Objective Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure. Methods We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation. Results In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10−5), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10−3). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10−3). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855). Conclusion In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.

A 66-year-old gentleman with no prior cardiac history presented with dyspnea on exertion and chest pain for 1 month. His workup included a transthoracic echocardiogram, which demonstrated findings suggestive of cor triatriatum (C-TAT) with uncertain degree of hemodynamic obstruction. In addition, mild left ventricular systolic dysfunction and segmental wall motion abnormalities suggestive of coronary artery disease were noted. The patient then underwent transesophageal echocardiography (TEE) to define better the structural characteristics and hemodynamic significance of the C-TAT, left and right heart catheterization to assess pressure gradients between the upper and lower left atrial chambers by simultaneous measurement of pulmonary capillary wedge and left ventricular end-diastolic pressures, and coronary angiography. Multiplane 2-dimensional TEE demonstrated an atrial membrane extending from the inferior portion of the interatrial septum to the superior aspect of the lateral atrial wall. This membrane exhibited a medial large oval opening with bidirectional flow and a ≤2 mm Hg gradient. Three-dimensional TEE imaging re-demonstrated this obliquely oriented membrane; however, of most importance, it revealed that the membrane divided the atria into a medial funnel and C-shaped cavity with a large distal oval shape opening and an even larger lateral atrial cavity. These findings were inconsistent with a true C-TAT and rather demonstrated what we defined as a pseudo-C-TAT membrane. Simultaneous right and left heart catheterization confirmed a minimal gradient of 3 to 5 mm Hg and coronary angiography demonstrated severe 3-vessel coronary disease as the primary cause of the patient’s clinical syndrome.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92–1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

BACKGROUND:Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS:We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS:The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS:Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99–1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18–1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04–1.09). Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Riyaz Patel, MD1,2*; Vinicius Tragante, PhD3*; Amand F. Schmidt, PhD1,3*; Raymond O. McCubrey, MS4; Michael V. Holmes, MD, PhD5-7; Laurence J. Howe, PhD1; Kenan Direk, PhD1; Axel Åkerblom, MD, PhD8,9; Karin Leander, PhD10; Salim S. Virani, MD, PhD11,12; Karol A. Kaminski, MD, PhD13,14; Jochen D. Muehlschlegel, MD, MMSc15,16; Hooman Allayee, PhD17; Peter Almgren, MSc18; Maris Alver, MSc19,20; Ekaterina V. Baranova, MSc21; Hassan Behloui, PhD22; Bram Boeckx, PhD23,24; Peter S. Braund, PhD25,26; Lutz P. Breitling, MD27; Graciela Delgado, MSc28; Nubia E. Duarte, PhD29; Marie-Pierre Dubé, PhD30,31; Line Dufresne, MSc22,32; Niclas Eriksson, PhD8; Luisa Foco, PhD33; Markus Scholz, PhD34,35; Crystel M. Gijsberts, MD, PhD36; Charlotte Glinge, MD37,38; Yan Gong, PhD39; Jaana Hartiala, PhD17,40; Mahyar Heydarpour, PhD15,16; Jaroslav A. Hubacek, DSc41; Marcus Kleber, PhD28; Daniel Kofink, PhD3; Salma Kotti, PharmD, PhD42; Pekka Kuukasjärvi, PhD43; Vei-Vei Lee, MS44; Andreas Leiherer, PhD45-47; Petra A. Lenzini, MS48; Daniel Levin, PhD49; Leo-Pekka Lyytikäinen, MD50,51; Nicola Martinelli, MD, PhD52; Ute Mons, PhD27; Christopher P. Nelson, PhD25,26; Kjell Nikus, PhD53,54; Anna P. Pilbrow, PhD55; Rafal Ploski, MD, PhD56; Yan V. Sun, PhD57,58; Michael W.T. Tanck, PhD59; W.H.Wilson Tang, MD60,61; Stella Trompet, PhD62,63; Sander W. van der Laan, PhD64; Jessica Van Setten, PhD65; Ragnar O. Vilmundarson, MSc66,67; Chiara Viviani Anselmi, PhD68; Efthymia Vlachopoulou, PhD69; Lawien Al Ali, MD70; Eric Boerwinkle, PhD71; Carlo Briguori, MD, PhD72; John F. Carlquist, PhD4,73; Kathryn F. Carruthers, MPhil74; Gavino Casu, MD75; John Deanfield, MD1,2; Panos Deloukas, PhD76,77; Frank Dudbridge, PhD78; Thomas Engstrøm, MD, PhD79,80; Natalie Fitzpatrick, MSc81; Kim Fox, MD, PhD82; Bruna Gigante, PhD10; Stefan James, MD, PhD8,83; Marja-Liisa Lokki, PhD69, Paulo A. Lotufo, MD, PhD84; Nicola Marziliano, PhD85; Ify R. Mordi, MD49; Joseph B. Muhlestein MD4,73; Christopher Newton-Cheh, MD86; Jan Pitha, PhD41; Christoph H. Saely, MD45,46,87; Ayman Samman-Tahhan, MD88; Pratik B. Sandesara, MD88; Andrej Teren, MD35,89, Adam Timmis, MD81,90; Frans Van de Werf, PhD91; Els Wauters, PhD92; Arthur A.M. Wilde, MD, PhD93,94; Ian Ford, MD, PhD95; David J. Stott, MD96; Ale Algra, MD97; Maria G. Andreassi, PhD98, Diego Ardissino, MD99, Benoit J. Arsenault, PhD100,101; Christie M. Ballantyne, MD12; Thomas O. Bergmeijer, MD102; Connie R. Bezzina, PhD93; Simon C. Body, MBChB, MPH16,103; Eric H. Boersma, MD, PhD104,105; Peter Bogaty, MD106; Michiel Bots, MD107; Hermann Brenner, MD, PhD27,108; Jasper J. Brugts, MD, PhD104; Ralph Burkhardt, MD35,109; Clara Carpeggiani, MD98; Gianluigi Condorelli, MD, PhD68,110; Rhonda M. Cooper-DeHoff, PharmD39,111; Sharon Cresci, MD48,112; Nicolas Danchin, MD, PhD113,114; Ulf de Faire, PhD10; Robert N. Doughty, MD115; Heinz Drexel, MD45,46,116; James C. Engert, PhD32,117,118; Keith A.A. Fox, MD, PhD119; Domenico Girelli, MD, PhD52; Diederick E. Grobbee, MD, PhD107; Emil Hagström, MD, PhD9,120; Stanley L. Hazen, MD, PhD60,121; Claes Held, MD, PhD8,9; Harry Hemingway, MD, PhD81; Imo E. Hoefer, MD, PhD122; G. Kees Hovingh, MD, PhD123; Reza Jabbari, MD, PhD124; Julie A. Johnson, PharmD39,125; J. Wouter Jukema, MD, PhD63,126,127; Marcin P. Kaczor, MD, PhD128; Mika Kähönen, PhD129,130; Jiri Kettner, PhD131; Marek Kiliszek, MD, PhD132; Olaf H. Klungel, PharmD, PhD21; Bo Lagerqvist, MD, PhD8,83; Diether Lambrechts, PhD23,24; Jari O. Laurikka, PhD133,134; Terho Lehtimäki, PhD50,51; Daniel Lindholm, MD, PhD8,9; B. K. Mahmoodi, MD, PhD102; Anke H. Maitland-van der Zee, PharmD, PhD21,135; Ruth McPherson, MD, PhD66,136; Olle Melander, MD, PhD18,137; Andres Metspalu, MD, PhD19,20; Anna Niemcunowicz-Janica, MD, PhD138; Oliviero Olivieri, MD52; Grzegorz Opolski, MD, PhD139; Colin N. Palmer, PhD140; Gerard Pasterkamp, MD, PhD141; Carl J. Pepine, MD125; Alexandre C. Pereira, MD, PhD29; Louise Pilote, MD22,142; Arshed A. Quyyumi, MD88; A. Mark Richards, MD, PhD55,143; Marek Sanak, MD, PhD128; Agneta Siegbahn, MD, PhD8,144; Tabassome Simon, MD, PhD145,146; Juha Sinisalo, MD, PhD147; J. Gustav Smith, MD, PhD148-150; John A. Spertus, MD, MPH151,152; Steen Stender, MD, DSc153; Alexandre F.R. Stewart, PhD66,67; Wojciech Szczeklik, MD, PhD128; Anna Szpakowicz, MD, PhD14; Jean-Claude Tardif, MD30,31; Jurriën M. ten Berg, MD, PhD102; Jacob Tfelt-Hansen, MD, DMSc154; George Thanassoulis, MD32,22,118; Joachim Thiery, MD35,155; Christian Torp-Pedrsen, MD, DSc156,157; Yolanda van der Graaf, MD107; Frank L.J. Visseren, MD158; Johannes Waltenberger159; Peter E. Weeke, MD, PhD160; Pim Van der Harst, MD, PhD70; Chim C. Lang MD49; Naveed Sattar, PhD96; Vicky A. Cameron, PhD55; Jeffrey L. Anderson, MD4,73; James M. Brophy, MD22,142; Guillaume Pare, MD161,162; Benjamin D. Horne, PhD, MPH4,163; Winfried März, MD28,164,165; Lars Wallentin, MD, PhD8,83; Nilesh J. Samani, MD, PhD25,26†; Aroon D. Hingorani, MD, PhD1†; Folkert W. Asselbergs, MD, PhD1,3,166†

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%–100%), mostly male (44%–91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14–1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13–1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35–1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor and has been shown to correlate with adverse cardiovascular (CV) outcome; however the underlying pathophysiology of this link is not well understood. The aim of this study was to evaluate the relationship between EAT and a comprehensive panel of cardiovascular risk biomarkers and pulse wave velocity (PWV) and indexed left ventricular mass (LVMI) in a cohort of patients with cardiovascular disease (CVD) and diabetes compared to controls.

BACKGROUND AND OBJECTIVE:Results of interventional trials in renovascular hypertension have been disappointing, and medical therapy is the current recommended gold standard. However, the comparative long-term benefits of different antihypertensive drug classes in atherosclerotic renal artery stenosis are not known. We aim to assess the effect of different antihypertensive drug classes on outcomes in renovascular hypertension DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Using Tayside Health Informatics Centre database, anonymized data over a 6-year period was analyzed. Biochemistry, prescribing data, morbidity, mortality, and demographic data were accessed via hospital medical records and electronic data stored in the Tayside Health Informatics Centre Safe Haven. General Registrar's Office data were used to identify patients who died from cardiovascular disease. Independent predictors of survival in each group were analyzed using Kaplan-Meier survival curves and Cox proportional hazard models, adjusted for a range of covariates, using time-updated drug analysis. Blood pressure data were obtained from primary and secondary care clinic blood pressure records for each patient. Adjustments for mean systolic blood pressure over the follow-up period and baseline blood pressure were made.RESULTS:A total of 579 patients with atherosclerotic renal artery stenosis were identified. In the unilateral renal artery stenosis cohort, calcium channel blockers but not ACE inhibitors/ARBs were associated with a significant reduction in all-cause (HR = 0.45, CI = 0.31, 0.65; P = <0.0001) and cardiovascular (HR = 0.51, CI = 0.29-0.90 P = 0.019) mortality. This was maintained after adjustment for blood pressure. In the bilateral renal artery stenosis cohort, both classes of drugs reduced all-cause but not cardiovascular mortality. Patients with moderate disease benefitted more than those with mild or severe disease.CONCLUSIONS:Calcium channel blockers are associated with significantly increased survival and lower cardiovascular mortality particularly in patients with moderate RAS disease.

Purpose To quantify the burden and distribution of asymptomatic atherosclerosis in a population with a low to intermediate risk of cardiovascular disease. Materials and Methods Between June 2008 and February 2013, 1528 participants with 10-year risk of cardiovascular disease less than 20% were prospectively enrolled. They underwent whole-body magnetic resonance (MR) angiography at 3.0 T by using a two-injection, four-station acquisition technique. Thirty-one arterial segments were scored according to maximum stenosis. Scores were summed and normalized for the number of assessable arterial segments to provide a standardized atheroma score (SAS). Multiple linear regression was performed to assess effects of risk factors on atheroma burden. Results A total of 1513 participants (577 [37.9%] men; median age, 53.5 years; range, 40-83 years) completed the study protocol. Among 46 903 potentially analyzable segments, 46 601 (99.4%) were interpretable. Among these, 2468 segments (5%) demonstrated stenoses, of which 1649 (3.5%) showed stenosis less than 50% and 484 (1.0%) showed stenosis greater than or equal to 50%. Vascular stenoses were distributed throughout the body with no localized distribution. Seven hundred forty-seven (49.4%) participants had at least one stenotic vessel, and 408 (27.0%) participants had multiple stenotic vessels. At multivariable linear regression, SAS correlated with age (B = 3.4; 95% confidence interval: 2.61, 4.20), heart rate (B = 1.23; 95% confidence interval: 0.51, 1.95), systolic blood pressure (B = 0.02; 95% confidence interval: 0.01, 0.03), smoking status (B = 0.79; 95% confidence interval: 0.44, 1.15), and socioeconomic status (B = -0.06; 95% confidence interval: -0.10, -0.02) (P < .01 for all). Conclusion Whole-body MR angiography identifies early vascular disease at a population level. Although disease prevalence is low on a per-vessel level, vascular disease is common on a per-participant level, even in this low- to intermediate-risk cohort. © RSNA, 2018 Online supplemental material is available for this article.

Given the cost and difficulties of bringing a new drug to market, repurposing of existing drugs presents an attractive proposition for new therapies. Metformin is an established treatment for diabetes which also appears to be associated with improved cardiovascular outcome. The exact mechanisms for this are unclear, but may be in part due to reductions in insulin resistance (IR) and inflammation. Both of these processes are linked with the development of adverse left ventricular remodelling, in particular, left ventricular hypertrophy (LVH), an independent cardiovascular risk factor. The aim of this series of studies was to utilise a translational approach involving ‘big data’, record linkage to a bio-resource, genomics and a proof-of-concept randomised controlled trial to determine whether metformin could be repurposed as a treatment for LVH. Three studies were conducted, first, a genomic study to determine whether genetically-determined IR was independently associated with echocardiographic LVH in patients with AS. Second, a large cohort study was analysed to determine whether metformin use was associated with improved cardiovascular outcome in diabetic patients with moderate/severe AS compared to non-metformin users. Finally, in a proof-of-concept study to assess the potential of metformin to cause regression of LVH, a randomised controlled trial of metformin vs. placebo was conducted in non-diabetic patients with IR and coronary artery disease without hypertension. After adjustment for AS severity, age, sex and systolic blood pressure (SBP), patients in the highest tertile of IR genetic risk were significantly more likely to have LVH than those in the lowest tertile (OR 1.71; 95% CI 1.13–2.61, p=0.012). In the longitudinal cohort study, although diabetic patients overall had a worse outcome than non-diabetics, metformin users actually had similar outcomes to non-diabetic patients (HR=1.24, 95% CI 0.84–1.82, p=0.28) whereas diabetic patients on drugs other than metformin had significantly higher risk than non-diabetic patients (HR 1.70; 95% CI 1.23–2.34, p=0.0012) after adjustment for relevant clinical variables including AS severity, duration of diabetes, medication use and SBP. Finally, in the randomised trial, 12 months of metformin treatment reduced indexed LVMI compared to placebo (intention-to-treat: −2.7±2.3 g/m 1.7 vs. −1.4±2.7 g/m 1.7; p=0.051; per-protocol: −3.1±1.9 g/m 1.7 vs. −1.2±2.7 g/m 1.7; p=0.005). By using a comprehensive translational approach including ‘big data’, genomics and a randomised clinical trial, these results suggest that metformin may have the potential to be repurposed as a treatment for cardiovascular disease and warrants further prospective trials to evaluate its use.

Left ventricular (LV) hypertrophy (LVH) is a heritable trait that is common in type 2 diabetes and is associated with the development of heart failure. The transcriptional factor Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy in experimental models. This study investigated if KLF15 gene variants were associated with LVH in type 2 diabetes. In stage 1 of a 2-stage approach, patients with type 2 diabetes and no known cardiac disease were prospectively recruited for a transthoracic echocardiographic assessment (Melbourne Diabetes Heart Cohort) (n=318) and genotyping of two KLF15 single nucleotide polymorphisms (SNPs) (rs9838915, rs6796325). In stage 2, the association of KLF15 SNPs with LVH was investigated in the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) type 2 diabetes cohort (n=5631). The KLF15 SNP rs9838915 A allele was associated in a dominant manner with LV mass before (P=0.003) and after (P=0.001) adjustment for age, gender, body mass index (BMI) and hypertension, and with adjusted septal (P<0.0001) and posterior (P=0.004) wall thickness. LVH was present in 35% of patients. Over a median follow up of 5.6years, there were 22 (7%) first heart failure hospitalizations. The adjusted risk of heart failure hospitalization was 5.5-fold greater in those with LVH and the rs9838915 A allele compared to those without LVH and the GG genotype (hazard ratio (HR) 5.5 (1.6–18.6), P=0.006). The association of rs9838915 A allele with LVH was replicated in the Go-DARTS cohort. We have identified the KLF15 SNP rs9838915 A allele as a marker of LVH in patients with type 2 diabetes, and replicated these findings in a large independent cohort. Studies are needed to characterize the functional importance of these results, and to determine if the SNP rs9838915 A allele is associated with LVH in other high risk patient cohorts.

Introduction Renal dysfunction in patients with heart failure (HF) has traditionally been attributed to poor cardiac output. There is currently a growing body of evidence to suggest that renal venous congestion (VC) plays a more important role than hypo-perfusion. However, a vast majority of them have been invasive studies measuring pulmonary artery and central venous pressures as markers of venous congestion. We, therefore, aimed to determine if VC as determined by inferior vena cava (IVC) dilatation using echocardiography was associated with worsening renal function, HF hospitalisation and all-cause mortality. Methods We designed a population-based, longitudinal cohort study of 1034 unselected (acute/chronic) HF patients. All patients were symptomatic and required the use of loop diuretic therapy. VC was defined as IVC diameter >2.1 cm as determined by echocardiography performed nearest to the time of recruitment into study. Renal function was determined by estimated glomerular filtration rate (eGFR) using the abbreviated MDRD equation. Logistic regression models were used to examine the association between VC and eGFR. Cox proportional hazard models were applied to examine the influence of VC on all-cause mortality and CHF hospitalisations. Results Logistic regression models showed that those with severe renal impairment (eGFR<30) were more likely to have VC compared to those with an eGFR >60 (Odds Ratio=7.7; 95% CI(1.6–10.5), p = 0.012). Multivariate analysis showed that those with VC had significantly worse survival than those without VC after adjusting for age, sex, eGFR and furosemide daily dose (hazard ratio [HR]: 1.6, 95% CI: 1.15–1.96; p = 0.002). There was also a nonsignificant trend towards shorter time to first hospitalisation for HF in the VC group compared to those without VC (hazard ratio [HR]: 1.22, 95% CI: 0.96–1.56; p = 0.103). Conclusions VC as determined by dilated IVC on echocardiography is associated with worsening renal function in an unselected group of HF patients. This readily available and non-invasive test can also be used to predict HF hospitalisation and all-cause death in this patient group.