Prediction of Life-Threatening Ventricular Arrhythmia in Patients With Arrhythmogenic Cardiomyopathy. A Primary Prevention Cohort Study

Objectives

The aim of this study was to identify clinical, electrocardiographic (ECG) and cardiac imaging predictors of first time life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy (AC).

Background

The role of clinical, electrocardiographic, and cardiac imaging parameters in risk stratification of patients without ventricular arrhythmia is less well defined.

Methods

AC probands and mutation-positive family members with no documented ventricular arrhythmia from the time of diagnosis to first event were included. Clinical, electrocardiographic and cardiac imaging parameters according to Task Force Criteria of 2010 in addition to left ventricular (LV) and strain parameters were assessed. High intensity exercise was defined as >6 metabolic equivalents.

Results

117 patients (29% probands, 50% female, age 40 ± 17 years) were included. During 4.2 (interquartile range [IQR]: 2.4 to 7.4) years of follow-up, 18 (15%) patients experienced life-threatening ventricular arrhythmias. The 1-, 2-, and 5-year incidence was 6%, 9%, and 22%, respectively. History of high-intensity exercise, T-wave inversions ≥ V3, and greater LV mechanical dispersion were the strongest risk markers (adjusted hazard ratio [HR]: 4.7 [95% confidence interval (CI): 1.2 to 17.5]; p = 0.02, 4.7 [95% CI: 1.6 to 13.9]; p = 0.005) and 1.4 [95% CI: 1.2 to 1.6] by 10-ms increments; p < 0.001, respectively). Median arrhythmia-free survival in patients with all risk factors was 1.2 (95% CI: 0.4 to 1.9) years, compared with an estimated 12.0 (95% CI: 11.5 to 12.5) years in patients without any risk factors.

Conclusions

History of high-intensity exercise, electrocardiographic T-wave inversions ≥V3 and greater LV mechanical dispersion were strong predictors of life-threatening ventricular arrhythmia with incremental prognostic value. Patients with no risk factors had minimal risk, whereas the presence of ≥2 risk factors increased the risk dramatically to 50% within 1.2 years. These findings may help decisions on primary preventive implantable cardioverter defibrillator (ICD) therapy.

Commentary 

Maria Touloupaki, A. Pantazis, London, UK

Arrhythmogenic Cardiomyopathy (AC) is a heterogeneous inherited heart muscle condition with a wide spectrum of clinical presentations. It is characterized by the presence of both electrical and structural abnormalities which can lead to life-threatening arrhythmias, sudden death and heart failure.

Interestingly and tragically, sudden death may be the first clinical manifestation of the disease, especially among young individuals and athletes. The recognition of patients at risk of life-threatening ventricular arrhythmias remains a major challenge in the management of arrhythmogenic cardiomyopathy.

Numerous predictors of adverse events and death have been identified from autopsy series and observational clinical studies.  The obvious risk marker is the history of cardiac arrest, sustained VT/VF. Unexplained syncope and non-sustained VT on 24-h Holter monitoring have been associated with an increased arrhythmic risk in some studies. Moderate to severe systolic dysfunction of the RV and/or LV has been consistently described to be independent predictor of poor outcome in prospective studies. Regarding the ECG parameters, greater extent of T-wave inversion across the 12 leads has been associated with unfavorable arrhythmic prognosis during follow- up. Low QRS amplitude and QRS fragmentation have been associated with adverse events as well. There are conflicting results about the prognostic role of VT/VF inducibility by programmed ventricular stimulation from different studies. The amount of electroanatomic scar and electroanatomic scar-related fractionated electrograms have also been correlated with adverse outcome. Male sex and multiple gene mutations are significant factors that impact the prognosis of AC. Compound or digenic heterozygosity is an independent predictor of more severe lifetime arrhythmic outcome (1, 3, 5).

However, the assessment of the relative weight of each prognostic marker is difficult because of the small sample sizes and the heterogeneity of variables tested in different studies.

Several predictive models have been proposed so far which have attempted to combine a number of these factors in order to risk stratify individuals and prevent sudden death (4). However, we still lack an evidence-based risk stratification scheme.

This very interesting study showed the incremental value of three combined risk markers from different categories to predict life-threatening ventricular arrhythmia. Patients with all 3 risk factors (history of high-intensity exercise, electrocardiographic T-wave inversions ≥V3 and greater LV mechanical dispersion) had almost 10-fold risk compared with those who had 2 risk factors, indicating that a primary prevention with ICD may be appropriate in this group.

Of note, it was the first study following AC patients with no previous life-threatening ventricular arrhythmia prospectively until their first event thus underlying the importance of close follow up and risk stratification in patients without prior severe arrhythmic manifestations of the disease.

Additionally, this study confirms prospectively the strong association between the expression of disease and exercise. Physical exercise is a critical environmental factor in the promotion of the development and progression of the disease. It may aggravate mechanical uncoupling of myocytes and trigger malignant ventricular arrhythmias. (2)

Apart from the conventional echocardiographic indexes, this group of researchers studied the LV and RV dispersion, highlighting the fact that AC is a biventricular disease. There are conflicting results regarding the ability of these markers to predict ventricular arrhythmias. Moreover, LV mechanical dispersion is dependent on temporal resolution thus it should be used as a global measure. The threshold of >45 ms was found to predict life-threatening ventricular arrhythmia in the current paper. However, the need for further research is acknowledged by the authors.

The limitations of this single-center study include the small sample size and the limited endpoints.  Moreover, pathogenic mutations in the plakophillin-2 gene were detected in the great majority of this population, possibly not allowing to generalize the findings to patients with variable genetic substrates. The use of CMR which is the main imaging diagnostic tool in ARVC was limited to a subset of patients and with a time delay so it may have been subject to selection bias.

In conclusion, this study is important in itself and a good step towards studies with larger cohorts. Multi-center studies are needed in order to obtain more data on long-term prognosis and be able to develop a multi-parameter algorithm for the risk stratification and death prevention of patients with Arrhythmogenic Cardiomyopathy.

References

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