Cardiac biomarkers in pediatric cardiomyopathy: Study design and recruitment results from the Pediatric Cardiomyopathy Registry

Background: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. Study Design: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. Results: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. Conclusion: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. Clinical Trial Registration: NCT01873976 https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study

Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Eliminating Fad Dieting With Vinegar

It is a family tradition to consume apple cider vinegar to reduce cholesterol levels; this influenced asking the question if it could also be used for weight loss. $40 billion is spent annually in America on fad diets, ones that have temporary popularity without manifesting long term results. Since vinegar proved effective for reducing cholesterol levels, it was assumed it would also reduce fat. By using the natural ingredients contained in vinegar, the same, if not better results can be reached as if one were to conform to a fad diet. The hypothesis was tested by: researching the chemical and enzymatic effects vinegar has on the body, investigating costs and side effects of different diets, how much weight was lost, if weight remained off and associated health hazards. Findings proved vinegar helped to prevent body fat accumulation and weight gain. It decreased activity of the enzymes that respond to sugars. Fad dieting analysis averaged at a cost of$91 per week where no diet, just vinegar, averaged $54. Results proved money can be saved; harmful side effects prevented and weight loss goals attained. Vinegar not only induced weight loss but also decreased cholesterol levels, promoted body detoxification and efficient digestion

Design and development of an automated flow injection instrument for the determination of arsenic species in natural waters

The design and development of an automated flow injection instrument for the determination of arsenite [As(III)] and arsenate [As(V)] in natural waters is described. The instrument incorporates solenoid activated self-priming micropumps and electronic switching valves for controlling the fluidics of the system and a miniature charge-coupled device spectrometer operating in a graphical programming environment. The limits of detection were found to be 0.79 and 0.98 μM for As(III) and As(V), respectively, with linear range of 1–50 μM. Spiked ultrapure water samples were analyzed and recoveries were found to be 97%–101% for As(III) and 95%–99% for As(V), respectively. Future directions in terms of automation, optimization, and field deployment are discussed

Increased energy intake entirely accounts for increase in body weight in women but not in men in the UK between 1986 and 2000

There is debate over the causal factors for the rise in body weight in the UK. The present study investigates whether increases between 1986 and 2000 for men and women were a result of increases in mean total energy intake, decreases in mean physical activity levels or both. Estimates of mean total energy intake in 1986 and 2000 were derived from food availability data adjusted for wastage. Estimates of mean body weight for adults aged 19-64 years were derived from nationally representative dietary surveys conducted in 1986-7 and 2000-1. Predicted body weight in 1986 and 2000 was calculated using an equation relating body weight to total energy intake and sex. Differences in predicted mean body weight and actual mean body weight between the two time points were compared. Monte Carlo simulation methods were used to assess the stability of the estimates. The predicted increase in mean body weight due to changes in total energy intake between 1986 and 2000 was 4.7 (95% credible interval 4.2, 5.3)kg for men and 6.4 (95% credible interval 5.9, 7.1)kg for women. Actual mean body weight increased by 7.7kg for men and 5.4kg for women between the two time points. We conclude that increases in mean total energy intake are sufficient to explain the increase in mean body weight for women between 1986 and 2000, but for men, the increase in mean body weight is likely to be due to a combination of increased total energy intake and reduced physical activity levels

Preventing pediatric cardiomyopathy: a 2015 outlook

Cardiomyopathies in children encompass a broad range of diseases, both genetic and acquired, which manifest as a primary cardiac disorder or as a cardiomyopathy secondary to systemic disease. The burden of this group of disorders is substantial, and growing on a global scale. The availability of disease altering treatments is limited, and therefore a focused review on the prevention of cardiomyopathies is justified. In this review, we address the prevention of cardiomyopathy in children by dealing with the root causes of disease at a molecular, clinical and population level. Recent years have yielded promising returns in basic research related to gene-targeted therapy, specific anti-viral therapies and modification of the effects of cardiotoxic drugs. Much work remains to be done in the fields of vaccine development, public health and adoption of available treatments. Effective research in this field will require that diagnostic methods are both refined, and made available more broadly, from imaging to gene testing. Much of our knowledge today is derived from the use of registries, which have successfully catalogued the detailed phenotype of affected patients, and provided long-term longitudinal follow up of affected individuals