Abstract
Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-γ, TGF-β1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function.
Highlights
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder, characterized by ventricular hypertrophy, often asymmetric in nature, frequently complicated by diastolic heart failure, left ventricular outflow tract (LVOT) obstruction, ventricular tachyarrhythmias, sudden cardiac death, microvascular angina, and atrial fibrillation (reviewed in (1))
We found that plasma protein profiles from Hypertrophic Cardiomyopathy (HCM) patients with Left Ventricular Outflow Tract (LVOT) obstruction can distinguish the preoperative from the postoperative state, and surgical myectomy results in a reduction of circulating plasma proteins, associated with a proinflammatory state
The association between HCM and a proinflammatory state was consistent with previous reports [4,14], but our study was the first, to the best of our knowledge, to demonstrate a potential improvement after surgical myectomy
Summary
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder, characterized by ventricular hypertrophy, often asymmetric in nature, frequently complicated by diastolic heart failure, left ventricular outflow tract (LVOT) obstruction, ventricular tachyarrhythmias, sudden cardiac death, microvascular angina, and atrial fibrillation (reviewed in (1)). In HCM patients, the presence of LVOT obstruction can be a life threatening complication, independently associated with adverse outcomes, affecting approximately 4.0/). In half of these affected patients, the outflow tract obstruction is dynamic, which is not apparent at rest but is readily provocable with exercise. Studies using other methods identified elevated levels of circulating cytokines in the plasma of HCM patients [4] and suggest that measurements of brain natriuretic peptide might be useful in monitoring outcome after percutaneous alcohol septal ablation. We report the use of a commercially available aptamer-based proteomics platform, SOMAscan (SomaLogic, Boulder, CO, USA), to identify biomarkers associated with LVOT obstruction, in patients with HCM, by measuring plasma levels before and after surgical myectomy. We demonstrate that plasma proteomic profiles can distinguish the preoperative from the postoperative state through changes in proteins linked to pathways that regulate inflammation, leukocyte migration, fibrosis, angiogenesis, and vasculogenesis, potentially implicating these processes as important in the pathogenesis of LVOT obstruction in HCM and identifying potential new therapeutic targets
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