Etiology and Pathogenesis

DCM is characterized by dilatation and impaired contraction of either the left ventricle or both ventricles, as a result of altered structure or function in diseased cardiomyocytes. Before the heart becomes dilated and weak, there is either an index event (e.g., a myocardial infarction [MI] or acute myocarditis) that leads to impaired ventricular contractility, or progression of underlying disease (e.g., severe valvular regurgitation) that leads to ventricular pressure overload causing systolic dysfunction. Because of ventricular systolic dysfunction, gradual compensatory responses of the cardiomyocytes lead to cardiac remodeling (Fig. 18-1). Initially the cardiomyocytes respond by becoming hypertrophied, but the poorly functioning ventricle gradually dilates to handle the progressive volume overload. In most cases, contractility is impaired initially and primarily in the left ventricle, but as systolic dysfunction progresses, the right ventricle also becomes enlarged and hypokinetic. Rarely, the cardiomyopathic process will affect primarily the right ventricle at the outset of the DCM.

Figure 18-1 Cardiac remodeling secondary to volume overload.

LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

In DCM and other types of HF there is an imbalance between the activation and effects of the vasoconstrictor hormones versus endogenous vasodilators. The effects of the vasoconstrictor hormones predominate in HF as a result of activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). These vasoconstrictor hormones (e.g., norepinephrine, angiotensin II) worsen hemodynamics by increasing vascular resistance and afterload, and hence myocardial work, resulting in progressive ventricular remodeling through abnormal cellular growth and other effects. Activation of the RAAS also produces salt and water retention, further elevating filling pressures and resulting in symptoms and signs of HF. Angiotensin II acts on the angiotensin II type 1 (AT1) receptor to cause vasoconstriction, sodium retention, and other physiologic effects.

In contrast, activation of the vasodilating natriuretic peptide system (e.g., atrial and B-type natriuretic peptides [ANPs, BNPs]) is beneficial in HF, resulting in vasodilation and sodium excretion. In decompensated HF patients, the vasodilatory systems are simply overwhelmed by the vasoconstricting neurohormones.

Interventions to prevent decompensated HF have focused on these neurohormonal targets in an effort to restore the balance of these competing systems and to reverse acute decompensated HF. Blocking the RAAS and sympathetic nervous system (e.g., by administrating angiotensin-converting enzyme [ACE] inhibitors and β-blockers) and augmenting the natriuretic peptide system (e.g., pharmacologic dosing of BNP) all have positive therapeutic effects in patients with DCM and systolic HF.

Of the many causes of DCM (Table 18-1), the most common in the United States is ischemic heart disease. After an MI, the infarct scar may expand to develop into a large area of nonfunctioning myocardium during the first hours and days after an acute MI. During this time, left ventricular (LV) systolic function may be maintained by hypercontractility of the noninfarcted portion of the left ventricle. Longer term, over days to months to years, global remodeling occurs, resulting in a dilated and poorly contractile ventricle. In some cases, a ventricular aneurysm may form (Fig. 18-2). Because coronary artery disease (CAD) is such a frequent cause of DCM—contributing to approximately two thirds of all cases of HF—the nomenclature for DCM is often subdivided into ischemic cardiomyopathy (ICM) versus nonischemic cardiomyopathy. To be classified as an ICM, the burden of coronary disease must be in proportion to the systolic dysfunction. The definition of ICM is thus based on systolic dysfunction in patients with a history of MI, patients who have undergone revascularization procedures (coronary artery bypass surgery or percutaneous coronary intervention), patients with 75% or greater stenosis of the left main or proximal left anterior descending artery, and patients with 75% or greater stenosis of two or more epicardial vessels.

Table 18-1 Etiologies of and Evaluation for Dilated Cardiomyopathy

* Diseases that can belong to more than one type of cardiomyopathy (e.g., hypertrophic or restrictive).

Figure 18-2 Dilated cardiomyopathy after myocardial infarction.

ECG, electrocardiographic.

Other common etiologies for DCM are end-stage hypertensive heart disease (Fig. 18-3) and valvular heart disease (“valvular cardiomyopathy”). Less common etiologies include cardiotoxins such as alcohol and anthracycline and herceptin chemotherapies; abnormal metabolic state or endocrinopathies such as thyroid disease, diabetes, acromegaly, adrenal cortical insufficiency, pheochromocytoma; autoimmune diseases such as connective tissue diseases (e.g., scleroderma, systemic lupus erythematosus) and giant cell myocarditis; infiltrative diseases such as sarcoidosis, hemochromatosis, and amyloidosis; nutritional deficiencies; peripartum state; and familial/genetic diseases (e.g., muscular dystrophies, MELAS [mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke] syndrome, and other recently discovered associated chromosomal abnormalities).

Figure 18-3 Hypertension and cardiomyopathy.

When the etiology is thought to be an infectious agent because of a viral prodrome, the specific pathogen is often not identified, in which case the generic term “viral myocarditis” is commonly used. Histologically there is usually a diffuse inflammatory response with lymphocytes infiltrating the myocardium (Fig. 18-4). Specific pathogens that have been associated with DCM development include viruses such as Coxsackie B virus, enterovirus, adenovirus, parvovirus, HIV, and cytomegalovirus; and parasites such as trypanosomiasis in Chagas disease (the most common cause of infectious cardiomyopathy in South America) and Lyme disease. Although no specific bacterium or fungus has been known to cause cardiomyopathy, acute ventricular systolic dysfunction has been seen in the setting of sepsis, presumably due to the effect of endotoxins or other mediators.

Figure 18-4 Diphtheritic and viral myocarditis.

When no specific cause is found the DCM is described as “idiopathic cardiomyopathy.” This is a common designation; in most studies, it is second only to ischemia in the etiology of DCM. It is quite possible that a genetic susceptibility to environmental factors (ranging from infectious or toxic exposures to factors such as hypertension, diabetes, and cigarette smoke) contributes to the etiology of idiopathic cardiomyopathy. Some authors have suggested that genetic abnormalities may be important in up to 30% of cases of idiopathic DCM. Some familial conditions that predispose to DCM have already been described, such as the muscular dystrophies (e.g., Duchenne, Becker), X-linked DCM (e.g., other dystrophin gene mutations), and autosomal-dominant forms of familial DCM (e.g., lamin A/C gene mutation). With advances in our knowledge of genetics, it is anticipated that this list will grow rapidly in coming years.