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Mayo Clin Proc. 2010 May; 85(5): 473–478.
PMCID: PMC2861977

Clinical Pearls in Cardiology

At the 2001 annual conference of the American College of Physicians, a new teaching format to aid physician learning, Clinical Pearls, was introduced. Clinical Pearls is designed with the 3 qualities of physician-learners in mind. First, we physicians enjoy learning from cases. Second, we like concise, practical points that we can use in our practice. Finally, we take pleasure in problem solving.

In the Clinical Pearls format, speakers present a number of short cases in their specialty to a general internal medicine audience. Each case is followed by a multiple-choice question answered live by attendees using an audience response system. The answer distribution is shown to attendees. The correct answer is then displayed and the speaker discusses teaching points, clarifying why one answer is most appropriate. Each case presentation ends with a Clinical Pearl, defined as a practical teaching point that is supported by the literature but generally not well known to most internists.

Clinical Pearls is currently one of the most popular sessions at the American College of Physicians meeting. As a service to its readers, Mayo Clinic Proceedings has invited a selected number of these Clinical Pearl presentations to be published in our Concise Reviews for Clinicians section. “Clinical Pearls in Cardiology” is one of them.

Case 1

A 51-year-old man with dilated cardiomyopathy whom you have been treating for the past 3 years has class II New York Heart Association (NYHA) heart failure (slight limitation of physical activity, can perform activities of daily living, can walk >2 blocks or climb >1 flight of stairs). Prior coronary angiography showed normal coronary arteries. He would like to be more active and asks if there is anything else that could be tried. He has been taking 100 mg/d of metoprolol and has had a resting heart rate of 58 beats/min. He has never been able to tolerate either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB), developing a severe cough in multiple previous trials of these agents. He denies any peripheral edema, orthopnea, or paroxysmal nocturnal dyspnea.

Medications

Metoprolol, 100 mg/d

Furosemide, 20 mg/d

Eplerenone, 50 mg/d

Digoxin, 0.125 mg/d

Findings

Electrocardiography. Sinus rhythm with PR interval of 147 ms and QRS interval of 98 ms

Echocardiography. Left ventricular ejection fraction (LVEF), stable at 42%; no significant valve disease; dilated left ventricle with global hypokinesis

Examination. Jugular venous pressure, 8 cm above the center of the right atrium (upper end of normal range); blood pressure, 137/76 mm Hg; heart rate, 58 beats/min; lungs clear; no peripheral edema

Cardiac Examination. Positive S3 present; 1/6 systolic ejection murmur at the left lower sternal border that decreases with Valsalva maneuver; enlarged and sustained point of maximum impulse

Question

Which one of the following is the most reasonable next step in the management of this patient?

  1. Prescribe a statin such as rosuvastatin, 5 mg/d
  2. Refer him to a cardiologist to be evaluated for an automatic implantable cardioverter-defibrillator (AICD)
  3. Refer him to a cardiologist to be evaluated for cardiac resynchronization therapy
  4. Initiate treatment with hydralazine and long-acting nitrates
  5. Increase furosemide to 80 mg/d

Discussion

Hydralazine and isosorbide dinitrate have been shown to be beneficial in patients intolerant of ACEIs or ARBs.1 This combination was shown to be more beneficial than placebo and comparable to enalapril in the early Department of Veteran Affairs studies.2 Recent updates have shown the benefit of hydralazine and isosorbide dinitrate when added to ACEIs or ARBs in African Americans.3 Doses should initally be low and then be up-titrated as tolerated to 50 mg of hydralazine 4 times daily and 40 mg of isosorbide dinitrate 3 times daily. In general, ACEIs and ARBs are used because adherence to a combined regimen of hydralazine and isosorbide dinitrate has been poor as a result of the large number of tablets required and adverse effects such as headaches that occur in some patients. A combined regimen of hydralazine and isosorbide dinitrate is a good option when ACEIs or ARBs cannot be used because of cough, hyperkalemia, or renal insufficiency. However, no trials have evaluated the use of this combination therapy in a population of patients who are intolerant of ACEIs and ARBs. In the current guidelines, this is a class IIb recommendation, meaning that it may be considered but is not without risk and that further studies are needed.

The patient's LVEF is high enough (>35%) that he does not meet criteria for an AICD and has no history of sudden cardiac death or ventricular tachycardia. He has a normal QRS interval and would not benefit from resynchronization therapy. Digoxin has been shown to be helpful in symptom relief in class III but not in class II patients. The patient's fluid status appears to be optimal, and so he is unlikely to benefit from an increased dose of diuretic agents.

Clinical Pearl

Hydralazine and isosorbide dinitrate can be effective therapy in patients unable to tolerate ACEIs and ARBs or in African Americans with heart failure.

Case 2

A 76-year-old man presents with shortness of breath on exertion that began 6 months ago and has since gradually worsened. He states that he can no longer perform normal activities without developing symptoms and that climbing more than one flight of stairs causes him to be profoundly short of breath, requiring him to stop and rest. When walking on level ground, he does well, but any hill causes dyspnea. He has a history of hypertension but no history of hyperlipidemia, diabetes, tobacco abuse, or family history of early coronary artery disease. He is taking no medications.

Findings

Electrocardiography. Normal sinus rhythm with normal intervals and no significant abnormality

Chest Radiography. Normal cardiac silhouette with clear lung fields

Echocardiography. LVEF, 64% with normal valves and normal left and right ventricular size and function; no regional wall motion abnormalities; normal wall thickness

Stress Test. Ability to walk for 4.8 min on Bruce protocol (78% of predicted functional aerobic capacity); heart rate, increased to 146 beats/min; blood pressure, 200/98 mm Hg; stopped test because of dyspnea; negative electrocardiographic findings for ischemia

Examination. Lungs clear; jugular venous pressure, elevated at 12 cm above the right atrium; peripheral edema, 1+; body mass index, 32 kg/m2

Question

Which one of the following actions would be least appropriate for this patient?

  1. Initiate treatment with an ACEI for blood pressure
  2. Initiate treatment with a diuretic agent to resolve his congestion and peripheral edema
  3. Recommend a regular exercise program, telling him to start low and increase gradually
  4. Encourage him to lose weight
  5. Refer him for coronary angiography

Discussion

The patient has heart failure with preserved ejection fraction (HFPEF). Recently, this entity has been shown to account for almost half of patients with symptoms of heart failure, specifically those with dyspnea on exertion, peripheral edema, or orthopnea. The long-term outcome (ie, mortality) of these patients is very similar to that of patients with decreased ejection fraction.

Heart failure with preserved ejection fraction is a particular problem in elderly patients. The prevalence of symptoms of heart failure increases from 3% in those aged 65 years to more than 80% in those older than 80 years. Heart failure is the most common reason for hospitalization in elderly patients, and the diagnosis of HFPEF is inadequately recognized and treated because both patients and physicians frequently attribute these symptoms to aging when echocardiography shows normal systolic function.4 Clinicians should always be alert to this diagnosis.

Although HFPEF can be associated with infiltrative diseases such as amyloidosis or, most commonly, with hypertension, it is also seen in patients with deconditioning, obesity, or coronary artery disease risk factors such as hyperlipidemia or diabetes. Patients with hypertension should be treated and volume overload appropriately managed. However, despite multiple randomized trials, no evidence suggests that patients without hypertension or fluid overload benefit from taking an ACEI, ARB, or β-blocker.5 Stress testing revealed no evidence of coronary artery disease in this patient. He has no significant risk factors, and coronary angiography is not indicated. Weight loss and a regular exercise program have been shown to be beneficial for symptoms; however, they do not necessarily reduce hospitalizations or major adverse cardiac events. Obesity is in the differential diagnosis along with hypertension.

Clinical Pearl

Accounting for one-half of all heart failure cases, HFPEF should be considered in patients (especially elderly patients) with unexplained dyspnea on exertion. In terms of long-term outcome and treatment, HFPEF is similar to heart failure with decreased ejection fraction.6

Case 3

A 66-year-old woman with known coronary artery disease has had 2 previous myocardial infarctions (MIs), the first 7 years previously and the second 11 months previously. After her last MI, her ejection fraction was documented to be 28%. She currently has class II NYHA heart failure.

Medications

Lisinopril, 40 mg/d

Carvedilol, 12.5 mg twice daily

Aldosterone, 25 mg/d

Aspirin, 81 mg/d

Pravastatin, 20 mg/d

Findings

Laboratory Tests. Sodium, 138 mEq/L (to convert to mmol/L, multiply by 1); potassium, 4.4 mmol/L; creatinine, 1.2 mg/dL (to convert to μmol/L, multiply by 88.4)

Echocardiography. Ejection fraction, 32% with mild mitral regurgitation; a markedly enlarged left ventricle with anterior wall hypokinesis

Electrocardiography. Heart rate, 60 beats/min with sinus rhythm; PR interval, 168 ms; QRS interval, 111 ms; corrected QT interval, 402 ms; prior anterior MI

Examination. Blood pressure, 116/72 mm Hg; heart rate, 60 beats/min and regular; jugular venous pressure, flat; no peripheral edema; lungs clear with good breath sounds at both bases

Cardiac Examination. Presence of S3 with an enlarged point of maximum impulse that is bifid; no murmur or rub

Question

Which one of the following would be the best therapy for this patient?

  1. Given that she has NYHA class II heart failure, continue current therapy
  2. Add in a diuretic agent such as furosemide, 20 mg/d
  3. Add in digoxin, 0.125 mg, every 6 hours for 4 times, 0.125 mg/d orally
  4. Refer for cardiac resynchronization therapy
  5. Refer for evaluation for an AICD

Discussion

This patient with class II NYHA heart failure is doing quite well and is already taking all the recommended medications, including those for afterload reduction (ACEIs/ARBs), good doses of β-blocker (metoprolol or carvedilol), and an aldosterone-inhibiting diuretic agent (spironolactone or eplerenone). A diuretic agent is not indicated because her examination revealed no peripheral edema or congestion. Digoxin is not indicated because the patient's functional class II heart failure is stable. Because her QRS interval is of normal width, it is unlikely that she would benefit from cardiac resynchronization therapy, which should be considered in patients with left bundle branch block or a widening QRS interval.7 To further evaluate the need for cardiac resynchronization therapy, echocardiography can be performed to evaluate dyssynchrony of the ventricular contraction. However, the American Society of Echocardiography guidelines suggest that echocardiography criteria not be used as part of the selection criteria for cardiac resynchronization therapy. The patient's ejection fraction has been depressed (<35%) for 11 months while she was receiving good medical therapy, and so she would meet indications for an AICD, which has been shown to decrease mortality more than routine care and/or antiarrhythmic therapy.8

Indications for AICD

Ischemic heart failure with prior MI and LVEF <35%.

Nonischemic heart failure with LVEF <35% for at least 9 months while receiving good medical therapy

Documented episode of cardiac arrest due to ventricular fibrillation, not due to transient or reversible cause

Documented sustained ventricular tachycardia, either spontaneous or induced by an electrophysiology study; not associated with an acute MI and not due to a transient or reversible cause

Documented familial or inherited conditions with a high risk of life-threatening ventricular tachycardia, such as long-QT syndrome or hypertrophic cardiomyopathy with a family history of sudden cardiac death. Exclusion criteria are NYHA class IV heart failure, cardiogenic shock, coronary artery bypass grafting or percutaneous coronary intervention in the past 3 months, a documented need for revascularization, irreversible brain damage, or anticipated survival of <1 year

Clinical Pearl

In patients with heart failure and prolonged depression of LVEF (<35%) while receiving optimal medical management, AICD has been shown to decrease mortality and should be considered.

Case 4

A 68-year-old man follows up with you after a hospitalization 2 weeks previously for an episode of acutely decompensated heart failure. During the hospitalization, he had undergone diuresis with intravenous furosemide to eliminate 4.5 kg (10 lb) of fluid. He has decreased left ventricular function, thought to be secondary to chronic mitral regurgitation. The patient's mitral valve had been repaired 2 years ago, but his ejection fraction of 42% has not improved significantly since then. He has a dilated left ventricle and has symptoms characteristic of functional NYHA class II heart failure.

The patient has trouble adhering to a sodium- and fluid-restricted diet. He lives alone and cooks his own food and tends to eat high-sodium items despite having been instructed by the dietitian many times not to do so.

Medications

Furosemide, 20 mg in the morning

Metoprolol, 25 mg/d

Lisinopril, 10 mg at bedtime

Findings

Laboratory Tests. Creatinine, 1.4 mg/dL; estimated glomerular filtration rate, 46 mL/min/1.73 m2 (reference range, >60 mL/min/1.73 m2); potassium, 4.5 mmol/L; clear lung fields with enlarged cardiac silhouette on cardiac radiography

Examination. Height, 177 cm; weight, 99 kg; blood pressure, 118/76 mm Hg; heart rate, 62 beats/min and regular; both lung bases clear; no edema in the extremities

Cardiac Examination. Enlarged bifid; lateral point of maximal impulse; 1/6 holosystolic murmur at the apex that decreases with Valsalva maneuver; positive S3; no S4; jugular venous pressure, 8 cm above the right atrium

Question

Which one of the following is the next best step in the treatment of this patient?

  1. Increase dose of lisinopril to 20 mg/d
  2. Add 30 mg of isosorbide mononitrate in the morning and increase to 60 mg as tolerated
  3. Refer to a dietitian for a low-sodium, fluid-restricted (1500 mL) diet
  4. Request that he weigh each morning; provide a schedule for increasing furosemide if he gains weight
  5. Refer him to an electrophysiologist for possible AICD implantation

Discussion

It has been shown that 76% of patients who are hospitalized for acute decompensated heart failure have a history of heart failure. A substantial increase in extracellular fluid volume may occur without evidence of peripheral edema or pulmonary congestion. An increase in self-reported body weight has been shown to occur about 11 days before a hospital admission for acute decompensated heart failure and about 3 days before the onset of dyspnea. Compared with a mean increase in weight of less than .91 kg (<2 lb), a weight gain between .91 and 2.3 kg (2-5 lb) is associated with an odds ratio (OR) of increased risk of hospitalization for heart failure of 2.8; between 2.3 to 4.5 kg (5-10 lb), with an OR of 4.5; and greater than 4.5 kg (10 lb), with an OR of 7.7.9 When a patient's weight increases by more than .91 kg (2 lb) in a day or 2.3 kg (5 lb) overall, it is beneficial to have the patient either call the nurse for instructions for increasing the dose of diuretic agents or double the furosemide dose for 3 days. The dose of supplemental potassium should be increased during this time.

Clinical Pearl

Increases in body weight are associated with hospitalization for heart failure and begin at least 1 week before admission. Identifying weight gain and treating it by increasing the dose of diuretic agents have been shown to be effective in reducing hospitalizations due to acute decompensated heart failure.10

Case 5

A 73-year-old woman with left ventricular systolic dysfunction whom you have been treating for several years presents to the emergency department. She is having palpitations and is diagnosed as having atrial fibrillation (heart rate, 130 beats/min) in the emergency department. She denies chest pain but is mildly short of breath with a rapid ventricular rate. The patient is not sure how long she has been having palpitations; she thinks they have been intermittent during the past few months but have always resolved after a few minutes. This episode, however, lasted for more than 2 hours, prompting her to seek treatment.

Medical History

Hypertension well controlled with hydrochlorothiazide

History of hypothyroidism treated medically with normal findings on sensitive thyroid-stimulating homone test

No history of bleeding problems, strokes, or transient ischemic attacks

No syncope or presyncope

Known coronary artery disease with 3-vessel coronary artery bypass graft performed 11 years previously

Medications

Hydrochlorothiazide, 25 mg/d

Lisinopril, 20 mg/d

Metoprolol, 12.5 mg/d

Aspirin, 81 mg/d

Social History

Not physically active

Lives in a high-rise retirement complex

Findings

Labortory Tests. Sensitive thyroid-stimulating hormone test, normal; electrolyte levels, normal; complete blood cell count, normal; troponin level, normal

Electrocardiography. Atrial fibrillation; old inferolateral MI; no acute ST-T changes

Echocardiography. Biatrial enlargement with enlarged left ventricle and decreased function; ejection fraction, 34%; evidence of prior inferolateral MI

Examination. Height, 167 cm; weight, 63 kg; lungs clear; rhythm, irregularly irregular; 1/6 systolic ejection murmur at the lower left sternal border; no edema

Question

Which one of the following is the best therapy for this woman with systolic left ventricular dysfunction presenting with atrial fibrillation?

  1. Control heart rate with β-blockers and/or digoxin and provide anticoagulation with warfarin to an international normalized ratio of 2 to 3
  2. Administer antiarrhythmic propafenone and perform direct-current cardioversion
  3. Administer antiarrhythmic propafenone, perform transesophageal echocardiography to rule out left atrial thombus, and perform direct-current cardioversion
  4. Refer to an electrophysiologist for consideration of atrioventricular node ablation with pacemaker implantation and long-term anticoagulation
  5. Refer to an electrophysiologist for pulmonary vein isolation ablation to eradicate the atrial fibrillation

Discussion

The best option is to control the patient's heart rate with β-blockers and/or digoxin and to provide anticoagulation with warfarin to an international normalized ratio of 2 to 3.

A 2008 study evaluated the hypothesis that patients with heart failure and atrial fibrillation need to be returned to sinus rhythm.11 The long-held belief was that patients with heart failure particularly needed their atrial kick to help their cardiac output and that patients with low ejection fraction should be returned to sinus rhythm. However, in this large study, no benefit was achieved by returning these patients to sinus rhythm. Patients prescribed class 1 antiarrhythmic agents were found not to respond favorably and were predisposed to proarrhythmic effects.12 Class 3 antiarrhythmic agents, such as sotalol, dofetilide, and amiodarone, can maintain sinus rhythm in some patients; however, treatment with these agents is associated with increased risk of organ toxicity (amiodarone) and proarrhythmic effects (dofetilide). Returning a patient to sinus rhythm has not been shown to obviate the need for long-term anticoagulation. Therefore, the best option is to control heart rate and recommend long-term anticoagulation. If controlling the heart rate is not possible, the next best option would be to consider atrioventricular node ablation with permanent pacemaker implantation; these patients would still need to continue anticoagulation therapy. Patients with an enlarged left atrium have less long-term benefit from the encircling atrial fibrillation ablation.

Clinical Pearl

Even in patients with heart failure and atrial fibrillation, heart rate control combined with anticoagulation therapy is the preferred first-line treatment for atrial fibrillation.

Case 6

A 78-year-old woman whom you have been treating for the past 10 years for chronic functional NYHA class III heart failure (ejection fraction, 28%) was admitted to the hospital 3 days previously for an episode of heart failure. A year earlier, she had an AICD/cardiac resynchronization device implanted. Since being admitted to the hospital, she has undergone diuresis (3.6 kg [8 lb]) and feels much better. You are ready to dismiss her today, with instructions to continue her usual home regimen of medications: furosemide, 20 mg; potassium 20 mmol/L; carvedilol, 25 mg twice a day; and lisinopril, 20 mg in the evening. The patient weighs herself daily and takes extra furosemide and potassium when her weight increases. She is currently adhering to a low-sodium diet with a 1500-mL fluid restriction. Her level of the N-terminal fragment of pro–brain-type natriuretic peptide (NT-proBNP) is 2186 pg/mL (to convert to ng/L, multiply by 1) (optimal for those >75 years, 1800 pg/mL). The etiology of her heart failure is coronary artery disease, but her last stress test 4 months previously showed a fixed anterior defect but no evidence of ischemia.

Question

Which one of the following would be the best treatment option for this patient at this point in her care?

  1. Continuation of current therapy
  2. Addition of an aldosterone inhibitor, such as spironolactone or eplerenone
  3. Augmentation of current therapy to reduce her NT-proBNP levels to normal and her functional status to NYHA class II or less
  4. Switch from carvedilol to metoprolol
  5. Follow-up stress test

Discussion

Addition of an aldosterone antagonist is recommended in patients with moderately severe to severe symptoms of heart failure (NYHA class III-IV) and reduced LVEF.13 An initial dose of 12.5 mg of spironolactone or 25 mg of eplerenone is recommended; if appropriate, the dose may be increased to 25 mg of spironolactone or 50 mg of eplerenone.

Levels of creatinine should be 2.5 mg/dL or less in men and 2.0 mg/dL or less in women, and potassium levels should be less than 5 mmol/L without a history of severe hyperkalemia. If monitoring the potassium or renal function is not feasible, then the risks may outweigh the benefits of aldosterone agents. Such therapy is not currently recommended without concomitant diuretic therapy in patients with chronic heart failure. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors should be avoided. The risk of hyperkalemia is increased with concomitant use of higher doses of ACEIs (captopril ≥75 mg/d; enalapril or lisinopril, ≥10 mg/d). The risk of hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL. In elderly patients or others with low muscle mass in whom the serum creatinine level does not accurately reflect glomerular filtration rate, it should be determined that glomerular filtration rate or creatinine clearance exceeds 30 mL/min. Diarrhea or other causes of dehydration should be addressed emergently.

Metoprolol has not been shown to be superior to carvedilol for treatment of patients with heart failure. Using standard medical therapy to treat to a NYHA class II or less heart failure has been compared to using it to achieve that goal and to lower NT-proBNP or BNP levels. Lowering the BNP or NT-proBNP levels has consistently been shown not to add benefit above that achieved by treating patients to NYHA class II or less heart failure.13 Therefore, it is not recommended that BNP levels be followed up regularly for treatment. However, BNP levels have been helpful in making a diagnosis for patients with unexplained dyspnea (who commonly present to the emergency department). Also, a BNP level of less than 600 pg/mL at the time of hospital discharge for acute decompensated heart failure correlates with a lower recurrent cardiovascular event rate.14,15

Clinical Pearl

Addition of aldosterone inhibitors has been recommended for patients with NYHA class III or IV heart failure to reduce symptoms and morbidity. Treating patients to achieve a certain BNP or NT-proBNP level does not help prevent recurrent episodes of acute decompensated heart failure any more than treating to symptoms of NYHA class II heart failure.

Notes

See end of article for correct answers to questions.

Correct answers: Case 1: d, Case 2: e, Case 3: e, Case 4: d, Case 5: a, Case 6: b

REFERENCES

1. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-310 [PubMed]
2. Loeb HS, Johnson G, Henrick A, et al. V-HeFT VA Cooperative Studies Group Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. Circulation 1993;87:VI78-VI87 [PubMed]
3. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057 [PubMed]
4. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-259 [PubMed]
5. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-781 [PubMed]
6. Kupari M, Lindroos M, Iivanainen AM, Heikkila J, Tilvis R. Congestive heart failure in old age: prevalence, mechanisms and 4-year prognosis in the Helsinki Ageing Study. J Intern Med. 1997;241:387-394 [PubMed]
7. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237 [PubMed]
8. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883 [PubMed]
9. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns of weight change preceding hospitalization for heart failure. Circulation 2007;116:1549-1554 [PMC free article] [PubMed]
10. Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure: symptoms, patterns of onset, and contributing factors. Am J Med. 2003;114:625-630 [PubMed]
11. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667-2677 [PubMed]
12. Boos CJ, Carlsson J, More RS. Rate or rhythm control in persistent atrial fibrillation? QJM 2003;96:881-892 [PubMed]
13. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717 [PubMed]
14. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119(14):1977-2016 [PubMed]
15. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006;27:330-337 [PubMed]

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