Scanning electron micrograph of extracellular vesicles (~100 nanometers) merging to form a microcalcification. Image courtesy of Joshua Hutcheson

A Super Resolution View of Vulnerable Atherosclerotic Plaques

Researchers are using high-resolution imaging techniques and a three-dimensional model of calcified plaques to trace the steps that lead from tiny build ups of calcium to plaque ruptures and heart failure. Coronary calcium scores can predict cardiovascular events in patients, but micro-calcifications in the coronary arteries can be so small (~5 micrometers) that traditional imaging techniques cannot detect them. By using super resolution microscopic techniques developed in recent years and a bioengineered model designed to mimic the connective tissue found in atherosclerotic plaques, BWH researchers were able to watch the formation of micro-calcifications in real time. The research team, led by Elena Aikawa, MD, PhD, and the first author on the publication, Joshua Hutcheson, PhD, pinpointed extracellular vesicles that led to the formation of micro-calcifications, and observed micro-calcifications grow into stable, larger structures or, at vulnerable sites, cause plaque destabilization and rupture—a major cause of heart attacks. Their results are published in Nature Materials.

“We can now use this system to visualize what is happening and explore how to intervene in this process,” said Elena Aikawa, MD, PhD, director of the Vascular Biology Program at BWH’s Center for Interdisciplinary Cardiovascular Sciences. “With the knowledge that we’ve gained here, we can now pick out the key extracellular vesicles, and find ways to target them before micro-calcifications take shape.”

The structured illumination and other high resolution microscopy techniques used in this research cannot currently be used in patients, but the researchers hope that innovations in imaging will help move this technology forward, and that future studies of the proteins involved in plaque formation will help identify points of therapeutic intervention.

Paper cited: Hutcheson JD et al. “Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.” Nature Materials DOI: 10.1038/NMAT4519

Agonist or Surgery? Comparing the Adverse Effects for Prostate Cancer Patients

For patients with metastatic prostate cancer, surgical or medical castration may be essential for controlling the disease. Since the introduction of gonadotropin-releasing hormone agonist (GnRHa) for medical castration, the rates of surgical castration have been declining, but the adverse effects of these two approaches have never been compared. BWH researchers set out to compare the effects of GnRHa versus bilateral orchiectomy (surgical removal of the testes), measuring a wide range of outcomes. Their results have been published in JAMA Oncology.

The team measured fractures, peripheral arterial disease, venous thromboembolism, cardiac-related complications, diabetes mellitus and cognitive disorders among 3,295 men who had been treated with medical or surgical castration between 1995 and 2009. Overall, it found that medical castration with GnRHa was associated with higher risk of fractures, peripheral artery disease and cardiac-related complications.

“In some patients who need permanent androgen suppression, surgical castration may represent a suitable alternative to medical castration,” said the study’s senior author Quoc-Dien Trinh, MD, a urologic surgeon at BWH. “Other considerations – such as young age and intermittent versus continuous androgen-deprivation therapy – must be taken into account, but our findings suggest that consideration should be given to better incorporate the use of orchiectomy for men who need permanent androgen suppression.”

Paper cited: Sun M et al. “Comparison of Gonadotropin-Releasing Hormone Agonists and Orchiectomy Effects of Androgen-Deprivation Therapy” JAMA Oncology DOI: 10.1001/jamaoncol.2015.4917

Exploring the Genetics of Sleep

In a study of more than 25,000 individuals, BWH rese
archers have investigated the genetic basis for sleep duration. The team found that changes in the dopamine D2 receptor gene (DRD2) were associated with sleep duration. Their results are published in Human Molecular Genetics.

Using self-reported information about sleep duration from individuals who participated in the Candidate Gene Association Resource (CARe), the research team looked across multi-ethnic U.S. populations, including individuals of African, Asian, European and Hispanic-American ancestry for a link between genetics and sleep duration. One particular signal within the DRD2 gene – a single “letter” difference known as rs17601612 – was significantly associated with sleep duration. Rs17601612 has also been reported in recent studies looking for genetic factors involved in schizophrenia, where a “C” at this particular location appears to protect against risk of schizophrenia. In the current study, this specific genetic difference was associated with shorter sleep duration.

“Our work suggests that DRD2 – a gene implicated in psychiatric disease – may also influence sleep duration,” said Susan Redline, MD, MPH, a senior physician in the Division of Sleep and Circadian Disorders. “This work represents one of the first genetic associations for sleep duration and may motivate further investigation of the genetic overlap between sleep and neuro-psychiatric traits.”

“DRD2 is the major target of current drugs treating schizophrenia and is also regulated by caffeine,” said Brian Cade, PhD, an associate geneticist in the Division of Sleep and Circadian Disorders. “Our study may help identify inter-individual differences in sleepiness and responses to caffeine and other drugs.”

Paper cited: Cade BE et al. “Common variants in DRD2 are associated with sleep duration: the CARe consortium.” Human Molecular Genetics DOI: 10.1093/hmg/ddv434

Genetics Shines Light on Risk of Neurodevelopmental Issues in Children with Congenital Heart Disease

Christine Seidman

Newborns with congenital heart disease (CHD) are at increased risk later in life for neurodevelopmental disorders and other abnormalities not related to the heart. The reason for this increased risk has been largely unknown. BWH’s Christine Seidman, MD, director of BWH’s Cardiovascular Genetics Center, and colleagues set out to find genetic clues in the genomes of children who had been born with heart defects and their parents, looking at data from more than 1,200 families. They narrowed in on “de novo” mutations – genetic alterations in the child’s genome, but not found in the parents’ – and identified many more mutations seen in children with both CHD and neurodevelopmental disabilities. These results indicate that mutations in a subset of genes strongly predicted future development of neurodevelopmental disabilities in infants with CHD. The team’s findings are published in Science.

“Through further analyses of these mutated genes, we expect to uncover new pathways that are critical for the development of the heart, brain and other organs — information that will contribute basic insights into the causes of many human congenital malformations,” said Seidman. “If the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests could be created for newborns with moderate-to-severe congenital heart abnormalities to stratify those at greatest risk for neurodevelopmental disabilities.”

Paper cited: Homsy J et al. “De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.” Science DOI: 10.1126/science.aac9396

Onychomycosis affects between 7 and 14 percent of adults in North America

Re-evaluating Guidelines for Testing and Treating Toenail Fungus

Onychomycosis – a fungal infection of the toenails – is the most common nail disease in adults. The American Board of Internal Medicine’s Choosing Wisely campaign recommends confirmatory testing before treatment begins, but this recommendation is based on data from 1999. BWH researchers led by Arash Mostaghimi, MD, MPA, MPH, of BWH’s Dermatology Department, set out to test whether such recommendations still make medical and economic sense. Their findings are published in JAMA Dermatology.

The research team evaluated treatment with one of two therapies: an oral pill called terbinafine or a topical solution of efinaconazole, 10 percent (Jublia). The team found that treatment and monitoring for the oral pill cost an average of $53; a full course of treatment with the topical solution costs $2,307 per nail. The team found that for the oral pill, the price of confirmatory testing exceeded the cost of treating all suspected cases. Researchers also note that cases of adverse effects from treatment are very rare—on average, it would cost between $18.2 and 90.2 million to avoid one case of liver injury. For the topical solution, however, confirmatory testing before treatment substantially reduced costs, suggesting that confirmatory testing should still be used before beginning treatment with efinaconazole.

“Blanket recommendations for confirmatory testing before systemic therapy should be reconsidered and replaced with recommendations tailored to specific therapies,” the authors write.

Paper cited: Mikailov A et al. “Cost-effectiveness of Confirmatory Testing Before Treatment of Onychomycosis.” JAMA Dermatology DOI: 10.1001/jamadermatol.2015.4190