Molecular Genetics

There is increasing evidence that a significant portion (30% to 50%) of idiopathic DCM is familial. Familial DCM is clinically and genetically heterogeneous and exhibits various patterns of hereditary transmission, including autosomal dominant with variable penetrance (the predominant pattern of transmission, accounting for about 90% of cases), X-linked (5% to 10%), autosomal recessive (rare), and maternal transmission through mitochondrial DNA (rare). It is also likely that many sporadic DCM cases can be due to genetic mutations. Although usually nonsyndromic, DCM can be included in syndromic disease involving various organ systems, most commonly skeletal muscle disease (muscular dystrophies).

To date, more than 40 genes have been linked to nonsyndromic familial DCM. Notably the frequencies of DCM mutations in any one gene are low (less than 1% to 8%), and a genetic cause is identified in only 35% to 40% of familial DCM cases. Most patients with familial DCM have isolated heart muscle disease; however, a minority of patients also manifest extracardiomyopathic phenotypes, including conduction system disease, supraventricular arrhythmias, sensorineural hearing loss, and skeletal myopathy ( Table 25.1 ). Clinical phenotypes and outcome in patients with DCM often vary according to the disease gene, penetrance, age, and type of mutation. At least four phenotypes are generally recognized: isolated DCM, DCM with cardiac conduction disease, DCM with concomitant skeletal myopathy (with or without conduction disease), and DCM with sensorineural deafness.

Familial forms of DCM can be due to mutations in cytoskeletal, sarcomeric, Z-disk, nuclear envelope, sarcolemmal, and intercalated disc protein genes. Several gene mutations have been identified in the autosomal form of familial DCM, including those encoding Z-disc proteins (alpha-actin-2, muscle LIM protein, titin-cap), costameres, adherens junctions, desmosomes, intermediate filaments, sarcomere proteins (cardiac alpha-actin, beta-myosin heavy chain, cardiac troponin T, alpha-tropomyosin, titin), sarcoplasmic reticulum proteins (phospholamban), and ion channel (SUR2A). Of note, different mutations in the sarcomere genes can cause hypertrophic cardiomyopathy (HCM). Mutations in the LMNA gene (which encodes Lamin A/C, a nuclear envelope protein) are involved in 8% of familial DCM and in 2% of sporadic DCM. Mutations in Lamin A/C also cause Emery-Dreifuss muscular dystrophy. Autosomal dominant DCM can exhibit either a pure DCM phenotype or DCM with cardiac conduction system disease. X-linked familial DCM is usually caused by mutations in the dystrophin gene and is typically associated with skeletal muscle involvement (Duchenne and Becker muscular dystrophy). The infantile form of X-linked DCM or Barth syndrome typically affects male infants (characterized by neutropenia and growth retardation). Mitochondrial cytopathies and inherited metabolic disorders such as hemochromatosis can also be associated with DCM.

Compared with sporadic cases of idiopathic DCM, familial DCM patients are younger and tend to have higher left ventricular ejection fraction (LVEF) and more significant myocardial fibrosis. In patients with idiopathic DCM, the proposed diagnostic criteria for the familial form of the disease are the existence of two or more affected family members, or of one first-degree relative with a documented history of unexplained sudden death before 35 years of age. In most cases, proof of a genetic cause of a cardiomyopathy has limited impact on the treatment of the index patient, but can have important implications in regard to family screening and genetic counseling. DCM in patients who do not have a known family history may also have a genetic basis.

A new nomenclature system (the MOGE[S]) was recently developed for the description of familial DCM. This system proposes a nosology that addresses five attributes of cardiomyopathies, including morphofunctional characteristic (M), organ involvement (O), genetic or familial inheritance pattern (G), and an explicit etiological annotation (E) with details of the genetic defect or underlying disease/cause, allowing complete description of the disease and precise communication among physicians.

Ventricular Arrhythmias

Patients with DCM can develop any variety of ventricular arrhythmias, including premature ventricular complexes (PVCs), nonsustained ventricular tachycardia (VT), sustained monomorphic VT, polymorphic VT, and ventricular fibrillation (VF). Cardiac arrest is usually precipitated by polymorphic VT or monomorphic VT degenerating to VF. Nonetheless, asystolic arrest and pulseless electric activity are common modes of death, particularly in patients with end-stage heart failure (HF).

Sustained monomorphic VT is less common in DCM than in patients with prior MI. In contrast to ischemic heart disease, the electrophysiological (EP) substrate for sustained monomorphic VT in patients with nonischemic DCM is not clearly defined. Although bundle branch reentry (BBR) VT is identified as the VT mechanism in a significant percentage of patients with monomorphic VT in the setting of nonischemic DCM, the majority (80%) of VTs appear to originate from the myocardium and are due to scar-related reentry rather than BBR. BBR VT is discussed separately in Chapter 26 .

On the other hand, PVCs and nonsustained VTs induced by programmed electrical stimulation or occurring spontaneously in patients with idiopathic DCM initiate primarily in the subendocardium by a focal mechanism without evidence of macroreentry. The nature of the focal mechanism remains unknown; triggered activity arising from early or delayed afterdepolarizations seems to be more likely than microreentry.

Myocardial fibrosis, myocyte disarray, and membrane abnormalities are important factors in the substrate, causing VT in patients with DCM. Sustained VT is associated with more extensive myocardial fibrosis and nonuniform anisotropy involving both the endocardium and epicardium, compared with patients without sustained reentry. The reentry circuits are typically associated with regions of low-voltage electrograms, consistent with scar. Catheter mapping studies of patients with nonischemic DCM point to reentry around scar deep in the myocardium, near the ventricular base and in the perivalvular region, as the underlying mechanism for VT. Studies of explanted hearts with nonischemic DCM have found unexcitable fibrosis creating regions of conduction block and surviving myocardium, providing the substrate for potential reentry circuits. Slow conduction through muscle bundles separated by interstitial fibrosis can cause a zigzag path and promote reentry. Furthermore, patients with nonischemic DCM who have predominance of scar distribution involving 26% to 75% of wall thickness (as quantified by cardiac magnetic resonance [CMR]) are more likely to have inducible VT. Delayed-enhancement CMR typically reveals nontransmural scar areas often distributed in the basal portion of the ventricular free wall or basal to midportion of the septum. Sustained VTs are observed more frequently in patients having a greater extent of fibrosis detected on CMR, and nontransmural scar tissue is observed at the VT circuit exit site in the majority of patients.

The cause of fibrosis in nonischemic DCM is not well defined. Scattered foci of myocyte necrosis and replacement fibrosis are commonly seen at autopsy (evident histologically in 35% of sections of the right ventricle [RV] and in 57% of sections of the left ventricle [LV]), but grossly visible confluent regions of scar are not common (observed in only 14% of subjects). The unique propensity for abnormal basal endocardial voltage and VT site of origin in patients with nonischemic DCM remains unexplained. Low-voltage areas have also been observed during electroanatomic mapping in patients with focal VT and BBR VT, although the scar areas appeared to be smaller.

The scar and fibrosis resulting from nonischemic etiologies are distinctly different from post-MI scar; hence the reentrant circuit may have different anatomical and functional properties that affect propagation. Compared with post-MI VT, the scar in DCM tends to be smaller and less confluent, the total number of the transmural scar segments is significantly smaller, and there is less endocardial involvement. Whereas ischemia produces a predictable wavefront of necrosis progressing from subendocardium to epicardium (and scar areas larger endocardially than epicardially), usually confined to a specific coronary vascular territory, scars in nonischemic DCM have been shown to have a predilection for the midmyocardium and epicardium. In contrast to the dense post-MI scar with isolated surviving myocardial bundles, scar in nonischemic DCM is patchy with fewer fixed boundaries and protected channels or isthmuses. In addition, the myopathic process in DCM can be dynamic and progressive over time, resulting in increasing myocardial fibrosis and, as a result, progressively worsening LV dilatation and systolic dysfunction, as well as the development of new VTs.

Nonetheless, several similarities of the arrhythmia substrate exist in myocardial reentry VT in patients with nonischemic DCM compared with that in post-MI patients. Low-voltage areas are observed in all patients, and the regions of scar are frequently adjacent to a valve annulus, as is often the case in VT after inferior wall MI. The annulus often seems to form a border for an isthmus in the reentry path, which suggests the formation of a long channel, or isthmus, along an annulus contributing to the formation of reentry circuits that can support VT.

Other factors may serve as triggers for ventricular arrhythmias, including electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), ischemia caused by small vessel disease, inflammation, heightened sympathetic tone, and stretch-induced shortening of the ventricular refractory period.

Initial Evaluation

Transthoracic echocardiography is the usual modality for diagnosis of DCM. Cardiac stress testing or coronary angiography is typically performed in patients with coronary risk factors and those with new-onset ventricular arrhythmias to exclude the presence of obstructive coronary artery disease.

Ambulatory cardiac monitoring is required for patients with symptoms suggestive of arrhythmias (e.g., palpitations, dizziness, syncope), but not for screening purposes.

CMR provides accurate assessment of ventricular chamber size, wall thickness, and systolic function. Furthermore, CMR is a useful tool to detect and assess the characteristics and heterogeneous distribution of scar tissue and its composition of the wall layer, as well as its precise location within the ventricle. CMR can also help determine the underlying etiology of cardiomyopathy in some patients, such as myocarditis, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy (ARVC). In addition, the findings on CMR can potentially have prognostic implications; the extent of myocardial fibrosis is associated with HF-related hospitalization and death, and is a powerful predictor of VT/VF.

Genetic testing can be considered in selected patients when familial DCM is suspected. This can be of particular value when the clinical management is influenced by the results of genetic testing (e.g., in patients with suspected cardiac sarcoidosis vs. familial DCM). Also, identification of a causative mutation can facilitate screening of family members. The likelihood of identifying a pathogenic mutation is less likely in older patients (older than 40 years) with nonfamilial disease.

Left Ventricular Ejection Fraction

LVEF remains the most studied and the most useful predictor of SCD despite limitations (see below) and is the primary method currently used in clinical decisions for the prevention of SCD in patients with HF. Depressed LVEF is also a powerful predictor of cardiac mortality. On the basis of the results of large studies, in clinical practice an LVEF ≤35% has become the primary criterion used for prophylactic implantable cardioverter-defibrillator (ICD) placement.

However, the use of LVEF as the predominant risk stratifier has serious limitations because it lacks both sensitivity and specificity for prediction of SCD. There is no evidence of any direct mechanistic link between low LVEF and mechanisms responsible for ventricular tachyarrhythmias, and no study has demonstrated that reduced LVEF is specifically related to SCD. Although low LVEF predicts total mortality (SCD and hear failure death), its value in predicting benefit from ICD implantation is limited. In these patients, ICD may reduce the risk of SCD but total mortality may not be modified. Even a very low LVEF (less than 20%) may not have a high positive predictive value for SCD. Many DCM patients who die from SCD have only a moderately depressed LVEF. Furthermore, the arrhythmic mechanisms underlying DCM and the risk of SCD can be different in different etiologies and clinical situations. Clinical factors such as functional class, symptomatic HF, nonsustained VT, age, LV conduction abnormalities, inducible sustained VT, and AF influence the risk of arrhythmic death and total mortality, and hence potentially influence the prognostic value of a depressed LVEF. Therefore patients with an LVEF greater than 30% and other risk factors may have a higher mortality and a higher risk of SCD than those with an LVEF less than 30% but no other risk factors.

Another limitation is that methods of LVEF determination lack precision. Different imaging modalities can produce significantly different LVEF values, and the accuracy of techniques varies among laboratories and institutions, and there is evidence that prognosis, and hence risk, depends on the method by which the LVEF is measured. Clinically, when a patient has multiple LVEF measurements over time, it raises the question of which of the many measurements should be used—the most recent, the average, or the lowest. In cases in which frequent atrial or ventricular ectopic complexes or AF is present, sampling of representative contractions for the estimation of LVEF is especially problematic.

Syncope

Syncope has been associated with a higher risk of SCD and mortality (exceeding 30% at 2 years) regardless of the proven etiology of the syncope. Further, ICD recipients with syncope experience a high frequency of appropriate ICD therapy at a rate comparable to a secondary prevention cohort.

Nonsustained Ventricular Tachycardia

PVCs and nonsustained VT correlate with the severity of cardiac disease and occur in the majority of patients with severe LV dysfunction. Although the negative predictive value of these arrhythmias is high (greater than 90%), the positive predictive value is relatively low (20% to 50%), which limits the usefulness of ventricular arrhythmias as risk stratifiers. In addition, the presence and characteristics (frequency, length, and rate) of nonsustained VT do not appear to predict increased risk of subsequent life-threatening ventricular arrhythmias in patients with severe LV impairment receiving optimal medical treatment.

Nevertheless, it has been suggested that the presence of nonsustained VT may be more specific in patients with only mild to moderate LV systolic dysfunction. Nonsustained VT significantly increases the risk of malignant ventricular arrhythmias in the subgroup with LVEF greater than 35%. In these patients, even without worsening LV systolic function and symptoms, survival free from malignant ventricular arrhythmias is similar to that of patients with LVEF less than 35% with or without nonsustained VT.

Electrophysiological Testing

In contrast to patients with ischemic cardiomyopathy, invasive EP testing with programmed ventricular stimulation to assess inducibility of sustained ventricular arrhythmias did not prove to be useful for SCD risk stratification in patients with DCM. EP testing was found to offer low VT inducibility (13% sustained monomorphic ventricular tachycardia [SMVT], 6% ventricular flutter, 9% polymorphic VT/VF), low reproducibility, and poor predictive value of induced VT. Also, failure to induce SMVT during programmed electrical stimulation can be associated with high rates of arrhythmia recurrence and SCD, although at lower incidence rates than in patients with inducible VT. A recent study in patients with idiopathic DCM found that, among ICD recipients, induction of sustained ventricular arrhythmias during invasive EP testing was associated with significantly higher rates of appropriate ICD therapies (73% vs. 18%).

Electrocardiographic Markers

DCM patients typically have wide QRS complexes during the baseline rhythm, often with left bundle branch block (LBBB) or nonspecific intraventricular conduction defect. Prolonged QRS duration has been associated with increased mortality in HF patients, but association with SCD has not been proven.

Fragmentation of the QRS complex on the 12-lead surface electrocardiogram (ECG; filter range, 0.15 to 100 Hz; AC filter, 60 Hz, 25 mm/s, 10 mm/mV) has been found to potentially predict increased risk of appropriate ICD therapies as well as a higher combined endpoint of ICD therapy and mortality in nonischemic DCM patients who received an ICD for primary and secondary prevention. The usefulness of this parameter needs further evaluation. During VT, QRS complexes are typically very wide and fragmented; most patients have multiple QRS morphologies of VT ( eFig. 25.1 ).

Surface 12-Lead Electrocardiograms of Two Different Ventricular Tachycardias Configurations in a Patient With Dilated Cardiomyopathy.

QRS morphology is suggestive of origin from basal septal left ventricular substrate. (A) Right bundle branch block morphology, positive precordial concordance, and inferior axis. (B) Left bundle branch block morphology, early precordial transition (leads V ₂ ), and inferior axis.

Prolongation of the QT interval, QT dispersion, and QT variability have had mixed predictive results with limited clinical applicability at present. The role of signal-averaged ECG is controversial.

Autonomic Testing

The prognostic value of autonomic tests, such as heart rate turbulence, heart rate variability, and baroreflex sensitivity, in DCM patients is questionable, and currently those parameters have little clinical application for risk stratification for SCD.

Microvolt T Wave Alternans

Microvolt T wave alternans provides a quantitative assessment of temporal and spatial heterogeneity of repolarization, which are linked to cellular arrhythmia mechanisms. Microvolt T wave alternans was found to have relatively modest (0.22) positive predictive value for SCD in patients with DCM, largely due to the high rates of abnormal results (37% to 51%) and the low event rate within a short follow-up period. Previous studies suggested a high negative predictive value for primary prevention of SCD, and T-wave alternans was hypothesized to be a useful tool to differentiate between patients who would benefit from ICD implantation and those who would not. However, results from subsequent studies failed to support this hypothesis and strongly suggested that a negative microvolt T-wave alternans result should not be used to withhold ICD therapy among patients who meet standard criteria.

Cardiac Magnetic Resonance Imaging

Late gadolinium enhancement on contrast CMR reflects myocardial fibrosis, which represents a potential substrate for ventricular arrhythmias. Fibrosis detected by CMR is evident in 40% to 50% of DCM patients. On average, regions of hyperenhancement indicative of fibrosis account for up to 10% to 12% of the ventricular mass.

The presence of myocardial scar, as assessed by late gadolinium enhancement CMR, has been reported to be an independent predictor of appropriate ICD therapies, SCD, and all-cause mortality in patients with nonischemic DCM. The pattern and extent of myocardial fibrosis was found to be a predictor of both inducible and spontaneous VT, independent of LVEF, and appear to be a stronger predictor of monomorphic VT than of polymorphic VT/VF. In addition, larger scar extent in basal LV segments, higher maximal signal intensity, and increased scar transmurality further indicate a predisposition for monomorphic VT. On the other hand, the absence of myocardial fibrosis on CMR was associated with a very low risk of arrhythmic events (0% to 3% per year).

It is likely that late gadolinium enhancement on CMR can contribute to risk stratification in patients with DCM. However, its utility for selecting DCM patients to receive an ICD has yet to be demonstrated.

Genetic Testing

Some familial forms of DCM are associated with a particularly high risk of arrhythmias and SCD, including LMNA, TNNT2, SGCD, RBM20, and CHRM2 mutations, whereas other forms (such as X-linked DCM related to dystrophin gene mutations) were found to have a high risk of severe HF but a lower risk of malignant ventricular arrhythmias. However, large studies documenting the correlation between individual genotypes and arrhythmogenicity are lacking, and current guidelines do not advise the use of genetic testing for SCD risk stratification in patients with DCM.

Pharmacological Therapy

Drug therapy, such as beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists, improves overall mortality in patients with HF and reduces the risk of SCD. In contrast, the use of antiarrhythmic drugs for primary prevention in patients with nonischemic DCM does not improve survival and is not recommended.

In patients with symptomatic ventricular arrhythmias, amiodarone is generally the preferred antiarrhythmic agent because of the absence of significant negative hemodynamic effects and low proarrhythmic potential, but controlled comparative trials of drugs are not available. Antiarrhythmic drug therapy can help improve quality of life in ICD patients receiving frequent appropriate shocks and those with incessant VT. Although amiodarone can potentially improve mortality and reduce the incidence of SCD in patients with nonischemic DCM, it is inferior to ICD therapy for secondary prevention of VT and VF. Treatment of asymptomatic PVCs or nonsustained VT with antiarrhythmic drug therapy has not been shown to improve survival and is not recommended.

Implantable Cardioverter-Defibrillator

Secondary Prevention

The benefit of ICD therapy in secondary prevention of SCD in nonischemic DCM has been well established and is superior to amiodarone or any other drug therapy. ICD implantation is recommended in patients with prior cardiac arrest or sustained VT—even in those undergoing catheter ablation of the VT or responding to antiarrhythmic therapy ( Table 25.2 ; Fig. 25.1 ).

TABLE 25.2

AHA/ACC/HRS Recommendations for Prevention of SCD in Patients With Nonischemic Cardiomyopathy

Secondary Prevention
• In patients who either survive SCA due to VT/VF or experience hemodynamically unstable VT or stable VT not due to reversible causes, an ICD is recommended if meaningful survival >1 year is expected.	Class I
• In patients who experience syncope presumed to be due to ventricular arrhythmias and who do not meet indications for a primary prevention ICD, an ICD or an electrophysiological study for risk stratification for SCD can be beneficial if meaningful survival >1 year is expected.	Class IIa
• In patients who survive a cardiac arrest, have sustained VT, or have symptomatic ventricular arrhythmias who are ineligible for an ICD (due to a limited life expectancy and/or functional status or lack of access to an ICD), amiodarone may be considered for prevention of SCD.	Class IIb
Primary Prevention
• In patients with NYHA class II–III symptoms and an LVEF of ≤35% despite GDMT, an ICD is recommended if meaningful survival of >1 year is expected.	Class I
• In patients with nonischemic cardiomyopathy due to a Lamin A/C mutation who have 2 or more risk factors (NSVT, LVEF <45%, non-missense mutation, and male sex), an ICD can be beneficial if meaningful survival of >1 year is expected.	Class IIa
• In patients with Emery-Dreifuss and limb-girdle type IB muscular dystrophies with progressive cardiac involvement, an ICD is reasonable if a meaningful survival of >1 year is expected.	Class IIa
• In patients with NYHA class I symptoms and an LVEF of ≤35% despite GDMT, an ICD may be considered if meaningful survival of >1 year is expected.	Class IIb
• In patients with myotonic dystrophy type 1 with an indication for a permanent pacemaker, an ICD may be considered to minimize the risk of SCA from VT if meaningful survival of >1 year is expected.	Class IIb
• In patients with medication-refractory NYHA class IV heart failure who are not also candidates for cardiac transplantation, an LVAD, or a CRT defibrillator that incorporates both pacing and defibrillation capabilities, an ICD should not be implanted.	Class III

 

ACC, American College of Cardiology; AHA, American Heart Association; CRT , cardiac resynchronization therapy; GDMT , guideline-directed management and therapy; HRS, Heart Rhythm Society; ICD , implantable cardioverter-defibrillator; LVAD , left ventricular assist device; LVEF , left ventricular ejection fraction; NSVT , nonsustained ventricular tachycardia; NYHA , New York Heart Association; SCA , sudden cardiac arrest; SCD , sudden cardiac death; VF , ventricular fibrillation; VT , ventricular tachycardia.

From Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm . 2017 Oct 26. [Epub ahead of print]

American Heart Association/American College of Cardiology/Heart Rhythm Society Recommendations for Secondary and Primary Prevention of Sudden Cardiac Death in Patients With Nonischemic Cardiomyopathy.

^a Implantable cardioverter-defibrillator (ICD) candidacy as determined by functional status, life expectancy, or patient preference. 2 °, Secondary; EP , electrophysiological; GDMT , guideline-directed management and therapy; HF , heart failure; LVEF , left ventricular ejection fraction; NICM , nonischemic cardiomyopathy; SCA , sudden cardiac arrest; VA , ventricular arrhythmia; VT , ventricular tachycardia; WCD , wearable cardiac-defibrillator.

(From Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm . 2017 Oct 26. [Epub ahead of print])

Primary Prevention

The benefit of ICD treatment in nonischemic DCM for primary prevention of SCD remains uncertain. Several randomized studies arrived at contradictory conclusions. Whereas prophylactic ICD implantation is of significant benefit in ischemic cardiomyopathy patients, the magnitude of absolute benefit in those with nonischemic DCM is relatively small (1.4% per year; cumulative, 7% over 5 years) at best. Nevertheless, a pooled analysis of six randomized primary prevention trials (2967 patients with nonischemic DCM) demonstrated that the use of prophylactic ICD is associated with a significant 22% reduction in total mortality and 54% reduction in arrhythmia-related death as compared with control ( eFig. 25.2 ). These findings reflect the fact that nonischemic DCM patients have a better prognosis and a lower rate of SCD than patients with ischemic cardiomyopathy.

The Benefit of Implantable Cardioverter Defibrillator (ICD) Treatment in Nonischemic Cardiomyopathy.

Forest plot of study-specific and pooled risk ratio and 95% confidence interval for the endpoint of total mortality among patients assigned to ICD versus control. AMIOVIRT , Randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia; CAT , cardiomyopathy trial; CI, confidence interval; COMPANION , comparison of medical therapy, pacing, and defibrillation in heart failure trial; DANISH, the Danish study to assess the efficacy of ICDs in patients with nonischemic systolic heart failure on mortality; DEFINITE , defibrillators in nonischemic cardiomyopathy treatment evaluation; IV, intravenous; SCD-HeFT , the sudden cardiac death in heart failure trial.

(From Stavrakis S, Asad Z, Reynolds D. Implantable cardioverter defibrillators for primary prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol . 2017;28:659–665.)

Vigorous efforts have been made in developing noninvasive stratification methods to identify the subgroup of nonischemic DCM patients at high risk for SCD. However, the best approach to identifying patients and the value of various risk stratification tools are not entirely clear. Currently there is no coherent strategy for intervention based on data integrating the results of these techniques. Many of the identified risk factors are also associated with increased risk for nonsudden death.

At the present time, LVEF remains the single most important risk stratification tool to identify individuals with a high risk of SCD, again emphasizing that it predicts all-cause mortality and not necessarily arrhythmic risk. Despite some uncertainty regarding ICD benefit for nonischemic DCM patients without HF, regardless of LVEF, the cumulative information available from clinical trials and observational data, in conjunction with opinions of experts in the field, support prophylactic ICD therapy among the subgroup of patients with nonischemic DCM and LVEF, ≤35% who remain in New York Heart Association (NYHA) functional class II or III HF on optimal medical therapy (provided that a reversible cause of transient LV function has been excluded and their response to optimal medical therapy has been assessed), and for those with a history of syncope and documented significant LV dysfunction (see Table 25.2 ; Fig. 25.1 ). Furthermore, cardiac resynchronization with an ICD was found to significantly reduce all-cause mortality compared with pharmacological therapy alone in patients with DCM, QRS prolongation, and mild-to-severe HF symptoms ( Box 25.1 ).

Box 25.1

Heart Rhythm Society Recommendations for Cardiac Resynchronization Therapy in Patients With Cardiomyopathy

Class I: CRT is indicated for:

• •
  

  Patients who have LVEF ≤35%; sinus rhythm; LBBB with a QRS duration ≥150 msec; and NYHA class II, III, or ambulatory IV; symptoms on GDMT

Class IIa: CRT is reasonable for:

• •
  

  Patients who have LVEF ≤35%, sinus rhythm; LBBB with a QRS duration 120–149 msec; and NYHA class II, III, or ambulatory IV symptoms on GDMT

  
  
• •
  

  Patients who have LVEF ≤35%, sinus rhythm; a non-LBBB pattern with a QRS duration ≥150 msec; and NYHA class III/ambulatory class IV symptoms on GDMT

  
  
• •
  

  Patients with atrial fibrillation and LVEF ≤35% on GDMT if (a) the patient requires ventricular pacing or otherwise meets CRT criteria and (b) AVN ablation or pharmacological rate control will allow near 100% ventricular pacing with CRT

  
  
• •
  

  Patients on GDMT who have LVEF ≤35% and are undergoing new or replacement device placement with anticipated requirement for significant (>40%) ventricular pacing

Class IIb: CRT may be considered for:

• •
  

  Patients who have LVEF ≤30%, ischemic etiology of heart failure, sinus rhythm, LBBB with a QRS duration ≥150 msec, and NYHA class I symptoms on GDMT

  
  
• •
  

  Patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with QRS duration 120–149 msec, and NYHA class III/ambulatory class IV on GDMT

  
  
• •
  

  Patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with a QRS duration ≥150 msec, and NYHA class II symptoms on GDMT.

Class III: CRT is not recommended for:

• •
  

  Patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration <150 msec

  
  
• •
  

  Patients whose comorbidities and/or frailty limit survival with good functional capacity to <1 year

AVN , Atrioventricular node; CRT , cardiac resynchronization therapy; GDMT , guideline-directed medical therapy; LBBB , left bundle branch block; LVEF , left ventricular ejection fraction; NYHA , New York Heart Association.

Modified from Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guide. Circulation . 2013;127:e283–e352.

The value of ICD therapy in primary prophylaxis in asymptomatic DCM patients with NYHA functional class I has not been adequately tested and remains unanswered. Nevertheless, since this patient population has a relatively low mortality rate, the benefit of ICD therapy probably is modest at best. In addition, ICD therapy is not recommended in DCM with advanced HF and NYHA functional class IV who are not candidates for cardiac resynchronization therapy. This group of patients has a high mortality rate driven mainly by progressive HF, and recurrent VT/VF can be a sign of progression of the impaired LV function. Therefore, in these patients, ICD therapy may shift the mode of death from SCD to HF death rather than reduce total mortality.

The appropriate timing to perform ICD implantation in DCM remains controversial. In general, implantation of an ICD for primary prevention is not recommended within the first 3 months after initial diagnosis of DCM. It is important to understand that medical management with angiotensin-converting enzyme inhibitors and beta-blockers (with or without aldosterone antagonists) has proven mortality benefit in these patients and should be optimized as much as possible before ICD placement. Furthermore, improvements of LVEF have been observed in about 50% of patients with recent onset DCM after a period of 3 to 9 months on guideline-directed medical therapy. Many of these patients may be excluded as candidates for an ICD after optimization of medical treatment. The deleterious effects of residual ventricular scarring, despite improvement in overall LV function, is unknown.

At initial evaluation, predicting the course of LV dysfunction is difficult. In one report, a smaller LV end-diastolic diameter, higher systolic blood pressure, and an acute inflammatory process identified at biopsy were associated with an increased likelihood of recovery of LV function. Conversely, black race and higher NYHA functional class were associated with a lower LVEF at follow-up. Furthermore, DCM due to cardiac sarcoidosis, giant cell myocarditis, or certain genetic mutations is unlikely to improve with medical therapy. On the other hand, peripartum cardiomyopathy, myocarditis, acute drug-induced cardiomyopathy, tachycardia-, or PVC-induced cardiomyopathy have higher likelihood of improvement with optimal medical therapy and elimination of underlying etiology, if possible.

There is no evidence that early ICD implantation benefits patients with newly diagnosed nonischemic DCM. Data suggest that the impact of defibrillators on reducing SCD in patients during the first 90 days on optimal medical therapy is low, and in most studies, ICD benefit did not become apparent for more than a year. Furthermore, a recent retrospective study reported a low incidence of appropriate ICD shocks in patients who received an ICD before mandated waiting periods were complete. Therefore, for patients with a new diagnosis of DCM, it is prudent to treat with optimal HF medications for at least 3 months and reassess for recovery of ventricular function before consideration of prophylactic ICD therapy, unless there are high-risk features such as sarcoidosis, giant cell myocarditis, or familial cardiomyopathy, known to be associated with malignant ventricular arrhythmias.

On the other hand, ICD implantation can be considered in patients with recent (less than 3 months) diagnosis of nonischemic DCM who also require nonelective permanent pacing, develop sustained (or hemodynamically significant) ventricular tachyarrhythmia, present with syncope that is thought to be due to a ventricular tachyarrhythmia (by clinical history, documented nonsustained ventricular tachycardia [NSVT], or EP study), or are listed for heart transplant or implanted with a LV assist device.

To mitigate the risk of arrhythmic SCD during the 90-day waiting period on optimal medical therapy before revaluation of LV function, wearable cardioverter defibrillators are frequently prescribed for patients with newly diagnosed nonischemic DCM. However, data to support such a practice are lacking. Observation studies demonstrated that the risk of SCD in this patient population is very low, and the utility of wearable cardioverter defibrillators is very limited and unlikely to be cost effective.

Catheter Ablation

While ICD therapy reduces the risk of arrhythmic death, it does not prevent the recurrence of symptomatic VT. Further, antiarrhythmic drug therapy has limited success rate for control of VT (approximately 40% of cases), leaving a significant proportion of patients with symptomatic VT or ICD shocks. Catheter ablation of VT in patients with nonischemic DCM is typically considered in those with incessant VT or with frequent ICD discharges (or electrical storm) refractory to antiarrhythmic drug therapy ( see Box 22.1 ). However, because of the future risk of life-threatening VT due to progression of the myopathic process, catheter ablation is not a substitute for an ICD, even when excellent short-term results are achieved.

In addition, limited data found that catheter ablation (in conjunction with ICD implantation) earlier in the course of treatment of VT or as a primary therapy (i.e., before antiarrhythmic drug therapy), with the goal of avoiding future ICD shocks, was associated with better acute procedural success as compared with delayed ablation. However, evidence for the efficacy and safety of such an approach in patients with nonischemic DCM remains limited.

The success rate for catheter ablation of VT in DCM is lower than that for ischemic VT, and depends on VT substrate location, which can be endocardial, intramural, or epicardial. An epicardial ablation approach is necessary in a large proportion of patients and is associated with higher complication rates. In experienced centers, catheter ablation is associated with acute success rates of up to 71%. VT recurs in 50% to 60% during the first year post ablation, although VT burden can be significantly reduced. Alcohol septal ablation can be particularly useful in patients with intramural septal VTs refractory to catheter ablation.

Furthermore, catheter ablation also should be considered for patients with BBR VT or interfascicular VT, and those with frequent PVCs, nonsustained VT, or sustained VT that is presumed to cause ventricular dysfunction. Box 22.1 lists the recommendation of ablation for VT in structural heart disease, in accordance with the published guidelines for management of patients with ventricular arrhythmias.

Anteroseptal Versus Inferolateral Ventricular Tachycardia

The VT substrate in patients with nonischemic DCM is often located in the basal LV, clustering around the mitral and aortic annuli, with variable extension toward the LV apex. Two predominant scar patterns account for the arrhythmogenic substrate in the majority of these patients: anteroseptal LV scar and inferolateral LV scar. VT morphologies consistent with anteroseptal substrate include (1) right bundle branch block (RBBB) morphology, positive precordial concordance, and inferior axis VTs; and (2) LBBB morphology, early precordial transition (leads V ₁ to V ₃ ), and inferior axis (see eFig. 25.1 ). In contrast, RBBB morphology, late precordial transition, and right (superior or inferior) axis during VT are consistent with an inferolateral scar ( Fig. 25.2 ).

Surface Electrocardiogram of Ventricular Tachycardias in a Patient With Dilated Cardiomyopathy.

QRS morphology is suggestive of origin from inferolateral left ventricular substrate. Right bundle branch block morphology, late precordial transition (leads V ₆ ), and right inferior axis.

Apical Ventricular Tachycardia

An apical VT origin is suggested by (1) LBBB morphology with late precordial transition (leads V ₅ to V ₆ ) to a dominant positive QRS complex; or (2) RBBB morphology and early precordial transition (leads V ₁ to V ₃ ) to a dominant negative QRS complex.

Septal Ventricular Tachycardia

In the setting of isolated septal substrates, VT morphologies can vary but predominantly exhibit RBBB, with either superior or inferior axis. About 40% of those VTs exhibit one of two particular configurations. The first is characterized by a precordial “transition pattern break” in lead V ₂ with qR/Rs morphology in leads V ₁ and V ₃ but reversal of this in lead V ₂ , usually in the presence of an inferior-axis RBBB configuration. The second is characterized by an inferior limb lead discordance, usually LBBB configuration with a net positive vector in II, negative in III, and positive in aVL.

Epicardial Ventricular Tachycardia

For VTs originating from the LV and having RBBB pattern, some findings on the surface ECG suggest an epicardial origin. These ECG characteristics, which generally rely on the late engagement of rapidly conducting His-Purkinje fibers by tachycardia circuit exits on the epicardium, include the following: (1) a pseudo-delta wave (measured from the earliest ventricular activation to the earliest fast deflection in any precordial lead) of 34 milliseconds or more (sensitivity, 83%; specificity, 95%); (2) a QRS duration exceeding 200 milliseconds; (3) a long R-wave peak time in lead V ₂ (i.e., an interval from the beginning of the QRS complex to the time of initial downstroke of the R wave after it has peaked [previously known as the intrinsicoid deflection ]) of at least 85 milliseconds (sensitivity, 87%; specificity, 90%); and (4) a shortest RS complex duration (measured from the earliest ventricular activation to the nadir of the first S wave in any precordial lead) of 121 milliseconds or more (sensitivity, 76%; specificity, 85%).

Importantly, ECG criteria for identifying an epicardial origin of VT appear to be region and substrate specific. ECG interval criteria that identify slow conduction in the initial portion of the QRS do not appear to be equally accurate among all LV regions and are not as reliable for consistently identifying the endocardial versus epicardial origin in the setting of nonischemic DCM, despite their proven value in patients without structural heart disease.

Given the limited predictive value of ECG criteria when applied individually, a multistep algorithm that incorporates several criteria (two morphology criteria and two adjusted interval criteria) was proposed to predict the site of origin of VTs from the basal-superior/lateral epicardium in patients with nonischemic DCM ( Fig. 25.3 ). The criteria included, in a stepwise fashion, (1) the absence of Q waves in inferior leads; (2) a pseudo-delta wave of at least 75 milliseconds; (3) a maximum deflection index of 0.59 or more; and (4) the presence of a Q wave in lead I. The maximum deflection index is defined as the shortest time to maximal deflection in the precordial leads, divided by the total QRS duration—that is, the interval measured from the earliest ventricular activation (or from the stimulation artifact) to the peak of the largest amplitude deflection in each precordial lead (taking the lead with shortest time), divided by the QRS duration.

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