EP News: Basic and Translational January 10, 2012

Genetic Testing as a Class I Indication for Patient Care

Gersh et al (Circulation 2011;13:124, PMID 22068435) updated the ACCF/AHA Guideline for the Diagnosis and treatment of Hypertrophic Cardiomyopathy (HCM).

In this updated recommendation for HCM, genetic testing is listed as a Class I recommendation to evaluate patients with HCM. All patients who undergo genetic testing should also undergo genetic counseling. Genetic screening is recommended in first-degree relatives of patients with HCM. In addition, genetic testing is recommended for patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause. However, the Task Force also played down the importance of using specific mutations to predict the likelihood of sudden cardiac death (SCD). While some earlier works found certain mutations are “malignant,” subsequent studies showed in some instances the rate of adverse events (and prevalence of associated SCD risk markers) was lower in patients with “malignant” mutations than it was in those with mutations believed to be “benign.”

The endorsement of ACCF and AHA on genetic testing in HCM is an important milestone for the translation of genetic research results into clinical practice.

Tbx-3 and Arrhythmia

TBX3 is critical gene for human development. Mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood.

Frank et al (PNAS 2011, ePub, PMID: 22203979) tested the requirements for Tbx3 in these processes. The authors generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias. The arrhythmias include sinus pauses and bradycardia (sinoatrial node dysfunction), preexcitation and atrioventricular block. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers.

The authors conclude that Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.

Fibroblasts and Complex Fractionated Electrograms

Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear.

Because atrial fibrosis is associated with persistent/permanent AF, Ashihara et al (Circ Res 2011, ePub, PMID: 22179057) hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation.

The authors used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone.

The authors conclude that fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/permanent AF. Their findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.

Effect of Chest Compressions on Ventricular Activation

Osorio et al (Am J Cardiol 2011, Epub, PMID 22177000) aimed to determine whether ventricular capture by chest compressions (CCs) occurs in humans. Electronic rhythm strips were analyzed in 31 cases of out-of-hospital cardiac arrest. The timing of the CCs was identified from the changes in thoracic impedance between the defibrillator pads. Ventricular capture was defined as QRS complexes of similar morphology occurring intermittently but synchronized with the CC artifact and impedance waveform. Of the 29 patients who received CCs for ≥1 minute, minimal or stable motion artifact was present in 24. Intermittent ventricular capture was found in 7 of the 24 patients. In the patients with ventricular capture, the number of ventricular activations (from ventricular capture and native beats) was greater during the CCs than when the CCs were not being performed. However, in patients without ventricular capture, they were similar. Refibrillation occurred in 22 patients; it began during the CCs in 16 and closely following their initiation in 3.

The authors conclude that CCs during cardiopulmonary resuscitation can electrically stimulate the heart.