TP53-mediated clonal hematopoiesis confers increased risk for incident peripheral artery disease

AbstractBackgroundSomatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP), particularly in DNMT3A, TET2, and JAK2, are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. However, whether CHIP is associated with increased risk of peripheral artery disease (PAD) remains unknown. In addition, chemotherapy frequently causes mutations in DNA Damage Repair (DDR) genes TP53 and PPM1D, and whether CHIP caused by somatic mutations in DDR genes results in increased risk of atherosclerosis is unclear. We sought to test whether CHIP, and CHIP caused by DDR genes, associates with incident peripheral artery disease (PAD) and atherosclerosis.MethodsWe identified CHIP among 50,122 exome sequences in individuals from UK and Mass General Brigham Biobanks and tested CHIP status (N=2,851) with incident PAD and atherosclerosis across multiple arterial beds. To mimic the human scenario of clonal hematopoiesis and test whether the expansion of p53-deficient hematopoietic cells contributes to atherosclerosis, a competitive bone marrow transplantation (BMT) strategy was used to generate atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% Trp53-/- hematopoietic cells (20% KO-BMT mice). We then evaluated aortic plaque burden and plaque macrophage accumulation 12 weeks after grafting.ResultsCHIP associated with incident PAD (HR 1.7; P=2.2x10-5) and atherosclerosis in multiple beds (HR 1.3; P=9.7x10-5), with increased risk among individuals with DDR CHIP (HR 2.0; P=0.0084). Among atherosclerosis-prone Ldlr null mice, the p53 -/- 20% KO-BMT mice demonstrated increased aortic plaque size (p=0.013) and accumulation of p53-/- plaque macrophages (P<0.001), driven by an abundance of p53-deficient plaque macrophages. The expansion of p53-deficient cells did not affect the expression of the pro-inflammatory cytokines IL-6 and IL-1β in the atherosclerotic aortic wall.ConclusionsOur findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system, with evidence of increased plaque among p53 -/- 20% KO-BMT mice via expansion of plaque macrophages. These observations provide new insight into the link between CHIP and cardiovascular disease, and lend human genetic support to the concept that post-cytotoxic chemotherapy patients may benefit from surveillance for atherosclerotic conditions in addition to therapy-related myeloid neoplasms.

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Novel Oral Anticoagulants in Peripheral Artery Disease: Current Evidence

Current Pharmaceutical Design ◽

10.2174/1381612825666181226151959 ◽

2019 ◽

Vol 24 (38) ◽

pp. 4511-4515 ◽

Cited By ~ 1

Author(s):

A. Koutsoumpelis ◽

C. Argyriou ◽

K.M. Tasopoulou ◽

E.I. Georgakarakos ◽

G.S. Georgiadis

Keyword(s):

Peripheral Artery Disease ◽

Oral Anticoagulants ◽

Novel Oral Anticoagulants ◽

Current Evidence ◽

Peripheral Artery ◽

Cardiac Events ◽

Traditional Therapy ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Artery Disease

Background: Peripheral artery disease is a common manifestation of systemic atherosclerosis which strongly correlates to cardiovascular morbidity and mortality. In addition, the progression of peripheral artery disease leads to an increased risk of limb loss. In order to reduce these events, the benchmark of treatment and research over the last years has been the antiplatelet therapy which aims at inhibition of platelet aggregation. Over the last years, new studies combining antiplatelet agents in different therapeutic schemes have been proven efficacious. Unfortunately, patients remain still at high risk of CV events. Novel Oral Anticoagulants have been introduced as alternatives to warfarin, in the prevention and treatment of venous thromboembolism. The rationale of using medication which acts on platelet activation and the coagulation pathway of thrombosis has led investigators to examine the role of Noac's in preventing CV events in patients with peripheral artery disease, stable or unstable. Methods: The aim of this study is to review the current evidence with respect to recently published studies concerning the use of Novel anticoagulants in peripheral artery disease. Results: The Compass trial has shown that a combination of rivaroxaban with traditional therapy may produce promising results in reducing amputation rates, stroke, cardiac events, and mortality, however, there are still safety issues with bleeding requiring acute care. The ePAD study has provided us with insight concerning safety and efficacy after peripheral angioplasty or stenting and actually the need for further research. The Voyager Pad study, following the steps of Compass, is studying the effect and safety of the addition of rivaroxaban to traditional therapy in the highest risk population aka patients undergoing peripheral revascularization. The evidence concerning patients with concomitant atrial fibrillation appears to be insufficient, however, recent guidelines propose the use of novel oral anticoagulants. Conclusion: For the time being, novel oral anticoagulants in combination with aspirin may provide an alternative treatment in PAD, however, it is deemed necessary to identify patient subgroups who will benefit the most.

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A Targeted Literature Review of the Disease Burden in Patients With Symptomatic Peripheral Artery Disease

Angiology ◽

10.1177/0003319719896477 ◽

2019 ◽

Vol 71 (4) ◽

pp. 303-314

Author(s):

Rupert Bauersachs ◽

Sebastian Debus ◽

Mark Nehler ◽

Maria Huelsebeck ◽

Janita Balradj ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Disease Burden ◽

Ankle Brachial Index ◽

Peripheral Artery ◽

Economic Burden Of Disease ◽

Surgical Interventions ◽

Treatment Practice ◽

Patient Profile ◽

Increased Risk ◽

Artery Disease

Patients with peripheral artery disease (PAD) have an increased risk of cardiovascular (CV) and limb events, but the disease is frequently underdiagnosed and treatment options are limited. This review examines the disease burden of symptomatic PAD as well as key guideline recommendations. Publications were identified using the ProQuest portal to access the Medline, Medline In-Process, and Embase databases. Search terms for symptomatic PAD were combined with terms relevant to epidemiology, burden, treatment practice, and physiopathology. Articles in English published between January 2001 and September 2016 were screened according to the population, interventions, comparator, outcomes, and study design criteria. Relevant publications (n = 200) were identified. The reported incidence and prevalence of PAD varied depending on the definitions used and the study populations. Patients generally had a poor prognosis, with an increased risk of mortality, CV, and limb events and decreased quality of life. Guideline recommendations included ankle–brachial index measurements, exercise testing, and angiography for diagnosis and risk factor modification, antiplatelets, cilostazol, exercise therapy, or surgical interventions for treatment, depending on the patient profile. The clinical, humanistic, and economic burden of disease in patients with symptomatic PAD is substantial and needs to be reduced through improved PAD management.

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Association between cholesterol efflux capacity and peripheral artery disease in coronary heart disease patients with and without type 2 diabetes: from the CORDIOPREV study

Cardiovascular Diabetology ◽

10.1186/s12933-021-01260-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Elena M. Yubero-Serrano ◽

Juan F. Alcalá-Diaz ◽

Francisco M. Gutierrez-Mariscal ◽

Antonio P. Arenas-de Larriva ◽

Patricia J. Peña-Orihuela ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Secondary Prevention ◽

Peripheral Artery Disease ◽

Cholesterol Efflux ◽

Newly Diagnosed ◽

Peripheral Artery ◽

Cholesterol Efflux Capacity ◽

Increased Risk ◽

Artery Disease

Abstract Background Peripheral artery disease (PAD) is recognized as a significant predictor of mortality and adverse cardiovascular outcomes in patients with coronary heart disease (CHD). In fact, coexisting PAD and CHD is strongly associated with a greater coronary event recurrence compared with either one of them alone. High-density lipoprotein (HDL)-mediated cholesterol efflux capacity (CEC) is found to be inversely associated with an increased risk of incident CHD. However, this association is not established in patients with PAD in the context of secondary prevention. In this sense, our main aim was to evaluate the association between CEC and PAD in patients with CHD and whether the concurrent presence of PAD and T2DM influences this association. Methods CHD patients (n = 1002) from the CORDIOPREV study were classified according to the presence or absence of PAD (ankle-brachial index, ABI ≤ 0.9 and ABI > 0.9 and < 1.4, respectively) and T2DM status. CEC was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma was performed. Results The presence of PAD determined low CEC in non-T2DM and newly-diagnosed T2DM patients. Coexisting PAD and newly-diagnosed T2DM provided and additive effect providing an impaired CEC compared to non-T2DM patients with PAD. In established T2DM patients, the presence of PAD did not determine differences in CEC, compared to those without PAD, which may be restored by glucose-lowering treatment. Conclusions Our findings suggest an inverse relationship between CEC and PAD in CHD patients. These results support the importance of identifying underlying mechanisms of PAD, in the context of secondary prevention, that provide potential therapeutic targets, that is the case of CEC, and establishing strategies to prevent or reduce the high risk of cardiovascular events of these patients. Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00924937. Unique Identifier: NCT00924937

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Guideline-Oriented Therapy of Lower Extremity Peripheral Artery Disease (PAD) – Current Data and Perspectives

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/a-0690-9365 ◽

2019 ◽

Vol 191 (04) ◽

pp. 311-322 ◽

Cited By ~ 3

Author(s):

Jonas Kersting ◽

Lars Kamper ◽

Marco Das ◽

Patrick Haage

Keyword(s):

Lower Extremity ◽

Peripheral Artery Disease ◽

Bypass Surgery ◽

Interdisciplinary Approach ◽

Current Data ◽

Arterial System ◽

Peripheral Artery ◽

Vascular Surgeon ◽

Technical Developments ◽

Artery Disease

Background Because of the demographic change, lower extremity peripheral artery disease (PAD) is becoming increasingly relevant with respect to health economics. PAD patients often suffer from multiple diseases. Consequently, therapy is commonly complex and requires an interdisciplinary approach. Because of rapid technical developments, interventional endovascular therapy regimens play an increasingly important role. Method Review and literature search on the basis of the current German S3 guidelines on the therapy of PAD as well as international guidelines. In terms of state-of-the-art therapies, relevant current studies were considered. Results Knowledge of existing guidelines and recommendations as well as new therapeutic approaches is essential for the adequate therapy of PAD patients. A close cooperation between the interventional radiologist and the vascular surgeon is the key to success. In addition to established conservative approaches and invasive bypass surgery, the endovascular approach has been a mainstay in the TASC A and B environment for years. It has recently shown promising results in advanced PAD conditions, such as TASC C and D. An endovascular-first strategy is defined in most guidelines. Conclusion A primarily endovascular-first strategy has become the standard in the majority of even complex lesions of the lower extremity arterial system. Regarding the crural segment, a decrease in mortality compared to bypass surgery has been demonstrated. Further evidence can be expected from ongoing randomized multicenter trials. Key Points: Citation Format

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Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study

10.1101/2020.08.23.20180240 ◽

2020 ◽

Author(s):

Michael G Levin ◽

Derek Klarin ◽

Venexia M Walker ◽

Dipender Gill ◽

Julie Lynch ◽

...

Keyword(s):

Blood Pressure ◽

Calcium Channel ◽

Peripheral Artery Disease ◽

Genetic Correlations ◽

Channel Blockers ◽

Peripheral Artery ◽

Antihypertensive Medications ◽

Increased Risk ◽

Genes Encoding ◽

Artery Disease

Aims: We aimed to estimate the effect of blood pressure and blood pressure lowering medications (via genetic proxies) on peripheral artery disease. Methods and Results: GWAS summary statistics were obtained for BP (International Consortium for Blood Pressure + UK Biobank GWAS; N = up to 757,601 individuals), peripheral artery disease (PAD; VA Million Veteran Program; N = 24,009 cases, 150,983 controls), and coronary artery disease (CAD; CARDIoGRAMplusC4D 1000 Genomes; N = 60,801 cases, 123,504 controls). Genetic correlations between systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and CAD and PAD were estimated using LD score regression. The strongest correlation was between SBP and CAD (rg = 0.36; p = 3.9 x 10-18). Causal effects were estimated by two-sample MR using a range of pleiotropy-robust methods. Increased SBP, DBP, and PP increased risk of both PAD (SBP OR 1.25 [1.19-1.31] per 10mmHg increase, p = 3 x 10-18; DBP OR 1.27 [1.17-1.39], p = 4 x 10-8; PP OR 1.51 [1.38-1.64], p = 1 x 10-20) and CAD (SBP OR 1.37 [1.29-1.45], p = 2 x 10-24; DBP OR 1.6 [1.45-1.76], p = 7 x 10-22; PP OR 1.56 [1.4-1.75], p = 1 x 10-15). The effects of SBP and DBP were greater for CAD than PAD (pdiff = 0.024 for SBP, pdiff = 4.9 x 10-4 for DBP). Increased liability to PAD increased PP (beta = 1.04 [0.62-1.45] mmHg per 1 unit increase in log-odds in liability to PAD, p = 1 x 10-6). MR was also used to estimate the effect of BP lowering through different classes of antihypertensive medications using genetic instruments containing BP-trait associated variants located within genes encoding protein targets of each medication. SBP lowering via calcium channel blocker-associated variants was protective of CAD (OR 0.38 per 10mmHg decrease in SBP; 95% CI 0.19-0.77; p = 0.007). Conclusions: Higher BP is likely to cause both PAD and CAD but may have a larger effect on CAD risk. BP-lowering through calcium-channel blockers (as proxied by genetic variants) decreased risk of CAD.

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Abstract 3073: Metabolic Syndrome, Inflammation and Risk of Symptomatic Peripheral Artery Disease in Women: A Prospective Study

Circulation ◽

10.1161/circ.118.suppl_18.s_809-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

David Conen ◽

Kathryn M Rexrode ◽

Paul M Ridker ◽

Aruna D Pradhan

Keyword(s):

Metabolic Syndrome ◽

Peripheral Artery Disease ◽

Cox Proportional Hazards ◽

Health Study ◽

Intercellular Adhesion Molecule ◽

Peripheral Artery ◽

Risk Increase ◽

Increased Risk ◽

Multivariable Models ◽

Artery Disease

Background Metabolic syndrome (MetS) includes a number of cardiovascular risk factors known to predict vascular disease. Little is known, however, about the interrelationships between MetS, inflammation and the risk of incident peripheral artery disease (PAD). Methods We conducted a prospective cohort study among 27111 women participating in the Women’s Health Study. Subjects were free of cardiovascular disease at baseline and followed for the incidence of symptomatic PAD (n=114) over a follow-up period of 13.3 years. We used Cox proportional-hazards models to compare the risk of PAD among women with and without the MetS. We also evaluated relationships between MetS and markers of subclinical inflammation including high sensitivity C-reactive protein (hsCRP) and soluble intercellular adhesion molecule-1 (sICAM-1) and adjusted for these biomarker levels in multivariable models. Results At study entry, 25.5% of participants had the MetS. Women with the MetS had a 62% increased risk of incident PAD (HR 1.62; 95% CI 1.10 –2.38). After multivariable adjustment, MetS remained significantly associated with incident PAD (Table ). Similar results were obtained when we assessed the risk of PAD according to the number of MetS defining traits (21% risk increase per additional trait) (Table ). Median plasma levels of hsCRP and sICAM-1 were 4.0 mg/L versus 1.53 mg/L (p<0.0001) and 374 ng/mL versus 333 ng/mL (p<0.0001) in women with and without MetS, respectively. From 0 to 5 MetS defining traits, median hsCRP levels gradually increased from 1.0 to 5.9 mg/L (p<0.0001) and median sICAM-1 levels increased from 321 to 413 ng/mL (p<0.0001). When hsCRP and sICAM-1 were added to multivariable models for incident PAD, risk estimates for the MetS were substantially attenuated and became non-significant (Table ). Conclusion Women with the MetS have an increased risk of incident PAD. This increased risk may be largely mediated by the effects of inflammation and/or endothelial activation. Metabolic Syndrome and Risk of PAD

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Abstract MP14: Proteinuria is Associated With a Greater Risk of Lower Limb Amputation in Patients With Peripheral Artery Disease

Circulation ◽

10.1161/circ.137.suppl_1.mp14 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Jung-Im Shin ◽

Morgan Grams ◽

Josef Coresh ◽

Alex Chang ◽

Kunihiro Matsushita

Keyword(s):

Peripheral Artery Disease ◽

Lower Limb ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Lower Limb Amputation ◽

Limb Amputation ◽

Antiplatelet Drug ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

Introduction: Proteinuria is shown to be associated with increased risk of peripheral artery disease (PAD). However, its association with the risk of lower limb amputation in patients with PAD is unknown. Hypothesis: We hypothesized that proteinuria is associated with the risk of amputation in patients with PAD in a graded fashion. Methods: We identified 3,388 PAD patients with data on urine dipstick proteinuria within two years prior to PAD diagnosis between 1997 and 2017 in the Geisinger Health System (mean age 69.7 years, 44.8% female, 97.4% non-Hispanic White, 57.8% diabetic). We quantified the association of proteinuria with the risk of amputation using Cox proportional hazards models, adjusting for demographics, calendar year, estimated glomerular filtration rate, HbA1c, comorbidities including diabetic retinopathy/neuropathy, and medication use (antiplatelet drug, statin, and renin-angiotensin system inhibitor). Results: There were 55.2% with negative dipstick proteinuria, 11.1% trace, 14.1% with 1+, and 19.5% with ≥2+. A total of 245 patients underwent amputations over a median follow-up of 3.4 years. Incidence rate of amputation was 1.15 per 100 person-years for dipstick negative, 1.47 for trace, 2.11 for 1+, and 3.78 for ≥2+. This dose-response relationship remained similar even after accounting for potential confounders (p-trend=0.015), with particularly evident association for ≥2+ of dipstick (an adjusted hazard ratio of 1.52 [95% confidence interval: 1.08-2.17, p=0.017) (Figure). When we added proteinuria to other covariates, the risk discrimination slightly improved (Δc-statistic 0.007 [0.001-0.014]). Conclusions: Higher proteinuria was associated with a greater risk of lower limb amputation among patients with newly diagnosed PAD. Our results suggest the importance of considering proteinuria in risk assessment of limb loss in PAD patients.

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P1234SNF472 IMPROVES LIMB BLOOD PERFUSION AND WALKING ABILITY IN A PERIPHERAL ARTERY DISEASE VASCULAR CALCIFICATION RAT MODEL

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa144.p1234 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Firas Bassissi ◽

Miguel David Ferrer Reynes ◽

M Mar Pérez ◽

Joan Perelló ◽

Carolina Salcedo

Keyword(s):

Peripheral Artery Disease ◽

Vascular Calcification ◽

Rat Model ◽

Blood Perfusion ◽

Walking Distance ◽

Arterial Calcification ◽

Walking Ability ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p< 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p<0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.

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Burden of hospitalization in clinically diagnosed peripheral artery disease: A community-based study

Vascular Medicine ◽

10.1177/1358863x17736152 ◽

2017 ◽

Vol 23 (1) ◽

pp. 23-31 ◽

Cited By ~ 5

Author(s):

Adelaide M Arruda-Olson ◽

Homam Moussa Pacha ◽

Naveed Afzal ◽

Sara Abram ◽

Bradley R Lewis ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Ankle Brachial Index ◽

Inception Cohort ◽

Peripheral Artery ◽

Community Based ◽

Increased Risk ◽

Artery Disease ◽

Recurrent Hospitalization ◽

Over Time

The burden and predictors of hospitalization over time in community-based patients with peripheral artery disease (PAD) have not been established. This study evaluates the frequency, reasons and predictors of hospitalization over time in community-based patients with PAD. We assembled an inception cohort of 1798 PAD cases from Olmsted County, MN, USA (mean age 71.2 years, 44% female) from 1 January 1998 through 31 December 2011 who were followed until 2014. Two age- and sex-matched controls ( n = 3596) were identified for each case. ICD-9 codes were used to ascertain the primary reasons for hospitalization. Patients were censored at death or last follow-up. The most frequent reasons for hospitalization were non-cardiovascular: 68% of 8706 hospitalizations in cases and 78% of 8005 hospitalizations in controls. A total of 1533 (85%) cases and 2286 (64%) controls ( p < 0.001) were hospitalized at least once; 1262 (70%) cases and 1588 (44%) controls ( p < 0.001) ≥ two times. In adjusted models, age, prior hospitalization and comorbid conditions were independently associated with increased risk of recurrent hospitalizations in both groups. In cases, severe PAD (ankle–brachial index < 0.5) (HR: 1.25; 95% CI: 1.15, 1.36) and poorly compressible arteries (HR: 1.26; 95% CI: 1.16, 1.38) were each associated with increased risk for recurrent hospitalization. We demonstrate an increased rate of hospitalization in community-based patients with PAD and identify predictors of recurrent hospitalizations. These observations may inform strategies to reduce the burden of hospitalization of PAD patients.

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