Rejection in heart transplantation for cardiac sarcoidosis mimicking idiopathic giant cell myocarditis: long-term follow-up.

: Heart transplantation is a life-saving therapy for some patients admitted for acute myocarditis. However, controversial exists about the major risk of rejection following heart transplantation in specific types of myocarditis. Because of relatively few data on the post heart transplant outcomes, we report the long-term follow-up of a 39-year-old patient with a previous history of ulcerative colitis, which rapidly worsened heart failure until an emergency heart transplant in 2004.The clinical course was complicated by many episodes of rejection; lastly, after the development of severe cardiac allograft vasculopathy, re-heart transplantation was needed. The main findings of this case are: 1) inflammatory aetiology should always be suspected in patients with concomitant autoimmune disease that developing rapidly progressing heart failure; 2) patients with inflammatory myocardial disease undergoing heart transplantation should also undergo strict immunological surveillance; 3) the option of performing the re-heart transplant in a patient with a so complex management in the first one could be uncertain, but in this case the young age and lack of noncardiac comorbidities were effective to favour the survivor after two immunologically so challenging heart transplantation.

Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists.

The ever-increasing use of immune checkpoint inhibitors in cancer is leading to a high incidence of autoimmune side effects. This report discusses an autoimmune fulminant myocarditis in an elderly patient with metastatic pulmonary adenocarcinoma in whom the most advanced invasive heart failure therapies were used successfully. She was treated with nivolumab. This case illustrates a severe cardiovascular complication of immunotherapy and highlights to cardiologists the importance of aggressive treatments in patients with metastatic cancers whose prognosis has improved dramatically.

Giant cell myocarditis successfully treated with antithymocyte globuline and extracorporeal membrane oxygenation for 21 days.

: A 31-year-old man presenting with cardiogenic shock and left ventricular ejection fraction of 10% received the diagnosis of giant cell myocarditis by endomyocardial biopsy. The patient was successfully treated with high-dose inotropes, intra-aortic balloon pump and venoarterial extracorporeal membrane oxygenation for 21 days associated with combined immunosuppression (thymoglobulin, steroids, cyclosporine). Immunosuppression including thymoglobulin is the regimen associated with the highest probability of recovery in case of giant cell myocarditis. Immunosuppression needs time to be effective; thus, hemodynamic support must be guaranteed. In the present case, we observed that full recovery can be obtained up to 21 days of support with extracorporeal membrane oxygenation and adequate immunosuppression.

sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models.

Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGC(alpha)(1)-deficient (sGC(alpha)(1)(-/-)) mice to unequivocally determine the role of sGC(alpha)(1)beta(1) in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGC(alpha)(1)(-/-) mice on the C57BL/6 background (sGC(alpha)(1)(-/-B6) mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC(alpha)(1)(-/-B6) than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca(2+) handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC(alpha)(1)(-/-B6) than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC(alpha)(1)(-/-B6) compared with WT mice. Together, these findings suggest that cGMP generated by sGC(alpha)(1)beta(1) protects against cardiac dysfunction and mortality in murine inflammatory shock models.

Successful treatment of cardiogenic shock caused by humoral cardiac allograft rejection.

The progress of immunosuppressive therapy has made heart transplantation the standard therapy for end-stage heart failure. However, humoral rejection of the cardiac allograft is still a challenging problem associated with high incidence of graft loss and patient mortality. The present patient developed profound cardiogenic shock requiring extracorporeal life support on the 8th day after heart transplantation. Endomyocardial biopsy revealed no cellular rejection, and complement component C4d was positively stained on the capillary endothelium. The patient was successfully treated with repeated plasmapheresis and administration of anti-CD20 monoclonal antibody, rituximab, as well as with steroid pulse and increased standard immunosuppressive medication.

CD14 expression on monocytes and TNF alpha production in patients with septic shock, cardiogenic shock or bacterial pneumonia.

OBJECTIVES: In patients with septic shock, circulating monocytes become refractory to stimulation with microbial products. Whether this hyporesponsive state is induced by infection or is related to shock is unknown. To address this question, we measured TNF alpha production by monocytes or by whole blood obtained from healthy volunteers (controls), from patients with septic shock, from patients with severe infection (bacterial pneumonia) without shock, and from patients with cardiogenic shock without infection. MEASUREMENTS: The numbers of circulating monocytes, of CD14+ monocytes, and the expression of monocyte CD14 and the LPS receptor, were assessed by flow cytometry. Monocytes or whole blood were stimulated with lipopolysaccharide endotoxin (LPS), heat-killed Escherichia coli or Staphylococcus aureus, and TNF alpha production was measured by bioassay. RESULTS: The number of circulating monocytes, of CD14+ monocytes, and the monocyte CD14 expression were significantly lower in patients with septic shock than in controls, in patients with bacterial pneumonia or in those with cardiogenic shock (p < 0.001). Monocytes or whole blood of patients with septic shock exhibited a profound deficiency of TNF alpha production in response to all stimuli (p < 0.05 compared to controls). Whole blood of patients with cardiogenic shock also exhibited this defect (p < 0.05 compared to controls), although to a lesser extent, despite normal monocyte counts and normal CD14 expression. CONCLUSIONS: Unlike patients with bacterial pneumonia, patients with septic or cardiogenic shock display profoundly defective TNF alpha production in response to a broad range of infectious stimuli. Thus, down-regulation of cytokine production appears to occur in patients with systemic, but not localised, albeit severe, infections and also in patients with non-infectious circulatory failure. Whilst depletion of monocytes and reduced monocyte CD14 expression are likely to be critical components of the hyporesponsiveness observed in patients with septic shock, other as yet unidentified factors are at work in this group and in patients with cardiogenic shock.

Catecholamines induce IL-10 release in patients suffering from acute myocardial infarction by transactivating its promoter in monocytic but not in T-cells.

The anti-inflammatory cytokine IL-10 is up-regulated in response to TNF-alpha suggesting a control mechanism of inflammation. In addition, we recently found systemic IL-10 release in response to acute stress reactions in the absence of any systemic inflammation. In vitro and in vivo studies in experimental models suggest that catecholamines induce IL-10 release via a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) dependent pathway. Here we studied patients for plasma IL-10 after acute myocardial infarction, a very stressful event without significant signs of systemic inflammation. In fact, the activation of the sympathetic system initiated by cardiac infarction was accompanied by a temporary systemic release of IL-10. Catecholamine induced IL-10 may be released by different cells. Recently, we demonstrated that catecholamines directly stimulate the IL-10 promoter/enhancer via a cAMP/PKA pathway in monocytic cells. A cAMP responsive element (CRE) was identified as major target. Here we show that there is no influence of catecholamines on the IL-10 promoter activity in T-cells. In contrast to monocytic cells, in T-cells cAMP-induced PKA-dependent phosphorylation of the CRE-binding protein 1 (CREB-1) seems to play a marginal role in IL-10 induction, which was reflected by a low cAMP-dependent IL-10-promoter/enhancer stimulation in reporter gene assays. Thus, catecholamines are directly involved in the regulation of IL-10 expression in monocytic but not in T-cells after acute stressful conditions.

Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the potential importance of bacterial translocation.

AIMS: Exposure to bacterial endotoxin, perhaps due to bowel congestion or ischaemia and altered gut permeability, may result in immune activation that is characteristic for patients with severe heart failure. It is known that blood procalcitonin rises in response to bacterial endotoxin exposure. METHODS: We measured procalcitonin in a group of 29 patients with acute cardiogenic shock and no sign of infection (all without bacteraemia) and 26 with septic shock. Blood was analysed for procalcitonin, interleukin-6, tumour necrosis factor-alpha (TNF-alpha), c-reactive protein (CRP) and neopterin. Patients were managed conventionally in an intensive care unit with no further experimental procedures. RESULTS: Three cardiogenic (10%) and seven septic shock patients (27%) survived. Most patients with acute heart failure surviving 12 h or more (18 of 20) developed a pyrexia (738.0 degrees C) of unknown origin in the absence of positive cultures, with a rise in procalcitonin (1.4+/-0.8 to 48.0+/-16.2 ng/ml, P<0.001), CRP (76.5+/-16.4 to 154.7+/-22.9 mg/l, P<0.001) and neopterin (20.7+/-3.5 to 41.2+/-6.7 nmol/l, P<0.001). Patients with septic shock had higher initial levels of cytokines, and higher peak levels. Those with heart failure surviving (n=3) and those dying in the first 12 h (n=9) had no rise in cytokine levels. The patients with high procalcitonin had a higher temperature (38.9+/-0.3 vs. 37.3+/-0.23 degrees C, P<0.05), TNF-alpha (43.95+/-9.64 vs. 16.43+/-4.33 pg/ml; P<0.005) and CRP (146.1+/-18.4 vs. 68.2+/-39.6 mg/ml, P<0.005). Peak procalcitonin levels correlated with peak temperature (r=0.74, P<0.001). CONCLUSION: Cardiogenic shock causes a pyrexia of unknown origin in patients surviving for 12 h and that is associated with a rise in procalcitonin levels. This lends support to the hypothesis that patients with cardiogenic shock may be being exposed to bacterial endotoxin at a time when bowel wall congestion and or ischaemia is likely to be present.

[Inflammatory mediators in patients with biventricular assist device systems]. / Inflammatorische Mediatoren bei Patienten mit biventrikulären Assist-Device-Systemen.

We studied the plasma levels of TNF-alpha, IL-6, IL-8 and soluble adhesion molecules (sE-Selectin, sL-Selectin, sVCAM-1) immediately before and during mechanical circulatory support with a Biventricular Assist Device System (BVAD-"Berlin Heart") in comparison to patients with chronic heart failure (NYHA classes II/III) and patients with coronary artery disease with normal ventricular function. Additionally, the biocompatibility of the membranes used in the "Berlin Heart" was tested in vitro. IL-6 and IL-8 but not TNF-alpha could only be detected in patients with cardiogenic shock immediately before starting circulatory support. Furthermore, plasma concentrations of soluble adhesion molecules were statistically significantly elevated in patients with cardiogenic shock compared to patients with coronary artery disease. This picture of a systemic inflammatory response syndrome without significant level of TNF-alpha looks quite similar to that seen in patients following trauma and severe operations. During mechanical circulatory support plasma levels of cytokines and soluble adhesion molecules dropped to low levels in patients, who were successfully maintained on BVAD. By contrast, we have found persistently elevated levels of these mediators in patients with fatal outcome. This seems not to be the result of individual distinct response of blood cells to contact with the artificial surfaces of the device. In summary, our data suggest the development of a systemic inflammatory response syndrome may be due to hypoxia during cardiogenic shock. Persistence of systemic inflammation suggests failing of the mechanical support. Therefore, the monitoring of inflammatory mediators may be relevant as a prognostic marker in these patients (disappearance of peripheral hypoxia).

[Comparative effectiveness of the peptide drugs finoptin, levamisole and prednisolone in immune cardiogenic shock in an experiment]. / Sravnitel'naia éffektivnost' peptidnykh preparatov finoptina, levamizola i prednizolona pri immunnom kardiogennom shoke v éksperimente.

The efficacy of dalargin, delta-sleep peptide, finoptin, levamisole, and prednisolone was studied in 104 white mice with experimental immune cardiogenic shock. The efficacy of finoptin was as high as that of prednisolone. Dalargin, delta-sleep peptide, levamisole, and T-activon decreased mice's life span and/or increased their mortality when the mice were given intravenous infusions of these agents.

Immunological aspects in various forms of shock

Se presenta un repaso sobre los aspectos inmunológicos en tres formas del síndrome clínico de shock: anafiláctico, séptico y cardiogénico. Se hace una discusión de la participación de los derivados del ácido araquidónico, de la activación del sistema de complemento y de los efectos de los mediadores producidos por diferentes células que explican el origen de varias de las manifestaciones clínicas de estas tres entidades