Background: We investigated whether and to what extent stenosis of predominant collateral donor artery (PCDA) affects coronary collateral flow in relation to blood pressure (BP) in type 2 diabetic patients with chronic total occlu- sion (CTO). Methods: Collateral flow index (CFI) as derived from intracoronary pressure distal to occluded segment and mean aortic pressure in 220 type 2 diabetic patients and 220 propensity score matched non-diabetic controls undergoing percutaneous coronary intervention for CTO. The severity of PCDA stenosis was graded according to lumen diameter narrowing. Results: CFI decreased stepwise from mild to severe stenosis of the PCDA and was lower in diabetic patients with moderate or severe PCDA stenosis than in non-diabetic controls (0.36 ± 0.10 vs. 0.45 ± 0.08, P < 0.001; 0.29 ± 0.09 vs. 0.35 ± 0.08, P = 0.008). When the PCDA was mildly stenotic, CFI increased initially along with a reduction in diastolic BP, and decreased when diastolic BP was below 60 mmHg in diabetic patients (0.38 ± 0.16 vs. 0.57 ± 0.09, P < 0.001). In the presence of moderate PCDA stenosis, diabetic patients had significantly lower CFI compared to non-diabetic controls, with a relative reduction of 19.8% at diastolic BP 70–79 mmHg, 28.2% at 60–69 mmHg and 38.2% below 60 mmHg (all P < 0.05). A severe PCDA stenosis resulted in a more pronounced decrease in CFI, with a relative reduc- tion of 37.3% for diabetics compared to non-diabetics when diastolic BP was below 60 mmHg (P = 0.050). Conclusions: In the setting of CTO, donor artery stenosis confers greater risk for reduced coronary collateral flow when diastolic BP is decreased. Even a moderate stenosis in the PCDA may be associated with lower collateral flow as diastolic BP decreases below 80 mmHg in type 2 diabetic than in non-diabetic patients. Keywords: Blood pressure, Collateral circulation, Diabetes, Coronary artery disease, Chronic total occlusion *Correspondence: email@example.com; firstname.lastname@example.org Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People’s Republic of China Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 2 of 11 re-established. Collateral flow index (CFI) was derived Background from intracoronary distal occluded pressure and cen- In patients with stable coronary artery disease, a grad- tral aortic pressure taking into account of central venous ual development of complete coronary obstruction may pressure [7, 13, 14], which has been considered as the lead to a sufficient compensation of blood supply via col - most accurate diagnostic tool to assess the capacity of lateral circulation to prevent myocardial damage from coronary collateral circulation as it correlates closely with ischemic insults . Protection of the jeopardized myo- clinical signs of myocardial ischemia [15, 16]. For avoid- cardium by coronary collaterals is clinical relevant, as ing potential confounding factors, each type 2 diabetic presence of well-formed collaterals has been associated patient was matched to a non-diabetic control for age, with reductions in the occurrence and transmural extent sex and risk factors for coronary artery disease. of myocardial infarction, and with increased survival . The mechanism of collateral vessel growth is complex Methods in situations where atherosclerosis affects large conduct - Study population ance arteries , and even become more complicated by In total, 1147 consecutive patients with stable coronary the presence of diabetes mellitus in which multiple bio- artery disease and CTO (> 3 months) of at least one chemical and cellular components are involved . Nev- major epicardial coronary artery between October 2010 ertheless, arteriogenesis with vessel outward remodeling and December 2016 were screened from the database of is prevail, and weights much more than angiogenesis Shanghai Rui Jin Hospital PCI Outcome Program [17, because it reduces dramatically collateral resistance to 18]. We excluded 238 patients who were referred for a negligible extent and enables delivery of blood flow to coronary artery bypass grafting (CABG). In the remain- the region at risk [5, 6]. Among numerous factors which ing 909 patients undergoing elective PCI, we further could influence coronary collateral flow [4, 7–10], blood excluded those who had a history of PCI within 3 months pressure (BP), especially diastolic BP, generates the distal (n = 42) or CABG (n = 46), renal failure requiring hemo- pressure within the occluded segment of the coronary dialysis (n = 4), type 1 diabetes (n = 4), chronic heart fail- artery, which constitutes a physical stimulus for arterio- ure with NYHA class III or IV (n = 12), pulmonary heart genesis and promotes collateral formation . Presence disease (n = 10) and malignant tumor or immune sys- of a chronic total occlusion (CTO) is frequently associ- tem disorders (n = 4). We also excluded those who had ated with multi-vessel coronary disease and has been failed PCI for CTO mostly due to inability of guide wire considered as a prerequisite for spontaneous collateral to cross the occluded segment (n = 73) and those who recruitment [7, 12]. Collaterals develop due to the pres- underwent PCI via a retrograde approach (n = 82). To sure gradient from donor to recipient being greater than reduce the selection bias, we then performed a propen- that of the recipient (often a CTO). Obviously, myocar- sity score matching analysis, resulting in a total number dium distal to the occlusion is almost entirely perfused of 440 patients (220 type 2 diabetics and 220 non-diabet- by retrograde collateral branches from another epicardial ics) into the final analyses (Fig. 1). coronary artery (i.e., predominant collateral donor artery The duration of CTO was estimated based on informa - [PCDA]), and successful recanalization of a chronically tion obtained from a previous angiogram, a history of occluded lesion has often led to a rapid reduction of myocardial infarction in the target vessel territory, or the pressure-derived recruitable collateral function and an first onset of an abrupt worsening of existing angina. The increase in fractional flow reserve of the PCDA . This diagnosis of type 2 diabetes was made according to the suggests a potential interaction between coronary col- criteria of the American diabetes association, including lateral flow and donor artery physiology in the setting of glycosylated hemoglobin (HbA1c) ≥ 6.5%, fasting plasma chronic coronary total occlusion. However, the effect of glucose concentration ≥ 7.0 mmol/L, 2-h postpran- donor artery stenosis on coronary collateral flow in rela - dial glucose concentration ≥ 11.1 mmol/L, or a random tion to BP for patients with diabetes remains unknown, plasma glucose ≥ 11.1 mmol/L in a patient with classic which partly reflects the heterogeneity of study popula - symptoms of hyperglycemia or hyperglycemic crisis . tion and semi-quantitative angiographic assessment of Hypertension was defined as systolic BP ≥ 140 mmHg coronary collateral circulation in most previous cohort and/or diastolic BP ≥ 90 mmHg, or use of anti-hyper- studies [8–10]. In this study, we investigated whether or tensive agents for controlling BP . Dyslipidemia was to what extent combined BP (particularly diastolic BP) defined according to the Third Report of The National and stenosis of the PCDA affects coronary collateral flow Cholesterol Education Program (NCEP) . Stable in type 2 diabetic and non-diabetic patients with chronic angina was diagnosed according to the criteria recom- coronary total occlusion. We examined the equilibrium mended by the American College of Cardiology/Ameri- of collateral supply at the time of advancing a micro- can Heart Association . catheter distal to the occlusion before antegrade flow is Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 3 of 11 Fig. 1 Flowchart of patient enrollment. CABG coronary artery bypass grafting, SCAD stable coronary artery disease, CHF chronic heart failure, PCI percutaneous coronary intervention, Pd mean intracoronary pressure distal to an occluded segment. *Risk factors for CAD indicate smoking, hypertension and dyslipidemia Biochemical investigation Angiography and analysis We obtained blood samples at the day of angiography Coronary angiography was performed via femoral or in all patients after an overnight fasting. Assessment radial access with 6Fr diagnostic catheters. Quantitative of serum levels of creatinine, blood urea nitrogen, uric angiographic assessment was done independently by two acid, lipid profiles, glucose, and glycosylated hemo - blinded interventional cardiologists according to lesion globin (HbA1c), was made with standard laboratory classification scheme of the American College of Cardi - techniques. Glomerular filtration rate (GFR) was esti - ology/American Heart Association . The PCDA was mated using the chronic kidney disease epidemiol- defined as a contra-lateral vessel making the largest col - ogy collaboration (CKD-EPI) equation: GFR (mL/ lateral contribution , and maximal diameter steno- EPI 2 α min/1.73 m ) = 141 × min (creatinine/k, 1) × max sis of the PCDA was classified as mild: < 50%, moderate: −1.209 age (creatinine/k, 1) × 0.993 × 1.018 [if female], 50–70% or severe: > 70% (GE Centricity VA 1000; GE where k is 0.7 for females and 0.9 for males, α is − 0.329 Healthcare). for females and − 0.411 for males, min indicates the minimum of creatinine/k or 1, and max indicates the Intracoronary pressure and collateral flow measurement maximum of creatinine/k or 1 . Serum high-sensi- Elective PCI for CTO was performed through an ante- tivity C-reactive protein (hsCRP) level was assayed by grade approach in all patients. After crossing the ELISA (Biocheck Laboratories, Toledo, OH, USA). occluded segment with various types of guide wire, a Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 4 of 11 microcatheter was advanced distal to the occlusion. normal distribution was evaluated with the Kolmogorov– Sometimes, a low-profile balloon catheter was passed Smirnov test, and differences among groups were ana - initially, and then was exchanged for a microcatheter. lyzed by one-way analysis of variance (ANOVA) followed Meticulous care was taken to ensure complete obstruc- by post hoc analysis with the Fisher’s least significant dif - tion of the coronary artery by lack of contrast passage ference (LSD) test. Pearson’s or Spearman’s correlation during proximal contrast injection through the guiding analysis was run to determine the relationship between catheter while the microcatheter was in place. Intrac- CFI and Pd or different levels of aortic BP. Multivariate oronary pressure distal to an occluded segment meas- linear regressions were used to explore the independ- ured through a microcatheter (Finecross, Terumo Co, ent determinants for CFI, and the covariates chosen to Japan) and central aortic pressure determined from a 6Fr enter the multivariate analysis model included diabetes guiding catheter were simultaneously recorded using a and aortic systolic, diastolic and mean BP, respectively, fluid-filled manometer system (Mac-Lab Hemodynamic as well as gender, age, body mass index (BMI), risk fac- Recording System, GE Healthcare, USA). The transducer tors for coronary artery disease (history of hypertension was kept at the level of mid axillary line, and zero cali- and dyslipidemia and smoking), history of myocardial brated to atmosphere before measurement . Despite infarction, severity of coronary artery disease, GFR, total a phasic waveform for distal coronary pressure, signifi - to high-density lipoprotein (HDL) cholesterol ratio, log- cant damping of high frequency pressure components transferred hsCRP and left ventricular ejection fraction. by the small lumen of microcatheter exhibited, thus only All analyses used 2-sided tests with an overall signifi - the mean distal occluded pressure was used. For meas- cance level of alpha = 0.05, and were performed with the urement of central aortic pressure, the guiding catheter SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL, USA). was kept away from the coronary orifice. The pressure- derived coronary collateral flow index (CFI) was calcu - Results lated as the ratio of (Pd − C VP)/(Pa − CVP), where Pd is Baseline characteristics mean distal occluded pressure, Pa is mean central aortic Mild, moderate and severe stenosis of the PCDA was pressure; and CVP is the central venous pressure, which observed in 99, 75 and 46 diabetic patients and 132, 60 was substituted by 5 mmHg, as all patients had no symp- and 28 non-diabetic patients, respectively. For diabetic toms and signs of heart failure [7, 14, 15]. and non-diabetic patients, age, proportion of male gen- We have validated the accuracy of intracoronary pres- der, dyslipidemia and prior myocardial infarction, and sure-derived collateral flow measurement using a micro - serum levels of creatinine and hsCRP increased whereas catheter against the standard pressure wire technique GFR, left ventricular ejection fraction and proportion (PressureWire Certus, St. Jude Medical, St. Paul, Min- of hypertension decreased stepwise from mild to severe nesota) with RadiAnalyzer Xpress System (St. Jude stenosis of the PDCA (all P < 0.05). Multivessel coronary Medical, St. Paul, Minnesota). Bland–Altman analy- disease was more prevalent in patients with moderate sis revealed that in 40 consecutive patients, Pd and CFI or severe PDCA stenosis. Medications were similar irre- determined with a microcatheter correlated significantly spective of stenosis severity of the PDCA (Table 1). with those by a pressure wire (r = 0.751 and r = 0.679, both P < 0.001), with an absolute difference in Pd and Collateral flow and BP CFI between the two techniques of 1.68 mmHg (95% CI Despite similar aortic systolic, diastolic and mean BP − 1.42 to 4.77, P = 0.280) and 0.019 (95% CI − 0.02 to (Table 1), CFI decreased stepwise from mild to severe 0.053, P = 0.279), respectively. stenosis of the PDCA in diabetic and non-diabetic patients (both P < 0.001), and were significantly lower Statistical analysis in diabetic patients than in non-diabetic controls with For patient selection, a propensity score matching anal- moderate (0.36 ± 0.10 vs. 0.45 ± 0.08, P < 0.001) or severe ysis was performed in advance with a match tolerance (0.29 ± 0.09 vs. 0.35 ± 0.08, P = 0.008) PCDA stenosis. of 0.02 and a ratio of 1:1 for diabetic and non-diabetic Furthermore, there was no difference in CFI between patients using a logistic regression model with age, sex diabetic patients with moderate PDCA stenosis and non- and risk factors for coronary artery disease (smoking diabetic controls with severe PCDA stenosis (P = 0.421) and history of hypertension or dyslipidemia). Continu- (Fig. 2). ous variables are presented as mean ± standard deviation (SD), and categorical data are summarized as frequen- Eec ff t of medical therapy cies (percentages). For categorical clinical variables, dif- Treatments with β-blockers and nitrates were associated ferences between groups were evaluated with the Chi with higher CFI in diabetic (0.42 ± 0.12 vs. 0.38 ± 0.13, square test. For continuous variables, the existence of a P = 0.026; 0.42 ± 0.12 vs. 0.39 ± 0.12, P = 0.033) and Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 5 of 11 Table 1 Baseline characteristics in patients with stable coronary artery disease and chronic total occlusion with mild, intermediate and severe stenosis of donor artery Variables Diabetes (n = 220) Non-diabetes (n = 220) Mild (n = 99) Moderate Severe (n = 46) P value Mild (n = 132) Moderate Severe (n = 28) P value (n = 75) (n = 60) Male, n (%) 94 (94.9) 59 (78.7) 24 (52.2) < 0.001 127 (96.2) 40 (66.7) 14 (50.0) < 0.001 Age, years 57.9 ± 11.7 67.9 ± 10.7 73.7 ± 9.3 < 0.001 61.3 ± 12.1 68.0 ± 9.3 74.6 ± 12.4 < 0.001 Body mass index, 25.4 ± 2.5 25.5 ± 2.6 25.9 ± 2.1 0.605 25.0 ± 2.5 25.0 ± 1.9 25.7 ± 2.4 0.294 kg/m Hypertension, 102 (77.3) 37 (61.7) 7 (25.0) < 0.001 91 (91.9) 42 (56.0) 11 (23.9) < 0.001 n (%) History of dyslipi- 23 (17.4) 25 (41.7) 14 (50.0) < 0.001 2 (2.0) 20 (26.7) 26 (56.5) < 0.001 demia, n (%) Smoking, n (%) 27 (27.3) 26 (34.7) 21 (45.7) 0.090 43 (32.6) 18 (30.0) 15 (53.6) 0.072 History of MI, 19 (19.2) 16 (21.3) 19 (41.3) 0.012 19 (14.4) 12 (20.0) 10 (35.7) 0.030 n (%) Severity of CAD, n (%) < 0.001 < 0.001 1-vessel 39 (39.4) 2 (2.7) 0 (0.0) < 0.001 51 (38.6) 5 (8.3) 5 (17.9) < 0.001 2-vessel 35 (35.4) 21 (28.0) 17 (37.0) 0.493 55 (41.7) 17 (28.3) 7 (25.0) 0.089 3-vessel 25 (25.2) 52 (69.3) 29 (63.0) < 0.001 26 (19.7) 38 (63.3) 16 (57.1) < 0.001 Multivessel 60 (60.6) 73 (97.3) 46 (100.0) < 0.001 81 (61.4) 55 (91.7) 23 (82.1) < 0.001 disease Stenosis of PCDA, 37.6 ± 8.5 58.9 ± 5.3 83.4 ± 8.5 < 0.001 33.5 ± 10.5 58.9 ± 5.4 82.6 ± 8.4 < 0.001 Fast blood glu- 6.3 ± 1.9 6.9 ± 2.2 6.5 ± 2.7 0.214 5.0 ± 0.7 4.7 ± 0.7 5.3 ± 0.6 < 0.001 cose, mmol/L HbA1c, % 7.2 ± 1.2 7.4 ± 1.5 7.1 ± 1.3 0.555 5.7 ± 0.4 5.7 ± 0.4 5.8 ± 0.4 0.980 Triglyceride, 1.55 ± 0.72 1.62 ± 0.63 1.68 ± 0.81 0.538 1.42 ± 0.71 1.45 ± 0.83 1.60 ± 0.71 0.521 mmol/L Total cholesterol, 3.75 ± 1.04 4.11 ± 1.12 4.29 ± 1.04 0.009 4.11 ± 1.34 3.89 ± 1.45 4.08 ± 0.88 0.571 mmol/L HDL cholesterol, 0.94 ± 0.20 0.99 ± 0.28 0.99 ± 0.16 0.312 1.01 ± 0.27 0.96 ± 0.19 1.00 ± 0.34 0.469 mmol/L LDL cholesterol, 2.23 ± 0.90 2.47 ± 0.93 2.71 ± 0.87 0.010 2.49 ± 1.05 2.45 ± 1.11 2.40 ± 0.84 0.891 mmol/L Serum creatinine, 85 ± 21 90 ± 30 110 ± 32 < 0.001 77 ± 14 94 ± 27 102 ± 29 < 0.001 μmol/L Uric acid, μmol/L 322 ± 79 315 ± 61 331 ± 76 0.515 337 ± 72 319 ± 96 339 ± 69 0.309 GFR, mL/ 86.8 ± 18.5 75.5 ± 24.9 55.9 ± 20.6 < 0.001 90.3 ± 15.8 70.7 ± 20.2 59.6 ± 21.8 < 0.001 min/1.73 m hsCRP, mg/L 1.58 (0.66–3.32) 2.46 (1.21–7.55) 4.23 (1.44–17.15) 0.031 0.97 (0.25–3.13) 1.20 (0.27–10.35) 2.66 (0.42–25.82) < 0.001 LVEF, % 60.5 ± 8.3 60.4 ± 9.3 54.7 ± 10.7 0.001 62.3 ± 9.0 61.3 ± 9.5 57.2 ± 12.8 0.042 Medication, n (%) ACE inhibitors/ 53 (53.5) 42 (56.0) 26 (56.5) 0.924 50 (37.9) 20 (33.3) 11 (39.3) 0.798 ARBs β blockers 41 (41.4) 30 (40.0) 20 (43.5) 0.931 51 (38.6) 25 (41.7) 15 (53.6) 0.345 Calcium channel 30 (30.3) 23 (30.7) 12 (26.1) 0.845 41 (31.1) 13 (21.7) 8 (28.6) 0.406 blockers Nitrates 57 (57.6) 41 (54.7) 24 (52.2) 0.819 59 (44.7) 32 (53.3) 16 (57.1) 0.339 Statins 69 (69.7) 59 (78.7) 36 (78.3) 0.328 77 (58.3) 33 (55.0) 12 (42.9) 0.325 Anti-diabetic 58 (58.6) 60 (80.0) 40 (87.0) < 0.001 0 (0.0) 0 (0.0) 0 (0.0) – therapy Aortic blood pressure, mmHg Systolic 150.2 ± 26.2 147.3 ± 23.4 141.2 ± 24.8 0.130 150.2 ± 29.2 147.0 ± 28.2 141.0 ± 17.9 0.260 Diastolic 77.1 ± 9.8 74.9 ± 9.4 73.5 ± 10.8 0.093 78.1 ± 13.2 75.9 ± 9.7 75.6 ± 11.5 0.388 Mean 101.5 ± 13.2 99.0 ± 11.8 96.1 ± 13.5 0.057 101.2 ± 14.7 101 ± 12.9 97.4 ± 7.7 0.407 Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 6 of 11 Table 1 (continued) Variables Diabetes (n = 220) Non-diabetes (n = 220) Mild (n = 99) Moderate Severe (n = 46) P value Mild (n = 132) Moderate Severe (n = 28) P value (n = 75) (n = 60) Pd, mmHg 52.1 ± 9.4 39.6 ± 11.0 32.5 ± 10.2 < 0.001 53.6 ± 7.1 48.3 ± 8.6 35.6 ± 7.8 < 0.001 Collateral flow 0.49 ± 0.09 0.36 ± 0.10 0.29 ± 0.09 < 0.001 0.51 ± 0.08 0.45 ± 0.08 0.35 ± 0.08 < 0.001 index Data are mean ± SD or median (25th–75th percentiles) or number (%) ACE angiotensin converting enzyme, ARB angiotensin receptor blocker, CAD coronary artery disease, GFR glomerular filtration rate, HbA1c glycosylated hemoglobin A1c, HDL high-density lipoprotein, hsCRP high-sensitivity C reactive protein, LDL low-density lipoprotein, LVEF left ventricular ejection fraction, MI myocardial infarction, PCDA predominant collateral donor artery, Pd mean pressure distal to occlusion PCDA stenosis (P = 0.011), but correlated positively with diastolic BP in diabetic patients with severe PCDA stenosis (P = 0.001). Further analysis showed an interaction between diabe- tes and diastolic BP in patients with moderate (P interac- tion = 0.008) and severe (P interaction = 0.032) stenosis of the PCDA (Table 2). When the PCDA was mildly sten- otic, CFI was gradually increased along with a reduc- tion in aortic diastolic BP, but it was decreased when diastolic BP was below 60 mmHg in diabetic patients, with a relative reduction of 32.1% compared with non- diabetic controls (0.38 ± 0.16 vs. 0.57 ± 0.09, P < 0.001). In the presence of moderate PCDA stenosis, with decreas- ing diastolic BP, the difference of CFI between diabetic and non-diabetic patients was gradually increased. When Fig. 2 Comparison of CFI between diabetic and non-diabetic diastolic BP was below 80 mmHg, diabetic patients had a patients with mild, moderate or severe stenosis of PCDA group. *P < 0.001 vs. mild; #P < 0.001 vs. moderate significantly lower CFI compared to non-diabetic con - trols, with a relative reduction of 19.8% at diastolic BP 70–79 mmHg (0.37 ± 0.10 vs. 0.46 ± 0.07, P < 0.001), 28.2% at 60–69 mmHg (0.33 ± 0.12 vs. 0.46 ± 0.10, P < 0.001) non-diabetic (0.49 ± 0.09 vs. 0.46 ± 0.10, P = 0.023; and 38.2% below 60 mmHg (0.28 ± 0.11 vs. 0.46 ± 0.11, 0.49 ± 0.10 vs. 0.46 ± 0.10, P = 0.019) patients whereas P = 0.002), respectively. A severe stenotic lesion in the other medications such as angiotensin-converting PCDA led to more pronounced decrease in CFI, with a enzyme inhibitors or angiotensin receptor blockers, cal- relative reduction of 37.3% for diabetic patients compared cium channel blockers, statins, oral hypoglycemic agents to non-diabetic controls when diastolic BP was below and insulin did not significantly affect CFI in both groups 60 mmHg (0.19 ± 0.07 vs. 0.30 ± 0.12, P = 0.050) (Fig. 3). (all P > 0.05). Discussion Multivariable analysis Our results support the hypothesis that in the setting of Multivariable linear regression models with systolic (per CTO, coronary collateral flow is adversely affected by the 20 mmHg), diastolic (per 10 mmHg) and mean (per combined effect of donor artery stenosis severity and aor - 10 mmHg) BP as well as potential confounding variables tic diastolic BP. Even a moderate stenosis in the PCDA such as gender, age, body mass index, history of hyper- resulted in lower collateral flow as diastolic BP decreases tension and dyslipidemia, smoking, prior myocardial below 80 mmHg for type 2 diabetic patients compared with infarction, severity of coronary artery disease, GFR, total- non-diabetic patients. to-HDL cholesterol ratio, log-transferred hsCRP and left ventricular ejection fraction, revealed that after multiple Interactive effects of PDCA stenosis and BP on collateral adjustments, CFI correlated negatively with systolic, dias- flow tolic, and mean BP in diabetic and non-diabetic patients Physiologically, coronary collateral inflow into the distal with mild PCDA stenosis (P ≤ 0.001), was inversely related vessel of a CTO through a variety of anatomic arteriolar to diastolic BP in non-diabetic patients with moderate Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 7 of 11 Table 2 Aortic blood pressure in relation to coronary flow index in diabetic and non-diabetic patients according to stenosis of PCDA Aortic BP Mild Moderate Severe Diabetes (n = 99) Non-diabetes (n = 132) Pint Diabetes (n = 75) Non-diabetes (n = 60) Pint Diabetes (n = 46) Non-diabetes Pint (n = 28) β ± SE P β ± SE P β ± SE P β ± SE P β ± SE P β ± SE P Systolic − 0.284 ± 0.073 < 0.001 − 0.352 ± 0.070 < 0.001 0.325 − 0.013 ± 0.062 0.840 0.065 ± 0.158 0.682 0.239 0.154 ± 0.204 0.464 0.025 ± 0.085 0.766 0.651 Diastolic − 0.275 ± 0.079* 0.001 − 0.525 ± 0.065 < 0.001 0.168 − 0.019 ± 0.066 0.774 − 0.303 ± 0.114 0.011 0.008 0.317 ± 0.087 0.001 0.199 ± 0.183 0.296 0.032 & & Mean − 0.334 ± 0.074 < 0.001 − 0.540 ± 0.061 < 0.001 0.081 − 0.018 ± 0.063 0.779 − 0.158 ± 0.136 0.253 0.067 0.604 ± 0.219 0.016 0.147 ± 0.087 0.008 0.669 Values are regression coefficient (β) ± SE, derived from multiple linear regression analyses of coronary flow index with central aortic systolic, diastolic and mean blood pressure, respectively, after adjustment for gender, age, body mass index, current smoking, history of hypertension and dyslipidemia, prior myocardial infarction, severity of coronary artery disease, GFR, total and HDL cholesterol ratio, log-transferred hsCRP and left ventricular ejection fraction. P values for interaction in group of mild, intermediate and severe stenosis of PCDA are given GFR glomerular filtration rate, HDL high-density lipoprotein, hsCRP high-sensitivity C reactive protein, PCDA predominant collateral donor artery # & * P < 0.001, P < 0.01 and P < 0.05 vs. the corresponding β value in non-diabetes Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 8 of 11 Fig. 3 Correlation between CFI and aortic BP in diabetic (red) and non-diabetic (blue) patients with mild (left), moderate (middle) or severe (right) stenosis of the PCDA, respectively. *P < 0.001, #P < 0.01, and P < 0.05 vs. diabetics connections is predominantly modulated by driving force type 2 diabetic and non-diabetic patients. The reason for for blood flow resulted mainly from pressure gradient this remains unclear, but a likely explanation is the pres- across the occluded site [1, 3–5]. Central aortic pres- ence of more diffuse coronary atherosclerosis in a dia - sure (especially diastolic BP) generates the distal pres- betic setting . As shown in this study, patients with sure within the occluded segment, and relatively high type 2 diabetes had more severe coronary artery disease intracoronary pressure and tangential fluid shear stress as evidenced by a higher percentage of multivessel dis- imposed on the collateral endothelium have been sug- ease and a greater stenosis severity of the PCDA. It has gested to constitute hemodynamic stimuli for arterio- been suggested that the presence of diffuse atheroscle - genesis [5–7] and promote collateral blood flow [14, 26, rotic disease in the collateral donor artery would be likely 27]. A collateral donor vessel will have a distal pressure to be associated with a reduced coronary flow reserve drop with an increasing stenosis and/or lowering of dias- , and the large increase in coronary flow through tolic BP (which contributes more to mean distal occluded collateral donor vessels as a result of the additional flow pressure as diastole is longer than systole) and hence through the collateral bed could be enough for minor both are expected to lead to lower distal occluded pres- atherosclerotic irregularities to generate sufficient resist - sure and CFI in the recipient CTO. In the setting of single ance to become flow limiting . Furthermore, data vessel occlusion, collateral function is directly affected by from prior studies which have assessed the microcircu- systemic arterial pressure . However, for patients with latory function in patients with and without diabetes, multi-vessel coronary disease, we would expect pressure have demonstrated that patients with diabetes have sub- gradient across a CTO to be reduced when the artery that stantially adverse functional and structural remodeling of supplies collateral blood flow exhibits a critical stenosis the coronary arterioles and even amongst those diabetic because of a pressure drop proximal to the origin of the patients without known coronary artery disease, the collaterals. This may result in a further reduction in coro - presence of an abnormal coronary flow reserve is asso - nary collateral flow particularly when BP is decreased. ciated with poor outcome, comparable to non-diabetic The major finding of this study is that coronary collat - patients with known coronary disease [31, 32]. Recently, eral flow decreased stepwise as the severity of PCDA ste - Hinkel et al.  reported that diabetic human myocar- nosis increased, and a moderate PDCA stenosis in type 2 dial explants revealed capillary rarefaction and pericyte diabetic patients could induce similar extent of collateral loss compared to non-diabetic explants. In a diabetic flow reduction to that caused by a severe PCDA stenosis pig model of hibernating myocardium, hyperglycemia in non-diabetic patients. Interestingly, our study showed induced microvascular rarefaction in the myocardium that at various degrees of PCDA stenosis, type 2 diabetic even without ischemia, and capillary density further patients had lower CFI when diastolic BP decreased decreased in chronic ischemia hearts. This indicates that below 60 mmHg, and even a moderate stenotic lesion in type 2 diabetes destabilized microvascular vessels of the the PCDA was associated with more reduced collateral heart and may impair the responsiveness of ischemic flow as diastolic BP decreased below 80 mmHg in type myocardium to pro-angiogenic factors . It has been 2 diabetic patients compared to non-diabetic controls. possible to determine microvascular resistance using the These findings highlight that the effect of PCDA stenosis pressure wire technique in diabetics and non-diabetics, on collateral flow relative to BP may be different between which could give more of an insight why diabetic patients Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 9 of 11 have a lower CFI in the CTO vessel and are particularly planning revascularization procedures, including susceptible to low diastolic BP. Previous studies have characteristics of totally occluded lesion, severity of shown that there exists a pronounced increase of col- PCDA stenosis, quality of collaterals, and clinical sta- lateral resistance  and obliteration of pre-existing tus of patients (diabetes and BP level) . PCI aimed blood vessels in diabetes , suggesting that diabetic at improving collateral flow could be accomplished microvascular resistance is higher in the donor vessel by reducing proximal donor artery stenosis, thereby and contributes to the obstruction of collateral flow to increasing pressure at the collateral takeoff . In the CTO. All these vascular changes could contribute to a patients with moderate PDCA stenosis (especially further reduction in collateral flow for patients with type those with type 2 diabetes), the use of fractional flow 2 diabetes. reserve to reveal ischemia can help in clinical decision- making . Furthermore, hypotension (especially low diastolic BP) should be avoided during the procedure. Clinical implications Whether such a strategy is particularly useful for type 2 Our study findings could partly highlight the importance diabetic patients with CTO and moderate PCDA steno- of an individualized BP lowering strategy [35–37] and sis warrants further investigation. a potential influence of stenotic lesions in the collateral donor coronary artery as a revascularization target [38– 40]. In patients with multivessel disease, caution should Limitations be taken when administering anti-hypertensive thera- We acknowledge there are limitations worth mention- pies, as aggressive reduction in systemic BP (especially ing. First, this study is cross-sectional for the point of diastolic BP) may compromise collateral recruitment and coronary collateral flow investigation, thereby allow - exacerbate myocardial ischemia particularly for those ing us to detect association, not to determine the dif- with type 2 diabetes and stenotic lesions in the PCDA. ference between diabetic and non-diabetic response of Similarly, if the vasodilatory reserve of the arterioles in CFI to increasing diastolic pressure and to establish a the vascular bed supplied by a chronically occluded coro- causative link and to predict clinical outcome. Second, nary artery is completely exhausted, whereas that of the the number of patients in this study is small as com- PCDA is still preserved, coronary (collateral) steal may pared to previous reports using angiography to assess result. This phenomenon has been reported to occur in coronary collateralization in diabetes. However, it was a very high proportion of well collateralized myocardial out-weighted by the use of a quantitative assessment of beds  and is most likely to occur in patients with collateral function, whereas the angiographic method is moderate or severe stenosis of the PCDA, as vasodila- a semi-quantitative grading of collateral contrast filling. tor-induced increase in flow could cause a pressure drop Third, the use of a microcatheter to measure pressure across the stenotic lesions, thereby lowering collateral distal to the occluded segment may be problematic as perfusion [3, 42]. Consistent with previous findings , the lesion may compress the catheter and cause inac- our present study also demonstrates a positive associa- curacy in the pressure measured. Although a pressure tion between β blockers and CFI. The use of β blockers sensowire would have been more accurate, the absolute reduces heart rate, improves fluid shear stress at the difference in intracoronary pressure measurement was endothelial wall, and decrease catecholamine-mediated small using a microcatheter or a pressure wire method. inflammatory response, favoring coronary collateral flow. Finally, central venous pressure was not measured, It is now generally accepted that when presented with which is not a major concern when measuring coronary multivessel disease, we should aim for complete rather fractional flow reserve but could significantly influ - than incomplete revascularization . PCI with drug- ence the CFI. Collaterals in the whole cohort were quite eluting stent implantation on severe coronary stenotic good (CFI > 0.25) for the majority of patients. This may lesions has become a routine clinical practice, and clin- be because CFI was determined on an assumption of ical evidence suggests that recanalization of a CTO as central venous pressure. Obviously, the accuracy of CFI a part of a complete revascularization procedure con- measurement could be significantly affected by minor fers a substantial benefit to survival . Previous stud - variation in actual central venous pressure. Likewise, ies reported that a hemodynamically ambiguous lesion measurement of left ventricular end-diastolic pressure would not necessarily be of low angiographic complex- (LVEDP) in these patients was also important as com- ity, and the need to treat it might alter the long-term pressive forces of the ventricle can influence collateral outcomes . Our observations on the relationship support via septal collaterals. It is possible that diabetic between PDCA stenosis and coronary collateral flow patients have stiffer left ventricle and increased LVEDP relative to diastolic BP supports a notion that multi- that impairs collateral support. ple aspects should be taken into consideration when Shen et al. Cardiovasc Diabetol (2018) 17:76 Page 10 of 11 Conclusions Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- In patients with stable coronary artery disease and lished maps and institutional affiliations. CTO, donor artery stenosis confers greater risk for reduced coronary collateral flow when diastolic BP is Received: 26 February 2018 Accepted: 26 May 2018 decreased. For type 2 diabetic patients, even a mod- erate stenosis in the PCDA is associated with more reduced collateral flow as diastolic BP decreases below References 80 mmHg compared with non-diabetic patients. These 1. Seiler C, Stoller M, Pitt B, Meier P. The human coronary collateral circula- findings may provide clinical insight into the manage - tion: development and clinical importance. Eur Heart J. 2013;34:2674–82. ment of patients with coronary artery disease. 2. Meier P, Hemingway H, Lansky AJ, Knapp G, Pitt B, Seiler C. The impact of the coronary collateral circulation on mortality: a meta-analysis. Eur Heart J. 2012;33:614–21. 3. Zimarino M, D’Andreamatteo M, Waksman R, Epstein SE, De Caterina Abbreviations R. The dynamics of the coronary collateral circulation. Nat Rev Cardiol. ANOVA: analysis of variance; BMI: body mass index; BP: blood pressure; CABG: 2014;11:191–7. coronary artery bypass grafting; CFI: collateral flow index; CKD-EPI: chronic 4. Shen Y, Ding FH, Dai Y, Wang XQ, Zhang RY, Lu L, Shen WF. Reduced kidney disease epidemiology collaboration; CTO: chronic total occlusion; coronary collateralization in type 2 diabetic patients with chronic total CVP: central venous pressure; GFR: glomerular filtration rate; HbA1c: glycated occlusion. Cardiovasc Diabetol. 2018;17:26. hemoglobin; HDL: high-density lipoprotein; hsCRP: high-sensitivity C-reactive 5. Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M, Ohanyan V, Logan S, protein; LSD: least significant difference; NCEP: national cholesterol education Yin L. Coronary collateral growth—back to the future. J Mol Cell Cardiol. program; NYHA: New York Heart Association; Pa: mean central aortic pressure; 2012;52:905–11. PCDA: predominant collateral donor artery; PCI: percutaneous coronary inter- 6. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. vention; Pd: mean distal occluded pressure; SD: standard deviation. 2000;6:389–95. 7. van der Heoven NW, Teunissen PF, Werner GS, Delewi R, Schirmer SH, Authors’ contributions Traupe T, van der Laan AM, Tijssen JG, Seiler C, van Royen N. Clinical YS, FHD, WFS wrote the article, substantially contributed to discussion of the parameters associated with collateral development in patients with content, and edited the manuscript. YS, YZK, HJ, WXQ, DY, ZS performed the chronic coronary total occlusion. Heart. 2013;99:1100–5. experiments and researched data for the article. FHD analyze the data; RYZ, 8. Shen Y, Lu L, Ding FH, Sun Z, Sun Z, Zhang RY, Zhang Q, Yang ZK, Hu J, LL substantially contributed to discussion of the content and reviewed the Chen QJ, et al. Association of increased serum glycated albumin levels manuscript. All authors read and approved the final manuscript. with low coronary collateralization in type 2 diabetic patients with stable angina and chronic total occlusion. Cardiovasc Diabetol. 2013;12:165. Author details 9. Shen Y, Ding FH, Zhang RY, Zhang Q, Lu L, Shen WF. Association of serum Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University mimecan with angiographic coronary collateralization in patients with School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People’s Republic stable coronary artery and chronic total occlusion. Atherosclerosis. of China. Institute of Cardiovascular Diseases, Shanghai Jiao Tong University 2016;252:75–81. School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People’s Republic 10. Shen Y, Lu L, Liu ZH, Wu F, Zhu JZ, Sun Z, Zhang RY, Zhang Q, Hu J, Chen of China. College of Biomedical Engineering, Jiao Tong University, Shang- QJ, et al. Increased serum level of CTRP1 is associated with low coronary hai 200031, People’s Republic of China. collateralization in stable angina patients with chronic total occlusion. Int J Cardiol. 2014;174:203–6. Acknowledgements 11. Ladwiniee A, Connington MS, Rossington J, Mather AN, Alahmar A, Oliver Not applicable. RM, Nijjer SS, Davies JE, Thackray S, Alamgir F, et al. Collateral donor artery physiology and the influence if a CTO on fractional flow reserve. Circ Competing interests Cardiovasc Interv. 2015;8:e002219. The authors declare that they have no competing interests. 12. Werner GS. The role of coronary collaterals in chronic total occlusion. Curr Cardiol Rev. 2014;10:57–64. Availability of data and materials 13. Seiler C, Fleisch M, Garachemani A, Meier B. Coronary collateral quantita- Data generated or analyzed during this study are included in this published tion in patients with coronary artery disease using intravascular flow article. velocity or pressure measurements. 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