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Selective decrease of components of the creatine kinase system and ATP synthase complex in chronic Chagas disease

Priscila Camillo Teixeira1, Ronaldo Honorato Barros Santos, Alfredo Inácio Fiorelli

  • 1Laboratory of Immunology, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil.

Plos Neglected Tropical Diseases
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Summary

Chronic Chagas disease cardiomyopathy (CCC) shows reduced levels of key enzymes for ATP production, indicating a more severe energy deficit compared to other cardiomyopathies. This impairment may explain the loss of contractile function in CCC patients.

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Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory condition with a poor prognosis.
  • Heart failure in CCC is linked to impaired myocardial energy metabolism and contractile dysfunction.
  • Trypanosoma cruzi infection causes CCC, prevalent in Latin America.

Purpose of the Study:

  • To investigate myocardial gene and protein expression of key ATP-producing mitochondrial enzymes.
  • To assess enzyme activity in end-stage CCC, idiopathic dilated cardiomyopathy (IDC), and ischemic cardiomyopathy (IC).
  • To correlate metabolic changes with contractile dysfunction in CCC.

Main Methods:

  • Analysis of myocardial samples from CCC, IC, IDC patients, and heart donors.
  • Quantification of mitochondrial creatine kinase (CKMit), muscular creatine kinase (CKM), and ATP synthase subunits (alpha, beta) using immunoblotting and real-time RT-PCR.
  • Assessment of total myocardial creatine kinase (CK) activity.

Main Results:

  • CKM protein levels and CK activity were reduced across all cardiomyopathy groups.
  • ATP synthase alpha chain protein levels and total CK activity were significantly lower in CCC compared to IC and IDC.
  • CCC myocardium exhibited a selective reduction in enzymes vital for cytoplasmic ATP maintenance.

Conclusions:

  • Selective impairment of the creatine kinase (CK) system in CCC may contribute to reduced inotropic reserve.
  • Lower ATP synthase alpha levels suggest decreased ATP generation via oxidative phosphorylation in CCC.
  • CCC patients exhibit a more pronounced myocardial energetic deficit than other dilated cardiomyopathies.