Left atrial structure and function in cardiac amyloidosis

Aims: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. // Methods and results: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E’) (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = −0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = −0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E’)]. // Conclusion: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA

Left atrial structure and function in cardiac amyloidosis

Aims: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. // Methods and results: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E’) (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = −0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = −0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E’)]. // Conclusion: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA

Personalised service? Changing the role of the government librarian

Investigates the feasibility of personalised information service in a government department. A qualitative methodology explored stakeholder opinions on the remit, marketing, resourcing and measurement of the service. A questionnaire and interviews gathered experiences of personalised provision across the government sector. Potential users were similarly surveyed to discuss how the service could meet their needs. Data were analysed using coding techniques to identify emerging theory. Lessons learned from government librarians centred on clarifying requirements, balancing workloads and selective marketing. The user survey showed low usage and awareness of existing specialist services, but high levels of need and interest in services repackaged as a tailored offering. Fieldwork confirmed findings from the literature on the scope for adding value through information management advice, information skills training and substantive research assistance and the need to understand business processes and develop effective partnerships. Concluding recommendations focus on service definition, strategic marketing, resource utilisation and performance measurement

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

BACKGROUND Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goat of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabotic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 +/- 6 years; 47% mate), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (beta-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (beta = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (beta = -3.2; 95% CI: -6.4 to 0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions. (C) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.Peer reviewe

The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans

BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro–brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.

Three-question set from Michigan Neuropathy Screening Instrument adds independent prognostic information on cardiovascular outcomes: analysis of ALTITUDE trial

Abstract: Aims/hypothesis The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes. Methods: In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set. Results: In the training set, three questions (‘Are your legs numb?’, ‘Have you ever had an open sore on your foot?’ and ‘Do your legs hurt when you walk?’) were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell’s C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007). Conclusions/interpretation: We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes

Contribution of cardiac and extra-cardiac disease burden to risk of cardiovascular outcomes varies by ejection fraction in heart failure.

AIMS: Patients with heart failure (HF) often have multiple co-morbidities that contribute to the risk of adverse cardiovascular (CV) and non-CV outcomes. We assessed the relative contribution of cardiac and extra-cardiac disease burden and demographic factors to CV outcomes in HF patients with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We utilized data from the CHARM trial, which enrolled HF patients across the ejection fraction spectrum. We decomposed the previously validated MAGGIC risk score into cardiac (LVEF, New York Heart Association class, systolic blood pressure, time since HF diagnosis, HF medication use), extra-cardiac (body mass index, creatinine, diabetes mellitus, chronic obstructive pulmonary disease, smoker), and demographic (age, gender) categories, and calculated subscores for each patient representing the burden of each component. Cox proportional hazards models were used to estimate the population attributable risk (PAR) associated with each component to the outcomes of death, CV death, HF, myocardial infarction, and stroke relative to patients with the lowest risk score. PARs for each component were depicted across the spectrum of LVEF. in 2675 chronic HF patients from North America [HFrEF (LVEF ≤40%): n = 1589, HFpEF (LVEF >40%): n = 1086] with data available for calculation of the MAGGIC score, the highest risk of death and CV death was attributed to cardiac burden. This was especially evident in HFrEF patients (PAR: 76% cardiac disease vs. 58% extra-cardiac disease, P < 0.05). Conversely, in HFpEF patients, extra-cardiac burden accounted for a greater proportion of risk for death than cardiac burden (PAR: 15% cardiac disease vs. 49% extra-cardiac disease, P < 0.05). For HF hospitalization, the contribution of both cardiac and extra-cardiac burden was comparable in HFpEF patients (PAR: 42% cardiac disease vs. 53% extra-cardiac disease, P = NS). In addition, demographic burden was especially high in HFpEF patients, with 62% of deaths attributable to demographic characteristics. CONCLUSION: In North American HF patients enrolled in the CHARM trials, the relative contribution of cardiac and extra-cardiac disease burden to CV outcomes and death differed depending on LVEF. The high risk of events attributable to non-cardiac disease burden may help explain why cardiac disease-modifying medication proven to be efficacious in HFrEF patients has not proven beneficial in HFpEF

A Single Visualization Technique for Displaying Multiple Metabolite-Phenotype Associations

To assist with management and interpretation of human metabolomics data, which are rapidly increasing in quantity and complexity, we need better visualization tools. Using a dataset of several hundred metabolite measures profiled in a cohort of similar to 1500 individuals sampled from a population-based community study, we performed association analyses with eight demographic and clinical traits and outcomes. We compared frequently used existing graphical approaches with a novel ` rain plot' approach to display the results of these analyses. The ` rain plot' combines features of a raindrop plot and a conventional heatmap to convey results of multiple association analyses. A rain plot can simultaneously indicate e ff ect size, directionality, and statistical significance of associations between metabolites and several traits. This approach enables visual comparison features of all metabolites examined with a given trait. The rain plot extends prior approaches and o ff ers complementary information for data interpretation. Additional work is needed in data visualizations for metabolomics to assist investigators in the process of understanding and convey large-scale analysis results e ff ectively, feasibly, and practically

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction

Background The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. Methods We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. Results There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. Conclusions Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.