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J Thorac Cardiovasc Surg 2009;137:1146-1153
© 2009 The American Association for Thoracic Surgery

Congenital Heart Disease

Right ventricular hypertrophy with early dysfunction: A proteomics study in a neonatal model

Amir M. Sheikh, MBBS, FRCS(C-Th)a,*, Cindy Barrett, MDb, Nestor Villamizar, MDc, Oscar Alzate, PhDd, Anne Marie Valente, MDe, J. Rene' Herlong, MDf, Damian Craig, MSc, Andrew Lodge, MDa, Jeffrey Lawson, MD, PhDc, Carmelo Milano, MDc, James Jaggers, MDa

a Department of Pediatric Cardiac Surgery, the Neuroproteomics Center, Durham, NC
b Department of Pediatric Critical Care, the Neuroproteomics Center, Durham, NC
c Department of Surgery, the Neuroproteomics Center, Durham, NC
d Department of Neurobiology, Duke Cardiovascular Magnetic Resonance Center, Durham, NC
e Department of Adult and Pediatric Cardiology, Duke University Medical Center, Durham, NC
f The Sanger Clinic, Charlotte, NC

Received for publication March 31, 2008; revisions received August 12, 2008; accepted for publication September 1, 2008.

* Address for reprints: Amir M. Sheikh, MBBS, FRCS(C-Th), 114 Rowlands Ave, Middlesex, HA5 4AP, United Kingdom. (Email: amsheikh10{at}hotmail.com).

Objective: Right ventricular hypertrophy and subsequent dysfunction is common in patients with congenital heart defects, but the molecular mechanisms underlying change from adaptive hypertrophy to dysfunction remain elusive. We used the novel technique of proteomics to characterize protein changes in right ventricular myocardium in a neonatal model of right ventricular hypertrophy and early dysfunction.

Methods: Twelve neonatal piglets were equally randomized to pulmonary artery banding (PAB group), or sham operation (thoracotomy without banding). After 4 weeks, right ventricular morphology and function were assessed in vivo using magnetic resonance imaging. Animals were humanely killed. Proteomics of right ventricular myocardium was performed. Purified right ventricular proteins were separated by 2-dimensional difference gel electrophoresis using fluorescent cyanine dyes. After gel imaging, software analysis revealed protein spots differentially expressed between the 2 groups; these spots were excised and identified by mass spectrometry.

Results: On magnetic resonance imaging, animals with pulmonary artery banding demonstrated significant right ventricular hypertrophy, cavity dilatation, and mild systolic impairment (right ventricular ejection fraction 39.8% ± 15% vs 56.7% ± 10% controls; P < .05). Right ventricular free wall mass on harvest confirmed right ventricular hypertrophy. Proteomic analysis revealed 18 proteins that were significantly differentially expressed: 5 structural proteins, 6 metabolic enzymes, 2 stress proteins, and 5 miscellaneous proteins. Expression of calsarcin-1 and vinculin was increased, as were certain metabolic enzymes, although F1-ATPase β-chain and heat shock protein 70 decreased.

Conclusions: This is the first study characterizing right ventricular protein changes in a large animal model specifically capturing the change from compensated to maladaptive hypertrophy. These findings can guide future work at elucidating the mechanisms in the pathophysiology of neonatal right ventricular hypertrophy and dysfunction.

Abbreviations and Acronyms FA = flip angle; FOV = field of view; HASTE = half-Fourier acquisition single-shot turbo spin-echo; HSF-1 = heat shock transcription factor-1; HSP = heat shock protein; LV = left ventricle; MALDI = matrix-assisted laser desorption/ionization; MRI = magnetic resonance image (imaging); MS = mass spectrometry; PA = pulmonary artery; PAB = pulmonary artery band (banding); RV = right ventricle; ST = slice thickness; TE = echo time; TOF = time of flight; TR = repetition time






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