Diabetes paradox and RBC distribution width

Column-Dr Ramon Abarquez photo

Medicine is Not an Exact Science

Ramon F. Abarquez, Jr., MD, EFACC, FAsCC, FPCP, FPCC, CSPSH

A META analysis among elective percutaneous coronary intervention (PCI) revealed a lower short and long term mortality in obese subjects compared with normal weight subjects. (Shenkeveld, BMJ. 2012; 2e000-535)

Would a similar finding be observed among cases with diabetes mellitus (DM)? DM patients approximately have a two-fold increase in the risk for coronary artery disease (CAD), stroke, and death from vascular causes compared with patients who do not have DM.

Interventions targeted at modifiable risk factors, such as smoking cessation, management of hypertension and dyslipidemia, reduce the risk of cardiovascular diseases (CVD) in DM patients.

Diabetes paradox

Paradoxically, large randomized studies have failed to conclusively show that intensively lowering glucose reduces CVD event rates in DM patients, despite pathophysiologic and epidemiologic evidence suggesting that hyperglycemia contributes to CVD despite intensive glycemic control early in the disease course.

This approach in those with long-standing or complicated DM is not of clear benefit and may even be harmful in some. Failure to mitigate risk with anti-hyperglycemic therapy and the potential for some treatments to increase CVD risk underlies a treatment paradox.

New glucose-lowering therapies are now subject to close scrutiny for CV safety before and after drug approval. Results from the first trials designed to meet the recent CV regulatory requirements have shown no increased risk of major adverse CV events but also no CV benefit from dipeptidyl peptidase- 4 inhibitor (DPP4i) therapy, as well as a potentially increased risk of hospitalization for heart failure with saxagliptin.

Conclusive evidence of CV risk reduction with glucose-lowering therapy is still lacking since DM is a heterogeneous disease, for which patient-centered, individualized care, and goal-setting is appropriate. (Green, Postgrad Med. 2014 May;126[3]:190-204.)

Diabetes-RBC relationship

In a variety of inflammatory diseases, where iron dysregulation occurs, a strong tendency for erythrocytes to lose their normal discoid shape and to adopt a skewed morphology (as judged by their axial ratios in the light microscope and by their ultra-structure in the scanning electron microscopy, SEM).

Similarly, the polymerization of fibrinogen, as induced in vitro by added thrombin, leads not to the common ‘spaghetti-like’ structures but into dense matted deposits.

Type 2 diabetes is a known inflammatory disease wherein axial ratio of the erythrocytes of poorly controlled (as suggested by increased HbA1c levels) type 2 diabetics was significantly increased, and including aberrant fibrin morphologies. As judged by scanning electron microscopy and in the atomic force microscope, these could be reversed, to some degree, by the addition of the iron chelators deferoxamine (DFO) or deferasirox (DFX). Thus, these morphological indicators may have prognostic value. (Pretorius, Cardiovasc Diabetol. 2015 Mar 8;14:30.)

Low RBC count high RDW

Red blood cell distribution width (RDW) is a measure of red blood cell volume variations (anisocytosis) and is reported as part of a standard complete blood count.

Recently, the importance of RDW as a predictor of poor clinical outcomes in the settings of various diseases has been noted. The negative prognostic effects of elevated RDW levels may be attributed to the adverse effects of independent risk factors such as inflammation, oxidative stress, and vitamin D3 and iron deficiency on bone marrow function (erythropoiesis).

Elevated RDW values may reflect the unfavorable impacts on bone marrow erythropoiesis. Previous studies have confirmed that the necrotic core of the plaque accumulates erythrocytes resulting to both plaque growth and plaque destabilization (Zhang, Cor Art D 2013;4(3):361-67)

Lipid disorders decrease red cell membrane fluidity, and higher RDW levels result in the deterioration of blood flow through the microcirculation. (Patel, Adv Exp Med Biol 2011;765:211-16) This mechanism may explain the well-documented relationship between red blood cell rheology and the lack of tissue reperfusion following PCI in MI cases. (Toth, Clin Hemorheol Microcirc 2014;56(3):197-204).

This effect may also explain the slow epicardial coronary arteries flow in symptomatic patients without CAD (Akpinar, J Cardiol 2014;63(2):112-15) Statin therapy, except atorvastatin, may increase RDW. (Kucera, Clin Biochem 2015;48(9):557-61) RDW correlated with disorders of iron metabolism and decreases both the production of and bone marrow responsiveness to erythropoietin, resulting in impaired hematopoiesis and increased RDW levels. (Emans, J Card Fail 2011;17(8);626-33) The correlation between HbA1C and RDW levels exist in DM patients with nephropathy and cardiovascular disease. (Magri, Diab Metab Synd 2014;8(1):13-17)

Furthermore, decreased red blood cell deformability among patients with higher RDW values impairs blood flow through the microcirculation, resulting in the diminution of oxygen supply at the tissue level, particularly among patients suffering from myocardial infarction treated with urgent revascularization.

RDW is an important risk factor for both mortality and cardiovascular events in patients with stable CAD or acute coronary syndrome. It has not yet been determined whether anisocytosis is the cause of the poorer prognosis observed among these patients or if it is simply a marker of multiple pathological states connected with said prognosis. In contrast to the markers of inflammation and oxidative stress, which are not routinely analyzed, RDW provides valuable information concerning prognosis in patients with CAD. (Bujak, Dis Markers. 2015;2015:824624)

Vital Signs Issue 87 Vol. 4, May 1-31 2016