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CHAPTER 8 Coronary Heart Disease
Fig. 8.8 Right coronary artery angiogram in a patient with acute inferior myocardial infarction. The left panel
93
discomfort suspicious for acute MI includes aortic dissection, pulmonary embolism, chest wall pain, esophageal reflux, acute pericarditis,
pleuritis, and panic attacks. Given the life-threatening nature of aortic
dissection and pulmonary embolism, these diagnoses should always
be paramount, along with acute MI, in patients presenting with chest
discomfort.
Physical examination. A comprehensive examination should be
undertaken if acute MI is suspected. Attention must be paid to vital
signs, because patients may be either hypertensive or hypotensive
during the course of an MI. In some cases, such as inferior MI, profound
bradycardia may be present. Auscultation of the heart may reveal an S4.
In the case of a large MI, the patient may have symptoms and signs of
heart failure such as dyspnea, rales, elevated central venous pressure,
and an S3. Severe heart failure may lead to cardiogenic shock with
hypotension and vasoconstriction causing the extremities to be cool to
touch. Patients with acute MI are also subject to mechanical problems
such as mitral regurgitation due to papillary muscle dysfunction.
Electrocardiogram. The ECG is an important tool in the diagnosis
of acute MI. ST elevation of 1 mm or greater in contiguous leads is seen
in most patients with acute MI. The initial ECG may be nondiagnostic,
so it is important to obtain serial tracings no more than 20 minutes
apart to detect the evolutionary changes characteristic of STEMI. The
first stage of ECG presentation is ST elevation that subtends the region
of the heart affected by transmural ischemia. ST depression may be
present in opposing leads, and these are termed reciprocal changes
(see Chapter 64, “ST Elevation Acute Myocardial Infarction and
Complications of Myocardial Infarction,” in Goldman-Cecil Medicine,
26th Edition). The presence of reciprocal changes may indicate a
larger and more threatening MI. As the MI progresses, ST elevation
gives way to T wave inversion. Varying degrees of resolution of ST
and T wave changes occur over time, but patients with transmural
MI develop pathologic Q waves in the leads subtending the infarcted
muscle. Other causes of ST elevation include pericarditis and a chronic
repolarization finding of “early repolarization.” The presence of either
cause of ST elevation can confound the early ECG diagnosis of acute
MI.
Approximately 30% of acute MIs originate from the circumflex coronary artery on the posterior wall of the heart. This type of MI appears
on the ECG as precordial ST depression. The presence of precordial
ST depression should raise suspicion of the presence of “true posterior MI,” and additional leads placed through the axilla to the back
may reveal the presence of posterior ST elevation. Echocardiography
demonstrating posterior hypokinesis is also useful in discriminating
true posterior MI. Acute inferior MI due to occlusion of the right coronary artery can also be associated with right ventricular infarction
if the right coronary artery’s acute marginal branch is compromised.
Right ventricular infarction can lead to some challenging management
issues, and its diagnosis is aided by the use of right precordial leads to
detect ST elevation.
LBBB or ventricular pacing can mask ST elevation due to acute MI.
Patients with clinical features of acute MI who have an LBBB (particularly a new LBBB) should be presumed to have STEMI and treated
appropriately. Right bundle branch block (RBBB) does not mask the
ST elevation of STEMI.
Differential Diagnosis
The diagnosis of STEMI is usually straightforward based on symptoms
and ECG findings, but a number of conditions can mimic the ST elevation of STEMI and confound the diagnosis. The ECG changes of early
repolarization, takotsubo syndrome, acute myocarditis, or pericarditis
can be difficult or impossible to distinguish from those of STEMI. In
the face of ST elevation and chest discomfort, it may be necessary to
perform coronary angiography in patients who ultimately are diagnosed with a condition other than STEMI so as to not miss this critical
diagnosis.
Diagnostic testing. Cardiac troponins (cTnI and cTnT) are
sarcomere proteins that, when measured in blood, are specific for
myocardial injury. The troponin level becomes elevated 2 to 4 hours
after the onset of injury, and the abnormal elevation can persist for
up to 2 weeks after the event. The CK-MB isomer is not as specific for
heart injury as troponin, but it can still be useful in documenting the
presence of MI. CK-MB is found elevated within 4 hours after an acute
MI, but it clears more rapidly than troponin. In the case of persistently
elevated troponin, a measurable increase in CK-MB may herald
another episode of myocardial necrosis. Chronic renal insufficiency
is associated with false-positive elevations of troponin T, more so
than troponin I. In addition to biomarkers of myocardial injury,
other laboratory studies obtained in patients with acute MI include
a complete blood count, blood chemistries, lipid panel, prothrombin
time (PT), and partial thromboplastin time (PTT). Leukocytosis is a
common finding in acute MI, reflecting the inflammatory nature of
myocardial necrosis.
At the time of admission, chest radiographs are obtained to
assess for the presence of pulmonary edema or mediastinal widening
94 SECTION II Cardiovascular Disease
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suspicious for dissection. Echocardiography is important in delineating the extent of MI and assessing EF. In cases of diagnostic ambiguity, early use of echocardiography can demonstrate the presence
of regional wall motion abnormalities consistent with acute MI.
Echocardiography with color Doppler is also helpful in diagnosing
complications of acute MI such as infarct-related mitral regurgitation
or ventricular septal defect (VSD), pericardial effusion, or evidence of
pseudoaneurysm as a result of myocardial rupture. Follow-up echocardiography in the months after acute MI can also reveal recovery of
LV function. Radionuclide tracer studies are not useful in diagnosing
acute MI. CT, cardiac MRI, and transesophageal echocardiography are
all useful in diagnosing aortic dissection when there is an increased
index of suspicion. Cardiac MRI can also distinguish myopericarditis.
Treatment
Acute STEMI is caused by occlusion of the epicardial coronary artery by
thrombus after rupture of a vulnerable plaque. The process of myocardial necrosis is time dependent, so diagnosis and treatment of STEMI
to preserve myocardium must occur as quickly as possible. More than
half of deaths occur within 1 hour after onset of symptoms, before the
patient can be reached for emergency care. Patients often delay seeking
care for symptoms of acute MI despite efforts to alert the public to
the risk of ignoring symptoms of chest discomfort. Emergency medical personnel who respond to patients with possible MI begin to institute initial therapy in the field. Patients are monitored with ECG for
rhythm disturbances such as ventricular tachycardia (VT) or ventricular fibrillation (VF) that require prompt cardioversion or defibrillation. Oxygen is administered via nasal cannula, and intravenous access
is established. Aspirin (162 to 325 mg) is administered to the patient,
and sublingual nitroglycerin may also be given in an attempt to relieve
chest discomfort. Some emergency response systems perform 12-lead
ECGs and telemeter the results to the emergency department, allowing for early diagnosis of STEMI and early decision making regarding
revascularization strategies.
Once the patient arrives in the emergency department, an ECG, if
not already available, will be performed within 5 minutes. If the ECG
is nondiagnostic, a second study is obtained no more than 20 minutes after presentation. A diagnosis of STEMI triggers decision making
regarding reperfusion strategies that are used by the particular institution (see Chapter 64, “ST Elevation Acute Myocardial Infarction and
Complications of Myocardial Infarction,” in Goldman-Cecil Medicine,
26th Edition). Hospitals that are capable of performing emergency
cardiac catheterization for the purpose of reperfusion therapy have an
established rapid response system to activate the catheterization laboratory for this urgent therapy. There is evidence that primary PCI therapy for STEMI is superior to fibrinolytic therapy, but its use depends
on the timely availability of a well-trained catheterization team. The
quality of primary PCI is signified by a so-called door-to-balloon time
of less than 90 minutes. Likewise, the standard for fibrinolytic therapy is a door-to-needle time of less than 30 minutes. Regardless of the
means of reperfusion, it is important for the hospital treating patients
with STEMI to have a structured protocol for timely diagnosis, decision making, and initiation of therapy.
In addition to aspirin, the patient should be given a loading dose
of a P2Y12 inhibitor (ticagrelor 180 mg, clopidogrel 600 mg or prasugrel 60 mg), assuming he or she will be treated with primary PCI.
Unfractionated heparin in a dose of 60 IU/kg should be administered
(no more than 4000 IU bolus) with a drip rate of 12 IU/kg/hour (maximum dose, 1000 IU/hour). LMW heparin may also be used (enoxaparin 30 mg IV bolus with 1 mg/kg subcutaneously every 12 hours for
patients younger than 75 years of age who have normal renal function).
Other agents such as glycoprotein IIb/IIIa inhibitors or bivalirudin
are administered depending on the protocols of the catheterization
laboratory.
Patients are commonly given sublingual nitroglycerin 0.4 mg
(repeat every 5 minutes for no more than three total doses), which often
helps to diminish chest discomfort. Intravenous nitroglycerin may be
helpful for control of both persistent pain and hypertension if present.
Intravenous morphine (2 to 4 mg, repeated every 5 to 15 minutes as
needed) is also frequently used for pain control. Although there has
been no consensus statement on the use of morphine in ACS, recently
there have been several studies that have suggested an increased risk
of in-hospital mortality associated with its use presumed secondary to
reduced antiplatelet activity of P2Y12 inhibitors. Intravenous β-block-
ers such as metoprolol (5-mg bolus every 10 minutes for a total dose of
15 mg) are indicated in the treatment of STEMI but should be avoided
in the face of heart failure, severe COPD, hypotension, or bradycardia. β-Blockers (metoprolol, propranolol, atenolol, timolol, and carvedilol) have been shown to significantly reduce the risk of future MI and
cardiovascular mortality. Statin therapy, as mentioned for NSTEMI, is
recommended for all patients with STEMI as a presenting symptom
regardless of their history of hypercholesterolemia. Other adjunctive
measures include bedrest for the first 12 hours, ongoing oxygen by
nasal cannula with pulse oximeter monitoring, continuous rhythm
monitoring, anxiolytic agents as needed, and stool softeners. Atropine
is kept in reserve for the treatment of hemodynamically significant
brad ycardia, which may occur with inferior MI.
ACE-inhibitor therapy also plays an important role in the longterm survival of patients after STEMI. ACE-inhibitor therapy has been
shown to reduce the incidence of heart failure, recurrent MI, and longterm mortality after STEMI. ACE inhibitors commonly used for this
purpose include lisinopril, captopril, enalapril, and ramipril. The decision to initiate ACE-inhibitor therapy is directed by the patient’s tolerance. Care is warranted early after STEMI, because the patient may
be prone to hypotension related to ACE-inhibitor therapy. A low dose
should be administered first, with gradual upward titration.
Aldosterone receptor blockade with eplerenone (25 to 50 mg/day)
reduces cardiovascular mortality after MI in patients with heart failure
and a reduced EF of less than 40% or diabetes. Spironolactone also
reduces mortality in patients with heart failure and a history of remote
MI.
Reperfusion therapy. Timely reperfusion therapy, either
thrombolytic therapy or primary PCI, is critical to limiting the extent of
MI and reducing the risks of future morbidity and mortality. Primary
PCI has been shown to have advantages over thrombolytic therapy,
with higher immediate and long-term vessel patency. Primary PCI
depends on the availability of cardiac catheterization facilities and staff
to conduct the reperfusion procedure quickly (see earlier discussion).
If the patient has not had access to a catheterization facility for longer
than 2 hours after presentation, thrombolytic therapy is a reasonable
alternative.
In the randomized, placebo-controlled Gruppo Italiano per lo
Studio della Streptochinasi nell’Infarto (GISSI) study, thrombolytic
therapy with intravenous streptokinase was shown to reduce the risk
of mortality in patients with STEMI if it was administered early after
presentation. The time-dependent nature of therapy was also demonstrated, in that patients treated more than 12 hours after the onset of
symptoms had no measurable benefit from thrombolysis. The next generation of thrombolytic agents, recombinant tissue-type plasminogen
activators (rt-PA), improved on mortality reduction when compared
with streptokinase (30-day mortality rate, 7.3% with streptokinase vs.
6.3% with rt-PA). The advantage of rt-PA appeared to be related to
enhanced vessel patency at 90 minutes after administration (80% with
rt-PA vs. 53% to 60% with streptokinase). Subsequent forms of rt-PA,
CHAPTER 8 Coronary Heart Disease
95
although easier to administer, did not further reduce mortality. The
major attribute of thrombolytic therapy is its ease of administration,
but there is a significant risk (0.5% to 1%) of catastrophic bleeding
complications in the form of intracerebral hemorrhage. Age older than
75 years, female gender, hypertension, and concomitant use of heparin
increase the risk of this complication. In the case of failed thrombolytic
therapy, rescue PCI may be pursued.
Primary PCI has been shown to be superior to thrombolytic therapy based on lower overall mortality rates and reduced risk of recurrent nonfatal MI. It is also associated with higher vessel patency rates
and a low risk of intracranial hemorrhage. Primary PCI is frequently
performed by mechanical aspiration of thrombus and placement
of a coronary stent. Balloon angioplasty may or may not be needed
during this procedure. Patients should receive preprocedure P2Y12
inhibitor (ticagrelor 180 mg, clopidogrel 600 mg or prasugrel 60 mg).
For patients who are not able to take oral medications, whose platelet
inhibition may not be at therapeutic levels at the time of stent placement, or who are at high risk for life-threatening bleeding requiring
cessation of antiplatelet therapy, cangrelor (an intravenous P2Y12
inhibitor given at 30 mcg/kg bolus followed by infusion of 4 mcg/kg/
minute) may be considered given its rapid onset and offset of platelet
inhibition.
Bivalirudin was shown in a clinical trial of primary PCI to be superior to both heparin- and glycoprotein IIb/IIIa–based anticoagulation with lower post-MI mortality and fewer bleeding complications.
Centers that are dedicated to primary PCI as the preferred therapy
are likely to have the best outcomes when operators are sufficiently
skilled and the institution cares for this patient population on a regular
basis. Primary PCI is the best option for patients in cardiogenic shock
(within 18 hours after onset of shock), for patients with prior CABG
(graft occlusion is not amenable to thrombolysis), and for patients
older than 70 years of age (conferring a reduced risk of intracerebral
hemorrhage compared with thrombolysis).
Complications of Myocardial Infarction
Recurrent Chest Pain
MI is associated with a number of possible problems related to the
extent of injury (Table 8.6). Patients can experience post-infarction
angina that may reflect re-occlusion of the infarct related vessel.
This can occur either in patients who underwent primary PCI with
stent placement (stent thrombosis) or thrombolysis. Post-infarction
angina usually requires cardiac catheterization for appropriate diagnosis and treatment. Patients with transmural MI are also subject to
pericarditis 2 to 4 days after the event. This diagnosis is usually established by the symptom nature and pattern (worse with inspiration
or supine position, improved with sitting), which is different from
their initial presentation with acute MI. A less common event is the
development of pericarditis due to Dressler syndrome up to 10 weeks
after acute MI. This is likely an immune-mediated phenomenon.
Pericarditis is treated with aspirin or nonsteroidal anti-inflammatory
drugs.
Arrhythmias
The highest risk of life-threatening arrhythmias is during the first 24
to 48 hours after the onset of acute MI. Ischemic myocardium is susceptible to arrhythmia generation, probably based on micro-reentry
associated with ischemic myocardium. The significant mortality risk
in the early hours of acute MI is largely attributed to arrhythmias such
as VF or VT. The risk of VF is about 3% to 5% in the early hours of
MI and diminishes over 24 to 48 hours. One of the benefits of rhythm
monitoring during the first 48 hours after presentation is prompt recognition and treatment of life-threatening ventricular arrhythmias.
TABLE 8.6 Complications of Acute
Myocardial Infarction
Functional
Left ventricular failure
Right ventricular failure
Cardiogenic shock
Mechanical
Free-wall rupture
Ventricular septal defect
Papillary muscle rupture with acute mitral regurgitation
Electrical
Bradyarrhythmias (first-, second-, and third-degree atrioventricular blocks)
Tachyarrhythmias (supraventricular, ventricular)
Conduction abnormalities (bundle branch and fascicular blocks)
Accelerated idioventricular rhythm occurs early in the course of MI
and may be associated with reperfusion. This arrhythmia is well tolerated and does not require specific therapy.
Ventricular arrhythmias occurring late (>48 hours) after acute MI
usually are associated with large underlying MIs and heart failure. Late
episodes of VF or VT portend a poor prognosis. Immediate therapy for
VF is electrical defibrillation. VT that causes hemodynamic embarrassment is treated with synchronized electrical cardioversion. β-Blocker
therapy may help to suppress arrhythmias in patients who are prone to
them, as may the use of amiodarone. Correction of residual ischemia
may also play a role in controlling VF or VT events. Patients with late
VF or hemodynamically significant VT are candidates for an implantable cardioverter defibrillator device (ICD). An ICD can also improve
survival in asymptomatic patients with a persistently reduced EF less
than 30% at 40 days after their acute MI. ICD therapy is also indicated
if the EF is less than 35% at 40 days after MI in a patient with symptomatic heart failure.
Atrial fibrillation (AF) occurs in 10% to 15% of patients after MI.
Those more prone to AF include patients with older age, large MI,
hypokalemia, hypomagnesemia, hypoxia, or increased sympathetic
activity. Rate control with β-blockers (e.g., metoprolol), digoxin, calcium-channel blockers (e.g., diltiazem) or some combination of these
agents is warranted, as is the use of intravenous heparin to reduce
the risk of systemic embolization. Cardioversion is warranted in the
face of rapid rates that cause ischemia, heart failure, or hypotension.
Amiodarone is sometimes used to help maintain sinus rhythm for the
first few months after MI-related AF.
Sinus bradycardia or AV block due to increased vagal tone is
common in cases of inferior MI (30% to 40%). Reperfusion of the
right coronary artery may be associated with significant bradycardia (Bezold-Jarisch reflex). Atropine (0.5 to 1.5 mg IV) can resolve
severe inferior MI–related bradycardia. In contrast, heart block and
wide-complex escape rhythms associated with anterior MI suggest an
infra–AV node block. This may be worsened by the use of atropine.
Advanced degrees of heart block may require the placement of a
permanent pacemaker. Intermittent second-degree or third-degree
AV block associated with bundle branch block or symptomatic AV
block are indications for a permanent pacemaker. Type I AV block
(Wenckebach) is usually not persistent and rarely causes symptoms
that warrant a permanent pacemaker.
Heart Failure and Low-Output States
MI involving 20% to 25% of the left ventricle can result in significant
heart failure manifesting with dyspnea due to pulmonary congestion
96 SECTION II Cardiovascular Disease
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and findings of LV dysfunction such as an S3 or S4. Cardiogenic shock
is associated with loss of 40% of the myocardium. This condition
carries a very high risk of mortality. In the era of widespread use of
reperfusion therapy, the incidence of post-MI heart failure or cardiogenic shock has declined. Early use of reperfusion therapies limits
infarct size and the risk of complications related to heart failure. When
acute heart failure occurs with MI, therapeutic interventions including oxygen, intravenous morphine, and diuretics can help stabilize the
patient. Nitroglycerin can also help by reducing the elevated preload.
Long-term therapy for heart failure related to reduced EF after acute
MI includes the use of ACE inhibitors (or ARBs), appropriate β-block-
ers, aldosterone receptor antagonists such as eplerenone or spironolactone, and diuretics as needed.
The acutely infarcted ventricle requires an increased filling pressure
and volume to optimize its performance. Patients with acute MI may
become relatively fluid depleted due to nausea, vomiting, or decreased
fluid intake, leading to reduced LV volume and a fall in cardiac output.
This can translate into hypotension that is best treated by judicious
administration of fluids.
Acute inferior MI is usually associated with a low mortality risk
once the early arrhythmia-prone hours have passed. Occlusion of
the right coronary artery and a significant acute marginal branch
can lead to right ventricular infarction. Approximately 10% to 15%
of patients with inferior MI have associated right ventricular infarction. This condition produces a significant increase in mortality risk
(in-hospital mortality, 25% to 30% vs. <6%). Hallmarks of right
ventricular infarction include elevated jugular venous pressure with
Kussmaul sign and hypotension. Right ventricular function frequently recovers, but it may be necessary to administer sufficient
volume to maintain right heart output. Short-term inotropic support with dobutamine is sometimes needed, and venodilators and
diuretics should be avoided. High-degree AV block, usually transient with inferior MI, may worsen hemodynamics and necessitate
temporary AV sequential pacing. AF may not be tolerated and may
require cardioversion.
Cardiogenic Shock
Cardiogenic shock is a clinical syndrome associated with extensive loss
of myocardium, which leads to a reduced cardiac index (<1.8 L/min/
m2) in the face of elevated LV filling pressures (pulmonary capillary
wedge pressure >18 mm Hg), resulting in systemic hypotension and
reduced organ perfusion. This shock state is associated with mortality
rates in the range of 70% to 80%. Aggressive diagnosis with hemodynamic monitoring and appropriate support with an inotropic agent
and invasive mechanical support as indicated can help to stabilize
the patient. Mechanical circulatory support includes the intra-aortic
balloon pump (IABP), Impella ventricular assist device (VAD), and
extracorporeal membrane oxygenation (ECMO). One benefit of the
IABP is that it can quickly be placed in the cath lab to both augment
cardiac output as well as diastolic filling of the coronary arteries. IABP
therapy is at best temporizing, and the patient’s survival depends on
the presence of reversible factors such as ischemia that respond to
revascularization or correction of a mechanical complication of MI
(e.g., mitral regurgitation or VSD). IABP therapy cannot be used in the
face of significant aortic insufficiency and may not be feasible in the
presence of significant peripheral vascular disease. Despite the hemodynamic support it provides, the IABP has never been proven in a
randomized trial to improve mortality, and thus its use is based on clinician decision making rather than routine use. Some centers now are
opting for more advanced levels of support in particularly ill patients
including the Impella or ECMO as a bridge to recovery or long-term
VAD/transplant.
In patients with cardiogenic shock secondary to acute MI it is key to
reestablish perfusion to affected areas of the heart as able. More recent
theories have suggested that rather than the “door to balloon time”
emphasized in STEMI, the emphasis in patients in shock should be
to achieve early improvement in perfusion with mechanical support
as needed and then address revascularization. If multivessel disease is
discovered in a patient in shock, the culprit lesion should be addressed,
and other high-grade diseases can be addressed at a later time.
Mechanical Complications
Mechanical complications of acute MI include mitral regurgitation
(due to ischemic papillary muscle dysfunction or rupture), VSD, free
wall rupture, and LV aneurysm formation. These problems usually
occur during the first week after MI, and they account for as much as
15% of MI-related mortality. A new murmur, sudden onset of heart
failure, or hemodynamic collapse should also raise suspicion of a
mechanical complication of MI. Patients who either were not reperfused or were reperfused late after onset of MI are most at risk for these
problems. Echocardiography usually identifies the mechanical problem, and hemodynamic assessment with right heart catheterization can
aid the diagnosis. Surgical correction of the defect is usually required.
Papillary muscle rupture or dysfunction leading to acute severe
mitral regurgitation results in severe heart failure and up to 75% mortality within 24 hours after onset. Afterload reduction with intravenous
nitroprusside and the use of IABP can help to stabilize the patient, but
surgical valve repair or replacement will be needed to provide some
chance of survival. Surgery is associated with a 25% to 50% mortality
risk, but that still is better than the risk with medical or IABP therapy
only.
Elderly patients, particularly those with hypertension, are more
prone to MI-related VSD. Thrombolytic therapy may also place
patients at risk for this complication. Acute VSD with resultant left-toright shunting can produce severe hemodynamic instability. As with
acute mitral regurgitation, afterload reduction and IABP may help to
stabilize the patient, but ultimately surgical repair will be required.
Moderate to large VSDs are not well tolerated and are associated with
significant mortality risk. VSDs related to anterior MI may offer a better opportunity for surgical repair than those resulting from inferior
MI. Some patients have been helped by the use of percutaneous closure
devices, which can afford an opportunity to delay surgery until there is
better tissue healing in the infarct area.
LV free wall rupture is similar to VSD in terms of risk for occurrence
and underlying myocardial pathology. Free wall rupture is usually
associated with sudden death due to cardiac tamponade. On occasion,
a pseudoaneurysm forms and the patient can be treated surgically.
Thromboembolic Complications
In earlier years, thromboembolism in the form of either cardioembolic
stroke or pulmonary embolism contributed to 25% of post-MI in-hospital mortality, and clinical events were diagnosed in 10% of patients.
The risk of thromboembolism is linked to the presence of LV mural
clot, which is more likely to be found in anterior MI with associated
apical akinesis and deep venous thrombosis due to prolonged bedrest.
Contemporary methods of care for acute MI have greatly reduced the
risk of post-MI thromboembolism.
Reperfusion therapy, when applied in a timely fashion, results in less
extensive MI and less impairment of LV function. Patients with anterior MI treated with reperfusion therapy are less likely to have extensive apical akinesis, which is the breeding ground for mural thrombus.
It is advised that patients treated for acute MI have an echocardiogram
to assess for overall LV function; in the case of anterior MI, the presence of apical mural thrombus can be detected by echocardiography.
CHAPTER 8 Coronary Heart Disease
97
If LV mural thrombus is present, the patient should receive therapeutic anticoagulation with unfractionated or LMW heparin while oral
anticoagulation with warfarin is initiated. Warfarin therapy should be
continued for 6 months after MI when LV apical mural thrombus is
detected. Early ambulation after MI, along with the use of compression
stockings and subcutaneous heparin prophylaxis (unfractionated or
LMW) for deep venous thrombosis, has greatly diminished the threat
of pulmonary embolism.
PROGNOSIS
Risk Stratification After Myocardial Infarction
Key to understanding an individual patient’s risk for future coronary
events or mortality related to MI is a thorough assessment of drivers for
those risks: status of LV function and its impact on clinical functional
status, residual myocardial ischemia, and spontaneous or exercise-induced arrhythmias. Appropriate predischarge assessments provide a
comprehensive picture of the patient’s risk status and prognosis.
Electrocardiographic Monitoring
Patients are routinely monitored by telemetry systems that capture
arrhythmic events in the first 48 hours after MI. Late ventricular
arrhythmias such as VF or sustained VT identify patients who are likely
to benefit from ICD therapy. This is particularly true if EF is reduced
to less than 40%. ICD implantation is also indicated for patients with
persistently reduced EF (<30%).
Cardiac Catheterization and Noninvasive Testing
Predischarge risk stratification may involve cardiac catheterization,
submaximal predischarge exercise stress testing (on days 4 to 6), or
maximal exercise stress testing after discharge (at 2 to 6 weeks). The
presence or absence of high-risk coronary anatomy is demonstrated
for patients who have undergone primary PCI at the time of presentation. Many patients who have been treated with thrombolytic therapy undergo coronary angiography before discharge to determine
the extent and severity of underlying CAD as well as the status of the
culprit lesion. If coronary angiography is not performed, predischarge
submaximal exercise testing (up to 70% of maximal predicted heart
rate) is done to identify those who are at increased risk for postdischarge coronary ischemic events. Patients who undergo submaximal
exercise stress testing in lieu of coronary angiography frequently have
a follow-up maximal exercise stress test within 2 to 6 weeks after discharge. During stress testing, positive results that suggest the need for
coronary angiography include exercise-induced angina, ST changes of
ischemia (ST depression), exercise-induced hypotension, exercise-induced ventricular arrhythmias, and low functional capacity. The sensitivity and specificity of stress testing after MI is enhanced by the use
of imaging modalities such as stress echocardiography or nuclear perfusion imaging. All patients should have their EF assessed, typically by
echocardiography, before discharge.
Secondary Prevention, Patient Education, and
Rehabilitation
The goal of secondary prevention is to reduce the risk of recurrent MI
and cardiovascular mortality. Risk factor modification is key to the
secondary prevention strategy. All patients should have their lipid status assessed at the time of admission, but statin therapy is warranted
in patients with acute MI at presentation. The target LDL level is less
than 100 mg/dL, preferably closer to 70 mg/dL. Smoking cessation is of
critical importance because it can reduce the risk of reinfarction, and
ongoing smoking can double the risk of recurrent MI or mortality in
the first year after MI. Structured smoking cessation programs and the
use of pharmacologic aids (e.g., nicotine patches or gum, bupropion,
varenicline) can increase the success of smoking cessation efforts.
Antiplatelet therapy with aspirin (75 to 162 mg/day) is given indefinitely to all patients after MI. Regardless of whether primary PCI
has been performed, patients will benefit from the additional use of
a P2Y12 inhibitor for the first year after MI. Those patients who have
received a stent during primary PCI should continue clopidogrel 75
mg/day, ticagrelor 90 mg twice daily, or prasugrel 10 mg/day for one
year. There are some data suggesting that if the patient is tolerating
dual-antiplatelet therapy (DAPT) well and has a low bleeding risk,
there may be additional benefit to continuing DAPT even for up to
three years.
The use of anticoagulation is indicated for patients with systemic
or pulmonary thromboembolism, as well as persistent or paroxysmal
AF, guided by their CHADS-2 score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke). Patients who are
at high risk for thromboembolism after acute MI, such as those with
low EF related to anterior MI, can also be considered for prophylactic
anticoagulation; however, there is no strong randomized data for this
indication.
The high prevalence of patients who have both AF and the need for
stent placement creates a conundrum involving the need for both anticoagulation and antiplatelet agents leading to a significantly increased
risk of bleeding. Warfarin (target international normalized ratio [INR],
2.0 to 3.0) has been the historical choice for anticoagulation. Its use in
conjunction with patients having undergone stenting was evaluated in
several clinical trials that suggested that therapy with warfarin and clopidogrel had similar outcomes for ischemic or embolic events compared
to “triple therapy” (warfarin, clopidogrel, and aspirin) but afforded a
lower risk of bleeding. Since then, newer anticoagulant medications have
been developed for nonvalvular AF that have merited their own series of
trials, including the thrombin inhibitor dabigatran and the direct factor
Xa inhibitors apixaban, edoxaban, and rivaroxaban. These drugs were
also demonstrated to be effective when paired with clopidogrel with a
lower bleeding risk compared to triple therapy. None of the trials referenced above utilized any other P2Y12 inhibitors aside from clopidogrel.
Ultimately the decision regarding antithrombotic therapy length and
composition will be provider dependent but should be based upon an
assessment of the patient’s bleeding and ischemic risk.
Acute anterior MI that has resulted in significant injury to the ventricle with an EF of less than 40% places the patient at risk for future
negative remodeling of the left ventricle and potential heart failure.
ACE-inhibitor therapy has been shown to reduce the risk of negative
remodeling and the occurrence of heart failure in such patients. This
group of patients also experiences a reduction in future recurrent MI
risk with the use of ACE-inhibitor therapy. This observation does not
appear to carry over to patients with stable CAD. ACE-inhibitor therapy (captopril, ramipril, lisinopril) is indicated for all patients after MI.
The use of ARBs (e.g., valsartan, losartan) is reasonable for patients
who are intolerant of ACE-inhibitor therapy. The aldosterone receptor
antagonist eplerenone (25 mg/day, titrated to 50 mg/day) is indicated
as additive therapy to ACE or ARB in MI patients who have reduced
EF (<40%) or diabetes. Careful monitoring of serum potassium is
required after initiation of eplerenone together with ACE or ARB.
β-Blocker therapy reduces mortality risk in patients who have
reduced EF post-MI. This therapy should be avoided in patients with
uncompensated heart failure early after MI or the presence of other
contraindications. Metoprolol succinate (25 mg/day titrated up to 200
mg/day) or carvedilol (3.125-6.25 mg titrated to 25 mg twice each day)
should be initiated at low doses and titrated upward as tolerated. The
role of β-blockers in patients with no residual myocardial ischemia,
arrhythmias, or normal EF is not clear.
98 SECTION II Cardiovascular Disease
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Nitrates, either short-acting sublingual nitroglycerin or long-acting
versions, may be useful in the treatment of stable angina. Calcium-channel
blocking drugs should be avoided in patients with reduced EF (<40%). In
patients with normal EF, either diltiazem or verapamil may useful as a substitute in patients who are intolerant of β-blockers when either antianginal
therapy or rate control for AF is needed. The dihydropyridine, amlodipine,
may be a useful adjunct for control of hypertension or treatment of angina.
It should be used with caution in the face of reduced EF.
After acute MI, women should refrain from initiating hormone
therapy with estrogen or estrogen/progesterone preparations; these
agents do not decrease the risk of recurrent MI but do increase the risk
of thromboembolic events. The ongoing use of hormone therapy in
women already receiving treatment should be individualized, with a
bias toward discontinuing therapy. Diabetic patients need attention to
their degree of glycemic control, with a target of hemoglobin A1c less
than 7%. Vitamin supplements have no clear role in therapy for MI
patients. Fish oil supplements do not appear to benefit patients who
have experienced acute MI.
Patient Education and Cardiac Rehabilitation
It is important to begin the education of patients early after acute MI
so that they understand the value of their various prescribed medical
therapies and the need for risk factor modification. Cardiac rehabilitation programs are very useful in the ongoing education of patients; they
reinforce positive lifestyle changes and provide exercise training in the
post-MI period. Such programs not only educate patients but also help
them to regain confidence in their ability to perform the tasks of daily
living and other activities they enjoy. Early follow-up with the physician
after discharge is also important to ensure clinical stability and tolerance
of medical therapy and to monitor the progress of lifestyle changes.
SUGGESTED READINGS
Amsterdam EA, Wenger NK, Brindis RG, et al: 2014 AHA/ACC Guideline
for the Management of Patients with Non–ST-Elevation Acute Coronary
Syndromes, J Am Coll Cardiol 64(24):e139–e228, 2014.
Arnett DK, Blumenthal RS, Albert MA, et al.: 2019 ACC/AHA Guideline on
the primary prevention of cardiovascular disease: A Report of the American College of Cardiology/American Heart Association Task Force on
Clinical Practice Guidelines, Circulation 140:e596–e646, 2019.
Fihn SD, Gardin JM, Abrams J, et al.: 2012 ACCF/AHA/ACP/AATS/PCNA/
SCAI/STS Guideline for the diagnosis and management of patients with
stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association,
Society for Cardiovascular Angiography And Interventions, and Society of
Thoracic Surgeons, J Am Coll Cardiol 60:e44–e164, 2012.
Hillis LD, Smith PK, Anderson JL, et al.: 2011 ACCF/AHA Guideline for coro-
nary artery bypass graft surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines. Developed in collaboration with the American Association for
Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society
of Thoracic Surgeons, J Am Coll Cardiol 58:e123–e210, 2011.
Levine GN, Bates ER, Bittl JA, et al.: 2016 ACC/AHA Guideline focused update
on duration of dual antiplatelet therapy in patients with coronary artery
disease, J Am Coll Cardiol 68(10):1082–1115, 2016.
Levine GN, Bates ER, Blankenship JC, et al.: 2011 ACCF/AHA/SCAI guideline
for percutaneous coronary intervention: a report of the American College
of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines and the Society for Cardiovascular Angiography and
Interventions, J Am Coll Cardiol 58:e44–e122, 2011.
Levine GN, Bates ER, Blankenship JC, et al.: 2015 ACC/AHA/SCAI focused
update on primary percutaneous coronary intervention for patients with
ST-elevation myocardial infarction, J Am Coll Cardiol 67(10):1235–1250,
2016.
O’Gara PT, Kushner FG, Ascheim DD, et al.: 2013 ACCF/AHA Guideline for
the management of ST-elevation myocardial infarction: a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines, J Am Coll Cardiol 61(4):e78–e140,
2013.
9
Cardiac Arrhythmias
Marcie G. Berger, Jason C. Rubenstein, James A. Roth
BASIC CELLULAR ELECTROPHYSIOLOGY
Cardiac myocytes actively maintain a negative resting membrane
potential (Em) through the differential distribution of ions between
intracellular and extracellular compartments, which is an energy-dependent process that relies on ion channels, pumps, and exchangers.
Transmembrane differences in voltage and ionic concentration create
electrical and chemical forces that drive charged ions in and out of
cells.
The resting Em of cardiac myocytes is controlled by potassium
ions (K+). Active K+ transport by the sodium-potassium adenosine
triphosphatase pump (Na+, K+-ATPase) produces a transmembrane
ionic gradient, with the intracellular concentration of K+ exceeding
the extracellular concentration. This favors the net efflux of K+ from
cells, down the chemical concentration gradient, yielding a resting negative charge within the cardiac myocytes. K+ continues to flow from
the intracellular to the extracellular compartment until the negative
intracellular charge counterbalances the transmembrane K+ concentration gradient at a potential called the equilibrium potential for K+.
This potential, at which the net K+ current is zero, is close to the resting
Em of nonpacemaker cardiac myocytes. Pacemaker cells (i.e., sinoatrial
and atrioventricular [AV] nodal cells) are characterized by a resting Em
of −50 to −60 mV. The resting Em of atrial and ventricular myocytes is
typically −80 to −90 mV.
The depolarization of a cardiac myocyte to threshold potential
triggers a sequence of ionic movements resulting in a cardiac action
potential (Fig. 9.1). The action potential is divided into five phases.
Phase 0 is the rapid depolarization of nonpacemaker myocytes resulting from rapid sodium ion (Na+) entry through fast Na+ channels.
These channels have three conformational states: closed (resting state),
open (conducting Na+ current), and inactivated, from which recovery
is voltage dependent. Phase 1 is early, rapid, partial repolarization of
the cell mediated by K+ efflux. During phase 2, the plateau phase, there
is a small net current flow, with inward calcium ion (Ca2+) flow balanced by outward K+ flow.
During phase 3, repolarization is mediated by an increase in K+
efflux and a decline in Ca2+ influx. The dominant repolarizing current is IKr, the rapidly activating delayed rectifier K+ current, a channel
encoded by the KCNE2 gene (also called HERG). The IKs current, or
slowly activating delayed rectifier K+ current, also contributes to repolarization. Phase 3 determines to a large degree the cellular refractory
period. Importantly, IKr is inhibited by a large number of drugs that
prolong the action potential duration.
Phase 4 is particularly significant in cardiac pacemaker cells because
slow depolarization occurs from the resting membrane potential to
the threshold potential. The resting Em, rate of spontaneous phase
4 depolarization, and rate of phase 0 depolarization differentiate
slow-response from fast-response cardiac myocytes. Slow-response
cells, located in the sinoatrial node and AV node, normally display
automaticity or spontaneous depolarization during phase 4. Resting
Em in slow-response cells is less negative, and Ca2+ current mediates
phase 0 depolarization. Conduction in these pacemaker cells is slow,
and recovery from inactivation is time dependent. The fast-response
cells found in atrial myocytes, ventricular myocytes, and the HisPurkinje system display slow phase 4 depolarization and do not typically display automaticity. Their resting Em is more negative, and the
fast Na+ current drives rapid phase 0 depolarization and rapid conduction. Recovery from inactivation in these cells is voltage dependent.
The sinus node typically displays the fastest phase 4 depolarization.
Other cardiac tissues have the capacity to depolarize spontaneously,
and subsidiary pacemakers may take over when sinus rates slow and
under conditions of increased automaticity. Typically, the AV node,
located above the AV ring, serves as the heart’s secondary pacemaker,
with a spontaneous rate of depolarization of 40 to 50 beats per minute.
Automaticity of cardiac myocytes is increased when the slope of phase
4 depolarization increases, with a shift of threshold potentials to more
negative values, or in the presence of more positive maximal diastolic
potentials.
The sinus node is the primary intrinsic pacemaker, and spontaneous depolarization leads to action potential generation, with normal
resting rates of 60 to 100 beats per minute. Depolarization then spreads
through the atria to the AV node, where conduction slows, introducing a delay between atrial and ventricular activation, and then to the
His-Purkinje system fibers, which originate at the AV node with the
bundle of His and split to form the left bundle branch and the right
bundle branch, rapidly conducting depolarization to the ventricular
myocardium. Cardiac myocytes are joined by electrical synapses called
gap junctions, which permit the flow of intracellular current from cell
to cell.
Classification of Arrhythmias
Mechanistically, cardiac arrhythmias can be broadly divided into disorders of action potential formation and disorders of impulse conduction. Clinically, arrhythmias are classified as bradycardias and
tachycardias, with further categorization according to arrhythmia
origin. This information is used to guide evaluation and management
strategies.
Electrophysiologic Mechanisms of Arrhythmias
Automaticity is a normal function of pacemaker cells, occurring during
phase 4 depolarization. Enhanced automaticity occurs when pacemaker
cells depolarize at a faster rate due to an increased slope of phase 4
depolarization, a shift of threshold potential to a more negative value,
99
100 SECTION II Cardiovascular Disease
AB
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1
+
K
2
2+
Ca
0
+
Na
−80 mV
A
2+
Ca
−60 mV
B
Fig. 9.1 Electrophysiologic basis of the cardiac cellular action poten-
tial. (A) Fast-response cells found in working myocardium and the
specialized infranodal conduction system maintain a strongly negative
resting membrane potential and a brisk phase 0 upstroke mediated by
rapid sodium influx at the start of the action potential. (B) In contrast,
slow-response cells found in the sinus node and atrioventricular nodal
tissue exhibit less-negative resting membrane potentials, slower calcium-channel–dependent action potential upstrokes, and phase 4 depolarization.
+
K
3
+
K
4
+
Na
+
K
I
f
Proximal common pathway
AB
Distal common pathway
A
Fig. 9.2 Mechanism of reentry. Reentry requires two distinct pathways
with different refractoriness and a region of slowed conduction. One
pathway (A) has normal rapid conduction but a long refractory period.
The second pathway (B) has slowed conduction but a relatively shorter
refractory period. To initiate reentry, conduction must fail down one
pathway in the antegrade direction but then permit later retrograde
reactivation of this pathway. This is referred to as a unidirectional block.
A fixed or functional obstacle must maintain separation of the two pathways. Although drawn schematically as a circular loop, the anatomy
of circuits is often complex and circuitous and is different in different
arrhythmia mechanisms. (A) In normal rhythm, the circuit is activated
in an antegrade direction down both pathways. However, because
of slowed conduction in the B limb, distal activation is mediated by
the faster A pathway, which arrives first and may activate the slowly
conducting pathway in a retrograde direction. This retrograde conduction is electrocardiographically concealed (invisible), collides with the
antegrade wave front, and is extinguished, and no tachycardia results.
(B) Reentry is usually initiated by a premature beat originating independently of the circuit. The premature beat fails to propagate down
the rapidly conducting A limb due to differential refractoriness of the
two limbs, but it is able to propagate down the slowly conducting B
pathway, where it may encounter substantial delay due to increased
conduction time with prematurity (i.e., decremental conduction), allowing recovery of the previously blocked rapidly conducting A limb. This
permits the rapidly conducting A limb to act as a return path and for
ultimate reentrant reactivation of the slowly conducting B pathway, initiating sustained reentrant tachycardia in the circuit.
Proximal common pathway
Distal common pathway
B
or a shift of the maximal diastolic potential to a more positive value.
These changes may occur with sympathetic stimulation. Enhanced
automaticity may be normal (e.g., appropriate sinus tachycardia) or
abnormal (e.g., inappropriate sinus tachycardia). Spontaneous depolarization occurring in nonpacemaker cardiac myocytes is called
abnormal automaticity. Conditions such as ischemia, electrolyte
abnormalities, and sympathetic stimulation may produce abnormal
automaticity. Premature atrial and ventricular depolarizations, atrial
tachycardia, and ventricular tachycardia (VT) may result.
Triggered activity occurs when secondary cardiac depolarizations
are initiated by prior depolarizations. If these secondary depolarizations reach threshold potential, they may generate action potentials
during or immediately after phase 3 of the action potential. Early after-
depolarizations (EADs) are observed when triggered depolarization
occurs during phase 3 of the action potential. Inciters of EADs include
QT-prolonging drugs, hypokalemia, and bradycardia. Patients with
congenital long QT syndrome (LQTS) are prone to develop EADS,
resulting in torsades de pointes (TdP).
When triggered activity occurs during phase 4, delayed afterdepo-
larizations (DADs) result. DADs are exaggerated at rapid heart rates
and observed with digoxin toxicity and high-level catecholamine
states, conditions that are associated with intracellular calcium overload. DADs are thought to be the chief arrhythmic mechanism underlying catecholaminergic polymorphic VT (CPVT).
Reentry is the dominant mechanism underlying clinical tachyarrhythmias. Reentry describes the reexcitation of a localized region of
cardiac tissue by the same impulse, requiring bifurcating conduction
pathways with different velocities and refractory periods. To permit
reentry, unidirectional block in one pathway and slowed conduction
in the other are required. Reentry is further categorized as anatomic,
circling around a fixed anatomic obstacle, or functional, in which the
unexcitable center of a reentrant circuit is not fixed but functionally
refractory. Fig. 9.2 illustrates reentry as an arrhythmic mechanism.
The two pathways join proximally and distally. Pathway A conducts
rapidly but has a long refractory period. Pathway B is slowly conducting but has a shorter refractory period. A normally timed impulse
enters the two pathways through the proximal common pathway,
conducting rapidly down A and slowly down B. As the impulse from
pathway A reaches the distal common pathway, while continuing distally, it may also turn around to activate B retrogradely. This impulse
collides with the slowly conducting antegrade impulse in pathway B,
extinguishing the impulse. However, a sufficiently premature stimulus
CHAPTER 9 Cardiac Arrhythmias
TABLE 9.1 Singh–Vaughan Williams Classification of Antiarrhythmic Drugs
Class Physiologic Effect
I Blocks sodium channels; predominantly reduces the maximum velocity of the
upstroke of the action potential (phase 0)
IA Intermediate-potency blockade Quinidine, procainamide, disopyramide
IB Least-potent blockade Lidocaine, tocainide, mexiletine, phenytoin
IC Most-potent blockade Flecainide, propafenone, moricizine
II β-Adrenergic receptor blockade Propranolol, metoprolol, atenolol
III Potassium-channel blockade: predominantly prolongs action potential duration Amiodarone, sotalol, bretylium, ibutilide, dofetilide, dronedarone
IV Calcium-channel blockade Verapamil, diltiazem
a
Several agents have physiologic effects characteristic of more than one class.
a
Examples
101
may enter the proximal common pathway, finding pathway A with
its long refractory period unexcitable, traveling slowly down pathway
B, and finally reaching the distal common pathway. Due to the slow
conduction velocity in pathway B, pathway A may no longer be refractory, and the impulse may successfully travel retrograde up pathway
A, potentially repeatedly activating the circuit. Reentry is the most
common mechanism producing supraventricular tachycardia (SVT)
and VT.
For a deeper discussion on this topic, please see Chapter 55,
“Principles of Electrophysiology,” in Goldman-Cecil Medicine, 26th
Edition.
GENERAL APPROACH TO MANAGEMENT
Diagnostic Procedures
Electrocardiography
The baseline 12-lead electrocardiogram (ECG) is essential for the initial evaluation of patients with arrhythmic symptoms. The baseline
ECG may indicate underlying structural heart disease, with Q waves
or fractionated QRS complexes suggesting prior myocardial infarction
(MI). Slow sinus rates or AV conduction abnormalities may point to
susceptibility to symptomatic bradycardia. Delta waves confirm an
accessory pathway and direct the evaluation of arrhythmic symptoms
toward the diagnosis of Wolff-Parkinson-White (WPW) syndrome
while localizing the accessory pathway.
Evidence for hereditary cardiomyopathies and cardiac ion channel
disorders that predispose to sudden death may be detected on a baseline
ECG. Patients with arrhythmogenic right ventricular (RV) dysplasia may
have epsilon waves and inverted T waves in the right precordial leads. QT
interval prolongation or shortening may indicate congenital or acquired
long QT or short QT syndrome, respectively. Brugada syndrome can be
diagnosed based on coved ST-segment elevation in leads V1 and V2.
A 12-lead ECG obtained during arrhythmic symptoms can establish the cause of a patient’s symptoms. The specific mechanism underlying bradycardia and tachycardia can often be inferred from the ECG.
Documentation of QRS morphology during VT or accessory pathway–
mediated tachycardia on a 12-lead ECG aids in localizing the site of
origin and guiding catheter ablation.
Ambulatory Monitoring
Although a 12-lead ECG obtained during arrhythmic symptoms is
ideal, it is difficult to obtain in practice because of the transient and
intermittent nature of these symptoms. Ambulatory recording devices
permit electrocardiographic monitoring over longer periods to establish symptom-rhythm correlations.
Three types of monitoring devices are available. Holter monitors
typically provide continuous electrogram storage for 24 to 48 hours.
Holter monitoring is helpful for patients with frequent symptoms. The
comprehensive rhythm record obtained during this sampling period
provides useful information about heart rate variability, rate control
with atrial fibrillation (AF), AF burden, asymptomatic arrhythmias,
and the frequency of ventricular ectopy.
External event monitors or loop recorders, which can be worn for
30 days, store electrograms when triggered by patients for symptoms.
Additionally, loop monitors employ algorithms to automatically detect
tachycardia, bradycardia, and atrial fibrillation. Episode storage varies
from seconds to minutes. After events are recorded, patients transmit
the data by telephone. External loop recorders are intended to identify
cardiac rhythm disturbances underlying infrequent symptoms.
For patients with arrhythmia symptoms occurring less than once
per month, implantable loop recorders may be useful. These small
devices implanted in a subcutaneous pocket in the left chest record
patient-triggered and auto-triggered ECGs based on heart rate and
AF detection criteria. With a 3-year anticipated battery longevity,
implantable loop recorders are valuable in establishing the cause of
recurrent infrequent syncope and arrhythmic symptoms. Implantable
loop recorders, with a reported 98% sensitivity for AF detection, are
useful both for AF management and AF surveillance in the setting of
cryptogenic stroke, resulting in higher utilization of appropriate oral
anticoagulation following stroke.
Electrophysiologic Testing
To perform electrophysiologic studies, temporary transvenous pacing
catheters are positioned in multiple locations in the heart, permitting
pacing and recording of intracardiac electrograms. Catheters are typically placed in the right atrium, the right ventricle, close to the bundle
of His, and in the coronary sinus for left atrial recording and pacing.
Electrophysiologic studies can define the mechanism of tachyarrhythmias and guide therapy. In patients with prior MI, induction of VT
may assist in determining patient susceptibility to life-threatening
arrhythmias and inform decisions regarding defibrillator implantation. Electrophysiologic testing also can evaluate sinus node function
and AV conduction.
Pharmacologic Therapy
Antiarrhythmic drugs are traditionally divided according to the Singh–
Vaughan Williams classification, which categorizes agents based on
their primary physiologic effect (Table 9.1). When this classification
system was first proposed, knowledge of electrophysiologic mechanisms was limited. Although the simplicity of categorizing antiarrhythmic drugs according to Singh–Vaughan Williams classes I through IV
is appealing, the system has many limitations. A hybrid classification
system, class I and III agents block ion channels, and class II and
IV drugs block receptors. Some drugs cross classes and have several
102 SECTION II Cardiovascular Disease
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TABLE 9.2 Selected Characteristics of Antiarrhythmic Drugs
Effect on Surface
Drug
Quinidine Prolongs QRS and QT Negative inotrope Increases digoxin level and warfarin
Procainamide Prolongs PR, QRS,
Disopyramide Prolongs QRS and QT Negative inotrope Phenobarbital, phenytoin, and rifampin
Lidocaine Shortens QT None Propranolol, metoprolol, and cimetidine
Mexiletine Shortens QT None Increases theophylline level
Flecainide Prolongs PR and QRS Negative inotrope Increases digoxin level Increases PT; variable effect
Propafenone Prolongs PR and QRS Negative inotrope Increases digoxin, theophylline, and
Dronedarone Prolongs PR and QT;
Amiodarone Prolongs PR and QT;
Sotalol Prolongs PR and QT;
Ibutilide Prolongs PR and QT None Additive effect on QT prolongation with
Dofetilide Prolongs QT None Verapamil, diltiazem, Cimetidine, and
DT, Defibrillation threshold; ECG, electrocardiogram; LV, left ventricle; PT, pacing threshold; TdP, torsades de pointes.
ECG
and QT
slows sinus rate
slows sinus rate
slows sinus rate
Effect on LV
Function Important Drug Interactions
effect
Cimetidine increases quinidine level
Phenobarbital, phenytoin, and rifampin
decrease quinidine level
Negative inotrope Cimetidine, alcohol, and amiodarone
increase procainamide level
decrease disopyramide level
increase lidocaine level
Phenobarbital, phenytoin, and rifampin
decrease mexiletine level
cyclosporine levels; increases warfarin
effect
Phenobarbital, phenytoin, and rifampin
decrease propafenone level
Cimetidine and quinidine increase
propafenone level
Negative inotrope CYP3A4 inhibitors (ketoconazole, clari-
thromycin, calcium-channel blockers)
increase dronedarone levels; additive
effect with drugs that prolong QT
(macrolides, class I and III antiarrhyth-
mics) increasing risk of TdP; increases
dabigatran levels
None Increases digoxin and cyclosporine levels;
increases warfarin effect
Negative inotrope Additive effects with other β-blockers Decreases DT Kidney
class IA and other class III antiarrhyth-
mic agents
ketoconazole increase dofetilide level
Effect on Pacing and
Defibrillation Thresholds
Increases PT and DT at high
doses
Increases PT at high doses Liver and kidney
Increases PT at high doses Liver (CYP3A4) and
Increases DT Liver (CYP2D6)
Various effects Liver (CYP2D6)
on DT
Increases PT; variable effect
on DT
Little effect Liver (CYP3A4)
Increases DT Liver (CYP3A4)
Decreases DT Liver
Decreases DT Liver and kidney
Major Route of
Elimination
Liver (CYP3A4) and
kidney
kidney
Liver (CYP2D6) and
kidney
Liver (CYP2D6)
mechanisms of action. There are drugs with antiarrhythmic action that
are excluded from the classification, such as digitalis and adenosine.
The system categorizes drugs based on their in vitro electrophysiologic
effects in normal cardiac tissues.
Available antiarrhythmic drugs have limited efficacy and carry the
risk of adverse events, including proarrhythmic potential. Knowledge
of drug metabolism, interactions, electrophysiologic effects, and side
effects is essential. Certain antiarrhythmics may suppress left ventricular systolic function and may impact pacing and defibrillation thresholds. Excepting β-blockers, none of the antiarrhythmics has been
demonstrated to reduce mortality rates. In fact, the use of antiarrhythmic agents may confer an increased risk of cardiovascular mortality,
particularly in heart failure patients. Tables 9.2 and 9.3 summarize
major characteristics and side effects of commonly used antiarrhythmic drugs.
Class I Antiarrhythmic Agents
Class I antiarrhythmic drugs include sodium-channel blockers that
bind fast sodium channels in their open and inactivated states and
dissociate from sodium channels during their resting state. Blocking
voltage-gated fast sodium channels slows phase 0 depolarization
and conduction velocity. Class I agents demonstrate use-dependent
blockade, and their effect is potentiated at faster heart rates. The drug
dissociation rate from sodium channels during phase 4 of the action
potential determines the degree to which these agents depress cardiac
conduction velocity.
Class IA agents have a slow rate of drug dissociation from sodium
channels, conferring moderate potency. In addition to blocking voltage-gated fast sodium channels, class IA drugs block delayed rectifier potassium channels. Slowing of conduction velocity and action
potential prolongation are observed. All are antimuscarinic, especially
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