Left Ventricular Involvement

ARVC/D has been classically defined as a selective disorder predominantly affecting the right ventricle [1]. Since the early description in the 1980s, left ventricular involvement has been recognized clinically with greater and greater frequency [2,43-45].

From the pathological point of view, several case reports of ARVC/D with histologic abnormalities of the left ventricle have been published [46-53], even in the absence of heart failure.

In the Padua series, Basso et al. [4] indicated that left ventricular free wall involvement is present in nearly half of cases, all with a fibro-fatty pattern (Table 4.1) (Figs. 6.2, 6.3, 6.8). Hearts with left ventricular involvement were from older individuals, were slightly heavier and more likely associated with a clinical picture of congestive heart failure. Corrado et al. [7] found a 76% incidence (32 cases) of left ventricular involvement in a study of 42 hearts from six European centers, all with fibro-fatty or mainly fibrous pattern. Fifteen showed only histologic changes, whereas 17 had both gross and histologic evidence of left ventricular involvement.

A study from Canada by Lobo et al. [54] found that 45% of hearts of ARVC/D showed left ventricular fibrous scars, although coronary atherosclerosis coexisted in some. In another North American series by Burke et al. [23], microscopic subepicardial left ventricular involvement was present in 64% of fibro-fatty ARVC/D. In a French series of sudden death due to ARVC/D, Fornes and colleagues [55] reported a 40% incidence of left ventricular disease. However, in all series a severe diffuse biventricular involvement, mimicking dilated cardiomyopathy requiring heart transplantation, appears to be rare. Recently, d'Amati et al. [25], in a series of transplanted hearts, found grossly biventricular involvement in 87% of cases with the so-called cardiomy-opathic pattern vs. 9% of those with the "infiltrative" (fatty) pattern.

To characterize the pathological features of left ventricular involvement in this disease, Lobo et al. [56] reviewed 17 hearts with ARVC/D, all with involvement of the left ventricle, seven of whom had evidence of left ventricular disease only at histology. In the involved areas, the left ventricle or ventricular septum were of nearly normal thickness. Full thickness transmural fatty replacement of the left ventricular myocardium was never observed nor were left ventricular aneurysms. At histology, the myocardial changes of the left ventricular free wall were typically subepicardial or midmural, with a greater amount of fibrous tissue deposition as compared to the right. On the basis of these findings, the authors concluded that pathologists may miss left ventricular involvement on gross examination, thus suggesting that multiple histological sections from the septum and left ventricular free walls should always be taken and observed.

There is a question of whether we should recognize within the spectrum of ARVC/D a condition of "pure" left ventricular involvement, without any ev

Fig.4.8 • A 35-year-old man who died suddenly with an in vivo diagnosis of ARVC/D with biventricular involvement belonging to a family found positive at genetic screening for desmoplakin mutation. (a) 12 lead ECG shows low voltage QRS complexes and inverted T waves in the lateral leads. (b) In vitro spin-echo cardiac magnetic resonance, short axis cut, shows biventricular dilatation, transmural fatty infiltration of the right ventricular free wall and spots of fatty tissue in the postero-lateral left ventricular free wall.(c) Panoramic histologic section of the right ventricular free wall transmural fibro-fatty replacement of the myocardium (Heidenhain trichrome).(d) Panoramic histologic section of the left ventricular lateral wall:fibro-fatty with prevalent fibrous tissue replacement is evident in the subepicardial and midmural layers (Heidenhain trichrome)

Fig.4.8 • A 35-year-old man who died suddenly with an in vivo diagnosis of ARVC/D with biventricular involvement belonging to a family found positive at genetic screening for desmoplakin mutation. (a) 12 lead ECG shows low voltage QRS complexes and inverted T waves in the lateral leads. (b) In vitro spin-echo cardiac magnetic resonance, short axis cut, shows biventricular dilatation, transmural fatty infiltration of the right ventricular free wall and spots of fatty tissue in the postero-lateral left ventricular free wall.(c) Panoramic histologic section of the right ventricular free wall transmural fibro-fatty replacement of the myocardium (Heidenhain trichrome).(d) Panoramic histologic section of the left ventricular lateral wall:fibro-fatty with prevalent fibrous tissue replacement is evident in the subepicardial and midmural layers (Heidenhain trichrome)

idence of right ventricular abnormalities, and whether we should update the disease nomenclature [57, 58]. The diagnosis of ARVC/D has been always a challenge both clinically and at autopsy. For this reason, standardized diagnostic criteria have been proposed and, as far as pathology is concerned, the presence of "transmural fatty or fibro-fatty myocardial replacement of the right ventricular free wall" has been usually considered the conditio sine qua non for diagnosis. This could explain why several cases with isolated left ventricular disease escaped the diagnosis of ARVC/D and were labeled as chronic myocarditis. Interestingly, in a study of ARVC/D as a cause of sudden death in Spain, Aguilera et al. [59] widened the inclusion criterion, by considering subepicardial or transmural fibro-fatty replacement of the ventricular, either left or right, myocardium. Based upon this definition, they found that ARVC/D accounted for 21 out of 264 (6.8%) sudden deaths in people less than 35 years of age. Noteworthy, it was mostly consistent with biventricular disease (62%), whereas isolated left ventricular or right ventricular involvement were each present in 19% of cases.

Collett et al. [60] reported two cases of sudden cardiac death with histopathological analysis, one showing extensive left ventricular fibrolipomatous in filtration in the setting of a completely normal right ventricle. In 1995 Okabe et al. [61] first proposed the possibility of isolated "arrhythmogenic left ventricular dysplasia," by reporting an unusual case of a patient who presented with ventricular tachycardia originating from the left ventricle who had severe left ventricular dysfunction and who eventually developed intractable heart failure. At autopsy, there was fibro-fatty replacement confined to the left ventricle, with normal coronary arteries. Since then there have been other articles, mostly single case reports with isolated or prevalent left ventricular involvement [62-65]. Recently our group reported the autopsy findings of a proband who died suddenly and belonged to a family with desmoplakin mutation, that showed massive left ventricular myocardial injury and only mild right ventricular involvement [36]. Soon after, Norman et al. [57] reported a family with a desmoplakin mutation, in which the proband presented with sudden death and there was fibro-fatty replacement of the left ventricular myocardium, thus introducing the term of arrhythmogenic left ventricular cardiomyopathy.

We must acknowledge that the left ventricle is more commonly involved in ARVC/D than initially thought and it should be carefully studied with pathologic investigation, both in patients dying suddenly and in those who die or are transplanted due to congestive heart failure. As emphasized previously, in the few publications in which the hearts came from genotyped patients, there was evidence of biventricular disease, either prevalent right or left. More often left ventricular involvement consists of either isolated or prevalent fibrous tissue deposition in the subepicardial or midmural layers, as compared to the usual pathology from the right side. These data suggest that the various locations and amounts of the fibro-fatty tissue are different expressions of the same disease entity. Therefore, consideration should be given to the use of terms like arrhythmogenic cardiomyopathy [66] or desmosomal cardiomyopathy [67].

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