F.S. de Man

SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean±sd of 106±7 mmHg in response to SuHx and decreased but remained elevated at 72±8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction. Telemetry studies can facilitate preclinical studies to further improve our understanding of drug actions in PAH http://ow.ly/uXhjf

Pressure-overload-induced right heart failure

Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure.

The striated muscles in pulmonary arterial hypertension: adaptations beyond the right ventricle

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterised by progressive remodelling of the small pulmonary vessels. The daily-life activities of patients with PAH are severely limited by exertional fatigue and dyspnoea. Typically, these symptoms have been explained by right heart failure. However, an increasing number of studies reveal that the impact of the PAH reaches further than the pulmonary circulation. Striated muscles other than the right ventricle are affected in PAH, such as the left ventricle, the diaphragm and peripheral skeletal muscles. Alterations in these striated muscles are associated with exercise intolerance and reduced quality of life. In this Back to Basics article on striated muscle function in PAH, we provide insight into the pathophysiological mechanisms causing muscle dysfunction in PAH and discuss potential new therapeutic strategies to restore muscle dysfunction. RV, LV, diaphragm and peripheral muscle dysfunction contributes to reduced quality of life in PAH patients http://ow.ly/NAyZP

The rise and fall of endothelin receptor antagonists in congestive heart failure

Since its discovery in 1988 1, the role of endothelin in cardiovascular disease has been intensively studied. Activation of the endothelin system is considered part of the neurohormonal response in congestive heart failure. Endothelin is produced by vascular endothelial cells and has potent vasoconstrictor effects 2. Elevated endothelin levels induce adverse cardiac remodelling and cause progressive aggravation of congestive heart failure by influencing loading conditions of the heart and by reducing coronary flow; endothelin also has direct (toxic) myocardial effects 2. Several clinical studies have demonstrated that higher plasma levels of endothelin-1 correlates with the degree of haemodynamic and functional impairment, and worse …

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

Quadriceps muscle fibre dysfunction in patients with pulmonary arterial hypertension

Despite improvements in disease targeted therapies, pulmonary arterial hypertension (PAH) is a progressive disease and PAH patients remain symptomatic [1]. Exercise intolerance is one of the main symptoms, which limit PAH patients in their daily life activities. Reduced exercise capacity is generally attributed to right ventricular dysfunction [1]. However, as with other cardiac and pulmonary diseases, PAH patients develop respiratory [2] and peripheral muscle [3, 4] weakness, which might also contribute to exercise intolerance. Indeed, exercise training improves exercise capacity in PAH patients and maximal oxygen consumption of PAH patients correlates with the functional decline of peripheral muscle strength [5, 6]. The underlying cause of the reduction in muscle strength is unclear. Some studies have reported muscle fibre atrophy and a shift towards more fast-twitch fatigable fibres in skeletal muscles of PAH patients [3, 7]; however, these are not consistent findings [4, 8]. Peripheral muscle weakness in PAH patients is at least partly caused by sarcomeric dysfunction http://ow.ly/J8LuE

Vascular remodelling in the pulmonary circulation after major lung resection

Lung resection is a standard treatment in patients with clinical stages I and II and selected patients with stage IIIA nonsmall cell lung cancer [1]. Major lung resection (MLR), such as (bi)lobectomy or pneumonectomy, occasionally lead to pulmonary hypertension (PH). Several studies report an increase in pulmonary artery pressures in about one-third of these patients up to 5 years postoperatively [2–4]. The development of PH after MLR may be explained simply by the fact that total cardiac output flows through a smaller vascular bed. Because there are no reports in the literature of histological studies performed after MLR, it remains unknown whether flow-induced structural changes in the remaining lung vasculature lead to progressive increases in pulmonary vascular resistance. Major lung resection results in mild pulmonary vascular remodelling http://ow.ly/JRvW30doTC0