1051 1052 ## Dilated Cardiomyopathy 1053 1054 Dilated cardiomyopathy (DCM) is characterized by progressive cardiac dilation and contractile (systolic) dysfunction, usually with concurrent hypertrophy; regardless of the cause, the clinicopathologic patterns are similar. 1055 1056 Pathogenesis. At diagnosis, dilated cardiomyopathy has usually progressed to end-stage disease marked by heart failure secondary to poor myocardial contractility and does not reveal any specific pathologic features. The damage that culminates in end-stage dilated cardiomyopathy can be initiated by inherited abnormalities or by environmental exposures, as follows: 1057 1058 Genetic causes. DCM has a hereditary basis in 20 % to 50 % of cases. Over 50 genes are known to be mutated in this form of cardiomyopathy, with autosomal dominant inheritance being the predominant pattern. It is most often caused by loss of function mutations affecting cytoskeletal proteins or proteins that link the sarcomere to the cytoskeleton (Fig. 9.24). Examples include mutations affecting the genes for β-myosin heavy chain, α-myosin heavy chain, cardiac troponin T, and titin. Of these, mutations affecting titin, which is a key component of sarcomeric force generation, are the most common. It should be noted that gain-of-function mutations in some of the same sarcomere genes cause hypertrophic cardiomyopathy. X-linked DCM is most frequently associated with mutations in dystrophin, a cell membrane protein that physically couples the intracellular cytoskeleton to the ECM (Chapter 20). Other genetic forms of DCM include those with mutations in cytoskeletal proteins such as desmin (the principal intermediate filament protein in cardiac myocytes) and nuclear lamins A and C. Since contractile myocytes and conduction fibers share a common developmental pathway, congenital conduction abnormalities also can be a feature of inherited forms of DCM. 1059 1060 Infection. In earlier studies, adenovirus and enterovirus were the most commonly implicated organisms. More recently, parvovirus B-19 and human herpesvirus 6 have been identified more frequently. The nucleic acid "footprints" of coxsackievirus B and other enteroviruses can occasionally be detected in the myocardium from patients with late-stage DCM. Moreover, sequential endo-myocardial biopsies have documented instances in which infectious myocarditis progressed to DCM. Simply identifying viral transcripts or demonstrating elevated antiviral antibody titers may be sufficient to invoke a myocarditis that was "missed" in its early stages. Consequently, many cases of DCM are attributed to viral infections, even though inflammation is absent from the end-stage heart. 1061 1062 Alcohol or other toxic exposure. Excess alcohol use is strongly asso- ciated with the development of DCM. Alcohol and its metabolites (especially acetaldehyde) have a direct toxic effect on the myocar- dium. Moreover, chronic alcohol use disorder can be associated 1063 1064 1065 1066 *Table 9.5 Cardiomyopathies: Functional Patterns, Causes* 1067 1068 1069

Functional Pattern	Left Ventricular Ejection Fraction^a	Mechanisms of Heart Failure	Causes	Secondary Myocardial Dysfunction (Mimicking Cardiomyopathy)
Dilated	<40%	Impairment of contractility (systolic dysfunction)	Genetic; alcohol; peripartum; myocarditis; hemochromatosis; chronic anemia; doxorubicin; sarcoidosis; idiopathic	Ischemic heart disease; valvular heart disease; hypertensive heart disease; congenital heart disease
Hypertrophic	50%–80%	Impairment of compliance (diastolic dysfunction)	Genetic; Friedreich ataxia; storage diseases; infants of mothers with diabetes	Hypertensive heart disease; aortic stenosis
Restrictive	25%–50%	Impairment of compliance (diastolic dysfunction)	A [... Output truncated due to length. 2991 tokens/11926 characters removed ...]