Prolonged Impella: Mode of Action and Clinical Implications

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Patients with myocarditis may present with severe unexplained acute new-onset heart failure (HF). The specific causes and extent of inflammation are associated with varied prognosis. Acute fulminant myocarditis has a moderate prognosis, while giant cell and eosinophilic myocarditis have poor prognoses.1,2 The known pathophysiological processes underlying myocarditis include pro-inflammatory and fibrotic processes that lead to cardiac remodelling and failure.

In an overloaded myocardium, such as during acute fulminant myocarditis, mechanical stress activates integrins (mechanoreceptors) in the heart, which are known to mediate pro-inflammatory and fibrotic processes. Furthermore, integrins are known to have direct detrimental effects on the contractile apparatus. These combined effects exacerbate myocarditis and contribute to the poor outcomes. This raises the question if haemodynamically unloading the heart by using mechanical circulatory support (thereby decreasing mechanical stress) is sufficient to overcome a severe cardiac inflammatory response.

Several case reports of the successful short-term use of Impella pumps in fulminant and giant cell myocarditis have been published.3–7 Dr Tschöpe presented the case of an HIV-positive patient in cardiogenic shock (CS) due to viral-negative fulminant myocarditis, proven by endomyocardial biopsy. The patient was treated with temporary mechanical unloading using an Impella CP in the absence of immunosuppressive therapy.

The Impella CP support for >20 days resulted in the improvement of left ventricular ejection fraction (LVEF) to 40% from a baseline of <10%. Furthermore, Impella CP support in the absence of immunosuppressive support led to a significant drop in the mRNA expression of the integrins and innate immune cells. This was paralleled by the decrease in immune cell infiltration and an increase in protein kinase A and G activity (decreased left ventricular stiffness).

Dr Tschöpe further hypothesised that prolonged unloading with an Impella device (PROPELLA) might offer the circulatory support and disease-modifying effects that are important for bridging patients with fulminant myocarditis to recovery. This hypothesis was tested in a 62-year-old patient admitted with severe myocarditis and pre-CS, despite immunosuppressive therapy. An axillary Impella 5.0 was implanted, which remained in place for 40 days. The patient was mobilised after 2 days of Impella 5.0 support. Steroid therapy and ventricular unloading led to a significant improvement in LVEF from day 5 after initiation of support. After 4 weeks, an echocardiogram showed the first signs of recovery. Serial left ventricular biopsies were taken at various time points during treatment to assess biomarkers of inflammation.

These data demonstrate that the inflammatory response was significantly reduced during concomitant treatment with Impella and immunosuppression. However, the inflammatory response significantly increased after removal of the Impella support, despite continued immunosuppression, indicating that ventricular unloading mitigates inflammation independent of immunosuppression. The patient was weaned off Impella support after 2 months and continued immunosuppressive therapy alone. However, the immunosuppressive therapy had to be stopped early due to the development of a life-threatening abscess. The patient developed recurrent myocarditis and CS and was bridged to a long-term left ventricular assist device (LVAD). Interestingly, unloading using an LVAD also led to a decrease in immune cell presence. This case provides proof of concept that unloading improves inflammation-induced remodelling.

Dr Tschöpe presented the case of another patient with fulminant myocarditis and severe impairment of the right ventricle (RV) and left ventricle (LV). The patient received concomitant therapy with extracorporeal membrane oxygenation (ECMO) and Impella (ECMELLA).8 The RV function improved over time resulting in weaning of the patient from ECMO, whereas the Impella support was continued (PROPELLA). Again, serial LV biopsies showed a significant decrease in integrins and immune cell presence with PROPELLA support, and this effect was maintained by providing additional immunosuppressive therapy after the Impella's removal. This result suggests that additional pharmacological intervention is needed after cessation of unloading to maintain the immune-modulating effect until total myocardial recovery. Also, these results provide evidence of correlation between mechanical unloading (decrease in LV pressures) with molecular unloading (decrease in integrins).

Dr Tschöpe also presented a case of PROPELLA support in end-stage dilated cardiomyopathy without severe inflammation. In this case, the LV function did not improve with or without unloading with Impella. In addition, the mRNA expression level of integrins and immune cell presence increased, suggesting a mismatch of molecular and mechanical unloading. The failure of molecular recovery correlated with the persistence of HF, and the patient was bridged to an LVAD. This result suggests that a mismatch of mechanical and molecular unloading correlates with no myocardial recovery.

In conclusion, experience to date suggests that the PROPELLA approach in fulminant myocarditis can serve as a bridge to recovery, due to the correlation of mechanical unloading with molecular unloading, with the maintenance of these immune-modulating effects using additional pharmacological immunosuppression therapy until total myocardial recovery. In contrast, the PROPELLA approach in end-stage dilated cardiomyopathy can serve as a bridge to LVAD due to the mismatch of mechanical unloading with molecular unloading, leading to persistent HF with no myocardial recovery.


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