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Myocardial perfusion measurement by contrast echocardiography in congenital heart disease
Progress in Pediatric Cardiology 34 (2012) 53–56
Contents lists available at SciVerse ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
Myocardial perfusion measurement by contrast echocardiography in congenital heart disease Tobias Rutz a, b, Stefano F. de Marchi a, Markus Schwerzmann a, b,⁎ a b
Congenital Cardiac Center, University Hospital Inselspital, Bern, Switzerland Department of Cardiology, University Hospital Inselspital, Bern, Switzerland
a r t i c l e
i n f o
Keywords: Myocardial contrast echocardiography Congenital heart disease Myocardial perfusion
a b s t r a c t Altered myocardial perfusion is frequent in patients with congenital heart disease. Measurement of myocardial blood flow per gram of myocardium at rest and during hyperemia is the most robust method to evaluate myocardial perfusion in absolute terms. So far, most studies in congenital heart disease patients used positron emission tomography to evaluate absolute myocardial blood flow. With the recent advances in contrast echocardiography, we have now a more easily applicable but similarly solid method at hand to assess myocardial perfusion in different clinical scenarios. Myocardial contrast echocardiography has proven its clinical and scientific value in coronary artery disease patients. In this review, we discuss the merits of myocardial perfusion assessment in patients with a systemic right ventricle, a univentricular heart physiology, and tetralogy of Fallot. We outline how myocardial contrast echocardiography can improve our understanding of ventricular function. We have to admit that its clinical value remains to be elucidated. For most congenital defects, the impact of impaired myocardial perfusion on ventricular function and clinical outcome is still poorly investigated. Myocardial contrast echocardiography can contribute to fill this gap. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Oxygen supply of the myocardium is assured by a vascular system consisting of epicardial coronary and intramyocardial arteries, arterioles, capillary vessels, venules and cardiac veins. As demonstrated in a pig model, the epicardial and intramyocardial arteries are a treelike structure, whereas the capillaries form a network [1]. Myocardial blood flow is mainly controlled by vessels with a diameter of below 300–400 mcm [2]. The autoregulation of this vascular system keeps the myocardial blood flow constant [3]. In the presence of a coronary artery stenosis with a lumen reduction of less than 70–80%, this autoregulation allows for a normal basal blood flow; maximum blood flow however is decreased [4]. Flow limitations due to a stenosis or an unmet demand of myocardial blood flow trigger the ischemic cascade, consisting of metabolic changes, diastolic dysfunction, followed by wall motion abnormalities, ECG changes and finally clinical symptoms [5]. Stress imaging modalities capable to assess myocardial blood flow are able to detect flow alterations very early in the disease course. In coronary artery disease patients, they have a superior prognostic value to imaging techniques evaluating only ventricular function changes, including wall motion abnormalities [6]. Single-photon emission computed tomography (SPECT), positron emission tomography (PET), cardiac magnetic resonance imaging ⁎ Corresponding author at: Congenital Cardiac Center, University Hospital Inselspital, 3010 Bern, Switzerland. Tel.: +41 31 632 78 59; fax: +41 31 632 89 45. E-mail address: [email protected] (M. Schwerzmann). 1058-9813/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2012.05.012
(CMR), cardiac computed tomography (CT) and myocardial contrast echocardiography are established perfusion imaging techniques. SPECT is widely available and well established in clinical routine. Its main limitation, besides a low spatial resolution, is that it provides only information about relative myocardial perfusion. Therefore it has a lower sensitivity to detect local coronary artery stenoses in already chronic ischemic myocardium [7], and it is not reliable for the diagnosis of an overall lowered myocardial perfusion, as may be encountered in patients with heavily hypertrophied ventricles, e.g. a systemic right ventricle. PET is the only technique besides myocardial contrast echocardiography to determine absolute myocardial perfusion. The limitations of a PET exam are a relatively low spatial resolution, a costly and demanding generation of imaging agents and the patients' exposure to a considerable dose of ionizing radiation. Currently available CT perfusion imaging methods require also a very high radiation dose, rendering this technique at the moment not applicable for routine clinical use. CMR provides a three-dimensional evaluation of cardiac structures and volumes, and is currently the most robust method for assessing right ventricular or single ventricular cardiac volume and systolic function. CMR is also useful for quantifying shunt ratios. With the recent development of high-field (3 Tesla) CMR, temporal and spatial resolution are sufficient to measure myocardial perfusion during the first pass myocardial transit of the contrast agent gadolinium [8]. However, myocardial perfusion assessment with CMR is not yet studied in congenital heart disease patients. Contrast echocardiography offers real time assessment of myocardial perfusion at bedside. It allows for calculation of absolute myocardial
54
T. Rutz et al. / Progress in Pediatric Cardiology 34 (2012) 53–56
blood flow, defined as blood flow (ml/min) into a myocardial region relative to its mass (g) and its constituents myocardial blood volume and blood flow velocity [9]. The determination of these two components offers further information about the underlying mechanisms of reduced myocardial perfusion: myocardial fibrosis leads to a reduction of relative myocardial blood volume, and coronary artery stenosis mainly to a reduction of the blood flow velocity.
constant reflecting tissue density [9]. The ratio of myocardial blood flow at rest and under hyperemia is called the myocardial perfusion reserve. Myocardial contrast echocardiography has also its limitations. Unfortunately, image quality is insufficient in 20–30% of patients to allow quantification of myocardial perfusion, and even in patients with good image quality, there is an attenuation of the video-intensity in the basal ventricular segments, rendering perfusion measurement less reliable in these segments.
2. Myocardial perfusion measurement by contrast echocardiography Myocardial contrast echocardiography uses microbubbles consisting of stable shells, filled with insoluble gas with a size and rheology similar to red blood cells [10]. Exposed to an ultrasound beam and depending on the energy they are exposed to, these bubbles respond with specific ultrasound frequencies in a linear or a non-linear manner. At low mechanical index, i.e. during insonation with low energy, these microbubbles return fundamental and harmonic frequencies, whereas the surrounding myocardium and other tissues exhibit primarily fundamental frequencies [11]. The ultrasound system is able to filter the harmonic signals of the microbubbles, allowing for a selective reception of contrast signals with a good signal-to-noise ratio. At a high mechanical index (>0.3), the microbubbles respond primarily in a non-linear manner and get destroyed by resonance effects. The intentional destruction of microbubbles within the myocardium with a high energy impulse offers the possibility to study the kinetics of contrast replenishment within the myocardium. In normally perfused myocardium, a more or less uniform opacification of the myocardium is the rule. In regions with impaired blood supply, the kinetics of the replenishment and the amount of opacification, depicted as the intensity of the acoustic signal, will be decreased. Measurements are usually performed at rest and during hyperemia induced by vasodilators like adenosine or dipyridamole. The blood flow velocity increases under stress in normally perfused myocardium up to 4–5 times [12]. Coronary artery stenosis causes reduced blood flow velocities and leads to a delayed or reduced echo-enhancement of the myocardium. Qualitative evaluation of myocardial perfusion relies on the visual assessment of the signal intensities in the myocardium relative to its surrounding regions. A scoring system is used to judge myocardial perfusion as normal, reduced or severely impaired [13]. For the quantitative assessment of myocardial perfusion with contrast agents, it is important that the relationship of the microbubble concentration in the myocardium and the signal-intensities recorded by the ultrasound system have a linear relationship. To meet this assumption, microbubbles are continuously infused intravenously at a sufficiently low rate to avoid oversaturation of the myocardium with contrast. After reaching a steady state concentration of the microbubbles within the myocardium, the bubbles are destroyed by a high energy echo impulse (mechanical index >0.3). The replenishment of the myocardium with microbubbles is subsequently measured with ultrasound insonation at a low mechanical index. The replenishment kinetics can be characterized by the time-intensity signals curve fitted to a monoexponential function: y=A(1−e− βt) [13] (Fig. 1). In this equation, A is the intensity signal in the steady state, reflecting the microvascular crosssectional area [10], and β (s− 1) represents the slope of the replenishment curve and is related to the blood flow velocity within the myocardium. The product of A (area) and β (blood velocity) allows calculating myocardial blood flow [14]. The acoustic-intensity of A is affected by the capillary density variations between myocardial regions, attenuation effects and technical settings. Vogel et al. have shown that normalizing A to the adjacent left ventricular cavity intensity, filled completely with microbubbles and representing 100% of capillary density, allows to adjust the measurement for attenuation effects and technical settings. They labeled this normalized intensity signal as relative myocardial blood volume, and it is reflecting capillary density [9]. Absolute myocardial blood flow (ml/min/g) is calculated by multiplying relative myocardial blood volume with β and dividing by a
3. Clinical relevance of perfusion measurement in congenital heart disease Most congenital heart disease patients live nowadays long enough to potentially experience the morbidity and mortality related to coronary artery disease. In a recent survey among adult congenital heart disease patients with follow-up at the Royal Brompton Hospital, 9% of 211 adults undergoing selective coronary angiography for reasons other than suspected coronary artery disease had a significant coronary artery stenosis [15]. As previously outlined, myocardial perfusion assessment is a sensitive and prognostic tool to detect coronary disease, and superior to standard exercise testing. In addition to the diagnosis of coronary artery disease, myocardial perfusion measurement provides answers to questions about unbalances between oxygen delivery and demand in different congenital heart disease settings. An elegant example in this respect is the study of Brunken et al., investigating myocardial perfusion reserve in cyanotic congenital heart disease patients [16]. With the use of PET, the authors showed that compensatory secondary erythrocytosis and its effects on blood viscosity do not impair myocardial perfusion, in contrast to the general belief that elevated hematocrit levels invariably increases viscosity and microvascular resistance, and decreases tissue perfusion. In their study, basal perfusion measurements were higher in the left and right ventricle of cyanotic patients compared to controls, and hyperemic flows were similar and did not differ between congenital heart disease patients and controls. However, as a consequence on the increased basal blood flow, the perfusion reserve was greater in controls than in patients in each ventricular region. On clinical grounds, this means that not only the epicardial coronary arteries are dilated in cyanotic patients, but also microcirculatory remodeling leading to augmented basal myocardial perfusion is present. However, during exercise or hyperemia, there is a lower than usual perfusion reserve, and therefore compensatory mechanisms may reach their limits, thereby explaining in parts the limited exercise capacity seen in these patients. Another interesting group of congenital heart disease patients is the adult with a systemic right ventricle and a biventricular circulation, i.e. after an atrial switch procedure for complete transposition of the great arteries, or the adult with a congenitally corrected transposition and no previous switch procedure. Singh et al. published one of the first PET studies assessing absolute myocardial blood flow and flow reserve in an adult systemic right ventricle after a Mustard procedure, compared to myocardial blood flow of an adult systemic left ventricle in healthy controls [17]. The authors speculated, that similar to patients with left ventricular hypertrophy due to arterial hypertension, the hypertrophied systemic right ventricle also shows an impaired coronary artery vasodilator reserve. The inability of the right coronary artery to supply sufficient blood flow to meet the myocardial demands during exercise may be one of the reasons, why these patients have a decreased exercise capacity and some systemic right ventricles even fail over time. At rest, there was no difference in myocardial blood flow in Mustard patients and controls. Absolute myocardial blood flow was 0.8 ± 0.2 vs. 0.74 ± 0.2 ml/g/min, respectively, representing normal absolute myocardial perfusion. During adenosine induced hyperemia, there was a 40% decreased peak coronary blood flow in the systemic right ventricles compared to the systemic left ventricles in controls, despite the fact that on qualitative analysis, no regional perfusion defects could be detected. Nevertheless,
T. Rutz et al. / Progress in Pediatric Cardiology 34 (2012) 53–56
55
0.09 0.08
A LV Acoustic Units
0.07 0.018
A
0.014
ß
relative Blood Volume rBV = A / A LV
0.01
0.006
0.002
Refill Curve Fitting y(t) = A · (1 - e -ß· t )
Myocardial Blood Flow MBF = ß· rBV / ρ
0
2
4
6
8
10
12
14
ρ = tissue density
Time (Seconds) Fig. 1. Segmental refill curves (red line) and corresponding left ventricular signal intensities (red dots) reconstructed from a myocardial contrast echocardiography (MCE) perfusion sequence at rest.
myocardial flow reserve was significantly reduced. Potential reasons for this reduction in hyperemic coronary blood flow are myocardial fibrosis secondary to myocardial ischemia (e.g. prolonged hypoxemia during infancy while awaiting the atrial switch procedure), or a decrease in myocardial capillary density as a consequence of prolonged right ventricular pressure overload. In a more recent PET study in adults with congenitally corrected transposition of the great vessels, Hauser et al. [18] demonstrated that lower myocardial perfusion reserve in systemic right ventricles correlated with a lower maximum oxygen consumption (peak VO2) during cardiopulmonary exercise testing, and with impaired systemic ventricular systolic function on echocardiography. Again, visual analysis revealed only one inducible perfusion defect in all fifteen patients, underscoring the limited value of visual or qualitative perfusion assessment in these patients. The proof of the clinical significance of these findings is still out, but the results so far are consistent and indicate that decreased coronary flow reserve in a systemic right ventricle is present and may contribute to ventricular dysfunction in the long run. Hauser et al. also used PET to assess myocardial blood flow in congenital heart disease in 10 adolescents with a Fontan circulation [19]. Ventricular function was normal in 4 and reduced in 6 patients. Compared to 10 healthy controls, myocardial blood flow at rest was higher in the Fontan group than in controls (0.99± 0.25 vs. 0.77 ± 0.2 ml/g/min, p b 0.05) whereas hyperemic absolute myocardial blood flow and coronary artery flow reserve were reduced, even more in patients with reduced systolic ventricular function [19]. Myocardial perfusion was not affected by the site of coronary venous drainage. Reduced coronary artery flow reserve, increased meridional wall stress, and impaired systolic ventricular function were common findings in their Fontan patients and significantly interrelated. As in patients with a biventricular circulation and a systemic right ventricle, decreased coronary flow reserve may contribute to ventricular dysfunction later in life. 4. Myocardial contrast echography Using myocardial contrast echocardiography, we recently focused our interest on the feasibility of myocardial perfusion measurement in adults with conotruncal defects [20]. In 22 adults with with dtransposition of great arteries and an atrial switch procedure, and in
18 patients with repaired tetralogy of Fallot and a hypertrophied and dilated right ventricle, we tried to quantify right ventricular free wall and midseptal myocardial perfusion, based on relative myocardial blood volume (i.e. capillary density) and myocardial blood flow kinetics. The aim of our study was to test the following hypotheses: 1. capillary density derived by myocardial contrast echocardiography is smaller in the right ventricle and midseptal wall of patients with congenital heart disease compared to the midseptal wall in healthy controls, and 2. the myocardial perfusion reserve of the right ventricle is smaller in patients with congenital heart disease than in the systemic ventricle of controls. Based on the preceding work of Indermühle et al. in patients with left ventricular hypertrophy due to an athlete's heart or due to arterial hypertension, we were confident that our non-invasive measurements were a reliable method to detect microvascular changes in the hypertrophied ventricle [21,22]: endurance exercise leads to physiological hypertrophy, characterized by a proportional increase in myocardial mass and vascularization. In case of a mismatch of myocardial mass and microvasculature, as seen in patients with hypertensive left heart disease, capillary density or relative myocardial blood volume, respectively, is reduced, compared to controls and compared to individuals with physiological hypertrophy. Myocardial contrast echocardiography was feasible in all study participants in the septal region. However, measurement of right ventricular free wall perfusion by echocardiography was only possible in half of all adults with transposition and 1 patient with repaired tetralogy of Fallot, but in none of the controls due to “shadowing” of the lung. Absolute septal myocardial blood flow did not differ between the three groups. Hyperemic septal myocardial blood flow and as a consequence also the flow reserve were significantly reduced in patients with dtransposition of great arteries and tetralogy of Fallot compared to controls, first due to a significantly lower regional myocardial blood volume in the septum of congenital heart disease patients, and second due to slower refill kinetics in the septum of adults with transposition. Myocardial blood flow reserve was 1.42 ± 0.68 in transposition patients vs. 2.44± 1.4 in adults with tetralogy of Fallot vs. 3.27 ± 1.3 in controls (p b 0.001). Hyperemic relative myocardial blood volume was 0.132 ± 0.04 in d-transposition of great arteries vs. 0.124 ± 0.06 in tetralogy of Fallot patients vs. 0.19±0.07 in controls (p=0.005). Septal myocardial
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blood flow reserve and hyperemic right ventricular blood flow showed a significant correlation with right ventricular systolic function (r=0.56, pb 0.001; r=0.38, p=0.04, respectively). Interestingly, tetralogy of Fallot patients with normal systolic right ventricular function had normal hyperemic relative myocardial blood volume, blood flow and reserve. Based on these findings, we concluded that in congenital heart disease patients with right ventricular hypertrophy, capillary density is not only reduced in the right ventricular free wall but also interventricular septum, and blood flow reserve is more impaired in transposition patients with a systemic right ventricle than the less hypertrophied right ventricle of repaired tetralogy of Fallot patients. Hence, in congenital heart disease patients with severe right ventricular hypertrophy, capillary vascularization cannot compensate the increase in myocardial growth, leading to a capillary – myocardial muscle mismatch, finally impairing ventricular systolic function [23]. This process seems to affect also the interventricular septum. 5. Safety of myocardial contrast echocardiography The American Society of Echocardiography and the European Association of Echocardiography have established recommendations for the use of echocardiographic contrast agents focusing on the left ventricle [24,25]. The consensus paper of the American Society of Echocardiography highlights that post-marketing studies in more than 1 million patients revealed no major risks besides rare allergic reaction in about 1 per 10,000. Infrequent adverse effects include unspecific complaints like headache and weakness. Very rarely, allergic life threatening hypersensitivity reactions have occurred. There are no studies or guidelines regarding the safety of the application of contrast agents in patients with congenital heart disease. At this point in time, myocardial perfusion measurement with echocardiography is still an investigational tool and not yet approved for clinical applications. 6. Conclusions Determination of myocardial perfusion is feasible with contrast echocardiography. Studies involving patients with congenital heart disease are scarce, so far. Quantification of absolute myocardial blood flow is superior to qualitative (visual) perfusion assessment, especially in patients with unmet metabolic cardiac demands due to ventricular hypertrophy, but no localized segmental perfusion deficits. In these patients, the calculation of relative myocardial blood volume can be used to estimate capillary density and provides additional information to the underlying pathology of reduced myocardial perfusion at rest or during adenosine-induced hyperemia. In the long term, knowledge of the clinical consequences of impaired myocardial perfusion and of the underlying pathophysiological mechanisms will hopefully guide our management in these patients. Conflict of interests The authors declared none.
References [1] Kassab GS, Fung YC. Topology and dimensions of pig coronary capillary network. Am J Physiol 1994;267:H319–25. [2] Spaan J, Kolyva C, van den Wijngaard J, et al. Coronary structure and perfusion in health and disease. Philos Transact A Math Phys Eng Sci 2008;366:3137–53. [3] Johnson PC. Autoregulation of blood flow. Circ Res 1986;59:483–95. [4] Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercise. Physiol Rev 2008;88:1009–86. [5] Nesto RW, Kowalchuk GJ. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;59: 23C–30C. [6] Tsutsui JM, Elhendy A, Anderson JR, Xie F, McGrain AC, Porter TR. Prognostic value of dobutamine stress myocardial contrast perfusion echocardiography. Circulation 2005;112:1444–50. [7] Lima RS, Watson DD, Goode AR, et al. Incremental value of combined perfusion and function over perfusion alone by gated SPECT myocardial perfusion imaging for detection of severe three-vessel coronary artery disease. J Am Coll Cardiol 2003;42:64–70. [8] Schwitter J. Myocardial perfusion imaging by cardiac magnetic resonance. J Nucl Cardiol 2006;13:841–54. [9] Vogel R, Indermuhle A, Reinhardt J, et al. The quantification of absolute myocardial perfusion in humans by contrast echocardiography: algorithm and validation. J Am Coll Cardiol 2005;45:754–62. [10] Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998;97:473–83. [11] de Jong N, Ten Cate FJ, Lancee CT, Roelandt JR, Bom N. Principles and recent developments in ultrasound contrast agents. Ultrasonics 1991;29:324–30. [12] Porter TR, Xie F. Myocardial perfusion imaging with contrast ultrasound. JACC Cardiovasc Imaging 2010;3:176–87. [13] Dijkmans PA, Senior R, Becher H, et al. Myocardial contrast echocardiography evolving as a clinically feasible technique for accurate, rapid, and safe assessment of myocardial perfusion: the evidence so far. J Am Coll Cardiol 2006;48:2168–77. [14] Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Basis for detection of stenosis using venous administration of microbubbles during myocardial contrast echocardiography: bolus or continuous infusion? J Am Coll Cardiol 1998;32:252–60. [15] Giannakoulas G, Dimopoulos K, Engel R, et al. Burden of coronary artery disease in adults with congenital heart disease and its relation to congenital and traditional heart risk factors. Am J Cardiol 2009;103:1445–50. [16] Brunken RC, Perloff JK, Czernin J, et al. Myocardial perfusion reserve in adults with cyanotic congenital heart disease. Am J Physiol Heart Circ Physiol 2005;289: H1798–806. [17] Singh TP, Humes RA, Muzik O, Kottamasu S, Karpawich PP, Di Carli MF. Myocardial flow reserve in patients with a systemic right ventricle after atrial switch repair. J Am Coll Cardiol 2001;37:2120–5. [18] Hauser M, Bengel FM, Hager A, et al. Impaired myocardial blood flow and coronary flow reserve of the anatomical right systemic ventricle in patients with congenitally corrected transposition of the great arteries. Heart 2003;89:1231–5. [19] Hauser M, Bengel FM, Kuhn A, et al. Myocardial perfusion and coronary flow reserve assessed by positron emission tomography in patients after Fontan-like operations. Pediatr Cardiol 2003;24:386–92. [20] Rutz T, de Marchi SF, Schwerzmann M, Vogel R, Seiler C. Right ventricular absolute myocardial blood flow in complex congenital heart disease. Heart 2010;96:1056–62. [21] Indermuhle A, Vogel R, Meier P, et al. The relative myocardial blood volume differentiates between hypertensive heart disease and athlete's heart in humans. Eur Heart J 2006;27:1571–8. [22] Indermuhle A, Vogel R, Rutz T, Meier P, Seiler C. Myocardial contrast echocardiography for the distinction of hypertrophic cardiomyopathy from athlete's heart and hypertensive heart disease. Swiss Med Wkly 2009;139:691–8. [23] Rakusan K, Flanagan MF, Geva T, Southern J, Van Praagh R. Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy. Circulation 1992;86:38–46. [24] Mulvagh SL, Rakowski H, Vannan MA, et al. American Society of Echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography. J Am Soc Echocardiogr 2008;21:1179–201 [quiz 281]. [25] Senior R, Becher H, Monaghan M, et al. Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography. Eur J Echocardiogr 2009;10:194–212.
Contents lists available at SciVerse ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
Myocardial perfusion measurement by contrast echocardiography in congenital heart disease Tobias Rutz a, b, Stefano F. de Marchi a, Markus Schwerzmann a, b,⁎ a b
Congenital Cardiac Center, University Hospital Inselspital, Bern, Switzerland Department of Cardiology, University Hospital Inselspital, Bern, Switzerland
a r t i c l e
i n f o
Keywords: Myocardial contrast echocardiography Congenital heart disease Myocardial perfusion
a b s t r a c t Altered myocardial perfusion is frequent in patients with congenital heart disease. Measurement of myocardial blood flow per gram of myocardium at rest and during hyperemia is the most robust method to evaluate myocardial perfusion in absolute terms. So far, most studies in congenital heart disease patients used positron emission tomography to evaluate absolute myocardial blood flow. With the recent advances in contrast echocardiography, we have now a more easily applicable but similarly solid method at hand to assess myocardial perfusion in different clinical scenarios. Myocardial contrast echocardiography has proven its clinical and scientific value in coronary artery disease patients. In this review, we discuss the merits of myocardial perfusion assessment in patients with a systemic right ventricle, a univentricular heart physiology, and tetralogy of Fallot. We outline how myocardial contrast echocardiography can improve our understanding of ventricular function. We have to admit that its clinical value remains to be elucidated. For most congenital defects, the impact of impaired myocardial perfusion on ventricular function and clinical outcome is still poorly investigated. Myocardial contrast echocardiography can contribute to fill this gap. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Oxygen supply of the myocardium is assured by a vascular system consisting of epicardial coronary and intramyocardial arteries, arterioles, capillary vessels, venules and cardiac veins. As demonstrated in a pig model, the epicardial and intramyocardial arteries are a treelike structure, whereas the capillaries form a network [1]. Myocardial blood flow is mainly controlled by vessels with a diameter of below 300–400 mcm [2]. The autoregulation of this vascular system keeps the myocardial blood flow constant [3]. In the presence of a coronary artery stenosis with a lumen reduction of less than 70–80%, this autoregulation allows for a normal basal blood flow; maximum blood flow however is decreased [4]. Flow limitations due to a stenosis or an unmet demand of myocardial blood flow trigger the ischemic cascade, consisting of metabolic changes, diastolic dysfunction, followed by wall motion abnormalities, ECG changes and finally clinical symptoms [5]. Stress imaging modalities capable to assess myocardial blood flow are able to detect flow alterations very early in the disease course. In coronary artery disease patients, they have a superior prognostic value to imaging techniques evaluating only ventricular function changes, including wall motion abnormalities [6]. Single-photon emission computed tomography (SPECT), positron emission tomography (PET), cardiac magnetic resonance imaging ⁎ Corresponding author at: Congenital Cardiac Center, University Hospital Inselspital, 3010 Bern, Switzerland. Tel.: +41 31 632 78 59; fax: +41 31 632 89 45. E-mail address: [email protected] (M. Schwerzmann). 1058-9813/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2012.05.012
(CMR), cardiac computed tomography (CT) and myocardial contrast echocardiography are established perfusion imaging techniques. SPECT is widely available and well established in clinical routine. Its main limitation, besides a low spatial resolution, is that it provides only information about relative myocardial perfusion. Therefore it has a lower sensitivity to detect local coronary artery stenoses in already chronic ischemic myocardium [7], and it is not reliable for the diagnosis of an overall lowered myocardial perfusion, as may be encountered in patients with heavily hypertrophied ventricles, e.g. a systemic right ventricle. PET is the only technique besides myocardial contrast echocardiography to determine absolute myocardial perfusion. The limitations of a PET exam are a relatively low spatial resolution, a costly and demanding generation of imaging agents and the patients' exposure to a considerable dose of ionizing radiation. Currently available CT perfusion imaging methods require also a very high radiation dose, rendering this technique at the moment not applicable for routine clinical use. CMR provides a three-dimensional evaluation of cardiac structures and volumes, and is currently the most robust method for assessing right ventricular or single ventricular cardiac volume and systolic function. CMR is also useful for quantifying shunt ratios. With the recent development of high-field (3 Tesla) CMR, temporal and spatial resolution are sufficient to measure myocardial perfusion during the first pass myocardial transit of the contrast agent gadolinium [8]. However, myocardial perfusion assessment with CMR is not yet studied in congenital heart disease patients. Contrast echocardiography offers real time assessment of myocardial perfusion at bedside. It allows for calculation of absolute myocardial
54
T. Rutz et al. / Progress in Pediatric Cardiology 34 (2012) 53–56
blood flow, defined as blood flow (ml/min) into a myocardial region relative to its mass (g) and its constituents myocardial blood volume and blood flow velocity [9]. The determination of these two components offers further information about the underlying mechanisms of reduced myocardial perfusion: myocardial fibrosis leads to a reduction of relative myocardial blood volume, and coronary artery stenosis mainly to a reduction of the blood flow velocity.
constant reflecting tissue density [9]. The ratio of myocardial blood flow at rest and under hyperemia is called the myocardial perfusion reserve. Myocardial contrast echocardiography has also its limitations. Unfortunately, image quality is insufficient in 20–30% of patients to allow quantification of myocardial perfusion, and even in patients with good image quality, there is an attenuation of the video-intensity in the basal ventricular segments, rendering perfusion measurement less reliable in these segments.
2. Myocardial perfusion measurement by contrast echocardiography Myocardial contrast echocardiography uses microbubbles consisting of stable shells, filled with insoluble gas with a size and rheology similar to red blood cells [10]. Exposed to an ultrasound beam and depending on the energy they are exposed to, these bubbles respond with specific ultrasound frequencies in a linear or a non-linear manner. At low mechanical index, i.e. during insonation with low energy, these microbubbles return fundamental and harmonic frequencies, whereas the surrounding myocardium and other tissues exhibit primarily fundamental frequencies [11]. The ultrasound system is able to filter the harmonic signals of the microbubbles, allowing for a selective reception of contrast signals with a good signal-to-noise ratio. At a high mechanical index (>0.3), the microbubbles respond primarily in a non-linear manner and get destroyed by resonance effects. The intentional destruction of microbubbles within the myocardium with a high energy impulse offers the possibility to study the kinetics of contrast replenishment within the myocardium. In normally perfused myocardium, a more or less uniform opacification of the myocardium is the rule. In regions with impaired blood supply, the kinetics of the replenishment and the amount of opacification, depicted as the intensity of the acoustic signal, will be decreased. Measurements are usually performed at rest and during hyperemia induced by vasodilators like adenosine or dipyridamole. The blood flow velocity increases under stress in normally perfused myocardium up to 4–5 times [12]. Coronary artery stenosis causes reduced blood flow velocities and leads to a delayed or reduced echo-enhancement of the myocardium. Qualitative evaluation of myocardial perfusion relies on the visual assessment of the signal intensities in the myocardium relative to its surrounding regions. A scoring system is used to judge myocardial perfusion as normal, reduced or severely impaired [13]. For the quantitative assessment of myocardial perfusion with contrast agents, it is important that the relationship of the microbubble concentration in the myocardium and the signal-intensities recorded by the ultrasound system have a linear relationship. To meet this assumption, microbubbles are continuously infused intravenously at a sufficiently low rate to avoid oversaturation of the myocardium with contrast. After reaching a steady state concentration of the microbubbles within the myocardium, the bubbles are destroyed by a high energy echo impulse (mechanical index >0.3). The replenishment of the myocardium with microbubbles is subsequently measured with ultrasound insonation at a low mechanical index. The replenishment kinetics can be characterized by the time-intensity signals curve fitted to a monoexponential function: y=A(1−e− βt) [13] (Fig. 1). In this equation, A is the intensity signal in the steady state, reflecting the microvascular crosssectional area [10], and β (s− 1) represents the slope of the replenishment curve and is related to the blood flow velocity within the myocardium. The product of A (area) and β (blood velocity) allows calculating myocardial blood flow [14]. The acoustic-intensity of A is affected by the capillary density variations between myocardial regions, attenuation effects and technical settings. Vogel et al. have shown that normalizing A to the adjacent left ventricular cavity intensity, filled completely with microbubbles and representing 100% of capillary density, allows to adjust the measurement for attenuation effects and technical settings. They labeled this normalized intensity signal as relative myocardial blood volume, and it is reflecting capillary density [9]. Absolute myocardial blood flow (ml/min/g) is calculated by multiplying relative myocardial blood volume with β and dividing by a
3. Clinical relevance of perfusion measurement in congenital heart disease Most congenital heart disease patients live nowadays long enough to potentially experience the morbidity and mortality related to coronary artery disease. In a recent survey among adult congenital heart disease patients with follow-up at the Royal Brompton Hospital, 9% of 211 adults undergoing selective coronary angiography for reasons other than suspected coronary artery disease had a significant coronary artery stenosis [15]. As previously outlined, myocardial perfusion assessment is a sensitive and prognostic tool to detect coronary disease, and superior to standard exercise testing. In addition to the diagnosis of coronary artery disease, myocardial perfusion measurement provides answers to questions about unbalances between oxygen delivery and demand in different congenital heart disease settings. An elegant example in this respect is the study of Brunken et al., investigating myocardial perfusion reserve in cyanotic congenital heart disease patients [16]. With the use of PET, the authors showed that compensatory secondary erythrocytosis and its effects on blood viscosity do not impair myocardial perfusion, in contrast to the general belief that elevated hematocrit levels invariably increases viscosity and microvascular resistance, and decreases tissue perfusion. In their study, basal perfusion measurements were higher in the left and right ventricle of cyanotic patients compared to controls, and hyperemic flows were similar and did not differ between congenital heart disease patients and controls. However, as a consequence on the increased basal blood flow, the perfusion reserve was greater in controls than in patients in each ventricular region. On clinical grounds, this means that not only the epicardial coronary arteries are dilated in cyanotic patients, but also microcirculatory remodeling leading to augmented basal myocardial perfusion is present. However, during exercise or hyperemia, there is a lower than usual perfusion reserve, and therefore compensatory mechanisms may reach their limits, thereby explaining in parts the limited exercise capacity seen in these patients. Another interesting group of congenital heart disease patients is the adult with a systemic right ventricle and a biventricular circulation, i.e. after an atrial switch procedure for complete transposition of the great arteries, or the adult with a congenitally corrected transposition and no previous switch procedure. Singh et al. published one of the first PET studies assessing absolute myocardial blood flow and flow reserve in an adult systemic right ventricle after a Mustard procedure, compared to myocardial blood flow of an adult systemic left ventricle in healthy controls [17]. The authors speculated, that similar to patients with left ventricular hypertrophy due to arterial hypertension, the hypertrophied systemic right ventricle also shows an impaired coronary artery vasodilator reserve. The inability of the right coronary artery to supply sufficient blood flow to meet the myocardial demands during exercise may be one of the reasons, why these patients have a decreased exercise capacity and some systemic right ventricles even fail over time. At rest, there was no difference in myocardial blood flow in Mustard patients and controls. Absolute myocardial blood flow was 0.8 ± 0.2 vs. 0.74 ± 0.2 ml/g/min, respectively, representing normal absolute myocardial perfusion. During adenosine induced hyperemia, there was a 40% decreased peak coronary blood flow in the systemic right ventricles compared to the systemic left ventricles in controls, despite the fact that on qualitative analysis, no regional perfusion defects could be detected. Nevertheless,
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0.09 0.08
A LV Acoustic Units
0.07 0.018
A
0.014
ß
relative Blood Volume rBV = A / A LV
0.01
0.006
0.002
Refill Curve Fitting y(t) = A · (1 - e -ß· t )
Myocardial Blood Flow MBF = ß· rBV / ρ
0
2
4
6
8
10
12
14
ρ = tissue density
Time (Seconds) Fig. 1. Segmental refill curves (red line) and corresponding left ventricular signal intensities (red dots) reconstructed from a myocardial contrast echocardiography (MCE) perfusion sequence at rest.
myocardial flow reserve was significantly reduced. Potential reasons for this reduction in hyperemic coronary blood flow are myocardial fibrosis secondary to myocardial ischemia (e.g. prolonged hypoxemia during infancy while awaiting the atrial switch procedure), or a decrease in myocardial capillary density as a consequence of prolonged right ventricular pressure overload. In a more recent PET study in adults with congenitally corrected transposition of the great vessels, Hauser et al. [18] demonstrated that lower myocardial perfusion reserve in systemic right ventricles correlated with a lower maximum oxygen consumption (peak VO2) during cardiopulmonary exercise testing, and with impaired systemic ventricular systolic function on echocardiography. Again, visual analysis revealed only one inducible perfusion defect in all fifteen patients, underscoring the limited value of visual or qualitative perfusion assessment in these patients. The proof of the clinical significance of these findings is still out, but the results so far are consistent and indicate that decreased coronary flow reserve in a systemic right ventricle is present and may contribute to ventricular dysfunction in the long run. Hauser et al. also used PET to assess myocardial blood flow in congenital heart disease in 10 adolescents with a Fontan circulation [19]. Ventricular function was normal in 4 and reduced in 6 patients. Compared to 10 healthy controls, myocardial blood flow at rest was higher in the Fontan group than in controls (0.99± 0.25 vs. 0.77 ± 0.2 ml/g/min, p b 0.05) whereas hyperemic absolute myocardial blood flow and coronary artery flow reserve were reduced, even more in patients with reduced systolic ventricular function [19]. Myocardial perfusion was not affected by the site of coronary venous drainage. Reduced coronary artery flow reserve, increased meridional wall stress, and impaired systolic ventricular function were common findings in their Fontan patients and significantly interrelated. As in patients with a biventricular circulation and a systemic right ventricle, decreased coronary flow reserve may contribute to ventricular dysfunction later in life. 4. Myocardial contrast echography Using myocardial contrast echocardiography, we recently focused our interest on the feasibility of myocardial perfusion measurement in adults with conotruncal defects [20]. In 22 adults with with dtransposition of great arteries and an atrial switch procedure, and in
18 patients with repaired tetralogy of Fallot and a hypertrophied and dilated right ventricle, we tried to quantify right ventricular free wall and midseptal myocardial perfusion, based on relative myocardial blood volume (i.e. capillary density) and myocardial blood flow kinetics. The aim of our study was to test the following hypotheses: 1. capillary density derived by myocardial contrast echocardiography is smaller in the right ventricle and midseptal wall of patients with congenital heart disease compared to the midseptal wall in healthy controls, and 2. the myocardial perfusion reserve of the right ventricle is smaller in patients with congenital heart disease than in the systemic ventricle of controls. Based on the preceding work of Indermühle et al. in patients with left ventricular hypertrophy due to an athlete's heart or due to arterial hypertension, we were confident that our non-invasive measurements were a reliable method to detect microvascular changes in the hypertrophied ventricle [21,22]: endurance exercise leads to physiological hypertrophy, characterized by a proportional increase in myocardial mass and vascularization. In case of a mismatch of myocardial mass and microvasculature, as seen in patients with hypertensive left heart disease, capillary density or relative myocardial blood volume, respectively, is reduced, compared to controls and compared to individuals with physiological hypertrophy. Myocardial contrast echocardiography was feasible in all study participants in the septal region. However, measurement of right ventricular free wall perfusion by echocardiography was only possible in half of all adults with transposition and 1 patient with repaired tetralogy of Fallot, but in none of the controls due to “shadowing” of the lung. Absolute septal myocardial blood flow did not differ between the three groups. Hyperemic septal myocardial blood flow and as a consequence also the flow reserve were significantly reduced in patients with dtransposition of great arteries and tetralogy of Fallot compared to controls, first due to a significantly lower regional myocardial blood volume in the septum of congenital heart disease patients, and second due to slower refill kinetics in the septum of adults with transposition. Myocardial blood flow reserve was 1.42 ± 0.68 in transposition patients vs. 2.44± 1.4 in adults with tetralogy of Fallot vs. 3.27 ± 1.3 in controls (p b 0.001). Hyperemic relative myocardial blood volume was 0.132 ± 0.04 in d-transposition of great arteries vs. 0.124 ± 0.06 in tetralogy of Fallot patients vs. 0.19±0.07 in controls (p=0.005). Septal myocardial
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blood flow reserve and hyperemic right ventricular blood flow showed a significant correlation with right ventricular systolic function (r=0.56, pb 0.001; r=0.38, p=0.04, respectively). Interestingly, tetralogy of Fallot patients with normal systolic right ventricular function had normal hyperemic relative myocardial blood volume, blood flow and reserve. Based on these findings, we concluded that in congenital heart disease patients with right ventricular hypertrophy, capillary density is not only reduced in the right ventricular free wall but also interventricular septum, and blood flow reserve is more impaired in transposition patients with a systemic right ventricle than the less hypertrophied right ventricle of repaired tetralogy of Fallot patients. Hence, in congenital heart disease patients with severe right ventricular hypertrophy, capillary vascularization cannot compensate the increase in myocardial growth, leading to a capillary – myocardial muscle mismatch, finally impairing ventricular systolic function [23]. This process seems to affect also the interventricular septum. 5. Safety of myocardial contrast echocardiography The American Society of Echocardiography and the European Association of Echocardiography have established recommendations for the use of echocardiographic contrast agents focusing on the left ventricle [24,25]. The consensus paper of the American Society of Echocardiography highlights that post-marketing studies in more than 1 million patients revealed no major risks besides rare allergic reaction in about 1 per 10,000. Infrequent adverse effects include unspecific complaints like headache and weakness. Very rarely, allergic life threatening hypersensitivity reactions have occurred. There are no studies or guidelines regarding the safety of the application of contrast agents in patients with congenital heart disease. At this point in time, myocardial perfusion measurement with echocardiography is still an investigational tool and not yet approved for clinical applications. 6. Conclusions Determination of myocardial perfusion is feasible with contrast echocardiography. Studies involving patients with congenital heart disease are scarce, so far. Quantification of absolute myocardial blood flow is superior to qualitative (visual) perfusion assessment, especially in patients with unmet metabolic cardiac demands due to ventricular hypertrophy, but no localized segmental perfusion deficits. In these patients, the calculation of relative myocardial blood volume can be used to estimate capillary density and provides additional information to the underlying pathology of reduced myocardial perfusion at rest or during adenosine-induced hyperemia. In the long term, knowledge of the clinical consequences of impaired myocardial perfusion and of the underlying pathophysiological mechanisms will hopefully guide our management in these patients. Conflict of interests The authors declared none.
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