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Cardiac molecular markers of programmed cell death are activated in end-stage heart failure patients supported by
Tommaso Prescimone1, Silvia Masotti2, Andrea D'Amico2
1CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy.
Insights
Left ventricular assist device (LVAD) support in heart failure patients increases apoptotic mediators, particularly Hsp72. This increase may protect against further cell death by reducing Caspase-3 activation, influencing cardiac remodeling.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Cardiomyocyte apoptosis is elevated in heart failure (HF) and contributes to disease progression.
- Left ventricular assist device (LVAD) support may offer therapeutic rescue of cellular functions in failing hearts.
- The precise impact of LVAD support on cardiomyocyte apoptosis remains debated in scientific literature.
Purpose of the Study:
- To investigate the effect of LVAD implantation on the apoptotic profile of cardiac tissue in patients with end-stage heart failure.
- To compare apoptotic markers in patients before and after LVAD support, and with medical therapy controls.
Main Methods:
- Cardiac tissue samples were obtained from end-stage HF patients pre-LVAD (n=22) and post-LVAD (n=6), and from heart transplant (HTx) controls (n=7).
- Expression of apoptosis-related genes (Caspase-3, Bax, Bcl-2) and Hsp72 was assessed using real-time PCR and Western blotting.
- Immunohistochemistry, TUNEL assay, DNA laddering, cellular size, and fibrosis were evaluated to determine apoptotic indices.
Main Results:
- Apoptotic indices, including pro-apoptotic Bax and anti-apoptotic Hsp72, were significantly increased post-LVAD compared to pre-LVAD.
- Specifically, Hsp72 levels rose from 0.76±0.14 to 3.27±0.41 (P<.001) and Bax from 1.10±0.29 to 2.15±0.38 (P=.035).
- Increased Hsp72 expression post-LVAD was confirmed by Western blotting and immunohistochemical analysis.
Conclusions:
- LVAD implantation appears to activate apoptotic mediators, primarily at the mitochondrial level.
- A significant increase in Hsp72 expression following LVAD support may mitigate Caspase-3 activation.
- Enhanced Hsp72 could play a crucial role in cardiac remodeling associated with LVAD therapy.
Background:
Cardiomyocyte apoptosis increases in heart failure (HF) and is implicated in disease progression. The apoptotic cell is not inevitably committed to death, and appropriate therapy like left ventricular assist device (LVAD) support could offer a rescue of cellular functions. Literature data regarding the modulation of the apoptotic process during LVAD support are still controversial.
Methods:
To assess whether LVAD implantation modifies the apoptotic profile in the heart, cardiac tissue was collected from end-stage HF patients before LVAD implant (pre-LVAD, n=22) and at LVAD removal (post-LVAD, n=6) and from stable HF patients on medical therapy without prior circulatory support (HTx, n=7) at heart transplantation as control. Caspase (Casp)-3, Bax, Bcl-2, and Hsp72 cardiac mRNA and protein expression were evaluated by real-time polymerase chain reaction and Western blotting (WB) in the three groups of patients. Immunohistochemical analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and DNA laddering analysis were performed; cellular size and interstitial fibrosis content were also determined.
Results:
All the apoptotic indices were increased in the post-LVAD group compared to pre-LVAD, specially antiapoptotic Hsp72 and proapoptotic Bax (Hsp72: 3.27±0.41 vs. 0.76±0.14, P<.001; Bax: 2.15±0.38 vs. 1.10 ± 0.29, P=.035; post-LVAD vs. pre-LVAD, respectively). The significant increase in Hsp72 was confirmed by WB and immunohistochemical analysis.
Conclusion:
LVAD appears to induce an activation of apoptotic mediators, mainly at the mitochondrial level, while the following activation of Casp-3 is reduced by the significant increase of Hsp72, whose enhancement could be an important factor in cardiac remodeling associated with LVAD support.
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