Stephen O. Brennan

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

BACKGROUND: Evidence-based practice relies on clinical guidelines, whose recommendations depend on the quality, relevance, and validity of supporting research. We evaluated the class/strength and level of evidence (LOE) or quality of evidence (QOE) supporting American Heart Association/American Stroke Association and European Stroke Organisation guideline recommendations, and examined temporal changes in LOE. METHODS: Stroke guidelines from American Heart Association/American Stroke Association (1995–2025) and European Stroke Organisation (2014–2025) were identified through society websites and EMBASE/MEDLINE. Eligible documents contained recommendations with class/strength and LOE/QOE. Consensus statements were excluded. Since 2006, American Heart Association/American Stroke Association has classified LOE as A (multiple or large randomized-controlled trials), B (single trial or observational studies), or C (expert opinion). European Stroke Organisation applies the Grading of Recommendations Assessment, Development, and Evaluation system (high, moderate, low, and very low QOE). RESULTS: Across 1102 recommendations in 9 current American Heart Association/American Stroke Association stroke guidelines, 156 (14.2%) were supported by LOE A, 559 (50.7%) by LOE B, and 387 (35.1%) by LOE C. Of 407 class I recommendations (ie, should do), and 117 class III recommendations (ie, should not do), 116 (22.1%), 258 (49.2%), and 150 (28.6%) were supported by LOE A, B, and C, respectively. Although the number of recommendations increased across guideline updates (median, 22 [interquartile range, 25th–75th percentiles, 18.0–42.0]), the proportion supported by LOE A declined (median, −4.6% [interquartile range, −7.8 to −0.8]). Across 260 recommendations in 30 European Stroke Organisation guidelines, 19 (7.3%) were supported by high, 62 (23.8%) by moderate, 81 (31.2%) by low, and 98 (37.7%) by very low QOE. Among 90 strong recommendations, 18 (20.0%) were supported by high QOE, and 66.7% of guideline topics had no recommendations supported by high QOE. There was insufficient evidence to make recommendations for 123 (32.7%) clinical questions. CONCLUSIONS: Due to limited randomized data for many important clinical questions, most stroke guideline recommendations are based on low-to-moderate–quality evidence. These findings emphasize the need to improve the funding, design, and delivery of efficient, patient-focused clinical trials.

Thoracic aortic aneurysm and dissection (TAAD) encompasses a clinically heterogeneous group of diseases characterized by high morbidity and mortality. Genetic studies over the past two decades have significantly expanded our understanding of the molecular landscape underlying heritable TAAD, revealing contributions from multiple interconnected biological pathways. This review systematically summarizes more than 75 genes implicated in TAAD pathogenesis, categorizing them according to major mechanistic roles including TGF-β signaling, extracellular matrix remodeling, smooth muscle cell contractility and cytoskeletal regulation, cell–matrix and cell–cell adhesion, metabolic processes, ion transport, and transcriptional regulation. Special emphasis is placed on emerging genes with variable or overlapping clinical phenotypes, dual-mechanism candidates, and their implications for personalized clinical management, including surveillance and surgical intervention thresholds. The integration of molecular insights into clinical practice, along with cautious consideration of genes of uncertain significance, promises to enhance diagnostic precision and risk stratification in individuals and families affected by heritable aortic disease.

BACKGROUND: Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy—both alone and in combination with existing lipid-lowering therapies—modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects. METHODS: We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points. RESULTS: Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets. CONCLUSIONS: Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors.

Phosphodiesterase−5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. We conducted a drug-target Mendelian randomization (MR) analysis to investigate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes and related phenotypes. We selected variants from around the PDE5A locus associated with diastolic and systolic blood pressure, as well as circulating PDE5A levels, to create three instruments for genetically proxied PDE5A inhibition. Using two-sample MR, we validated the instruments against erectile dysfunction and pulmonary arterial hypertension before assessing their associations with dementia subtypes, dementia-related proteins, and neuroimaging traits. After correcting for multiple comparisons, genetically proxied PDE5 inhibition, per one SD lower in diastolic blood pressure, was associated with higher odds of Alzheimer’s disease (OR 1.09, 95% CI 1.07–1.11) and Lewy body dementia (OR 1.32, 95% CI 1.23–1.41), but a trend towards lower odds of vascular dementia across all instruments. Genetically proxied PDE5 inhibition was associated with both beneficial and adverse effects on brain MRI traits. This included lower volumes of white matter hyperintensities (SD change − 0.035, 95% CI − 0.025, − 0.045), indicating potential benefits, but also reduced volumes of other structures, including the thalamus, suggesting potential adverse effects. PDE5 inhibition was associated with the concentrations of several proteins implicated in dementia pathophysiology. Our findings suggest that while PDE5 inhibition may be associated with a lower risk of vascular dementia, possibly by preventing white matter hyperintensities, it may increase risk of Alzheimer’s disease and Lewy body dementia, warranting further investigation before clinical trials.

Background: Inflammation is an emerging target for the prevention and treatment of cardiovascular disease (CVD). This drug-target Mendelian randomization (MR) study aimed to predict the on-target effects of IL-18 inhibition on CVD risk. Furthermore, we aimed to explore the effects of IL-18 inhibition on cardio-metabolic traits, cardiac structure, and function, and identify potential adverse outcomes. Methods: We selected five independent circulating IL-18-lowering variants around the IL-18 gene locus from the Systematic and Combined AnaLysis of Olink Proteins (SCALLOP) consortium. We then performed two-sample MR analyses to investigate the association of genetically proxied IL-18-inhibition on downstream inflammatory markers, risk of CVD, cardiac magnetic resonance (CMR) imaging measurements of cardiac structure and function, cardiometabolic traits, and a selection of potential adverse effects. We utilized data from the UK Biobank, Cardiogram, GIGASTROKE, and other large genomic consortia (sample range: 3,301-1,320,016). Results: Following correction for multiple comparisons, one standard deviation (SD) lower in genetically-predicted circulating IL-18 was associated with reductions in downstream biomarkers of IL-18 signaling, including C-reactive protein (SD change -0.02, 95% CI -0.03, -0.02), tumor necrosis factor (SD change -0.19, CI -0.25, -0.14), interferon-gamma (SD change -0.15, CI -0.22, -0.08), and CXCL10 (SD change -0.13, CI -0.16, -0.09). Lower genetically-predicted IL-18 levels were associated with reduced risk of cardioembolic stroke (Odds Ratio [OR] 0.85, CI 0.79-0.92), but not other stroke subtypes. Furthermore, lower genetically predicted IL-18 levels were associated with reduced risk of peripheral arterial disease (OR 0.91, CI 0.84-0.97), atrial fibrillation (OR 0.94, CI 0.89-0.99), and heart failure (OR 0.84, CI 0.77-0.92), as well as improvements in CMR traits, including a reduction in left atrial volume (β -0.02, CI -0.03, -0.00). Lower genetically-predicted IL-18 levels were associated with lower risk of chronic kidney disease, autoimmune diseases, a favorable cardio-metabolic profile, and higher odds of lung cancer, but not infections. Conclusions: Our study provides genetic support that impaired IL-18 signaling may be causally associated with a lower risk of cardioembolic stroke, possibly mediated through prevention of cardiac re-modelling, heart failure and atrial fibrillation. IL-18 represents a potential target for anti-inflammatory therapy in stroke and CVD that warrants further investigation in clinical trials. Clinical Perspective: What is new? Using multi-omic data, this Mendelian Randomization study provides evidence that IL-18 lowering is associated with a lower lifetime risk of cardiac remodeling, heart failure, and cardioembolic stroke. A significant proportion of the protective effect of impaired IL-18 signaling on cardioembolic stroke was mediated through a reduced risk of AF. What are the clinical implications? These data provide compelling evidence that the IL-18 signaling pathway is a promising druggable target for the treatment of heart failure and the prevention of cardioembolic stroke. Several monoclonal antibodies targeting IL-18 are in development for the treatment of atopic dermatitis and could be considered for re-purposing for cardiovascular disease.

Background: Phosphodiesterase-5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. This drug- target Mendelian Randomisation (MR) study aims to elucidate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes, cognitive traits, and neuro-imaging phenotypes. Methods: Two independent (r ² <0.001) blood pressure lowering variants from around the PDE5A locus were used in two-sample MR to assess the effect of genetically proxied PDE5 inhibition on risk of dementia subtypes, cognitive performance, and neuroimaging traits (cortical thickness, surface area and volume of white matter hyperintensities) in large-scale genomic consortia. The instrument’s predictive validity was assessed against erectile dysfunction and pulmonary arterial hypertension (PAH) as positive controls. Results: Following correction for multiple comparisons, genetically proxied PDE5 inhibition was associated with lower odds of erectile dysfunction (OR 0.85, 95% CI 0.83-0.87) and PAH (OR 0.58, 95% CI 0.55-0.61), and higher odds of Alzheimer’s disease (OR 1.07, 95% CI 1.04-1.10), Lewy body dementia (OR 1.20, 95% CI 1.17-1.23) and vascular dementia (OR 1.04, 95% CI 1.02-1.07). Furthermore, genetically proxied PDE5 inhibition was associated with reduced cortical thickness (SD change -0.003, 95% CI -0.004, -0.002) and cognitive performance (SD change -0.010, 95% CI -0.013, -0.007), but not cortical surface area nor volume of white matter hyperintensities. Conclusion: In contrast to evidence from observational studies, our findings indicate that inhibition of PDE5 is associated with a higher risk of dementia and an unfavourable neurocognitive profile. This risk should be further investigated prior to clinical trials of pharmacological PDE5 inhibition for the treatment and prevention of dementia.

Background: Left ventricular pseudoaneurysm (LVP) is an uncommon but serious mechanical complication of acute myocardial infarction (AMI). The immediate medical complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are well recognized, but its indirect effect on patients and healthcare systems is potentially less perceivable. Case summary: In this report, a 72-year-old man who was anxious about attending hospital during the SARS-CoV-2 pandemic was eventually found to have a total right coronary artery occlusion after a delayed emergency department presentation. He ultimately developed severe symptomatic heart failure and cardiac magnetic resonance imaging (CMR) revealed that a large LVP with concomitant severe ischaemic mitral regurgitation had evolved from his infarct. The patient was successfully discharged home after the surgical replacement of his mitral valve and repair of his LVP. Discussion: This case highlights a salient downstream effect of Coronavirus disease 2019 (COVID-19): the delay in presentation, diagnosis, and management of common treatable conditions such as AMI. It also underscores the importance of non-invasive multimodal imaging on the timely identification of the mechanical complications of AMI. In particular, CMR can play a crucial role in the characterization and management of LVP.

(2002). Hb MANAWATU [α37(C2)Pro→Leu]: A NEW MILDLY UNSTABLE MUTATION AT AN INVARIANT PROLINE RESIDUE. Hemoglobin: Vol. 26, No. 4, pp. 389-392. doi: 10.1081/HEM-120016376