Contractile dysfunction of left ventricular cardiomyocytes in patients with pulmonary arterial hypertension

Emmy Manders, Harm Jan Bogaard, M. Louis Handoko, Marielle C. Van De Veerdonk, Anne Keogh, Nico Westerhof, Ger J.M. Stienen, Cristobal G. Dos Remedios, Marc Humbert, Peter Dorfmüller, Elie Fadel, Christophe Guignabert, Jolanda Van Der Velden, Anton Vonk-Noordegraaf, Frances S. De Man, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

BACKGROUND: After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. OBJECTIVES: The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. METHODS: LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. RESULTS: Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. CONCLUSIONS: The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalJournal of the American College of Cardiology
Volume64
Issue number1
DOIs
StatePublished - Jul 8 2014
Externally publishedYes

Keywords

  • contractile protein phosphorylation
  • left ventricular dysfunction
  • myocyte physiology
  • pulmonary arterial hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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