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. Author manuscript; available in PMC: 2023 Jul 1.
Published in final edited form as: J Vasc Access. 2021 Jun 18;24(1):124–132. doi: 10.1177/11297298211026083

Cardiac Changes Following Arteriovenous Fistula Creation in a Mouse Model

Kevin Ingle 1, Linh Pham 1, Viangkaeo Lee 1, Lingling Guo 1, Tatyana Isayeva-Waldrop 1, Maheshika Somarathna 1, Timmy Lee 1,2
PMCID: PMC9013201  NIHMSID: NIHMS1788256  PMID: 34144670

Abstract

Background:

Arteriovenous fistula (AVF) creation may negatively affect cardiac structure and function and impact cardiovascular mortality. The objective of this study was to develop and characterize the cardiac changes following AVF creation in a murine AVF model.

Methods:

AVFs were constructed using the carotid artery and jugular vein in C57BL/6 mice. Sham-operated AVF mice served as the control group. 2D-echocardiography was performed prior to AVF creation (baseline) and at 7 and 21 days after creation in AVF and sham-operated mice. Picrosirius red was used to stain the left ventricle for collagen production.

Results:

The cardiac output (CO), left ventricular end diastolic (LVEDD) and systolic (LVESD) diameter, and end-diastolic (LVEDV) and systolic (LVESV) volume was significantly increased at 7 and 21 days in AVF compared to sham-operated mice. There was also a significant increase in CO, LVEDD, LVESD, LVEDV, and LVESV from baseline to 21 days within the AVF group, but not the sham-operated mice. There was a significant decrease in ejection fraction and fractional shortening at 21 days in AVF compared to sham-operated mice. Picrosirius red was significantly more prominent around both the perivascular and interstitial areas of the cardiac tissue from AVF mice compared to sham-operated AVF mice at 21 days.

Conclusions:

The creation of an AVF in our murine model leads to cardiac changes such as increased cardiac output, left ventricular dilation, and cardiac fibrosis, while showing reductions of ejection fraction and fractional shortening.

Keywords: End stage renal disease, Heart Failure, Arteriovenous Fistula

INTRODUCTION

The hemodialysis vascular access is the “lifeline” for the hemodialysis patients, as it provides the conduit for thrice weekly dialysis treatments for the patient. The arteriovenous fistula (AVF) is the recommended vascular access for hemodialysis patients1–3 because AVFs require fewer maintenance interventions, greater longevity, and lowest risk of infections compared to other vascular access types4. However, AVF creation results in several physiologic changes, which includes an acute decrease in systemic vascular resistance, subsequently followed by an increase in cardiac output5,6. End stage kidney disease (ESKD) patients have a high underlying cardiovascular burden and cardiac events are the most common etiology of death in hemodialysis patients7. The increased cardiac output (CO) following AVF creation may produce structural and functional cardiac changes, which may include left ventricular remodeling and development of left ventricular hypertrophy (LVH)8–10. LVH is a major risk factor for the development of congestive heart failure in dialysis patients, which predicts an increase in cardiovascular events in advanced chronic kidney disease and ESKD patients11. The volume overload-like state resulting after AVF creation may further contribute to the high morbidity and mortality in hemodialysis patients8,12. The pathophysiologic mechanisms of cardiac changes following AVF creation is poorly understood and has hindered efforts to effectively treat this clinical problem.

Previous animal models used to study ventricular remodeling and heart failure have primarily utilized aortocaval AVF models 13–15. The murine carotid artery to jugular vein AVF has recently been published as a AVF model used to study pathophysiology of AVF development16–19. This model has several advantages to elucidate mechanisms of cardiac changes following AVF creation: (1) the anatomical location of the carotid artery to internal jugular vein AVF located in the major upper vessels in the mouse simulates where AVFs are created in humans, the upper extremities, (2) the configuration used to create the murine AVF, an end (vein) to side (artery) anastomosis, is also the most common AVF configuration in humans, and also replicates similar AVF hemodynamics, and (3) the murine AVF model allows for more detailed future studies using transgenic animals. Our study describes a murine AVF model that can be used to understand pathophysiologic mechanisms of cardiac remodeling in a volume-overload state following AVF creation.

MATERIAL AND METHODS

Surgical Creation of Murine Arteriovenous Fistula

All animal procedures and experiments were approved by the University of Alabama at Birmingham Institutional Animal Care and Use Committee and conformed with the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Our studies utilized male C57BL/6 mice ordered from Taconic Biosciences aged 10 weeks at arrival and up to 18 weeks by the end of the 21-day AVF or sham timepoint. The murine AVFs were created using an end (jugular vein) to side (carotid artery) anastomosis. (Figure 1). Details of our murine AVF surgical procedure have been described in detail and published previously16,19 and are also described in the Figure 1 legend. Sham-operated mice were created and age matched to AVF mice. Mice had baseline 2D echocardiography performed at 10 weeks of age, then AVF and sham operations were created in mice from ages 11-15 weeks with echocardiograms and sacrifices occurring at 7- and 21-days post AVF or sham operation (Figure 2).

Figure 1: Representative Figure Highlighting Steps of Carotid Artery-Jugular Vein Arteriovenous Fistula Creation.

Figure 1:

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(A) The external jugular vein is isolated using blunt dissection. (B-C). 7-0 sutures are permanently tied on the distal end of the vein and 6-0 suture is tied on the proximal end in a releasable knot. The carotid artery is tied with releasable knots on both proximal and distal ends using 6-0 sutures. (D-E). The vein is partially cut to expose the lumen and a small incision is made into the artery to fit the vein. The firsts half of the anastomosis is created using 10-0 needle suture placing outside to in the vein then inside out to the artery at the closest side. Sutures are filled in above and below the first connection until the inner side is complete. (F) The remaining side of the vein is cut and connected to the other side of the artery using 10-0 sutures and 11-0 to fill in any gaps. (G-H) The sutures are released and after a few minutes blood flow is established to the vein and the dilation increases.

Figure 2: Representative Two-Dimensional Echocardiographic Images of the Left Ventricle in Sham-operated and AVF Mice in Diastole.

Figure 2:

Figure 2:

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(A) Representative diastolic B-Mode images of the LV in the sham-operated and AVF group. The diastolic area of the LV is outlined in red. (B) Representative M-Mode Echocardiograms from the sham-operated and AVF groups. Note dilated left ventricle in AVF versus sham group. Red lines represent LVEDD and green lines represent LVESD. Scale bar on right shown in millimeter increments.

Echocardiography Image Acquisition and Analysis

Cardiac structure and function in adult male C57BL/6 mice (Taconic Biosciences, Hudson, NY) were assessed using a VEVO 2100 micro-ultrasound system with a 24-30 MHz bifrequency transducer (Visual Sonics, Toronto, Canada). The mice were anesthetized with 2% isoflurane in a 100% oxygen mix during the induction period. The mice subsequently were placed on an imaging stage equipped with electrode pads for continuous ECG and heart rate monitoring along with a heater to maintain body temperature at 37°C. Following induction, the anesthesia was maintained using 1.50% isoflurane. The probe was positioned in the parasternal long and short axis orientations to acquire B-mode and M-mode images of the left ventricle (LV) at both positions. The following M-Mode measurements (Figure 2b) were performed on the left ventricle for systole(s) and diastole(d): Inter ventricular septum (IVS) and left ventricular posterior wall (LVPW) to assess LV wall thickness. The LV trace feature was used to measure long axis mid papillary M-mode images of the LV over the course of at least 3 consecutive heart beats. This tool measures the diastolic and systolic diameters of the LV chamber between the IVS and LVPW (LVEDD and LVESD), which in turn is used to calculate fractional shortening (FS), a measure of how well the heart is contracting between systole and diastole. FS is a ratio which is difference between the diastolic and systolic diameter as a percentage of the diastolic diameter. Left ventricle end diastolic and systolic area (A;d/s) and volumes (LVEDV/LVESV) were also calculated using the LV trace feature which was used to calculate ejection fraction (EF) and cardiac output (CO) that characterize how effectively the LV is pumping blood. EF is a ratio that is generated by the difference between diastolic and systolic volumes, also known as stroke volume (SV), as a percentage of the diastolic volume. EF and FS are both indicators of how well the LV is contracting and pumping blood. CO is a measure of the rate of blood pumping out of the heart in ml/min calculated using SV and heart rate. B-mode long axis images were used to visualize the size increase of post AVF hearts (Figure 2a).

Picrosirius Red Staining (PSR) and Image Analysis

The middle section of the left ventricle was fixed with 10% formalin for 24 hours, embedded in paraffin and cut into 5 micrometer sections on glass microscope slides. These slides were then stained for collagen using picrosirius red staining. Briefly, slides are deparaffinized in HistoPrep xylene (Fisherbrand HC7001GAL), rehydrated through decreasing concentrations of ethanol, treated with 0.2% aqueous phosphomolybdic acid (Electron Microscopy Sciences 26367-05) and washed with deionized water. Sections are then treated with sirius red, 0.1% in picric acid (Electron Microscopy Sciences 19550; CAS#88-89-1) followed by 0.01 N hydrochloric acid (Fisher Scientific SA62-1; CAS#7647-01-0) and dehydrated through increasing concentrations of ethanol and xylene before being mounting using Cytoseal XYL (ThermoFisher Scientific 8312-4).

For interstitial sections, a total of 4-10 images at 40x magnification were collected in PSR stained LV tissues of d21 sham and AVF mice. Sections that were analyzed for interstitial fibrosis focused on the interior LV area and avoided perivascular areas and the inner/outer edges of the LV. Images were captured using an Olympus IX73 Brightfield microscope with an attached Olympus LC30 camera with the imaging software CellSens dimensions (Olympus version 3.1). The PSR stain in the interstitial sections was selected using the software and a % of the total image area stained red was produced. For each sample, 4-10 interstitial images were captured and the red PSR stain counted as % of the total image area to calculate a % stained area (Figure 4A) For perivascular staining, only the PSR stain around vessels were analyzed. A range of 4-10 vessel images in the LV were analyzed per sample (Figure 4B). The total outer perimeter and area of the vessels were measured along with the inner lumen perimeter and area so % of stain within the media area could be generated for comparison between the groups.

Figure 4: Picrosirius Red Staining in Sham-operated and AVF Mice at 21 days.

Figure 4:

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(A) Interstitial Staining of Left Ventricle. (B) Perivascular Staining of Left Ventricle. N=4 for sham-operated group. N=10 for AVF group. Unpaired t-test analysis was used to compare sham-operated and AVF group. Left ventricular perivascular staining showed an increase in fibrosis in the left ventricular vessel areas of day 21 AVF group as compared to sham-operated group (*p<0.05). Scale bar=20 micrometers.

Statistical Analysis

All data are expressed as mean and standard error of mean (S.E.M). Analyses between groups in the echocardiographic data were performed using a two-way ANOVA with Tukey’s multiple comparison test. A one-way ANOVA was performed to assess linear trends within each group by time point. Multiple t test analysis was performed to assess necropsy parameters by timepoint. Results for perivascular and interstitial PSR staining was analyzed using an unpaired t-test. GraphPad Prism version 8.0 (La Jolla, CA) was used for statistical analysis and p<0.05 was considered as statistically significant.

RESULTS

Body Weights and Organ Weights

Body and organ weight are shown in Table 1. There was no significant difference in body weight or heart rate in AVF mice as compared to sham-operated mice at 7 and 21 days. The mean total heart (LV and right ventricle)/body weight was significantly greater in AVF group, as compared to sham-operated control at 7 (5.2± 0.2 vs 4.6±0.1 mg/g; p<0.05) and 21 days (5.4±0.2 vs 4.7±0.2 mg/g; p<0.05), respectively.

Table 1.

Sham-operated and Arteriovenous Fistula (AVF) Body Weight, Heart rate, and Heart Weight.

Measurement 7 Day Sham 7 Day AVF 21 Day Sham 21 Day AVF
Body Weight, g 25.8±0.5 26.5±1.0 26.8±1.3 30.3±0.8
HR, beats/min 529±23 525±37 496±18 469±16
LV + RV (mg) 117.3±2.1 137.9±5.4* 125.8±4.7 157.8±3.1*
LV+RV/BW, mg/g 4.6±0.1 5.2±0.2* 4.7±0.2 5.4±0.2*
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Values are mean ± S.E.M; HR, heart rate; LV, left ventricle; RV, right ventricle; BW, body weight; AVF, arteriovenous fistula

*

p<0.05 between sham-operated AVF and AVF at 7 and 21 days using multiple t-test analysis.

N=4 for sham-operated group. N=4-11 for AVF.

Cardiac Output Following Arteriovenous Fistula Creation

Baseline cardiac output was similar between the sham-operated control group versus AVF group (19.1±1.3 vs 19.0±0.9 ml/min; p>0.99)(Figure 3a). CO was significantly greater in the AVF group compared to the sham-operated control group at 7 (24.3±0.7 vs. 18.4±1.0 ml/min; p<0.01) and 21 days (25.6±1.7 vs. 17.7±0.9 ml/min; p<0.01), respectively (Figure 3a). There was not a significant difference in CO within the sham-operated control group from baseline to 21 days (Figure 3a). However, there was a significant increase within the AVF group from baseline to 21 days (p<0.01)(Figure 3a).

Figure 3: Echocardiographic Measurements in Sham-operated and AVF Mice.

Figure 3:

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(A) Cardiac Output (CO), (B) Left Ventricular End-Diastolic Diameter (LVEDD), (C) Left Ventricular End-Systolic Diameter (LVESD), (D) Left Ventricular End Diastolic Volume (LVEDV), (E) Left Ventricular End Systolic Volume (LVESV), (F) Left Ventricular Ejection Fraction (LVEF), and (G) Left Ventricular Fractional Shortening (LVFS). N=4-8 animals in sham-operated group and N=8-12 in AVF group. NS, non-significant; Two way ANOVA with Tukey’s multiple comparison test used to compare between sham-operated control group and AVF group at day 7 and 21. *p<0.01; **p<0.001; ***p<0.0001; NS, nonsignificant; One way ANOVA use for comparison within with sham-operated group and AVF group. ANOVA within AVF group, p<0.0001 and NS with sham-operated control group.

Left Ventricular Cardiac Dimension

Baseline LVEDD was similar between the sham-operated control group versus AVF group (3.7±0.09 vs. 3.6±0.06 mm; p=0.87)(Figure 3b). LVEDD was significantly greater in the AVF group at 7 days (4.4±0.05 vs 3.7±0.09 mm; p<0.0001) and 21 days (4.8±0.07 vs. 3.6±0.04 mm; p<0.0001)(Figure 3b), respectively. There was not a significant difference in LVEDD within the sham-operated control group from baseline to 21 days (Figure 3b). However, there was a significant increase in LVEDD within the AVF group from baseline to 21 days (p<0.0001)(Figure 3b).

Baseline LVESD was similar between the sham-operated control group versus AVF group (2.5±0.07 vs. 2.3±0.08 mm; p=0.95)(Figure 3c). LVESD was significantly greater in the AVF group at 7 days (3.1±0.06 vs 2.5±0.06 mm; p<0.0001) and 21 days (3.5±0.07 vs. 2.4±0.04 mm; p<0.0001)(Figure 3c), respectively. There was not a significant difference in LVESD within the sham-operated control group from baseline to 21 days (Figure 3c). However, there was a significant increase in LVESD within the AVF group from baseline to 21 days (p<0.0001)(Figure 3c).

Left Ventricular Cardiac Volume

There was no significant difference in baseline LVEDV between the sham-operated control group versus AVF group (54.4±1.6 vs. 59.6±3.6 μL; p=0.82)(Figure 3d). LVEDV was significantly greater in the AVF, as compared to the sham-controlled group at 7 days (88.8±2.6 vs 56.9±3.5 μL; p<0.0001) and 21 days (106.4±3.5 vs. 54.6±1.6 μL; p<0.0001)(Figure 3d), respectively. There was not a significant difference in LVEDV within the sham-operated control group from baseline to 21 days (Figure 3d). However, there was a significant increase in LVEDV within the AVF group from baseline to 21 days (p<0.0001)(Figure 3d).

There was no significant difference in baseline LVESV between the sham-operated control group versus AVF group (21.6±1.6 vs. 19.1±1.6 μL; p=0.93)(Figure 3e). LVESV was significantly greater in the AVF, as compared to the sham-controlled group at 7 days (39.9±1.8 vs 22.4±1.4 μL; p<0.0001) and 21 days (52.4±2.7 vs. 19.6±0.85 μL; p<0.0001)(Figure 3e), respectively. There was not a significant difference in LVESV within the sham-operated control group from baseline to 21 days (Figure 3e). However, there was a significant increase in LVESV within the AVF group from baseline to 21 days (p<0.0001)(Figure 3e).

Plasma B-type natriuretic peptide (BNP) levels were also measured to assess volume overload state. Plasma BNP levels were significantly greater in AVF mice at 21 days compared to 21 day sham mice (p<0.05)(Supplemental methods and supplemental figure 1).

Left Ventricular Cardiac Contractility

Baseline LVEF% was similar between the sham-operated control group versus AVF group (63.0±1.9 vs 65.3±2.3%; p=0.93)(Figure 3f), respectively. LVEF% was significantly reduced in the AVF group compared to the sham-operated group at 21 days (64.3±1.1 vs. 50.9±1.6%; p<0.001)(Figure 3f), respectively. There was not a significant difference in LVEF% within the sham-operated control group from baseline to 21 days (Figure 3f). However, there was a significant decrease in LVEF% within the AVF group from baseline to 21 days (p<0.0001)(Figure 3f).

Baseline LVFS% was similar between the sham-operated control group versus AVF group (33.9±1.5 vs 35.3±1.7%; p=0.93)(Figure 3g), respectively. LVFS% was significantly reduced in the AVF group compared to the sham-operated group at 21 days (28.7±0.87 vs. 31.6±0.65%; p<0.01)(Figure 3g), respectively. There was not a significant difference in LVFS% within the sham-operated control group from baseline to 21 days (Figure 3g). However, there was a significant decrease in LVFS% within the AVF group from baseline to 21 days (p<0.0001)(Figure 3g).

Cardiac Fibrosis

Picrosirius red staining was performed on the left ventricle (LV) of 21-day sham-operated and AVF mice. LV interstitial staining was more prominent in the21-day AVF group as compared to the sham-operated control group (2.16 % vs 0.84 % interstitial area stain; p<0.05), respectively (Figure 4a). Left ventricular perivascular staining showed an increase in fibrosis in the LV vessel areas of the 21-day AVF group as compared to the sham-operated group (25.97% vs 17.07% perivascular stain; p<0.05) (Figure 4b), respectively.

DISCUSSION

Cardiovascular disease is the primary cause of mortality in hemodialysis patients. Very little is known about the pathophysiology of cardiac remodeling following AVF creation. The objective of the current study was to develop and characterize the cardiovascular changes following AVF creation in a murine AVF model. In our study, we found several important structural and functional differences at 7 and 21 days post-AVF creation in the AVF group as compared to a sham-operated control group. First, CO was significantly increased in the AVF group compared to the sham-operated control group at 7 and 21 days from baseline. Moreover, the increase in CO from baseline to 21 days within the AVF group was also significant. Second, LVEDV and LVEDD was significantly increased in the AVF group compared to the sham-operated control group at 7 and 21 days. In the AVF group, LVEDV and LVEDD was significantly increased from baseline to 21 days. Third, LVEF% and FS% was significantly decreased in the AVF group compared to the sham-operated control group at 7 and 21 days from baseline. Within the AVF group, LVEF% and LVFS% is significantly decreased from baseline to 21 days. Finally, cardiac fibrosis was greater in both interstitial and perivascular LV areas of 21-day AVF group compared to 21-day sham-operated control group.

The physiologic response following creation of an AVF is an acute decrease in systemic vascular resistance and a secondary increase in CO5,6,20. The increased CO and workload from creation of an AVF, induces structural and functional cardiac changes, such as left ventricular hypertrophy and dilation, and causes a long-term volume overload state9,10,14. Several clinical studies have examined the early impact on cardiovascular hemodynamics and cardiac remodeling. These studies have demonstrated significant increases in CO at 2 weeks following AVF creation21,22 with the left ventricle dilating and EF reduced over time23,24. Moreover, a significant increase in LV mass and left atrial area has been reported at 3 months following AVF creation25,26. Our murine AVF model recapitulates the cardiac workload changes seen following human AVF creation, as we demonstrate a progressive increase in CO at 7 days after AVF creation with continued increase in CO at 21 days (Figure 3a).

Our murine AVF also demonstrates progressive changes in cardiac structure, suggesting cardiac remodeling following AVF creation. These changes in cardiac structure are reflected with increased LVEDD and LVEDV as early as 7 days following AVF creation and with continued increase at 21 days (Figure 3 b–c). Our results in our murine model are consistent with previously published clinical studies, which have reported that within 1 week of AVF creation, circulating blood volume increases, resulting in increased left atrial and left end-diastolic diameter and volume21. Our results also further demonstrate pathologic cardiac changes with increased fibrosis in both interstitial and perivascular LV areas following AVF creation (Figure 4). These structural changes over time may lead to left ventricular hypertrophy (LVH). LVH is an adaptive response secondary to increased cardiac workload and subsequently results in eccentric or concentric hypertrophy. LVH is a major risk factor for development of congestive heart failure in dialysis patients27,28 and increased cardiovascular mortality11.

The prolonged increase in CO may not only result in increase in blood volume and LVEDD, but also result in myocardial decompensation. Several clinical studies have reported that ejection fraction is reduced over time following AVF creation due to left ventricular dilation23,24. In our murine AVF models, LVEF% and LVFS% began to decrease at 7 days after AVF creation and was significantly decreased at 21 days following AVF creation, as compared to sham-operated controls. One possible explanation is that the increased CO following AVF placement increases myocardial oxygen demand and perfusion requirements, which has been reported in animal29 and clinical studies30. Savage et al., using a pulse wave analysis in order to determine the subendocardial viability ratio (SEVR) in a group of CKD patients before and following AVF creation31, demonstrated that SEVR decreased immediately after AVF creation and remained depressed during 6 month study period31, suggesting that a significant impact on subendocardial perfusion following AVF creation.

Overall, there is a paucity of literature evaluating the cardiovascular impact following AVF creation. From the clinical perspective, AVFs provide an effective means of vascular access for hemodialysis but may alter cardiac structure and function in patients with already a high burden of cardiovascular disease. At present the only means of mitigating the cardiac effects from AVF creation is closure of the AVF. Clinical studies of AVF closure in kidney transplant patients have shown significant improvements in LV structure and function32,33. However, closure of AVFs is not a reasonable solution or management strategy for the majority of hemodialysis patients (and should be reserved for those who are clinically symptomatic10), because the AVF serves as the patient’s “lifeline” for the hemodialysis procedure. Thus, a better of understanding the pathophysiologic mechanisms that result in alterations in cardiac structure and function following AVF creation is a more practical approach, which will lead to development of therapies to mitigate these adverse cardiac changes. Our murine AVF model serves as a tool to study both physiologic and pathologic changes following AVF creation.

We acknowledge that our study has several limitations. First, our murine model was not conducted in the setting of CKD where human AVFs are created. In future studies we will create AVFs in the setting of CKD to further investigate the role of kidney disease on cardiac remodeling and dysfunction. Second, our studies only evaluated up to 21 days post-AVF creation, thus there may be further long-term cardiac changes and remodeling that we were not able capture. Third, our studies included only male mice. Female mice may have different patterns of cardiac remodeling.

CONCLUSIONS

Our murine AVF model demonstrates that the creation of an AVF results in immediate increase in CO, followed by structural changes to the left ventricle and reduction in ejection fraction and fractional shortening. These findings confirm that our murine AVF model recapitulates the findings seen following human AVF creation. Thus, our murine AVF model will allow for future studies that elucidate the pathophysiology governing cardiac changes following AVF creation and development of therapeutic strategies that improve the cardiac complications resulting from AVF creation.

Supplementary Material

Supplemental Figure 1
Supplemental Methods

Funding Sources

Dr. Lee is supported by grant R44DK109789 from National Institutes of Diabetes, Digestive and Kidney Diseases (NIDDK), grant 1R01HL139692 from the National Heart, Lung, and Blood Institutes, and grant 1I01BX003387 from a Veterans Affairs Merit Award.

Footnotes

Conflict of Interests

Dr. Lee is a consultant for BD Bard and Merck.

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Associated Data

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Supplementary Materials

Supplemental Figure 1
NIHMS1788256-supplement-Supplemental_Figure_1.jpg (173.7KB, jpg)
Supplemental Methods
NIHMS1788256-supplement-Supplemental_Methods.docx (15.6KB, docx)

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