European Journal of Radiology, 14 (1992) 0
1992 Elsevier
EURRAD
Science Publishers
97-103
97
B.V. All rights reserved. 0720-048X/92/$03.50
00257
Cardiovascular applications of magnetic resonance imaging and phosphorus-31 spectroscopy* Albert de Roos *, Joost Doornbos I, Sidney Rebergen 3, Paul van Rugge*l’ Peter Pattynama and Ernst E. van der Wall2 ‘Department
of Diagnostic Radiology and %ardiology.
University Hospital Leiden, and 3The Interuniversity Cardiology Institute of The
Netherlands,
Utrecht, The Netherlands
(Accepted
Key words: Magnetic resonance,
technology;
*
6 November
1991)
Magnetic resonance, cardiovascular; spectroscopy, phosphorus-3
Magnetic resonance, 1
spectroscopy;
Magnetic resonance
Abstract
Recent advances in cardiovascular applications of magnetic resonance (MR) imaging and phosphorus-31 spectroscopy are reported. MR velocity mapping is a valuable adjunct to conventional imaging techniques, providing information on flow velocities as well as on absolute blood flow volume in the aorta and pulmonary arteries. Recently, ultrafast MR techniques have become available to evaluate myocardial perfusion with the aid of MR contrast agents as perfusion marker. Dynamic MR imaging is a powerful tool to assess cardiac function and ventricular mass. In particular, right ventricular function and mass can be evaluated with great accuracy, contributing to improved assessment of the significance of disease processes which may affect the right heart. The role of phosphorus-3 1 spectroscopy of the heart is expanding for the evaluation of ischemic myocardial disease and cardiomyopathies. The phosphocreatine to adenosine triphosphate ratio appears to be a marker of disease in patients with cardiac hypertrophy. In conclusion, MR imaging and phosphorus-31 spectroscopy is gaining widespread acceptance for evaluation of many cardiovascular disease processes.
Introduction Several recent review articles have summarized the current status of magnetic resonance (MR) imaging and phosphorus-3 1 spectroscopy for cardiovascular diagnosis [l-3]. MR imaging is an established modality in the workup of patients with congenital abnormalities of the heart and great vessels and might be an alternative imaging procedure to repeated cardiac catheterization for the follow-up of patients after corrective surgery [4]. MR velocity mapping is capable to assess flow velocities (m/s) and flow volume (ml/min), which is useful to
Address for reprints: Dr. Albert de Roos, Department of Diagnostic Radiology, University Hospital Leiden, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands. * This study was supported by grant No. 90.0.76 of the Dutch Heart Foundation to P.v.R.
evaluate the pulmonary circulation in patients with atriopulmonary shunt operations. The use of interventional therapy in acute myocat-dial infarction enhances clinical interest in noninvasive imaging modalities to evaluate the success of interventions designed to salvage myocardium early in the course of acute myocardial infarction. MR imaging offers the potential to estimate non-invasively infarct size and myocardial perfusion. Furthermore, dynamic MR imaging is well suited to assess many functional parameters of cardiac function, including regional and global ventricular wall motion, enddiastolic and endsystolic dimensions, ejection fraction, and right and left ventricular mass. These parameters provide a thorough assessment of normal and abnormal cardiac function. Recently, clinical results of phosphorus-3 1 spectroscopy have been reported in patients with ischemic and cardiomyopathic heart disease. Phosphorus-3 1 spectra disclose high-energy phosphate metabolism, which may be altered in abnormal myocardial muscle.
98
Ultimately, phosphorus-3 1 spectroscopy may be useful to assess myocardial disease and monitor the effect of treatment options. In conclusion, MR imaging techniques and phosphorus-31 studies may be combined for a complete evaluation of many cardiovascular disease processes.
ing diastole, and on the other hand when diastolic right ventricular filling was impaired, maximum flow occurred during systole. MR velocity mapping has also been applied to study mitral and pulmonary venous flow [6]. Under normal conditions, flow through the mitral valve occurs in two phases as recognized by MR velocity mapping. The initial phase of passive flow is due to ventricular relaxation, whereas the second phase of flow is caused by atrial contraction, Pulmonary venous flow showed also a typical pattern, which may be useful to study the dynamics of ventricular filling. Furthermore, mitral flow velocity measurements obtained from MR velocity maps in 5 patients with mitral stenosis correlated well with measurements from Doppler echocardiography. When optimal alignment of the imaging plane is achieved, MR velocity mapping is very accurate to measure jet velocities across stenotic valves and then allows estimation of the pressure drop across the stenosis. Caputo et al. applied MR velocity mapping for measurement of flow velocities in the main, right, and left pulmonary arteries [7]. MR velocity mapping pro-
Evaluation of heart disease using MR velocity mapping MR imaging is now a well-established imaging modality in the work-up and follow-up of patients with congenital heart and large vessel disease. Recently, the value of MR velocity mapping has been demonstrated as a valuable adjunct to conventional spin-echo imaging (Fig. 1). Both flow velocity and volume of blood flow can accurately be measured by MR velocity mapping techniques. Mohiaddin et al. used tine MR velocity mapping to study venous blood flow to the heart [5]. Under normal circumstances the superior and inferior caval vein displayed a systolic and diastolic flow peak. However, when tricuspid regurgitation was present, maximal forward flow was noted dur-
a
b 500
: ;
-400 0
R C
400
200 time
after
800
600 R-wave
(msec)
1000
Fig. 1. Magnetic resonance velocity mapping of aortic flow. Cine MR image (a) discloses tracing of the contour of the ascending aorta (tracing 1) and descending aorta (tracing 2). Corresponding MR velocity map (b) shows bright pixels in the ascending aorta and dark pixels in the descending aorta. Pixel intensity is determined by flow velocity and flow direction. In addition to flow velocities also flow volume can be derived from the velocity map. Plot (c) of blood flow in the ascending and descending aorta throughout the cardiac cycle as derived from MR velocity mapping.
vided accurate and reproducible measurements of flow velocities in the pulmonary circulation, as well as of absolute blood flow in the pulmonary arteries. Abnormal distribution of pulmonary blood flow may occur in a wide variety of disease processes. Recently, we have applied MR velocity mapping to evaluate flow in the Fontan circulation in patients after surgery for tricuspid atresia [ 81. The Fontan operation is designed to connect the right atrium to the pulmonary circulation in patients with tricuspid atresia and other complex cardiac malformations. MR velocity mapping is capable to assess pulmonary flow dynamics after Fontan surgery. Therefore, this MR technique is well suited to evaluate the function of Fontan conduits by measuring both flow velocities and flow volume. In contrast, Doppler echocardiography only relies on measuring peak flow velocities for determining the pulmonary flow dynamics after surgical repair. Assessment of flow volume curves with the aid of MR velocity mapping offers a more complete evaluation of shunt performance. Evaluation of myocardial perfusion and wall motion Myocardial perfusion
Assessment of the early dynamics of myocardial contrast enhancement using Gadolinium-DTPA may identify the presence or absence of coronary artery reperfusion after thrombolysis [9]. The availability of ultrafast MR scanning may be useful to assess first-pass myocardial perfusion with the aid of GadoliniumDTPA as a perfusion marker [ 10,111. Although, no simple relationship between myocardial signal intensity after Gadolinium-DTPA and the concentration of the contrast agent exists, ultrafast techniques with contrast agents may be helpful to assess qualitatively the perfusion of the myocardium distal to coronary artery stenoses and after reperfusion. Recently, we have investigated the value of subsecond MR imaging for the assessment of cardiac first pass and myocardial perfusion in seven normal subjects after intravenous administration of Gadolinium-DTPA [ 111. After bolus injection of Gadolinium-DTPA, progressively increasing signal intensity was measured in the right ventricular cavity, the left ventricular cavity, and the myocardial wall (Fig. 2). Ultimately, contrastenhanced subsecond imaging may be used to detect regional myocardial perfusion distal to coronary artery stenoses. Furthermore, the effect of reperfusion therapies before and after intervention may be evaluated with this technique.
Fig. 2. Baseline MR scan (top left) and MR scans of sequential signal enhancement following administration of Gd-DTPA in the right ventricular cavity (top right), the pulmonary vasculature, the left ventricular cavity, the aorta and the myocardium (bottom panels). (Reproduced with permission from Ref. 11).
Wall motion
MR imaging during physical exercise is limited due to space restrictions and motion artifacts. Pharmacologically induced stress offers an alternative method to investigate the cardiovascular system during stress. Dipyridamole stress testing is a well established method for evaluating the heart in patients with coronary artery disease. Due to its vasodilating properties, dipyridamole is well suited to reveal abnormalities in myocardial perfusion in the presence of coronary artery stenoses. Pennell et al. demonstrated the capability of MR imaging under dipyridamole-induced vasodilatation to detect transient wall motion abnormalities in myocardial segments perfused by coronary vessels with significant stenoses [ 121. After dipyridamole reversible wall motion abnormalities in conjunction with decreased subendocardial wall signal were noted on MR images corresponding to reversible perfusion defects seen on thallium imaging. This study demonstrates the value of stress MR imaging in evaluating myocardial ischemia, which may further be enhanced by using high-speed MR imaging in conjunction with MR contrast agents. Dobutamine can also be applied as a pharmacological stressor in patients with coronary artery disease. Dobutamine induces myocardial ischemia by augment-
100
ing myocardial contractility and an increased heart rate, resulting in elevated myocardial oxygen demands. In addition, an increased systolic blood pressure and heterogeneity in myocardial perfusion contribute to an imbalance in myocardial oxygen requirements. The use of myocardial tagging methods will further reline the evaluation of wall motion dysfunction by direct tracking of specific myocardial points during contraction. Myocardial tagging has been used to study relative rotation of the left ventricular apex with respect to the base of the heart using short-axis imaging planes [9]. A systolic counterclockwise rotation of the epicardium and endocardium at succeeding imaging planes was found with respect to the base, which increased with increasing distance from the base. Torsion of the endocardium was greater than that of the epicardium, indicating that shear occurs between epicardial and endocardial layers [ 131. Furthermore, transmural dependence of wall thickening can be assessed with myocardial tagging, indicating the value of this technique for evaluating subendocardial wall dynamics early after myocardial ischemia. Evaluation of ventricular function and mass Dynamic tine MR imaging is more accurate for defining regional myocardial function and dysfunction than contrast ventriculography, because the latter depends upon the evaluation of wall motion and is hindered by superimposition of anatomic structures. Measurements of cardiac volumes, mass and wall motion from tine MR studies are highly reproducible for assessing these parameters both in normally and abnormally shaped ventricles [ 14,151. Therefore, tine MR may be well suited for the assessment of changes over time after therapeutic interventions. Wang et al. used short-axis spin-echo images to study the progression of left ventricular hypertrophy after surgically induced aortic stenosis [ 161. During a 7-months follow-up period a significant increase of myocardial hypertrophy was measured. Manning et al. showed that estimates of in vivo left ventricular mass determined with the use of MR imaging were reliable and highly reproducible over a wide range of heart sizes in an experimental animal model [ 171. Only limited experience is available with in vivo quantification of right ventricular (RV) mass in human studies. MR imaging may become a powerful noninvasive tool for quantitating RV mass and function to determine the functional significance of many disease processes which may affect the right heart. Mackey et al. quantified RV myocardial mass in vitro in 12 normal human hearts obtained at necropsy [ 181. This study demonstrated
that RV mass can accurately and reproducibly be estimated in autopsied human hearts by using MR imaging. Turnbull et al. explored the use of MR imaging for quantification of RV mass in patients with severe car pulmonale [ 191. The right ventricular free wall volume correlated in that study with systolic and mean pulmonary arterial pressure, pulmonary vascular resistance, and arterial carbon dioxide tension [ 191. From our institution, Pattynama et al. reported the measurement of RV chamber volumes, RV ejection fraction and RV wall mass in 17 patients with moderate chronic obstructive pulmonary disease as defined by testing of pulmonary function and gas exchange [20]. RV mass was the most sensitive parameter to distinguish normal subjects from patients with chronic obstructive pulmonary disease (Fig. 3). In contrast, RV ejection fraction was not significantly different between normal subjects and patients, suggesting that RV ejection fraction is not a reliable parameter to evaluate the effect of chronic obstructive pulmonary disease on the right heart. It was concluded that MR imaging has the potential to diagnose car pulmonale in the early stage of disease before irreversible changes in the right ventricle occur. Therefore, MR imaging may become a valuable modality to monitor right ventricular mass and function in patients with chronic obstructive pulmonary disease and may lead to the institution of therapy when there is still some reversible component of the disease process. 31P-MR spectroscopy of the heart Myocardial energy metabolism
Cardiac contraction and cellular function requires the availability of energy. The energy present in the foods is made available for cardiac function in the form of adenosine triphosphate (ATP) by oxidative metabolism offree fatty acids or glucose. Under normal physiological circumstances, free fatty acids (in particular, palmitate) provide most of the ATP used by the heart, whereas glucose is an important alternative fuel for ATP production [21]. Before entering the citric acid cycle (also known as Krebs’ cycle or tricarboxylic acid cycle), free fatty acids and glucose are converted to acetyl-coenzyme A. After uptake of the glucose molecule into the cells, glucose is converted to pyruvate by the process of gfycolysis. The next stage in the degradation of glucose is conversion of pyruvate molecules into acetyl-coenzyme A, which then can enter the citric acid cycle. Free fatty acids are converted to acetyl-coenzyme A by /?-oxidation. The citric acid cycle yields a large number of hydro-
a
b
Fig. 3. Measurement of right ventricular mass using spin-echo magnetic resonance images. Short-axis view before (a) and after (b) tracing of right ventricular contours. MR imaging is well suited to evaluate right ventricular function and mass. (Reproduced with permission from Ref. 20).
gen atoms that enter the electron transport chain. The in the mitochondria during subsequent oxidation of the released hydrogen atoms by the process of oxidative phosphorylation.
final ATP is formed
3’P-MR spectroscopy
3’P-MR spectroscopy is a noninvasive tool for the investigation of high-energy phosphate metabolism of the heart [ 221. Three-dimensionally localized P-3 1 spectra can be obtained from the myocardium using a surface coil placed on the chest over the cardiac apex and a precise localization technique. The spectrum provides quantifiable information on the concentration of multiple metabolic high-energy phosphate compounds (Fig. 4). P-3 1 heart spectra disclose metabolites such as inorganic phosphate, phosphomonoesters, phosphodiesters, phosphocreatine, and three peaks from adenosine triphosphate (ATP). The phosphomonoester region often includes 2,3-diphophosglycerate contained in the blood pool of cardiac chambers, overlapping the inorganic phosphate peak. Furthermore, technically it is difficult to separate myocardial signal from that of chest wall muscle and that of the nearby blood pool. However, when the inorganic phosphate peak is resolv-
ed, the intracellular pH of the myocardium can be estimated from the distance between the peaks of inorganic phosphate and phosphocreatine. The ratio between phosphocreatine and inorganic phosphate is an indicator of the energy reserve of the heart and this ratio will promptly change when ischemia develops. With reduction of myocardial blood flow, myocardial contraction will cease, followed by a rapid fall in phosphocreatine and rise in inorganic phosphate resulting in tissue acidosis, while the ATP levels are maintained until phosphocreatine is depleted. 3‘P-spectroscopy can detect myocardial infarction and ischemia by profound changes in high-energy phosphate compounds. 3’ P-spec troscopy in ischemic heart disease Conway et al. studied cardiac metabolism using 3’Pspectroscopy in 6 healthy subjects during steady-state dynamic quadriceps exercise [23]. The ratio of phosphocreatine to ATP did not differ during rest and exercise, indicating that during exercise the energy requirements of the normal heart are adequately supplied. However, in the presence of severe reductions in coronary blood flow, the heart may not be capable to maintain high-energy phosphate levels during rest or
102
31P MR Heart
Spectrum:
Normal
Volunteer
One Dimensional Phase Encoding and Column Selection ‘Cr
Slice:
10 mm Column: 80 x 75 mm Tr: 3 s MS: 514
2,3 DPG
1
,
L I
5.0
I
I
0.0
I
I
-5.0
I
I
-10.0
1
1
I
-15.0
-I
_
[pwl
V
Fig. 4. Phosphorus-31 spectrum from the human heart obtained 3’P-specfroscopy using image-selected with proton-decoupled in vivo spectroscopy (ISIS) at 1.5 Tesla (Philips Gyroscan S15, Best, The Netherlands). Note resonances from 2,3-diphosphoglycerate (DPG) contained in the biood, blood phospholipids (SPL), phosphocreatine (PCr), and the three peaks from adenosine triphosphate (y, CIand j? ATP). (Reproduced with permission from Ref. 2).
exercise. Weiss et al. studied the value of 3’P-spectroscopy for the detection of ischemic metabolic changes in 16 patients with more than 70% stenosis of the left anterior descending or left coronary arteries [24]. 31Pspectra were collected from the anterior myocardium before, during, and after isometric hand-grip exercise. The mean ratio of phosphocreatine to ATP in the left ventricular wall decreased transiently during hand-grip exercise in patients with coronary artery disease, indicating that a transient imbalance between oxygen supply and demand can de detected in the myocardium of patients with severe coronary artery disease. Furthermore, the exercise-induced metabolic changes resolved in the subgroup of patients who underwent revascularization [ 241.
In cardiac hypertrophy decreased rates of oxidative metabolism and increased anaerobic metabolism have been demonstrated. Anaerobic glycolysis can partly compensate for impaired oxidative metabolism. However, enhanced anaerobic glycolytic metabolism results in the accumulation of glycolytic catabolites (in particular, lactate), which may be responsible for increased ischemic injury in hypertrophied hearts. In general, cardiac hypertrophy contributes to enhanced susceptibility of the myocardium to ischemic damage, resulting in greater mortality and more rapidly developing and larger infarcts. Currently, myocardial hypertrophy is considered to be a phenomenon of adaption and is associated with alterations in intermediate myocardial metabolism (increased glycolytic capacity), energy conservation (impaired regulation of mitochondrial oxygen consumption by creatine kinase flux), energy consumption at the level of the contractile units, and adrenoceptor mediated regulatory mechanisms of cardiac performance. Several studies have demonstrated that hypertrophied myocardium has relatively higher glycolytic capacity. Smith et al. demonstrated increased lactate dehydrogenase activity in hypertrophied myocardium, indicating a relatively high glycolytic capacity of the myocardium [ 271. In addition, this effect may be further enhanced in the presence of high blood pressure. Anderson et al. found that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased accumulation of by-products of anaerobic glycolytic metabolism (lactate, NADH, or H + ) during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury [ 281. As further evidence for enhanced glycolytic activity in hypertrophied myocardium, Kagaya et al. reported increased uptake of labeled glucose in hypertrophied myocardium, whereas the extraction of labeled free fatty acids was decreased [29]. In conclusion, 31P-spectroscopy is a promising technique to evaluate normal and abnormal myocardial metabolism. Specific derangements in energy myocardial metabolism may be detected in patients with cardiac hypertrophy, indicating increased glycolytic activity of hypertrophied hearts.
Altered myocardiai energy metabolism in cardiac hypertrophy
31P-spectroscopy may be helpful in assessing highenergy phosphate metabolism in patients with cardiac hypertrophy and may be useful for planning treatment options. A few preliminary reports have shown that 31P-spectroscopy may reveal decreased phosphocreatine to ATP ratios in patients with hypertrophic cardiomyopathy [25,26].
References 1 De Roos A, Van Voorthuisen AE. Magnetic resonance imaging of the heart: perfusion, function and structure. Curr Opin Radio1 1991; 3: 525-532. 2 De Roos A, Van der Wall EE. Magnetic resonance imaging and spectroscopy of the heart. Curr Opin Cardiol 1991; 946-952. 3 De Roos A, Van der Wall EE, Bruschke AVG, Van Voorthuisen
103
4
5
6
7
8
9
10
11
12
13
14
15
AE. Magnetic resonance imaging in the diagnosis and evaluation of myocardial infarction. Magn Reson Quart 199; 1991; 7: 191-207. Kersting-Sommerhoff BA, Seelos KC, Hardy C, Kondo C, Higgins SS, Higgins CB. Evaluation of surgical procedures for cyanotic congenital heart disease by using MR imaging. AJR 1990; 155: 259-266. Mohiaddin RH, Wann SL, Underwood R, Firmin DN, Rees S, Longmore DB. Vena caval flow: assessment with tine MR velocity mapping. Radiology 1990; 177: 537-541. Mohiaddin RH, AmanumaM, Kilner PJ, Pennell DJ, Manzara C, Longmore DB. MR phase-shift velocity mapping of mitral and pulmonary venous flow. J Comput Assist Tomogr 1991; 15: 237-243. Caputo GR, Kondo C, Masui T et al. Right and left lung perfusion: in vitro and in vivo validation with oblique-angle, velocity-encoded tine MR imaging. Radiology 1991; 180: 693-698. Rebergen SA, Doornbos J, Guit GL et al. Quantification of blood flow in the pulmonary arteries and Fontan conduits with velocity phase mapping. Society of Magnetic Resonance in Medicine. San Francisco. Book of abstracts 1991; 74. Van Rossum AC, Visser FC, Van Eenige MJ et al. Value of Gadolinium-diethylenetriaminepentaacetic acid dynamics in magnetic resonance imaging of acute myocardial infarction with occluded and reperfused coronary arteries after thrombolysis. Am J Cardiol 1990; 65: 845-851. Atkinson DJ, Burstein D, Edelman RR. First-pass cardiac perfusion: evaluation with ultrafast MR imaging. Radiology 1990; 174: 757-762. Van Rugge FP, Boreel JJ, Van der Wall EE et al. Cardiac first pass and myocardial perfusion in normal subjects assessed by Gd-DTPA enhanced subsecond MR imaging. J Comput Assist Tomogr 1991; 15: 959-965. Pennell DJ, Underwood SR, El1 PJ, Swanton RH, Walker JM, Longmore DB. Dipyridamole magnetic resonance imaging: a comparison with thallium-201 emission tomography. Br Heart J 1990; 64: 362-369. Buchalter MB, Weiss JL, Rogers WJ, et al. Noninvasive quantification of left ventricular rotational deformation in normal humans using magnetic resonance imaging myocardial tagging. Circulation 1990; 81: 1236-1244. Semelka RC, Tomei E, Wagner S et al. Normal left ventricular dimensions and function; interstudy reproducibility of measurements with tine MR imaging. Radiology 1990; 174: 763-768. Semelka RC, Tomei E, Wagner S et al. Interstudy reproducibility of dimensional and functional measurements between tine magnetic resonance studies in the morphologically abnormal left ventricle. Am Heart J 1990: 119: 1367-1373.
16 Wang, JZ, Mezrich RS, Scholz P, Als A, Douglas F. MRI evaluation of left ventricular hypertrophy in a canine model of aortic stenosis, Invest Radio1 1990; 25: 783-788. 17 Manning WJ, Wei JY, Fossel ET, Burstein D. Measurement of left ventricular mass in rats using electrocardiogram-gated magnetic resonance imaging. Am J Physiol (Heart Circ Physiol) 1990; 258: Hll81-H1186. 18 Mackey ES, Sandler MP, Campbell RM, et al. Right ventricular myocardial mass quantification with magnetic resonance imaging. Am J Cardiol 1990; 65: 529-532. 19 Turnbull LW, Ridgway JP, Biernacki W, et al. Assessment ofthe right ventricle by magnetic resonance imaging in chronic obstructive lung disease. Thorax 1990; 45: 597-601. 20 Pattynama P, Willems LNA, Smit AH, Van der Wall EE, De Roos A. Early diagnosis of car pulmonale by magnetic resonance imaging of the right ventricle. Radiology 1992; in press. 21 Brown JJ, Mirowitz SA, Sandstrom JC, Perman WH. MR spectroscopy of the heart. AJR 1990; 155: l-l 1. 22 Schaefer S. Clinical nuclear magnetic resonance spectroscopy: insight into metabolism. Am J Cardiol 1990; 66: 45F-50F. 23 Conway MA, Bristow JD, Blackledge MJ, Rajagopalan B, Radda GK. Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy. Br Heart J 1991; 65: 25-30. 24 Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med 1990; 323: 1593-1600. 25 Sukuma H, Takeda K, Yamakado K, et al. “P-NMR spectroscopy in patients with hypertrophic cardiomyopathy. In: Book of abstracts: Society of Magnetic Resonance in Medicine 1990. Berkeley, Calif: Society of Magnetic Resonance in Medicine, 1990; 248. 26 De Roos A, Luyten PR, Maritin AJH, Doornbos J, Van der Wall EE, Den Hollander J. Metabolite ratios in normal human myocardium and cardiomyopathy: quantification by “P-spectroscopy. J Am Co11 Cardiol 1991; 17: 77A. 27 Smith SH, Kramer MF, Reis I, Bishop SP, Ingwall JS. Regional changes in creatine kinase and myocyte size in hypertensive and nonhypertensive cardiac hypertrophy. Circ Res 1990; 67: 1334-1344. 28 Anderson PG, Allard MF, Thomas GD, Bishop SP, Digerness SB. Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts. Circ Res 1990; 67: 948-959. 29 Kagaya Y, Kanno Y, Takeyama D et al. Effects of long-term pressure overload on regional myocardial glucose and free fatty acid uptake in rats. A quantitative autoradiographic study. Circulation 1990; 81: 1353-1361.
1992 Elsevier
EURRAD
Science Publishers
97-103
97
B.V. All rights reserved. 0720-048X/92/$03.50
00257
Cardiovascular applications of magnetic resonance imaging and phosphorus-31 spectroscopy* Albert de Roos *, Joost Doornbos I, Sidney Rebergen 3, Paul van Rugge*l’ Peter Pattynama and Ernst E. van der Wall2 ‘Department
of Diagnostic Radiology and %ardiology.
University Hospital Leiden, and 3The Interuniversity Cardiology Institute of The
Netherlands,
Utrecht, The Netherlands
(Accepted
Key words: Magnetic resonance,
technology;
*
6 November
1991)
Magnetic resonance, cardiovascular; spectroscopy, phosphorus-3
Magnetic resonance, 1
spectroscopy;
Magnetic resonance
Abstract
Recent advances in cardiovascular applications of magnetic resonance (MR) imaging and phosphorus-31 spectroscopy are reported. MR velocity mapping is a valuable adjunct to conventional imaging techniques, providing information on flow velocities as well as on absolute blood flow volume in the aorta and pulmonary arteries. Recently, ultrafast MR techniques have become available to evaluate myocardial perfusion with the aid of MR contrast agents as perfusion marker. Dynamic MR imaging is a powerful tool to assess cardiac function and ventricular mass. In particular, right ventricular function and mass can be evaluated with great accuracy, contributing to improved assessment of the significance of disease processes which may affect the right heart. The role of phosphorus-3 1 spectroscopy of the heart is expanding for the evaluation of ischemic myocardial disease and cardiomyopathies. The phosphocreatine to adenosine triphosphate ratio appears to be a marker of disease in patients with cardiac hypertrophy. In conclusion, MR imaging and phosphorus-31 spectroscopy is gaining widespread acceptance for evaluation of many cardiovascular disease processes.
Introduction Several recent review articles have summarized the current status of magnetic resonance (MR) imaging and phosphorus-3 1 spectroscopy for cardiovascular diagnosis [l-3]. MR imaging is an established modality in the workup of patients with congenital abnormalities of the heart and great vessels and might be an alternative imaging procedure to repeated cardiac catheterization for the follow-up of patients after corrective surgery [4]. MR velocity mapping is capable to assess flow velocities (m/s) and flow volume (ml/min), which is useful to
Address for reprints: Dr. Albert de Roos, Department of Diagnostic Radiology, University Hospital Leiden, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands. * This study was supported by grant No. 90.0.76 of the Dutch Heart Foundation to P.v.R.
evaluate the pulmonary circulation in patients with atriopulmonary shunt operations. The use of interventional therapy in acute myocat-dial infarction enhances clinical interest in noninvasive imaging modalities to evaluate the success of interventions designed to salvage myocardium early in the course of acute myocardial infarction. MR imaging offers the potential to estimate non-invasively infarct size and myocardial perfusion. Furthermore, dynamic MR imaging is well suited to assess many functional parameters of cardiac function, including regional and global ventricular wall motion, enddiastolic and endsystolic dimensions, ejection fraction, and right and left ventricular mass. These parameters provide a thorough assessment of normal and abnormal cardiac function. Recently, clinical results of phosphorus-3 1 spectroscopy have been reported in patients with ischemic and cardiomyopathic heart disease. Phosphorus-3 1 spectra disclose high-energy phosphate metabolism, which may be altered in abnormal myocardial muscle.
98
Ultimately, phosphorus-3 1 spectroscopy may be useful to assess myocardial disease and monitor the effect of treatment options. In conclusion, MR imaging techniques and phosphorus-31 studies may be combined for a complete evaluation of many cardiovascular disease processes.
ing diastole, and on the other hand when diastolic right ventricular filling was impaired, maximum flow occurred during systole. MR velocity mapping has also been applied to study mitral and pulmonary venous flow [6]. Under normal conditions, flow through the mitral valve occurs in two phases as recognized by MR velocity mapping. The initial phase of passive flow is due to ventricular relaxation, whereas the second phase of flow is caused by atrial contraction, Pulmonary venous flow showed also a typical pattern, which may be useful to study the dynamics of ventricular filling. Furthermore, mitral flow velocity measurements obtained from MR velocity maps in 5 patients with mitral stenosis correlated well with measurements from Doppler echocardiography. When optimal alignment of the imaging plane is achieved, MR velocity mapping is very accurate to measure jet velocities across stenotic valves and then allows estimation of the pressure drop across the stenosis. Caputo et al. applied MR velocity mapping for measurement of flow velocities in the main, right, and left pulmonary arteries [7]. MR velocity mapping pro-
Evaluation of heart disease using MR velocity mapping MR imaging is now a well-established imaging modality in the work-up and follow-up of patients with congenital heart and large vessel disease. Recently, the value of MR velocity mapping has been demonstrated as a valuable adjunct to conventional spin-echo imaging (Fig. 1). Both flow velocity and volume of blood flow can accurately be measured by MR velocity mapping techniques. Mohiaddin et al. used tine MR velocity mapping to study venous blood flow to the heart [5]. Under normal circumstances the superior and inferior caval vein displayed a systolic and diastolic flow peak. However, when tricuspid regurgitation was present, maximal forward flow was noted dur-
a
b 500
: ;
-400 0
R C
400
200 time
after
800
600 R-wave
(msec)
1000
Fig. 1. Magnetic resonance velocity mapping of aortic flow. Cine MR image (a) discloses tracing of the contour of the ascending aorta (tracing 1) and descending aorta (tracing 2). Corresponding MR velocity map (b) shows bright pixels in the ascending aorta and dark pixels in the descending aorta. Pixel intensity is determined by flow velocity and flow direction. In addition to flow velocities also flow volume can be derived from the velocity map. Plot (c) of blood flow in the ascending and descending aorta throughout the cardiac cycle as derived from MR velocity mapping.
vided accurate and reproducible measurements of flow velocities in the pulmonary circulation, as well as of absolute blood flow in the pulmonary arteries. Abnormal distribution of pulmonary blood flow may occur in a wide variety of disease processes. Recently, we have applied MR velocity mapping to evaluate flow in the Fontan circulation in patients after surgery for tricuspid atresia [ 81. The Fontan operation is designed to connect the right atrium to the pulmonary circulation in patients with tricuspid atresia and other complex cardiac malformations. MR velocity mapping is capable to assess pulmonary flow dynamics after Fontan surgery. Therefore, this MR technique is well suited to evaluate the function of Fontan conduits by measuring both flow velocities and flow volume. In contrast, Doppler echocardiography only relies on measuring peak flow velocities for determining the pulmonary flow dynamics after surgical repair. Assessment of flow volume curves with the aid of MR velocity mapping offers a more complete evaluation of shunt performance. Evaluation of myocardial perfusion and wall motion Myocardial perfusion
Assessment of the early dynamics of myocardial contrast enhancement using Gadolinium-DTPA may identify the presence or absence of coronary artery reperfusion after thrombolysis [9]. The availability of ultrafast MR scanning may be useful to assess first-pass myocardial perfusion with the aid of GadoliniumDTPA as a perfusion marker [ 10,111. Although, no simple relationship between myocardial signal intensity after Gadolinium-DTPA and the concentration of the contrast agent exists, ultrafast techniques with contrast agents may be helpful to assess qualitatively the perfusion of the myocardium distal to coronary artery stenoses and after reperfusion. Recently, we have investigated the value of subsecond MR imaging for the assessment of cardiac first pass and myocardial perfusion in seven normal subjects after intravenous administration of Gadolinium-DTPA [ 111. After bolus injection of Gadolinium-DTPA, progressively increasing signal intensity was measured in the right ventricular cavity, the left ventricular cavity, and the myocardial wall (Fig. 2). Ultimately, contrastenhanced subsecond imaging may be used to detect regional myocardial perfusion distal to coronary artery stenoses. Furthermore, the effect of reperfusion therapies before and after intervention may be evaluated with this technique.
Fig. 2. Baseline MR scan (top left) and MR scans of sequential signal enhancement following administration of Gd-DTPA in the right ventricular cavity (top right), the pulmonary vasculature, the left ventricular cavity, the aorta and the myocardium (bottom panels). (Reproduced with permission from Ref. 11).
Wall motion
MR imaging during physical exercise is limited due to space restrictions and motion artifacts. Pharmacologically induced stress offers an alternative method to investigate the cardiovascular system during stress. Dipyridamole stress testing is a well established method for evaluating the heart in patients with coronary artery disease. Due to its vasodilating properties, dipyridamole is well suited to reveal abnormalities in myocardial perfusion in the presence of coronary artery stenoses. Pennell et al. demonstrated the capability of MR imaging under dipyridamole-induced vasodilatation to detect transient wall motion abnormalities in myocardial segments perfused by coronary vessels with significant stenoses [ 121. After dipyridamole reversible wall motion abnormalities in conjunction with decreased subendocardial wall signal were noted on MR images corresponding to reversible perfusion defects seen on thallium imaging. This study demonstrates the value of stress MR imaging in evaluating myocardial ischemia, which may further be enhanced by using high-speed MR imaging in conjunction with MR contrast agents. Dobutamine can also be applied as a pharmacological stressor in patients with coronary artery disease. Dobutamine induces myocardial ischemia by augment-
100
ing myocardial contractility and an increased heart rate, resulting in elevated myocardial oxygen demands. In addition, an increased systolic blood pressure and heterogeneity in myocardial perfusion contribute to an imbalance in myocardial oxygen requirements. The use of myocardial tagging methods will further reline the evaluation of wall motion dysfunction by direct tracking of specific myocardial points during contraction. Myocardial tagging has been used to study relative rotation of the left ventricular apex with respect to the base of the heart using short-axis imaging planes [9]. A systolic counterclockwise rotation of the epicardium and endocardium at succeeding imaging planes was found with respect to the base, which increased with increasing distance from the base. Torsion of the endocardium was greater than that of the epicardium, indicating that shear occurs between epicardial and endocardial layers [ 131. Furthermore, transmural dependence of wall thickening can be assessed with myocardial tagging, indicating the value of this technique for evaluating subendocardial wall dynamics early after myocardial ischemia. Evaluation of ventricular function and mass Dynamic tine MR imaging is more accurate for defining regional myocardial function and dysfunction than contrast ventriculography, because the latter depends upon the evaluation of wall motion and is hindered by superimposition of anatomic structures. Measurements of cardiac volumes, mass and wall motion from tine MR studies are highly reproducible for assessing these parameters both in normally and abnormally shaped ventricles [ 14,151. Therefore, tine MR may be well suited for the assessment of changes over time after therapeutic interventions. Wang et al. used short-axis spin-echo images to study the progression of left ventricular hypertrophy after surgically induced aortic stenosis [ 161. During a 7-months follow-up period a significant increase of myocardial hypertrophy was measured. Manning et al. showed that estimates of in vivo left ventricular mass determined with the use of MR imaging were reliable and highly reproducible over a wide range of heart sizes in an experimental animal model [ 171. Only limited experience is available with in vivo quantification of right ventricular (RV) mass in human studies. MR imaging may become a powerful noninvasive tool for quantitating RV mass and function to determine the functional significance of many disease processes which may affect the right heart. Mackey et al. quantified RV myocardial mass in vitro in 12 normal human hearts obtained at necropsy [ 181. This study demonstrated
that RV mass can accurately and reproducibly be estimated in autopsied human hearts by using MR imaging. Turnbull et al. explored the use of MR imaging for quantification of RV mass in patients with severe car pulmonale [ 191. The right ventricular free wall volume correlated in that study with systolic and mean pulmonary arterial pressure, pulmonary vascular resistance, and arterial carbon dioxide tension [ 191. From our institution, Pattynama et al. reported the measurement of RV chamber volumes, RV ejection fraction and RV wall mass in 17 patients with moderate chronic obstructive pulmonary disease as defined by testing of pulmonary function and gas exchange [20]. RV mass was the most sensitive parameter to distinguish normal subjects from patients with chronic obstructive pulmonary disease (Fig. 3). In contrast, RV ejection fraction was not significantly different between normal subjects and patients, suggesting that RV ejection fraction is not a reliable parameter to evaluate the effect of chronic obstructive pulmonary disease on the right heart. It was concluded that MR imaging has the potential to diagnose car pulmonale in the early stage of disease before irreversible changes in the right ventricle occur. Therefore, MR imaging may become a valuable modality to monitor right ventricular mass and function in patients with chronic obstructive pulmonary disease and may lead to the institution of therapy when there is still some reversible component of the disease process. 31P-MR spectroscopy of the heart Myocardial energy metabolism
Cardiac contraction and cellular function requires the availability of energy. The energy present in the foods is made available for cardiac function in the form of adenosine triphosphate (ATP) by oxidative metabolism offree fatty acids or glucose. Under normal physiological circumstances, free fatty acids (in particular, palmitate) provide most of the ATP used by the heart, whereas glucose is an important alternative fuel for ATP production [21]. Before entering the citric acid cycle (also known as Krebs’ cycle or tricarboxylic acid cycle), free fatty acids and glucose are converted to acetyl-coenzyme A. After uptake of the glucose molecule into the cells, glucose is converted to pyruvate by the process of gfycolysis. The next stage in the degradation of glucose is conversion of pyruvate molecules into acetyl-coenzyme A, which then can enter the citric acid cycle. Free fatty acids are converted to acetyl-coenzyme A by /?-oxidation. The citric acid cycle yields a large number of hydro-
a
b
Fig. 3. Measurement of right ventricular mass using spin-echo magnetic resonance images. Short-axis view before (a) and after (b) tracing of right ventricular contours. MR imaging is well suited to evaluate right ventricular function and mass. (Reproduced with permission from Ref. 20).
gen atoms that enter the electron transport chain. The in the mitochondria during subsequent oxidation of the released hydrogen atoms by the process of oxidative phosphorylation.
final ATP is formed
3’P-MR spectroscopy
3’P-MR spectroscopy is a noninvasive tool for the investigation of high-energy phosphate metabolism of the heart [ 221. Three-dimensionally localized P-3 1 spectra can be obtained from the myocardium using a surface coil placed on the chest over the cardiac apex and a precise localization technique. The spectrum provides quantifiable information on the concentration of multiple metabolic high-energy phosphate compounds (Fig. 4). P-3 1 heart spectra disclose metabolites such as inorganic phosphate, phosphomonoesters, phosphodiesters, phosphocreatine, and three peaks from adenosine triphosphate (ATP). The phosphomonoester region often includes 2,3-diphophosglycerate contained in the blood pool of cardiac chambers, overlapping the inorganic phosphate peak. Furthermore, technically it is difficult to separate myocardial signal from that of chest wall muscle and that of the nearby blood pool. However, when the inorganic phosphate peak is resolv-
ed, the intracellular pH of the myocardium can be estimated from the distance between the peaks of inorganic phosphate and phosphocreatine. The ratio between phosphocreatine and inorganic phosphate is an indicator of the energy reserve of the heart and this ratio will promptly change when ischemia develops. With reduction of myocardial blood flow, myocardial contraction will cease, followed by a rapid fall in phosphocreatine and rise in inorganic phosphate resulting in tissue acidosis, while the ATP levels are maintained until phosphocreatine is depleted. 3‘P-spectroscopy can detect myocardial infarction and ischemia by profound changes in high-energy phosphate compounds. 3’ P-spec troscopy in ischemic heart disease Conway et al. studied cardiac metabolism using 3’Pspectroscopy in 6 healthy subjects during steady-state dynamic quadriceps exercise [23]. The ratio of phosphocreatine to ATP did not differ during rest and exercise, indicating that during exercise the energy requirements of the normal heart are adequately supplied. However, in the presence of severe reductions in coronary blood flow, the heart may not be capable to maintain high-energy phosphate levels during rest or
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31P MR Heart
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10 mm Column: 80 x 75 mm Tr: 3 s MS: 514
2,3 DPG
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-5.0
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Fig. 4. Phosphorus-31 spectrum from the human heart obtained 3’P-specfroscopy using image-selected with proton-decoupled in vivo spectroscopy (ISIS) at 1.5 Tesla (Philips Gyroscan S15, Best, The Netherlands). Note resonances from 2,3-diphosphoglycerate (DPG) contained in the biood, blood phospholipids (SPL), phosphocreatine (PCr), and the three peaks from adenosine triphosphate (y, CIand j? ATP). (Reproduced with permission from Ref. 2).
exercise. Weiss et al. studied the value of 3’P-spectroscopy for the detection of ischemic metabolic changes in 16 patients with more than 70% stenosis of the left anterior descending or left coronary arteries [24]. 31Pspectra were collected from the anterior myocardium before, during, and after isometric hand-grip exercise. The mean ratio of phosphocreatine to ATP in the left ventricular wall decreased transiently during hand-grip exercise in patients with coronary artery disease, indicating that a transient imbalance between oxygen supply and demand can de detected in the myocardium of patients with severe coronary artery disease. Furthermore, the exercise-induced metabolic changes resolved in the subgroup of patients who underwent revascularization [ 241.
In cardiac hypertrophy decreased rates of oxidative metabolism and increased anaerobic metabolism have been demonstrated. Anaerobic glycolysis can partly compensate for impaired oxidative metabolism. However, enhanced anaerobic glycolytic metabolism results in the accumulation of glycolytic catabolites (in particular, lactate), which may be responsible for increased ischemic injury in hypertrophied hearts. In general, cardiac hypertrophy contributes to enhanced susceptibility of the myocardium to ischemic damage, resulting in greater mortality and more rapidly developing and larger infarcts. Currently, myocardial hypertrophy is considered to be a phenomenon of adaption and is associated with alterations in intermediate myocardial metabolism (increased glycolytic capacity), energy conservation (impaired regulation of mitochondrial oxygen consumption by creatine kinase flux), energy consumption at the level of the contractile units, and adrenoceptor mediated regulatory mechanisms of cardiac performance. Several studies have demonstrated that hypertrophied myocardium has relatively higher glycolytic capacity. Smith et al. demonstrated increased lactate dehydrogenase activity in hypertrophied myocardium, indicating a relatively high glycolytic capacity of the myocardium [ 271. In addition, this effect may be further enhanced in the presence of high blood pressure. Anderson et al. found that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased accumulation of by-products of anaerobic glycolytic metabolism (lactate, NADH, or H + ) during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury [ 281. As further evidence for enhanced glycolytic activity in hypertrophied myocardium, Kagaya et al. reported increased uptake of labeled glucose in hypertrophied myocardium, whereas the extraction of labeled free fatty acids was decreased [29]. In conclusion, 31P-spectroscopy is a promising technique to evaluate normal and abnormal myocardial metabolism. Specific derangements in energy myocardial metabolism may be detected in patients with cardiac hypertrophy, indicating increased glycolytic activity of hypertrophied hearts.
Altered myocardiai energy metabolism in cardiac hypertrophy
31P-spectroscopy may be helpful in assessing highenergy phosphate metabolism in patients with cardiac hypertrophy and may be useful for planning treatment options. A few preliminary reports have shown that 31P-spectroscopy may reveal decreased phosphocreatine to ATP ratios in patients with hypertrophic cardiomyopathy [25,26].
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