic cardiomyopathy. , 1985, The American journal of cardiology.

[148]  B. Lüderitz,et al.  Relation between symptoms and profiles of coronary artery blood flow velocities in patients with aortic valve stenosis: a study using transoesophageal Doppler echocardiography. , 1996, Heart.

[149]  J. Yap,et al.  Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[150]  G. Glatting,et al.  Treatment of radioactive decay in pharmacokinetic modeling: influence on parameter estimation in cardiac 13N-PET. , 1999, Medical physics.

[151]  J B Bassingthwaighte,et al.  Stability of heterogeneity of myocardial blood flow in normal awake baboons. , 1985, Circulation research.

[152]  J B Bassingthwaighte,et al.  Regional myocardial flow heterogeneity explained with fractal networks. , 1989, The American journal of physiology.

[153]  B. Strauer,et al.  Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. , 1993, Circulation.

[154]  A. Nitenberg,et al.  Impairment of Coronary Vascular Reserve and ACh-Induced Coronary Vasodilation in Diabetic Patients With Angiographically Normal Coronary Arteries and Normal Left Ventricular Systolic Function , 1993, Diabetes.

[155]  P A Poole-Wilson,et al.  17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. , 1995, Circulation.

[156]  M. Phelps,et al.  Effect of beta 1 adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[157]  D. Neglia,et al.  Homogeneously reduced versus regionally impaired myocardial blood flow in hypertensive patients: two different patterns of myocardial perfusion associated with degree of hypertrophy. , 1998, Journal of the American College of Cardiology.

[158]  E. Hoffman,et al.  Regional myocardial perfusion assessed with N-13 labeled ammonia and positron emission computerized axial tomography. , 1979, The American journal of cardiology.

[159]  L. Johnson,et al.  Myocardial Blood Flow in Congestive and Hypertrophic Cardiomyopathy: Relationship to Peak Wall Stress and Mean Velocity of Circumferential Fiber Shortening , 1976, Circulation.

[160]  E. Lakatta.  Deficient Neuroendocrine Regulation of the Cardiovascular System With Advancing Age in Healthy Humans , 1993, Circulation.

[161]  W. Mckenna,et al.  Chest pain during daily life in patients with hypertrophic cardiomyopathy: an ambulatory electrocardiographic study. , 1996, European heart journal.

[162]  D. Bhatnagar,et al.  Indications for cholesterol-lowering medication: comparison of risk-assessment methods , 1999, The Lancet.

[163]  D. Neglia,et al.  Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction , 2002, Circulation.

[164]  M. Creager,et al.  Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans. , 1995, Circulation.

[165]  J M Fauvel,et al.  Microcirculation in the Ventricle of the Dog and Turtle , 1974, Circulation research.

[166]  D. Pennell,et al.  Mechanisms of Coronary Microcirculatory Dysfunction in Patients With Aortic Stenosis and Angiographically Normal Coronary Arteries , 2002, Circulation.

[167]  D L Bailey,et al.  Experience with fully 3D PET and implications for future high-resolution 3D tomographs. , 1998, Physics in medicine and biology.

[168]  W. Weintraub,et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. , 1995, The New England journal of medicine.

[169]  H. Drexler,et al.  Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine , 1991, The Lancet.

[170]  J. Perloff,et al.  Isolated noncompaction of left ventricular myocardium. A study of eight cases. , 1990, Circulation.

[171]  J. Bassingthwaighte,et al.  Temporal fluctuations in regional myocardial flows , 1989, Pflügers Archiv.

[172]  E. Hoffman,et al.  Quantitative measurement of myocardial blood flow with oxygen-15 water and positron computed tomography: an assessment of potential and problems. , 1985, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[173]  S. Nees.  The adenosine hypothesis of metabolic regulation of coronary flow in the light of newly recognized properties of the coronary endothelium. , 1989, Zeitschrift fur Kardiologie.

[174]  A. Luxen,et al.  Direct Comparison of [13N]Ammonia and [150]Water Estimates of Perfusion With Quantification of Regional Myocardial Blood Flow by Microspheres , 1993, Circulation.

[175]  W. Roberts,et al.  Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy. , 1986, Journal of the American College of Cardiology.

[176]  Hiroshi Ito,et al.  Microvasculature in acute myocardial ischemia: part I: evolving concepts in pathophysiology, diagnosis, and treatment. , 2004, Circulation.

[177]  T. Lehtimäki,et al.  Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23 , 1998, Nature Genetics.

[178]  C. Oakley,et al.  The natural (and unnatural) history of hypertrophic obstructive cardiomyopathy. , 1974, Circulation research.

[179]  H A O'Brien,et al.  Relation between regional myocardial uptake of rubidium-82 and perfusion: absolute reduction of cation uptake in ischemia. , 1982, The American journal of cardiology.

[180]  P. Nihoyannopoulos,et al.  Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy. A study with positron emission tomography. , 1997, European heart journal.

[181]  D. Celermajer,et al.  Cigarette Smoking Is Associated With Dose‐Related and Potentially Reversible Impairment of Endothelium‐Dependent Dilation in Healthy Young Adults , 1993, Circulation.

[182]  V. Dilsizian,et al.  Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. , 1993, Journal of the American College of Cardiology.

[183]  M. Marcus,et al.  Alterations in the coronary circulation in hypertrophied ventricles. , 1987, Circulation.

[184]  L. Kuo,et al.  LDLs impair vasomotor function of the coronary microcirculation: role of superoxide anions. , 1998, Circulation research.

[185]  G. Brownell,et al.  Assessment of Regional Myocardial Perfusion by Positron Emission Tomography after Intracoronary Administration of Gallium‐68 Labeled Albumin Microspheres , 1979, Journal of computer assisted tomography.

[186]  C K Stone,et al.  Technetium 94m-labeled methoxyisobutyl isonitrile: Dosimetry and resting cardiac imaging with positron emission tomography , 1994, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[187]  D E Kuhl,et al.  Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. , 1990, Journal of the American College of Cardiology.

[188]  M E Phelps,et al.  Quantification of myocardial blood flow using 13N-ammonia and PET: comparison of tracer models. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[189]  W. Roberts,et al.  Hypertrophic cardiomyopathy and transmural myocardial infarction without significant atherosclerosis of the extramural coronary arteries. , 1979, The American journal of cardiology.

[190]  O. Hess,et al.  Influence of Serum Cholesterol and Other Coronary Risk Factors on Vasomotion of Angiographically Normal Coronary Arteries , 1993, Circulation.

[191]  P. Camici,et al.  Effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. , 1996, The American journal of physiology.

[192]  A. Quyyumi,et al.  Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. , 1990, The New England journal of medicine.

[193]  M. Marcus,et al.  Microvascular distribution of coronary vascular resistance in beating left ventricle. , 1986, The American journal of physiology.

[194]  T. Momose,et al.  Reduced myocardial flow reserve in anatomically normal coronary arteries due to elevated baseline myocardial blood flow in men with old myocardial infarction , 2002, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[195]  E. Picano,et al.  Dipyridamole-induced ischemia as a prognostic marker of future adverse cardiac events in adult patients with hypertrophic cardiomyopathy. Echo Persantine Italian Cooperative (EPIC) Study Group, Subproject Hypertrophic Cardiomyopathy. , 1997, Circulation.

[196]  M. Phelps,et al.  Influence of Age and Hemodynamics on Myocardial Blood Flow and Flow Reserve , 1993, Circulation.

[197]  C. Lambrew,et al.  Idiopathic Hypertrophic Subaortic Stenosis: I. A Description of the Disease Based Upon an Analysis of 64 Patients , 1964, Circulation.

[198]  P. Kaufmann,et al.  Reversal of abnormal coronary vasomotion by calcium antagonists in patients with hypercholesterolemia. , 1998, Circulation.

[199]  M. Mintun,et al.  The kinetics of copper-62-PTSM in the normal human heart. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[200]  G W Hamilton,et al.  Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. , 1974, The American journal of cardiology.

[201]  D. Tousoulis,et al.  Coronary Vasodilator Reserve, Pain Perception, and Sex in Patients With Syndrome X , 1994, Circulation.

[202]  K. Kjeldsen,et al.  Intimal Ultrastructure of Human Umbilical Arteries: OBSERVATIONS ON ARTERIES FROM NEWBORN CHILDREN OF SMOKING AND NONSMOKING MOTHERS , 1975, Circulation research.

[203]  M E Phelps,et al.  Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease. , 1995, Circulation.

[204]  R. Kerber,et al.  Spatial and temporal heterogeneity of left ventricular perfusion in awake dogs. , 1977, American heart journal.

[205]  M. Marcus,et al.  Effects of Duration and Severity of Arterial Hypertension and Cardiac Hypertrophy on Coronary Vasodilator Reserve , 1982, Circulation research.

[206]  M. Omata,et al.  Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. , 1996, Circulation.

[207]  B. Pitt,et al.  Comparison of Regional Myocardial Perfusion Determined by Ionic Potassium‐43 to That Determined by Microspheres , 1974, Circulation.

[208]  J. Viikari,et al.  Coronary flow reserve in young men with familial combined hyperlipidemia. , 1999, Circulation.

[209]  Rolf Jenni,et al.  Persisting myocardial sinusoids of both ventricles as an isolated anomaly: Echocardiographic, angiographic, and pathologic anatomical findings , 2007, CardioVascular and Interventional Radiology.

[210]  S. Kety.  The theory and applications of the exchange of inert gas at the lungs and tissues. , 1951, Pharmacological reviews.

[211]  P. Marraccini,et al.  Altered coronary vasodilator reserve and metabolism in myocardium subtended by normal arteries in patients with coronary artery disease. , 1993, Journal of the American College of Cardiology.

[212]  T. Lehtimäki,et al.  Coronary Flow Reserve Is Reduced in Young Men With IDDM , 1998, Diabetes.

[213]  R Guzzardi,et al.  Simultaneous in vitro and in vivo validation of nitrogen-13-ammonia for the assessment of regional myocardial blood flow. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[214]  I. Olivotto,et al.  Effect of aging on myocardial perfusion reserve. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[215]  James P. Martucci,et al.  Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. , 1994, Circulation.

[216]  Farris K. Timimi,et al.  Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. , 1998, Circulation.

[217]  W. Mckenna,et al.  Management of hypertrophic cardiomyopathy. , 1993 .

[218]  T. Imaizumi,et al.  Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy. , 1998, Journal of the American College of Cardiology.

[219]  E. Picano,et al.  Assessment of Anatomic and Physiological Severit of Single‐Vessel Coronary Artery Lesions by Dipyridamole Echocardiography: Comparison With Positron Emission Tomography and Quantitative Arteriography , 1994, Circulation.

[220]  R. Bonow,et al.  Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. , 1988, The New England journal of medicine.

[221]  M. Sugimachi,et al.  Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. , 1994, Circulation.

[222]  D. Turton,et al.  Validation of quantitation of regional myocardial blood flow in vivo with 11C-labeled human albumin microspheres and positron emission tomography. , 1984, Circulation.

[223]  J. Greenfield,et al.  Regional myocardial blood flow in awake dogs. , 1974, The Journal of clinical investigation.

[224]  C. Lau,et al.  Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients , 1993, The Lancet.

[225]  M. Sugimachi,et al.  Effects of Age on Endothelium‐Dependent Vasodilation of Resistance Coronary Artery by Acetycholine in Humans , 1993, Circulation.

[226]  H A O'Brien,et al.  Myocardial perfusion with rubidium-82. I. Measurement of extraction fraction and flow with external detectors. , 1983, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.