Biology Reference
In-Depth Information
However, since the main cause of morbidity and mortality in PAH is right
ventricular (RV) failure, and there is limited access to lung transplantation, future
therapeutic approaches must seek to preserve RV function but knowledge is
incomplete regarding the mechanisms for RV failure. In some patients, failure of
the RV progresses even when mPAP is attenuated (Badesch et al.
2009
; Bogaard
et al.
2009
). RV hypertrophy is a protective mechanism by which the heart
compensates for the increase in PAP, however sustained, high pulmonary pressure
leads to maladaptive remodeling, dilatation, and eventually RV failure. PDE1A,
1C, 3A, 3B, and 5A are all expressed in the heart and PDE family-specific inhibitors
enhance contractility and ameliorate LV hypertrophy, although given the difference
in the structure and function of the ventricles this may not be true for RV hypertro-
phy (Miller et al.
2009
; Takimoto et al.
2005
; Yan et al.
2007
; Zaccolo and
Movsesian
2007
). Both in experimental and in clinical
in vivo
studies (referenced
above), sildenafil and milrinone reverse RV hypertrophy, suggesting that in
addition to improving the hemodynamics of the pulmonary circulation, PDE
inhibitors help preserve RV function, by enhancing contractility and increasing
cardiac output.
Limited data exist as to whether the attenuation of RV hypertrophy by PDE
inhibition is due to a direct cardiac effect or the result of a decrease in mPAP.
Sildenafil significantly increases contractility in both the perfused heart and the
isolated cardiomyocytes with RV hypertrophy; PDE5, but not PDE3, mRNA,
protein and activity are markedly upregulated in hypertrophied RV myocardium
(Nagendran et al.
2007
). In contrast, sildenafil does not reverse or prevent RV
hypertrophy when the pressure load is kept constant by surgical banding of the PA,
suggesting that PDE5 inhibitors act indirectly to decrease RV hypertrophy via RV
unloading (Andersen et al.
2008
; Schafer et al.
2009
).
In isolated heart and myocytes, PDE5 inhibitors do not enhance PKG signaling
but instead increase [cAMP]
i
(Nagendran et al.
2007
). It has been proposed that
increased cGMP (via sildenafil) competitively inhibits PDE3, thereby elevating
cAMP since PKA inhibitors block the positive inotropic effect of sildenafil and
no increase in PKG phosphorylation is observed in the RV after treatment with
PDE5 inhibitors (Mouchaers et al.
2009
; Nagendran et al.
2007
). Sildenafil also
improves NOS coupling and decreases superoxide levels (which participate in the
transition from hypertrophy to heart failure) in the heart, thus contributing to its
beneficial effects in the RV (Hemnes et al.
2008
). Treatment of monocrotaline-
treated rats with bosentan and sildenafil reduces the formation of fibrosis by
increasing the activity of mitochondrial enzymes (succinate dehydrogenase and
cytochrome
c
oxidase) in the RV (Hemnes et al.
2008
; Mouchaers et al.
2009
).
More research is needed to determine whether components that contribute to the
protective effect of PDE inhibitors on LV failure, such as RGS2, are also impor-
tant in RV failure and whether their short-term benefits can be translated into long-
term clinical utility.
