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

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

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

High-resolution transthoracic echocardiography accurately detects pulmonary arterial pressure and decreased right ventricular contractility in a mouse model of pulmonary fibrosis and secondary pulmonary hypertension

BACKGROUND: To date, assessment of right ventricular (RV) function in mice has relied extensively on invasive measurements. Echocardiographic advances have allowed adaptation of measures used in humans for serial, noninvasive RV functional assessment in mice. We evaluated the diagnostic performance of tricuspid annular plane systolic excursion (TAPSE), RV peak systolic myocardial velocity (s'), RV myocardial performance index (MPI), and RV fractional area change (FAC) in a mouse model of pulmonary hypertension. METHODS AND RESULTS: Echocardiography was performed on mice at baseline and 3 weeks after induction of pulmonary hypertension using inhaled bleomycin or saline, including adapted measures of TAPSE, s', MPI, and FAC. RV systolic pressure was measured by invasive catheterization, and RV contractility was measured as the peak slope of the RV systolic pressure recording (maximum change pressure/change time). Postmortem morphological assessment of RV hypertrophy was performed. RV systolic pressure was elevated and maximum change pressure/change time was reduced in bleomycin versus control (n=8; P=0.002). Compared with controls, bleomycin mice had reduced TAPSE (0.79±0.05 versus 1.06±0.04 mm; P=0.003), s' (21.3±1.2 versus 29.2±1.3 mm/s; P<0.001), and FAC (20.3±0.7% versus 31.0±1.3%; P<0.001), whereas MPI was increased (0.51±0.03 versus 0.37±0.01; P=0.006). All measures correlated with RV systolic pressure and maximum change pressure/change time. Intraobserver and interobserver variability were minimal. Receiver operating characteristic curves demonstrated that TAPSE (<0.84 mm), s'(<23.3 mm/s), MPI (0.42), and FAC (<23.3%) identified maximum change pressure/change time ≤2100 mm Hg/s with high accuracy. CONSLUSIONS: TAPSE, s', MPI, and FAC are measurable consistently using high-resolution echocardiography in mice, and are sensitive and specific measures of pulmonary pressure and RV function. This validation opens the opportunity for serial noninvasive measures in mouse models of pulmonary hypertension, enhancing the statistical power of preclinical studies of novel therapeutics

Polygenic risk score and coronary artery disease:A meta-analysis of 979,286 participant data

BACKGROUND AND AIMS: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD. METHODS: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis. RESULTS: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001). CONCLUSIONS: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD

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

Current Concepts on Antiplatelet Therapy: Focus on the Novel Thienopyridine and Non-Thienopyridine Agents

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate (ADP) 2 receptor. They significantly reduce platelet activity and are therefore clinically beneficial in settings where platelet activation is a key pathophysiological feature, particularly myocardial infarction. Ticlopidine, the first of the class introduced to clinical practice, was soon challenged and almost completely replaced by clopidogrel for its better tolerability. More recently, prasugrel and ticagrelor have been shown to provide a more powerful antiplatelet action compared to clopidogrel but at a cost of higher risk of bleeding complications. Cangrelor, a molecule very similar to ticagrelor, is currently being evaluated against clopidogrel. Considering the key balance of ischemic protection and bleeding risk, this paper discusses the background to the development of prasugrel, ticagrelor, and cangrelor and aims to characterise their risk-benefit profile and possible implementation in daily practice

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