- Email: [email protected]
Intra-scar perfusion heterogeneity by cardiac magnetic resonance in a porcine model of non-reperfused myocardial infarction
International Journal of Cardiology 176 (2014) 1288–1289
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Intra-scar perfusion heterogeneity by cardiac magnetic resonance in a porcine model of non-reperfused myocardial infarction☆,☆☆ Gabriela Guzmán-Martínez a,b,c,⁎, Leticia Fernández-Friera b,d, Sergio Moral e, Scott Shapiro f, David Bates g, Roger Hajjar a, Mario J. García h, Valentín Fuster a,b, Javier Sanz a a
Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA Centro Nacional de Investigaciones Cardiovasculares (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain Cardiology Department, Hospital Universitario La Paz, IdiPaz, Madrid, Spain d Hospital Universitario Montepríncipe, Madrid, Spain e Hospital Universitari Vall D'Hebrón, Barcelona, Spain f George Washington University Medical Center, Division of Cardiology, Washington, DC, USA g Departament of Radiology, Boston University Medical Center, USA h Montefiore-Einstein Center for Heart and Vascular Care, Albert Einstein College of Medicine, Bronx, New York, NY, USA b c
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 27 July 2014 Available online 4 August 2014 Keywords: Non-reperfused myocardial infarction Cardiac magnetic resonance Myocardial perfusion Delayed enhancement peri-infarct border zone
We attempted to demonstrate and semiquantify perfusion heterogeneity within myocardial infarction (MI) using cardiac magnetic resonance (CMR) in experimental acute, non-reperfused MI. Additionally, we performed detailed characterization of regional left ventricular (LV) function, perfusion, and viability. The protocol was approved by the Institutional Animal Care and Use Committee. Eleven pigs underwent permanent percutaneous occlusion of the left anterior descending artery. CMR studies were performed 6 ± 1 days after MI creation using a 3.0 T magnet and included shortaxis cine imaging with steady-state free precession, rest perfusion imaging with saturation-recovery turbo field echo after administration of 0.05 mmol/kg of gadolinium-based contrast, and delayed enhancement (DE) scar imaging with inversion-recovery 2D fast field echo 10 min after 0.2 mmol/kg of contrast agent. ☆ Sources of funding: G.G. is supported by a Cardio-Image Program CNIC-MSSM 2008 fellowship. ☆☆ Disclosures: None. ⁎ Corresponding author at: Cardiac Imaging Unit, Cardiology Department, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. Tel.: + 34 91 2071605. E-mail address: [email protected] (G. Guzmán-Martínez).
http://dx.doi.org/10.1016/j.ijcard.2014.07.179 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
We matched cine, perfusion, and DE short-axis images and divided each into 24 equiangular segments. For each segment, we calculated percentage of systolic wall thickening, maximal myocardial perfusion upslope normalized to LV blood pool upslope and expressed as a percentage, and DE transmurality (defined as percentage of myocardium with signal intensity N 2 standard deviations of average signal in remote myocardium). Two adjacent segments on both ends of the scar where DE was still (near)transmural were labeled “scar periphery” (SP). Remaining segments in the scar were designated “scar center” (SC). Segments at the edges of the scar containing both enhanced and non-enhanced myocardium were termed “border zone” (BZ). Adjacent non-enhanced myocardium was named “normal peri-infarct” (NP) and remaining segments “normal remote” (NR). As shown in the Table 1 and Fig. 1, wall thickening and perfusion differed significantly amongst segment types and progressively increased from SC to RN myocardium (linear trend p b 0.0001). After post-hoc Bonferroni correction, we observed the following (Fig. 1): 1. Myocardial perfusion at rest was significantly lower in the scar core versus the periphery (SC 4.1% vs. SP 5.8%, p = 0.03) despite no differences on DE extent or systolic dysfunction. 2. Non-enhanced segments had comparable perfusion, but systolic thickening was higher in remote myocardium (NP 37.5% vs. NR 61.6%, p = 0.04). 3. Border zone perfusion and wall thickening did not differ from those in the scar periphery despite markedly lower amount of DE BZ 60.5% vs. SP 88.6%, p b 0.001. Our results, using noninvasive in-vivo CMR, agree with prior postmortem studies of experimental coronary occlusion demonstrating perfusion gradients n from the scar core to remote myocardium using radioactive microspheres [1–3]. Characterization of heterogeneous intrascar perfusion patterns may be of relevance when evaluating, for example, myocardial regenerative therapies, which may exert beneficial effects predominantly at or near the MI periphery [4]. Our data also confirms that systolic dysfunction is present not only within the MI but also in adjacent non-infarcted segments [5], probably
G. Guzmán-Martínez et al. / International Journal of Cardiology 176 (2014) 1288–1289 Table 1 Regional systolic wall thickening, extent of delayed enhancement, and normalized upslope of first-pass perfusion of each segment category.
Systolic thickening (%)
Normalized maximal upslope (%)
Delayed enhancement (%)
Region
Estimator ± standard error
Mixed model p-value
SC SP BZ NP NR SC SP BZ NP NR SC SP BZ NP NR
17.59 ± 5.65 17.60 ± 6.26 23.77 ± 6.33 37.50 ± 7.02 61.55 ± 4.43 4.12 ± 0.38 5.80 ± 0.42 6.04 ± 0.42 6.82 ± 0.47 6.60 ± 0.29 96.69 ± 2.74 89.57 ± 3.04 60.53 ± 3.07 – –
b0.0001
b0.0001
1289
detection which could provide further insights into the interactions between perfusion, contractility, and inflammation. In conclusion, CMR at 3 T can demonstrate and semiquantify intrascar perfusion heterogeneity in MI, with a core-to-periphery gradient despite similar degrees of transmural scarring. CMR can also provide detailed characterization of regional function, perfusion and necrosis in a noninvasive fashion. These abilities may have important implications for the evaluation of myocardial regenerative therapies. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
b0.0001
SC, scar center; SP, scar periphery; BZ, border zone; NP, normal periphery; NC, normal center.
in relation to stunning. The lower contractility of these segments in comparison with remote normal myocardium is unlikely explained by increased compensatory contractility in the latter, which showed systolic thickening values largely within normal limits [6]. More likely, hypokinesis is due to passive tethering from neighboring infarcted segments causing increased wall stress [7,8]. The well known “border zone” of an MI containing intermixed viable and necrotic myocardium [9] did not differ in terms of perfusion or contractility from nearby, completely infarcted regions, despite significantly lower amount of scar. This is not surprising since these segments demonstrated an average of 61% of DE transmurality, and thickening is abolished when scar involves the endocardial half of a myocardial segment [10]. A limitation of our study is that the method employed for analysis of CMR perfusion is only semiquantitative. We included a relatively small number of animals and we did not acquire sequences for edema
References [1] Becker LC, Ferreira R, Thomas M. Mapping of left ventricular blood flow with radioactive microspheres in experimental coronary artery occlusion. Cardiovasc Res 1973;7(3):391–400. [2] White FC, Sanders M, Bloor CM. Regional redistribution of myocardial blood flow after coronary occlusion and reperfusion in the conscious dog. Am J Cardiol 1978; 42(2):234–43. [3] Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC. Myocardial infarction in the conscious dog: three-dimensional mapping of infarct, collateral flow and regional risk. Circulation 1979;60(5):1141–50. [4] Jin P, Wang E, Wang YH, et al. Central zone of myocardial infarction: a neglected target area for heart cell therapy. J Cell Mol Med 2012;16(3):637–48. [5] Lima JA, Becker LC, Melin JA, et al. Impaired thickening of nonischemic myocardium during acute regional ischemia in the dog. Circulation 1985;71(5):1048–59. [6] Holman ER, Buller VG, de Roos A, et al. Detection and quantification of dysfunctional myocardium by magnetic resonance imaging. A new three-dimensional method for quantitative wall-thickening analysis. Circulation 1997;95(4):924–31. [7] Bogen DK, Rabinowitz SA, Needleman A, McMahon TA, Abelmann WH. An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle. Circ Res 1980;47(5):728–41. [8] Ashikaga H, Mickelsen SR, Ennis DB, et al. Electromechanical analysis of infarct border zone in chronic myocardial infarction. Am J Physiol Heart Circ Physiol 2005; 289(3):H1099–105. [9] Factor SM, Sonnenblick EH, Kirk ES. The histologic border zone of acute myocardial infarction—islands or peninsulas? Am J Pathol 1978;92(1):111–24. [10] Mahrholdt H, Wagner A, Parker M, et al. Relationship of contractile function to transmural extent of infarction in patients with chronic coronary artery disease. J Am Coll Cardiol 2003;42(3):505–12.
Fig. 1. Regional systolic wall thickening, extent of delayed enhancement, and normalized upslope of first-pass perfusion of each segment category.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Intra-scar perfusion heterogeneity by cardiac magnetic resonance in a porcine model of non-reperfused myocardial infarction☆,☆☆ Gabriela Guzmán-Martínez a,b,c,⁎, Leticia Fernández-Friera b,d, Sergio Moral e, Scott Shapiro f, David Bates g, Roger Hajjar a, Mario J. García h, Valentín Fuster a,b, Javier Sanz a a
Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA Centro Nacional de Investigaciones Cardiovasculares (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain Cardiology Department, Hospital Universitario La Paz, IdiPaz, Madrid, Spain d Hospital Universitario Montepríncipe, Madrid, Spain e Hospital Universitari Vall D'Hebrón, Barcelona, Spain f George Washington University Medical Center, Division of Cardiology, Washington, DC, USA g Departament of Radiology, Boston University Medical Center, USA h Montefiore-Einstein Center for Heart and Vascular Care, Albert Einstein College of Medicine, Bronx, New York, NY, USA b c
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 27 July 2014 Available online 4 August 2014 Keywords: Non-reperfused myocardial infarction Cardiac magnetic resonance Myocardial perfusion Delayed enhancement peri-infarct border zone
We attempted to demonstrate and semiquantify perfusion heterogeneity within myocardial infarction (MI) using cardiac magnetic resonance (CMR) in experimental acute, non-reperfused MI. Additionally, we performed detailed characterization of regional left ventricular (LV) function, perfusion, and viability. The protocol was approved by the Institutional Animal Care and Use Committee. Eleven pigs underwent permanent percutaneous occlusion of the left anterior descending artery. CMR studies were performed 6 ± 1 days after MI creation using a 3.0 T magnet and included shortaxis cine imaging with steady-state free precession, rest perfusion imaging with saturation-recovery turbo field echo after administration of 0.05 mmol/kg of gadolinium-based contrast, and delayed enhancement (DE) scar imaging with inversion-recovery 2D fast field echo 10 min after 0.2 mmol/kg of contrast agent. ☆ Sources of funding: G.G. is supported by a Cardio-Image Program CNIC-MSSM 2008 fellowship. ☆☆ Disclosures: None. ⁎ Corresponding author at: Cardiac Imaging Unit, Cardiology Department, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. Tel.: + 34 91 2071605. E-mail address: [email protected] (G. Guzmán-Martínez).
http://dx.doi.org/10.1016/j.ijcard.2014.07.179 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
We matched cine, perfusion, and DE short-axis images and divided each into 24 equiangular segments. For each segment, we calculated percentage of systolic wall thickening, maximal myocardial perfusion upslope normalized to LV blood pool upslope and expressed as a percentage, and DE transmurality (defined as percentage of myocardium with signal intensity N 2 standard deviations of average signal in remote myocardium). Two adjacent segments on both ends of the scar where DE was still (near)transmural were labeled “scar periphery” (SP). Remaining segments in the scar were designated “scar center” (SC). Segments at the edges of the scar containing both enhanced and non-enhanced myocardium were termed “border zone” (BZ). Adjacent non-enhanced myocardium was named “normal peri-infarct” (NP) and remaining segments “normal remote” (NR). As shown in the Table 1 and Fig. 1, wall thickening and perfusion differed significantly amongst segment types and progressively increased from SC to RN myocardium (linear trend p b 0.0001). After post-hoc Bonferroni correction, we observed the following (Fig. 1): 1. Myocardial perfusion at rest was significantly lower in the scar core versus the periphery (SC 4.1% vs. SP 5.8%, p = 0.03) despite no differences on DE extent or systolic dysfunction. 2. Non-enhanced segments had comparable perfusion, but systolic thickening was higher in remote myocardium (NP 37.5% vs. NR 61.6%, p = 0.04). 3. Border zone perfusion and wall thickening did not differ from those in the scar periphery despite markedly lower amount of DE BZ 60.5% vs. SP 88.6%, p b 0.001. Our results, using noninvasive in-vivo CMR, agree with prior postmortem studies of experimental coronary occlusion demonstrating perfusion gradients n from the scar core to remote myocardium using radioactive microspheres [1–3]. Characterization of heterogeneous intrascar perfusion patterns may be of relevance when evaluating, for example, myocardial regenerative therapies, which may exert beneficial effects predominantly at or near the MI periphery [4]. Our data also confirms that systolic dysfunction is present not only within the MI but also in adjacent non-infarcted segments [5], probably
G. Guzmán-Martínez et al. / International Journal of Cardiology 176 (2014) 1288–1289 Table 1 Regional systolic wall thickening, extent of delayed enhancement, and normalized upslope of first-pass perfusion of each segment category.
Systolic thickening (%)
Normalized maximal upslope (%)
Delayed enhancement (%)
Region
Estimator ± standard error
Mixed model p-value
SC SP BZ NP NR SC SP BZ NP NR SC SP BZ NP NR
17.59 ± 5.65 17.60 ± 6.26 23.77 ± 6.33 37.50 ± 7.02 61.55 ± 4.43 4.12 ± 0.38 5.80 ± 0.42 6.04 ± 0.42 6.82 ± 0.47 6.60 ± 0.29 96.69 ± 2.74 89.57 ± 3.04 60.53 ± 3.07 – –
b0.0001
b0.0001
1289
detection which could provide further insights into the interactions between perfusion, contractility, and inflammation. In conclusion, CMR at 3 T can demonstrate and semiquantify intrascar perfusion heterogeneity in MI, with a core-to-periphery gradient despite similar degrees of transmural scarring. CMR can also provide detailed characterization of regional function, perfusion and necrosis in a noninvasive fashion. These abilities may have important implications for the evaluation of myocardial regenerative therapies. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
b0.0001
SC, scar center; SP, scar periphery; BZ, border zone; NP, normal periphery; NC, normal center.
in relation to stunning. The lower contractility of these segments in comparison with remote normal myocardium is unlikely explained by increased compensatory contractility in the latter, which showed systolic thickening values largely within normal limits [6]. More likely, hypokinesis is due to passive tethering from neighboring infarcted segments causing increased wall stress [7,8]. The well known “border zone” of an MI containing intermixed viable and necrotic myocardium [9] did not differ in terms of perfusion or contractility from nearby, completely infarcted regions, despite significantly lower amount of scar. This is not surprising since these segments demonstrated an average of 61% of DE transmurality, and thickening is abolished when scar involves the endocardial half of a myocardial segment [10]. A limitation of our study is that the method employed for analysis of CMR perfusion is only semiquantitative. We included a relatively small number of animals and we did not acquire sequences for edema
References [1] Becker LC, Ferreira R, Thomas M. Mapping of left ventricular blood flow with radioactive microspheres in experimental coronary artery occlusion. Cardiovasc Res 1973;7(3):391–400. [2] White FC, Sanders M, Bloor CM. Regional redistribution of myocardial blood flow after coronary occlusion and reperfusion in the conscious dog. Am J Cardiol 1978; 42(2):234–43. [3] Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC. Myocardial infarction in the conscious dog: three-dimensional mapping of infarct, collateral flow and regional risk. Circulation 1979;60(5):1141–50. [4] Jin P, Wang E, Wang YH, et al. Central zone of myocardial infarction: a neglected target area for heart cell therapy. J Cell Mol Med 2012;16(3):637–48. [5] Lima JA, Becker LC, Melin JA, et al. Impaired thickening of nonischemic myocardium during acute regional ischemia in the dog. Circulation 1985;71(5):1048–59. [6] Holman ER, Buller VG, de Roos A, et al. Detection and quantification of dysfunctional myocardium by magnetic resonance imaging. A new three-dimensional method for quantitative wall-thickening analysis. Circulation 1997;95(4):924–31. [7] Bogen DK, Rabinowitz SA, Needleman A, McMahon TA, Abelmann WH. An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle. Circ Res 1980;47(5):728–41. [8] Ashikaga H, Mickelsen SR, Ennis DB, et al. Electromechanical analysis of infarct border zone in chronic myocardial infarction. Am J Physiol Heart Circ Physiol 2005; 289(3):H1099–105. [9] Factor SM, Sonnenblick EH, Kirk ES. The histologic border zone of acute myocardial infarction—islands or peninsulas? Am J Pathol 1978;92(1):111–24. [10] Mahrholdt H, Wagner A, Parker M, et al. Relationship of contractile function to transmural extent of infarction in patients with chronic coronary artery disease. J Am Coll Cardiol 2003;42(3):505–12.
Fig. 1. Regional systolic wall thickening, extent of delayed enhancement, and normalized upslope of first-pass perfusion of each segment category.