Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

Insights into human health from phenome- and genome-wide analyses of UK Biobank retinal optical coherence tomography phenotypes.

The human retina is a complex multi-layered tissue which offers a unique window into systemic health and disease. Optical coherence tomography (OCT) is widely used in eye care and allows the non-invasive, rapid capture of retinal measurements in exquisite detail. We conducted genome- and phenome-wide analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed phenome-wide association analyses, associating retinal thicknesses with 1,866 incident ICD-based conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association analyses, identifying inherited genetic markers which influence the retina, and replicated our associations among 6,313 individuals from the LIFE-Adult Study. And lastly, we performed comparative association of phenome- and genome- wide associations to identify putative causal links between systemic conditions, retinal layer thicknesses, and ocular disease. Independent associations with incident mortality were detected for photoreceptor thinning and ganglion cell complex thinning. Significant phenotypic associations were detected between retinal layer thinning and ocular, neuropsychiatric, cardiometabolic and pulmonary conditions. Genome-wide association of retinal layer thicknesses yielded 259 loci. Consistency between epidemiologic and genetic associations suggested putative causal links between thinning of the retinal nerve fiber layer with glaucoma, photoreceptor segment with AMD, as well as poor cardiometabolic and pulmonary function with PS thinning, among other findings. In conclusion, retinal layer thinning predicts risk of future ocular and systemic disease. Furthermore, systemic cardio-metabolic-pulmonary conditions promote retinal thinning. Retinal imaging biomarkers, integrated into electronic health records, may inform risk prediction and potential therapeutic strategies.

TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease.

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

The Reintervention Index: A New Outcome Measure for Comparative Effectiveness of Lower Extremity Revascularization.

BACKGROUND: Reinterventions after lower extremity revascularization (LER) are common. Current outcome measures assessing durability of revascularization rely on freedom from reintervention but do not account for the frequency of repeated LER. The aim of this study is to compare the reintervention index, defined as the mean number of repeat LER, after open and endovascular revascularization. We hypothesized that endovascular procedures have reduced durability and increased frequency of reinterventions. METHODS: A retrospective review of the charts of consecutive patients undergoing LER for peripheral artery disease (PAD) in 2013-2014 by multiple specialties in a tertiary care center was performed. Patients were divided into open and endovascular groups based on the first LER procedure performed during the study period. Patient characteristics and outcomes were compared between the 2 groups. Multivariable regression was performed to determine factors associated with reintervention. RESULTS: There were 367 patients (Endo = 316, Open = 51). A total of 211 patients underwent 497 reinterventions (reintervention rate = 57.5%, reintervention index = 2.35 ± 2.02 procedures [range 1-11]). Patients in the open group were more likely to be smokers (P = 0.018) and to have prior open LER (P = 0.003), while patients in the endovascular group were older (P < 0.001) and more likely to have cardiovascular comorbidities. On follow-up, there was no difference in overall or ipsilateral reintervention rates or reintervention indices between endovascular and open LER. Major amputation was significantly higher after open LER (19.61% vs. 8.54%, P = 0.013) but there was no difference in survival (P = 0.448). Multivariable analysis did not show a significant relationship between type of procedure and reintervention. CONCLUSIONS: The reintervention index provides a measure to assess the frequency of repeat LER. Patients with PAD, in this study, are afflicted with similar extent of reinterventions after open and endovascular LER.

Variations in the Management of Claudication in a Tertiary Care Center.

BACKGROUND: Multiple societal guidelines recommend medical optimization and exercise therapy for patients with claudication prior to lower extremity revascularization (LER). However, the application of those guidelines in practice remains unknown. Our hypothesis is that vascular surgeons (VS) are more adherent to guidelines compared to non-VS treating claudication. METHODS: The records of patients undergoing LER for claudication in a single center were reviewed, and adherence to guidelines prior to LER was assessed. Patients received conservative therapy if the impact of claudication on quality of life was documented, ankle-brachial index (ABI) was obtained, and patients were treated with at least 3 months of walking exercise and smoking cessation when indicated. RESULTS: There were 187 patients treated for claudication (VS = 65, non-VS = 122). There were 161 patients who underwent endovascular intervention, 19 patients had an open revascularization, and 7 patients had a hybrid procedure. Patients treated by VS were younger and more likely to be African American. Patients treated by non-VS were more likely to have hyperlipidemia, coronary artery disease, smoke, and be on antiplatelet and statin medications. VS was more likely to assess pattern of symptoms with claudication and obtain ABIs compared to non-VS, although the mean ABIs were no different. VS was more likely to use walking exercises and smoking cessation when indicated before LER. Even though 70.8% and 31.1% of patients treated by VS and non-VS respectively were recommended walking exercises, only 33.8% and 18.0% were given a period of 3 months to benefit from it prior to LER. Conservative therapy was significantly higher among VS compared to non-VS but was overall low (VS = 12.3%, non-VS = 3.3%, P = 0.016). After a mean follow-up of 3.1 ± 1.3 years, there was no difference in mortality or major amputation. CONCLUSIONS: Although adherence to guidelines in the medical management of vascular claudication prior to LER was higher among VS compared with non-VS, overall rates of adherence were low. Stricter institutional protocols and oversight across specialties are needed to reinforce the application of the established standards of care.

Hybrid surgery for bilateral lower extremity inflow revascularization.

OBJECTIVE: Aortobifemoral (ABF) bypass is the preferred method of bilateral inflow revascularization, with axillobifemoral (AXBF) bypass reserved for high-risk patients. Hybrid (HYB) surgery in the form of femorofemoral bypass and retrograde endovascular aortoiliac intervention is increasingly being used to achieve the same goal. This study compared the perioperative outcomes of HYB surgery with traditional surgery for bilateral inflow revascularization. METHODS: The American College of Surgeons National Surgical Quality Improvement Program files for the years 2012 to 2015 were reviewed, and all patients undergoing ABF bypass, AXBF bypass, and HYB surgery (femoral-femoral bypass and retrograde endovascular intervention) were included. Patients' demographics, comorbidities, and outcomes were compared between the three groups. A propensity-matched analysis was subsequently performed to compare HYB surgery with ABF bypass only. The χ2 test and analysis of variance with post hoc analysis were conducted to evaluate between-group differences in risk factors and outcomes. SPSS statistical software (IBM Corp, Armonk, NY) was used. RESULTS: There were 1426 patients (ABF bypass, 976; AXBF bypass, 257; HYB surgery, 193). There were significant differences in the three populations of patients, with ABF bypass patients significantly more likely to have age <70 years (ABF bypass, 84.2%; AXBF bypass, 49.8%; HYB surgery, 58%; P < .001) and more likely to be independent (ABF bypass, 98%; AXBF bypass, 89.1%; HYB surgery, 93.2%; P < .001). Patients undergoing AXBF bypass were significantly more likely to be treated for critical limb ischemia (ABF bypass, 46.5%; AXBF bypass, 72.4%; HYB surgery, 51.8%; P < .001) under emergent conditions (ABF bypass, 0.9%; AXBF bypass, 5.1%; HYB surgery, 3.6%; P < .001). There was no difference in mortality between the three groups (P = .178). After propensity matching, a total of 571 patients with ABF bypass were compared with HYB surgery patients. HYB surgery patients had significantly less pneumonia (ABF bypass, 8.7%; HYB surgery, 1.6%; P < .001), unplanned intubation (ABF bypass, 7.7%; HYB surgery, 3.1%; P = .032), cardiac arrest (ABF bypass, 3.7%; HYB surgery, 0.5%; P = .025), transfusion (ABF bypass, 44.4%; HYB surgery, 18.1%; P < .001), and composite morbidity (ABF bypass, 55%; HYB surgery, 32.6%; P < .001). Patients undergoing ABF bypass had significantly higher mortality (ABF bypass, 4.2%; HYB surgery, 1%; P = .043) and 30-day reoperation (ABF bypass, 17.5%; HYB surgery, 9.3%; P = .009) and longer total hospital length of stay (ABF bypass, 9.79 ± 10.69 days; HYB surgery, 5.79 ± 9.72 days; P < .001). There was no difference in major amputation (P = .607) and readmission (P = .495) between the two groups. CONCLUSIONS: ABF bypass is the most common surgery for bilateral lower extremity revascularization in the American College of Surgeons National Surgical Quality Improvement Program database and continues to have good outcomes. In selected patients, HYB surgery was associated with improved perioperative, 30-day outcomes compared with ABF bypass.

Hybrid femoropopliteal procedures are associated with improved perioperative outcomes compared with bypass.

OBJECTIVE: Hybrid procedures have gained momentum as less invasive operations that can potentially improve outcomes for patients. However, there is a paucity of data comparing hybrid procedures with traditional bypass. This study compares the perioperative outcomes of hybrid and bypass surgery for femoropopliteal (FP) revascularization. METHODS: The American College of Surgeons National Surgical Quality Improvement Program files (2012-2015) were reviewed, and three groups of patients undergoing isolated FP revascularization were identified by Current Procedural Terminology codes. All patients underwent femoral endarterectomy. The hybrid group (HYB) had a concomitant antegrade endovascular FP intervention and was compared with patients with concomitant FP bypass with vein (BPV) and FP bypass with nonvein graft (BPG). The demographics, comorbidities, and outcomes of the three groups were analyzed. The χ2 and analysis of variance tests with post hoc analysis were used. A multivariable logistic regression analysis was performed to identify predictors of readmission, reoperation, and mortality. RESULTS: There were 1480 patients in the analysis. Compared with patients undergoing BPV and BPG, patients in the HYB group tended to be older (P = .016) and were less likely to be smokers (P < .001). They had fewer infected wounds (P = .001) and were more likely to have American Society of Anesthesiologists score ≤3 (P = .01) and claudication (P < .01). HYB patients had significantly fewer bleeding transfusions (P = .01) and less overall morbidity (P < .001) compared with BPV and BPG patients. The three treatment groups did not differ in frequencies of mortality and major amputation. Among the groups, BPV was associated with the longest operating time (P < .001), whereas HYB had significantly shorter hospital stay (P < .001). HYB was also associated with significantly lower rates of reoperation (P = .017) and readmission (P = .007). On multivariable regression, patients undergoing BPG were at increased risk of readmission (odds ratio [OR], 1.48 [1.00-2.17]) compared with HYB. HYB surgery was associated with less morbidity compared with BPV (OR, 1.38 [1-1.9]) and BPG (OR, 1.77 [1.3-2.38]). CONCLUSIONS: Hybrid procedures have favorable perioperative outcomes compared with open bypass for FP revascularization. Additional research on the long-term outcomes of hybrid procedures is needed.