© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12180
Echocardiography
IMAGING THE RIGHT HEART
Nuclear Assessment of Right Ventricle Paola Gargiulo, M.D.,* Alberto Cuocolo, M.D.,*† Santo Dellegrottaglie, M.D., Ph.D.,‡§ Maria Prastaro, M.D.,* Gianluigi Savarese, M.D.,* Roberta Assante, M.D.,¶ Emilia Zampella, M.D.,¶ Stefania Paolillo, M.D.,* Oriana Scala, M.D.,* Donatella Ruggiero, M.D.,* Fabio Marsico, M.D.,* and Pasquale Perrone Filardi, M.D., Ph.D.* *Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; †Department of Biomorphological and Functional Sciences, Federico II University, Naples, Italy; ‡Division of Cardiology, Ospedale Medico-Chirurgico Accreditato Villa dei Fiori, Acerra, Naples, Italy; §Z. and M.A. Wiener Cardiovascular Institute, M.J. and H.R. Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, New York, New York; and ¶SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy
For many years, the right ventricle (RV) has been considered a passive chamber with a relatively insignificant role in the overall functionality of the heart. More recently, the role of performance of RV in the clinical presentation and long-term prognosis of multiple pathological states, such as congenital heart diseases, chronic heart failure, pulmonary hypertension, and chronic obstructive pulmonary disease. Despite echocardiography and cardiac magnetic resonance are the 2 most commonly used imaging techniques for noninvasive assessment of RV, nuclear imaging provides new opportunities for comprehensive evaluation of RV from a single study, because it can assess right ventricular perfusion and metabolism as well as morphology and ejection fraction. In this review, we summarize the application of radionuclide techniques (nuclear cardiology) for evaluation of the RV, focusing on its emerging role in the assessment of right ventricular perfusion and metabolism. (Echocardiography 2014;0:1-6) Key words: right ventricle, radionuclide imaging, morphology, function, metabolism
For many years, the right ventricle (RV) has been considered a passive chamber with a relatively insignificant role in the overall functionality of the heart. Unlike the left ventricle (LV), RV has a complex morphology with thin wall and coarse trabeculations, and its shape cannot be defined with a simple geometrical model. This makes difficult a careful study of morphology and function of RV, contributing to the overshadowing of right ventricular function by the status of the LV. More recently, the role of performance of RV in the clinical presentation and long-term prognosis of multiple pathological states has become increasingly evident.1 The relevance of right ventricular function is obvious for congenital heart diseases involving the RV such as pulmonary valve stenosis, tetralogy of Fallot, and Ebstein malformation.2 In chronic heart failure, dysfunction of RV is a determinant of symptoms3 and prognosis, independently of cardiopulmonary exercise testing parameters and function of LV.4 In pulmonary arterial hypertension,5 much of Address for correspondence and reprint requests: Pasquale Perrone Filardi, M.D., Ph.D., Division of Cardiology, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Via Pansini, 5, 80131, Naples, Italy. Fax: +39 081 746 22 32; E-mail: [email protected]
morbidity and mortality are directly linked to failure of RV, and changes in its function guide pharmacological therapy and timing referral for lungs transplantation.6,7 Finally, the development of failure of RV in chronic obstructive pulmonary disease is correlated with the rate of hospital admission and increased mortality.8 Recent improvements in understanding right ventricular physiology and pathology have been mostly driven by developments in noninvasive imaging modalities. In evaluation of disorders involving RV, nuclear techniques more commonly are employed in detection of chronic thromboembolic pulmonary hypertension (PH).9 While pulmonary computed tomography (CT) is preferred to detect acute pulmonary embolism, ventilation/ perfusion scanning is favored to exclude chronic thromboembolic PH because of its higher sensitivity (96–97%). In fact, in patients with PH and low clinical probability of chronic thromboembolic PH (e.g. no history of pulmonary embolism, venous thrombosis, or risk factors), a normal or low probability ventilation/perfusion scan excludes chronic thromboembolic PH.9 In evaluation of disorders involving RV, nuclear techniques more commonly are employed in detection of chronic thromboembolic PH.9 Indeed, decades 1
Gargiulo, et al.
ago radionuclide techniques have been the first imaging modalities used to provide accurate and reproducible measurements of structure and function of RV.10 Subsequently, echocardiography and cardiac magnetic resonance (CMR) have become the 2 most commonly used imaging techniques for noninvasive assessment of RV11 and replaced radionuclide modalities in most clinical settings. Nonetheless, nuclear imaging may still play a role to identify myocardial ischemia of RV in patients in whom CMR is contraindicated.12 Recent data13,14 have suggested that impairment of right ventricular perfusion and metabolism are major determinants of failure of RV. Since nuclear imaging with application of recent techniques can assess right ventricular perfusion and metabolism as well as morphology and ejection fraction, radionuclide techniques might provide new opportunities for comprehensive evaluation of RV from a single study. In this review, we summarize the application of nuclear cardiology for evaluation of the RV, focusing on its emerging role in the assessment of right ventricular perfusion and metabolism. Systolic Function of RV: Three types of radionuclide angiographic techniques have been utilized for assessing systolic function of RV: first-pass radionuclide angiography, equilibrium radionuclide angiography, and, more recently, single photon emission CT (SPECT) equilibrium radionuclide angiography. First-pass radionuclide angiography technique consists in intravenous administration of a bolus of technetium-99m (99Tc) with immediate dynamic image acquisition, followed by summation of data spanning several cardiac cycles. Differently, in the equilibrium radionuclide angiography technique red blood cells are labeled with 99Tc, allowing imaging of the RV during the entire half-life of the tracer. First-pass
radionuclide angiography and equilibrium radionuclide angiography have been extensively validated and, because ejection fraction of RV is derived from end-systolic and end-diastolic count densities, it is not dependent on geometric assumption as it is for other modalities (Fig. 1).15,16 Although this characteristic could make them ideal for right ventricular evaluation, these techniques have some disadvantages. Indeed, for good diagnostic accuracy, first-pass radionuclide angiography requires very quick image acquisition (about 30 seconds), high radiopharmaceutical dose, placement of a large intravenous catheter in the antecubital or external jugular vein, and high experience to perform technique and interpret images.15 The administration of a radiotracer labeling red blood cells allows equilibrium radionuclide angiography E-RNA to overcome the main limitation of firstpass radionuclide angiography, that is, the need for fast data collection, although use of equilibrium radionuclide angiography to evaluate function of RV may be limited by a systematic underestimation of its ejection fraction due to overlapping of right atrial and RV counts during systole.16 In SPECT equilibrium radionuclide angiography, after administration of 99Tc labeled red blood cells, tomographic ECG-gated data acquisition is performed, similar to gated-SPECT perfusion image acquisition. Due to its threedimensional view, SPECT equilibrium radionuclide angiography improves spatial separation and resolution of cardiac chambers. Compared to other RNA techniques, SPECT equilibrium radionuclide angiography has been shown to provide accurate and reproducible assessment of volumes and ejection fraction of RV.17 Thus, it represents a reasonable alternative when CMR is not available or not feasible in several clinical conditions, including detection of right ventricu-
Figure 1. Radionuclide angiography analysis. End-diastolic A. and end-systolic B. frames and correspondent outlines of the right ventricle (RV). C. Time-activity curve and the measured RV ejection fraction.
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Nuclear Assessment of Right Ventricle
lar dysfunction in patients with chronic heart failure18 or in patients with congenital heart disease to evaluate function of RV in the presurgical phase19 and at follow-up after surgical preparation.20 In addition, it might be routinely used in selected subgroups of patients, such as those undergoing chemotherapy with anthracyclines or other cardiotoxic chemotherapeutic agents, in whom SPECT equilibrium radionuclide angiography has been demonstrated able to identify subclinical impairment of RV.21 Yet, additional studies are needed to definitively validate automatic measurement algorithms before their implementation for routine clinical use. Perfusion of RV: Due to its relatively thin wall, RV is rarely visualized on conventional myocardial perfusion imaging in healthy subjects. However, in patients with right ventricular disease increased tracer uptake due to hypertrophy of RV allows its visualization.22 However, to improve visualization of RV, it also possible to use a dedicated computed postprocessing technique that is able to mask activity of LV.23 Right ventricular perfusion study can be performed in patients with known or suspected coronary artery disease (CAD), to detect isolated infarction of RV or infarction of LV with right ventricular involvement. SPECT provides accurate detection of ischemia in patients with suspected CAD24; it is identified by reversible defects in the RV and interventricular septum and decreased right ventricular ejection fraction during stress (Fig. 2).25 Positron emission tomography (PET) allows noninvasive quantification of regional
myocardial blood flow and coronary flow reserve in RV mostly using nitrogen-13 ammonia (Fig. 3). In pulmonary arterial hypertension, increased wall stress of RV, impaired microvascular coronary flow reserve,26 and/or reduced right coronary blood flow due to elevated right ventricular systolic pressure27 often determine ischemia of RV in the absence of epicardial CAD. Gomez et al.13 have suggested that RV ischemia is a major contributor to failure of RV in pulmonary arterial hypertension patients. Evaluating 23 subjects with pulmonary arterial hypertension with SPECT myocardial perfusion imaging to search for right ventricular inducible ischemia, they have reported that patients with myocardial ischemia of RV have higher right atrial pressure and right ventricular end-diastolic pressure as well as lower mixed venous oxygen saturation, compared to pulmonary arterial hypertension patients without ischemia of RV. In addition, these authors have also shown that the RV/LV tracer uptake ratio, used to estimate hypertrophy of RV, a surrogate marker for right ventricular pressure overload, correlates with echocardiographic free wall thickness of RV, pulmonary systolic pressure, and several other invasive indices of right pressure overload measured with right heart catheterization in pulmonary arterial hypertension patients. Altogether, these findings suggest that right ventricular perfusion assessed by nuclear-imaging techniques might be used as clinical marker of disease severity and response to therapy in pulmonary arterial hypertension patients. In addition, in patients with RV-originated ventricular tachycardia due to organic disease
Figure 2. Myocardial perfusion using gated SPECT after treadmill stress test and at rest. Stress images and rest images in the short axis and horizontal long axis are depicted. In the current example, no persistent perfusion defects were observed. Reversible perfusion defects were observed in the lateral region of the LV and in the anterior region of the RV. SPECT = single photon emission computed tomography; LV = left ventricle; RV = right ventricle.
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Figure 3. Positron emission tomography (PET) N-13 ammonia images of the heart in short-axis and horizontal long-axis views in a patient with biventricular cardiomyopathy. The short-axis images are oriented with the anterior wall on the top and the inferior wall on the bottom.
Figure 4. A. CT, B. PET, and C. fused PET/CT transaxial images in a 47-year-old woman with newly diagnosed biventricular cardiomyopathy after 1 year of chemotherapy for breast cancer. Echocardiography demonstrated decreased left and right ventricular function, with a left ventricular ejection fraction of less than 40%. Transaxial PET/CT image demonstrates increased FDG uptake in the right and left ventricular myocardium. CT = computed tomography; PET = positron emission tomography; FDG = 2-fluoro 2deoxyglucose.
(such as arrhythmogenic dysplasia of RV, myocarditis, and sarcoidosis), significantly greater right ventricular myocardial perfusion abnormalities have been observed compared with patients with idiopathic RV-originated ventricular tachycardia,28 highlighting the usefulness of nuclear imaging in characterizing disease of RV. Metabolism of RV: Radionuclide imaging techniques are of particular interest for assessing myocardial metabolism. Healthy myocardium mainly uses fatty acids as primary energy source, with little contribution of glucose and lactate. In several pathological conditions, glucose oxidation is increased and fatty acid utilization is reduced by metabolic energy shifting.29 Left ventricular metabolism has been 4
extensively evaluated with nuclear imaging in several clinical scenarios, including hypertrophy of LV,30 myocardial ischemia,31 and chronic heart failure.32 Although less extensively studied, changes in metabolism of RV are possible in response to various stimuli.33 Shift in fatty acid metabolism can be assessed by SPECT with b-methyl-p-iodine-123 iodophenyl-pentadecanoid acid (BMIPP) and 99Tc sestamibi and by PET with F-18 2-fluoro 2-deoxyglucose (FDG) or carbon-11 labeled palmitate. In a study involving 46 patients with right ventricular pressure overload undergoing SPECT with BMIPP, a radiolabeled fatty acid, and thallium201 reported that RV/LV ratio and the right ventricular metabolic index (RVMI) = (RV/LV ratio of BMIPP)/(RV/LV ratio of 201Tl) significantly corre-
Nuclear Assessment of Right Ventricle
lated with several hemodynamic indices, including mean pulmonary arterial pressure and total pulmonary resistance,34 suggesting that these may be useful parameters to characterize the presence and severity of impairment of RV in patients with right ventricular pressure overload. In the evaluation of metabolism of RV, PET has higher spatial resolution and allows attenuation correction compared with SPECT, resulting in improved visualization of RV and potential for quantifying substrate utilization.35 These applications of PET imaging are generally based on administration of FDG to distinguish viable from infarcted myocardium whereas use of 11C palmitate, a radiolabeled fatty acid, to study myocardial metabolism has been less frequently investigated.36 The potential advantages of PET imaging for assessment of RV have been reported in several clinical conditions and mostly in patients with pulmonary arterial hypertension. Otani et al.37 demonstrated that in patients with cardiac defect leading to pulmonary artery pressure increase abnormalities in FDG-PET images can be detected prior to the development of pressure overload. In particular, in 11 patients with atrial septum defects, and still normal pulmonary artery pressure, regional differences in FDG uptake in the interventricular septum, compared to free wall of LV, were observed. In addition, it has been reported that increased right ventricular FDG uptake, reflecting increased loading of RV, correlates with prognostic markers in pulmonary arterial hypertension, including reduced exercise capacity, elevated brain natriuretic peptide and echocardiographic variables of tricuspid annular function.38 Finally, FDG-PET could be useful to monitor the effect of pulmonary arterial hypertension therapy, as suggested by animal39 and human14 studies. Oikawa et al.14 have documented in 24 patients with pulmonary arterial hypertension a significant correlation between right ventricular FDG uptake and pulmonary vascular resistances, mean pulmonary artery pressure, and right atrial pressure. They also have observed decreases FDG uptake after 3 months of treatment with epoprostenol in parallel with the reduction of pulmonary vascular resistances and right ventricular peak-systolic wall stress.14 Also, in patients with ischemic and nonischemic dilated cardiomyopathy, increased RV/LV FDG uptake ratio is associated with severity of dysfunction of RV and elevation of right ventricular systolic pressure, but not related to size and function of LV.40 PET scanners have now been combined with CT scanners, which are digital radiological systems that acquire data in the axial plane, producing images of internal organs at high spatial and
contrast resolution.41 The combination of PET and CT in a single unit provides spatial and pathological correlation of the abnormal functional and/or metabolic activities, allowing images from both systems to be obtained by a single instrument in one examination procedure with optimal coregistration. The resulting fusion images facilitate interpretation of PET and CT studies (Fig. 4). CT attenuation maps from these integrated systems are used for rapid and optimal attenuation correction of PET images. Thus, although further studies are warranted, potential clinical applications of FDG-PET might include evaluation of metabolic abnormalities of RV, prediction of short- and long-term prognosis and assessment of response to pharmacology or surgical treatment. Conclusion: Although nuclear assessment of the RV still suffers several technical limitations, it allows accurate characterization of function, perfusion, and metabolism of RV, providing diagnostic and prognostic information that can be integrated with data of other noninvasive imaging techniques. In addition, in selected clinical situations, it can overcome limitations of other techniques (e.g. dependency on geometric assumption for function evaluation of RV as required by other imaging systems) or replace other modalities, when they are not indicated, as in the case of CMR in patients with implantable devices. References 1. Haddad F, Doyle R, Murphy DJ, et al: Right ventricular function in cardiovascular disease, Part II: Pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008;117:1717–1731. 2. Warnes CA: Adult congenital heart disease importance of the right ventricle. J Am Coll Cardiol 2009;54:1903–1910. 3. Zornoff LA, Skali H, Pfeffer MA, et al: Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol 2002;39:1450– 1455. 4. de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948–954. 5. Paolillo S, Farina S, Bussotti M, et al: Exercise testing in the clinical management of patients affected by pulmonary arterial hypertension. Eur J Prev Cardiol 2012;19: 960–971. 6. Savarese G, Musella F, D’Amore C, et al: Hemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension. Eur Respir J 2012 Oct 25 [Epub ahead of print]. 7. Savarese G, Paolillo S, Costanzo P, et al: Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192– 1201. 8. Almagro P, Barreiro B, Ochoa de Echaguen A, et al: Risk factors for hospital readmission in patients with chronic
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9. 10. 11. 12.
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21. 22. 23. 24. 25. 26. 27.
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obstructive pulmonary disease. Respiration 2006;73:311– 317. Lang IM, Plank C, Sadushi-Kolici R, et al: Imaging in pulmonary hypertension. JACC Cardiovasc Imaging 2010; 3:1287–1295. Rich JD, Ward RP: Right-ventricular function by nuclear cardiology. Curr Opin Cardiol 2010;25:445–450. Mertens LL, Friedberg MK: Imaging the right ventricle – Current state of the art. Nat Rev Cardiol 2010;7:551–563. Ramani GV, Gurm G, Dilsizian V, et al: Noninvasive assessment of right ventricular function: Will there be resurgence in radionuclide imaging techniques? Curr Cardiol Rep 2010;12:162–169. Gomez A, Bialostozky D, Zajarias A, et al: Right ventricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol 2001;38:1137–1142. Oikawa M, Kagaya Y, Otani H, et al: Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 2005;45:1849– 1855. Friedman JD, Berman DS, Borges-Neto S, et al: First-pass radionuclide angiography. J Nucl Cardiol 2006;13:e42– e55. Corbett JR, Akinboboye OO, Bacharach SL, et al: Equilibrium radionuclide angiocardiography. J Nucl Cardiol 2006;13:e56–e79. Nichols K, Saouaf R, Ababneh AA, et al: Validation of SPECT equilibrium radionuclide angiographic right ventricular parameters by cardiac magnetic resonance imaging. J Nucl Cardiol 2002;9:153–160. Brieke A, DeNofrio D: Right ventricular dysfunction in chronic dilated cardiomyopathy and heart failure. Coron Artery Dis 2005;16:5–11. Davlouros PA, Niwa K, Webb G, et al: The right ventricle in congenital heart disease. Heart 2006;92(Suppl 1):i27–i38. Hornung TS, Anagnostopoulos C, Bhardwaj P, et al: Comparison of equilibrium radionuclide ventriculography with cardiovascular magnetic resonance for assessing the systemic right ventricle after Mustard or Senning procedures for complete transposition of the great arteries. Am J Cardiol 2003;92:640–643. Nichols KJ, Jain D: Right ventricular parameters: Prospect for routine assessment by equilibrium radionuclide angiographic SPECT. Nucl Med Commun 2007;28:155–157. Khaja F, Alam M, Goldstein S, et al: Diagnostic value of visualization of the right ventricle using thallium-201 myocardial imaging. Circulation 1979;59:182–188. DePuey EG, Jones ME, Garcia EV: Evaluation of right ventricular regional perfusion with technetium-99m-sestamibi SPECT. J Nucl Med 1991;32:1199–1205. Rambihar S, Dokainish H: Right ventricular involvement in patients with coronary artery disease. Curr Opin Cardiol 2010;25:456–463. Schulman DS: Assessment of the right ventricle with radionuclide techniques. J Nucl Cardiol 1996;3:253–264. Brooks H, Kirk ES, Vokonas PS, et al: Performance of the right ventricle under stress: Relation to right coronary flow. J Clin Investig 1971;50:2176–2183. van Wolferen SA, Marcus JT, Westerhof N, et al: Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J 2008;29:120–127.
28. Eguchi M, Tsuchihashi K, Nakata T, et al: Right ventricular abnormalities assessed by myocardial single-photon emission computed tomography using technetium-99m sestamibi/tetrofosmin in right ventricle-originated ventricular tachyarrhythmias. J Am Coll Cardiol 2000; 36:1767–1773. 29. Kodde IF, van der Stok J, Smolenski RT, et al: Metabolic and genetic regulation of cardiac energy substrate preference. Comp Biochem Physiol A Mol Integr Physiol 2007;146:26–39. 30. Perrone-Filardi P, Bacharach SL, Dilsizian V, et al: Regional systolic function, myocardial blood flow and glucose uptake at rest in hypertrophic cardiomyopathy. Am J Cardiol 1993;72:199–204. 31. Perrone-Filardi P, Bacharach SL, Dilsizian V, et al: Regional left ventricular wall thickening. Relation to regional uptake of 18fluorodeoxyglucose and 201Tl in patients with chronic coronary artery disease and left ventricular dysfunction. Circulation 1992;86:1125–1137. 32. Marin-Neto JA, Dilsizian V, Arrighi JA, et al: Thallium scintigraphy compared with 18F-fluorodeoxyglucose positron emission tomography for assessing myocardial viability in patients with moderate versus severe left ventricular dysfunction. Am J Cardiol 1998;82:1001– 1007. 33. Altin SE, Schulze PC: Metabolism of the right ventricle and the response to hypertrophy and failure. Prog Cardiovasc Dis 2012;55:229–233. 34. Matsushita T, Ikeda S, Miyahara Y, et al: Use of [123I]BMIPP myocardial scintigraphy for the clinical evaluation of a fatty-acid metabolism disorder of the right ventricle in chronic respiratory and pulmonary vascular disease. J Int Med Res 2000;28:111–123. 35. Heller GV: Practical issues regarding the incorporation of PET into a busy SPECT practice. J Nucl Cardiol 2012;19 (Suppl 1):S12–S18. 36. Bergmann SR: Imaging of myocardial fatty acid metabolism with PET. J Nucl Cardiol 2007;14:S118–S124. 37. Otani H, Kagaya Y, Yamane Y, et al: Long-term right ventricular volume overload increases myocardial fluorodeoxyglucose uptake in the interventricular septum in patients with atrial septal defect. Circulation 2000; 101:1686–1692. 38. Can MM, Kaymaz C, Tanboga IH, et al: Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin Nucl Med 2011;36:743– 748. 39. Piao L, Fang YH, Cadete VJ, et al: The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: Resuscitating the hibernating right ventricle. J Mol Med 2010;88:47–60. 40. Mielniczuk LM, Birnie D, Ziadi MC, et al: Relation between right ventricular function and increased right ventricular [18F]fluorodeoxyglucose accumulation in patients with heart failure. Circ Cardiovasc Imaging 2011;4:59–66. 41. Petretta M, Costanzo P, Acampa W, et al: Noninvasive assessment of coronary anatomy and myocardial perfusion: Going toward an integrated imaging approach. J Cardiovasc Med (Hagerstown) 2008;9:977–986.
Echocardiography
IMAGING THE RIGHT HEART
Nuclear Assessment of Right Ventricle Paola Gargiulo, M.D.,* Alberto Cuocolo, M.D.,*† Santo Dellegrottaglie, M.D., Ph.D.,‡§ Maria Prastaro, M.D.,* Gianluigi Savarese, M.D.,* Roberta Assante, M.D.,¶ Emilia Zampella, M.D.,¶ Stefania Paolillo, M.D.,* Oriana Scala, M.D.,* Donatella Ruggiero, M.D.,* Fabio Marsico, M.D.,* and Pasquale Perrone Filardi, M.D., Ph.D.* *Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; †Department of Biomorphological and Functional Sciences, Federico II University, Naples, Italy; ‡Division of Cardiology, Ospedale Medico-Chirurgico Accreditato Villa dei Fiori, Acerra, Naples, Italy; §Z. and M.A. Wiener Cardiovascular Institute, M.J. and H.R. Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, New York, New York; and ¶SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy
For many years, the right ventricle (RV) has been considered a passive chamber with a relatively insignificant role in the overall functionality of the heart. More recently, the role of performance of RV in the clinical presentation and long-term prognosis of multiple pathological states, such as congenital heart diseases, chronic heart failure, pulmonary hypertension, and chronic obstructive pulmonary disease. Despite echocardiography and cardiac magnetic resonance are the 2 most commonly used imaging techniques for noninvasive assessment of RV, nuclear imaging provides new opportunities for comprehensive evaluation of RV from a single study, because it can assess right ventricular perfusion and metabolism as well as morphology and ejection fraction. In this review, we summarize the application of radionuclide techniques (nuclear cardiology) for evaluation of the RV, focusing on its emerging role in the assessment of right ventricular perfusion and metabolism. (Echocardiography 2014;0:1-6) Key words: right ventricle, radionuclide imaging, morphology, function, metabolism
For many years, the right ventricle (RV) has been considered a passive chamber with a relatively insignificant role in the overall functionality of the heart. Unlike the left ventricle (LV), RV has a complex morphology with thin wall and coarse trabeculations, and its shape cannot be defined with a simple geometrical model. This makes difficult a careful study of morphology and function of RV, contributing to the overshadowing of right ventricular function by the status of the LV. More recently, the role of performance of RV in the clinical presentation and long-term prognosis of multiple pathological states has become increasingly evident.1 The relevance of right ventricular function is obvious for congenital heart diseases involving the RV such as pulmonary valve stenosis, tetralogy of Fallot, and Ebstein malformation.2 In chronic heart failure, dysfunction of RV is a determinant of symptoms3 and prognosis, independently of cardiopulmonary exercise testing parameters and function of LV.4 In pulmonary arterial hypertension,5 much of Address for correspondence and reprint requests: Pasquale Perrone Filardi, M.D., Ph.D., Division of Cardiology, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Via Pansini, 5, 80131, Naples, Italy. Fax: +39 081 746 22 32; E-mail: [email protected]
morbidity and mortality are directly linked to failure of RV, and changes in its function guide pharmacological therapy and timing referral for lungs transplantation.6,7 Finally, the development of failure of RV in chronic obstructive pulmonary disease is correlated with the rate of hospital admission and increased mortality.8 Recent improvements in understanding right ventricular physiology and pathology have been mostly driven by developments in noninvasive imaging modalities. In evaluation of disorders involving RV, nuclear techniques more commonly are employed in detection of chronic thromboembolic pulmonary hypertension (PH).9 While pulmonary computed tomography (CT) is preferred to detect acute pulmonary embolism, ventilation/ perfusion scanning is favored to exclude chronic thromboembolic PH because of its higher sensitivity (96–97%). In fact, in patients with PH and low clinical probability of chronic thromboembolic PH (e.g. no history of pulmonary embolism, venous thrombosis, or risk factors), a normal or low probability ventilation/perfusion scan excludes chronic thromboembolic PH.9 In evaluation of disorders involving RV, nuclear techniques more commonly are employed in detection of chronic thromboembolic PH.9 Indeed, decades 1
Gargiulo, et al.
ago radionuclide techniques have been the first imaging modalities used to provide accurate and reproducible measurements of structure and function of RV.10 Subsequently, echocardiography and cardiac magnetic resonance (CMR) have become the 2 most commonly used imaging techniques for noninvasive assessment of RV11 and replaced radionuclide modalities in most clinical settings. Nonetheless, nuclear imaging may still play a role to identify myocardial ischemia of RV in patients in whom CMR is contraindicated.12 Recent data13,14 have suggested that impairment of right ventricular perfusion and metabolism are major determinants of failure of RV. Since nuclear imaging with application of recent techniques can assess right ventricular perfusion and metabolism as well as morphology and ejection fraction, radionuclide techniques might provide new opportunities for comprehensive evaluation of RV from a single study. In this review, we summarize the application of nuclear cardiology for evaluation of the RV, focusing on its emerging role in the assessment of right ventricular perfusion and metabolism. Systolic Function of RV: Three types of radionuclide angiographic techniques have been utilized for assessing systolic function of RV: first-pass radionuclide angiography, equilibrium radionuclide angiography, and, more recently, single photon emission CT (SPECT) equilibrium radionuclide angiography. First-pass radionuclide angiography technique consists in intravenous administration of a bolus of technetium-99m (99Tc) with immediate dynamic image acquisition, followed by summation of data spanning several cardiac cycles. Differently, in the equilibrium radionuclide angiography technique red blood cells are labeled with 99Tc, allowing imaging of the RV during the entire half-life of the tracer. First-pass
radionuclide angiography and equilibrium radionuclide angiography have been extensively validated and, because ejection fraction of RV is derived from end-systolic and end-diastolic count densities, it is not dependent on geometric assumption as it is for other modalities (Fig. 1).15,16 Although this characteristic could make them ideal for right ventricular evaluation, these techniques have some disadvantages. Indeed, for good diagnostic accuracy, first-pass radionuclide angiography requires very quick image acquisition (about 30 seconds), high radiopharmaceutical dose, placement of a large intravenous catheter in the antecubital or external jugular vein, and high experience to perform technique and interpret images.15 The administration of a radiotracer labeling red blood cells allows equilibrium radionuclide angiography E-RNA to overcome the main limitation of firstpass radionuclide angiography, that is, the need for fast data collection, although use of equilibrium radionuclide angiography to evaluate function of RV may be limited by a systematic underestimation of its ejection fraction due to overlapping of right atrial and RV counts during systole.16 In SPECT equilibrium radionuclide angiography, after administration of 99Tc labeled red blood cells, tomographic ECG-gated data acquisition is performed, similar to gated-SPECT perfusion image acquisition. Due to its threedimensional view, SPECT equilibrium radionuclide angiography improves spatial separation and resolution of cardiac chambers. Compared to other RNA techniques, SPECT equilibrium radionuclide angiography has been shown to provide accurate and reproducible assessment of volumes and ejection fraction of RV.17 Thus, it represents a reasonable alternative when CMR is not available or not feasible in several clinical conditions, including detection of right ventricu-
Figure 1. Radionuclide angiography analysis. End-diastolic A. and end-systolic B. frames and correspondent outlines of the right ventricle (RV). C. Time-activity curve and the measured RV ejection fraction.
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lar dysfunction in patients with chronic heart failure18 or in patients with congenital heart disease to evaluate function of RV in the presurgical phase19 and at follow-up after surgical preparation.20 In addition, it might be routinely used in selected subgroups of patients, such as those undergoing chemotherapy with anthracyclines or other cardiotoxic chemotherapeutic agents, in whom SPECT equilibrium radionuclide angiography has been demonstrated able to identify subclinical impairment of RV.21 Yet, additional studies are needed to definitively validate automatic measurement algorithms before their implementation for routine clinical use. Perfusion of RV: Due to its relatively thin wall, RV is rarely visualized on conventional myocardial perfusion imaging in healthy subjects. However, in patients with right ventricular disease increased tracer uptake due to hypertrophy of RV allows its visualization.22 However, to improve visualization of RV, it also possible to use a dedicated computed postprocessing technique that is able to mask activity of LV.23 Right ventricular perfusion study can be performed in patients with known or suspected coronary artery disease (CAD), to detect isolated infarction of RV or infarction of LV with right ventricular involvement. SPECT provides accurate detection of ischemia in patients with suspected CAD24; it is identified by reversible defects in the RV and interventricular septum and decreased right ventricular ejection fraction during stress (Fig. 2).25 Positron emission tomography (PET) allows noninvasive quantification of regional
myocardial blood flow and coronary flow reserve in RV mostly using nitrogen-13 ammonia (Fig. 3). In pulmonary arterial hypertension, increased wall stress of RV, impaired microvascular coronary flow reserve,26 and/or reduced right coronary blood flow due to elevated right ventricular systolic pressure27 often determine ischemia of RV in the absence of epicardial CAD. Gomez et al.13 have suggested that RV ischemia is a major contributor to failure of RV in pulmonary arterial hypertension patients. Evaluating 23 subjects with pulmonary arterial hypertension with SPECT myocardial perfusion imaging to search for right ventricular inducible ischemia, they have reported that patients with myocardial ischemia of RV have higher right atrial pressure and right ventricular end-diastolic pressure as well as lower mixed venous oxygen saturation, compared to pulmonary arterial hypertension patients without ischemia of RV. In addition, these authors have also shown that the RV/LV tracer uptake ratio, used to estimate hypertrophy of RV, a surrogate marker for right ventricular pressure overload, correlates with echocardiographic free wall thickness of RV, pulmonary systolic pressure, and several other invasive indices of right pressure overload measured with right heart catheterization in pulmonary arterial hypertension patients. Altogether, these findings suggest that right ventricular perfusion assessed by nuclear-imaging techniques might be used as clinical marker of disease severity and response to therapy in pulmonary arterial hypertension patients. In addition, in patients with RV-originated ventricular tachycardia due to organic disease
Figure 2. Myocardial perfusion using gated SPECT after treadmill stress test and at rest. Stress images and rest images in the short axis and horizontal long axis are depicted. In the current example, no persistent perfusion defects were observed. Reversible perfusion defects were observed in the lateral region of the LV and in the anterior region of the RV. SPECT = single photon emission computed tomography; LV = left ventricle; RV = right ventricle.
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Figure 3. Positron emission tomography (PET) N-13 ammonia images of the heart in short-axis and horizontal long-axis views in a patient with biventricular cardiomyopathy. The short-axis images are oriented with the anterior wall on the top and the inferior wall on the bottom.
Figure 4. A. CT, B. PET, and C. fused PET/CT transaxial images in a 47-year-old woman with newly diagnosed biventricular cardiomyopathy after 1 year of chemotherapy for breast cancer. Echocardiography demonstrated decreased left and right ventricular function, with a left ventricular ejection fraction of less than 40%. Transaxial PET/CT image demonstrates increased FDG uptake in the right and left ventricular myocardium. CT = computed tomography; PET = positron emission tomography; FDG = 2-fluoro 2deoxyglucose.
(such as arrhythmogenic dysplasia of RV, myocarditis, and sarcoidosis), significantly greater right ventricular myocardial perfusion abnormalities have been observed compared with patients with idiopathic RV-originated ventricular tachycardia,28 highlighting the usefulness of nuclear imaging in characterizing disease of RV. Metabolism of RV: Radionuclide imaging techniques are of particular interest for assessing myocardial metabolism. Healthy myocardium mainly uses fatty acids as primary energy source, with little contribution of glucose and lactate. In several pathological conditions, glucose oxidation is increased and fatty acid utilization is reduced by metabolic energy shifting.29 Left ventricular metabolism has been 4
extensively evaluated with nuclear imaging in several clinical scenarios, including hypertrophy of LV,30 myocardial ischemia,31 and chronic heart failure.32 Although less extensively studied, changes in metabolism of RV are possible in response to various stimuli.33 Shift in fatty acid metabolism can be assessed by SPECT with b-methyl-p-iodine-123 iodophenyl-pentadecanoid acid (BMIPP) and 99Tc sestamibi and by PET with F-18 2-fluoro 2-deoxyglucose (FDG) or carbon-11 labeled palmitate. In a study involving 46 patients with right ventricular pressure overload undergoing SPECT with BMIPP, a radiolabeled fatty acid, and thallium201 reported that RV/LV ratio and the right ventricular metabolic index (RVMI) = (RV/LV ratio of BMIPP)/(RV/LV ratio of 201Tl) significantly corre-
Nuclear Assessment of Right Ventricle
lated with several hemodynamic indices, including mean pulmonary arterial pressure and total pulmonary resistance,34 suggesting that these may be useful parameters to characterize the presence and severity of impairment of RV in patients with right ventricular pressure overload. In the evaluation of metabolism of RV, PET has higher spatial resolution and allows attenuation correction compared with SPECT, resulting in improved visualization of RV and potential for quantifying substrate utilization.35 These applications of PET imaging are generally based on administration of FDG to distinguish viable from infarcted myocardium whereas use of 11C palmitate, a radiolabeled fatty acid, to study myocardial metabolism has been less frequently investigated.36 The potential advantages of PET imaging for assessment of RV have been reported in several clinical conditions and mostly in patients with pulmonary arterial hypertension. Otani et al.37 demonstrated that in patients with cardiac defect leading to pulmonary artery pressure increase abnormalities in FDG-PET images can be detected prior to the development of pressure overload. In particular, in 11 patients with atrial septum defects, and still normal pulmonary artery pressure, regional differences in FDG uptake in the interventricular septum, compared to free wall of LV, were observed. In addition, it has been reported that increased right ventricular FDG uptake, reflecting increased loading of RV, correlates with prognostic markers in pulmonary arterial hypertension, including reduced exercise capacity, elevated brain natriuretic peptide and echocardiographic variables of tricuspid annular function.38 Finally, FDG-PET could be useful to monitor the effect of pulmonary arterial hypertension therapy, as suggested by animal39 and human14 studies. Oikawa et al.14 have documented in 24 patients with pulmonary arterial hypertension a significant correlation between right ventricular FDG uptake and pulmonary vascular resistances, mean pulmonary artery pressure, and right atrial pressure. They also have observed decreases FDG uptake after 3 months of treatment with epoprostenol in parallel with the reduction of pulmonary vascular resistances and right ventricular peak-systolic wall stress.14 Also, in patients with ischemic and nonischemic dilated cardiomyopathy, increased RV/LV FDG uptake ratio is associated with severity of dysfunction of RV and elevation of right ventricular systolic pressure, but not related to size and function of LV.40 PET scanners have now been combined with CT scanners, which are digital radiological systems that acquire data in the axial plane, producing images of internal organs at high spatial and
contrast resolution.41 The combination of PET and CT in a single unit provides spatial and pathological correlation of the abnormal functional and/or metabolic activities, allowing images from both systems to be obtained by a single instrument in one examination procedure with optimal coregistration. The resulting fusion images facilitate interpretation of PET and CT studies (Fig. 4). CT attenuation maps from these integrated systems are used for rapid and optimal attenuation correction of PET images. Thus, although further studies are warranted, potential clinical applications of FDG-PET might include evaluation of metabolic abnormalities of RV, prediction of short- and long-term prognosis and assessment of response to pharmacology or surgical treatment. Conclusion: Although nuclear assessment of the RV still suffers several technical limitations, it allows accurate characterization of function, perfusion, and metabolism of RV, providing diagnostic and prognostic information that can be integrated with data of other noninvasive imaging techniques. In addition, in selected clinical situations, it can overcome limitations of other techniques (e.g. dependency on geometric assumption for function evaluation of RV as required by other imaging systems) or replace other modalities, when they are not indicated, as in the case of CMR in patients with implantable devices. References 1. Haddad F, Doyle R, Murphy DJ, et al: Right ventricular function in cardiovascular disease, Part II: Pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008;117:1717–1731. 2. Warnes CA: Adult congenital heart disease importance of the right ventricle. J Am Coll Cardiol 2009;54:1903–1910. 3. Zornoff LA, Skali H, Pfeffer MA, et al: Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol 2002;39:1450– 1455. 4. de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948–954. 5. Paolillo S, Farina S, Bussotti M, et al: Exercise testing in the clinical management of patients affected by pulmonary arterial hypertension. Eur J Prev Cardiol 2012;19: 960–971. 6. Savarese G, Musella F, D’Amore C, et al: Hemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension. Eur Respir J 2012 Oct 25 [Epub ahead of print]. 7. Savarese G, Paolillo S, Costanzo P, et al: Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192– 1201. 8. Almagro P, Barreiro B, Ochoa de Echaguen A, et al: Risk factors for hospital readmission in patients with chronic
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