Faculty Bibliography

Arsenic (As), a ubiquitous environmental toxicant, has recently been linked to disrupted immune function and enhanced infection susceptibility in highly exposed populations. In drinking water, as levels above the EPA maximum contaminant level occur in our US study area and are a particular health concern for pregnant women and infants. As a part of the New Hampshire Birth Cohort Study, we investigated whether in utero exposure to As affects risk of infant infections. We prospectively obtained information on 4-month-old infants (n=214) using a parental telephone survey on infant infections and symptoms, including respiratory infections, diarrhea and specific illnesses, as well as the duration and severity of infections. Using logistic regression and Poisson models, we evaluated the association between maternal urinary As during pregnancy and infection risks adjusted for potentially confounding factors. Maternal urinary As concentrations were related to total number of infections requiring a physician visit (relative risk (RR) per one-fold increase in As in urine=1.5; 95% confidence interval (CI)=1.0, 2.1) or prescription medication (RR=1.6; 95% CI=1.1, 2.4), as well as lower respiratory infections treated with prescription medication (RR=3.3; 95% CI=1.2, 9.0). Associations were observed with respiratory symptoms (RR=4.0; 95% CI=1.0, 15.8), upper respiratory infections (RR=1.6; 95% CI=1.0, 2.5), and colds treated with prescription medication (RR=2.3; 95% CI=1.0, 5.2). Our results provide initial evidence that in utero As exposure may be related to infant infection and infection severity and provide insight into the early life impacts of fetal As exposure.

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.

OBJECTIVES: This study sought to identify the frequency, pattern, and prognostic significance of left ventricular (LV) late gadolinium enhancement (LGE) in patients with atrial fibrillation (AF). BACKGROUND: There are limited data on the presence, pattern, and prognostic significance of LV myocardial fibrosis in patients with AF. LGE during cardiac magnetic resonance imaging is a marker for myocardial fibrosis. METHODS: A group of 664 consecutive patients without known prior myocardial infarction who were referred for radiofrequency ablation of AF were studied. Cardiac magnetic resonance imaging was requested to assess pulmonary venous anatomy. RESULTS: Overall, 73% were men, with a mean age of 56 years and a mean LV ejection fraction of 56 +/- 10%. LV LGE was found in 88 patients (13%). The endpoint was all-cause mortality, and in this cohort, 68 deaths were observed over a median follow-up period of 42 months. On univariate analysis, age (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.03 to 1.08; chi-square likelihood ratio [LRchi(2)]: 15.2; p = 0.0001), diabetes (HR: 2.39; 95% CI: 1.41 to 4.09; LRchi(2): 10.3; p = 0.001), a history of heart failure (HR: 1.78; 95% CI: 1.09 to 2.91; LRchi(2): 5.37; p = 0.02), left atrial dimension (HR: 1.04; 95% CI: 1.01 to 1.08; LRchi(2): 6.47; p = 0.01), presence of LGE (HR: 5.08; 95% CI: 3.08 to 8.36; LRchi(2): 28.8; p < 0.0001), and LGE extent (HR: 1.15; 95% CI: 1.10 to 1.21; LRchi(2): 35.6; p < 0.0001) provided the strongest associations with mortality. The mortality rate was 8.1% per patient-year in patients with LGE compared with 2.3% patients without LGE. In the best overall multivariate model for mortality, age and the extent of LGE were independent predictors of mortality. Indeed, each 1% increase in the extent of LGE was associated with a 15% increased risk for death. CONCLUSIONS: In patients with AF, LV LGE is a frequent finding and is a powerful predictor of mortality.

OBJECTIVES: This study sought to determine whether the extent of late gadolinium enhancement (LGE) can provide additive prognostic information in patients with a nonischemic dilated cardiomyopathy (NIDC) with an indication for implantable cardioverter-defibrillator (ICD) therapy for the primary prevention of sudden cardiac death (SCD). BACKGROUND: Data suggest that the presence of LGE is a strong discriminator of events in patients with NIDC. Limited data exist on the role of LGE quantification. METHODS: The extent of LGE and clinical follow-up were assessed in 162 patients with NIDC prior to ICD insertion for primary prevention of SCD. LGE extent was quantified using both the standard deviation-based (2-SD) method and the full-width half-maximum (FWHM) method. RESULTS: We studied 162 patients with NIDC (65% male; mean age: 55 years; left ventricular ejection fraction [LVEF]: 26 +/- 8%) and followed up for major adverse cardiac events (MACE), including cardiovascular death and appropriate ICD therapy, for a mean of 29 +/- 18 months. Annual MACE rates were substantially higher in patients with LGE (24%) than in those without LGE (2%). By univariate association, the presence and the extent of LGE demonstrated the strongest associations with MACE (LGE presence, hazard ratio [HR]: 14.5 [95% confidence interval (CI): 6.1 to 32.6; p < 0.001]; LGE extent, HR: 1.15 per 1% increase in volume of LGE [95% CI: 1.12 to 1.18; p < 0.0001]). Multivariate analyses showed that LGE extent was the strongest predictor in the best overall model for MACE, and a 7-fold hazard was observed per 10% LGE extent after adjustments for patient age, sex, and LVEF (adjusted HR: 7.61; p < 0.0001). LGE quantitation by 2-SD and FWHM both demonstrated robust prognostic association, with the highest MACE rate observed in patients with LGE involving >6.1% of LV myocardium. CONCLUSIONS: LGE extent may provide further risk stratification in patients with NIDC with a current indication for ICD implantation for the primary prevention of SCD. Strategic guidance on ICD therapy by cardiac magnetic resonance in patients with NIDC warrants further study.

BACKGROUND: Sleep apnea (SA) is associated with an increased risk of atrial fibrillation (AF). We sought to determine the effect of SA on cardiac structure in patients with AF, whether therapy for SA was associated with beneficial cardiac structural remodelling, and whether beneficial cardiac structural remodelling translated into a reduced risk of recurrence of AF after pulmonary venous isolation (PVI). METHODS AND RESULTS: A consecutive group of 720 patients underwent a cardiac magnetic resonance study before PVI. Patients with SA (n=142, 20%) were more likely to be male, diabetic, and hypertensive and have an increased pulmonary artery pressure, right ventricular volume, atrial dimensions, and left ventricular mass. Treated SA was defined as duration of continuous positive airway pressure therapy of >4 hours per night. Treated SA patients (n=71, 50%) were more likely to have paroxysmal AF, a lower blood pressure, lower ventricular mass, and smaller left atrium. During a follow-up of 42 months, AF recurred in 245 patients. The cumulative incidence of AF recurrence was 51% in patients with SA, 30% in patients without SA, 68% in patients with untreated SA, and 35% in patients with treated SA. In a multivariable model, the presence of SA (hazard ratio 2.79, CI 1.97 to 3.94, P<0.0001) and untreated SA (hazard ratio 1.61, CI 1.35 to 1.92, P<0.0001) were highly associated with AF recurrence. CONCLUSIONS: Patients with SA have an increased blood pressure, pulmonary artery pressure, right ventricular volume, left atrial size, and left ventricular mass. Therapy with continuous positive airway pressure is associated with lower blood pressure, atrial size, and ventricular mass, and a lower risk of AF recurrence after PVI.

IMPORTANCE: There is a need to describe contemporary outcomes of surgical aortic valve replacement (AVR) as the population ages and transcatheter options emerge. OBJECTIVE: To assess procedure rates and outcomes of surgical AVR over time. DESIGN, SETTING, AND PARTICIPANTS: A serial cross-sectional cohort study of 82,755,924 Medicare fee-for-service beneficiaries undergoing AVR in the United States between 1999 and 2011. MAIN OUTCOMES AND MEASURES: Procedure rates for surgical AVR alone and with coronary artery bypass graft (CABG) surgery, 30-day and 1-year mortality, and 30-day readmission rates. RESULTS: The AVR procedure rate increased by 19 (95% CI, 19-20) procedures per 100,000 person-years over the 12-year period (P<.001), with an age-, sex-, and race-adjusted rate increase of 1.6% (95% CI, 1.0%-1.8%) per year. Mortality decreased at 30 days (absolute decrease, 3.4%; 95% CI, 3.0%-3.8%; adjusted annual decrease, 4.1%; 95% CI, 3.7%- 4.4%) per year and at 1 year (absolute decrease, 2.6%; 95% CI, 2.1%-3.2%; adjusted annual decrease, 2.5%; 95% CI, 2.3%-2.8%). Thirty-day all-cause readmission also decreased by 1.1% (95% CI, 0.9%-1.3%) per year. Aortic valve replacement with CABG surgery decreased, women and black patients had lower procedure and higher mortality rates, and mechanical prosethetic implants decreased, but 23.9% of patients 85 years and older continued to receive a mechanical prosthesis in 2011. CONCLUSIONS AND RELEVANCE: Between 1999 and 2011, the rate of surgical AVR for elderly patients in the United States increased and outcomes improved substantially. Medicare data preclude the identification of the causes of the findings and the trends in procedure rates and outcomes cannot be causally linked. Nevertheless, the findings may be a useful benchmark for outcomes with surgical AVR for older patients eligible for surgery considering newer transcatheter treatments.

OBJECTIVES: The aim of this study was to examine the prescribing patterns of medications quantified by the performance measures for acute myocardial infarction (AMI). BACKGROUND: Current performance measures for AMI are designed to improve quality by quantifying the use of evidence-based treatments. However, these measures only assess medication prescription. Whether patients receive optimal dosing of secondary prevention medications at the time of and after discharge after AMI is unknown. METHODS: We assessed treatment doses of beta-blockers, statins, and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) at discharge and 12 months after AMI among 6,748 patients from 31 hospitals enrolled in 2 U.S. registries (2003 to 2008). Prescribed doses were categorized as none, low (<50% target [defined from seminal clinical trials]), moderate (50% to 74% target), or goal (>/= 75% target). Patients with contraindications were excluded from analyses for that medication. RESULTS: Most eligible patients (>87%) were prescribed some dose of each medication at discharge, although only 1 in 3 patients were prescribed these medications at goal doses. Of patients not discharged on goal doses, up-titration during follow-up occurred infrequently (approximately 25% of patients for each medication). At 12 months, goal doses of beta-blockers, statins, and ACEI/ARBs were achieved in only 12%, 26%, and 32% of eligible patients, respectively. After multivariable adjustment, prescription of goal dose at discharge was strongly associated with being at goal dose at follow-up: beta-blockers, adjusted odds ratio (OR): 6.08 (95% confidence interval [CI]: 3.70 to 10.01); statins, adjusted OR: 8.22 (95% CI: 6.20 to 10.90); ACEI/ARBs, adjusted OR: 5.80 (95% CI: 2.56 to 13.16); p < 0.001 for each. CONCLUSIONS: Although nearly all patients after an AMI are discharged on appropriate secondary prevention medications, dose increases occur infrequently, and most patients are prescribed doses below those with proven efficacy in clinical trials. Integration of dose intensity into performance measures might help improve the use of optimal medical therapy after AMI.

BACKGROUND: Despite the fact that 80% of patients with heart failure are aged more than 65 years, recognition of cognitive impairment by physicians in this population has received relatively little attention. The current study evaluated physician documentation (as a measure of recognition) of cognitive impairment at the time of discharge in a cohort of older adults hospitalized for heart failure. METHODS: We performed a prospective cohort study of older adults hospitalized with a primary diagnosis of heart failure. Cognitive status was evaluated with the Folstein Mini-Mental State Examination at the time of hospitalization. A score of 21 to 24 was used to indicate mild cognitive impairment, and a score of