Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

The number of androgen receptor CAG repeats and mortality in men.

INTRODUCTION: The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. METHODS: Men aged 40-79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). RESULTS: 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). CONCLUSION: Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

Serial cardiac biomarker assessment in adults with congenital heart disease hospitalized for decompensated heart failure☆.

Background: Biomarkers are increasingly part of assessing and managing heart failure (HF) in adults with congenital heart disease (CHD). Objectives: To understand the response of cardiac biomarkers with therapy for acute decompensated heart failure (ADHF) and the relationship to prognosis after discharge in adults with CHD. Design: A prospective, observational cohort study with serial blood biomarker measurements. Settings: Single-center study in the inpatient setting with outpatient follow-up. Participants: Adults (≥18 years old) with CHD admitted with ADHF between August 1, 2019, and March 1, 2020. Exposure: We measured body mass, Kansas City Cardiomyopathy Questionnaire (KCCQ-12) score, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) at enrollment, discharge, and 1st clinic follow-up visit; soluble suppression of tumorigenicity 2 (sST2) was measured at the first two time points. Measures: Univariate regression assessed the association between changes in weight, biomarkers, and changes in KCCQ-12 scores, between enrollment and discharge (Δ Hospitalization ) and between discharge and 1st clinical follow-up visit (Δ Post-discharge ). Wilcoxon rank-sum tests assessed the association between change in biomarkers, KCCQ-12 scores, and the composite outcome of cardiovascular death or rehospitalization for ADHF. Results: A total of 26 patients were enrolled. The median age was 51.9 years [IQR: 38.8, 61.2], 13 (54.2%) were women, and median hospital stay was 6.5 days [IQR: 4.0, 15.0] with an associated weight loss of 2.8 kg [IQR -5.1, -1.7]. All three cardiac biomarkers decreased during hospitalization with diuresis while KCCQ-12 scores improved; a greater decrease in sST2 was associated with an improved KCCQ-12 symptom frequency (SF) subdomain score (p = 0.012), but otherwise, there was no significant relationship between biomarkers and KCCQ-12 change. Change in hsCRP and NT-proBNP after discharge was not associated with the composite outcome (n = 8, vs. n = 16 who did not experience the outcome; Δ Post-discharge hsCRP +5.1 vs. -1.0 mg/l, p = 0.061; NT-proBNP +785.0 vs. +130.0 pg/ml, p = 0.220). Conclusions: Serial biomarker measurements respond to acute diuresis in adults with CHD hospitalized for ADHF. These results should motivate further research into the use of biomarkers to inform HF therapy in adults with CHD.

Timing of Delivery in Women with Cardiac Disease.

OBJECTIVE: Guidelines do not exist to determine timing of delivery for women with cardiovascular disease (CVD) in pregnancy. The neonatal benefit of a term delivery as compared with an early term delivery is well described. We sought to examine maternal outcomes in women with CVD who delivered in the early term period (370/7 through 386/7 weeks) compared with those who delivered later. STUDY DESIGN: This is a prospective cohort study examining cardiac and obstetric outcomes in women with CVD delivering between September 2011 and December 2016. The associations between gestational age at delivery and maternal, fetal, and obstetric characteristics were evaluated. RESULTS: Two-hundred twenty-five women with CVD were included, 83 (37%) delivered in the early term period and 142 (63%) delivered at term. While the early term group had significantly higher rates of any hypertension during pregnancy (18.1 vs. 7%, p = 0.01) and intrauterine growth restriction (22.9 vs. 2.8%, p < 0.001), there was no difference in high-risk cardiac or obstetric characteristics. No difference in composite cardiac morbidity was found (4.8 vs. 3.5%, p = 0.24). Women in the early term group were more likely to undergo cesarean delivery than women in the term group (43.4 vs. 24.7%, p = 0.004). CONCLUSION: There is no maternal benefit of an early term delivery in otherwise healthy women with CVD. Given the known fetal consequences of early term delivery, this study offers support to existing literature suggesting term delivery in these women. KEY POINTS: · Question of delivery timing in women with cardiac disease.. · No difference in cardiac morbidity, term versus early term.. · Term delivery in women with asymptomatic cardiac disease..

Associations Between Clinical Outcomes and a Recently Proposed Adult Congenital Heart Disease Anatomic and Physiological Classification System.

Background American Heart Association and American College of Cardiology consensus guidelines introduce an adult congenital heart disease anatomic and physiological (AP) classification system. We assessed the association between AP classification and clinical outcomes. Methods and Results Data were collected for 1000 outpatients with ACHD prospectively enrolled between 2012 and 2019. AP classification was assigned based on consensus definitions. Primary outcomes were (1) all-cause mortality and (2) a composite of all-cause mortality or nonelective cardiovascular hospitalization. Cox regression models were developed for AP classification, each component variable, and additional clinical models. Discrimination was assessed using the Harrell C statistic. Over a median follow-up of 2.5 years (1.4-3.9 years), the composite outcome occurred in 185 participants, including 49 deaths. Moderately or severely complex anatomic class (class II/III) and severe physiological stage (stage D) had increased risk of the composite outcome (AP class IID and IIID hazard ratio, 4.46 and 3.73, respectively, versus IIC). AP classification discriminated moderately between patients who did and did not suffer the composite outcome (C statistic, 0.69 [95% CI, 0.67-0.71]), similar to New York Heart Association functional class and NT-proBNP (N-terminal pro-B-type natriuretic peptide); it was more strongly associated with mortality (C statistic, 0.81 [95% CI, 0.78-0.84]), as were NT-proBNP and functional class. A model with AP class and NT-proBNP provided the strongest discrimination for the composite outcome (C statistic, 0.73 [95% CI, 0.71-0.75]) and mortality (C statistic, 0.85 [95% CI, 0.82-0.88]). Conclusions The addition of physiological stage modestly improves the discriminative ability of a purely anatomic classification, but simpler approaches offer equivalent prognostic information. The AP system may be improved by addition of key variables, such as circulating biomarkers, and by avoiding categorization of continuous variables.

Comparing Physician Assistant and Nurse Practitioner Practice in U.S. Emergency Departments, 2010-2017.

INTRODUCTION: We sought to compare physician assistant (PA) and nurse practitioner (NP) practice in United States emergency departments (ED) based on ED visits as reported by the National Hospital Ambulatory Medical Care Survey (NHAMCS). METHODS: We performed a retrospective, secondary analysis of the 2010 to 2017 NHAMCS with analysis of ED visits, patient demographics, and hospital characteristics. RESULTS: Between 2010 to 2017, 21.0% (95% confidence interval, [CI] +/-3.1%) of ED visits were seen by either a PA/NP (with and without physician involvement) and 8.6% (+/-2.9%) were seen by PA/NP alone. We identified an increase for NP visits between 2014-2016 and found that PA/NP visits share many of the same characteristics. CONCLUSION: While emergency medicine has predominately been a specialty for PAs, the number of ED visits with NPs has been increasing over the past several years. While there are some differences, PAs/NPs share many similar practice characteristics in the ED.

Atrial pacing in Fontan patients: The effect of transvenous lead on clot burden.

BACKGROUND: Transvenous permanent pacemaker (PPM) implantation is an available option for Fontan patients with sinus node dysfunction. However, the thrombogenic potential of leads within the Fontan baffle is unknown. OBJECTIVE: The purpose of this study was to compare the clot burden in Fontan patients with a transvenous atrial PPM to those without a PPM and those with an epicardial PPM. METHODS: This was a retrospective cohort study of all transvenous PPM implantations in Fontan patients followed at our institution (2000-2018). We performed frequency matching on Fontan type and age group. Primary outcome was identification of intracardiac clot, pulmonary embolus, or embolic stroke. RESULTS: Of 1920 Fontan patients, 58 patients (median age 23 years; interquartile range [25th-75th percentiles] 14-33) at the time of transvenous PPM implantation and 174 matched subjects formed our cohort. The type of Fontan performed in case subjects was right atrium-pulmonary artery or right atrium-right ventricle conduit (54%), lateral tunnel (43%), and extracardiac (3%). The cumulative incidence of clot was highest in patients with transvenous PPM, followed by patients with epicardial PPM and no PPM (1.2 vs 0.87 vs 0.67 per 100 person-years of follow-up, respectively). In multivariable analysis, anticoagulation and/or antiplatelet therapy were protective against clot and resulted in reduction of clot risk by 3-fold (incidence rate ratio 0.33; 95% confidence interval 0.21-0.53; P <.001). CONCLUSION: In a large cohort of Fontan patients matched for age and Fontan type, patients with transvenous PPM had a higher but not statistically significant incidence of clot compared to those with no PPM and epicardial PPM. Patients treated with warfarin/aspirin had lower clot risk.

The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease.

Viral proteases are highly specific and recognize conserved cleavage site sequences of ∼6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We hypothesized that these sequences corresponded to specific host protein targets since >40 host proteins have been shown to be cleaved by Group IV viral proteases and one Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences, we searched the human proteome for host targets and analyzed the hit results. Although the polyprotein and host proteins related to the suppression of the innate immune responses may be the primary targets of these viral proteases, we identified other cleavable host proteins. These proteins appear to be related to the virus-induced phenotype associated with Group IV viruses, suggesting that information about viral pathogenesis may be extractable directly from the viral genome sequence. Here we identify sequences cleaved by the SARS-CoV-2 papain-like protease (PLpro) in vitro within human MYH7 and MYH6 (two cardiac myosins linked to several cardiomyopathies), FOXP3 (an X-linked Treg cell transcription factor), ErbB4 (HER4), and vitamin-K-dependent plasma protein S (PROS1), an anticoagulation protein that prevents blood clots. Zinc inhibited the cleavage of these host sequences in vitro. Other patterns emerged from multispecies sequence alignments of the cleavage sites, which may have implications for the selection of animal models and zoonosis. SSHHPS/nsP is an example of a sequence-specific post-translational silencing mechanism.

Fontan-Associated Dyslipidemia.

Background Hypocholesterolemia is a marker of liver disease, and patients with a Fontan circulation may have hypocholesterolemia secondary to Fontan-associated liver disease or inflammation. We investigated circulating lipids in adults with a Fontan circulation and assessed the associations with clinical characteristics and adverse events. Methods and Results We enrolled 164 outpatients with a Fontan circulation, aged ≥18 years, in the Boston Adult Congenital Heart Disease Biobank and compared them with 81 healthy controls. The outcome was a combined outcome of nonelective cardiovascular hospitalization or death. Participants with a Fontan (median age, 30.3 [interquartile range, 22.8-34.3 years], 42% women) had lower total cholesterol (149.0±30.1 mg/dL versus 190.8±41.4 mg/dL, P<0.0001), low-density lipoprotein cholesterol (82.5±25.4 mg/dL versus 102.0±34.7 mg/dL, P<0.0001), and high-density lipoprotein cholesterol (42.8±12.2 mg/dL versus 64.1±16.9 mg/dL, P<0.0001) than controls. In those with a Fontan, high-density lipoprotein cholesterol was inversely correlated with body mass index (r=-0.30, P<0.0001), high-sensitivity C-reactive protein (r=-0.27, P=0.0006), and alanine aminotransferase (r=-0.18, P=0.02) but not with other liver disease markers. Lower high-density lipoprotein cholesterol was independently associated with greater hazard for the combined outcome adjusting for age, sex, body mass index, and functional class (hazard ratio [HR] per decrease of 10 mg/dL, 1.37; 95% CI, 1.04-1.81 [P=0.03]). This relationship was attenuated when log high-sensitivity C-reactive protein was added to the model (HR, 1.26; 95% CI, 0.95-1.67 [P=0.10]). Total cholesterol, low-density lipoprotein cholesterol, and triglycerides were not associated with the combined outcome. Conclusions The Fontan circulation is associated with decreased cholesterol levels, and lower high-density lipoprotein cholesterol is associated with adverse outcomes. This association may be driven by inflammation. Further studies are needed to understand the relationship between the severity of Fontan-associated liver disease and lipid metabolism.

Physician assistant utilization in U.S. emergency departments; 2010 to 2017.

BACKGROUND: Physician Assistants (PAs) are widely used in United States (US) Emergency Departments (EDs). We sought to characterize ED PA utilization and practice characteristics in US EDs 2010-2017. METHODS: A retrospective, secondary analysis of the 2010 to 2017 Center for Disease Control's National Hospital Ambulatory Medical Care Survey (NHAMCS) was performed. National estimates of ED visits involving PAs alone (PA), PAs with physician involvement (PA+), or physician only (PHYS) were analyzed for patient demographics and hospital characteristics. RESULTS: Between 2010 and 2017, an estimated 1 billion US ED visits occurred. 5.0% (95% confidence interval [CI] ±2.7%) of visits were seen by a PA, and 8.2% (±2.7%) by a PA+; 76.3% (±7.2%) by PHYS. No linear trends by year were identified in PA or PA+ visits. PA acuity was highest for semi-urgent/nonurgent (56.4%, ±10.7%). PA see the minority of ambulance arrival [5.8% (±1.3)] and admit less patients [1.7% (±0.7%)]. Less laboratory [53.3% (±10.2%) vs. 67.0% (±6.2%)] and radiographic [38.8% (±6.6%) vs. 51.6% (±4.6%) studies were performed during PA vs. PHYS visits. PA visits were most common for patients 25-44 years old (yo) (32.9%, ±6.2%) and 15-24 yo (19.2%, ±3.7%). Most PA visits result in a length of stay (LOS) between 1 and 1.9 h (32.9%, ±6.7%) compared to most PHYS visits resulting in a LOS >3 h (40.3%, ±3%). CONCLUSIONS: From 2010 to 2017, no linear trends in US ED PA and PA+ utilization were identified. PHYS continue to see the majority of ED patients.

Cardiovascular outcomes of pregnancy in Turner syndrome.

OBJECTIVES: Women with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease. METHODS: Retrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005-2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period. RESULTS: Sixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%). CONCLUSIONS: This study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

Intraperitoneal corticosteroids for recurrent ascites in patients with Fontan circulation: Initial clinical experience.

Individuals with single-ventricle congenital heart disease who are palliated to a Fontan circulation are at risk for heart failure and liver disease, with recurrent ascites being a potentially debilitating cause of late morbidity. Although ascites associated with heart failure or liver failure is usually characterized by a high serum-ascites albumin gradient (SAAG), we have observed multiple instances of ascites in Fontan patients with low SAAG, suggesting an inflammatory process. We present three cases in which recalcitrant ascites severely and adversely impacted the quality of life and describe our initial experience with intraperitoneal corticosteroids in this setting.

Physician assistant and nurse practitioner utilization in U.S. emergency departments, 2010 to 2017.

BACKGROUND: Physician Assistants (PAs) and Nurse Practitioners (NPs) are widely utilized in United States (US) Emergency Departments(EDs). We sought to characterize ED PA and NP utilization and practice characteristics in US EDs 2010-2017. METHODS: A retrospective, secondary analysis of the Center for Disease Control's National Hospital Ambulatory Medical Care Survey was performed. National estimates of ED visits involving PAs/NPs alone (PA/NP), PAs/NPs with physician involvement (PA/NP+), or physician only (PHYS) were analyzed for patient demographics and hospital characteristics. RESULTS: Between 2010 and 2017, 1 billion US ED visits occurred. 8.4% (±4.2%) of visits were seen by a PA/NP, and 11.8% (±4.5%) by a PA/NP+; 76.3% (±7.2%) by PHYS. There was an increase in utilization by PA/NP observed in 2016. PA/NP acuity was highest for semi-urgent/nonurgent (53.2%, ±8.6%). PA/NP see the minority of ambulance arrivals [5.4% (±1.2%)] and admit less patients overall [1.6% (±0.7%)]. Less laboratory [53.6% (±10.0%) vs. 67.0% (±6.2%)] and radiographic [38.0% (±7.0%) vs. 51.6% (±4.6%)] studies were performed during PA/NP only vs. PHYS visits. PA/NP visits were most common for patients 25-44 years old (yo) (31.1%, ±5.5%) and 0-15 yo (23.9%, ±4.7%). Most PA/NP visits result in a length of stay (LOS) between 1 and 1.9 h (33.4%, ±5.7%) compared to most PHYS visits resulting in a LOS greater than 3 h (40.3%, ±3%). CONCLUSIONS: From 2010 to 2015, PA/NP utilization remained stable until an increase in 2016. There was a decrease in 2017. Various PA/NP patient characteristics are significant compared to PHYS. PHYS continue to see most ED patients.

Assessment and management of heart failure in the systemic right ventricle.

Transposition of the great arteries (TGA) is a common congenital cardiac malformation, in which many patients survive into adulthood. From the 1960s through much of the 1980s, the majority of those with D-TGA were repaired with an atrial switch procedure, in which the right ventricle (RV) remains the systemic ventricle. Congenitally corrected TGA patients often remain with a systemic RV. In these patients, heart failure risks result from residual sequelae of childhood repair, which often include tricuspid regurgitation, RV failure, and atrial and ventricular arrhythmias. Imaging techniques, including echocardiography, cardiac magnetic resonance imaging, multi-detector computed tomography, and radionuclide ventriculography focus on evaluation of anatomy and function as both diagnostic and prognostic tools. Biomarkers are used for risk stratification. Structural and surgical interventions are targeted for palliation and prevention of further decompensation in conjunction with pharmacologic, ablative, and device-based therapies for acute and chronic management of heart failure.