Delivery of a Small-For-Gestational-Age Infant and Risk of Maternal Cardiovascular Disease – A Population-Based Record Linkage Study

Background. Delivery of small for gestational age (SGA) infants has been associated with increased risk of future maternal cardiovascular disease (CVD). However, whether the risk increases progressively with the greater severity of SGA and number of SGA infants has not been explored. Methods. A population-based record linkage study was conducted among 812,732 women delivering live born, singleton infants at term between 1994 and 2011 in New South Wales, Australia. Birth records were linked to the mothers’ subsequent hospitalization or death records to identify CVD events (coronary heart disease, cerebrovascular events, and chronic heart failure) after a median of 7.4 years. Cox proportional hazard regression was used to estimate adjusted hazard ratios (AHR) [95% confidence interval (CI)] for the associations between the severity (moderate or extreme) of SGA and number of SGA infants and subsequent risk of maternal CVD, accounting for maternal age at last birth, socioeconomic status, parity, smoking, (pre-gestational and gestational) diabetes, and (chronic and pregnancy) hypertension. Results. Compared to mothers of non-SGA infants, AHRs [95%CI] of CVD among mothers of moderately and extremely SGA infants were 1.36 [1.23-1.49], and 1.66 [1.47-1.87], respectively, while AHRs among mothers with 1, 2, and ≥3 SGA infants were 1.42 [1.30-1.54], 1.65 [1.34-2.03], and 2.42 [1.52-3.85], respectively, indicating a dose-response relationship. AHRs of specific CVD categories showed a similar pattern. Conclusions. Delivery of an SGA infant was associated with a dose-dependent increase in the risk of maternal CVD according to both the severity of SGA and number of previous SGA infants.NHMRC, Heart Foundation (Australia

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

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

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

A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease:The role of implantable loop recorders (RaILRoAD) compared with current standard practice

Background: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. Aim: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. Methods: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations - blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging - at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. Discussion: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. Trial registration: ClinicalTrials.gov (NCT03305250). Registered on 9 October 2017

The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program. Methods and results: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk. Effects were estimated using mixed-effects models for continuous measures and Cox regression models for other outcomes. Randomized treatment by subgroup interaction terms were used to compare effects of canagliflozin versus placebo across subgroups defined by baseline use of GLP1-RA. There were 10,142 participants, of whom 407 (4%) were using GLP1-RA therapy at baseline. Those using GLP1-RA at baseline were less likely to have a history of cardiovascular disease (60.4% vs 65.8%), had a longer duration of diabetes (152 vs 13.5 years) and a higher body mass index (BMI; 35.6 vs 31.8 kg/m(2)) but were otherwise similar. There were greater reductions with canagliflozin versus placebo for HbA1c (-0.75% versus -0.58%; P = .0091), SBP (-6.26 versus -3.83 mmHg; P = .0018), and body weight (-3.79 versus -2.18 kg; P <.0001) in those on baseline GLP1-RA therapy. Effects across subgroups were similar for UACR (P = .21), eGFR slope (A - .72), major adverse cardiac events (P = .94) and total serious adverse events (P = .74). Conclusions: There may be a synergistic effect of SGLT2 inhibition when used on a background of GLP1-RA for intermediate cardiometabolic markers. (C) 2020 Elsevier B.V. All rights reserved

Effects of canagliflozin on myocardial infarction:a post hoc analysis of the CANVAS Program and CREDENCE trial

AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial.METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1 MI or type 2 MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93).CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.</p