Paulina Elena Stürzebecher

Background: In Peripheral Artery Disease (PAD), there is an association between risk factors, the location of atherosclerotic lesions, and outcomes. Methods: This is a retrospective single-center analysis of adult PAD patients admitted between 2018 and 2021 with a follow-up until the end of 2023. Lesions were allocated to “suprainguinal”, “infrainguinal-to-popliteal”, “infrapopliteal”, “two of three levels” and “all three levels” categories based on angiogram findings. The primary endpoint at the patient level was amputation-free survival and was major adverse limb events (MALEs) at the limb level. Results: A total of 2067 patients with 2633 affected limbs were analyzed, and 28.8% were female. At first admission, the median age was 68, and the most frequent PAD Fontaine stage was IIb (44.9%). Lesions were suprainguinal in 11.6%, infrainguinal-to-popliteal in 18.3%, infrapopliteal in 11.4%, two levels in 36.0%, and all three levels in 8.3%. Over 1020 days as the median follow-up, amputation-free survival was 67.6%, highest (92.5%) for suprainguinal lesions, and lowest (59.3%) for infrapopliteal lesions. At the patient level, the risk of major amputation or death was highest in infrapopliteal lesions and was equally likely in cases of two or three affected locations and was reduced in infrainguinal-to-popliteal lesions (Hazard Ratio, HR 0.62, 95% CI 0.44–0.87, p = 0.007) and suprainguinal lesions (HR 0.42, 95% CI 0.21–0.79, p = 0.008). At the limb level, compared to lesions in all three locations, the risk of MALEs was reduced in infrainguinal-to-popliteal lesions (HR 0.51, 95% CI 0.27–0.98, p = 0.044) and was equally likely in all other cases. Conclusions: Amputation-free survival was lowest in cases of infrapopliteal lesions or multi-level disease. At the limb level, isolated infrainguinal-to-popliteal lesions were associated with the lowest risk of MALEs.

Background: Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI. Methods: 756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1–4 follow ups, ~1 year apart). Results: The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0–28.3). Lp(a) concentrations between 30–50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements. Conclusions: The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD. Impact: In youth, Lp(a) levels are not affected by age, sex and BMI. Lp(a) risk categories remain stable over time in repeated measurements in children. Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening.

Zusammenfassung: Einleitung Die ESC/EAS-Leitlinien von 2019 zum Dyslipidämie-Management empfehlen LDL-Cholesterin (LDL-C) Zielwerte gemäß dem kardiovaskulären (CV) Risiko des Patienten. SANTORINI untersucht als erste große europäische Beobachtungsstudie seit Einführung der Leitlinien 2019, ob sich das Lipidmanagement von Patienten mit hohem und sehr hohem CV Risiko verbessert hat. Methoden SANTORINI ist eine multinationale Registerstudie an 9602 Patienten ≥ 18 Jahre mit hohem und sehr hohem CV Risiko, die eine lipidsenkende Therapie benötigen. Primäres Ziel der Studie ist die Dokumentation der Effektivität aktueller Behandlungsstrategien zum LDL-C-Management in der täglichen Praxis. Ergebnisse Für diese Analyse lagen vollständige Baselinedaten für 2086 Patienten in Deutschland und 6958 Patienten in Europa vor. Die CV Risikoklassifizierung durch die Behandler erfolgte bei > 50 % der Patienten auf Basis der ESC/EAS-Leitlinien von 2019 und ergab ein hohes CV Risiko für 15,6 % (173/1112) bzw. ein sehr hohes CV Risiko für 84,4 % (939/1112) der Patienten in Deutschland (Europa: 20,7 % [743/3594] hohes, 79,3 % [2851/3594] sehr hohes CV Risiko). Eine unabhängige Nachberechnung, basierend auf diesen Guidelines, ergab dagegen ein hohes bzw. sehr hohes CV Risiko für 4,1 % (46/1112) bzw. 94,5 % (1051/1112) der Patienten in Deutschland. Auch im europäischen Vergleich wurde das CV Risiko in ca. 10 % der Fälle unterschätzt.Zu Studienbeginn erhielten 59,5 % (1241/2086) der Patienten in Deutschland und 52,6 % (3661/6958) der Patienten in Europa eine lipidsenkende Monotherapie und 19,9 % (416/2086, Deutschland) bzw. 25,2 % (1753/6958, Europa) eine Kombinationstherapie. 78,6 % (1640/2086) der Patienten in Deutschland verfehlten die in den ESC/EAS-Leitlinien empfohlenen LDL-C-Zielwerte (Europa: 71,7 % [4989/6958]). Fazit Die ESC/EAS Leitlinien-Empfehlungen von 2019 werden nur bei einer Minderheit der Patienten umgesetzt. Die Studie identifiziert Chancen zur Verbesserung der Prävention von CV Erkrankungen in Deutschland.

Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2–induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr ^−/− ; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 ( GDF15 ). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15 .