Ebook Symptom to diagnosis (3/E): Part 2

Part 2 book “Symptom to diagnosis” has contents: Wheezing and stridor, sore throat, weight loss, unintentional, kidney injury, acute, jaundice and abnormal liver enzymes, hematuria, hypertension, hypercalcemia, GI bleeding, fatigue, edema,… and other contents.

Mr C is a 64-year-old man who comes to see you complaining of shortness of breath.

What is the differential diagnosis of dyspnea? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

Heart disease, lung disease, and anemia are the most common causes of dyspnea Neuromusculardisease and anxiety are less common causes The simplest approach to the differential diagnosis is to

consider the anatomical components of each of these systems This allows us to develop a fairly

comprehensive differential diagnosis of dyspnea

Differential Diagnosis of Dyspnea

A Heart

1 Endocardium: Valvular heart disease (ie, aortic stenosis, aortic regurgitation, mitral

regurgitation, and mitral stenosis)

a Systolic failure (coronary artery disease [CAD], hypertension, alcohol abuse)

b Diastolic failure (hypertension, aortic stenosis, hypertrophic cardiomyopathy)

4 Coronary arteries (ischemia)

5 Pericardium (tamponade, constrictive pericarditis)

(a) Tuberculosis (b) Cancer

(c) Parapneumonic effusions (d) Connective tissue diseases (e) PE

5 Interstitium

a Edema

b Inflammatory

(1) Organic exposures (eg, hay, cotton, grain)

(2) Mineral exposures (eg, asbestos, silicon, coal)

(3) Idiopathic diseases (eg, sarcoidosis, scleroderma, systemic lupus erythematosus,

granulomatosis with polyangiitis [formerly Wegener granulomatosis])

c Infectious

C Anemia

The extensive differential diagnosis for dyspnea necessitates a careful and detailed history, physicalexam and review of basic laboratory examinations including chest film, ECG, and hematocrit Thehistory should detail the time course of the complaint, its severity, associated symptoms, and thepatient’s past medical history The physical exam should include vital signs, a detailed cardiac andpulmonary exam, and a search for signs suggestive of anemia (conjunctival pallor or palmar creasepallor) This process often suggests the diagnosis However, when the diagnosis is not

straightforward, certain pivotal findings can narrow the differential diagnosis and focus the

diagnostic search (Figure 15-1) One such pivotal clue is fever Fever is typically seen in pneumoniabut could also be seen in asthma or COPD with concomitant infection Less common causes of feverand dyspnea include valvular heart disease due to endocarditis, pulmonary emboli, acute respiratorydistress syndrome, or interstitial lung disease Chest pain (covered extensively in Chapter 9) is

another pivotal clue in patients with dyspnea Chest pain may be pleuritic or nonpleuritic and acute orchronic/recurrent Each of these features can help focus the differential diagnosis (see Figure 15-1,

Table 15-1) In brief, common causes of dyspnea and pleuritic chest pain are pneumonia, PE,

pneumothorax, asthma, and COPD On the other hand, many diseases may cause nonpleuritic chestpain (including those diseases already mentioned that may cause pleuritic chest pain) In these

patients, the acuity of the chest pain can help narrow the differential diagnosis Common causes ofdyspnea associated with acute chest pain include myocardial infarction (MI), aortic dissection, PE,pneumothorax, arrhythmias (causing angina), and pneumonia Common causes of dyspnea associatedwith chronic/recurrent chest pain include angina (caused by CAD, severe anemia, or aortic stenosis),asthma or COPD (which are often associated with chest tightness), and recurrent intermittent

arrhythmias

Figure 15-1 A diagnostic approach to dyspnea.

Table 15-1 Differential diagnosis of dyspnea and chest pain.

In patients with any of any of the aforementioned pivotal clues (fever, chest pain), a search for riskfactors, associated symptoms and signs of those diseases can help rank the differential diagnosis

Table 15-2 lists the highly suggestive risk factors as well as associated symptoms and signs of

common diseases causing dyspnea

Table 15-2 Common causes of dyspnea: highly suggestive risk factors, associated symptoms, signs,

and tests

When these pivotal clues are absent, it is appropriate to evaluate the most common causes of

dyspnea, namely HF, pneumonia, asthma, COPD, and pulmonary emboli Once again, looking for theirrespective risk factors, associated symptoms and specific signs can help determine their likelihood.Features that suggest HF include a history of MI, CAD risk factors, long-standing uncontrolled

hypertension, or alcohol abuse Furthermore, an S3 gallop or jugular venous distention (JVD) arefingerprints for HF Fever and cough raise the possibility of pneumonia and a significant smokinghistory (≥ 20 pack years) raises the possibility of COPD Wheezing—defined as a multi-pitched

sound on exhalation—suggests COPD or asthma Finally, PE can be obvious or subtle and should be

considered in patients with risk factors such as recent immobilization, surgery, a history of cancer, oruse of estrogen, or suggestive signs (eg, unilateral leg swelling)

Some patients remain difficult to diagnose For such patients a more comprehensive review of riskfactors, associated symptoms and signs (Table 15-2) as well as a careful review of their chest filmfindings may be helpful (Table 15-3) A normal chest radiograph makes pneumonia, interstitial lungdisease, and acute respiratory distress syndrome unlikely and rules out pneumothorax Focal

infiltrate(s) suggest pneumonia and can also be seen with COPD or asthma due to atelectasis or

superimposed infection Diffuse infiltrates or edema may be seen in a variety of settings including anycause of HF, acute respiratory distress syndrome, and certain pneumonias The presence of a pleuraleffusion is a critical clue that should be evaluated

Table 15-3 Typical radiographic patterns found in dyspneic patients.

Other diagnostic testing that is often necessary includes echocardiography, pulmonary functiontests, B-type natriuretic peptide (BNP), and CT angiography (CTA) Echocardiography can revealunsuspected HF or valvular heart disease Pulmonary function tests can help determine whether thepatient has obstructive, restrictive, or vascular lung disease (Table 15-4) Figure 15-1 summarizes adiagnostic approach to patients with dyspnea.

Table 15-4 Pulmonary function test (PFT) abnormalities in lung disease.

Over the last 2 years, Mr C has noticed worsening dyspnea on exertion He complains of

shortness of breath with minimal exertion He is unable to walk around his house without resting.Several years ago, Mr C could walk several blocks without any difficulty He notes that he isunable to sleep lying flat due to shortness of breath (orthopnea), and he has slept on a reclinerfor the last 6 months Occasionally, he awakes from sleep acutely short of breath (paroxysmalnocturnal dyspnea) He complains that his feet are swollen.

Always quantify the increase in dyspnea from baseline Significant changes suggest serious

disease and warrant thorough evaluations

Past medical history is notable for an MI 2 years ago Vital signs are temperature, 37.0°C; RR,

24 breaths per minute; pulse, 110 bpm; BP, 120/78 mm Hg His pulse is regular with an

occasional irregularity Cardiac exam reveals JVD to the angle of the jaw in the upright position,

a grade II/VI systolic murmur at the apex, and a positive S3 gallop Lung exam reveals crackleshalf of the way up from the bases bilaterally He has 2+ pretibial edema to the knees

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Although the differential diagnosis of dyspnea is broad, the patient’s risk factors, symptoms and signspoint to a cardiac etiology and immediately focus the differential diagnosis His past history of MI is

a clear risk factor for HF Furthermore, the JVD, S3 gallop, and peripheral edema are all very

suggestive of HF making this the leading hypothesis His physical exam also reveals a heart murmurraising several alternative diagnoses (ie, mitral regurgitation, aortic stenosis, or aortic regurgitation).This particular murmur is most consistent with mitral regurgitation Mr C’s irregular pulse also

raises the possibility of atrial fibrillation Finally, cardiac ischemia presenting as dyspnea rather thanpain is a must not miss possibility Table 15-5 lists the differential diagnosis

Table 15-5 Diagnostic hypotheses for Mr C.

Pursue highly specific positive physical findings (in this case the S3 gallop and JVD); they shouldhelp drive the diagnostic search.

A chest radiograph, HCT, and ECG are performed

Is the clinical information sufficient to make a diagnosis of HF? If not, what other

information do you need?

A HF refers to any cardiac pathology that impairs left ventricular filling or ejection, which may arise

from diseases of the pericardium, myocardium, or valves The remainder of this discussion willfocus on myocardial causes of HF Valvular heart disease is discussed separately

B Affects 5.8 million patients in the United States and accounts for 1 million hospitalizations and

53,000 deaths annually Each year, HF is diagnosed in 670,000 patients

C Pathophysiologic classification: HF may occur in patients with impaired emptying (and an ejection

fraction ≤ 40%) or impaired filling (with a preserved ejection fraction ≥ 50%) The distinction isimportant because both the etiologies and treatments of these 2 groups are different HF may also

be classified based on whether the primary process affects the left ventricle (LV) or the right

ventricle (RV)

1 Heart failure with reduced ejection fraction (HFrEF)

a Previously called systolic HF or systolic dysfunction, HFrEF accounts for approximately

50% of cases of HF

b HFrEF develops when systolic dysfunction impairs LV emptying.

c CAD accounts for 66% of all cases of HFrEF.

d Other common causes include long-standing hypertension and alcohol abuse.

e Less common causes include viral cardiomyopathy, postpartum cardiomyopathy, drug toxicity

(ie, adriamycin), and idiopathic cardiomyopathy

f Most patients with HFrEF (impaired emptying) also have diastolic dysfunction (impaired

2 Heart failure with preserved ejection fraction (HFpEF)

a Previously referred to as diastolic HF, HFpEF accounts for approximately 50% of all HF

cases

b HFpEF develops when an increase in myocardial muscle mass (thickness), infiltration, or

fibrosis decreases LV compliance

(1) Decreased LV compliance impairs LV filling.

(2) Note that although LV filling is compromised, contractility is preserved and the ejection

fraction is normal.

c The most common cause of HFpEF is hypertension Less common causes include aortic

stenosis, hypertrophic cardiomyopathy, and infiltrative cardiomyopathies (eg,

hemochromatosis, amyloidosis)

3 The mortality in patients with HFrEF and HFpEF are similar.

4 Patients with ejection fraction of 41–49% are classified as HFpEF, borderline Their treatment

and outcomes appear similar to patients with HFpEF.

5 Right- versus left-sided HF

a HF may involve the LV, the RV, or both.

b Common causes of LV failure include CAD, hypertension, and alcoholic cardiomyopathy.

c Common causes of RV failure include severe pulmonary disease (especially COPD) and

advanced LV failure

d Peripheral edema, JVD, and fatigue may be seen in LV or RV failure Pulmonary edema may

also be seen in LV failure but not isolated RV failure

6 Progression

a HF triggers maladaptive neurohormonal changes including increased activation of the

renin-angiotensin-aldosterone system and the sympathetic nervous system

b These neurohormonal responses promote sodium retention, increase afterload, and contribute

to edema and progressive HF

c Therapies that interrupt these responses reduce mortality (see below).

D Classifications of HF

1 New York Heart Association functional classification is descriptively useful but is limited by

the ability of patients to move from 1 class to another with therapy

a Class I: Asymptomatic (ie, symptoms only at levels of exertion that would make healthy

patients dyspneic)

b Class II: Slight limitation of physical activity (eg, climbing stairs)

c Class III: Marked limitation of physical activity (eg, walking on flat surface)

d Class IV: Symptoms at rest or with any physical activity

2 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) stages

of HF were developed to facilitate identifying stage-specific therapies

a Stage A: Patients at high risk for HF without structural heart disease or symptoms (eg,

patients with hypertension or CAD but normal LV function)

b Stage B: Patients with structural heart disease (eg, LV hypertrophy or decreased ejection

fraction) without signs or symptoms of HF

c Stage C: Structural heart disease and prior or current symptoms.

d Stage D: Refractory HF symptoms despite therapy.

b Risk increases if atrial fibrillation coexists

4 Mitral regurgitation (LV dilatation may lead to sufficient dilatation of the mitral annulus that it

causes secondary mitral regurgitation [see below])

5 Death

a Symptomatic mild to moderate HF: 20–30% per year

b Symptomatic severe HF: up to 50% per year

c Mechanism of death

(1) Sudden in 50% (secondary to ventricular tachycardia or asystole)

(2) Progressive HF in 50%

Evidence-Based Diagnosis

A The history should assess risk factors for HF, including hypertension, CAD, alcohol abuse, illicit

drug use, and adriamycin exposure

B Common symptoms include dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea

(Table 15-6)

Table 15-6 Accuracy of clinical findings in heart failure.

C Physical exam

1 Clinical signs and symptoms are affected by

a Patient’s current volume status

b Chronicity In chronic HF, signs and symptoms are frequently absent despite marked

impairment of LV function and marked volume overload.

2 S3 gallop

a An S3 gallop occurs when a large volume of blood rushes from the left atrium (LA) into the

LV at the start of diastole (just after S2)

b Virtually pathognomonic of volume overload and occurs most commonly in patients with

decompensated HF

3 S4 gallop

a Occurs when the LA contracts and sends blood into the LV (just before S1)

b An S4 gallop may be heard in some normal patients and in many patients with LV hypertrophydue to hypertension or other causes

c S4 is not specific for HF.

4 JVD

a Defined as > 3 cm of elevation above the sternal angle (Figure 15-2)

Figure 15-2 Measurement of jugular venous distention (JVD) Modified from McGee S Evidence

Based Physical Diagnosis, p 402 Copyright ©2001 With permission from Elsevier

b Highly specific for HF (> 95%); may occur in RV or LV failure.

5 Table 15-6 summarizes the sensitivities, specificities, and LRs of clinical findings for HF inpatients with dyspnea

a Classic signs and symptoms (orthopnea, paroxysmal nocturnal dyspnea, crackles, gallops and

edema) are not sensitive for HF and their absence does not rule out HF Indeed, even insevere chronic HF (mean ejection fraction 18%, pulmonary capillary wedge pressure

[PCWP] > 22 mm Hg), 42% of patients did not have crackles, increased JVP, or edema

Signs of HF are commonly absent even in advanced HF

b However, certain findings are highly specific and significantly increase the likelihood of HF

when present An S3 (but not an S4) and JVD strongly suggest HF

c Other classic symptoms, like orthopnea, paroxysmal nocturnal dyspnea, and crackles, are not

specific for HF

D Chest radiography

1 Cardiomegaly is the most sensitive finding on chest film (74% sensitive, 78% specific), and its

absence modestly decreases the likelihood of HF (LR– 0.33)

2 Pulmonary venous congestion and interstitial edema are highly specific (96–97%) and when

present strongly suggest HF (LR+ 12)

3 Pleural effusions are seen in 26% of patients with HF.

a The effusions are usually small to moderate in size and unilateral or bilateral.

b These effusions are transudative.

c When due to HF, pleural effusions are usually accompanied by cardiomegaly, pulmonary

vascular redistribution, or edema

d The absence of these findings or the presence of massive pleural effusions suggests some

other etiology and warrants further evaluation

4 Table 15-7 summarizes the accuracy of the chest radiograph in the diagnosis of HF

Table 15-7 Accuracy of chest radiography in heart failure.

E ECG, though not diagnostic for HF, can be suggestive if signs of prior MI or LV hypertrophy are

present

F BNP

1 Secreted by LV or RV in response to increased volume, pressure, or both.

2 May be elevated in systolic or diastolic HF

3 Levels increase proportionately to the degree of HF

4 Low BNP levels decrease the likelihood of HF in patients with dyspnea.

5 High levels of BNP increase the likelihood of HF but are still not entirely specific.

6 The accuracy of the BNP is summarized in Table 15-8

Table 15-8 Accuracy of BNP in heart failure.

7 BNP is also elevated in many patients with pulmonary embolus (average 702 ng/L, and 1876

ng/L in patients with central PE)

8 The ACCF/AHA concluded that elevated BNP levels lend weight to a diagnosis of HF but

should not be used in isolation to confirm or exclude HF

G Two-dimensional echocardiogram is the test of choice to diagnose HF and is recommended for all

patients with known or suspected HF

1 Systolic and diastolic function can be evaluated.

2 Regional systolic dysfunction suggests an ischemic etiology.

3 Valve function can be assessed.

4 Bedside hand-carried ultrasound accurately identifies patients with ejection fraction < 40%

when performed by internal medicine residents with limited training (sensitivity, 94%;

specificity, 94%; LR+, 15.7; LR– 0.06)

H Radionuclide tests can quantify ejection fraction but cannot assess LV wall thickness or valvular

abnormalities

I Cardiac MR, although more costly and difficult to perform than echocardiography, is another option

for the evaluation of HF

1 Cardiac MR can accurately measure ejection fraction and LV volume as well as assess

myocardial perfusion, viability, and fibrosis

2 Appropriate in the initial evaluation of patients with new or suspected HF.

3 Cardiac MR combined with magnetic resonance angiography and gadolinium enhancement can

detect underlying CAD and ischemia (sensitivity 100%, specificity 96% in patients in sinusrhythm)

J HF and COPD

1 HF is frequently present but unsuspected in patients in whom COPD is diagnosed.

2 Diagnosis is more difficult in these patients.

a Studies report unsuspected HF in ≈25% of patients with COPD These patients had fewer

pack years of tobacco use than patients without HF (9.6 vs 22.7)

b Pleural fluid, pulmonary revascularization, and edema were uncommon even in the subgroup

with HF (9.1%) but when present strongly suggested HF (LR+ 9.1)

c BNP is less sensitive in patients with COPD (sensitivity, 35%; specificity, 90%; LR+, 3.5;

B Evaluation

1 Initial history and physical exam should assess functional capacity and volume status (weight,

vital signs, lung exam, JVD, S3 gallop and edema)

2 Routine laboratory tests recommended by the ACCF/AHA

a HF develops secondary to ischemia in approximately two-thirds of patients with HFrEF.

b Identifying underlying CAD allows clinicians to optimize medical therapy and identify which

patients can benefit from revascularization

c CAD should be suspected in patients with chest pain, CAD risk factors, ischemic ECG

findings, or regional wall motion abnormalities on noninvasive imaging

d Stress test or angiography can be used depending on the pretest probability of CAD.

C Treatment

1 Certain treatments benefit all patients with HF whereas others have greater proven efficacy in

patients with HFrEF.

2 All HF patients

a Sodium restriction is recommended for all HF patients A high sodium diet is associated with

a marked increase in acute decompensated HF (an absolute increased risk 31–34%, NNH ≈3), hospitalizations, and all-cause mortality

b Diuretics (loop or thiazides)

(1) Mainstay of therapy to treat edema and pulmonary congestion (should be used in

combination with salt restriction)

(2) The clinical assessment of volume status is critical Increasing weight, edema, JVD,

pulmonary edema, or an S3 gallop suggests patients are volume overloaded

(3) However, multiple studies demonstrate that despite severe chronic HF and marked

volume overload (measured by PCWP) patients may not have signs of HF

(4) Therefore, dyspneic HF patients should undergo aggressive diuresis while monitoring

renal function

(5) LV filling pressures can also be indirectly estimated using hand carried ultrasound

evaluation of the inferior vena cava (IVC)

(a) Hand carried devices can measure IVC diameter and collapsibility with inspiration (b) HF (right or left) is associated with an increase in IVC diameter and a decrease in the

normal collapsibility with inspiration.

(c) IVC diameter > 2.0 cm suggests elevated PCWP ≥ 17 mm Hg (75% sensitive, 83%

specific, LR+ 4.4, LR– 0.3)

(d) IVC collapsibility < 45% suggests elevated PCWP ≥ 17 mm Hg (83% sensitive, 71%

specific, LR+ 2.9, LR– 0.24)

(e) IVC measurements may prove useful as an adjunct to determine the need for further

diuresis Larger IVC diameters and less collapsibility on discharge predicted thesubsequent need for readmission

(6) Input and output, daily weights, lung and cardiac exam, electrolytes, BUN and creatinine

should be monitored daily in hospitalized patients

c Control of hypertension

d CAD revascularization: Coronary artery bypass surgery can improve cardiovascular

outcomes in select patients with CAD and HF Recommendations include the following:

(1) Coronary artery bypass surgery should be considered in patients who have HF (HFrEF or

HFpEF) with angina and left main stenosis or left main equivalent disease.

(2) Coronary artery bypass surgery is also recommended for select patients with HFrEF and

multivessel or proximal LAD disease

e Influenza and pneumococcal vaccination

f Nonsteroidal antiinflammatory drugs and thiazolidinediones increase fluid retention and have

been associated with worsening and precipitating HF and should be avoided

3 Patients with HFrEF

a Therapy with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, aldosterone

antagonists, and hydralazine combined with nitrates have been shown to reduce morbidity and

mortality in patients with HFrEF.

b ACE inhibitors

(1) Indicated in patients with HFrEF or patients with a prior MI

(2) Angiotensin receptor blockers (ARBs) may be used in place of ACE inhibitors when a

troublesome cough develops in patients taking ACE inhibitors

(3) ARBs may cause angioedema in patients who had angioedema while taking ACE

inhibitors

c Beta-blockers

(1) Beta-blockers reduce morbidity and mortality in all stages of HF, including severe HF

(ejection fraction < 25%)

(2) Indicated in patients with HFrEF or patients with a prior MI Beta-blockers with proven

efficacy include carvedilol, sustained-release metoprolol and bisoprolol

(3) Initiate therapy at low doses, when patients are euvolemic and not requiring inotropes (4) Beta-blockers can precipitate fatal asthma and should be avoided in patients with severe

or decompensated reactive airway disease Selective beta-1-agonists can be used withcaution in patients with controlled reactive airway disease

d Aldosterone antagonist (eg, spironolactone)

(1) Reduces mortality in patients with class II–IV HF and ejection fraction ≤ 35% (< 40%

with prior MI)

(2) Should be avoided in patients with a glomerular filtration rate ≤ 30 mL/min, K+ ≥ 5.0

mEq/dL, or patients who cannot have their serum potassium adequately monitored

e Statins should be used in patients with HFrEF and prior MI.

f Hydralazine and nitrates, in addition to ACE inhibitors and beta-blockers, have been

demonstrated to reduce mortality in black patients with class III or IV HF They may also beuseful in patients who are unable to tolerate ACE inhibitors/ARBs

g Digoxin

(1) Reduces hospitalizations but not mortality

(2) Low serum concentrations (0.5–0.8 mg/dL) are as effective as higher concentrations.

(3) ACCF/AHA guidelines recommend digoxin only in symptomatic patients with HFrEF (4) Digoxin may increase mortality in women and is not advised for women by some

authorities

h Cardiac resynchronization therapy: Some patients with HF have prolonged QRS intervals,

associated with prolonged and dyssynchronous depolarization This nonuniform

depolarization results in poorly organized contraction and contributes to LV dysfunction Inaddition, it contributes to mitral regurgitation and LV remodeling

(1) In cardiac resynchronization, wires are implanted in the atria and both ventricles to allow

precise and coordinated depolarization of the atria and left and right ventricles

(2) Cardiac resynchronization therapy improves ejection fraction, quality of life, and

functional status, and it reduces hospitalizations and mortality in select patients

(3) Indications are complex and detailed but include patients with symptomatic HF despite

optimal medical therapy, an ejection fraction ≤ 35% and a QRS ≥ 0.15 s (and in certainpatients ≥ 0.12s)

i Implantable cardiac defibrillator

(1) A substantial proportion of patients with HF experience sudden death (30% in dilated

cardiomyopathy), presumably secondary to ventricular tachycardia and ventricular

fibrillation

(2) Implantable cardiac defibrillators are recommended in the following select HF patients: (a) Patients who have survived cardiac arrest, ventricular fibrillation, or

hemodynamically destabilizing ventricular tachycardia

(b) Symptomatic HF patients (NYHA class II–III) with ischemic or nonischemic HFrEF

with ejection fraction ≤ 35%, at least 40 days post MI while taking appropriatetherapy

(c) Asymptomatic patients with ischemic HF and an ejection fraction ≤ 30%, at least 40

days post MI while taking appropriate medical therapy

(d) Placement could be considered in HF patients with unexplained syncope.

j Heart transplantation is an option for a few patients with severe HF refractory to intensive

medical therapy

4 Patients with HFpEF

a Systolic and diastolic hypertension should be controlled.

b Diuretics can be used to treat pulmonary congestion or edema.

c Digoxin has no proven benefit.

d Control ventricular rate for patients with atrial fibrillation.

e The effectiveness of ACE inhibitors, beta-blockers, or ARBs is less well established Recent

studies suggest ARBs decrease hospitalizations in patients with HFpEF.

5 See ACCF/AHA guidelines for the treatment of patients with refractory HF and cardiogenic

shock

MAKING A DIAGNOSIS

Mr C has several features that are highly specific for HF His history of prior MI, orthopnea,

and most importantly the clinical findings of JVD and an S3 gallop are highly specific for HF

Have you crossed a diagnostic threshold for the leading hypothesis, HF? Have you ruled

out the active alternatives? Do other tests need to be done to exclude the alternative

Disease Highlights

A Trivial asymptomatic mitral regurgitation is commonly discovered on echocardiogram The

remainder of the discussion will focus on patients with more significant regurgitation

B Etiologies: Mitral regurgitation develops secondary to damaged mitral leaflets (primary) or a

dilated mitral annulus (secondary)

1 Primary mitral regurgitation

a Etiologies: mitral valve prolapse, rheumatic heart disease, and endocarditis.

b Although most patients with mitral valve prolapse never require valve replacement, it is the

most common cause of mitral regurgitation and the need for valve replacement/repair

2 Secondary mitral regurgitation

a HF: LV dilatation leads to mitral annular dilatation and mitral regurgitation.

b Ischemic mitral regurgitation: Leaflet tethering shortens the mitral apparatus, resulting in

mitral regurgitation

C Pathophysiology

1 Compensated mitral regurgitation: Mitral regurgitation leads to LA dilatation, and

compensatory LV dilatation If systolic function is maintained, ejection fraction remains normal

to high and LV end-systolic volume remains low because mitral regurgitation reduces LV

afterload

2 Decompensated mitral regurgitation: Systolic function may fail leading to increased LV end

systolic volume, decreased stroke volume, and decreased ejection fraction This may be

irreversible

3 LA dilatation may lead to atrial fibrillation.

D Disease progression is slow Average delay from diagnosis to symptoms is 16 years However, in

patients with severe mitral regurgitation, the annual mortality is 5%

E Complications include dyspnea, pulmonary edema, atrial fibrillation, and sudden death.

Evidence-Based Diagnosis

A Physical exam: The typical murmur is a blowing, holosystolic murmur heard at the apex that

radiates to the axilla S2 may be inaudible

1 Grade 3 or louder systolic murmur

a 85% sensitive, 81% specific for moderate to severe mitral regurgitation

b LR+, 4.5; LR–, 0.19

2 S3 gallop may be heard due to increased flow across the mitral valve

B ECG may demonstrate LA enlargement or LV hypertrophy, neither sensitive nor specific for the

diagnosis

C Chest radiograph may demonstrate LA or LV enlargement, neither sensitive nor specific for the

diagnosis

D Echocardiography is the test of choice to diagnose and quantify mitral regurgitation and is

recommended in all patients with suspected mitral regurgitation Transesophageal

echocardiography provides more precise details on valve anatomy and may help determine

whether valve repair (versus replacement) is an option

Treatment

A Serial echocardiography

1 Serial echocardiography is important to detect signs of LV dysfunction, which may occur

despite the absence of symptoms.

2 Echocardiography is recommended annually or semiannually in patients with moderate to

severe mitral regurgitation and after a change in signs or symptoms in patients with any degree

of mitral regurgitation

3 Serial echocardiography is not recommended for asymptomatic patients with mild mitral

regurgitation with normal LV size and function.

B Valve repair versus replacement

1 Valve repair is superior to valve replacement (when technically feasible).

2 Valve repair is associated with substantially decreased operative mortality (2% vs 6%), a

lower rate of endocarditis, and is associated with a significantly better ejection fraction

Importantly, valve repair does not require subsequent anticoagulation

C ACCF/AHA guidelines for valve repair are summarized below.

1 Mitral valve repair is reserved for patients with severe mitral regurgitation and any of the

2 Decisions in patients with severe LV dysfunction (ejection fraction < 30%, LV end-systolic

diameter > 55 mm) and severe mitral regurgitation are complex

a Mitral valve repair or replacement increases afterload (by preventing ejection of blood from

the LV to the LA) and may worsen HF

b Consultation is recommended HF therapy should be optimized.

3 Isolated mitral valve surgery is not indicated in patients with mild to moderate mitral

regurgitation

D Medical therapy of mitral regurgitation

1 Chronic primary asymptomatic mitral regurgitation with preserved LV function: No medical

therapy has been demonstrated to be useful

2 Secondary mitral regurgitation: Optimize HF regimen ACE inhibitors, beta-blockers

(particularly carvedilol), diuretics, and digoxin can be useful Biventricular pacing reduces theseverity of mitral regurgitation

3 Mitral regurgitation with hypertension: Treat hypertension with ACE inhibitors, diuretics, or

beta-blockers

4 Treat underlying ischemia.

5 Endocarditis prophylaxis is recommended for patients following mitral valve replacement with

a mechanical or bioprosthetic device and for repairs utilizing a bioprosthetic annuloplasty ring

It is also recommended for patients with a history of endocarditis

Alternative Diagnosis: Chronic Aortic Regurgitation

Textbook Presentation

Patients with chronic aortic regurgitation typically complain of progressive dyspnea on exertion orthe sensation of a pounding heart Alternatively, the patient may be asymptomatic, and the diagnosis

may be suspected when a careful examiner detects an early diastolic murmur.

Disease Highlights

A Secondary to damaged aortic leaflets or dilated aortic root

B Etiologies

1 Valvular abnormalities: Rheumatic carditis, bacterial endocarditis, collagen vascular disease,

calcific degeneration, fenfluramine and phentermine

2 Aortic root dilatation: Hypertension, ascending aortic aneurysm, Marfan syndrome, aortic

dissection, syphilitic aortitis

3 Bicuspid aortic valve disease

a Most common form of congenital heart disease affecting 1% of population, and transmitted in

an autosomal dominant pattern

b Affects the aortic valve (AV) and the aorta.

c Aortic regurgitation may occur due to valve changes or dilation of the proximal aorta.

d Dilation of the proximal ascending aorta is due to associated changes in the aortic media

independent of the AV function

e Complications include aneurysms, aortic regurgitation, and dissection.

C Pathophysiology

1 Regurgitation results in LV remodeling and eccentric and concentric LV hypertrophy to maintain

wall stress LV end-diastolic volume increases to augment the stroke volume so that forwardflow remains in the normal range despite the regurgitant volume During the compensated stagethe ejection fraction is normal

2 The increasing preload and afterload may eventually result in LV systolic dysfunction, and the

LV end-systolic volume increases and ejection fraction decreases LV end-diastolic pressureincreases and pulmonary congestion and dyspnea result Exertional angina may also occur

3 Significant LV dysfunction can become irreversible Valve replacement should be performed

before irreversible LV dysfunction and HF develop (see below)

4 Progression to symptoms or LV dysfunction in patients with normal LV function develops in 4%

of patients per year Sudden death occurred in 0.2% per year

Evidence-Based Diagnosis

A The pulse pressure (systolic–diastolic BP) is often wide in aortic regurgitation due to 2 processes.

First, the large stroke volume increases the systolic BP, and second, the regurgitation of bloodback into the LV rapidly lowers the diastolic BP

1 The wide pulse pressure causes many of the classic physical findings, such as bounding pulses

and head bobbing

2 Wide pulse pressures (typically defined as systolic BP – diastolic BP ≥ 50% of systolic BP)

are not specific for aortic regurgitation Other causes include anemia, fever, pregnancy, largearteriovenous fistula, cirrhosis, thyrotoxicosis, and patent ductus arteriosa Elderly patientswith systolic hypertension commonly have a widened pulse pressure

B Auscultation

1 May demonstrate an early decrescendo diastolic murmur following S2 Best heard at the leftsternal border

a Auscultation is more sensitive for moderate to severe aortic regurgitation.

b Sensitivity is 0–64% among students and residents.

c Sensitivity is 80–95% among experienced cardiologists.

d Another study reported that the diastolic murmur of mild to moderate aortic regurgitation was

rarely detected by attending noncardiologists (sensitivity 4% mild aortic regurgitation, 14%moderate aortic regurgitation)

e However, the finding of a diastolic murmur is highly specific (98%).

A diastolic murmur is always abnormal and warrants evaluation (echocardiography)

2 A systolic murmur suggesting aortic stenosis may be heard.

a Regurgitation results in increasing end-diastolic volumes.

b Stroke volumes increase to maintain forward flow.

c The increased cardiac output may exceed the capacity of even a normal aortic valve to

accommodate flow, resulting in a high flow systolic murmur across the aortic valve One

study reported that 51% of patients with mild to moderate aortic regurgitation had a systolic

murmur (86% in moderate aortic regurgitation and 50% in mild aortic regurgitation)

Although a diastolic murmur strongly suggests aortic regurgitation, systolic murmurs are often the

only murmur heard in patients with aortic regurgitation.

3 Austin Flint murmur

a Aortic regurgitant streams may impact the mitral valve leaflets during diastole resulting in

functional mitral stenosis and a late diastolic murmur over the apex

b Sensitivity varies from 0% to 100%.

C Doppler echocardiography is the test of choice and should be performed in all patients with a

diastolic murmur and in those patients with a dilated aortic root

D Patients with biscuspid valves in whom the aortic root is not adequately visualized with

transthoracic echocardiography should undergo additional imaging to evaluate the aortic root (eg,transesophageal echocardiography or cardiac MR)

E Exercise testing can help assess LV function during stress.

Treatment

A Serial echocardiography is important to detect signs of LV dysfunction, which may occur in

patients without symptoms It should be performed 3 months after the initial study to ensure

stability and then periodically and whenever there is a change of symptoms

B AV replacement

1 LV dysfunction and death are more common in symptomatic patients and those with depressed

ejection fraction or an increased LV systolic volume

a Mortality in symptomatic patients without surgery is 10–20% per year.

b Outcomes are worse in medically treated asymptomatic patients with a LV end-systolic

diameter > 50 mm Symptoms, LV dysfunction, and death develop at 19% per year, comparedwith 6% per year with a LV end-systolic diameter 40–50 mm and none with a LV end-

systolic diameter < 40 mm

2 AV replacement is recommended for select groups with severe aortic regurgitation.

a All symptomatic patients

b Asymptomatic patients with an ejection fraction ≤ 50%

c Asymptomatic patients with a LV end-diastolic diameter > 75 mm or a LV end-systolic

diameter > 55 mm

d When aortic regurgitation is secondary to dilatation of the aortic root, valve repair is

recommended in patients with aortic regurgitation of any severity associated with an aorticroot > 4.5–5 cm

C Replacement valves may be either mechanical or bioprosthetic (eg, porcine valves).

1 Mechanical valves are more durable and are often chosen for young patients to minimize the

need for subsequent AV replacement However, patients with mechanical valves require

lifelong anticoagulation

2 Bioprosthetic valves are used more often in older patients (> 70 years) with shorter life

expectancies and patients at greater risk for bleeding while receiving anticoagulation therapy

3 Endocarditis prophylaxis is recommended for patients following AV replacement with a

mechanical or bioprosthetic device and for repairs utilizing a bioprosthetic material It is alsorecommended for patients with a history of endocarditis

D Afterload reduction

1 Should not be substituted for AV replacement in patients with an indication for valve

replacement

2 Indications

a Severe aortic regurgitation

(1) Symptomatic patients or those with LV dysfunction as short-term preoperative therapy to

improve their hemodynamic function

(2) Symptomatic patients or those with LV dysfunction who are not surgical candidates

(3) For asymptomatic patients with LV dilatation but normal systolic function, the

ACCF/AHA concluded that vasodilators “may be considered.” The evidence isinconclusive

b Recommended for patients with any degree of aortic regurgitation and hypertension

3 Not indicated in asymptomatic, normotensive patients with normal systolic function and mild to

moderate aortic regurgitation

E Beta-blockers are relatively contraindicated Prolonged diastole increases regurgitation and

accelerates progression

Alternative Diagnosis: Aortic Stenosis

See Chapter 31, Syncope

Alternative Diagnosis: Atrial Fibrillation

A Atrial fibrillation is the most common clinical arrhythmia; its incidence increases with age (3.8%

of patients ≥ 60 years old to 9% in those ≥ 80 years old)

B May be episodic or persistent

C Secondary to multiple wavelets of excitation that meander around the atria

D Etiologies

1 Most common etiologies are hypertension, CAD, and HF.

2 Acute coronary syndrome: In 2–5% of patients presenting to the emergency department with

new-onset atrial fibrillation, it is secondary to an acute MI

3 Other etiologies include alcoholic heart disease, valvular heart disease, cor pulmonale,

thyrotoxicosis, and PE

E Complications

1 Stroke: Stasis promotes thrombus formation within the atria Subsequent embolization results in

stroke and other systemic emboli

a Atrial fibrillation accounts for one-sixth of all strokes.

b Stroke is more common in patients with atrial fibrillation who have other clinical risk factors: (1) Valvular heart disease

(2) Prior transient ischemic attack or stroke

c The annual stroke rate in atrial fibrillation patients not receiving anticoagulation is 4.1% per

year However, there is substantial variation depending on the presence or absence of theseother risk factors For the subgroup of patients with a prior transient ischemic attack or

stroke, the annual stroke rate increases to 13% per year

2 Worsening HF due to loss of atrial kick; especially important in patients with stiff LV (ie,

diastolic dysfunction)

Evidence-Based Diagnosis

A Easily recognized on ECG (Figure 15-3)

Figure 15-3 ECG of atrial fibrillation demonstrating irregularly spaced QRS complexes and

fibrillatory p waves

B Episodic atrial fibrillation can be detected with Holter monitoring or event recorders.

Treatment

A Evaluation

1 ECG can document atrial fibrillation, as well as suggest underlying etiologies (ischemia or right

heart strain in PE.)

2 Baseline echocardiogram to assess LV function and stroke risk

3 Thyroid function tests, electrolytes, BUN and creatinine are recommended.

4 Consider evaluation for other etiologies (eg, MI, PE).

B Rhythm control versus rate control

1 Cardioversion should be performed immediately in unstable patients (with ischemia,

hypotension, or HF)

2 In stable patients, 2 options exist: rhythm control or rate control.

a Rhythm control attempts to restore normal sinus rhythm using cardioversion and

antiarrhythmic agents

b Rate control allows persistent atrial fibrillation The ventricular response is controlled with

atrioventricular nodal blocking agents (eg, beta-blockers, diltiazem, verapamil, or digoxin).Anticoagulation is used to prevent stroke.

c Studies show that rhythm control and rate control results in similar mortality and stroke rates,

even in patients with underlying HF

d Long-term anticoagulation: The American College of Chest Physicians (ACCP) recommends

continuing long-term antithrombotic therapy in patients managed with a rate or rhythm controlstrategy based on their risk factors regardless of the appearance of persistent normal sinusrhythm (see below)

e Rate control is the recommended strategy in most patients (Patients with their first episode of

atrial fibrillation or with symptoms or exercise intolerance may choose rhythm control.)

(1) A resting HR of < 110 bpm is recommended.

(2) Uses beta-blockers, diltiazem, verapamil, or digoxin

(3) Beta-blockers, diltiazem, and verapamil should be avoided in patients with

decompensated HF

(4) Digoxin

(a) Less effective at controlling ventricular response during activity and in paroxysmal

atrial fibrillation

(b) Should not be used as the sole agent for patients with paroxysmal atrial fibrillation

(c) Useful in patients with HFrEF

(d) Second-line drug

(5) Combination therapy

(a) Verapamil and beta-blockers should not be used concurrently in the same patient due

to a high frequency of complications (bradycardia or HF)

(b) Digoxin and beta-blockers or digoxin and diltiazem or verapamil may be used

concurrently to achieve HR control

(6) AV ablation can be used to achieve rate control when pharmacologic therapy is

unsuccessful or not tolerated

(7) Amiodarone can be used for HR control if other measures fail.

f Rhythm control therapy

(1) Cardioversion options

(a) Flecainide, dofetilide, propafenone, ibutilide, amiodarone, or direct current

cardioversion can be used to restore normal sinus rhythm

(b) Electrical cardioversion is contraindicated in patients with hypokalemia or digoxin

toxicity

(2) The probability of conversion to normal sinus rhythm decreases the longer the atrial

fibrillation lasts

(3) The maintenance of sinus rhythm is complex and beyond the scope of this text.

(4) Cardiology consultation is recommended.

(5) Anticoagulation therapy for cardioversion.

(a) Anticoagulation is often used preceding and following cardioversion (whether

electrical or chemical) to decrease the risk that preexistent or new thrombi form orembolize.

(b) Cardioversion should not be delayed in unstable patients If the atrial fibrillation was

< 48 hours in duration they should undergo cardioversion without delay If theduration of atrial fibrillation was ≥ 48 hours or unknown, patients should undergocardioversion while concurrently receiving an unfractionated heparin bolus andmaintenance therapy to achieve an activated partial thromboplastin time of 1.5–2times control until warfarin increases the INR to 2.0-3.0

(c) Anticoagulation for 3 weeks prior to cardioversion is recommended in stable patients

with atrial fibrillation ≥ 48 hours or of unknown duration For patients with atrialfibrillation < 48 hours, anticoagulation decisions may be based on other patient riskfactors, (eg, mitral valve disease, HF, or prior embolism)

(d) Low-risk patients (without the aforementioned risk factors) and atrial fibrillation of

recent onset (< 48 hours) can undergo cardioversion without delay

(e) Alternatively, a transesophageal echocardiography can be performed to look for

thrombi Patients without thrombi can receive unfractionated heparin and then undergocardioversion Patients with thrombi should receive 3 weeks of anticoagulation

therapy prior to cardioversion

(f) Patients typically receive a vitamin K antagonist (target INR 2.0–3.0) for 4 weeks

following cardioversion Patients with left atrial thrombi seen on a transesophagealechocardiogram should probably receive anticoagulation therapy longer

C Stroke prevention

1 Antithrombotic therapy with anticoagulants, typically using vitamin K antagonists, or

antiplatelet agents (typically aspirin) has been used to prevent strokes in atrial fibrillation

patients

2 The 2 most widely studied therapies are warfarin and aspirin.

a Multiple studies suggest that warfarin is superior to aspirin at preventing stroke with a

relative risk reduction of 64% compared to 19% for aspirin In the absence of

contraindications, the benefit of warfarin usually outweighs the risk

b The standard INR target is 2.0–3.0.

c The absolute benefit of warfarin increases as the risk of stroke increases.

d Warfarin reduces the absolute rate of stroke on average by 2.7% per year, but in patients with

prior transient ischemic attack/cerebrovascular accident, the absolute risk reduction is 8.4%per year

e Contraindications to warfarin therapy include recent gastrointestinal or central nervous

system hemorrhage, recent trauma or surgery, uncontrolled hypertension, noncompliance,syncope, or alcoholism

f The ACCF/AHA have published guidelines for stroke prevention in persistent or paroxysmal

atrial fibrillation (Table 15-9)

Table 15-9 Recommendations to prevent stroke in patients with persistent or paroxysmal atrial

3 Two special groups are worth mentioning.

a Although physicians worry about bleeding complications in the elderly, studies show that

elderly patients with atrial fibrillation are at high risk for stroke and benefit from

anticoagulation if they are carefully selected

b Patients with lone atrial fibrillation (age < 60 years, no heart disease, hypertension or risk

factors) are at the lowest risk for stroke (< 1% per year when treated with aspirin)

(1) The absolute risk reduction from warfarin is very small and similar in magnitude to the

risk of hemorrhage from warfarin

(2) The AHA/ACC/ACCP does not recommend warfarin in these patients.

(3) The utility of aspirin is uncertain and the AHA/ACC concluded that the effectiveness of

aspirin for this population has not been established

4 New oral anticoagulants provide alternatives to vitamin K antagonist.

a The new anticoagulants directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and

apixaban)

b Rivaroxaban and dabigatran accumulate in renal impairment.

c Compared with warfarin, dosing is easier, anticoagulation does not require monitoring, and

there are fewer drug and food interactions

d However, unlike warfarin, antidotes are not available to reverse anticoagulation in

hemorrhaging patients

(1) Vitamin K and fresh frozen plasma are ineffective.

(2) Preliminary data suggest that prothrombin complex concentrate may reverse

anticoagulation due to Xa inhibitors (eg, rivaroxaban)

e The precise role of these agents compared with vitamin K antagonist remains an area of

active clinical research

5 Aspirin combined with clopidogrel has been compared with either aspirin or warfarin

monotherapy in the prevention of stroke in patients with atrial fibrillation

a Combination therapy is less effective than warfarin at stroke prevention but associated with

the same rate of major bleeding Annual event rate on combination therapy of 5.6% vs 3.9%

on warfarin

b Combination therapy was slightly more effective than aspirin alone at preventing stroke,

(0.9% per year absolute risk reduction), but associated with a 0.7% per year absolute

increase in the rate of major bleeding

Alternative Diagnosis: CAD

See Chapter 9, Chest Pain

CASE RESOLUTION

Mr C undergoes an ECG, chest film, CBC, and transthoracic echocardiogram His CBC is

normal and his chest film reveals cardiomegaly His ECG demonstrates normal sinus rhythm

with pathologic Q waves in leads V1–V4, and his echocardiogram reveals marked systolic

dysfunction and an ejection fraction of 18% There are regional wall motion abnormalities andthe anterior wall is akinetic There is no significant aortic stenosis or aortic regurgitation Mitralregurgitation is mild

Mr C’s echocardiogram confirms HF and rules out significant valvular heart disease as the primaryetiology of his dyspnea Similarly his ECG does not demonstrate atrial fibrillation The likely

etiology of his HFrEF is ischemia given his history of MI, ECG, and regional wall motion

abnormalities on echocardiogram An angiogram would be recommended by the AHA/ACC

guidelines if not already performed

An angiogram is performed This reveals an unobstructed right coronary artery and circumflexbut an occluded left anterior descending artery supplying the area of his large prior MI The

ejection fraction is 20%

The angiogram confirms CAD as the cause of Mr C’s HF

Mr C is admitted for treatment of his HF He starts a salt-restricted diet and is given diuretics,ACE inhibitors, beta-blockers (when his HF is controlled) and an aldosterone antagonist Thediuresis results in a 20-pound weight loss, and his dyspnea on exertion improves markedly Hisorthopnea resolves He declines discussing the possibility of coronary artery bypass surgery butagrees to an implantable cardiac defibrillator He remains stable at follow-up 5 years later

CHIEF COMPLAINT

PATIENT

Mrs L is a 58-year-old woman who arrives at the emergency department with a chief complaint

of shortness of breath She reports that this has developed gradually over the last 3–6 months.Six months ago, she was able to walk as far as she wanted without any shortness of breath Nowshe is experiencing dyspnea even walking around her house She denies any episodes of acuteshortness of breath, fever, chest pain, or hemoptysis She denies wheezing She has no history of

MI, hypertension, or known heart disease She smoked 1 pack of cigarettes per day for 10 yearsand quit when she was 28 years old She has no history of prior venous thromboembolism

(VTE), cancer or immobilization She drinks 1 glass of wine per week She works as an

accountant and spends her free time with her grandchildren She has no unusual hobbies.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Mrs L’s shortness of breath is not only severe but markedly worse than baseline Both of these

features should prompt a thorough investigation Unfortunately, the clinical information does not

suggest a specific diagnosis (Figure 15-1) She has no pivotal clues that can help limit the differentialdiagnosis (fever, pleuritic chest pain, or other chest pain.) Furthermore, there are no clues that mightsuggest one of the common causes of dyspnea: No risk factors for HF (CAD, hypertension, or alcoholabuse that commonly cause HF), no history of wheezing or smoking to suggest asthma or COPD, nofever or cough to suggest pneumonia, and no associated symptoms or risk factors to suggest PE (chestpain, cancer, immobilization, prior VTE) A careful exam is vital to look for helpful clues

On physical exam, the patient appears comfortable at rest but becomes markedly dyspneic withambulation Vital signs are BP, 140/70 mm Hg; pulse, 72 bpm; temperature, 37.1°C; RR, 20

breaths per minute Conjunctiva are pink Lung exam is clear to percussion and auscultation

There are no crackles or wheezes Cardiac exam reveals a regular rate and rhythm S1 and S2 arenormal There is no JVD, S3, S4, or murmur There is only trace peripheral edema Abdominalexam is normal A chest radiograph, ECG, and CBC are normal

Despite a thorough exam, the leading diagnosis is unclear In such cases, it is particularly

important to systematically review the differential diagnosis in order to arrive at the correct diagnosis(Table 15-2) Each item on the list should be reviewed in light of the history and physical to

determine whether it remains in the differential and should be explored further, or whether the

existing information makes it highly unlikely

Reviewing Table 15-2, the absence of a murmur makes mitral regurgitation and aortic stenosisunlikely, since the clinical exam is 85–90% sensitive for these conditions The clinical exam is lesssensitive for aortic regurgitation (see above) Therefore, aortic regurgitation remains on the

differential diagnosis An arrhythmia is essentially ruled out by the patient’s normal heart rate during

symptoms HF is not particularly suggested by the history and physical exam, but it cannot be

excluded given the low sensitivity of the S3 gallop and JVD The patient denies any history of chestpain, but dyspnea is occasionally an anginal equivalent, thus CAD remains a possibility Pneumonia

is highly unlikely given the normal chest film and the lack of fever and cough Asthma remains a

possibility although this is not particularly suggested by the history or physical exam COPD is

effectively ruled out by the trivial smoking history PE cannot be excluded by the current information

and remains on the list, although the presentation is not particularly classic for PE Since PE isassociated with a high mortality, it should be considered a must not miss possibility A significantpleural effusion and pneumothorax are ruled out by the normal chest radiograph, which also makesinterstitial disease unlikely (although not impossible) Anemia is ruled out by the normal CBC Wecan now focus on the clinical clues and diagnostic tests for these remaining possible diagnoses(aortic regurgitation, HF, CAD, asthma, and PE) Table 15-10 lists the differential diagnosis.

Table 15-10 Diagnostic hypotheses for Mrs L.

A methodical approach to the differential diagnosis is vital whenever the leading diagnosis isunclear or when the leading hypothesis cannot be confirmed.

In terms of CAD, she denies any history of exertional chest pain or pressure and has minimal

coronary risk factors (Her last cholesterol level was normal [180 mg/dL] with an HDL of 70

mg/dL She has no history of diabetes mellitus, no family history of CAD, and no recent tobaccouse.) With respect to asthma, she denies any history of wheezing or worsening cough associatedwith cold, exercise, pets, or dust With respect to PE, she denies sudden onset of chest pain,

chest pain with inspiration, hemoptysis, immobilization, cancer, surgery, family history of VTE

or leg swelling She does take hormone replacement therapy

An echocardiogram reveals normal LV function and a normal aortic valve Pulmonary

function tests reveal normal total lung capacity, forced expiratory volume in 1 second (FEV1),and single-breath diffusing capacity (DLCO) A methacholine challenge test is also normal

Considering each diagnosis in turn, the patient’s physical exam and echocardiogram exclude HFand aortic regurgitation The patient’s pretest probability of CAD is quite low given her age, sex, andrisk factors (3.2%; see Chapter 9, Chest Pain) In addition, the Framingham data suggest the

likelihood of a coronary event in a female patient with these CAD risk factors to be < 1% over theensuing 8 years The history and normal pulmonary function tests with methacholine challenge makeasthma very unlikely Although her history sounds atypical for PE, she is taking hormone replacementtherapy, a known risk factor for VTE Given the exclusion of the other diagnoses, PE becomes moreprobable You revise your differential diagnosis and make PE both your leading and must not missdiagnosis

Is the clinical information sufficient to make a diagnosis of PE? If not, what other

information do you need?

Leading Hypothesis: PE

Textbook Presentation

Classically, patients with PE experience the sudden onset of shortness of breath and severe chest painthat increases with inspiration Patients may complain of hemoptysis and associated unilateral legswelling

Disease Highlights

A Pathophysiology: Most commonly occurs when a lower extremity venous thrombosis embolizes to

the lung Upper extremity thrombi may also cause PE

1 80% of patients with PE have deep venous thrombosis (DVT).

2 48% of patients with DVT have PE (often asymptomatic).

B Symptoms vary markedly Massive obstruction may result in RV failure and death, whereas lesser

obstruction may be asymptomatic

C 3-month mortality is 17.5%

D Risk factors

1 A variety of risk factors increase the odd ratio for VTE including a personal history of VTE

(2.9), estrogen use (2.3), surgery within the last 4 weeks (2.3), personal history of

thrombophilia (2.0), active or metastatic cancer (1.9), immobilization (1.7), age over 50 (1.5)

2 Thrombophilia

a Antiphospholipid antibodies: Present in 2–8.5% of patients with VTE

b Factor V Leiden

(1) Most common thrombophilia

(2) Mutation in factor V causes resistance to cleavage by activated protein C

(3) 11% of patients with DVT

(4) Confers a 2.7 × increased risk of VTE

(5) Combined with oral birth control pill, mutation increases risk 35 times

c Prothrombin gene mutation

d Protein C or S deficiency (rare)

(1) Protein C and S are naturally occurring anticoagulants

(2) Deficiency is associated with hypercoagulability.

(3) Synthesis of protein C and S requires vitamin K.

(4) Warfarin decreases synthesis of both factors.

(5) Assays for protein C and S must be performed while patients are not taking warfarin.

e Antithrombin III deficiency (also rare): Assay must be done while patient is not taking

heparin

f Hyperhomocysteinemia: 3 × increased risk of VTE

g Increased factor VIII: 6 × increased risk

E PE commonly presents as a “COPD exacerbation.”

1 Studies have reported that 16% of patients with a COPD exacerbation have pulmonary emboli.

2 The rate was 25% among patients with an unexplained exacerbation of COPD, compared with

8% in those with an exacerbation of known etiology

3 Unexplained exacerbation was defined as patients without parenchymal consolidation on chest

radiograph without fever or chills (ie, not obviously due to pneumonia) and patients who lackedthe common factors precipitating COPD exacerbations: