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CHF: What works and what doesn't? (Proceedings)


Congestive heart failure (CHF) is not a primary disease; rather it is the clinical manifestation of the failing heart and describes a syndrome characterized by complex interactions of the heart with neurohumoral compensatory responses.

Congestive heart failure (CHF) is not a primary disease; rather it is the clinical manifestation of the failing heart and describes a syndrome characterized by complex interactions of the heart with neurohumoral compensatory responses. 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 cardiac 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. During this initial phase, falling CO results in a decrease in blood pressure, which rapidly stimulates the adrenergic system. Sympathetic stimulation can rapidly normalize a mild drop in CO via increased inotropy and heart rate; however, in order to preserve blood flow to the heart and brain, arterial vasoconstriction also occurs. 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 initially 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 produce a proportionate increase CO.

It is at this point that the exuberance of the compensatory mechanisms of the heart is 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 aid particular structural deficits. Therapy of CHF is generally palliative, as the underlying cause of most cardiac disease cannot be addressed. 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 pharmacological manipulation.

Therapies to reduce preload and afterload

Primarily consist of diuretics, nitrodilators, calcium channel blockers, hydralazine, and ACE inhibitors. The most efficacious diuretics are the loop diuretics, furosemide and torsemide. Torsemide may be safer than furosemide, as furosemide is more likely to cause hypokalemia. The addition of a second mechanistic class of diuretic agent, such as chlorothiazide, may be necessary to 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. 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 that must be monitored, 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.

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. 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. and is also commonly used in cats, 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 with enalapril therapy as compared to standard therapy (furosemide ± digoxin) in dogs with CHF due to mitral regurgitation or dilated cardiomyopathy. 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. 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. 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 over enalapril 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.

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. Diltiazem appears to improve cardiac function in cats with hypertrophic cardiomyopathy, but is associated with gastrointestinal side effects and weight loss at higher doses. The dihydropyridine calcium channel blocker amlodipine is used to treat hypertension in cats, and it does appear to be effective for that purpose. Amlodipine induces less negative inotropy than does diltiazem, but is more likely to cause hypotension. 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.

Positive inotropic

Drugs are those that increase cardiac contractility, such as the β1-adrenergic agonists, phosphodiesterase inhibitors, and cardiac glycosides. The most potent inotropes are the β1-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 constant rate infusion. Therefore, the phosphodiesterase inhibitors were developed to be positive inotropes that could be administered orally for chronic therapy. 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. Other trials have indicated superior survival times with pimobendan as compared to the ACE inhibitors ramipril and benazepril. 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 hastened the progression of valvular disease in beagles has spurred considerable debate. 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 administered is worth considering, this hypothesis would seem to require further testing before affecting clinical use, especially in light of the benefits ascribed to pimobendan therapy reported in several large clinical trials in symptomatic dogs.

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: digitalis inhibits the Na+, K+-ATPase, which results in increased intracellular Na+. Therefore, extracellular Ca++ is exchanged for the intracellular Na+, resulting in increased intracellular concentrations of Ca++. This increase in intracellular calcium concentrations finally produces the desired effect of increased contractility 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 as a consequence of a decrease in end systolic volume and a beneficial negative chronotropic effect. Digoxin is generally given orally, due to adverse effects associated with IV administration. Following oral dosing, peak concentrations are reached at about one hour and are maintained throughout a 12 hour dosing interval due to the long but variable elimination half-life (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, the milder signs of gastrointestinal upset can precede more severe toxicity. Due to the narrow therapeutic index and variable elimination rate 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. However, like furosemide, digoxin was a component of several of the clinical trials that demonstrated the efficacy of drugs like enalapril and pimobendan. 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.


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