Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiomyopathy characterised by fibrofatty replacement primary of the right ventricular myocytes and electrical instability associated with ventricular tachycardia (VT). Early reports have emphasised the localised right ventricular involvement but it is now well-known that ARVD/C can progress to diffuse right ventricular and left ventricular involvement with overt left and right heart failure . The estimated prevalence of ARVD/C in the general population is about 1 in 5000 . The disease affects young adult men approximately three times more frequently than women . A higher prevalence (up to 0.8%) has been reported in certain parts of Italy (Veneto) and Greece (Naxos Island) [4, 5]. ARVD/C is a major cause of sudden cardiac death (SCD) in the young and athletes .
Arrhythmogenic right ventricular dysplasia, also called right ventricular cardiomyopathy, is a genetically determined heart muscle disease, characterised by life-threatening ventricular arrhythmias in apparently healthy young people. The primary myocardial pathology is that the myocardium of the right ventricular free wall is replaced by fibrous or fibrofatty tissue, with scattered residual myocardial cells. Right ventricular function is abnormal and in severe cases is associated with global right ventricular dilation and overt biventricular heart failure. Although still relatively rare, arrhythmogenic right ventricular cardiomyopathy is a well recognised cause of sudden unexpected peri-operative death. In this review, we describe the basic characteristics of this disease, emphasising the diagnosis and we offer some suggestions for the anaesthetic management of these patients in the peri-operative period.
ARVD/C is characterised by diffuse or segmental loss of right ventricular myocytes with replacement of fibrofatty tissue and thinning of the right ventricular wall (Fig. 1). The process begins at the epicardium and spreads gradually through the myocardium toward the endocardium. The most commonly affected areas in the right ventricle (RV) are the RV outflow tract, apex, and the subtricuspid area. The left ventricle (usually posterobasal wall or apex) and the interventricular septum may be involved, typically in later stages of disease . The myocardium of the trabeculae and the coronary arteries are not involved in the disease process . Whether the specialised conduction system is involved remains controversial .
A familial predilection of ARVD/C has been recognised. Evidence has been found for autosomal dominant inheritance with variable penetrance and polymorphic phenotypic expression in about 50% of cases . Two autosomal recessive forms, less common, called Naxos Disease and Carvajal Syndrome have been also described [5, 9]. Until now, 11 different ARVD/C loci have been described on the human genome. Nine of these are connected with genes encoding for any of the five desmosomal proteins: plakophilin-2, desmoglein-2, desmoplakin, desmocollin-2 and junctional plakoglobin. Desmosomes comprise multiple proteins that form a macromolecular complex attaching cells together and linking the intermediate filaments of neighboring cells (desmin in cardiac myocytes) at the intercalated disc. The desmosomal disruption associated with possessing these alleles causes cardiomyocyte death in response to mechanical stress and offers a potential explanation for the increased prevalence in athletes and electrical instability during exercise, which is seen in ARVD/C.
Only two extradesmosomal genes have been identified in ARVD/C. The first is the cardiac ryanodine receptor (RYR2) responsible for release of calcium from the sarcoplasmic reticulum into the cytosol. A mutation of this receptor results in an increased risk of after-depolarisation and stress-induced polymorphic VTs . The second gene decodes for the transforming growth factor (TGF-β3), a pleotropic cytokine involved in tissue differentiation and repair with fibrosis. Mutation of TGF-β3 results in increased expression of this cytokine and may explain the excessive fibrosis observed in this disease .
Despite these genetic advances, no specific genetic testing for ARVD/C is yet available and data from genotype-phenotype studies are too limited to permit speculation on the possible impact of genetic analysis on risk stratification or therapy.
Clinical presentation and natural history
The clinical spectrum of ARVD/C can range from symptomless presentation detected at the time of screening of relatives to sudden cardiac death. This heterogeneity is thought to be related to both the variable temporal progression of the disease and variable gene expression. If it occurs, clinical presentation is most common between the ages of 10–50 years, with a mean of ∼30 years . The most common symptoms are palpitations, syncope, atypical chest pain and dyspnoea. Other signs are right ventricular failure or arrhythmias (Fig. 2). It has been proposed that ARVD/C passes into four phases, and a patient may be accidentally discovered in any phase :
- 1 The ‘concealed’ phase: characterised by subtle right ventricular structural abnormalities with or without VTs. Sudden cardiac death may occasionally be the first manifestation of the disease;
- 2 ‘Overt arrhythmia’ phase: in which symptomatic ventricular arrhythmias may be associated with overt structural and functional RV abnormalities;
- 3 Isolated right heart failure;
- 4 Biventricular failure: with significant left ventricular involvement mimicking dilated cardiomyopathy.
The annual mortality rate of patients with ARVD/C is about 3%, which can be decreased by medical therapy to 1% . Sudden cardiac death accounts for one-third of deaths, with chronic heart failure responsible for the remainder . Although risk stratification is still incomplete, several clinical variables have been proposed to indicate a higher risk of sudden death or VT: a history of cardiac arrest or syncope, severe ventricular dysfunction, younger age at diagnosis, family history of juvenile sudden cardiac death, certain ECG features (discussed below), inducibility of VT during programmed stimulation.
ARVD/C should be considered as a diagnosis in patients with symptomatic or asymptomatic VT (of left bundle branch block, LBBB, configuration) in the absence of apparent heart disease, especially if there is a family history. Post mortem, it should be considered a diagnosis in cases of sudden cardiac death particularly during exercise or peri-operatively, especially in young men. Proposed diagnostic criteria based on family history as well as structural, functional, and electrocardiographic abnormalities [15, 16]. Numerous diagnostic modalities assist in the diagnosis and evaluation of ARVD/C of which the ECG, echocardiography, angiography, radionuclide ventriculography, computed tomography and magnetic resonance imaging (MRI) are useful but depend in part on availability of local expertise.
Emergency physicians and anaesthesiologists should at least be aware of common ECG patterns in ARVD/C. About ∼50% of patients have an abnormal ECG at presentation  but within 6 years of diagnosis, virtually all patients will have one or more of the following findings during sinus rhythm:
- • complete or incomplete right bundle branch block, RBBB;
- • QRS prolongation (in the absence of RBBB);
- • epsilon wave in leads V1-V2 (Fig. 3);
- • T-wave inversion in leads V1-V3;
- • delayed (i.e. ≥ 55 ms) S-wave upstroke in leads V1-V3.
Strategies for treatment appear to be based on local experience gained at the different centers. Broadly, the main therapeutic options are the same as for any arrhythmia and/or superimposed heart failure. Thus, implantable cardioverter-defribrillator (ICD) is suitable for the secondary prevention of sudden cardiac death in those who have experienced a sustained VT and for primary prevention in selected high risk patients. Antiarrhythmic agents (sotalol or amiodarone) may be effective for sustained VT in patients in whom (ICD) implantation is not feasible, or as adjunctive therapy in patients with an ICD who have frequent VTs and ICD shocks . Catheter ablation of diseased areas of myocardium that may be acting as an arrhythmogenic focus may be considered in case of drug intolerance or ineffectiveness. When the disease has progressed to ventricular failure, treatment consists of the current therapy for heart failure, including diuretics, beta-blocking agents, angiotensin-converting enzyme inhibitors, and anticoagulants. In case of refractory heart failure and/or arrhythmias, cardiac transplantation may be the only remaining alternative. Occasionally, disconnection surgery or cardiomyoplasty is a useful therapeutic option .
ARVD/C and anaesthetic considerations
Although ARVD/C is a fairly rare heart disease, it seems that ARVD/C is one of the main causes of sudden unexpected peri-operative death. Among 50 forensic autopsies performed after peri-operative death, ARVD/C was detected in 18 patients in one series . This probably overestimates the incidence because autopsies are performed more frequently when the cause of peri-operative death is unknown. Nonetheless it is interesting that all these cases underwent relatively low-risk surgery (e.g. appendectomy, epistaxis, Caesarean section) and the patients had no prior cardiac history. Four patients died at induction of anaesthesia, nine during the surgical procedure, five within 2 h after surgery was complete. No data regarding the anaesthesia protocol were presented. There are only a few reports of patients with known ARVD/C undergoing surgical procedures under general or regional anaesthesia [21–26]. Sudden unexpected peri-operative death can clearly occur in patients with ARVD/C who have previously undergone multiple anaesthetic procedures without complications [22, 24].
Given this extremely limited evidence base, we can make only general suggestions for the conduct of anaesthesia. It is useful to regard ARVD/C as a state of actual or impending heart failure with a propensity to serious arrhythmias.
Patients with known ARVD/C who present for elective surgery with clear evidence on ongoing symptoms of heart failure or arrhythmias (e.g. polymorphic extrasystoles, short or sustained VT) should have the procedure postponed until the arrhythmia and the symptoms are controlled and the patient optimised. Because it is known that acute emotional stress can trigger ARVD/C , anxiolysis before induction of anaesthesia seems prudent. If a patient is being actively treated with beta-blockers for ARVD/C, they should continue to beta-blocked peri-operatively and should be given their usual dose the morning of the surgery.
When peri-operative death occurs as a result of refractory arrhythmias or asystole, an autopsy should be done, and when ARVD/C is diagnosed, familial counseling should be given.
There are insufficient data in the literature to make specific recommendations on the use or avoidance of any particular anaesthetic drug or technique. Thus, whether general or regional anaesthesia is used depends upon the procedure and the degree of cardiac dysfunction. It is perhaps better to avoid epinephrine as an adjunct to the local anaesthetic and perhaps also avoid large doses of bupivacaine to reduce risks of potential cardiac toxicity .
There is likely to be a lower threshold for considering invasive arterial blood pressure monitoring, transesophageal echocardiography (TOE) or central venous pressure monitoring to help guide intra-operative decision-making, especially for prolonged or major surgery. TOE may also provide additional diagnostic information in patients with intra-operative cardiac arrest and may directly guide specific, potentially life-saving therapy . Pulmonary artery catheters should probably be avoided in patients with ARVD/C as these patients are likely more susceptible to complications of catheter placement (mainly VTs induction and ventricular perforation) and the benefits of any information gained from the catheter are probably outweighed by the risks.
Propofol appears suitable for induction and maintenance of anaesthesia in patients with ARVD/C  and etomidate or ketamine have a generally favorable cardiovascular profile. We make one comment relating to the use of muscle relaxants and volatile anaesthetics: as discussed above, one type of ARVD/C is linked with mutations in the cardiac isoform of the calcium-release channel, RYR2. Mutations of the skeletal muscle RYR1 isoform predisposes carriers to malignant hyperthermia, triggered by succinylcholine or volatile anaesthetics. However, these drugs fortuitously do not appear to have a clinically significant effect on cardiac intracellular calcium handling even if they are administered to patients carrying the abnormal cardiac RYR2 allele . There is probably an isoform-specific effect of these anaesthetics on RYR1 alleles. The newer neuromuscular blocking drugs such as vecuronium, cis-atracurium, doxacurium, and rocuronium have virtually no cardiovascular side effects and can be safely used in patients with ARVC/D. Pancuronium is probably not the first choice because it increases sympathetic activity. Halothane, as a more potent negative inotropic agent than other halogenated agents, is, arguably, best avoided.
Implantable devices and arrhythmias
The anaesthetic management of patients with an ICD has been reviewed recently [32–34]. There are no additional issues specific to the management of patients with ARVD/C and an ICD, so where a patient with ARVD/C has an ICD in situ previous recommendations are relevant [32–34].
In the absence of an ICD, cardiovascular collapse during anaesthesia in patients with ARVD/C could be relatively unresponsive to resuscitation because of apoptosis. Apoptotic myocytes are frequently found in the regions of myocardium which are not subjected to the invasion of adipocytes and fibrosis, and probably the loss of myocytes through apoptosis occurs as a primary process before the fat and fibrous tissues fill the cellular space . It is known that apoptosis may promote arrhythmogenesis in several ways . In the process of apoptosis, a myocytes passes through phases of increased excitability. Furthermore, from a random grouping of several such apoptotic cells, the process of normal activation in that area of the heart must be deranged and redirected in a way that would provide a suitable anatomical substrate for re-entrant arrhythmias. Moreover, the apoptotic death of nerves of gangli in the heart may have their own influence on the function of both dying and surviving cardiomyocytes.
ARVD/C is a rare condition encountered during anaesthesia, but the highly lethal complications associated with it should be kept in mind, especially as the condition may explain a relatively high proportion of unanticipated peri-operative sudden cardiac death. The anaesthetic management should be based on as accurate a risk stratification as possible, itself largely based on the individual patient’s history and the surgical procedure planned. Close cooperation between anaesthetists, cardiologists and surgeons is essential to provide optimum care of these patients.