Chapter 25 Ventricular Tachycardia in Nonischemic Dilated Cardiomyopathy

Pathophysiology

Cardiomyopathies are traditionally defined on the basis of structural and functional phenotypes, notably dilated, hypertrophic, and restrictive. The dilated cardiomyopathy (CMP) phenotype is the most common and is often viewed as a “final common pathway” of numerous types of cardiac injuries.

The diagnosis of nonischemic dilated CMP is established by the absence of significant (>75% stenosis) coronary artery disease and prior myocardial infarction (MI). Nonischemic dilated CMP is not a single disease entity. Valvular heart disease, hypertension, sarcoidosis, amyloidosis, Chagas disease, alcohol abuse, infections, and pregnancy, among others, need to be considered as possible etiologies. An underlying etiology for adult dilated CMP is found in only 50% of patients. The remaining 50% are considered idiopathic. Idiopathic dilated CMP is characterized by an increase in myocardial mass and a reduction in ventricular wall thickness. The heart assumes a globular shape, and there is a pronounced ventricular chamber dilation and atrial enlargement.¹

There is increasing evidence that a significant portion (35%) of idiopathic dilated CMP is secondary to familial forms of dilated CMP. Familial dilated CMP is clinically and genetically heterogeneous and it exhibits various patterns of hereditary transmission, including autosomal dominant with variable penetrance (most common, accounting for about 90% of cases), X-linked (5% to 10%), autosomal recessive (rare), and maternal transmission through mitochondrial DNA (rare).

To date, 33 genes have been linked to nonsyndromic familial dilated CMP. Notably, the frequencies of dilated CMP mutations in any one gene are low (<1% to 8%), and a genetic cause is identified in only 30% to 35% of familial dilated CMP cases. Although usually nonsyndromic, dilated CMP can be included in syndromic disease involving various organ systems, most commonly skeletal muscle disease (muscular dystrophy).²

Mutations in the genes responsible for sarcomere and cytoskeletal protein synthesis have been identified as the cause of familial dilated CMP, and several hypotheses have been put forward to explain the etiology and pathology of the disease. Several gene mutations have been identified in the autosomal form of familial dilated CMP, 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 (phospho-lamban), and ion channel (SUR2A). Of note, different mutations in the sarcomere genes can cause hypertrophic CMP. Mutations in lamin A/C also cause Emery-Dreifuss muscular dystrophy. Autosomal dominant dilated CMP can exhibit either a pure CMP phenotype or dilated CMP with cardiac conduction system disease. X-linked familial CMP is usually caused by defects in the dystrophin gene and is typically associated with skeletal muscle involvement (Duchenne and Becker muscular dystrophy). The infantile form of X-linked dilated CMP or Barth syndrome typically affects male infants (characterized by neutropenia and growth retardation).

As compared with sporadic cases of idiopathic dilated CMP, familial CMP patients are younger and tend to have higher left ventricular ejection fraction (LVEF) and more significant myocardial fibrosis. In patients with idiopathic dilated CMP, 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 CMP has a limited impact on the treatment of the index patient, but can have important implications in regard to family screening and genetic counseling. Dilated CMP in patients who do not have a known family history may also have a genetic basis.³

In contrast to ischemic heart disease, the electrophysiological (EP) substrate for sustained monomorphic ventricular tachycardia (VT) in patients with nonischemic dilated CMP 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 CMP, the majority (80%) of VTs appear to originate from the myocardium and are due to scar-related reentry rather than BBR.⁴ BBR VT is discussed separately in Chapter 26.

On the other hand, premature ventricular complexes (PVCs) and nonsustained VTs induced by programmed electrical stimulation or occurring spontaneously in patients with end-stage idiopathic dilated CMP 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 dilated CMP. 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 CMP 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 dilated nonischemic CMP have found inexcitable 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 CMP and predominance of scar distribution involving 26% to 75% of wall thickness (as quantified by magnetic resonance [MR] imaging) are more likely to have inducible VT. Delayed-enhancement MR imaging 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 volume of hyperenhanced areas and greater number of hyperenhanced segments, and nontransmural scar tissue was present at the VT circuit exit site in the majority of patients.^5,⁶

The cause of fibrosis in CMP is not well defined. Scattered regions of replacement fibrosis are commonly seen at autopsy, but confluent regions of scar are not common. The unique propensity for abnormal basal endocardial voltage and VT site of origin in patients with nonischemic CMP remains unexplained. Low-voltage areas have also been observed during electroanatomical 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 tends to be smaller and less confluent, the total number of the transmural scar segments is significantly smaller, and with less endocardial involvement in nonischemic CMP.⁴ 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 CMP have been shown to have a predilection for the midmyocardium and epicardium. In contrast to the dense scar with isolated surviving myocardial bundles, scar in nonischemic CMP is patchy and may have fewer fixed boundaries and protected channels or isthmuses, which can alter the extent of local conduction slowing.⁷

Nonetheless, several similarities of the arrhythmia substrate exist in myocardial reentry VT in patients with dilated nonischemic CMP compared with that in patients with previous MI. 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.

Clinical Considerations

Epidemiology

The incidence of nonischemic dilated CMP in adults in Western countries varies from 5 to 8 per 100,000 person-years, with a prevalence of 36 to 40 per 100,000 individuals. The 5-year mortality for dilated CMP has been estimated at 20%, with sudden cardiac death (SCD) accounting for approximately 30% (8% to 51%) of deaths. Nonetheless, nonischemic dilated CMP patients may represent a low arrhythmic death risk subgroup among all CMP patients.

Ventricular arrhythmias, both symptomatic and asymptomatic, are common in patients with nonischemic dilated CMP. Nonsustained VT can be observed in 30% to 50% of patients, but its incidence decreases significantly after optimization of medical treatment.⁸ However, syncope and SCD are infrequent initial manifestations of the disease. The incidence of SCD is highest among patients with indicators of more advanced cardiac disease who are also at highest risk of all-cause mortality. Although VT, ventricular fibrillation (VF), or both are considered the most common mechanism of SCD, bradycardia, pulmonary embolism, electromechanical dissociation, and other causes account for up to 50% of SCDs in patients with advanced heart failure.