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Contains fulltext : 220480.pdf (publisher's version ) (Open Access), Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Item does not contain fulltext, BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59x10(-43); odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27x10(-17); OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

Objectives: CASE: A previously well 62-year-old female presented to the emergency department with central chest pain. Initial electrocardiogram demonstrated sinus rhythm with ST-elevation in V1-V2 and she underwent emergent coronary angiography which demonstrated no obstructive coronary artery stenosis, however left ventriculography demonstrated focal dyskinesis / aneurysm of the mid anterior left ventricular (LV) wall. Contrast enhanced transthoracic echocardiography (TTE) confirmed the appearance and demonstrated a pericardial effusion, raising the suspicion of a contained LV rupture. Cardiacmagnetic resonance (CMR) imaging confirmed the presence of an anterior wall aneurysm with associated oedema on T2 weighted images (Fig 1) however there was no evidence of associated late gadolinium enhancement (LGE) in the region (Fig 1). The patient had been involved in an argument before presenting to hospital and the findings were thought to be most consistent with an atypical Takotsubo cardiomyopathy (TC), and repeat transthoracic echocardiography 1 month later demonstrated complete normalisation of LV contraction. DISCUSSION: TC is a rare syndrome characterized by transient regional systolic dysfunction of the LV, mimickingmyocardial infarction, but in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. Focal involvement of the myocardium is its rarest form. A large multi-centre study in this population found CMR can accurately identify TC through a typical pattern of LV dysfunction and demonstrates myocardial edema in 81% patients, and no significant LGE in 91%. These findings were consistent with our patient. Interestingly in this study 40% of this patient population also had a pericardial effusion. (Figure Presented).

BACKGROUND: Computed tomographic coronary angiography is a noninvasive imaging modality that permits identification and characterization of coronary plaques. Despite consensus statements supporting routine reporting of computed tomographic coronary angiography plaque characteristics, there remains uncertainty whether these data convey prognostic information. We performed a systematic review and meta-analysis assessing the strength of association between computed tomographic coronary angiography-derived plaque characterization and major adverse cardiovascular events (MACE). METHODS AND RESULTS: Electronic databases were searched for studies reporting computed tomographic coronary angiography plaque characterization and MACE. Data were gathered on plaque morphology (noncalcified, partially calcified, and calcified) and high-risk plaque (HRP) features, including low-attenuation plaque, napkin-ring sign, spotty calcification, and positive remodeling. Of 5496 citations, 13 studies met inclusion criteria. Five hundred fifty-two (3.9%) MACE occurred in 13977 patients with mean follow-up ranging between 1.3 and 8.2 years. In terms of plaque morphology, the strongest association was observed for noncalcified plaque (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.24-1.70; P<0.001), with weaker associations found for partially calcified (HR, 1.37; 95% CI, 1.18-1.60; P<0.001) and calcified plaques (HR, 1.23; 95% CI, 1.16-1.30; P<0.001). All HRP features were strongly associated with MACE, including napkin-ring sign (HR, 5.06; 95% CI, 3.23-7.94; P<0.001), low-attenuation plaque (HR, 2.95; 95% CI, 2.03-4.29; P<0.001), positive remodeling (HR, 2.58; 95% CI, 1.84-3.61; P<0.001), and spotty calcification (HR, 2.25; 95% CI, 1.26-4.04; P=0.006). The presence of >=2 HRP features had highest risk of MACE (HR, 9.17; 95% CI, 4.10-20.50; P<0.001). CONCLUSION(S): These data demonstrate that HRP is most likely an independent predictor of MACE, which supports the inclusion of HRP re

Work-life balance is as a contributor to gender disparity in Cardiology despite equal gender distribution in medical schools [1,2]. Aim(s): To understand the opinions of the current trainees and recent graduates of the FRACP Cardiology Advanced Training programme regarding gender-neutral part-time, flexible training options, work-life balance and gender parity. Method(s): An anonymous, non-identifiable ten question survey link was emailed to the Victorian, NSW group (n = 180), then the remaining group in February and March 2019, respectively. Part-time and flexible training were defined respectively as amount of full-time equivalent/week (eg 0.5 EFT) and block intervals worked (eg alternate 6 months on/off). Result(s): Of the 79 (44%) respondents thus far, 64% were male and 78.5% felt gender neutral part-time/flexible training options should be available. While 29% would apply for part-time/flexible training if available, 77% worried about applying due to non-favourable perception by employers and colleagues. Training options favoured were flexible 30%, both 61%, and 76% favoured combined responsibility by the institution and trainees to manage work-flow. Gender imbalance and graduate quality were concerning to 60% and 19% respectively. Significant personal/family sacrifices were made by 82%, and concerningly 44% had experienced mood, depression or anxiety issues due to inflexible training hours. Conclusion(s): Part-time/flexible training options during the FRACP Advanced Cardiology training programme should be available as it is favoured by the majority of trainees and may improve work-life balance, depression and anxiety issues and gender imbalance in cardiology.Copyright © 2019

Background: Recent research has shown clinical benefits with intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) in comparison with angiography guidance alone. However, it remains unclear if the benefit of IVUS-guided implantation is the same regardless of stent generation. We performed a systematic review and meta-analysis of trials studying IVUS and specifying outcomes of patients who received first and/or second-generation stents. Method(s): Studies that reported clinical outcomes and compared first-and second-generation stents implanted with IVUS or angiography guidance were included. Peto analysis was used to estimate effect size. Result(s): Fifteen studies with a total of 9,313 patients were included; 4,592 patients underwent IVUS-guided and 4,721 angiography-guided PCI. Comparison of IVUS-and angiography-guided PCI for first-generation stents yielded an odds ratio (OR) of 0.79 (95% confidence interval 0.67-0.92) favouring IVUS guidance for major adverse cardiovascular events (MACE). In contrast, the same comparison for second-generation stents yielded an OR of 0.57 (95% confidence interval 0.43-0.77) for MACE. IVUS-guided PCI was associated with a significant reduction in target lesion revas-cularisation (OR 0.66; 95% confidence interval 0.52-0.84) and stent thrombosis (OR 0.52; 95% confidence interval 0.38-0.72) in both stent generations. Conclusion(s): IVUS-guided PCI is associated with a significant reduction in MACE when utilised during PCI with both first-and second-generation DES stents. These data should support the use of IVUS-guided PCI for contemporary revascularisation procedures.

Background: Previous studies using intracoronary imaging have found associations between coronary plaque morphology and MACE, but are limited in clinical translation due to their invasive nature. CTCA is an alternative, non-invasive modality that also allows plaque characterisa-tion. We performed a meta-analysis assessing the association between plaque characteristics and MACE in stable patients undergoing CTCA. Method(s): Digital databases were systematically searched until October 2016. Outcomes were regarded as trial-specific definitions of MACE, with plaque on CTCA classified as calcified, non-calcified (NCP) or mixed. High risk plaque (HRP) included spotty calcification (SC), low-attenuation plaque (LAP), positive remodelling (PR) and napkin-ring sign (NRS). Random effects modelling was used and results are reported as pooled hazard ratio (HR) with 95% confidence intervals (95% CI). Heterogeneity was measured with I2 statistic. Result(s): Nineteen studies with 19,943 subjects were identified, with 7 studies (n = 7,348) evaluating specific HRP features. Mean follow-up ranged from 1.5-8 years with 1,048 total MACE. The pooled HR for the presence of plaque-type on MACE was 1.27 (95% CI 1.17-1.38, p< 0.001) I2 = 86%. Mixed plaque demonstrated the highest risk plaque-type, HR 1.42 (95% CI 1.16-1.68, p< 0.001) followed by NCP 1.29 (95% CI 1.10-1.48, P < 0.001) and calcified plaque 1.18 (95% CI 1.06-1.31, P < 0.001), all I2 > 75%. Individual HRP components demonstrated higher MACE risk: LAP 3.21 (95% CI 2.02-5.10, p< 0.001) I2 =26%; PR 3.22 (95% CI 1.74-5.94, p< 0.001) I2 = 69%; SC 2.26 (95% CI 1.26-4.04, P = 0.006) I2=0%; NRS 5.06 (95% CI 3.23-7.94, P < 0.001), I2 = 0%. Conclusion(s): CTCA-derived plaque morphology is associated with future prognosis, with the strongest association seen with HRP features.

BACKGROUND Intravascular ultrasound (IVUS)-guidance use decreases major adverse cardiovascular events (MACE), including restenosis, during implantation of bare-metal stents. However, there is debate whether IVUS improves outcomes and lowers restenosis rates when utilized during PCI with first or second-generation drugeluting stent (DES) platforms. METHODS MEDLINE, Embase and PubMed were searched for studies comparing outcomes between IVUS and angiography guided PCI. Among 909 potentially relevant studies, 15 trials (6 randomized controlled trials) comprising 8,265 patients met inclusion criteria by specifying DES type. The primary endpoint was MACE, defined as death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. RESULTS Overall, 3,974 patients underwent IVUS-guided and 4,291 angiography-guided PCI. There was no statistical heterogeneity (I2=0%, p=0.66). Overall, IVUS-guidance was associated with significant reduction in MACE (Figure). In total, 5,108 and 3,157 patients received first- and second-generation DES, respectively. IVUSguidance was associated with significant reduction in MACE in both first- (OR 0.79, 95%CI 0.67-0.92, p=0.03) and second-generation DES (OR 0.56, 95%CI 0.41-0.77, p<0.001). Importantly, IVUS-guidance significantly reduced TVR rates in second- (OR 0.47, 95%CI 0.28- 0.79, p=0.008), but not first-generation DES (OR 0.88, 95%CI 0.70- 1.11, p=0.73). CONCLUSION IVUS-guidance is associated with improved clinical outcomes in PCI with DES, although reduced restenosis rates were only observed in second-generation DES platforms. (Table Presented).

Introduction: Cardiac resynchronisation therapy (CRT) is an established therapy for symptomatic patients with advanced heart failure. However, traditional left ventricular lead placement may not always be technically feasible via the coronary sinus approach. Left ventricular (LV) endocardial lead implantation via a transseptal atrial approach may be a potential alternative. Purpose(s): We sought to review the feasibility and clinical outcomes in patients undergoing LV lead implantations in a single-centre, tertiary, Australian institution. Endpoints included: technical success, peri-procedural complication rates, percent LV pacing load, change in New York Heart Association (NYHA) class and change in LV ejection fraction (LVEF). Method(s): and Results: Between August 2015 and December 2016, four patients underwent endocardial LV lead implantation (3 males, mean age 71 +/-5 years). All patients had previously failed LV lead placement via the coronary sinus. Mean pre-procedural LVEF was 24 +/-8%, mean QRS duration 161+/- 19ms and baseline NYHA was III (n=3) and IV (n=1). All patients had existing indications for therapeutic anticoagulation and were anticoagulated with warfarin (3 for atrial fibrillation, 1 for mechanical aortic valve). Warfarin was withheld for 3 days prior to the procedure. Mean international normalized ratio (INR) at the time of the procedure was 1.6+/-0.3. LV access was via an inferior approach, using femoral transseptal access, with a snare from superior subclavian venous access providing access to the left atrium. The lead was then inserted via the deflectable guiding sheath into the lateral LV endocardial wall. Successful implantation was achieved in all patients. One patient had a thromboembolic complication (non disabling stroke) post procedure, despite an INR of 2.1 at the time. That patient subsequently died from progressive heart failure within a month of the procedure. The 3 remaining patients have a mean follow up of 10 +/-7 months. The me

Case: An 82-year-old Malaysian man presented with a 3- day history of respiratory symptoms to a regional Victorian hospital. Chest X-ray demonstrated a unilateral infiltrate. He was referred for admission with a presumed diagnosis of pneumonia. Whilst in the emergency department the patient had a marked respiratory deterioration into acute pulmonary oedema. Repeat X-ray showed worsening right upper lobe opacification (Figure 1). Despitemanagementwith diuretics, nitrate therapy and non-invasive positive pressure ventilation the patient required intubation. With ventilation and heart failure treatment the patient made a rapid clinical improvement over the subsequent 12 hours. Repeat chest X-ray revealed near complete resolution of the right upper lobe opacification (Figure 2). Transthoracic echocardiogram revealed severe eccentric mitral regurgitation with a flail anterior leaflet. The right-sided chest X-ray changes most likely represent unilateral cardiogenic pulmonary oedema- a diagnosis supported by the transthoracic echocardiogram, the rapid resolution of the CXR changes, and clinical improvement with heart failure management Discussion points: 2% of cardiogenic pulmonary oedema presents unilaterally. Severe mitral regurgitation is the most common cause. Early echocardiography is essential to allow diagnosis and initiation of appropriate management. (Figure presented).