Clinical trial NCT03784963
Conditions: Heart Failure Gastrointestinal Bleeding
Keywords: Angiogenesis Inflammation Microbiome
Sponsor: University of Chicago
Start date: 2019-01-23; Completion date: 2020-07-15
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the efficacy of high-dose fish oil in decreasing rates of gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices. Half of the patients without history of bleeding will receive fish oil while the other half will not. Half of the patients with history of bleeding will receive fish oil while the other half will not. Markers of angiogenesis and inflammation, as well as changes in the microbiome will be assessed in each group.

Detailed description:
A potential mechanism of bleeding in patients with continuous-flow left ventricular assist devices (CF-LVAD) is dysfunctional angiogenesis. Angiogenesis is a complicated process controlled by several markers. Previous studies have shown that elevated Angiopoietin-2 and TNF-alpha are associated with bleeding events in CF-LVAD patients.

Fish oil has anti-inflammatory and potentially anti-angiogenic properties. A retrospective study of CF-LVAD patients on high-dose fish oil showed a marked decrease in gastrointestinal bleeding rates in these patients. Additionally, these patients had lower levels of circulating Angiopoietin-2. Fish oil is known to have an effect on the microbiome, and the aforementioned effects may be seen in changes of the microbiota.

Arms: arm 1: In patients with CF-LVAD who have not had a gastrointestinal bleed, patients randomized to intervention will receive 4 grams of Nature Made Ultra Omega-3 Fish Oil once daily for 1 year along with standard of care. arm 2: In patients with CF-LVAD who have not had a gastrointestinal bleed, patients randomized to placebo will receive no fish oil and only standard of care. arm 3: In patients with CF-LVAD who have had a gastrointestinal bleed, patients randomized to intervention will receive 4 grams of Nature Made Ultra Omega-3 Fish Oil once daily for 1 year along with standard of care. arm 4: In patients with CF-LVAD who have had a gastrointestinal bleed, patients randomized to placebo will receive no fish oil and only standard of care.
Interventions: intervention 1: Omega 3 fatty acids intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive 4 grams fish oil once daily intervention 2: Standard of care

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE 
Open-Label Prospective Randomized Control Trial to Investigate the Efficacy of Omega-3 Fatty Acid 
Therapy in Preventing Gastrointestinal Bleeding in Patients with Continuous-Flow Left Ventricular Assist 
Device 
 
Version: 05Jun2019 
 
NCT03784963 


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PROTOCOL TITLE 
Open-Label Prospective Randomized Control Trial to Investigate the Efficacy of Omega-3 Fatty 
Acid Therapy in Preventing Gastrointestinal Bleeding in Patients with Continuous-Flow Left 
Ventricular Assist Device 
 
 
PRINCIPAL INVESTIGATOR   
Gene Kim, MD 
Department of Medicine, Section of Cardiology 
(773) 702-9396 
 
 
 
OBJECTIVES 
Aim 1: We will evaluate whether high-dose omega-3 fatty acid (O3FA) supplementation alters 
markers of angiogenesis and inflammation in patients with continuous-flow left ventricular assist 
devices (CF-LVAD). 
• 
Aim 1a will assess the effect of high-dose O3FA in patients who have not experienced 
an episode of gastrointestinal (GI) bleeding.  Patients will be enrolled up to 3 months 
following CF-LVAD implantation and randomized to high-dose O3FA or none.  Markers 
of angiogenesis and inflammation will be assessed prior to and following initiation of 
high-dose O3FA therapy. 
• 
Aim 1b will assess the effect of high-dose O3FA in CF-LVAD patients who have already 
experienced a GI bleeding event.  Patients who have experienced a prior bleeding event 
will be enrolled and randomized to high-dose O3FA or none. Markers of angiogenesis 
and inflammation will be assessed prior to and following initiation of high-dose O3FA 
therapy. 
 
Aim 2: We will assess the changes that occur to the microbiome of CF-LVAD patients following 
O3FA supplementation. 
 
Aim 3: We will assess the effect of high-dose O3FA supplementation on GI bleeding events in 
both the population without prior GI bleeding events, and the population with prior GI bleeding 
events.  
 
 
BACKGROUND 
Continuous-flow left ventricular assist devices (CF-LVAD) have become the mainstay of therapy 
for advanced heart failure, both as bridge to transplantation and as destination therapy, allowing 
significant improvement in survival. However, this therapy is limited by a high adverse event 
profile, specifically those related to hemocompatibility. 
 
One of the leading causes for readmission after CF-LVAD implantation is gastrointestinal (GI) 
bleeding, representing nearly 30% of both early and late readmissions following device 
implantation1.  Multiple reports found that 25-40% of the patients will experience GI bleeding, 
with 15.9% in the first 6 months in the MOMENTUM 3 trial, and 35.1% in the ENDURANCE trial 
2, 3.  Originally, pathophysiology of GI bleeding was attributed to Von Willebrand factor deficiency 
4, 5.  More recently, focus has shifted to the development of arteriovenous malformations (AVMs) 
in the GI tract as a major contributor to the development of GI bleeding in patients supported 
with CF-LVADs 6.   
 


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The process of angiogenesis is controlled by angiopoietins 1 and 2 (Ang-1 and Ang-2), and 
vascular endothelial growth factor (VEG-F).  Ang-1 leads to normal angiogenesis in conjunction 
with VEG-F, while Ang-2 promotes dysfunctional vessel growth with an expression that is highly 
regulated by the thrombin receptor PAR-1.  Our group recently demonstrated that an abnormal 
ratio of Ang-1 and Ang-2 has a key role in abnormal angiogenesis, due to elevated Ang-2 and 
reduced Ang-17.  CF-LVAD patients with Ang-2 levels above the mean had more nonsurgical 
bleeding events compared to those with levels below the mean 7.  Furthermore, we found that 
tumor necrosis factor-α (TNF-α) was significantly higher in serum of patients with CF-LVAD 
compared to patients with heart failure or heart transplantation, and contributes to abnormal 
angiogenesis by killing pericytes and reducing Ang-1 levels 8.  We have confirmed these 
findings in a larger cohort from the PREVENT biobank.  114 paired samples obtained before 
and 3 months after CF-LVAD implantation were analyzed.  69% of patients with increased levels 
of Ang-2 and TNF-α experienced significant GI bleeding 6 months after implantation while only 
38% of patients with Ang-2 and TNF-α levels below the mean had GI bleeding (p=0.02). 
 
To further implicate the role of dysregulated angiogenesis in GI bleeding in CF-LVAD patients, 
Houston et al. evaluated the use of angiotensin-converting enzyme inhibitor (ACEI) and 
angiotensin receptor blocker (ARB) therapy in reducing the risk of GI bleeding.  Ang-2 
expression has previously been shown to be induced through angiotensin II signaling 9.  
Houston et al showed that of the patients who did not receive angiotensin II antagonism, 48% 
experienced GI bleeding.  In contrast, only 24% of the patients who received ACEI or ARB 
experienced GI bleeding 10.   
 
In the most recent J-MACS (Japanese registry for Mechanically Assisted Circulatory Support 
registry) report, GI bleeding occurred in 4 of 259 patients followed during a 5-year period 11.  
This is in stark contrast to the latest INTERMACS update that reports a rate of 16.24 events of 
GI bleeding per 100 patient months in the first 3 months after implantation, and 4.08 events per 
100 patient months in the 3-12 months after implantation 12.  What accounts for this difference?  
One possibility may lie in the Japanese diet, which is rich in omega 3 fatty acids (O3FA) 
compared to the diet of patients in the United States.  We performed a retrospective study in a 
cohort of 166 patients with CF-LVAD to assess this theory.  Patients who received high-dose 
O3FA as part of a recovery protocol were compared to those who did not.  The frequency of GI 
bleeding was significantly lower in the O3FA group compared with the control group (0.077 ± 
0.419 events/year vs. 0.305 ± 0.847 events/year, p = 0.033), leading to a higher 1-year event-
free rate in the O3FA group compared to the control group (97% vs. 79%, p = 0.046).  
 
In the past decade, there has been an emergence of interest in the human gut microbiota.  
Using next-generation sequencing (NSG), studies have been able to characterize with great 
detail the gut microbiome in humans.  Further studies have shown that the microbiota is affected 
by patient characteristics (age, sex, body mass index, lifestyle), diet, and pathologic diseases 13.  
In particular, O3FA and its effect on the gut microbiota has been studied, showing that an 
increase in dietary or supplemental O3FA changes the fingerprint of the microbiome 14-16.  O3FA 
and the microbiome also have a presence in the cancer literature.  It is postulated that O3FA 
play a role in the prevention and treatment of cancer by reduction in cell proliferation, cell 
survival, angiogenesis, and inflammation 17.   
 
The data presented thus far shows a possible link between O3FA, GI bleeding, and abnormal 
angiogenesis, and may be related to the microbiome in CF-LVAD patients.  This prospective 
randomized study aims to evaluate the effect of supplemental O3FA on the frequency of GI 
bleeding in patients implanted with CF-LVAD both as primary and secondary prevention.  


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Additionally, we will investigate the effect of O3FA on angiogenesis parameters (Ang-1, Ang-2, 
VEGF, TNF-α) and the microbiome.   
  
 
STUDY ENDPOINTS 
The primary endpoint will be a change in angiogenesis markers resulting in dysregulated 
angiogenesis, as described above.  Secondary endpoints include rate of GIB and improvement 
in inflammatory markers. 
 
 
STUDY INTERVENTION 
The study intervention being evaluated is high-dose O3FA (4,000 mg), which is an over-the-
counter supplement. Heart failure patients are routinely instructed to take an O3FA supplement 
for heart health.  The research team will fund the supplement, which will be stored in the heart 
failure office.  Once a patient is enrolled, a total of 1 year of supplement will be given to the 
patient for consumption at home. 
 
 
PROCEDURES INVOLVED 
We will perform an open-label, prospective, randomized control study in which 120 CF-LVAD 
patients are enrolled.  We plan to have 2 separate arms: primary prevention and secondary 
prevention (60 in each arm).  In the primary prevention arm, 60 patients who have received CF-
LVAD implantation and have not experienced any episodes of GI bleeding will be assigned to 
an O3FA group or a control group, with 30 patients in each group.  In the secondary prevention 
arm, 60 LVAD patients who have experienced at least 1 episode of GI bleeding after CF-LVAD 
implantation will be assigned to an O3FA group or a control group, with 30 patients in each 
group.  Randomization will be performed using computer software, and initiation of therapy will 
start within 24 hours of randomization.  O3FA will be given at a dose of 4,000 mg orally per day, 
and all patients will receive guideline-directed medical therapy during the study period.  
 
The following study procedures will be performed: 
 
Baseline 
Subject to sign consent 
Verify inclusion/exclusion criteria 
Record medical history and medications 
Collect stool sample 
Collect blood sample 
Randomization 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
 
1.5 months post-randomization 
Record medical history and medications 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 


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3 months post-randomization 
Record medical history and medications 
Collect stool sample 
Collect blood sample 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 
4.5 months post-randomization 
Record medical history and medications 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 
6 months post-randomization 
Record medical history and medications 
Collect stool sample 
Collect blood sample 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 
7.5 months post-randomization 
Record medical history and medications 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 
9 months post-randomization 
Record medical history and medications 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 
 
10.5 months post-randomization 
Record medical history and medications 
Record adverse events 
For 03FA subjects: 
-Provide O3FA supplement  
-Subjects will be instructed to take 4 pills a day 
-Study drug compliance check 


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1 year post-randomization 
Record medical history and medications 
Collect stool sample 
Collect blood sample 
Record adverse events 
For 03FA subjects: 
-No more O3FA supplements will be provided by the study 
-Study drug compliance check 
 
 
Stool Collection for Microbiome Sequencing Analysis 
Stool will be collected in the hospital prior to CF-LVAD implantation, as most patients have 
prolonged hospitalizations prior to implantation.  Additional stool samples will be collected at 
home after CF-LVAD implantation at 3 months, 6 months, and 1 year.  Stool samples will be 
collected using home stool sample kits.  The stool will be kept cool in anaerobic conditions and 
will be shipped directly to Dr. Jack Gilbert’s laboratory at the University of Chicago for 
microbiome analysis.  For whole stool samples, we will employ the BioCollector at home stool 
sampling kit (BioCollective, Denver CO, USA).  Smaller stool samples will be collected using a 
non-invasive double-tipped sterile polyester culture swabs (Becton-Dickinson catalog # BD 
220135).  All samples will be shipped straight to Dr. Gilbert’s lab for aliquot and storage at -80C 
until DNA extraction of microbiome samples. Microbiome DNA will be isolated with the MoBio 
Powersoil kit with the addition of mechanical lysis.  DNA samples will be subsequently 
quantified by Quant-iT PicoGreen dsDNA Assay (Life Technologies) and normalized to a 
concentration of 50 pg/mL.  Whole-genome shotgun sequencing libraries will be prepared 
according to the manufacturer’s instructions using the Nextera XT DNA Library Preparation kit 
(Illumina) with 100-250 pg input DNA.  Libraries will be pooled by transferring equal volumes of 
each library using a Labcyte Echo 550 liquid handler.  The concentrations and insert size 
ranges for each pooled library will be checked using an Agilent Bioanalyzer DNA 1000 kit 
(Agilent Technologies).  Libraries will be subsequently sequenced on the Illumina HiSeq 2500 
platform in paired-end mode (2x151bp) targeting ~10Gb of sequences per sample. 
 
Blood Collection 
Complete metabolic panel including liver function tests, complete blood count, lipid profile, and 
inflammatory markers (hs-CRP and ESR) will be collected as standard of care.  Approximately 
20mL of peripheral blood will be collected and tested for markers of angiogenesis using a 
multiplex immunoassay system (Biorad).  The angiogenesis factors to be measured are 
angiopoetin-2, epidermal growth factor (EGF), endoglin, sCD40L, vascular endothelial growth 
factor A, C and D, (VEGF-A, -C, -D), placental growth factor (PlGF), heparin-binding EGF-like 
growth factor (HB-EGF), plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor 
binding protein (IGFBP)-1, transforming growth factor alpha (TGF-α), and urokinase-type 
plasminogen activator (uPA). The inflammatory markers to be measured are Interleukin-6 (IL-6), 
Interleukin-8, Interleukin-18 (IL-18), sCD40L, soluble Fas ligand (sFASL), and TNFα.  
 
Data will be collected from the subjects’ medical records for up to 2 years post-randomization to 
collect outcomes and adverse events.   
 
GIB episodes will be defined by INTERMACS: 
 
An episode of SUSPECTED INTERNAL OR EXTERNAL BLEEDING that results in 1 or more of 
the following: 


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1. Death 
2. Re-operation 
3. Hospitalization 
4. Transfusion of red blood cells as follows: 
• 
During first 7 days post implant (>4 units packed red blood cells within any 
24-hour period in patients >50kg or >20cc/kg packed red blood cells within 
any 24-hour period in patients <50kg) 
• 
After 7 days post implant (transfusion of packed red blood cells (PRBC) after 
7 days following implant with the investigator recording the number of units 
given.) 
 
During the 1-year study period, clinical events including GIB and other major adverse events will 
be recorded and evaluated on a regular basis.   
 
 
DATA AND SPECIMEN BANKING 
Peripheral blood collected from consented participants will be stored in refrigerators at -80C for 
the duration of the study.  All members of the research team will have access to the specimens.  
 
Stool samples collected from consented participants will be shipped straight to Dr. Gilbert’s 
laboratory for microbiome analysis and storage.  All samples will receive a designated study 
code.  This code will be linked to the patient’s data.  
 
All samples, blood and stool, will be stored indefinitely for future research related to heart 
failure, GI bleeding, Omega-3 supplements, and microbiome. 
 
 
STUDY TIMELINES 
Each subject will actively participate in the study for 1 year after randomization. We will collect 
data from the subjects’ medical records for an additional year.  It will take approximately 6 
months to enroll all study participants.  Once the study is complete, it will take approximately 3 
months to complete the primary analysis. 
 
 
INCLUSION AND EXCLUSION CRITERIA 
Inclusion Criteria 
1. Subject has signed consent 
2. Age > 18 years 
3. Subjects with a CF-LVAD or are scheduled to receive a CF-LVAD implant 
 
Exclusion Criteria: 
1. Psychiatric disorder or disease, irreversible cognitive dysfunction or psychosocial issues 
that might impair compliance with the study. 
2. Patients already taking O3FA. 
 
RECRUITMENT METHODS 
Patients with advanced heart failure will be seen in clinic, in the cardiac catheterization 
laboratory, or inpatient wards or intensive care units.  If the patient goes on to have an 
evaluation for LVAD during their clinical course, a member of the research team will approach 
the patient.    We currently implant approximately 60 CF-LVAD per year at the University of 


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Chicago.  Recruitment from the recently implanted cohort and newly implanted patients should 
provide us with sufficient patients for this study. 
 
 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES 
There will be no compensation to participants in this study. 
 
 
WITHDRAWAL OF PARTICIPANTS 
Participants can be withdrawn without consent if they are not compliant with taking O3FA daily.  
They will be notified of withdrawal and all their data will be permanently erased.  If participants 
decide to withdraw from the study, all of the O3FA will be returned to the research team, and the 
all of their data will be permanently erased. 
 
 
RISKS TO PARTICIPANTS 
There is a slight risk associated with vein punctures. We will make every effort to obtain the 
samples during a standard of care blood draw.  If this is not possible, the risks associated with a 
blood draw include pain, dizziness, fainting, infection (rare), and redness.  There is also a risk of 
loss of confidentiality, which will be minimized by efforts to secure the data. 
 
 
POTENTIAL BENEFITS TO PARTICIPANTS 
There will be no direct benefit to patient.  We hope that the existence of this data will facilitate 
fundamental and significant research in advanced heart failure, ultimately benefitting patients in 
the future.  
 
 
STATISTICAL ANALYSIS, DATA MANAGEMENT, AND CONFIDENTIALITY 
Statistical analysis will be performed using SPSS Statistics 22 (SPSS Inc, Chicago, IL, USA). 
Variables with 2-tailed p value <0.05 will be considered significant.  Clinical parameters and 
outcomes including rates of GI bleeding, angiogenesis-related biomarkers, inflammatory 
markers, and microbiome data will be compared between the O3FA and control groups, both 
among the primary and secondary prevention arms using unpaired t-test or Mann-Whitney U 
test as appropriate.  A necessary patient number for each group is calculated as 26 (total 104) 
by power analysis with 0.05 of α, 0.8 of effect size, 0.8 of 1-β.   
 
 
A master list maintaining patient names and code numbers will be stored in locked files.  A 
password-protected computer located in the heart failure main office will contain a database for 
data collected in this study.  Case report forms (CRF’s) will be generated and filled out for each 
subject enrolled in this study. 
 
There is a risk of loss of confidentiality.  If a patient agrees to participate, and signs an informed 
consent, a signed copy of the consent will be given to them, a copy placed in their record and 
then the data will be abstracted into an electronic database.  The database will be within the 
Department of Medicine, Section of Cardiology.  The data will be password protected and 
covered by all of the firewalls and security features of the Department of Medicine. 
 
The investigators seek to minimize these risks by labeling the study related data and specimens 
with a study code. This study code will be linked with the patient’s data.  Only the investigators 


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and their designated staff will have access to the databases and the link between study code 
numbers and patient identifying information.   
 
 
Data and samples may be utilized by faculties who have the proper IRB approval to do so, and 
whose study objective meets with the overall objective of this research. 
 
We may share coded data and/or samples outside of the institution in collaboration efforts. An 
IRB amendment will be submitted to the IRB for review if this happens. Additionally, if NIH 
funding is obtained for any proposed study, it is possible that the PI will be required to provide a 
copy of coded data to the NIH for public use. In either case, direct patient identifiers will never 
be shared. 
 
 
ECONOMIC BURDEN TO PARTICIPANTS 
There will be no economic burden to the participants. 
 
 
CONSENT PROCESS 
The consent process will take place in either clinic, cardiac catheterization laboratory, and 
inpatient wards or intensive care units.  Patients will be given an informed consent and allowed 
as much time as needed to read all components and be provided time to formulate questions.  If 
questions arise, the PI or a member of the research team will provide answers to the patient 
regarding participation in the research study. 
 
 
REFERENCES 
1. 
Hasin T, Marmor Y, Kremers W, Topilsky Y, Severson CJ, Schirger JA, et al. 
Readmissions after implantation of axial flow left ventricular assist device. J Am Coll 
Cardiol. 2013;61:153-163 
2. 
Mehra MR, Naka Y, Uriel N, Goldstein DJ, Cleveland JC, Colombo PC, et al. A fully 
magnetically levitated circulatory pump for advanced heart failure. N Engl J Med. 
2017;376:440-450 
3. 
Rogers JG, Pagani FD, Tatooles AJ, Bhat G, Slaughter MS, Birks EJ, et al. 
Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med. 
2017;376:451-460 
4. 
Uriel N, Pak SW, Jorde UP, Jude B, Susen S, Vincentelli A, et al. Acquired von 
willebrand syndrome after continuous-flow mechanical device support contributes to a 
high prevalence of bleeding during long-term support and at the time of transplantation. 
J Am Coll Cardiol. 2010;56:1207-1213 
5. 
Crow S, Chen D, Milano C, Thomas W, Joyce L, Piacentino V, et al. Acquired von 
willebrand syndrome in continuous-flow ventricular assist device recipients. Ann Thorac 
Surg. 2010;90:1263-1269; discussion 1269 
6. 
Demirozu ZT, Radovancevic R, Hochman LF, Gregoric ID, Letsou GV, Kar B, et al. 
Arteriovenous malformation and gastrointestinal bleeding in patients with the heartmate 
ii left ventricular assist device. J Heart Lung Transplant. 2011;30:849-853 
7. 
Tabit CE, Chen P, Kim GH, Fedson SE, Sayer G, Coplan MJ, et al. Elevated 
angiopoietin-2 level in patients with continuous-flow left ventricular assist devices leads 
to altered angiogenesis and is associated with higher nonsurgical bleeding. Circulation. 
2016;134:141-152 


IRB18-0576 
Version: 05Jun2019              
 
 
 
Page 9
8. 
Tabit CE, Coplan MJ, Chen P, Jeevanandam V, Uriel N, Liao JK. Tumor necrosis factor-
α levels and non-surgical bleeding in continuous-flow left ventricular assist devices. J 
Heart Lung Transplant. 2018;37:107-115 
9. 
Otani A, Takagi H, Oh H, Koyama S, Honda Y. Angiotensin ii induces expression of the 
tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. Diabetes. 
2001;50:867-875 
10. 
Houston BA, Schneider AL, Vaishnav J, Cromwell DM, Miller PE, Faridi KF, et al. 
Angiotensin ii antagonism is associated with reduced risk for gastrointestinal bleeding 
caused by arteriovenous malformations in patients with left ventricular assist devices. J 
Heart Lung Transplant. 2017;36:380-385 
11. 
Nakatani T, Sase K, Oshiyama H, Akiyama M, Horie M, Nawata K, et al. Japanese 
registry for mechanically assisted circulatory support: First report. J Heart Lung 
Transplant. 2017;36:1087-1096 
12. 
Kirklin JK, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers SL, et al. Eighth 
annual intermacs report: Special focus on framing the impact of adverse events. J Heart 
Lung Transplant. 2017;36:1080-1086 
13. 
Costantini L, Molinari R, Farinon B, Merendino N. Impact of omega-3 fatty acids on the 
gut microbiota. Int J Mol Sci. 2017;18 
14. 
Balfegó M, Canivell S, Hanzu FA, Sala-Vila A, Martínez-Medina M, Murillo S, et al. 
Effects of sardine-enriched diet on metabolic control, inflammation and gut microbiota in 
drug-naïve patients with type 2 diabetes: A pilot randomized trial. Lipids Health Dis. 
2016;15:78 
15. 
Noriega BS, Sanchez-Gonzalez MA, Salyakina D, Coffman J. Understanding the impact 
of omega-3 rich diet on the gut microbiota. Case Rep Med. 2016;2016:3089303 
16. 
Menni C, Zierer J, Pallister T, Jackson MA, Long T, Mohney RP, et al. Omega-3 fatty 
acids correlate with gut microbiome diversity and production of n-carbamylglutamate in 
middle aged and elderly women. Sci Rep. 2017;7:11079 
17. 
Jing K, Wu T, Lim K. Omega-3 polyunsaturated fatty acids and cancer. Anticancer 
Agents Med Chem. 2013;13:1162-1177