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Therapy of CHF: choices and controversies (Proceedings)

Article

Congestive heart failure (CHF) is not a primary disease; rather it is the manifestation of the failing heart that arises from neurohumoral compensation. The primary problems that underlie CHF can be diverse, but commonly involve myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) in dogs and hypertrophic cardiomyopathy in cats.

Congestive heart failure (CHF) is not a primary disease; rather it is the manifestation of the failing heart that arises from neurohumoral compensation. The primary problems that underlie CHF can be diverse, but commonly involve myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) in dogs and hypertrophic cardiomyopathy in cats. Despite the diversity of the underlying problems, the body's repertoire of compensatory responses is largely lacking in plasticity. Therefore, the spectrum of signs that are seen in CHF are generally similar, irrespective of the origin of cardiac disease, with circulatory congestion and the resulting edema being the cardinal sign of CHF. The first step in the formation of edema in CHF is a decrease in cardiac output (CO) as a result of the primary cardiac condition. This drop in CO may initially be quite mild and can be quickly normalized by the compensatory mechanisms. Initially, as CO falls, the resulting drop in blood pressure rapidly stimulates the adrenergic system, causing increased inotropy and arterial vasoconstriction. Stimulation of the adrenergic system can rapidly normalize a mild drop in CO. Meanwhile, renal arterial vasoconstriction decreases glomerular filtration rate (GFR) and stimulates renin release, with resulting activation of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II further contributes to vasoconstriction, whereas aldosterone and the fall in GFR increase the tubular reabsorption of sodium and water, increasing preload. The increased preload will further augment CO and a new equilibrium will be reached and temporarily maintained. This increase in preload will increase cardiac output by improving ventricular force in accordance with Starling's law of the heart. However, the increase in afterload will actually decrease cardiac output: . As the underlying cardiac abnormality worsens, falling CO and compensation also continue, until the resulting increase in preload overwhelms the ability of increased filling pressures in the ventricle to generate commensurately greater force according to Starling's law. The equation for CO given above will no longer strictly apply, as this equation operates within physiological constraints. In particular, increases in heart rate and preload will not indefinitely increase CO.

It is at this point that the exuberance of the compensatory mechanisms of the heart are operating to the detriment of the patient. The high preload contributes to both low plasma oncotic pressures and to high plasma hydrostatic pressures, such that the oncotic forces in the blood are insufficient to offset the hydrostatic pressures, resulting in leakage of fluid from the capillaries. As the neurohumoral pathways that promote and support CHF are generally similar between different etiologies of heart failure, symptomatic drug therapy for CHF also tends to be similar. Nevertheless, specific diseases do require that additional therapy be tailored to particular structural deficits. Therapy of CHF is generally palliative, as the underlying cause of most cardiac disease is beyond reach. As in other chronic, untreatable diseases, quality of life and financial issues will generally dictate the selection and duration of therapy. Symptomatic therapy to reduce edema is indicated. However, more direct pharmacological support for the failing heart, such as the use of positive inotropes, may also allow some amelioration of the primary problem, in the form of augmentation of cardiac function. Most cardiac drugs work on some factor or factors in the simplistic equation given above, with contractility, preload, and afterload being most amenable to treatment.

Preload can be rapidly reduced by the use of diuretics and nitrodilators. Nitroglycerin and nitroprusside are nitrodilators that act by stimulating the release of nitric oxide, which in turn relaxes vascular smooth muscle via the secondary messenger cGMP. Venodilation is predominant at low doses, but arterial vasodilation will also occur as the dose increases. Nitroglycerin appears to more specifically produce venodilation, and thus preload reduction, than does nitroprusside. As nitroprusside is administered intravenously, has a short duration of action, and can cause marked hypotension, it is used in the acute care setting. Nitroglycerin is usually administered as a topical gel in veterinary medicine, and tolerance rapidly develops, unlike in the case of nitroprusside. The most efficacious diuretics are the loop diuretics, furosemide and torsemide. Torsemide may be safer than furosemide, which is more likely to cause hypokalemia.1 The addition of a second mechanistic class of diuretic agent, such as a thiazide diuretic like chlorothiazide, will increase the diuretic effect. As these diuretic agents can result in hypokalemia, a potassium-sparing diuretic agent, such as spironolactone, may also be administered in combination with the more powerful diuretics. In addition to its potassium-sparing effects, spironolactone may have additional beneficial effects that result in reduced cardiac mortality in dogs with CHF.2

Afterload can be reduced using calcium channel blockers, hydralazine, and ACE inhibitors. Reduction of afterload can be expected to decrease peripheral vascular resistance and thus increase cardiac output. The calcium channel blockers include diltiazem and amlodipine and relax vascular smooth muscle by inhibiting voltage-gated calcium channels. This mode of action is also responsible for the negative inotropic side effect associated with these agents. Other side effects include hypotension and gastrointestinal side effects. In addition to afterload reduction, calcium channel blockers act as antiarrhythmic agents, slowing conduction through the AV node. These agents are particularly useful for the therapy of hypertension. In cats, diltiazem may improve cardiac function in cats with hypertrophic cardiomyopathy, but is associated with gastrointestinal side effects and weight loss at higher doses.3,4

Diltiazem appears to improve cardiac function in cats with hypertrophic cardiomyopathy, but is associated with gastrointestinal side effects and weight loss at higher doses.3,4 The dihydropyridine calcium channel blocker amlodipine is used to treat hypertension in cats, and it does appear to be effective for that purpose.5 Amlodipine induces less negative inotropy than does diltiazem, but is more likely to cause hypotension as a side effect. Hypertension can also be treated with the primary arterial vasodilator hydralazine. Hydralazine appears to alter calcium activity in the vascular smooth muscle cell. In addition to hypotension, tachycardia and gastrointestinal distress may occur. Hydralazine is used in conjunction with a diuretic agent to counter hydralazine's indirect stimulation of the RAAS. Hydralazine use in CHF has been largely supplanted by the advent of the ACE inhibitors, such that its use is generally reserved for those patients that respond poorly to ACE inhibitors.

Both preload and afterload can be reduced by the ACE inhibitors. These agents inhibit angiotensin converting enzyme, decreasing the formation of angiotensin II from angiotensin I. Enalapril is approved for the treatment of heart failure in dogs in the U.S., whereas benazepril is approved in other countries, such as the U.K., for use in dogs and cats. Enalapril and benazepril are widely used and well-studied in dogs with CHF. Several well-controlled, multi-center clinical trials have shown increased survival associated with enalapril therapy as compared to standard therapy (furosemide +/- digoxin) in dogs with CHF due to mitral regurgitation or dilated cardiomyopathy.6,7 Benazepril therapy has been found to reduce signs of disease due to CHF in dogs and cats, but there is little available evidence supporting a reduction in mortality.8,9 The use of ACE inhibitors for the prevention of disease in dogs with early valvular heart disease (prior to the development of CHF) is controversial. Whereas there are contradictory results regarding the efficacy of enalapril to delay the onset of CHF in dogs with valvular disease, the drug does not appear to improve survival in this setting.10,11 Enalapril and benazepril differ with respect to their route of clearance, with the active metabolite of benazepril, benazeprilat, being cleared by the kidneys to a greater extent than is enalaprilat. This difference in disposition may favor the use of benazepril in the patient with hepatic disease. Although both enalapril and benazapril are prodrugs that require hepatic metabolism for activation, other ACE inhibitors, such as captopril and lisinopril, are not prodrugs.

Positive inotropic drugs are those that increase cardiac contractility, such as the 1-adrenergic agonists, phosphodiesterase inhibitors, and cardiac glycosides. The most potent inotropes are the 1-agonists, of which, Dobutamine and dopamine are most commonly used for the acute control of decompensated cardiac failure and cardiogenic shock. These catecholamines act on G-protein receptors to stimulate adenyl cyclase and increase intracellular concentrations of the secondary messenger, cAMP. The side effects associated with these agents are similar to those of the endogenous catecholamine, epinephrine, and include ectopic beats, tachycardia, and hypertension. The β1-adrenergic agonists are not used long-term due to the potential for adverse effects and the very short elimination half-life of these agents that necessitate CRIs. Therefore, the phosphodiesterase inhibitors were developed to be positive inotropes that could be administered chronically. The phosphodiesterase inhibitors currently in use for the therapy of CHF are milrinone, inamrinone, and pimobendan. By inhibiting the enzyme phosphodiesterase (PDE III), these drugs prevent the breakdown of cAMP, the secondary messenger for the adrenergic metabotropic receptor. Milrinone and inamrinone increase cardiac contractility and cause arterial vasodilation, which are beneficial in the emergency treatment of cardiogenic shock. However, the inhibition of PDE III also produces some β1-adrenergic like effects, and may be responsible for their pro-arrhythmic side effects in humans. The vasodilatory effect may also cause hypotension. As milrinone and inamrinone are presently only available in injectable formulations, they are used for short-term management of cardiogenic shock. Enthusiasm for the veterinary use of milrinone and inamrinone has been dampened by their propensity to cause sudden death (probably due to arrhythmias) in humans. A phosphodiesterase inhibitor that is much more widely used in veterinary medicine is pimobendan, which both inhibits PDE III and has the added effect of sensitizing the heart to calcium. Pimobendan is thus a positive inotrope and a vasodilator, or inodilator. Pimobendan has been recently approved in the U.S. for oral administration to dogs with heart failure. Pimobendan extended survival time in Doberman Pinchers with dilated cardiomyopathy when co-administered with furosemide and enalapril, but did not impact survival in English Cocker Spaniels.12 Other trials have indicated superior survival times with pimobendan as compared to the ACE inhibitors ramipril and benazepril.13-15 Despite these successes, there is lingering concern about the potential of pimobendan to produce arrhythmias or to negatively affect cardiac remodeling in dogs with subclinical valvular disease. A recent paper that claims that chronic pimobendan therapy negatively affects the progression of valvular disease in beagles has spurred considerable debate.16 Although the study was prospective, its reliability was questioned due to the small sample size, lack of a control group, choice of study breed, and the possibility of a conflict of interest. While the possibility that pimobendan has negative effects on the heart when long-term, therapeutic doses are given is worth considering, this hypothesis would seem to require further testing before gaining widespread acceptance, especially in light of the benefits reported in the larger clinical trials with pimobendan therapy.

The cardiac glycosides include digoxin and digitoxin, but digoxin is most commonly used, partly because there was once a U.S. veterinary product approved for use in dogs with heart failure. Unfortunately, this veterinary product is no longer available, although both digoxin and digitoxin are still available as human drugs. The cardiac glycosides appear to act by a rather convoluted mechanism of action: the Na+, K+ -ATPase is inhibited, which results in increased intracellular Na+. Therefore, extracellular Ca++ is exchanged for the intracellular Na+, resulting in increased intracellular concentrations of Ca++. The increased intracellular calcium concentrations finally produce the desired effect of increased force of cardiac contractions due to the related increase in Ca++ release from the sarcoplasmic reticulum during cardiac muscle contraction, which in turn shifts troponin/tropomyosin and increases actin and myosin contact. Digoxin therapy is generally thought to increase cardiac output without increasing myocardial energy consumption, because the alterations in intracellular calcium provide greater mechanical advantage that compensates for the increase in work. Digoxin therapy produces a reduction in blood volume, venous pressure, and heart size with lower end systolic volume and a beneficial negative chronotropic effect. Dixon is generally given orally, due to adverse effects with IV administration. Following oral dosing, peak concentrations are reached in about one hour, and are maintained throughout a 12 hour dosing interval due to the long but variable elimination half-life of 14-56 hours in dogs. Digoxin can be associated with considerable toxicity, with arrhythmias such as heart block and ectopic beats being the most worrying. However, signs of gastrointestinal upset can precede more severe toxicity. Due to the narrow therapeutic index and variable elimination of digoxin, therapeutic drug monitoring is recommended. The target serum free drug concentration is generally 0.9 – 3.0 ng/ml in dogs and 0.9 – 2.0 ng/ml in cats, and the first samples are typically collected one week after beginning therapy to allow time for steady state to be reached. A trough sample is usually submitted, but a peak may be indicated if toxicity is suspected. Despite its long historical use, the current place of digoxin in the therapy of CHF is somewhat uncertain. Evidence for a reduction of mortality in dogs and cats treated with digoxin is lacking, and digoxin therapy may increase the risk of sudden death (presumably due to pro-arrhythmic effects) in humans.17 However, like furosemide, digoxin was a component of several of the clinical trials that demonstrated the efficacy of drugs like enalapril and pimobendan.6,7,12 As the effects of digoxin therapy were not specifically isolated from those of enalapril and pimobendan, it may be that the combination of digoxin with ACE inhibitors, pimobendan, and diuretic agents contributes to improved longevity in some of the dogs with CHF.

REFERENCES

1. Caro-Vadillo A, Ynaraja-Ramirez E, Montoya-Alonso JA. Effect of torsemide on serum and urine electrolyte levels in dogs with congestive heart failure. Vet Rec 2007;160(24):847-8.

2. Bernay F, Bland JM, Haggstrom J, et al. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease. J Vet Intern Med 2010;24(2):331-41.

3. Bright JM, Golden AL, Gompf RE, et al. Evaluation of the calcium channel-blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Intern Med 1991;5(5):272-82.

4. Wall M, Calvert CA, Sanderson SL, et al. Evaluation of extended-release diltiazem once daily for cats with hypertrophic cardiomyopathy. J Am Anim Hosp Assoc 2005;41(2):98-103.

5. Snyder PS. Amlodipine: a randomized, blinded clinical trial in 9 cats with systemic hypertension. J Vet Intern Med 1998;12(3):157-62.

6. Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213(11):1573-7.

7. Woodfield JA, Bauer TG, Ettinger SJ, et al. Controlled clinical-evaluation of enalapril in dogs with heart-failure - results of the cooperative veterinary enalapril study-group. J Vet Intern Med 1995;9(4):243-252.

8. Taillefer M, Di Fruscia R. Benazepril and subclinical feline hypertrophic cardiomyopathy: a prospective, blinded, controlled study. Can Vet J 2006;47(5):437-45.

9. Kitagawa H, Wakamiya H, Kitoh K, et al. Efficacy of monotherapy with benazepril, an angiotensin converting enzyme inhibitor, in dogs with naturally acquired chronic mitral insufficiency. J Vet Med Sci 1997;59(7):513-20.

10. Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc 2007;231(7):1061-9.

11. Kvart C, Haggstrom J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med 2002;16(1):80-8.

12. Fuentes VL, Corcoran B, French A, et al. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med 2002;16(3):255-261.

13. Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc 2006;42(4):249-261.

14. Smith PJ, French AT, Van Israel N, et al. Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease. J Small Anim Pract 2005;46(3):121-130.

15. Haggstrom J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med 2008;22(5):1124-35.

16. 1Chetboul V, Lefebvre HP, Sampedrano CC, et al. Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. J Vet Intern Med 2007;21(4):742-53.

17. Gavaghan BJ. Is there still a role for digoxin in the treatment of cardiac disease? Aust Vet J 2000;78(8):528-9.

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