There is evidence that non-pulsatile flow from LVADs can cause vascular remodeling of the aorta over time: (1) Histological studies show decreases in medial wall thickness, elastin content, and smooth muscle cells along with increases in fibrosis and atherosclerosis. (2) Explant studies demonstrate thinning of the adventitia and reductions in elastin with increases in collagen. (3) Non-pulsatile flow is associated with increased aortic stiffness, which could negatively impact myocardial recovery and increase bleeding and stroke risk. Further research is needed to fully understand the clinical implications of vascular remodeling from non-pulsatile LVAD support.

1. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
JoAnn Lindenfeld, MD
Professor of Medicine
Director, Heart Failure and Heart
Transplantation Program
Vanderbilt Heart and Vascular Institute
Nashville, TN

2. Presenter Disclosure Information
Vascular Remodeling
•I will not discuss off label use or investigational use in
my presentation.
•I have financial relationships to disclose:
•Employee of: none
•Consultant for: Abbott, Gambro, St Jude,
Boston Scientific, Resmed, Sorin, Relypsa,
Cardiokinetix
•Stockholder in: none
•Research support from: AHA, NIH, Skaggs
Pharmacy Grants, ADA, Jaqueline Leaffer
Research Fund

3. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
• Why might vascular remodeling be important?
• What is the evidence for vascular remodeling?

4. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
√ End-organ function is not compromised

5. End-organ Function is Comparable
with Pulsatiile vs Non-Pulsatile LVAD
Centrifugal (n = 10) Axial (n = 30) Pulsatile (n = 18)
Baseline Month 3 Baseline Month 3 Baseline Month 3
P
value
Creatinine 1.3 ± 0.53 1.0 ± 0.3 2.3 ± 4.2 1.2 ± 0.5 1.2 ± 0.2 1.1 ± 0.3 NS
BUN 23.9 ± 13 18.3 ± 6.7 34.9 ± 19 22.6 ± 13 25.5 ± 12 20.3 ± 9.5 NS
CrCl 90.6 ± 43 104 ± 42 68.6 ± 31 90 ± 31 90.8 ± 24 102 ± 34 NS
T. Bilirubin
mg/dL
1.37 ± 1.6 0.4 ± 0.2 .32 ± 0.9 0.7 ± 0.5 1.29 ± 1.0 0.6 ± 0.4 NS
AST U/liter 36.8 ± 12 34.8 ± 15 69.1 ± 104 36.2 ± 19 29.8 ± 7.8 28.6 ± 22 NS
Hemoglobin
g/dL
12.1 ± 1.5 normal 11.9 ± 1.8 normal 11.5 ± 1.9 normal NS
Platelets 197 ± 58.5 normal 218 ± 104 normal 191 ± 51.9 normal NS
Kamdar F et al. J Heart Lung Transplant 2009;28:352-8

6. End-organ Function is Restored with both
pulsatile and non-pulsatile LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
√ End-organ function does not seem
compromised
• But there are some concerning problems with
non-pulsatile flow LVADs
√ Bleeding
√ Low rate of myocardial recovery
√ High stroke rate

7. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
• Why might vascular remodeling be important?
• What is the evidence for vascular remodeling?

8. GI Bleeding with Non-Pulsatile Flow

9. Crow S et al. The Journal of Thoracic and Cardiovascular Surgery, Volume 137, Issue 1, 2009, 208 - 215
GI Bleeding Events are more common
in Patients with Non-Pulsatile Flow
Devices
“If anticoagulation alone were the cause
for our findings, we would expect to see a
higher rate of bleeding from all causes in
nonpulsatile device recipients. Overall
bleeding rates for patients with
nonpulsatile and pulsatile LVADs,
however, are quite similar.”

10. Angiodysplasia is a significant cause of
bleeding in non-pulsatile vs pulsatile
LVADs
• The explanation given is that bleeding is due to acquired
von Willebrand disease
This is the same syndrome seen in aortic stenosis
Is this only due to acquired VWF abnormalities?
• Bleeding due to angiodysplasia has been reported in Von
Willebrand disease but only in a single case report
• Is it possible there is vascular remodeling with less
elasticity in these small vessels?

11. Myocardial Recovery in Uncommon
following LVAD
Study [Reference] Design
No. of
Pts.
Standardiz
ed Med
Therapy
Duration
(months)
Recovery
n (%)
Durabilityc
LVAD Working Group, 2007 P 67 No 4.5 6 (9) 100/6m
Berlin, 2008 and 2011 P 188 No 4 35 (19) 74/3y; 66/5y
Harefield, 2006 P 15 Yes 11 11 (73) 100/1y; 89/4y
Harefield, 2011 P 20 Yes 9 12 (60) 88/3y
Athens-Harefield, 2007 P 8 Yes 7 4 (50) 100/2y
Vancouver, 2011 [ P 17 No 7 4 (23) 100/2y
Gothenburg, 2007 P 18 No 7 3 (17) 33/8y
Pittsburgh, 2003] R 18 No 8 6 (33) 67/1y
Osaka, 2005 R 11 No 15 5 (45) 100/8m–29m
Pittsburgh, 2010 R 102 NA 5 14 (14) 71/5y
Multicenter, 2002 R 271 NA 2 22 (8) 77/3y
Columbia, 1998 R 111 NA 6 5 (4.5) 20/15m
Montefiore, 2013 P 21 Yes ? 5 (23%) 100/>3y
Selzman CH et al. The Annals of Thoracic Surgery, 2015;99:, 360 - 367

12. Myocardial Recovery is Uncommon
with Non-pulsatile Flow LVADs
• Is this only due to the severity of
myocardial dysfunction?
• Is it possible that aortic remodeling creates
an “afterload mismatch” that adds an
additional problem for myocardial
recovery?

13. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
• Why might vascular remodeling be important?
• What is the evidence for vascular remodeling?

14. 2
Figure 1
1 Birukov KG et al. Mod Cell Biochem 1995; 144:131-9. 2 Sumpio BE et al. J Vasc Surg 1987;6:252-6.
3 Sumpio BE et al. Surgery 1990; 108:277-81. 4 Wilson E et al. J Cell Biol 1993;123:741-7
.
Vascular Remodeling with Non-Pulsatile Flow
Effects of Cyclic Mechanical Stretching on
Isolated Vasular Smooth Muscle Cells
• Increase in proliferation
• Increase in expression of contractile phenotype
• Production of an autocrine growth factor and DNA systhesis
• Increase in endothelin

15. Diminished Vasoconstrictive Function Caused
by Long‐Term Nonpulsatile Left Heart Bypass
Nshimura T et al. Artifical Organs 2001 10:722-6

16. Diminished Vasoconstrictive Function Caused
by Long‐Term Nonpulsatile Left Heart Bypass
Nshimura T et al. Artifical Organs 2001 10:722-6
The increase in
with
norepinephrine
SVR is diminished
by 40% after 4
weeks

17. 2
Figure 1
Westaby, S et al. Journal of Thoracic & Cardiovascular Surgery. 2007; 133:575-576.
Vascular Remodeling with Non-Pulsatile Flow
N =7
Jarvik 2000

18. 2
Figure 2
Westaby, S et al. Journal of Thoracic & Cardiovascular Surgery. 2007; 133:575-576.
Decrease in Medial Wall Thickness and
Elastin Content over TimeContent

19. Vascular Remodeling with Non-
Pulsatile FLow
Segura AM e al. Journal of Heart and Lung Transplantation, 2013; 11:, 1096 - 1100
• 11 patients studied before and at removal of
Heartmate II (5 for transplant, 6 autopsy)
• Mean duration 140 (87-580 days)
• Stained with H and E, Masson’s trichrome,
Movat’s pentachrome

20. Vascular Remodeling with Non-
Pulsatile FLow
Histopathologic
parameter
LVAD
implantation
LVAD
explantation
p-value
Medial thickness (μ) 1.46 ± 0.22 1.30 ± 0.22 0.389
Medial degeneration 0.83 ± 0.38 1.14 ± 0.74 0.042
Smooth muscle cell
disorientation and
depletion
1.18 ± 0.82 1.60 ± 0.77 0.048
Elastic fiber
fragmentation and
depletion
0.95 ± 0.49 1.40 ± 0.83 0.017
Fibrosis 1.21 ± 0.62 1.54 ± 0.59 0.039
Atherosclerosis 1.31 ± 1.38 2.91 ± 2.32 0.004
Segura AM e al. Journal of Heart and Lung Transplantation, 2013; 11:, 1096 - 1100

21. Clinical characteristics
Age (y) 65 ± 7
Gender
Women 2 (18%)
Men 9 (82%)
Follow-up
Heart transplant 5 (45%)
Autopsy 6 (55%)
Heart failure etiology
Ischemic 4 (36%)
Idiopathic 7 (64%)
LVAD supporta (days) 140 ± 136 (range 87–580)
History of hypertension 6 (55%)
Myocardial infarction 4 (36%)
Cardiac index
(liters/min/m2)
1.88 ± 0.38
Pulmonary capillary wedge
pressure (mm Hg)
29 ± 12
Ejection fraction (%) 19 ± 3
Mean blood pressure (mm
Hg)
90.7 ± 14.3
Angiotensin-converting
enzyme inhibitor
4 (36%)
Aldosterone antagonists 6 (55%)
Table 1.
Clinical
Characteristics
of Study
Patients
(n = 11)
All with Heart Mate II
Ambardekar A et al submitted

22. The Adventita is Thickened
Ambardekar A et al. Sumbitted

23. Elastin Decreases and Collagen Increases
in the Aorta post Nonpulsatile LVAD
Ambardekar A et al. Submitted

24. Aortic Stiffness Also Increased
Ambardekar A et al. Submitted

25. Vascular Remodeling in Patients
with “non-pulsatile” flow LVADs
• Is there a “downside” with non-pulsatile flow
compared to pulsatile flow?
• Why might vascular remodeling be important?
• What is the evidence for vascular remodeling?