Diana Domingo

Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

AIMS The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Deregulated hepatic microRNAs underlie the association between non-alcoholic fatty liver disease and coronary artery disease

Non‐alcoholic fatty liver disease (NAFLD) appears to be a new risk factor for the development of coronary artery disease (CAD). Members of a class of non‐coding RNAs, termed microRNAs (miRNAs), have been identified as post‐transcriptional regulators of cholesterol homoeostasis and can contribute to the development of NAFLD. The aims of this study were to (i) to assess the relationship between NAFLD and sudden cardiac death (SCD) from severe CAD in forensic autopsies and (ii) to quantify several hepatic miRNAs previously associated with lipid metabolism and NAFLD to correlate their expression with the presence of NAFLD, CAD, obesity parameters and postmortem lipid profile.

A misleading wide complex tachycardia with unusual features after carotid sinus pressure: what is the diagnosis?

Electrocardiographic differential diagnosis of a wide complex tachycardia (WCT) is challenging. During the last years different algorithms have tried to overcome these difficulties. The present article presents a case of a WCT in which traditional algorithms fail to give a definitive diagnosis that can be facilitated by a simple manoeuvre: carotid sinus pressure (CSP). An unusual response of the tachycardia after CSP is also discussed.

Sensitivity and Negative Predictive Value of Treadmill Exercise Stress Testing for the Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia. Response

during exercise stress testing or following catecholamine infusion. Recently, there have been reports of the use of diagnostic thresholds such as more than 10 premature ventricular contractions/minute, * Corresponding author: E-mail address: pabloruizher@secardiologia.es (P.M. Ruiz Hernández). bigeminy, or couplets as the ‘‘minimum’’ ventricular arrhythmia, whose presence is indicative of a diagnosis of CPVT. In addition, although catecholamine infusion is not a totally reliable test, it continues to be used to enhance sensitivity in the diagnosis of this disease, especially when dealing with an index case. However, recent studies have reported the limited usefulness of catecholamine infusion because of its very low sensitivity (28%) and specificity for the diagnosis of CPVT. In one study, it was positive in 56 patients with a negative exercise stress test. The reality is that the available tests are insufficiently sensitive, and their negative predictive value is much lower than desired. However, the articles referred to in this letter reports results in terms of sensitivity (89%) and negative predictive value (93%) that do not agree with those reported to date, and convey the message that a negative exercise stress test rules out CPVT. These data probably require an in-depth study of a larger number of members of the family in question and, of course, cannot be extrapolated to other populations with other mutations in what, in our opinion, constitutes a selection bias. In accordance with the recommendation of the scientific societies, a negative exercise stress test does not rule out CPVT. The disease can be confirmed by the presence of specific ventricular arrhythmias during exercise but, in the context of family screening, just 1 premature ventricular contraction is enough to render the results of the test abnormal, and probably justifies the introduction of preventive treatment with betablocker therapy. Moreover, the use of catecholamine infusion should be restricted to selected cases, and should not be included in the protocol to be applied on a general basis.

Familial Left Ventricular Noncompaction Associated With a Novel Mutation in the Alpha-cardiac Actin Gene

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