Morphological and molecular changes of the myocardium after left ventricular mechanical support

Abstract

Left ventricular assist devices (LVAD) are currently used to either "bridge" patients with terminal congestive heart failure (CHF) until cardiac transplantation is possible or optionally for patients with contraindications for transplantation ("destination therapy"). Mechanical support is associated with a marked decrease of cardiac dilation and hypertrophy as well as numerous cellular and molecular changes ("reverse cardiac remodeling"), which can be accompanied by improved cardiac function ("bridge to recovery") in a relatively small subset of patients with heart transplantation no longer necessary even after removal of the device ("weaning"). In the recent past, novel pharmacological strategies have been developed and are combined with mechanical support, which has increased the percentage of patients with improved clinical status and cardiac performance. Gene expression profiles have demonstrated that individuals who recover after LVAD show different gene expression compared to individuals who do not respond to unloading. This methodology holds promise for the future to develop read out frames to identify individuals who can recover after support. Aside from describing the morphological changes associated with "reverse cardiac remodeling", this review will focus on signal transduction, transcriptional regulation, apoptosis, cell stress proteins, matrix remodeling, inflammatory mediators and aspects of neurohormonal activation in the failing human heart before and after ventricular unloading.

Keywords: Congestive heart failure (CHF); left ventricular assist device (LVAD); morphology; reverse cardiac remodeling; ventricular unloading; weaning..

Fig. (1)

Simplified schematic diagram of the role of matrix metalloproteinases (MMP) and their inhibitors (TIMPS) during chronic heart failure (CHF) and reverse cardiac remodelling: increased expression of MMP and decreased expression of TIMPS during CHF increase turnover of extracellular matrix constituents and favour cardiac dilation, these mechanisms are reversed after ventricular unloading and therefore induce geometrical reshaping of the heart.

Fig. (2)

During CHF, besides receptor uncoupling, the density of β-adrenoreceptors and their responsiveness are decreased leading to decreased cardiac function and contractility. Some of these molecular changes are reversed by mechanical ventricular support.

Fig. (3)

CHF and cardiac hypertrophy are associated with increased expression of ANP and BNP (natriuretic peptides, NP), which are considered to be induced by tensile stretch during cardiac dilation. The NP receptor responsiveness is blunted. Chromogranin A, another neuroendocrine protein is increased during CHF and has been shown to exert cardiodepressive effects in animal studies. LVAD is associated with decreased expression of NP and Chromogranin A.

Fig. (4)

Colocalisation of BNP and Chromogranin A during CHF (A), which is considerably decreased by unloading (B). Normal control hearts are devoid of this colocalisation (C). Red arrow indicates Chromogranin A, green arrow indicates BNP and yellow arrows indicate colocalisation of Chromogranin A with BNP. Despite being significantly decreased in the myocardium after unloading, owing to its low expression in the myocardium, Chromogranin A plasma levels do not reflect hypertrophy regression after LVAD (D). ANP and BNP are significantly decreased in the plasma after unloading (E and F).

Fig. (5)

Cardiomyocytes with expression of Cyclooxygenase-2 have significantly larger diameters than COX-2 negative cardiomyocytes.

Fig. (6)

Significant Colocalisation of COX-2 (red signals) and p-Akt ^(Thr308) (green signals) resulting in yellow overlay signals (see arrows) during CHF (A). This is reversed by LVAD support (B). Controls do not show signals for COX-2 but only few for p-Akt ^(Thr308) (C).

Fig. (7)

Stressful stimuli lead to COX-2 expression in some, but not all cardiomyocytes, which become hypertrophic leading to organ enlargement. Ventricular unloading significantly decreases COX-2 expression, which is significantly correlated with hypertrophy regression, suggesting a pivotal role of COX-2 in the pathogenesis of maladaptive hypertrophic growth.

Fig. (8)

Schematic overview of molecular and morphological changes during CHF (A) and after LVAD support (B).