Sage Journals: Discover world-class research

Abstract

Background:

This study investigated whether postprandial hyperglycaemia has an adverse effect on coronary microvascular function and left ventricular diastolic function.

Methods:

In all, 28 patients with type 2 diabetes mellitus with no significant stenosis in left anterior descending artery were enrolled. In all subjects, plasma 1,5-anhydroglucitol was measured, and coronary flow reserve in the left anterior descending artery was evaluated using a Doppler wire. Membrane type-1 matrix metalloproteinase expression on circulating peripheral blood mononuclear cells was measured by flow cytometry. Correlation analyses were performed for coronary flow reserve and 1,5-anhydroglucitol, other coronary risk factors, membrane type-1 matrix metalloproteinase and E/e′.

Results:

Strong correlations were found only between 1,5-anhydroglucitol and coronary flow reserve and membrane type-1 matrix metalloproteinase. On multiple regression analysis, 1,5-anhydroglucitol remained an independent predictor of coronary flow reserve (β = 0.38, p = 0.048).

Conclusion:

Postprandial hyperglycaemia appears to have an adverse effect on coronary microvascular function, suggesting that improvement of postprandial hyperglycaemia may contribute to the improvement of coronary microvascular dysfunction.

Keywords

Postprandial hyperglycaemia coronary flow reserve coronary heart disease

Introduction

Postprandial hyperglycaemia (PPH) is defined as a blood glucose level greater than 140 mg/dL 2 h after eating. PPH is very often seen in diabetic patients, even those with adequate glycosylated haemoglobin (HbA1c) levels under conventional management.¹ Though increasing HbA1c levels are involved in the onset and development of diabetic macrovascular disease,^2,3 data on the relationship between microvascular complications and PPH are limited. In recent prospective observational studies in Japan, PPH was a more useful predictor of diabetic retinopathy than HbA1c and was independently correlated with the onset of diabetic retinopathy, despite not being correlated with the onset of diabetic neuropathy.⁴

The acute hyperglycaemia that occurs in response to an oral glucose load in patients with type 2 diabetes impairs nitric oxide release from the endothelium, which is a main mediator of endothelium-dependent vasodilatation.⁵ In another study, it was shown that acute hyperglycaemia in healthy people also impaired endothelium-dependent vasodilation,⁶ which causes thrombosis and an increase in soluble adhesion molecules.⁷ In the postprandial state, myocardial blood volume (MBV) and myocardial blood flow (MBF) decrease significantly in diabetic patients.⁸ Moreover, coronary flow reserve (CFR) is reduced in diabetes mellitus (DM) patients without coronary stenosis compared with normal subjects.⁹ However, there have been few reports of clinical studies on the implications of PPH in microcirculatory disturbances, especially in coronary arteries. The purpose of this study was to clarify whether PPH has an adverse effect on coronary microcirculation.

Methods

Patient selection

For this study, 44 patients with impaired glucose tolerance (IGT) or type 2 DM who underwent coronary angiography were screened. Type 2 DM was defined as HbA1c 6.5 or more, IGT was defined as fasting plasma glucose <100 mg/dL and 2-h plasma glucose ⩾140 mg/dL and 2-h plasma glucose <200 mg/dL after the oral glucose tolerance test. Patients with any of the following were excluded from the study: (1) acute coronary syndrome, (2) acute congestive heart failure, (3) ejection fraction <40%, (4) severe renal failure, (5) severe valvular disease and (6) those judged by the attending physician as unable to be included in the study. Risk factors including age, sex, hypertension (HT) (defined as systolic blood pressure ⩾140 mmHg or diastolic blood pressure ⩾90 mmHg, or treatment with antihypertensive medication), current or prior smoking and low-density lipoprotein (LDL) levels were recorded. This study was approved by the Institutional Review Board of the University of Fukui. The patients included in the study provided informed consent for participation after the purpose and method of the study were explained to them. Of the 44 patients who consented, 16 had physiologically obstructive disease [angiographic stenosis >75% or fractional flow reserve (FFR) <0.80]¹⁰ and were therefore excluded from this analysis; thus, 28 patients were investigated.

Study procedures

Coronary angiography and physiologic evaluation

Coronary angiography was performed by a standard technique using a 4-French coronary catheter. After administration of 3000 IU of intravenous heparin and 4 mg of intracoronary isosorbide dinitrate, a 0.014-in, pressure and Doppler flow velocity monitoring guidewire (ComboWire^®; Volcano Therapeutics, Inc., San Diego, CA, USA) was advanced to the tip of the catheter, and the aortic pressure and wire pressures were equalized. Heart rate, aortic pressure, distal pressure and Doppler signals were continuously recorded during maximal hyperaemia with intracoronary bolus injection of 50 µg of adenosine in the left coronary artery.¹¹ FFR was calculated as the ratio of the mean distal intracoronary pressure to the mean arterial pressure at maximal hyperaemia. Microvascular function was assessed by measuring CFR. The earliest abnormality associated with coronary artery disease is the demonstration of abnormal CFR, an integrating parameter of endothelial function and vascular smooth muscle relaxation.¹² CFR was calculated from the ratio of hyperaemic/basal average peak blood flow velocity during maximal hyperaemia.¹³

Measurement parameters

Plasma 1,5-anhydroglucitol

Plasma 1,5-anhydroglucitol (1,5-AG) has been proposed as a short-term marker for PPH.¹⁴ 1,5-AG, a major 6-carbon unmetabolizable dietary monosaccharide that structurally resembles glucose, is filtered and completely reabsorbed by the kidneys during periods of euglycaemia. However, if glucose levels exceed 10.0 mmol/L (the average renal threshold for glucose), plasma 1,5-AG levels fall in direct proportion to the severity of glycosuria because of competitive inhibition by glucose for renal tubular reabsorption. Thus, even in patients who are below the target range for A1C, 1,5-AG could be used to monitor PPH¹⁵ and be useful as a surrogate measure of PPH.¹⁶

Membrane type-1 matrix metalloproteinase

The most well-characterized membrane-type matrix metalloproteinase is membrane type-1 matrix metalloproteinase (MT1-MMP), and it has been the focus of several in vitro and in vivo studies.¹⁷ It has been demonstrated that MT1-MMP degrades fibrillar collagens and a wide range of extracellular matrix (ECM) glycoproteins and proteoglycans. Thus, the MT-MMPs are an area of active research and are likely to play an important role in ECM degradation localized to the basement membrane and cell–cell contact points.

The expression of MT1-MMP in peripheral blood mononuclear cells (PBMNCs) was determined on a FACScan flow cytometer (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) using leukocytes from heparinized whole blood. MT1-MMP expression was defined as the proportion of MT1-MMP-positive cells in CD14-positive cells.¹⁸

Tissue Doppler measurement

To evaluate left ventricular diastolic function, the mitral annulus moving speed waveform using the tissue Doppler method was used.¹⁹

E/e′ is the ratio of the left ventricular inflow blood flow early diastolic wave (E) and the early diastolic mitral annulus velocity wave movement (e)′ and is used as an indicator of left ventricular end-diastolic pressure. It has been reported that left ventricular end-diastolic pressure is low when E/e′ is ⩽8, and it is increased when left ventricular end-diastolic pressure is ⩾15; this ratio is widely used in clinical practice.²⁰

Statistical analysis

All measured values are expressed as means ± standard deviation. Spearman’s correlation coefficient was used to assess the relationships between CFR, 1,5 AG, traditional coronary risk factors ((LDL-cholesterol, incidence of HT, smoking, body mass index (BMI)) and MT1-MMP in all patients. Multivariate linear regression analysis was carried out to identify the parameters affecting CFR. Individual models were assessed for goodness of fit using R values. The p values reported are two-sided with a significance level of 0.05. SPSS software (Windows ver.20; Chicago, IL, USA) was used for all statistical analyses.

Results

Patients’ clinical characteristics

A total of 28 patients (mean age, 69.3 ± 11.0 years; 68% male) were enrolled. Cardiovascular risk factors included HT (85.7%), hyperlipidaemia (89.2%), current and previous tobacco smoking (64.3%) and BMI (24.7 ± 3.4 kg/m²).

Treatment of DM included insulin (7.1%), sulfonylurea (25.0%), α-glucosidase inhibitors (28.5%) and dipeptidyl peptidase-4 inhibitors (10.7%). Treatment of HT and hyperlipidaemia is presented in Table 1.

Table 1.

Patients’ characteristics.

Variables
Age (years)	69.3 ± 11.0
Sex (M/F)	19/9
Risk factor
Hypertension, n (%)	24 (85.7)
Hyperlipidaemia, n (%)	25 (89.2)
Smoking, n (%)	18 (64.3)
Body mass index (kg/m²)	24.7 ± 3.4
HbA1c (%)	6.8 ± 0.7
Low-density lipoprotein (mg/dL)	97.8 ± 27.7
Medications
CCB, n (%)	13 (46.4)
ACE-I/ARB, n (%)	24 (85.7)
β-Blocker, n (%)	6 (21.4)
Statin, n (%)	21 (75.0)
Insulin, n (%)	2 (7.1)
Sulfonylurea, n (%)	7 (25.0)
α-Glucosidase inhibitors, n (%)	8 (28.5)
DPP-4 inhibitors, n (%)	3 (10.7)

HbA1c: glycosylated haemoglobin; CCB: calcium channel blocker; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; DPP-4: dipeptidyl-peptidase IV inhibitor.

Measurement parameters and coronary physiological data

The data are summarized in Table 2. CFR was slightly low, and coronary endothelial function was reduced. The average E/e′ was about 15, so slight left ventricular diastolic failure was observed.

Table 2.

Coronary physiological data and parameters.

Variables
Physiological data from angiography
CFR of LAD	2.07 ± 0.60
FFR of LAD	0.91 ± 0.06
Biomarker
1,5-AG (µg/mL)	15.9 ± 8.0
MT1-MMP (%)	33.7 ± 3.3
Left ventricular diastolic function
E/e′	13.9 ± 4.9

CFR: coronary flow reserve; LAD: left anterior descending artery; FFR: fractional flow reserve; 1,5-AG: 1,5-anhydroglucitol; MT1-MMP: membrane type-1 matrix metalloproteinase.

Relationship between coronary microvascular function and traditional coronary risk factors and MT1-MMP

The relationships between coronary microvascular and traditional coronary risk factors and MT1-MMP are shown in Table 4. The CFR level was positively correlated with 1,5-AG (R = 0.46, p = 0.01, Figure 1), but there was no correlation between CFR and MT1-MMP (R = −0.30, p = 0.12, Table 3). On the other hand, MT1-MMP was negatively correlated with 1,5-AG (R = −0.43, p = 0.02, Table 3).

Figure 1.

Relationship between CFR and the plasma 1,5-AG level.

Table 3.

Univariate relationship between microvascular function and traditional coronary risk factors and membrane type-1 matrix metalloproteinase levels.

	CFR	1,5-AG	MT1-MMP	E/e′	EF	LDL-C	BMI	HT	Smoking
CFR	1	0.46*	−0.30	−0.31	−0.14	−0.10	−0.04	0.24	−0.24
1,5-AG		1	−0.43*	−0.06	−0.10	0.25	0.13	0.17	0.07
MT1-MMP			1	0.23	0.07	−0.16	0.10	0.01	0.05
E/e′				1	0.05	0.22	0.16	0.10	−0.30
EF					1	−0.05	0.32	0.16	0.12
LDL-C						1	0.08	−0.02	0.01
BMI							1	0.03	−0.04
HT								1	−0.30
Smoking									1

CFR: coronary flow reserve; 1,5-AG: 1,5-anhydroglucitol; MT1-MMP: membrane type-1 matrix metalloproteinase; EF: ejection fraction; LDL-C: low-density lipoprotein cholesterol-cholesterol; BMI: body mass index; HT: hypertension.

p < 0.05.

On multiple regression analysis (objective variable CFR, explanatory variables 1,5-AG, MT1-MMP), 1,5-AG remained an independent predictor of CFR (β = 0.38, p = 0.048, Table 4).

Table 4.

Multiple regression analysis for CFR.

Variables	Unstandardized coefficients			β	t Value	p Value
Variables	β	SE	95% CI	β	t Value	p Value
1,5-AG	0.03	0.01	1.11–2.11	0.38	2.08	0.048
MT1-MMP				0.01	0.05	0.96

SE: standard error; CI: confidence interval; 1,5-AG: 1,5-anhydroglucitol; MT1-MMP: membrane type-1 matrix metalloproteinase.

Discussion

Major findings of this study

This study was conducted to determine whether PPH plays an important role in endothelial dysfunction of coronary arteries. In patients with DM and IGT, CFR was positively correlated with PPH, and 1,5-AG was an independent factor related to CFR on multivariate analysis. Thus, PPH may have an important impact on endothelial dysfunction of coronary arteries.

PPH and cardiovascular events and endothelial dysfunction

It has been reported that the relative contribution of postprandial blood glucose levels to overall glycaemic control is increased as the HbA1c value decreases.²¹ The postprandial 2-h blood glucose level is a better predictor of all-cause mortality and cardiovascular disease than the fasting blood glucose level.²² Furthermore, PPH may reduce the flow-mediated endothelium-dependent vasodilation (FMD) as an indicator of endothelial function by impairing nitric oxide release from vascular endothelial cells.⁵ Cardiovascular events are increased in a low FMD state.²³ In addition, myocardial flow and MBF are reduced after meals in patients with type 2 diabetes.⁸ From these reports, it was clear that PPH caused systemic vascular endothelial dysfunction and impaired myocardial microvascular dysfunction. In this study, coronary endothelial function was evaluated clinically by measuring CFR.

CFR and vulnerable plaque

Impaired CFR is an independent predictor of coronary events in diabetic patients.²⁴ In this study, whether CFR was correlated with plaque disability, possibly triggering coronary events, was evaluated using the expression of MT1-MMP in PBMNCs. The expression of MT1-MMP, which is an activated form of pro-MMP2, has an important role in ECM remodelling of human atherosclerotic plaques.²⁵ We have previously shown that macrophages accumulate in the shoulder region and are prone to plaque disruption in human coronary atherosclerotic plaques, and that MT1-MMP is expressed in the macrophages.²⁶ Thus, determining MT1-MMP expression levels on the monocyte surface is useful for the direct evaluation of unstable plaque. After treatment of DM by acarbose, which improves PPH, MT1-MMP expression in PBMNCs decreased.¹⁸ In this study, there was no correlation between CFR and MT1-MMP expression. Therefore, CFR does not appear to be directly associated with plaque vulnerability in the early phase of DM.

Clinical implications

There has not yet been any research specifically examining the effect of management of postprandial blood glucose levels on the microcirculatory dysfunction of coronary arteries. There has been some evidence to support treatment for postprandial blood glucose levels for reducing the incidence of major cardiovascular events. The STOP-NIDDM²⁷ and MERIA studies²⁸ showed that the risk of cardiovascular events is significantly reduced when acarbose is used for the treatment of PPH. In this study, the levels of 1,5-AG, which is a short-term marker for PPH, were associated with MT1-MMP expression, suggesting that PPH is one of the mechanisms of plaque instability. Risk stratification and new targets for therapeutic intervention may be clarified by measuring 1,5-AG levels and MT1-MMP expression

Study limitations

First, the 50 µg intracoronary adenosine dose may be insufficient for the maximum hyperaemia. We determined 50 µg on the basis of 20–40 µg bolus adenosine dose in the reference,¹¹ but several recent articles have indicated that there might be a dose–response relationship for adenosine doses.^29,30 Although the dose of 50 µg might not reach the maximum hyperaemia, we could be able to evaluate CFR adequately.¹¹ Second, the sample size was small, and the design was a single-centre study. It was not possible to investigate the effects of other drugs or oxidative stress markers that might be expected to affect endothelial function, such as angiotensin converting enzyme inhibitor (ACE-I)/angiotensin II receptor blockers (ARBs), statins and high-sensitive C-reactive protein (CRP), because the number of patients analyzed was too small in this study. Third, this study was an evaluation of the left anterior descending artery (LAD) alone, and it does not necessarily reflect overall microcirculatory dysfunction of the coronary arteries. Since the flow pattern of each coronary artery is different, for evaluation of coronary microcirculatory dysfunction, each coronary artery should be considered separately.

Furthermore, a cause-and-effect relationship was not established for coronary microvascular dysfunction and PPH. This mechanistic study, despite its limited size, provides hypothesis-generating data for future, larger, prospective studies.

Conclusion

In diabetic patients, PPH was found to have an adverse effect on coronary microvascular function, suggesting that improvement of PPH may contribute to the improvement of coronary microvascular dysfunction.

Footnotes

Acknowledgements

The authors would like to thank Hiromi Nishimura, Yumie Yasusaki, Motoko Oku, Mari Kurata and Yoshiko Kurose for providing excellent technical assistance and for their significant contribution to this research.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

References

Erlinger

Brancati

. Postchallenge hyperglycemia in a national sample of US adults with type 2 diabetes. Diabetes Care 2001; 24: 1734–1738.

Borch-Johnsen

Neil

Balkau

. Glucose tolerance and cardiovascular mortality – comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 2001; 161: 397–405.

Levitan

Song

Ford

. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med 2004; 164: 2147–2155.

Shiraiwa

Kaneto

Miyatsuka

. Post-prandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients. Biochem Biophys Res Commun 2005; 336: 339–345.

Kawano

Motoyama

Hirashima

. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 1999; 34: 146–154.

Williams

Goldfine

Timimi

. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998; 97: 1695–1701.

Marfella

Quagliaro

Nappo

. Acute hyperglycemia induces an oxidative stress in healthy subjects. J Clin Invest 2001; 108: 635–636.

Scognamiglio

Negut

De Kreutzenberg

. Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation 2005; 112: 179–184.

Pitkanen

Nuutila

Raitakari

. Coronary flow reserve is reduced in young men with IDDM. Diabetes 1998; 47: 248–254.

10.

Pijls

NHJ

DeBruyne

Peels

. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996; 334: 1703–1708.

11.

Van de Hoef

van Lavieren

Damman

. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv 2014; 7: 301–311.

12.

Dayanikli

Grambow

Muzik

. Early detection of abnormal coronary flow reserve in asymptomatic men at high-risk for coronary-artery disease using positron emission tomography. Circulation 1994; 90: 808–817.

13.

Gould

Kirkeeide

Buchi

. Coronary flow reserve as a physiologic measure of stenosis severity. J Am Coll Cardiol 1990; 15: 459–474.

14.

McGill

JRB

Cole

Nowatzke

. Circulating 1,5-anhydroglucitol levels in adults patients with diabetes reflect longitudinal changes of glycemia. Diabetes Care 2004; 27: 1859–1865.

15.

Yamanouchi

Ogata

Tagaya

. Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycaemic control. Lancet 1996; 347: 1514–1518.

16.

Won

Park

C-Y

Park

H-S

. 1,5-Anhydroglucitol reflects postprandial hyperglycemia and a decreased insulinogenic index, even in subjects with prediabetes and well-controlled type 2 diabetes. Diabetes Res Clin Pract 2009; 84: 51–57.

17.

Miyamori

Takino

Seiki

. Human membrane type-2 matrix metalloproteinase is defective in cell-associated activation of progelatinase A. Biochem Biophys Res Commun 2000; 267: 796–800.

18.

Uzui

Nakano

Mitsuke

. Acarbose treatments improve arterial stiffness in patients with type 2 diabetes mellitus. J Diabetes Investig 2011; 2: 148–153.

19.

Sohn

Chai

Lee

. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997; 30: 474–480.

20.

Ommen

Nishimura

Appleton

. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures – a comparative simultaneous Doppler-catheterization study. Circulation 2000; 102: 1788–1794.

21.

Monnier

Lapinski

Colette

. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients – variations with increasing levels of HbA(1c). Diabetes Care 2003; 26: 881–885.

22.

Nakagami

Qiao

Tuomilehto

. Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five populations of Asian origin: the DECODA study. Eur J Cardiovasc Prev Rehabil 2006; 13: 555–561.

23.

Schachinger

Britten

Zeiher

. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899–1906.

24.

Murthy

Naya

Foster

. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation 2012; 126: 1858–1868.

25.

Rajavashisth

Jovinge

. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques – evidence for activation by proinflammatory mediators. Circulation 1999; 99: 3103–3109.

26.

Uzui

Harpf

Liu

. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque – role of activated macrophages and inflammatory cytokines. Circulation 2002; 106: 3024–3030.

27.

Chiasson

Josse

Gomis

. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance – the STOP-NIDDM trial. JAMA 2003; 290: 486–494.

28.

Hanefeld

Cagatay

Petrowitsch

. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J 2004; 25: 10–16.

29.

Casella

Leibig

Schiele

. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004; 148: 590–595.

30.

De Luca

Venegoni

Iorio

. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv 2011; 4: 1079–1084.

Effect of postprandial hyperglycaemia on coronary flow reserve in patients with impaired glucose tolerance and type 2 diabetes mellitus