Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure

Rondelet, Benoît; Dewachter, Céline; Kerbaul, François; Kang, Xin; Fesler, Pierre; Brimioulle, Serge; Naeije, Robert; Dewachter, Laurence

doi:10.1093/eurheartj/ehr111

Cited by 77 publications

(78 citation statements)

References 51 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: 85%

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: 85%

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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“…3 The current understanding of the pathophysiology of RV failure involves neurohumoral activation, expression of inflammatory mediators, apoptosis, capillary loss, oxidative stress, and metabolic shifts, with variable fibrosis and hypertrophy. 3,42 The exact sequence of events and interactions is being explored, and each has still to be referred to sound measurements of function, as illustrated in recent studies that showed inflammation and apoptosis to be correlated with decreased E max /E a in acute 43 as well as chronic 25,44 models of RV failure as a universal relationship ( Figure 5). …”

Section: Coupling Of Systolic Function To Afterloadmentioning

confidence: 99%

Biomechanics of the Right Ventricle in Health and Disease (2013 Grover Conference Series)

Naeije¹,

Brimioulle²,

Dewachter³

2014

Pulm. circ.

107

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Right ventricular (RV) function is a major determinant of the symptomatology and outcome in pulmonary hypertension. The normal RV is a thin-walled flow generator able to accommodate large changes in venous return but unable to maintain flow output in the presence of a brisk increase in pulmonary artery pressure. The RV chronically exposed to pulmonary hypertension undergoes hypertrophic changes and an increase in contractility, allowing for preserved flow output in response to peripheral demand. Failure of systolic function adaptation (homeometric adaptation, described by Anrep's law of the heart) results in increased dimensions (heterometric adaptation; Starling's law of the heart), with a negative effect on diastolic ventricular interactions, limitation of exercise capacity, and vascular congestion. Ventricular function is described by pressure-volume relationships. The gold standard of systolic function is maximum elastance (E max ), or the maximal value of the ratio of pressure to volume. This value is not immediately sensitive to changes in loading conditions. The gold standard of afterload is arterial elastance (E a ), defined by the ratio of pressure at E max to stroke volume. The optimal coupling of ventricular function to the arterial circulation occurs at an E max /E a ratio between 1.5 and 2. Patients with severe pulmonary hypertension present with an increased E max , a trend toward decreased E max /E a , and increased RV dimensions, along with progression of the pulmonary vascular disease, systemic factors, and left ventricular function. The molecular mechanisms of RV systolic failure are currently being investigated. It is important to refer biological findings to sound measurements of function. Surrogates for E max and E a are being developed through bedside imaging techniques.Keywords: right ventricle, pulmonary hypertension, preload, afterload, maximum elastance, end-systolic elastance, arterial elastance. One must inquire how increasing pulmonary vascular resistance results in impaired right ventricular function.-J. T. Reeves, 1989 1 In 1988, Jack Reeves and his colleagues noted that pulmonary hypertension is a common complication of cardiac and pulmonary diseases, that associated alterations in right ventricular (RV) function cause symptoms and limit survival, and that, paradoxically, research in this area had been relatively scarce. 1 Accordingly, they called for more studies to improve the understanding of RV failure in health and disease. Twenty-five years later, there has been significant progress, but our present knowledge remains incomplete, and calls for more research have been repeated. 2,3 The right ventricle (RV) in mammals and birds is a thin-walled flow generator, designed to accommodate the entire systemic venous return undergoing gas exchange in the pulmonary circulation, which is a separate high-flow, low-pressure system. 4 The pulmonary vascular pressures at rest and at mild levels of exercise are so low that a mean systemic filling pressure in the range of 10-15 m...

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Section: Article See P 2859mentioning

confidence: 99%

“…In fact, only recently has consideration been given to RV function within the context of the larger lung-pulmonary circulatory-RV apparatus. 5,9 This is a critical distinction, however, because defining the right heart axis in this way reidentifies the RV as a specific participant in the pathobiology of pulmonary hypertension and potential therapeutic target per se, thereby parting from traditional dogma in which RV dysfunction is a consequence of pulmonary vascular disease, an indicator of irreversible cardiac injury, and a dismal prognostic marker.Current work in the field has advanced our understanding of RV myocyte pathobiology significantly in the context of pulmonary vascular disease, particularly with respect to maladaptive molecular mechanisms that modulate RV failure through changes in cellular metabolism, 10 nitric oxide bioavailability, 11,12 and ion channel dysfunction. 13 These basic and translational scientific models, which emphasize novel RV-specific targets to improve RV performance, have illuminated a number of cell-signaling pathways with future therapeutic promise for patients afflicted with pulmonary hypertension-induced RV dysfunction.…”

mentioning

confidence: 99%

Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension

Maron

2012

Circulation

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A dverse remodeling of the right ventricle (RV) that affects RV systolic or diastolic function directly or indirectly by modulating changes to cavitary geometry is a principal determinant of poor outcome across the global spectrum of cardiopulmonary diseases. 1,2 Indeed, even subclinical increases in RV mass are associated with substantially elevated risk for future heart failure and decreased lifespan. 3 Unique embryological and anatomic features of the RV provide a pathophysiological basis by which to account for this observation. For example, precursor cells of the RV and left ventricle (LV) derive from the primary and anterior heart fields, 4 respectively, indicating a different cellular lineage for each ventricle despite their close proximity and placement in series. In contrast to the LV, the RV is a triangular structure that is thin walled and noncompacted, and, thus, tolerates pressure-loading conditions poorly. 5 Moreover, poor coronary blood flow reserve with increased RV strain due to elevations in wall tension is associated with decreased RV microvascular perfusion. 6 Article see p 2859Although these properties establish the RV-specific pressure-volume relationship profile, factors that precipitate impaired RV performance are less well characterized. Take, for example, the wide swath of classical reports that describe LV hemodynamic (patho)physiological responses to acute and chronic myocardial ischemia, systemic hypertension, valvular dysfunction, and pericardial disease. 7 By contrast, a paucity of data exists to characterize the mechanistic and clinical contributions of similar processes (including LV dysfunction) to the natural history of adverse RV remodeling in noncongenital heart disease patients, despite the attendant clinical relevance of RV failure. Furthermore, the basic mechanism(s) that underpin RV dysfunction when contemporaneous with pulmonary hypertension, the most common end-pathophenotype associated with changes to RV loading, 8 are largely unknown. In fact, only recently has consideration been given to RV function within the context of the larger lung-pulmonary circulatory-RV apparatus. 5,9 This is a critical distinction, however, because defining the right heart axis in this way reidentifies the RV as a specific participant in the pathobiology of pulmonary hypertension and potential therapeutic target per se, thereby parting from traditional dogma in which RV dysfunction is a consequence of pulmonary vascular disease, an indicator of irreversible cardiac injury, and a dismal prognostic marker.Current work in the field has advanced our understanding of RV myocyte pathobiology significantly in the context of pulmonary vascular disease, particularly with respect to maladaptive molecular mechanisms that modulate RV failure through changes in cellular metabolism, 10 nitric oxide bioavailability, 11,12 and ion channel dysfunction. 13 These basic and translational scientific models, which emphasize novel RV-specific targets to improve RV performance, have illuminated a number of cell-sig...

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Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure

Abstract: Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy, but is a cause of RV failure, which appears related to an activation of apoptosis and inflammation.

Cited by 77 publications

References 51 publications

Distinct loading conditions reveal various patterns of right ventricular adaptation

Distinct loading conditions reveal various patterns of right ventricular adaptation

Biomechanics of the Right Ventricle in Health and Disease (2013 Grover Conference Series)

Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension

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