Canagliflozin and heart failure in Type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)

BACKGROUND : Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure and cardiovascular death overall, in those with and without a baseline history of heart failure, and in other participant subgroups. METHODS : The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized heart failure. RESULTS : Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03). CONCLUSIONS : In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized heart failure across a broad range of different patient subgroups. Benefits may be greater in those with a history of heart failure at baseline. CLINICAL TRIAL REGISTRATION : URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754

Insight into hypertrophied hearts: a cardiovascular magnetic resonance study of papillary muscle mass and T1 mapping

AIMS: Left ventricular papillary muscles (LVPM) can appear disproportionately hypertrophied, particularly in Fabry disease (FD) where storage appears detectable by cardiovascular magnetic resonance (CMR) T1 mapping. The aim of the study was to measure LVPM mass in heart diseases with left ventricular hypertrophy (LVH) and to gain insight into the mechanisms of LVPM hypertrophy in FD. METHODS AND RESULTS: Four hundred and seventy-eight cases were retrospectively recruited: 125 FD, 85 hypertrophic cardiomyopathy (HCM), 67 amyloid, 82 aortic stenosis (AS), 40 hypertension, 79 controls. LVPM contribution to LVM was manually contoured on CMR short axis cines. T1 values (septal, LVPM) were measured using ShMOLLI sequences in FD and controls. LVPM contribution to LVM was highest in LVH+ve FD and significantly increased compared to all other LVH+ve groups (FD 13 ± 3%, HCM 10 ± 3%, amyloid 8 ± 2%, AS 7 ± 3%, hypertension 7 ± 2%, controls 7 ± 1%; P < 0.001). LVH+ve HCM also had significantly increased LVPM. In LVH−ve cohorts, only FD had significantly increased LVPM (11 ± 3%; P < 0.001). In FD there was concordant septal and LVPM T1. LVH+ve FD: when septal T1 was low, LVPM T1 was low in 90%. LVH−ve FD: when septal T1 was normal, LVPM T1 was normal in 70% (indicating no detectable storage); when septal T1 was low, 75% had low LVPM T1 (indicating storage). LVPM hypertrophy was similar between the low and normal septal T1 groups (11 ± 3% vs. 10 ± 3%, P = 0.08). CONCLUSION: Disproportionate hypertrophy of LVPMs in LVH+ve hearts occurred in FD and HCM. This phenomenon also occurred in LVH−ve FD. Low T1 was not always present in FD LVPM hypertrophy, implying additional mechanisms activating hypertrophy signalling pathways

Modifiable risk factors and cardiovascular outcomes

To the Editor: The results of an investigation of risk factors on the incidence of cardiovascular disease and death from any cause, as reported by Magnussen et al. on behalf of the Global Cardiovascular Risk Consortium (Oct. 5 issue), show that these risk factors accounted for a population-attributable fraction of the 10-year incidence of cardiovascular disease of 52.6% among men and 57.2% among women. The factors that were investigated are five modifiable risk factors (body-mass index, systolic blood pressure, the level of non–high-density lipoprotein [HDL] cholesterol, current smoking, and diabetes). It is disappointing that current smoking and diabetes were selected

Cardiac spheroids as promising in vitro models to study the human heart microenvironment.

Three-dimensional in vitro cell systems are a promising alternative to animals to study cardiac biology and disease. We have generated three-dimensional in vitro models of the human heart ("cardiac spheroids", CSs) by co-culturing human primary or iPSC-derived cardiomyocytes, endothelial cells and fibroblasts at ratios approximating those present in vivo. The cellular organisation, extracellular matrix and microvascular network mimic human heart tissue. These spheroids have been employed to investigate the dose-limiting cardiotoxicity of the common anti-cancer drug doxorubicin. Viability/cytotoxicity assays indicate dose-dependent cytotoxic effects, which are inhibited by the nitric oxide synthase (NOS) inhibitor L-NIO, and genetic inhibition of endothelial NOS, implicating peroxynitrous acid as a key damaging agent. These data indicate that CSs mimic important features of human heart morphology, biochemistry and pharmacology in vitro, offering a promising alternative to animals and standard cell cultures with regard to mechanistic insights and prediction of toxic effects in human heart tissue

Heart valve prostheses in pregnancy: Outcomes for women and their babies

Background: As the prognosis of women with prosthetic heart valves improves more of these individuals are contemplating and undertaking pregnancy. Accurate knowledge of perinatal outcomes is essential, assisting counselling and guiding care. The aim of this study was to assess outcomes in a contemporary population of women with heart valve prostheses undertaking pregnancy, and to compare outcomes for women with mechanical and bioprosthetic prostheses. Method and results: Longitudinally-linked population health datasets containing birth and hospital admissions data were obtained for all women giving birth in New South Wales, Australia, 2000-2011. This included information identifying presence of maternal prosthetic heart valve. Cardiovascular and birth outcomes were evaluated. Among 1 144 156 pregnancies, 136 involved women with a heart valve prosthesis (1 in 10 000). No maternal mortality was seen among these women, although the relative risk for an adverse event was higher than the general population, including severe maternal morbidity (13.9% v. 1.4%, RR=9.96, 95% CI 6.32-15.7), major maternal cardiovascular event (4.4% v. 0.1%, RR 34.6, 95% CI 14.6-81.6), preterm birth (18.3% v. 6.6%, RR=2.77, 95% CI 1.88-4.07) and small-for-gestational-age infants (19.3% v. 9.5%, RR=2.12, 95% CI 1.47-3.06). There was a trend towards increased maternal and perinatal morbidity in women with a mechanical valve compared to bioprosthetic. Conclusions: Pregnancies in women with a prosthetic heart valve demonstrate an increased risk of an adverse outcome, for both mothers and babies, compared with pregnancies in the absence of heart valve prostheses. In this contemporary population, the risk was lower than previously reported.NHMRC 1001066, NHMRC 1021025, NHMRC 1062262, ARC FT120100069, Australian Heart Foundatio

Chikungunya as a cause of acute febrile illness in southern Sri Lanka

10.1371/journal.pone.0082259PLoS ONE812-POLN

Prosthetic heart valves in pregnancy, outcomes for women and their babies: A systematic review and meta-analysis

Background Historically, pregnancies among women with prosthetic heart valves have been associated with an increased incidence of adverse outcomes. While there have been advances in prosthetic heart valve design, obstetric and medical care, subsequent impact on incidence of adverse outcomes during pregnancy has not been quantified. Objectives To assess the risk of adverse pregnancy outcomes among women with a prosthetic heart valve(s) in the contemporary setting. Search Strategy Electronic literature search of Medline, The Cochrane Library, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Embase to find recent studies. Selection Criteria Studies of pregnant women with heart valve prostheses including trials, cohort studies and unselected case series. Data Collection and Analysis Absolute risks and 95% confidence intervals for pregnancy outcomes were calculated using either a random effects model or the logit transformation of total events and participants (the latter method when multiple studies had event counts of zero). Main Results Eleven studies capturing 499 pregnancies among women with heart valve prostheses were eligible for inclusion. Pooled maternal mortality rate was 0.8/100 pregnancies (95% CI 0.3-2.1), pregnancy loss rate 32.1/100 pregnancies (95% CI 28.1-36.3) and perinatal mortality rate 4.7/100 births (95% CI 2.7-7.9). Conclusions Women with heart valve prostheses experienced higher rates of adverse outcomes then would be expected in a general obstetric population, however lower than previously reported. Multidisciplinary pre-pregnancy counselling and vigilant cardiac and obstetric surveillance throughout the perinatal period remains warranted for these women and their infantsNHMRC 1001066, NHMRC 1021025, NHMRC 1062262, ARC FT120100069 and Australian Heart Foundatio

Transmission and control of Plasmodium knowlesi: a mathematical modelling study.

INTRODUCTION: Plasmodium knowlesi is now recognised as a leading cause of malaria in Malaysia. As humans come into increasing contact with the reservoir host (long-tailed macaques) as a consequence of deforestation, assessing the potential for a shift from zoonotic to sustained P. knowlesi transmission between humans is critical. METHODS: A multi-host, multi-site transmission model was developed, taking into account the three areas (forest, farm, and village) where transmission is thought to occur. Latin hypercube sampling of model parameters was used to identify parameter sets consistent with possible prevalence in macaques and humans inferred from observed data. We then explore the consequences of increasing human-macaque contact in the farm, the likely impact of rapid treatment, and the use of long-lasting insecticide-treated nets (LLINs) in preventing wider spread of this emerging infection. RESULTS: Identified model parameters were consistent with transmission being sustained by the macaques with spill over infections into the human population and with high overall basic reproduction numbers (up to 2267). The extent to which macaques forage in the farms had a non-linear relationship with human infection prevalence, the highest prevalence occurring when macaques forage in the farms but return frequently to the forest where they experience higher contact with vectors and hence sustain transmission. Only one of 1,046 parameter sets was consistent with sustained human-to-human transmission in the absence of macaques, although with a low human reproduction number (R(0H) = 1.04). Simulations showed LLINs and rapid treatment provide personal protection to humans with maximal estimated reductions in human prevalence of 42% and 95%, respectively. CONCLUSION: This model simulates conditions where P. knowlesi transmission may occur and the potential impact of control measures. Predictions suggest that conventional control measures are sufficient at reducing the risk of infection in humans, but they must be actively implemented if P. knowlesi is to be controlled

Heart valve prostheses in pregnancy: Outcomes for women and their babies

Background: As the prognosis of women with prosthetic heart valves improves more of these individuals are contemplating and undertaking pregnancy. Accurate knowledge of perinatal outcomes is essential, assisting counselling and guiding care. The aim of this study was to assess outcomes in a contemporary population of women with heart valve prostheses undertaking pregnancy, and to compare outcomes for women with mechanical and bioprosthetic prostheses. Method and results: Longitudinally-linked population health datasets containing birth and hospital admissions data were obtained for all women giving birth in New South Wales, Australia, 2000-2011. This included information identifying presence of maternal prosthetic heart valve. Cardiovascular and birth outcomes were evaluated. Among 1 144 156 pregnancies, 136 involved women with a heart valve prosthesis (1 in 10 000). No maternal mortality was seen among these women, although the relative risk for an adverse event was higher than the general population, including severe maternal morbidity (13.9% v. 1.4%, RR=9.96, 95% CI 6.32-15.7), major maternal cardiovascular event (4.4% v. 0.1%, RR 34.6, 95% CI 14.6-81.6), preterm birth (18.3% v. 6.6%, RR=2.77, 95% CI 1.88-4.07) and small-for-gestational-age infants (19.3% v. 9.5%, RR=2.12, 95% CI 1.47-3.06). There was a trend towards increased maternal and perinatal morbidity in women with a mechanical valve compared to bioprosthetic. Conclusions: Pregnancies in women with a prosthetic heart valve demonstrate an increased risk of an adverse outcome, for both mothers and babies, compared with pregnancies in the absence of heart valve prostheses. In this contemporary population, the risk was lower than previously reported.NHMRC 1001066, NHMRC 1021025, NHMRC 1062262, ARC FT120100069, Australian Heart Foundatio