Marloes Van den berg

Interests

Research

Respiratory (diaphragm dysfunction) and skeletal muscle disease, cardiopulmonary disease

Courses

Scholarly Contributions

Journals/Publications

• Flanigan, E., Farman, G., Dennis, M., Wollman, L., Berg, M., Granzier, H., Banek, C., & Fregosi, R. (2024). Developmental nicotine exposure alters cardiovascular structure and function in neonatal and juvenile rats. American Journal of Physiology - Heart and Circulatory Physiology, 327(6). doi:10.1152/ajpheart.00558.2024
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  Here we test the hypothesis that continuous nicotine exposure throughout pre- and postnatal development (developmental nicotine exposure, DNE) alters the cardiovascular structure and function in neonatal and juvenile rats. Echocardiography showed that DNE reduced left ventricular mass, left ventricular outflow tract (LVOT) diameter, and posterior wall thickness, but only in females. Both male and female DNE rats had a lower end-systolic volume, higher ejection fraction, and increased fractional shortening, with unchanged stroke volume and cardiac output. Left ventricular single cardiac myocytes from male and female DNE animals exhibited increased calcium-evoked maximal tension with no effect on EC50. Tail-cuff plethysmography in awake rats showed that DNE males had lower systolic blood pressure and higher heart rate than control males. No significant changes in preload, afterload, or the in vitro renal artery response to vasodilators were observed. The results suggest that DNE enhances myocyte tension-generating capacity, possibly compensating for an unknown developmental insult, which may differ in males and females. Although this adaptation maintains normal resting cardiac function, it may lead to reduced cardiac reserve, increased energy demand, and elevated oxidative stress, potentially compromising both short- and long-term cardiovascular health in developing neonates.
• van den Berg, M., Shi, Z., Claassen, W., Hooijman, P., Lewis, C., Andersen, J., van der Pijl, R., Bogaards, S., Conijn, S., Peters, E., Begthel, L., Uijterwijk, B., Lindqvist, J., Langlais, P., Girbes, A., Stapel, S., Granzier, H., Campbell, K., Ma, W., , Irving, T., et al. (2024). Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients. Science Translational Medicine, 16(758). doi:10.1126/scitranslmed.adg3894
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  Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients (N = 54) to those of non-ICU patients undergoing thoracic surgery (N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.
• Berg, M. v., Ottenheijm, C. A., Granzier, H. L., Heunks, L. M., Shen, S., Pijl, R. J., & Peters, E. L. (2022). Rbm20ΔRRM Mice, Expressing a Titin Isoform with Lower Stiffness, Are Protected from Mechanical Ventilation-Induced Diaphragm Weakness. International Journal of Molecular Sciences. doi:10.3390/ijms232415689
• Berg, M. v., Ottenheijm, C. A., Heunks, L., Beishuizen, A., Paul, M., Conijn, S., Bogaards, S., & Zhou, J. (2022). Replacement Fibrosis in the Diaphragm of Mechanically Ventilated Critically Ill Patients. American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.202208-1608le
• Jansen, D., Jonkman, A. H., Vries, H. J., Wennen, M., Elshof, J., Hoofs, M. A., van den Berg, M., Man, A. M., Keijzer, C., Scheffer, G. J., van der Hoeven, J. G., Girbes, A., Tuinman, P. R., Marcus, J. T., Ottenheijm, C. A., & Heunks, L. (2021). Positive end-expiratory pressure affects geometry and function of the human diaphragm. Journal of applied physiology (Bethesda, Md. : 1985), 131(4), 1328-1339.
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  Positive end-expiratory pressure (PEEP) is routinely applied in mechanically ventilated patients to improve gas exchange and respiratory mechanics by increasing end-expiratory lung volume (EELV). In a recent experimental study in rats, we demonstrated that prolonged application of PEEP causes diaphragm remodeling, especially longitudinal muscle fiber atrophy. This is of potential clinical importance, as the acute withdrawal of PEEP during ventilator weaning decreases EELV and thereby stretches the adapted, longitudinally atrophied diaphragm fibers to excessive sarcomere lengths, having a detrimental effect on force generation. Whether this series of events occurs in the human diaphragm is unknown. In the current study, we investigated if short-term application of PEEP affects diaphragm geometry and function, which are prerequisites for the development of longitudinal atrophy with prolonged PEEP application. Nineteen healthy volunteers were noninvasively ventilated with PEEP levels of 2, 5, 10, and 15 cmHO. Magnetic resonance imaging was performed to investigate PEEP-induced changes in diaphragm geometry. Subjects were instrumented with nasogastric catheters to measure diaphragm neuromechanical efficiency (i.e., diaphragm pressure normalized to its electrical activity) during tidal breathing with different PEEP levels. We found that increasing PEEP from 2 to 15 cmHO resulted in a caudal diaphragm displacement (19 [14-26] mm, < 0.001), muscle shortening in the zones of apposition (20.6% anterior and 32.7% posterior, < 0.001), increase in diaphragm thickness (36.4% [0.9%-44.1%], < 0.001) and reduction in neuromechanical efficiency (48% [37.6%-56.6%], < 0.001). These findings demonstrate that conditions required to develop longitudinal atrophy in the human diaphragm are present with the application of PEEP. We demonstrate that PEEP causes changes in diaphragm geometry, especially muscle shortening, and decreases in vivo diaphragm contractile function. Thus, prerequisites for the development of diaphragm longitudinal muscle atrophy are present with the acute application of PEEP. Once confirmed in ventilated critically ill patients, this could provide a new mechanism for ventilator-induced diaphragm dysfunction and ventilator weaning failure in the intensive care unit (ICU).
• Mangner, N., Garbade, J., Heyne, E., van den Berg, M., Winzer, E. B., Hommel, J., Sandri, M., Jozwiak-Nozdrzykowska, J., Meyer, A. L., Lehmann, S., Schmitz, C., Malfatti, E., Schwarzer, M., Ottenheijm, C. A., Bowen, T. S., Linke, A., & Adams, V. (2021). Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure. Circulation research, 128(6), 706-719.
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  [Figure: see text].
• Ottenheijm, C. A., Granzier, H., Langlais, P., van den Berg, M., van der Pijl, R. J., van de Locht, M., Shen, S., Bogaards, S. J., Conijn, S., Hooijman, P. E., Labeit, S., & Heunks, L. M. (2021). Muscle ankyrin repeat protein 1 (MARP1) locks titin to the sarcomeric thin filament and is a passive force regulator. Journal of General Physiology, 153(7). doi:10.1085/jgp.202112925
• Shi, Z., Bogaards, S. J., Conijn, S., Onderwater, Y., Espinosa, P., Bink, D. I., van den Berg, M., van de Locht, M., Bugiani, M., van der Hoeven, H., Boon, R. A., Heunks, L., & Ottenheijm, C. A. (2021). COVID-19 is associated with distinct myopathic features in the diaphragm of critically ill patients. BMJ open respiratory research, 8(1).
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  The diaphragm is the main muscle of inspiration, and its dysfunction contributes to adverse clinical outcomes in critically ill patients. We recently reported the infiltration of SARS-CoV-2, and the development of fibrosis, in the diaphragm of critically ill patients with COVID-19. In the current study, we aimed to characterise myofiber structure in the diaphragm of critically ill patients with COVID-19.
• Shi, Z., de Vries, H. J., Vlaar, A. P., van der Hoeven, J., Boon, R. A., Heunks, L. M., Ottenheijm, C. A., & , D. C. (2021). Diaphragm Pathology in Critically Ill Patients With COVID-19 and Postmortem Findings From 3 Medical Centers. JAMA internal medicine, 181(1), 122-124.
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  This case-control study examines the association of COVID-19 with the respiratory muscles in Dutch critically ill patients.
• Berg, M. v., Ottenheijm, C. A., Engelen, B. G., Maarel, S. M., Küsters, B., Hees, H. W., Heerschap, A., Pijl, R. v., Voermans, N. C., & Lassche, S. (2020). Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy. Neurology. doi:10.1212/wnl.0000000000008977
• Berg, M. v., Granzier, H., Ottenheijm, C. A., Heunks, L. M., Paul, M. A., Musters, R. J., Kole, J., Strom, J., Shen, S., Bogaards, S. J., Brom, C. E., Shi, Z. H., Man, A. M., Girbes, A. R., Waard, M. C., Elshof, J., Beishuizen, A., Hooijman, P. E., Pijl, R. v., & Lindqvist, J. (2018). Positive End-Expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers. American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.201709-1917oc
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  Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers.We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance.PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H2O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy.Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.
• Lindqvist, J., van den Berg, M., van der Pijl, R., Hooijman, P. E., Beishuizen, A., Elshof, J., de Waard, M., Girbes, A., Spoelstra-de Man, A., Shi, Z. H., van den Brom, C., Bogaards, S., Shen, S., Strom, J., Granzier, H., Kole, J., Musters, R. J., Paul, M. A., Heunks, L. M., & Ottenheijm, C. A. (2018). Positive End-Expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers. American journal of respiratory and critical care medicine, 198(4), 472-485.
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  Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.
• Berg, M. v., Ottenheijm, C. A., Wüst, R. C., Heunks, L. M., Stienen, G. J., Pellegrino, M. A., Bottinelli, R., Brocca, L., Lawlor, M. W., Hees, H. W., Hartemink, K. J., Paul, M. A., Waard, M. C., Beishuizen, A., & Hooijman, P. E. (2017). Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill. American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.201703-0501oc

Proceedings Publications

• Berg, M. v., Ottenheijm, C. A., Wst, R. C., Pellegrino, M. A., Bottinelli, R., Paul, M. A., Hartemink, K. J., Stienen, G. J., Lawlor, M. W., Zaremba, R., Man, A. M., Girbes, A. R., Waard, M. C., Beishuizen, A., & Hooijman, P. E. (2015). LATE-BREAKING ABSTRACT: Disturbed mitochondrial dynamics and network in diaphragm muscle fibers of mechanically ventilated critically ill patients. In European Respiratory Society.