LVAD-Induced Reverse Modeling:

Basic and Clinical Implications for

Myocardial Recovery
K. Kosalathip
Biomedical Engineering Student, Mahidol University
 What is
Heart Failure?

Heart failure is a state in which

the heart is unable to pump blood at a rate
commensurate with the requirements of
the body’s tissues or can do so only at
elevated filling pressure.
 Symptoms of Heart Failure
(Heart Failure Syndrome)
• Low output (forward failure)
Fatigue, dizziness, muscle weakness, and
shortness of breath, which is aggravated by
physical exercise.

• Increased filling pressure (backward failure)

Congestion of the organs upstream of the heart,
for example, peripheral or pulmonary edema,
maldigestion, and ascites.
 What is
End-Stage Heart Failure?

AHA/ACC 2013 Heart Failure

Treatment Guidelines
Temporary or permanent
mechanical support
Temporary mechanical support
↓
Bridge-to-Transplantation (BTT)

Permanent mechanical support

↓
Destination therapy (DT)
 What is LVAD?

• Acronym for
Left Ventricular Assist Device (LVAD)

• A mechanical pump that pump the blood

from the left ventricle to the arterial system
Some patients exhibit recovery
of the ventricular function during
LVAD use
 Possibility of
Bridge-to-Recovery Therapy
(BRT)
How does LVAD support
influence an end-stage
failing heart?
Hemodynamics
in heart failure
Volume

Pressure
• Restore normal cardiac output and blood pressure

• LV pressure and volume unloading

↓ pulmonary venous and arterial pressure
↓ right ventricular afterload

• Improve perfusion to all body organs

Improve autonomic function
Normalization of the neurohormonal and cytokine milieu

• RV volume overload
RV dissension
Right-sided heart failure

• Allow reduction or elimination of the need for toxic level of

vasopressors and inotropes
RV
What’s pathologically altered
in the heart failure state ?

Hemodynamic factors
+
Neurohormonal factors
LVAD-Heart Interactions
Ventricular, Structural, Cellular, Extracellular
matrix, Molecular, Biochemical, and Metabolic
Concept of reverse
modeling
Ventricular Structural
Reverse Remodeling
Higher slope End-Diastolic Pressure Volume Relationship (EDPVR)

Higher ventricular compliance

Higher slope End-Diastolic Pressure Volume Relationship (EDPVR)

Higher ventricular compliance

V30

the volume required to achieve

an end-diastolic pressure of 30 mm Hg
 Higher slope End-Diastolic Pressure Volume Relationship (EDPVR)

Higher ventricular compliance

Normal heart Maximal reverse Without LVAD

remodeling support

100 mL 150 mL 280 mL

Higher degree of myocardial hypertrophy

 Higher slope End-Diastolic Pressure Volume Relationship (EDPVR)

Higher ventricular compliance

↓ LV dilatation
↓ Myocardial hypertrophy
↑ Interstitial fibrosis

Higher degree of myocardial hypertrophy

 These changes are not observed in RV
signifies that
ventricular structural reverse remodeling
is primarily mediated by
the hemodynamic unloading (preload),
not by normalized neurohormonal milieu.
 Improved
Myocardial Function
• ↑ Contractile responses to increased frequency of
stimulation (force-frequency relationship, FFR)
↑ Expression of calcium cycling genes
↑ Calcium accumulating efficacy of the sarcoplasmic reticulum

FFR improved in LV myocardium but not in RV myocardium

→ regulated by hemodynamic factors

• ↑ Contractile responses to b-adrenergic stimulation

(↑ contractile strength)
↑ b-receptor density
Normalized phosphorylation of the calcium release channel

Improved in myocardium of both RV and LV

→ regulated by normalized neurohormonal milieu
Extracellular matrix
• ↑ Collagen deposition in LV myocardium
↓ MMP-1 and MMP-9 (matrix metalloproteinases)
↑ TIMP-1 (tissue inhibitors of metalloproteinases)
↑ Myocardial tissue levels of angiotensin I and II
(regulators of myocardial collagen synthesis)

• ↑ Myocardial stiffness
Collagen production shift from type III to a more
(abnormal) stiff type I collagen

• These effects maybe contributed by both neurohormonal

and mechanical factors
Molecular, Biochemical,
and Metabolic Changes
 LVAD support only partially reverses
depressed expression of genes involved in
metabolism in the failing human heart

Down-regulated ↓ Myocardial hypertrophy

toward normal ↓ Vascular signaling

↑ Calcium-handling genes
Up-regulated ↑ Myocardial mitochondrial function ↑ Expression
toward normal of uncoupling protein ↑ Caveolin expression
(improved lipid metabolism)

Glucose transporter 1 and 4 Muscle carnitine

down-regulated
palmityl transferase-1 Regulation of myocardial
and not normalized
fibrosis
Pulsatile and non-pulsatile
LVADs
Pulsatile LVADs Higher LV volume unloading
Lower inflammatory markers (TNF-a and C5a)

Similar LV pressure unloading

Normalizing cell size and TNF-a levels
Biochemical marker of brain damage
LVAD-Induced Ventricular
Contractile Recovery
 Bridge-To-Recovery
Challenges
“…5 patients from among 111 patients
with chronic heart failure who exhibited
sufficient recovery to permit LVAD
explantation without transplantation. All
of these patients eventually developed
recurrent heart failure…”
eventually developed recurrent heart failure
 Higher frequency of
LVAD-induced myocardial recovery in patients
with chronic idiopathic cardiomyopathy

• >33% have undergone device explantation

• 85% 5-year survival
• 32% recurrence of heart failure by 2 year
Predictors of sustained recovery

LV end-diastolic dimension <55 mm

Ejection fraction >45%

during a 15-minute pump stop experiment

<5 years history of heart failure

Strategies to Enhance
Ventricular
Contractile Recovery
 Success in bridging
cardiomyopathic
patients to full recovery
 Aggressive medical therapy post
device implant — Harefield group
• Angiotensin-converting enzyme inhibitors (ACEIs)

• Angiotensin receptor blockers (ARBs)

• Aldosterone antagonists

• b-Blockers

• Clenbuterol (b-2 adrenergic receptor agonist)

Animal models show increased skeletal and cardiac
muscle hypertrophy and improved contractile strength
• 70% (11 patients) demonstrated sufficient
recovery to allow device explantation

• EF remains between 60-65% after 3 years

of follow-up
• Clenbuterol induces insulin-like growth factor I (IGF-I) in cardiac myocytes
in vitro. Animal models show increased skeletal and cardiac muscle
hypertrophy and improved contractile strength.

• Patients with low IGF-I mRNA levels at implantation showed significant

increase during recovery.

• Patients with high IGF-I mRNA at implantation remained high.

• Levels returned to normal by 1 year after explantation.

↓
Elevated myocardial IGF-I mRNA levels could play a
role in recovery by limiting atrophy and apoptosis
during reverse remodeling
 A multicenter study is planned to
determine whether the results obtained
at Harefield can be replicated

“Harefield Recovery Protocol Study”