Background: Large networks of interstitial glycosaminoglycans help to regulate water and electrolyte homeostasis. The relation between dermal interstitial alterations and occurrence of edema in heart failure patients with reduced ejection fraction (HFrEF) is unknown. We hypothesize that in HFrEF patients (1) interstitial glycosaminoglycan density is increased, (2) changes in the interstitial glycosaminoglycan network are associated with interstitial fluid accumulation, and (3) there is a link between the interstitial glycosaminoglycan network and the renin-angiotensin-aldosterone system.

Methods and Results: Two punch biopsies of the skin were obtained in healthy subjects (n=18) and HFrEF patients (n=29). Alcian blue staining and immunostaining for the angiotensin II type 1 receptor was performed. After obtaining tissue water content, total interstitial glycosaminoglycan (uronic acid) and sulfated glycosaminoglycan were quantified. A venous blood sample, clinical examination, and echocardiography were obtained. A significantly higher interstitial glycosaminoglycan content was observed in HFrEF patients compared with healthy subjects (uronic acid: 13.0±4.2 versus 9.6±1.6 μg/mg; P=0.002; sulfated glycosaminoglycan: 14.1 [11.7; 18.1] versus 10.0 [9.1; 10.8] μg/mg; P<0.001). Uronic acid and sulfated glycosaminoglycan density were strongly associated with tissue water content and peripheral edema (uronic acid: ρ=0.66; P<0.0001 and sulfated glycosaminoglycan: τ=0.58; P<0.0001). Expression of the angiotensin II type 1 receptor was found on dermal cells, although use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker was associated with significantly lower levels of interstitial glycosaminoglycans in HFrEF patients.

Conclusions: Interstitial glycosaminoglycan concentration is significantly increased in HFrEF patients compared with healthy subjects and correlated with tissue water content and clinical signs of volume overload. A better appreciation of the interstitial compartment might improve management of volume overload in HF.

背景：大量的间质糖胺聚糖网络有助于调节水和电解质的体内平衡。射血分数降低（HFrEF）的心力衰竭患者的皮肤间质改变与水肿发生之间的关系尚不清楚。我们假设在HFrEF患者中（1）间质糖胺聚糖密度增加，（2）间质糖胺聚糖网络的变化与间质液积聚有关，（3）间质糖胺聚糖网络与肾素-血管紧张素-醛固酮系统。

方法和结果：在健康受试者（n = 18）和HFrEF患者（n = 29）中进行了两次皮肤活检。进行了阿尔辛蓝染色和血管紧张素II 1型受体的免疫染色。获得组织含水量后，定量组织间总糖胺聚糖（糖醛酸）和硫酸化糖胺聚糖。获得静脉血样本，临床检查和超声心动图。与健康受试者相比，HFrEF患者的间质糖胺聚糖含量明显更高（尿酸：13.0±4.2对9.6±1.6μg/ mg；P = 0.002；硫酸化糖胺聚糖：14.1 [11.7; 18.1]对10.0 [9.1; 10.8]微克/毫克;磷<0.001）。糖醛酸和硫酸化糖胺聚糖的密度与组织含水量和周围水肿密切相关（糖醛酸：ρ= 0.66；P <0.0001；硫酸盐化糖胺聚糖：τ= 0.58；P <0.0001）。在真皮细胞上发现了血管紧张素II 1型受体的表达，尽管在HFrEF患者中使用血管紧张素转化酶抑制剂/血管紧张素受体阻滞剂与间质糖胺聚糖水平明显降低有关。

结论：与健康受试者相比，HFrEF患者的间质糖胺聚糖浓度显着增加，并且与组织含水量和容量超负荷的临床体征相关。更好地了解间质隔室可能会改善HF容量超负荷的管理。