InternalMed_Harrison

InternalMed_Harrison. ablation can be considered. The antiarrhythmic agents flecainide, propafenone, mexiletine, and amiodarone can be effective, but the potential for side effects warrants careful consideration. Catheter ablation can be effective if the arrhythmia occurs with sufficient frequency or is readily provoked such that its origin can be identified for ablation in a similar manner to that for idiopathic monomorphic VT as discussed below. Benefit must be carefully weighed against the procedure-related risks (see below). pvcs and nonsustainEd vt associatEd with acutE coronary syndromEs


InternalMed_Harrison

InternalMed_Harrison. pvcs and nonsustainEd vt associatEd with acutE coronary syndromEs During and early after acute myocardial infarction (MI), PVCs and nonsustained VT are common and can be an early manifestation of ischemia and a harbinger of subsequent VF. Treatment with β-adrenergic blockers and correction of hypokalemia and hypomagnesemia reduce the risk of VF. Routine administration of the antiarrhythmic drugs such as lidocaine has not been shown to reduce mortality and is not indicated for suppression of PVCs or asymptomatic nonsustained VT.


InternalMed_Harrison

InternalMed_Harrison. Following recovery from acute MI, frequent PVCs (typically >10 PVCs per hour), repetitive PVCs with couplets, and nonsustained VT are markers for depressed ventricular function and increased mortality, but routine antiarrhythmic drug therapy to suppress these arrhythmias is not warranted. Treatment with the sodium channel blocker flecainide increased mortality. Amiodarone therapy reduces sudden death, but does not improve total mortality. Therefore, amiodarone is an option for treatment of symptomatic arrhythmias in this population when the potential benefit outweighs its potential toxicities. β-Adrenergic blockers reduce sudden death but have limited effect on spontaneous arrhythmias.


InternalMed_Harrison

InternalMed_Harrison. For survivors of an acute MI, an ICD reduces mortality in certain high-risk groups: patients who have survived >40 days after the acute MI and have a left ventricular (LV) ejection fraction of ≤0.30 or who have an ejection fraction <0.35 and have symptomatic heart failure (functional class II or III); and patients >5 days after MI who have a reduced LV ejection fraction, nonsustained VT, and inducible sustained VT or VF on electrophysiologic testing. ICDs do not reduce mortality when routinely implanted soon after MI or in patients after recent coronary artery revascularization surgery.


InternalMed_Harrison

InternalMed_Harrison. pvcs and nonsustainEd vt associatEd with dEprEssEd vEntricular function and hEart failurE PVCs and nonsustained VT are common in patients with depressed ventricular function and heart failure and are markers for disease severity and increased mortality, but antiarrhythmic drug therapy to suppress these arrhythmias has not been shown to improve survival. Antiarrhythmic drugs whose major action is blockade of the cardiac sodium channel (flecainide, propafenone, mexiletine, quinidine, and disopyramide) are avoided in patients with structural heart disease because of a


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InternalMed_Harrison. FIGURE 277-6 Precordial chest leads V1–V3 showing typical abnormalities of arrhyth-risk of proarrhythmia, negative inotropic effects, mogenic right ventricular cardiomyopathy (ARVC) (A) and Brugada syndrome (B). and increased mortality. Therapy with the potas-In ARVC, there is T inversion and delayed ventricular activation manifest as epsilon waves sium channel blockers, e.g., dofetilide, does not (arrows). Panel B shows ST elevation in V1 and V2 typical of the Brugada syndrome. (Figures reduce mortality. Amiodarone suppresses venreproduced from F Marchlinski: The tachyarrhythmias. In Longo DL et al [eds]: Harrison’s tricular ectopy and reduces sudden death but does Principles of Internal Medicine, 18th edition. New York, McGraw-Hill, 2012, pp 1878–1900.) not improve overall survival. ICDs are the major 1494 therapy to protect against sudden death in patients at high risk and are recommended for those with LV ejection fraction <0.35 and New York Heart Association class II and III


InternalMed_Harrison

InternalMed_Harrison. ICDs are the major 1494 therapy to protect against sudden death in patients at high risk and are recommended for those with LV ejection fraction <0.35 and New York Heart Association class II and III heart failure, in whom they reduce mortality by 20%, from 36% to 29%, over 5 years.


InternalMed_Harrison

InternalMed_Harrison. othEr cardiac disEasEs Ventricular ectopy is associated with increased mortality in patients with hypertrophic cardiomyopathy (Chap. 287) or with congenital heart disease (Chap. 282) associated with right ventricular or LV dysfunction. In these patients, management is similar to that for patients with ventricular dysfunction. Pharmacologic suppression of the arrhythmia has not been shown to improve mortality. ICDs are indicated for patients considered at high risk for sudden cardiac death.


InternalMed_Harrison

InternalMed_Harrison. pvc-inducEd vEntricular dysfunction Very frequent ventricular ectopy and repetitive nonsustained VT (Fig. 277-2) can depress ventricular function, possibly through an effect similar to chronic tachycardia or by inducing ventricular dyssynchrony. Depression of ventricular function rarely occurs unless PVCs account for more than 10–20% of total beats over a 24-h period. Often the PVCs are idiopathic and unifocal, most commonly originating from the LV papillary muscles or outflow tract regions where they can be targeted for ablation. The distinction between PVC-induced ventricular dysfunction as compared to a cardiomyopathic process causing ventricular dysfunction and arrhythmia is difficult and in some cases can be made only retrospectively by observing an improvement in ventricular function after the arrhythmia is suppressed with an antiarrhythmic drug, such as amiodarone, or by catheter ablation.


InternalMed_Harrison

InternalMed_Harrison. Idioventricular Rhythms Three or more ventricular beats at a rate slower than 100 beats/min are termed idioventricular rhythm (Fig. 277-1C). Automaticity is the likely mechanism. Idioventricular rhythms are common during acute MI (Chap. 295) and may emerge during sinus bradycardia. Atropine may be administered to increase the sinus rates if the loss of atrioventricular synchrony leads to hemodynamic compromise. This rhythm is also common in patients with cardiomyopathies or sleep apnea. It can also be idiopathic, often emerging when the sinus rate slows during sleep. Therapy should target any underlying cause and correction of bradycardia. Specific therapy for asymptomatic idioventricular rhythm is not necessary.


InternalMed_Harrison

InternalMed_Harrison. Sustained Monomorphic VT Sustained monomorphic VT presents as a wide QRS tachycardia that has the same QRS configuration from beat to beat, indicating an identical sequence of ventricular depolarization for each beat (Fig. 277-3A). VT originates from a stable focus or reentry circuit. In structural heart disease, the substrate is often an area of patchy replacement fibrosis due to infarction, inflammation, or prior cardiac surgery that creates anatomical or functional reentry pathways (Fig. 277-5). Less commonly, VT is related to reentry or automaticity in a diseased Purkinje system. In the absence of structural heart disease, idiopathic VT can present as sustained monomorphic VTs that are due to focal automaticity or reentry involving a portion of the Purkinje system.


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InternalMed_Harrison. The clinical presentation can vary depending on the rate of the arrhythmia, underlying cardiac function, and autonomic adaptation in response to the arrhythmia. Whereas patients with normal cardiac function might tolerate rapid VTs, those with severe LV dysfunction often experience symptoms of hypotension, even if VT is not particularly fast. Monomorphic VT may deteriorate to VF, which may be the initial cardiac rhythm recorded at the time of resuscitation.


InternalMed_Harrison

InternalMed_Harrison. diagnosis Sustained monomorphic VT has to be distinguished from other causes of uniform wide QRS tachycardia. These include supra-ventricular tachycardia with left or right bundle branch block aberrant conduction, supraventricular tachycardias conducted to the ventricles over an accessory pathway (Chap. 276), and rapid cardiac pacing in a patient with a pacemaker or defibrillator. In the presence of known heart disease, VT is the most likely diagnosis of a wide QRS tachycardia. Hemodynamic stability during the arrhythmia does not exclude VT. A number of ECG criteria have been evaluated. The presence of AV dissociation is usually a reliable marker for VT (Fig. 277-7), but P waves can be difficult to define. A P wave following each QRS does not VT versus Supraventricular Tachycardia with Aberrancy VT any of V1 toV6 Possible SVT with aberrancy VT still possible


InternalMed_Harrison

InternalMed_Harrison. VT versus Supraventricular Tachycardia with Aberrancy VT any of V1 toV6 Possible SVT with aberrancy VT still possible FIGURE 277-7 Algorithm for differentiation of ventricular tachycardia (VT) from supraventricular tachycardia (SVT) with aberration. AV, atrioventricular.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 277-7 Algorithm for differentiation of ventricular tachycardia (VT) from supraventricular tachycardia (SVT) with aberration. AV, atrioventricular. exclude VT because 1:1 conduction from ventricle to atrium can occur. A monophasic R wave or Rs complex in AVR or concordance from V1 to V6 of monophasic R or S waves is also relatively specific for VT (Fig. 277-7). Other QRS morphology criteria have also been described, but all have limitations and are not very reliable in patients with severe heart disease. In patients with known bundle branch block, the same QRS morphology during tachycardia as during sinus rhythm suggests supraventricular tachycardia rather than VT, but is not absolutely reliable. An electrophysiologic study is sometimes required for definitive diagnosis. Rarely, noise and movement artifacts on telemetry recordings can simulate VT; prompt recognition can avoid unnecessary tests and interventions.


InternalMed_Harrison

InternalMed_Harrison. When LV function is depressed or there is evidence of structural myocardial disease, scar-related reentry is the most likely diagnosis. Scars are suggested by pathologic Q waves on the ECG, segmental left or right ventricular wall motion abnormalities on echocardiogram or nuclear imaging, and areas of delayed gadolinium enhancement during MRI (Fig. 277-5).


InternalMed_Harrison

InternalMed_Harrison. trEatmEnt and prognosis Initial management follows Advanced Cardiac Life Support (ACLS) guidelines. If hypotension, impaired consciousness, or pulmonary edema is present, QRS synchronous electrical cardioversion should be performed, ideally after sedation if the patient is conscious. For stable tachycardia, a trial of adenosine is reasonable, as this may clarify a supraventricular tachycardia with aberrancy (Chap. 276). Intravenous amiodarone is the drug of choice if heart disease is present. Following restoration of sinus rhythm, hospitalization and evaluation to define underlying heart disease are required. Assessment of cardiac biomarkers for evidence of MI is appropriate, but acute MI is rarely a cause of sustained monomorphic VT, and elevations in troponin or creatine kinase (CK)-MB are more likely to indicate myocardial damage that is secondary to hypotension and ischemia from the VT. Subsequent management is determined by the underlying heart disease and frequency of VT. If VT


InternalMed_Harrison

InternalMed_Harrison. are more likely to indicate myocardial damage that is secondary to hypotension and ischemia from the VT. Subsequent management is determined by the underlying heart disease and frequency of VT. If VT recurs frequently or is incessant, administration of antiarrhythmic medications or catheter ablation may be required to restore stability. More commonly, sustained monomorphic VT occurs as an isolated episode, but with a risk of recurrence. ICDs are usually considered for VT associated with structural heart disease.


InternalMed_Harrison

InternalMed_Harrison. Patients who present with sustained VT associated with coronary artery disease typically have a history of prior large MI and present years after the acute infarct with a remodeled ventricle and markedly depressed LV function. Even when there is biomarker evidence of acute MI, a preexisting scar from previous MI should be suspected as the cause of the VT. Infarct scars provide a durable substrate for sustained VT, and up to 70% of patients have a recurrence of the arrhythmia within 2 years. Scar-related reentry is not dependent on recurrent acute myocardial ischemia, so coronary revascularization cannot be anticipated to prevent recurrent VT, even when it may be appropriate for other indications. Depressed ventricular function, which is a risk factor for sudden death, is usually present. Implantation of an ICD is warranted for most patients provided that there is a reasonable expectation of survival with acceptable functional status for the next year after recovery from the VT


InternalMed_Harrison

InternalMed_Harrison. Implantation of an ICD is warranted for most patients provided that there is a reasonable expectation of survival with acceptable functional status for the next year after recovery from the VT episode. ICDs reduce annual mortality from 12.3% to 8.8% and lower arrhythmic deaths by 50% in patients with hemodynamically significant sustained VT or a history of cardiac arrest compared with pharmacologic therapy. Chronic amiodarone therapy may be considered for patients who are not candidates for or who decline ICD placement.


InternalMed_Harrison

InternalMed_Harrison. Following ICD implantation, patients remain at risk for heart failure, recurrent ischemic events, and recurrent VT, with a 5-year mortality that exceeds 30%. Attention to therapies with survival benefit, including β-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and statins, is important. Patients with frequent symptomatic recurrences of VT require antiarrhythmic drug therapy or catheter ablation.


InternalMed_Harrison

InternalMed_Harrison. nonischEmic dilatEd cardiomyopathy Sustained monomorphic VT associated with nonischemic cardiomyopathy is usually due to scar-related reentry. The etiology of scar is often unclear, but progressive replacement fibrosis is the likely cause. On cardiac MRI, scars are detectable as areas of delayed gadolinium enhancement and are more often intramural or subepicardial in location as compared with patients with prior MI. Scars that cause VT are often located adjacent to a valve annulus and can occur in either ventricle. Any cardiomyopathic process can cause scars and VT, but cardiac sarcoidosis (Chap. 390) and Chagas’ disease (Chap. 252) are particularly associated with monomorphic VT (Table 277-2). An ICD is usually indicated with additional drugs or ablation for control of recurrent VT.


InternalMed_Harrison

InternalMed_Harrison. monomorphic vt in arvc ARVC (Chap. 287) is a rare genetic disorder most commonly due to mutations in genes encoding for cardiac desmosomal proteins. Approximately 50% have a familial transmission with autosomal dominant inheritance. A less common, autosomal recessive form is associated with cardiocutaneous syndromes that include Naxos disease and Carvajal syndrome. Patients typically present between the second and fifth decade with palpitations, syncope, or cardiac arrest owing to sustained monomorphic VT, although polymorphic VT can also occur. Fibrosis and fibro-fatty replacement most commonly involve the right ventricular myocardium and provide the substrate for reentrant VT that usually has a left bundle branch block–like configuration, consistent with the right ventricular origin. The sinus rhythm ECG suggests the disease in more than 85% of patients, most often showing T-wave inversions in V1–V3 (Fig. 277-6). Delayed activation of the right ventricle may cause a widened QRS


InternalMed_Harrison

InternalMed_Harrison. The sinus rhythm ECG suggests the disease in more than 85% of patients, most often showing T-wave inversions in V1–V3 (Fig. 277-6). Delayed activation of the right ventricle may cause a widened QRS (≥110 ms) in the right precordial leads and a prolonged S-wave upstroke in those leads, and occasionally a deflection at the end of the QRS known as an epsilon wave (Fig. 277-6). Cardiac imaging may show right ventricular enlargement or areas of abnormal motion or reveal areas of scar on CMR imaging with gadolinium. The monomorphic VT of early ARVC can sometimes be difficult to differentiate from idiopathic right ventricular outflow tract VT.


InternalMed_Harrison

InternalMed_Harrison. LV involvement can occur and occasionally precede manifest right ventricular disease. Heart failure is rare except in late stages, and survival to advanced age can be anticipated provided that VT can be controlled. An ICD is recommended. When VT is exercise-induced, it may respond to β-adrenergic blockers and limiting exercise. Sotalol, amiodarone, and catheter ablation have been used to reduce recurrences. Ablation targets are often located in the subepicardium of the RV. tEtralogy of fallot VT occurs in 3–14% of patients late after repair of tetralogy of Fallot (Chap. 282) and contributes to a 2% per decade risk of I. Idiopathic VT without structural heart disease A. Outflow tract origin 1. RV outflow tract: left bundle branch block pattern with inferior axis (tall QRS in inferior leads) and late transition in the precordial leads 2. LV outflow tract: prominent R in V1 with inferior axis


InternalMed_Harrison

InternalMed_Harrison. LV outflow tract: prominent R in V1 with inferior axis B. Left posterior fascicular VT 1. Right bundle branch block pattern with left axis deviation (most common) II. A. Monomorphic VT is common with prior large myocardial infarction B. III. A. Polymorphic VT and VF more common but fibrotic scars can cause monomorphic VT especially with sarcoidosis and Chagas’ disease IV. A. Monomorphic VT usually of right ventricular origin (left bundle branch morphology) B. Polymorphic VT and VF can occur independently or through degeneration of monomorphic VT V. Repaired tetralogy of Fallot A. Monomorphic VT of right ventricular origin (usually left bundle branch morphology) VI. A. B. Less commonly, monomorphic VT associated with myocardial scars VIII. A. Long QT syndrome: torsade de pointes VT B. Brugada syndrome: VF C. Catecholaminergic polymorphic VT: polymorphic VT or bidirectional VT D. Short QT syndrome: ventricular fibrillation E.


InternalMed_Harrison

InternalMed_Harrison. A. Long QT syndrome: torsade de pointes VT B. Brugada syndrome: VF C. Catecholaminergic polymorphic VT: polymorphic VT or bidirectional VT D. Short QT syndrome: ventricular fibrillation E. Early repolarization syndrome: polymorphic VT or VF Abbreviation: RV, right ventricle. See text for other abbreviations. sudden death. Monomorphic VT is due to reentry around areas of surgically created scar in the RV (Table 277-2). Factors associated with VT risk include age >5 years at the time of repair, high-grade ventricular ectopy, inducible VT on an electrophysiologic study, abnormal right ventricular hemodynamics, and sinus rhythm QRS duration >180 ms. An ICD is usually warranted for patients who have a spontaneous episode of VT, but criteria for a prophylactic ICD in other patients have not been established. Catheter ablation is used to control recurrent episodes.


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InternalMed_Harrison. BundlE Branch rEEntry vt Reentry through the Purkinje system occurs in approximately 5% of patients with monomorphic VT in the presence of structural heart disease. The reentry circuit typically revolves retrograde via the left bundle and anterograde down the right bundle, thereby producing VT that has a left bundle branch block configuration. Catheter ablation of the right bundle branch abolishes this VT. Bundle branch reentry is usually associated with severe underlying heart disease. Other scar-related VTs are often present and often require additional therapy or ICD implantation.


InternalMed_Harrison

InternalMed_Harrison. idiopathic monomorphic vt Idiopathic VT in patients without structural heart disease usually presents with palpitations, lightheadedness, and occasionally syncope, often provoked by sympathetic stimulation during exercise or emotional upset. The QRS morphology of the arrhythmia suggests the diagnosis (see below). The sinus rhythm ECG is normal. Cardiac imaging shows normal ventricular function and no evidence of ventricular scar. Occasionally a patient with structural heart disease is found to have concomitant idiopathic VT, unrelated to the structural disease. Sudden death is rare. Outflow tract VTs originate from a focus, usually with features consistent with triggered automaticity. The arrhythmia may present with 1. Congenital long QT syndromes (see text for details) Long QT syndrome type 1: Reduced repolarizing current IKs due to mutation in KCNQ1 gene Long QT syndrome type 2: Reduced repolarizing current IKr due to mutation in KCNH2 gene


InternalMed_Harrison

InternalMed_Harrison. Long QT syndrome type 1: Reduced repolarizing current IKs due to mutation in KCNQ1 gene Long QT syndrome type 2: Reduced repolarizing current IKr due to mutation in KCNH2 gene Long QT syndrome type 3: Delayed inactivation of the INa due to mutations in SCN5A gene Others: Several other types of long QT syndromes have been described; long QT types 1, 2, and 3 account for 80–90% of cases 2. Acquired prolongation of QT interval Class IA: Quinidine, disopyramide, procainamide Class III: Sotalol, amiodarone (QT prolongation common but torsade ventricular tachycardia is rare), ibutilide, dofetilide, almokalant Macrolides: Erythromycin, clarithromycin, azithromycin Fluoroquinolones: Levofloxacin, moxifloxacin, gatifloxacin Antifungals: Ketoconazole, itraconazole Antivirals: Amantadine


InternalMed_Harrison

InternalMed_Harrison. Haloperidol, phenothiazines, thioridazine, trifluoperazine, sertindole, zimelidine, ziprasidone Tricyclic and tetracyclic antidepressants sustained VT, nonsustained VT, or PVCs often provoked by exercise or emotional upset. Repeated bursts of nonsustained VTs, which may occur incessantly, are known as repetitive monomorphic VTs and can cause tachycardia-induced cardiomyopathy with depressed ventricular function that recovers after suppression of the arrhythmia (Fig. 277-2). Most originate in the right ventricular outflow tract, which gives rise to VT that has a left bundle branch block configuration in V1 and an axis that is directed inferiorly, with tall R waves in leads II, III, and AVF (Fig. 277-2). Idiopathic VT can also arise in the LV outflow tract or in sleeves of myocardium that extend along the aortic root. LV origin is suspected when lead V1 or V2 has prominent R waves. Although this typical outflow tract QRS morphology favors idiopathic VT, some cardiomyopathies, notably


InternalMed_Harrison

InternalMed_Harrison. extend along the aortic root. LV origin is suspected when lead V1 or V2 has prominent R waves. Although this typical outflow tract QRS morphology favors idiopathic VT, some cardiomyopathies, notably ARVC, can cause PVCs or VT from this region. Excluding these diseases is an initial focus of evaluation.


InternalMed_Harrison

InternalMed_Harrison. LV intrafascicular VT presents with sustained VT that has a right bundle branch block–like configuration. It is often exercise-induced and occurs more often in men than women. The mechanism is reentry in or near the septal ramifications of the LV Purkinje system. This VT can be terminated by intravenous administration of verapamil. managEmEnt of idiopathic vt Treatment is required for symptoms or when frequent or incessant arrhythmias depress ventricular function. β-Adrenergic blockers are first-line therapy. Nondihydropyridine calcium channel blockers (diltiazem and verapamil) are sometimes effective. Catheter ablation is warranted for severe symptoms or when beta blockers or calcium channel blockers are not effective or not desired. Efficacy and risks of catheter ablation vary with the specific site of origin of the VT, being most favorable for arrhythmias originating in the right ventricular outflow tract.


InternalMed_Harrison

InternalMed_Harrison. LV fascicular VT can be terminated by intravenous administration of verapamil, although chronic therapy with oral verapamil is not Terfenadine, astemizole, diphenhydramine, hydroxyzine Cholinergic antagonists: Cisapride, organophosphates Citrate (massive blood transfusions) Cocaine Methadone Fluoxetine (in conjunction with other drugs that prolong QT) Cardiac conditions always effective. Catheter ablation is recommended if β-adrenergic blockers or calcium channel blockers are ineffective or not desired.


InternalMed_Harrison

InternalMed_Harrison. Polymorphic VT Sustained polymorphic VT can be seen with any form of structural heart disease (Table 277-2). However, unlike sustained monomorphic VT, polymorphic VT does not always indicate a structural abnormality or focus of automaticity. Reentry with continually changing reentrant paths, spiral wave reentry, and multiple automatic foci are potential mechanisms (Chap. 278e). Sustained polymorphic VT usually degenerates into VF. Polymorphic VT is typically seen in association with acute MI or myocardial ischemia, ventricular hypertrophy, and a number of genetic mutations that affect cardiac ion channels (Table 277-3).


InternalMed_Harrison

InternalMed_Harrison. polymorphic vt associatEd with acutE mi/myocardial ischEmia Acute MI or ischemia is a common cause of polymorphic VT and should be the initial consideration in management. Approximately 10% of patients with acute MI develop VT that degenerates to VF, related to reentry through the infarct border zone. The risk is greatest in the first hour of acute MI. Following resuscitation as per the ACLS guidelines, management is as for acute MI (Chap. 295). β-Adrenergic blockers, correction of electrolyte abnormalities, and prompt myocardial reperfusion are required. Repeated episodes of polymorphic VT suggest ongoing myocardial ischemia and warrant assessment of adequacy of myocardial reperfusion. Polymorphic VT and VF that occur within the first 48 h of acute MI are associated with greater in-hospital mortality, but those who survive past hospital discharge are not at increased risk for arrhythmic sudden death. Long-term therapy for postinfarct ventricular arrhythmia is determined by residual


InternalMed_Harrison

InternalMed_Harrison. mortality, but those who survive past hospital discharge are not at increased risk for arrhythmic sudden death. Long-term therapy for postinfarct ventricular arrhythmia is determined by residual LV function, with an ICD being indicated for persistent severe LV dysfunction (LV ejection fraction <0.35).


InternalMed_Harrison

InternalMed_Harrison. congenital long Qt syndrome The con-1497 genital long QT syndrome (LQTS) is caused by mutations in genes coding for cardiac ion channels responsible for ventricular repolarization. The corrected QT (QTc) is typically prolonged to greater than 440 ms in men and 460 ms in women. Symptoms are due to Torsade de Pointes VT (Fig. 277-8). Several forms of congenital LQTS have been identified, but three groups of mutations that lead to LQTS type 1 (LQTS-1), LQTS type 2 (LQTS-2), or LQTS type 3 (LQTS-3) account for A 90% of cases. The most frequently encountered mutations, LQTS1 and LQTS2, are due to abnormalities of potassium channels, but mutations affecting the sodium channel (LQTS3) and calcium channels have also been described (Table 277-3).


InternalMed_Harrison

InternalMed_Harrison. Patients often present with syncope or cardiac arrest, usually during childhood. In LQTS-1, episodes tend to occur during exertion, particularly swimming. In LQTS-2, sudden auditory stimuli or emotional upset predispose to events. In LQTS-3, sudden death during sleep is a notable feature. FIGURE 277-8 Electrocardiogram (ECG) of a patient with prolonged QT and episodes of torsade de pointes ventricular tachycardia (VT). A. Twelve-lead ECG showing a heart rate of 54, anterior ered in the course of family screening wall T inversion, and QT interval of 600 ms. The corrected QT interval (QTc) is 585 ms. B. Telemetry or on a routine ECG. Genotyping can


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InternalMed_Harrison. ECG tracing with digital pulse waveform demonstrating bursts of torsade de pointes VT. The initiating sequence of the VT is characteristic, with a PVC inducing a pause followed by a sinus beat that had a to provide reassurance regarding the longer QT and interruption of the T wave by a PVC that is the first beat of VT. The VT is self-terminat diagnosis. Correlations of genotype ing in this case.


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InternalMed_Harrison. RepolaRization abnoRmalities and genetic aRRhythmia syndRomes • acquired long Qt Abnormal prolongation of the QT interval is associated with the polymorphic VT Torsade de Pointes (Fig. 277-8). The VT often has a characteristic initiation sequence of a premature ventricular beat that induces a pause, followed by a sinus beat that has a longer QT interval and interruption of the T wave by the PVC that is the first beat of the polymorphic VT. This characteristic initiation is termed “pause-dependent” (Fig. 277-8). Causes of QT prolongation include electrolyte abnormalities, bradycardia, and a number of medications that block repolarizing potassium currents, notably the antiarrhythmic drugs sotalol, dofetilide, and ibutilide, but also a number of other medications used for noncardiac diseases, including erythromycin, pentamidine, haloperidol, phenothiazines, and methadone (Table 2773). Individual susceptibility may be related to genetic polymorphisms or mutations that influence


InternalMed_Harrison

InternalMed_Harrison. diseases, including erythromycin, pentamidine, haloperidol, phenothiazines, and methadone (Table 2773). Individual susceptibility may be related to genetic polymorphisms or mutations that influence repolarization.


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InternalMed_Harrison. Patients typically present with near-syncope, syncope, or cardiac arrest. Sustained episodes degenerate to VF requiring defibrillation. PVCs and nonsustained VT often precede episodes of sustained VT. Intravenous administration of 1–2 g of magnesium sulphate usually suppresses recurrent episodes. If magnesium alone is ineffective, increasing heart rate with isoproterenol infusion or pacing, to a rate of 100–120 beats/min as required to suppress PVCs, usually suppresses VT recurrences. These maneuvers allow time for correction of associated electrolyte disturbance (hypokalemia and hypocalcemia) and bradycardia and removal of any causative drugs (Table 277-3). Drug interactions that elevate levels of the offending agent are often a precipitating factor. Patients who experience a polymorphic VT induced by QT prolongation should be considered to have a susceptibility to the arrhythmia and should avoid all future exposure to medications known to prolong the QT interval.


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InternalMed_Harrison. with risk and response to therapy are beginning to emerge. In most patients with LQTS-1 or LQTS-2, adequate doses of beta blocker therapy (the non-selective agents nadolol or propranolol) are sufficient protection from arrhythmia episodes. Markers of increased risk include QTc interval exceeding 0.5 s, female gender, and a history of syncope or cardiac arrest. Recurrent syncope despite beta blocker therapy or a high-risk profile merits consideration of an ICD. Avoidance of QT-prolonging drugs is critical for all patients with LQTS, including those who are genotype positive but have normal QT intervals. short Qt syndrome Short QT syndrome is very rare compared to LQTS. The QTc is shorter than 0.36 s, and usually less than 0.3 s. The genetic abnormality causes a gain of function of the potassium channel (I Kr) or reduced inward depolarizing currents. The abnormality is associated with atrial fibrillation, polymorphic VT, and sudden death.


InternalMed_Harrison

InternalMed_Harrison. Brugada syndrome Brugada syndrome is a rare syndrome characterized by >0.2 mV of ST-segment elevation with a coved ST segment and negative T wave in more than one anterior precordial lead (V1–V3) (Fig. 277-6) and episodes of syncope or cardiac arrest due to polymorphic VT in the absence of structural heart disease. Cardiac arrest may occur during sleep or be provoked by febrile illness. Males are more commonly affected than females. Mutations involving cardiac sodium channels are identified in approximately 25% of cases. Distinction from patients with similar ST elevation owing to LV hypertrophy, pericarditis, myocardial ischemia or MI hyperkalemia, hypothermia, right bundle branch block, and ARVC is often difficult. Furthermore, the characteristic ST-segment elevation can wax and wane over time and may become pronounced during acute illness and fever. Administration of the sodium channel blocking drug flecainide, ajmaline, or procainamide can augment or unmask ST elevation in


InternalMed_Harrison

InternalMed_Harrison. wane over time and may become pronounced during acute illness and fever. Administration of the sodium channel blocking drug flecainide, ajmaline, or procainamide can augment or unmask ST elevation in affected individuals. An ICD is indicated for individuals who have had unexplained syncope or been resuscitated from cardiac arrest.


InternalMed_Harrison

InternalMed_Harrison. 1498 Quinidine has been used successfully to suppress frequent episodes of VT. Early repolarization syndrome Patients resuscitated from VF who have no structural heart disease or other identified abnormality have a higher prevalence of J-point elevation with notching in the terminal QRS. A family history of sudden death is present in some patients, suggesting a potential genetic basis. J-point elevation is also seen in some patients with the Brugada syndrome and associated with a higher risk of arrhythmias. An ICD is recommended for those who have had prior cardiac arrest. It should be noted that J-point elevation is commonly seen as a normal variant, and in the absence of specific symptoms, the clinical relevance is not known.


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InternalMed_Harrison. catecholaminergic polymorphic vt This rare familial syndrome is due to mutations in the cardiac ryanodine receptor and, less commonly, the sarcoplasmic calcium binding protein, calsequestin 2. These mutations result in abnormal sarcoplasmic calcium handling and polymorphic ventricular arrhythmias that resemble those seen with digitalis toxicity. The VT is polymorphic or has a characteristic alternating QRS morphology termed bidirectional VT. Patients usually present during childhood with exerciseor emotion-induced palpitations, syncope, or cardiac arrest. β-Adrenergic blockers (e.g., nadolol and propranolol) and an ICD are recommended. Verapamil, flecainide, or surgical left cardiac sympathetic denervation reduces or prevents recurrent VT in some patients.


InternalMed_Harrison

InternalMed_Harrison. hypertrophic cardiomyopathy (hcm) HCM is the most common genetic cardiovascular disorder, occurring in 1 in 500 individuals, and is a prominent cause of sudden death before the age of 35 years (Chap. 287). Sudden death can be due to polymorphic VT/VF. Rarely, sustained monomorphic VT occurs related to areas of ventricular scar. Risk factors include young age, nonsustained VT, failure of blood pressure to increase during exercise, recent (within 6 months) syncope, ventricular wall thickness >3 cm, and possibly the severity of LV outflow obstruction. An ICD is generally indicated for high-risk patients, but the specific risk profile warranting an ICD continues to be debated. Surgical myectomy, performed to relieve outflow obstruction, has been associated with a sudden death rate of less than 1% per year. The reported annual rate of sustained VT or sudden death after transcoronary ethanol septal ablation done to relieve outflow obstruction has been reported to range between 1 and 5%.


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InternalMed_Harrison. genetic dilated cardiomyopathies Genetic dilated cardiomyopathies account for 30–40% of cases of nonischemic dilated cardiomyopathies. Some are associated with muscular dystrophy. Autosomal dominant, recessive, X-linked, and mitochondrial inheritance patterns are recognized. Mutations in genes coding for structural proteins of the nuclear lamina (lamin A and C) and the SCN5A gene are particularly associated with conduction system disease and ventricular arrhythmias. Patients can experience polymorphic VT and cardiac arrest or develop areas of scar causing sustained monomorphic VT. ICDs are recommended for those who have had a sustained VT or are at high risk due to significantly depressed ventricular function (LV ejection fraction of ≤0.35 and associated with heart failure) or a malignant family history of sudden death.


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InternalMed_Harrison. Ventricular Fibrillation VF is characterized by disordered electrical ventricular activation without identifiable QRS complexes (Fig. 2773E). Spiral wave reentry and multiple circulating reentry wavefronts are possible mechanisms. Sustained polymorphic or monomorphic VT that degenerates to VF is a common cause of out-of-hospital cardiac arrest. Treatment follows ACLS guidelines with defibrillation to restore sinus rhythm. If resuscitation is successful, further evaluation is performed to identify and treat underlying heart disease and potential causes of the arrhythmia, including the possibility that monomorphic or polymorphic VT could have initiated VF. If a transient reversible cause such as acute MI is not identified, therapy to reduce the risk of sudden death with an ICD is often warranted. Chronic amiodarone therapy may be considered for individuals who are not ICD candidates.


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InternalMed_Harrison. Incessant VT and Electrical Storm VT is incessant when it continues to recur shortly after electrical, pharmacologic, or spontaneous conversion to sinus rhythm. “VT storm” or “electrical storm” refers to three or more separate episodes of VT within 24 h, most commonly encountered in patients with ICDs. Slow incessant VT is sometimes asymptomatic, but can cause heart failure or tachycardia-induced cardiomyopathy. More commonly, these presentations are life-threatening and require emergent therapy. Measures to reduce sympathetic tone, including β-adrenergic blockade, sedation, and general anesthesia, have been used effectively. Intravenous administration of amiodarone and lidocaine can be effective for suppression. Urgent catheter ablation can be lifesaving.


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InternalMed_Harrison. Use of antiarrhythmic drugs is based on consideration of the risks and potential benefit for the individual patient. The potential to increase the frequency of VT or cause a new VT, an undesirable effect known as “proarrhythmia,” is a potential risk. Many drugs have multiple effects, often blocking more than one channel. Drug doses, metabolism, and adverse effects are summarized in Chap. 277. β-Adrenergic Blockers Many ventricular arrhythmias are sensitive to sympathetic stimulation, and β-adrenergic stimulation also diminishes the electrophysiologic effects of many antiarrhythmic drugs. The safety of β-blocking agents makes them the first choice of therapy for most ventricular arrhythmias. They are particularly useful for exercise-induced arrhythmias and idiopathic arrhythmias, but have limited efficacy for most arrhythmias associated with heart disease. Bradyarrhythmias are the major cardiac toxicity.


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InternalMed_Harrison. Calcium Channel Blockers The nondihydropyridine calcium channel blockers diltiazem and verapamil can be effective for some idiopathic VTs. The risk of proarrhythmia is low, but they have negative inotropic and vasodilatory effects that can aggravate hypotension.


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InternalMed_Harrison. Sodium Channel-Blocking Agents Drugs whose major effect is mediated through sodium channel blockade include mexiletine, quinidine, disopyramide, flecainide, and propafenone, which are available for chronic oral therapy (Table 277-3). Lidocaine, quinidine, and procainamide are available as intravenous formulations. Quinidine, disopyramide, and procainamide also have potassium channel-blocking effects that prolong the QT interval. These agents have potential proarrhythmic effects and, with the possible exception of quinidine, also have negative inotropic effects that may contribute to increased mortality observed in patients with prior MI. Long-term therapy is generally avoided in patients with structural heart disease but may be used to reduce symptomatic arrhythmias in patients with ICDs.


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InternalMed_Harrison. Potassium Channel-Blocking Agents Sotalol and dofetilide block the delayed rectifier potassium channel IKr, thereby prolonging the QT interval. Sotalol also has nonselective β-adrenergic blocking activity. It has a modest effect on reducing ICD shocks due to ventricular and atrial arrhythmias. Proarrhythmia with Torsade de Pointes due to QT prolongation occurs in 3–5% of patients. Both sotalol and dofetilide are excreted via the kidneys, necessitating dose adjustment or avoidance in renal insufficiency. These drugs must be avoided in patients with other risk factors for Torsade de Pointes, including QT prolongation, hypokalemia, and significant bradycardia.


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InternalMed_Harrison. Amiodarone and Dronedarone Amiodarone, which blocks multiple cardiac ionic currents and has sympatholytic activity, suppresses a variety of ventricular arrhythmias. It is administered intravenously for life-threatening arrhythmias. During chronic oral therapy, electrophysiologic effects develop over several days. It is more effective than sotalol in reducing ICD shocks and is the preferred drug for ventricular arrhythmias in patients with heart disease who are not candidates for an ICD. Bradyarrhythmias are the major cardiac adverse effect. Ventricular proarrhythmia can occur, but Torsade de Pointes VT is rare. Noncardiac toxicities are a major problem and contribute to drug discontinuation in approximately a third of patients during long-term therapy. Pneumonitis or pulmonary fibrosis occurs in approximately 1% of patients. Photosensitivity is common, and neuropathy and ocular toxicity can occur. Systematic monitoring is recommended during chronic therapy, including assessment for


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InternalMed_Harrison. occurs in approximately 1% of patients. Photosensitivity is common, and neuropathy and ocular toxicity can occur. Systematic monitoring is recommended during chronic therapy, including assessment for thyroid and liver toxicity every 6 months and lung toxicity with a chest radiograph and/or determination of lung diffusing capacity annually. Dronedarone has structural similarities to amiodarone but without the iodine moiety. Efficacy for ventricular arrhythmias is poor, and it increases mortality in patients with heart failure.


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InternalMed_Harrison. ICDs are highly effective for termination of VT and VF and also provide bradycardia pacing. ICDs decrease mortality in patients at risk for sudden death due to structural heart diseases. In all cases, ICDs are recommended only if there is also expectation for survival of at least a year with acceptable functional capacity. The exception is in cases of patients with end-stage heart disease who are awaiting cardiac transplantation outside the hospital, or who have left bundle branch block QRS prolongation such that they are likely to have improvement in ventricular function with cardiac resynchronization therapy from a biventricular ICD.


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InternalMed_Harrison. ICDs can often terminate monomorphic VT by a burst of rapid pacing faster than the VT, known as antitachycardia pacing (ATP) (Fig. 277-9A). If ATP fails or is not a programmed treatment, as is often the case for rapid VT or VF, a shock is delivered (Fig. 277-9B). Shocks are painful if the patient is conscious. The most common ICD complication is the delivery of unnecessary therapy (either ATP or shocks) in response to a rapid supraventricular tachycardia or electrical noise as a result of an ICD lead fracture. Interrogation of 1499 the ICD, which can be performed remotely and communicated via Internet, is critical after an ICD shock to determine the arrhythmia diagnosis and exclude an unnecessary therapy. Device infection occurs in approximately 1% of patients.


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InternalMed_Harrison. Despite prompt termination of VT or VF by an ICD, the occurrence of these arrhythmias predicts subsequent increased mortality and risk of heart failure. Occurrence of VT or VF should therefore prompt assessment for potential causes including worsening heart failure, electrolyte abnormalities, and ischemia. Repeated shocks, even if appropriate, often induce posttraumatic stress disorder. Antiarrhythmic drugs mostly in the form of amiodarone or catheter ablation are often required for suppression of recurrent arrhythmias. Antiarrhythmic drug therapy can alter the VT rate and the energy required for defibrillation, thereby necessitating programming changes in the ICD’s algorithms for detection and therapy.


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InternalMed_Harrison. Catheter ablation is performed by guiding an electrode catheter to the arrhythmia origin and producing a thermal injury with radiofrequency current. The size and location of the arrhythmia substrate determine the ease and likely effectiveness of the procedure, as well as potential complications. The most common complications, which occur in <5% of patients, are related to vascular access, including bleeding, femoral hematomas, arteriovenous fistulae, and pseudoaneurysms. Catheter ablation is a reasonable first-line therapy for many patients with symptomatic idiopathic VTs. Success rates for those originating from a focus in the right ventricular outflow tract are in the range of 80–90% but lower for idiopathic VTs arising in less common locations such as from the LV outflow tract or aortic root, along the atrioventricular valve annuli, and from the papillary muscles. Failure of ablation is often due to inability to induce the


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InternalMed_Harrison. FIGURE 277-9 Implantable cardioverter-defibrillator (ICD) and therapies for ventricular arrhythmias. A. A monomorphic ventricular tachycardia (VT) is terminated by a burst of pacing impulses at a rate faster than VT (antitachycardia pacing). B. A rapid VT is converted with a high-voltage shock (arrow). The chest x-ray in panel C shows the components of an ICD capable of biventricular pacing. ICD generator in the subcutaneous tissue of the left upper chest, pacing leads in the right atrium and the left ventricular (LV) branch of the coronary sinus (LV lead), and a pacing/defibrillating lead in the right ventricle (RV lead) are shown.


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InternalMed_Harrison. 1500 arrhythmia for precise localization or because the origin of the VT is from a site that is inaccessible or in close proximity to a coronary artery. Complications are infrequent but can include perforation with cardiac tamponade, atrioventricular block due to injury to the conduction system, and coronary artery injury for foci in proximity to a coronary vessel. In patients with scar-related VT due to prior infarction or cardiomyopathy, ablation targets abnormal regions in the scar. Because these scars often contain multiple reentry circuits over relatively large regions, extensive areas of ablation are required, and these areas are often identified as regions of low voltage displayed on anatomic reconstructions of the ventricle (Fig. 277-5). If the circuits are not confined to the subendocardial scar, epicardial mapping and ablation can be performed via a subxiphoid pericardial puncture, similar to a pericardiocentesis. Epicardial mapping and ablation are often required for VTs


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InternalMed_Harrison. scar, epicardial mapping and ablation can be performed via a subxiphoid pericardial puncture, similar to a pericardiocentesis. Epicardial mapping and ablation are often required for VTs due to nonischemic cardiomyopathy, but also have potentially greater risks of bleeding, coronary injury, and post-procedure pericarditis, which is usually transient. For drug-refractory VT due to prior MI, ablation abolishes VT in approximately half of patients and reduces the frequency of VT in an additional 20%. More than one procedure is necessary in up to 30% of patients. Ablation can be lifesaving for patients with very frequent or incessant VT. Procedure-related mortality is in the range of 3%, with most mortality due to continued uncontrollable VT when the procedure fails. In nonischemic heart disease, the arrhythmia substrate locations are more variable and outcomes are less well defined. Catheter ablation can also be lifesaving for rare patients with recurrent polymorphic VT and VF that is


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InternalMed_Harrison. the arrhythmia substrate locations are more variable and outcomes are less well defined. Catheter ablation can also be lifesaving for rare patients with recurrent polymorphic VT and VF that is repeatedly initiated by a uniform PVC. The initiating ectopic beat often originates from the Purkinje system or the right ventricular outflow tract and can be targeted for ablation. When antiarrhythmic drug therapy and catheter ablation fail or are not options, surgical cryoablation, often combined with aneurysmectomy, can be effective therapy for recurrent VT due to prior MI and has also been used successfully in a few patients with nonischemic heart disease. Few centers now maintain the expertise for this therapy. Injection of absolute ethanol into the coronary arterial blood supply of the arrhythmia substrate has also been used for ablation in a small number of patients who have failed catheter ablation and drugs.


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InternalMed_Harrison. Patients with ventricular arrhythmias fall into three general groups. The first are those who have associated structural heart disease that must be detected. The risk of life-threatening arrhythmias causing sudden death is indicated by the nature of the arrhythmia—sustained (or causing cardiac arrest) or nonsustained, in which case the risk of life-threatening arrhythmias is assessed from the severity of the heart disease, usually the severity of ventricular dysfunction. ICDs provide the most protection from sudden arrhythmic death. The second group comprises those who do not have recognizable structural heart disease, but have a genetic syndrome associated with increased risk of sudden death. A family history of sudden death and abnormal electrocardiogram most frequently suggest the diagnosis. The third group includes individuals with benign idiopathic arrhythmias who may require therapy to control symptoms, but who are not at significant risk for life-threatening arrhythmias. The


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InternalMed_Harrison. The third group includes individuals with benign idiopathic arrhythmias who may require therapy to control symptoms, but who are not at significant risk for life-threatening arrhythmias. The appropriate recognition of these patients is facilitated by thoughtful application of ECG and cardiac imaging. High-risk individuals benefit from specialized care for consideration of ICDs, catheter ablation, and antiarrhythmic drug therapy.


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InternalMed_Harrison. Atlas of Cardiac Arrhythmias Ary L. Goldberger The electrocardiograms in this atlas supplement those illustrated in Chaps. 274 and 276. The interpretations emphasize findings of specific teaching value. All of the figures are adapted from cases in ECG Wave-Maven, Copyright 2003, Beth Israel Deaconess Medical Center, http://ecg .bidmc.harvard.edu. The abbreviations used in this chapter are as follows: CHAPTER 278e Atlas of Cardiac Arrhythmias Figure 278e-1 Respiratory sinus arrhythmia, a physiologic finding in a healthy young adult. The rate of the sinus pacemaker is relatively slow at the beginning of the strip during expiration, then accelerates during inspiration and slows again with expiration. Changes are due to cardiac vagal tone modulation with breathing. PART 10 Disorders of the Cardiovascular System


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System Figure 278e-2 Sinus tachycardia (110/min) with first-degree AV “block” (conduction delay) with PR interval = 0.28 s. The P wave is visible after the ST-T wave in V1−V3 and superimposed on the T wave in other leads. Atrial (nonsinus) tachycardias may produce a similar pattern, but the rate is usually faster. Figure 278e-3 Sinus rhythm (P wave rate about 60/min) with 2:1 AV (second-degree) block causing marked bradycardia (ventricular rate of about 30/min). LVH is also present, along with left atrial abnormality. Figure 278e-4 Sinus rhythm (P wave rate about 60/min) with 2:1 (second-degree) AV block yielding a ventricular (pulse) rate of about 30/min. Left atrial abnormality. RBBB with left anterior fascicular block. Possible inferior MI. CHAPTER 278e Atlas of Cardiac Arrhythmias


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InternalMed_Harrison. CHAPTER 278e Atlas of Cardiac Arrhythmias Figure 278e-5 Marked junctional bradycardia (25 beats/min). Rate is regular with a flat baseline between narrow QRS complexes, without evident P waves. Patient was on atenolol, with possible underlying sick sinus syndrome. The serum potassium was slightly elevated at 5.5 mEq/L. PART 10 Disorders of the Cardiovascular System Figure 278e-6 Sinus rhythm at a rate of 64/min (P wave rate) with third-degree (complete) AV block yielding an effective heart (pulse) rate of 40/min. The slow, narrow QRS complexes indicate an AV junctional escape pacemaker. Left atrial abnormality. Figure 278e-7 Sinus rhythm at a rate of 90/min with advanced second-degree AV block and possible transient complete heart block with Lyme carditis.


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InternalMed_Harrison. Figure 278e-7 Sinus rhythm at a rate of 90/min with advanced second-degree AV block and possible transient complete heart block with Lyme carditis. Figure 278e-8 Multifocal atrial tachycardia with varying P-wave morphologies and P-P intervals; right atrial overload with peaked P waves in II, III, and aVF (with vertical P-wave axis); superior QRS axis; slow R-wave progression with delayed transition in precordial leads in patient with severe chronic obstructive lung disease. Figure 278e-9 NSR in a patient with Parkinson’s disease. Tremor artifact, best seen in limb leads. This tremor artifact may sometimes be confused with atrial flutter/fibrillation. Borderline voltage criteria for LVH are present. CHAPTER 278e Atlas of Cardiac Arrhythmias PART 10 Disorders of the Cardiovascular System


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InternalMed_Harrison. CHAPTER 278e Atlas of Cardiac Arrhythmias PART 10 Disorders of the Cardiovascular System Figure 278e-10 Atrial tachycardia with atrial rate of about 200/min (note lead V1), 2:1 AV block (conduction), and one premature ventricular complex. Also present: LVH with intraventricular conduction delay and slow precordial R-wave progression (cannot rule out prior anterior MI). Figure 278e-11 Atrial tachycardia with 2:1 block. P-wave rate is about 150/min, with ventricular (QRS) rate of about 75/min. The nonconducted (“extra”) P waves just after the QRS complex are best seen in lead V1. Also, note incomplete RBBB and borderline QT prolongation. Figure 278e-12 Atrial tachycardia (180/min with 2:1 AV block [see lead V1]). LVH by precordial voltage and nonspecific ST-T changes. Slow R-wave progression (V1−V4) raises consideration of prior anterior MI.


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InternalMed_Harrison. Figure 278e-13 AV nodal reentrant tachycardia (AVNRT) at a rate of 150/min. Note subtle “pseudo” R waves in lead aVR due to retrograde atrial activation, which usually occurs nearly simultaneous with ventricles in AVNRT. Left-axis deviation consistent with left anterior fascicular block (hemiblock) is also present. CHAPTER 278e Atlas of Cardiac Arrhythmias PART 10 Disorders of the Cardiovascular System Figure 278e-14 Atrial flutter with 2:1 AV conduction. Note typical atrial flutter waves, partly hidden in the early ST segment, seen, for example, in leads II and V1. Figure 278e-15 Atrial flutter with atrial rate 300/min and variable (predominant 2:1 and 3:1) AV conduction. Typical flutter waves are best seen in lead II.


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InternalMed_Harrison. Figure 278e-15 Atrial flutter with atrial rate 300/min and variable (predominant 2:1 and 3:1) AV conduction. Typical flutter waves are best seen in lead II. Figure 278e-16 Wide complex tachycardia. Atrial flutter with 2:1 AV conduction (block) and LBBB, not to be mistaken for VT. Typical atrial flutter activity is clearly present in lead II, at a cycle rate of about 320/min, yielding an effective ventricular rate of about 160/min. Figure 278e-17 AF with LBBB. The ventricular rhythm is erratically irregular. Coarse fibrillatory waves are best seen in lead V1, with a typical LBBB pattern. CHAPTER 278e Atlas of Cardiac Arrhythmias PART 10 Disorders of the Cardiovascular System Figure 278e-18 AF with complete heart block and a junctional escape mechanism causing a slow regular ventricular response (45/ min). The QRS complexes show an intraventricular conduction delay with left-axis deviation and LVH. Q-T (U) prolongation is also present.


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InternalMed_Harrison. Figure 278e-19 AF with right-axis deviation and LVH. Tracing suggests biventricular hypertrophy in a patient with mitral stenosis and aortic valve disease. Figure 278e-20 WPW preexcitation pattern, with triad of short PR, wide QRS, and delta waves. Polarity of the delta waves (slightly positive in leads V1 and V2 and most positive in lead II and lateral chest leads) is consistent with a right-sided bypass tract. Figure 278e-21 AF in patient with the WPW syndrome and antegrade conduction down the bypass tract leading to a wide complex tachycardia. Rhythm is “irregularly irregular,” and rate is extremely rapid (about 230/min). Not all beats are preexcited. CHAPTER 278e Atlas of Cardiac Arrhythmias PART 10 Disorders of the Cardiovascular System Figure 278e-22 Accelerated idioventricular rhythm (AIVR) originating from the LV and accounting for RBBB morphology. ST elevations in the precordial leads from underlying acute MI.


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InternalMed_Harrison. Figure 278e-22 Accelerated idioventricular rhythm (AIVR) originating from the LV and accounting for RBBB morphology. ST elevations in the precordial leads from underlying acute MI. Figure 278e-23 Prolonged (0.60 s) QT interval in a patient with a hereditary long QT syndrome. CHAPTER 278e Atlas of Cardiac Arrhythmias Figure 278e-24 Monomorphic VT at rate of 170/min. The RBBB morphology in V1 and the R:S ratio <1 in V6 are both suggestive of VT. The morphology of the VT is suggestive of origin from the left side of the heart, near the base (RBBB with inferior/rightward axis). Baseline artifact is present in leads V1−V3. Heart Failure: Pathophysiology and Diagnosis Douglas L. Mann, Murali Chakinala HEART FAILURE DEFINITION 279 SEC Tion 4


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InternalMed_Harrison. Heart Failure: Pathophysiology and Diagnosis Douglas L. Mann, Murali Chakinala HEART FAILURE DEFINITION 279 SEC Tion 4 Despite repeated attempts to develop a mechanistic definition that encompasses the heterogeneity and complexity of heart failure (HF), no single conceptual paradigm has withstood the test of time. The current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines define HF as a complex clinical syndrome that results from structural or functional impairment of ventricular filling or ejection of blood, which in turn leads to the cardinal clinical symptoms of dyspnea and fatigue and signs of HF, namely edema and rales. Because many patients present without signs or symptoms of volume overload, the term “heart failure” is preferred over the older term “congestive heart failure.”


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InternalMed_Harrison. HF is a burgeoning problem worldwide, with more than 20 million people affected. The overall prevalence of HF in the adult population in developed countries is 2%. HF prevalence follows an exponential pattern, rising with age, and affects 6–10% of people over age 65. Although the relative incidence of HF is lower in women than in men, women constitute at least one-half the cases of HF because of their longer life expectancy. In North America and Europe, the lifetime risk of developing HF is approximately one in five for a 40-year-old. The overall prevalence of HF is thought to be increasing, in part because current therapies for cardiac disorders, such as myocardial infarction (MI), valvular heart disease, and arrhythmias, are allowing patients to survive longer. Very little is known about the prevalence or risk of developing HF in emerging nations because of the lack of population-based studies in those countries. HF was once thought to arise primarily in the setting of a depressed


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InternalMed_Harrison. the prevalence or risk of developing HF in emerging nations because of the lack of population-based studies in those countries. HF was once thought to arise primarily in the setting of a depressed left ventricular (LV) ejection fraction (EF); however, epidemiologic studies have shown that approximately one-half of patients who develop HF have a normal or preserved EF (EF ≥50%). Accordingly, the historical terms “systolic” and “diastolic” HF have been abandoned, and HF patients are now broadly categorized into HF with a reduced EF (HFrEF; formerly systolic failure) or HF with a preserved EF (HRpEF; formerly diastolic failure).


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InternalMed_Harrison. As shown in Table 279-1, any condition that leads to an alteration in LV structure or function can predispose a patient to developing HF. Although the etiology of HF in patients with a preserved EF differs from that of patients with depressed EF, there is considerable overlap between the etiologies of these two conditions. In industrialized countries, coronary artery disease (CAD) has become the predominant cause in men and women and is responsible for 60–75% of cases of HF. Hypertension contributes to the development of HF in 75% of patients, including most patients with CAD. Both CAD and hypertension interact to augment the risk of HF, as does diabetes mellitus.


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InternalMed_Harrison. In 20–30% of the cases of HF with a depressed EF, the exact etiologic basis is not known. These patients are referred to as having nonischemic, dilated, or idiopathic cardiomyopathy if the cause is unknown (Chap. 287). Prior viral infection or toxin exposure (e.g., alcoholic or chemotherapeutic) also may lead to a dilated cardiomyopathy. Moreover, it is becoming increasingly clear that a large number of cases of dilated cardiomyopathy are secondary to specific genetic defects, most notably those in the cytoskeleton. Most forms of familial dilated cardiomyopathy are inherited in an autosomal dominant fashion. Mutations of genes that encode cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear membrane proteins (laminin) have been identified thus far. Dilated cardiomyopathy also is associated with Duchenne’s, Becker’s, and limb-girdle muscular dystrophies. Conditions that lead to a high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the


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InternalMed_Harrison. also is associated with Duchenne’s, Becker’s, and limb-girdle muscular dystrophies. Conditions that lead to a high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the development of HF in a normal heart; however, in the presence of underlying structural heart disease, these conditions can lead to overt HF.


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InternalMed_Harrison. Chronic volume overload Chagas’ disease Regurgitant valvular disease Disorders of rate and rhythm Intracardiac (left-to-right) shunting Chronic bradyarrhythmias Extracardiac shunting Chronic tachyarrhythmias Primary (hypertrophic cardiomy-Infiltrative disorders (amyloidosis, opathies) sarcoidosis) Metabolic disorders Excessive blood flow requirements Thyrotoxicosis Systemic arteriovenous shunting Nutritional disorders (beriberi) Chronic anemia aIndicates conditions that can also lead to heart failure with a preserved ejection fraction. Class I Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain. Class II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.


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InternalMed_Harrison. Class III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. Source: Adapted from New York Heart Association, Inc., Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little Brown, 1964, p. 114.


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InternalMed_Harrison. Source: Adapted from New York Heart Association, Inc., Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little Brown, 1964, p. 114. Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young. Hypertension is an important cause of HF in the African and African-American populations. Chagas’ disease is still a major cause of HF in South America. Not surprisingly, anemia is a frequent concomitant factor in HF in many developing nations. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with CAD emerging as the single most common cause of HF. Although the contribution of diabetes mellitus to HF is not well understood, diabetes accelerates atherosclerosis and often is associated with hypertension.


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InternalMed_Harrison. Despite many recent advances in the evaluation and management of HF, the development of symptomatic HF still carries a poor prognosis. Community-based studies indicate that 30–40% of patients die within 1 year of diagnosis and 60–70% die within 5 years, mainly from worsening HF or as a sudden event (probably because of a ventricular arrhythmia). Although it is difficult to predict prognosis in an individual, patients with symptoms at rest (New York Heart Association [NYHA] class IV) have a 30–70% annual mortality rate, whereas patients with symptoms with moderate activity (NYHA class II) have an annual mortality rate of 5–10%. Thus, functional status is an important predictor of patient outcome (Table 279-2).


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InternalMed_Harrison. Figure 279-1 provides a general conceptual framework for considering the development and progression of HFrEF. As shown, HF may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or, alternatively, disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of an MI; it may have a gradual or insidious onset, as in the case of hemodynamic pressure or volume overloading; or it may be hereditary, as in the case of many of the genetic cardiomyopathies. Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all in some manner produce a decline in the pumping capacity of the heart. In most instances, patients remain asymptomatic or minimally symptomatic after the initial decline in pumping capacity of the


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InternalMed_Harrison. in some manner produce a decline in the pumping capacity of the heart. In most instances, patients remain asymptomatic or minimally symptomatic after the initial decline in pumping capacity of the heart or develop symptoms only after the dysfunction has been present for some time.


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InternalMed_Harrison. Although the precise reasons why patients with LV dysfunction may remain asymptomatic is not certain, one potential explanation is that a number of compensatory mechanisms become activated in the presence of cardiac injury and/or LV dysfunction allowing patients Heart Failure: Pathophysiology and Diagnosis Time, years


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InternalMed_Harrison. FIGURE 279-1 Pathogenesis of heart failure with a depressed ejection fraction. Heart failure begins after an index event produces an initial decline in the heart's pumping capacity. After this initial decline in pumping capacity, a variety of compensatory mechanisms are activated, including the adrenergic nervous system, the reninangiotensin-aldosterone system, and the cytokine system. In the short term, these systems are able to restore cardiovascular function to a normal homeostatic range with the result that the patient remains asymptomatic. However, with time, the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening left ventricular remodeling and subsequent cardiac decompensation. (From D Mann: Circulation 100:999, 1999.) to sustain and modulate LV function for a period of months to years. The compensatory mechanisms that have been described thus far include (1) activation of the renin-angiotensin-aldosterone (RAA) and


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InternalMed_Harrison. sustain and modulate LV function for a period of months to years. The compensatory mechanisms that have been described thus far include (1) activation of the renin-angiotensin-aldosterone (RAA) and adrenergic nervous systems, which are responsible, respectively, for maintaining cardiac output through increased retention of salt and water (Fig. 279-2), and (2) increased myocardial contractility. In addition, there is activation of a family of countervailing vasodilatory molecules, including the atrial and brain natriuretic peptides (ANP and BNP), prostaglandins (PGE2 and PGI2), and nitric oxide (NO), that offsets the excessive peripheral vascular vasoconstriction. Genetic background, sex, age, or environment may influence these compensatory mechanisms, which are able to modulate LV function within a physiologic/homeostatic range so that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for


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InternalMed_Harrison. within a physiologic/homeostatic range so that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for a period of years; however, at some point patients become overtly symptomatic, with a resultant striking increase in morbidity and mortality rates. Although the exact mechanisms that are responsible for this transition are not known, as will be discussed below, the transition to symptomatic HF is accompanied by increasing activation of neurohormonal, adrenergic, and cytokine systems that lead to a series of adaptive changes within the myocardium collectively referred to as LV remodeling.


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InternalMed_Harrison. In contrast to our understanding of the pathogenesis of HF with a depressed EF, our understanding of the mechanisms that contribute to the development of HF with a preserved EF is still evolving. That is, although diastolic dysfunction (see below) was thought to be the only mechanism responsible for the development of HF with a preserved EF, community-based studies suggest that additional extracardiac mechanisms may be important, such as increased vascular stiffness and impaired renal function. BASIC MECHANISMS OF HEART FAILURE Heart Failure with a Reduced Ejection Fraction LV remodeling develops in response to a series of complex events that occur at the cellular and molecular levels (Table 279-3). These changes include (1) myocyte hypertrophy; (2) alterations in the contractile properties of the myocyte; (3) progressive loss of myocytes through necrosis,


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InternalMed_Harrison. FIGURE 279-2 Activation of neurohormonal systems in heart failure. The decreased cardiac output in heart failure (HF) patients results in an "unloading" of high-pressure baroreceptors (circles) in the left ventricle, carotid sinus, and aortic arch. This unloading of the peripheral baroreceptors leads to a loss of inhibitory parasympathetic tone to the central nervous system (CNS), with a resultant generalized increase in efferent sympathetic tone, and nonosmotic release of arginine vasopressin (AVP) from the pituitary. AVP (or antidiuretic hormone [ADH]) is a powerful vasoconstrictor that increases the permeability of the renal collecting ducts, leading to the reabsorption of free water. These afferent signals to the CNS also activate efferent sympathetic nervous system pathways that innervate the heart, kidney, peripheral vasculature, and skeletal muscles.


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InternalMed_Harrison. Sympathetic stimulation of the kidney leads to the release of renin, with a resultant increase in the circulating levels of angiotensin II and aldosterone. The activation of the renin-angiotensin-aldosterone system promotes salt and water retention and leads to vasoconstriction of the peripheral vasculature, myocyte hypertrophy, myocyte cell death, and myocardial fibrosis. Although these neurohormonal mechanisms facilitate short-term adaptation by maintaining blood pressure, and hence perfusion to vital organs, the same neurohormonal mechanisms are believed to contribute to end-organ changes in the heart and the circulation and to the excessive salt and water retention in advanced HF. (Modified from A Nohria et al: Neurohormonal, renal and vascular adjustments, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia, Current Medicine Group 2002, p. 104.) apoptosis, and autophagic cell death; (4) β-adrenergic desensitization; (5) abnormal


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InternalMed_Harrison. Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia, Current Medicine Group 2002, p. 104.) apoptosis, and autophagic cell death; (4) β-adrenergic desensitization; (5) abnormal myocardial energetics and metabolism; and (6) reorganization of the extracellular matrix with dissolution of the organized structural collagen weave surrounding myocytes and subsequent replacement by an interstitial collagen matrix that does not


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InternalMed_Harrison. Source: Adapted from D. Mann: Pathophysiology of heart failure, in Braunwald's Heart Disease, 8th ed, PL Libby et al (eds). Philadelphia, Elsevier, 2008, p. 550. provide structural support to the myocytes. The biologic stimuli for these profound changes include mechanical stretch of the myocyte, circulating neurohormones (e.g., norepinephrine, angiotensin II), inflammatory cytokines (e.g., tumor necrosis factor [TNF]), other peptides and growth factors (e.g., endothelin), and reactive oxygen species (e.g., superoxide). The sustained overexpression of these biologically active molecules is believed to contribute to the progression of HF by virtue of the deleterious effects they exert on the heart and the circulation. Indeed, this insight forms the clinical rationale for using pharmacologic agents that antagonize these systems (e.g., angiotensin-converting enzyme [ACE] inhibitors and beta blockers) in treating patients with HF (Chap. 280).


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InternalMed_Harrison. To understand how the changes that occur in the failing cardiac myocyte contribute to depressed LV systolic function in HF, it is instructive first to review the biology of the cardiac muscle cell (Chap. 265e). Sustained neurohormonal activation and mechanical overload result in transcriptional and posttranscriptional changes in the genes and proteins that regulate excitation-contraction coupling and cross-bridge interaction (see Figs. 265e-6 and 265e-7). The changes that regulate excitation-contraction include decreased function of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2A), resulting in decreased calcium uptake into the sarcoplasmic reticulum (SR), and hyperphosphorylation of the ryanodine receptor, leading to calcium leakage from the SR. The changes that occur in the cross-bridges include decreased expression of α-myosin heavy chain and increased expression of β-myosin heavy chain, myocytolysis, and disruption of the cytoskeletal links between the sarcomeres and


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InternalMed_Harrison. cross-bridges include decreased expression of α-myosin heavy chain and increased expression of β-myosin heavy chain, myocytolysis, and disruption of the cytoskeletal links between the sarcomeres and the extracellular matrix. Collectively, these changes impair the ability of the myocyte to contract and therefore contribute to the depressed LV systolic function observed in patients with HF.


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InternalMed_Harrison. Myocardial relaxation is an adenosine triphosphate (ATP)dependent process that is regulated by uptake of cytoplasmic calcium into the SR by SERCA2A and extrusion of calcium by sarcolemmal pumps (see Fig. 265e-7). Accordingly, reductions in ATP concentration, as occurs in ischemia, may interfere with these processes and lead to slowed myocardial relaxation. Alternatively, if LV filling is delayed because LV compliance is reduced (e.g., from hypertrophy or fibrosis), LV filling pressures will similarly remain elevated at end diastole (see Fig. 265e-11). An increase in heart rate disproportionately shortens the time for diastolic filling, which may lead to elevated LV filling pressures, particularly in noncompliant ventricles. Elevated LV end-1503 diastolic filling pressures result in increases in pulmonary capillary pressures, which can contribute to the dyspnea experienced by patients with diastolic dysfunction. In addition to impaired myocardial relaxation, increased myocardial


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InternalMed_Harrison. increases in pulmonary capillary pressures, which can contribute to the dyspnea experienced by patients with diastolic dysfunction. In addition to impaired myocardial relaxation, increased myocardial stiffness secondary to cardiac hypertrophy and increased myocardial collagen content may contribute to diastolic failure. Importantly, diastolic dysfunction can occur alone or in combination with systolic dysfunction in patients with HF.


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InternalMed_Harrison. Left Ventricular Remodeling Ventricular remodeling refers to the changes in LV mass, volume, and shape and the composition of the heart that occur after cardiac injury and/or abnormal hemodynamic loading conditions. LV remodeling may contribute independently to the progression of HF by virtue of the mechanical burdens that are engendered by the changes in the geometry of the remodeled LV. In addition to the increase in LV end-diastolic volume, LV wall thinning occurs as the left ventricle begins to dilate. The increase in wall thinning, along with the increase in afterload created by LV dilation, leads to a functional afterload mismatch that may contribute further to a decrease in stroke volume. Moreover, the high end-diastolic wall stress might be expected to lead to (1) hypoperfusion of the subendocardium, with resultant worsening of LV function; (2) increased oxidative stress, with the resultant activation of families of genes that are sensitive to free radical generation (e.g.,


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InternalMed_Harrison. of the subendocardium, with resultant worsening of LV function; (2) increased oxidative stress, with the resultant activation of families of genes that are sensitive to free radical generation (e.g., TNF and interleukin 1β); and (3) sustained expression of stretch-activated genes (angiotensin II, endothelin, and TNF) and/or stretch activation of hypertrophic signaling pathways. Increasing LV dilation also results in tethering of the papillary muscles with resulting incompetence of the mitral valve apparatus and functional mitral regurgitation, which in turn leads to further hemodynamic overloading of the ventricle. Taken together, the mechanical burdens that are engendered by LV remodeling contribute to the progression of HF. Recent studies have shown that LV remodeling can be reversed following medical and device therapy and that reverse LV remodeling is associated with improved clinical outcomes in patients with HFrEF. Indeed, one of the goals of therapy for HF is to prevent and/or


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InternalMed_Harrison. medical and device therapy and that reverse LV remodeling is associated with improved clinical outcomes in patients with HFrEF. Indeed, one of the goals of therapy for HF is to prevent and/or reverse LV remodeling.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Symptoms The cardinal symptoms of HF are fatigue and shortness of breath. Although fatigue traditionally has been ascribed to the low cardiac output in HF, it is likely that skeletal-muscle abnormalities and other noncardiac comorbidities (e.g., anemia) also contribute to this symptom. In the early stages of HF, dyspnea is observed only during exertion; however, as the disease progresses, dyspnea occurs with less strenuous activity, and it ultimately may occur even at rest. The origin of dyspnea in HF is probably multifactorial (Chap. 47e). The most important mechanism is pulmonary congestion with accumulation of interstitial or intra-alveolar fluid, which activates juxtacapillary J receptors, which in turn stimulate the rapid, shallow breathing characteristic of cardiac dyspnea. Other factors that contribute to dyspnea on exertion include reductions in pulmonary compliance, increased airway resistance, respiratory muscle and/or diaphragm fatigue, and anemia.


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InternalMed_Harrison. cardiac dyspnea. Other factors that contribute to dyspnea on exertion include reductions in pulmonary compliance, increased airway resistance, respiratory muscle and/or diaphragm fatigue, and anemia. Dyspnea may become less frequent with the onset of right ventricular (RV) failure and tricuspid regurgitation.


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InternalMed_Harrison. orthopnEa Orthopnea, which is defined as dyspnea occurring in the recumbent position, is usually a later manifestation of HF than is exertional dyspnea. It results from redistribution of fluid from the splanchnic circulation and lower extremities into the central circulation during recumbency, with a resultant increase in pulmonary capillary pressure. Nocturnal cough is a common manifestation of this process and a frequently overlooked symptom of HF. Orthopnea generally is relieved by sitting upright or sleeping with additional pillows. Although orthopnea is a relatively specific symptom of HF, it may occur in patients with abdominal obesity or ascites and patients with pulmonary disease whose lung mechanics favor an upright posture. paroxysmal nocturnal dyspnEa (pnd) This term refers to acute episodes of severe shortness of breath and coughing that generally occur at night and awaken the patient from sleep, usually 1–3 h after the


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InternalMed_Harrison. Heart Failure: Pathophysiology and Diagnosis 1504 patient retires. PND may manifest as coughing or wheezing, possibly because of increased pressure in the bronchial arteries leading to airway compression, along with interstitial pulmonary edema that leads to increased airway resistance. Whereas orthopnea may be relieved by sitting upright at the side of the bed with the legs in a dependent position, patients with PND often have persistent coughing and wheezing even after they have assumed the upright position. Cardiac asthma is closely related to PND, is characterized by wheezing secondary to bronchospasm, and must be differentiated from primary asthma and pulmonary causes of wheezing.


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InternalMed_Harrison. chEynE-stokEs rEspiration Also referred to as periodic respiration or cyclic respiration, Cheyne-Stokes respiration is present in 40% of patients with advanced HF and usually is associated with low cardiac output. Cheyne-Stokes respiration is caused by an increased sensitivity of the respiratory center to arterial PCO2. There is an apneic phase, during which arterial PO2 falls and arterial PCO2 rises. These changes in the arterial blood gas content stimulate the respiratory center, resulting in hyperventilation and hypocapnia, followed by recurrence of apnea. Cheyne-Stokes respirations may be perceived by the patient or the patient’s family as severe dyspnea or as a transient cessation of breathing. acutE pulmonary EdEma See Chap. 326


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InternalMed_Harrison. acutE pulmonary EdEma See Chap. 326 Other Symptoms Patients with HF also may present with gastrointestinal symptoms. Anorexia, nausea, and early satiety associated with abdominal pain and fullness are common complaints and may be related to edema of the bowel wall and/or a congested liver. Congestion of the liver and stretching of its capsule may lead to right upper-quadrant pain. Cerebral symptoms such as confusion, disorientation, and sleep and mood disturbances may be observed in patients with severe HF, particularly elderly patients with cerebral arteriosclerosis and reduced cerebral perfusion. Nocturia is common in HF and may contribute to insomnia.


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InternalMed_Harrison. A careful physical examination is always warranted in the evaluation of patients with HF. The purpose of the examination is to help determine the cause of HF as well as to assess the severity of the syndrome. Obtaining additional information about the hemodynamic profile and the response to therapy and determining the prognosis are important additional goals of the physical examination.


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InternalMed_Harrison. General Appearance and Vital Signs In mild or moderately severe HF, the patient appears to be in no distress at rest except for feeling uncomfortable when lying flat for more than a few minutes. In more severe HF, the patient must sit upright, may have labored breathing, and may not be able to finish a sentence because of shortness of breath. Systolic blood pressure may be normal or high in early HF, but it generally is reduced in advanced HF because of severe LV dysfunction. The pulse pressure may be diminished, reflecting a reduction in stroke volume. Sinus tachycardia is a nonspecific sign caused by increased adrenergic activity. Peripheral vasoconstriction leading to cool peripheral extremities and cyanosis of the lips and nail beds is also caused by excessive adrenergic activity.


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InternalMed_Harrison. Jugular Veins (See also Chap. 267) Examination of the jugular veins provides an estimation of right atrial pressure. The jugular venous pressure is best appreciated with the patient lying recumbent, with the head tilted at 45°. The jugular venous pressure should be quantified in centimeters of water (normal ≤8 cm) by estimating the height of the venous column of blood above the sternal angle in centimeters and then adding 5 cm. In the early stages of HF, the venous pressure may be normal at rest but may become abnormally elevated with sustained (~15 seconds) pressure on the abdomen (positive abdominojugular reflux). Giant v waves indicate the presence of tricuspid regurgitation.


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InternalMed_Harrison. Pulmonary Examination Pulmonary crackles (rales or crepitations) result from the transudation of fluid from the intravascular space into the alveoli. In patients with pulmonary edema, rales may be heard widely over both lung fields and may be accompanied by expiratory wheezing (cardiac asthma). When present in patients without concomitant lung disease, rales are specific for HF. Importantly, rales are frequently absent in patients with chronic HF, even when LV filling pressures are elevated, because of increased lymphatic drainage of alveolar fluid. Pleural effusions result from the elevation of pleural capillary pressure and the resulting transudation of fluid into the pleural cavities. Since the pleural veins drain into both the systemic and the pulmonary veins, pleural effusions occur most commonly with biventricular failure. Although pleural effusions are often bilateral in HF, when they are unilateral, they occur more frequently in the right pleural space.


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InternalMed_Harrison. Cardiac Examination Examination of the heart, although essential, frequently does not provide useful information about the severity of HF. If cardiomegaly is present, the point of maximal impulse (PMI) usually is displaced below the fifth intercostal space and/or lateral to the midclavicular line, and the impulse is palpable over two interspaces. Severe LV hypertrophy leads to a sustained PMI. In some patients, a third heart sound (S3) is audible and palpable at the apex. Patients with enlarged or hypertrophied right ventricles may have a sustained and prolonged left parasternal impulse extending throughout systole. An S3 (or protodiastolic gallop) is most commonly present in patients with volume overload who have tachycardia and tachypnea, and it often signifies severe hemodynamic compromise. A fourth heart sound (S4) is not a specific indicator of HF but is usually present in patients with diastolic dysfunction. The murmurs of mitral and tricuspid regurgitation are frequently


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InternalMed_Harrison. compromise. A fourth heart sound (S4) is not a specific indicator of HF but is usually present in patients with diastolic dysfunction. The murmurs of mitral and tricuspid regurgitation are frequently present in patients with advanced HF.


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InternalMed_Harrison. Abdomen and Extremities Hepatomegaly is an important sign in patients with HF. When it is present, the enlarged liver is frequently tender and may pulsate during systole if tricuspid regurgitation is present. Ascites, a late sign, occurs as a consequence of increased pressure in the hepatic veins and the veins draining the peritoneum. Jaundice, also a late finding in HF, results from impairment of hepatic function secondary to hepatic congestion and hepatocellular hypoxemia and is associated with elevations of both direct and indirect bilirubin.


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InternalMed_Harrison. Peripheral edema is a cardinal manifestation of HF, but it is nonspecific and usually is absent in patients who have been treated adequately with diuretics. Peripheral edema is usually symmetric and dependent in HF and occurs predominantly in the ankles and the pretibial region in ambulatory patients. In bedridden patients, edema may be found in the sacral area (presacral edema) and the scrotum. Long-standing edema may be associated with indurated and pigmented skin. Cardiac Cachexia With severe chronic HF, there may be marked weight loss and cachexia. Although the mechanism of cachexia is not entirely understood, it is probably multifactorial and includes elevation of the resting metabolic rate; anorexia, nausea, and vomiting due to congestive hepatomegaly and abdominal fullness; elevation of circulating concentrations of cytokines such as TNF; and impairment of intestinal absorption due to congestion of the intestinal veins. When present, cachexia augurs a poor overall prognosis.


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InternalMed_Harrison. The diagnosis of HF is relatively straightforward when the patient presents with classic signs and symptoms of HF; however, the signs and symptoms of HF are neither specific nor sensitive. Accordingly, the key to making the diagnosis is to have a high index of suspicion, particularly for high-risk patients. When these patients present with signs or symptoms of HF, additional laboratory testing should be performed. Routine Laboratory Testing Patients with new-onset HF and those with chronic HF and acute decompensation should have a complete blood count, a panel of electrolytes, blood urea nitrogen, serum creatinine, hepatic enzymes, and a urinalysis. Selected patients should have assessment for diabetes mellitus (fasting serum glucose or oral glucose tolerance test), dyslipidemia (fasting lipid panel), and thyroid abnormalities (thyroid-stimulating hormone level).


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InternalMed_Harrison. Electrocardiogram (ECG) A routine 12-lead ECG is recommended. The major importance of the ECG is to assess cardiac rhythm and determine the presence of LV hypertrophy or a prior MI (presence or absence of Q waves) as well as to determine QRS width to ascertain whether the patient may benefit from resynchronization therapy (see below). A normal ECG virtually excludes LV systolic dysfunction. Chest X-Ray A chest x-ray provides useful information about cardiac size and shape, as well as the state of the pulmonary vasculature, and may identify noncardiac causes of the patient’s symptoms. Although patients with acute HF have evidence of pulmonary hypertension, interstitial edema, and/or pulmonary edema, the majority of patients with chronic HF do not. The absence of these findings in patients with chronic HF reflects the increased capacity of the lymphatics to remove interstitial and/or pulmonary fluid.


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InternalMed_Harrison. Assessment of LV Function Noninvasive cardiac imaging (Chap. 270e) is essential for the diagnosis, evaluation, and management of HF. The most useful test is the two-dimensional (2-D) echocardiogram/ Doppler, which can provide a semiquantitative assessment of LV size and function as well as the presence or absence of valvular and/ or regional wall motion abnormalities (indicative of a prior MI). The presence of left atrial dilation and LV hypertrophy, together with abnormalities of LV diastolic filling provided by pulse-wave and tissue Doppler, is useful for the assessment of HF with a preserved EF. The 2-D echocardiogram/Doppler is also invaluable in assessing RV size and pulmonary pressures, which are critical in the evaluation and management of cor pulmonale (see below). Magnetic resonance imaging (MRI) also provides a comprehensive analysis of cardiac anatomy and function and is now the gold standard for assessing LV mass and volumes. MRI also is emerging as a useful and accurate


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InternalMed_Harrison. imaging (MRI) also provides a comprehensive analysis of cardiac anatomy and function and is now the gold standard for assessing LV mass and volumes. MRI also is emerging as a useful and accurate imaging modality for evaluating patients with HF, both in terms of assessing LV structure and for determining the cause of HF (e.g., amyloidosis, ischemic cardiomyopathy, hemochromatosis).


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InternalMed_Harrison. The most useful index of LV function is the EF (stroke volume divided by end-diastolic volume). Because the EF is easy to measure by noninvasive testing and easy to conceptualize, it has gained wide acceptance among clinicians. Unfortunately, the EF has a number of limitations as a true measure of contractility, since it is influenced by alterations in afterload and/or preload. Nonetheless, with the exceptions indicated above, when the EF is normal (≥50%), systolic function is usually adequate, and when the EF is significantly depressed (<30–40%), contractility is usually depressed.


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InternalMed_Harrison. Biomarkers Circulating levels of natriuretic peptides are useful and important adjunctive tools in the diagnosis of patients with HF. Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), which are released from the failing heart, are relatively sensitive markers for the presence of HF with depressed EF; they also are elevated in HF patients with a preserved EF, albeit to a lesser degree. In ambulatory patients with dyspnea, the measurement of BNP or NT-proBNP is useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty. Moreover, the measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF and can be useful to achieve optimal dosing of medical therapy in select clinically euvolemic patients. However, it is important to recognize that natriuretic peptide levels increase with age and renal impairment, are more elevated in women, and can be elevated in


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InternalMed_Harrison. select clinically euvolemic patients. However, it is important to recognize that natriuretic peptide levels increase with age and renal impairment, are more elevated in women, and can be elevated in right HF from any cause. Levels can be falsely low in obese patients. Other biomarkers, such as soluble ST-2 and galectin-3, are newer biomarkers that can be used for determining the prognosis of HF patients.


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InternalMed_Harrison. Exercise Testing Treadmill or bicycle exercise testing is not routinely advocated for patients with HF, but either is useful for assessing the need for cardiac transplantation in patients with advanced HF (Chap. 281). A peak oxygen uptake (vo2) <14 mL/kg per min is asso-1505 ciated with a relatively poor prognosis. Patients with a vo2 <14 mL/ kg per min have been shown, in general, to have better survival when transplanted than when treated medically.