Maartje de Vroomen

Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle

Right ventricular (RV) failure due to pressure or volume overload is a major risk factor for early mortality in congenital heart disease and pulmonary hypertension, but currently treatments are lacking. We aimed to demonstrate that the phosphodiesterase 5A inhibitor sildenafil can prevent adverse remodelling and improve function in chronic abnormal RV overload, independent from effects on the pulmonary vasculature.

Distinct loading conditions reveal various patterns of right ventricular adaptation

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 + shunt). We performed pressure-volume analysis and voluntary exercise measurements at 4 wk. We compared PAB to PH (part I) and PH + 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. Frank-Starling 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 + 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.

Sildenafil treatment in established right ventricular dysfunction improves diastolic function and attenuates interstitial fibrosis independent from afterload

Right ventricular (RV) function is an important determinant of prognosis in congenital heart diseases, pulmonary hypertension, and heart failure. Preventive sildenafil treatment has been shown to enhance systolic RV function and improve exercise capacity in a model of fixed RV pressure load. However, it is unknown whether sildenafil has beneficial effects when treatment is started in established RV dysfunction, which is clinically more relevant. Our aim was to assess the effects of sildenafil treatment on RV function and fibrosis in a model of established RV dysfunction due to fixed afterload. Rats were subjected to pulmonary artery banding (PAB), which induced RV dysfunction after 4 wk, characterized by reduced exercise capacity, decreased tricuspid annular plane systolic excursion, and RV dilatation. From week 4 onward, 50% of rats were treated with sildenafil (100 mg·kg(-1)·day(-1), n = 9; PAB-SIL group) or vehicle (n = 9; PAB-VEH group). At 8 wk, exercise capacity was assessed using cage wheels, and RV function was assessed using invasive RV pressure-volume measurements under anesthesia. Sildenafil treatment, compared with vehicle, improved RV ejection fraction (44 ± 2% vs. 34 ± 2%, P < 0.05, PAB-SIL vs. PAB-VEH groups), reduced RV end-diastolic pressure (2.3 ± 0.5 vs. 5.1 ± 0.9 mmHg, P < 0.05), and RV dilatation (end-systolic volume: 468 ± 45 vs. 643 ± 71 μl, P = 0.05). Sildenafil treatment also attenuated RV fibrosis (30 ± 6 vs. 17 ± 3‰, P < 0.05) but did not affect end-systolic elastance, exercise capacity, or PKG or PKA activity. In conclusion, sildenafil improves RV diastolic function and attenuates interstitial fibrosis in rats with established RV dysfunction, independent from afterload. These results indicate that sildenafil treatment has therapeutic potential for established RV dysfunction.

Endothelin-1 plasma concentration increases in the early phase of pulmonary hypertension development during respiratory distress syndrome: a study in newborn lambs

OBJECTIVE Elevated plasma concentrations of endothelin-1 (ET-1) have been reported with pulmonary hypertension during respiratory distress syndrome (RDS). However, the exact role of ET-1 in the development of pulmonary hypertension during RDS is unclear. The relative time-course of changes in ET-1 concentrations and pulmonary artery pressure (P(ap)) during RDS may give insight in the role of ET-1. METHODS ET-1 and P(ap) changes were studied in an experimental model of RDS, induced by lung lavages in seven newborn lambs. Five other lambs served as controls. RESULTS Lung lavages induced a twofold increase of mean P(ap) (from 15 to 34 mm Hg) that remained present throughout the 4-h study period. Along with the increased P(ap), ET-1 plasma concentration showed a significant increase 15 min after induction of RDS at all three sample locations (pulmonary artery 198%, aorta 181% and right atrium 195% compared to baseline). This increased concentration remained high at 1 and 4 h of RDS. In control animals, no significant changes in ET-1 concentrations were observed. Plotting ET-1 concentration values against mean P(ap), in RDS and control animals at all time points, a correlation was found between the severity of the pulmonary hypertension and ET-1 concentration. CONCLUSION This experimental model of RDS shows that ET-1 concentration increases concomitant with the development of pulmonary hypertension, from an early time point onward. More severe pulmonary hypertension is associated with higher ET-1 concentrations, but whether ET-1 is a marker or a mediator of pulmonary hypertension remains as yet unsettled.

Calcitonin gene-related peptide increases pulmonary blood flow in fetal sheep

Calcitonin gene-related peptide (CGRP) may play a role in regulation of pulmonary vascular tone in adults. We set out to establish whether or not CGRP has any effect on the fetal pulmonary circulation. Hemodynamic effects of exogenous CGRP were studied in seven near-term fetal sheep. Single CGRP injections into left pulmonary artery (LPA), compared with acetylcholine, and five repeated CGRP injections were studied. Single CGRP injections (1.36 ± 0.13 μg/kg) increased LPA blood flow (transit time ultrasound) significantly, from 26 ± 22 to 202 ± 86 ml/min ( P < 0.05), and decreased pulmonary and aortic pressures, from 58 ± 5 to 48 ± 6 mmHg and from 56 ± 3 to 46 ± 5 mmHg, respectively ( P < 0.05). LPA resistance decreased from 3.69 to 0.24 mmHg ⋅ min ⋅ ml-1( P < 0.05). These changes were similar to those with acetylcholine. Five CGRP injections at 5-min intervals increased LPA flow significantly, in stepwise fashion, and LPA resistance decreased. Heart rate increased stepwise, without changes in pulmonary or carotid arterial pressures. Exogenous CGRP is a potent pulmonary vasodilator in fetal sheep and increases pulmonary flow. CGRP-induced increases in heart rate are not secondary to decreased systemic blood pressure but reflect a positive chronotropic effect. These findings suggest a role for endogenous CGRP in the remarkable decrease in pulmonary vascular resistance during the transition to extrauterine life.Calcitonin gene-related peptide (CGRP) may play a role in regulation of pulmonary vascular tone in adults. We set out to establish whether or not CGRP has any effect on the fetal pulmonary circulation. Hemodynamic effects of exogenous CGRP were studied in seven near-term fetal sheep. Single CGRP injections into left pulmonary artery (LPA), compared with acetylcholine, and five repeated CGRP injections were studied. Single CGRP injections (1.36 +/- 0.13 micrograms/kg) increased LPA blood flow (transit time ultrasound) significantly, from 26 +/- 22 to 202 +/- 86 ml/min (P < 0.05), and decreased pulmonary and aortic pressures, from 58 +/- 5 to 48 +/- 6 mmHg and from 56 +/- 3 to 46 +/- 5 mmHg, respectively (P < 0.05). LPA resistance decreased from 3.69 to 0.24 mmHg.min.ml-1 (P < 0.05). These changes were similar to those with acetylcholine. Five CGRP injections at 5-min intervals increased LPA flow significantly, in stepwise fashion, and LPA resistance decreased. Heart rate increased stepwise, without changes in pulmonary or carotid arterial pressures. Exogenous CGRP is a potent pulmonary vasodilator in fetal sheep and increases pulmonary flow. CGRP-induced increases in heart rate are not secondary to decreased systemic blood pressure but reflect a positive chronotropic effect. These findings suggest a role for endogenous CGRP in the remarkable decrease in pulmonary vascular resistance during the transition to extrauterine life.

RIGHT VENTRICULAR FAILURE IS DIASTOLIC HEART FAILURE AND IS NOT CAUSED BY HYPERTROPHY OR FIBROSIS

Right ventricular failure (RVF) is a main determinant of outcome in congenital heart diseases and pulmonary hypertension. Unfortunately, little is known about its causes. Our aim was to study the pathophysiology of RVF by comparing rats with clinical RVF to rats without clinical RVF, in a model of

SILDENAFIL IMPROVES ESTABLISHED RIGHT VENTRICULAR DYSFUNCTION VIA ENHANCEMENT OF DIASTOLIC FUNCTION

Right ventricular (RV) failure is a major determinant of mortality in pulmonary hypertension or congenital heart diseases. Sildenafil (SIL) benefits the RV when started at the onset of pressure load (prevention). However, it is unknown whether SIL is effective in established RV dysfunction (