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Journal of Cardiovascular Magnetic Resonance
Published in: Journal of Cardiovascular Magnetic Resonance 1/2021

01-12-2021 | Cardiomyopathy | Research

Cardiovascular magnetic resonance detects microvascular dysfunction in a mouse model of hypertrophic cardiomyopathy

Authors: Min-Chi Ku, Frank Kober, Yi-Ching Lai, Andreas Pohlmann, Fatimunnisa Qadri, Michael Bader, Lucie Carrier, Thoralf Niendorf

Published in: Journal of Cardiovascular Magnetic Resonance | Issue 1/2021

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Abstract

Background

Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM.

Methods

We used a mouse model (DBA/2 J; D2 mouse strain) that spontaneously carries variants in the two most susceptible HCM genes—Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds (male: n = 4, female: n = 4) underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps (male: n = 5, female: n = 5 in each group) were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group).

Results

LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, p < 0.001; female: D2 LV wall thickness = 1.0 ± 0.1 mm vs B6 LV wall thickness = 0.8 ± 0.1 mm, p < 0.01). The resting global myocardial perfusion (myocardial blood flow; MBF) was lower in D2 than in B6 mice (end-diastole: D2 MBFglobal = 7.5 ± 0.6 vs B6 MBFglobal = 9.3 ± 1.6 ml/g/min, p < 0.05; end-systole: D2 MBFglobal = 6.6 ± 0.8 vs B6 MBFglobal = 8.2 ± 2.6 ml/g/min, p < 0.01). This myocardial microvascular dysfunction was observed and associated with a reduction in regional MBF, mainly in the interventricular septal and inferior areas of the myocardium. Immunofluorescence revealed a lower number of vessel densities in D2 than in B6 (D2 capillary = 31.0 ± 3.8% vs B6 capillary = 40.7 ± 4.6%, p < 0.05). Myocardial collagen volume fraction (CVF) was significantly higher in D2 LV versus B6 LV mice (D2 CVF = 3.7 ± 1.4% vs B6 CVF = 1.7 ± 0.7%, p < 0.01). Furthermore, a higher ratio of perivascular fibrosis (PFR) was found in D2 than in B6 mice (D2 PFR = 2.3 ± 1.0%, B6 PFR = 0.8 ± 0.4%, p < 0.01).

Conclusions

Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM.
Literature
1.
Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249–54.PubMedCrossRef
2.
Franz WM, Muller OJ, Katus HA. Cardiomyopathies: from genetics to the prospect of treatment. Lancet. 2001;358(9293):1627–37.PubMedCrossRef
3.
Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, et al. A prospective study of sudden cardiac death among children and young adults. N Engl J Med. 2016;374(25):2441–52.PubMedCrossRef
4.
Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation. 2009;119(8):1085–92.PubMedCrossRef
5.
Michels M, Soliman OI, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, Majoor-Krakauer D, Ten Cate FJ. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur Heart J. 2009;30(21):2593–8.PubMedCrossRef
6.
7.
Ingles J, Goldstein J, Thaxton C, Caleshu C, Corty EW, Crowley SB, Dougherty K, Harrison SM, McGlaughon J, Milko LV, et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med. 2019;12(2):e002460.PubMedPubMedCentralCrossRef
8.
9.
Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64(1):83–99.PubMedCrossRef
10.
11.
12.
Weissler-Snir A, Adler A, Williams L, Gruner C, Rakowski H. Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge. Eur Heart J. 2017;38(22):1728–37.PubMed
13.
Maron BJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med. 2018;379(7):655–68.PubMedCrossRef
14.
Soler R, Mendez C, Rodriguez E, Barriales R, Ochoa JP, Monserrat L. Phenotypes of hypertrophic cardiomyopathy. An illustrative review of MRI findings. Insights Imaging. 2018;9(6):1007–20.PubMedPubMedCentralCrossRef
15.
Raman B, Ariga R, Spartera M, Sivalokanathan S, Chan K, Dass S, Petersen SE, Daniels MJ, Francis J, Smillie R, et al. Progression of myocardial fibrosis in hypertrophic cardiomyopathy: mechanisms and clinical implications. Eur Heart J Cardiovasc Imaging. 2019;20(2):157–67.PubMedCrossRef
16.
Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD, Francis JM, Doll HA, Selvanayagam JB, Neubauer S, Watkins H. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007;115(18):2418–25.PubMedCrossRef
17.
Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349(11):1027–35.PubMedCrossRef
18.
Timmer SA, Knaapen P. Coronary microvascular function, myocardial metabolism, and energetics in hypertrophic cardiomyopathy: insights from positron emission tomography. Eur Heart J Cardiovasc Imaging. 2013;14(2):95–101.PubMedCrossRef
19.
Rosen BD, Lima JA, Nasir K, Edvardsen T, Folsom AR, Lai S, Bluemke DA, Jerosch-Herold M. Lower myocardial perfusion reserve is associated with decreased regional left ventricular function in asymptomatic participants of the multi-ethnic study of atherosclerosis. Circulation. 2006;114(4):289–97.PubMedCrossRef
20.
Duncker DJ, Koller A, Merkus D, Canty JM Jr. Regulation of coronary blood flow in health and ischemic heart disease. Prog Cardiovasc Dis. 2015;57(5):409–22.PubMedCrossRef
21.
22.
Huelnhagen T, Ku MC, Reimann HM, Serradas Duarte T, Pohlmann A, Flemming B, Seeliger E, Eichhorn C, Ferrari VA, Prothmann M, et al. Myocardial effective transverse relaxation time T 2(*) is elevated in hypertrophic cardiomyopathy: A 7.0 T magnetic resonance imaging study. Sci Rep. 2018;8(1):3974.PubMedPubMedCentralCrossRef
23.
Huelnhagen T, Hezel F, Serradas Duarte T, Pohlmann A, Oezerdem C, Flemming B, Seeliger E, Prothmann M, Schulz-Menger J, Niendorf T. Myocardial effective transverse relaxation time T2* Correlates with left ventricular wall thickness: a 7.0 T MRI study. Magn Reson Med. 2017;77(6):2381–9.PubMedCrossRef
24.
Troalen T, Capron T, Bernard M, Kober F. In vivo characterization of rodent cyclic myocardial perfusion variation at rest and during adenosine-induced stress using cine-ASL cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2014;16:18.PubMedPubMedCentralCrossRef
25.
26.
Naresh NK, Chen X, Moran E, Tian Y, French BA, Epstein FH. Repeatability and variability of myocardial perfusion imaging techniques in mice: Comparison of arterial spin labeling and first-pass contrast-enhanced MRI. Magn Reson Med. 2016;75(6):2394–405.PubMedCrossRef
27.
Thomson KL, Ormondroyd E, Harper AR, Dent T, McGuire K, Baksi J, Blair E, Brennan P, Buchan R, Bueser T, et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet Med. 2019;21(7):1576–84.PubMedCrossRef
28.
Zhao W, Zhao T, Chen Y, Zhao F, Gu Q, Williams RW, Bhattacharya SK, Lu L, Sun Y. A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain. PLoS ONE. 2015;10(8):e0133132.PubMedPubMedCentralCrossRef
29.
Ku MC, Huelnhagen T, Niendorf T, Pohlmann A. Cardiac MRI in Small Animals. Methods Mol Biol. 2018;1718:269–84.PubMedCrossRef
30.
Troalen T, Capron T, Cozzone PJ, Bernard M, Kober F. Cine-ASL: a steady-pulsed arterial spin labeling method for myocardial perfusion mapping in mice. Part I. Experimental study. Magn Reson Med. 2013;70(5):1389–98.PubMedCrossRef
31.
Jung B, Odening KE, Dall’Armellina E, Foll D, Menza M, Markl M, Schneider JE. A quantitative comparison of regional myocardial motion in mice, rabbits and humans using in-vivo phase contrast CMR. J Cardiovasc Magn Reson. 2012;14:87.PubMedPubMedCentralCrossRef
32.
Ide S, Riesenkampff E, Chiasson DA, Dipchand AI, Kantor PF, Chaturvedi RR, Yoo SJ, Grosse-Wortmann L. Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients. J Cardiovasc Magn Reson. 2017;19(1):10.PubMedPubMedCentralCrossRef
33.
Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1+/- haploinsufficient mice. Circulation. 2005;112(19):2959–65.PubMedPubMedCentralCrossRef
34.
Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358(18):1899–908.PubMedPubMedCentralCrossRef
35.
Del-Canto I, Lopez-Lereu MP, Monmeneu JV, Croisille P, Clarysse P, Chorro FJ, Bodi V, Moratal D. Characterization of normal regional myocardial function by MRI cardiac tagging. J Magn Reson Imaging. 2015;41(1):83–92.PubMedCrossRef
36.
Do HP, Ramanan V, Qi X, Barry J, Wright GA, Ghugre NR, Nayak KS. Non-contrast assessment of microvascular integrity using arterial spin labeled cardiovascular magnetic resonance in a porcine model of acute myocardial infarction. J Cardiovasc Magn Reson. 2018;20(1):45.PubMedPubMedCentralCrossRef
37.
Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol. 2000;31(8):988–98.PubMedCrossRef
38.
39.
Villemain O, Correia M, Mousseaux E, Baranger J, Zarka S, Podetti I, Soulat G, Damy T, Hagege A, Tanter M, et al. Myocardial stiffness evaluation using noninvasive shear wave imaging in healthy and hypertrophic cardiomyopathic adults. JACC Cardiovasc Imaging. 2019;12(7 Pt 1):1135–45.PubMedPubMedCentralCrossRef
40.
Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1986;8(3):545–57.PubMedCrossRef
41.
Camaioni C, Knott KD, Augusto JB, Seraphim A, Rosmini S, Ricci F, Boubertakh R, Xue H, Hughes R, Captur G, et al. Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy. Heart. 2020;106(11):824–9.PubMedCrossRef
42.
Dai Z, Aoki T, Fukumoto Y, Shimokawa H. Coronary perivascular fibrosis is associated with impairment of coronary blood flow in patients with non-ischemic heart failure. J Cardiol. 2012;60(5):416–21.PubMedCrossRef
43.
de Boer RA, De Keulenaer G, Bauersachs J, Brutsaert D, Cleland JG, Diez J, Du XJ, Ford P, Heinzel FR, Lipson KE, et al. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur J Heart Fail. 2019;21(3):272–85.PubMedCrossRef
44.
Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure with preserved ejection fraction: from mechanisms to therapies. Eur Heart J. 2018;39(30):2780–92.PubMedCrossRef
45.
Seferovic PM, Polovina M, Bauersachs J, Arad M, Gal TB, Lund LH, Felix SB, Arbustini E, Caforio ALP, Farmakis D, et al. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21(5):553–76.PubMedCrossRef
46.
Maron BJ, Rowin EJ, Casey SA, Link MS, Lesser JR, Chan RH, Garberich RF, Udelson JE, Maron MS. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol. 2015;65(18):1915–28.PubMedCrossRef
47.
Marstrand P, Han L, Day SM, Olivotto I, Ashley EA, Michels M, Pereira AC, Wittekind SG, Helms A, Saberi S, et al. Hypertrophic cardiomyopathy with left ventricular systolic dysfunction: insights from the SHaRe registry. Circulation. 2020;141(17):1371–83.PubMedPubMedCentralCrossRef
48.
Crea F, Bairey Merz CN, Beltrame JF, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Camici PG, Coronary Vasomotion Disorders International Study Group. The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J. 2017;38(7):473–7.PubMed
49.
D’Amario D, Migliaro S, Borovac JA, Restivo A, Vergallo R, Galli M, Leone AM, Montone RA, Niccoli G, Aspromonte N, et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2019;10:1347.PubMedPubMedCentralCrossRef
50.
Joung S, Wei J, Nelson MD, Aldiwani H, Shufelt C, Tamarappoo B, Berman D, Thomson LEJ, Bairey Merz CN. Progression of coronary microvascular dysfunction to heart failure with preserved ejection fraction: a case report. J Med Case Rep. 2019;13(1):134.PubMedPubMedCentralCrossRef
51.
52.
Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012;60(16):1455–69.PubMedCrossRef
53.
Fernlund E, Gyllenhammar T, Jablonowski R, Carlsson M, Larsson A, Arnlov J, Liuba P. Serum biomarkers of myocardial remodeling and coronary dysfunction in early stages of hypertrophic cardiomyopathy in the young. Pediatr Cardiol. 2017;38(4):853–63.PubMedPubMedCentralCrossRef
54.
Jacquier A, Kober F, Bun S, Giorgi R, Cozzone PJ, Bernard M. Quantification of myocardial blood flow and flow reserve in rats using arterial spin labeling MRI: comparison with a fluorescent microsphere technique. NMR Biomed. 2011;24(9):1047–53.PubMedCrossRef
55.
Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020;396(10250):565–82.PubMedPubMedCentralCrossRef
56.
Kadkhodayan A, Lin CH, Coggan AR, Kisrieva-Ware Z, Schechtman KB, Novak E, Joseph SM, Davila-Roman VG, Gropler RJ, Dence C, et al. Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure. J Nucl Cardiol. 2017;24(4):1226–35.PubMedCrossRef
57.
Nickander J, Themudo R, Sigfridsson A, Xue H, Kellman P, Ugander M. Females have higher myocardial perfusion, blood volume and extracellular volume compared to males—an adenosine stress cardiovascular magnetic resonance study. Sci Rep. 2020;10(1):10380.PubMedPubMedCentralCrossRef
58.
Abdesselam I, Pepino P, Troalen T, Macia M, Ancel P, Masi B, Fourny N, Gaborit B, Giannesini B, Kober F, et al. Time course of cardiometabolic alterations in a high fat high sucrose diet mice model and improvement after GLP-1 analog treatment using multimodal cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2015;17:95.PubMedPubMedCentralCrossRef
59.
Vandsburger MH, French BA, Helm PA, Roy RJ, Kramer CM, Young AA, Epstein FH. Multi-parameter in vivo cardiac magnetic resonance imaging demonstrates normal perfusion reserve despite severely attenuated beta-adrenergic functional response in neuronal nitric oxide synthase knockout mice. Eur Heart J. 2007;28(22):2792–8.PubMedCrossRef
60.
Streif JU, Nahrendorf M, Hiller KH, Waller C, Wiesmann F, Rommel E, Haase A, Bauer WR. In vivo assessment of absolute perfusion and intracapillary blood volume in the murine myocardium by spin labeling magnetic resonance imaging. Magn Reson Med. 2005;53(3):584–92.PubMedCrossRef
61.
Kober F, Iltis I, Cozzone PJ, Bernard M. Myocardial blood flow mapping in mice using high-resolution spin labeling magnetic resonance imaging: influence of ketamine/xylazine and isoflurane anesthesia. Magn Reson Med. 2005;53(3):601–6.PubMedCrossRef
Metadata
Title
Cardiovascular magnetic resonance detects microvascular dysfunction in a mouse model of hypertrophic cardiomyopathy
Authors
Min-Chi Ku
Frank Kober
Yi-Ching Lai
Andreas Pohlmann
Fatimunnisa Qadri
Michael Bader
Lucie Carrier
Thoralf Niendorf
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Cardiovascular Magnetic Resonance / Issue 1/2021
Electronic ISSN: 1532-429X
DOI
https://doi.org/10.1186/s12968-021-00754-z

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