Editors: Foster, Corey; Mistry, Neville F.; Peddi, Parvin F.; Sharma, Shivak

Title: Washington Manual® of Medical Therapeutics, The, 33rd Edition

Copyright ©2010 Lippincott Williams & Wilkins

> Table of Contents > 4 - Heart Failure, Cardiomyopathy, and Valvular Heart Disease

4

Heart Failure, Cardiomyopathy, and Valvular Heart Disease

Brian R. Lindman

Stacy A. Mandras

Benico Barzilai

Susan M. Joseph

Gregory A. Ewald

Heart Failure

GENERAL PRINCIPLES

Definition

Heart failure (HF) is a clinical syndrome in which either structural or functional abnormalities in the heart impair its ability to meet the metabolic demands of the body. HF is a progressive disorder and is associated with extremely high morbidity and mortality.

Classification

HF may be due to abnormalities in myocardial contraction (systolic dysfunction), relaxation and filling (diastolic dysfunction), or both.

Almost half of patients admitted with HF have preserved systolic function.

HF may be classified either by ACC/AHA HF stage or by New York Heart Association (NYHA) Functional Class (Tables 1 and 2).

Epidemiology

In the United States there are approximately 5 million people living with HF.

Over 550,000 new cases of HF are diagnosed each year.

HF accounts for over 1 million hospitalizations per year.

Estimated 1- and 5-year mortality is 30% and 50%, respectively.

Etiology

Coronary artery disease (CAD) is the most frequent cause of HF in the United States, accounting for over 50% of cases (Arch Intern Med 2001;161:996). Diabetes and hypertension are other major contributors.

Other causes include valvular heart disease, toxins induced (alcohol, cocaine, chemotherapy), myocarditis (infectious or autoimmune), familial cardiomyopathy, infiltrative disease (amyloidosis, sarcoidosis, hemochromatosis), peripartum cardiomyopathy, hypertrophic cardiomyopathy [HCM], constrictive pericardial disease, high-output states (i.e., arteriovenous malformation or fistula), generalized myopathy (Duchenne or Becker muscular dystrophy), tachycardia-induced cardiomyopathy, and idiopathic cardiomyopathy.

HF is often precipitated by dietary and medication noncompliance; however, myocardial ischemia, HTN, arrhythmias (particularly atrial fibrillation), infection, volume overload, alcohol/toxins, thyroid disease, drugs (nonsteroidal

P.156

anti-inflammatory drugs [NSAIDs], calcium channel blockers [CCBs], doxorubicin), and pulmonary embolism are also potential triggers.

Table 1 American College of Cardiology/American Heart Association Guidelines of Evaluation and Management of Chronic Heart Failure in Adults

Stage

Description

Treatment

A

No structural heart disease and no symptoms but risk factors: CAD, HTN, DM, cardio toxins, familial cardiomyopathy

Lifestyle modification—diet, exercise, smoking cessation; treat hyperlipidemia and use ACEI for HTN

B

Abnormal LV systolic function, MI, valvular heart disease but no HF symptoms

Lifestyle modifications, ACEI, β-adrenergic blockers

C

Structural heart disease and HF symptoms

Lifestyle modifications, ACEI, β-adrenergic blockers, diuretics, digoxin

D

Refractory HF symptoms to maximal medical management

Therapy listed under A, B, C and mechanical assist device, heart transplantation, continuous IV inotropic infusion, hospice care in selected patients

ACEI, angiotensin-converting enzyme inhibitor; CAD, coronary artery disease; DM, diabetes mellitus; HF, heart failure; HTN, hypertension; LV, left ventricular; MI, myocardial infarction. Adapted from Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. J Am Coll Cardiol 2005;46:1116-1143.

Pathophysiology

HF begins with injury to or stress on the heart.

Regardless of etiology, the myocardial injury is associated with adverse remodeling, manifested as an increase in left ventricular (LV) size (dilation) and/or mass

P.157

(hypertrophy), and a change in shape (the heart becomes more spherical). These changes in geometry result in hemodynamic stresses on the heart and further impair cardiac function.

Compensatory adaptations occur, including activation of the renin-angiotensin-aldosterone system (RAAS) and vasopressin (antidiuretic hormone), which lead to increased sodium retention and peripheral vasoconstriction. The sympathetic nervous system is also activated, with increased levels of circulating catecholamines, resulting in increased myocardial contractility. Ultimately these neurohormonal pathways result in direct cellular toxicity, fibrosis, arrhythmias, and pump failure.

The reduction in cardiac output results in organ hypoperfusion, and pulmonary and systemic venous congestion.

Table 2 New York Heart Association Functional Classification

NYHA class

Symptoms

I (mild)

No symptoms or limitation while performing ordinary physical activity (walking, climbing stairs, etc.)

II (mild)

Mild symptoms (mild shortness of breath, palpitations, fatigue, and/or angina) and slight limitation during ordinary physical activity

III (moderate)

Marked limitation in activity due to symptoms, even during less-than-ordinary activity (walking short distances [20-100 m]). Comfortable only at rest

IV (severe)

Severe limitations with symptoms even while at rest. Mostly bedbound patients

DIAGNOSIS

Clinical Presentation

Affected patients most commonly present with symptoms of HF including:

Dyspnea (on exertion and/or at rest)

Fatigue

Exercise intolerance

Orthopnea, paroxysmal nocturnal dyspnea

Systemic or pulmonary venous congestion (lower extremity swelling or cough/wheezing)

Presyncope, palpitations, and angina may also be present

Other presentations include incidental detection of asymptomatic cardiomegaly or symptoms related to coexisting arrhythmia, conduction disturbance, thromboembolic complications, or sudden death (J Am Coll Cardiol 1989;13:1219; N Engl J Med 1994;331:1564).

Clinical manifestations of HF vary depending on the rapidity of cardiac decompensation, underlying etiology, age, and comorbidities of the patient.

Extreme decompensation presents as hypoperfusion of vital organs with renal failure (decreased urine output), mental status changes (confusion and lethargy), and cardiogenic shock.

Physical Examination

Systemic and pulmonary venous congestion result in lower extremity edema, pulmonary crackles, jugular venous distension, diminished carotid upstrokes, pleural and pericardial effusions, hepatic congestion, and ascites.

Third or fourth heart sound may be present, as well as the holosystolic murmurs of tricuspid or mitral regurgitation (MR).

Diagnostic Testing

Laboratories

Initial laboratory studies should include complete blood count, comprehensive metabolic panel (including electrolytes, BUN, creatinine, calcium, magnesium, fasting glucose, and liver function tests), fasting lipid profile, urinalysis, and thyroid function tests.

B-type natriuretic peptide (BNP) is released by myocytes in response to stretch, volume overload, and increased filling pressures. Elevated BNP is present in patients with asymptomatic LV dysfunction as well as symptomatic HF.

P.158

BNP levels have been shown to correlate with HF severity and predict survival (N Engl J Med 2002;347:161). A serum BNP > 400 is consistent with HF; however, specificity is reduced in patients with renal dysfunction. A serum BNP level < 100 has a good negative predictive value to exclude HF in patients presenting with dyspnea (Curr Opin Cardiol 2006;21:208).

Additional laboratory testing in a patient with new-onset HF without CAD should include diagnostic tests for HIV, hepatitis, and hemochromatosis. When clinically suspected, serum tests for rheumatologic diseases (ANA, ANCA, etc.), amyloidosis (SPEP/UPEP), or pheochromocytoma should be considered (Circulation 2009;119:1977).

Electrocardiography

An electrocardiogram (ECG) should be performed to look for evidence of ischemia (ST-T wave abnormalities), previous myocardial infarction (MI) (Q waves), conduction delays, and arrhythmias (supraventricular and ventricular).

Imaging

Chest radiography should also be performed to evaluate the presence of pulmonary edema or cardiomegaly, and rule out other etiologies of dyspnea (pneumonia, pneumothorax).

An echocardiogram should be performed to assess LV function and structure, evaluate valvular heart disease, and exclude cardiac tamponade.

LV function may also be evaluated using radionuclide ventriculography or cardiac catheterization with ventriculography.

Cardiac magnetic resonance imaging (MRI) may also be useful in assessing ventricular function and evaluating the presence of valvular heart disease, infiltrative cardiomyopathies (amyloid and sarcoid), myocarditis, and previous MI.

Diagnostic Procedures

Coronary angiography should be performed in patients with angina or evidence of ischemia by ECG or stress testing unless the patient is not a candidate for revascularization (Circulation 2009;119:1977).

Right heart catheterization with placement of a pulmonary artery (PA) catheter may help guide therapy in patients with hypotension and evidence of shock.

Cardiopulmonary exercise testing with measurement of peak oxygen consumption is useful in assessing functional capacity and in identifying candidates for heart transplantation (Circulation 2009;83:778; J Heart Lung Transplant 2003;22:70).

Endomyocardial biopsy may be useful in making the diagnosis if infiltrative cardiomyopathy is suspected; however in most cases of nonischemic cardiomyopathy, only nonspecific findings of hypertrophy or fibrosis are seen and biopsy results rarely alter management (Eur Heart J 2007;28:3076; Circulation 2009;119:1977).

TREATMENT

Medications

In general, pharmacologic therapy in chronic HF is aimed at blocking the neurohormonal pathways that contribute to the progression of HF, and reducing symptoms, hospitalizations, and mortality.

The cornerstone of medical therapy for HF includes vasodilators, β-adrenergic blockade, and diuretic therapy for volume overload. Most patients require a multidrug regimen.

P.159

β-Adrenergic receptor antagonists (β-blockers) (Table 3). β-Blockers are a critical component of HF therapy and work by blocking the toxic effects of chronic adrenergic stimulation on the heart.

Many large randomized trials have documented the beneficial effects of β-blockers on functional status, disease progression, and survival in patients with NYHA class II-IV symptoms.

Improvement in ejection fraction (EF), exercise tolerance, and functional class are common after the institution of a β-blocker.

P.160

Typically, 2 to 3 months of therapy is required to observe significant effects on LV function, but reduction of cardiac arrhythmia and incidence of sudden cardiac death (SCD) may occur much earlier (JAMA 2003;289:712).

β-Blockers should be instituted at a low dose and titrated with careful attention to blood pressure (BP) and heart rate. Some patients experience volume retention and worsening HF symptoms that typically respond to transient increases in diuretic therapy.

Individual β-blockers have unique properties, and the beneficial effect of β-blockers may not be a class effect. Therefore, one of three β-blockers with proven benefit on mortality in large clinical trials should be used (Circulation 2009;119: 1977; Circulation 2005;112:e154):

Carvedilol (N Engl J Med 2001;344:1651; Lancet 2003;362:7)

Metoprolol succinate (JAMA 2000;283:1295)

Bisoprolol (Lancet 1999;353:9)

Vasodilators

Vasodilator therapy is a mainstay of treatment in patients with HF. The RAAS and sympathetic nervous system, as well as increased secretion of arginine vasopressin increase arterial vasoconstriction (afterload) and venous vasoconstriction (preload) in patients with HF. Agents with predominantly venodilatory properties decrease preload and ventricular filling pressures. In the absence of LV outflow tract obstruction, arterial vasodilators reduce afterload by decreasing systemic vascular resistance (SVR), resulting in increased cardiac output, decreased ventricular filling pressure, and decreased myocardial wall stress. The efficacy and toxicity of vasodilator therapy depend on intravascular volume status and preload. Vasodilators should be used with caution in patients with a fixed cardiac output [e.g., aortic stenosis (AS) or HCM] or with predominantly diastolic dysfunction.

Oral vasodilators should be the initial therapy in patients with symptomatic chronic HF and in patients in whom parenteral vasodilators are being discontinued. When treatment with oral vasodilators is being initiated in hypotensive patients, it is prudent to use agents with a shorter half-life.

ACE (angiotensin-converting enzyme) inhibitors (Table 3) attenuate vasoconstriction, vital organ hypoperfusion, hyponatremia, hypokalemia, and fluid retention attributable to compensatory activation of the renin-angiotensin system. They are the first choice for antagonism of the RAAS.

Multiple large clinical trials have clearly demonstrated that ACE inhibitors improve symptoms and survival in patients with LV systolic dysfunction (Circulation 2009;119:1977; Circulation 2005;112:e154).

ACE inhibitors may also prevent the development of HF in patients with asymptomatic LV dysfunction and in those at high risk of developing structural heart disease or HF symptoms (i.e., patients with CAD, diabetes mellitus, HTN). Currently, no consensus has been reached regarding the optimal dosing of ACE inhibitors in HF, although higher doses have been shown to reduce morbidity without improving overall survival (Circulation 1999;100:2312).

Absence of an initial beneficial response to treatment with an ACE inhibitor does not preclude long-term benefit.

Most ACE inhibitors are excreted by the kidneys, necessitating careful dose titration in patients with renal insufficiency. Acute renal insufficiency may occur in patients with bilateral renal artery stenosis. Additional adverse effects include rash, angioedema, dysgeusia, increases in serum creatinine, proteinuria, hyperkalemia, leukopenia, and cough.

P.161

Oral potassium supplements, potassium salt substitutes, and potassium-sparing diuretics should be used with caution during treatment with an ACE inhibitor.

Agranulocytosis and angioedema are more common with captopril than with other ACE inhibitors, particularly in patients with associated collagen vascular disease or serum creatinine >1.5 mg/dL.

ACE inhibitors are contraindicated in pregnancy.

Angiotensin II receptor blockers (ARBs) (Table 3) inhibit the renin-angiotensin system via specific blockade of the angiotensin II receptor.

ARBs reduce morbidity and mortality associated with HF in patients who are not receiving an ACE inhibitor (N Engl J Med 2001;345:1667; Lancet 2000;355:1582; Lancet 2003;362:777), and therefore should be instituted when ACE inhibitors are not tolerated (Circulation 2009;119:1977; Circulation 2005;112:e154).

In contrast to ACE inhibitors, they do not increase bradykinin levels, which may be responsible for the cough associated with ACE inhibitors.

Caution should be exercised when ARBs are used in patients with renal insufficiency and bilateral renal artery stenosis because hyperkalemia and acute renal failure can develop.

Renal function and potassium levels should be periodically monitored.

ARBs are contraindicated in pregnancy.

Hydralazine acts directly on arterial smooth muscle to produce vasodilation and to reduce afterload. In combination with nitrates, hydralazine improves survival in patients with HF (N Engl J Med 1986;314:1547).

A combination of hydralazine and isosorbide dinitrate (starting dose: 37.5/20 mg three times daily) when added to standard therapy with β-blockers and ACE inhibitors has been shown to reduce mortality in black patients (N Engl J Med 2004;351:2049).

Reflex tachycardia and increased myocardial oxygen consumption may occur, requiring cautious use in patients with ischemic heart disease.

Nitrates are predominantly venodilators and help relieve symptoms of venous and pulmonary congestion. They reduce myocardial ischemia by decreasing ventricular filling pressures and by directly dilating coronary arteries. Nitrate therapy may precipitate hypotension in patients with reduced preload.

Parenteral vasodilators should be reserved for patients with severe HF or those who are unable to take oral medications. Intravenous vasodilator therapy may be guided by central hemodynamic monitoring (PA catheterization) to assess efficacy and avoid hemodynamic instability. Parenteral agents should be started at low doses, titrated to the desired hemodynamic effect, and discontinued slowly to avoid rebound vasoconstriction.

Nitroglycerin is a potent vasodilator, with effects on venous and, to a lesser extent, arterial vascular beds. It relieves pulmonary and systemic venous congestion and is an effective coronary vasodilator. Nitroglycerin is the preferred vasodilator for treatment of HF in the setting of acute MI or unstable angina.

Sodium nitroprusside is a direct arterial vasodilator with less potent venodilatory properties. Its predominant effect is to reduce afterload, and it is particularly effective in patients with HF who are hypertensive or who have severe aortic or mitral valvular regurgitation. Nitroprusside should be used cautiously in patients with myocardial ischemia because of a potential reduction in regional myocardial blood flow (coronary steal).

The initial dose of 0.25 mcg/kg/min can be titrated (maximum dose of 10 mcg/kg/min) to the desired hemodynamic effect or until hypotension develops. The

P.162

half-life of nitroprusside is 1 to 3 minutes, and its metabolism results in the release of cyanide, which is metabolized by the liver to thiocyanate and is then excreted via the kidney.

Toxic levels of thiocyanate (>10 mg/dL) may develop in patients with renal insufficiency. Thiocyanate toxicity is manifested as nausea, paresthesias, mental status changes, abdominal pain, and seizures.

Methemoglobinemia is a rare complication of treatment with nitroprusside.

Recombinant BNP (nesiritide) is an arterial and venous vasodilator.

Intravenous infusion of nesiritide reduces right atrial and LV end-diastolic pressures (LVEDP) and SVR and results in an increase in cardiac output.

It is administered as a 2-mcg/kg IV bolus, followed by a continuous IV infusion starting at 0.01 mcg/kg/min. Nesiritide is approved for use in acute HF exacerbations and relieves HF symptoms early after its administration (JAMA 2002;287:1531).

It should not be used to improve renal function or to enhance diuresis. Nesiritide is not recommended for intermittent outpatient use.

Hypotension is the most common side effect of nesiritide, and its use should be avoided in patients with systemic hypotension (systolic BP < 90 mm Hg) or evidence of cardiogenic shock. Episodes of hypotension should be managed with discontinuation of nesiritide and cautious volume expansion or pressor support if necessary.

Enalaprilat is an active metabolite of the ACE inhibitor enalapril that is available for IV administration. Its onset of action is more rapid and its pharmacologic half-life shorter than that of enalapril. The initial dosage is 1.25 mg IV q6h, which can be titrated to a maximum dosage of 5 mg IV q6h. Patients who take diuretics or those with impaired renal function (serum creatinine > 3 mg/dL, creatinine clearance < 30 mL/min) should initially receive 0.625 mg IV q6h. When dosing is being converted from IV to PO administration, enalaprilat, 0.625 mg IV q6h, is approximately equivalent to enalapril, 2.5 mg PO daily.

α-Adrenergic receptor antagonists have not been shown to improve survival in HF, and hypertensive patients treated with doxazosin as first-line therapy had an increased risk of developing HF (JAMA 2000;283:1967).

Digitalis glycosides increase myocardial contractility and may attenuate the neurohormonal activation associated with HF. Digoxin decreases the number of HF hospitalizations without improving overall mortality (N Engl J Med 1997;336:525).

Discontinuation of digoxin in patients who are stable on a regimen of digoxin, diuretics, and an ACE inhibitor may result in clinical deterioration (N Engl J Med 1993;329:1).

The usual daily dose is 0.125 to 0.25 mg and should be decreased in patients with renal insufficiency. Clinical benefits may not be related to the serum levels, and, although serum digoxin levels of 0.8 to 2.0 ng/mL are considered “therapeutic,” toxicity can occur in this range.

The toxic-therapeutic ratio is narrow, and serum levels should be followed closely, particularly in patients with unstable renal function.

Observations suggest that women and patients with higher serum digoxin levels (1.2 to 2.0 ng/mL) have an increased mortality risk (JAMA 2003;289:871; N Engl J Med 2002;347:1403).

Drug interactions with digoxin are common. Oral antibiotics such as erythromycin and tetracycline may increase digoxin levels by 10% to 40%. Quinidine, verapamil, flecainide, and amiodarone also increase digoxin levels significantly.

P.163

Digoxin toxicity may be caused or exacerbated by drug interactions, electrolyte abnormalities (particularly hypokalemia), hypoxemia, hypothyroidism, renal insufficiency, and volume depletion.

Diuretic therapy (Table 3), in conjunction with restriction of dietary sodium and fluids, often leads to clinical improvement in patients with symptomatic HF. Frequent assessment of the patient's weight along with careful observation of fluid intake and output is essential during initiation and maintenance of therapy. Frequent complications of therapy include hypokalemia, hyponatremia, hypomagnesemia, volume contraction alkalosis, intravascular volume depletion, and hypotension. Serum electrolytes, BUN, and creatinine levels should be followed after institution of diuretic therapy. Hypokalemia may be life threatening in patients who are receiving digoxin or in those who have severe LV dysfunction that predisposes them to ventricular arrhythmias. Potassium supplementation or a potassium-sparing diuretic should be considered in addition to careful monitoring of serum potassium levels.

Thiazide diuretics (hydrochlorothiazide, chlorthalidone) can be used as initial agents in patients with normal renal function in whom only a mild diuresis is desired. Metolazone, unlike other thiazides, exerts its action at the proximal as well as the distal tubule and may be useful in combination with a loop diuretic in patients with a low glomerular filtration rate.

Loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid) should be used in patients who require significant diuresis and in those with markedly decreased renal function.

Furosemide reduces preload acutely by causing direct venodilation when administered IV, making it useful for managing severe HF or acute pulmonary edema.

Use of loop diuretics may be complicated by hyperuricemia, hypocalcemia, ototoxicity, rash, and vasculitis. Furosemide and bumetanide are sulfa derivatives and may rarely cause drug reactions in sulfa-sensitive patients. Ethacrynic acid can generally be used safely in such patients.

Potassium-sparing diuretics do not exert a potent diuretic effect when used alone.

Spironolactone (12.5 to 25 mg daily) is an aldosterone receptor antagonist that has been shown to improve survival and decrease hospitalizations in NYHA class III-IV patients with low EF (N Engl J Med 1999;341:709) and is therefore indicated in such patients if the creatinine is <2.5 mg/dL and potassium is <5.0 mEq/L (Circulation 2009;119:1977).

The potential for development of life-threatening hyperkalemia exists with the use of these agents. Gynecomastia may develop in 10% to 20% of men treated with spironolactone. Serum potassium must be monitored closely after initiation; concomitant use of ACE inhibitors and NSAIDs and the presence of renal insufficiency increase the risk of hyperkalemia.

Eplerenone, a selective aldosterone receptor antagonist without the hormonal side effects of spironolactone, is Food and Drug Administration (FDA)-approved drug for treatment of HTN and HF and reduces mortality in patients with HF associated with acute MI (N Engl J Med 2003;348:1309).

Inotropic agents

Sympathomimetic agents are potent drugs that are primarily used to treat severe HF. Beneficial and adverse effects are mediated by stimulation of myocardial β-adrenergic receptors. The most important adverse effects are related to the arrhythmogenic nature of these agents and the potential for exacerbation of myocardial ischemia. Treatment should be guided by careful hemodynamic and ECG monitoring. Patients with refractory chronic HF may benefit symptomatically

P.164

from continuous ambulatory administration of IV inotropes as palliative therapy or as a bridge to mechanical ventricular support or cardiac transplantation. However, this strategy may increase the risk of life-threatening arrhythmias or indwelling catheter-related infections (Circulation 2009;119:1977; Circulation 2005; 112:e154).

Dopamine (Table 4) should be used primarily for stabilization of the hypotensive patient.

Dobutamine (Table 4) is a synthetic analog of dopamine. Dobutamine tolerance has been described, and several studies have demonstrated increased mortality in patients treated with continuous dobutamine. Dobutamine has no significant role in the treatment of HF resulting from diastolic dysfunction or a high-output state.

Phosphodiesterase inhibitors increase myocardial contractility and produce vasodilation by increasing intracellular cyclic adenosine monophosphate. Milrinone is currently available for clinical use and is indicated for treatment of refractory HF. Hypotension may develop in patients who receive vasodilator therapy or have intravascular volume contraction, or both. Milrinone may improve hemodynamics in patients who are treated concurrently with dobutamine or dopamine. Data suggest that in-hospital short-term milrinone administration in addition to standard medical therapy does not reduce the length of hospitalization or the 60-day death or rehospitalization rate when compared with placebo (JAMA 2002;287:1541).

Table 3 Drugs Commonly Used for Treatment of Heart Failure

Drug

Initial dose

Target

Angiotensin-converting enzyme inhibitors

Captopril

6.25-12.5 mg q6-8h

50 mg tid

Enalapril

2.5 mg bid

10 mg bid

Fosinopril

5-10 mg daily; can use bid

20 mg daily

Lisinopril

2.5-5.0 mg daily; can use bid

10-20 mg bid

Quinapril

2.5-5.0 mg bid

10 mg bid

Ramipril

1.25-2.5 mg bid

5 mg bid

Trandolapril

0.5-1.0 mg daily

4 mg daily

Angiotensin receptor blockers

Valsartana

40 mg bid

160 mg bid

Losartan

25 mg daily; can use bid

25-100 mg daily

Irbesartan

75-150 mg daily

75-300 mg daily

Candesartana

2-16 mg daily

2-32 mg daily

Olmesartan

20 mg daily

20-40 mg daily

Thiazide diuretics

HCTZ

25-50 mg daily

25-50 mg daily

Metolazone

2.5-5.0 mg daily or bid

10-20 mg total daily

Loop diuretics

Bumetanide

0.5-1.0 mg daily or bid

10 mg total daily (maximum)

Furosemide

20-40 mg daily or bid

400 mg total daily (maximum)

Torsemide

10-20 mg daily or bid

200 mg total daily (maximum)

Aldosterone antagonists

Eplerenone

25 mg daily

50 mg daily

Spironolactone

12.5-25.0 mg daily

25 mg daily

β-Blockers

Bisoprolol

1.25 mg daily

10 mg daily

Carvedilol

3.125 mg q12h

25-50 mg q12h

Metoprolol succinate

12.5-25.0 mg daily

200 mg daily

Digoxin

0.125-0.25 mg daily

0.125-0.25 mg daily

HCTZ, hydrochlorothiazide.

a Valsartan and Candesartan are the only U.S. Food and Drug Administration-approved angiotensin II-receptor blockers in the treatment of heart failure.

Table 4 Inotropic Agents

Dose

Mechanism

Effects/Side Effects

1-3 mcg/kg/min

Dopaminergic receptors

Splanchnic vasodilation

2-8 mcg/kg/min

β1-Receptor agonist

+Inotropic

7-10 mcg/kg/min

α-Receptor agonist

↑ SVR

2.5-15.0 mcg/kg/min

β1-receptor agonist >β2-receptor agonist >α-receptor agonist

+Inotropic, ↓ SVR, tachycardia

50-mcg/kg bolus IV over 10 min, 0.375-0.75 mcg/kg/min

↑ cAMP

↓ SVR, +inotropic; atrial and ventricular tachyarrhythmias

cAMP, cyclic adenosine monophosphate; SVR, systemic vascular resistance; ↑, increased; ↓, decreased.

Needs dose adjustment for creatinine clearance.

Other Nonoperative Therapies

Coronary revascularization reduces ischemia and may improve systolic function in some patients with CAD.

Cardiac resynchronization therapy or biventricular pacing (see Chapter 5, Cardiac Arrhythmias) appears to be beneficial in patients with an EF of 35% or less, NYHA class III-IV HF, and conduction abnormalities (left bundle branch block

P.165

and atrioventricular delay). It has been demonstrated to improve quality of life and reduce the risk of death in carefully selected patients (N Engl J Med 2005;352: 1539).

Implantable Cardiac Defibrillator (ICD) placement is recommended for all HF patients with an EF ≤35% for primary prevention of SCD. Sudden death occurs six to nine times more often in patients with HF compared to the general population and is the leading cause of death in ambulatory HF patients.

Multiple large randomized trials have demonstrated a survival benefit of 1% to 1.5% per year in patients with both ischemic and nonischemic cardiomyopathy (Circulation 2009;119:1977; N Engl J Med 2005;352:1539).

Patients should receive at least 3 months of optimal medical therapy prior to reassessment of EF and implantation of an ICD.

Following an acute MI or revascularization, EF should be assessed following 40 days of optimal therapy prior to ICD implantation.

ICD therapy should be deferred in patients with advanced age, life-shortening comorbidities, and end-stage HF patients who are not candidates for transplantation.

An intraaortic balloon pump (IABP) can be considered for patients in whom other therapies have failed, have transient myocardial dysfunction, or are awaiting a definitive procedure such as transplantation. Severe aortoiliac atherosclerosis and aortic valve insufficiency are contraindications to IABP placement.

Surgical Management

Ventricular assist devices (VADs) require surgical implantation and are indicated for patients with severe HF after cardiac surgery, for individuals with intractable cardiogenic shock after acute MI, and as a “bridge to transplantation” for patients awaiting heart transplantation. Consideration of a LV assist device as permanent or “destination” therapy is reasonable in highly selected patients with refractory end-stage HF and an estimated 1-year mortality over 50% with medical therapy (Circulation 2009;119:1977).

Currently available devices vary with regard to degree of mechanical hemolysis, intensity of anticoagulation required, and difficulty of implantation. The decision to institute VAD circulatory support must be made in consultation with a cardiac surgeon who has experience with this procedure.

Cardiac transplantation is an option for selected patients with severe end-stage HF that has become refractory to aggressive medical therapy and for whom no other conventional treatment options are available.

Approximately 2,200 heart transplants are performed each year in the United States.

Candidates considered for transplantation should generally be younger than 65 years (although selected older patients may also benefit), have advanced HF (NYHA class III-IV), have a strong psychological support system, have exhausted all other therapeutic options, and be free of irreversible extracardiac organ dysfunction that would limit functional recovery or predispose them to posttransplant complications (J Am Coll Cardiol 1993;22:1).

Survival rates post heart transplant are approximately 90%, 70%, and 50% at 1, 5, and 10 years since the induction of calcineurin-inhibitor based immunosuppression. Annual statistics can be found on the United Network for Organ Sharing Web site (www.unos.org).

P.166

In general, functional capacity and quality of life improve significantly after transplantation.

Posttransplant complications include acute and chronic rejection, typical and atypical infections, and adverse effects of immunosuppressive agents. Cardiac allograft vasculopathy (CAD/chronic rejection) and malignancy are the leading causes of death after the first posttransplant year.

Lifestyle/Risk Modification

Dietary counseling for sodium and fluid restriction should be provided.

Smoking cessation should be strongly encouraged.

Exercise training is recommended in stable HF patients as an adjunct to pharmacologic treatment. Exercise training in patients with HF has been shown to improve exercise capacity (peak VO2 max as well as 6-minute walk time), improve quality of life, and decrease neurohormonal activation. The HF-ACTION Trial randomized over 2,300 patients with HF to exercise training versus standard medical therapy, and demonstrated a decrease in the combined end point of all-cause death or hospitalization in the exercise group (JAMA 2009;301:1451; JAMA 2009;301:1439). Treatment programs should be individualized and include a warm-up period, 20 to 30 minutes of exercise at the desired intensity, and a cool-down period 3 to 5 days a week (Circulation 2003;107:1210).

Weight loss should be recommended when appropriate.

SPECIAL CONSIDERATIONS

Fluid and free water restriction (<1.5 L/d) is especially important in the setting of hyponatremia (serum sodium < 130 mEq/L) and volume overload.

Minimization of medications with deleterious effects in HF should be attempted.

Negative inotropes (e.g., verapamil, diltiazem) should be avoided in patients with impaired ventricular contractility, as should over-the-counter β stimulants (e.g., compounds containing ephedra, pseudoephedrine hydrochloride).

NSAIDs, which antagonize the effect of ACE inhibitors and diuretic therapy, should be avoided if possible.

Administration of supplemental oxygen may relieve dyspnea, improve oxygen delivery, reduce the work of breathing, and limit pulmonary vasoconstriction in patients with hypoxemia.

Sleep apnea has prevalence as high as 37% in the HF population. Treatment with nocturnal positive airway pressure improves symptoms and EF (N Engl J Med 2003;348:1233; Am J Respir Crit Care Med 2001;164:2147).

Dialysis or ultrafiltration may be beneficial in patients with severe HF and renal dysfunction who cannot respond adequately to fluid and sodium restriction and diuretics (J Am Coll Cardiol 2007;49:675). Other mechanical methods of fluid removal such as therapeutic thoracentesis and paracentesis may provide temporary symptomatic relief of dyspnea. Care must be taken to avoid rapid fluid removal and hypotension.

End-of-life considerations may be necessary in the patient with advanced HF that is refractory to therapy. Discussions regarding the disease course, treatment options, survival, functional status, and advance directives should be addressed early in the treatment of the patient with HF. For those with end-stage disease (stage D, NYHA class IV) with multiple hospitalizations and severe decline in their functional status and quality of life, hospice and palliative care should be considered.

P.167

Acute Heart Failure and Cardiogenic Pulmonary Edema

GENERAL PRINCIPLES

Pathophysiology

Cardiogenic pulmonary edema (CPE) occurs when the pulmonary capillary pressure exceeds the forces that maintain fluid within the vascular space (serum oncotic pressure and interstitial hydrostatic pressure).

Increased pulmonary capillary pressure may be caused by LV failure of any cause, obstruction to transmitral flow [e.g., mitral stenosis (MS), atrial myxoma], or, rarely, pulmonary veno-occlusive disease.

Alveolar flooding and impairment of gas exchange follow accumulation of fluid in the pulmonary interstitium.

DIAGNOSIS

Clinical Presentation

Clinical manifestations of CPE may occur rapidly and include dyspnea, anxiety, and restlessness.

The patient may expectorate pink frothy fluid.

Physical signs of decreased peripheral perfusion, pulmonary congestion, use of accessory respiratory muscles, and wheezing are often present.

Diagnostic Testing

Imaging

Radiographic abnormalities include cardiomegaly, interstitial and perihilar vascular engorgement, Kerley B lines, and pleural effusions.

The radiographic abnormalities may follow the development of symptoms by several hours, and their resolution may be out of phase with clinical improvement.

TREATMENT

Supplemental oxygen should be administered initially to raise the arterial oxygen tension to >60 mm Hg.

Mechanical ventilation is indicated if oxygenation is inadequate by noninvasive means or if hypercapnia coexists.

Placing the patient in a sitting position improves pulmonary function.

Strict bed rest, pain control, and relief of anxiety can decrease cardiac workload.

Precipitating factors should be identified and corrected, as resolution of pulmonary edema can often be accomplished with correction of the underlying process. The most common precipitants are:

Severe HTN

MI or myocardial ischemia (particularly if associated with MR)

Acute valvular regurgitation

New-onset tachyarrhythmias or bradyarrhythmias

Volume overload in the setting of severe LV dysfunction

P.168

Medications

Morphine sulfate reduces anxiety and dilates pulmonary and systemic veins. Two to five milligrams can be given intravenously over several minutes and can be repeated every 10 to 25 minutes until an effect is seen.

Furosemide is a venodilator that decreases pulmonary congestion within minutes of IV administration, well before its diuretic action begins. An initial dose of 20 to 80 mg IV should be given over several minutes and can be increased based on response, to a maximum of 200 mg in subsequent doses.

Nitroglycerin is a venodilator that can potentiate the effect of furosemide. IV administration is preferable to oral and transdermal forms as it can be rapidly titrated.

Nitroprusside is an effective adjunct in the treatment of acute CPE and is useful when CPE is brought on by acute valvular regurgitation or HTN (see Valvular Heart Disease). Pulmonary and systemic arterial catheterization should be considered to guide titration of nitroprusside therapy.

Inotropic agents, such as dobutamine or phosphodiesterase inhibitors, may be helpful after initial treatment of CPE in patients with concomitant hypotension or shock.

Recombinant BNP (nesiritide) is administered as an IV bolus followed by an IV infusion.

Nesiritide reduces intracardiac filling pressures by producing vasodilation and indirectly increases the cardiac output.

In conjunction with furosemide, nesiritide produces natriuresis and diuresis.

SPECIAL CONSIDERATIONS

Right heart catheterization (e.g., Swan-Ganz catheter) may be helpful in cases in which a prompt response to therapy does not occur by allowing differentiation between cardiogenic and noncardiogenic causes of pulmonary edema via measurement of central hemodynamics and cardiac output. It may then be used to guide subsequent therapy.

Acute hemodialysis and ultrafiltration may be effective, especially in the patient with significant renal dysfunction and diuretic resistance (J Am Coll Cardiol 2007;49:675; Congest Heart Fail 2008;14:19).

CARDIOMYOPATHY

Dilated Cardiomyopathy

GENERAL PRINCIPLES

Definition

Dilated cardiomyopathy (DCM) is a disease of heart muscle characterized by dilation of the cardiac chambers and reduction in ventricular contractile function.

Epidemiology

DCM is the most common form of cardiomyopathy and is responsible for approximately 10,000 deaths and 46,000 hospitalizations each year. The lifetime incidence of DCM is 36.5 cases per 100,000 persons.

P.169

Pathophysiology

DCM may be secondary to progression of any process that affects the myocardium and dilation is directly related to neurohormonal activation. The majority of cases are idiopathic (Am J Cardiol 1992;69:1458).

Dilation of the cardiac chambers and varying degrees of hypertrophy are anatomic hallmarks. Tricuspid and MR are common due to the effect of chamber dilation on the valvular apparatus.

Atrial and ventricular arrhythmias are present in as many as one-half of these patients and are probably responsible for the high incidence of sudden death in this population.

DIAGNOSIS

Clinical Presentation

Symptomatic HF (dyspnea, volume overload) is often present.

A portion of patients with preclinical disease may be asymptomatic.

The ECG is usually abnormal, but changes are typically nonspecific.

Diagnostic Testing

Imaging

Diagnosis of DCM can be confirmed with echocardiography or radionuclide ventriculography.

Two-dimensional and Doppler echocardiography is helpful in differentiating this condition from hypertrophic or restrictive cardiomyopathy (RCM), pericardial disease, and valvular disorders.

Diagnostic Procedures

Endomyocardial biopsy provides little information that affects treatment of patients with dilated cardiomyopathies and is not routinely recommended (Circulation 2009;119:1977; Eur Heart J 2007;28:3076).

TREATMENT

Medications

The medical management of symptomatic patients is identical to that for HF from other causes.

Therapeutic strategies include control of total body sodium and volume in addition to appropriate preload and afterload reduction using vasodilator therapy.

β-Adrenergic antagonists should be used unless contraindicated.

Immunizations against influenza and pneumococcal pneumonia are recommended.

Chronic oral anticoagulation has not been shown to decrease the risk of thromboembolism in patients with LV dysfunction. Anticoagulation should be strongly considered in individuals with a history of thromboembolic events, atrial fibrillation, or evidence of an LV thrombus. The level of anticoagulation recommended varies but is generally an international normalized ratio of 2.0 to 3.0.

Immunosuppressive therapy with agents such as prednisone, azathioprine, and cyclosporine for biopsy-proven myocarditis has been advocated by some, but efficacy has not been established (Circulation 2009;119:1977; N Engl J Med 1995;333: 269).

P.170

Other Nonoperative Therapies

DCM (of nonischemic origin) is associated with an increased incidence of SCD and ventricular arrhythmia. In comparison to NYHA class IV HF patients who are more likely to die of progressive pump failure, SCD is relatively more common in patients with mild to moderate symptoms.

Suppression of asymptomatic ventricular premature beats or nonsustained ventricular tachycardia (NSVT) using antiarrhythmic drugs in patients with HF does not improve survival and may increase mortality as a result of the proarrhythmic effects of the drugs (N Engl J Med 1989;321:406; N Engl J Med 2005;352:225; N Engl J Med 1995;333:77).

Primary prevention of SCD is recommended by implantation of an ICD in patients with DCM who continue to have an EF of 35% or less and NYHA class II-III symptoms despite maximal medical therapy for 3 months.

Cardiac resynchronization therapy is beneficial in selected patients with symptomatic HF (N Engl J Med 2005;352:1539; N Engl J Med 2004;350:2140).

Surgical Management

Cardiac transplantation should be considered for selected patients with HF due to DCM that is refractory to medical therapy.

IABP or placement of a VAD may be necessary for stabilization of patients in whom cardiac transplantation is an option or before other definitive surgical therapies.

Mitral valve annuloplasty or replacement can be used for symptomatic relief in patients with severe MR.

Diastolic Dysfunction

GENERAL PRINCIPLES

Definition

Diastolic dysfunction refers to abnormality in the mechanical function of the heart during diastole or the relaxation phase of the cardiac cycle. Usually, this involves elevated filling pressures and impairment of ventricular filling.

Diastolic heart failure (DHF) refers to the syndrome of HF in the presence of preserved systolic function.

Epidemiology

Almost half of patients admitted to the hospital with HF have a normal or near-normal EF.

DHF is most prevalent in elderly women, most of whom have HTN and/or DM. Many of these women also have CAD and/or atrial fibrillation.

Etiology

The vast majority of patients with DHF have hypertension and LV hypertrophy.

Myocardial disorders associated with DHF include RCM, obstructive and nonobstructive HCM, infiltrative cardiomyopathies, and constrictive pericarditis.

Pathophysiology

Reduced ventricular compliance plays a major role in the pathophysiology of DHF.

Abnormal sodium handling by the kidneys and arterial stiffness also contribute.

P.171

DIAGNOSIS

Diagnostic Testing

Imaging

Differentiating between diastolic and systolic HF cannot be reliably accomplished without two-dimensional echocardiography.

Diagnosis is based on echocardiographic criteria and Doppler findings of normal LV systolic function with impaired diastolic relaxation and elevated filling pressures.

TREATMENT

Treatment is directed toward improving the symptoms with diuretic therapy and correcting the precipitating factors (e.g., hypertension, CAD, tachycardia).

Hypertrophic Cardiomyopathy

GENERAL PRINCIPLES

Definition

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by ventricular hypertrophy, diminished LV cavity dimensions, normal or enhanced contractile function, and impaired ventricular relaxation in the absence of an identifiable cause.

Epidemiology

HCM is the most common inherited heart defect, occurring in 1 of 500 individuals.

Approximately 500,000 people have HCM in the United States, yet most are unaware. An estimated 36% of young athletes who die suddenly have probable or definite HCM, making it the leading cause of SCD in young people in the United States, including trained athletes (Circulation 2009;119:1977).

The idiopathic form of HCM has an early onset (as early as the first decade of life) without associated HTN.

An acquired form also occurs in elderly patients with chronic HTN.

Pathophysiology

The pathophysiologic change in HCM is myocardial hypertrophy that is typically predominant in the ventricular septum (asymmetric hypertrophy) but may involve all ventricular segments.

Many cases of HCM have a genetic component, with mutations in the myosin heavy-chain gene that follow an autosomal dominant transmission with variable phenotypic expression and penetrance.

HCM can be classified according to the presence or absence of LV outflow tract obstruction.

LV outflow obstruction may occur at rest, but is enhanced by factors that increase LV contractility or decrease ventricular volume.

Delayed ventricular diastolic relaxation and decreased compliance are common and may lead to pulmonary congestion.

Myocardial ischemia is frequently secondary to a myocardial oxygen supply-demand mismatch.

P.172

Systolic anterior motion of the anterior leaflet of the mitral valve is often associated with MR and may contribute to LV outflow tract obstruction.

DIAGNOSIS

Clinical Presentation

Presentation varies, but may include dyspnea, angina, arrhythmias, syncope, cardiac failure, or sudden death.

Sudden death is most common in children and young adults between the ages of 10 and 35 years and often occurs during periods of strenuous exertion.

History

Family history of HCM or sudden death is suggestive of the familial subtype.

Physical Examination

Physical findings include bisferious carotid pulse (in the presence of obstruction).

Forceful double or triple apical impulse and a coarse systolic outflow murmur localized along the left sternal border that is accentuated by maneuvers that decrease preload (e.g., standing, Valsalva maneuver) may also be found.

Diagnostic Testing

Electrocardiography

The ECG of HCM is usually abnormal, and invariably so in symptomatic patients with LV outflow tract obstruction. The most common abnormalities are ST segment and T-wave abnormalities, followed by evidence of left ventricular hypertrophy (Am J Cardiol 2002;90:1020).

Imaging

Two-dimensional echocardiography and Doppler flow studies can establish the presence of a significant LV outflow gradient at rest or with provocation.

Additional risk stratification should be pursued with 24- to 48-hour Holter monitoring and exercise testing.

TREATMENT

Management is directed toward relief of symptoms and prevention of endocarditis, arrhythmias, and sudden death.

Treatment in asymptomatic individuals is controversial, and no conclusive evidence has been found that medical therapy is beneficial.

All individuals with HCM should avoid strenuous physical activity, including most competitive sports.

Medications

β-Blockers may reduce symptoms of HCM by reducing myocardial contractility and heart rate. However, symptoms may recur during long-term therapy.

Calcium channel antagonists, particularly verapamil and diltiazem, may improve the symptoms of HCM, primarily by augmentation of diastolic ventricular filling. Therapy should be initiated at low doses, with careful titration in patients with outflow obstruction. The dose should be increased gradually over several days to

P.173

weeks if symptoms persist. Dihydropyridines should be avoided in patients with LV outflow tract obstruction as a result of their vasodilatory properties.

Diuretics may improve pulmonary congestive symptoms in patients with elevated pulmonary venous pressures. These agents should be used cautiously in patients with severe LV outflow obstruction because excessive preload reduction worsens the obstruction.

Nitrates and vasodilators should be avoided because of the risk of increasing the LV outflow gradient.

Treatment of arrhythmias. Atrial and ventricular arrhythmias occur commonly in patients with HCM. Supraventricular tachyarrhythmias are tolerated poorly and should be treated aggressively; cardioversion is indicated if hemodynamic compromise develops.

Digoxin is relatively contraindicated because of its positive inotropic properties and potential for exacerbating ventricular outflow obstruction.

Atrial fibrillation should be converted to sinus rhythm when possible, and anticoagulation is recommended if paroxysmal or chronic atrial fibrillation develops.

Diltiazem, verapamil, or β-blockers can be used to control the ventricular response before cardioversion. Procainamide, disopyramide, or amiodarone (see Chapter 5, Cardiac Arrhythmias) may be effective in the chronic suppression of atrial fibrillation.

Patients with NSVT detected on ambulatory monitoring are at increased risk for sudden death. However, the benefit of suppressing these arrhythmias with medical therapy has not been established, and the risk of a proarrhythmic effect of antiarrhythmic drugs exists.

ICD placement should be considered in high-risk patients: those with genetic mutations associated with SCD; prior SCD or sustained ventricular tachyarrhythmia; a history of syncope or near-syncope, recurrent or exertional, in young patients; multiple nonsustained episodes of VT on Holter recordings; hypotensive response to exercise; LV hypertrophy with a wall thickness >30 mm in young patients; and a history of sudden, premature death in close relatives (JAMA 2007;298:405). There is very limited benefit for invasive electrophysiologic testing in the risk stratification of patients with HCM.

Symptomatic ventricular arrhythmias should be treated as outlined in Chapter 5, Cardiac Arrhythmias.

Dual-chamber pacing (see Chapter 5, Cardiac Arrhythmias) improves symptoms in some patients with HCM. Alteration of the ventricular activation sequence via right ventricular (RV) pacing may minimize LV outflow tract obstruction secondary to asymmetric septal hypertrophy.

Only 10% of the patients with HCM meet the criteria for pacemaker implantation, and the effect on decreasing the left ventricular outflow tract (LVOT) gradient is only 25%. Dual-chamber pacing has not been demonstrated to decrease morbidity and mortality in patients with HCM.

Surgical Management

Surgical therapy is useful in the treatment of symptoms but has not been shown to alter the natural history of HCM.

The most frequently used operative procedure involves septal myotomy-myectomy with or without mitral valve replacement (MVR).

Alcohol septal ablation, a catheter-based alternative to surgical myotomy-myectomy, seems to be equally effective at reducing obstruction and providing symptomatic

P.174

relief when compared to the gold standard surgical procedure (J Am Coll Cardiol 2007;50:831).

Cardiac transplantation should be reserved for patients with end-stage HCM with symptomatic HF.

PATIENT EDUCATION

Genetic counseling and family screening are recommended for first-degree relatives of patients at high risk for SCD, because the disease is transmitted as an autosomal dominant trait.

Restrictive Cardiomyopathy

GENERAL PRINCIPLES

Definition

Restrictive cardiomyopathy (RCM) is characterized by a rigid heart with poor ventricular filling.

Both infiltrative (amyloidosis or sarcoidosis) and noninfiltrative (diabetic or idiopathic) forms exist.

Pericardial disease (constrictive pericarditis) can present in a similar fashion but carries a different prognosis and treatment options and so must be excluded.

Pathophysiology

In amyloidosis, amyloid deposits in the interstitium replace the normal myocardial contractile units and cause restriction.

Approximately 5% of sarcoidosis cases have cardiac involvement in which scar formation leads to restriction.

Other etiologies included hemochromatosis, Gaucher's and Hurler's cardiomyopathies (rare, inherited glycogen storage diseases), hypereosinophilic syndrome, and carcinoid heart disease.

DIAGNOSIS

Diagnostic Testing

Electrocardiography

The classic ECG finding in amyloidosis is low voltage with poor R-wave progression. In sarcoidosis, conduction disease is often present.

Imaging

In RCM, echocardiography with Doppler analysis may demonstrate thickened myocardium with normal or abnormal systolic function, abnormal diastolic filling patterns, and elevated intracardiac pressure.

Cardiac MRI, PET, and CT are emerging as useful diagnostic tools as granulomas, inflammation, and edema may be seen in patients with cardiac sarcoid which appear to improve with therapy (Am Heart J 2009;157:746).

Diagnostic Procedures

On cardiac catheterization, elevated RV and LV filling pressures are seen with a classic dip-and-plateau pattern in the RV and LV pressure tracing.

P.175

RV endomyocardial biopsy may be diagnostic and should be considered in patients in whom a diagnosis is not established.

TREATMENT

Specific therapy aimed at amelioration of the underlying cause should be initiated.

Cardiac hemochromatosis may respond to reduction of total body iron stores via phlebotomy or chelation therapy with deferoxamine.

Cardiac sarcoidosis may respond to glucocorticoid therapy, but prolongation of survival with this approach has not been established.

In those with syncope and/or ventricular arrhythmias, placement of an ICD is indicated. Those patients with high-grade conduction disease also warrant pacemaker placement.

No therapy is known to be effective in reversing the progression of cardiac amyloidosis. Digoxin should be avoided in patients with cardiac amyloidosis because of enhanced susceptibility to digoxin toxicity.

Peripartum Cardiomyopathy

GENERAL PRINCIPLES

Definition

Peripartum cardiomyopathy (PPCM) is defined as LV systolic dysfunction diagnosed in the last month of pregnancy up to 5 months postpartum.

The incidence of PPCM is 1 in 3,000 to 4,000 pregnancies in the United States

Etiology

The etiology of PPCM remains unclear. There is evidence to support viral triggers, including coxsackievirus, parvovirus B19, adenovirus, and herpesvirus, which may replicate unchecked in the reduced immunologic state brought on by pregnancy.

Fetal microchimerism has also been a suggested cause, in which fetal cells escape into the maternal circulation and induce an autoimmune myocarditis (Lancet 2006;368:687).

Recently, a cleavage product of prolactin has also been implicated in the development of PPCM (Cell 2007;128:589).

Risk Factors

Risk factors that predispose a woman to PPCM include advanced maternal age, multiparity, multiple pregnancy, preeclampsia, and gestational hypertension. There is a higher risk in African-American women, but this may be confounded by the higher prevalence of hypertension in this population.

DIAGNOSIS

Clinical Presentation

Clinically, women with PPCM present with the signs and symptoms of HF.

As dyspnea on exertion and lower extremity edema are common in late pregnancy, PPCM may be difficult to recognize. Cough, orthopnea, and paroxysmal nocturnal dyspnea are warning signs that PPCM may be present, as is the presence of a displaced apical impulse and a new MR murmur on exam.

P.176

Most commonly, patients present with New York Heart Association (NYHA) class III and IV HF, although more mild cases and sudden cardiac arrest also occur.

Diagnostic Testing

Electrocardiography

On ECG, LVH is often present, as are ST-T wave abnormalities.

Imaging

Diagnosis requires an echocardiogram with a depressed EF and/or LV dilatation.

TREATMENT

Medications

The mainstay of treatment is afterload and preload reduction.

ACE inhibitors are used in the postpartum patient, while hydralazine is used in the patient who is still pregnant.

β-Blockers are used to reduce tachycardia, arrhythmia, and risk of SCD, and are relatively safe, though β1-selective blockers (metoprolol and atenolol) are preferred because they avoid peripheral vasodilation and uterine relaxation.

Digoxin is also safe during pregnancy and should be used to augment contractility and rate control, although levels need to be closely monitored in the pregnant patient.

Diuretics are used for preload reduction and symptom relief and are also safe. In those with thromboembolism, heparin is required, followed by Coumadin after delivery.

OUTCOME/PROGNOSIS

The prognosis in PPCM is better than that seen in other forms of nonischemic cardiomyopathy.

The extent of ventricular recovery at 6 months post delivery can predict overall recovery, although continued improvement has been seen 2 to 3 years after diagnosis.

Subsequent pregnancies in patients with PPCM are associated with significant deterioration in LV function and can even result in death. Family planning counseling is essential after the diagnosis of PPCM is made, and women who do not recover their LV function should be encouraged to consider forgoing future pregnancy.

PERICARDIAL DISEASE

Constrictive Pericarditis

GENERAL PRINCIPLES

Constrictive pericarditis, as a cause of right-sided HF, often goes undiagnosed.

Constrictive pericarditis is often difficult to distinguish from RCM.

Multiple imaging modalities and invasive hemodynamics are often needed to confirm the diagnosis.

Etiology

Common

Idiopathic

P.177

Viral pericarditis (chronic or recurrent)

Postcardiotomy

Chest irradiation

Less common

Autoimmune connective tissue disorders

End-stage renal disease, uremia

Malignancy (e.g., breast, lung, lymphoma)

Tuberculosis (most common cause in developing countries)

Pathophysiology

The pericardium is a fibrous sac surrounding the heart consisting of two layers, a thin visceral layer attached to the pericardium and a thicker parietal layer. The pericardial space is normally filled with 15 to 50 mL of fluid. In the setting of chronic inflammation, the pericardial layers become thickened, scarred, and calcified; the pericardial space is obliterated and the pericardium becomes noncompliant. This external constraint impairs cardiac filling and leads to an equalization of pressures in all four chambers.

DIAGNOSIS

Clinical Presentation

History

The clinical presentation of constrictive pericarditis is insidious, with gradual development of fatigue, exercise intolerance, and venous congestion; if it goes undiagnosed for a long period, it is not unusual for patients to have undergone an extensive GI/liver evaluation, including a liver biopsy (showing cirrhosis—“nutmeg liver”) before the diagnosis is made.

Physical Examination

Features of right-sided HF:

Lower extremity edema, hepatomegaly, ascites, and elevated Jugular Venous Pressure (JVP)

Features more specific for constriction:

Increased JVP with prominent y descent

Kussmaul's sign: lack of expected decrease or obvious increase of JVP upon inspiration

Pericardial knock: early, loud, high-pitched S3

Differential Diagnosis

Pericardial constriction

Ventricular interdependence present

Abnormal pericardial features (thickened, adherent, and/or calcified)

Preserved (or increased) tissue Doppler velocities on echo

Pulmonary HTN mild or absent

Septal bounce seen on noninvasive imaging

Equalization of pressures in all cardiac chambers (LVEDP - RVEDP < 5 mm Hg)

RVEDP/RVSP > 1/3

BNP low or mildly elevated (usually <200, unless postcardiotomy or radiation with concomitant LV dysfunction)

P.178

Restrictive cardiomyopathy

Ventricular interdependence absent

Abnormal myocardial features (infiltration, thickened, fibrotic, conduction system disease)

Decreased tissue Doppler velocities on echo

Pulmonary HTN present

Normal septal motion

LVEDP - RVEDP > 5 mm Hg

RVEDP/RVSP < 1/3

BNP elevated (>200)

Diagnostic Testing

Echo

First-line diagnostic test

Helpful for distinguishing constriction from restriction (see above)

Ventricular systolic function is often normal and can lead to the false assessment that the heart function is “normal” as not a cause of the patient's symptoms

May require a fluid bolus to elicit some of the hemodynamic findings of constriction

Features suggestive of constriction include:

Thickened, echogenic pericardium

Tethering of the pericardium to the myocardium

Dilated, incompressible IVC

Septal bounce

Inspiratory variation in mitral flow velocity curves

Expiratory reversal of hepatic vein flow

Preserved (or increased) tissue Doppler velocities of the mitral annulus

Cath

Often required to make the diagnosis of constriction

Method of choice for an accurate hemodynamic assessment

CT and MRI

Provide excellent anatomy of the pericardium (thickness and calcification)

An MRI and gated CT can show evidence of ventricular interdependence (septal bounce); this may be particularly important if echo images are poor

Can provide other anatomical information that may be helpful in making the diagnosis of constriction (i.e., engorgement of IVC and hepatic veins) and its etiology (i.e., lymph nodes, tumors)

TREATMENT

Limited role for medical therapy: diuretics and low-salt diet to alleviate edema

Patients with constriction often have a resting sinus tachycardia to maintain cardiac output in the setting of a reduced stroke volume (from reduced diastolic filling); β-blockers and CCBs to slow the heart rate should be avoided

Surgical Management

Surgical pericardiectomy is the only definitive treatment and should be pursued once the diagnosis is made

Five to fifteen percent operative mortality; the highest mortality is in those with more advanced HF symptoms

A significant majority experience a symptomatic benefit from surgery

P.179

Cardiac Tamponade

GENERAL PRINCIPLES

Cardiac tamponade is a clinical diagnosis and is considered a medical emergency

Etiology

More likely to cause tamponade:

Idiopathic pericarditis

Infection (bacterial, including mycobacteria; fungal; and viral, including HIV)

Neoplasms (sometimes initially diagnosed during a workup for a pericardial effusion)

Postcardiotomy

Autoimmune connective tissue disorders

Uremia

Trauma

Radiation

Myocardial infarction (subacute)

Drugs (hydralazine, procainamide, isoniazid, phenytoin)

Hypothyroidism

Pathophysiology

Fluid accumulation in the pericardial space increases the pericardial pressure; the pressure depends on the amount of fluid, the rate of accumulation, and the compliance of the pericardium. If there is a rapid accumulation of fluid (e.g., trauma or perforation during PCI), a small volume of fluid can raise the pericardial pressure substantially; if the accumulation of fluid is more insidious, the pericardium can stretch and a large amount of fluid can accumulate at a lower pressure. Tamponade develops when the pressure in the pericardial space is sufficiently high to interfere with cardiac filling, resulting in a decrease in cardiac output.

DIAGNOSIS

Clinical Presentation

History

The diagnosis of cardiac tamponade should be suspected in patients with elevated jugular venous pressure, hypotension, and distant heart sounds (Beck's triad)

Symptoms can include dyspnea, fatigue, anxiety, presyncope, chest discomfort, abdominal fullness, slowed sensorium, and a vague sense of being “uncomfortable;” patients often feel more comfortable sitting forward

Physical Examination

Pulsus paradoxus >10 mm Hg

Jugular venous distention

Diminished heart sounds

Tachycardia, hypotension, and signs of shock

Diagnostic Testing

EKG

Low voltage

P.180

Tachycardia

Electrical alternans (due to the swinging of the heart within the pericardium; specific but not sensitive)

TTE

First-line diagnostic test to diagnose an effusion and evaluate its hemodynamic significance

The size of the effusion can be misleading; its hemodynamic impact depends on the rate of fluid accumulation

Important to assess the location of the effusion and determine the width of the fluid rim around the heart; this has implications for the approach taken to drain the fluid

Features suggestive of a hemodynamically significant effusion:

Dilated, incompressible IVC

Significant respiratory variation of tricuspid and mitral inflow velocities

Early diastolic collapse of the right ventricle and collapse of the right atrium (during ventricular diastole)

Usually the effusion is circumferential

TEE

Helpful when TTE images are poor or when there is a suspicion for a loculated effusion (particularly those that might develop at the atrial level after cardiac surgery)

CT and MRI

Can be helpful in assessing the anatomical location of the effusion (particularly if loculated)

May be helpful in determining the etiology of the effusion and the content of the pericardial fluid

These imaging studies should be avoided in an unstable patient

RHC

Usually not necessary to establish the diagnosis

Hemodynamic assessment showing equalization of atrial and ventricular diastolic pressures

TREATMENT

Limited role for medical therapy

Maintain adequate filling pressures with IV fluids

Avoid diuretics, nitrates, and any other preload-reducing medications

Avoid efforts to slow sinus tachycardia; it compensates for a reduced stroke volume to try to maintain adequate cardiac output

If intubation is to be performed for respiratory distress before the fluid is drained, make sure volume status is replete and a pericardiocentesis needle is immediately available before any sedatives are given (a patient in particularly “severe tamponade” can arrest with the preload reduction from sedation)

Other Nonoperative Therapies

Percutaneous pericardiocentesis with echocardiographic guidance can be a relatively safe and effective way to drain the pericardial fluid if there is an adequate amount of fluid; the approach should be guided by where the predominant collection of fluid is located and is usually easiest when the effusion is anterior

P.181

Surgical Management

Open pericardiocentesis with the creation of a window is a minimally invasive procedure and is preferred for recurring effusions, loculated effusions, or those not safely accessible percutaneously

Allows pericardial biopsies to be taken which may be helpful in making a diagnosis

VALVULAR HEART DISEASE

Mitral Stenosis

GENERAL PRINCIPLES

Mitral stenosis (MS) is characterized by incomplete opening of the mitral valve during diastole, which limits antegrade flow and yields a sustained diastolic pressure gradient between the left atrium (LA) and the left ventricle (LV).

Because of antibiotics, the incidence of rheumatic heart disease (and MS) has decreased in the developed world.

Etiology

Rheumatic

Predominant cause of MS

Two-thirds are females

May be associated with MR

Stenotic orifice often shaped like a “fish mouth”

Rheumatic fever can cause fibrosis, thickening, and calcification leading to fusion of the commissures, leaflets, chordae, and/or papillary muscles

Other causes

SLE

Rheumatoid arthritis

Congenital

Substantial mitral annular calcification

Mitral valve prosthesis dysfunction or “patient-prosthesis” mismatch

Oversewn or small mitral annuloplasty ring

“Functional MS” may occur with obstruction of left atrial outflow due to:

Tumor, particularly myxoma

LA thrombus

Endocarditis with a large vegetation

Congenital membrane of the LA (i.e., cor triatriatum)

Pathophysiology

Physiologic states that either increase the transvalvular flow (enhance cardiac output) or decrease diastolic filling time (via tachycardia) can increase symptoms at any given valve area. Pregnancy, exercise, hyperthyroidism, atrial fibrillation with rapid ventricular response, and fever are examples in which either or both of these conditions occur. Symptoms are often first noticed at these times (Fig. 1).

P.182

Figure 1. Pathophysiology of mitral stenosis. LA, left atrium; LV, left ventricle; CO, cardiac output; HR, heart rate; LAP, left atrial pressure; LAE, left atrial enlargement; PVR, pulmonary vascular resistance; RV, right ventricle; RVH, right ventricular hypertrophy; CO, cardiac output.

P.183

DIAGNOSIS

Clinical Presentation

History

After a prolonged asymptomatic period, depending on when they present, patients may report any of the following: dyspnea, decreased functional capacity, orthopnea and/or PND, fatigue, palpitations (often due to atrial fibrillation), systemic embolism, hemoptysis, chest pain, and/or signs and symptoms of infective endocarditis.

Physical Examination

Findings on physical exam will depend on the severity of valve obstruction and the associated adaptations that have had time to develop in response to it; they may include:

Accentuation of S1 may occur when the leaflets are flexible.

Opening snap (OS)—caused by sudden tensing of the valve leaflets; the A2-OS interval varies inversely with the severity of stenosis (shorter interval ~ more severe stenosis).

Mid-diastolic rumble—low-pitched murmur heard best at the apex with the bell of the stethoscope; the severity of stenosis is related to the duration of the murmur, not intensity (more severe ~ longer duration).

Loud P2, TR murmur, PA tap, and/or RV heave can indicate pulmonary hypertension.

↑JVP, hepatic congestion, and peripheral edema can indicate varying degrees of right heart.

Diagnostic Testing

ECG

P mitrale (P-wave duration in lead II ≥0.12 seconds indicating LAE)

Atrial fibrillation

RVH

CXR

LAE

Enlarged RA/RV and/or enlarged pulmonary arteries

Calcification of the MV and/or annulus

TTE

Assess etiology of MS

Assess leaflets and subvalvular apparatus to determine candidacy for percutaneous mitral balloon valvotomy (PMBV)

Determine mitral valve area and mean transmitral gradient

Estimate PA systolic pressure and evaluate RV size and function

Exercise testing with echo

Helpful in clarifying functional capacity of those with an unclear history

Assess transmitral gradient and PA pressure with exercise when there is a discrepancy between resting Doppler findings, clinical findings, signs, and symptoms

TEE

Assess presence or absence of clot and severity of MR in patients being considered for PMBV

Evaluate MV morphology and hemodynamics in patients with MS for whom TTE was suboptimal

P.184

Cath

Indicated to determine severity of MS when clinical and echo assessment are discordant

Reasonable in patients with MS to assess the cause of severe pulmonary hypertension when out of proportion to the severity of MS as determined by noninvasive testing; can also assess the reversibility of pulmonary hypertension

Severe MS

Mean gradient (mm Hg) > 10

PASP (mm Hg) > 50

Valve area (cm2) < 1.0

TREATMENT

Medical

Medical therapy is aimed at slowing progression of pulmonary HTN, preventing endocarditis, reducing the risk of thromboembolism, and reducing HF symptoms

For HF, intermittent diuretics and a low-salt diet are often adequate

For patients who develop symptoms only with exercise (likely associated with tachycardia), negative chronotropic agents such as β-blockers or non-dihydropyridine CCBs may be of benefit

Since most MS is rheumatic in origin, prophylaxis against rheumatic fever is appropriate

Atrial fibrillation

Patients with MS are particularly prone to develop A-fib and/or flutter (30% to 40% of patients with MS)

Can exacerbate and worsen symptoms (particularly when there is a rapid ventricular response) due to a shortened diastolic filling period and loss of atrial kick

Therapy is mostly aimed at rate control and prevention of thromboembolism

Rate control: β-blockers or non-dihydropyridine CCBs tend to be more effective than digoxin for tachycardia associated with exertion

ACC/AHA Guidelines—Class I Indications for Anticoagulation for Prevention of Systemic Embolization in Patients with Mitral Stenosis:

MS and AF (paroxysmal, persistent, or permanent)

MS and a prior embolic event, even in sinus rhythm

MS with left atrial thrombus

Efforts to maintain sinus rhythm (through DCCV, ablation, or with drugs) are focused on those patients with symptoms from their AF, but can be particularly challenging in patients with MS.

Other Nonoperative Therapies

Percutaneous mitral balloon valvotomy (PMBV)

ACC/AHA Guidelines—Class I Indications for PMBV

Symptomatic (NYHA class II, III, or IV) with moderate or severe MS and valve morphology favorable for PMBV in the absence of LA thrombus or moderate to severe MR

Asymptomatic with moderate or severe MS and valve morphology favorable for PMBV who have pHTN (PASP >50 mm Hg at rest or >60 mm Hg with exercise) in the absence of LA thrombus or moderate to severe MR

Balloon inflation separates the commissures and fractures some of the nodular calcium in the leaflets, yielding an increased valve area

P.185

Hemodynamic results often observed: transmitral gradient ↓50% to 60%, cardiac output ↑10% to 20%, and valve area increases from 1.0 to 2.0 cm2

Contraindications: LA thrombus, moderate to severe MR, and an echo score of >8 (this score reflects the thickening, mobility, and calcification of the leaflets and subvalvular apparatus; this is a relative contraindication)

Complications: death (~1%), stroke, cardiac perforation, severe MR requiring surgical correction, and residual ASD requiring closure

When done in patients with favorable MV morphology, event-free survival (freedom from death, repeat valvotomy, or MV replacement) is 80% to 90% at 3 to 7 years (Circulation 1992;85:448)

It compares favorably with surgical mitral commissurotomy (open or closed) and is the valvotomy procedure of choice in experienced centers in patients without contraindications

Surgical Management

ACC/AHA Guidelines—Class I Indications for Surgery for Mitral Stenosis

MV surgery (repair if possible) is indicated in symptomatic patients (NYHA III or IV) with moderate or severe MS in a patient with acceptable operative risk when:

PMBV is unavailable

PMBV is contraindicated because of LA thrombus despite anticoagulation or because concomitant moderate to severe MR is present, or

Valve morphology is not favorable for PMBV

Symptomatic patients with moderate or severe MS who also have moderate to severe MR should receive valve replacement unless valve repair is possible at the time of surgery

Surgical treatment is usually reserved for those who are not candidates for PMBV because of the presence of one or more contraindications to PMBV or because the percutaneous option is unavailable

Surgical valvotomy can be done either closed (bypass unnecessary) or open (done under direct visualization on bypass)

OUTCOME/PROGNOSIS

MS usually progresses slowly with a long latent period (several decades) between rheumatic fever and the development of stenosis severe enough to cause symptoms. Ten-year survival of untreated patients with MS depends on the severity of symptoms at presentation: asymptomatic or minimally symptomatic patients have an 80% 10-year survival, whereas those with significant limiting symptoms have a 0% to 15% 10-year survival. Once severe pulmonary hypertension develops, mean survival is 3 years. The mortality of untreated patients is due mostly to progressive pulmonary and systemic congestion, systemic embolism, pulmonary embolism, and infection (in order of frequency).

Aortic Stenosis

GENERAL PRINCIPLES

Aortic stenosis (AS) is the most common cause for obstruction of flow from the LV into the aorta—it is present in 2% of those >65 years of age and 4% of those >85 years of age.

P.186

Other causes of obstruction occur above the valve (supravalvular) and below the valve (subvalvular), both fixed (i.e., subaortic membrane) and dynamic (i.e., HCM with obstruction).

Aortic sclerosis is thickening of the aortic valve leaflets that cause turbulent flow through the valve and a murmur but no significant gradient; over time it can develop into AS.

Epidemiology

Calcific/degenerative

Most common cause in United States

Trileaflet calcific AS usually presents in the 7th to 9th decades (mean age mid-70s)

Risk factors similar to CAD, exacerbated by abnormal Ca metabolism

Active biological process with bone formation in the valve

Calcification leading to stenosis affects both trileaflet and bicuspid valves

Bicuspid

Occurs in 1% to 2% of population (congenital lesion)

Usually presents in the 6th to 8th decades (mean age mid-late 60s)

~50% of patients needing AVR for AS have a bicuspid valve

More prone to endocarditis than trileaflet valves

Associated with aortopathies (i.e., dissection, aneurysm) in a significant proportion of patients

Rheumatic

More common cause worldwide, much less common in the United States

Usually presents in the 3rd to 5th decades

Almost always accompanied by mitral valve disease

Pathophysiology

The pathophysiology for calcific AS involves both the valve and the ventricular adaptation to the stenosis. Within the valve, there is growing evidence for an active biological process that begins much like the formation of an atherosclerotic plaque and eventually leads to calcified bone formation (Fig. 2).

DIAGNOSIS

Clinical Presentation

History

The classic triad of symptoms includes angina, syncope, and HF.

Frequently patients will gradually limit themselves in ways that mask the presence of symptoms, but indicate a progressive and premature decline in functional capacity. In the setting of severe AS, these patients should be viewed as symptomatic.

Physical Examination

Harsh systolic crescendo-decrescendo murmur heard best at the right upper sternal border and radiating to both carotids; time to peak intensity correlates with severity (later peak ~ more severe).

Diminished or absent A2 (soft S2) suggests severe AS.

An OS suggests bicuspid AS.

S4 reflects atrial contraction on a poorly compliant ventricle.

Pulsus parvus et tardus: late-peaking and diminished carotid upstroke in severe AS.

P.187

Gallavardin phenomenon is an AS murmur heard best at the apex (easily confused with MR).

Between extremes, it is often difficult to assess AS severity on exam.

Figure 2. Pathophysiology of aortic stenosis. CO, cardiac output; LVH, left ventricular hypertrophy; LVEDP, left ventricular end-diastolic pressure; EF, ejection fraction.

Diagnostic Testing

ECG: LAE and LVH

CXR: LVH, cardiomegaly, and calcification of the aorta, aortic valve, and/or coronaries

TTE

Leaflet number, morphology, and calcification

Calculate valve area using continuity equation and measure transvalvular mean and peak gradients

Severe AS

Peak jet velocity (m/s) >4.0

Mean gradient (mm Hg) >40

Valve area (cm2) <1.0

Further evaluation in selected patients

TEE

Clarify whether there is a bicuspid valve if unclear on TTE

P.188

Occasionally needed to evaluate for other or additional causes of LVOT obstruction

Exercise testing: Performed in the patient presumed to be asymptomatic or in whom symptoms are unclear: evaluate for exercise capacity, abnormal blood pressure response (<20 mm Hg increase with exercise), or exercise induced symptoms

Dobutamine stress echo: Useful to assess the patient with LV dysfunction with a small calculated valve area (suggesting severe AS) but a low (<30 to 40 mm Hg) mean transvalvular gradient (suggesting less severe AS)

Can help distinguish truly severe AS from pseudo severe AS

Assess for the presence of contractile reserve

Cath

In patients undergoing AVR who are at risk for CAD

Evaluate for CAD in patients with moderate AS and symptoms of angina

Hemodynamic assessment of severity of AS in patients in whom noninvasive tests are inconclusive or when there is discrepancy between noninvasive tests and clinical findings regarding AS severity (utilizes the Gorlin formula)

CTA: CTA may be an alternative to cath to evaluate coronary anatomy prior to valve surgery (the role and accuracy of CTA is still being investigated)

BNP or NtBNP

Predicts symptom-free survival in asymptomatic patients and preoperative level predicts postoperative survival, functional class, and LV function (Circulation 2004;109:2302)

BNP is higher in patients with truly severe AS versus pseudo severe AS and predicts survival among patients with low-flow, low-gradient AS (Circulation 2007;115:2848)

TREATMENT

Severe symptomatic AS is a surgical disease; currently, there are no medical treatments proven to decrease mortality or delay surgery

HTN: treat with appropriate antihypertensive agents cautiously to avoid hypotension

ACEI: some data suggest that ACE inhibition may advantageously interfere with the valvular biology that leads to valve calcification

Statins: some clinical evidence suggests statins may slow progression of AS (J Am Coll Cardiol 2007;47:2141), but the data are mixed and may depend on the severity of AS when the statin is initiated

Avoid overdiuresis and loss of preload which may precipitate hypotension

Use vasodilators, particularly nitroglycerin, very cautiously so as to avoid hypotension

Severe AS with decompensated HF

Patients with severe AS and LV dysfunction may experience decompensated HF; depending on the clinical scenario, several options may help bridge the patient to definitive surgical management (AVR):

IABP (contraindicated in patients with moderate to severe AR)

Sodium nitroprusside

Balloon aortic valvuloplasty

Each of the above measures provides some degree of afterload reduction, either at the level of the valve (valvuloplasty) or SVR (IABP, Nipride); this afterload reduction can facilitate forward flow; as the HF becomes more compensated and transient end-organ damage is reversed (i.e., renal failure, respiratory failure), operative mortality can decrease

P.189

Percutaneous

Balloon aortic valvuloplasty has a limited role in the treatment of patients with severe AS; the improvement in valve area is modest and the clinical improvement that it provides usually lasts weeks to months

Transcatheter aortic valve replacement (AVR) has recently been introduced as an option for patients at high risk for AVR

Performed via a transfemoral or transapical approach

There are ongoing trials to assess the safety and efficacy of this approach in high-risk surgical candidates and those who are inoperable

These techniques and device characteristics are rapidly evolving

Surgical Management

Symptomatic severe AS is a deadly disease; AVR is the only currently effective treatment

Certain associated high-risk features or the need for another cardiac surgical intervention may lead to the recommendation for an AVR even when the patient is asymptomatic or has less than severe AS

Operative mortality varies significantly depending on age, comorbidities, surgical experience, and concurrent surgical procedures to be performed

ACC/AHA Guidelines—Class I Indications for AVR

Symptomatic patients with severe AS

Patients with severe AS undergoing CABG

Patients with severe AS undergoing surgery on the aorta or other heart valves

Patients with severe AS and LV systolic dysfunction (EF <50%)

OUTCOME/PROGNOSIS

AS is a progressive disease typically characterized by an asymptomatic phase until the valve area reaches a minimum threshold, generally <1 cm2. In the absence of symptoms, patients with AS have a good prognosis with a risk of sudden death estimated to be <1% per year. Predictors of decreased event-free survival (free of AVR or death) include higher peak aortic jet velocity, extent of valve calcification, and coexistent CAD. Once patients experience symptoms, their average survival is 2 to 3 years with a high risk of sudden death.

Mitral Regurgitation

GENERAL PRINCIPLES

Prevention of mitral regurgitation (MR) is dependent on the integrated and proper function of the mitral valve (annulus and leaflets), subvalvular apparatus (chordae tendineae and papillary muscles), left atrium, and the ventricle; abnormal function or size of any one of these components can lead to MR.

Organic MR refers to MR caused primarily by lesions to the valve leaflets and/or chordae tendineae (i.e., myxomatous degeneration, endocarditis, and rheumatic).

Functional MR refers to MR caused primarily by ventricular dysfunction usually with accompanying annular dilatation (i.e., DCM and ischemic MR).

It is critical to define the mechanism of MR and the time course (acute vs. chronic) as these significantly impact clinical management.

P.190

Etiology

Degenerative (overlap with mitral valve prolapse syndrome)

Usually occurs as a primary condition (Barlow's disease or fibroelastic deficiency), but has also been associated with heritable diseases affecting the connective tissue including Marfan's syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, etc.

May be familial or nonfamilial

Occurs in 1% to 2.5% of the population (based on stricter echo criteria)

Female to male 2:1

Either or both leaflets may prolapse

Most common reason for MV surgery

Myxomatous proliferation and cartilage formation can occur in the leaflets, chordae tendineae, and/or annulus

Dilated Cardiomyopathy (DCM)

Mechanism of MR due to both:

Annular dilatation from ventricular enlargement

Papillary muscle displacement due to ventricular enlargement and remodeling prevents adequate leaflet coaptation

May occur in the setting of nonischemic DCM or ischemic DCM (there is often an overlap of mechanism for MR in the setting of previous infarction)

Ischemic

Ischemic MR is mostly a misnomer, as this is primarily postinfarction MR, not MR caused by active ischemia (although MR can be do to ischemia alone or postinfarct MR can be exacerbated by ischemia)

Mechanism of MR usually involves one or both of the following:

Annular dilatation from ventricular enlargement

Local LV remodeling with papillary muscle displacement (both the dilatation of the ventricle and the akinesis/dyskinesis of the wall to which the papillary muscle is attached can prevent adequate leaflet coaptation)

Rarely, MR may develop acutely from papillary muscle rupture (more commonly of the posteromedial papillary muscle)

Rheumatic

May be pure MR or combined MR/MS

Caused by thickening and/or calcification of the leaflets and chords

Infective Endocarditis: Usually caused by destruction of the leaflet tissue (i.e., perforation)

Other causes

Congenital (cleft, parachute, or fenestrated mitral valves)

Infiltrative diseases (i.e., amyloid)

Systemic Lupus Erythematosus (Libman-Sacks lesion)

HCM with obstruction

Mitral annular calcification

Paravalvular prosthetic leak

Drug toxicity (e.g., Phen-fen)

Acute causes

Ruptured papillary muscle

Ruptured chordae tendineae

Infective endocarditis

P.191

Figure 3. Acute mitral regurgitation. LA, left atrium; LV, left ventricle; LVEDP, left ventricular end-diastolic pressure; LAP, left atrial pressure; SV, stroke volume; CO, cardiac output; EF, ejection fraction.

Pathophysiology

Acute MR (Fig. 3)

Chronic MR (Fig. 4)

DIAGNOSIS

Clinical Presentation

History

Acute MR

Most prominent symptom is relatively rapid onset of significant shortness of breath which may lead quickly to respiratory failure

Symptoms of reduced forward flow may also be present depending on the patient's ability to compensate for the regurgitant volume

Chronic MR

The etiology of MR and the time at which the patient presents will influence the symptoms reported

In degenerative MR that has gradually progressed, the patient may be asymptomatic even when the MR is severe. As compensatory mechanisms fail, patients may note:

Dyspnea on exertion (may be due to pHTN and/or pulmonary edema)

Palpitations (from an atrial arrhythmia)

Fatigue

Volume overload

P.192

Patients with ischemic MR and MR due to a DCM may report similar symptoms; in general, these patients will tend to be more symptomatic because almost all of them have associated LV dysfunction

Figure 4. Chronic mitral regurgitation. LA, left atrium; LV, left ventricle; LVEDP, left ventricular end-diastolic pressure; LAP, left atrial pressure; SV, stroke volume; CO, cardiac output; EF, ejection fraction; pHTN, pulmonary hypertension.

Physical Examination

Acute MR

Tachypnea with respiratory distress

Tachycardia

Systolic murmur, usually at the apex—may not be holosystolic and may be absent

Relative hypotension (even shock)

P.193

Chronic MR

Apical holosystolic murmur that radiates to the axilla

The murmur may radiate to the anterior chest wall if the posterior leaflet is prolapsed or toward the back if the anterior leaflet is prolapsed

In mitral valve prolapse, there is a midsystolic click heard before the murmur

S2 may be widely split due to an early A2

Other signs of CHF (LE edema, ↑ central venous pressure, crackles, etc.)

Diagnostic Testing

ECG

LAE, LVH/LVE

Atrial fibrillation

Pathologic Q waves from previous MI in ischemic MR

CXR

Enlarged LA

Pulmonary edema

Enlarged pulmonary arteries

Cardiomegaly

TTE

Assess etiology of MR

LA size and LV dimensions (should be dilated in chronic severe MR of any etiology)

Ejection fraction (LV dysfunction is present if EF ≤60%)

Qualitative and quantitative measures of MR severity

TEE

Provides better visualization of the valve to help define anatomy, presence of endocarditis, and feasibility of repair

May help determine severity of MR when TTE is nondiagnostic, particularly in the setting of an eccentric jet

3D echo: May provide additional and more accurate anatomic insights that can guide repair

Exercise Testing with Echo

Helpful in clarifying functional capacity of those with an unclear history

Assess severity of MR with exercise in patients with exertional symptoms that seem discordant with the assessment of MR severity at rest

Assess PA pressure with exercise

MRI

Assess EF in patients with severe MR, but with an inadequate assessment of EF by echo

Assess quantitative measures of MR severity when echo is nondiagnostic

Viability assessment may play a role in considering therapeutic strategy in ischemic MR

Nuclear

Assess EF in patients with severe MR, but with an inadequate assessment of EF by echo

Viability assessment may play a role in considering therapeutic strategy in ischemic MR

Cath

Right heart cath to evaluate:

Pulmonary hypertension in patients with chronic severe MR

P.194

LA filling pressure in patients with unclear symptoms

Giant V waves on PCWP tracing may suggest severe MR

Left heart cath:

May influence therapeutic strategy in ischemic MR

Evaluation of CAD in patients with risk factors undergoing MV surgery

Left ventriculogram can evaluate LV function and severity of MR

CTA: CTA may be an alternative to LHC to evaluate coronary anatomy prior to valve surgery (the role and accuracy of CTA is still being investigated)

TREATMENT

Acute:

While awaiting surgery, aggressive afterload reduction with IV nitroprusside or an IABP can diminish the amount of MR and stabilize the patient by promoting forward flow and reducing pulmonary edema

These patients are usually tachycardiac, but attempts to slow their heart rate should be avoided as they are often heart rate dependent for an adequate forward cardiac output

Chronic: The role for medical therapy may differ depending on the etiology of the MR

Degenerative MR:

In the asymptomatic patient with normal LV function and chronic severe MR due to leaflet prolapse, there is generally no accepted medical therapy

In the absence of systemic HTN, there is no known indication for vasodilating drugs

Whether ACEI or β-blockers delay ventricular remodeling and the need for surgery is being investigated in prospective studies

Functional MR:

Treat as other patients with LV dysfunction

ACEI and β-blockers are indicated and have been shown to reduce mortality and the severity of MR

Some patients may also qualify for cardiac resynchronization therapy, which has also been shown to reduce the severity of MR

Percutaneous

Various approaches target each of the interrelated components that can contribute to MR: annular dilatation, lack of leaflet coaptation, and ventricular remodeling causing papillary muscle displacement

Currently, the most developed device may be the placement of a mitral clip, which pinches the leaflets together in an attempt to enhance coaptation

This is a rapidly developing field with new devices and several trials in progress

Surgical Management

ACC/AHA Guidelines—Class I Indications for Surgery in Mitral Regurgitation

Symptomatic acute severe MR

Chronic severe MR and NYHA functional class II, III, or IV symptoms in the absence of severe LV dysfunction (EF < 30%) and/or end-systolic dimension (ESD) > 55 mm

Asymptomatic with chronic severe MR and mild-moderate LV dysfunction (EF 30% to 60%) and/or ESD ≥ 40 mm

P.195

MV repair is recommended over MV replacement in the majority of patients with severe chronic MR who require surgery, and patients should be referred to surgical centers experienced in MV repair

Surgery for MR is most commonly performed in patients with degenerative mitral valve disease

Advances in surgical technique and lower operative mortality are causing some centers to operate earlier on patients with severe MR, even when they are asymptomatic

Preoperative factors that increase operative and/or postoperative mortality include: worse NYHA functional class, LV dysfunction (EF < 60%), age, associated CAD, and atrial fibrillation

Surgery for patients with ischemic MR and MR due to a DCM is more controversial and potentially more complex; the MR is largely due to a ventricular problem, so an isolated annuloplasty likely will not solve the problem; this is an active area of research and debate

Certain patients with atrial fibrillation should be considered for a concomitant surgical MAZE procedure

Aortic Regurgitation

GENERAL PRINCIPLES

Aortic regurgitation (AR) may result from pathology of the aortic valve, the aortic root, or both; it is important that both the valve and the root are evaluated to determine the appropriate management and treatment.

AR usually develops insidiously with a long asymptomatic period; when it occurs acutely, it is often associated life threatening and must be managed aggressively.

Etiology

More common

Bicuspid aortic valve

Rheumatic disease

Calcific degeneration

Infective endocarditis

Idiopathic dilatation of the aorta

Myxomatous degeneration

Systemic hypertension

Dissection of the ascending aorta

Marfan's syndrome

Less common

Traumatic injury to the aortic valve

Collagen vascular diseases (ankylosing spondylitis, rheumatoid arthritis, Reiter's syndrome, giant cell aortitis, and Whipple's disease)

Syphilitic aortitis

Discrete subaortic stenosis

VSD with prolapse of an aortic cusp

Acute

Infective endocarditis

Dissection of the ascending aorta

Trauma

P.196

Figure 5. Acute aortic regurgitation. LV, left ventricle; LVEDP, left ventricular end-diastolic pressure; LAP, left atrial pressure; CO, cardiac output; HR, heart rate; SV, stroke volume.

Pathophysiology

Acute AR (Fig. 5)

Chronic AR (Fig. 6)

DIAGNOSIS

Clinical Presentation

History

Acute: Patients with acute AR may present with symptoms of cardiogenic shock and severe dyspnea. Other presenting symptoms may be related to the cause of acute AR.

Chronic: Symptoms depend on the presence of LV dysfunction and whether the patient is in the compensated versus decompensated stage. Compensated patients are typically asymptomatic, whereas those in the decompensated stage may note decreased exercise tolerance, dyspnea, fatigue, and/or angina.

Physical Examination

Acute

Tachycardia

Wide pulse pressure may be present, but is often not present because forward stroke volume (and therefore systolic blood pressure) is reduced

Brief soft diastolic murmur heard best at 3rd left intercostal space (often not heard)

P.197

Systolic flow murmur (due to volume overload and hyperdynamic LV)

Look for evidence of aortic dissection, infective endocarditis, and Marfanoid characteristics

Chronic

LV heave, and PMI is laterally displaced

Diastolic decrescendo murmur heard best at LSB leaning forward at end-expiration (severity of AR correlates with duration, not intensity, of the murmur)

Systolic flow murmur (due mostly to volume overload; concomitant AS may also be present)

Austin Flint murmur

Widened pulse pressure (often >100 mm Hg) with a low diastolic pressure; there are numerous eponyms for the characteristic signs related to a wide pulse pressure.

Figure 6. Chronic aortic regurgitation. LV, left ventricle; LVED, left ventricular end-diastolic; LVEDP, left ventricular end-diastolic pressure; EF, ejection fraction; SV, stroke volume; CO, cardiac output; CHF, congestive heart failure.

Diagnostic Testing

The diagnostic evaluation will likely depend somewhat on the acuity of the presentation, but will likely include:

P.198

ECG

Tachycardia

LVH and LAE (more common in chronic AR)

New conduction block may suggest an aortic root abscess

CXR: Look for pulmonary edema, widened mediastinum, and cardiomegaly

TTE

LV systolic function

LV dimensions at end-systole and end-diastole

Leaflet number and morphology

Assessment of the severity of AR

Look for evidence of endocarditis or aortic dissection

Dimension of aortic root

TEE

Clarify whether there is a bicuspid valve if unclear on TTE

Better sensitivity and specificity for aortic dissection than TTE

Clarify whether there is endocarditis ± root abscess if unclear on TTE

Better visualization of aortic valve in patients with a prosthetic aortic valve

Cath

In patients undergoing AVR who are at risk for CAD

Assessment of LV pressure, LV function, and severity of AR (via aortic root angiography) is indicated in symptomatic patients in whom the severity of AR is unclear on noninvasive imaging or discordant with clinical findings

Imaging

MRI/CT

Depending on the institution, either of these may be the imaging modality of choice for evaluating aortic dimensions and/or for evaluation of aortic dissection

If echo assessment of the severity of AR is inadequate, MRI is useful for assessing the severity of AR

CTA may be an alternative to cath to evaluate coronary anatomy prior to valve surgery (the role and accuracy of CTA are still being investigated)

TREATMENT

The role of medical therapy in patients with AR is limited; there are currently no randomized, placebo-controlled data showing that vasodilator therapy delays the development of symptoms or

LV dysfunction warranting surgery

Vasodilator therapy (i.e., nifedipine, ACEI, hydralazine) is indicated to reduce systolic blood pressure in hypertensive patients with AR

Other than for treating hypertension, vasodilator therapy has a potential role in three situations:

As chronic therapy in patients with severe AS who have symptoms or LV dysfunction but are not surgical candidates

As a short-term therapy to improve hemodynamics in patients with severe HF and severe LV dysfunction prior to surgery

May be considered for long-term therapy in asymptomatic patients with severe AS who have some LV dilatation but normal LV systolic function

When endocarditis is suspected or confirmed, appropriate antibiotic coverage is critical

P.199

Surgical Management

ACC/AHA Guidelines—Class I Indications for Aortic Valve Replacement for AR

Symptomatic with severe AR irrespective of LV systolic function

Asymptomatic with chronic severe AR and LV systolic dysfunction (EF ≤50%)

Chronic severe AR while undergoing CABG, surgery on the aorta, or other valve surgery

Acute, severe AR is almost universally symptomatic and is treated surgically

If the aortic root is dilated, it may be repaired or replaced at the time of AVR

For patients with a bicuspid valve, Marfan's syndrome (or related genetically triggered aortopathy), surgery on the aorta should occur at the time of AVR if the aortic root or ascending aorta is >4.5 cm

Although worse NYHA functional class, LV dysfunction, and the chronicity of these abnormalities are predictors of higher operative and postoperative mortality, AVR is usually a better alternative than medical therapy in improving overall mortality and morbidity

OUTCOME/PROGNOSIS

Asymptomatic patients with normal LV systolic function (JACC 2006;48(3):e1-e148)

Progression to symptoms and/or LV dysfunction <6% per year

Progression to asymptomatic LV dysfunction <3.5% per year

Sudden death <0.2% per year

Asymptomatic patients with LV dysfunction

Progression to cardiac symptoms >25% per year

Symptomatic patients

Mortality rate >10% per year

Prosthetic Heart Valves

GENERAL PRINCIPLES

The choice of valve prosthesis depends on many factors including the patient, surgeon, cardiologist and clinical scenario. With improvements in bioprosthetic valves, the recommendation for a mechanical valve in patients <65 years of age is no longer as firm and bioprosthetic valve use has increased in younger patients.

Mechanical

Ball-and-cage (Starr-Edwards)—rarely, if ever, used today

Bileaflet (i.e., St. Jude, Carbomedics)—most commonly used

Single-tilting disk (i.e., Björk-Shiley, Medtronic Hall, Omnicarbon)

Advantages: structurally stable, long-lasting, relatively hemodynamically efficient (particularly bileaflet)

Disadvantages: need for anticoagulation, risk of bleeding, risk of thrombosis/embolism despite anticoagulation, severe hemodynamic compromise if disk thrombosis or immobility occurs (single-tilting disk), risk of endocarditis

Bioprosthetic

Porcine aortic valve tissue (i.e., Hancock, Carpentier-Edwards)

Bovine pericardial tissue (i.e., Carpentier-Edwards Perimount)

P.200

Stented or stentless

Advantages: no need for anticoagulation, low thromboembolism risk, low risk of catastrophic valve failure

Disadvantages: structural valve deterioration, imperfect hemodynamic efficiency, risk of endocarditis, still a small risk (0.7% per year) of thromboembolism without anticoagulation

Homograft (cadaveric)

Rarely used for AV surgery; the only remaining use for aortic valve/root homograft may be in the setting AV endocarditis, particularly complex aortic root endocarditis

Most commonly used to replace the pulmonic valve

Table 5

Valve and Duration

Aspirin (75-100 mg)

Warfarin (INR 2-3)

Warfarin (INR 2.5-3.5)

No Warfarin

Mechanical

AVR—low risk

<3 months

Class I

Class I

Class IIa

>3 months

Class I

Class I

AVR—high risk

Class I

Class I

MVR

Class I

Class I

Biological

AVR—low risk

<3 months

Class I

Class IIa

Class IIb

>3 months

Class I

Class IIa

AVR—high risk

Class I

Class I

MVR—low risk

<3 months

Class I

Class IIa

>3 months

Class I

Class IIa

MVR—high risk

Class I

Class I

TREATMENT

Medications

Risk factors include atrial fibrillation, previous thromboembolism, LV dysfunction, and hypercoagulable condition. Low risk means no risk factors. INR should be maintained between 2.5 and 3.5 for aortic disk valves and Starr-Edwards valves regardless of risk factors (JACC 2006;48(3):e1-e148) (Table 5).