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Coronary volume to left ventricular mass ratio in patients with diabetes mellitus

Open AccessPublished:January 31, 2022DOI:https://doi.org/10.1016/j.jcct.2022.01.004

      Abstract

      Background

      Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and may provoke structural and functional changes in coronary vasculature. The coronary volume to left ventricular mass (V/M) ratio is a new anatomical parameter capable of revealing a potential physiological imbalance between coronary vasculature and myocardial mass. The aim of this study was to examine the V/M derived from coronary computed tomography angiography (CCTA) in patients with diabetes.

      Methods

      Patients with clinically suspected CAD enrolled in the ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) registry and known diabetic status were included. Coronary artery volume and left ventricular myocardial mass were analyzed from CCTA and the V/M ratio was calculated and compared between patients with and without diabetes.

      Results

      Of the 3053 patients (age 66 ​± ​10 years; 66% male) with known diabetic status, diabetes was present in 21.9%. Coronary volume was lower in patients with diabetes compared to those without diabetes (2850 ​± ​940 ​mm3 vs. 3040 ​± ​970 ​mm3, p ​< ​0.0001), whereas the myocardial mass was comparable between the 2 groups (122 ​± ​33 ​g vs. 122 ​± ​32 ​g, p ​= ​0.70). The V/M ratio was significantly lower in patients with diabetes (23.9 ​± ​6.8 ​mm3/g vs. 25.7 ​± ​7.5 ​mm3/g, p ​< ​0.0001). Among subjects with obstructive CAD (n ​= ​2191, 24.0% diabetics) and non-obstructive CAD (16.7% diabetics), the V/M ratio was significantly lower in patients with diabetes compared to those without (23.4 ​± ​6.7 ​mm3/g vs. 25.0 ​± ​7.3 ​mm3/g, p ​< ​0.0001 and 25.6 ​± ​6.9 ​mm3/g vs. 27.3 ​± ​7.6 ​mm3/g, respectively, p ​= ​0.006).

      Conclusion

      The V/M ratio was significantly lower in patients with diabetes compared to non-diabetics, even after correcting for obstructive coronary stenosis. The clinical value of the reduced V/M ratio in diabetic patients needs further investigation.

      Graphical abstract

      Keywords

      List of abbreviations

      ADVANCE
      Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care registry
      CAD
      Coronary artery disease
      CCTA
      Coronary computed tomography angiography
      FFR
      Fractional flow reserve
      FFRCT
      CCTA-derived fractional flow reserve
      LV
      Left ventricular
      V/M
      Coronary artery volume to left ventricular myocardial mass

      1. Introduction

      The ratio of the total epicardial coronary artery lumen volume to left ventricular (LV) myocardial mass (V/M) is a newly available anatomical parameter capable of revealing a potential physiological imbalance between the supply (coronary artery epicardial volume) and demand (myocardial mass).
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      Coronary lumen volume to myocardial mass ratio in primary microvascular angina.
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      Effect of the ratio of coronary arterial lumen volume to left ventricle myocardial mass derived from coronary CT angiography on fractional flow reserve.
      Previous studies observed that low V/M ratios derived from coronary computed tomography angiography (CCTA) were related with more advanced CAD, reduced myocardial blood flow and lesion-specific fractional flow reserve (FFR) ≤0.80 suggesting ischemia.
      • Taylor C.A.
      • Gaur S.
      • Leipsic J.
      • et al.
      Effect of the ratio of coronary arterial lumen volume to left ventricle myocardial mass derived from coronary CT angiography on fractional flow reserve.
      ,
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      • Bom M.J.
      • et al.
      The association of coronary lumen volume to left ventricle mass ratio with myocardial blood flow and fractional flow reserve.
      Diabetes mellitus is a major risk factor for CAD affecting millions of people worldwide.
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      • Abbott R.D.
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      Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study.
      ,
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      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas.
      Moreover, diabetes has been associated with increased total coronary artery plaque burden, more advanced coronary atherosclerosis, and increased risk of adverse cardiovascular events.
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      • et al.
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
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      • Framingham Heart S.
      The significant effect of diabetes duration on coronary heart disease mortality: the Framingham Heart Study.
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      • Schuijf J.D.
      • Jukema J.W.
      • et al.
      Type 2 diabetes is associated with more advanced coronary atherosclerosis on multislice computed tomography and virtual histology intravascular ultrasound.
      • Kim J.J.
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      • Choi I.J.
      • et al.
      Impact of diabetes duration on the extent and severity of coronary atheroma burden and long-term clinical outcome in asymptomatic type 2 diabetic patients: evaluation by Coronary CT angiography.
      • van den Hoogen I.J.
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      • Lin F.Y.
      • et al.
      Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: propensity score-based analysis of diabetic and non-diabetic patients.
      In addition, diabetes has been associated with abnormalities in the coronary circulation including microvascular dysfunction and reduced vasodilation capacity.
      • Galderisi M.
      • Capaldo B.
      • Sidiropulos M.
      • et al.
      Determinants of reduction of coronary flow reserve in patients with type 2 diabetes mellitus or arterial hypertension without angiographically determined epicardial coronary stenosis.
      The high rate of adverse events in diabetic patients with CAD has raised questions about the roles of anatomic and functional characteristics of diabetic coronary arteries. The V/M ratio might provide additional insight into the epicardial vascular characteristics and risk in patients with diabetes. However, data examining the V/M ratio in patients with diabetes are lacking. The aim of this study is to evaluate the association of the V/M ratio with the diabetic status using the data from a large multicenter registry comprising diabetic and non-diabetic subjects with clinically suspected CAD.

      2. Methods

      2.1 Study populations

      Patients were selected from the Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care (ADVANCE) registry (NCT02499679). ADVANCE is an international multicenter, prospective registry designed to evaluate the utility of CCTA-derived Fractional Flow Reserve (FFRCT) in the clinical setting. The design of the study has been described in detail previously.
      • Chinnaiyan K.M.
      • Akasaka T.
      • Amano T.
      • et al.
      Rationale, design and goals of the HeartFlow assessing diagnostic value of non-invasive FFRCT in Coronary Care (ADVANCE) registry.
      In short, subjects were enrolled in 38 sites across North America, Europe, and Asia between July 2015–October 2017. Patients with clinically suspected CAD >18 years of age with documented atherosclerosis on CCTA and ability to provide written informed consent were included. The patients without CAD on CCTA, insufficient CCTA image quality, life expectancy <1 year and inability to comply with follow-up were excluded. In the present analysis, only patients with a) known diabetic status and b) coronary artery lumen volume and LV myocardial mass analysis were included. The study complied with the Declaration of Helsinki. All subjects provided written informed consent following local Institutional Review Board approval.

      2.2 CCTA acquisition and image analysis

      CCTA was performed in accordance with local and international guidelines using ≥64-row multidetector computed tomography scanners.
      • Abbara S.
      • Blanke P.
      • Maroules C.D.
      • et al.
      SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography: a report of the society of cardiovascular computed tomography guidelines committee: endorsed by the North American society for cardiovascular imaging (NASCI).
      ,
      • Leipsic J.
      • Abbara S.
      • Achenbach S.
      • et al.
      SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee.
      Sublingual nitrates were administered before scanning in all subjects and, if necessary, beta-blockers were administered in order to achieve a heart rate <60 bpm. All coronary arteries ≥2 ​mm diameter were evaluated for stenosis severity in accordance with current guidelines.
      • Leipsic J.
      • Abbara S.
      • Achenbach S.
      • et al.
      SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee.
      The strategy of visual CCTA assessment was left to the discretion of the local investigators of each site. CCTA images were submitted to a central core laboratory for FFRCT and V/M analysis (HeartFlow Inc., Redwood City, California, USA) which has been described previously.
      • Grover R.
      • Leipsic J.A.
      • Mooney J.
      • et al.
      Coronary lumen volume to myocardial mass ratio in primary microvascular angina.
      ,
      • Chinnaiyan K.M.
      • Akasaka T.
      • Amano T.
      • et al.
      Rationale, design and goals of the HeartFlow assessing diagnostic value of non-invasive FFRCT in Coronary Care (ADVANCE) registry.
      ,
      • Taylor C.A.
      • Fonte T.A.
      • Min J.K.
      Computational fluid dynamics applied to cardiac computed tomography for noninvasive quantification of fractional flow reserve: scientific basis.
      • Gaur S.
      • Achenbach S.
      • Leipsic J.
      • et al.
      Rationale and design of the HeartFlowNXT (HeartFlow analysis of coronary blood flow using CT angiography: NeXt sTeps) study.
      • Kitabata H.
      • Leipsic J.
      • Patel M.R.
      • et al.
      Incidence and predictors of lesion-specific ischemia by FFRCT: learnings from the international ADVANCE registry.
      In brief, a 3-dimensional model of the coronary tree was derived from the CCTA datasets provided. For FFRCT analysis, the luminal boundaries of all vessels >1 ​mm diameter were extracted, the total coronary flow was computed and coronary resistance under hyperemia was calculated. For V/M analysis, the total coronary arterial lumen volume and LV myocardial volume were measured.
      • Fairbairn T.A.
      • Dobson R.
      • Hurwitz-Koweek L.
      • et al.
      Sex differences in coronary computed tomography angiography-derived fractional flow reserve: lessons from ADVANCE.
      The volume of the extracted myocardium was multiplied by 1.05 ​g/ml to calculate the myocardial mass. Subsequently, the ratio between the coronary arterial lumen volume and LV myocardial mass was calculated (Fig. 1).
      Figure 1
      Figure 1Graphical presentation of the coronary artery volume and left ventricular myocardial mass and the coronary volume to left ventricular mass ratio showing the difference between a non-diabetic (top of figure) and a diabetic patient (bottom of figure). Both subjects had non-obstructive coronary artery disease (0–30% diameter stenosis).

      2.3 Clinical endpoints

      The diagnosis of diabetes was based on the medical history in the electronic case report forms. There was no sub-classification of Type 1 or 2 diabetes. Baseline patient characteristics, including cardiac risk factors and symptom status, and CCTA data were obtained and compared between patients with and without diabetes. In addition, the coronary volume and LV myocardial mass were separately analyzed among subjects with anatomically obstructive and non-obstructive CAD. Obstructive CAD was defined as any atherosclerotic lesion ≥50% diameter stenosis.

      2.4 Statistical analysis

      Continuous variables following a normal distribution are presented as mean ​± ​standard deviation (SD). Continuous variables were compared using a 2-sample t-test with Satterthwaite approximation for the degrees of freedom. Categorical variables are presented as absolute numbers and percentages (%) and were compared using the χ2 test. Analysis of covariance (ANCOVA) models were used to correct for the potential confounding effect of age, body mass index, hypertension, hyperlipidemia, smoking status and the number of vessels with obstructive CAD on the coronary volume and LV myocardial mass as well as V/M ratio, and were used as covariates. The differences in coronary volume, LV myocardial mass and the V/M ratio between patients with and without diabetes in the ANCOVA models are presented as least square (LS) mean difference estimate with 95% confidence intervals (CI). A p-value <0.05 was considered significant. All statistical analysis were performed using SAS version 9.4 (SAS institute, Cary, North Carolina, USA).

      3. Results

      3.1 Study population

      A total of 5083 patients were enrolled in the ADVANCE registry. Of these, 3053 patients (age 66.4 ​± ​10.3 years; 66% male) with known diabetic status and measured V/M ratio were included in this analysis. A flowchart of patient enrolment and follow-up is shown in Fig. 2. Comparison of the patients included in the analysis versus those excluded due to missing V/M ratios is shown in the Supplemental Table 1. Diabetes was present in 670 patients (21.9%). Baseline patient demographic and clinical characteristics are summarized in Table 1. Patients with diabetes had a higher cardiovascular risk profile, were older (67.6 ​± ​9.8 vs 66.1 ​± ​10.4 years, p ​= ​0.001), had a higher body mass index (BMI) (27.0 ​± ​5.2 vs 26.1 ​± ​4.7 ​kg/m2, p ​< ​0.0001) and were more likely to be current smokers (p ​= ​0.039) as compared to patients without diabetes. In addition, hypertension and hyperlipidemia were more often present among patients with diabetes (both p ​< ​0.0001).
      Figure 2
      Figure 2Flowchart study population. CAD ​= ​coronary artery disease, CCTA ​= ​coronary computed tomography angiography, LV ​= ​left ventricular, V/M ​= ​coronary volume and left ventricular mass.
      Table 1Baseline patient demographic and clinical characteristics of patients according to diabetic status.
      Total (n ​= ​3053)Diabetes (n ​= ​670)No diabetes (n ​= ​2383)p-value
      Age, y66.4 ​± ​10.367.6 ​± ​9.866.1 ​± ​10.40.001
      Male sex, n (%)2021 (66.2)453 (67.6)1568 (65.8)0.38
      Body mass index, kg/m226.3 ​± ​4.827.0 ​± ​5.226.1 ​± ​4.7<0.0001
      Diamond Forrester CAD likelihood51 ​± ​2052 ​± ​2051 ​± ​200.14
      Hypertension, n (%)1856 (60.8)510 (76.1)1346 (56.5)<0.0001
      Hyperlipidemia, n (%)1851 (60.6)482 (71.9)1369 (57.4)<0.0001
      Tobacco use, n (%)
      Current smoker496 (16.2)131 (19.6)365 (15.3)0.039
      Ex-Smoker1046 (34.3)230 (34.3)816 (34.2)
      Never Smoked1291 (42.3)269 (40.1)1022 (42.9)
      Unknown220 (7.2)40 (6.0)180 (7.6)
      Angina status, n (%)
      Typical597 (19.6)131 (19.6)466 (19.6)0.042
      Atypical1098 (36.0)228 (34.0)870 (36.5)
      Dyspnea343 (11.2)68 (10.1)275 (11.5)
      Non-cardiac Pain181 (5.9)31 (4.6)150 (6.3)
      None811 (26.6)206 (30.7)605 (25.4)
      Unknown23 (0.8)6 (0.9)17 (0.7)
      CCS Angina class, n (%)
      Grade I141/597 (23.6)32/131 (24.4)109/466 (23.4)0.067
      Grade II334/597 (55.9)69/131 (52.7)265/466 (56.9)
      Grade II62/597 (10.4)20/131 (15.3)42/466 (9.0)
      Grade IV11/597 (1.8)5/131 (3.8)6/466 (1.3)
      Unknown49/597 (8.2)5/131 (3.8)44/466 (9.4)
      Data are presented as mean ​± ​SD or n (%). CAD ​= ​coronary artery disease; CCS = Canadian Cardiovascular Society.

      3.2 CCTA parameters and coronary volume to mass ratio in diabetic and non-diabetic patients

      The main CCTA characteristics are reported in Table 2. Patients with diabetes had more frequently obstructive CAD and severe stenosis by anatomical CCTA evaluation (both p ​< ​0.0001). In the quantitative analysis, epicardial coronary artery volume was lower in patients with diabetes (2850 ​± ​940 ​mm3 vs. 3040 ​± ​970 ​mm3, p ​< ​0.0001), whereas the LV myocardial mass was comparable between patients with and without diabetes (122 ​± ​33 ​g vs. 122 ​± ​32 ​g, p ​= ​0.70). The V/M ratio was significantly lower in patients with diabetes (23.9 ​± ​6.8 ​mm3/g vs. 25.7 ​± ​7.5 ​mm3/g, p ​< ​0.0001, Fig. 3).
      Table 2Coronary computed tomography angiography parameters of patients according to diabetic status.
      Total (n ​= ​3053)Diabetes (n ​= ​670)No diabetes (n ​= ​2383)p-value
      CCTA anatomical stenosis, n (%)
      Non-obstructive stenosis <50%856 (28.0)143 (21.3)713 (29.9)<0.0001
      Obstructive stenosis ≥50%2191 (71.8)525 (74.4)1666 (69.9)
      Unknown6 (0.2)2 (0.3)4 (0.2)
      Non-severe stenosis ≤70%2069 (67.8)388 (57.9)1681 (70.5)<0.0001
      Severe stenosis >70%978 (32.0)280 (41.8)698 (29.3)
      Unknown6 (0.2)2 (0.3)4 (0.2)
      Degree stenosis, n (%)
      Normal (0%)18 (0.6)3 (0.4)15 (0.6)<0.0001
      Minimal (0–30%)158 (5.2)22 (3.3)136 (5.7)
      Mild (30–50%)680 (22.3)118 (17.6)562 (23.6)
      Moderate (50–70%)1213 (39.7)245 (36.6)968 (40.6)
      Severe (70–90%)687 (22.5)194 (29.0)493 (20.7)
      Sub-total/occluded (≥90%)291 (9.5)86 (12.8)205 (8.6)
      Unknown6 (0.2)2 (0.3)4 (0.2)
      Number of vessels with anatomically obstructive CAD ≥50% DS, n (%)
      0856 (28.0)143 (21.3)713 (29.9)<0.0001
      11355 (44.4)290 (43.3)1065 (44.7)
      2557 (18.2)137 (20.4)420 (17.6)
      3279 (9.1)98 (14.6)181 (7.6)
      4000
      Unknown6 (0.2)2 (0.3)4 (0.2)
      Rate of obstructive CAD per vessel, n (%)
      LAD stenosis <50%1319 (43.2)247 (36.9)1072 (45.0)0.0002
      LAD stenosis ≥50%1734 (56.8)423 (63.1)1311 (55.0)
      LCX stenosis <50%2321 (76.0)457 (68.2)1864 (78.2)<0.0001
      LCX stenosis ≥50%732 (24.0)213 (31.8)519 (21.8)
      RCA stenosis <50%2213 (72.5)448 (66.9)1765 (74.1)0.0002
      RCA stenosis ≥50%840 (27.5)222 (33.1)618 (25.9)
      Coronary volume – myocardial mass
      Epicardial coronary artery volume, mm33000 ​± ​9702850 ​± ​9403040 ​± ​970<0.0001
      LV myocardial mass, g122 ​± ​32122 ​± ​33122 ​± ​320.70
      Coronary volume/mass ratio, mm3/g25.3 ​± ​7.423.9 ​± ​6.825.7 ​± ​7.5<0.0001
      Data are presented as mean ​± ​SD or n (%). CAD ​= ​coronary artery disease; CCTA ​= ​coronary computed tomography angiography; DS ​= ​diameter stenosis; LAD ​= ​left anterior descending artery; LCX ​= ​left circumflex artery; LV ​= ​left ventricular; RCA ​= ​right coronary artery.
      Figure 3
      Figure 3Bar chart showing the mean coronary artery volume, LV myocardial mass and V/M ratio for patients with and without diabetes.

      3.3 Clinical and CCTA parameters and coronary volume to mass ratio in patients with obstructive CAD

      Obstructive CAD was present in 2191 subjects (71.9%) of which 525 (24.0%) had diabetes. Baseline patient demographic and clinical characteristics for patients with obstructive CAD are shown in Table 3. In subjects with obstructive CAD, patients with diabetes were older (p ​= ​0.03), had a higher BMI (p ​= ​0.0003), had more frequently a history of hypertension and hyperlipidemia (p ​< ​0.0001 for both), and were more likely to be current smokers (p ​= ​0.045).
      Table 3Baseline patient demographic and clinical characteristics of patients with anatomically obstructive and non-obstructive CAD according to diabetic status.
      Obstructive CAD (≥50% DS)Non-obstructive CAD (<50% DS)
      Total (n ​= ​2191)Diabetes (n ​= ​525)No diabetes (n ​= ​1666)p-valueTotal (n ​= ​856)Diabetes (n ​= ​143)No diabetes (n ​= ​713)p-value
      Age, y66.8 ​± ​10.167.7 ​± ​9.766.6 ​± ​10.30.0365.3 ​± ​10.667.2 ​± ​10.164.9 ​± ​10.70.02
      Male sex, n (%)1526 (69.6)374 (71.2)1152 (69.1)0.3637492 (57.5)78 (54.5)414 (58.1)0.44
      Body mass index, kg/m226.1 ​± ​4.626.8 ​± ​5.025.9 ​± ​4.50.000326.7 ​± ​5.327.9 ​± ​5.626.4 ​± ​5.20.005
      Diamond Forrester CAD likelihood53 ​± ​2054 ​± ​2053 ​± ​200.3746 ​± ​1946 ​± ​1946 ​± ​190.95
      Hypertension, n (%)1365 (62.3)397 (75.6)968 (58.1)<0.0001487 (56.9)111 (77.6)376 (52.7)<0.0001
      Hyperlipidemia, n (%)1332 (60.8)372 (70.9)960 (57.6)<0.0001514 (60.0)108 (75.5)406 (56.9)<0.0001
      Tobacco use, n (%)
      Current smoker386 (17.6)112 (21.3)274 (16.4)0.045109 (12.7)18 (12.6)91 (12.8)0.99
      Ex-Smoker758 (34.6)182 (34.7)576 (34.6)286 (33.4)48 (33.6)238 (33.4)
      Never Smoked896 (40.9)202 (38.5)694 (41.7)393 (45.9)67 (46.9)326 (45.7)
      Unknown151 (6.9)29 (5.5)122 (7.3)68 (7.9)10 (7.0)58 (8.1)
      Angina status, n (%)
      Typical500 (22.8)118 (22.5)382 (22.9)0.03296 (11.2)13 (9.1)83 (11.6)0.74
      Atypical740 (33.8)172 (32.8)568 (34.1)356 (41.6)56 (39.2)300 (42.1)
      Dyspnea222 (10.1)45 (8.6)177 (10.6)121 (14.1)23 (16.1)98 (13.7)
      Non-cardiac Pain120 (5.5)20 (3.8)100 (6.0)59 (6.9)9 (6.3)50 (7.0)
      None594 (27.1)166 (31.6)428 (25.7)216 (25.2)40 (28.0)176 (24.7)
      Unknown15 (0.7)4 (0.8)11 (0.7)8 (0.9)2 (1.4)6 (0.8)
      CCS Angina class, n (%)
      Grade I117/500 (23.4)27/118 (22.9)90/382 (23.6)0.04823/96 (24.0)5/13 (38.5)18/83 (21.7)0.64
      Grade II284/500 (56.8)62/118 (52.5)222/382 (58.1)50/96 (52.1)7/13 (53.8)43/83 (5.8)
      Grade III58/500 (11.6)20/118 (16.9)38/382 (9.9)4/96 (4.2)0/134/83 (4.8)
      Grade IV10/500 (2.0)5/118 (4.2)5/382 (1.3)1/96 (1.0)0/131/83 (1.2)
      Unknown31/500 (6.2)4/118 (3.4)27/382 (7.1)18/96 (18.8)1/13 (7.7)17/83 (20.5)
      Coronary volume – myocardial mass
      Epicardial coronary artery volume, mm32940 ​± ​9502800 ​± ​9202990 ​± ​950<0.00013150 ​± ​10103030 ​± ​10003170 ​± ​10200.13
      LV myocardial mass, g123 ​± ​32122 ​± ​32123 ​± ​320.63120 ​± ​33122 ​± ​39119 ​± ​320.31
      Coronary volume/mass ratio, mm3/g24.6 ​± ​7.223.4 ​± ​6.725.0 ​± ​7.3<0.000127.0 ​± ​7.525.6 ​± ​6.927.3 ​± ​7.60.006
      Data are presented as mean ​± ​SD or n (%). CAD ​= ​coronary artery disease; CCS = Canadian Cardiovascular Society; LV ​= ​left ventricular.
      Coronary volume was significantly lower in patients with diabetes compared to non-diabetic patients who had obstructive coronary disease (2800 ​± ​920 ​mm3 vs. 2990 ​± ​950 ​mm3, p ​< ​0.0001). LV mass was not significantly different between groups (122 ​± ​31 ​g vs. 123 ​± ​32 ​g, respectively, p ​= ​0.63). Accordingly, the V/M ratio was significantly lower in patients with diabetes (23.4 ​± ​6.7 ​mm3/g vs. 25.0 ​± ​7.3 ​mm3/g, p ​< ​0.0001, Fig. 4).
      Figure 4
      Figure 4Bar chart showing the mean coronary artery volume, LV myocardial mass and V/M ratio for diabetic and non-diabetic patients in subjects with anatomically obstructive and non-obstructive CAD.

      3.4 Clinical and CTA parameters and coronary volume to mass ratio in patients with non-obstructive CAD

      Diabetes was present in 143 out of 856 (16.7%) patients with non-obstructive CAD. Patients with diabetes were older (p ​= ​0.02), had a higher BMI (p ​= ​0.005), had more frequently a history of hypertension and hyperlipidemia (p ​< ​0.0001 for both). Smoking status was similar between patients with and without diabetes in subjects with non-obstructive CAD (p ​= ​0.99, Table 3) which was in contrast to those with obstructive coronary disease.
      Coronary volume was not significantly different between patients with and without diabetes who did not have obstructive coronary disease (3030 ​± ​1000 ​mm3 vs. 3170 ​± ​1020 ​mm3, p ​= ​0.13). Moreover, LV mass was comparable between groups (122 ​± ​39 ​g vs. 119 ​± ​32 ​g, respectively, p ​= ​0.31). Still, the V/M ratio was significantly lower in patients with diabetes (25.6 ​± ​6.9 ​mm3/g vs. 27.3 ​± ​7.6 ​mm3/g, p ​= ​0.006, Fig. 4).
      Similar results were observed when correcting for the differences in baseline and CCTA characteristics between patients with and without diabetes: significantly lower coronary volume and V/M ratio in patients with diabetes versus those without (LS mean difference estimate: −209 (95% CI: −295,-123) mm3, p ​< ​0.001 and −1.4 (95% CI: −2.0, −0.8) mm3/g, p ​< ​0.001, respectively), whereas the myocardial mass was comparable in both groups (LS mean difference estimate: −2.3 (95% CI: −5.0, 0.5) g, p ​= ​0.19).

      4. Discussion

      We examined the coronary V/M ratio in patients with and without diabetes in the multicenter ADVANCE registry comprising subjects with suspected stable CAD. We found that patients with diabetes had a significantly lower V/M ratio compared to those without diabetes. This difference was observed not only in diabetic patients with obstructive CAD but also among those with non-obstructive CAD or when corrected for differences in baseline characteristics.
      The principle of the V/M ratio is based on allometric scaling laws and was first described by Gould et al. over 40 years ago.
      • Gould K.L.
      • Lipscomb K.
      • Hamilton G.W.
      Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve.
      More recently, CCTA proved to be an excellent noninvasive instrument capable to perform coronary volume and myocardial mass analysis. Previous studies including data from the NXT (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps) and PACIFIC (Prospective Comparison of CCTA, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease using FFR) trials reported that patients with a low V/M ratio had more extensive atherosclerosis and also reduced myocardial blood flow on positron emission tomography compared to patients with a high V/M ratio.
      • van Diemen P.A.
      • Schumacher S.P.
      • Bom M.J.
      • et al.
      The association of coronary lumen volume to left ventricle mass ratio with myocardial blood flow and fractional flow reserve.
      Furthermore, the V/M ratio was independently associated with an FFR ≤0.80.
      • Taylor C.A.
      • Gaur S.
      • Leipsic J.
      • et al.
      Effect of the ratio of coronary arterial lumen volume to left ventricle myocardial mass derived from coronary CT angiography on fractional flow reserve.
      Diabetes has been linked with increased risk of atherosclerosis but also abnormalities in the coronary circulation including microvascular dysfunction and reduced vasodilation capacity.
      • Galderisi M.
      • Capaldo B.
      • Sidiropulos M.
      • et al.
      Determinants of reduction of coronary flow reserve in patients with type 2 diabetes mellitus or arterial hypertension without angiographically determined epicardial coronary stenosis.
      We observed that the decreased V/M ratio in patients with diabetes was mainly driven by lower coronary artery volume while LV myocardial mass was comparable between the groups. As the presence of atherosclerosis has been linked with reduced coronary volume, we analyzed separately the patients with and without obstructive CAD. The V/M ratio in diabetic patients was found to be reduced in both groups.
      The question arises why the V/M ratio is lower in patients with diabetes compared to non-diabetics. Since the LV mass is similar in both groups, the difference in the V/M ratio is explained by the lower coronary volume. There are several potential mechanisms by which the coronary volume - and thus the V/M ratio - is reduced in patients with diabetes. One explanation is that atherosclerosis is more advanced, even in the group without obstructive CAD. Patients with diabetes have shown increased plaque burden and more advanced atherosclerosis compared to non-diabetic patients with a subsequent augmented risk of adverse outcome.
      • Fox C.S.
      • Sullivan L.
      • D'Agostino RB, Sr
      • Wilson P.W.
      • Framingham Heart S.
      The significant effect of diabetes duration on coronary heart disease mortality: the Framingham Heart Study.
      ,
      • Rana J.S.
      • Dunning A.
      • Achenbach S.
      • et al.
      Differences in prevalence, extent, severity, and prognosis of coronary artery disease among patients with and without diabetes undergoing coronary computed tomography angiography: results from 10,110 individuals from the CONFIRM (COronary CT Angiography EvaluatioN for Clinical Outcomes): an InteRnational Multicenter Registry.
      ,
      • Pundziute G.
      • Schuijf J.D.
      • Jukema J.W.
      • et al.
      Noninvasive assessment of plaque characteristics with multislice computed tomography coronary angiography in symptomatic diabetic patients.
      Atherosclerosis may also reduce the coronary volume, not only directly via its lumen narrowing effect, but also as a result of impaired endothelial function with a subsequent reduction of vasodilator capacity.
      • Davignon J.
      • Ganz P.
      Role of endothelial dysfunction in atherosclerosis.
      The vascular complications of diabetes independent of atherosclerosis might provide a second explanation for the lower V/M ratios in diabetic patients. As a result of insulin resistance, chronic hyperglycemia and autonomic dysfunction, diabetes may alter vascular structure and function. High glucose concentrations lead to endothelial dysfunction due to several pathophysiological mechanisms including an imbalance between nitric oxide bioavailability and accumulation of reactive oxygen species.
      • Paneni F.
      • Beckman J.A.
      • Creager M.A.
      • Cosentino F.
      Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I.
      Accordingly, endothelial dysfunction results in reduced vasodilatation after the admission of nitrates. Moreover, this impaired response to hyperemia has been found even in the absence of atherosclerosis.
      • Gargiulo G.
      • Stabile E.
      • Ferrone M.
      • et al.
      Diabetes does not impact the diagnostic performance of contrast-based fractional flow reserve: insights from the CONTRAST study.
      Microvascular dysfunction has been linked with reduced V/M ratio in a retrospective case-control study by Grover et al.
      • Grover R.
      • Leipsic J.A.
      • Mooney J.
      • et al.
      Coronary lumen volume to myocardial mass ratio in primary microvascular angina.
      that reported significantly lower V/M ratios in patients who met the criteria for microvascular angina as compared to their matched controls. This difference was mainly driven by lower coronary artery volumes. These results support the hypothesis that a lower V/M ratio could be linked with microvascular dysfunction in patients with diabetes, although no direct evidence for this was provided by the present study.

      4.1 Limitations

      This study has some limitations. First, the ADVANCE registry, as with all registries, may have been affected by referral bias. Second, of the total of 5083 subjects enrolled in the ADVANCE registry, diabetic status was unknown in 47 patients. In addition, the V/M ratio analysis was performed in only 3053 studies because of software development during the study time period. However, the patient characteristics of the population with measured V/M ratio were comparable with the total population in this registry (Supplemental Table 1). Fourth, this study lacked the ability to further characterize atherosclerosis. In addition, right ventricular mass was not measured in the current analysis. At last, the diagnosis of diabetes was based on medical history and detailed information about the severity and duration as well as type and treatment of the diabetes was lacking.

      5. Conclusion

      The coronary volume to myocardial mass ratio was significantly lower in patients with diabetes compared to non-diabetics, even after correcting for obstructive coronary stenosis and differences in baseline characteristics. Whether this is due to more advanced CAD in diabetics or diabetic-related changes in coronary structure and function remains unclear. These intriguing findings provide interesting data for future studies. The clinical value of the V/M ratio needs also further investigation.

      Funding

      This study was supported by HeartFlow Inc., Redwood City, CA, USA .

      Declaration of competing interest

      The department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands has received unrestricted research grants from Medtronic, Biotronik, Boston Scientific, and Edwards Lifesciences . Dr. Patel has received research grants from HeartFlow, Bayer, Janssen, and the National Heart, Lung, and Blood Institute ; and has served on the advisory board for HeartFlow, Bayer, and Janssen. Dr. Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr. Fairbairn has served on the Speakers Bureau for HeartFlow. Dr. Nieman has received institutional research support from Siemens Healthineers, HeartFlow, GE Healthcare, and Bayer Healthcare. Dr. Berman has received unrestricted research support from HeartFlow. Dr. Hurwitz Koweek has received research support and speaking fees from HeartFlow and Siemens. Dr. Pontone has received institutional research grant and/or honorarium as consultant/speaker from GE Healthcare, Boehringer, Bracco, Medtronic, Bayer, and HeartFlow. Dr. Sonck has received research grant support from the Cardiopath PhD program. Dr. Rabbat has served as a consultant for HeartFlow. Dr. De Bruyne has received consulting fees from Abbott, Opsens, and Boston Scientific; and is a shareholder for Siemens, GE Healthcare, Bayer, Philips, HeartFlow, Edwards Lifesciences, and Sanofi. Dr. Rogers is employee of and owns equity in HeartFlow. Dr. Leipsic has received research grants from GE Healthcare and Edwards Lifesciences; and has served as a consultant for and holds stock options in Circle Cardiovascular Imaging and HeartFlow Inc. Dr. Bax has received speaker fees from Abbot Vascular. Dr. Knuuti has received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim and Merck, outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

      Acknowledgements

      The authors would like to thank Ms. Amy Flynt (PharPoint Research), Ms. Whitney Huey and Ms. Sarah Mullen for their contribution towards data collection and analysis.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

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