Natural History Mode of Death and Risk Stratification

It is now appreciated that the spectrum of clinical presentation of ARVC/D is characterized by heterogeneity. Individual patients may be symptomatic or asymptomatic and, in addition, asymptomatic relatives of patients with ARVC/D may have ARVC/D. Given this relatively diverse phenotypic expression, risk stratification for sudden death or arrhythmia is crucial in the clinician's decision whether to recommend implantation of an ICD.

Cardiovascular death is a recognized complication of ARVC/D [1], and generally takes the form of SCD, often without any precursor symptoms [2-4]. In a series of patients with SCD under 65 years of age, ARVC/D is reported as the cause of death in 3%-20% [5-7]. Recent single center series aimed at defining the natural history of ARVC/D have demonstrated that cardiac death occurred in approximately 16% of their cohorts during follow-up of between 4 and 8 years (annual mortality rate, 2.3%-4%) [8, 9]. These observations may suggest that, as a group, patients with ARVC/D are at increased risk of SCD rel ative to other cardiomyopathies and thus should be offered an ICD. Among the many questions that need to be considered when managing patients with ARVC/D are: (1) which patients are at highest risk for arrhythmic death; and (2) whether implantation of an ICD necessarily confers an improvement in survival in patients with ARVC/D.

Risk stratification for sudden cardiac death in ARVC/D has been addressed in small natural history series of cases from tertiary referral centers [8,9]. Such series may potentially overestimate annual mortality, and may disproportionately represent higher risk patients referred for evaluation and management. Nevertheless, the observations derived from such studies are instructive, particularly in light of the considerable length of follow-up, allowing valuable insights into the natural history of ARVC/D. Sudden death (presumably arrhythmic) accounts for the majority of cardiovascular deaths in ARVC/D, as it has been shown in earlier series. However, other modes of cardiovascular death are also encountered. In one series of 130 patients, followed for 8.1 ±7.8 years, of which ten (7.7%) patients received an ICD, a surprisingly high prevalence of death caused by heart failure (HF) emphasizes the propensity for development of right and/or left ventricular dysfunction over time. Of the 24 patients who died, 21 died of cardiovascular causes: 59% of these were deemed to have died from progressive HF, and 29% experienced sudden death [8].

In a second group of 61 patients followed for 55±47 months, ten patients died of cardiovascular causes: eight died of presumed arrhythmic causes (SCD), and two died of advanced heart failure [9]. Thirty-nine percent of this cohort had an ICD.

It is not clear whether the former finding represents the true natural history of the disease, or a change in the course of the disease due to contemporary heart failure and/or arrhythmia management (several patients in both series received ICDs and were on antiarrhythmic drugs). It is plausible that progressive myocardial dysfunction may result in a higher incidence of arrhythmias over time. Howev er, conclusive clinical observations to support this notion in this group are not yet available.

Clinically relevant risk factors may be identified, largely from observational series. The risk factors most significantly linked with sudden death in two recent series include severe right ventricular dilatation and reduction in right ventricular function [8, 9]. Left ventricular involvement on echocardiography or clinical left ventricular failure, left atrial dilatation, previous aborted cardiac death or ventricular fibrillation (VF), and (to a lesser degree) certain electrocardiographic markers (including first degree heart block, bundle branch block, and long QRS duration in lead V1) also serve as markers of risk [8,9].

These risk factors are important in the clinical decision process of whether or not to implant an ICD. Figure 20.1 illustrates survival data in the form of a Kaplan-Meier analysis from a group of 130 ARVC/D patients followed over a mean of 8.1±7.8 years. From these observations it is evident that the group of patients with ventricular tachycardia (VT) and clinical heart failure (left or right) fared significantly worse than those without VT or those with VT but without heart failure. Figure 20.2 presents data from another series of ARVC/D patients followed for a mean of 55±47 months. This also illustrates that the presence of congestive heart failure or left ventricular abnormalities on echocardiography predict worse survival.

  1. 20.1 • Kaplan-Meier analysis of cumulative survival from cardiovascular death according to a combination of risk factors in a series of patients with ARVC/D: Group I: absence of VT (solid line); Group II: VT without signs of HF (clinical signs of RV failure and/or LV dysfunction) (dashed line); Group III:VT and signs of HF (dotted line). From [8] with permission from Lippincott Williams & Wilkins
  2. 20.1 • Kaplan-Meier analysis of cumulative survival from cardiovascular death according to a combination of risk factors in a series of patients with ARVC/D: Group I: absence of VT (solid line); Group II: VT without signs of HF (clinical signs of RV failure and/or LV dysfunction) (dashed line); Group III:VT and signs of HF (dotted line). From [8] with permission from Lippincott Williams & Wilkins

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Fig. 20.2 • (a) Kaplan-Meier survival analysis (cumulative proportion surviving) of 57 patients with ARVC/D, comparing the group of patients with congestive heart failure (CHF) (n=7) with the group without CHF (n=50) (p<0.0001).The numbers of patients remaining at risk of death or heart transplantation during follow up are listed beneath the plot.(b) Kaplan-Meier survival analysis (cumulative proportion surviving) of 57 patients with ARVC/D, comparing the group of patients with left ventricular abnormalities (LVA) (n=23) with the group without LVA (n=34) (p=0.0003).The numbers of patients remaining at risk for death or heart transplantation during follow-up are listed beneath the plot. Reproduced from [9] with permission from the BMJ Publishing Group

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