Coronary Artery Remodeling and Fibrosis With Continuous-Flow Left Ventricular Assist Device Support
Abstract
Background:
Coronary artery fluid dynamics may be altered because of the nonphysiological flow seen in continuous-flow left ventricular assist devices (CF-LVADs). Our aim was to study the structure and composition of coronary vessels after CF-LVAD.
Methods and Results:
Coronary arteries were collected from patients with heart failure (HF) at the time of transplantation, of whom 15 were supported with a CF-LVAD before transplant (HF+LVAD group) and 9 were not (HF non-LVAD group). In addition, coronary samples were obtained from 5 nonfailing age-matched donors (nonfailing group). Histological analysis was performed to quantify coronary morphology, composition, vascular fibrosis, and vasa vasorum density. The age and sex mix of the 3 groups were similar, and the mean duration of LVAD support was 213 days. Compared with patients with HF and nonfailing donors, the arteries from patients with HF+LVAD had expansion of the adventitia, breakdown of the internal elastic lamina, and increased adventitial collagen deposition and density of vasa vasorum.
Conclusions:
Among patients supported with CF-LVADs, the coronary arteries develop marked remodeling with increased adventitial fibrosis. The physiological consequences of these structural changes are unknown, but it is possible that arterial contractility may be impaired, thus limiting coronary flow reserve and promoting myocardial ischemia. This may contribute to CF-LVAD complications, such as ventricular arrhythmias and right ventricular failure. As more patients receive CF-LVADs and new pump technology attempts to modulate flow profiles and pulsatility, further research is needed to understand the mechanisms and long-term sequela of these changes in coronary arteries and other vascular beds.
Introduction
WHAT IS NEW?
•
Continuous-flow left ventricular assist devices (CF-LVADs) create a unique physiology where blood flow is minimally pulsatile without a clear mechanical systole and diastole.
•
The influence of this unique physiology on coronary fluid dynamics and coronary arterial structure and composition is unknown.
•
In this study, coronary artery samples collected from patients with CF-LVADs at the time of heart transplantation showed evidence of structural remodeling compared with patients with heart failure without CF-LADs and healthy organ donors.
•
The most significant remodeling of the coronaries involved adventitial collagen deposition and fibrosis.
WHAT ARE THE CLINICAL IMPLICATIONS?
•
Compared with older pulsatile devices, patient outcomes have dramatically improved with modern CF-LVADs. However, minimization of CF-LVAD complications is of paramount importance.
•
Fibrotic changes within the coronary arteries of patients with CF-LVAD may result in chronic myocardial ischemia and contribute to the pathophysiology of complications, such as ventricular arrhythmias and right ventricular failure, as well as partially explain the low rates of cardiac recovery with CF-LVADs.
•
Further research is needed to better understand the mechanisms that induce structural remodeling of the coronary arteries and long-term sequelae of the unique flow profiles with CF-LVAD on the coronary arteries, as well as other vascular beds. Modulation of LVAD flow characteristics may be a simple therapeutic tool for reducing complications.
Continuous-flow left ventricular assist devices (CF-LVADs) have now replaced the first generation of pulsatile devices and are becoming an increasingly common treatment option for end-stage heart failure (HF).1 Despite the dramatic survival advantage and increased durability of continuous-flow devices, patients living with CF-LVADs face several complications, especially with longer durations of support.2 Ventricular arrhythmias and late-onset right ventricular failure are particularly common after CF-LVAD implantation and may be related to myocardial ischemia, yet little is known about the influence of nonpulsatile blood flow from CF-LVADs on the coronary arteries.
In normal physiology, myocardial perfusion occurs predominantly in diastole when left ventricular pressures are lower and the coronary arteries are more dilated. The use of CF-LVADs alters this physiology. Unloading with a CF-LVAD lowers left ventricular end-diastolic pressures, but there is no clear mechanical systole and diastole. Additionally, there are alterations in the normal laminar flow patterns in the ascending aorta as a result of the LVAD outflow graft. It is increasingly recognized that there are changes in the structure, collagen content, and elastin content of the aortic wall, which result in dynamic changes in vascular distensibility and stiffness.3,4 However, whether such changes contribute to the common CF-LVAD complications of ventricular arrhythmias and right ventricular failure is unknown. The purpose of this study was to examine the structure and composition of coronary vessels immediately after CF-LVAD support.
Methods
Patient Selection and Coronary Artery Tissue Acquisition
The authors declare that all supporting data and analytic methods are available within the article. Additional images of deidentified clinical variables may be obtained by reasonable request via e-mail to the corresponding author for purposes of reproducing the results. Coronary artery tissue samples were collected from patients with end-stage HF at the time of cardiac transplantation at the University of Colorado LVAD Transplant Program during a 2-year period from June 2014 through May 2016. Coronary artery samples were reviewed after hematoxylin and eosin histological stains to exclude those samples that had coexisting atherosclerotic plaque. This review resulted in coronary samples from a total of 29 patients during this time period, of which, 15 patients were supported with a CF-LVAD before transplant (HF+LVAD group), and 9 patients did not have an LVAD before transplant (HF non-LVAD group). In addition, age-matched control coronary artery samples were obtained during the same period from 5 nonfailing donor hearts that were available for transplant but then unused for noncardiac reasons (nonfailing group).
The proximal right coronary, left main, left anterior descending, and left circumflex arteries with their surrounding epicardial fat were dissected from myocardial tissue, fixed overnight with 4% paraformaldehyde, and processed for paraffin embedding and transverse artery sections. Hematoxylin and eosin–stained coronary sections were reviewed and selected for analysis if they lacked significant atherosclerotic plaque or evidence of >250 μ of intimal hyperplasia to lessen any concurrent effects of atherosclerosis on artery structure and to allow for comparisons between nonfailing donors, as well as patients with ischemic and nonischemic pathogeneses of HF. A total of 57 coronary segments without atherosclerotic plaque or intimal hyperplasia were selected for analysis, which included 25 vessels from patients with HF+LVAD, 17 vessels from patients with HF non-LVAD, and 15 vessels from nonfailing patients. The Colorado Multicenter Institutional Review Board approved the protocol for the collection, storage, and analysis of human tissue.
In addition, a trained physician retrospectively reviewed medical records and recorded deidentified clinical variables for each patient in a securely stored Research Electronic Data Capture database. The clinical data were collected from the time closest to cardiac transplantation and included medications, echocardiography, and hemodynamics. The data obtained from HF+LVAD group reflect the LVAD device settings that were clinically indicated at that time. As was the standard of care for CF-LVAD management during this time period, antihypertensive medical therapy was titrated to maintain a goal mean arterial blood pressure of <90 mm Hg throughout the duration of CF-LVAD support.
Coronary Artery Morphology
The structure and composition of coronary arteries was evaluated with Russell–Movat pentachrome staining, which allows for the differentiation of the tissue components, including collagen (yellow), elastin fibers (black), mucin (blue), muscle or fibrinous deposits (red), and nuclei (dark blue). The areas of the intima, media, and adventitia layers were measured for each coronary artery segment and normalized to the lumen area to adjust for vessel caliber. In addition, the adventitia area was normalized by media dimensions to adjust for the amount of hypertrophy that occurs in the media, such that values >1 indicate adventitia layers that had a larger size and proportionally greater remodeling than their same vessel media counterparts. The percent area of the internal elastic lamina (IEL) and external elastic lamina (EEL) was measured relative to the vessel media area. Image analysis was performed with Image J software (National Institutes of Health).
Measurement of Coronary Adventitial Collagen Content and Fibrosis
To quantify the degree of fibrosis within the vessel adventitia, we measured the quantity and density of collagen using 2 additional techniques: PicroSirius red (PSR) staining and second harmonic generation (SHG) microscopy. PSR staining and darkfield polarized light microscopy allows for the detection of thin collagen fibrils that are detected poorly with traditional histological Masson trichrome and Movat pentachrome stains.5,6 In addition, collagen fibers were detected by SHG microscopy that images fibrillar collagen based on its physical and structural properties and does not require special staining.7 Although both PSR staining and SHG signals show a strong spatial correlation within tissue, the modalities have some differences. PSR values tend to be higher, whereas SHG microscopy is more sensitive to fibrillar collagen and does not detect type IV collagen.7,8 Thus, both modalities provide complementary information and were, therefore, utilized to accurately assess for differences in fibrosis between each study group.
The PSR signals in polarized light microscopy images were selected by Image J threshold parameters, which measured the area and the percent content of PSR birefringence within the area of the adventitia. Values were combined from nonoverlapping ×4 images of the entire coronary artery wall. To control for differences in vessel size, the PSR birefringence signal in the adventitia was normalized to the media area, and comparisons were made between the study groups.
For SHG imaging, paraffin sections of artery segments were rehydrated and imaged via multiphoton excitation using a Zeiss LSM780 light microscope equipped with a femtosecond-pulsed Ti Sapphire laser (Chameleon Ultra; Coherent, Santa Clara) and ZEN software (2012 SP1 Black Edition). Images were acquired at 1024×1024 pixels (708.49×708.49 µ)using a Zeiss C-Apochromat 20× objective. The excitation source was tuned for 800 nm to generate an SHG 400 nm signal that was collected via a 390- to 410-nm emission filter. Besides the SHG signal, the autofluorescence was also observed via a wide-range visible filter (420–700 nm). The area and percent content of SHG+ collagen in the adventitia were measured in 4 nonoverlapping 20× images of the coronary artery. As with other analyses, the SHG+ collagen in the adventitia was normalized to the media area to control for differences in vessel size.
Adventitial Vasa Vasorum Density Measurements
Normal coronary arteries develop vasa vasorum (VV) that are confined to the outer media and adventitia but show dramatic proliferation and a less-ordered structure in the presence of vascular diseases, such as atherosclerosis and vasculitis.9–11 To determine whether the density of VV was altered in association with nonpulsatile LVAD support, VV profiles were identified and counted from Movat pentachrome-stained tissue sections by the presence of a vessel lumen containing red blood cells or leukocytes and a border of red-stained pericytes. Additional slides were stained with an antibody reactive to CD34 (QBEND-10 clone; ThermoFisher) that is expressed by mature endothelial cells lining small and large caliber vessels,12 as well as adventitia vascular progenitor cells as described previously.13–15 The density of adventitia VV was calculated as the number of VV vessels per millimeter squared area of adventitia. The relative number of VV was also normalized to the media area to control for differences in the size of coronary arteries.
Statistical Analysis
Data were analyzed using PRISM 5 (GraphPad Software, Inc) and presented as the mean±SD. The D'Agostino and Pearson omnibus tests were performed to assess normality. For normal data, a 1-way ANOVA was used to determine whether the overall P value was significant and then followed by Bonferroni multiple comparison to determine differences between the 3 (HF+LVAD, HF non-LVAD, and nonfailing) groups. For non-normal data, a Kruskal–Wallis test was used to compare the 3 groups followed by Dunn multiple comparison tests. For comparisons between 2 groups, the unpaired t test for normal data and the Mann–Whitney U test for non-normal data were used. Statistical significance was defined as a 2-tailed P value of <0.05.
Results
The mean age of individuals in the nonfailing (48±23 years; 60% women), HF non-LVAD (46±14 years; 33% women), and HF+LVAD (46±13 years; 33% women) groups was similar. Sex mix was similar for HF non-LVAD and HF+LVAD groups, but there was a higher proportion of women in the nonfailing group because female donor organs have a higher chance of not being used for transplant and being collected for research purposes. Of the 10 patients with HF+LVAD with nonischemic cardiomyopathy, the specific pathogeneses included idiopathic dilated cardiomyopathy (6 patients), sarcoid cardiomyopathy (2 patients), chemotherapy-related cardiomyopathy (1 patient), and familial/genetic cardiomyopathy (1 patient). Of the 8 patients with HF non-LVAD with nonischemic cardiomyopathy, the specific pathogeneses included idiopathic dilated cardiomyopathy (3 patients), familial/genetic cardiomyopathy (3 patients), congenital heart disease (1 patient), and hypertrophic cardiomyopathy (1 patient).
Among the HF+LVAD group, 9 (60%) patients were O blood type, compared with only 1 (11%) patient with O blood type in the HF non-LVAD group. These differences in blood type and anticipated regional transplant listing wait times largely determined whether a patient received a bridge to transplant LVAD. The mean duration of LVAD support among patients with HF+LVAD was 213±209 days (median, 142; range, 27–661 days). There were expected differences in ejection fraction, natriuretic peptide levels, some hemodynamic parameters, and medications related to a nonfailing heart and unloading with an LVAD as summarized in the Table. Importantly, the mean arterial blood pressure was similar between the groups.
| Nonfailing (5 Patients) | HF Non-LVAD (9 Patients) | HF+LVAD (15 Patients) | P Value | |
|---|---|---|---|---|
| Clinical data | ||||
| Age, y | 48±23 | 46±14 | 46±13 | 0.980 |
| Female sex | 3 (60%) | 3 (33%) | 5 (33%) | 0.535 |
| Duration of LVAD support, d | … | … | 213±209 | … |
| Ischemic cardiomyopathy | … | 1 (11%) | 5 (33%) | 0.351 |
| Nonischemic cardiomyopathy | … | 8 (89%) | 10 (67%) | 0.351 |
| Prior sternotomy | … | 4 (44%)* | 15 (100%)* | 0.003 |
| Ejection fraction, % | 67±13† | 27±15† | 27±9† | 0.021 |
| Left ventricular internal dimension diastole, cm | … | 6.5±1.5* | 5.5±1.5* | 0.029 |
| Left ventricular end-diastolic volume, mL | … | 208±122* | 152±144* | 0.042 |
| Brain natriuretic peptide, pg/mL | NA | 639±533* | 265±206* | 0.022 |
| Hemodynamics | ||||
| Heart rate, beats per min | 92±9 | 90±15 | 92±18 | 0.862 |
| Systolic blood pressure, mm Hg | 118±15 | 112±8 | NA | 0.494 |
| Diastolic blood pressure, mm Hg | 63±10 | 70±9 | NA | 0.177 |
| Mean arterial pressure, mm Hg | 81±8 | 84±8 | 81±11 | 0.644 |
| Right atrial pressure, mm Hg | 7±3 | 6±3 | 8±5 | 0.932 |
| Mean pulmonary artery pressure, mm Hg | 27±8 | 28±7 | 22±7 | 0.110 |
| Pulmonary capillary wedge pressure, mm Hg | 15±2 | 17±6* | 11±7* | 0.037 |
| Cardiac index, L/min per m2 | 4.4±0.8† | 2.7±1.4† | 2.4±0.4† | 0.009 |
| Medications and interventions before transplant (during LVAD support if applicable)‡ | ||||
| Aspirin | 0 (0%) | 1 (11%) | 14 (93%) | 0.001 |
| HMG-CoA reductase inhibitor | 1 (20%) | 3 (33%) | 6 (40%) | 0.715 |
| ACE inhibitor or ARB | 0 (0%) | 1 (11%) | 6 (40%) | 0.191 |
| β-Blocker | 0 (0%) | 2 (22%) | 9 (60%) | 0.105 |
| Aldosterone antagonist | 0 (0%) | 8 (89%) | 11 (73%) | 0.615 |
| Hydralazine/nitrates | 0 (0%) | 5 (56%) | 0 (0%) | 0.003 |
| Calcium channel blocker | 0 (0%) | 0 (0%) | 3 (20%) | 0.266 |
| Diuretic | 0 (0%) | 8 (89%) | 7 (47%) | 0.080 |
| Digoxin | 0 (0%) | 5 (56%) | 0 (0%) | 0.003 |
| Intravenous inotrope | 0 (0%) | 4 (44%) | 1 (7%) | 0.047 |
| Intravenous vasodilator | 0 (0%) | 0 (0%) | 0 (0%) | … |
| Intravenous vasopressor | 1 (20%) | 0 (0%) | 0 (0%) | … |
| Intra-aortic balloon pump | 0 (0%) | 0 (0%) | 0 (0%) | … |
ACE inhibitor indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure; and LVAD, left ventricular assist device.
*
P<0.05 for comparison of HF non-LVAD vs HF+LVAD.
†
P<0.05 for comparison of nonfailing vs HF non-LVAD, and P<0.05 for comparison of nonfailing vs HF+LVAD.
‡
P values denote comparisons of HF non-LVAD vs HF+LVAD.
Expansion of the Coronary Artery Adventitia With CF-LVADs
Quantification of coronary artery vessel morphology revealed no significant differences in the mean intima-to-lumen areas among the groups: nonfailing (0.59±0.29 μ), HF non-LVAD (0.62±0.37 μ), and HF+LVAD (0.52±0.25 μ); P=nonsignificant. The mean media-to-lumen areas among the 3 groups were also similar: nonfailing (1.00±0.43), HF non-LVAD (1.21±0.64), and patients with HF+LVAD (1.06±0.41); P=nonsignificant. However, the most dramatic changes were observed in the adventitia layer of HF+LVAD coronaries as shown in Figure 1. The ratios of adventitia-to-lumen areas from patients with HF+LVAD (2.35±0.97) were significantly greater than nonfailing (0.97±0.50) and HF non-LVAD (1.18±0.60) patients; P<0.001 for both comparisons. Furthermore, the relative adventitia area normalized to the media area was also significantly higher among patients with HF+LVAD (1.51±0.53) compared with nonfailing (1.06±0.24; P<0.01) and HF non-LVAD (1.14±0.37; P<0.05).
Elastic Lamina Remodeling With CF-LVAD
The IEL runs along the intima–media border, and the EEL runs along the media–adventitia border as shown in Figure 2. In normal coronary arteries, the IEL and EEL are similar in thickness as was the case for vessels from the nonfailing and HF non-LVAD groups. However, there was significant breakage and attenuation of the IEL compared with the EEL in the HF+LVAD group (2.0±1.1% versus 4.8±2.1% of the media area; P<0.0001). In addition, there was attenuation of the coronary artery IEL in patients with HF+LVAD (2.0±1.1% of the media area) compared with nonfailing (3.1±0.9%; P<0.05) and HF non-LVAD patients (3.2±1.3%; P<0.01). Finally, there was thickening of the vessel EEL in patients with HF+LVAD (4.8±2.1% of the media area) compared with nonfailing (3.4±0.9%; P<0.05) and HF non-LVAD (3.4±1.1%; P<0.05). In contrast, the content of black-stained elastic fibers that are dispersed within the interior of the media and visible at higher magnification was not significantly altered among the 3 groups.
Increased Coronary Adventitial Collagen Deposition and Fibrosis With CF-LVADs
Polarized light microscopy images of coronary arteries show intense PSR signals in the adventitia layers, indicative of collagen deposition, as shown in Figure 3. The degree of collagen deposition as assessed by this PSR signal within the adventitia was significantly higher in the HF+LVAD group (2.1±0.8 mm2) compared with the nonfailing (1.4±0.5 mm2; P<0.01) and HF non-LVAD groups (1.0±0.4 mm2; P<0.0001). In addition, the density of collagen fibrils in the adventitia as the percent content of PSR birefringence was significantly higher in the HF+LVAD group (53.1±6.1%) compared with the nonfailing (46.3±3.0%; P<0.05) and HF non-LVAD groups (45.4±8.7%; P<0.01). Finally, after adjusting for differences in vessel size by normalizing the collagen area to the vessel media area, the ratio of adventitia collagen density-to-media area in the HF+LVAD group (1.3±0.2) remained significantly higher compared with the nonfailing (0.8±0.2; P<0.0001) and HF non-LVAD groups (0.7±0.1; P<0.0001).
The changes in the quantity and density of collagen as assessed by PSR staining were also confirmed with SHG microscopy as summarized in Figure 4. Specifically, the percent content of SHG+ collagen in the adventitia—a correlate of collagen density—was higher in coronary arteries from patients with HF+LVAD (19.2±3.2%) compared with nonfailing (13.3±1.9%; P<0.001) and HF non-LVAD patients (13.0±3.5%; P<0.0001).
Increased Adventitia VV Density in Coronary Arteries With CF-LVAD
In addition, there was an increase in the raw number of VV associated with growth within the coronary adventitia layer. Specifically, the relative density of VV, measured as the number of vessels counted in the entire adventitia area, was 2-fold greater in HF+LVAD coronary arteries (38.7±14.3 vessels per mm2) compared with nonfailing (19.5±7.4; P<0.0001) and HF non-LVAD (21.8±10.4; P<0.0001) coronary arteries as seen in Figure 5. Because the density of VV may be higher in larger caliber blood vessels, the mean number of VV was normalized to the media area of the coronary vessel and compared among groups: the relative abundance of VV was higher in HF+LVAD vessels (57.7±25.8 vessels per mm2 media) compared with nonfailing (19.9±7.2; P<0.0001) and HF non-LVAD (22.7±8.8; P<0.0001).
Finally, because systemic factors may influence vascular remodeling in individual patients, all figures displaying the primary data from each coronary artery sample (n) were analyzed again on a per individual (N) basis and summarized in Figure 6. Statistical analysis by individual confirmed there is attenuation of the IEL, and there are statistically significant increases in the adventitia area, area of adventitia fibrosis, and VV density of coronary arteries from HF+LVAD individuals.
Duration of CF-LVAD Support and Coronary Artery Remodeling
We performed a preliminary exploratory analysis as to whether the duration of CF-LVAD support influenced the extent of coronary artery remodeling. Therefore, data of coronary samples from the quartile of individuals who had the shortest duration of LVAD support (median, 40 days; range, 27–81 days; n=4 individuals, 6 samples) were compared with data of coronary samples from the upper quartile of individuals with the longest LVAD duration (median, 477 days; range, 233–661 days; n=4 individuals, 6 samples). The mean areas for adventitia/media ratio, EEL, adventitia collagen, and the densities of VV in the short- and long-duration LVAD subgroups were each greater than the nonfailing and HF non-LVAD groups. Remarkably, only the VV density had a significant difference in the magnitude of the increase between the short and long duration of LVAD subgroups (54.0±9.4 versus 31.6±8.1 vessels per mm2; P<0.01). Although the sample numbers in the subgroups were too small to make definitive conclusions on the influence of CF-LVAD duration, these data imply that adventitial remodeling and, in particular, the expansion of VV occurs early after LVAD implantation.
Effect of Prior Sternotomy on Coronary Adventitia Fibrosis
To address the possibility that the structural changes in the HF+LVAD coronaries were related to the sternotomy procedure necessary for CF-LVAD implantation, the surgical history of HF non-LVAD individuals was reviewed to identify 4 individuals who had a prior sternotomy and 5 individuals who did not have a prior sternotomy. As shown in Figure 7, there were no significant differences in adventitia-to-lumen areas between vessels from HF non-LVAD individuals with and without prior sternotomy. Each of these HF non-LVAD subgroups had smaller adventitia areas and fibrosis compared with vessels from HF+LVAD individuals (P≤0.01 for HF no sternotomy versus HF+LVAD and for HF+ sternotomy versus HF+LVAD). Representative images of the adventitia and surrounding margins of periaortic fat show a pattern of adventitia fibrosis adjacent to the media and not extending into the more peripheral periaortic fat.
Discussion
The main finding of this study is that the coronary arteries from patients with CF-LVAD undergo marked structural remodeling with an expansion of the adventitia, an increase in collagen deposition, and proliferation of the VV within the adventitia compared with age-matched patients with non-LVAD HF and nonfailing donors. These fibrotic changes were observed in spite of some inhibition of the renin–angiotensin–aldosterone system with medications in the majority of patients with CF-LVAD suggesting that alternate pathways may be contributing to vascular fibrosis. Although the mechanisms for this remodeling within the adventitia layer of coronary arteries are yet to be determined, these findings raise questions about how CF-LVADs induce adventitial remodeling and structural changes that may impact coronary perfusion.
First, continuous flow compared with normal pulsatile blood flow has been reported to impair endothelial cell function via oxidative stress and cytoskeletal and mitochondrial alterations.16 In turn, endothelial dysfunction in the artery lumen impacts the adventitia by increasing hydraulic transport of solutes, microparticles, and oxidation products through the vessel wall.17,18 Hemodynamic conditions, including pulsatility, arterial pressure, and wall permeability, further influence outward mass transport in the artery wall.19 Others have shown endothelial injury or dysfunction is soon followed by the accumulation of inflammatory cells and VV proliferation in the adventitia during early stages of coronary artery disease.10,20,21 Thus, altered mass transport and delivery of vascular mediators to the adventitia is a probable determinant for the expansion of adventitial fibrosis and VV in coronary arteries exposed to CF-LVAD.22
Adventitia VVs have arterial and venous connections that perfuse the vessel wall and remove waste substances in the adventitia.22,23 The hemodynamics of VV are poorly understood but are likely to be affected by more dense adventitial fibrosis and the loss of the usual diastolic coronary filling with CF-LVADs. Future studies with contrast-enhanced ultrasound might be feasible to measure VV blood flow in a given artery under pulsatile and nonpulsatile flow conditions.24–26 Prior studies have shown that coronary flow reserve is reduced in patients with LVAD support.27 In addition, the extensive adventitia fibrosis in the coronary arteries of patients with HF+LVAD can exert vascular compression to further reduce coronary flow reserve, which directly influences myocardial perfusion and could lead to chronic myocardial ischemia during CF-LVAD support.
Another important finding from this study is that the coronary artery elastic lamina is changed in patients with CF-LVAD. In normal coronary arteries, the IEL and the EEL that delineate the media borders are similar in thickness, but we observed significant breakdown and attenuation of the IEL with thickening of the EEL in CF-LVAD coronary arteries. The internal and external fibrillar elastin lamina have hydrophobic properties that impede the migration and adhesion of inflammatory cells and support the relative immune privilege of the media layer.28,29 The breakdown of elastin fibers also releases proteolytic products that are chemotactic for inflammatory cells and capable of inducing neovascularization.30,31 These structural changes imply that CF-LVAD coronary arteries are exposed to a pathological or inflammatory process. Indeed, a greater increase in markers of vascular inflammation has been reported in the aortic endothelium from patients with continuous versus pulsatile LVADs.32 Similar changes in other systemic vessels may contribute to the pathophysiology of intestinal arteriovenous malformations and inflammatory complications, such as allosensitization.
Remodeling within the coronary artery adventitia is a known early indicator of pathology in other vascular disease models.10 We have also previously reported similar adventitial thickening with increased collagen deposition in the aorta after CF-LVAD support.3 The degree to which these observed vascular changes in CF-LVAD coronary arteries occur in distal coronary arterioles and other vascular beds warrant further investigation. For example, in patients with renal dysfunction undergoing CF-LVAD implantation, there is an initial dramatic improvement in renal function—likely related to the restoration of cardiac output and improvement in hemodynamics with the device.33 However, after 1 year of chronic CF-LVAD support, renal function deteriorates back to nearly the same level of renal dysfunction as seen before CF-LVAD implantation. Animal studies have shown that nonpulsatile flow from CF-LVADs results in marked renal arterial remodeling highlighted by medial smooth muscle hypertrophy and inflammatory cell infiltration of the vessel wall.34,35 Taken together, these findings suggest that vascular remodeling in more distal territories may occur and have clinically significant consequences.
Limitations
We acknowledge several limitations to our study. The coronary artery tissue samples were obtained after the heart was removed at transplant. For obvious patient safety reasons, we were unable to obtain CF-LVAD coronary vessels or serial tissue samples before initiation of CV-LVAD support to allow for direct temporal comparisons in the same patient. This was a small single-center study; so an institution-specific effect cannot be excluded. In addition, the number of available patients and vessel samples that lacked concurrent atherosclerosis and rare number of nonfailing donor samples limits the power to discern variations because of different HF pathogeneses (ischemic, nonischemic, and familial cardiomyopathy), medications, and duration of CF-LVAD support or other LVAD modalities. We also focused on the proximal coronary artery segments for this initial analysis and did not look for differential effects in more distal arterioles. Additional studies would be required to assess whether CF-LVADs alter the progression of existing atherosclerosis and effects on the coronary microcirculation.
Conclusions
Among patients supported with CF-LVADs, there are changes in the structure and composition of the coronary vessels compared with age-matched patients with HF and nonfailing donors. The most notable of these changes is remodeling and expansion of the adventitia with increased fibrosis and VV density. Such fibrotic changes within the coronary arteries may contribute to common CF-LVAD complications, such as ventricular arrhythmias and right ventricular dysfunction, and may also be an explanation for the low rates of myocardial recovery with CF-LVAD support. As a greater number of patients are supported with CF-LVADs and new pump technology attempts to modulate pulsatility, further research is needed to better understand the mechanisms and long-term sequela of these observed changes in the coronary arteries and other vascular beds.
Acknowledgments
We wish to acknowledge Drs Peter Buttrick and Michael Bristow and the University of Colorado Division of Cardiology for ongoing maintenance of the human cardiac tissue biobank. In addition, we thank Radu Moldovan and Greg Glazner of the University of Colorado Advanced Microscopy Core Facility for assistance with confocal microscopy.
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© 2018 American Heart Association, Inc.
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Published in print: May 2018
Published online: 18 June 2018
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Sources of Funding
Dr Ambardekar is supported by a Scientist Development Grant from the American Heart Association and by the Boettcher Foundation Webb-Waring Biomedical Research Program. Studies were supported, in part, by National Institutes of Health (NIH) grant number 1R01 HL123616 (Dr Weiser-Evans). Research Electronic Data Capture was provided by NIH/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical and Translational Science Awards grant number UL1 TR001082. Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core supported, in part, by NIH/NCATS Colorado Clinical and Translational Science Institute grant number UL1 TR001082. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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