In the current study, we surveyed the predictor of poor coronary collaterals in 202 Chinese CKD patients and found there were three major findings. First, high percentages of CKD patients (42.6%) with significant coronary artery disease have no coronary collaterals. Second, hypertension and diabetes are significantly independent predictors of poor coronary collaterals. Third, there was a synergistic effect on poor coronary collateral development between hypertension and diabetes.
CKD and poor coronary collateral formation
Tissue hypoxia is a pathologic feature of many human diseases like CAD, stroke, and kidney disease. In patients with CKD, Chronic hypoxia in the kidney has been suggested as a final common pathway to end-stage renal disease. It not only induces regulatory mechanisms but also has a significant influence on gene expression [22–24]. Several hypoxia-induced proteins such as hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), erythropoietin, and glucose transporter 1 are reported to have protective effects in CKD . HIF and VEGF are also involved in angiogenesis and associated with coronary collateral development [26–28]. Furthermore, previous studies have reported the association between CKD and poor coronary collateral formation. Sezer M et al. stated that coronary collateral formation is significantly poorer in patients with renal failure (eGFR < 80 ml/min/1.73 m2) than in non-uremic (eGFR ≧ 80 ml/min/1.73 m2) patients . Xie SL et al. also showed that lower eGFR is associated with poorer coronary vessel development in patients experiencing mild to moderate renal insufficiency . Similar to previous studies, CKD patients with significant coronary artery disease have high percentage of poor coronary collaterals development. However, there is no literature discussing about the predictor of poor coronary collaterals in the CKD population with SCAD.
The association between hypertension and coronary collaterals
Microvascular rarefaction is known as a phenomenon revealing there is smaller number of arterioles and capillaries in hypertensive subjects compared with non-hypertensive subjects . Recent studies have suggested that capillary rarefaction in hypertension is likely to be a primary or a very early structural abnormality. However, the detailed mechanism is still not well understood. Impaired angiogenesis or microvascular rarefaction could contribute to increased peripheral resistance and raise blood pressure. There are several theories explaining microvascular rarefaction in hypertension. Rarefaction not only can antedate the onset of hypertension but also occurs as a consequence of prolonged elevation of blood pressure. Primary rarefaction might result from impaired angiogenesis and collateral network formation . However, there are conflicting results about the association between hypertension and coronary collaterals existing in clinical studies. Few studies in the past suggest that there is a paradoxical increase in collateral circulation in patients with hypertension and CAD but Koerselman J et al. reported that hypertension is inversely associated with the presence and extent of coronary collaterals . In our study, hypertension is not only correlated with poor collaterals in the univariate analysis but also a significant predictor of poor collateral formation in the multivariate analysis. These findings are similar to the study of Koerselman J et al.’s study. In addition, recent clinical research has also shown that long term treatment of hypertension can prevent microvascular rarefaction in hypertensive patients.
The association between diabetes and coronary collaterals
Diabetic patients have a less favorable cardiovascular outcome and higher mortality than non-diabetic patients [32, 33]. However, the precise mechanism is still not clearly clarified. According to the literature, high glucose levels could cause endothelial dysfunction and endothelial cell is vital for coronary collateral formation . In addition, nitric oxide production, HIF-1, and vascular endothelial growth factor (VEGF) expressions, which are associated with angiogenesis, were also reported to be impaired in hyperglycemic condition.[35, 36]. These findings all suggest that diabetes might lead to poor coronary collateral development. In animal studies, hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism in dog model . In human angiographic studies, Abaci A et al. demonstrated that coronary collateral development in the diabetes group was significantly poorer than in the nondiabetic group . In our study, we found diabetes is a significant predictor of poor collateral formation in the multivariate analysis.
Furthermore, we also found there was a synergistic effect of hypertension and diabetes on the poor coronary collateral formation. Hypertension is both a cause and consequence of CKD. Blood pressure in CKD patients is increased due to fluid overload and production of vasoactive hormones via renin-angiotensin system which might aggravate hypertension. Diabetes is also another leading cause of CKD. Insulin and glucose homeostasis are altered in the patients of end stage renal disease and even in the early stages of CKD, leading to insulin resistance by a variety of pathways [39, 40]. Insulin resistance is reported to increase with the progression of CKD, which also plays an important role in the pathogenesis of hypertension . Hence, CKD might further potentiate hypertension and diabetes and cause poor coronary collateral formation.
Limitations of the present study
First, the collateral formation was assessed by coronary angiography in this study. Measuring collateral flow index by intravascular Doppler guidewire may provide a more objective physiological measurement of collateral grade. However, the invasiveness of intravascular ultrasound limits its use in large-scale studies. Second, since this was only a clinical association study, potential mechanisms were not fully elucidated.