LVAD Flashcards
LV assist devices (LVADs) can reverse adverse remodeling in end-stage DCM. But what is the paradox/problem?
there is a disconnect between the benefits of prolonged unloading with LVAD at molecular and cellular levels and the low rate of bridge to recovery (BTR).
Potential explanations for this paradox include insufficient reverse ECCM remodeling and/or excessive reverse cardiomyocyte remodeling with atrophy.
type of cardiomyopathy and response to LVAD - significance?
The response of patients with end-stage DCM to LVAD therapy is of particular interest because the myocardium is dysfunctional yet viable unlike end-stage ischemic cardiomyopathy.
DCM is caused by a diverse group of myocardial insults accounting for further heterogeneity in response to therapy.
what are the neurohormonal effects on remodelling?
AngII is also involved in adverse ventricular remodeling through its effects on fibroblast proliferation and increased collagen deposition in the ECM and myocyte hypertrophy. The effects are inhibited by ACE inhibitors and selective AngII type 1 receptor blockers (ARBs. High levels of circulating catecholamines seen in HF produce significant adverse remodeling. Chronic elevation of norepinephrine (NE) levels leads to altered myocyte calcium handling, impaired myocyte energetics, and increased apoptosis and necrosis [14]. Beta-adrenergic blockade in HF reduces collagen turnover.
Inhibition of the effects of AngII has been shown to reduce hypertrophy independent of their effects on afterload reduction [5, 23]. Beta-adrenergic blockade has also been shown to reduce hypertrophy in patients with HF.
what happens to the heart in the face of pressure overload (very generally)?
Cardiac hypertrophy is a non-specific reaction to ventricular pressure or volume overload [16] and has independent prognostic implications for HF.
In HF, myocyte hypertrophy is moduled how?
Myocyte hypertrophy is modulated by mechanical stress as well as load independent hormonal control.
ECM composition
ECM is composed of fibrous proteins that provide structural support for normal myocyte function and maintenance of ventricular geometry.
fibroblasts and their regulation
The fibroblast is the most abundant cell in the extracellular matrix and its principal role is the synthesis of collagen [25]. The RAAS plays an important role in fibroblast proliferation and therefore collagen production. AngII and aldosterone stimulate fibroblast hyperplasia and collagen synthesis. AngII has a direct effect on fibroblasts and increases transforming growth factor (TGF)-b which in turn increases collagen production.
Collagen: types, influence on remodelling, turnover
Collagen composition (quantity, type, and quality) rather than total collagen volume has been increasingly recognized as a significant determinant of ventricular size and function. Collagen type I and type III are the most abundant subtypes of collagen in the ECM. Type 1 collagen is relatively older, and more heavily cross-linked making it more stiff and inelastic. Conversely type III collagen is relatively newer, has fewer cross-linkages, and therefore displays greater plasticity.
The relative proportion of type I and type III collagen depends on the rates of collagen degradation and synthesis (i.e., turnover) in the ECM. When collagen turnover is high, there is a greater proportion of immature (type III) collagen that is more plastic and is thought to mediate eccentric hypertrophy and ventricular dilatation.
Collagen composition/turnover regulation
he rate of collagen turnover is controlled by the balance between matrix metalloproteinases (MMPs), which break down collagen, and tissue inhibitors of matrix metalloproteinases (TIMPs), which prevent the breakdown of collagen.
In general, advanced HF is associated with the upregulation of MMP and downregulation of TIMP, leading to high collagen turnover and adverse remodeling. MMPs are regulated by multiple factors such as mechanical stretch, AngII, norepinephrine, and inflammatory cell signaling pathways
Pro-inflammatory response short- and long-term: effects on the heart
Pro-inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-a are a part of the body’s compensatory mechanisms to HF and play a role in the pathogenesis of HF
Following myocardial injury, these proinflammatory cytokines are initially compensatory. Animal studies demonstrate that cytokines released early after myocyte injury reduce apoptosis, reduce infarct size [46], and upregulate protective proteins such as heat shock proteins and manganese superoxide dismutase.
Despite these short-term benefits, long-term exposure to pro-inflammatory cytokines has been shown to adversely remodel myocytes and the ECM. Cytokine exposure causes myocyte hypertrophy, impaired contractility, and increased rates of apoptosis. Sivasubramanian et al. showed that transgenic mice that over-express cardiac TNF display increased activity of MMP and undergo progressive ventricular dilation
what changes does LVAD produce?
Mechanical LV support provides profound pressure and volume unloading of the LV.
Evidence shows that LVAD support leads to improved haemodynamics, reduced LV chamber size, reduced LV mass, reduced myocyte size and improved myocyte function. It also reduces circulating levels of neurohormones, inflammatory mediators and improves calcium cycling.
in addition to LVAD what can improve outcomes?
Higher rates of concomitant ACEi and Bblocker therapy were associated with higher rates of BTR compared to those who didn’t receive such medications.
the effects (detailed list) and the paradox of LVAD
The central paradox of LVAD therapy is that the rates of ventricular recovery sufficient to permit LVAD removal remain small, despite well-documented improvements in hemodynamics, ventricular size, ventricular shape, myocyte hypertrophy, neurohumoral levels, metabolism, calcium handling, inflammatory cytokines, and gene regulation. There are several possible explanations for the disconnection between the many benefits of LVAD therapy and the low rates of ventricular recovery.
possible explanations for the disconnection between the many benefits of LVAD therapy and the low rates of ventricular recovery.
First, patient heterogeneity poses a significant obstacle to understanding the effects of LVAD on end-stage DCM. The group of patients frequently lumped together in the DCM category differ significantly with respect to the etiology of their cardiomyopathy, the severity of their disease, and the duration of their disease.
Evidence clearly suggests that the beneficial effects of LVAD are in part related to the etiology of the underlying HF.
End-stage HF related to myocardial infarction has been shown to have much poorer response to LVAD therapy than non-ischemic DCM
Second, heterogeneity of disease is another important consideration in understanding myocardial response to LVAD. Clinical assessment of HF severity is most commonly performed using the New York Heart Association (NYHA) classes (I through IV) and ACC/AHA Stages (A through D). Both of these classification schemes provide important information about functional class and symptoms but tell us nothing about an individual’s myocardial substrate.
A third possible explanation for low rates of LVAD explantation is that our current method of surveillance is inadequate to correctly identify people in whom LVAD could be explanted.
End-stage HF related to myocardial infarction has been shown to have much poorer response to LVAD therapy than non-ischemic DCM. What is still missing from the data?
End-stage HF related to myocardial infarction has been shown to have much poorer response to LVAD therapy than non-ischemic DCM. What is not clear is to what degree non-ischemic DCM of different etiologies respond to LVAD therapy. For example, DCM related to specific protein mutations (i.e., epicardin, desmin, muscle LIM, sarcomere) may have more limited improvement to LVAD therapy than acquired forms of DCM (i.e., postpartum cardiomyopathy, toxin-mediated cardiomyopathy, viral myocarditis). However, this hypothesis has not been tested in the literature.
The more accurate we are in diagnosing the specific cause of a DCM, the greater will be our ability to assess which patients will respond most favorably to LVAD therapy.
