Genetic and functional insights into the fractal structure of the heart.

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

Coupled myovascular expansion directs cardiac growth and regeneration.

Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study.

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.

Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization.

BACKGROUND: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. METHODS: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. RESULTS: Forty-four of ninety proteins were positively associated with risk of incident HF (P<6.0×10-4). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. CONCLUSIONS: We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Radiofrequency Pulmonary Vein Isolation in a Patient with Dextrocardia With Situs Inversus Totalis.

BACKGROUND: We present a case report of a 67-year-old male with dextrocardia situs inversus totalis and persistent atrial fibrillation who presented for radiofrequency pulmonary vein isolation. METHODS: Pulmonary vein isolation was performed using the St Jude Medical Ensite NavX 3D mapping system with AccuNav ICE guidance. RESULTS: All pulmonary veins were successfully isolated. The procedure time was 125 mins with a fluoroscopy time of 44.3 mins. The fluoro dose was 2095cGycm2. There were no procedural complications. CONCLUSIONS: Radiofrequency pulmonary vein isolation can be performed safely and successfully in patients with dextrocardia and situs inversus totalis.

The relationship between adiposity and cognitive function: a bidirectional Mendelian randomization study in UK Biobank.

BACKGROUND: There may be a bidirectional relationship between cognition and adiposity, whereby poor cognition leads to increased adiposity and vice versa. We aimed to determine whether these findings are causal, by undertaking a bidirectional Mendelian randomization (MR) study. METHODS: A total of 378 877 UK Biobank participants had three adiposity indicators [body fat percentage (BF%), body mass index (BMI) and waist-hip ratio] and two cognitive function measures (reaction time, visual memory). We examined observational associations between each adiposity indicator and cognitive function and vice versa. Using bidirectional inverse-variance weighted MR, we estimated the strength of the adiposity-cognitive function association using genetic instruments for adiposity indicators as our exposures, and we repeated this in the opposite direction using instruments for cognitive function. RESULTS: In the direction adiposity to cognitive function, MR analyses were generally directionally consistent with observational findings, but all confidence intervals contained the null. In the opposite direction, MR estimates for all adiposity measures on reaction time were imprecise and directionally inconsistent. MR estimates for the effects of visual memory on all adiposity measures indicated worse visual memory was associated with lower adiposity. For example, a 1-unit worse visual memory score was associated with a 1.32% [ß = -1.32; 95% confidence interval (CI): -0.77,-1.88] and 3.57% (ß = -3.64; 95% CI: -1.84,-5.15) lower absolute body fat percentage and relative body mass index, respectively. CONCLUSIONS: Observational associations of adiposity on cognitive function are likely not causal. In the reverse direction, our consistent findings that worse visual memory is associated with three adiposity indicators provide support for a causal link between worse visual memory and lower adiposity.

Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity.

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm.

BACKGROUND: There is debate concerning whether an aneurysmal ascending aorta should be replaced when associated with a dysfunctioning aortic valve that is to be replaced. To examine this issue, we divided the patients by type of aortic valve dysfunction-either aortic stenosis (AS) or pure aortic regurgitation (AR)-something not previously undertaken. METHODS AND RESULTS: Of 122 patients with ascending aortic aneurysm (unassociated with aortitis or acute dissection), the aortic valve was congenitally malformed (unicuspid or bicuspid) in 58 (98%) of the 59 AS patients, and in 38 (60%) of the 63 pure AR patients. Ascending aortic medial elastic fiber loss (EFL) (graded 0 to 4+) was zero or 1+ in 53 (90%) of the AS patients, in 20 (53%) of the 38 AR patients with bicuspid valves, and in all 12 AR patients with tricuspid valves unassociated with the Marfan syndrome. An unadjusted analysis showed that, among the 96 patients with congenitally malformed valves, the 38 AR patients had a significantly higher likelihood of 2+ to 4+ EFL than the 58 AS patients (crude odds ratio: 8.78; 95% confidence interval: 2.95, 28.13). CONCLUSIONS: These data strongly suggest that the type of aortic valve dysfunction-AS versus pure AR-is very helpful in predicting loss of aortic medial elastic fibers in patients with ascending aortic aneurysms and aortic valve disease.

Life-Time Covariation of Major Cardiovascular Diseases: A 40-Year Longitudinal Study and Genetic Studies.

BACKGROUND: It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs. METHODS: The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has been followed for 40 years regarding 4 major CVDs (incident myocardial infarction, ischemic stroke, heart failure, and atrial fibrillation). For the genetic analyses, publicly available data were used. RESULTS: Using multistate modeling, significant relationships were seen between pairs of all of the 4 investigated CVDs. However, the risk of obtaining one additional CVD differed substantially both between different CVDs and between their temporal order. The relationship between heart failure and atrial fibrillation showed a high risk ratio (risk ratios, 24-26) regardless of the temporal order. A consistent association was seen also for myocardial infarction and atrial fibrillation but with a lower relative risk (risk ratios, 4-5). In contrast, the risk of receiving a diagnosis of heart failure following a myocardial infarction was almost twice as high as for the reverse temporal order (risk ratios, 16 versus 9). Genetic loci linked to traditional risk factors could partly explain the observed associations between the CVDs, but pathway analyses disclosed also other pathophysiological links. CONCLUSIONS: During 40 years, all of the 4 investigated CVDs were pairwise associated with each other regardless of the temporal order of occurrence, but the risk magnitude differed between different CVDs and their temporal order. Genetic analyses disclosed new pathophysiological links between CVDs.

The genomics of heart failure: design and rationale of the HERMES consortium.

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

The relationship between sleep duration, cognition and dementia: a Mendelian randomization study.

BACKGROUND: Short and long sleep duration have been linked with poorer cognitive outcomes, but it remains unclear whether these associations are causal. METHODS: We conducted the first Mendelian randomization (MR) study with 77 single-nucleotide polymorphisms (SNPs) for sleep duration using individual-participant data from the UK Biobank cohort (N = 395 803) and summary statistics from the International Genomics of Alzheimer's Project (N cases/controls = 17 008/37 154) to investigate the potential impact of sleep duration on cognitive outcomes. RESULTS: Linear MR suggested that each additional hour/day of sleep was associated with 1% [95% confidence interval (CI) = 0-2%; P = 0.008] slower reaction time and 3% more errors in visual-memory test (95% CI = 0-6%; P = 0.05). There was little evidence to support associations of increased sleep duration with decline in visual memory [odds ratio (OR) per additional hour/day of sleep = 1.10 (95% CI = 0.76-1.57); P = 0.62], decline in reaction time [OR = 1.28 (95% CI = 0.49-3.35); P = 0.61], all-cause dementia [OR = 1.19 (95% CI = 0.65-2.19); P = 0.57] or Alzheimer's disease risk [OR = 0.89 (95% CI = 0.67-1.18); P = 0.41]. Non-linear MR suggested that both short and long sleep duration were associated with poorer visual memory (P for non-linearity = 3.44e-9) and reaction time (P for non-linearity = 6.66e-16). CONCLUSIONS: Linear increase in sleep duration has a small negative effect on reaction time and visual memory, but the true association might be non-linear, with evidence of associations for both short and long sleep duration. These findings suggest that sleep duration may represent a potential causal pathway for cognition.

Valve structure and survival in quinquagenarians having aortic valve replacement for aortic stenosis (+/-aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005).

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in quinquagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 120 quinquagenarians having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 44 (37%) with and 76 (63%) without simultaneous CABG. Of the 120 patients, 2 (2%) died within 30 days of operation and none from 31 to 60 days postoperatively. Fifteen other patients (13%) died from >60 days to up to 13 years postoperatively. The unadjusted survival analysis showed that late survival was significantly better in the unicuspid/bicuspid valve structure group than in the tricuspid valve structure group (log-rank test p = 0.001), but that it was not affected by gender (male vs female), preoperative severity of the AS (transvalvular peak pressure gradient >50 vs < or =50 mm Hg), or by performance of CABG. The aortic valve was congenitally unicuspid in 18 patients (15%), congenitally bicuspid in 84 (70%), and 3-cuspid in 18 (15%). In conclusion, aortic valve structure affected the unadjusted late survival in quinquagenarians undergoing AVR for AS, but concomitant CABG, gender, and transvalvular peak systolic gradient had no effect.

Valve structure and survival in quadragenarians having aortic valve replacement for aortic stenosis (+/-aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005).

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in quadragenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 48 adults (12 women), aged 40 to 49 years, having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 7 (15%) with and 41 (85%) without simultaneous CABG. Of the 48 quadragenarians, none died within 60 days of operation. Assessment of the relation between long-term survival and gender, aortic valve structure, preoperative severity of the AS, and concomitant CABG was not possible due to the low mortality. Four patients (9%) died >60 days after AVR: at 1.8, 6.3, 7.1, and 9.9 years, respectively. The aortic valve was congenitally unicuspid in 15 patients (31%), congenitally bicuspid in 32 (67%), and 3-cuspid in 1 (2%). In conclusion, of the 48 quadragenarians having AVR for AS, 47 (98%) had a congenitally malformed aortic valve, 60-day mortality was zero, and late mortality was low (8%).

Valve structure and survival in septuagenarians having aortic valve replacement for aortic stenosis (+/-aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005).

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in septuagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed valve structure in 424 septuagenarians having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 254 (60%) with and 170 (40%) without simultaneous CABG. Of the 424 patients, 8 (2%) had a congenitally unicuspid aortic valve, 179 (42%), a congenitally bicuspid aortic valve, 235 (55%), a 3-cuspid valve, and in 2 patients (1%) the valve structure was indeterminate. Survival data were available in 418 of the 424 patients: 23 (5.5%) died within 30 days of AVR and 9 other patients from 31 to 60 days after AVR (7.7% 60-day mortality). Sixty-day mortality was not affected by congenital valve abnormality (unicuspid/bicuspid 8.5% vs tricuspid 7.0%). In contrast, late survival (up to 13-year follow-up) was affected by valve structure: it was longer in the unicuspid/bicuspid valve structure group than in the tricuspid valve structure (hazard ratio 0.54, 95% confidence intervals 0.36 to 0.81). The hazard ratio was estimated after adjusting for concomitant CABG. In conclusion, aortic valve structure affected late, but not early survival in septuagenarians undergoing AVR for AS.

Valve structure and survival in sexagenarians having aortic valve replacement for aortic stenosis (+/-aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005).

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in sexagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 289 sexagenarians having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 147 (51%) with and 142 (49%) without simultaneous CABG. Of the 282 patients with information available, 13 (4.6%) died within 30 days of operation and 1 additional patient, from 31 to 60 days after operation (5.0% 60-day mortality). Sixty-day mortality was similar (6% and 4%) in the groups with and without simultaneous CABG. A total of 66 patients (23%) died from >60 days up to 13 years postoperatively. The unadjusted survival analysis showed that late survival was not affected by gender (male versus female), aortic valve structure (unicuspid, bicuspid, and quadricuspid versus tricuspid) or preoperative severity of the AS (transvalvular peak pressure gradient >50 mm Hg versus < or =50 mm Hg), or by performance of CABG. The aortic valve was congenitally unicuspid in 10 patients (3%), congenitally bicuspid in 170 (59%), 3-cuspid in 107 (37%), congenitally quadricuspid in 1 patient, and the valve structure was indeterminate in 1 patient. In conclusion, gender, valve structure, preoperative severity of the AS, or performance of simultaneous CABG did not effect unadjusted survival in sexagenarians undergoing AVR for AS.

Valve structure and survival in octogenarians having aortic valve replacement for aortic stenosis (+/- aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005).

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and valve structure on both early and late survival in octogenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). Although a number of reports are available in octogenarians having AVR for AS, none have described aortic valve structure. Most have limited numbers of patients and few have described late results. We analyzed survival and valve structure in 196 octogenarians having AVR for AS from 1993 to 2005 at Baylor University Medical Center, including 118 (60%) with and 78 (40%) without simultaneous CABG. Sixty-day mortality, which was identical to 30-day mortality, was similar (10% and 11%) in the groups with and without simultaneous CABG. Unadjusted analysis of late survival (up to 13 year follow-up) was not affected by gender (male vs female), aortic valve structure (bicuspid vs tricuspid) or preoperative severity of the AS (transvalvular peak pressure gradient > 50 vs < or =50 mm Hg), or by performance of CABG. Of the 196 patients, 54 (28%) had a congenitally bicuspid aortic valve, and 142 (72%) had a tricuspid aortic valve. In conclusion, gender, valve structure, preoperative severity of the AS, or performance of simultaneous CABG did not effect survival in octogenarians having AVR for AS.