Cardiophysiology Illustrated by Comparing Ventricular Volumes in Healthy Adult Males and Females

  • Peter L. M. KerkhofEmail author
  • Tatiana Kuznetsova
  • J. Yasha Kresh
  • Neal Handly
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1065)


Recent advances in cardiac imaging techniques have substantially contributed to a growing interest in the analysis of global cardiac chamber dimensions and regional myocardial deformation. During the cardiac cycle, ventricular luminal volume varies due to the contraction process, which also confers a shape change including substantial alteration of long axis length, as well as rotation of the base compared to the apex. Local deformation can be assessed by strain (rate) analysis. Reviewing the present literature, it must be concluded that there is no single metric available to comprehensively characterize ventricular function. Every candidate advanced thus far has been found to incompletely reflect ventricular performance. This observation is not surprising in view of the complexity of the cardiac pump system. Additionally, sex-specific modifiers may play a role. More than three decades ago, it was shown that on average the ventricular volume is smaller in healthy women compared to matched males. Therefore, the present contribution concerns the interpretation of data derived from the healthy heart in both men and women. Starting from the classical Starling concept, we apply a simple mathematical transformation which permits an insightful representation of ventricular mechanics. Relating end-systolic volume (ESV) to end-diastolic volume creates the ventricular volume regulation graph which features the pertinent working point of an individual heart. This fundamental approach illustrates why certain proposed performance indexes cannot individually reveal the essence of ventricular systolic function. We demonstrate that particular metrics are highly interconnected and just tell us the same story in a different disguise. It is imperative to understand which associations exist and if they expectedly are (nearly) linear or frankly nonlinear. Notably, ejection fraction (EF) is primarily determined by ESV, while in turn EF is not much different from ventriculo-arterial coupling (VAC). Insight into cardiac function is promoted by identification of the paramount/essential components involved. The smaller ESV (p < 0.0001) implies that EF is higher in women and may also have consequences for VAC.


Ventricular volume Sex-specific analysis Starling concept Ejection fraction Cardiac output Heart rate End-systolic volume Systolic elastance Ventriculo-arterial coupling Pressure–volume loop History of cardiology Titin isoforms Soltis–Saucerman model Cardiomyogenesis Review 


  1. 1.
    Asanoi H, Sasayama S, Kameyama T. Ventriculoarterial coupling in normal and failing heart in humans. Circ Res. 1989;65:483–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Ayaz O, Howlett SE. Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms. Biol Sex Differ. 2015;6:9. Scholar
  3. 3.
    Baan J, Jong TT, Kerkhof PL, Moene RJ, van Dijk AD, van der Velde ET, Koops J. Continuous stroke volume and cardiac output from intra-ventricular dimensions obtained with impedance catheter. Cardiovasc Res. 1981;15:328–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Bataille G. The cradle of humanity, prehistoric art and culture. New York: Zone Books; 2009.Google Scholar
  5. 5.
    Beringer JY, Kerkhof PLM. A unifying representation of ventricular volumetric indexes. IEEE Trans BME. 1998;45:365–71.CrossRefGoogle Scholar
  6. 6.
    Blaudszun G, Morel DR. Relevance of the volume-axis intercept, Vo, compared with the slope of end-systolic pressure-volume relationship in response to large variations in inotropy and afterload in rats. Exp Physiol. 2011;96:1179–95.CrossRefPubMedGoogle Scholar
  7. 7.
    Buonanno C. The female left ventricle: a pathophysiological entity? Int J Cardiol. 1983;4:382–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Buonanno C, Arbustini E, Rossi L, Dander B, Vassanelli C, Paris B, Poppi A. Left ventricular function in men and women. Another difference between sexes. Eur Heart J. 1982;3:525–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Coronado MJ, Fairweather D, Bruno KA. Sex determines cardiac myocyte stretch and relaxation. Circ Cardiovasc Genet. 2017;10(5):e001950.CrossRefPubMedGoogle Scholar
  10. 10.
    Farrell SR, Ross JL, Howlett SE. Sex differences in mechanisms of cardiac excitation-contraction coupling in rat ventricular myocytes. Am J Physiol Heart Circ Physiol. 2010;299:H36–45. Scholar
  11. 11.
    Fazal L, Azibani F, Vodovar N, Cohen Solal A, Delcayre C, Samuel JL. Effects of biological sex on the pathophysiology of the heart. Br J Pharmacol. 2014;171:555–66. Scholar
  12. 12.
    Gebhard C, Buechel RR, Stähli BE, Gransar H, Achenbach S, Berman DS, et al. Impact of age and sex on left ventricular function determined by coronary computed tomographic angiography: results from the prospective multicentre CONFIRM study. Eur Heart J Imag. 2017;18:990–1000.Google Scholar
  13. 13.
    Hales S. Statical essays. London: Innys & Co; 1733. See also
  14. 14.
    Harvey W. Exercitatio anatomica de motu cordis et sanguinis in animalibus. Frankfurt a Main: W. Fitzer; 1628.Google Scholar
  15. 15.
    Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003;121:97–110.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Holt JP. Estimation of the residual volume of the ventricle of the dog's heart by two indicator dilution technics. Circ Res. 1956;4:187–95.CrossRefPubMedGoogle Scholar
  17. 17.
    Holt JP. Regulation of the degree of emptying of the left ventricle by the force of ventricular contraction. Circ Res. 1957;5:281–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Holt JP, Allensworth J. Estimation of the residual volume of the right ventricle of the dog’s heart. Circ Res. 1957;5:323–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Huxley AF. Muscle structure and theories of contraction. Prog Biophys Biophys Chem. 1957;7:255–318.PubMedCrossRefGoogle Scholar
  20. 20.
    Kajstura J, Gurusamy N, Ogórek B, et al. Myocyte turnover in the aging human heart. Circ Res. 2010;107:1374–86. Scholar
  21. 21.
    Kerkhof PLM. Importance of end-systolic volume for the evaluation of cardiac pump performance. In: Chazov EI, Smirnov VN, Oganov RG, editors. Cardiology, an international perspective. New York: Plenum Press; 1984. p. 1339–52.Google Scholar
  22. 22.
    Kerkhof PLM. Combination of Millar and conductance catheter to assess equine left ventricular function. In: Conference Proceedings: annual International Conference of the IEEE Engineering in Medicine and Biology Society, Atlanta. 1999.Google Scholar
  23. 23.
    Kerkhof PLM. Fundamentals of left ventricular volume representation. Conf Proc IEEE Eng Med Biol Soc. 2016Aug;2016:3294–3297. doi: PMID: 28227221.
  24. 24.
    Kerkhof PLM. Physiological modeling survey. In: Webster J, editor. Encyclopedia of electrical and electronics engineering. 3rd revised ed. New York: Wiley; 2018.Google Scholar
  25. 25.
    Kerkhof PLM, Kresh JY, Li JK-J, Heyndrickx GR. Left ventricular volume regulation in heart failure with preserved ejection fraction. Physiol Rep. 2013;1:e00007.CrossRefGoogle Scholar
  26. 26.
    Kerkhof PLM, Heyndrickx GR, Li JK. Hemodynamic determinants and ventriculo-arterial coupling are sex-associated in heart failure patients. Conf Proc IEEE Eng Med Biol Soc. 2016 Aug;2016:3286–3289. doi: PMID: 28227219.
  27. 27.
    Kerkhof PLM, Yoo BW, Merillon JP, Peace RA, Handly N. Monte Carlo method applied to the evaluation of the relationship between ejection fraction and its constituent components. Conf Proc IEEE Eng Med Biol Soc. 2017a;2017:1295–8. Scholar
  28. 28.
    Kerkhof PLM, Yoo BW, van de Ven PM, Handly N. Sex-specific aspects of left and right ventricular volume regulation in patients following tetralogy of Fallot repair. Conf Proc IEEE Eng Med Biol Soc. 2017b;2017:1303–6. Scholar
  29. 29.
    Kerkhof PLM, Peace RA, Handly N. The importance of (measuring) the end-systolic volume index in predicting survival. Heart. 2018a;104:180. Scholar
  30. 30.
    Kerkhof PLM, van de Ven PM, Yoo BW, Peace RA, Heyndrickx GR, Handly N. Ejection fraction as related to basic components in the left and right ventricular volume domains. Intern J Cardiol. 2018b;255:105–10.CrossRefGoogle Scholar
  31. 31.
    Kerkhof PLM, Heethaar RM, Pearce JA. Bioimpedance: principles, measurements, and applications, In: Webster J, editor. Encyclopedia of electrical and electronics engineering. 3rd revised ed. New York Wiley; 2018c.Google Scholar
  32. 32.
    Kerkhof PLM, Kuznetsova T, Ali R, Handly N. Left ventricular volume analysis as a basic tool to describe cardiac function. Adv Physiol Educ. 2018d;42(1):130–139. doi: Scholar
  33. 33.
    Kulpa J, Chinnappareddy N, Pyle WG. Rapid changes in cardiac myofilament function following the acute activation of estrogen receptor-alpha. PLoS One. 2012;7(7):e41076. Scholar
  34. 34.
    Kuznetsova T, Haddad F, Tikhonoff V, et al. Impact and pitfalls of scaling of left ventricular and atrial structure in population-based studies. J Hypertens. 2016;34:1186–94.CrossRefPubMedGoogle Scholar
  35. 35.
    Ky B, French B, May Khan A, Plappert T, Wang A, Chirinos JA, et al. Ventricular-arterial coupling, remodeling, and prognosis in chronic heart failure. J Am Coll Cardiol. 2013;62:1165–72.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lancet October 5, 1974.Google Scholar
  37. 37.
    Maffessanti F, Muraru D, Esposito R, Gripari P, Ermacora D, Santoro C, et al. Age-, body size-, and sex-specific reference values for right ventricular volumes and ejection fraction by three-dimensional echocardiography: a multicenter echocardiographic study in 507 healthy volunteers. Circ Cardiovasc Imaging. 2013;6:700–10.CrossRefPubMedGoogle Scholar
  38. 38.
    Mazzoni M. Dario Maestrini e la legge del cuore Storia di un mancato Premio Nobel. Notizie dalla Delfico. 2005; 1–2. See also
  39. 39.
    Negroni JA, Morotti S, Lascano EC, Gomes AV, Grandi E, Puglisi JL, Bers DM. β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. Mol Cell Cardiol. 2015;81:162–75.CrossRefGoogle Scholar
  40. 40.
    Parks RJ, Howlett SE. Sex differences in mechanisms of cardiac excitation-contraction coupling. Pflugers Arch. 2013 May;465(5):747–63. doi: CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Peace RA, Adams PC, Lloyd JJ. Effect of sex, age, and weight on ejection fraction and end-systolic volume reference limits in gated myocardial perfusion SPECT. J Nucl Cardiol. 2008;15:86–93.CrossRefPubMedGoogle Scholar
  42. 42.
    Pijnenburg HLM, Kerkhof PLM, Kocsis S, Voorhout G. Ventricular volume regulation in dogs as a function of gender, age and breed. FASEB J. 1996;10:A346.Google Scholar
  43. 43.
    Previato M, Kerkhof PLM, Osto E, Parry G, Tona F. Heart transplantation survival and sex-related differences. In: Kerkhof PLM, Miller VM, editors. Sex-specific analysis of cardiovascular function. New York: Springer; 2018.Google Scholar
  44. 44.
    Puglisi JL, Negroni JA, Chen-Izu Y, Bers DM. The force-frequency relationship: insights from mathematical modeling. Adv Physiol Educ. 2013;37:28–34.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Putscher M. Geschichte der medizinischen Abbildung. Heinz Moos Verlag: Muenchen; 1972.Google Scholar
  46. 46.
    Robotham JL, Takata M, Berman M, Harasawa Y. Ejection fraction revisited. Anesthesiology. 1991;74(1):172–83.CrossRefPubMedGoogle Scholar
  47. 47.
    Sakai S. Jacob Berengario. Igaku Toshokan. 1986;33:29–31. [The Japan Medical Library Association].CrossRefGoogle Scholar
  48. 48.
    Sandberg K, Ji H. Sex differences in primary hypertension. Biol Sex Differ. 2012;3:7. Scholar
  49. 49.
    Sequeira V, van der Velden J. Historical perspective on heart function: the Frank–Starling law. Biophys Rev. 2015;7:421–47.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Shannon TR, Wang F, Puglisi J, Weber C, Bers DM. A mathematical treatment of integrated ca dynamics within the ventricular myocyte. Biophys J. 2004;87:3351–71.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014;115:79–96.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Shavik SM, Wall ST, Sundnes J, Burkhoff D, Lee LC. Organ-level validation of a cross-bridge cycling descriptor in a left ventricular finite element model: effects of ventricular loading on myocardial strains. Physiol Rep. 2017;5(21):e13392. Scholar
  53. 53.
    Singer C. A short history of anatomy and physiology from the Greeks to Harvey. New York: Dover Publications; 1957.Google Scholar
  54. 54.
    Soltis AR, Saucerman JJ. Synergy between CaMKII substrates and β-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling. Biophys J. 2010;99:2038–47.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Touma M, Kang X, Gao F, Zhao Y, Cass AA, Biniwale R, Xiao X, Eghbali M, Coppola G, Reemtsen B, Wang Y. Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight. 2017;2(17):94904.CrossRefPubMedGoogle Scholar
  56. 56.
    Trexler CL, Odell AT, Jeong MY, Dowell RD, Leinwand LA. Transcriptome and functional profile of cardiac myocytes is influenced by biological sex. Circ Cardiovasc Genet. 2017;10(5):e001770. Scholar
  57. 57.
    Van Liere EJ, Stickney JC, Marsh DF. Sex differences in blood pressure of dogs. Science. 1949;109:489.CrossRefPubMedGoogle Scholar
  58. 58.
    Wheelan C. Naked statistics. New York: WW Norton; 2013.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiology and Nuclear Medicine, Amsterdam Cardiovascular SciencesVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of Cardiovascular SciencesUniversity of LeuvenLeuvenBelgium
  3. 3.Departments of Cardiothoracic Surgery and Medicine (Cardiology), Drexel University College of MedicineIME, University of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of Emergency MedicineDrexel University College of MedicinePhiladelphiaUSA

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