Inhibitors of the renin-angiotensin-aldosterone system

Question 1

ACE inhibitors act on the crucial enzyme that generates …………and mediates the breakdown of ……….. whereas the ARBs act directly by blocking the major ………. that responds to angiotensin-II stimulation.

Answer 1

ACE inhibitors act on the crucial enzyme that generates angiotensin II and mediates the breakdown of bradykinin, whereas the ARBs act directly by blocking the major angiotensin II receptor subtype 1 (AT-1 subtype) that responds to angiotensin-II stimulation.

Question 2

As the result of many careful long and large trials, it is now clear that ACE inhibitors give both primary and secondary protection from cardiovascular disease (CVD), thereby interrupting the vicious circle from risk factors to LV failure at many sites (Fig. 5-1).3

Answer 2

As the result of many careful long and large trials, it is now clear that ACE inhibitors give both primary and secondary protection from cardiovascular disease (CVD), thereby interrupting the vicious circle from risk factors to LV failure at many sites (Fig. 5-1).3

Question 3

The ARBs are very well tolerated, and have been shown in several but not all outcome trials to give benefits equal to those provided by the ACE inhibitors.

Answer 3

The ARBs are very well tolerated, and have been shown in several but not all outcome trials to give benefits equal to those provided by the ACE inhibitors.

Question 4

The final step in the RAAS, aldosterone, is increased in heart failure. Aldosterone inhibitors have additive protective effects to those of ACE inhibitors in heart failure and in high-risk postmyocardial infarction (MI) patients. The newer direct renin inhibitors are antihypertensive, but clinical outcome data are currently lacking.

Answer 4

The final step in the RAAS, aldosterone, is increased in heart failure. Aldosterone inhibitors have additive protective effects to those of ACE inhibitors in heart failure and in high-risk postmyocardial infarction (MI) patients. The newer direct renin inhibitors are antihypertensive, but clinical outcome data are currently lacking.

Question 5

Mechanisms of action of ACE inhibitors:

Logically, ACE inhibition should work by lessening the complex and widespread effects of angiotensin II (Table 5-1). This octapeptide is formed from its precursor, a decapeptide angiotensin I, by the activity of the ACE. ACE activity is found chiefly in ……….. but occurs in all vascular beds, including the coronary arteries.

Answer 5

Logically, ACE inhibition should work by lessening the complex and widespread effects of angiotensin II (Table 5-1). This octapeptide is formed from its precursor, a decapeptide angiotensin I, by the activity of the ACE. ACE activity is found chiefly in the vascular endothelium of the lungs, but occurs in all vascular beds, including the coronary arteries.

Question 6

Angiotensin I originates in the …… from angiotensinogen under the influence of the enzyme renin, a …… that is formed in the renal juxtaglomerular cells.

Answer 6

Angiotensin I originates in the liver from angiotensinogen under the influence of the enzyme renin, a protease that is formed in the renal juxtaglomerular cells.

Question 7

Classic stimuli to the release of renin include…?

Answer 7

(1) impaired renal blood flow as in ischemia or hypotension,
(2) salt depletion or sodium diuresis, and
(3) β-adrenergic stimulation.

Question 8

The ACE is a protease that has two zinc groups, only one of which participates in the high-affinity binding site that interacts with angiotensin I or with the ACE inhibitors. ACE not only converts angiotensin I to angiotensin II, but also inactivates the breakdown of ……..

Answer 8

The ACE is a protease that has two zinc groups, only one of which participates in the high-affinity binding site that interacts with angiotensin I or with the ACE inhibitors. ACE not only converts angiotensin I to angiotensin II, but also inactivates the breakdown of bradykinin.

Question 9

ACE inhibition is vasodilatory by decreased formation of ……. and potentially by decreased degradation of ……. (Fig. 5-2).

Answer 9

ACE inhibition is vasodilatory by decreased formation of angiotensin II and potentially by decreased degradation of bradykinin (Fig. 5-2).

Question 10

TABLE 5-1 Potential Pathogenic Properties of Angiotensin II

Answer 10

TABLE 5-1 Potential Pathogenic Properties of Angiotensin II

Question 11

Alternate modes of angiotensin II generation

Not all angiotensin II is generated by ACE. Non-ACE pathways, involving ……………., can also form angiotensin II, but their exact role is still the subject of controversy.

Answer 11

Alternate modes of angiotensin II generation

Not all angiotensin II is generated by ACE. Non-ACE pathways, involving chymaselike serine proteases, can also form angiotensin II, but their exact role is still the subject of controversy. One view is that more than 75% of the cardiac angiotensin II formed in severe human heart failure is formed by chymase activity, and that inhibition of chymase prevents cardiac fibrosis and limits experimental heart failure. However, because ARBs are not more efficacious than ACE inhibitors in heart failure, this view is not supported by the clinical trial data.

Question 12

Angiotensin II and intracellular messenger systems

There are many complex steps between occupation of the angiotensin II receptor and ultimate mobilization of calcium with a vasoconstrictor effect in vascular smooth muscle.

Answer 12

Angiotensin II and intracellular messenger systems

There are many complex steps between occupation of the angiotensin II receptor and ultimate mobilization of calcium with a vasoconstrictor effect in vascular smooth muscle.

Question 13

Occupation of the angiotensin II receptor stimulates the …….. (called phospholipase ….) that leads to a series of signals that activate a specialized enzyme, ………, that in turn evokes the activity growth pathways that stimulate ventricular remodelling.5 Phospholipase ……. also activates the…………. signaling pathway in blood vessels to liberate ………….from the intracellular sarcoplasmic reticulum to promote ……………..as well as cardiac and vascular …………………….

Answer 13

Occupation of the angiotensin II receptor stimulates the phosphodiesterase (called phospholipase C) that leads to a series of signals that activate a specialized enzyme, protein kinase C, that in turn evokes the activity growth pathways that stimulate ventricular remodelling.5 Phospholipase C also activates the inositol trisphosphate signaling pathway in blood vessels to liberate calcium from the intracellular sarcoplasmic reticulum to promote vasoconstriction as well as cardiac and vascular structural alterations.

Question 14

Angiotensin II receptor subtypes: The AT-1 and AT-2 receptors

There are at least two angiotensin II receptor subtypes, the ………. receptors (Fig. 5-3). Note the potentially confusing nomenclature: both receptors respond to angiotensin II, but are subtypes …… These link to separate internal signaling paths. Clinically used ARBs should be considered as AT-……blockers.

Answer 14

Angiotensin II receptor subtypes: The AT-1 and AT-2 receptors

There are at least two angiotensin II receptor subtypes, the AT-1 and AT-2 receptors (Fig. 5-3). Note the potentially confusing nomenclature: both receptors respond to angiotensin II, but are subtypes 1 and 2. These link to separate internal signaling paths.6 Clinically used ARBs should be considered as AT-1 blockers.

Question 15

The effects of angiotensin II acting via AT-1 receptors on the diseased heart and failing circulation are often regarded as adverse, such as stimulation of contraction, vasoconstriction, myocyte hypertrophy, fibrosis, and antinatriuresis.

Answer 15

The effects of angiotensin II acting via AT-1 receptors on the diseased heart and failing circulation are often regarded as adverse, such as stimulation of contraction, vasoconstriction, myocyte hypertrophy, fibrosis,7 and antinatriuresis.

Question 16

The effects of angiotensin II acting via AT-1 receptors on the diseased heart and failing circulation are often regarded as adverse, such as stimulation of contraction, vasoconstriction, myocyte hypertrophy, fibrosis, and antinatriuresis. In fetal life, these AT-1 receptors act as ……………, which explains why ACE inhibitors and ARBs are prohibited therapy in pregnancy.

Answer 16

The effects of angiotensin II acting via AT-1 receptors on the diseased heart and failing circulation are often regarded as adverse, such as stimulation of contraction, vasoconstriction, myocyte hypertrophy, fibrosis, and antinatriuresis. In fetal life, these AT-1 receptors act as teratogenic growth stimulators, which explains why ACE inhibitors and ARBs are prohibited therapy in pregnancy.

Question 17

The physiologic role of the AT-2 receptor includes the …… In adult life, the role of the AT-2 receptors is much less well understood and controversial, but could become more relevant in pathophysiologic conditions, the receptors being upregulated in hypertrophy and in heart failure and having a postulated protective function. Again, the comparable clinical results of ACE inhibitors and ARBs (see p. 145) raise questions about the importance of unopposed AT-2 stimulation with ARBs.

Answer 17

The physiologic role of the AT-2 receptor includes the inhibition of growth in the late fetal phase (growth can’t keep on forever). In adult life, the role of the AT-2 receptors is much less well understood and controversial, but could become more relevant in pathophysiologic conditions, the receptors being upregulated in hypertrophy and in heart failure and having a postulated protective function. Again, the comparable clinical results of ACE inhibitors and ARBs (see p. 145) raise questions about the importance of unopposed AT-2 stimulation with ARBs.

Question 18

Renin-angiotensin-aldosterone system

The major factors stimulating renin release from the juxtaglomerular cells of the kidney and, hence, angiotensin activation are (Fig. 5-4) ?

Answer 18

(1) a low arterial blood pressure (BP); (2) decreased sodium reabsorption in the distal tubule, as when dietary sodium is low or during diuretic therapy; (3) decreased blood volume; and (4) increased beta1-sympathetic activity.

Question 19

Stimulation of aldosterone by angiotensin II means that the latter stimulus releases the sodium-retaining hormone aldosterone from the adrenal cortex. Hence ACE inhibition is associated with aldosterone reduction and has potential indirect natriuretic and potassium-retaining effects. Aldosterone formation does not, however, stay fully blocked during prolonged ACE-inhibitor therapy. This late …… does not appear to compromise the antihypertensive effects achieved by ACE inhibitors; nonetheless, it might detract from the prolonged benefit of these agents in heart failure. In the RALES study, added low-dose spironolactone on top of diuretics and ACE inhibition reduced mortality (see p. 159).

Answer 19

Stimulation of aldosterone by angiotensin II means that the latter stimulus releases the sodium-retaining hormone aldosterone from the adrenal cortex. Hence ACE inhibition is associated with aldosterone reduction and has potential indirect natriuretic and potassium-retaining effects. Aldosterone formation does not, however, stay fully blocked during prolonged ACE-inhibitor therapy. This late “escape” does not appear to compromise the antihypertensive effects achieved by ACE inhibitors; nonetheless, it might detract from the prolonged benefit of these agents in heart failure. In the RALES study, added low-dose spironolactone on top of diuretics and ACE inhibition reduced mortality (see p. 159).

Question 20

Adverse effects of excess aldosterone

Aldosterone, released either in response to ….. or to stimulation by …… or increased ……., has major effects on electrolyte balance.

Answer 20

Adverse effects of excess aldosterone

Aldosterone, released either in response to angiotensin II or to stimulation by adrenocorticotropic hormone (ACTH) or increased potassium, has major effects on electrolyte balance.

Question 21

Aldosterone acts on the distal tubule to retain ….. and excrete …… by inhibition of …… (see Fig. 5-4). Water is retained with …….

Answer 21

Aldosterone acts on the distal tubule to retain sodium and excrete potassium by inhibition of sodium-potassium exchange (see Fig. 5-4). Water is retained with sodium.

Question 22

In heart failure, plasma aldosterone rises up to 20 times normal, in response to increased ……… coupled with decreased ……….. Aldosterone, some of it locally produced, may adversely alter the structure of the myocardium by promotion of ………… Aldosterone also promotes ……………

Answer 22

In heart failure, plasma aldosterone rises up to 20 times normal, in response to increased angiotensin II, coupled with decreased hepatic clearance. Aldosterone, some of it locally produced, may adversely alter the structure of the myocardium by promotion of cardiac fibrosis. Aldosterone also promotes endothelial dysfunction.

Question 23

Autonomic interactions of angiotensin II

ACE inhibitors have indirect permissive antiadrenergic effects. Angiotensin II promotes the release of ……… from adrenergic terminal neurons, and also enhances …………. by central activation and by facilitation of ganglionic transmission. Furthermore, angiotensin II amplifies the ………. achieved by ………-receptor stimulation. Thus angiotensin II has facilitatory adrenergic actions leading to increased activity of ………..

Answer 23

Autonomic interactions of angiotensin II

ACE inhibitors have indirect permissive antiadrenergic effects. Angiotensin II promotes the release of norepinephrine from adrenergic terminal neurons, and also enhances adrenergic tone by central activation and by facilitation of ganglionic transmission. Furthermore, angiotensin II amplifies the vasoconstriction achieved by alpha1-receptor stimulation. Thus angiotensin II has facilitatory adrenergic actions leading to increased activity of vasoconstrictor norepinephrine.

Question 24

Autonomic interactions of angiotensin II:

……..effects could explain why tachycardia is absent despite peripheral ……… The combined ………. mechanisms could contribute to the antiarrhythmic effects of ACE inhibitors and the reduction of sudden death in several trials in congestive heart failure (CHF), especially post-MI. An additional factor is probably better ……. retention (as a result of aldosterone inhibition).

Answer 24

Vagomimetic effects could explain why tachycardia is absent despite peripheral vasodilation. The combined antiadrenergic and vagomimetic mechanisms could contribute to the antiarrhythmic effects of ACE inhibitors and the reduction of sudden death in several trials in congestive heart failure (CHF), especially post-MI.10 An additional factor is probably better potassium retention (as a result of aldosterone inhibition).

Question 25

Kallikrein-kinin system and bradykinin

Besides decreased formation of angiotensin II, increased …… is another alternate site of action of ACE inhibitors (see Fig. 5-2; Table 5-2). This nonapeptide, originally described as causing slow contractions in the gut (hence the …… in the name) is of potential CV importance.

Answer 25

Kallikrein-kinin system and bradykinin

Besides decreased formation of angiotensin II, increased bradykinin is another alternate site of action of ACE inhibitors (see Fig. 5-2; Table 5-2). This nonapeptide, originally described as causing slow contractions in the gut (hence the brady in the name) is of potential CV importance.

Question 26

Bradykinin is inactivated by two kininases, …….. The latter is identical to ACE. ACE inhibition therefore also leads to …………bradykinin, as well as a reduction in angiotensin II production.

Answer 26

Bradykinin is inactivated by two kininases, kininase I and II. The latter is identical to ACE. ACE inhibition therefore also leads to increased local formation of bradykinin, as well as a reduction in angiotensin II production.

Question 27

Bradykinin acts on its receptors in the vascular endothelium to promote the release of two vasodilators (Table 5-2), ………………

Answer 27

Bradykinin acts on its receptors in the vascular endothelium to promote the release of two vasodilators (Table 5-2), nitric oxide and vasodilatory prostaglandins, such as prostacyclin and prostaglandin E2 (PGE2).

Question 28

Indomethacin, which inhibits prostaglandin synthesis, partially reduces the hypotensive effect of ACE inhibitors. The current concept is that bradykinin formation, occurring locally and thus not easily measured, can participate in the ……… effect of ACE inhibitors and may act via …….. to protect the endothelium.

These potentially favorable actions of an ACE inhibitor, mediated via bradykinin, would not occur with an ARB (but there would also be fewer adverse effects of bradykinin such as cough and angioedema).

Answer 28

Indomethacin, which inhibits prostaglandin synthesis, partially reduces the hypotensive effect of ACE inhibitors. The current concept is that bradykinin formation, occurring locally and thus not easily measured, can participate in the hypotensive effect of ACE inhibitors and may act via nitric oxide to protect the endothelium.

These potentially favorable actions of an ACE inhibitor, mediated via bradykinin, would not occur with an ARB (but there would also be fewer adverse effects of bradykinin such as cough and angioedema).

Question 29

ACE 2

A newly described enzyme, ACE 2, generates angiotensin-(1-7) (Ang-[1-7]) from angiotensin II. Ang-(1-7) acts on its vascular receptor to inhibit vasoconstriction and sodium retention11 and metabolize angiotensin II to Ang-(1-7). Ang-(1-7) antagonizes angiotensin II actions via the G-coupled Mas receptor.12 Genetic ablation of ACE 2 leads to heart failure in mice.13 ACE 2 also acts on angiotensin I to form Ang-(1-9).14 Ang-(1-9) blocks cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Ang-(1-9) infusion acted on the AT-2 receptor to lessen cardiac fibrosis in stroke-prone rats, thereby supporting a direct role for Ang-(1-9) in the renin-angiotensin system (RAS).14 Furthermore, Ang-(1-9) can be hydrolyzed to form Ang-(1-7).12 ACE 2 agonists may soon have clinical testing because similar paths exist in human heart tissue.15

Answer 29

ACE 2

A newly described enzyme, ACE 2, generates angiotensin-(1-7) (Ang-[1-7]) from angiotensin II. Ang-(1-7) acts on its vascular receptor to inhibit vasoconstriction and sodium retention11 and metabolize angiotensin II to Ang-(1-7). Ang-(1-7) antagonizes angiotensin II actions via the G-coupled Mas receptor.12 Genetic ablation of ACE 2 leads to heart failure in mice.13 ACE 2 also acts on angiotensin I to form Ang-(1-9).14 Ang-(1-9) blocks cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Ang-(1-9) infusion acted on the AT-2 receptor to lessen cardiac fibrosis in stroke-prone rats, thereby supporting a direct role for Ang-(1-9) in the renin-angiotensin system (RAS).14 Furthermore, Ang-(1-9) can be hydrolyzed to form Ang-(1-7).12 ACE 2 agonists may soon have clinical testing because similar paths exist in human heart tissue.15

Question 30

Tissue renin-angiotensin systems

Although the acute hypotensive effects of ACE inhibition can clearly be linked to decreased circulating levels of angiotensin II, during chronic ACE inhibition there is a reactive ………… linked to reemergence of circulating angiotensin II and aldosterone. Hence, the present proposal is that ACE inhibitors exert their sustained antihypertensive, favorable structural effects, and antiheart failure effects at least in part by acting on the……………. , lessening formation of angiotensin II within the target organ. Likewise, this is the proposed site of action, in addition to BP reduction, in the regression of left ventricular hypertrophy (LVH) and vascular remodeling (Fig. 5-5).

Answer 30

Tissue renin-angiotensin systems

Although the acute hypotensive effects of ACE inhibition can clearly be linked to decreased circulating levels of angiotensin II, during chronic ACE inhibition there is a reactive hyperreninemia linked to reemergence of circulating angiotensin II and aldosterone. Hence, the present proposal is that ACE inhibitors exert their sustained antihypertensive, favorable structural effects, and antiheart failure effects at least in part by acting on the tissue RASs, lessening formation of angiotensin II within the target organ. Likewise, this is the proposed site of action, in addition to BP reduction, in the regression of left ventricular hypertrophy (LVH) and vascular remodeling (Fig. 5-5).

Question 31

Cerebral effects and renin-angiotensin inhibitors

In patients with heart failure, central mechanisms play an important role in postinfarct remodelling.5 Do brain-penetrant renin-angiotensin inhibitors improve cognition? If so, such agents could preferentially be used in the therapy of hypertension in older adults. However, in ONTARGET and TRANSCEND, large double-blind studies with telmisartan, ramipril, and their combination, different approaches to blocking the RAS had no clear effects on cognitive outcomes.18 More specific prospective studies due to be presented soon are awaited.17

Answer 31

Cerebral effects and renin-angiotensin inhibitors

In patients with heart failure, central mechanisms play an important role in postinfarct remodelling.5 Do brain-penetrant renin-angiotensin inhibitors improve cognition?16,17 If so, such agents could preferentially be used in the therapy of hypertension in older adults. However, in ONTARGET and TRANSCEND, large double-blind studies with telmisartan, ramipril, and their combination, different approaches to blocking the RAS had no clear effects on cognitive outcomes.18 More specific prospective studies due to be presented soon are awaited.17

Question 32

Pharmacologic characteristics of ACE inhibitors

Major indications?

Answer 32

Major indications are heart failure, hypertension, acute and chronic MI, renoprotection, diabetic nephropathy and hypertension, and CV protection. ACE inhibitors play a major role in secondary CVD prevention (Table 5-3 and Fig. 5-6).

Question 33

Side effects of ACE inhibitors?

Answer 33

Cough remains as one of the most troublesome and common of the various side-effects (Fig. 5-7; see later, Table 5-6), some serious and some not.

Patients with heart failure often cough as a result of pulmonary congestion (which may need more rather than less ACE inhibitor), and in patients with hypertension such side effects are generally discovered only if volunteered. In some centers, the incidence of cough is thought to be as high as 10% to 15%, whereas others report a much lower incidence such as 5.5% in HOPE.19 The cough is due to an increased sensitivity of the cough reflex resulting in a dry, irritating, nonproductive cough, quite different from bronchospasm. Increased formation of bradykinin and prostaglandins may play a role because ARBs have a much lower incidence of cough. Several studies suggest relief of the cough by added nonsteroidal antiinflammatory drugs (NSAIDs),20 with the downside of diminished antihypertensive effects. Logically, and most often tried with success, a change to an angiotensin II receptor blocker consistently lessens the cough.21

Question 34

Side effects of ACE inhibitors?

Answer 34

Hypotension
Particularly in CHF, orthostatic symptoms caused by excess hypotension are common and may necessitate dose reduction or even cessation of ACE-inhibitor therapy. In general, so long as orthostatic symptoms do not occur, the absolute BP is not crucial and some heart failure patients do well with systolic pressures of 80 to 90 mm Hg.

Hyponatremia can be an indicator of heightened RAAS activity, and when present, there is an increased risk of hypotension (see later in this chapter).

Hyperkalemia is a risk, especially when ACE inhibitors are given with aldosterone antagonists, ARBs, or potassium-sparing diuretics, or in the presence of renal failure. A rough rule is that increasing RAAS block may improve the heart failure at the risk of increasing hyperkalemia. The RALES study showed the safety and efficacy of low doses of spironolactone when carefully added to β-blockers, ACE inhibitors, and diuretics in the therapy of severe systolic heart failure.22 Careful monitoring of serum potassium is essential because hyperkalemia is potentially lethal.

Question 35

Side effects of ACE inhibitors?

Answer 35

Renal side effects and hyponatremia

Reversible renal failure can be precipitated by hypotension, and hyponatremia is the most reliable sign of trouble. Predisposing characteristics are a fixed low renal blood flow as in severe CHF or severe sodium and volume depletion, or underlying renal disease, including renal artery stenosis. In these conditions, efferent glomerular arterial constriction resulting from angiotensin II may be crucial in retaining the glomerular filtration rate (GFR). Rarely, irreversible renal failure has occurred in patients with bilateral renal artery stenosis, a contraindication to ACE inhibitors. In unilateral renal artery disease, with high circulating renin values, ACE inhibitors may also cause excessive hypotensive responses with oliguria or azotemia. To obviate such problems, and especially when there is unilateral renal artery stenosis or a low sodium state, a low first test dose of the ACE inhibitor should be given, although this is seldom done. An arbitrary high value of serum creatinine is often taken as a contraindication (see later in chapter). A slight stable increase in serum creatinine after the introduction of an ACE inhibitor should not limit use. A 20% rise in creatinine should make one consider renal artery stenosis.

Question 36

Side effects of ACE inhibitors?

Answer 36

Angioedema
Although uncommon (approximately 0.3% in ALLHAT, rising to 0.6%-1.6% in black individuals),23,24 this condition can very rarely be fatal, the incidence of death increasing from 0 in a large study on 12,634 patients given enalapril for 24 weeks24 to approximately 1 in 5-10,000 patients.23,25 The mechanism depends on bradykinin,26 with a further contribution from impaired breakdown of substance P.27 The enzyme breaking down both peptides is dipeptidyl peptidase IV, which is inhibited by a group of antidiabetic drugs (see Chapter 11, page 451). Indirect evidence suggests increased angioedema in patients taking antidiabetics such as sitagliptin.27 For urgent therapy, prompt subcutaneous epinephrine and rarely even intubation may be needed.28 The ACE inhibitor must be stopped. Switching to an ARB may be considered,21 yet there are isolated instances of ARB-associated angioedema.

Question 37

ACE inhibitors: Contraindications

Answer 37

Contraindications include bilateral renal artery stenosis, pregnancy, known allergy or hypersensitivity, and hyperkalemia. Often a high serum creatinine of more than 2.5-3 mg/dL (220-265 μmol/L) is taken as an arbitrary cut-off point for the use of ACE inhibitors and for ARBs, especially in heart failure. However, patients with higher creatinine values might be evaluated in the context of the renoprotection that may be achieved and nephrologists might elect to start ACE inhibition with caution. Overall benefits can be attained with lesser degrees of renal insufficiency.30

Question 38

ACE inhibitors for heart failure.

Neurohumoral effects of overt heart failure?

Answer 38

A crucial problem in CHF is the inability of the left ventricle to maintain a normal BP and organ perfusion. Enhanced activity of the RAS (Fig. 5-8) follows from (1) hypotension, which evokes baroreflexes to increase sympathetic adrenergic discharge, thereby stimulating the beta1 renal receptors involved in renin release; (2) activation of chemoreflexes and ergoreflexes; (3) decreased renal perfusion resulting in renal ischemia, which enhances renin release; and (4) β-adrenergic simulation. However, even in compensated CHF, plasma renin may not be persistently elevated31 without simultaneous diuretic therapy. Angiotensin II promotes secretion of aldosterone and the release of vasopressin. Both contribute to abnormal fluid retention and volume regulation in severe CHF. Generally, such changes are thought to be adverse because of the resultant increased vasoconstriction, fluid and sodium retention, and dilutional hyponatremia.

Question 39

Neurohumoral effects of overt heart failure?

Answer 39

The peripheral vascular resistance is greatly increased. Thus the greater afterload against which the failing heart must work is explained by (1) increased formation of angiotensin II, (2) reflex release of norepinephrine, (3) release of vasoconstrictor endothelin from the dysfunctional vascular endothelium, (4) reduced muscle mass, (5) thickened capillary membranes, and (6) altered endothelial cell response to muscle metabolites. Systemic and renal vascular vasoconstriction reduces renal plasma flow, which detrimentally affects salt excretion and further promotes renin formation. Vasodilator hormones of cardiac origin such as atrial and brain natriuretic peptides (BNPs), and prostaglandins of vascular origin, are also activated, but fail to achieve compensatory vasodilation for complex reasons including receptor downgrading.

Question 40

Neurohumoral effects of overt heart failure?

Answer 40

The LV wall stress increases. Especially during exertion, both systolic and diastolic wall stresses become too high for the depressed contractility of the failing myocardium. The inability of the left ventricle to empty itself during systole increases the preload. The combination of increased pre- and afterload, so common in CHF, leads to progressive ventricular dilation with wall remodeling (myocyte hypertrophy and slippage with matrix changes) so that the ejection fraction progressively declines with time. Load reduction and in particular angiotensin II inhibition retards this detrimental remodeling process.32 According to Laplace’s law, the stress on the wall of a thin-walled sphere is proportional to the product of the intraluminal pressure and the radius, and inversely related to the wall thickness. Wall stress is one of the major determinants of myocardial oxygen uptake. Afterload and preload reduction, by decreasing the radius of the left ventricle, decreases the myocardial oxygen demand. ACE inhibition, by reducing the preload and the afterload, lessens excessive LV wall stress, limits remodeling, and enhances ventricular emptying.33 Inhibiting these factors improves the myocardial oxygen balance and attenuates further LV chamber enlargement.

Question 41

Neurohumoral effects of overt heart failure?

Answer 41

Beneficial neurohumoral effects of ACE-inhibitors are as follows: ACE inhibitors have a consistent effect in increasing plasma renin and decreasing angiotensin II and aldosterone, with a fall in norepinephrine, epinephrine, and in vasopressin. Angiotensin II production falls. Parasympathetic activity, reduced in heart failure, is improved by ACE inhibition. Although there are some exceptions to the patterns noted, most of the results are reasonably consistent. From these data it can be concluded that chronic ACE inhibition ameliorates the neurohumoral changes found in CHF.

Question 42

ACE inhibitors as preventative therapy in early LV dysfunction?

Answer 42

ACE inhibitors have earned their place as preventative therapy in early LV dysfunction, as shown for captopril in SAVE34 and enalapril in SOLVD.35 Longer-term 12-year follow up of such asymptomatic patients has revealed a mortality benefit of early ACE-inhibitor use.36 This mortality benefit of ACE inhibitors can be found even in the absence of initial diuretic therapy.37 Note the challenge posed by β-blockers to ACE inhibitors as first-line therapy in early chronic heart failure (see Chapter 6, p. 195).

Question 43

How do diuretics compare with ACE inhibitors?

Answer 43

In postinfarct patients without clinical heart failure but with modestly depressed LV function, the ACE inhibitor captopril was better able to maintain LV function and size than the diuretic furosemide.38 There could be many adverse effects of diuretics, including activation of the renin-angiotensin axis. Yet in overt LV failure and in CHF, diuretic therapy is still universally accepted as first-step therapy to reduce symptoms because diuretics are superior to ACE in diminishing sodium and water retention. There is no evidence that chronic diuretic therapy prolongs life, although it is clinically evident that an intravenous loop diuretic is life-saving when given to a patient with severe LV failure and pulmonary edema. Long term, it is now clear that ACE inhibitors prolong life, whereas digoxin does not, so that the automatic choice of agent to combine with a diuretic in CHF is an ACE inhibitor.

Question 44

Is it ok to combine ACE inhibitors plus β-blockers for heart failure?

Answer 44

Historically, ACE inhibitors came first in the therapy of heart failure, before β-blockers, which were better at reducing mortality. The consistently positive survival-prolonging results with bisoprolol,39 the MERIT study with metoprolol, and several carvedilol studies40 given in addition to ACE inhibitors were such that β-blockers are now viewed as an integral part of the standard therapy of heart failure. Thus the combination we should strive for is that of ACE inhibitors plus β-blockers. The β-blocker should be carefully introduced when the patient is stable, not when there is hemodynamic deterioration (see Table 1-2). Mortality reductions with β-blockers (relative risk of 0.68) was demonstrated with and without an ACE inhibitor and the combination was optimal (relative risk of 0.83).37 The β-blocker can be given first.39

Question 45

Potential problems with drug combinations in CHF: Diuretics plus ACE inhibitors.

Answer 45

Diuretics plus ACE inhibitors. Additive effects on the preload may lead to syncope or hypotension; thus the diuretic dose is usually halved before starting ACE inhibitors. The result may be a true diuretic-sparing effect in approximately half of patients with mild CHF following the addition of the ACE-inhibitor, whereas in others the full diuretic dose must be reinstituted.

Question 46

Potential problems with drug combinations in CHF:

ACE inhibitors plus spironolactone or eplerenone.

Answer 46

The major danger is hyperkalemia and the lesser is an increasing serum creatinine,22,41 so frequent checks are needed. Some safety guidelines to evaluate before using this combination are the prior use of potassium-retaining diuretics, a serum creatinine exceeding 2.5 mg/dL (220 μmol/L) or an estimated glomerular filtration rate (eGFR) of less than 30 (mL/min/1.73 m2 of body-surface area) and a serum potassium exceeding 5 mm/L. Sometimes the dose of the ACE inhibitor must be adjusted downward.

Question 47

Potential problems with drug combinations in CHF: ACE inhibitors and aspirin or NSAIDs

Answer 47

Formation of bradykinin and thereby prostaglandins may play an important role in peripheral and renal vasodilation. Hence, NSAIDs, especially indomethacin, lessen the effectiveness of ACE inhibitors in hypertension.42 Sulindac may have less effect and ARBs seem to interact less.42 In CHF the interaction with NSAIDs is less studied. Restrictions on renal blood flow invoked by NSAIDs are most likely to be serious in those with major renin-angiotensin inhibition receiving high-dose diuretics and with hyponatremia. If an NSAID has to be used in heart failure, frequent checks of renal function are required. In practice, low-dose (approximately 80 mg daily) aspirin is often combined with an ACE inhibitor in the therapy of ischemic heart failure.

Question 48

How to start an ACE inhibitor in severe heart failure

Answer 48

First the patient must be fully assessed clinically, including measurements of serum creatinine, eGFR, and electrolytes. It is important to avoid first-dose hypotension and thereby lessen the risk of temporary renal failure. Patients at high risk of hypotension include those with serum sodium levels less than 130 mmol/L, a increased serum creatinine in the range of 1.5 to 3 mg/dL or 135 to 265 μmol/L. Hyponatremia is serious. Patients with creatinine values exceeding 3 mg/dL should be considered separately (see later in this chapter). All these patients need to have diuretic therapy stopped for 1 to 2 days and are then ideally given a test dose under supervision. Alternatively, a low initial dose of enalapril (1.25 mg) or 2 mg of perindopril (with its slow onset of action) is given. If there is no symptomatic hypotension, the chosen drug is continued, renal function is monitored, and the dose gradually is increased. Absence of first-dose hypotension suggests but does not securely establish that the subsequent course will be smooth. If the patient is fluid overloaded with an elevated jugular venous pressure, then the test dose of the ACE inhibitor can be given without first having to stop diuretic therapy.

Question 49

How to start an ACE inhibitor in severe heart failure if there also is a preexisting renal failure?

Answer 49

Preexisting renal failure
In general, the serum creatinine can be expected to rise modestly and then to stabilize. In severe CHF, in which renal function is already limited by hypotension and by poor renal blood flow, it may be difficult to decide whether to introduce ACE-inhibitor therapy. For example, the serum creatinine may exceed 2.5-3 mg/dL or 220-265 μmol/L. The danger of exaggeration of renal failure must be balanced against the possible benefit from an improved cardiac output and decreased renal afferent arteriolar vasoconstriction resulting from ACE-inhibitor therapy. Problems can be expected, especially when the eGFR is low and the renin-angiotensin axis is highly stimulated. The best policy may be to improve the hemodynamic status as far as possible by the combined use of optimal doses of diuretics and other agents. Then the diuretic dose could be briefly reduced or stopped, and a very low dose of an ACE inhibitor introduced.

Question 50

How to start an ACE inhibitor in severe heart failure if there is also hyponatremia and salt and water limitation?

Answer 50

Patients with severe hyponatremia are 30 times more likely to develop hypotension in response to ACE-inhibitor therapy and require special care. The cause of the hyponatremia is, at least in part, release of vasopressin (antidiuretic hormone) as can result from renin-angiotensin activation following intense diuretic therapy. Vasopressin antagonists (see Fig. 4-4) may be tried to combat hyponatremia. Modest, tolerable salt restriction is standard practice. Patients already on strict low-sodium diets are at increased risk of first-dose hypotension. In patients who are not volume depleted, restriction of water intake is advisable because delayed water diuresis may contribute to hyponatremia in severe CHF.

Question 51

Outstanding clinical problems in the therapy of heart failure:

Answer 51

1.
Drug dose. Whereas in hypertension the dose-response curve is flat and can be monitored from the BP response, in CHF the problem of the optimal dose does arise. Is the dose large enough to give as complete renin-angiotensin inhibition as possible? Standard medium doses were not tested. In the case of enalapril, the standard target dose is 10 mg twice daily. Increasing this to 60 mg/day did not alter death rate nor hemodynamic parameters.43 In clinical practice lower doses than in the trials are commonly used. Although the optimal doses of ACE inhibitors in CHF have not been established by clinical studies, our opinion is that the dose should be titrated upward to the effective trial doses without going higher.

Question 52

Outstanding clinical problems in the therapy of heart failure:

Answer 52

2.
Diastolic dysfunction. Most heart failure studies have concentrated on the role of ACE inhibition in systolic failure. Diastolic failure is an early event, particularly in LVH in response to hypertension or aortic stenosis, as well as in older adults. Therapy remains challenging (see Chapter 6, p. 207).

Question 53

Outstanding clinical problems in the therapy of heart failure:

Answer 53

3.
Myopathies. The skeletal muscle myopathy found in heart failure is associated with increased proton production that stimulates the ergoreflexes that worsen the symptoms of exertional intolerance.44 The causes of the myopathy are not clear. Increased circulating angiotensin II may play a role. Clinical studies with ACE inhibitors or ARBs geared to this problem are still lacking, yet may be very difficult to interpret because deconditioning may play a prominent role in the skeletal weakness in heart failure,45 making exercise a more logical choice of therapy. In some patients there is a genetic link between heart failure and myopathy.46 In a small study on Duchenne muscular dystrophy, perindopril decreased mortality at 10 years.47

Question 54

Outstanding clinical problems in the therapy of heart failure:

Answer 54

4.
Anemia. A low hemoglobin is a poorly understood risk factor for CVD.48 A small decrease in hemoglobin to the order of 0.3 g/dL may occur and ACE inhibitors may be used therapeutically to treat the erythrocytosis that follows renal transplantation.49 Attention should be paid to the possible development of anemia during ACE inhibitor therapy, especially because anemia is now recognized as an adverse risk factor in heart failure.50 However, the development of anemia should generally not be attributed to an ACE inhibitor and other investigations should be pursued.

Question 55

ACE inhibitors for hypertension

Answer 55

The RAAS is one of several major mechanisms that help to maintain the BP both in normal persons and in persons with essential hypertension, especially when sodium is restricted or diuretics are in use. In malignant hypertension or in renal artery stenosis, renal ischemia stimulates the release of renin from the juxtaglomerular apparatus to increase the BP. Although ACE inhibition leads to the most dramatic falls of BP in the presence of such an underlying renal mechanism, ACE inhibition is also effectively antihypertensive in mild to moderate hypertension even when plasma renin is not high. ACE inhibitors lower BP by multiple mechanisms (see Fig. 7-9). In general, ACE inhibitors are more effective in white patients who also respond to β-blockers.51 Lesser BP efficacy in black patients, especially in older adults, can be overcome by addition of low-dose diuretics or higher doses of the ACE inhibitor. In the ALLHAT trial, the somewhat lesser efficacy of an ACE inhibitor than the diuretic23 may be ascribed to (1) the trial design, which did not allow addition of a diuretic; and (2) the relatively high proportion of black patients, approximately one third of the study population, in whom the lack of diuretic was more serious. In the Australian study on older white subjects, enalapril gave overall better results than did the diuretic at equal BP control.52 Because ACE inhibitors do not alter glucose tolerance, blood uric acid, or cholesterol levels with few side effects apart from cough, their use in hypertension has rapidly increased. Their ideal combination may well not be with a diuretic, as often thought, but with a calcium channel blocker (CCB), as in the ACCOMPLISH study.53