Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

AbstractIntensive participation in sport has positive physiological effects on the heart. The contractility of the heart improves, the ejection fraction increases and the muscle mass of the heart increases, thus leading to a greater cardiac output. Despite these positive effects, there is still an increased risk for acute cardiac events. The workload of the heart can be very high in some sports and may in some cases be the reason for sudden cardiac death. In these cases, there is often an underlying heart disease (cardiomyopathy) unknown before the actual event. Electrocardiographic examination (ECG) may reveal some of these diseases but although ECG examinations can be a useful tool to discover pathological conditions, there could be difficulties in interpreting different ECG patterns, especially in athletes. In some cases, athletes may exhibit ECG patterns that are similar to those in heart diseases such as cardiomyopathies (QRS-amplitudes, ST-segment elevation and T wave inversions in lateral leads). This pattern is even more common in athletes of African origins. Furthermore, cardiomyopathies such as hypertrophic cardiomyopathy (HCM) are more common among athletes with African heritage than in white athletes. Thus correct interpretation of ECG is crucial for several reasons: to distinguish between benign physiological (‘athlete’s heart’) and pathological changes, to lower the risk of sudden cardiac death, and to save time and money by not undertaking further examination of the heart.

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Abstract 4413: Accelerated Inactivation of the L-type Calcium due to a Mutation in CACNB2b Underlies the Development of a Brugada ECG Phenotype

Circulation ◽

10.1161/circ.118.suppl_18.s_884-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jonathan M Cordeiro ◽

Mark Marieb ◽

Ryan Pfeiffer ◽

Kirstine Calloe ◽

Elena Burashnikov ◽

...

Keyword(s):

Action Potential ◽

Calcium Channel ◽

Brugada Syndrome ◽

Vasovagal Syncope ◽

Total Charge ◽

Loss Of Function ◽

St Segment Elevation ◽

St Segment ◽

Steady State Inactivation ◽

The Right

Background: Ion channelopathies are responsible for a number of genetic cardiac arrhythmia syndromes. Recent work demonstrated an association between mutations in CACNA1c and CACNB2b, the genes that encode the α and β subunits of the L-type calcium channel, and the Brugada syndrome (BrS). The mutations previously described all caused a loss of function secondary to a major reduction in peak calcium channel current (I Ca ). In the present study we describe a novel CACNB2b mutation associated with BrS in which loss of function was caused by accelerated inactivation of I Ca . Methods and Results: The proband, a 32 yo male, displayed a saddleback ST segment elevation in the right precordial leads that converted to a coved-type ECG following a procainamide challenge. His EP study was positive with double extrastimuli inducing polymorphic VT/VF. He was also diagnosed with vasovagal syncope. Genomic DNA was isolated from blood lymphocytes. All exons and intron borders of 12 ion channel genes were amplified and sequenced. The only mutation uncovered was a missense mutation (T11I) in CACNB2b. The effect of this mutation was studied by expression of WT or T11I CACNB2b in TSA201 cells co-transfected with WT CANCA1c and CACNA2d. Patch clamp analysis showed no difference in I Ca density between WT and T11I (17.9±1.8 vs 22.5±4.3 pA/pF, respectively at +20mV). Similarly, steady-state inactivation and channel recovery was not different between WT and T11I mutant channels. However, both the fast and slow decay of I Ca produced by T11I mutant were significantly faster compared to WT at potentials between −10 to +30 mV, suggesting a reduction in depolarizing current during the course of an action potential. Application of action potential voltage clamp pulses confirmed that T11I total charge was reduced by 42±2.3% compared to WT (p<0.05). Conclusion: We report the first Brugada syndrome mutation in CaCNB2b resulting in accelerated inactivation of the L-type calcium channel. The T11I mutation caused a faster decay of cardiac L-type calcium current but did not significantly alter the magnitude of the peak current. Our results suggest that a reduced total charge carried by I Ca during the plateau of the action potential predisposes to the Brugada phenotype.

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