DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

806
Pressure (mm Hg)
ESPVR
EDPVR
(diastolic
dysfunction)
EDPVR
(normal)
Although hypervolemic patients generally benefit from
careful intravascular volume reduction, this should be
accomplished gradually and treatment goals reassessed
frequently. Maintaining synchronous atrial contraction
(or at least ventricular rate response control) helps to
maintain adequate LV filling during the latter phase of
diastole and is therefore a paramount goal in the management
of CHF from diastolic dysfunction. Evaluation
and treatment of predisposing conditions to impaired
diastolic function, such as myocardial ischemia and
poorly controlled systemic hypertension, are fundamental
to the overall pharmacotherapeutic strategy of this
complex form of CHF.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Volume (ml)
Figure 28–6. Pressure-volume relationships in normal heart and
heart with diastolic dysfunction. Normal P-V loo (green) based
on normal end diastolic pressure-volume relationship
(EDPVR). P-V loop with diastolic dysfunction is shown in red.
ESPVR, end-systolic pressure– volume relationship.
LV pressure–volume relationship during diastole, which
is shifted upward and to the left relative to normal subjects
(Figure 28–6). Consonant with the definition of
CHF outlined earlier in this chapter, the diagnosis of
diastolic CHF is made when the LV is unable to maintain
adequate cardiac output without filling at an abnormally
elevated end- diastolic filling pressure.
In patients with primary diastolic dysfunction, the
myocardial abnormality that accounts for abnormal filling
is intrinsic to the myocardium; e.g., by infiltrative
disorders including cardiac amyloidosis, hemochromatosis,
sarcoidosis, and rarer conditions such as
endomyocardial fibrosis and Fabry’s disease. Although
not a disease of myocardium infiltration, clinically evident
CHF may occur despite intact LV systolic function
in familial hypertrophic cardiomyopathy.
Secondary diastolic dysfunction occurs as a consequence
of excessive preload (e.g., renal failure),
excessive afterload (e.g., systemic hypertension), or
changes in LV geometry that occur in response to
chronically abnormal loading conditions. Diastolic
CHF also is observed in patients with long- standing
epicardial coronary artery or pericardial disease. The
prevalence of secondary diastolic dysfunction is higher
in women and with advanced age. Reported annual
mortality rates for diastolic CHF are 5-8%, although
this range likely represents an underestimation (Jones
et al., 2004).
Patients with diastolic CHF are typically dependent
on preload to maintain adequate cardiac output.
Future Therapies: Targeting Vascular
Dysfunction in Congestive Heart Failure
from Systolic Dysfunction
Vascular dysfunction is an established component of the
CHF syndrome and has evolved into a novel pharmacotherapeutic
target for the clinical management of
patients with this disease (Varin et al., 2000) (Figure 28–7).
Contemporary scientific observations suggest that the
blood vessel is a dynamic structure integral to normal
myocardial function. This represents a paradigm shift
away from the traditional perspective that blood vessels
are conduit “tubes” necessary only for blood transport.
Elevated levels of oxidant, nitrosative, and other forms of
inflammatory stress observed in patients with CHF may
impair vascular reactivity by disruption of normal
vasodilatory cell signaling pathways (Erwin et al., 2005;
Doehner et al., 2001). The precise mechanism by which
impaired vascular reactivity is aligned with the progressive
natural history of CHF is unresolved; when
present, however, vascular dysfunction is associated with
decreased exercise tolerance and a poorer clinical outcome.
For example, hyperaldosteronism due to overactivation
of the renin–angiotensin–aldosterone axis in
the setting of LV dysfunction adversely affects both
endothelium- dependent and endothelium-independent
vascular reactivity (Leopold et al., 2007, Maron et al.,
2009) enfothelium XO-I zenthine oxidase inhibitor vascular
reactivity. This process is in part mediated by
increased levels of reactive oxygen species, decreased
endogenous levels of antioxidant enzymes, and decreased
levels of bioavailable NO (Leopold et al., 2007;
Farquharson and Struthers, 2000).As discussed previously,
the undesirable effects of hyperaldosteronism on vascular
dysfunction are attenuated clinically by aldosterone receptor
blockade, resulting in significantly decreased CHFassociated
morbidity and mortality (Pitt et al., 1999).