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Personalized Immune Cocktails for Heart Recovery

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Julia Kzhyshkowska, PhD
Head of Dept. of Innate Immunity and Tolerance
Institute of Transfusion Medicine and Immunology,
Medical Faculty Mannheim, Heidelberg University;
German Red Cross Blood Service Baden-Württemberg - Hessen
Mannheim, Germany

Advanced heart failure (HF) in cardiomyopathy is a life-threatening disorder affecting 2-3% of the adult population and 6-10% of people over the age of 65, with a tendency to increase steadily with age. All cardiomyopathies are associated with premature death from arrhythmia and progressive HF. Heart failure is also a major health economic factor: 5% of all hospitalizations in Europe and other developed countries around the world are attributed to HF and it is the number one cause of hospitalization in the population over age 65. The prognosis of HF remains dismal with less than 50% of patients surviving 5 years after the first symptoms are identified. The terminal stage of advanced HF in dilated cardiomyopathy is characterized by shortness of breath, lung edema, dizziness, tiredness (fatigue) and weakness, weight gain due to swelling in ankles, legs and abdomen, rapid or irregular heartbeat and chest pain.

Advanced HF in end-stage dilated cardiomyopathy is treated with implantation of a mechanical circulatory support device, most often to assist the left ventricle (LVAD, left ventricular assist device), and primarily as a bridge to transplantation. Due to the scarcity of donor hearts, nowadays the LVAD is used not only as a bridge to transplantation, but mainly as a destination therapy. The cost of LVAD implantation surgery is 150,000 EUR, and up to 5,000 EUR is needed for the follow-up each month. Despite recent advances in surgical technique and implant design, LVAD implantation continues to be associated with significant morbidity and mortality during follow-up, with thromboembolic events being one of the main causes. Inflammation is estimated to cause up to 80% of pump thromboses and thromboembolic events. Suppression of LVAD-induced inflammation around the cannula would reduce the risk for thromboembolic events.

The outcome of LVAD therapy differs significantly between patients. Some patients can be weaned from the device following myocardial recovery. However, the processes underlying the recovery of the myocardium are still unclear. Previous attempts to identify specific clinical or pathological parameters have not given rise to a reliable system to predict the outcome of LVAD implantation. Identifying the immunopathological mechanisms and biomarkers of patients' reactions to their LVAD would identify patients who have the potential to be weaned from mechanical circulatory support and provide a basis for developing immunomodulatory therapy for all LVAD patients, thus promoting improved implant tolerance and better healing of the heart.

Which tools can immunology offer us today? First of all, our over 100-year experience in immune cell function research indicates that key cells of the innate immune system—macrophages—are responsible for initiation of acute inflammation caused by trauma, resolution of inflammation and switch to the healing phase. Since 1908, when Ilja Mechnikoff received the Nobel Prize for the discovery of first immune cells (macrophages), these cells have gone through a scientific evolution that can be compared to the development of the telephone from Bell's first device patented in 1876 to our modern smart phone - from a single-function instrument to a versatile, adaptable, mobile gadget. Today we know that macrophages are intelligent, versatile and plastic cells designed by evolution to control our health.

Now we aim to use our knowledge about macrophage functions to control the switch from inflammation to the healing phase that fails in some LVAD patients. This failure results in chronic inflammatory reactions of the myocardium, not only in the tissue immediately surrounding the LVAD during the whole period of implantation, but also in the ventricular walls distant from the device, resulting in pathological remodeling of the myocardium, insufficient supply of oxygen to the hypertrophied cardiomyocytes and poorer contractibility of the muscular walls. Currently the types and levels of innate immune system activation associated with effective healing or chronic inflammation in patients with LVAD are unknown.

Our recent pioneering pilot examination of apical left ventricular myocardial tissue from the site of LVAD implantation using morphological, immunohistochemical, and advanced imaging methods indicates that 1) patients differ significantly in the level of local chronic inflammation in tissues from the site of LVAD implantation, 2) major differences between patients include the activation status of key innate immune cells (macrophages) and amount and content of inflammatory infiltrates, 3) status of macrophage activation at the moment of LVAD implantation is indicative of the level of inflammation and fibrosis at the moment of LVAD explanation.

Of course, larger clinical studies are needed to identify the prognostic significance of macrophage biomarkers to predict the outcome of LVAD therapy. However, we can already predict that local modulation of macrophage phenotype is a highly promising therapeutic approach to support healthy healing of the heart.

When it comes to satisfying our tastes and providing us with our favorite food, drinks, cosmetics, clothing, sport equipment and dream holiday destinations our personal preferences and reactions are investigated in great detail. But when it comes to life-saving VAD implantation, our individual differences and the specific needs of our immune system are ignored for practical reasons.

Individualized macrophage phenotype modulation offers us a unique opportunity to design implant-based therapy in a personalized way (compare it to personalizing your smart phone!). In order to avoid disappointing results with blocking of single cytokine functions (as was the case with a TNF-? therapy) elegant cocktails of cytokines, growth factors and blocking antibodies have to be prepared for each individual patient. This is not a short-cut to making profits for industry, rather it is the only way to save the most valuable resource we have—human life.

Disclosure Statement: The author has no conflicts of interest to disclose.

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