Objective Giant cell arteritis (GCA) is the most common systemic vasculitis in individuals aged ≥50 years. Its course is marked by a high relapse rate requiring long-term glucocorticoid use with its inherent adverse effects. We aimed to identify factors associated with relapses or recurrences in GCA at diagnosis. Methods We reviewed the medical records of consecutive patients with GCA diagnosed between 2009 and 2019 and followed for at least 12 months. We recorded their characteristics at onset and during follow-up. Factors associated with relapses or recurrences were identified using multivariable analysis. Results We included 153 patients, among whom 68% were female with a median age of 73 (47–98) years and a median follow-up of 32 (12–142) months. Seventy-four patients (48.4%) had at least 1 relapse or recurrence. Headache and polymyalgia rheumatica were the most frequent manifestations of relapses. The first relapse occurred at a median time of 13 months after the diagnosis, with a median dose of 5.5 (0–25) mg/d of glucocorticoids. In multivariable analysis, patients with relapses or recurrences had a higher frequency of cough and scalp tenderness at diagnosis (20.3% vs 5.1%; odds ratio [OR], 4.73; 95% confidence interval [CI], 1.25–17.94; p = 0.022; and 41.9% vs 29.1%; OR, 2.4; 95% CI, 1.07–5.39; p = 0.034, respectively). Patients with diabetes mellitus at diagnosis had fewer relapses or recurrences during follow-up (5.4% vs 19%; OR, 0.24; 95% CI, 0.07–0.83; p = 0.024). Conclusions Cough and scalp tenderness at diagnosis were associated with relapses or recurrences, whereas patients with diabetes experienced fewer relapses or recurrences.

Background Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

Objective Giant cell arteritis (GCA) is the most frequent vasculitis affecting adults aged > 50 years. Cardiac involvement in GCA is considered rare, and only a few cases of pericarditis have been reported. The aim of this study was to determine the characteristics and prognosis of GCA patients suffering from pericardial involvement at diagnosis. Methods We conducted a single-centre, retrospective chart review of patients with GCA in internal medicine departments (from 2000 to 2020). Patients were identified through a centralized hospital database. We retrospectively collected demographic, clinicobiological, histological, imaging, treatment and outcome data. Patients with pericardial effusion, defined as an effusion visible on the CT-scan performed at GCA diagnosis were compared to those without pericardial involvement. Results Among the 250 patients with GCA, 23 patients (9.2%) had pericardial effusion on CT-scan. The comparison between the groups revealed similar distribution of age, gender, cranial symptoms and ocular ischaemic complications. Patients with pericardial effusion had a higher frequency of weight loss. They also had lower haemoglobin levels and higher platelet levels (p = 0.006 and p = 0.002, respectively), and they more frequently had positive temporal artery biopsy. There were no differences concerning the treatment, relapses, follow-up duration or deaths. Conclusions This case series sheds light on GCA as a cause of unexplained pericardial effusion or symptomatic pericarditis among adults aged > 50 years and elevated inflammatory biological markers. Fortunately, pericardial involvement is a benign GCA manifestation. In that context, the search for constitutional symptoms, cranial symptoms and associated signs of polymyalgia rheumatica is crucial for rapidly guiding GCA diagnosis.

In France, the Omicron variant (Pango lineage B.1.1.529) accounted for 99.3% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnoses at the country level in the last survey conducted on February 18 2022, with the BA.2 variant (B.1.1.529.2) accounting for 10.7% of cases which was a 2.4-fold increase as compared to the previous week.1 The Omicron BA.2 variant has spread in other European countries and became predominant in Denmark.2 The objective of this study is to describe the first 207 Omicron BA.2 cases diagnosed at the Institut Hospitalo-Universitaire Méditerranée Infection located in Marseille, France, which manages the vast majority of patients in the area, and to provide early information on its severity, in comparison with that of the Omicron BA.1 variant (B.1.1.529.1). All available SARS-CoV-2 positive results obtained by our laboratory between December 27, 2021 (the date of the first identification of an Omicron BA.2 case) and February 14, 2022 led to genotyping using real-time reverse transcription-quantitative polymerase chain reaction (qPCR) and next-generation genome sequencing (NGS). Briefly, qPCR assays specific to variants included detection of spike mutations L452R, K417N, E484K, and/or P681H (Thermo Fisher Scientific), combined with the targeting of viral genes ORF1, N (nucleocapsid), and S (spike) with the TaqPath COVID-19 assay (Thermo Fisher Scientific). NGS used the Illumina CovidSeq or Artic combined with Oxford Nanopore Technologies procedures and genome assembly and analyses were done as previously described.3 SARS-CoV-2 genome sequences have been deposited in the GISAID database (https://www.gisaid.org/).4 Demographics and clinical data were retrospectively obtained from electronic medical files and anonymized before analysis. Hospitalization, transfer to intensive care unit (ICU), and death rate were used for severity assessment. In case a patient had several conditions (being hospitalized, transferred later to ICU, and then dying), conditions were not mutually exclusive. Records with missing information on severity were excluded. This study project was validated by the ethics committee of the Méditerranée Infection Institute under reference 2022-001. Access to the patients' biological and registry data issued from the hospital information system was approved by the data protection committee of Assistance Publique-Hôpitaux de Marseille (AP-HM) and was recorded in the European General Data Protection Regulation Registry under number RGPD/AP-HM 2019-73. As of February 14, 2022, 207 cases of the SARS-CoV-2 Omicron BA.2 variant were included and compared to 2793 cases of the SARS-CoV-2 Omicron BA.1 variant diagnosed during the same timeframe. Vaccination status against COVID-19 was available for 1573 patients (52.4%) infected with an Omicron variant, of whom 96.6% were vaccinated. The majority of vaccinated patients (89.8%) received at least two doses of vaccine and 12.9% of infections occurred during the first 21 days following the last dose. (Table 1). The median age of patients infected with Omicron BA.1 was 36 years and 55.8% were females. Their hospitalization rate was low (1.4%), only 3 patients (0.1%) were transferred to ICU and 10 (0.4%) died. Eight patients who died were older than 65 years old with comorbidities including cancer, chronic respiratory diseases, and diabetes. The two others suffered from leukemia and asthma. Five were unvaccinated, one patient received one dose of vaccine, one received two doses, and three received three doses. This pattern is consistent with that of the 1119 first patients diagnosed with the Omicron BA.1 variant between November 28 and December 31, 2021, at our institute.5 The proportion of patients aged 65 years and more was higher in patients infected with Omicron BA.2 as compared to those infected with Omicron BA.1. Patients infected with the Omicron BA.2 variant were significantly more likely to be hospitalized (6.3%, p < 10−2) (Table 1). None was transferred to ICU and three (1.5%) died. The three patients who died were aged 80, 97, and 99 years and two suffered from diabetes. Two (aged 80 and 97 years old) were vaccinated against COVID-19 (three doses). The median age of patients who died with Omicron BA.2 infection (97 years old, 100% ≥80 years old) was significantly higher than that of those who died with Omicron BA.1 infection (72.5 years, 30% ≥80 years old) (Table 2). In multivariate analysis, independent risk factors for hospitalization were older age and infection with the BA.2 variant while only older age was associated with death risk (Tables S1 and S2). Our study has some limitations including its small number of patients and a lack of documentation of vaccination status in 47.6% of patients. Notwithstanding, severe infections with Omicron BA.2 were only observed in patients ≥80 years old. Given its increased transmissibility suggested by the UK and Danish data,6, 7 its close monitoring will be required in the near future. Philippe Gautret analyzed and wrote the first draft, Van T. Hoang performed the statistical analysis, Pierre E. Fournier and Philippe Colson provided virological data, and Marie T. Jimeno, Jean-Christophe Lagier, and Pascal Rossi provided clinical data. Didier Raoult supervised the work. All authors contributed significantly to this manuscript. All authors reviewed and approved the final submission. The authors would like to thank Prof. Gilles Kaplanski for his help with patient data. Didier Raoult has a conflict of interest, having been a consultant for Hitachi High-Technologies Corporation, Tokyo, Japan, from 2018 to 2020. He is a scientific board member of Eurofins company and a founder of a microbial culture company (Culture Top). Other authors declare no conflicts of interest. The data that supports the findings of this study are available in the supplementary material of this article. Data are available on request to the corresponding author. The data that supports the findings of this study are available in the supplementary material of this article. Data are available on request to the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.

Background Prognosis of herpetic encephalitis remains severe, with a high proportion of deaths and sequelae. Its treatment is based on acyclovir, but the precise and most effective modalities of this treatment are not established. The objective of this study was to determine them. Methods For this, we carried out a descriptive, retrospective, monocentric study, using the current coding database at Marseille University Hospitals. Cohort was intended to be exhaustive for the disease, from January 2000 to June 2019, including patients hospitalized in intensive care and conventional hospitalization sector. Patients (n = 76) included were at least 16 years of age and had a clinical presentation, cerebral Magnetic Resonance Imaging, and/or electroencephalogram abnormalities consistent with herpetic encephalitis confirmed by a positive HSV-PCR in the CSF. Clinical data and treatment, including the doses actually administered to the patient, were compared according to patient's outcome. Results The mortality rate was 12%, whereas 49% had complete recovery and 39% sequelae impeding independence. Poor outcome was statistically associated with persistence of confusion, aphasia, and impaired consciousness lasting more than 5 days, superinfection, status epilepticus, and length of stay in intensive care unit. A statistical decision tree, constructed using the Classification And Regression Tree model, to prioritize treatment management, showed two main factors that influence the outcome: the patient's weight, and the average daily acyclovir dose actually administered. Conclusion These results suggest to modify acyclovir management in herpetic encephalitis, for low-weight patients (< 79 kg) with a minimum dosage of 2550 mg/day (850 mg/ 8 h), when possible.

BACKGROUND:The detection of additional autoantibodies is of great concern in systemic sclerosis (SSc) when those included in the ACR/EULAR classification are negative. In this context, the interest of antifibrillarin (anti-U3RNP) autoantibodies (AFAs) in the routine evaluation of SSc remains unclear. We aimed to assess the relevance of AFAs and their clinical association in SSc patients.METHODS:In a multicenter observational retrospective study, we collected immunological and clinical data associated with AFA positivity in SSc (n = 42) and non-SSc patients (n = 13). Patients with SSc negative for AFAs (n = 83) were considered as a control group. AFAs were detected by indirect immunofluorescence (IIF) using HEp-2 cells, EliA or immunoblot techniques.RESULTS:We confirmed a typical nuclear IIF pattern and showed that AFAs are mostly exclusive towards SSc conventional autoantibodies. Although also observed in non-SSc patients, high levels of AFAs with the ELiA technique allowed the diagnosis of SSc. Compared to AFA-negative SSc patients, AFA-positive SSc patients more frequently exhibited visceral involvements. They more frequently suffered from the diffuse cutaneous form and had a higher global severity of the disease.CONCLUSIONS:We demonstrate the usefulness of quantifying AFAs in the immunological exploration of SSc, especially when patients are seronegative for SSc conventional autoantibodies and display a typical IIF pattern. AFAs might constitute an interesting marker of SSc severity.

Adverses pregnancy outcomes are commonly encountered with autoimmune disease (AID). Although antinuclear antibodies (ANA) are often present several years before AID diagnosis, the importance of ANA testing has not been evaluated in this context. The objective of this study was to determine if ANA discovery after obstetrical complications is associated with a diagnosis of AID and improves the prognosis of subsequent pregnancies. All patients presented at the multidisciplinary board meeting (MBM) "Thrombophilia and Pregnancy", whose ANA were discovered after an obstetrical complication, were included in a multicenter descriptive study. All patients were referred to an internal medicine consultation for diagnosis. Data were collected retrospectively by computer chart analysis and updated by phone. A total of 404 patients were included, of which 50 (12.4 %) had a diagnosis of AID related to ANA. Patients with AID had higher ANA levels (p < 0.001), with more frequent specificity (26%, versus 6.7%, p < 0.0001), and more often persistent (84% versus 30.8%, p < 0.0001) compared to patients without AID. Subsequent pregnancy outcomes were not significantly affected by ANA levels and AID diagnoses. Our study shows that the discovery of ANA after obstetrical complications may lead to an early diagnosis of AID. It makes us reconsider the systematic determination of ANA after an obstetrical event because in the case where ANA are found positive, an adapted follow-up would reduce the negative impact of ANA presence on subsequent pregnancies.

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Objective: Systemic sclerosis mainly affects the microvascular network. However, macrovascular manifestations have been reported. We aimed to investigate the characteristics of systemic sclerosis patients with an amputation of a lower limb segment. Methods: We designed a retrospective, case-control, multicentric study on systemic sclerosis patients with amputation of a lower limb segment secondary to critical ischemia via the French Research Group on Systemic Sclerosis. For each case, a control (systemic sclerosis patient without lower limb symptom) was matched with sex, age (+/- 5 years), and cutaneous subset of systemic sclerosis. Results: In total, 26 systemic sclerosis patients (mean age of 67.2 +/- 10.9 years, 20 females, 21 limited cutaneous forms) with a lower limb amputation and 26 matched controls (mean age of 67.3 +/- 11.2 years, 20 females, 22 limited cutaneous forms) were included. At the time of amputation, the mean disease duration was 12.8 (+/- 8.6) years. In comparison to controls, systemic sclerosis patients with amputation had more digital ulcers (p = 0.048), history of digital ulcers (p = 0.026), and a higher prevalence of pulmonary arterial hypertension (p = 0.024). Systemic sclerosis patients with amputation were more often smokers (p = 0.008) and under corticosteroids (p = 0.015). In the multivariate model, pulmonary arterial hypertension, smoking status, and corticosteroids were independent markers associated with lower limb amputation in systemic sclerosis. In the follow-up, 10 patients (38.5%) had recurrent ischemia requiring a new limb amputation, and five patients (19.2%) had an amputation of the contralateral limb. Conclusion: This study identifies some markers associated with lower limb amputation in systemic sclerosis such as digital ulcers and pulmonary arterial hypertension and points out the high risk associated with tobacco consumption and corticosteroid use.

The role of serum uric acid in coronary artery disease has been extensively investigated. It was suggested that serum uric acid level (SUA) is an independent predictor of endothelial dysfunction and related to coronary artery lesions. However, the relationship between SUA and severity of coronary atherosclerosis evaluated via endothelial dysfunction using peripheral arterial tone (PAT) and the reactive hyperhemia index (RHI) has not been investigated during a first episode of acute coronary syndrome (ACS). The aim of our study was to address this point. We prospectively enrolled 80 patients with a first episode of ACS in a single-center observational study. All patients underwent coronary angiography, evaluation of endothelial function via the RHI, and SUA measurement. The severity of the coronary artery lesion was assessed angiographically, and patients were classified in three groups based on the extent of disease and Gensini and SYNTAX scores. Endothelial function was considered abnormal if RHI < 1.67. We identified a linear correlation between SUA and RHI (R 2 = 0.66 P < 0.001). In multivariable analyses, SUA remained associated with RHI, even after adjustment for traditional cardiovascular risk factors and renal function. SUA was associated with severity of coronary artery disease. SUA is associated with severity of coronary atherosclerosis in patients with asymptomatic hyperuricemia. This inexpensive, readily measured biological parameter may be useful to monitor ACS patients.

Background: The relation between telomere dynamics and obesity remains unclear. Cross-sectional studies found associations between short leukocyte telomere length (LTL) and high body mass index (BMI) but longitudinal studies did not find any association between LTL attrition and BMI. In two parallel studies, we aimed to assess the relationship between obesity and telomere dynamics in different tissues. Methods: Study 1: Measurements of LTL and TL in skeletal muscle (MTL) were performed in 53 subjects with severe obesity (BMI > 35) and in 53 age- and sex-matched without obesity (21 < BMI < 30). MTL is a proxy of TL at birth and the LTL/MTL ratio represents life-long telomere attrition. Study 2: Measurements of TL in subcutaneous fat (SCF), a high proliferative adipose tissue, and visceral fat (VF), a low proliferative one in 50 severe obese bariatric patients. TL measurements were performed by Southern blot. Results: Study 1: In younger (<55 years), but not in older, LTL and LTL/MTL were shorter in obese patients vs controls (7.16 kb vs 7.54 kb, p < 0.05 for LTL and 81% vs 84%, p < 0.05 for LTL/MTL). Study 2: Within obese bariatric patients, SCF/VF TL ratio was lower in those with early onset obesity (96% for obesity since childhood vs 97% since adolescence vs 100% for adult development of obesity; p < 0.05). Conclusions: Early life obesity is associated with higher TL attrition leading to shorter TL in high proliferative tissues.

The pathophysiology of systemic sclerosis (SSc) involves early endothelial and immune activation, both preceding the onset of fibrosis. We previously identified soluble fractalkine and circulating endothelial microparticles (EMPs) as biomarkers of endothelial inflammatory activation in SSc. Fractalkine plays a dual role as a membrane-bound adhesion molecule expressed in inflamed endothelial cells (ECs) and as a chemokine involved in the recruitment, transmigration, and cytotoxic activation of immune cells that express CX3CR1, the receptor of fractalkine, namely CD8 and gamma delta T cells and natural killer (NK) cells. We aimed to quantify circulating cytotoxic immune cells and their expression of CX3CR1. We further investigated the expression profile of NK cells chemokine receptors and activation markers and the potential of NK cells to induce EC activation in SSc. We performed a monocentric study (NCT 02636127) enrolling 15 SSc patients [15 females, median age of 55 years (39-63), 11 limited cutaneous form and 4 diffuse] and 15 healthy controls. Serum fractalkine levels were significantly increased in SSc patients. Circulating CD8 T cells numbers were decreased in SSc patients with no difference in their CX3CR1 expression. Circulating gamma delta T cells and NK cells numbers were preserved. CX3CR1 expression in CD8 and gamma delta T cells did not differ between SSc patients and controls. The percentage and level of CX3CR1 expression in NK cells were significantly lowered in SSc patients. Percentages of CXCR4, NKG2D, CD69-expressing NK cells, and their expression levels were decreased in NK cells. Conversely, CD16 level expression and percentages of CD16(+) NK cells were preserved. The exposure of human microvascular dermic EC line (HMVEC-d) to peripheral blood mononuclear cells resulted in similar NK cells degranulation activity in SSc patients and controls. We further showed that NK cells purified from the blood of SSc patients induced enhanced release of EMPs than NK cells from controls. This study evidenced a peculiar NK cells phenotype in SSc characterized by decreased chemokine and activation receptors expression, that might reflect NK cells involvement in the pathogenic process. It also highlighted the role of NK cells as a potent mechanism inducing endothelial activation through enhanced EMPs release.

We aimed to assess the clinical significance of Krebs von den Lungen-6 (KL-6) in the diagnosis and severity of interstitial lung disease (ILD) in a French cohort of patients with systemic sclerosis (SSc).

Background: The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity.Methods: We conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34(+) progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses.Results: Enhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34(+)CD45(-) endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34(+)CD45(-) EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34(+)CD45(-) EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion.Conclusions: This study identifies the mobilisation of CD34(+)CD45(-) EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.

Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue. Objective: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD. Methods and Results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTL A ) was longer than LTL and the LTL-MTL A gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL ( P =0.005), but not MTL A ( P =0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTL A ) was wider ( P =0.0003), and the TL ratio between leukocytes and muscle (LTL/MTL A ) was smaller ( P =0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals. Conclusions: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02176941.

Objective: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ACVD). It is unknown whether this relationship is due to a shorter leukocyte TL (LTL) at birth or, alternatively, to a faster LTL attrition thereafter, before or during ACVD manifestation. To assess the temporal relation of LTL with ACVD, we draw on the following findings: wide LTL variation exists across individuals, but at birth TLs are similar across the individual's somatic tissues. After birth, TL attrition varies in proportion to the replicative activities of tissues. Consequently, skeletal muscle (M), a minimally proliferative tissue, displays a longer TL than LTL, which represents the highly proliferative hematopoietic system. Accordingly, the difference between LTL and MTL and the ratio of (LTL-MTL)/MTL provides additional information on LTL attrition since early life. Design and method: We studied 271 individuals (82 women/189 men) aged 63 ± 14 years (mean ± SD), undergoing surgery. Their TL in leukocytes and in muscle biopsies (obtained during surgery) was measured by Southern blots. We tested the following variables for association with ACVD: LTL, MTL adjusted for muscle biopsy site (MTLA), LTL-MTLA and (LTL-MTLA)/ MTLA. Results: In all subjects, MTLA was longer than LTL and LTL-MTLA difference became wider with age similarly in ACVD patients (15.9 ± 0.5 bp/year; mean ± SE) and controls (14.4 ± 0.3 bp/year). Age- and sex-adjusted LTL (P = 0.005), but not MTLA (P = 0.68), was shorter in patients with ACVD than controls. LTL-MTLA (−272 ± 73 bp) and (LTL-MTLA)/MTLA (−3.2 ± 0.8%) were wider in ACVD than in controls (P = 0.0003 and 0.0001, respectively). Both composite variables that combined LTL and MTL yielded better fitting models than either LTL or MTLA by themselves, and (LTL-MTLA)/MTLA explained ACVD slightly better than LTL-MTLA. Conclusions: This first study applying the “blood-and-muscle” TL model in patients with ACVD shows more pronounced TL attrition in ACVD patients than controls. The difference in attrition rates was not modified by age during adulthood indicating that accelerated attrition in early life is likely to be a major explanation of the shorter LTL in ACVD patients.