Potential therapeutic strategies

By | 2011-12-12

Aldosterone antagonists The neurohormonal hypothesis of heart failure gains further support from the fact that the aldosterone antagonist spironolactone has proved efficacious in the management of severe heart failure in humans. Studies have recognized that small concentrations of aldosterone can stimulate cardiac fibroblast expression of type 1 and type III collagen, thereby promoting myocardial fibrosis. Although angiotensin-converting enzyme Inhibitors are considered effective at reducing aldosterone levels by inhibiting the formation of aldosterone’s primary secretagogue, angiotensin II, there is mounting evidence of a phenomenon called aldosterone escape. Increased potassium levels induced by angiotensin-converting enzyme inhibitors and decreased hepatic clearance may contribute to this RAS-independent increase in aldosterone. It also has become apparent that local tissue pathways for the production of aldosterone exist in extra-adrenal sites, although the importance of these tissue pathways has not been clarified. Because aldosterone impairs normal vasodilative responses, promotes myocardial fibrosis, potentiates the sympathetic nervous system, and influences electrolyte transport, a recent strategy to target heart failure has been the administration of aldosterone antagonists.

Addition of the aldosterone antagonist spironolactone to the baseline therapy of patients with severe heart failure produced a 30% reduction in mortality and a 35% reduction in the frequency of hospitalization for worsening heart failure. Although identification of the mechanism by which spironolactone exerts its beneficial effects was not the aim of the Randomized Aldactone Evaluation Study (RALES) group, a small substudy of 261 participants suggests that limitation of aldosterone-stimulated collagen synthesis is the major contributor. In a recent model of experimental heart failure created in dogs, the aldosterone antagonist eplerenone was able to attenuate the development of interstitial fibrosis and cardiomyocyte hypertrophy while increasing capillary density. Although the frequency and likelihood of aldosterone escape are unknown in dogs treated with angiotensin-converting enzyme inhibitors, it seems prudent to consider spironolactone administration for natients treated with enalapril. Currently the optimal dosing scheme for dogs is unknown; however, the authors combine spironolactone (2 mg/kg given orally twice daily) with their standard therapy (furosemide and enalapril with or without digoxin) to further combat the detrimental consequences of aldosterone. Whether this is the optimal regimen or whether spironolactone promotes symptomatic or survival benefit in dogs with heart failure is unknown at this time.

Beta-blockers Similar to what happens in humans, in dogs with congestive heart failure the body activates the sympathetic nervous system and renin-angiotensin-aldosterone system in an effort to maintain homeostasis. Unfortunately these short-term compensatory mechanisms promote adverse hemodynamic and biochemical alterations that ultimately contribute to weakness, debilitating congestive signs, deterioration of cardiac function, and ultimately death. The IMPROVE and COVE investigators identified the short-term utility of enalapril in combating dilated cardiomyopathy, and since then angiotensin-converting enzyme inhibition has become routine therapy. Although it has not been evaluated in controlled clinical trials, the loop diuretic furosemide appears to have a potent effect in alleviating the congestive clinical signs that frequently accompany heart failure. The efficacy, safety, and affordability of furosemide have made it a mainstay in the management of heart failure. Because systolic dysfunction is the primary phenotypic manifestation of dilated cardiomyopathy, the authors’ ideal therapy would further use an agent that augments systolic performance without promoting adverse events. In humans, long-term administration of beta agonists and phosphodiesterase inhibitors is marred by the resultant increase in mortality and in hospitalizations for heart failure. Whether these findings would also be reflected in large-scale canine trials is unknown, but the historical adverse events have caused pharmaceutical companies to abandon their marketing in the United States. Thus digoxin is the primary positive inotrope available to improve systolic function. Although it has been reported to produce echocardiographically identifiable improvements in fractional shortening in some dogs, it remains a relatively weak positive inotrope.

Just when some investigators had given up on the search for a safe positive inotropic agent, new investigations have identified a drug class that increased measures of systolic performance while decreasing mortality and hospitalizations. Surprisingly, this class of drugs is the beta blockers.

Agents that antagonize beta receptors act by interfering with the endogenous neurohormonal system. The primary integrator of the neurohormonal response to arterial underfilling appears to be the sympathetic nervous system. Excessive catecholamine levels promote a daunting number of detrimental effects: peripheral vasoconstriction, impaired sodium excretion by the kidneys, myocardial hypertrophy with impaired coronary flow, provocation of arrhythmias, apoptosis, and myocytolysis. Some researchers suggested that blockade of this primary integrator may retard the unrelenting nature of heart failure, whereas others were reluctant to blunt the effects (e.g., positive inotropic and chronotropic) of this potentially beneficial system. The proponents of beta blockade contended that these potential benefits are already self-limited by internalization and degradation of beta receptors in response to elevated circulating levels of norepinephrine. To settle the controversy, large-scale, placebo-controlled trials were conducted to identify the potential benefits of antiadrenergic therapy. In these studies, the second-generation beta blockers bisoprolol and metoprolol and the third-generation beta blocker carvedilol were shown to reduce mortality substantially in patients with a reduced ejection fraction. Because the study protocols included stringent observation, slow upward drug titration, and recruitment of patients with stable rather than decompensated heart failure, most of the patients enrolled in these trials were able to tolerate the short-term negative inotropic effects associated with beta blocker administration. With long-term administration, at 4 to 12 months of treatment beta blockers were found to induce a time-dependent process of reverse remodeling in which systolic function improved as myocardial hypertrophy regressed and the ventricular geometry normalized. Among the medications used to treat heart failure, this improvement in intrinsic systolic function appears to be unique to beta blockers. Based on these results, beta blocker administration currently is recommended for humans with stable heart failure secondary to systolic dysfunction.

The primary types of beta blockers evaluated thus far have been those that selectively inhibit the beta! receptor (metopro-lol and bisoprolol) and that antagonize beta1, beta2, and alpha1-adrenergic receptors (carvedilol). Although carvedilol blocks peripheral vasodilative beta2 receptors, it concurrently blocks vasoconstrictive alpha 1-adrenergic receptors, thereby enhancing its tolerance in patients afflicted with systolic dysfunction. In patients with mild to moderate heart failure, the reported tolerance for beta1-selective antagonists ranges from 79% to 100%, whereas carvedilol is tolerated by approximately 92% of patients. The most recent carvedilol study was performed in patients with stable NYHA class IV heart failure and an ejection fraction of less than 25%. Despite the severity of their disease, at 4 months 65% of patients assigned to carvedilol were receiving the target dose of their assigned medication.

The safety and efficacy of beta blockers in the management of heart failure have been more critically evaluated in controlled drug trials than has any other class of drugs. A meta-analysis of 18 published double-blind, placebo-controlled trials involving primarily NYHA class II and class III heart failure that were conducted through 1998 revealed persuasive positive effects on mortality, hospitalization, and the ejection fraction. Beta blockers reduced the risk of death by 32% and the risk of hospitalization for heart failure by 41% while increasing the ejection fraction by 29%.a Patients assigned to beta blockers were 32% more likely to show improvement in their heart failure class and 30% less likely to experience worsening heart failure. Large-scale trials of bisoprolol, metoprolol, and carvedilol have been reported since 1998, in which mortality reductions of 34%, 34%, and 35%, respectively, were identified. These impressive findings have led to small-scale investigations into the management of canine heart failure with carvedilol. While the results of those trials are awaited, new treatment strategies for the management of canine dilated cardiomyopathy and degenerative mitral valve disease can be hypothesized.

Beta-blockers for the management of dilated cardiomyopathy The management of canine dilated cardiomyopathy is often frustrating and unrewarding. Two retrospective analyses have shown median survival times of 65 days and 27 days, and 1-year survival probabilities of 37.5% and 17.5% have been reported. The prognosis for Doberman pinschers appears even worse, with a reported median survival time of 6.5 weeks and a 1-year survival probability of 3%. Survival times may since have improved with more robust use of angiotensin-converting enzyme inhibitors, but dilated cardiomyopathy seems to progress much more rapidly in dogs than in humans. Approximately 25% of human patients referred to major medical centers with newly diagnosed dilated cardiomyopathy die within 1 year, and the 5-year survival rate is 50%.

This discrepancy between humans and dogs in the rate of disease progression poses a problem for the management of dilated cardiomyopathy in dogs. As previously described, beta blockers have proved to be one of the most effective agents for combating heart failure, because their antiadrenergic properties offset the toxic and hemodynamic derangements induced by norepinephrine. Unfortunately, therapy for 1 to 3 months appears to be necessary before any improvement in systolic function is recognized, and administration for up to 18 months is needed for reversal of maladaptive remodeling with reduction in left ventricular volumes. It therefore seems that many dogs with dilated cardiomyopathy would not live long enough to reap the beneficial effects of beta blockers. The percentage of dogs that would tolerate the short-term negative inotropic effects induced by beta blockade also is uncertain.

A potential remedy for this situation may be concurrent, low-dose administration of a positive inotropic agent during the uptitration and early target phases of beta blocker therapy. The phosphodiesterase inhibitor and calcium sensitizer pimobendan may satisfactorily fulfill this role. A study evaluating the effectiveness of carvedilol therapy compared with a combination of carvedilol and pimobendan found that withdrawal of therapy because of worsening of heart failure occurred less often in the combination group.

Similar to amrinone and milrinone, pimobendan is able to improve cardiac contractility, promote ventricular relaxation, and induce vasodilatation by increasing cyclic adenosine monophosphate levels. However, pimobendan also has calcium-sensitizing properties that increase contractility by enhancing the interaction between troponin C and the prevailing cytosolic calcium level. Compared with agents that increase cAMP, a calcium sensitizer has several benefits: (1) it lowers the risk of induction of arrhythmias; (2) it reduces cell injury and death caused by calcium overload; (3) it exerts its effects without increasing energy demands; and (4) it has the potential to reverse systolic dysfunction in the face of acidosis and myocardial stunning. In a study of humans with heart failure, pimobendan was able to increase exercise capacity significantly without increasing oxygen consumption. Proarrhythmic effects were not identified during 24-hour electrocardiography, but a trend toward increased mortality was seen in the patients assigned to pimobendan. Enrollment criteria excluded any patients treated with beta blockers, therefore whether combination therapy may have reduced the trend toward increased mortality is speculative. Nonetheless, the concept of combining a novel positive inotropic agent with a slowly titrated beta blocker may very well deserve attention. Unfortunately, pimobendan currently is not available in the United States, and the use of beta blockers in the management of dilated cardiomyopathy should be considered purely investigational.

Beta-blockers for the management of chronic degenerative valve disease The authors currently manage CDVD with furosemide, an angiotensin-converting enzyme inhibitor, and digoxin, with the addition of spironolactone in moderate to severe cases. This combination directly targets excessive plasma volume and the renin-angiotensin system while indirecdy combating activation of the sympathetic nervous system. A new concept may include the addition of a beta blocker to antagonize directly the detrimental consequences of adrenergic activation. A recent study evaluated the hemodynamic effects of the angiotensin-converting enzyme inhibitor lisinopril versus a combination of lisinopril and the beta blocker atenolol in the treatment of experimental mitral regurgitation. Lisinopril was found to reduce significandy left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and end-diastolic stress, but it had no marked effect on forward stroke volume or left ventricular contractility. Three months after the addition of atenolol to this regimen, forward stroke volume and left ventricular contractility had returned to normal. Whether this effect occurred subsequent to an additional 3 months of angiotensin-converting enzyme inhibition or was mediated by the beta blockade is uncertain. Regardless, this study suggests that direct adrenergic antagonism may prove beneficial in the management of CDVD, and further studies may be warranted.