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Calcium uptake by the sarcoplasmic reticulum, high energy content and histological changes in ischemic cardiomyopathy
K Mubagwa1, P Kaplan, B Shivalkar
1Laboratory of Experimental Cardiac Surgery, Katholieke Universiteit Leuven, Belgium. kanigula.mubagwa@med.kuleuven.ac.be
Insights
Sarcoplasmic reticulum Ca2+ uptake is reduced in specific zones of the heart in ischemic cardiomyopathy, indicating a decrease in SR Ca(2+)-ATPase activity. This impaired calcium handling is not uniform across the ventricular wall.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cardiac Pathophysiology
Background:
- Ischemic cardiomyopathy significantly impacts cardiac function, affecting myocardial energy metabolism and cellular integrity.
- Understanding alterations in sarcoplasmic reticulum (SR) calcium handling is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the spatial heterogeneity of SR Ca2+ uptake and its relationship with myocardial histology in ischemic cardiomyopathy.
- To assess changes in SR Ca2+ uptake, high-energy phosphate content, and fibrosis in different ventricular wall zones.
Main Methods:
- Left ventricular samples were obtained from infarct-remote, outer peri-infarct, and inner peri-infarct zones.
- Oxalate-supported 45Ca2+ uptake was measured to determine the maximum rate (Vmax) and affinity for Ca2+.
- Histological analysis quantified fibrosis and cell abnormalities; adenine nucleotide content was also measured.
Main Results:
- SR Ca2+ uptake (Vmax) was significantly lower in both inner and outer peri-infarct zones compared to infarct-remote myocardium.
- Fibrosis was markedly increased in the inner peri-infarct zone, but myocardial ATP content and DNA were similar across all zones.
- No significant differences were observed in Ca2+ affinity or Hill coefficients, suggesting preserved receptor function.
Conclusions:
- The reduction in SR Ca2+ uptake in ischemic cardiomyopathy is spatially heterogeneous within the ventricular wall.
- This impairment is primarily attributed to a decreased number or activity of the SR Ca(2+)-ATPase.
- Altered Ca2+ affinity or increased ryanodine receptor-mediated Ca2+ leak do not appear to be major contributing factors.
Objectives:
Sarcoplasmic reticulum (SR) Ca2+ uptake, myocardial high energy content and histology were examined in different zones of hearts from patients with ischemic cardiomyopathy.
Methods And Results:
Unfractionated homogenates were prepared from left ventricular samples obtained in three zones of each heart: an infarct-remote zone, an outer peri-infarct zone, and an inner peri-infarct zone. Oxalate-supported 45Ca2+ uptake was measured at 37 degrees C using a filtration method. Maximum rate (Vmax) of uptake in absence or in presence of ryanodine was lower in inner peri-infarct (7.4 +/- 0.7 and 9.5 +/- 0.8 nmol min-1 mg-1 of protein, respectively; mean +/- SEM) and outer peri-infarct tissues (8.8 +/- 0.8 and 12.0 +/- 0.8 nmol min-1 mg-1) than in infarct-remote myocardium (12.7 +/- 2.1 and 15.8 +/- 2.2 nmol min-1 mg-1). The apparent affinity constants for Ca2+ (KCa) as well as the Hill coefficients were not different. Homogenate DNA (1.6 +/- 0.1, 1.6 +/- 0.1 and 1.7 +/- 0.1 mg/g of remote, inner peri-infarct and outer peri-infarct myocardium, respectively) and adenine nucleotides contents (ATP: 15 +/- 1.3, 14 +/- 0.8 and 15 +/- 1.0 mumol/g dry weight, respectively) were similar in all tissues. Fibrosis was increased in inner peri-infarct tissue (37 +/- 6%; vs. 13 +/- 2% and 12 +/- 2% in both remote and outer peri-infarct tissues, respectively), but the number of abnormal cells was not significantly different.
Conclusion:
The decrease of Ca2+ uptake in ischemic cardiomyopathy is not homogeneous in the ventricular wall, and reflects a decreased number/activity of SR Ca(2+)-ATPase, without altered Ca(2+)-affinity or increased Ca2+ leakage through ryanodine receptors.