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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
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
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?
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
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
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
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?
GI Bleeding with Non-Pulsatile Flow
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.”
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?
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
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?
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?
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
Diminished Vasoconstrictive Function Caused by Long‐Term Nonpulsatile Left Heart Bypass
Nshimura T et al. Artifical Organs 2001 10:722-6
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
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
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
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
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
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
The Adventita is Thickened
Ambardekar A et al. Sumbitted
Elastin Decreases and Collagen Increases in the Aorta post Nonpulsatile LVAD
Ambardekar A et al. Submitted
Aortic Stiffness Also Increased
Ambardekar A et al. Submitted
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?