Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease.

BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors. METHODS: A multitiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison among >500 000 British adults in the UK Biobank. ACHD diagnoses were subclassified as isolated aortic valve and noncomplex defects. Time-to-event analyses were conducted for the primary end points of fatal or nonfatal acute coronary syndrome, ischemic stroke, heart failure, and atrial fibrillation and a secondary combined end point for major adverse cardiovascular events. Maximum follow-up time for the study period was 22 years with retrospectively and prospectively collected data from the UK Biobank. RESULTS: We identified 2006 individuals with lower-complexity ACHD and 497 983 unexposed individuals in the UK Biobank (median age at enrollment, 58 [interquartile range, 51-63] years). Of the ACHD-exposed group, 59% were male, 51% were current or former smokers, 30% were obese, and 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes mellitus, respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary end points, with hazard ratios ranging from 2.0 (95% CI, 1.5-2.8; P<0.001) for acute coronary syndrome to 13.0 (95% CI, 9.4-18.1; P<0.001) for heart failure. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of major adverse cardiovascular events, in contrast to 13% in individuals without ACHD with ≥5 risk factors. CONCLUSIONS: Individuals with lower-complexity ACHD had a higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

Risks and outcomes of direct current cardioversion in children and young adults with congenital heart disease.

OBJECTIVES: Evaluate the efficacy, outcomes, and complications associated with direct current cardioversion (DCCV) in the treatment of arrhythmias in pediatric and adult congenital heart disease (CHD) populations and identify patient and procedural characteristics associated with adverse events. BACKGROUND: Pediatric and adult patients with CHD are at risk of atrial arrhythmias. DCCV is effective but is associated with potential complications. METHODS: In this single-center retrospective series, patients who underwent DCCV between January 2010 and May 2015 were identified and categorized as pediatric (<18 years) or adult (> 18 years). Records were reviewed for demographic, arrhythmic, and CHD-specific characteristics; acute efficacy; and 3-month arrhythmia recurrence. Complications were categorized as life-threatening (LT) or non-life-threatening (NLT). Univariate followed by multiple variable and logistic regression (LR) analyses were used to identify characteristics associated with complications. RESULTS: We identified 104 patients with 152 discrete DCCV events with median age 17.4 years (0.15-62.2). DCCV efficacy was 89% with 3-month recurrence of 46%. There were 52 complications among 24 patients, median age 17.7 years (0.15-49). Risks associated with NLT complications are as follows: moderate-severe systolic dysfunction (8/152 encounters, P = < 0.01) and more than one shock per DCCV encounter (P = < 0.01). Six of eight encounters with moderate-severe systolic dysfunction were <18 years (P = 0.1). Risks for LT complications included age >18 years and associated NLT complication. Adults had more frequent arrhythmia recurrence within 3 months than children (P = < 0.01). CONCLUSIONS: DCCV is effective for arrhythmias but is associated with frequent recurrence, particularly in adult patients. Complications associated with DCCV may be greater than previously reported. Additional support and precautions should be in place for those at greatest risk.

Dry-powder pulmonary insufflation in the mouse for application to vaccine or drug studies.

Pulmonary delivery of substances in small animal models is often useful for experimental testing of various vaccine and drug candidates. One of the most challenging elements to such protocols is the efficient disposition of test materials in the lungs of mice. Herein we detail a means to deliver dry powders of an inhalant live-attenuated Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine against Mycobacterium tuberculosis to the lungs of mice. The direct delivery methodology is quick, safe, and allows for repeated pulmonary insufflation of substances if boosting is desired. This model system could be easily adapted for use with other dry-powder vaccine and drug candidates.

A genetic network for the clock of Neurospora crassa.

A diverse array of organisms from bacteria to humans may have evolved the ability to tell time in the presence or absence of external environmental cues. In the lowly bread mould, Neurospora crassa, biomolecular reactions involving the white-collar-1 (wc-1), white-collar-2 (wc-2), and frequency (frq) genes and their products constitute building blocks of a biological clock. Here we use genetic network models to explain quantitatively, from a systems perspective, how these building blocks interact, and how a complex trait like clock oscillation emerges from these interactions. We use a recently developed method of genetic network identification to find an ensemble of oscillating network models quantitatively consistent with available RNA and protein profiling data on the N. crassa clock. Predicted key features of the N. crassa clock system are a dynamically frustrated closed feedback loop, cooperativity in frq gene activation, and/or WC-1/WC-2 protein complex deactivation and substantial posttranscriptional enhancement of wc-1 RNA lifetime. Measuring the wc-1 mRNA lifetime provides a critical test of the genetic networks.