Heart failure:
A neurohormonal approach to treatment

Heart failure (HF) is a chronic progressive disease affecting over five million Americans, with an incidence of 450,000 cases a year. Its rapidly increasing prevalence corresponds, in part, to the aging U.S. population. Clinical studies have shown that left ventricular diastolic function declines with age, though contractility does not, although myocardial stiffness does increase in response to such factors as tachycardia, hypertension, and ischemia.

Annually, HF costs the U.S. $10 billion in direct health-care expenditures. It is the most frequent cause of hospitalization among the elderly, costing on average $7,700 per admission. This is an important component of uncompensated hospital care, with a mean hospital charge for Medicare patients of about $8,500 and a reimbursement of less than $4,200.

Currently, the term heart failure is preferred to congestive heart failure because patients can have the clinical syndrome of HF without symptoms of congestion.

The prognosis is grim. After the onset of symptoms, patients often show a marked decline in the quality of life and functional status. More than a third die within two years, and six-year mortality is high and rising–80% in men, 65% in women. According to Matthew Sorrentino, M.D., and Amy Bales, M.D., both assistant professors of clinical medicine at the University of Chicago, early detection and treatment using a multidisciplinary approach may impact this significantly. HF causes 220,000 deaths each year.

A result of contractile failure, systolic HF is the most common form of HF.

The most common cause of systolic HF is ischemic heart disease. Other causes include hypertension and many endocrine and metabolic disorders including hypothyroidism, acromegaly, diabetes, pheochromocytoma, and thiamin and ascorbic acid deficiencies. Myocarditis is caused by such viruses as coxsackievirus, hepatitis, adenovirus, cytomegalovirus (CMV), and HIV; and bacteria such as Brucella, Clostridium, Salmonella, and the agent of Lyme disease have all been implicated. Drugs such as doxorubicin (Adriamycin, Pharmacia) and substances of abuse such as alcohol or cocaine can also result in systolic dysfunction. The causes of systolic HF are numerous but important to identify, according to Sorrentino and Bales, since appropriate treatment–such as revascularization for ischemic heart disease or replacement therapy for hypothyroidism–may reverse the process.

The definition of HF has changed over the years. In 1950, Paul Wood used a hemodynamic perspective, defining CHF as "inadequate circulation despite satisfactory filling pressures." In other words, the heart was not working well as a pump, despite the fact that it had plenty of blood to pump. Eugene Brunwald used a more pathophysiologic approach in the 1980s, defining congestive heart failure as an abnormality of cardiac function, a failure of the heart to pump blood at a rate commensurate with the requirements of metabolizing tissue.

Thomas Giles, M.D., professor of medicine at Louisiana State University, stated, "As a clinical syndrome, HF is caused by an abnormality of the heart, and is recognized by a characteristic pattern of hemodynamic, renal, neural, and hormonal responses, and ventricular dysfunction with symptoms. Key symptoms that most often bring patients to the attention of physicians include dyspnea on exertion and fatigue. Fatigue often dominates the clinical picture, so that one must be astute in diagnosing those with multiple medical problems. Other clinical symptoms may include paroxysmal nocturnal dyspnea, orthopnea, pulmonary or peripheral edema, crackles, jugular venous distention, and gallop rhythms of the heart."

The most widely used classification system, the New York Heart Association Functional Classification (FC) system, defines functional classes (FC)-I to (FC)-IV according to increasing limitations of physical activity. Progressive classes correlate well with HF morbidity and mortality, but are of little use as a staging system, according to Michael Bottoroff, Pharm.D., a professor at the University of Cincinnati. This is due to the relative interpretation and variability in assessing (FC)-II and (FC)-III progression. There is a large range of normal physical activity and what constitutes limitations for basis of classification. Bottoroff, who chairs a committee for the HF Society of America, suggests a new way to classify HF based on cardiomyopathy.

Simply defined, cardiomyopathy is a disease of heart muscle. Many factors may act in concert to affect the myocardium. Myocytes destroyed as a result of infarct or other injury do not regenerate because the heart is a terminally differentiated organ. Alternatively, myocytes can simply become dysfunctional in response to an infarct. They can be stunned/hibernating as a result of ischemia, thyroid deficiency, or diabetes and related glucose toxicity.

When the myocardium is injured, the remaining myocytes must compensate for those lost. Following a sustained period of high physical stress, left ventricular hypertrophy and remodeling occurs. Though this effect may initially appear to increase cardiac efficiency, it is a pathological change in the composition of the heart.

Bottoroff suggests the following classification scheme:

Stage 1 — Individual with a gene for cardiomyopathy who’s never had a symptom. Depending on the penetrance and expressivity of the gene, a problem may never arise.

Stage 2 — Individual with an irregular phenotypic expression in the heart muscle. This may be due to diabetes, infarction, or some other cause. Still, there are no symptoms.

Stage 3 — This is what has been treated as (FC)-IV. At this point, the disease stage is more complex. The Frank-Starling mechanism is in full force. As the heart begins to dilate, it is at a mechanical disadvantage. Myocardial wall tension increases and systolic dysfunction occurs. In some, pathological hypertrophy may offset this briefly, but it inhibits the ability of the heart to relax, resulting in diastolic dysfunction.

As cardiac function decreases, neurohormonal mechanisms are activated in an effort to maintain normal circulation. These involve the sympathetic nervous system and the renin/angiotensin system. Although these mechanisms are meant to be compensatory or reparative at first, they initiate vicious cycles that lead to continued worsening of HF. The sympathetic system is responsible for maintaining circulatory stability in the face of decreased cardiac output. However, high levels of norepinephrine result in down-regulation of cardiac ß-adrenergic receptors, thus decreasing contractile response to sympathetic stimulation.

The renin/angiotensin/aldosterone system is activated in response to decreased cardiac output, causing increased plasma levels of renin, angiotensin II, and aldosterone, resulting in sodium retention and systemic vasoconstriction. The activated system has both peripheral vascular and cardiac effects. Angiotensin II, produced locally, increases peripheral arterial tone and acts directly on cardiac sympathetic nerve endings to release norepinephrine. Increased sympathetic outflow in turn stimulates b 1 receptors in the kidney to produce renin. Thus, each system augments the effects of the other.

Angiotensin II is also a potent releaser of endothelin from vascular endothelial cells. Endothelin is a potent peripheral vasoconstrictor and, in an autocrine fashion, is involved in ventricular remodeling. Endothelin can cause hypertrophy, coronary arteriolar constriction, and increased myocardial oxygen consumption through increased contractility. Arginine vasopressin is another systemic vasoconstrictor found in elevated levels in HF patients. Other counter-regulatory vasodilatory substances that are elevated include atrial natriuretic hormone and endothelium-derived relaxing factor. The overall effect is decreased left ventricular ejection fraction. Further, plasminogen activator inhibitor 1 production is increased, thus increasing thrombosis. Lastly, oxidative stress is increased from all these processes.

Thus, we are now moving beyond the hemodynamic or mechanical understanding of the pathogenesis of HF into the neurohormonal. "If you look for a common thread," Bottoroff said, "to help predict what drugs work and what drugs don’t necessarily work in HF, you can point to those drugs that have a positive impact on the neurohormonal system…whether that’s angiotensin converting enzyme inhibitors (ACEIs), ß-blockers, spironolactone, or potentially the angiotensin receptor blockers (ARBs), the drugs that might block the release of vasopressin, endothelin…and one of the good things that might be produced in HF–natriuretic peptides–we might also be looking for drugs to promote the activity of these peptides. So not only will it help explain for you the reason why the drugs we’re using today work, it will also help predict for you the drugs that are under development and have the potential to work in the future."

According to Sorrentino, drug therapy can markedly relieve symptoms and prolong life in patients with HF. Treatment focuses on counteracting overcompensatory mechanisms. Despite well-documented trials that proved the efficacy of medications such as ACEIs, these drugs remain underutilized or are used at inadequate doses. It is also important to recognize that medications such as first-generation calcium channel blockers and NSAIDs are harmful in patients with HF.

Another important parameter to consider in drug selection is the comorbid conditions of patients. For example, ACEI can also be useful for hypertension and diabetes. ß-blockers can be useful in coronary disease and hypertension as well as being combined with digoxin for supraventricular tachycardia. It is also important to be aware of side effects that might affect comorbid conditions adversely, such as ß-blockers in asthma patients.

Evidence-based medicine is important. For example, ß-blockers have been contraindicated for HF patients in the past. However, Bottoroff pointed out, major trials involving their use have been uniformly successful. There are now more data to support the use of these agents in HF than exist for ACEI. It was thought originally that ß-blockers carried the potential hazard of depressing myocardial contractility and precipitating more severe HF. Though not necessarily untrue, the use of a non-specific agent might eliminate this effect. In the U.S. carvedilol trials, it was hypothesized that b ₂ and a receptors play a role in the diseased myocardium in addition to the b ₁ receptor. In the four trials, there appeared to be such a reduction in mortality that the trials were stopped early at 65% reduction in mortality, and a significant reduction in cardiovascular hospitalizations as well. This led the way for the bisoprolol (Zebeta, Lederle) trials, then the MERIT metoprolol (Toprol, AstraZeneca) sustained-release studies, which were also successful. A head-to-head comparative trial of carvedilol (Coreg, SmithKline Beecham) and metoprolol in patients with HF is now in progress in Europe. A major problem with ß-blockers, however, is a three-month lag time before the benefits are seen.

The combination of ARBs and ACEIs may be beneficial. ACEIs prevent the degradation of bradykinin by angiotensin-converting enzyme (ACE), leading to higher levels, thus increasing nitric oxide and substance P levels and resulting in vasodilation. Together with the complete blockade of the effects of angiotensin II, this should lead to better control.

Use of spironolactone may also be considered as a further extension of the neurohormonal hypothesis, affecting angiotensin II and aldosterone. According to the RALES trial, the effects appear to be additive to the benefits of ACEI, and it is appropriate and safe to use if renal function is adequate.

Some current guidelines include the Action Heart Failure Panel guideline and the Heart Failure Society of America guideline (www.hsfa.org ).

The Action Heart Failure Panel guideline, published two years ago, is now recommending diuretics for all patients with fluid retention, though they should not be used alone. In other words, diuretics are good for controlling symptoms, but may not halt disease progression. ACEIs are to be considered for all patients. ß-blockers are to be considered as they can alter progression of the disease, and the lag time can be safely managed. Spironolactone is recommended for more advanced forms of HF only, since only that group was studied. It may be effective for less-advanced HF, but trial data are not available. Digoxin (Digitek, Bertek), may still be useful in conjunction with other therapies. ARBs should be reserved for patients who cannot tolerate adverse effects, such as cough, or have angioedema on ACEI until further studies become available.

Similarly, an algorithm presented in Lancet at the end of 1999 suggests diuretics and ACEI as the cornerstones of therapy, with the addition of ß-blockers farther down the road, as well as spironolactone. Digoxin may be used whenever necessary, though the data for its use are inferior to the data supporting the use of the other drugs. Heroic measures included dobutamine (Dobutrex, Lilly) infusions, furosemide (Furosemide, Mylan) drips, or consideration for transplant.

ACEI therapy was once identified as the most important therapy a HF patient could receive. Data have shown ß -blockers to be at least on a par with that, and ACEI and spironolactone are indicated in advanced HF, pending further data.

"It is my own belief," said Bottoroff, "that digoxin’s use will decline as more and more effective therapies become available. The optimal treatment for HF, given what we know now, involves at least three drugs, maybe four, and in some patients maybe even five. So it’s your job to try to manage and juggle around what might be the best combination of drugs for individual patients…to maximally not only reduce their symptoms, but to optimize their outcome."

Yael Waknine, Pharm.D. candidate

The author is a medical writer based in Augusta, Ga.

Yael Waknine. Heart failure: A neurohormonal approach to treatment.

Drug Topics

2001;9.