The quest for the holy grail—lva ds as bridge to recovery

1. Myocardial Remodeling with
Continuous-Flow LVADs
Amrut V. Ambardekar, MD, FACC
University of Colorado

2. The Quest for the Holy Grail—LVADs as Bridge to Recovery
“Choose Poorly”
 LVAD Explant for
Remodeling alone
without Recovery
 Patient develops
recurrent HF
“Choose Wisely”
 LVAD Explant for
Remodeling and
Recovery
 Pt free of HF, without
LVAD or transplant
“You must choose…”
22yo man s/p CF-LVAD 4 months ago
for new HF, EF 10%, and shock. Now
has with LVEF 45%.

3. Review of the Journey Towards the Holy Grail
• What is LVAD related myocardial remodeling: organ level vs. cellular level?
• Does myocardial remodeling equate to recovery (i.e.. LVAD explant) in clinical
practice?
• What are the obstacles in the path towards the holy grail of full recovery?
– Incomplete cellular and molecular recovery
– Differences between pulsatile vs continuous unloading
– Possibilities of functional atrophy
• What further questions need answers to move us along
the correct pathway?

4. Theoretical Rationale for LVAD Induced
Remodeling
• Excess pressure/volume loading of the myocardium is an established stimulus for HF
– Examples: Valvular disease, Hypertension
• LVADs dramatically unload the LV and remove this stimulus
– Mechanical unloading results in normalization of abnormal filling pressures
• LVADs allow for complete restoration of cardiac output
– Improvement in end-organ perfusion decreases stimulus for neurohormonal activation
– Breaks the vicious cycle: ↓cardiac function↑compensatory neurohormones↓cardiac
function
– Hemodynamic stability to add neurohormonal antagonists

5. Remodeling at the Organ Level
Ambardekar et al. Circ HF. 2011; 4:425.
• Normalization of hemodynamics
after LVAD
• LV changes after LVAD
• Decreased chamber size
• Decreased hypertrophy and mass
• Improved ejection fraction
• This reversal of the seemingly
irreversible failing LV phenotype is
termed “Reverse Remodeling”

6. Remodeling at the Cellular Level
Ambardekar et al. Circ HF. 2011; 4:425.
• Pathological hypertrophy is a
hallmark feature of the failing
myocyte
• Numerous studies have suggested
that LVAD support helps myocytes
regress toward dimensions of
nonfailing myocytes
• Overt structural atrophy has not
been found

7. Early success in the Quest for the Holy Grail
• 15 patients with nonischemic cardiomyopathy
treated with a combination of LVAD followed by
conventional HF medical therapy (ACE, β-blocker,
spironolactone, ARB) and then the selective β2
adrenergic receptor agonist clenbuterol.
• 11 had successful LVAD explant
• Survival free of HF was 100% at 1 year and 88.9%
at 4 years
Birks et al. NEJM. 2006; 355: 1873-84.

8. Subsequent Crusades with Variable Results
Drakos et al. Circ. 2012; 126:230-241.

9. If you are not searching for grail, you won’t find it…
Sixth INTERMACS Report. JHLT. 2014; 33:555-564.

10. Summary of Clinical Recovery/LVAD Explant Data
• Rates of LV recovery are highly variable
• LVAD alone likely not sufficient for recovery
• Adjunct therapies are needed, but unclear role of individual agents
• Role of atrophy and methods to combat atrophy not defined
• Differences between those who recover vs. those that don’t
• Younger age
• Shorter HF duration
• Is the lack of prior exposure to β-blockade the key to recovery?
• Systematic protocols to monitor and assess for recovery needed
• May partly explain low rates of recovery in INTERMACS Registry
• If you don’t look for something, you can’t find it…

11. Cellular & Molecular Mechanisms for Remodeling
• Bridge to transplant LVAD placement allows collection of discard tissue for cellular and
molecular analysis
• LV apical core removed for insertion of LVAD inflow cannula
• Entire heart removed at time of cardiac transplantation
• Paired comparisons from the same patient before/after LVAD allows for some control of
multiple variables that come from human samples
• Comparisons of different diseases (ischemic CM vs. familial)
• Medication differences may be a confounding variable
• Numerous studies have investigated mechanism of remodeling

12. Incomplete Recovery of Myocyte Contractility
Ambardekar et al. Circ HF. 2011; 4:425.
• In vitro assessments of contractility
have suggested that there is an
improvement in myocyte force with
LVAD support.
• Myocytes from LVAD supported
patients:
• Greater magnitude of shortening
• Faster time to peak contraction
• Faster time to shortening
• Improvements ≠ normalization

13. Incomplete Molecular Recovery with LVAD
Margulies, KB et al. Circ Res 2005; 96:592-599.
Gene Expression Data
• 3088 genes
Dysregulated in HF
vs. Nonfailing
• Minority with
normalization or
overcorrection
• Majority with
persistent or
exacerbation

14. Remodeling ≠ Recovery: Elastic vs. Plastic Deformation
Mann et al. JACC. 2012; 60:2465-72.
Capable of Remodeling
(but Not Recovery)
Capable of Remodeling
and Recovery

15. Greater Unloading with Pulsatile vs. Continuous LVADs
• Retrospective analysis of 31 pulsatile vs. 30 continuous flow
LVADs from Columbia
• Higher EF, smaller LV dimensions, and lower LV pressure by
echocardiography in pulsatile flow LVAD group
• Lower serum BNP and extracellular matrix biomarkers in pulsatile
group
• Is pulsatile unloading need to foster recovery?
Kato et al. Circ HF. 2011;4:546.

16. Potential Negative Consequences of Mechanical Unloading:
(Pulsatile) LVAD Working Group Data
• One third of patients had an
improvement in EF to >40% with
LVAD support by 30 days
• Prolonged LVAD support to 120
days resulted in declining EF
that approached values before
LVAD support.
• LV Mass decreased by 30 days
and stabilized thereafter
Maybaum Circ. 2007; 115: 2497-2505.

17. EF and Myocardial Strain Improvements Attenuated with
Prolonged CF-LVAD Unloading
Ambardekar et al.
JHLT 2012; 31; 1311-
1313.

18. Unanswered questions in the quest for the Holy Grail
• Dosage of Unloading?
– Type of unloading: pulsatile vs. continuous, full vs. partial
– Duration of unloading: daytime only vs 24/7, total duration, weaning
• Adjuvant therapy?
– Neurohormonal antagonists, anti-atrophy agents, cell or gene based therapies
• Optimal strategy for in vivo assessment of recovery?
– How long do you turn down an LVAD
• Prediction of who will have sustained recovery?
– Etiology of cardiomyopathy (ischemic vs. genetic vs. idiopathic), duration of HF
• Non-cardiac effects of LVADs which may impede recovery?

19. Conclusions
• Heart failure has been conceptualized as an end-stage disease,
however many physiological parameters can improve and even
normalize with LVAD therapy.
• LVAD implantation allows for both mechanical unloading as well as
positively impacting systemic and biochemical responses that might
ultimately recover LV contractile performance.
• Such changes can be observed clinically but also extend to the most
basic aspects of genetic regulation and involve a complex,
interconnected cascade of changes.
• BTT LVADs allow for unique access to tissue to better define the
cellular and molecular mechanisms behind unloading and heart failure
as a whole.
• Many crusades lay ahead, but the holy grail (LV Recovery) is worth
pursuing…