The Effects of Vasodilators in Pulmonary Hypertension

Abstract

W hen primary pulmonary hypertension (PPH) was first described in the medical literature, it was characterized from a cardiac catheterization on a young woman who had an elevated pulmonary arterial pressure of unknown origin which, after the intravenous administration of acetylcholine, promptly fell. 1 The sentinel description of this phenomenon led to the acceptance of PPH as a medical entity in which inappropriate pulmonary vasoconstriction was a central feature. 2 Since then many series of patients with PPH (now referred to as idiopathic pulmonary arterial hypertension [IPAH]) have been published which document a variable ability to respond to acute vasodilator challenge. Although, the approach to therapy has emphasized the initial classification of responder or nonresponder, most patients demonstrate only a small decrease in pulmonary pressure (PAP) in response to vasodilators. 3 However, vasodilators are widely prescribed in patients who are nonresponders, based on clinical trials that established the response to a 6-minute walk (6 MW) test as the primary end point. 4 The consistent improvement in 6 MW reflects the complexity of exercise intolerance, which may be strongly influenced not only by cardiopulmonary factors, but by peripheral factors such as the muscle ergoreflex. 5 Who is a Responder?In the current era, patients with PAH 6 who undergo acute vasoreactivity testing at the time of diagnosis are classified as responders or nonresponders based on the change in PAP from select agents. 7 The definition of a responder has changed many times, the most recent being a fall in the mean PAP of at least 10 mm Hg to a level below 40 mm Hg without any fall in cardiac output. 4 However, the response is in reality a continuum, and not an all or none phenomenon. It is notable that in 2 large series of patients who were deemed acute responders, the characteristic of those who had near perfect survival on calcium blockers (CCB) for up to 18 years had an acute fall in mean PAP of 39% and an acute fall in pulmonary vascular resistance (PVR) of 50%. 3,8 It is remarkable how similar the experiences from the 2 series are, supporting the validity of the observations. Who is a Nonresponder?The majority of patients with IPAH are nonresponders. Although this implies lack of vasoreactivity, this is clearly not the case. In an observational study of patients with IPAH who were monitored with a pulmonary artery catheter over 6 hours without an intervention, considerable variability was noted in the PAP (Ϯ8%) and PVR (Ϯ13%), suggesting that changing vasomotor tone is common in these patients. 9 In the 2 series on long-term calcium blocker therapy, the nonresponders also had an acute fall in mean PAP and PVR, but of a lesser magnitude than the responder group. In one series, the fall in PAP was 8%, and fall in PVR was 17%. 8 In the other, nonresponders were noted to have a fall in PVR of less than 20%. 3 Thus, the characterization of a patient as a nonresponder actually means a minimal response, not lack of response. Although the...

Kinetics of skeletal muscle O2 delivery and utilization at the onset of heavy-intensity exercise in pulmonary arterial hypertension

“…Our data, therefore, indicate that intra-myocyte abnormalities, if present, were overshadowed by the extensive impairment in the ''central'' (and/or ''peripheral'') cardiocirculatory adjustments. It should also be noted that our results do not rule out the hypothesis of impaired peripheral microvascular function (Rich 2009), independent of the ''central'' cardiovascular dysfunction. In fact, PAH patients may present with heightened sympathetic tonus (Nootens et al 1995a, b;Velez-Roa et al 2004;Wensel et al 2009) and endothelial dysfunction (Wolff et al 2007;Peled et al 2009) which could reduce muscle blood flow (Saltin 2007).…”

“…Mb] OS (Koga et al 2007). Therefore, although the sluggish increase in muscle microvascular O 2 delivery seemed to be determined mainly by the ''central'' cardiovascular effects of PAH, microvascular dysfunction per se should not be neglected in these patients (Rich 2009). In fact, 6/14 patients in the present study had a collagenovascular disease which is known to predispose patients to microvascular dysfunction.…”

Strategic Plan for Lung Vascular Research

“…Although a minority (,15%) of patients with severe PAH respond significantly to acute pulmonary vasodilators and can be treated successfully with calcium channel blockers, most are not responsive to vasodilators and are currently treated with prostacyclin analogs, endothelin-1 receptor blockers, type 5 phosphodiesterase inhibitors, or various combinations of these agents (58). These treatments provide some improvement in the quality of life of patients, but there is no convincing evidence that they significantly prolong survival (59).…”

Are Hemodynamics Surrogate End Points in Pulmonary Arterial Hypertension?

“…For example, effects on the systemic circulation or other organ systems rather than changes in the pulmonary vasculature could contribute substantially to therapeutic benefit. 41 Treatment could also affect right ventricular (RV) loading conditions in complex ways not adequately captured by invasive central measurements at rest. Small observational studies have used cardiac magnetic resonance imaging (MRI) to study the effects of PAH therapy on RV structure and function, and one has shown worsening RV performance is associated with poor outcomes independent of improvements in PVR.…”