Dilated Cardiomyopathy Treatment & Management

Treatment of dilated cardiomyopathy is essentially the same as treatment of chronic heart failure (CHF). CHF is a complex clinical syndrome for which many treatment modalities have emerged. Research into the biochemical alterations that occur in persons with cardiomyopathies has led to the development of many medications designed to affect these alterations. Some therapeutic interventions treat symptoms, whereas others treat factors that affect survival.

Drug classes used include the following:

• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Beta-blockers
• Aldosterone antagonists
• Cardiac glycosides
• Diuretics
• Vasodilators
• Antiarrhythmics
• Human B-type natriuretic peptide
• Inotropic agents

Anticoagulants may be used in selected patients.

Various surgical options are available for patients with disease refractory to medical therapy. These include the following:

• Left ventricular assist devices
• Cardiac resynchronization therapy (biventricular pacing)
• Automatic implantable cardioverter-defibrillators
• Ventricular restoration surgery
• Heart transplantation

In cases of severe acute heart failure, emergency medical services (EMS) personnel may initiate treatment with oxygen, nitrates, and furosemide en route to the hospital. Cardiac monitoring, continuous pulse oximetry, and electrocardiography (ECG) may also be performed by units with advanced life support (ALS) certification. Further ventilatory support or even intubation may be indicated if the patient is in extremis.

Treatment of dilated cardiomyopathy is essentially the same as treatment of chronic heart failure (CHF) and pulmonary edema; however, obtaining a thorough history from patients with dilated cardiomyopathy helps determine the etiology. When beginning treatment, administer oxygen, initiate continuous pulse oximetry and cardiac monitoring, and obtain intravenous access.

Mainstays of medical therapy are preload reduction, afterload reduction, diuresis, and airway support. In patients with severe refractory pulmonary edema, a trial of continuous positive airway pressure (CPAP) or bimodal positive airway pressure (BiPAP) may obviate intubation.

Appropriate control of blood pressure is essential to effective therapy for persons with heart failure. The systolic blood pressure must be less than 120 mm Hg (preferably < 110 mm Hg).

Patients taking medications should not be deemed hypotensive based solely on blood pressure measurements; instead, this determination should be made based primarily on symptoms and the effectiveness of organ perfusion.

Use of ACE inhibitors (when not contraindicated) is the current criterion standard in the treatment of left ventricular dysfunction. ACE inhibitors have been shown to decrease mortality rates in both symptomatic and asymptomatic patients with left ventricular dysfunction and to reduce readmissions caused by heart failure. The absolute benefits are greater in patients with severe heart failure.

The dosage necessary for maximal benefit is debatable. One study that investigated low- and high-dose lisinopril found no significant difference in mortality rates, although it did find a difference in a combined endpoint of rehospitalization and death in favor of high-dose lisinopril.

A study by van Veldhuisen et al examined high- and low-dose ACE inhibition using imidapril and demonstrated improved exercise capacity and decreased levels of neurohormonal markers of CHF (atrial and B-type natriuretic peptides).^[8] Authorities have generally accepted that maximizing ACE inhibitor therapy is important and should be accomplished in conjunction with other necessary therapies.

The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) group in 1987 showed that the addition of enalapril to the conventional treatment of CHF yielded a 31% reduction in mortality rate at 1 year.^[9] A similar study by Studies of Left Ventricular Dysfunction (SOLVD) investigators in 1991 revealed a 16% risk reduction.^[10] Losartan, an ARB, also has been effective in decreasing mortality rates.

Other ACE inhibitor trials include the following:

• Vasodilator Heart Failure Trial II (VHeFT II) (enalapril vs hydralazine plus isosorbide dinitrate) - Improved survival better than with combined treatment with hydralazine and isosorbide dinitrate
• Assessment of Treatment with Lisinopril and Survival in Heart Failure (ATLAS; lisinopril [low and high dose]) - Insignificant trend toward reduced mortality rate with high-dose lisinopril and significant reduction in hospitalization^[11]
• Survival and Ventricular Enlargement (SAVE) (captopril vs placebo) - Decreased mortality rate, progression of disease, and recurrent myocardial ischemia^[12]

Previously believed to be contraindicated in patients with left ventricular dysfunction, this class of medications has moved to the forefront of heart failure treatment. Several trials have shown that beta-blockers are both safe and effective in the treatment persons with any class of heart failure and that adding beta-blockers to outpatient management of CHF yields great reductions in mortality rates.

Carvedilol, bisoprolol, and metoprolol CR/XL are the only agents currently approved by the US Food and Drug Administration (FDA) for use in patients with heart failure. Head-to-head studies (Carvedilol or Metoprolol European Trial [COMET], carvedilol vs metoprolol) indicated that carvedilol (a beta-1, alpha, and beta-2 receptor blocker), improved survival and cardiovascular hospitalizations more than the beta-1 selective beta-blocker metoprolol tartrate.^[13]

In 1993, the Metoprolol in Dilated Cardiomyopathy (MDC) study reported a 34% reduction in primary endpoints (ie, need for heart transplant, death) in heart failure patients who were treated with metoprolol in addition to conventional therapies.^[14] In 1996, the US Carvedilol Study showed a 65% reduction in mortality in patients with heart failure treated with carvedilol.^[15]

The international Metoprolol CR/XL Randomized Intervention Trial in CHF (MERIT-HF), the largest trial ever completed using a beta-blocker in heart failure, closed prematurely following an interim analysis that identified a highly positive effect of metoprolol-XL on all causes of mortality.^[16] MERIT-HF was a randomized, double-blind trial that compared the effects of extended-release metoprolol (metoprolol-XL) with the effects of a placebo on survival and other outcome measures (eg, sudden death, hospitalization for heart failure, quality of life).

A statistically significant 34% reduction in relative risk for total mortality at 1 year was observed; mortality rates were 7.2% in the metoprolol-XL group and 11% in the placebo group. Results at the time of study termination also revealed a 38% reduction in cardiovascular mortality, a 41% reduction in sudden death, and a 49% reduction in CHF mortality.^{[17, 16]}

Beta-blocker trials include the following (all trials used beta-blockers in addition to standard therapy for heart failure):

• US Carvedilol Heart Failure Study Group from 1996
• Cardiac Insufficiency Bisoprolol Study II (CIBIS II) from 1999 (bisoprolol vs placebo), NYHA class III-IV: reduced mortality and hospitalization rates^[18]
• Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) from 2000 (carvedilol vs placebo): terminated because of a significant reduction in mortality^[19]

Angiotensin receptor blockers

Data have demonstrated that ARBs are as effective as ACE inhibitors in the treatment of heart failure. Their adverse-effect profile is similar to that of ACE inhibitors with regard to renal insufficiency or hyperkalemia, but they do not cause potentiation of bradykinin and therefore do not cause cough.

ARB trials include the following:

• Evaluation of Losartan in the Elderly (ELITE) (losartan vs captopril): Losartan was associated with lower mortality and was better tolerated^[20]
• Evaluation of Losartan in the Elderly II (ELITE II): Losartan was not superior to captopril in elderly patients with left ventricular dysfunction but was better tolerated^[21]
• Valsartan Heart Failure Trial (VALHeFT; valsartan vs placebo) in addition to standard therapy: Combined mortality and morbidity rates from heart failure decreased by 13.3% in patients receiving valsartan in addition to standard therapy

Spironolactone acts as an aldosterone receptor blocker and, with concomitant use of ACE inhibitors, helps break the cycle of sodium retention and fluid overload via the renin-aldosterone axis. In the Randomized Aldactone Evaluation Study (RALES) (spironolactone vs placebo), the addition of 25 mg of spironolactone daily to a standard treatment regimen for CHF yielded a 35% reduction in hospitalization, significant improvements in New York Heart Association (NYHA) functional class, and a 30% reduction in risk of death.^[22]

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (eplerenone vs placebo), the addition of eplerenone to standard therapy resulted in a 15% reduction in all-cause mortality and a 17% reduction in cardiovascular mortality; the combined primary endpoint of CV mortality and CV hospitalization was reduced by 13%. EPHESUS was conducted in patients with ejection fractions less than 40% post myocardial infarction and either clinical symptoms of decompensated heart failure or diabetes.^[23]

The Emphasis-HF trial noted a 30% reduction in mortality and heart failure hospitalizations when eplerenone was used in addition to standard therapy in patients with class II heart failure who had a left ventricular ejection fraction (LVEF) of less than 35%. However, an increased risk of hyperkalemia was noted.^[24]

Foxglove and its derivatives are the oldest treatment of heart failure, but they still have a place in medicine despite advances in other drug categories. Although little controversy exists as to the benefit of digoxin in patients with symptomatic left ventricular dysfunction and concomitant atrial fibrillation, the debate continues over its role in patients with normal sinus rhythm.

A meta-analysis of 7 double-blind, placebo-controlled trials by Jaeschke et al revealed that 1 in 9 patients with CHF showed significant clinical benefit from treatment with digoxin, but not a reduction in mortality.^[25] The Digitalis Investigation Group trial demonstrated that digoxin decreases heart failure hospitalizations but has no effect on long-term survival.^[26]

Loop diuretics are necessary adjuncts in the medical therapy for heart failure when symptoms are due to sodium and water retention. They are the mainstay of diuretic therapy because they produce significantly more natriuresis than other diuretics, particularly in the setting of decreased glomerular rate. They provide symptomatic relief without prolonging life or altering disease course.

Despite clear indications for loop diuretics in the reduction of volume overload, controversy exists regarding their use in acute decompensated failure. For patients with acute decompensated heart failure, administering diuretic therapy by bolus or continuous infusion at a high dose or a low dose resulted in no significant differences in symptoms or renal function in a single, medium-sized study.^[27]

Loop diuretics have a tendency to cause hypokalemia and hypomagnesemia. Therefore, monitor electrolyte levels and replace as necessary.

Antiarrhythmics are useful in patients with supraventricular and nonsustained ventricular tachycardias. Not all antiarrhythmics are considered safe in patients with structural heart disease. The Cardiac Arrhythmia Suppression Trial (CAST) 1 and 2 implicated class IC agents as causing increased mortality in this population.

Similarly, the Survival With Oral d-Sotalol (SWORD) trial reported increased total and cardiac mortality in patients after myocardial infarction with a reduced left ventricular ejection fraction when treated with oral d-sotalol. The class III antiarrhythmics amiodarone and dofetilide are favored in these patients for the treatment of supraventricular and ventricular dysrhythmias.

In 1986, the US Veterans Administration Cooperative study showed a 36% mortality risk reduction in patients treated with preload and afterload reducers (eg, isosorbide dinitrate, hydralazine) in addition to conventional heart failure medications.^[28] Sublingual nitroglycerin spray, nitro paste, and intravenous nitroglycerin have also been advocated in the treatment of pulmonary edema secondary to CHF.

The combination of isosorbide dinitrate and hydralazine is indicated for heart failure in black patients, based in part on results of the African American Heart Failure Trial.^[29] Two previous trials in patients with severe heart failure had found no benefit in the general population but suggested a benefit in black patients. Compared with placebo, black patients showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure.

Intravenous nitrate therapy resulted in acute improvement of dyspnea in 2 randomized trials. Similarly, morphine acts as a venodilator, and it suppresses symptoms of breathlessness; however, no rigorous studies of morphine have been performed in acute decompensated heart failure.

Human B-type natriuretic peptide (BNP; Nesiritide [Natrecor]) is a new class of drug in the treatment of heart failure. It is produced through recombinant DNA technology and has the same amino acid sequence as naturally occurring human BNP.

Natriuretic peptides have demonstrated effectiveness in correcting hemodynamic derangements in patients with acutely decompensated heart failure via their vasodilatory and diuretic effects. Data suggest that combined blockade of ACE and neutral endopeptidase also has hemodynamic and clinical benefits.

In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial (nesiritide vs nitroglycerin vs placebo plus standard care), human BNP improved hemodynamics and symptomatology more effectively and with fewer adverse effects than intravenous nitroglycerin during 24 hours in patients with acute decompensated CHF.^[30] In the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) trial, nesiritide was not associated with the increased heart rate or ventricular ectopy that occurred with dobutamine therapy.^[31]

Long-term use of the phosphodiesterase inhibitor milrinone has deleterious effects on survival in patients with heart failure. Improvement of CHF symptoms occurs as the trade-off for this increase in mortality. Inotropic agents are reserved for patients who need hemodynamic-directed treatment during acute decompensation, for those who are refractory to maximal standard therapy, as palliation for end-stage heart failure, or as a bridge to transplantation for appropriate candidates.

Inotrope trials include the following:

• Prospective Randomized Milrinone Survival Evaluation (PROMISE) (milrinone vs placebo) NYHA class III-IV: increased mortality and morbidity rates with long-term therapy^[32]
• Xamoterol in Severe Heart Failure Study (xamoterol vs placebo), NYHA class III-IV: terminated because of excess mortality in xamoterol group^[33]
• Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) (milrinone or dobutamine vs placebo): routine administration of inotrope to hospitalized patients with decompensation who normally would not require it showed no impact on length of hospitalization and increased adverse events with milrinone
• Vesnarinone Trial (VEST) (vesnarinone vs placebo), NYHA class III-IV: increased mortality rates

Restrict the use of anticoagulants to those patients in atrial fibrillation, with artificial valves, or with known mural thrombus.

In 1994, Baker et al reviewed the incidence of thromboembolism in patients with heart failure due to left ventricular systolic dysfunction and found no clinical evidence to support the use of anticoagulants in those patients who were in sinus rhythm.^[34]

Portable electric left ventricular assist devices (LVADs) have been proven as the standard of care when a bridge to transplantation is needed. LVADs are being evaluated as permanent implantations (ie, as destination therapy) in patients who are not candidates for heart transplantation.

The HeartMate XVE LVAD (HeartMate I; Thoratec Corp) and HeartMate II LVAD (Thoratec Corp) have been approved for destination therapy by the US Food and Drug Administration.

For biventricular pacing, a pulse generator is implanted under the skin, with leads positioned in the right atrium, right ventricle, and coronary sinus. Resynchronization pacing generators also have defibrillation capabilities. The benefits of pacing solutions for dyssynchrony were confirmed in multiple studies from the mid-1990s, which demonstrated acute functional improvements and reduced mortality and hospitalization rates compared with optimal medical therapy.^[35]

A Dutch study found that heart failure patients with impaired renal function were less likely to respond to cardiac resynchronization therapy and have higher mortality rates. In patients who do respond to resynchronization, however, renal function is preserved.^[36]

Current indications for cardiac resynchronization therapy are as follows:

• NYHA class III or IV heart failure and intraventricular conduction delay
• Persistent symptoms despite optimal medical therapy with ACE inhibitors, beta-blockers, and/or other appropriate pharmacologic measures

Automatic implantable cardioverter-defibrillators (AICDs) are designed to detect and correct ventricular tachycardia/ventricular fibrillation. Programmable therapies include antitachycardia pacing for ventricular tachycardia and/or defibrillatory shocks when appropriate.

Indications for implantation continue to evolve, and the patient populations eligible for AICDs continue to expand. Current recommendations include patients who are clearly at high risk for ventricular arrhythmias and sudden cardiac death. Those with moderately severe left-sided ventricular dysfunction account for a significant proportion of these patients.

AICD trials (ie, the Multicenter Automatic Defibrillator Implantation Trial II [MADIT II], Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) have defined a clear mortality benefit in patients with a history of significant left-sided ventricular dysfunction. Updated guidelines published by the American College of Cardiology and the American Heart Association have defined MADIT II criteria for AICD implantation as class IIa indications.^{[37, 38]}

Several surgical procedures have been devised to restore the normal geometry of the left ventricle. The endoventricular circular patch-plasty (Dor procedure) is used for patients with ischemic cardiomyopathy who have dyskinetic, aneurysmal, or akinetic left ventricle walls.

Partial left ventriculectomy (Batista procedure) for idiopathic dilated cardiomyopathy was intended to improve ventricular function by reducing left ventricular diameter (Laplace law).

Early high failure rates dampened enthusiasm for this technique, and its use is currently limited largely to Japan, where the procedure has been refined and is considered an important option for end-stage heart failure.^[39]

When progressive end-stage heart failure occurs despite maximal medical therapy, when the prognosis is poor, and when there is no viable therapeutic alternative, the criterion standard for therapy has been heart transplantation. Absolute indications for heart transplantation are as follows:

• Refractory cardiogenic shock
• Dependence on intravenous inotropes for organ perfusion
• Peak oxygen consumption (VO₂) less than 10 mL/kg/min with achievement of anaerobic threshold
• Severe ischemia not amenable to any intervention
• Symptomatic ventricular arrhythmias refractory to all therapies

Relative indications are as follows:

• Peak VO₂ of 11-14 mL/kg/min (or < 50-55% predicted for age and sex) and major limitation of daily activity
• Recurrent instability of CHF not due to noncompliance or suboptimal medical therapy

The importance of patient education cannot be overemphasized, especially regarding dietary restrictions. Dietary recommendations include sodium and water restrictions. An average American diet contains 6 g of salt per day. Avoiding extra table salt decreases this intake to 3 g/day. Patients with CHF should restrict their salt intake to less than 2-4 g/day.

Fluid restriction is only necessary in very late stages of the disease. Patients with hyperkalemia due to ACE inhibitor therapy sometimes respond to a low-potassium diet.

Encourage patients to exercise moderately, because deconditioning is a very common cause of dyspnea. Cardiac rehabilitation has been shown to improve patient outcomes.

Investigational Therapy for Heart Failure

The next generation of medications affecting the renin-angiotensin-aldosterone system (RAAS) are the selective aldosterone receptor antagonists. Eplerenone is currently being evaluated in the treatment of heart failure.

Based on findings of tumor necrosis factor (TNF)–alpha involvement in persons with cardiomyopathies, agents aimed at blocking TNF-alpha have been developed. Etanercept has shown benefit in animal models and short clinical trials. However, phase 3 trials were discontinued because of a lack of benefit.

Endothelin-1 has deleterious hemodynamic effects on left ventricular dysfunction. Over 6 months, bosentan has been shown to increase the likelihood of improvement and decrease the likelihood of deterioration in persons with New York Heart Association (NYHA) class IIIB-IV. Trials with other agents are under way.

Protein, stem cell, and gene therapies

Early animal studies using recombinant adeno-associated viral gene therapy with gene transfer of phospholamban prevented deterioration of left ventricular systolic and diastolic function in genetically predisposed animals.

The use of vascular endothelial growth factor may have beneficial effects in persons with ischemic cardiomyopathies. This form of gene therapy has demonstrated the benefits of reducing revascularization and improving angina and quality of life. Many formats of gene delivery are under investigation. Fibroblast growth factor has also been investigated in the realm of ischemic heart disease, with mixed results.

Myoblast transplantation

This procedure involves the injection of skeletal myoblasts as an autograft into damaged myocardium (scar) at the time of bypass surgery. In early investigations, this therapy has consistently resulted in improved contraction and viability of the myocardium. Further investigation is needed to establish a more prominent role for myoblast transplantation in heart failure therapy. Additional studies are also being performed with other progenitor cells.

Embryonic stem cells

Human embryo stem cells have been differentiated ex-vivo to derive cardiac myocyte stem cells. When transplanted into rats who had left anterior descending coronary artery ligation, these stem cells have been shown to attenuate the adverse remodeling seen with extensive infarct.^[40]

Autologous stem cells have been given both intramyocardially and intravenously for the treatment of congestive heart failure, with varying results. Much of the early data from these trials seem to suggest that delivery mechanisms to the myocardium and the use of concomitant cytokines are equally in need of further investigation.^[41]

Consult an internist, an intensivist, or a cardiologist as indicated for admission when a patient has been diagnosed with dilated cardiomyopathy for the first time or for continued inpatient treatment or monitoring. Emergent consultation with a cardiologist may also be indicated for echocardiography in the ED. Refer patients with NYHA functional class III-IV dilated cardiomyopathy to a cardiothoracic surgeon for possible surgical intervention (eg, partial left ventriculectomy, heart transplant).

Patients with familial dilated cardiomyopathy can register with the Familial Dilated Cardiomyopathy registry. Contact information is as follows:

Familial Dilated Cardiomyopathy Project Group

Oregon Health Sciences University

Portland, OR 97201

Telephone (toll free): (877) 800-3430

E-mail: fdcgroup@mail.fdc