Myocardial Remodeling with Continuous-Flow LVADs

Amrut V. Ambardekar, MD, FACC

University of Colorado

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%.

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?

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

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”

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

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.

Subsequent Crusades with Variable Results

Drakos et al. Circ. 2012; 126:230-241.

If you are not searching for grail, you won’t find it…

Sixth INTERMACS Report. JHLT. 2014; 33:555-564.

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…

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

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

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

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

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.

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.

EF and Myocardial Strain Improvements Attenuated with

Prolonged CF-LVAD Unloading

Ambardekar et al. JHLT 2012; 31; 1311-1313.

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?

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…