Remote ischemic conditioning fails to protect against ischemia-reperfusion injury in patients with untreated familial hypercholesterolemia
Authors: Kovamees O , Mahdi A , Wodaje T , Verouhis D , Brinck J , Pernow J 
Published: October 2021

Abstract

Background/Introduction
Remote ischemic conditioning (RIC) is the action of brief periods of ischemia to a remote tissue and has been suggested to protect against myocardial ischemia-reperfusion (IR) injury. The outcomes of clinical trials in terms of clinical endpoints and infarct size reduction have been variable, which may be related to influence of comorbidities on the effect of RIC. Animal studies suggest that hypercholesterolemia attenuates the cardioprotective effect of RIC, but no data from study on patients are available. Hence, our aim was to investigate the response of RIC on IR-induced endothelial dysfunction in patients with familial hypercholesterolemia (FH).

Purpose
To investigate if RIC protects against endothelial dysfunction induced by IR in patients with FH with high (≥5.5 mmol/L) and low (≤2.5 mmol/L) LDL-cholesterol levels.

Methods
All subjects with FH (n=12) with LDL ≥5.5 mmol/L, FH with LDL &lt;2.5 mmol/L (n=12), and age-matched healthy control subjects (n=12) participated in two protocols separated by at least one week. In both protocols, endothelium-dependent vasodilatation was assessed by determination of flow-mediated vasodilatation (FMD) of the brachial artery at baseline and again after 20 minutes of forearm ischemia and 20 minutes of reperfusion. Forearm ischemia was induced by inflating a blood pressure cuff on the upper arm to 200 mmHg. An additional inflatable cuff was placed around the left thigh. In one protocol (IR+sham), this cuff was left uninflated. In the second protocol (IR+RIC), it was inflated to 200 mmHg in four cycles of 5 minutes inflation and 5 min deflation with the first cycle starting at the onset of forearm ischemia.

Results
Plasma mean LDL-cholesterol was significantly higher in the FH group with high LDL (6.6±1.4 mmol/L) compared to the control group (2.4±0.7 mmol/L; p&lt;0.01) and the low LDL FH group (2.0±0.6 mmol/L; p&lt;0.001). FMD was markedly reduced (p&lt;0.05) in all subjects following IR+sham, indicating IR-induced endothelial dysfunction in all three groups. As expected, RIC prevented the reduction in FMD after IR in the control group (Fig 1). By contrast, in the FH group with high LDL, RIC failed to protect from IR-induced endothelial dysfunction. Thus, in this group the decrease in FMD was similar after IR+RIC and IR+ sham (Fig 1). In the FH group with LDL &lt;2.5 mmol/L, the decrease in FMD induced by IR was attenuated by RIC (p=0.05).

Conclusion
These observations suggest that RIC, which protects from IR-induced endothelial dysfunction in healthy controls, fails to protect from IR-induced endothelial dysfunction in patients with FH and LDL-cholesterol &gt;5.5 mmol/L. The protective effect of RIC is restored after treatment of hypercholesterolemia. This finding may have bearings on the clinical efficacy of RIC in patients with ST-elevation myocardial infarction.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Heart-lung foundation