Abstract
Introduction: Neuroischemic (NI) diabetic foot (DF) is an advanced complication leading to limb amputations and cardiac mortality. We contributed to demonstrate that bone marrow (BM) T2D neuropathy impairs vascular regenerative hematopoietic cell mobilization. We here hypothesize that autonomic neuropathy (DAN) and pathological orthostatic hypotension (reducing systolic and diastolic blood pressure -BP at least 30 and 10 mm Hg) convert to cardiovascular death in T2D patients with NI-DF. Subjects and Methods: We performed DAN and postural hypotension tests in 204 surgical-treated neuropathic T2D without (87 N) or with (117 NI) critical limb ischemia (pO2 <30 mm Hg). In peripheral blood (PB) (204) and BM (65) samples we evaluated: percentage of haematopoietic precursor CD34+, VEGF receptor KDR+ (PreC) and neurokinin-1 receptor on BM-CD34+ cells (BM-NK1R+preC) by flow cytometry; circulating P substance neuropeptide by ELISA. Results: We observed 46 NI cardiac deaths (DD) and 158 alive patients (AD) after prospective 5 years. DD were older but comparable for diabetes age, BMI, HbA1c, post-revascularization oximetry and TUC lesion grade. All T2D had autonomic failure but only DD were orthostatically hypotensive (-BP -35±2 and -21± 3 mm Hg p<0.01 vs. AD) with different BM/PB preC incremental ratio (8.8±4 vs. 1.5 ±0.3 106 events p<0.0003 vs. AD), similar circulating P levels, reduced BM-NK1R+preC (14.5±8.5 vs. 36.4±5 % p<0.04). Both -BP correlate with BM/PB preC (p< 0.04) but not with BM-NK1R+preC. Conclusions: We prospectively confirm that autonomic failure impacts on vascular homeostasis and cardiac mortality in T2D with prevalent NI-DF. Now we demonstrate that pathological orthostatic hypotension, a simple clinical measure, could contribute to persistent ischemic bone marrow signal in neuroreceptor reduced BM-derived stem cells, worsening BM vascular regenerative capacity and cardiac performance. Disclosure M. Sambataro: None. L. Sambado: None. G. Spinetti: None. E. Seganfreddo: None. E. Trevisiol: None. M. Marcon: None. P. Stefani: None. A. Furlan: None. M. Cacciatore: None. A. Paccagnella: None. Funding Italian Diabetic Patients' Association of Treviso and Oderzo
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