Impact of age and hyperglycemia on the mechanical behavior of intact human coronary arteries: an ex...

Hyperglycemia, age and coronary mechanics 1

Impact of age and hyperglycemia on the mechanical

behavior of intact human coronary arteries: an ex-vivo

intravascular ultrasound study

Azita Tajaddini *1, Deborah L. Kilpatrick 4, Paul Schoenhagen 2, E. Murat Tuzcu 2,

Michael Lieber 3, D. Geoffrey Vince. 1

The Cleveland Clinic Foundation

1 Departments of Biomedical Engineering, 2 Cardiovascular Medicine,

and 3 Biostatistics and Epidemiology

Cleveland, OH 44195

4 Guidant Corporation, Vascular Intervention Group

Santa Clara, CA 95054

Supported by The Whitaker Foundation (97-0332, DGV-PI), The National Institute of

Health (RO1-HL64686, DGV-PI), and the Guidant Corporation

Running Head: Hyperglycemia, age and coronary mechanics

* Address for correspondence:

Azita Tajaddini, D. Eng.

Department of Biomedical Engineering/ND20

The Cleveland Clinic Foundation

9500 Euclid Avenue, Cleveland, OH 44195

Phone: (216) 445-4692, Fax: (216) 444-9198 Email: [email protected]

Articles in PresS. Am J Physiol Heart Circ Physiol (August 26, 2004). doi:10.1152/ajpheart.00646.2004

Copyright © 2004 by the American Physiological Society.

mailto:[email protected]


Abstract

Background: Despite their advantages, percutaneous coronary interventional (PCI)

procedures are less effective in diabetic patients. Changes in the mechanical properties

of vascular walls secondary to long-term hyperglycemia as well as other factors such as

age may influence coronary distensibility. This investigation is aimed at deciphering the

extent of these effects on distensibility of post-mortem human coronary arteries in a

controlled manner. Methods and Results: Excised human left anterior descending

coronary arteries (LAD) were obtained within 24 hours post mortem. Using

intravascular ultrasound (IVUS), vascular deformation was analyzed at mid-regions of

51 moderate lesions. Intraluminal pressure was systematically altered using a

computerized pressure pump system, and monitored by a pressure sensing guidewire.

Distensibility, a normalized compliance term, was defined as the change in lumen area

normalized by the initial reference area, over a given pressure interval. Using

multivariate analysis, repeated measures ANOVA, coronary distensibility was

independently influenced by hyperglycemia, and age (p<0.05) through the entire

pressure range. Within physiological pressure range, distensibility was significantly

reduced with age in non-hyperglycemic coronary specimens (10.55 ± 4.41 vs. 6.99 ±

2.45, x103 kPa-1, p=0.01), while the hyperglycemic vessels were stiff even in the

younger group (7.90 ± 5.82 vs. 7.20 ± 3.36, x103 kPa-1, p=0.79). Similar results were

observed with stiffness index (β) and elastic modulus (E) of the arteries. Conclusions:

Hyperglycemia and age independently influenced the distensibility of moderately


atherosclerotic LAD coronary arteries. The stiffening with age was overshadowed in the

hyperglycemic group by as yet undetermined factors.

Keywords: Arteriosclerosis, Coronary disease, Diabetes mellitus, Elasticity.

Introduction

Diabetes mellitus is associated with a 2-3 fold increase in the incidence of coronary

artery disease (CAD). Micro-and macrovascular complications of diabetes result in

increased cardiovascular morbidity and mortality. (7) Diabetic patients have a higher

tendency for thrombogenesis and neointimal proliferation following intervention, (20) as

well as multiple coexisting risk factors for CAD such as hypertension and age.

Additionally, atherosclerosis in diabetic patients tends to be more diffuse with more

complex lesions. (28) Despite improvements in percutaneous coronary interventional

technology, the outcome of these procedures is still less favorable for the diabetic

patients. (7, 8, 20) The underlying pathophysiologic mechanism is not completely

understood, but changes in the elastic properties of coronary arterial walls could

contribute to such increased morbidity.

The approach of this study was to quantify local coronary distensibility using diagnostic

tools such as IVUS catheters and pressure sensing guidewires. The results could

elucidate the factors affecting wall properties of moderately diseased vascular regions

that would potentially impact the rate of disease progression and the complication rates

of interventional procedures, particularly in the patients with diabetes.


Materials and Methods

Vessels: A total of fifty-one human left anterior descending (LAD) coronary arteries

were examined within 24 hours post-mortem according to institutional regulations.

Subjects with prior history of cardiac intervention and chemotherapy were excluded. An

approximately 40 mm thick portion of myocardium, which contained the LAD from its

ostium to apex, was dissected from the heart. This extravascular tissue supported the

LAD structurally by keeping its natural boundary conditions. Blood samples were also

collected to analyze the glycohemoglobin level (HbA1c%), where a level of 6.0 and

above indicates hyperglycemia. The age of subjects was between 40 to 75 years old.

Experimental set-up: The harvested tissue was mounted in a tissue bath, cannulated

and secured at the ostium, maintaining its in-vivo orientation. The tissue bath

containing phosphate buffered saline (PBS) was kept at 37 ± 1°C to reproduce in-vivo

conditions. Luminal pressure was altered with a computer-controlled pump system, as

described previously. (30) To measure intraluminal variations accurately, a pressure

sensing guidewire (Pressurewire®, RADI medical systems, Sweden) was calibrated and

inserted proximally into the mounted vessel. The Pressurewire®, with a diameter of 360

microns, was positioned to avoid contact with the vascular wall. The input pressure,

vascular pressure, and temperature of the PBS entering the LAD were continuously

monitored and displayed.

To measure the arterial wall dimensions, a 2.9 F, 30 MHz IVUS catheter (Scimed, CA)

was inserted into the vessel over the Pressurewire®. While applying a low pressure


(<100 mmHg), side branches were ligated until the measured lumen pressure

approached the input. When the pressure stabilized, usually in 30-45 minutes, the

catheter was manually pulled back for an overview of the vessel geometry and extent of

atherosclerosis. Vessels were excluded if they failed to reach a stable pressure due to

excessive leakage at branch sites.

Site selection: A site with concentric intimal thickening with plaque burden less than

50 % (by area) was selected from each vessel (Figure 1) to examine the properties of a

homogenous section of the arterial wall. This single site was chosen from the middle

section of the lesion to represent the behavior of that particular lesion.

Distensibility tests: Following mechanical preconditioning of the vessel, the IVUS

catheter was placed at the selected site and secured externally. The pressure

transducer was retracted a few millimeters to avoid its reflection on IVUS images. The

vessel was pressurized from 0 to 260 mm Hg in 20 mm Hg increments and held for 5

seconds each to allow the tissue to stabilize for collection of vascular images and

pressure data. For subsequent histological examination, a needle was used as an

acoustic reflector to locate the imaged site prior to marking it with a suture.

Histological Examination: Subsequent to distensibility testing, the entire vessel was

fixed with Histochoice (Amresco®, OH) at a pressure of 100-120 mm Hg for at least 8

hours in order to preserve lumen/wall structure and size. Sections from the sutured site

were prepared using H&E and Movat pentachrome stains to identify tissue components

such as collagen, elastin, smooth muscle fibers, and macrophage-derived foam cells.


Data Analysis: The mean pressure was obtained by averaging the last five data points

from the pressure sensing guidewire for each loading step. To calculate vascular cross-

sectional area (CSA), frames of digitized IVUS images were selected (Adobe Premiere,

Adobe Systems, CA) from the mid-point in time for each pressure step. Borders were

traced using a semi-automatic segmentation software package, developed at the

Cleveland Clinic Foundation (Figure 1). (15) CSA of lumen, external elastic membrane

(EEM), and lesion (plaque plus media CSA= EEM CSA – lumen CSA) were calculated

along with plaque burden (100 * lesion CSA / EEM CSA) according to published IVUS

guidelines. (22) Various biomechanical measures of arterial behavior were calculated

as follows, which accounted for the size and structure of the arteries. The vascular

distensibility was calculated as changes in lumen CSA (∆CSA) normalized by the initial

lumen CSA (CSAi), for each pressure interval (∆P) as: D = ∆CSA / (CSAi . ∆P)

Distensibility at physiological coronary pressure, Dp, was defined for each subject at ∆P

between 60 –140 mmHg. (24) A stiffness index (β) was also calculated based on the

same pressure range as β=(ln (P2/P1)) / ((r2-r1)/r1)), where r is the radius of the vessel at

the corresponding pressure, P. (9, 11) Similar to distensibility the stiffness index

provides a normalized compliance term including a logarithmic pressure term. Elasticity

of a material can also be defined using structural independent terms of stress and strain

commonly used in engineering discipline. Circumferential Cauchy stress, σ, was

calculated in the middle of the arterial wall using the equation for thick wall cylinders.


σ=P*(ri2/(ro

2-ri2))*(1+(ro

2/r2)), where r, ri and ro, indicate mid-wall, inner and outer radii

respectively. Circumferential strain was defined as the change in mid-wall radius within

the same pressure range as above with respect to the reference radius ε=(r2/r1)-1

The elastic modulus (E) was calculated as the slope of the stress-strain curve in the

physiological range of pressure. Elastic modulus is a material property independent of

the structure of the specimen. However calculation of stress depends on the structure

of the specimen, which in this case was assumed to be a thick walled cylinder.

Statistical Analysis: For each case, the subject’s age, plaque burden, and %HbA1c

levels were included. A statistical mixed model of repeated measures ANOVA (SAS,

release 6.12, SAS Institute Inc., NC) was used to extract the influence of fixed variables

on distensibility. Continuous variables such as age, plaque burden, and Dp were

described by mean and standard deviation. They were compared between the subject

groups using a t-test assuming an equal variance. Chi-square test was used for gender

differences. A significance level at 0.05 was used for all tests.

Results

A summary of subject and vessel characteristics is shown in Table 1. Age, HbA1c, and

plaque burden ranged between 40-75 years, 4.5-14.1%, and 20-50%, respectively. The

majority of the subjects were males (n=39), some of whom were hyperglycemic (n=12).

Most of the subjects were Caucasian (n=32), mostly non-hyperglycemic.

Hyperglycemic subjects were not significantly older (p=0.06). Also there was no

difference in age between male and female subjects (51.3 ± 8.0, 53.3 ± 0.3,


respectively, p=0.48). The LAD sections had a similar plaque burden compared to the

non-hyperglycemic group (p=0.38). The morphometric measurements of the two

groups are similar at intracoronary pressure of 100 mmHg (Table 1). The LAD sections

had similar histological profiles, including fibrous or fibrolipidic intima without

calcification.

Based on multifactorial analysis, hyperglycemia influenced distensibility both

independently and significantly (p=0.02) for the entire CSA-P curve of each subject.

The CSA-P curves (Figure 2) for subject groups based on median age and

hyperglycemia reflect their differences. Vessels from older individuals without

hyperglycemia were significantly stiffer than the young individuals (10.55 ± 4.41 vs 6.99

± 2.45, p=0.01) within physiological coronary pressure. Such a difference was not

observed in the hyperglycemic group (7.90 ± 5.82 vs. 7.20 ± 3.36, p=0.76)(Figure 3).

Distensibility decreased with age by about 12% per year with a higher decline in the

non-hyperglycemic subjects (16% vs. 10%). The age distribution within each group is

depicted in Table 2 as well as the indices of mechanical behavior, namely, distensibility,

beta stiffness index and elastic modulus. Stiffness index, β, was higher but not

significantly with hyperglycemia with or without outliers, which were taken as one order

of magnitude away from the group mean (52.6 ± 88.0 vs. 21.6 ± 10.8, p=0.14, and 24.4

± 20.3 vs. 21.6 ± 10.8, p=0.6, respectively). However, when age and hyperglycemia

were considered, the influence of age on β was significant on nonhyperglycemic

subjects and lacking in hyperglycemic group (Figure 4), as seen with distensibility.


Similarly elastic modulus significantly increased with age only in the non-hyperglycemic

group (Figure 5).

Discussion

Both age and long-term glycemic state reflected by HbA1c (29) were found to

significantly influence the distensibility-pressure relationship of moderately diseased

regions of human LAD coronary arteries. A significant reduction in distensibility was

observed with age within the physiological pressure range for non-hyperglycemic

subjects. However the LAD of younger hyperglycemic subjects was as stiff as the older

non-hyperglycemic subjects, illustrating the impact of hyperglycemia on coronary

distensibility. In all biomechanical indices used, distensibility, stiffness index (β) and

elastic modulus (E), hyperglycemia masked the effect of aging clearly seen in non-

hyperglycemic group.

Fundamental biomechanical vascular changes with early metabolic dysfunction are

likely to impact the clinical complication rates in diabetic patients as suggested by these

results. Although the components of diabetic lesions do not differ greatly from those in

non-diabetic patients, (29) hyperglycemia could affect the inherent properties of

components in the vascular walls. Several molecular and cellular changes in diabetic

vessels occur in their basement membrane, (5) connective tissue matrix, (6) and

platelet function. (4) Impairment of endothelial function in NO production (31) as well as

decreased smooth muscle responsiveness influences the effective arterial capability for

vasodilation (4) and distension. (1, 23, 27) Long-term hyperglycemia leads to non-


enzymatic glycation of proteins such as collagen fibers, and accumulation of the

byproducts, advanced glycation end products (AGEs), which may contribute to vascular

stiffness in both diabetes and aging. Recent studies have verified an increase in mean

arterial compliance of older diabetic patients after using a cross-link breaker to reduce

glycation. (14) As a result of such findings, vascular stiffness has been attracting more

attention in the study of diabetic CVD.

Due to the difficulty of testing small coronary vessels, most detailed vascular studies

have examined non-coronary/peripheral arteries as surrogates of the extent and impact

of disease in the coronary tree. Arterial compliance has been reported to change in

large arteries even prior to any evidence of complications from type I diabetes. (26)

Direct ex-vivo studies of aortic tissue in mechanical testing systems, (25) and various

non-coronary vessels in animals have shown a reduction of compliance with diabetes.

(19) Non-coronary, indirect methods, such as measuring carotid intima-media thickness

with Doppler ultrasound techniques, and pulse wave velocity methods have been used

to investigate vasculopathy in diabetic patients. Using these methods, loss of

compliance (up to 20%) of various non-coronary arteries is reported with both type I,

and II diabetes. (2, 10, 13, 18, 21, 26)Such techniques apply to large and relatively

superficial vessels with inherent limitations in studying smaller vessels, such as the

coronaries. Although all evidence point to the stiffening of vascular tissue with diabetes,

the data collected in a controlled manner from coronary arteries is scarce, underscoring

the need for a direct and accurate investigation as attempted in this study.


The unique capability of IVUS in showing the arterial wall layers with a resolution of 125

µm axially and 250 µm laterally, (22) has been utilized in vascular elasticity testing with

few studies including diabetes vasculopathy. (1, 23, 27, 31-33) While showing the

feasibility of coronary distensibility studies in a clinical setting, selection criteria for both

subjects and lesions are varied in these studies as well as including a few diabetic

patients. (1, 23, 27, 31, 33) Coronary compliance has been shown to correlate

negatively with lesion area. Specifically the content, severity and distribution of a lesion

alter the local mechanical behavior of the artery. (3, 12) To remove the effect of lesion

distribution on the arterial wall, this study focused on the relatively homogenous

concentric sections with moderate plaque burden (<50% by area). Calcified regions

were specifically avoided to ensure a uniform distribution of material properties as

evidenced by histology.

Due to the nonlinear viscoelasticity of arteries, using isobaric settings is essential for

vascular studies, (1, 12, 21, 23, 31, 33) emphasizing the benefits of local intracoronary

pressure measurement. The aforementioned studies were based on the pulse pressure

measured in a vessel other than the one imaged. Pressure sensing guidewires used in

this study are small enough to allow measurement very close to the imaged site, with a

design easily allowing for future in-vivo studies in both animals and humans.

Employing the IVUS imaging capability in arteries with isobaric conditions measured at

the lesion site, the arterial distensibility was significantly reduced in uniform lesions from

excised coronary LADs by both aging and hyperglycemia. Similar to studies of larger,


non-coronary arteries, the present data showed the extent of hyperglycemia to be a

significant independent factor in arterial distensibility. Within the physiological range of

coronary pressure, the influence of age was even more distinct than that of

hyperglycemia. Other indices of the arterial behavior, stiffness index (β) and elastic

modulus (E), calculated over the physiological range of pressure also showed that

hyperglycemia overshadowed the effect of age in stiffening of the arterial walls. Aging

has been associated with reduced large artery (2) and coronary compliance, (1, 27) as

well as linked to higher prevalence of both diabetes and CVD. Cross-linking of collagen

fibers, common in both aging and diabetes, may contribute to arterial stiffness and be

physically influenced by the extent of hyperglycemia, its duration, and treatment

approaches.

Beyond the biomechanical changes reported in this study, higher systolic pressure has

been reported in some diabetic patients (26) which would further compromise the

overall distensibility range of their vessels. Therefore, the combined effect of aging,

hyperglycemia and accompanying problems such as high blood pressure impact the

predisposition for CVD and treatment challenges and complications in diabetic patients.

Further combined biochemical and distensibility studies would elucidate the relationship

between local physiological factors such as coronary pressure, vascular wall

composition, and the state of the connective tissue fibers and matrix components in

arterial tissue layers, with the pathologic arterial mechanics in diabetic patients.

Limitations: The main limitation from a clinical standpoint is the lack of data from


individual cases, which may affect the development and progression of CVD, (20)

including the duration, extent and treatment of diabetes.

From the experimental perspective, the maximum pressure obtained was variable

among the specimens, due to unpredictable remaining leakage from branches of the

post-mortem vessels. However, in this study, unlike previous ones, (16, 18, 21, 25-27,

33) local pressure was measured within millimeters of the target lesion for accurate

assessment of the true arterial pressure. The catheter was centrally placed within the

vessel and externally secured to avoid increased local pressure due to its contact with

the wall. Minor inaccuracy in plaque burden resulted due to the well-known IVUS

challenge in discerning the media-intima border in images. Therefore the reported

plaque area includes media, leading to a consistent overestimation of plaque burden

throughout the study.

Other studies have found diabetic patients to have smaller lumen CSA, larger plaque

CSA, and similar EEM CSA compared to non-diabetic patients. (17, 27) But due to the

focus on homogenous moderately diseased lesions, arterial sections in this study were

not selected based on the same anatomical reference point rather on size and

distribution. This led to the variation in mean CSA shown in Table 1, which is mostly

attributable to the site selection within the LAD. Therefore no conclusions can be drawn

regarding the arterial size and hyperglycemic status.


Conclusions

With a systematic study, long-term hyperglycemia as indicated by HbA1c was found to

influence distensibility of moderately occluded (<50%) atherosclerotic coronary arteries.

This relationship persisted even when controlling for potential confounding factors such

as age and plaque burden. Within physiological pressures, distensibility decreased

significantly with age for non-hyperglycemic subjects. All measures of arterial stiffness

in this study indicated a significant change with age in non-hyperglycemic subjects only.

The results imply that the changes in coronary artery mechanics due to hyperglycemia

occur even prior to the processes associated with aging and with progression of

atherosclerosis in terms of increasing vascular wall thickness. These findings could

ultimately impact the use of interventional techniques and devices as applied to the

diabetic population through using clinically available diagnostic tools. Further detailed

biochemical and distensibility studies would improve our understanding of the changes

in behavior of lesions with various extent of atherosclerosis in hyperglycemic patients.

Acknowledgements

The authors are grateful to Barry Kuban, Jon Klingensmith, Anuja Nair, Misty Garcia,

and our students for their assistance with this project.

Grants

This study was supported by a grant from The Whitaker Foundation (97-0332, DGV-PI),

The National Institute of Health (RO1-HL64686, DGV-PI), and Guidant Corporation.

Disclosures


The authors have no conflict of interest for disclosure.

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Legends

Figure 1. a) An intravascular ultrasound image of a LAD coronary artery with lumen

and external elastic membrane (EEM) borders traced. b) A histological slide of a LAD

section from a diabetic subject indicating both internal elastic membrane (IEM) and

EEM. The bar in each figure measures 1 mm.

Figure 2. Relationship between lumen cross sectional area and pressure based on

hyperglycemia and median age.

Figure 3. Coronary distensibility based on hyperglycemia and median age. The

distensibility was calculated within physiological pressures as changes in lumen CSA


(∆CSA) normalized by the initial lumen CSA (CSAi), for each pressure interval (∆P) as:

D = ∆CSA / (CSAi . ∆P)

Figure 4. Stiffness index (β) based on hyperglycemia and median age, where β=(ln

(P2/P1)) / ((r2-r1)/r1)). Pressure (P) is defined within physiological range and r refers to

lumen radius at each pressure level.

Figure 5. Elastic Modulus (E) based on hyperglycemia and median age. E is the

slope of stress/strain curve defined over the physiological range of pressure.

List of Tables

Table 1. Number of subjects (n), and their demographics data expressed as mean

± standard deviation. The cross sectional area (CSA), and plaque burden (100 * lesion

CSA / EEM CSA) were calculated at intraluminal pressure of 100mmHg. Stiffness

index (β) was calculated within the physiological range of pressure. * Statistical

significance, p-value< 0.05, † See Limitations.

Table 2. Mechanical behavior of arteries from hyperglycemic and non-

hyperglycemic subjects in terms of distensibility, Elastic modulus (E) and stiffness index

(β). Data is indicated as mean ± standard deviation. A significant difference between

younger and older groups is based on t-test and indicated by *.


Figure 1. a) An intravascular ultrasound image of a LAD coronary artery with lumen

and external elastic membrane (EEM) borders traced. b) A histological slide of a LAD

section from a diabetic subject indicating both internal elastic membrane (IEM) and

EEM. The bar in each figure measures 1 mm.

1mm

1mm


Fig

hy

ure 2. Relationship between lumen cross sectional area and pressure based on

perglycemia and median age.


Figure 3. Coronary distensibility based on hyperglycemia and median age. The

distensibility was calculated within physiological pressures as changes in lumen CSA

(∆CSA) normalized by the initial lumen CSA (CSAi), for each pressure interval (∆P) as:

D = ∆CSA / (CSAi . ∆P)


F

(

l

igure 4. Stiffness index (β) based on hyperglycemia and median age, where β=(ln

P2/P1)) / ((r2-r1)/r1)). Pressure (P) is defined within physiological range and r refers to

umen radius at each pressure level.


Figure 5. Elastic Modulus (E) based on hyperglycemia and median age. E is the

slope of stress/strain curve defined over the physiological range of pressure.


Variables Hyperglycemic Non-hyperglycemic

p

n 19

32

NA

Male/Female

12/7

27/5

0.08

HbA1c (%)

7.33 ± 2.1

5.29 ± 0.3

<0.01*

Age (years)

56.2 ± 9.0

50.8 ± 9.8

0.06

Lumen CSA (mm2) 8.7 ± 3.3

8.1 ± 3.4

NA†

Plaque CSA (mm2) 3.9 ± 1.9

3.9 ± 1.8

0.93

Plaque burden (%)

30.1 ± 6.0

31.9 ± 7.3

0.38

β, Stiffness index

52.6 ± 88.0

21.6 ± 10.8

0.14

β, Stiffness index without outliers

24.4 ± 20.3 n=16

21.6 ± 10.8 n=32

0.60

Table 1. Number of subjects (n), and their demographics data expressed as mean

± standard deviation. The cross sectional area (CSA), and plaque burden (100 * lesion

CSA / EEM CSA) were calculated at intraluminal pressure of 100mmHg. Stiffness

index (β) was calculated within the physiological range of pressure. * Statistical

significance, p-value< 0.05, † See Limitations.


Non- Hyperglycemic HyperglycemicMedian Age 49 52 n 17 15 9 10 Age 43.8 ± 3.3 58.8 ± 8.6 48.2 ± 2.0 63.3 ± 6.3 Distensibility x1000(1/kPa)

10.6 ± 4.4

7.0 ± 2.5* 7.9 ± 5.8 7.2 ± 3.4

E (kPa) 1412 ± 721 3086 ± 2468* 1720 ± 1319 1564 ± 896 β 16.9 ± 7.1 26.9 ± 12.0* 25.1 ± 28.5 23.9 ± 12.9

Table 2. Mechanical behavior of arteries from hyperglycemic and non-

hyperglycemic subjects in terms of distensibility, Elastic modulus (E) and stiffness index

(β). Data is indicated as mean ± standard deviation. A significant difference between

younger and older groups is based on t-test and indicated by *.

Impact of age and hyperglycemia on the mechanical behavior of intact human coronary arteries: an ex...

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