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Background: Reverse homodigital island flaps (RHIFs) are increasingly used to reconstruct traumatic fingertip injuries, but there is limited evidence on the efficacy of this technique. We performed a systematic review of the literature to establish the safety and functional outcomes of RHIF for traumatic fingertip injuries. Methods: Electronic searches were performed using 3 databases (PubMed, Ovid Medline, Cochrane CENTRAL) from their date of inception to April 2020. Relevant studies were required to report on complications and functional outcomes for patients undergoing RHIF for primary fingertip reconstruction. Data were extracted from included studies and analyzed. Results: Sixteen studies were included, which produced a total cohort of 459 patients with 495 fingertip injuries. The index and middle fingers were involved most frequently (34.6% and 34.1%, respectively), followed by the ring finger (22%), the little finger (6.7%), and the thumb (2.6%). The mean postoperative static and moving 2-point discrimination was 7.2 and 6.7 mm, respectively. The mean time to return to work was 8.4 weeks. The mean survivorship was 98.4%, with the pooled complication rate being 28%. The pooled complication rate of complete flap necrosis was 3.6%, of partial flap necrosis was 10.3%, of venous congestion was 14.6%, of pain or hypersensitivity was 11.5%, of wound infection was 7.2%, of flexion contractures was 6.3%, and of cold intolerance was 17.7%. Conclusions: Reverse homodigital island flaps can be performed safely with excellent outcomes. To minimize complications, care is taken during dissection and insetting, with extensive rehabilitation adhered to postoperatively. Prospective studies assessing outcomes of RHIF compared with other reconstruction techniques would be beneficial. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES The age at which the Fontan operation is performed varies globally. Over the last decade, the median age of patients having the Fontan in Australia and New Zealand has been 4.6 years, including 6% of patients younger than 3 years. Long-term outcomes of an early Fontan operation are unclear and are described in this study. METHODS Patients from the Australian and New Zealand Fontan Registry were grouped by age at Fontan. A Fontan before 3 years (early Fontan) was compared to the combined second and third quartiles by age at surgery in the Registry (3.6–6.1 years; control). Outcomes included Fontan failure (death, transplant, New York Heart Association functional group III/IV heart failure, Fontan takedown or conversion, protein losing enteropathy and plastic bronchitis), arrhythmias, thromboembolism and reinterventions. RESULTS A total of 191 patients who had early Fontan operations were compared to 781 controls. Profound or progressive cyanosis was noted more frequently in the early than in the control group (63% vs 23%; P  <   0.001). The early group was followed up for a median 22.1 years. The incidence of long-term failure was similar between the 2 groups (early, 1.08 failures per 100 patient-years of follow-up vs control, 0.99; log-rank P  =   0.79). Adjusted for risk factors, early age at Fontan was not a risk factor for long-term failure [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.77–1.76; P  =   0.48], new-onset arrhythmia (HR 0.93, 95% CI 0.63–1.39; P  =   0.73), thromboembolism (HR 0.50, 95% CI 0.28–0.91; P  =   0.024) or reintervention (HR 1.08, 95% CI 0.80–1.45; P  =   0.62). CONCLUSIONS Having the Fontan operation at an early age was not a risk factor for short- or long-term adverse outcomes in our cohort. [ABSTRACT FROM AUTHOR]

Aim: To explore the relationship between baseline uric acid (UA) levels and long‐term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA‐lowering effects. Methods: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6‐week, active fenofibrate run‐in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre‐to‐post run‐in reductions in UA and long‐term cardiovascular outcomes. Results: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long‐term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13‐1.29, P <.001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run‐in was also a significant predictor of long‐term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long‐term risk (HR 0.86, 95% CI 0.76‐0.97, P =.015). This effect was not modified by treatment allocation (Pinteraction =.77). Conclusions: UA is a strong independent predictor of long‐term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate. [ABSTRACT FROM AUTHOR]

Aims: Sudden cardiac death (SCD) accounts for up to 25% of deaths in the adult congenital heart disease (ACHD) population. Current guidelines for defibrillator implantation are either extrapolated from acquired cardiac disease or are based upon single lesion studies, predominantly Tetralogy of Fallot (TOF). Defibrillator‐related morbidity appears to be substantially higher in ACHD patients. Methods: We retrospectively evaluated all patients in our ACHD database who received an implantable cardioverter‐defibrillator (ICD) between 2000 and 2019, and who were ≥16 years old at time of implant. Patients were followed for appropriate shocks, inappropriate shocks, and complications. Results: Of 4748 patients in our database, 59 patients (1.2%) underwent ICD implantation. ICDs were for primary prevention in 63% and secondary prevention in 37%. Over a median follow‐up of 6.6 years, 24% received an appropriate shock, 27% an inappropriate shock, and 42% suffered a device‐related complication (annualized risks of 3.2%, 3.6%, and 5.7%, respectively). There were no significant predictors of appropriate shocks or inappropriate shocks. All appropriate shocks in primary prevention patients occurred in TOF or transposition of the great arteries (TGA) with atrial switch, typically in the presence of multiple SCD risk factors. The majority of inappropriate shocks were due to supraventricular arrhythmias. Device‐related mortality was 1.7% (0.3% per annum). Conclusions: Appropriate shocks were relatively common in an ACHD ICD population followed in the long term. Device‐related morbidity was significant. Although risk factors have been established for TOF, and to a lesser extent TGA, risk stratification for ICD implantation in ACHD remains challenging. [ABSTRACT FROM AUTHOR]

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource. Study of human heart failure is limited by access to human tissue. Here, the authors apply multi-omic screening in human ischaemic and dilated myocardial tissue and matched controls to determine molecular changes common and unique to each aetiology and to reveal differences between male and female hearts. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a seasonal mucosal pathogen that infects the ciliated respiratory epithelium and results in the most severe morbidity in the first six months of life. RSV is a common cause of acute respiratory infection during infancy and is an important early-life risk factor strongly associated with asthma development. While this association has been repeatedly demonstrated, limited progress has been made on the mechanistic understanding in humans of the contribution of infant RSV infection to airway epithelial dysfunction. An active infection of epithelial cells with RSV in vitro results in heightened central metabolism and overall hypermetabolic state; however, little is known about whether natural infection with RSV in vivo results in lasting metabolic reprogramming of the airway epithelium in infancy. To address this gap, we performed functional metabolomics, 13C glucose metabolic flux analysis, and RNA-seq gene expression analysis of nasal airway epithelial cells (NAECs) sampled from infants between 2–3 years of age, with RSV infection or not during the first year of life. We found that RSV infection in infancy was associated with lasting epithelial metabolic reprogramming, which was characterized by (1) significant increase in glucose uptake and differential utilization of glucose by epithelium; (2) altered preferences for metabolism of several carbon and energy sources; and (3) significant sexual dimorphism in metabolic parameters, with RSV-induced metabolic changes most pronounced in male epithelium. In summary, our study supports the proposed phenomenon of metabolic reprogramming of epithelial cells associated with RSV infection in infancy and opens exciting new venues for pursuing mechanisms of RSV-induced epithelial barrier dysfunction in early life. [ABSTRACT FROM AUTHOR]

Background: Fenofibrate increases renal clearance of uric acid (UA). Relationships between baseline and short-term changes in plasma UA with fenofibrate and subsequent cardiovascular risk in patients with type 2 diabetes (T2D) are unknown. Method: Post hoc analyses of the FIELD trial explored the relationships between CVD events and 1) baseline UA level; and 2) short-term change in UA level over 6-week single-blind active fenofibrate run-in. Results: The FIELD trial showed 11% fewer cardiovascular events in patients with T2D assigned to fenofibrate compared to placebo over 5 years (HR = 0.89, 95% CI: 0.80-0.99, p = 0.035). Baseline UA (n=9622) ranged between 0.11 to 0.79 mmol/L (mean = 0.33, SD = 0.078). Each 0.1 mmol/L higher baseline UA increased CVD events by 21% (HR = 1.21 95% CI: 1.13-1.29, p < 0.001; Fig. 1A), and remained after adjusting for other classic risk factors (HR = 1.12, 95% CI: 1.04-1.21, p = 0.002). Fall in UA level with fenofibrate run-in also predicted lower CVD risk, adjusted for baseline UA and irrespective of trial treatment allocation (HR = 0.86, 95% CI: 0.76-0.97, p = 0.015; Fig. 1B). Discussion: Baseline and short-term fenofibrate-induced lowering of UA predict cardiovascular risk in patients with T2D, irrespective of long-term trial treatment allocation. The reduction in total CVD events with fenofibrate was not shown to be mediated through lowering of UA levels. Disclosure: J.Y. Cao: None. B. Waldman: None. R.L. OConnell: None. D. Sullivan: None. V. Gebski: None. A.S. Januszewski: None. I. Marschner: None. R. Scott: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc. R. Simes: None. N. McGill: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.C. Keech: None. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation (AF) is a major cause of stroke and premature death. Current AHA/ESC guidelines define subtypes of AF but these are not incorporated into risk scores of the complications of AF. Aims: To compare all cause mortality, ischaemic stroke and systemic thromboembolism in patients categorised by AF type (paroxysmal, persistent and permanent). Methods: Electronic searches were performed using Medline, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews up until November 15, 2017. Results: Eleven studies with a total of 81030 patients were included for analyses, comprising 26753 paroxysmal, 18098 persistent and 36179 permanent AF patients. There were no baseline differences in gender and hypertension but diabetes, heart failure, previous stroke and CHADS score were different between subtypes and highest in permanent AF. The risk of ischemic stroke was higher in permanent compared with paroxysmal or persistent AF (permanent vs. paroxysmal: RR = 1.34, 95% CI: 1.12-1.59, p = 0.001; permanent vs. persistent: RR = 1.44, 95% CI: 1.22-1.69, p < 0.001; Fig. 1). A similar result was seen for systemic embolism. All-cause mortality was significantly higher in permanent compared with paroxysmal AF (RR = 1.62, 95% CI: 1.37-1.9, p < 0.001), and trended higher for permanent compared with persistent AF (RR = 1.51, 95% CI: 0.94-2.44, p = 0.09). Conclusion: Permanent AF, compared with paroxysmal and persistent AF, is associated with increased risk of ischemic stroke, systemic embolism and mortality. Our findings have implications for incorporation of AF duration and subtype into stroke risk assessment, as well as the development of therapies to halt and reverse progression of AF. Figure 1. Rate of ischaemic strokes comparing A) permanent vs. persistent AF; B) permanent vs. paroxysmal AF. AF = atrial fibrillation. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary hypertension complicating left heart disease (PH-LHD) is the most common cause of PH. Off-label use of pulmonary arterial hypertension (PAH) medications for PH-LHD is prevalent, despite a lack of clinical data supporting their use. Hypothesis: We hypothesized that PAH agents, when used for PH-LHD, would not produce any improvements in clinical outcomes. Methods: A systematic review and meta-analysis was performed. Comprehensive search of all available literature to date identified ten randomized, placebo controlled trials comprising 439 treated (Phosphodiesterase 5 inhibitors: n=206; guanylate cyclase stimulators: n=132; endothelin receptor antagonists: n=101) and 338 placebo patients. Random effects model was employed to assess outcomes in the treatment compared to the placebo control arm. Results: The risks of all-cause mortality, cardiovascular mortality and worsening heart failure were numerically higher in the treated compared to the control group, although not statistically (all-cause mortality: Risk Ratio (RR) = 1.97, 95% CI: 0.64-6.05, p = 0.24; cardiovascular mortality: RR = 2.01, 95% CI: 0.39-10.34, p = 0.4; worsening heart failure: RR = 1.23, 95% CI: 0.68-2.25, p = 0.49). Conversely, right heart hemodynamics improved numerically in the treated group, also without being significant (mean pulmonary artery pressure: Mean Weighted Difference (MWD) = -5.13 mmHg, 95% CI: -13.2-2.9, p = 0.21; systolic pulmonary artery pressure: MWD = -4.14 mmHg, 95% CI: -16.6-8.37, p = 0.52; pulmonary vascular resistance: MWD = -0.87 WU, 95% CI: -1.75-0.1, p = 0.053. Conclusions: This meta-analysis demonstrated that there is no current evidence to support the widespread use of PAH therapy in PH-LHD. On the basis of a numerically increased risk of clinical harm, these agents should not be prescribed in this situation, unless further evidence of benefit arises in the future. [ABSTRACT FROM AUTHOR]

Introduction: Our previous work revealed that uridine and UDP were associated with 4 separate coronary artery disease (CAD) loci in >1000 subjects in the Framingham Heart Study. Using cryopreserved human myocardial tissue, we now extend our investigations of the uridine, and other pathways, in human ischemic heart disease (IHD). Aims: 1. Determine if previously implicated IHD pathway perturbations in human plasma were also dysregulated in human IHD myocardial tissue; 2. Comprehensively examine the functional genomic pathway perturbations in human IHD myocardium. Methods: 193 metabolites and 5,400 proteins were measured by LC-MS in myocardial tissue from cryopreserved hearts of 14 patients with ischaemic heart disease and 10 healthy donor hearts. Mann-Whitney tests were used to compare the protein and metabolite data in IHD versus controls, and permutation-based FDR. Results: Uridine metabolites uridine (P=7E-6) and uridine metabolite 2-deoxycitidine (P=4.6E-5), and protein uridine 5-monophosphate synthase (P=3.7E-2) were significantly elevated, and proteins pseudouridine 5-phosphatase (P=1.3E-2), and UDP-N-acetlyglucosamine-peptide N-acetlyglucosaminyltansferase (P=2E-3) were significantly decreased in IHD myocardium compared to control. Plasma methionine was previously associated with two CAD loci: WDR12 (P=3.5E-2), and COL4A1/COL4A2 (P=1.5E-2). In IHD myocardium, methionine metabolites taurine (P=1.2E-3) and cysteamine (P=2.7E-4) were significantly elevated, whereas methionine (P=5E-4) was significantly reduced. Purines allantoin and guanosine monophosphate (GMP) were previously associated with two CAD loci: allantoin with PPAP2B (P=1.2E-2); GMP with CDKN2B (P=1.95E-2). Purines allantoin (P=1E-6), ADP (P=1.3E-2), xanthosine (P=3.1E-2) and xanthenuric acid (P=2E-4) were significantly elevated in ischaemic myocardium, whereas cAMP was reduced (P=4.8E-2). Conclusions: Integration of genomic, proteomic, and metabolomic data in a large community-based cohort and in human IHD myocardium implicates the uridine, methionine, and purine pathways. These highly novel findings may offer new therapeutic strategies in IHD, which we will investigate mechanistically in model systems. [ABSTRACT FROM AUTHOR]

The hybrid strategy is an alternative to the traditional Norwood procedure for initial palliation of infants with hypoplastic left heart syndrome (HLHS) who are deemed to be at high surgical risk. Numerous single-center studies have compared the two procedures, showing similar early outcomes, although the cohort sizes are likely insufficiently powered to detect significant differences. The current meta-analysis aims to explore the early morbidity and mortality associated with the hybrid compared to the Norwood procedure. MEDLINE, Cochrane Libraries, and Embase were systematically searched, and 14 studies were included for statistical synthesis, comprising 263 hybrid and 426 Norwood patients. Early mortality was significantly higher in the hybrid patients (relative risk [RR] = 1.54, P < .05, 95% confidence interval [CI]: 1.02-2.34), whereas interstage mortality was comparable between the two groups (RR = 0.88, P > .05, 95% CI: 0.46-1.70). Six-month (RR = 0.89, P < .05, 95% CI: 0.80-1.00) and one-year (RR = 0.88, P < .05, 95% CI: 0.78-1.00) transplant-free survival was also inferior among the hybrid patients. Furthermore, the hybrid patients required more reinterventions following initial surgical palliation (RR = 1.48, P < .05, 95% CI: 1.09-2.01), although the two groups had comparable length of hospital and intensive care unit stay postoperatively. In conclusion, our results suggest that the hybrid procedure is associated with worse early survival compared to the traditional Norwood when used for initial palliation of infants with HLHS. However, due to the hybrid being used preferentially for high-risk patients, definitive conclusions regarding the efficacy of the procedure cannot be drawn.