CHF and ANGIOTENSION

     As the only common cardiovascular condition increasing in incidence, prevalence, and mortality, congestive heart failure (CHF) has been the subject of increased interest among researchers evaluating various therapeutic options on clinical endpoints. Treating major risk factors like hypertension and atherosclerosis effectively has been shown to help prevent CHF, delay progression, and improve survival of CHF.
     Diuretics remain essential for patients with fluid retention; but they typically fail to prevent progression or improve prognosis. Addition of digoxin in symptomatic CHF due to systolic dysfunction tends to retard progression without improving survival. Addition of angiotensin-converting enzyme (ACE) inhibitors, on the other hand, has been shown to both decrease mortality and retard progression; and they are recommended as early therapy in left ventricular dysfunction, whether symptomatic or asymptomatic. Combinations of hydralazine and isosorbide dinitrate are typically less effective than ACE inhibitors.
     Digoxin can reduce the risk of exacerbation irrespective of rhythm, systolic function, severity of CHF, or addition of ACE inhibitors; but other oral inotropic agents like amrinone, pimobendan, vesnarinone, and ibopamine increase mortality significantly and fail to improve other clinical endpoints during long-term therapy. While amlodipine and mibefradil appear relatively safe treatments of angina or hypertension in CHF, calcium antagonists, in general may actually increase mortality in CHF. Use of amiodarone is gaining popularity for patients with sustained ventricular tachycardia or ventricular fibrillation; but antiarrhythmic agents should generally be avoided in the absence of arrhythmia.
     The beta-blockers, carvedilol and metoprolol, have been shown to prolong survival and retard progression in combination with digoxin, diuretics, and ACE inhibitors; and recent studies support the use of spironolactone to current treatment recommendations.
Halawa B. Trends in pharmacological treatment of congestive heart failure]
Pol Merkuriusz Lek 1999 Mar 6:33 152-6.

Background
Autonomic Nervous Involvement
     Elevated plasma levels of norepinephrine (NE) are a hallmark of CHF, both at rest and during exercise, that is associated with deteriorating prognosis. The heart and kidneys produce about 60% of the excess. The ratio of release rate versus clearance rate (spillover) in symptomatic failure is twice that of non-CHF individuals, with a decrease in clearance of about 30%. This elevation is due in part, to a loss of tonic inhibitory control of central sympathetic activity from cardiopulmonary baroreceptors in the failing heart, resulting in a generalized increase in basal sympathetic outflow, significant for at least these two important reasons:

1. Apoptosis -- Unlike in other tissues, where cells undergo mitosis to replenish the ranks of demised cells, myocytes lose this ability between 3 and 6 months after birth. Thus, as myocytes die, they are not replenished. Since the individual’s complement of myocytes remains the same chronological age as the individual, the likelihood of developing CHF increases with age from about 18% in one’s fifties to almost 60% by age 70.
     Apoptosis, or programmed cell suicide, is a genetically programmed process abnormally triggered by several aspects of CHF. Elevations in levels of angiotensin II and other growth factors, persistent elevations in cardiac intracellular calcium (due to dilated cardiomyopathy), monocyte hypoxia (due to left ventricular hypertrophy), and elevations in basal sympathetic outflow all accelerate rates of apoptosis.

2.  The heart depends primarily upon beta-1 adrenergic support to meet both basal and sustained hemodynamic demands. The constant exposure to adrenergic stimulation by elevated NE levels a) reduces the sensitivity and response of cardiac functional beta-1 receptors, b) reduces the production and number of functional receptors, and c) perpetuates cellular calcium overload, leading to cardiotoxicity.

The Renin-Angiotensin-Aldosterone System      
     The roles of the Renin-Angiotensin-Aldosterone system in regulating 1) fluid and electrolyte balance, 2) vascular smooth muscle tone, and 3) growth of smooth and cardiac muscle make it a logical target for pharmacological intervention in congestive heart failure (CHF) as well as hypertension. In brief:      Renin, an enzyme produced and stored in the renal juxtaglomerular apparatus, catalyzes production of Angiotensin I (a peptide) from Angiotensinogen, a glycoprotein supplied from the liver, kidney, brain, and lipoid and other tissues. Angiotensin Converting Enzyme (ACE) is a non-specific enzyme that catalyzes hydrolysis of numerous peptides in various tissues; but of course the conversion important to this discussion is that of Angiotensin I to Angiotensin II, the primary vasoactive entity in the system. Angiotensin II also stimulates adrenal delivery of aldosterone, which helps to regulate sodium/potassium/fluid homeostasis by stimulating potassium secretion and sodium reabsorption.

Table 1 (under construction)

Kidney Renin Angiotensin Converting Enzyme


Angiotensinogen Angiotensin I Angiotensin II



Adrenals Vasoconstriction

Aldosterone

Angiotensin II Pharmacology in CHF      
     While Angiotensin I-7, Angiotensin III and Angiotensin IV also have some activity, Angiotensin II is by far the most active and exerts its pharmacological effects primarily on AT1 receptors. Angiotensin III exerts effects similar to but generally weaker than those of Angiotensin II; Angiotensin I-7 exerts comparable effects in the central nervous system, but none peripherally; and Angiotensin IV is believed to help regulate cerebral blood flow, acting only on AT4 receptors there. AT2 receptors, most prolific in neonatal tissues are thought to function in growth regulation and vascular smooth muscle differentiation. Recent studies suggest that the AT2 receptor may have some counter-regulatory protective function involving bradykinin and nitric oxide against the antinatriuretic and pressor actions of AT1 stimulation.      
     Angiotensin II increases the release of norepinephrine in response to low-frequency sympathetic stimulation, acting at presynaptic receptors of postganglionic sympathetic neurons. It also has direct stimulatory action on sympathetic ganglia and the adrenal medulla, the latter increasing aldosterone secretion without increasing glucocorticoid production. Increases in both arterial and peripheral blood pressure are thought to result from central efferent sympathetic activity as well as direct receptor-mediated contraction of vascular smooth muscle.      
     Normal increases in circulating aldosterone and angiotensin are essential for maintaining homeostasis as changes in sodium and water volume occur. Abnormal sustained elevations, though, disrupt the homeostasis to cause hypertension and CHF. Resulting “salt-avid” renal function leads to both intravascular and interstitial fluid overload that overworks the heart; while peripheral edema and congested organs tax the whole circulatory system, reducing the efficiency of most organ systems.
    While reflex bradycardia often causes reduced cardiac output, Angiotensin II increases vascular endothelial permeability to contribute to edema. Angiotensin II also tends to generate hyperplasia of cardiac fibroblasts and myocytes and vascular smooth muscle; and it perpetuates hypertrophy via protein deposition in these tissues as well. The heart and vasculature undergo progressive changes that thus perpetuate the condition. Angiotensin II often increases thirst by central nervous stimulation and exerts antinatriuretic and antidiuretic effects to ultimately increase fluid volume, all further contributing to the pathophysiologies of hypertension and CHF.

Casis L. The Renin-Angiotensin System and Other Vasoactive Substances. Modern Pharmacolgy With Clinical Applications, Fifth Edition. Little, Brown and Company, 1997. Yamada H, Akishita M, Ito M, Tamura K, Daviet L, Lehtonen JY, Dzau VJ, Horiuchi MAT2 receptor and vascular smooth muscle cell differentiation in vascular development. Hypertension 1999 Jun 33:6 1414-9.
Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A 1999 May 25 96:11 6506-10. Weber T. Aldosterone and spironolactone in Heart Failure. NEJM Editorial. http://www.nejm.org/content/weber/1.asp. Downloaded 7-30-99.

Spironolactone Added to CHF Treatment Recommendations      
     Treatment strategies aim to increase survival by preventing or delaying progression. Diuretics have long been the standard first-line therapy, as reducing fluid overload is essential for ameliorating symptoms; but diuretics generally fail to arrest progression or improve survival. Having recognized the involvement of Angiotensin II and aldosterone in CHF, established treatment guidelines have included an ACE inhibitor and a loop diuretic, either with or without digoxin for New York Heart Association CHF classes II or IV.
     Studies have shown the value of such combinations, with both progression and mortality effectively reduced by adding an ACE inhibitor to the standard regimen. Where systolic dysfunction is present, combinations of digoxin and a diuretic often retard progression but fail to improve survival. ACE inhibitor therapy is now recommended early in treatment of even asymptomatic left ventricular failure. The assumption is that limiting the production of Angiotensin II logically limits the ensuing production of aldosterone as well, thus attacking the problem from several directions and helping to restore homeostasis.
     Other studies, though, have shown ACE inhibition only partially and transiently effective at blocking production of Angiotensin II and ensuing reductions in aldosterone levels. Identification of other pathways utilizing enzyme systems other than ACE in various tissues to generate Angiotensin II have helped to explain such breakthrough production. These avenues have been identified in the heart, the aorta, and other vasculature and utilize tissue plasminogen activator (tPA), cathepsin G, tonin, elastase, and chymase to produce Angiotensin II directly from angiotensinogen without the intermediary angiotensin I, completely subverting the efficacy of ACE inhibitory agents. Recent evidence suggests that ACE inhibitors actually reflexively increase total tissue and serum ACE concentrations.
     Since doses of ACE inhibitors are frequently limited by side effects, and in light of the above-mentioned mechanisms of angiotensin II escape, addition of an AT1 receptor antagonist to the regimen can both improve and prolong reductions. Substitution of the AT1 receptor antagonist (as opposed to addition to existing regimens) can also often provide improvement over ACE inhibition alone.
     Aldosterone levels in the CHF patient, that may approach 20 times those in normal individuals, may remain high in spite of all efforts to suppress the action of Angiotensin II, as other reasons for aldosterone elevations become important factors.
*  Aldosterone secretion independent of Angiotensin II activity continues in response to potassium levels.
*  Sodium restriction below 3 grams per day, and even physical activity can increase renin production beyond the capabilities of ACE inhibition and/or AT1 blockade to compensate.
*  CHF often reduces the capacity of the liver to eliminate aldosterone and its active metabolites effectively.
    As with Angiotensin II, long-term elevations in aldosterone levels stimulate proliferation of fibroblasts to remodel the heart, blood vessels, and other organs.

     A new study reported in the New England Journal of Medicine has evaluated the benefits suppressing the effects of this breakthrough aldosterone with spironolactone. In CHF patients already taking an ACE inhibitor, a diuretic, and possibly digoxin, adding spironolactone, even in small doses, was shown to reduce the risk of death by 30%. Further it reduced hospitalizations for progressing CHF by 35%.
     The results are considered so important that the NEJM posted the report on its web site in advance of publication, a measure taken only rarely when a report is expected to greatly impact the lives of many people.

http://www.nejm.org/content/pitt/1.asp
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Beta-Blockers in CHF
     Beta-blockers have been long avoided in CHF due to their negative inotropic tendencies; but some patients with CHF may benefit from adding specific beta-blockers to standard regimens, as much of the myocardial damage seen with CHF may be related to sympathetic activation.
     Though beta-blockers are not recommended as first-line therapy and should not be used for acute failure, studies have shown symptomatic and hemodynamic improvements with beta-1 selective agents, particularly among patients with idiopathic dilated cardiomyopathy. Strong evidence suggests that beta-blockers retard progression of left ventricular dilatation and even improve left ventricular ejection fraction after several months of treatment, with predictive value for survival. Patients with NYHA II-III CHF due to nonischemic cause are particularly apt to benefit from beta-blockade.      
     Metoprolol, as a selective beta-1 blocker, is often used as adjunctive therapy in CHF. Carvedilol is a multiple-action neurohormonal agent that bears the official indication for CHF, and with non-selective beta effects as well as alpha-adrenergic blockade, it is effective in nonselective beta-blockade and vasodilation. Via blockade of beta1-, beta2-, and alpha1-adrenoceptors, carvedilol reduces total peripheral vascular resistance and preload without significantly reducing cardiac output or causing reflex tachycardia.       Formation of oxygen free radicals is associated with apoptosis, which is implicated in the continued loss of myocardial cells and causing progressive decrease in left ventricular function. Since carvedilol is a potent antioxidant, it may actually prevent some of the damage produced by oxygen radicals to inhibit apoptosis in the myocardium. In clinical trials, carvedilol decreased mortality by 65%.
     A significant correlation is observed between plasma immunoreactive endothelin-1 (ET-1) levels and the severity of CHF. Carvedilol also directly inhibits the biosynthesis of endothelin-1. Endothelins, the most potent vasoconstrictors known, are currently subjects of intense study. The 3 endothelins are neurohormonal peptides (ET1, ET2, and ET3) with different affinities for 2 major known receptors (ETA and ETB). Elevated levels of ET-1 are seen in CHF, with known association with positive inotropic effects and to induction of hypertrophy in cardiomyocytes. In addition, both the ETA- and ETB-receptor systems are greatly accelerated in the failing heart.
     ET-1 is produced from big ET-1 by endothelin-converting enzyme (ECE), and elevated plasma levels of both big ET-1 and ET-1 are negatively associated with survival in patents with CHF, similar to the situation with the Angiotensins and aldosterone. Elevations in endogenous ET-1 levels produce arterial vasoconstriction, slow LV relaxation, and depress LV contractile performance. In one recent animal study, ETA receptor antagonism produced greater in CHF than ECE inhibition, but ECE inhibition reduced production of neurohumoral factors activated in proportion to CHF severity. ET-1 also plays an important role in cardiomyopathy, so ETA antagonists may help reduce progression of CHF due to cardiomyopathy.
     One recent study estimates the cost of improved survival because of carvedilol therapy at some $29,000 per year on a single-patient basis. In spite of all the apparent advantages of carvedilol, one recent study discovered virtually no difference between outcomes with carvedilol and metoprolol. Both reduced mortality and progression, but metoprolol, at substantially lower cost, produced the same results as the more costly agent. The theoretical advantages of the multiple-action neurohormonal agent evidently do not add up to more effective therapy or superior outcomes.

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