In this randomised placebo controlled crossover study, we have shown, for the first time, that there are small but significant haemodynamic differences between the responses to selective ET-A and non-selective ET-A/B receptor blockade in patients with chronic heart failure. Both selective ET-A and non-selective ET-A/B receptor blockade increased cardiac output and reduced mean arterial pressure and systemic vascular resistance. However, selective ET-A receptor blockade caused a greater increase in cardiac output and reduction in systemic vascular resistance than non-selective ET-A/B receptor blockade. In contrast, selective ET-A and non-selective ET-A/B blockade caused similar reductions in both pulmonary artery pressure and pulmonary vascular resistance. There was a greater reduction in pulmonary artery pressure with non-selective blockade than with selective ET-A blockade after low dose infusion, although this difference was not apparent after high dose infusion.
This is the first study to directly compare systemic selective ET-A and non-selective ET-A/B blockade in patients with heart failure. Our findings are consistent with other short term studies, which have shown that both selective ET-A17
and non-selective ET-A/B20–22
blockade increase cardiac output and reduce systemic vascular resistance, importantly with no change in heart rate, and that both selective ET-A16,17
and non-selective ET-A/B20–22
blockade reduce pulmonary vascular resistance and pulmonary artery wedge pressure. Comparing magnitude of response between different ET antagonists in different patient populations is difficult but we have shown in this head to head study that selective ET blockade had greater effects than non-selective ET antagonism on the systemic vasculature.
There is increasing evidence that the ET-B receptor has a role in the clearance of plasma ET-1. Plasma ET-1 concentration increases after systemic selective ET-B blockade in healthy people8
and after non-selective ET-A/B blockade in healthy people28
and in patients with hypertension4
and with chronic heart failure.18,20
However, the effects of systemic ET-A blockade alone are less consistent with little, if any, increase in plasma ET-1 concentrations in most studies,6,15,16
although one study did report an increase at higher degrees of ET-A blockade.17
These results are confirmed in our study, in which selective ET-A receptor blockade had no effect, whereas plasma ET-1 concentrations were increased by non-selective blockade. Because there was no change in plasma big ET-1 concentration, increased plasma ET-1 is likely to reflect interference with its clearance rather than an increase in its synthesis and release. Thus, selective ET-A blockade has a theoretical benefit of leaving the ET clearance receptor (ET-B) functional. Nevertheless, if the ET-A receptor is also effectively blocked during ET-B receptor blockade then the high circulating concentrations of ET-1 may not be of clinical importance.
Although selective ET-A receptor blockade had greater effects on systemic vascular resistance, there may be clinical situations in which blockade of the ET-B receptor is desirable. There is a higher density of ET-B receptors in the pulmonary vasculature and these may be upregulated in pulmonary arterial hypertension,29
though selective ET-A and non-selective ET-A/B receptor blockade have not yet been compared head to head in this condition. Also, ET-1 release across the pulmonary vascular bed correlates strongly with the pulmonary vascular resistance in chronic heart failure.30
Raised pulmonary artery pressure is an independent risk factor in chronic heart failure and responds poorly to conventional treatments. Here, we showed that both selective ET-A and non-selective ET-A/B receptor blockade reduce pulmonary artery pressures.
These observations suggest that ET antagonism may benefit patients with heart failure who also have raised pulmonary artery pressures, although we did not directly address this condition in our study. Indeed, the non-selective antagonist bosentan has recently been approved to treat primary pulmonary arterial hypertension based on its effectiveness in this situation.31
The long term clinical effects of ET receptor blockade in patients with pulmonary hypertension secondary to chronic heart failure are unknown, but it is tempting to speculate that ET receptor blockade may also be more effective in this setting. We have failed to show convincingly whether there are true haemodynamic differences between selective ET-A and non-selective ET-A/B receptor antagonism in the pulmonary circulation. However, none of the patients in the present study had significant pulmonary hypertension. We believe that the role of ET antagonism now warrants further careful assessment in a much larger trial of patients with both heart failure and a significant degree of pulmonary hypertension.
Many studies use agents that, while termed “selective” or “dual” inhibitors of ET-A and ET-B receptors, have a range of receptor selectivities, mostly inhibiting the ET-A receptor at much lower concentrations than at the ET-B receptor.26
In this study we have used two receptor antagonists, BQ-123 and BQ-788, given separately and with selectivity for the ET-A and ET-B receptor, respectively. Therefore, it is important to recognise that we have examined mechanistically the influence of major blockade of the ET-B receptor on responses to full ET-A blockade. This may not exactly represent the clinical situation that exists with non-selective antagonists, such as bosentan, which are relatively selective for the ET-A receptor (ET-A:ET-B selectivity > 10). The doses of BQ-123 given here have been shown to produce maximum systemic haemodynamic effects and to block responses to forearm artery infusion of ET-1, but not to increase plasma ET-1 concentrations. Given that BQ-123 caused greater systemic vasodilatation than the combination with BQ-788, the overall haemodynamic effect of ET-B blockade in patients with heart failure is likely to be vasoconstriction, a finding consistent with other work.23,32
As a limitation, this was an acute haemodynamic study and we have not assessed whether these effects are sustained in the long term. Nevertheless, previous haemodynamic studies indicate that the acute effects of both selective ET-A24
ET receptor blockade are maintained, or even enhanced, over several weeks and therefore likely to be sustained. The clinical impact of these haemodynamic changes is, of course, uncertain and can only be clarified in the context of large scale clinical outcome studies. We have shown that selective ET-A blockade causes more major systemic vasodilatation than non-selective ET-A/B receptor blockade in New York Heart Association (NYHA) class II–III patients with heart failure. To date, there have been only two as yet unpublished large scale, randomised controlled trials of ET receptor blockade in patients with heart failure (NYHA class III–IV), both of which observed no major clinical benefit of either bosentan (ET-A:ET-B selectivity ~10)25
or darusentan (ET-A:ET-B selectivity > 500).24
The results of these longer term studies were disappointing, although perhaps it is not surprising that two agents with 10 to > 500 selectivity for the ET-A receptor yielded similar results given the small haemodynamic differences found in the current study, when much greater relative ET-B receptor blockade was achieved. Nevertheless, bosentan has found utility in the treatment of primary pulmonary hypertension and whether it may have utility in a subset of patients with CHF with secondary pulmonary hypertension remains to be seen.
In this study both selective ET-A and non-selective ET-A/B blockade cause acute systemic and pulmonary haemodynamic changes in patients with heart failure. However, differences exist and selective ET-A blockade causes greater systemic haemodynamic effects than non-selective ET-A/B blockade.