Fig. 5.1
(a). Hypertrophic cardiomyopathy . Left ventricular outflow tract view showing marked left ventricular hypertrophy, outflow tract obstruction, and systolic anterior motion lesion. (b) Closer view of systolic anterior motion lesion (arrow) in left ventricular outflow tract. (c) Myocyte disarray, hallmark histologic feature of hypertrophic cardiomyopathy (H&E; 40×)
Microvascular ischemia and myocardial fibrosis may be present, and intramyocardial arteries are often dysplastic.
Hemodynamically, patients with asymmetrical HCM often exhibit dynamic LV outflow obstruction either at rest or with physiological provocation. Mitral valvular regurgitation related to systolic anterior motion of the anterior leaflet of the mitral valve also may contribute to the outflow tract obstruction. With the onset of ventricular systole, there is normally rapid early ejection of blood into the aorta; then, as the anterior leaflet of the mitral valve contacts the ventricular septum, a marked reduction in outflow takes place until late systole. The degree of obstruction is affected by changes in myocardial contractility, afterload, and preload. An increase in contractility as from inotropic agents, a decrease in preload as from a Valsalva maneuver, or a decrease in afterload from standing increases the gradient between the left ventricle and aorta . The opposite effects in each of these changes results in a decreased gradient.
In both forms of the condition, in addition to the development of systolic dysfunction, the left ventricle becomes stiffer because of myocardial hypertrophy and fibrosis. Ventricular relaxation becomes limited. Adverse effects of systolic and diastolic dysfunction result.
The LV outflow obstruction may cause dyspnea, chest pain, and presyncope. Heart failure is uncommon, except in the subgroup of patients who develop end-stage disease, which manifests itself as extensive myocardial fibrosis, often with markedly dysplastic intramyocardial arteries. Sudden death may be the initial presentation of the disease and represents the target of preventive efforts.
On physical examination, the arterial pulses are sharp from the rapid ejection during the first part of systole. The apex may be displaced leftward and a left ventricular heave palpated. The first and second heart sounds are normal, but the third and fourth heart sounds are present in about half of patients. A systolic ejection murmur is present in most patients, its loudness increases with maneuvers, which accentuate contractility or reduce pre- or afterload (standing, straining on a Valsalva maneuver, nitroglycerine).
Echocardiography enables assessment of the degree and location of ventricular hypertrophy, the degree of obstruction, and its significance. Systolic and diastolic function can be assessed (◘ Fig. 5.2a, b). Mitral regurgitation can be recognized and its severity analyzed. If the ratio of the ventricular septum to free wall exceeds 1.2:1, the diagnosis of HCM is strongly suspected. Also, absolute measurements of the free wall and septum can be made and compared to normal.
Fig. 5.2
(a) Hypertrophic cardiomyopathy . Transesophageal echocardiogram. Four-chamber view. Markedly thickened interventricular septum (IVS) (arrow). The anterior leaflet of mitral valve displaced toward the IVS (SAM) narrows the LV outflow tract (arrows). (b) Color Doppler shows posteriorly directed jet of mitral regurgitation. (c) Cardiac MRI. Axial view. Marked thickness of IVS (arrow). In contrast, thickness of posterior wall (PWLV) is normal
Although echocardiography is an excellent technique for assessing patients with HCM, it is occasionally limited by poor acoustical windows, incomplete visualization of the left ventricular wall, and inaccurate evaluation of the left ventricular mass. MRI has the ability to evaluate wall thickness and the distribution of involvement better than echocardiography, especially in the anterolateral wall of the LV (◘ Fig. 5.2c).
In the differential diagnosis, glycogen storage diseases must be considered. Although uncommon, their clinical features and prognosis differ from classic hypertrophic cardiomyopathy. Mutations have been found in LAMP2 and PRKAG2 genes in patients with ventricular hypertrophy. In the LAMP2 variant, myocardial cells have prominent cytoplasm, many vacuoles, and pleomorphic nuclei (◘ Fig. 5.3). Patients present with symptoms similar to hypertrophic cardiomyopathy, but usually at a younger age, and the prognosis is poor. Patients have concentric hypertrophy and pre-excitation electrocardiographically. In the PRKAG2, variant shows ventricular hypertrophy and prolonged survival. Progressive conduction system involvement may require placement of a pacemaker and control of arrhythmias .
Fig. 5.3
Markedly hypertrophic myocytes with numerous cytoplasmic vacuoles, characteristic of glycogen storage disease, which may mimic hypertrophic cardiomyopathy clinically (H&E; 40×)
Arrhythmogenic Ventricular Cardiomyopathy
Historically, this condition has been called dysplasia, but this is inaccurate, and the term has largely been eliminated [8]. This is a common genetically determined myocardial disorder, which may involve primarily the right ventricle, primarily the left ventricle, or both. It is characterized by fibrofatty replacement of the right ventricular (RV) or left ventricular (LV) myocardium. In the early disease stage, structural changes may be absent or subtle. The changes are initially confined to a localized region of a ventricle. In the right ventricle, the area may be in the inflow tract, outflow tract, or apex. In the left ventricle, the findings are within the subepicardial myocardium (◘ Fig. 5.4a).
Fig. 5.4
(a) Arrhythmogenic cardiomyopathy /ventricular cross-sectional slice containing circumferential subepicardial fibrofatty replacement of the left ventricular free walls and compact myocardium of the septum, characteristic gross finding of arrhythmogenic cardiomyopathy, left ventricular dominant form (arrows point to subepicardial and septal fibrofatty replacement). (b) Arrhythmogenic cardiomyopathy. Cardiac MRI. Axial views. Right ventricular (RV) enlargement. Fatty replacement (arrows) of cardiac muscle in RV wall
Patients are often asymptomatic in the early disease stages but are at risk of sudden death, particularly with exercise. In the electrical phase, individuals present with symptomatic arrhythmias and morphological RV abnormalities, recognized by imaging of the heart (◘ Fig. 5.4b). Later still, with more diffuse involvement, biventricular heart failure develops, resembling dilated cardiomyopathy.
Arrhythmogenic cardiomyopathy (AC) is familial with autosomal dominant inheritance. There are recessive forms, however, including Naxos disease and Carvajal syndrome.
Left Dominant Arrhythmogenic Cardiomyopathy (LDAC)
As the study of ARVC progressed, it became evident that the spectrum was broader than originally thought. Recently, forms of predominant involvement of the left ventricle have been reported [9]. These patients tend to have inverted T waves in the lateral and inferior EKG leads and ventricular arrhythmias of left ventricular origin. The frequency and severity of arrhythmias are greater than the extent of left ventricular dysfunction. There is an enlargement of the left ventricle with reduced systolic function. Dyskinesis may coexist. Pathologically, this form of the condition is characterized by subepicardial fibrofatty replacement of the myocardium and compact myocardium of the septum. These changes are often circumferential but may be confined to the free walls only. The posterior wall is the most frequently involved wall. Myocyte degeneration is present in myocytes entrapped within the areas of fibrosis, and foci of myocarditis are often present (◘ Fig. 5.5).
Fig. 5.5
(a) Fibrofatty replacement of the subepicardial myocardium of the free wall of the left ventricle in a band-like distribution, hallmark histologic finding of arrhythmogenic cardiomyopathy, left ventricular dominant form (Masson’s trichrome; 1.25×). (b) Photomicrograph demonstrating degeneration of entrapped myocytes within the areas of fibrofatty replacement (at arrows), a histologic requirement of arrhythmogenic cardiomyopathy (Mason trichrome; 40×)
LV Noncompaction (LVNC)
LVNC, previously termed “spongy myocardium,” is a rare cardiomyopathy that can be diagnosed at any age. It probably results from arrest of the compaction process during development. During cardiac development, the myocardium is trabeculated and gradually becomes denser and compacted. If this process does not occur, a spongiform cardiomyopathy results.
LVNC is characterized by a thin, compacted subepicardial layer and an extensive noncompacted subendocardial layer. The subendocardium has prominent trabeculations and deep recesses that communicate with the cavity of the LV, particularly at the apex and mid-portion of the ventricle (◘ Fig. 5.6a, b). It does not communicate with the coronary circulation. The compacted section may be thinned. A ratio of noncompacted to compacted myocardium of 2:1 at the end of systole has been considered a criterion for diagnosis. The trabeculae have the same appearance as the noncompacted myocardium and move synchronously with ventricular contraction. A second form characterized by hypertrabeculation also is recognized.
Fig. 5.6
(a) Noncompaction . Left ventricular apex with poorly formed compact myocardium, large trabeculae, and apical mural thrombus. (b) Photomicrograph from (a) demonstrating the large trabeculae and intratrabecular recesses with mural thrombus. There is marked myocardial fibrosis (Mason trichrome; 1.25×). (c) Left ventricular noncompaction. Cardiac MRI. Axial view. Noncompacted areas (arrows) show prominent trabeculation and deep intertrabecular recesses
Since it was relatively recently described, we do not know the exact occurrence of LVNC, but it may be present in 1:500 individuals. It may be isolated or coexist with cardiac abnormalities. The proportion coexisting with other abnormalities of the heart may be exaggerated, since it is identified by echocardiography or other imaging techniques which many cardiac patients undergo. The prevalence lies between 0.014 and 1.3 % in the general population as observed on echocardiographic examinations.
Symptoms of LVNC vary. Many patients are asymptomatic. Symptomatic patients can have congestive heart failure, life-threatening ventricular arrhythmias, and embolic events [10]. There may be both systolic and diastolic dysfunction contributing to the failure. In children, Wolff-Parkinson-White syndrome and ventricular tachycardia occur more commonly, while atrial fibrillation and ventricular arrhythmias are found in adults. Embolization is secondary to mural thrombi in the trabeculations, ventricular dysfunction, or atrial fibrillation. Sudden death is uncommon in this disease.
Both familial and nonfamilial forms have been reported [4]. In familial forms, inheritance may be autosomal dominant, X-linked, or mitochondrial. A number of genes may be associated with LVNC. Family members of a patient with this condition should be screened to identify individuals who may be asymptomatic. The increased incidence of neuromuscular diseases in patients with LVNC suggests careful clinical evaluation of the muscular and neurological systems.
In making this diagnosis, it is critical to have images of the cardiac apex. These are obtained best by magnetic resonance imaging (◘ Fig. 5.6c).
Molecular Cardiomyopathies
Ion Channelopathies
Ion channelopathies are probably more common than HCM. They are inherited disorders causing arrhythmias [11]. They are associated with mutations of the genes encoding ionic channel proteins, which modulate cell membrane transit of sodium, potassium, and calcium ions. Several specific conditions have been identified which can be identified by their electrocardiographic features. They are associated with cardiac dysrhythmias, syncope, and sudden death. They may be transmitted in autosomal dominant or recessive patterns; however, autosomal dominant is more common.
The most common of these is the long QT syndrome in which the QT interval is prolonged. It is associated with a polymorphic ventricular tachycardia and a considerable risk of syncope and sudden death. Many mutations are associated with this condition. It can coexist with deafness and is termed the Jervell and Lange-Nielsen syndrome [12], or, without deafness, called Romano-Ward syndrome [13]. The former is an autosomal recessive trait and the latter an autosomal dominant trait. Several individual genes controlling primarily potassium channels have been identified and, if found, these are useful in making the diagnosis.
Another channelopathy is the Brugada syndrome [14]. It has a characteristic electrocardiographic pattern showing complete right bundle branch block and ST segment elevation in the anterior precordial leads. It is associated with sudden death. The Brugada syndrome is found in Southeastern Asian men and, in that culture, has been given various names associated with beliefs about the causation.
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