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Calibrated histochemistry applied to oxygen supply and demand in hypertrophied rat myocardium
A L Des Tombe1, B J Van Beek-Harmsen, M B E Lee-De Groot
1Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.
Insights
Myocardial hypertrophy can cause a critical oxygen supply-demand mismatch in cardiomyocytes. Increased cardiomyocyte size, not oxygen consumption or myoglobin, is the main driver of critical oxygen tension, potentially leading to heart failure.
Area of Science:
- Cardiovascular Physiology
- Cellular Biology
- Biochemistry
Background:
- Myocardial hypertrophy involves increased cardiomyocyte size and oxygen demand.
- Understanding oxygen supply-demand balance is crucial for preventing hypoxia during cardiac growth.
Purpose of the Study:
- To investigate oxygen supply and demand in cardiomyocytes during hypertrophy.
- To determine factors influencing critical oxygen tension (PO(2,crit)) in hypertrophic cells.
- To explore the link between oxygen imbalance and the progression to heart failure.
Main Methods:
- Utilized calibrated histochemical methods to assess succinate dehydrogenase activity, cardiomyocyte size, and myoglobin concentration.
- Employed an oxygen diffusion model to calculate critical extracellular oxygen tension (PO(2,crit)).
- Investigated hypoxia-inducible factor 1alpha expression via immunohistochemistry.
Main Results:
- Cardiomyocyte cross-sectional area increase was the primary determinant of PO(2,crit), while succinate dehydrogenase activity and myoglobin concentration remained relatively constant.
- A mismatch between oxygen supply and demand was observed in cardiomyocytes with high PO(2,crit).
- Hypoxia-inducible factor 1alpha was detected in cardiomyocytes experiencing limited oxygen supply, indicating affected gene expression.
Conclusions:
- Hypertrophic growth can lead to an oxygen supply-demand mismatch at the cardiomyocyte level.
- This oxygen imbalance may contribute to the transition from myocardial hypertrophy to heart failure.
- Calibrated histochemical methods and oxygen diffusion modeling are essential for accurate assessment.
Abstract:
Oxygen supply and demand of individual cardiomyocytes during the development of myocardial hypertrophy is studied using calibrated histochemical methods. An oxygen diffusion model is used to calculate the critical extracellular oxygen tension (PO(2,crit)) required by cardiomyocytes to prevent hypoxia during hypertrophic growth, and determinants of PO(2,crit) are estimated using calibrated histochemical methods for succinate dehydrogenase activity, cardiomyocyte cross-sectional area, and myoglobin concentration. The model calculation demonstrates that it is essential to calibrate the histochemical methods, so that absolute values for the relevant parameters are obtained. The succinate dehydrogenase activity, which is proportional to the maximum rate of oxygen consumption, and the myoglobin concentration hardly change while the cardiomyocytes grow. The cross-sectional area of the cardiomyocytes, which increases up to threefold in the right ventricular wall due to pulmonary hypertension in monocrotaline-treated rats, is the most important determinant of PO(2,crit) in this model of myocardial hypertrophy. The relationship between oxygen supply and demand at the level of the cardiomyocyte can be investigated using paired determinations of spatially integrated succinate dehydrogenase activity and capillary density. Hypoxia-inducible factor 1alpha can be demonstrated by immunohistochemistry in cardiomyocytes with high PO(2,crit) and increased spatially integrated succinate dehydrogenase activity, indicating that limited oxygen supply affects gene expression in these cells. We conclude that a mismatch of oxygen supply and demand may develop during hypertrophic growth, which can play a role in the transition from myocardial hypertrophy to heart failure.
