A Vasodilator Is a Vasodilator Is a Vasodilator?

The report by Supino et al. [1] provides needed information about the potential role of vasodilators in one type of valvular heart disease (VHD), mitral regurgitation (MR). The primary finding that vasodilators, mainly by angiotensin blockade (AB) with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, were of no overall survival benefit in patients with MR may come as a surprise, considering the generally favorable perceptions of vasodilators, in particular AB in heart failure (HF), a major complication of MR. There was a suggestion that patients with hypertension may have benefitted. These results raise some issues deserving further consideration, including the differences between direct and indirect vasodilators, the role of hypertension as a risk factor in VHD, and the utility of observational studies like this one.By definition, vasodilation refers to an increase in the caliber of blood vessels. However, although all vasodilators may in general produce this effect, they differ in potentially important ways, especially in the site of their activity and the mechanism by which they exert their effects. As a drug class, vasodilators are used effectively in a variety of cardiovascular disorders, including angina pectoris, hypertension, peripheral vascular disease and HF. However, differences among individual vasodilators contribute to their individual utility and safety in these diverse disorders. Despite their early consideration and promise as useful agents in VHD, especially MR, experience with vasodilators has been quite limited in primary VHD [2,3]. This may be due in part to the fact that large clinical trials of vasodilators in nonvalvular cardiovascular disease have tended to exclude patients with primary VHD on the assumption that their treatment would ultimately be surgical, thereby compromising interpretation of the trial outcomes. Obviously aware of the differences among vasodilators and the general acceptance of the consistently beneficial effects of these agents, Supino et al. [1] have wisely used the term ‘indirect vasodilators' in describing their experience, which involved almost entirely the use of AB.A detailed discussion of the mechanisms involved in producing vasodilation is beyond the scope of this commentary. Direct vasodilators are those which act directly on vascular smooth muscle cells by a variety of possible mechanisms, including endothelial factors, nitric oxide pathways and the transmembrane movement of calcium ions [4,5,6]. Indirect vasodilators ultimately involve these same mechanisms but require initiation of the process via neurohormonal factors such as angiotensin-converting enzyme or neurotransmitters released from specialized cells [7]. These actions take place to varying degrees in different tissues, such as the central nervous system, renal vasculature, peripheral vasculature and adrenal glands. These various sites are under the control of multiple regulatory mechanisms. Thus, AB activity depends on the release of angiotensin which in turn is influenced by renal hemodynamics. Direct vasodilators, such as nitrates and hydralazine, are more dependent on local vascular factors, such as endothelin, nitric oxide and ion flux. Thus, it is not surprising that responsiveness to different vasodilators may vary under different pathophysiological conditions.In the above context, the observations of Supino et al. [1] may not be so surprising. Historically, direct-acting vasodilators, specifically nitrates and hydralazine, were among the first shown to produce a hemodynamic improvement and eventually clinical benefits in patients with HF. Subsequently, AB was shown to produce similar benefits in HF. In fact, current guidelines for HF management recommend the routine use of nitrates, hydralazine and AB in the therapeutic regimen for appropriate patients with HF. It should be noted that other direct vasodilators, like minoxidil, and other indirect vasodilators, like prazosin, were not shown to be clinically effective in HF, analogous to the observations of Supino et al. [1].Despite their early promise, the utility of vasodilators has not been established in VHD, partly due to the reasons stated above. This uncertainty is reinforced by the observations of Supino et al. [1], which are consistent with previous experiences with vasodilators in VHD. Prior experience in HF, especially in the V-HeFT trials, suggests that AB may be less effective in certain populations, just as was observed by Supino et al. [1] in VHD. In V-HeFT I the combination of the direct vasodilator isosorbide dinitrate and hydralazine was superior to placebo in reducing mortality when added to digitalis and diuretics in patients with HF. However, in V-HeFT II the direct vasodilator combination was not different from the angiotensin-converting enzyme inhibitor enalapril when added to digitalis and diuretics. However, when the subgroups were analyzed, African-American patients treated with the direct vasodilator did show a significant reduction in mortality compared to those receiving the AB, thereby suggesting less efficacy of AB in this subpopulation. The subsequent A-HeFT trial confirmed these results in an exclusively African-American study population [8]. These differing responses to direct and indirect vasodilators may be attributable to the deficiency of nitric oxide availability in African-Americans, which direct vasodilators may ameliorate. On the other hand, AB may be less effective in these same patients, at least partly due to genetic polymorphisms affecting responsiveness to AB [9]. The observation of Supino et al. [1] that a subgroup of their patients with hypertension and VHD may respond better to AB is not inconsistent with A-HeFT, as hypertension is a major component of the increased burden of HF in African-Americans and its presence may override the contribution of genetic variations as a determinant of responsiveness. Unfortunately, Supino et al. [1] did not provide any subgroup analysis by race, presumably because of the relatively small sample size. It is well know that hypertension in African-Americans is less dependent on the activity of the renin-angiotensin system [10].Much of the above discussion is highly speculative, which affirms the value of the report of Supino et al. [1]. Observational studies like theirs are almost never conclusive, but serve primarily to provoke thought and generate hypotheses for future studies. These authors have indeed provided somewhat surprising and provocative observations regarding the role of vasodilators in VHD. Their observation that indirect vasodilators, particularly AB, may be of value in some patients with severe MR is a hypothesis that should be tested in properly designed clinical trials, as they have called for. Hopefully that call will not go unheeded and will acknowledge: (1) that vasodilators are not all the same, and (2) that study populations must be large enough and broad enough to include representative demographics and underlying comorbidities.