Right ventricular failure secondary to chronic overload in congenital heart disease: An experimental model for therapeutic innovation

Lambert, Virginie; Capderou, André; Bret, Emmanuel Le; Rücker‐Martin, Catherine; Deroubaix, E; Gouadon, Elodie; Raymond, Nicolas; Stos, Bertrand; Sérraf, Alain; Renaud, Jean‐François

doi:10.1016/j.jtcvs.2009.11.028

Cited by 37 publications

(43 citation statements)

References 25 publications

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“…This is in line with reports that the chronically volume-overloaded RV cannot increase contractility in response to acute pressure overload (46). Studies in large animal models of combined volume and pressure overload have shown that during disease progression contractility initially increases, but falls back to pseudonormal levels in a more advanced stage of RV dysfunction (28,40,41). Causal factors for the blunted contractility response may include loss of peristaltic contraction pattern (33), disturbed calcium homeostasis (8,26), and changes in coronary perfusion (46).…”

Section: Additional Volume Overload In Ph Blunts the Contractility Resupporting

confidence: 86%

Distinct loading conditions reveal various patterns of right ventricular adaptation

Borgdorff

Bartelds

Dickinson

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Borgdorff MA, Bartelds B, Dickinson MG, Steendijk P, de Vroomen M, Berger RM. Distinct loading conditions reveal various patterns of right ventricular adaptation. Am J Physiol Heart Circ Physiol 305: H354 -H364, 2013. First published May 31, 2013 doi:10.1152/ajpheart.00180.2013.-Right ventricular (RV) failure due to chronically abnormal loading is a main determinant of outcome in pulmonary hypertension (PH) and congenital heart disease. However, distinct types of RV loading have been associated with different outcomes. To determine whether the adaptive RV response depends on loading type, we compared hemodynamics, exercise, and hypertrophy in models of pressure overload due to pulmonary artery banding (PAB), pressure overload due to PH, combined pressure and volume overload, and isolated volume load. Ninety-four rats were subjected to either PAB, monocrotaline-induced PH (PH), aortocaval shunt (shunt), or combined monocrotaline and aortocaval shunt (PH ϩ shunt). We performed pressure-volume analysis and voluntary exercise measurements at 4 wk. We compared PAB to PH (part I) and PH ϩ shunt to either isolated PH or shunt (part II). In part I, enhanced contractility (end-systolic elastance and preload recruitable stroke work) was present in PH and PAB, but strongest in PAB. FrankStarling mechanism was active in both PAB and PH. In PAB this was accompanied by diastolic dysfunction (increased end-diastolic elastance, relaxation constant), clinical signs of RV failure, and reduced exercise. These distinct responses were not attributable to differences in hypertrophy. In part II, in PH ϩ shunt the contractility response was blunted compared with PH, which caused pseudonormalization of parameters. Additional volume overload strongly enhanced hypertrophy in PH. We conclude that different types of loading result in distinct patterns of RV adaptation. This is of importance for the approach to patients with chronically increased RV load and for experimental studies in various types of RV failure. right ventricular failure; contractility; pressure-volume analysis; pulmonary hypertension; monocrotaline RIGHT VENTRICULAR FAILURE is a detrimental condition that is associated with significant morbidity and mortality in patients with congenital heart disease and/or pulmonary hypertension (PH) (11,19,34,38). In these conditions, persistent abnormal loading of the right ventricle (RV) leads to RV failure in the long term (17, 50). However, physiological and molecular mechanisms of RV adaptation to these abnormal loading conditions and its derailment into RV failure are largely unknown (3, 50). As a consequence, no heart failure therapy exists that specifically targets the RV. Different animal models have been used to study the abnormally loaded RV, but interpretation of data and translation to the clinical setting are hampered by conceptual concerns.First, distinct types of RV overload are used in experimental models. These include the induction of PH, where the RV interacts with an increased dynamic load due to a highresistance p...

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Section: Additional Volume Overload In Ph Blunts the Contractility Resupporting

confidence: 86%

Distinct loading conditions reveal various patterns of right ventricular adaptation

Borgdorff

Bartelds

Dickinson

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, similar discrepancies were found in animal models of rTOF. An APD prolongation was found in isolated RV myocytes from a similar rTOF pig model22 whereas a recent study in a dog model noted the absence of APD change in the endocardium 23. Our results suggest these discrepancies are likely related to regional APD variations in rTOF RVs.…”

Section: Discussioncontrasting

confidence: 49%

Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot

Benoist

Dubes

Roubertie

et al. 2016

Heart

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ObjectiveThe growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV) structural and electrophysiological remodelling to arrhythmia generation in a preclinical animal model of repaired TOF (rTOF).Methods and resultsPigs mimicking rTOF underwent cardiac MRI functional characterisation and presented with pulmonary regurgitation, RV hypertrophy, dilatation and dysfunction compared with Sham-operated animals (Sham). Optical mapping of rTOF RV-perfused wedges revealed a significant prolongation of RV activation time with slower conduction velocities and regions of conduction slowing well beyond the surgical scar. A reduced protein expression and lateralisation of Connexin-43 were identified in rTOF RVs. A remodelling of extracellular matrix-related gene expression and an increase in collagen content that correlated with prolonged RV activation time were also found in these animals. RV action potential duration (APD) was prolonged in the epicardial anterior region at early and late repolarisation level, thus contributing to a greater APD heterogeneity and to altered transmural and anteroposterior APD gradients in rTOF RVs. APD remodelling involved changes in Kv4.3 and MiRP1 expression. Spontaneous arrhythmias were more frequent in rTOF wedges and more complex in the anterior than in the posterior RV.ConclusionSignificant remodelling of RV conduction and repolarisation properties was found in pigs with rTOF. This remodelling generates a proarrhythmic substrate likely to facilitate re-entries and to contribute to sudden cardiac death in patients with rTOF.

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“…Other groups have used the pig for studying PR [18][19][20]. Our porcine model was the first pure model, free of scar tissue, which was examined with morphometric methods and electrophysiology.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the hearts were not examined pathologically like in the present study. Nevertheless, Lambert et al also made a porcine 4 months PR model using the surgical methods of Zeltser et al [18]. They examined RV histology and cellular electrical properties.…”

Section: Discussionmentioning

confidence: 99%

Myocardial hypertrophy after pulmonary regurgitation and valve implantation in pigs

Smith

Goetze

Søndergaard

et al. 2012

International Journal of Cardiology

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Right ventricular failure secondary to chronic overload in congenital heart disease: An experimental model for therapeutic innovation

Cited by 37 publications

References 25 publications

Distinct loading conditions reveal various patterns of right ventricular adaptation

Distinct loading conditions reveal various patterns of right ventricular adaptation

Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot

Myocardial hypertrophy after pulmonary regurgitation and valve implantation in pigs

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