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?