Dataset Information

The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy.

ABSTRACT:

Aims

To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression.

Methods and results

We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (-/GAG), Asp261del (GAT/-), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 +/- 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183-42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838-20.967; P = 0.018).

Conclusion

The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

SUBMITTER: Arvanitis DA

PROVIDER: S-EPMC2567024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. However, the precise mechanisms affecting SR function and leading to arrhythmias remain elusive. METHODS AND RESULTS:We generated transgenic mice with cardiac-specific expression of human Ala96 HRC or Ser96 HRC in the null background to assess function in absence of endogenous protein. Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC in the absence of any structural or histological abnormalities. Furthermore, the frequency of Ca2+ waves was significantly higher (10-fold), although SR Ca2+ load was reduced (by 27%) in Ala96 HRC cells. The underlying mechanisms involved diminished interaction of Ala96 HRC with triadin, affecting ryanodine receptor (RyR) stability. Indeed, the open probability of RyR, assessed by use of ryanodine binding, was significantly increased. Accordingly, stress conditions (5 Hz plus isoproterenol) induced aftercontractions (65% in Ala96 versus 12% in Ser96) and delayed afterdepolarizations (70% in Ala96 versus 20% in Ser96). The increased SR Ca2+ leak was accompanied by hyperphosphorylation (1.6-fold) of RyR at Ser2814 by calmodulin-dependent protein kinase II. Accordingly, inclusion of the calmodulin-dependent protein kinase II inhibitor KN93 prevented Ser2814 phosphorylation and partially reversed the increases in Ca2+ spark frequency and wave production. Parallel in vivo studies revealed ventricular ectopy on short-term isoproterenol challenge and increased (4-fold) propensity to arrhythmias, including nonsustained ventricular tachycardia, after myocardial infarction in Ala96 HRC mice. CONCLUSIONS:These findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers.

Project description:AimsPatients with non-ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter-defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM.Methods and resultsWe searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow-up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74-1.00)], hypertension [HR 1.95; 95% CI (1.26-3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32-13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19-1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02-7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non-sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin-C (FLNC)] were associated with arrhythmic outcome in non-pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high.ConclusionsIn patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non-)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter-defibrillator implantation.

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