Outline the pathophysiological basis for the use of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) in congestive cardiac failure.

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College Answer

The renin-angiotensin system plays a central role in the pathophysiology of heart failure.
Thus this question required integration of knowledge of the renin-angiotensin system and
how pharmacological agents affect it in the treatment of cardiac failure. Candidates were
expected to describe the pathway and the influence of these drug groups on cardiac failure
and to recognise underlying basic physiological principles such as the interaction between
AT1 and AT2 receptors along with awareness of production of Ang II by ACE-independent
enzymes.
A good answer was expected to contain the following points: Angiotensinogen is cleaved by
kidney-derived renin to form the decapeptide angiotensin I (Ang I); ACE converts Ang I to
Ang II; Ang II is a potent arterial vasoconstrictor and an important mediator of Na+ and water
retention through its effects on glomerular filtration pressure and aldosterone secretion; Ang
II potentiates neural catecholamine release, is a secretagogue for catecholamine release from
the adrenal medulla, promotes vascular hyperplasia and pathologic myocardial hypertrophy.
ACE inhibitors suppress Ang II and aldosterone production, decrease sympathetic nervous
system activity, and potentiate the effects of diuretics in heart failure. ACE is identical to
kininase II, which degrades bradykinin and other kinins that stimulate production of NO,
cyclic GMP, and vasoactive eicosanoids; these vasodilator substances seem to oppose the
effects of Ang II on the growth of vascular smooth muscle and cardiac fibroblasts and on
production of extracellular matrix. Thus, the increased levels of bradykinin that result from
ACE inhibition may play a role in the hemodynamic and anti-remodeling effects of ACE
inhibitors.
An alternative means of attenuating the haemodynamic and vascular impact of the reninangiotensin
system is through inhibition of angiotensin receptors. Most of the known clinical
actions of angiotensin II are mediated through the AT1 angiotensin receptor. AT1 receptor
antagonists may provide more potent reduction of the effects of angiotensin II than do ACE
inhibitors.
Syllabus C2d 1 and part C2b 2f
Reference Goodman and Gilman 561-7, Guyton Chp 22

Discussion

Trying some basic Google searches to figure out where this weirdly extensive CICM examiner comment has come from, one will eventually come across this Brainscape online flashcard quizlet for cardiovascular medicine, where it appears verbatim. It is hard to know who plagiarised whom, because this question is very old.

Anyway, the question specifically asks not for the pharmacology of ARBs and ACE-inhibitors, but for the pathophysiological basis of their use, i.e. how are they suited to their purpose in the management of CCF. The expected answers would probably have needed quite a lot of focus on the RAAS.  The trick in a question like this would be structure. How to design an answer which addresses both the physiology and the pharmacology systematically, in a logical sequence, and all within ten minutes? Judging by the pass rate (0%) this was a bar too high. Undoubtedly, most of the trainees at this level have some idea of what ACE-Is and ARBs do, but none were able to articulate their thoughts under duress. The college clearly recognised this as a flaw in their SAQ design; at the time of writing (early 2021) this question has not been repeated for thirteen years.

Anyway: what follows is an attempt to squeeze all this into a bullet-point answer which hits all the important notes. After some pruning, it was actually possible to compress this into a fairly compact form. Most of the information came from Ferrario et al (2006), which is unfortunately not available in free full text.

Mechanism of action

  • The RAAS is a major system involved in the medium-term regulation of blood pressure and blood volume.
  • Many of these regulatory effects are mediated by the activity of angiotensin-II on the AT1 receptor
  • ACE inhibitors block the conversion of angiotensin I into angiotensin II by ACE
  • ARBs block the binding of angiotensin II to its AT1 receptor

Positive clinical effects in CCF from the blockade of Ang-II or its receptors:

  • Antihypertensive (afterload-reducing) effects: 
    • Decreased catecholamine sensitivity
    • Decreased vasopressin release
    • Thus, decreased systemic vascular resistance
    • Thus, decreased afterload and myocardial oxygen demand
  • Preload-reducing effects:
    • Decreased vasopressin release
    • Decreased aldosterone release
    • Decreased Na+/H+ exchange in the proximal tubules
    • Thus increased sodium excretion and decreased water retention
    • Thus, potentiated effects of diuretics and decreased preload
  • Long term non-antihypertensive effects:
    • By restraining the degradation of angiotensin 1:
      • Anti-inflammatory effect on vascular smooth muscle
      • Anti-fibroproliferative effect on vascular smooth muscle
      • Thus, decreased hyperplasia of vascular smooth muscle
      • Thus, reduced rate of atheroscleoris
    • By reduced degradation of bradykinin:
      • Reduced proliferation of vascular endothelium
      • Reduced 
    • Anti-inflammatory effects:
      • Decreased upregulation of inflammatory receptors (VCAM-1, ICAM-1,  P-selectin) and downregulation of inflammatory mediator transcription
      • Thus, reduced endothelial inflammation
    • Decreased cardiac myocyte hypertrophy (indirectly, by suppression of aldosterone secretion)

References

Regulski, Milosz, et al. "Chemistry and pharmacology of angiotensin-converting enzyme inhibitors." Current pharmaceutical design 21.13 (2015): 1764-1775.

Miura, Shin-ichiro, Sadashiva S. Karnik, and Keijiro Saku. "Angiotensin II type 1 receptor blockers: class effects versus molecular effects." Journal of the Renin-Angiotensin-Aldosterone System 12.1 (2011): 1-7.

Salvador, Gabriel LO, et al. "Angiotensin-converting enzyme inhibitors reduce mortality compared to angiotensin receptor blockers: Systematic review and meta-analysis." European Journal of Preventive Cardiology 24.18 (2017): 1914-1924.