Arunima Misra, MD, FACC, Kumudha Ramasubbu, MD, FACC, Shawn T. Ragbir, MD, Glenn N. Levine, MD, FACC, FAHA and Biykem Bozkurt, MD, PhD, FACC, FAHA

1. What are the most common causes of heart failure?

    Ischemic heart disease, hypertension, and valvular heart disease are the most common causes of heart failure. Less common causes include diabetes; microvascular disease; genetic cardiomyopathies and muscular dystrophies; autoimmune and collage vascular diseases such as systemic lupus, dermatomyositis, or scleroderma; toxic cardiomyopathies, including alcohol or illicit drugs such as cocaine; chemotherapy induced cardiomyopathies (e.g., Adriamycin); myocarditis and viral cardiomyopathy; postpartum cardiomyopathy; tachycardia-mediated heart failure; hypothyroidism- or hyperthyroidism-related cardiomyopathies; infiltrative disorders such as sarcoidosis, hemochromatosis, and amyloidosis; high-output states (thyrotoxicosis, beriberi, systemic arteriovenous shunting, chronic anemia); and stress-induced (Tako-tsubo) cardiomyopathy.

2. What elements should the initial assessment of the patient with heart failure include?

    Initial assessment of the patient with heart failure should include:

3. How are heart failure symptoms classified?

    Symptoms are most commonly classified using the New York Heart Association (NYHA) classification system:

4. What is the stage system for classifying heart failure?

    In 2001, the American College of Cardiology/American Heart Association (ACC/AHA) introduced a system to categorize the stages of heart failure. This system is somewhat different in focus than the previous NYHA classification system and was intended, in part, to emphasize the prevention of the development of symptomatic heart failure. In addition, the 2009 update on the 2005 Heart Failure Guidelines suggest appropriate therapy for each stage (Figure 23-1).

5. Which patients with heart failure should be considered for endomyocardial biopsy (EMB)?

    In 2007, the ACC/AHA/European College of Cardiology (ACC/AHA/ECC) issued a scientific statement on the role of EMB. Most patients who are seen for heart failure should not be referred for EMB. Biopsy results are often nonspecific or unrevealing, and in most cases there is no specific therapy based on biopsy results that have been shown to improve prognosis. However, in certain clinical scenarios, EMB should be performed (class I recommendation) or can be considered and is considered reasonable (class IIa recommendation). As given in that document, these scenarios include the following:

6. What are the general treatments for patients with heart failure?

The elements of long-term management of patients with CHF resulting from depressed LV systolic function are summarized in Table 23-1.

7. How do ACE inhibitors and ARBs work?

    ACE inhibitors inhibit ACE, thus blocking the conversion of angiotensin I to angiotensin II. ACE is predominantly found in the pulmonary and to a lesser extent in the renal endothelium. By decreasing the production of angiotensin II, ACE inhibitors attenuate sympathetic tone, decrease arterial vasoconstriction, and attenuate myocardial hypertrophy. Because angiotensin II stimulates aldosterone production, circulating levels of aldosterone are reduced. This results in decreased in sodium chloride absorption, decreased potassium excretion in the distal tubules, and decreased water retention. Through a decrease in antidiuretic hormone (ADH) production, ACE inhibitors also decrease water absorption in the collecting ducts.

    ARBs selectively block the binding of angiotensin II to the AT₁ receptor, thereby blocking the effect of angiotensin II on end organs. This results in attenuation of sympathetic tone, decrease in arterial vasoconstriction, and attenuation of myocardial hypertrophy. Because angiotensin II stimulates aldosterone production, circulating levels of aldosterone are reduced. This results in a decrease in sodium chloride absorption, potassium excretion in the distal tubules, and water retention.

8. What approach should be taken if a patient treated with an ACE inhibitor develops a cough?

    Nonproductive cough related to ACE inhibitors occurs in 5% to 10% of white patients of European descent and in up to 50% of Chinese patients. The cough is believed related to kinin potentiation. The cough usually develops within the first months of therapy and disappears within 1 to 2 weeks of discontinuation of therapy. ACC/AHA guidelines suggest one should first make sure the cough is related to treatment and not to another condition. The guidelines state that the demonstration that the cough disappears after drug withdrawal and recurs after rechallenge with another ACE inhibitor strongly suggests that ACE inhibition is the cause of the cough. They emphasize that patients should be rechallenged, because many will not redevelop a cough, suggesting the initial development of cough was coincidental and may have been related to heart failure. Patients who do have ACE inhibitor–related cough and cannot tolerate symptoms should be treated with an ARB.

9. What is the efficacy of ARBs compared with ACE inhibitors in patients with chronic heart failure?

    Trials comparing the efficacy of ARBs with ACE inhibitors in chronic heart failure revealed that treatment with ARB was equivalent to ACE inhibition (trials using valsartan and candesartan); however, a trend toward improved outcomes was noted with ACE inhibitors in a trial using the ARB losartan.

    In view of the vast experience with the ACE inhibitors as compared with ARBs, ACE inhibitors continue to be the recommended agents of choice for patients with heart failure and depressed LV systolic function. That said, ARBs—specifically, candesartan and valsartan—confer significant benefit on mortality and morbidity in patients with heart failure who are intolerant of ACE inhibitors, and therefore offer a good alternative strategy in these patients. Candesartan and valsartan are the recommended ARBs for patients with heart failure who are intolerant of ACE inhibitors.

10. When should ARBs be added to ACE inhibitors in patients with chronic heart failure?

    Theoretically, the more complete angiotensin II inhibition using a combination of ACE inhibitors and ARBs in patients with heart failure may translate into improved clinical outcomes.

    Two large clinical trials in patients with heart failure, the Val-HeFT and the CHARM-Added trial, evaluated the impact on morbidity and mortality of adding ARBs to ACE inhibitors. Both trials suggest that adding an ARB to an ACE inhibitor leads to a reduction in heart failure hospitalizations, although combination therapy had no impact on mortality. Thus, the current Heart Failure Society of America guidelines recommend the addition of ARBs to ACE inhibitors in patients who meet the following conditions:

11. How do aldosterone antagonists work?

    Aldosterone receptor blockers block the mineralocorticoid receptor in the distal renal tubules, thereby decreasing sodium chloride absorption, potassium excretion, and water retention. In addition, they block the direct deleterious effects of aldosterone on the myocardium and may thus decrease myocardial fibrosis and its consequences.

12. List the indications and recommended dosing of aldosterone antagonists in heart failure.

    Current indications include the following:

Dosing is as follows:

The initial and target doses for aldosterone antagonists and other drugs used to treat patients depressed systolic ejection fraction and/or CHF are listed in Table 23-2.

13. Can all patients with heart failure safely be started on an aldosterone antagonist?

    No. Aldosterone antagonists should not be started in men with creatinine more than 2.5 mg/dL or women with creatinine more than 2 mg/dL, patients with potassium more than 5 mEq/L, those in whom monitoring for hyperkalemia and renal function is not anticipated to be feasible, and those not already on other diuretics.

14. Describe common adverse effects of ACE inhibitors, ARBs, and aldosterone antagonists.

    Common adverse effects include the following:

ARBs are as likely as ACE inhibitors to produce hypotension, worsening renal function, and hyperkalemia. Otherwise, ARBs are better tolerated than ACE inhibitors. The incidence of cough is much lower in ARBs (approximately 1%) compared with ACE inhibitors (approximately 10%). The incidence of angioedema with ACE inhibitors is rare (less than 1%; more common in African Americans) and even more rare with ARBs. However, because there have been case reports of patients developing angioedema on ARBs, the guidelines advise that ARBs may be considered in patients who have had angioedema while taking an ACE inhibitor, albeit with extreme caution. Practically, if a patient develops angioedema while taking an ACE inhibitor, an ARB is generally not initiated.

Gynecomastia and other antiandrogenic effects can occur with spironolactone and are not generally seen with eplerenone.

15. What are the indications and dosing of nitrates/hydralazine in patients with chronic heart failure?

    The vasodilator combination of isosorbide dinitrate (Isordil) and hydralazine (I/H) has been shown to produce modest benefit in patients with heart failure, compared with placebo. The combination has, however, been shown to be less effective than ACE inhibitors. The recent A-Heft trial, which was limited to African-American patients with class III-IV heart failure, showed that the addition of I/H to standard therapy with ACE inhibitor or a β-blocker conferred significant morbidity and mortality benefit.

    Taking all the evidence together, the I/H combination is indicated in the following patients:

Dosages are as follows:

16. How should patients be treated with β-blockers?

    Certain β-blockers have been convincingly shown to decrease mortality in patients with depressed ejection fraction and symptoms of heart failure, and thus it is a class I indication to treat such patients with β-blockers, with an attempt to reach target doses. The β-blockers shown to decrease mortality, their starting doses, and their target doses are given in Table 2. Recommendations from the Heart Failure Society of America and other organizations include the following:

17. What is the mechanism of action of digoxin?

    Digoxin is a cardiac glycoside and is an inhibitor of the Na⁺,K⁺-ATPase pump in the sarcolemmal membrane of the myocyte and other cells. This inhibition causes intracellular accumulation of Na⁺, which makes the Na⁺-Ca²⁺ pump extrude less Ca²⁺, causing Ca²⁺ to accumulate inside the cell. This effect results in increased force of contraction. Cardiac glycosides also have effects in the central nervous system, enhancing parasympathetic and reducing sympathetic outputs to the heart, through carotid sinus baroreceptor reflex sensitization. This is the mechanism that underlies the reduction in sinus node activity and slowing in atrioventricular (AV) conduction, which makes digoxin the only agent with a positive inotropic-bradycardic effect and is the basis for its use in the control of some supraventricular arrhythmias.

18. Is there scientific evidence for the use of digoxin?

    The Digitalis Investigation Group (DIG) trial was a multicenter, randomized, double-blinded, placebo-controlled study of 6801 symptomatic patients with heart failure and ejection fraction less than 45%, who were in sinus rhythm. Mean follow-up was 37 months. Patients already receiving digoxin were allowed into the trial and randomized to digoxin or placebo without a washout period. About 95% of patients in both groups received ACE inhibitors; β-blockers were not in use for heart failure at the time. The primary outcome was total mortality. Digoxin did not improve total mortality (34.8% versus 35.1% in the placebo group, P = 0.80) or deaths from cardiovascular causes (29.9% versus 29.5%, P = 0.78). Hospitalizations as a result of worsening heart failure (a secondary endpoint) were significantly reduced by digoxin (26.8% versus 34.7% in the placebo group, risk ratio 0.72, P < 0.001). Hospitalizations for suspected digoxin toxicity were higher in the digoxin group (2% versus 0.9%, P < 0.001). In an ancillary, parallel trial in patients with ejection fraction greater than 45% and sinus rhythm, the findings were consistent with the results of the main trial. Whether these results hold with contemporary heart failure treatment that includes β-blockers, aldosterone-receptor blockers, and resynchronization therapy is not known.

19. What are some of the relevant drug interactions of digoxin?

20. What are the clinical manifestations of digoxin toxicity?

    Digoxin has a narrow safety margin (the difference in plasma drug concentrations between therapeutic and toxic levels is small). Patients with digoxin toxicity may manifest nausea, vomiting, anorexia, diarrhea, fatigue, generalized malaise, visual disturbances (green or yellow halos around lights and objects), and arrhythmias. In the presence of hypokalemia, digoxin toxicity may occur within the therapeutic level. Digoxin dose should be reduced in elderly patients, in patients with renal insufficiency (glomerular filtration rate [GFR] less than 60 mL/min), and when combined with certain drugs. To guide dosing during chronic therapy, digoxin levels should be measured 6 to 8 hours after a dose.

21. What are the electrocardiographic findings of digoxin toxicity?

    Digoxin toxicity can result in a variety of ventricular and supraventricular arrhythmias and AV conduction abnormalities, including:

These arrhythmias result from the electrophysiologic effects of digoxin: Increased intracellular Ca²⁺ levels predispose to Ca²⁺-induced delayed afterdepolarizations and, hence, increased automaticity (especially in the junction, Purkinje system, and ventricles); excessive vagal effects predispose to sinus bradycardia and/or arrest, and AV block. Bradyarrhythmias and blocks are more common when the patient is also taking amiodarone.

22. How is digoxin toxicity treated?

    It depends on the clinical severity. Digoxin withdrawal is sufficient with only suggestive symptoms. Activated charcoal may enhance the gastrointestinal (GI) clearance of digoxin if given within 6 hours of ingestion. Drugs that increase plasma digoxin levels (see Question 19) should be discontinued (except amiodarone, because of its long half-life). Correction of hypokalemia is vital (intravenous [IV] replacement through a large vein is preferred with life-threatening arrhythmias), but judgment is needed in the presence of high degrees of AV block. Symptomatic AV block may respond to atropine or to phenytoin (100 mg IV every 5 minutes up to 1000 mg until response or side effects); if no response, use digoxin immune Fab (ovine) (Digibind). The use of temporary transvenous pacing should be avoided. Patients with severe bradycardia should be given Digibind, even if they respond to atropine. Lidocaine and phenytoin may be used to treat ventricular arrhythmias, but for potentially life-threatening bradyarrhythmias or tachyarrhythmias, Digibind should be used. IV magnesium may be given 2 grams over 5 minutes and has been shown to help with digoxin toxicity related arrhythmias. Dialysis has no role because of the high tissue-binding of digoxin.

23. What are the indications for Digibind?

    The indications for Digibind include life-threatening bradyarrhythmias and tachyarrhythmias; hemodynamic instability caused by digoxin, potassium level of more than 5 mEq/L in the setting of acute ingestion, regardless of symptoms or ECG findings; and digoxin level of more than 10 ng/mL or the ingestion of more than 10 mg of digoxin, regardless of symptoms or ECG findings. Digibind is an antibody that binds to digoxin in the plasma and interstitial space, creating a concentration gradient for the exit of intracellular digoxin. As poisoning of the Na⁺,K⁺-ATPase is relieved, K⁺ is pumped intracellularly with the potential of causing hypokalemia; potassium levels should be monitored when Digibind is used. The half-life of the digoxin-Digibind complex is 15 to 20 hours if renal function is normal. Serum digoxin concentration rises significantly after Digibind use (as tissue digoxin is released into the bloodstream, bound to the antibody) and should not be measured.

24. What three classes of drugs exacerbate the syndrome of CHF and should be avoided in most CHF patients?

25. Is dietary restriction of sodium recommended in patients with symptomatic heart failure?

    Yes. In general, patients should restrict themselves to 2 to 3 g sodium daily, and less than 2 g daily in moderate to severe cases of heart failure.

26. Is fluid restriction recommended in all patients with heart failure?

    Not necessarily. Expert opinion differs, although some believe fluid restriction generally is not necessary unless the patient (a) is hyponatremic (sodium less than 130 mEq/L) or (b) fluid retention is difficult to control despite high doses of diuretics and sodium restriction. In such cases, patients are generally restricted to less than 2 L/day.

27. Should patients with CHF be told to use salt substitutes instead of salt?

    In some cases, the answer is no. Many salt substitutes contain potassium chloride in place of sodium chloride. This could lead to potential hyperkalemia in patients on potassium-sparing diuretics, ACE inhibitors or ARBs, or aldosterone antagonists, and those with chronic kidney disease (or those with the potential to develop acute renal failure). Patients who are permitted to use salt substitutes need to be cautioned about potassium issues.

28. What are the current criteria for consideration of CRT with biventricular pacing?

    Patients who should be considered for referral of CRT (class I indication) with or without ICD are those who meet the following criteria:

29. Which patients with heart failure should be considered for an ICD?

    In the 2008 ACC/AHA/Heart Rhythm Society (ACC/AHA/HRS) guidelines on device-based therapy, the writing group stated that they believed guidelines for ICD implantation should reflect the ICD trials that were conducted. Thus, there are many very specific indications for ICD placement, based on symptom class, ischemic or nonischemic causes of heart failure, and ejection fraction. Because ejection fraction may improve significantly after MI (as a result of myocardial salvage and myocardial stunning) and with optimal medical therapy (including ACE inhibitors/ARBs and β-blockers), patients being considered for ICD implantation for primary prevention should be optimally treated and have their ejection fraction reassessed on optimal medical therapy. ICD should only be considered in patients with a reasonable expectation of survival with an acceptable functional status for at least 1 year. Class I recommendations for ICD include the following:

 ICD therapy is recommended to improve survival in patients who have survived cardiac arrest or who have sustained VT, which is either poorly tolerated or associated with reduced systolic LV function (class I; level of evidence A).

 ICD implantation is reasonable in selected patients with LVEF less than 30% to 35%, not within 40 days of an MI, on optimal background therapy including ACE inhibitor, ARB, β-blocker, and an aldosterone antagonist, where appropriate, to reduce likelihood of sudden death (class I; level of evidence A).

 ICD implantation in combination with biventricular pacing can be considered in patients who remain symptomatic with severe heart failure, NYHA class III-IV, with LVEF 35% or less and QRS 120 ms or more to improve mortality or morbidity (class IIa; level of evidence B).

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