ARVC/D is an inherited disease of the heart muscle that predominantly affects the right ventricle (RV). It is characterized by the progressive loss of the right ventricular myocardial tissue and its replacement for fibrous and fatty tissue.
Originally described by Fontaine and Marcus in 1982, ARVC/D is one of the leading causes of sudden arrhythmic death (SAD) in young people and athletes.
The disease was initially referred to as dysplasia because it was thought to be a congenital defect of the RV myocardial development. The subsequent finding that the disease is caused by a genetic defect in cardiac desmosomes allowed its description as cardiomyopathy, and its inclusion in the classification of cardiomyopathies by the American Heart Association (AHA).
The characteristic histopathological finding of ARVC/D is the progressive loss of RV myocardial tissue that is replaced by fibrous and fatty tissue.
The presence of irregular mononuclear inflammatory infiltrate (predominantly lymphocytic) is common, suggesting that the process may have an immunological mediation.
Contrary to what was observed in several forms of heart disease, in which there was a predominance of subendocardial muscle involvement, in the ARVC/D the greatest impairment is evident in the subepicardial region of the RV free wall. In addition, segments of the RV free wall that experience the greatest mechanical stress during the cardiac cycle are more impaired. In general, the trabecular muscles of the RV endocardial region and the interventricular septum (relevant aspect when differentiating from sarcoidosis) are spared. When the left ventricle (LV) is involved, myocardial degeneration and fibrosis are more visible in the subepicardium and in the middle myocardium of the lateral wall.
In the typical ARVC/D form, the LV is affected to a lesser degree than the RV; however, there are variants of the disease characterized by equivalent or even predominant involvement of the LV.
In most cases, ARVC/D is an inherited disease with an autosomal dominant pattern, with variable penetrance and expressivity. Among the probands diagnosed with the disease, a screening of first-degree relatives allows the identification of the presence of genetic mutations in approximately 50% of cases, regardless of gender. In a small number of cases, ARVC/D has an autosomal recessive pattern as part of a cardiocutaneous syndrome (Naxos disease or Carvajal syndrome), characterized by woolly hair and palmoplantar keratoderma.
As observed in other familial diseases, there is a high degree of heterogeneity in ARVC/D. To date, mutations in more than 12 genes have been identified as causing ARVC/D, although many of these genes are also responsible for other diseases.
Other patients with ARVC/D may have genetic abnormalities whose mutations have not been identified yet. These mutations may be inherited from family members or be the result of a new mutation.
An individual who has a ARVC/D mutation may or may not develop signs and symptoms of the disease. Recent studies suggest the presence of one or more additional genetic abnormalities in a single gene class, such as plakophilin-2 (PKP2), for example, which may determine when a mutation-carrier individual may be clinically affected by the disease.
Mutations may be in desmosomal and non-desmosomal genes. These mutations can be found and registered at the electronic address:
Genetic testing can be useful to determine the diagnosis in an individual suspected of having ARVC/D, and to identify relatives who do not have signs and symptoms of ARVC/D but who are carriers of the genetic defect. If an abnormal gene is identified in a proband and not in family members, it is unlikely that these members will have the disease based on this genetic abnormality.
The proband may have a second unidentifiable genetic defect. The gene most commonly related to the manifestation of signs and symptoms of ARVC/D is that of Not being able to identify all the genes associated with the pathology, as well as the existence of combined mutations, make ARVC/D a genetically complex disease, which makes family counseling difficult.
Periodic examinations should be performed on all individuals with genetic abnormalities for ARVC/D. It is recommended that cardiac evaluation be started between 10 and 12 years of age, because the manifestation of the disease before this age is rare. It is suggested that the tests include electrocardiogram, high resolution electrocardiogram (ECG-HR), echocardiogram and, if possible, CMR and 24-hour Holter. It is recommended that this evaluation is repeated every 2 years, between 10 and 20 years of age, and every 5 years after 20 years of age. The evaluation may be interrupted between 50 and 60 years of age because the presentation of the disease in this age group is uncommon.
An additional advantage of the genetic test lies in the aid of the differential diagnosis, as in the case of cardiac sarcoidosis, which can mimic the signs and symptoms of ARVC/D.
In addition, recent molecular biology studies have again put into perspective the debate about a possible pathogenic link between ARVC/D and Brugada syndrome (BS).
ARVC/D has an age-dependent penetrance and is typically manifested between the 3rd and 5th decade of life in the form of episodes of ventricular arrhythmias that may progress to SAD. The estimated prevalence ranges from 1:2,000 to 1:5,000, with a predominance in the Caucasian population and in participants in strenuous exercise or competitive sports.
Despite its low prevalence, ARVC/D accounts for approximately 5% to 20% of SAD cases in young people. The occurrence of ARVC/D in individuals younger than 12 years of age, or older than 60 years is extremely rare.
The disease is more malignant in men than in women, a finding that can be explained by a direct influence of sex hormones on the mechanisms involved in the phenotypic expression of the disease, or by differences in the amount and intensity of physical effort.
The natural history of ARVC/D, in its classic form (dominant RV), can be classified into 4 distinct phases, according to the progression of structural alterations and clinical symptomatology:
Recently, Calkins et al.
In general, the diagnosis of ARVC/D should be considered in any young or middle-aged individual presenting: (1) frequent ventricular ectopies; (2) ventricular tachycardia with LBBB morphology with superior or multiple QRS morphologies; and (3) SAD. This hypothesis is reinforced in cases of arrhythmic events that occur during exercise in individuals with inverted T-waves in right precordial leads.
Although these clinical indicators lead to the diagnostic hypothesis, the definitive diagnosis of ARVC/D remains a challenge because it is a disease with a low prevalence that lacks a single conclusive diagnostic test.
To standardize the clinical diagnosis of ARVC/D, in 1994 an international task force (TFC 94) proposed guidelines in the form of a qualitative scoring system with major and minor criteria.
| 1. Structural changes and global or regional dysfunction |
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| • Two-dimensional echocardiogram |
| □ Akinesia, dyskinesia or regional RV aneurysm associated with one of the following diastole measures: |
| – PLAX RVOT ≥ 32 mm (PLAX / BSA ≥ 19 mm/m2) or |
| – PSAX RVOT ≥ 36 mm (PSAX/BSA ≥ 21 mm/m2) or |
| – Fractional area change ≤ 33% |
| • CMR |
| □ Akinesia or regional RV dyskinesia or dyssynchronism of RV contraction associated with one of the following measures: |
| – RV EDV/BSA ≥ 110 mL/m2 (male) or ≥ 100 mL/m2 (fem.) |
| – RV ejection fraction ≤ 40% |
| • Right ventriculography |
| □ Akinesia, dyskinesia or RV aneurysm |
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| • Two-dimensional echocardiogram |
| □ Akinesia, RV dyskinesia or dissyncronism of RV contraction and one of the measures of diastolic function below: |
| – PLAX RVOT ≥ 29 to < 32 mm (PLAX/BSA ≥ 16 to < 19 mm/m2) or |
| – PSAX RVOT ≥ 32 to < 36 mm (PSAX/BSA ≥ 18 to < 21 mm/m2) or |
| – Fractional area change> 33% ≤40% |
| • CMR |
| □ Akinesia or regional RV dyskinesia or dyssynchronism of RV contraction and one of the following measures: |
| – RV EDV/BSA ≥ 100 to 110 mL/m2 (male) or ≥ 90 to 100 mL/m2 (fem.) |
| – RV ejection fraction > 40 to ≤ 45% |
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| • Residual myocyte count <60% by morphometric analysis (or <50%, if estimated), with fibrous RV free wall replacement in ≥1 sample, with or without fat replacement of endomyocardial biopsy tissue |
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| • Residual myocyte count of 60% to 75% by morphometric analysis (or 50% to 65% if estimated), with fibrous RV free wall replacement in ≥1 sample, with or without fat replacement of endomyocardial biopsy tissue |
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| • Inverted T waves in the right precordial vessels (V1, V2, and V3) or extending beyond V3 in individuals > 14 years of age (in the absence of RBBB-QRS ≥ 120 ms) |
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| • Inverted T waves in V1 and V2 in ind. > 14 years of age (in the absence of RBBB) |
| • Inverted T waves in V1, V2, V3, AND V4 in ind. > 14 years, in the presence of RBBB |
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| • Epsilon wave (reproducible low amplitude signals between the end of the QRS and the beginning of the T wave) in the right precordial leads (V1 - V3) |
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| • Late potentials on the ECG-HR in ≥ 1 of the 3 parameters in the absence of QRSd ≥ 110 msec in the 12-lead ECG: |
| □ Filtered QRS duration (fQRS) ≥ 114 msec |
| □ Duration of terminal QRS < 40 micro V ≥ 38 ms |
| □ Root-mean-square voltage of terminal 40 ms ≤ 20 micro V |
| • Duration of the final QRS portion ≥ 55 ms (measurement of nadir from S wave to end of ventricular depolarization - including R’) in V 1, V 2 or V 3 |
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| • Non-sustained or sustained VT with RBBB type morphology and upper axis |
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| • Non-sustained or sustained VT with RVOT morphology (LBBB type morphology and lower or indeterminate axis) > 500E vs/24h - 24h Holter |
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| • ARVC/D in first-degree relative who meets TFC2010 criteria |
| • ARVC/D pathologically confirmed in first degree relative (autopsy or biopsy) |
| • Identification of pathogenic mutation classified as associated or probably associated with ARVC/D in the patient under evaluation |
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| • History of ARVC/D in first degree relatives |
| • History of ARVC/D in a first-degree relative for whom it is not possible to determine whether it meets TFC criteria |
| • Sudden premature death (< 35 years of age) with suspected ARVC/D in first degree relative |
| • ARVC/D confirmed pathologically or through TFC in second degree relative |
Adapted from Pinamonti et al., 2014.
Although it is the current gold standard, TFC 2010 does not apply to the predominant forms of involvement of the left chambers
Patients are diagnosed as having ARVC/D if they present a total of 4 points considering that the major criterion value is 2 points; and the minor criterion, 1 point. Patients who reach the “3-point” score are classified as probable ARVC/D carriers, while those with 1 or 2 points are classified as not meeting the criteria for ARVC/D.
The initial evaluation consists of non-invasive examinations (ECG, ECG-HR, echocardiogram (ECHO) and/or CMR, 24-hour Holter and genetic analysis), while invasive examinations (right ventriculography and endomyocardial biopsy) are recommended only for individuals with high risk of the disease.
The tissue criteria used in TFC 2010, obtained by endomyocardial biopsy, focused on the severity of myocyte loss and the quantification of fibrosis.
The 12-lead ECG usually presents abnormalities in most patients with ARVC/D, indicating that electrocardiographic changes may precede the development of malignant ventricular arrhythmias (
In addition to electrocardiographic changes classically described in ARVC/D, other alterations can be identified in the baseline ECG: sinus bradycardia, P wave abnormalities (secondary to atrial involvement), and AV conduction disorder (more often first-degree AVB). The occurrence of severe atrioventricular conduction disturbance in ARVC/D is rare.
Several multicenter studies have shown that T-wave inversion in V1-3 is the most common ECG finding in ARVC/D. As a result, in TFC 2010, this T wave alteration was considered a major criterion for its diagnosis. The presence of inversion of the T wave only in V1 and V2 is a minor criterion. The inversion of T is secondary to the structural alterations of the RV. The observation of inversion beyond V3 translates a very advanced stage of the disease with severe RV dilation and possible LV involvement and can therefore be considered as indicative of worse prognosis (
One of the common findings of ARVC/D is complete or incomplete right bundle branch block (RBBB), especially in patients with severe structural impairment, and its presence may compromise the interpretation of ventricular depolarization abnormalities.
Epsilon wave, a low-frequency deflection that occurs at the end of the QRS and before the T wave (
Also included as a diagnostic criterion was the detection of a final activation delay, which is defined as prolongation of QRS duration (> 110 ms) and S wave (≥ 55 ms) in V1-3.
Increased susceptibility to ventricular tachyarrhythmia and SAD is the main characteristic of ARVC/D.
Frequent ventricular ectopy recording in the 24-hour Holter (> 500 VEx/24h) is considered a minor criterion.
Few studies have evaluated the frequency of supraventricular arrhythmia in ARVC/D. Although not related to mortality, the presence of atrial arrhythmia is associated with an increase in disease morbidity, and to the increase of inappropriate therapies by ICD. The incidence of atrial arrhythmia in ARVC/D varies between 14% and 24%, and atrial fibrillation is the most prevalent supraventricular arrhythmia (
A structural and functional evaluation is fundamental for the diagnosis of ARVC/D. Echocardiography, as a result of its accessibility, has been the image exam of choice for the beginning of the investigation of ARVC/D. However, the unique geometry and complex pattern of RV contraction, together with the increased recognition that structural abnormalities may not be apparent in the earlier stages of the disease, limit its diagnostic utility.
In the last decade, CMR has emerged as the image modality of choice in the ARVC/D investigation, because it allows for a non-invasive morphological and functional evaluation, as well as for analysis of the tissue changes (fibro-fatty transformation) that characterize this pathology.
This “pathological” connotation given to the existence of fat in the RV led to a high incidence of false positivity, especially when using the TFC criteria of 1994. 2010 TFC brought a better definition of the criteria to be sought in the CMR, leaving the use of specific protocols for fat screening in the right chamber aside.
Abnormalities of CMR in ARVC/D can be grouped into morphological and functional abnormalities (
| Functional abnormalities |
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| Regional abnormalities of RV wall movement |
| Focal aneurysms |
| RV Dilation |
| Diastolic/systolic dysfunction of the RV |
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| Intramyocardial fat infiltration |
| Focal fibrosis |
| Focal decrease of RV wall thickness |
| Wall hypertrophy |
| Trabecular disarrangement |
| Hypertrophy of the moderating band |
| RVOT diameter change |
RV: right ventricle; RVOT: right ventricular outflow tract.
In addition to the parameters included in the TFC 2010, there are other characteristic abnormalities of the ARVC/D that can also be visualized by the CMR. These parameters include the RV microaneurysms and the presence of an “accordion signal”, which is the focal wrinkling of the RVOT or RV free subtricuspid wall, which is more prominent during the systole. In addition, the presence of intramyocardial fat in the RV suggests ARVC/D; however, its presence is not specific and has been observed in the elderly, in chronic users of steroids, and in other cardiomyopathies.
Although the increase in late enhancement by gadolinium (LE) has been frequently detected in patients with ARVC/D, this criterion was not incorporated in 2010 TFC due to several limitations (RV thin walls, difficulty in differentiating fat from fibrosis, and irregular impairment of the RV). Despite this, we believe that it is of diagnostic value, especially those with biventricular or left dominant forms.
The increasing use of CMR is leading to the recognition that LV is more frequently changed than previously thought, leading to the expression arrhythmogenic cardiomyopathy. LV involvement is mainly located in the inferior and basal inferolateral walls, typically in the form of fat infiltration extending from the epicardium to the myocardium. These sites may also present LE, often without an association of ventricular wall motility abnormality.
The electrophysiological study (EFS) with programmed ventricular pacing is nowadays less used in the diagnostic and therapeutic evaluation of ARVC/D.
In spite of these recent results, 2010 TFC considers that the EFS should be taken into account for the diagnosis and evaluation of patients with suspected ARVC/D (class IIa) and may also be used in the risk stratification of asymptomatic patients (class IIb).
Recent studies using electroanatomic voltage mapping (bipolar and unipolar) to assess the existence and extent of the scar area in the RV have added interest in the use of EFS in the evaluation of ARVC/D (
This mapping technique proved to be useful in directing the region to be biopsied, as it is more sensitive than the CMR to identify myocardial scar areas, and in the differential diagnosis between an idiopathic VT of the RVOT, and a VT in a patient with ARVC/D. Nevertheless, due to the fact that it is an invasive, high cost and dependent operator, this diagnostic method should be reserved for cases with a high index of suspicion and an indefinite diagnosis.
The main differential diagnoses that should be considered in suspected cases of ARVC/D include: idiopathic RVOT VT, VT originating from the aortic cusps, and cardiac sarcoidosis.
The idiopathic RVOT VT is a generally benign form of ventricular arrhythmia without association with cardiac structural alteration.
Another differential diagnosis is sarcoidosis. This granulomatous disease, when it involves the heart, may be very similar to ARVC/D. Cardiac sarcoidosis should be suspected when cardiac manifestations are associated with mediastinal lymphadenopathy, extracardiac sarcoidosis, especially the pulmonary one, to severe atrioventricular conduction disturbances, and the presence of a scar in the interventricular septum in the imaging evaluation.
Other less frequent pathologies are: myocarditis; Brugada syndrome;
Recently, there has been much discussion of the phenotypic overlap between ARVC/D and Brugada syndrome.
The natural history of ARVC/D is predominantly related to electrical instability that can lead to arrhythmic SAD, especially in young athletes. At a later stage of the disease, progressive RV impairment and left ventricular involvement may result in right and/or left failure.
Data regarding the clinical progress come from small cohorts performed in tertiary centers and with a relatively short clinical follow-up. The total mortality estimated in these studies ranges from 0.08% to 3.6% per year. In community studies, which provide real-world data, annual mortality is < 1%.
Several factors were proposed for stratification of mortality risk and / or ventricular tachyarrhythmias in the ARVC/D. Corrado et al.34 developed a risk stratification categorized as high, intermediate and low risk. Thus, the authors sought to facilitate the early recognition of individuals who would benefit from ICD implantation (
The main clinical variables considered as independent predictors of worse evolutionary prognosis are: arrhythmic malignant events (SAD, cardiac arrest due to VF, appropriate intervention of ICD, or therapy of ICD for fast VT/VF); heart transplantation; and in some studies, unexplained syncope.
Other criteria, such as the result of genetic mapping and the invasive electrophysiological study, are still controversial in the literature.
The most important goals of treating patients with ARVC/D include:
Reduction in mortality from arrhythmic SAD or death from heart failure. Prevention of disease progression with consequent RV, LV or biventricular dysfunction and heart failure. Improvement of symptoms and quality of life by means of reduction/abolition of palpitations, VT relapses, or discharges from ICD (appropriate or inappropriate). Limitation of symptoms of heart failure and increased functional capacity.
Therapeutic options consist of lifestyle changes, pharmacological treatment, catheter ablation, ICD, and cardiac transplantation.
Competitive sports activity increases the risk of SAD by two to five times in adolescents and young adults with ARVC/D.
In a recent study, Ruwald et al. have established a link between SAD and intense effort in young individuals with ARVC/D. The authors followed 108 probands and demonstrated that competitive sports practice is associated with a significant increase in the VT/death combined outcome, and early phenotypic manifestation when compared to the inactivity of sedentary patients, or to the practice of recreational sports.
Early identification, prior to the symptomatic phase, of athletes affected by preparatory screening for the onset of physical activity and their disqualification from competitive sports activity may “save lives” (Italian experience).
It is postulated that myocyte intercellular adhesion impairment can lead to tissue and organ vulnerability with consequent death of myocytes, especially during mechanical stress that occurs during competitive sports activity.
Based on this, ITF recommends that patients with a definitive diagnosis of ARVC/D do not participate in competitive or resistance sports (class I), and may only participate in low intensity recreational sports (class IIa). The same restrictions can be applied to relatives with negative phenotype, even those that do not carry genetic mutations or with unseen genotype (class IIb).
The pharmacological treatment of ARVC/D consists of the use of antiarrhythmic drugs, beta-blockers and drugs used in the treatment of heart failure.
The goal of antiarrhythmic treatment in ARVC/D is to prevent arrhythmic events. Literature data suggest that antiarrhythmic drugs are ineffective in preventing the occurrence of severe tachyarrhythmias in high-risk patients with ICD.
Amiodarone alone or in combination with beta-blockers (because it combines the synergistic effects of class III antiarrhythmic and beta-adrenergic blockade properties) is the most commonly used therapeutic regimen for the treatment of ARVC/D.
Although not available in our country, flecainide, when associated with a beta-blocker, may be an effective antiarrhythmic strategy of control in patients that are refractory to treatment with amiodarone or sotalol and/or catheter ablation.
The ventricular arrhythmia in the ARVC/D often manifests itself in a situation of increased sympathetic tone. The current consensus is that beta-blocker therapy should be empirically instituted in all patients with a clinical diagnosis of ARVC/D.
Preload reduction drug therapy (usually diuretics and nitrates) is not yet part of the regular therapeutic arsenal of ARVC/D patients.
Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers have been advocated in patients with ARVC/D, especially in patients with evidence of structural impairment, although there are no studies demonstrating this indication in this specific condition.
Continuous oral anticoagulant use is indicated for secondary prevention in patients with documented intracavitary thrombus, atrial flutter or fibrillation type arrhythmias, or with a history of thromboembolic event.
VT catheter ablation is a therapeutic option for patients with continuing VT, or appropriate ICD shocks, despite optimal pharmacological therapy, including the use of amiodarone (
Long-term VT relapses have been attributed to the progressive nature of ARVC, which leads to the development of multiple arrhythmogenic foci over time. The epicardial location of many TV reentry circuits, which reflects the propensity of the ARVC lesions to originate and progress from the epicardium, may also explain the failure of conventional endocardial mapping and catheter-only endocardial ablation.
The increasing understanding of the arrhythmogenic substrate and the possibility of an epicardial approach allowed the observation of a significant increase in the success rate of catheter ablation in the treatment of VT in ARVC/D in recent years.
The advent of three-dimensional (3D) navigation systems has enabled a significant advance in VT ablation in ARVC/D patients. This technique allows the mapping of the endocardial and epicardial substrate using a colored tissue voltage map, particularly in the areas that are adjacent to the tricuspid valve region and the RVOT (
The technique used for ablation depends on the patient's hemodynamic response during tachycardia. In cases of well-tolerated VT, the electrophysiological mapping and activation mapping techniques with the 3D system are the most commonly used. In the case of a VT with hemodynamic instability, the treatment consists of modifying the arrhythmogenic substrate, with ablation being done on the possible channels between areas with different voltages in combination with the elimination of fractional endocardial and epicardial signals (
CDI implantation is the most accepted therapeutic strategy for ARVC/D patients, because the natural history of this pathology is characterized mainly by the risk of SAD, and only secondarily by contractile dysfunction that leads to progressive heart failure.
An observational study evaluated the clinical impact of ICD in the natural history of ARVC/D patients. At an average follow-up of 3.3 years, 24% of the patients had as an arrhythmic manifestation an episode of VF/VFL that would have been fatal in the absence of an ICD.
Despite these results, it is important to note that the survival benefit with ICD is obtained at the expense of a high prosthesis cost, and a significant rate of complications during follow-up, mainly related to the occurrence of inappropriate therapies around 4%/year and changes in the electrodes.
Unicameral ICDs are recommended to minimize the risk of complications related to prolonged use of this device, especially in young patients. Although the number of inadequate interventions can be reduced by a dual chamber detection system, the additional lead predisposes to a greater risk of short-and long-term complications.
Based on the results of studies that defined independent predictors of major arrhythmic events (i.e. SAD, cardiac arrest due to VF, sustained VT and appropriate ICD interventions), ITF proposed an ICD indication flowchart based on three categories (
It is rare for a ARVC/D patient to require a heart transplant. Transplantation would be indicated as final therapy in cases of severe heart failure, and when not responsive to pharmacological treatment and resynchronization therapy (in those patients with significant LV involvement), or in patients with intractable arrhythmias (eg, incessant VT, or VF storms refractory to catheter ablation and ICD therapy).
The last aspect to be considered in patients with ARVC/D is the prevention of disease progression. It is important to note that no study examined aspects that signal the evolutionary characteristics and the rate of progression of ARVC/D. Progression is slow but steady. It is suggested that the restriction of physical exercise may interfere with the rate of disease progression.
Significant advances were achieved if we consider the 30 years or more of the diagnosis of this pathology. However, given its rarity, many gaps persist.
It is possible to define some areas of interest that will allow better clinical management of patients and definition of the population at risk of sudden death:
Although not yet routinely available, the future possibility of genetic screening of patients and family members with clinical suspicion of ARVC/D may become of extreme relevance with potential implications for understanding the pathogenesis and management of affected individuals. Further refinement in the detection of morphological abnormalities will allow a greater refinement in the algorithm for the identification of ARVC/D carriers and a better understanding of their natural history. An improvement in imaging techniques (magnetic resonance imaging and echocardiography), and the possibility of MR follow-up in patients who received MR-compatible ICD implantation. Studies that try to analyze the phenotype-genotype correlation may clarify the natural history of the disease, and the greater propensity for the development of malignant arrhythmias and, therefore, define the best time to initiate a medical intervention.
The denomination of this cardiomyopathy has been discussed for years. The debate between naming it RVAD or RVAC is the representation of two different views of its pathophysiology, degenerative process or developmental abnormality. Probably both visions are involved; although the terminology initially proposed by Fontaine - “dysplasia” - is probably questionable, this term has been used and accepted for 40 years, and it will persist, incorporated to the history and description of this cardiomyopathy.