Bilateral Internal Thoracic Artery Grafting Improves Survival for Severe Left Ventricular Dysfunction and Diabetes

Abstract

Background: In patients with severe left ventricular (LV) dysfunction requiring coronary artery bypass grafting (CABG), the association between diabetic status and outcomes after surgery, as well as with survival benefit following bilateral internal thoracic artery (ITA) grafting, remain largely unknown.

Methods and Results: Patients (n=188; mean [±SD] age 67±9 years) with LV ejection fraction ≤40% who underwent isolated initial CABG were classified into non-diabetic (n=64), non-insulin-dependent diabetic (NIDM; n=74), and insulin-dependent diabetic (IDM; n=50) groups. During follow-up (mean [±SD] 68±47 months), the 5-year survival rate was 84% and 65% among non-diabetic and diabetic patients, respectively (P=0.034). After adjusting for all covariates, both NIDM and IDM were associated with increased mortality, with hazard ratios (HRs) of 1.9 (95% confidence interval [CI] 1.0–3.7; P=0.049) and 2.4 (95% CI 1.2–4.8; P=0.016), respectively. Among non-diabetic patients, there was no difference in the 5-year survival rate between single and bilateral ITA grafting (86% vs. 80%, respectively; P=0.95), whereas bilateral ITA grafting increased survival among diabetic patients (57% vs. 81%; P=0.004). Multivariate analysis revealed that bilateral ITA was significantly associated with a decreased risk of mortality (HR 0.3; 95% CI 0.1–0.8; P=0.024).

Conclusions: NIDM and IDM were significantly associated with worse long-term clinical outcome after CABG for severe LV dysfunction. Bilateral ITA grafting has the potential to improve survival in diabetic patients with severe LV dysfunction.

Coronary artery disease and diabetes mellitus (DM) are major health problems worldwide. Coronary artery disease is the leading cause of mortality in diabetic patients, whereas DM is strongly associated with poor outcomes in patients with coronary artery disease. The 2 conditions share a number of risk factors, including hypertension, chronic kidney disease, and impaired left ventricular (LV) function.¹ The increase in the number of patients with diabetes has led to increased referrals for percutaneous or surgical revascularization for severe coronary artery disease and LV dysfunction.^2,3

Editorial p 2002

Numerous studies have shown detrimental effects of diabetes on short- and long-term outcomes in patients who undergo coronary artery bypass grafting (CABG), although the associations of non-insulin-dependent DM (NIDM) and insulin-dependent DM (IDM) with late outcomes after surgery remain largely unknown.^4,5 Some studies have reported that patients with diabetes, especially IDM, have higher rates of perioperative morbidity and mortality and reduced long-term survival after CABG than patients without diabetes, but most patients in those studies did not present with LV dysfunction at the time of surgery.^6,7 Therefore, it remains unknown whether diabetic status affects surgical outcome in patients with severe LV dysfunction. Furthermore, it remains controversial whether the use of bilateral internal thoracic arteries (ITA) is associated with improved long-term outcomes following surgical revascularization, especially in patients with LV dysfunction. In the present study, we evaluated the associations of diabetic status with postoperative LV reverse remodeling, changes in renal function, and late outcomes following surgical revascularization, with a focus on patients with severely impaired LV function. We also investigated the survival benefit of bilateral ITA grafting over single ITA grafting according to diabetic status.

Methods

Study Patients

In all, 533 patients with chronic coronary disease suitable for surgical revascularization and severe LV dysfunction (defined as severely impaired LV systolic function with ejection fraction [EF] ≤40%) who underwent CABG between 1995 and 2015 were identified. Among patients, those who underwent other concomitant cardiac procedures (n=335) and those with a history of open heart surgery (n=9) were excluded from the present study. Supplementary Figure 1 shows selection of the patient population.

Patients were classified into the following 3 groups based on diabetic status at the time of surgery: (1) no evidence of diabetes (non-diabetic group); (2) patients with NIDM treated with diet or oral hypoglycemic agents; and (3) patients with IDM. The final study protocol was approved by the Institutional Review Board of Osaka University Hospital (Reference no. 08218-6), and all participants provided written informed consent.

Echocardiography

Two-dimensional and Doppler echocardiography were performed prior to surgery (baseline), 1 and 6 months after surgery, and annually thereafter. Anatomic and Doppler measurements were performed according to the recommendations of the American Society of Echocardiography.⁸

Surgical Procedures

All patients received a median sternotomy. In general, the off-pump revascularization technique was favored in patients with high risks or contraindications for cardiopulmonary bypass and aortic cross-clamping (e.g., extensive atherosclerotic disease of the ascending aorta). The on-pump technique was favored when manipulation of the heart was likely to induce hemodynamic instability. In situ right or left ITA was used to bypass to the left anterior descending artery when indicated. The use of bilateral ITA was favored in younger patients when anatomically and clinically suitable. Choices of ITA harvesting technique, the use of second or third conduits for target vessel revascularization, and graft design were based on the clinical condition and coronary anatomy of individual patients, as well as the attending surgeon’s preference.

Outcomes, Definitions, and Clinical Follow-up

The primary outcome of interest was time to all-cause death during follow-up. The secondary outcome of interest was time to when any of the following events occurred first: all-cause death, heart failure readmission, myocardial infarction and/or any repeat revascularization procedure, and stroke. Patients who had not experienced any of these events up to the end of the follow-up period or who were lost to the follow-up were censored at the date of the last follow-up. In addition, we evaluated longitudinal changes in LV dimension, LVEF, left atrial (LA) dimension, Doppler-derived systolic pulmonary artery pressure (SPAP), inferior vena cava (IVC) dimension, and renal function, assessed by the estimated glomerular filtration rate (eGFR). The eGFR was calculated using the Modification of Diet in Renal Disease equation.⁹

Statistical Analysis

Continuous variables are summarized as the mean±SD or as the median with interquartile range (IQR) and were compared using Welch’s t-test or the Mann-Whitney U-test, as appropriate. Categorical variables are summarized as frequencies with proportions and were compared using a Chi-squared test or Fisher’s exact test, as appropriate. Echocardiographic and renal function variables over time were analyzed by a mixed-effects model for repeated measures, including factors for group, time, and their interaction. The variance-covariance matrix in the linear mixed-effects models was assumed to be unstructured.

Associations of preoperative and surgical variables with in-hospital mortality were examined using univariable and multivariable logistic regression analyses. Factors with P<0.1 in the univariable analysis were included in the multivariable logistic regression analysis. The results are summarized as odds ratios (ORs) and 95% confidence intervals (CIs). Survival analysis was performed using the Kaplan-Meier method for estimation of a time-to-event curve and the log-rank test for comparisons between patient groups (non-diabetic vs. diabetic groups). In addition, a treatment group was created based on the bypass strategy (single vs. bilateral ITA grafting) and comparisons were also made between the 2 strategies according to diabetic status. Univariable and multivariable analyses based on Cox’s proportional hazards models were used to examine the association of each group with all-cause mortality and composite adverse events. The interaction between patient group and treatment strategy was investigated by Wald’s test in the Cox proportional hazards model. Results are summarized as hazard ratios (HRs) and 95% CIs.

All probability values are 2-sided and P<0.05 was considered to indicate statistical significance. Statistical analyses were performed using JMP 7.0 (SAS Institute, Cary, NC, USA).

Results

Patient Demographics and Surgical Data

In our surgical registry database, 188 patients met the inclusion criteria and were included in the study (Supplementary Figure 1). Of those, 124 (66%) and 64 (34%) were diabetic and non-diabetic, respectively (Table 1). Compared with non-diabetic patients, patients in the NIDM and IDM groups had a greater prevalence of comorbidities, including renal insufficiency and peripheral vascular disease, and a greater use of angiotensin II receptor blockers and diuretics. Patients with IDM showed relatively small LV dimensions, larger LA dimension and higher estimated SPAP.

Table 1. Patient Demographics

	Non-DM (n=64)	DM (n=124)	P value	NIDM (n=74)	IDM (n=50)	P value
Clinical variables
Age (years)	67 [60–76]	68 [61–74]	0.953	68 [61–75]	67 [61–74]	0.667
Male sex	57 (89)	108 (87)	0.697	65 (88)	43 (86)	0.765
BMI (kg/m2)	23 [21–25]	23 [20–25]	0.828	20 [19–25]	23 [20–25]	0.944
NYHA Class III or IV	25 (39)	60 (48)	0.224	35 (47)	25 (50)	0.768
Preoperative catecholamine use	6 (9.4)	13 (10)	0.811	7 (9.5)	6 (12)	0.651
No. diseased vessels
Triple vessel disease	55 (86)	107 (86)	0.947	65 (88)	42 (84)	0.542
Left main disease	14 (22)	23 (19)	0.567	18 (24)	5 (10)	0.044
Blood test
HbA1c (%)	5.4 [5.1–5.8]	7.1 [6.3–8.4]	<0.001	7.0 [6.3–7.9]	7.5 [6.6–8.8]	0.150
Renal function
eGFR ≥30 mL/min/1.73 m2	58 (91)	93 (75)	0.037	61 (82)	32 (64)	0.063
eGFR <30 mL/min/1.73 m2	4 (6.3)	18 (15)		8 (11)	10 (20)
Hemodialysis	2 (3.1)	13 (10)		5 (6.8)	8 (16)
Comorbidities
Peripheral vascular disease	4 (6.3)	26 (21)	0.009	10 (14)	16 (32)	0.013
Stroke/TIA history	3 (4.7)	10 (8.1)	0.548	4 (5.4)	6 (12)	0.186
Medications
β-blockers	22 (34)	45 (36)	0.795	25 (34)	20 (40)	0.480
ARBs	9 (14)	41 (33)	0.005	20 (27)	21 (42)	0.082
Diuretics	19 (30)	63 (51)	0.006	35 (47)	28 (56)	0.342
Echocardiographic data
LVEDD (mm)	60 [57–65]	58 [54–63]	0.021	59 [55–63]	57 [53–62]	0.255
LVESD (mm)	51 [46–56]	49 [45–56]	0.136	50 [46–55]	48 [45–53]	0.163
LVEF (%)	32 [26–36]	33 [28–37]	0.190	32 [26–36]	34 [30–37]	0.093
LA dimension (mm)	39 [35–46]	41 [38–45]	0.227	40 [37–43]	43 [39–46]	0.015
SPAP (mmHg)	31 [27–33]	34 [27–45]	0.034	33 [27–38]	43 [30–56]	0.042
IVC dimension (mm)	12 [9–15]	13 [10–16]	0.451	13 [10–16]	13 [9–15]	0.716
Surgical data
Off-pump	18 (28)	45 (36)	0.140	25 (34)	20 (40)	0.119
On-pump beating	38 (59)	55 (44)		38 (51)	17 (34)
On-pump arrest	8 (13)	24 (19)		11 (15)	13 (26)
Graft selection
No ITA use	2 (3.1)	7 (5.6)	0.745	5 (6.8)	2 (4.0)	0.778
Single ITA use	37 (58)	70 (56)		42 (57)	28 (56)
Bilateral ITA use	25 (39)	47 (38)		27 (36)	20 (40)
Distal anastomoses	3 [3–4]	3 [2–4]	0.231	3 [2–4]	3 [2–4]	0.890

Data are given as the median [interquartile range] or n (%). ARBs, angiotensin II receptor blockers; BMI, body mass index; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; IDM, insulin-dependent diabetes mellitus; ITA, internal thoracic artery; IVC, inferior vena cava; LA, left atrial; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; NIDM, non-insulin-dependent diabetes mellitus; NYHA, New York Heart Association; SPAP, systolic pulmonary artery pressure; TIA, transient ischemic attack.

The baseline characteristics of the patients and surgical data according to diabetic status and ITA strategy (single vs. bilateral ITA) are presented in Table 2. Among non-diabetic patients, there were no differences in clinical demographics and surgical data between those who received bilateral and single ITA grafting. Similarly, among diabetic patients, there were no differences in age, the prevalence of New York Heart Association functional class III or IV, comorbidities and revascularization strategies between those receiving bilateral and single ITA grafting, whereas patients with single ITA grafting were less likely to have triple vessel disease and had a lower LVEF.

Table 2. Patient Demographics for Bilateral vs. Single ITA Grafting According to Diabetic Status

	Non-DM		P value	DM		P value
	Bilateral ITA (n=25)	Single ITA (n=37)		Bilateral ITA (n=47)	Single ITA (n=70)
Clinical variables
Age (years)	65 [58–72]	70 [61–79]	0.135	65 [58–74]	69 [62–74]	0.137
Male sex	24 (96)	31 (84)	0.136	42 (89)	61 (87)	0.717
BMI (kg/m2)	23 [21–24]	23 [21–25]	0.518	23 [21–25]	22 [20–25]	0.223
NYHA Class III or IV	10 (40)	13 (35)	0.697	22 (47)	32 (46)	0.907
Preoperative catecholamine use	2 (8.0)	4 (11)	0.714	2 (4.3)	7 (10)	0.253
No. diseased vessels
Triple vessel disease	21 (84)	32 (86)	0.785	44 (94)	57 (81)	0.049
Left main disease	6 (24)	8 (22)	0.826	8 (17)	14 (20)	0.686
Blood test
HbA1c (%)	5.5 [5.2–5.8]	5.3 [5.0–5.6]	0.155	7.0 [6.4–8.1]	7.3 [6.3–8.5]	0.265
Renal function
eGFR ≥30 mL/min/1.73 m2	24 (96)	33 (89)	0.336	35 (74)	53 (76)	0.569
eGFR <30 mL/min/1.73 m2	0 (0)	3 (8.1)		8 (17)	8 (11)
Hemodialysis	1 (4.0)	1 (2.7)		4 (8.5)	9 (13)
Comorbidities
Peripheral vascular disease	2 (8.0)	2 (5.4)	0.683	13 (28)	13 (19)	0.246
Stroke/TIA history	2 (8.0)	0 (0)	0.159	4 (8.5)	5 (7.1)	0.786
Medications
β-blockers	11 (44)	11 (30)	0.249	17 (36)	27 (39)	0.793
ARBs	4 (16)	5 (14)	0.785	18 (38)	23 (33)	0.545
Diuretics	9 (36)	10 (27)	0.452	23 (49)	38 (54)	0.570
Echocardiographic data
LVEDD (mm)	60 [56–67]	60 [58–64]	0.840	57 [53–62]	59 [55–64]	0.231
LVESD (mm)	50 [45–56]	52 [46–56]	0.442	47 [45–54]	50 [46–55]	0.078
LVEF (%)	33 [28–37]	30 [23–34]	0.070	35 [30–38]	31 [25–36]	0.014
LA dimension (mm)	38 [35–43]	42 [34–47]	0.533	41 [38–45]	41 [38–45]	0.976
SPAP (mmHg)	30 [27–32]	32 [26–38]	0.269	34 [30–51]	35 [26–44]	0.547
IVC dimension (mm)	13 [11–14]	12 [9–15]	1.000	13 [12–16]	12 [9–16]	0.353
Surgical data
Off-pump	11 (44)	6 (16)	0.051	20 (43)	24 (34)	0.612
On-pump beating	12 (48)	25 (68)		20 (43)	32 (46)
On-pump arrest	2 (3.2)	6 (16)		7 (15)	14 (20)
Distal anastomoses	3 [3–4]	3 [3–4]	0.696	4 [3–4]	3 [2–4]	0.062

Data are given as the median [interquartile range] or n (%). Abbreviations as in Table 1.

In-Hospital Outcomes

There were no differences in the operative and in-hospital mortalities between the non-diabetic and diabetic patients. Early morbidity, including mediastinitis, prolonged ventilation requiring a tracheotomy and bleeding reoperation, were not significantly different between the groups (Table 3).

Table 3. Early and Late Outcomes

	Entire cohort (n=188)	Non-DM (n=64)	DM (n=124)	P value	NIDM (n=74)	IDM (n=50)	P value
Early outcomes
30-day mortality	9 (4.8)	1 (1.6)	8 (6.5)	0.170	4 (5.4)	4 (8.0)	0.564
Hospital mortality	13 (6.9)	1 (1.6)	12 (9.7)	0.064	6 (8.1)	6 (12)	0.472
Mediastinitis	4 (2.1)	0 (0)	4 (3.2)	0.301	1 (1.4)	3 (6.0)	0.302
Tracheotomy	11 (5.9)	3 (4.7)	8 (6.5)	0.752	5 (6.8)	3 (6.0)	0.999
Bleeding reoperation	5 (2.7)	2 (3.1)	3 (2.4)	0.999	3 (4.1)	0 (0)	0.272
Late outcomes
Death	67 (36)	17 (27)	50 (40)	0.034*	26 (35)	24 (48)	0.300*
Heart failure readmission	55 (29)	10 (16)	45 (36)	0.003	21 (28)	24 (48)	0.026
MI and/or revascularization	25 (13)	6 (9.4)	19 (15)	0.255	8 (11)	11 (22)	0.090
Stroke	18 (9.6)	4 (6.3)	14 (11)	0.266	7 (9.5)	7 (14)	0.433
Composite adverse events	109 (58)	27 (42)	82 (66)	0.001*	43 (58)	39 (78)	0.018*

Data are presented as n (%). *These were analyzed using Kaplan-Meier analysis (log-rank test). MI, myocardial infarction. Other abbreviations as in Table 1.

In univariate analysis, catecholamine use and dialysis- and non-dialysis-dependent renal failure were associated with increased hospital mortality, whereas the use of either single or bilateral ITA was associated with decreased hospital mortality. Multivariate analysis showed that preoperative catecholamine use (adjusted OR 8.6; 95% CI 1.8–40; P=0.006) and dialysis-dependent renal failure (adjusted OR 7.1; 95% CI 1.3–38; P=0.022) were independently associated with hospital mortality. There was a trend for NIDM and IDM to be associated with increased hospital mortality, although the level of statistical significance was not reached (P=0.13 and 0.11, respectively).

Late Outcomes

Clinical follow-up was performed for 95.2% of patients, with a mean duration of 68±47 months (range 1.7–239 months). During the follow-up period, there were 67 deaths and the actuarial survival rate at 1, 5, and 10 years was 88%, 71%, and 54%, respectively, in the entire cohort (Table 3). The causes of death are shown in Supplementary Figure 2. The majority of patients died from cardiac causes (e.g., heart failure), whereas other common causes were sudden cardiac death, pneumonia, and cancer (Supplementary Figure 2). Notably, diabetic patients were more likely to die from heart failure or renal failure than non-diabetic patients (P=0.036 and 0.097, respectively). The 5-year survival rate in the non-diabetic and diabetic groups was 84% and 65%, respectively (P=0.034; Figure 1A).

Figure 1.

(A,B) Freedom from all-cause mortality (A) and composite adverse events (B) according to diabetic status. DM, diabetes mellitus. (C,D) Freedom from all-cause mortality (C) and composite adverse events (D) according to the severity of diabetes (i.e., non-insulin-dependent diabetes [NIDM] vs. insulin-dependent diabetes [IDM]).

As for adverse events, there were 55 cases of heart failure readmission, 25 of myocardial infarction and/or revascularization, and 18 of stroke. Although there were no differences regarding the prevalence of myocardial infarction and/or any repeat revascularization procedure and stroke, diabetic patients were more likely to experience heart failure readmission than non-diabetic patients (Table 3). The rate of 5-year freedom from adverse events in the non-diabetic and diabetic groups was 65% and 36%, respectively (P=0.001; Figure 1B).

When we compared outcomes between patients with NIDM and IDM, there was no significant difference in the 5-year survival rate (68% vs. 61%; P=0.433; Figure 1C). However, the rate of 5-year freedom from adverse events was significantly higher in patients with IDM than NIDM (43% vs. 26%; P=0.018; Figure 1D).

Detrimental Effects of NIDM and IDM on Late Outcomes

After adjusting for all covariates, both NIDM and IDM were independently associated with mortality and composite adverse events (Table 4). Preoperative age and non-dialysis-dependent renal failure with an eGFR of ≤30 mL/min/1.73 m² were also independent risk factors for mortality and adverse events.

Table 4. Covariates Associated With Mortality and Composite Adverse Events (Cox Proportional Hazards Models)

	Univariable		Multivariable
	P value	HR (95% CI)	P value	HR (95% CI)
Mortality
Clinical variables (n=188)
Age (years)	<0.001	1.04 (1.02–1.06)	0.002	1.05 (1.02–1.08)
Male sex	0.194
BMI	0.018	0.9 (0.8–1.0)	0.195
Preoperative catecholamine use	0.056		0.088
Diabetic status
Non-DM	1.000		1.000
NIDM	0.135		0.049	1.9 (1.0–3.7)
IDM	0.019	2.1 (1.1–4.0)	0.016	2.4 (1.2–4.8)
Blood test
HbA1c (%)	0.661
HbA1c ≥7.0%	0.443
Renal function
eGFR ≥30 mL/min/1.73 m2	1.000		1.000
eGFR <30 mL/min/1.73 m2	<0.001	3.0 (1.6–5.6)	0.006	2.5 (1.3–4.8)
Hemodialysis	0.059		0.080
Comorbidities
Peripheral vascular disease	0.025	1.8 (1.1–3.1)	0.109
Surgical data (n=188)
No ITA use	1.000		1.000
Single ITA use	0.073		0.152
Bilateral ITA use	0.005	0.2 (0.1–0.6)	0.024	0.3 (0.1–0.8)
No. distal anastomoses	0.030	0.8 (0.6–1.0)	0.097
Composite adverse events
Age (years)	<0.001	1.04 (1.02–1.06)	0.002	1.04 (1.01–1.06)
Male sex	0.132
BMI	0.047	0.9 (0.9–1.0)	0.352
Preoperative catecholamine use	0.665
Diabetic severity
Non-DM	1.000		1.000
NIDM	0.043	1.6 (1.0–2.7)	0.038	1.7 (1.0–2.8)
IDM	<0.001	2.8 (1.7–4.5)	<0.001	3.0 (1.7–5.1)
Blood test
HbA1c (%)	0.532
HbA1c ≥7.0%	0.241
Renal function
eGFR ≥30 mL/min/1.73 m2	1.000		1.000
eGFR <30 mL/min/1.73 m2	<0.001	2.7 (1.6–4.5)	0.005	2.2 (1.3–3.7)
Hemodialysis	0.513		0.365
Comorbidities
Peripheral vascular disease	0.089		0.915
Surgical data (n=188)
No ITA use	1.000
Single ITA use	0.331
Bilateral ITA use	0.122
No. distal anastomoses	0.010	0.8 (0.6–0.9)	0.015	0.8 (0.6–1.0)

CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Effects of Bilateral vs. Single ITA in Patients With and Without Diabetes

Of the entire cohort, patients who underwent CABG with bilateral ITA had better survival than those with single ITA (5-year survival 81% vs. 68%; P=0.019). Notably, no survival benefit from bilateral ITA was seen in non-diabetic patients (P=0.95), but it was apparent in diabetic patients, with a 5-year survival rates of 57% for patients who received single ITA grafting and 81% for those who underwent bilateral ITA grafting (P=0.004; Figure 2). The P value for interaction based on Wald’s test was 0.025. Multivariate analysis revealed that the use of bilateral ITA was significantly associated with decreased risk of mortality (Table 4).

Figure 2.

Comparison of survival rates between patients who underwent bilateral internal thoracic artery (ITA) grafting and single ITA grafting according to diabetic status.

Longitudinal Echocardiographic Assessment

LV function parameters improved up to 12 months after surgery in both diabetic and non-diabetic patients, with greater improvements for the latter (Figure 3A–C). LA dimension was significantly decreased at 1 month after surgery, with a trend for steady increases thereafter with no intergroup differences (Figure 3D). Estimated SPAP was significantly decreased at 1 month after surgery in both groups; however, differences subsequently emerged between the 2 groups, with estimated SPAP unchanged during follow-up in non-diabetic patients, but increasing again in diabetic patients, resulting in higher SPAP values in diabetic patients at any follow-up time point (Figure 3E). The IVC dimension generally remained unchanged, but was significantly larger in the diabetic than non-diabetic patients, especially at the latest follow-up examination (Figure 3F).

Figure 3.

Longitudinal changes in (A) left ventricular (LV) end-diastolic dimension, (B) LV end-systolic dimension, (C) LV ejection fraction, (D) left atrial (LA) dimension, (E) systolic pulmonary artery (PA) pressure, and (F) inferior vena cava (IVC) dimension in patients with and without diabetes mellitus (DM). Data are the mean±SD.

When evaluated according to diabetes status, patients with IDM showed less improvement in LV dimension and LVEF than patients in the non-diabetic and NIDM group, whereas there were no differences in LA dimension improvements among the groups (Figure 4A–D). Patients with IDM also had higher SPAP and larger IVC dimension than patients in the NIDM and non-diabetic groups (Figure 4E,F).

Figure 4.

Longitudinal changes in (A) left ventricular (LV) end-diastolic dimension, (B) LV end-systolic dimension, (C) LV ejection fraction, (D) left atrial (LA) dimension, (E) systolic pulmonary artery (PA) pressure, and (F) inferior vena cava (IVC) dimension in the control (non-diabetic) group and in patients with non-insulin-dependent diabetes (NIDM) and insulin-dependent diabetes (IDM).

Mitral regurgitation grade did not change during follow-up, with no intergroup differences for the distribution of mitral regurgitation status at the latest follow-up (P=0.55; Supplementary Figure 3).

Changes in Renal Function

There were no changes in eGFR in non-diabetic patients during the follow-up period (from 59±26 mL/min/1.73 m² at baseline [preoperatively] to 56±23, 58±23, and 58±22 mL/min/1.73 m² at 1, 6, and 12 months after surgery, respectively). However, in diabetic patients, there was a steady decrease in eGFR over time (from 51±27 mL/min/1.73 m² at baseline to 50±25, 46±22, and 44±23 mL/min/1.73 m² at 1, 6, and 12 months after surgery, respectively; time effect, P=0.002; group effect, P=0.043). Among 173 patients not dependent on dialysis prior to surgery, dialysis was initiated in 10 cases; the rate of 5-year freedom from dialysis initiation in the non-diabetic, NIDM, and IDM groups was 98%, 97%, and 85%, respectively (P=0.022).

Discussion

The major findings of this study are that: (1) in patients with severe LV dysfunction, surgical revascularization could be performed with acceptable operative mortality and morbidity; (2) the detrimental effects of NIDM or IDM on in-hospital early outcome were limited, whereas both were significantly associated with increased long-term mortality and composite adverse events, the latter of which was largely attributed to the preponderance of heart failure admission events; (3) patients with IDM showed less improvement in LV function parameters, higher SPAP and larger IVC dimension during follow-up, as indicated by longitudinal echocardiography findings; (4) diabetic patients showed significant deterioration in renal function over time, resulting in a higher incidence of dialysis initiation, particularly in the IDM group; and (5) the survival benefit of bypass grafting with bilateral ITA over single ITA was apparent in diabetic but not non-diabetic patients.

Long-Term Outcomes

Diabetic patients dependent on insulin usually have poor glycemic control and are expected to suffer more complications than patients with NIDM. However, it remains unclear whether and how diabetes treated with and without insulin affects late outcomes after CABG. In a study of patients with preserved EF (EF >35%, 94.5%) who underwent primary isolated CABG, Mohammadi et al found that NIDM was not an independent risk factor for long-term mortality, whereas IDM had a negative effect (adjusted HRs 1.1 [P=0.41] and 2.2 [P<0.0001] for NIDM and IDM, respectively).⁶ Based on that finding, Mohammadi et al concluded that long-term survival was not adversely affected by non-insulin treatment, but by the need for insulin therapy.⁶ Conversely, using a large cohort with a mean EF of approximately 60%, an observational study by Zhang et al demonstrated that NIDM and IDM were both significantly associated with mortality after CABG (adjusted HR 1.3 for both).⁷ In the present study, we found significant detrimental effects of both NIDM and IDM on long-term outcomes, which is partly consistent with the latter study. Notably, the HRs for the NIDM and IDM groups in the present study were relatively large compared with previous studies, providing further confirmation that the negative effect of diabetes on late outcomes after CABG is greater in patients with severely impaired than preserved LV function.

Diabetes Induces Myocardium Disorder and Renal Dysfunction

Numerous studies have identified diabetes as a major independent risk factor for the development of heart failure, which is partly explained not only by microvascular disorder (increased myocardial stiffness, reduction of LV myocardial compliance) induced by long-standing hyperglycemia, clinically characterized by LV diastolic dysfunction, but also by volume overload secondary to diabetic nephropathy.^10,11 Risk factor analysis findings in the present study confirmed that IDM is the most important and strongest predictor for composite adverse events. The greater negative effect of IDM on composite adverse events over mortality (adjusted HRs 3.0 and 2.4, respectively) was attributed, at least in part, to the significantly higher prevalence of heart failure admission among IDM patients during follow-up (Tables 3 and 4). There are several possible reasons for the exaggerated prevalence of heart failure in the IDM patients in the present study. First, those with IDM were more likely to have several comorbidities, such as peripheral vascular disease and chronic renal failure, at baseline. Thus, the higher frequency of diuretic use may imply that a greater number of patients with IDM required volume control for heart failure symptoms to a certain extent prior to surgery. Second, although there were no significant differences in the status of coronary artery disease (i.e., frequency of triple vessel disease or left main disease) and LV systolic function at baseline, the IDM patients may have been complicated with LV diastolic dysfunction, as shown by the relatively small LV dimension, large LA dimension, and substantially higher SPAP, which is in accordance with previous findings.¹¹ Furthermore, these patients failed to show sustained improvements in LV function parameters after surgical revascularization. The steady increases in LA dimension and SPAP in the absence of significant deterioration of mitral regurgitation implies substantially elevated LV filling pressure, which may be attributed to residual LV diastolic dysfunction. In addition, this unfavorable hemodynamic condition may easily cause volume overload in IDM patients. Finally, IVC dimension was larger in patients with IDM than in the other groups at the latest follow-up. Because IVC dimension indicates volume status in patients with heart failure, this finding led us to speculate that it was more difficult to manage volume status appropriately for patients with IDM compared with non-diabetic and NIDM patients, possibly because of worse LV systolic and diastolic function, and progressive renal impairment (e.g., cardiorenal syndrome). Our speculation may also be supported by multivariate analysis findings showing that non-dialysis-dependent renal failure, but not dialysis-dependent renal failure, was independently associated with adverse events after CABG, consistent with previous reports.^12,13 This result is interesting, although also reasonable, because it is more difficult to control body fluid volume balance in patients with renal failure who do not undergo hemodialysis than in those with renal failure and dependent on hemodialysis. Together, these findings underscore the importance of postoperative volume management for better long-term outcome in patients with advanced cardiomyopathy undergoing CABG; thus, meticulous monitoring of volume status is mandatory, especially for IDM patients.

Survival Benefit of Bilateral ITA Grafting in Patients With Severe LV Dysfunction

It remains controversial whether the use of bilateral ITA is associated with improved long-term outcome following surgical revascularization, especially in patients with LV dysfunction. Galbut et al showed a survival advantage of bilateral over single ITA grafting in patients with moderately impaired LV function (i.e., EF 30–50%), with a 10-year survival rate of 62% for bilateral ITA and 58% for single ITA (P=0.016).¹⁴ In contrast, Mohammadi et al failed to show a long-term survival advantage of bilateral ITA grafting over single ITA among patients with systolic LV dysfunction (i.e., EF ≤40%), and noted a 10-year survival rate of 78% and 68% for bilateral and single ITA, respectively (P=0.3).¹⁵ The findings of the present study are consistent with those of Galbut et al, with 10-year survival rates of 71% and 44% for the bilateral and single ITA groups, respectively (P=0.019). Interestingly, this survival advantage of bilateral over single ITA grafting was clearly evident in the diabetic patients in the present study, but not in those without diabetes. The inconsistency in the clinical impact of bilateral ITA between diabetic and non-diabetic patients can be explained by differences in the degree of improvement in LV systolic function; in the diabetic group, the amount of change (increase) in the LVEF at 6 months after the surgery was significantly greater in patients undergoing CABG with bilateral ITA than in those undergoing CABG with single ITA (10% vs. 4.0%, respectively; P=0.028). Conversely, in the non-diabetic group, there was no difference in the LVEF change between patients with bilateral and single ITA grafting (11% vs. 10%, respectively; P=0.942). The 10-year survival rate of diabetic patients with bilateral ITA grafting was comparable with that of non-diabetic patients (71% vs. 61%), suggesting the possible effectiveness of bilateral ITA-based bypass grafting for modifying the natural history of the disease. Interestingly, the change in the LVEF was comparable between diabetic and non-diabetic patients who underwent CABG with the use of bilateral ITA, which may explain the comparable survival rate. Our findings may also be supported by the results of Dorman et al, who showed that bilateral ITA grafting in propensity score-matched diabetic patients offered enhanced survival without an increase in perioperative morbidity or mortality.¹⁶ Together, these findings may support the recommendation of bilateral ITA grafting for patients with severe LV dysfunction and diabetes if life expectancy exceeds 5 years. Nevertheless, a future study with a more sophisticated design is warranted to determine whether the perioperative risk of bilateral ITA-based coronary revascularization is offset by its potential long-term survival benefit in this specific patient population.

Association Between Diabetic Control and Surgical Outcomes After CABG

The optimal glucose-lowering therapy for patients with concurrent diabetes and coronary artery disease is unclear. In general, there is a strong relationship between HbA1c levels and mortality in the general population, as well as in patients with ischemic heart disease, independent of other risk factors.¹⁷ Similarly, previous studies have found an association between HbA1c levels and the risk of cardiovascular events in patients with diabetes.¹⁸ However, another study found that intensive blood glucose-lowering therapy, which leads to a decrease in HbA1c levels, was not associated with a reduced incidence of macrovascular complications or mortality.¹⁹ In the present study, the high HbA1c level did not appear to have a negative effect on mortality and composite adverse events, although the absolute risks of those events were higher in diabetic patients treated with insulin. This finding is not inconsistent with that from a previous study that found the association between mortality and HbA1c in patients with DM and heart failure appears U-shaped, with the lowest risk of death in patients with modest glucose control (7.1%<HbA1c≤7.8%) and the increased risk in those with extremely high or low HbA1c levels.²⁰ It is quite difficult for us to determine whether insulin treatment directly contributes to the worse prognosis, or whether insulin treatment is just a marker of more advanced diabetes. The latter concept was applicable in this study because, compared with non-diabetic and NIDM patients, those with IDM had a higher frequency of renal failure at baseline, which was identified as an important and independent risk factor of worse prognosis after surgical revascularization. These findings lead us to consider that patients treated with insulin may have had more advanced disease, in which decreasing glucose levels was of no help. This indicates that special attention should be paid to patients being treated with insulin in terms of secondary prevention measures other than decreasing glucose levels, with a focus on lowering blood pressure, decreasing cholesterol levels, preventing progressive renal impairment, and life-style changes.²¹

Study Limitations

This study has several major limitations. First, the study was a retrospective study without randomization, and the small numbers of patients in each group made case matching impractical. Thus, any conclusions are limited and should be cautiously interpreted until verified by an independent prospective study. Second, with regard to surgical procedures, different bypass strategies, including the use of cardiopulmonary bypass, ITA harvesting technique, ITA use, and graft design, may have affected the results, although these factors were not significantly different between the diabetic and non-diabetic patients. Third, the decision whether to use a bilateral ITA strategy was related to patient characteristics at presentation, as well as to other unknown selection biases on the part of the surgeons. Fourth, the lack of moving images on preoperative coronary angiography in some patients did not allow us to exactly determine the correlations between outcomes and the SYNTAX score. Finally, the lack of an untreated control group did not allow us to evaluate the effect of surgery on prognosis or to determine the optimal treatment strategy for patients with severe LV dysfunction with and without diabetes.

Conclusions

NIDM and IDM were significantly associated with worse long-term clinical outcomes after CABG for severe LV dysfunction. Diabetes may adversely affect postoperative reverse LV remodeling, accompanied by progressive renal impairment. Bilateral ITA grafting has the potential to improve survival in diabetic patients with severe LV dysfunction.

Acknowledgments

None.

Sources of Funding

This work was supported, in part, by Takeda Science Foundation and research funds to promote hospital function from the Japan Labor Health and Welfare Organization.

Disclosures

Y. Sawa is a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to report.

IRB Information

This study was approved by the Institutional Review Board of Osaka University Hospital (Reference no. 08218-6).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0907

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