Unplanned Rehospitalisation due to Medication Harm following an Acute Myocardial Infarction.

INTRODUCTION: The contribution of medication harm to rehospitalisation and adverse patient outcomes after an acute myocardial infarction (AMI) needs exploration. Rehospitalisation is costly to both patients and the healthcare facility. Following an AMI, patients are at risk of medication harm as they are often older and have multiple comorbidities and polypharmacy. This study aimed to quantify and evaluate medication harm causing unplanned rehospitalisation after an AMI. METHODS: This was a retrospective cohort study of patients discharged from a quaternary hospital post-AMI. All rehospitalisations within 18 months were identified using medical record review and coding data. The primary outcome measure was medication harm rehospitalisation. Preventability, causality, and severity assessments of medication harm were conducted. RESULTS: A total of 1,564 patients experienced an AMI, and 415 (26.5%) were rehospitalised. Eighty-nine patients (5.7% of total population; 6.0% of those discharged) experienced a total of 101 medication harm events. Those with medication harm were older (p = 0.007) and had higher rates of heart failure (p = 0.005), chronic kidney disease (p = 0.046), chronic obstructive pulmonary disease (p = 0.037), and a prior history of ischaemic heart disease (p = 0.005). Gastrointestinal bleeding, acute kidney injury, and hypotension were the most common medication harm events. Forty percent of events were avoidable, and 84% were classed as "serious." Furosemide, antiplatelets, and angiotensin-converting enzyme inhibitors were the most commonly implicated medications. The median time to medication harm rehospitalisation was 79 days (interquartile range: 16-200 days). CONCLUSION: Medication harm causes unplanned rehospitalisation in 5.7% of all AMI patients (1 in 17 patients; 6.0% of those discharged). The majority of harm was serious and occurred within the first 200 days of discharge. This study highlights that measures to attenuate the risk of medication harm rehospitalisation are essential, including post-discharge medication management.

Gender differences in cardiovascular disease risk: Adolescence to young adulthood.

BACKGROUND AND AIMS: Gender differences in cardiovascular disease (CVD) have been well documented but rarely for young adults and the extent to which gender related lifestyle differences may contribute to gender differences in CVD risk experienced by young adults have not been reported. METHODS AND RESULTS: Data are from a long-running cohort study, the Mater-University of Queensland Study of Pregnancy (MUSP). We track gender differences in CVD related behaviours at 21 and 30 years (consumption of a Western Diet/Health-Oriented Diet, cigarette smoking, vigorous physical exercise, heavy alcohol consumption). At 30 years we compare males and females for CVD risk, and the extent to which lifestyle behaviours at 21 and 30 years contribute to CVD risk. At both 21 and 30 years of age, males more frequently consume a Western Diet and less often a Health Oriented Diet. By contrast, males are also much more likely to report engaging in vigorous physical activity. On most CVD markers, males exhibit much higher levels of risk than do females at both 21 and 30 years. At 30 years of age males have about five times the odds of being at high risk of CVD. Some lifestyle behaviours contribute to this additional risk. CONCLUSION: Young adult males much more frequently engage in most CVD related risk behaviours and males have a higher level of CVD risk. Gender differences in CVD risk remain high even after adjustment for CVD lifestyles, though dietary factors independently contribute to CVD risk at 30 years.

Rapid magnetically directed assembly of pre-patterned capillary-scale microvessels.

Capillary scale vascularization is critical to the survival of engineered 3D tissues and remains an outstanding challenge for the field of tissue engineering. Current methods to generate micro-scale vasculature such as 3D printing, two photon hydrogel ablation, angiogenesis, and vasculogenic assembly face challenges in rapidly creating organized, highly vascularized tissues at capillary length-scales. Within metabolically demanding tissues, native capillary beds are highly organized and densely packed to achieve adequate delivery of nutrients and oxygen and efficient waste removal. Here, we adopt two existing techniques to fabricate lattices composed of sacrificial microfibers that can be efficiently and uniformly seeded with endothelial cells (ECs) by magnetizing both lattices and ECs. Ferromagnetic microparticles (FMPs) were incorporated into microfibers produced by solution electrowriting (SEW) and fiber electropulling (FEP). By loading ECs with superparamagnetic iron oxide nanoparticles (SPIONs), the cells could be seeded onto magnetized microfiber lattices. Following encapsulation in a hydrogel, the capillary templating lattice was selectively degraded by a bacterial lipase that does not impact mammalian cell viability or function. This work introduces a novel approach to rapidly producing organized capillary networks within metabolically demanding engineered tissue constructs which should have broad utility for the fields of tissue engineering and regenerative medicine.

Dietary patterns and young adult body mass change: A 9-year longitudinal study.

PURPOSE: While excessive weight gain is highest during young adulthood, the extent to which specific dietary patterns are associated with changes in measures of body mass in this course of life remains unknown. We aimed to examine the associations of dietary patterns at 21 years with changes in body weight and body mass index (BMI) between 21 and 30 years. METHODS: We used data on young adults from a long-running birth cohort in Australia. Western and prudent dietary patterns were identified applying principal component analysis to 33 food groups obtained by a food frequency questionnaire at 21 years. Body weight and height were measured at 21 and 30 years. Multivariable regression models, using generalized estimating equations, were adjusted for concurrent changes in sociodemographic and lifestyle variables in evaluating the effect of identified dietary patterns on changes in weight and BMI over time. RESULTS: In the fully adjusted model, young adults in the highest tertile of the Western pattern had a mean weight gain of 9.9 (95% CI 8.5, 11.3) kg compared to those in the lowest that had a mean weight gain of 7.1 (95% CI 5.6, 8.5) kg, P-for linear trend = 0.0015. The corresponding values for mean gains in BMI were 3.1 (95% CI 2.7, 3.6) kg/m2 for young adults in the highest tertile compared to 2.4 (95% CI 1.9, 2.9) kg/m2 for those in lowest, P-for linear trend = 0.0164. There was no evidence of a significant association between the prudent pattern and mean changes in each outcome over time in this study. CONCLUSIONS: The findings of the current study show that greater adherence to the Western diet at 21 years was positively associated with increases in body weight and BMI from 21 to 30 years of age, whereas the prudent diet had no significant association with these outcomes. The findings provide evidence that the adverse effects of the Western diet on weight gain in young adulthood could partly be prevented through optimising diet in the early course of life.

Dietary patterns explaining variations in blood biomarkers in young adults are associated with the 30-year predicted cardiovascular disease risks in midlife: A follow-up study.

BACKGROUND AND AIMS: To examine a combined effect of dietary intakes, blood lipid and insulin resistance in young adulthood on the risk of predicted CVD through midlife. METHODS AND RESULTS: Data of young adults from a birth cohort study in Australia were used. Reduced rank regression (RRR) and partial least squares (PLS) methods identified dietary patterns rich in meats, refined grains, processed and fried foods, and high-fat dairy and low in whole grains and low-fat dairy from dietary intakes obtained at 21-years, and blood lipids and measures of insulin resistance measured at 30-years of age. Using standard CVD risk factors measured at 30-years of age, the Framingham Heart Study risk-prediction algorithms were used to calculate the 30-year predicted Framingham CVD risk scores. The scores represent Hard CVD events; coronary death, myocardial infarction and stroke and Full CVD events; Hard CVD plus coronary insufficiency and angina pectoris, transient ischaemic attack, intermittent claudication, and congestive heart failure in midlife. Sex-specific upper quartiles of CVD risk scores were used to define high-risk groups. Modified Poisson regression models were used to estimate relative risks (RRs) with 95% CI. Greater adherence to the diet identified applying RRR in young adulthood was associated with higher risks of predicted Hard CVD (RR: 1.60; 1.14, 2.25) and Full CVD (RR: 1.46; 1.04, 2.05) events in midlife. The diet from PLS showed similar trend of association for the risk of predicted Hard CVD events (RR: 1.49; 1.03, 2.16) in adjusted models. CONCLUSION: Dietary patterns associated with variations in blood lipids and insulin resistance in young adulthood are associated with increased risks of predicted CVD events in midlife. The findings suggest that diet induced altered blood lipids and insulin resistance in the life course of young adulthood could increase the risks of CVD events in later life.

Physical and Soluble Cues Enhance Tendon Progenitor Cell Invasion into Injectable Synthetic Hydrogels.

Synthetic hydrogels represent an exciting avenue in the field of regenerative biomaterials given their injectability, orthogonally tunable mechanical properties, and potential for modular inclusion of cellular cues. Separately, recent advances in soluble factor release technology have facilitated control over the soluble milieu in cell microenvironments via tunable microparticles. A composite hydrogel incorporating both of these components can robustly mediate tendon healing following a single injection. Here, a synthetic hydrogel system with encapsulated electrospun fiber segments and a novel microgel-based soluble factor delivery system achieves precise control over topographical and soluble features of an engineered microenvironment, respectively. It is demonstrated that three-dimensional migration of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle-delivered soluble cues in both a tendon progenitor cell spheroid model and an ex vivo murine Achilles tendon model. These results indicate that fiber reinforced hydrogels can drive the recruitment of endogenous progenitor cells relevant to the regeneration of tendon and, likely, a broad range of connective tissues.

Dietary patterns and the risk of abnormal blood lipids among young adults: A prospective cohort study.

BACKGROUND AND AIMS: The extent to which dietary patterns influence the risk of abnormal blood lipids throughout young adulthood remains unclear. The aim was to investigate whether early young adulthood dietary patterns predict the risk of abnormal blood lipids during later young adulthood. METHODS AND RESULTS: We used data from a long running birth cohort study in Australia. Western dietary pattern rich in meats, processed foods and high-fat dairy products and prudent pattern rich in fruit, vegetables, fish, nuts, whole grains and low-fat dairy products were derived using principal component analysis at the 21-year follow-up from dietary data obtained using a food frequency questionnaire. After 9-years, fasting blood samples of all participants were collected and their total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols and triglyceride (TG) levels were measured. Abnormal blood lipids were based on clinical cut-offs for total, LDL and HDL cholesterols, and TG and relative distributions for total:HDL and TG:HDL cholesterols ratios. Log-binomial models were used to estimate risk of each outcome in relation to dietary patterns. Greater adherence to the Western pattern predicted increased risks of high LDL (RR: 1.47; 95%CI: 1.06, 2.03) and TG (1.90; 1.25, 2.86), and high ratios of total:HDL (1.48; 1.00, 2.19) and TG:HDL (1.78; 1.18, 2.70) cholesterols in fully adjusted models. Conversely, a prudent pattern predicted reduced risks of low HDL (0.58; 0.42, 0.78) and high TG (0.66; 0.47, 0.92) and high total:HDL (0.71; 0.51, 0.98) and TG:HDL (0.61; 0.45, 0.84) cholesterols ratios. CONCLUSION: This is the first prospective study to show greater adherence to unhealthy Western diet predicted increased risks of abnormal blood lipids, whereas healthy prudent diet predicted lower such risks in young adults. Addressing diets in early course may improve cardiovascular health of young adults.

Spatiotemporal control of micromechanics and microstructure in acoustically-responsive scaffolds using acoustic droplet vaporization.

Acoustically-responsive scaffolds (ARSs), which are composite fibrin hydrogels, have been used to deliver regenerative molecules. ARSs respond to ultrasound in an on-demand, spatiotemporally-controlled manner via a mechanism termed acoustic droplet vaporization (ADV). Here, we study the ADV-induced, time-dependent micromechanical and microstructural changes to the fibrin matrix in ARSs using confocal fluorescence microscopy as well as atomic force microscopy. ARSs, containing phase-shift double emulsion (PSDE, mean diameter: 6.3 µm), were exposed to focused ultrasound to generate ADV - the phase transitioning of the PSDE into gas bubbles. As a result of ADV-induced mechanical strain, localized restructuring of fibrin occurred at the bubble-fibrin interface, leading to formation of locally denser regions. ADV-generated bubbles significantly reduced fibrin pore size and quantity within the ARS. Two types of ADV-generated bubble responses were observed in ARSs: super-shelled spherical bubbles, with a growth rate of 31 µm per day in diameter, as well as fluid-filled macropores, possibly as a result of acoustically-driven microjetting. Due to the strain stiffening behavior of fibrin, ADV induced a 4-fold increase in stiffness in regions of the ARS proximal to the ADV-generated bubble versus distal regions. These results highlight that the mechanical and structural microenvironment within an ARS can be spatiotemporally modulated using ultrasound, which could be used to control cellular processes and further the understanding of ADV-triggered drug delivery for regenerative applications.

Mobile echodensities on intracardiac device leads: Is it always a cause for concern?

BACKGROUND: Patients with cardiac implantable electronic devices (CIEDs) frequently undergo transthoracic echocardiography (TTE). As a result, incidental mobile echodensities (MEDs) attached to device leads are commonly detected. The aim of this study was to estimate the incidence and clinical outcomes of incidental MEDs on CIED leads. METHODS: A retrospective analysis performed between 2011 and 2018 identified 3548 TTE studies performed on 1849 patients with CIEDs. RESULTS: MEDs were identified in 30 patients (1.6%) without clinical suspicion of infective endocarditis (IE). Patients with incidental MEDs were apyrexial, and those tested demonstrated low inflammatory markers and negative blood cultures (BC). In this group, the majority (83%) of MEDs were in the right atrium and no MEDs were detected near the tricuspid valve. Transesophageal echocardiography (TEE) did not influence clinical outcomes. No patient required long-term antibiotics or lead extraction and no IE-related deaths were identified from electronic health records during a mean follow-up period of 43 months (1-89). In contrast, nine patients with suspected IE were all pyrexial with elevated inflammatory markers, had positive BC, and had proven IE. In these cases, the majority of MEDs were at the device lead/tricuspid valve interface. MEDs close to the tricuspid valve were strongly associated with IE (P < .0001). CONCLUSIONS: The incidence of MEDs on CIED leads detected on routine TTE was 1.6%. Conservative management of asymptomatic patients with normal inflammatory markers and BC without TEE, antibiotics, or lead extraction did not reveal any signal for long-term adverse events within the limitations of the study.

Fiber Crimp Confers Matrix Mechanical Nonlinearity, Regulates Endothelial Cell Mechanosensing, and Promotes Microvascular Network Formation.

Mechanical interactions between cells and their surrounding extracellular matrix (ECM) guide many fundamental cell behaviors. Native connective tissue consists of highly organized, 3D networks of ECM fibers with complex, nonlinear mechanical properties. The most abundant stromal matrix component is fibrillar type I collagen, which often possesses a wavy, crimped morphology that confers strain- and load-dependent nonlinear mechanical behavior. Here, we established a new and simple method for engineering electrospun fibrous matrices composed of dextran vinyl sulfone (DexVS) with controllable crimped structure. A hydrophilic peptide was functionalized to DexVS matrices to trigger swelling of individual hydrogel fibers, resulting in crimped microstructure due to the fixed anchorage of fibers. Mechanical characterization of these matrices under tension confirmed orthogonal control over nonlinear stress-strain responses and matrix stiffness. We next examined ECM mechanosensing of individual endothelial cells (ECs) and found that fiber crimp promoted physical matrix remodeling alongside decreases in cell spreading, focal adhesion area, and nuclear localization of Yes-associated protein (YAP). These changes corresponded to an increase in migration speed, along with evidence for long-range interactions between neighboring cells in crimped matrices. Interestingly, when ECs were seeded at high density in crimped matrices, capillary-like networks rapidly assembled and contained tube-like cellular structures wrapped around bundles of synthetic matrix fibers due to increased physical reorganization of matrix fibers. Our work provides an additional level of mechanical and architectural tunability to synthetic fibrous matrices and implicates a critical role for mechanical nonlinearity in EC mechanosensing and network formation.

Rural and Remote Cardiology During the COVID-19 Pandemic: Cardiac Society of Australia and New Zealand (CSANZ) Consensus Statement.

THE CHALLENGES: Rural and remote Australians and New Zealanders have a higher rate of adverse outcomes due to acute myocardial infarction, driven by many factors. The prevalence of cardiovascular disease (CVD) is also higher in regional and remote populations, and people with known CVD have increased morbidity and mortality from coronavirus disease 2019 (COVID-19). In addition, COVID-19 is associated with serious cardiac manifestations, potentially placing additional demand on limited regional services at a time of diminished visiting metropolitan support with restricted travel. Inter-hospital transfer is currently challenging as receiving centres enact pandemic protocols, creating potential delays, and cardiovascular resources are diverted to increasing intensive care unit (ICU) and emergency department (ED) capacity. Regional and rural centres have limited staff resources, placing cardiac services at risk in the event of staff infection or quarantine during the pandemic. MAIN RECOMMENDATIONS: Health districts, cardiologists and government agencies need to minimise impacts on the already vulnerable cardiovascular health of regional and remote Australians and New Zealanders throughout the COVID-19 pandemic. Changes in management should include.

Anticoagulation in atrial fibrillation with heart failure.

Heart failure (HF) and atrial fibrillation (AF) frequently coexist, and they can beget one another due to similar factors and shared pathophysiology. These pathophysiologic changes promote the episodes of AF, while they in turn predispose to the exacerbation of HF. In this review, we will discuss pathophysiological mechanisms shared by AF and HF. Patients with concomitant HF and AF are at a particularly high risk of thromboembolism, which contribute to even worse symptoms and poorer prognosis. Vitamin K antagonists (VKA) (warfarin) were the traditional medication in AF patients for the prevention of stroke, whereas the advance of novel non-VKA oral anticoagulants (NOACs) (dabigatran, apixaban, rivaroxaban, and edoxaban) is challenging these standard prescriptions. NOACs' potential advantages over warfarin, including fixed dosing regimens, wide therapeutic window, and more sustained anticoagulant response, promote clinicians to consider these novel agents in the first place. However, some data suggested patients with AF and HF may receive different therapeutic response than those with AF alone in anticoagulant treatment. Accordingly, we aim to assess the potential role of oral anticoagulants, especially NOACs, in the management of patients with concomitant AF and HF.

Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments.

To investigate how cells sense stiffness in settings structurally similar to native extracellular matrices, we designed a synthetic fibrous material with tunable mechanics and user-defined architecture. In contrast to flat hydrogel surfaces, these fibrous materials recapitulated cell-matrix interactions observed with collagen matrices including stellate cell morphologies, cell-mediated realignment of fibres, and bulk contraction of the material. Increasing the stiffness of flat hydrogel surfaces induced mesenchymal stem cell spreading and proliferation; however, increasing fibre stiffness instead suppressed spreading and proliferation for certain network architectures. Lower fibre stiffness permitted active cellular forces to recruit nearby fibres, dynamically increasing ligand density at the cell surface and promoting the formation of focal adhesions and related signalling. These studies demonstrate a departure from the well-described relationship between material stiffness and spreading established with hydrogel surfaces, and introduce fibre recruitment as a previously undescribed mechanism by which cells probe and respond to mechanics in fibrillar matrices.

An Unusual Cause of Out-of-Hospital Cardiac Arrest Recorded on a Heartrate Monitor.

Coronary vasospasm is an uncommon, but perhaps under-recognised, cause of cardiac arrest. We present a novel case of an exercise-induced out-of-hospital cardiac arrest due to coronary vasospasm, captured on a heartrate monitor, and discuss the management options for this condition.

Exploring Noninvasive Tricuspid dP/dt as a Marker of Right Ventricular Function.

BACKGROUND: Right ventricular (RV) function assumes prognostic significance in various disease states, but RV geometry is not amenable to volumetric assessment by two-dimensional echocardiography. Intra-ventricular pressure rate of rise (dP/dt) predicts myocardial contractility and adjusting for the maximal regurgitant velocity (Vmax) corrects for preload. We examined the relationship of noninvasive tricuspid dP/dt and dP/dt/Vmax with RV ejection fraction (RVEF) by cardiac magnetic resonance imaging (CMR) as a measure of RV function. METHODS: Fifty CMRs and echocardiograms performed within 30 days were included. Tricuspid regurgitation (TR) spectral Doppler trace was analyzed offline. TR dP/dt was calculated using simplified Bernoulli equation (dP/dt between 1 and 2 m/sec). dP/dt/Vmax was calculated as a ratio of dP/dt and TR Vmax . RV end-diastolic (EDV) and end-systolic volumes (ESV) were obtained from contouring of steady-state-free precession axial stack CMR images; RVEF was calculated as [(RVEDV - RVESV)/RVEDV] × 100. RVEF >42% was considered normal. RESULTS: Majority of studies were suitable for analysis. Median age was 48 years (IQR = 36-63); 56.4% were female (n = 22/39). There was correlation between dP/dt and RVEF (r(2) = 0.51, P < 0.01) which improved with dP/dt/Vmax (r(2) = 0.59, P < 0.01). dP/dt >400 mmHg/sec had a positive predictive value of 91%, sensitivity and specificity of 74% and 84% respectively for normal RVEF. Inter-observer agreement and repeatability analysis showed no significant difference. CONCLUSION: Tricuspid dP/dt correlates well with CMR RVEF. A dP/dt of more than 400 mmHg/sec strongly predicts normal RVEF. Adjusting for preload (dP/dt/Vmax) further improves this correlation.

Prognostication and Interventional Guidance Using Acceleration-Ejection Time Ratio in Undifferentiated Paradoxical Low-Flow Low-Gradient Aortic Stenosis.

BACKGROUND: Studies in paradoxical low-flow low-gradient aortic stenosis (PLFAS) have demonstrated conflicting outcomes with variable survival advantage from aortic valve replacement (AVR). PLFAS is a heterogeneous composition of patients with uncertainty regarding true stenosis severity that continues to confound decision-making for AVR. OBJECTIVES: The purpose of this study was to investigate the utility of the Doppler acceleration (AT) to ejection (ET) time ratio (AT:ET) for prediction of prognosis and benefit from AVR in undifferentiated PLFAS. METHODS: Patients with echocardiographic findings of PLFAS (aortic valve area <1.0 cm2 or indexed aortic valve area <0.6 cm2/m2, mean gradient <40 mm Hg, indexed stroke volume <35 mL/m2, and left ventricular ejection fraction ≥50%) were identified and grouped according to an AT:ET cutoff of 0.35. The primary outcome was a 5-year composite of cardiac mortality or AVR. Secondary outcomes included the individual components of the primary endpoint and all-cause mortality at 5 years. Effect of AVR was analyzed in the AT:ET <0.35 and ≥0.35 groups. RESULTS: A total of 171 PLFAS patients (median age 77.0 years, 57% women) were followed for a median of 8.9 years. AT:ET ≥0.35 was an independent predictor of the primary outcome (HR: 4.77 [95% CI: 2.94-7.75]; P < 0.001) with incremental value over standard indices of stenosis severity (net reclassification improvement: 0.57 [95% CI: 0.14-0.84]). AT:ET ≥0.35 also remained predictive of increased cardiac death (HR: 2.91 [95% CI: 1.47-5.76]; P = 0.002) and AVR (HR: 8.45 [95% CI: 4.16-17.1]; P < 0.001), respectively, following competing risk analysis. No difference in all-cause mortality was observed. AVR in the AT:ET ≥0.35 group was associated with significant reductions in 5-year cardiac (HR: 0.09 [95% CI: 0.02-0.36]; P < 0.001) and all-cause mortality (HR: 0.16 [95% CI: 0.07-0.38]; P < 0.001). No improvement in survival from AVR was demonstrated in AT:ET <0.35 patients. CONCLUSIONS: AT:ET ≥0.35 in PLFAS predicts poorer outcomes and/or need for AVR. In undifferentiated PLFAS patients, AT:ET may have a potential role in improving patient selection for prognostic AVR.

Mechanical Intercellular Communication via Matrix-Borne Cell Force Transmission During Vascular Network Formation.

Intercellular communication is critical to the formation and homeostatic function of all tissues. Previous work has shown that cells can communicate mechanically via the transmission of cell-generated forces through their surrounding extracellular matrix, but this process is not well understood. Here, mechanically defined, synthetic electrospun fibrous matrices are utilized in conjunction with a microfabrication-based cell patterning approach to examine mechanical intercellular communication (MIC) between endothelial cells (ECs) during their assembly into interconnected multicellular networks. It is found that cell force-mediated matrix displacements in deformable fibrous matrices underly directional extension and migration of neighboring ECs toward each other prior to the formation of stable cell-cell connections enriched with vascular endothelial cadherin (VE-cadherin). A critical role is also identified for calcium signaling mediated by focal adhesion kinase and mechanosensitive ion channels in MIC that extends to multicellular assembly of 3D vessel-like networks when ECs are embedded within fibrin hydrogels. These results illustrate a role for cell-generated forces and ECM mechanical properties in multicellular assembly of capillary-like EC networks and motivates the design of biomaterials that promote MIC for vascular tissue engineering.