Key result
Among RYR2 P2328S mutation carriers, a maximum rate of premature ventricular contractions >30/min during an exercise stress test was associated with a significantly higher rate of cardiac events (HR 7.13).
Why the study?
CPVT is a severe inherited arrhythmic disease with risk of syncope and sudden cardiac death, prompting the identification of RYR2 P2328S founder mutation carriers and description of their clinical course.
Cohort (n=62)
Hazard Ratio: 7.13 (95% CI 1.31–38.8)
Absolute Event Rate: 68% vs 17%
p-value: p=0.02
The RYR2 P2328S founder mutation causes a potentially severe but variably expressed CPVT phenotype, where a maximum PVC rate >30/min during exercise stress testing strongly predicts future cardiac events.
May support PVC-based risk stratification on exercise testing in RYR2 P2328S carriers; leaves open prospective validation before guiding therapy.
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). AIMS: We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. METHODS: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. RESULTS: Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during β-blocker medication. CONCLUSIONS: Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.
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Koponen et al. (2020) conducted a cohort in Catecholaminergic polymorphic ventricular tachycardia (CPVT) (n=62). Maximum rate of premature ventricular contractions >30/min in exercise stress test vs. Maximum rate of premature ventricular contractions ≤30/min was evaluated on First cardiac event (CPVT-related syncope, aborted cardiac arrest, appropriate ICD shock, or sudden cardiac death) (HR 7.13, 95% CI 1.31-38.8, p=0.02). Among RYR2 P2328S mutation carriers, a maximum rate of premature ventricular contractions >30/min during an exercise stress test was associated with a significantly higher rate of cardiac events (HR 7.13).
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