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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 3  |  Page : 127-132

Correlation of HbA1c with coronary flow velocity and disease severity in chronic stable angina


1 Department of Cardiology, SKIMS, Srinagar, Jammu and Kashmir, India
2 Department of Anesthesiology, Shardha Medical College and University, Greater Noida, Uttar Pradesh, India

Date of Submission25-Jul-2020
Date of Decision12-Sep-2020
Date of Acceptance23-Sep-2020
Date of Web Publication26-Nov-2020

Correspondence Address:
Dr. Aamir Rashid
Department of Cardiology, SKIMS, Soura, Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_26_20

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  Abstract 


Introduction: Increasing hemoglobin A1c (HbA1c) levels in individuals with and without diabetes mellitus are risk factors for cardiovascular events and atherosclerosis.
Aims and Objectives: The aim and objective was to study the association of HbA1c with coronary flow velocity (CFV).
Materials and Methods: This was a single-center, hospital-based, nonrandomized, prospective observational study. All consecutive patients admitted in the department of cardiology with the diagnosis of chronic stable angina who underwent coronary angiography from April 1, 2017, to October 31, 2018, were subjected to the eligibility criteria. The patients were divided into the four HbA1c quartiles based on the HbA1c at hospital admission: Group A (HbA1c < 5.2%), Group B (HbA1c: 5.2–5.6), Group C (HbA1c: 5.7–6.4), and Group D (HbA1c: ≥6.5%). Corrected TIMI frame count (TFC) was used to assess the CFV. The severity of coronary artery disease (CAD) was studied by Gensini score.
Results: A total of 263 consecutive patients with a mean age of 56.71 ± 10.59 years were included. Nearly 70% (n = 184) of the patients were males. The mean HbA1c was statistically significantly higher in obstructive CAD versus nonobstructive versus no CAD (6.06 vs. 5.63 vs. 5.23) (P < 0.001). Increasing HbA1c among all quartiles was statistically significantly associated with increasing TFC in all coronary arteries (left anterior descending artery [LAD] 30.32 vs. 34.05 vs. 36.72 vs. 36.94; left circumflex artery [LCX] 19.89 vs. 22.41 vs. 24.05 vs. 23.76; right coronary artery [RCA] 19.42 vs. 22.02 vs. 23.24 vs. 23.50, respectively, for the four HbA1c quartiles; P < 0.001). HbA1c had a significant linear correlation with TFC of LAD, LCX, and RCA (r = 0.6, 0.54, and 0.51, respectively). Among the various quartiles of HbA1c, CAD was significantly more common in patients with higher HbA1c values (P < 0.0001) (1.03% vs. 33.89% vs. 73.33% vs. 82.35%, respectively). The mean Gensini score increased with increasing HbA1c quartiles (0.40 vs. 4.68 vs. 21.63 vs. 30.52, respectively, P < 0.001).
Conclusion: HbA1c has a significant association with CFV even in subdiabetic range. However, the therapeutic strategies and benefit of lower HbA1c in nondiabetic patients are still uncertain. Large randomized trials are needed to address this issue.

Keywords: Coronary artery disease, coronary flow velocity, hemoglobin A1c


How to cite this article:
khan A, Rashid A, Wani I, Iqbal MD, Hafeez I, Tramboo N, Lone A, Jamil S. Correlation of HbA1c with coronary flow velocity and disease severity in chronic stable angina. Heart India 2020;8:127-32

How to cite this URL:
khan A, Rashid A, Wani I, Iqbal MD, Hafeez I, Tramboo N, Lone A, Jamil S. Correlation of HbA1c with coronary flow velocity and disease severity in chronic stable angina. Heart India [serial online] 2020 [cited 2021 Jan 23];8:127-32. Available from: https://www.heartindia.net/text.asp?2020/8/3/127/301594




  Introduction Top


Cardiovascular diseases are the leading cause of mortality and morbidity in industrialized countries, and they are also emerging as a prominent public health problem in developing countries.[1] Diabetes mellitus is becoming a pandemic worldwide. The UKPDS-35 demonstrated that each 1% reduction in hemoglobin A1c (HbA1c) was associated with a 14% decrease in risk for myocardial infarction.[2] HbA1c is shown to be a predictor of cardiovascular mortality.[3],[4]

Increasing HbA1c levels irrespective of the diabetic status is a risk factor for cardiovascular events and subclinical atherosclerosis.[5],[6] Many studies have shown a relationship between the severity of coronary artery disease (CAD) and cardiovascular mortality with HBA1c levels in nondiabetic individuals in acute coronary syndromes.[7] Besides, the risk of developing CAD is higher with higher HBA1c levels even in the normal range.[8] The risk of CVD may begin at the levels of only moderately elevated HBA1c levels well below the threshold for diabetes.[9],[10]

Slow coronary flow (SCF) refers to the delayed flow of contrast agent to the distal vasculature without significant stenosis of the coronary lumen on angiography. The incidence varies from 5.5% to 23%. It is associated with increased microvascular resistance though with normal coronary anatomy. It may be due to endothelial damage, loss of lumen diameter, or capillary loss.[11],[12]

Increasing HBA1c levels reflect the ongoing hyperglycemic state that injures endothelial cells. HBA1c ≥7 is correlated with significantly reduced coronary flow velocity (CFV).[13] The effect of increasing HbA1c levels on coronary flow as measured by the TIMI frame count has been studied in diabetic patients [13] and those undergoing percutaneous coronary intervention (PCI),[14] however there are very few studies analyzing the relationship between HbA1c levels and CFV irrespective of the diabetic status in patients presenting with chronic stable angina. We aimed to analyze the relationship between HBA1c and CFV in patients who presented with chronic stable angina.

Aims and objectives

The aim and objective was to study the association of HbA1c with CFV and disease severity in patients presenting with chronic stable angina.


  Materials and Methods Top


This was a single-center, hospital-based, nonrandomized prospective observational study.

All consecutive patients admitted in the department of cardiology with the diagnosis of stable angina and normal left ventricular (LV) systolic function who underwent coronary angiography from April 1, 2017, to October 31, 2018, were subjected to the eligibility criteria.

Inclusion criteria

All patients who presented with chronic stable angina with objective evidence of ischemia by TMT or stress MIBI were included in the study.

Exclusion criteria

Previously known diabetic, those with LV dysfunction (ejection fraction < 50%), those with sepsis, those with cardiogenic shock anytime before the procedure, those with prior MI, those with prior PCI, those with contrast allergy, those with acute coronary syndromes, those with chronic kidney disease, those with severe liver disease, and those with malignancy were excluded from the study.

The patients were divided into four groups/quartiles based on the HbA1c at hospital admission: Group A (HbA1c <5.2%), Group B (HbA1c: 5.2–5.6), Group C (HbA1c: 5.7–6.4), and Group D (HbA1c: ≥6.5%). Obstructive CAD was defined as a 50% reduction in luminal diameter by visual assessment of epicardial coronary arteries. HbA1c was tested using an HbA1c automatic analyzer (HLC-723G8, Tosoh Corp., Tokyo. Japan). The standard protocol was followed for angiography and stenting, if needed. Corrected TIMI frame count (TFC) was used to assess the CFV. The severity of the CAD was studied by Gensini scoring system.

Informed written consent was obtained from each participant before enrollment into the study. Each patient's data were recorded and stored in a specifically predesigned study pro forma. Ethical clearance was taken for the study.

Standard statistical procedures were used to analyze the data. Data were described as mean ± standard deviation and percentages. ANOVA and Fisher's exact test were used to calculate P values. SPSS 20.0 (IBM SPSS Statistics for Windows, IBM Corp, Armonk, NY, USA) and Microsoft Excel software were used for data analysis. P < 0.05 was considered statistically significant.


  Results Top


Baseline characteristics

Two hundred and sixty-three consecutive patients were included in the study. Their mean age was 56.71 ± 10.59 years (23–84 years). Nearly 70% of the patients (n = 184) were males. The baseline characteristics are shown in [Table 1]. A total of 145 patients were diagnosed with CAD (101 patients with obstructive CAD and 44 with nonobstructive CAD). A total of 118 patients were found to have normal coronaries. The prevalence of newly detected diabetes was 6.5% (n = 17). Nearly 34.2% (n = 90) of the patients were diagnosed with prediabetes (HbA1c between 5.7 and 6.4), 22.4% (n = 59) had HbA1c between 5.2 and 5.6, and the rest 36.9% of the patients had HbA1c 5.2 (n = 97).
Table 1: Baseline characteristics

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Correlation of hemoglobin A1c with diagnosis of coronary artery disease

The mean HbA1c was 5.345 ± 0.418. The mean HbA1c was statistically significantly higher in obstructive CAD versus non-obstructive versus no CAD (6.06 vs. 5.63 vs. 5.23, respectively) (P < 0.001). We also compared the four quartiles of HbA1c with a diagnosis of CAD and found that single-vessel disease, double-vessel disease, and triple-vessel disease were more common in patients with higher HbA1c values (P < 0.001) [Table 2]. There was a linear correlation between HbA1c and the number of vessels involved (r = 0.436; P < 0.001). The positive predictive value of HbA1c to identify CAD patients in our study with stable angina was 74.76% if the cutoff was kept at HbA1c >5.7. The negative predictive value of HbA1c to identify CAD patients in our study with stable angina with the same cutoff was 86.53%. The area under the curve for HbA1c and CAD with the receiver operating characteristic curve was 0.893 [Figure 1].
Table 2: Relationship of severity of coronary artery disease with different HbA1c quartiles

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Figure 1: Hemoglobin A1c as a predictor of coronary artery disease (area under the curve = 0.893)

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Correlation of hemoglobin A1c with coronary flow velocity

It was observed that the mean TFC increased as the levels of HbA1c increased [Table 3]. TFC was not calculated for three patients of left anterior descending artery (LAD), two patients for left circumflex artery (LCX), and two patients for right coronary artery (RCA) as these vessels were found to have 100% occlusion and were not revascularized during our study time. Increasing HbA1c among all quartiles was statistically significantly associated with increasing TFC in all coronary arteries (ANOVA, P < 0.001). HbA1c had a significant linear correlation with TFC of LAD, LCX, and RCA [Figure 2], [Figure 3], [Figure 4].
Table 3: Relationship of coronary flow velocity of each vessel with HbA1c quartiles

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Figure 2: Scatter plot showing the correlation of HbA1c with TFC of LAD (r = 0.6, r2 = 0.36, P = 0.000). TFC: TIMI frame count, LAD: Left anterior descending artery, HbA1c: Hemoglobin A1c

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Figure 3: Scatter plot showing the correlation of HbA1c with TFC of LCX (r = 0.545, r2 = 0.297, P = 0.000). TFC: TIMI frame count, LCX: Left circumflex artery, HbA1c: Hemoglobin A1c

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Figure 4: Scatter plot showing the correlation of HbA1c with TFC of RCA (r = 0.51, r2 = 0.26, P = 0.000). TFC: TIMI frame count, RCA: Right coronary artery, HbA1c: Hemoglobin A1c

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Correlation of hemoglobin A1c with the severity of coronary artery disease by Gensini score

The mean Gensini score for the whole study group was 10.578 ± 18.555 (range, 0–112). The HbA1c quartiles were compared for the severity of CAD by Gensini score [Table 4]. The mean Gensini score increased with the increasing four levels of HbA1c quartiles (0.40 vs. 4.68 vs. 21.63 vs. 30.52) (ANOVA, P < 0.001). We also compared the HbA1c levels with CAD severity by using Syntax Score in SYNTAX subgroups (<23, 23–32, and >32), and the corresponding mean HbA1c values were 5.21 ± 0.4, 5.74 ± 1.3, and 6.36 ± 1.94, respectively (P < 0.05).
Table 4: Relation between HbA1c quartiles and Gensini score

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  Discussion Top


The relationship between HbA1c and CFV has not been adequately studied. For this purpose, we analyzed the correlation between HbA1c level and CFV and the severity of CAD in 263 consecutive patients over 2 years, who presented to us with chronic stable angina and had objective evidence of ischemia and underwent coronary angiography. We stratified our patient population into four HbA1c quartiles (<5.2, 5.2–5.6, 5.6–6.5, and ≥6.5) to analyze the effect of increasing HbA1c levels on CFV and disease severity. We found a significant association of HbA1c with CFV and disease severity in these patients.

Correlation of hemoglobin A1c with the diagnosis and severity of coronary artery disease

In nondiabetics, prediabetics, and newly diagnosed diabetics, HbA1c values significantly correlated with the severity of CAD. Increasing HbA1c levels not only correlated with the diagnosis of CAD but also with the severity of CAD (r = 0.436). Other studies have shown similar results.[15],[16],[17],[18] Diabetes is one of the most important causes of atherosclerosis.[19] Inflammation plays an important role in the initiation, development, and evolution of atherosclerosis, suggesting that atherosclerosis is an inflammatory disease. HbA1c is also a strong inflammatory marker.[20] In our study, we found that Gensini score and Syntax score increased with increasing HbA1c levels. Similar results were reported by other authors.[21],[22],[23]

Correlation of hemoglobin A1c with coronary flow velocity

Although many studies have analyzed the association between CAD and HbA1c, there are very few studies comparing the association of HbA1c with CFV. We examined the relationship between HbA1c and SCF. We found a statistically significant positive correlation between HbA1c and TFCs of all the three coronary arteries examined. The mean TFC of LAD, LCX, and RCA was statistically significantly higher in diabetics ascompared to nondiabetics (36.94 ± 4.25 vs. 30.32 ± 2.45, 23.76 ± 3.36 vs 19.89 ± 1.89 and 23.50 ± 2.63 vs.19.42 ± 1.55, respectively) (P = 0.0001), suggesting that as the glycemic control worsens, the coronary flow becomes slower.

HbA1c had a significant linear correlation with TFC of LAD, LCX, and RCA (r = 0.6, 0.54, and 0.51, respectively). Chronic hyperglycemia is associated with long-term damage, dysfunction, and failure of various organs, especially the heart and blood vessels.[24],[25] Increased glucose levels result in increased oxidative stress and protein glycation of vessel walls, accelerating the atherosclerotic process.[24] Several studies have shown that insulin has a regulatory effect on coronary vasoreactivity in healthy individuals. Rogers et al.[26] showed that glucose–insulin–potassium infusion increased coronary sinus blood flow. Laine et al.[27] showed that insulin was capable of modulating coronary vasoreactivity in healthy controls by acting as a vasoactive peptide in peripheral and myocardial vasculature. Considering the established finding that SCF causes anginal symptoms,[28] the complaints of the patients should be approached in the context of glycemic control.

Our study showed a strong relationship between SCF and high HbA1c levels. Advanced glycation end products (AGEs) play a major role in the mechanism of plaque formation and rupture. The underlying reason for increased AGE in serum is mostly poor glycemic control.[29] These end products show their effects mainly by increasing oxidative stress in the arterial wall and impairing endothelial functions.[30],[31],[32] It has been demonstrated that both extensive atherosclerosis and endothelial dysfunction may alter the coronary flow rate.[33]

Limitations

It was a single-center study. Long-term and clinical outcomes were not studied.


  Conclusion Top


HbA1c has a significant association with CFV even in the subdiabetic range. HbA1c is potentially used as a biomarker for risk stratification of patients who present to us with chronic stable angina, even in nondiabetics. Besides, our study opens a new horizon for any therapeutic benefit of lowering of HbA1c in nondiabetic individuals. Large randomized trials are needed to address this issue.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Author Contribution

All authors have contributed equally.

Ethical Approval

Study clearance was taken by Institute Ethical Committee.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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