Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study

Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction.

Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk

Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain.

Excision of high and mid cervical spinal cord arteriovenous malformations by anterior operation

Symptomatic cervical spinal arteriovenous malformations (AVMs) located on the anterior aspect of the spinal cord are rare and surgical removal of these AVMs presents considerable challenges and risks. Surgical techniques to date have usually been by posterior approach and lateral dissection around the cord or via midline myelotomy, both approaches involving cord manipulation and retraction and in the latter, dissection through the spinal cord. We present two teenage patients with symptomatic anteriorly placed mid to high cervical spinal AVMs and associated aneurysm in which excision of the AVMs and aneurysm was performed by an anterior approach using vertebrectomy/corpectomy. The first case had a small perimedullary glomus-type AVM with an aneurysm on the anterior aspect of the cord at the C3/4 level; excision was performed using a single level vertebrectomy/corpectomy, the patient remaining neurologically intact. The second case had a medium-sized juvenile AVM with an aneurysm, both perimedullary and intramedullary, centred at the C5/6 level; excision was performed using a two-level vertebrectomy/corpectomy with no deterioration in the marked pre-operative tetraparesis, which at long-term follow up had improved and stabilised. Anterior approaches have been recently described for treatment of anteriorly placed cervical arteriovenous fistulas (AVFs) and an intramedullary haemangioblastoma, but not as yet for spinal AVMs. These are the first two reported cases of anteriorly situated cervical AVMs successfully removed surgically by an anterior approach and with good neurological outcomes.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.