A Textbook of Clinical Pharmacology and Therapeutics

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.

Treatment of heart failure is aimed at reversing these counter-

regulatory 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 counter-
  regulatory 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 contrac-
  tion 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).

212 HEART FAILURE

1.00

0.75

0.50

0.25

No CHF

CHS only

Framingham only

Concordant

0.00

0246

Time since index date (years)

Proportion surviving

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 Epidemiology2004;
160 : 628–35.)

↓ Renal perfusion Activation of

renin–angiotensin–

aldosterone system

Vasoconstriction

Salt and water retention

Activation of

sympathetic

nervous system

Short-term

Longer-term

Worsening of tissue

perfusion

Worsening of fluid

retention

Progressive cardiomyocyte

death and fibrosis

Death

Maintenance of

blood pressure

Endothelial

dysfunction

↑ Endothelin

↓ Nitric oxide

↓ Cardiac
output

↓ Firing of arterial

baroreceptors

(Carotid sinus,

Aortic arch)

Figure 31.3:Compensatory counter-regulatory responses in heart failure and their consequences.