New insight into the intraventricular pressure gradient as a sensitive indicator of diastolic cardiac dysfunction in patients with childhood cancer after anthracycline therapy

  • Sachie Shigemitsu
  • Ken TakahashiEmail author
  • Kana Yazaki
  • Maki Kobayashi
  • Mariko Yamada
  • Katsumi Akimoto
  • Hiroyuki Tamaichi
  • Junya Fujimura
  • Masahiro Saito
  • Masaki Nii
  • Keiichi Itatani
  • Toshiaki Shimizu
Original Article


Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in survivors of childhood cancer. The intraventricular pressure gradient (IVPG) of the left ventricle (LV) is the suction force of blood from the left atrium to the LV apex during early diastole and is a sensitive indicator of diastolic function. We assessed IVPG as a new indicator of the cardiac dysfunction in survivors of childhood cancer after anthracycline therapy. We performed a prospective echocardiographic study on 40 survivors of childhood cancer aged 6–26 years who received anthracycline therapy (group A) and 53 similar-age normal controls (group N). The subjects were divided into the younger groups, N1 and A1 (age < 16 years); older groups, N2 and A2 (age ≥ 16 years). IVPG was calculated using color M-mode Doppler imaging of the mitral inflow using Euler’s equation. Total IVPG was divided into the basal and mid-to-apical IVPG to demonstrate more clearly the mechanisms of the LV diastolic suction force. The total anthracycline dose was 16.2–600.0 mg/m2 (median 143.5 mg/m2). Total IVPG significantly decreased in group A2 compared with that in group N2 (0.39 ± 0.07 vs. 0.29 ± 0.11 mmHg/cm; p = 0.010). The mid-to-apical IVPG significantly decreased in groups A1 and A2 compared with that in groups N1 and N2, respectively (N1 vs. A1: 0.20 ± 0.05 vs. 0.16 ± 0.05 mmHg/cm, p = 0.036; N2 vs. A2: 0.21 ± 0.06 vs. 0.14 ± 0.06 mmHg/cm, p = 0.001). Basal IVPG, E wave, and E/e′ were not significantly different between patients and normal controls. The total and mid-to-apical IVPG, especially mid-to-apical IVPG, could be sensitive new indicators in survivors of childhood cancer after anthracycline therapy.


Intraventricular pressure gradient Childhood cancer Anthracycline Cardiotoxicity Diastolic function 



We thank the staff of Shizuoka Children’s Hospital for collecting the echocardiographic data of children and adults with no cardiac defects (healthy group).

Compliance with ethical standards

Conflict of interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Supplementary material

380_2018_1332_MOESM1_ESM.docx (24 kb)
Supplementary file1 (DOCX 24 kb)


  1. 1.
    van der Pal HJ, van Dalen EC, van Delden E, van Dijk IW, Kok WE, Geskus RB, Sieswerda E, Oldenburger F, Koning CC, van Leeuwen FE, Caron HN, Kremer LC (2012) High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30:1429–1437CrossRefGoogle Scholar
  2. 2.
    Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voûte PA (2001) Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 19:191–196CrossRefGoogle Scholar
  3. 3.
    Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME, Skinner R, Stevens MC, Hawkins MM; British Childhood Cancer Survivor Study Steering Group (2010) Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304:172–179CrossRefGoogle Scholar
  4. 4.
    Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342:1077–1084CrossRefGoogle Scholar
  5. 5.
    Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH (2014) Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. 63:2751–2768CrossRefGoogle Scholar
  6. 6.
    Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, Rubino M, Veglia F, Fiorentini C, Cipolla CM (2010) Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 55:213–220CrossRefGoogle Scholar
  7. 7.
    Cheung YF, Hong WJ, Chan GC, Wong SJ, Ha SY (2010) Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy. Heart 96:1137–1141CrossRefGoogle Scholar
  8. 8.
    Poterucha JT, Kutty S, Lindquist RK, Li L, Eidem BW (2012) Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction. J Am Soc Echocardiogr 25:733–740CrossRefGoogle Scholar
  9. 9.
    Negishi K, Negishi T, Haluska BA, Hare JL, Plana JC, Marwick TH (2014) Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection. Eur Heart J Cardiovasc Imaging 15:324–331CrossRefGoogle Scholar
  10. 10.
    Grossman W (1990) Diastolic dysfunction and congestive heart failure. Circulation 81: III1–III7CrossRefGoogle Scholar
  11. 11.
    Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A (2009) Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 22:107–133CrossRefGoogle Scholar
  12. 12.
    Armstrong GT, Joshi VM, Ness KK, Marwick TH, Zhang N, Srivastava D, Griffin BP, Grimm RA, Thomas J, Phelan D, Collier P, Krull KR, Mulrooney DA, Green DM, Hudson MM, Robison LL, Plana JC (2015) Comprehensive echocardiographic detection of treatment-related cardiac dysfunction in adult survivors of childhood cancer: results from the St. Jude Lifetime Cohort Study. J Am Coll Cardiol 65:2511–2522CrossRefGoogle Scholar
  13. 13.
    Nikolic SD, Feneley MP, Pajaro OE, Rankin JS, Yellin EL (1995) Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol 268:H550–H557Google Scholar
  14. 14.
    Firstenberg MS, Smedira NG, Greenberg NL, Prior DL, McCarthy PM, Garcia MJ, Thomas JD (2001) Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation 104:I330–335CrossRefGoogle Scholar
  15. 15.
    Popović ZB, Richards KE, Greenberg NL, Rovner A, Drinko J, Cheng Y, Penn MS, Fukamachi K, Mal N, Levine BD, Garcia MJ, Thomas JD (2006) Scaling of diastolic intraventricular pressure gradients is related to filling time duration. Am J Physiol Heart Circ Physiol 291:H762–H769CrossRefGoogle Scholar
  16. 16.
    Takahashi K, Nii M, Takigiku K, Toyono M, Iwashima S, Inoue N, Tanaka N, Matsui K, Shigemitsu S, Yamada M, Kobayashi M, Yazaki K, Itatani K, Shimizu T (2018) Development of suction force during early diastole from the left atrium to the left ventricle in infants, children, and adolescents. Heart Vessels (online). Google Scholar
  17. 17.
    Takayasu H, Takahashi K, Takigiku K, Yasukochi S, Furukawa T, Akimoto K, Kishiro M, Shimizu T (2011) Left ventricular torsion and strain in patients with repaired tetralogy of Fallot assessed by speckle tracking imaging. Echocardiography 28:720–729CrossRefGoogle Scholar
  18. 18.
    Yazaki K, Takahashi K, Shigemitsu S, Yamada M, Iso T, Kobayashi M, Akimoto K, Tamaichi H, Fujimura J, Saito M, Nii M, Shimizu T (2018) In-depth insight into the mechanisms of cardiac dysfunction in patients with childhood cancer after anthracycline treatment using layer-specific strain analysis. Circ J 82:715–723CrossRefGoogle Scholar
  19. 19.
    Greenberg NL, Vandervoort PM, Firstenberg MS, Garcia MJ, Thomas JD (2001) Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 280:H2507–H2515CrossRefGoogle Scholar
  20. 20.
    Kobayashi M, Takahashi K, Yamada M, Yazaki K, Matsui K, Tanaka N, Shigemitsu S, Akimoto K, Kishiro M, Nakanishi K, Kawasaki S, Nii M, Itatani K, Shimizu T (2017) Assessment of early diastolic intraventricular pressure gradient in the left ventricle among patients with repaired tetralogy of Fallot. Heart Vessels 32:1364–1374CrossRefGoogle Scholar
  21. 21.
    Ohara T, Niebel CL, Stewart KC, Charonko JJ, Pu M, Vlachos PP, Little WC (2012) Loss of adrenergic augmentation of diastolic intra-LV pressure difference in patients with diastolic dysfunction: evaluation by color M-mode echocardiography. JACC Cardiovasc Imaging 5:861–870CrossRefGoogle Scholar
  22. 22.
    Iwano H, Kamimura D, Fox E, Hall M, Vlachos P, Little WC (2015) Altered spatial distribution of the diastolic left ventricular pressure difference in heart failure. J Am Soc Echocardiogr 28:597–605CrossRefGoogle Scholar
  23. 23.
    Steine K, Stugaard M, Smiseth OA (1999) Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation 99:2048–2054CrossRefGoogle Scholar
  24. 24.
    Yu HK, Yu W, Cheuk DK, Wong SJ, Chan GC, Cheung YF (2013) New three-dimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors. J Am Soc Echocardiogr 26:846–852CrossRefGoogle Scholar
  25. 25.
    Wang J, Kurrelmeyer KM, Torre-Amione G, Nagueh SF (2007) Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol 49:88–96CrossRefGoogle Scholar
  26. 26.
    Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, Orav EJ, Gelber RD, Colan SD (1995) Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332:1738–1743CrossRefGoogle Scholar
  27. 27.
    Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM; ESC Scientific Document Group (2016) 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37:2768–2801CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Sachie Shigemitsu
    • 1
    • 2
  • Ken Takahashi
    • 1
    Email author
  • Kana Yazaki
    • 1
  • Maki Kobayashi
    • 1
  • Mariko Yamada
    • 1
  • Katsumi Akimoto
    • 1
  • Hiroyuki Tamaichi
    • 1
  • Junya Fujimura
    • 1
  • Masahiro Saito
    • 1
  • Masaki Nii
    • 3
  • Keiichi Itatani
    • 4
  • Toshiaki Shimizu
    • 1
  1. 1.Department of Pediatrics, Faculty of MedicineJuntendo UniversityTokyoJapan
  2. 2.Department of PediatricsKawasaki Kyodo HospitalKawasaki-ku, Kawasaki-cityJapan
  3. 3.Department of CardiologyShizuoka Children’s HospitalShizuoka-city, ShizuokaJapan
  4. 4.Department of Cardiovascular Surgery, Cardiovascular Imaging Research LaboratoryKyoto Prefectural University of MedicineKyoto-city, KyotoJapan

Personalised recommendations