Genetic Determinants and Biochemical Correlates of Slow Coronary Flow: A Systematic Review and Meta-analysis

Introduction: Slow coronary flow (SCF) is an angiographically observed phenomenon that is characterized by slow antegrade progression of radio-opaque contrast agent in the epicardial arteries and without any evidence of obstructive coronary artery disease. Published reports suggest that apart from having several established clinical and physical etiological factors, SCF might have some genetic determinants, along with some easily detectible biochemical correlates. Materials and methods: We set out to consolidate the information from all published articles exploring genetic determinants, specifically, single nucleotide polymorphisms (SNPs), and/or biochemical correlates of SCF, employing a systematic review and possibly a meta-analysis. Results: After a rigorous, well-defined, online database search, we identified 25 relevant original articles published up to December 2016. These articles reported on a total of 60 studies, including 14 for genetic determinants (nst=14) and 46 for biochemical correlates of SCF (nst=46). The present meta-analysis evaluating genetic determinants indicated statistically significant associations of two SNPs with SCF: nitric oxide synthase 3 (NOS3) gene variations of −849 G>T (rs1799983) and the 4b/a 27 base pair (bp) variable number tandem repeat (VNTR). Both of these SNPs provide dominant as well as allelic genetic models. For rs1799983 (nst=2), the odds ratio (OR) range was 2.11–2.71, with a Z value range of 2.91–3.00 and a p-value range of 0.003–0.004. For 27bp VNTR (nst=2), the OR range was 2.18–2.37, with a Z value range of 3.02–3.10 and p-value range of 0.002–0.003. We also noted possible involvement of some other SNPs which were reported to be associated with SCF in single studies. Our metaanalysis also aimed to assess biochemical correlates of SCF and deduced some noteworthy results. Plasma/serum levels of homocysteine [nst=10, standard mean difference (SMD): 1.45 (95% CI: 0.95–1.95, p<0.00001], endothelin-1 [nst=3, SMD: 2.33 (95%CI: 0.16–4.49), p=0.03] and C-reactive protein [nst=2, SMD: 0.39 (95% CI: 0.06–0.72), p=0.02] were found to be positively correlated with SCF, yielding statistically significant results. On the other hand, plasma levels of nitric oxide [nst=8, SMD: −0.93 (95%CI: −1.59 to −0.28), p=0.005] and folate [nst=3, SMD: −0.62 (95%CI=−0.88 to −0.36), p<0.00001] were found to be significantly, but negatively, correlated with SCF. A few lesser-known biochemical entities reported to be associated with SCF were also identified by single studies.