Clinical Pharmacology and Therapeutics

212 HEART FAILURE
we focus on aspects common to heart failure irrespective of
aetiology.
Heart failure triggers ‘counter-regulatory’ responses (Figure
31.3), which make the situation worse, not better. Our ancestors
encountered low cardiac output during haemorrhage rather
than as a result of heart failure. Mechanisms to conserve blood
volume and maintain blood pressure would have provided
selective advantage. However, reflex and endocrine changes
that are protective in the setting of haemorrhage (volume
depletion ‘shock’) negatively impact patients with low cardiac
output due to pump failure.
Proportion surviving
1.00
0.75
0.50
0.25
0.00
No CHF
CHS only
Framingham only
Concordant
0 2 4 6
Time since index date (years)
Figure 31.2: Kaplan–Meier survival curves for subjects in the
Cardiovascular Health Study (CHS), United States, 1989–2000.
Subjects either had no congestive heart failure (CHF) or had CHF
diagnosed by different criteria (Framingham only, CHS only or
both, i.e. concordant). (Redrawn with permission from
Schellenbaum GD et al. American Journal of Epidemiology 2004;
160: 628–35.)
Treatment of heart failure is aimed at reversing these counterregulatory
changes, which include:
• activation of the renin–angiotensin–aldosterone system;
• activation of the sympathetic nervous system;
• release of vasopressin (an antidiuretic hormone, see
Chapter 42).
Cardiac performance is determined by preload, afterload,
myocardial contractility and heart rate. Treatment targets
these aspects, often by blocking one or other of the counterregulatory
mechanisms.
PRELOAD
Cardiac preload, the cardiac filling pressure, is determined by
blood volume – increased by salt and water retention – and
capacitance vessel tone, increased by sympathetic nervous
system activation. Drugs can reduce blood volume (diuretics)
and reduce capacitance vessel tone (venodilators).
AFTERLOAD
Afterload is determined by the systemic vascular resistance
and by aortic stiffness. Drugs that relax arterial smooth muscle
reduce cardiac afterload.
MYOCARDIAL CONTRACTILITY
Positive inotropes (i.e. drugs that increase the force of contraction
of the heart) can improve cardiac performance temporarily
by increasing contractility, but at the expense of increased oxygen
consumption and risk of dysrhythmia.
HEART RATE
Cardiac function deteriorates as heart rate increases beyond
an optimum, due to insufficient time for filling during diastole.
Heart rate can usefully be slowed by negative chronotropes
(i.e. drugs that slow the heart).
↓ Renal perfusion
Activation of
renin–angiotensin–
aldosterone system
↓ Cardiac
output
↓ Firing of arterial
baroreceptors
(Carotid sinus,
Aortic arch)
Activation of
sympathetic
nervous system
Vasoconstriction
Salt and water retention
Endothelial
dysfunction
↑ Endothelin
↓ Nitric oxide
Short-term
Maintenance of
blood pressure
Longer-term
Worsening of tissue
perfusion
Worsening of fluid
retention
Progressive cardiomyocyte
death and fibrosis
Death
Figure 31.3: Compensatory counter-regulatory responses in heart failure and their consequences.