Introduction:
Cardiac resynchronization therapy (CRT) is an effective treatment for patients with advanced heart failure (HF). The management of these patients depends on biomarkers for monitoring disease progression and therapeutic response. HF patients exhibit a pathologic remodeling of Ryanodine Receptors (RyRs) in heart, muscle, as well as circulating lymphocytes, leading to intracellular calcium leak, which has been shown to correlate with the clinical outcome.
Hypotheses:
1) post-translational modifications of RyR in circulating lymphocytes in HF patients can predict CRT response; 2) CRT can improve the remodeling of RyRs and intracellular calcium leak.
Methods:
To test this hypothesis, we enrolled 34 patients who underwent CRT and examined RyR remodeling in peripheral lymphocytes before and 1 year after CRT using established biochemical and flow-cytometry assays. Non-responders to CRT were defined after 1 year of follow-up as patients with at least one of the following characteristics: deteriorating function (HF-related death, need for heart transplantation), increase in LVEF ≤ 4%, worsening in peak O
2
consumption, in Quality-of-Life score, or in the distance walked in 6 min.
Results:
We found that post-translational remodeling of RyR (
i.e.
oxidation, phosphorylation, glycation) was significantly (
P<0.01
) reduced in circulating lymphocytes isolated from CRT responders compared to pre-CRT levels and to non-responders. Similarly, the binding to RyR of its stabilizing subunit (calstabin) was markedly increased by CRT, whereas intracellular Ca
2+
leak was attenuated (
P<0.01
). Importantly, these phenomena were not observed in CRT non-responders. Moreover, in a multivariate regression analysis, we observed that RyR glycation in peripheral lymphocytes at baseline was independently associated with CRT response at 1-year follow-up (
P<0.05
).
Conclusions:
This is the first study showing that CRT response can be predicted by the level of RyR glycation in peripheral blood lymphocytes. Moreover, we demonstrate that CRT responders exhibit a significantly reduced intracellular Ca
2+
leak through RyR in lymphocytes, mirrored by diminished post-translational modifications compared to baseline and to CRT non-responders.
