A Notch more: Molecular players in bicuspid aortic valve disease.

The prevalence of calcification of human aortic valve in populations 65 years old and greater is estimated to be 2-3%. Bicuspid aortic valve disease (BAVD) is a common etiology of aortic stenosis in populations aged 60-75 years of age; 30-50% of operated cases of aortic stenosis were due to calcified BAVD. Dysregulation of the Notch and the canonical Wnt pathway has been well documented to be associated with calcification of the aortic valve. However, recent studies have increased this scope to include the non-canonical pathway where Wnt5a, Wnt5b and Wnt 11 levels were significantly greater in calcified human aortic valves than normal valves, and with Wnt5b specifically being implicated in BAVD pathogenesis. More recently, Lipoprotein(a) [Lp(a)] has been implicated as a key player in the pathogenesis of calcific aortic valve disease. It has been shown that the osteogenic effect of Lp(a) is mediated through the oxidized phospholipid pathway as well as oxidized phospholipid independent pathways involving mitogen-activated protein kinases (MAPK), glycogen synthase kinase (GSK) and Wnt. Moving forward, further work needs to be conducted in order to elucidate the crosstalk between the different signaling cascades, specifically with regard to BAVD.

Sex differences in the etiology and burden of heart failure across country income level: analysis of 204 countries and territories 1990-2019.

BACKGROUND: Heart failure (HF) is a global epidemic. OBJECTIVE: To assess global sex differences in HF epidemiology across country income levels. METHODS AND RESULTS: Using Global Burden of Disease (GBD) data from 204 countries and territories 1990-2019, we assessed sex differences in HF prevalence, etiology, morbidity, and temporal trends across country sociodemographic index or gross national income. We derived age-standardized rates. Of 56.2 million (95% uncertainty interval [UI] 46.4-67.8 million) people with HF in 2019, 50.3% were females and 69.2% lived in low- and middle-income countries; age-standardized prevalence was greater in males and in high-income countries. Ischaemic and hypertensive heart disease were top causes of HF in males and females, respectively. There were 5.1 million (95% UI 3.3-7.3 million) years lived with disability, distributed equally between sexes. Between 1990 and 2019, there was an increase in HF cases, but a decrease in age-standardized rates per 100 000 in males (9.1%, from 864.2 to 785.7) and females (5.8%, from 686.0 to 646.1). High-income regions experienced a 16.0% decrease in age-standardized rates (from 877.5 to 736.8), while low-income regions experienced a 3.9% increase (from 612.1 to 636.0), largely consistent across sexes. There was a temporal increase in age-standardized HF from hypertensive, rheumatic, and calcific aortic valvular heart disease, and a decrease from ischaemic heart disease, with regional and sex differences. CONCLUSION: Age-standardized HF rates have decreased over time, with larger decreases in males than females; and with large decreases in high-income and small increases in low-income regions. Sex and regional differences offer targets for intervention.

Factors Associated With Racial and Ethnic Diversity Among Heart Failure Trial Participants: A Systematic Bibliometric Review.

BACKGROUND: Heart failure has a disproportionate burden on patients who are Black, Indigenous, and people of color (BIPOC), but not much is known about representation of these groups in randomized controlled trials (RCTs). We explored temporal trends in and RCT factors associated with the reporting of race and ethnicity data and the enrollment of BIPOC in heart failure RCTs. METHODS: We searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with an impact factor ≥10 between January 1, 2000 and June 17, 2020. We used the Cochran-Armitage and Jonchkeere-Terpstra tests to examine temporal trends, and multivariable regression to assess the association between trial characteristics and outcomes. RESULTS: Of 414 RCTs meeting inclusion criteria, only 157 (37.9% [95% CI, 33.2%-2.8%]) reported race and ethnicity data. Among 158 200 participants in these 157 RCTs, 29 512 (18.7% [95% CI, 18.5%-18.9%]) were BIPOC. There was a temporal increase in reporting of race and ethnicity data (29.5% in 2000-2003 to 54.7% in 2016-2020, P<0.001) and in enrollment of BIPOC (14.4% in 2000-2003 to 22.2% in 2016-2020, P=0.038). Trial leadership by a woman was independently associated with twice the odds of reporting race and ethnicity data (odds ratio, 2.0 [95% CI, 1.1-3.8]; P=0.028) and an 8.4% increase (95% CI, 1.9%-15.0%; P=0.013) in BIPOC enrollment. CONCLUSIONS: A minority of heart failure RCTs reported race and ethnicity data, and among these, BIPOC were under-enrolled relative to disease distribution. Both reporting of race and ethnicity as well as enrollment of BIPOC increased between 2000 and 2020. After multivariable adjustment, trials led by women had greater odds of reporting race and ethnicity and enrolling BIPOC. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021237497.

Global representation of heart failure clinical trial leaders, collaborators, and enrolled participants: a bibliometric review 2000-20.

AIMS: The geographic representation of investigators and participants in heart failure (HF) randomized controlled trials (RCTs) may not reflect the global distribution of disease. We assessed the geographic diversity of RCT leaders and explored associations with geographic representation of enrolled participants among impactful HF RCTs. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with impact factor ≥ 10 between January 2000 and June 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to explore associations between predictors and outcomes. There were 414 eligible RCTs. Only 80 of 828 trial leaders [9.7%; 95% confidence interval (CI): 7.8-11.8%] and 453 of 4656 collaborators (9.7%; 95% CI: 8.8-10.6%) were from outside Europe and North America, with no change in temporal trends and with greater disparities in large RCTs. The adjusted odds of trial leadership outside Europe and North America were lower with industry funding [adjusted odds ratio (aOR): 0.33; 95% CI: 0.15-0.75; P = 0.008]. Among 157 416 participants for whom geography was reported, only 14.5% (95% CI: 14.3-14.7%) were enrolled outside Europe and North America, but odds of enrolment were 10-fold greater with trial leadership outside Europe and North America (aOR: 10.0; 95% CI: 5.6-19.0; P < 0.001). CONCLUSION: Regions disproportionately burdened with HF are under-represented in HF trial leadership, collaboration, and enrolment. RCT leadership outside Europe and North America is independently associated with participant enrolment in under-represented regions. Increasing research capacity outside Europe and North America could enhance trial diversity and generalizability.

Musculoskeletal deformities after thoracic surgery in children: An observational long-term follow-up study.

PURPOSE: This study reports the incidence, severity, and predictors of musculoskeletal deformities (MD), including scoliosis and chest wall anomalies, following thoracic procedures in children. METHODS: Children younger than 14 years who had thoracic surgery between 1997 and 2012 and had no other predispositions to MD, underwent longitudinal follow-ups with dedicated musculoskeletal examination performed in an esophageal atresia, orthopedic, or research clinic. Incidence of MD was calculated, and logistic regression methods were used to determine independent predictors, including sex, gestational age, age at procedure, serratus anterior muscle division, and chest tube placement. RESULTS: The study cohort consisted of 104 patients followed for a median of 10.8 years (range 3-21). A total of 56 MD developed in 41 patients (39%), including scapular winging (24; 23%), scoliosis (17; 16%), and chest wall anomalies (15; 14%). The majority of MD were subclinical, with only 8 patients [8% (6 thoracotomies, 2 thoracoscopies)] requiring intervention. Among patients who underwent thoracotomies (93, 89%), serratus anterior muscle division was the only significant predictor of the development of MD [OR 8.9; 95% CI 2.8-32.6]. CONCLUSION: Musculoskeletal deformities develop in a significant proportion of children following thoracic surgery, but most are subclinical. A muscle-sparing technique decreases the incidence of these deformities. TYPE OF STUDY: Prospective Cohort Study. LEVEL OF EVIDENCE: Level II.

Does the presence of non-refluxing hydroureter impact the management and outcome of high-grade hydronephrosis?

INTRODUCTION: We aimed to evaluate the impact of non-refluxing hydroureter on the initial management of high-grade hydronephrosis (HGH) management. Moreover, we evaluated the occurrence of febrile urinary tract infection (fUTI) and surgical intervention for conservatively managed units. METHODS: Patients' charts with postnatal hydronephrosis from 2008-2014 were retrospectively reviewed. We included patients who presented in the first year of life. All included patients had HGH (Society of Fetal Ultrasound [SFU] grades 3 and 4) and all were non-refluxing using voiding cystourethrogram (VCUG). We categorized renal units into two groups: with hydroureteronephrosis (HUN) and without hydroureter (isolated hydronephrosis [IH]). We recorded the initial management. We evaluated the impact of non-refluxing hydroureter on hydronephrosis fate, fUTI, and change to surgery for those managed conservatively. RESULTS: We included 169 patients (180 units). IH was diagnosed in 146 units (137 patients), whereas 34 units (32 patients) had HUN. Median followup was 42.9 months. A total of 25.3% (37/146) of IH units had initial surgical management in comparison to 5.1% (2/34) of HUN units (p=0.01). During conservative management, nine HUN patients (30%) and 11 IH patients (10.7%) experienced fUTI (p=0.009). Surgical intervention after failed conservative management was indicated for 12 IH units (11%) and six HUN units (18.8%) (p=0.25). Anteroposterior diameter (APD) worsening was significantly associated with the change to surgery in IH group (p=0.003). More than half (52.3%) of IH units resolved during conservative management in comparison to 18.7% of HUN (p<0.001). HUN had longer time to resolution (log rank=0.004). CONCLUSIONS: IH units had more initial surgical interventions. The fUTI rate was much higher in association with dilated ureter even under antibiotic coverage. HUN was associated with less and slower resolution rate.

Musculoskeletal deformities following neonatal thoracotomy: long-term follow-up of an esophageal atresia cohort.

BACKGROUND: Musculoskeletal deformities (MD), including scoliosis and chest wall anomalies, are potential long-term complications of neonatal thoracotomies. METHODS: We studied the incidence of MD in patients who underwent open repair of esophageal atresia between 1997 and 2012, had no other predisposition to MD, and subsequently received longitudinal follow-up in a multidisciplinary esophageal atresia clinic. Detailed chest wall and musculoskeletal exams were performed at each visit. Incident rate and incident rate ratios were used to determine the incidence of deformities. Logistic regression methods were used to test the effect of independent variables including sex, gestational age, muscle division, number of thoracotomies, and operative complications on the occurrence of MD. RESULTS: The study cohort consisted of 52 patients followed for a median of 8 (range 1-19) years. MD developed in 13 (25%), with an incident rate of 2.92 per 100 child-years. Division of the serratus anterior was associated with a significantly higher probability of developing MD (log-rank p=.0237) and was also a strong predictor of the same [OR 8.6 (95% CI 1.8-42.1)] after adjusting for possible confounders. CONCLUSIONS: Musculoskeletal deformities develop in a significant proportion of neonates following thoracotomy. A muscle-sparing technique decreases the incidence of these deformities. TYPE OF STUDY: Prospective Cohort Study. LEVEL OF EVIDENCE: II.