Factors associated with shunt dynamic in patients with cryptogenic stroke and patent foramen ovale: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>As previously reported there is evidence for a reduction in right to left shunt (RLS) in stroke patients with patent foramen ovale (PFO). This occurs predominantly in patients with cryptogenic stroke (CS). We therefore analysed factors associated with a shunt reduction on follow-up in stroke patients suffering of CS.</p> <p>Methods</p> <p>On index event PFO and RLS were proven by transesophageal echocardiography and contrast-enhanced transcranial Doppler-sonography (ce-TCD). Silent PE was proved by ventilation perfusion scintigraphy (V/Q) within the stroke work-up on index event; all scans were re-evaluated in a blinded manner by two experts. The RLS was re-assessed on follow-up by ce-TCD. A reduction in shunt volume was defined as a difference of ≥20 microembolic signals (MES) or the lack of evidence of RLS on follow-up. For subsequent analyses patients with CS were considered; parameters such as deep vein thrombosis (DVT) and silent pulmonary embolism (PE) were analysed.</p> <p>Results</p> <p>In 39 PFO patients suffering of a CS the RLS was re-assessed on follow-up. In all patients (n = 39) with CS a V/Q was performed; the median age was 40 years, 24 (61.5%) patients were female. In 27 patients a reduction in RLS was evident. Silent PE was evident in 18/39 patients (46.2%). Factors such as atrial septum aneurysm, DVT or even silent PE were not associated with RLS dynamics. A greater time delay from index event to follow-up assessment was associated with a decrease in shunt volume (median 12 vs. 6 months, <it>p </it>= 0.013).</p> <p>Conclusions</p> <p>In patients with CS a reduction in RLS is not associated with the presence of a venous embolic event such as DVT or silent PE. A greater time delay between the initial and the follow-up investigation increases the likelihood for the detection of a reduction in RLS.</p

Decrease in shunt volume in patients with cryptogenic stroke and patent foramen ovale

<p>Abstract</p> <p>Background</p> <p>In patients with patent foramen ovale (PFO) there is evidence supporting the hypothesis of a change in right-to-left shunt (RLS) over time. Proven, this could have implications for the care of patients with PFO and a history of stroke. The following study addressed this hypothesis in a cohort of patients with stroke and PFO.</p> <p>Methods</p> <p>The RLS volume assessed during hospitalisation for stroke (index event/T0) was compared with the RLS volume on follow-up (T1) (median time between T0 and T1 was 10 months). In 102 patients with a history of stroke and PFO the RLS volume was re-assessed on follow-up using contrast-enhanced transcranial Doppler/duplex (ce-TCD) ultrasound. A change in RLS volume was defined as a difference of ≥20 microembolic signals (MES) or no evidence of RLS during ce-TCD ultrasound on follow-up.</p> <p>Results</p> <p>There was evidence of a marked reduction in RLS volume in 31/102 patients; in 14/31 patients a PFO was no longer detectable. An index event classified as cryptogenic stroke (P < 0.001; OD = 39.2, 95% confidence interval 6.0 to 258.2) and the time interval to the follow-up visit (P = 0.03) were independently associated with a change in RLS volume over time.</p> <p>Conclusions</p> <p>RLS volume across a PFO decreases over time, especially in patients with cryptogenic stroke. These may determine the development of new strategies for the management in the secondary stroke prevention.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A -10T genotype

Background: Fabry disease (FD) is a multisystemic disorder with typical neurological manifestations such as stroke and small fiber neuropathy (SFN), caused by mutations of the alpha-galactosidase A (GLA) gene. We analyzed 15 patients carrying the GLA haplotype -10C>T [rs2071225], IVS2-81_-77delCAGCC [rs5903184], IVS4-16A>G [rs2071397], and IVS6-22C>T [rs2071228] for potential neurological manifestations. Methods and results: Patients were retrospectively analyzed for stroke, transient ischemic attack (TIA), white matter lesions (WML) and SFN with neuropathic pain. Functional impact of the haplotype was determined by molecular genetic methods including real-time PCR, exon trapping, promoter deletion constructs and electrophoretic mobility shift assays. Symptomatic -10T allele carriers suffered from stroke, TIA, WML, and SFN with neuropathic pain. Patients’ mean GLA mRNA expression level was reduced to ~70% (p < 0.0001) and a dose-dependent effect of the -10T allele on GLA mRNA expression was observed in hemi/homozygous compared to heterozygous patients (p < 0.0001). Molecular analyzes revealed that the -10T allele resulted in a reduced promoter activity and an altered transcription factor binding, while a functional relevance of the co-segregated intronic variants was excluded by exon trapping. Conclusions: Based on this complementary approach of clinical observation and functional testing, we conclude that the GLA -10T allele could be causal for the observed neurological manifestations. Future studies are needed to clarify whether affected patients benefit from GLA enzyme replacement therapy for end-organ damage prevention.<br