Survival, ventricular arrhythmia, and implantable cardioverter-defibrillator usefulness in toxic cardiomyopathy due to substance abuse.

BACKGROUND: Toxic dilated cardiomyopathy (T-DCM) due to substance abuse is now recognized as a potential cause of severe left ventricular dysfunction. The burden of ventricular arrhythmias (VA) and the role of a prophylactic implantable cardioverter-defibrillator (ICD) are not well documented in this population. We aim to assess the usefulness of ICD implantation in a T-DCM cohort. METHODS: Patients younger than 65 years with a left ventricular ejection fraction (LVEF) < 35% followed at a tertiary center heart failure (HF) clinic between January 2003 and August 2019 were screened for inclusion. The diagnosis of T-DCM was confirmed after excluding other etiologies, and substance abuse was established according to the DSM-5 criteria. The composite primary endpoints were arrhythmic syncope, sudden cardiac death (SCD), or death of unknown cause. The secondary endpoints were the occurrence of sustained VA and/or appropriate therapies in ICD carriers. RESULTS: Thirty-eight patients were identified, and an ICD was implanted in 19 (50%) of these patients, only one for secondary prevention. The primary outcome was similar between the two groups (ICD vs. non-ICD; p = 1.00). After a mean follow-up of 33 ± 36 months, only two VA episodes were reported in the ICD group. Three patients received inappropriate ICD therapies. One ICD implantation was complicated with cardiac tamponade. Twenty-three patients (61%) had an LVEF ≥35% at 12 months. CONCLUSION: VA are infrequent in the T-DCM population. The prophylactic ICD benefit was not observed in our cohort. The ideal timing for potential prophylactic ICD implantation in this population needs further studies.

Heavy Burden of Toxic Dilated Cardiomyopathy Among Young Adults: A Retrospective Study and Review of the Literature.

BACKGROUND: Dilated cardiomyopathy (DCM) is a well described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognised as potential triggers for DCM. The aim of this study was to assess the survival in patients ≤ 65 years of age with toxic cardiomyopathy (TCM). Left ventricular remodelling and the potential usefulness of left ventricular assist devices (LVADs) was also assessed. METHODS: This was a single-centre retrospective study from January 2003 to August 2019 of 553 patients ≤ 65 years old with LVEF < 40% at a tertiary-care cardiology centre. RESULTS: A total of 201 patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17 ± 8% at presentation, most patients (n = 27; 71%) had event-free survival with guideline-directed medical therapy, and 61% (n = 23) recovered an LVEF ≥ 40% after a median follow-up of 21 ± 23 months. Seven patients (18%) required an LVAD and 1 patient (3%) a transplantation. All LVADs were explanted or decommissioned after partial or complete LVEF recovery after a median support time of 11 ± 4 months. CONCLUSIONS: TCM induced by substance abuse is a frequent cause of HF, accounting for almost 20% of patients ≤ 65 years of age with DCM of unknown etiology. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

Effect of Acute Immunosuppression on Left Ventricular Recovery and Mortality in Fulminant Viral Myocarditis: A Case Series and Review of Literature.

BACKGROUND: Fulminant viral myocarditis (FVM) is a rare cause of cardiogenic shock associated with high morbidity and mortality rates. An inappropriately activated immune system results in severe myocardial inflammation. Acute immunosuppressive therapy for FVM therefore gained in popularity and was described in numerous retrospective studies. METHODS: We conducted an extensive review of the literature and compared it with our single-centre retrospective review of all cases of FVM from 2009-2019 to evaluate the possible effect of acute immunosuppression with intravenous immunoglobulins and/or high dose corticosteroids in patients with FVM. RESULTS: We report on 17 patients with a mean age of 46 ± 15 years with a mean left ventricular ejection fraction (LVEF) of 15 ± 9% at admission. Fourteen (82%) of our patients had acute LVEF recovery to ≥ 45% after a mean time from immunosuppression of 74 ± 49 hours (3.1 days). Extracorporeal membrane oxygenation (ECMO) was required in 35% (6/17) of our patients for an average support of 126 ± 37 hours. Overall mortality was 12% (2/17). No patient needed a long-term left ventricular assist device or heart transplant. All surviving patients achieved complete long-term LVEF recovery. CONCLUSIONS: Our cohort of 17 severely ill patients received acute immunosuppressive therapy and showed a rapid LVEF recovery, short duration of ECMO support, and low mortality rate. Our suggested scheme of investigation and treatment is presented. These results bring more cases of successfully treated FVM with immunosuppression and ECMO to the literature, which might stimulate further prospective trials or a registry.

CONTEXTE: La myocardite virale fulminante (MVF) est une cause rare de choc cardiogénique, un état associé à des taux élevés de morbidité et de mortalité. L'activation inappropriée du système immunitaire entraîne une inflammation grave du myocarde. Le recours à un traitement immunosuppresseur aigu en cas de MVF a donc gagné en popularité et a fait l'objet de nombreuses études rétrospectives. MÉTHODOLOGIE: Nous avons effectué une revue exhaustive de la littérature et comparé nos observations avec les résultats de notre examen rétrospectif de tous les cas de MVF traités dans un même centre entre 2009 et 2019, afin d'évaluer l'effet possible d'une immunosuppression aiguë par des immunoglobulines administrées par voie intraveineuse et/ou par une corticothérapie à forte dose chez les patients présentant une MVF. RÉSULTATS: Nous rapportons les cas de 17 patients dont l'âge moyen était de 46 ± 15 ans et qui avaient une fraction d'éjection ventriculaire gauche (FEVG) moyenne de 15 ± 9 % à l'admission. Chez 14 (82 %) d'entre eux, la FEVG aiguë s'est rétablie à une valeur ≥ 45 % dans les 74 ± 49 heures (3,1 jours) en moyenne après l'administration d'un traitement immunosuppresseur. Un soutien par oxygénation extracorporelle par membrane (ECMO) a dû être administré à 35 % (6/17) des patients, pendant 126 ± 37 heures en moyenne. Le taux global de mortalité s'établissait à 12 % (2/17). Aucun patient n'a eu besoin d'assistance ventriculaire gauche de façon prolongée ni d'une transplantation cardiaque. La FEVG a fini par se rétablir complètement chez tous les patients qui ont survécu. CONCLUSIONS: Les 17 patients gravement malades de notre cohorte qui ont reçu un traitement immunosuppresseur aigu ont vu leur FEVG se rétablir rapidement, n'ont eu besoin d'ECMO que pendant une courte période et ont affiché un faible taux de mortalité. Nous présentons notre algorithme d'investigation et de traitement. Nos résultats s'ajoutent à ceux d'autres études témoignant de l'efficacité du traitement de la MVF par immunosuppression et ECMO, ce qui pourrait stimuler la réalisation de nouveaux essais prospectifs ou l'établissement d'un registre.

Do Energy Drinks Really Give You Wings? Left Ventricular Assist Device Therapy as a Bridge to Recovery for an Energy Drink-Induced Cardiomyopathy.

The deleterious effect of energy drinks is increasingly recognized. We present a 26-year-old woman with inotrope-dependent severe dilated cardiomyopathy, potentially caused by chronic ingestion of energy drinks. The results of extensive investigation-consisting of cardiac magnetic resonance, F-18-fluorodesoxyglucose-positron emission tomography, coronary angiography, and endomyocardial biopsy-were normal. A left ventricular assist device (LVAD) was implanted as a potential bridge to recovery. After 10 months of mechanical support and pharmacological treatment, cardiac function was recovered, and the LVAD was successfully explanted. This is the first case report of energy drink abuse leading to severe heart failure requiring mechanical support for recovery.

Giant Left Atrial Appendage Aneurysm Mimicking Mediastinal Mass and Associated with Incessant Atrial Arrhythmias.

Left atrial appendage aneurysm (LAAA) is a rare entity. Clinical manifestations include arrhythmias and systemic embolization. We show here an example of a large and ectopic LAAA mimicking a mediastinal mass on chest X-ray and presenting with incessant atrial arrhythmias. Subsequent investigations leading to the correct diagnosis are described.

Effects of chronic sildenafil use on pulmonary hemodynamics and clinical outcomes in heart transplantation.

BACKGROUND: Elevated pulmonary vascular resistance (PVR) in heart transplant (HT) candidates is associated with poor survival after HT. This study assessed the effect of peri-operative sildenafil administration on pulmonary hemodynamics and clinical outcomes in patients with advanced heart failure who were considered high-risk for HT because of elevated PVR and transpulmonary gradient (TPG). METHODS: The study included 119 consecutive patients who underwent HT between 2004 and 2011. Fifteen patients (Group A) had severe pulmonary hypertension (PH), defined as mean pulmonary pressure (MPAP)>25 mm Hg and PVR>2.5 Wood units (WU), and/or TPG>12 mm Hg after vasodilator test or the continuous administration of inotropics drugs, and 104 patients (Group B) were without severe PH. Group A received sildenafil therapy. Pulmonary hemodynamics were evaluated before HT with and without sildenafil therapy. Right catheterization was performed early after HT with sildenafil therapy and late after HT without sildenafil. Survival after HT was compared between the groups. RESULTS: The sildenafil dosage was 109±42 mg/day during 163±116 days before HT. After sildenafil therapy MPAP, PVR, and TPG decreased from 43.9±12.5 to 33.4±5.8 mm Hg, 5.0±1.1 to 3.0±1.6 WU, and 17.3±3.2 to 10.2±4.1 mm Hg, respectively (p<.01). All patients underwent successful HT. Sildenafil dosage was 140±70 mg/day for 43±45 days after HT. There were no differences in PVR and TPG with sildenafil therapy early after HT and without sildenafil 6 months after HT. Survival after HT was similar between the groups. CONCLUSION: Sildenafil therapy before and after HT in patients with severe PH is associated with improved pulmonary hemodynamics and successful HT, without an increase in post-HT mortality.

Usefulness and limitations of rituximab in managing patients with lymphoproliferative disorder after heart transplantation.

Posttransplant lymphoproliferative disorders remain an uncommon complication of heart transplant with a high mortality rate reported after conventional therapies. Four patients with posttransplant lymphoproliferative disorders, of whom 3 were CD20 positive, received intravenous dosages of rituximab, 375 mg/m(2), weekly, for 6 ± 2 weeks. The overall response rate was 75% with 3 complete responses (CD20 positive) and 1 case of progressive disease (CD20 negative). Rituximab should be considered as a first-line therapy for patients with CD20 positive posttransplant lymphoproliferative disorders.

Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system.

NOD mice spontaneously develop insulin-dependent diabetes around 10-40 wk of age. Numerous immune gene variants contribute to the autoimmune process. However, genes that direct the autoimmune response toward ß cells remain ill defined. In this study, we provide evidence that the Icos and Icosl genes contribute to the diabetes process. Protection from diabetes in ICOS(-/-) and ICOSL(-/-) NOD mice was unexpectedly associated with the development of an autoimmune disorder of the neuro-muscular system, characterized by myositis, sensory ganglionitis and, to a reduced extent, inflammatory infiltrates in the CNS. This syndrome was reproduced upon adoptive transfer of CD4(+) and CD8(+) T cells from diseased donors to naïve NOD.scid recipients. Our data further show that protection from diabetes results from defective activation of autoimmune diabetogenic effector T cells in ICOS(-/-) NOD mice, whereas acceleration of diabetes in BDC2.5 ICOS(-/-) NOD mice is induced by a dominant defect in Treg. Taken together, our findings indicate that costimulation signals play a key role in regulating immune tolerance in peripheral tissues and that the ICOS/ICOSL costimulatory pathway influences the balance between Treg and diabetogenic effector T cells.

Mapping of the murine type 1 diabetes locus Idd20 by genetic interaction.

In the nonobese diabetes mouse, the murine type 1 diabetes susceptibility locus Idd20 interacts genetically with the diabetes resistance locus Idd19. Both Idds are located on distal mouse Chromosome 6, and previous studies on NOD.C3H congenic strains have shown that C3H alleles at Idd20 can suppress the disease-promoting effects of C3H alleles at Idd19 in both spontaneous and cyclophosphamide-induced diabetes. In this article we present the construction of novel congenic strains which, while maintaining the C3H alleles at Idd19, have allowed the candidate interval of Idd20 to be reduced from 4 to 1.8 cM. The analysis of these strains shows that Idd20 controls the progression of insulitis. Idd20 also increases the suppressive but not the pathogenic activity of splenocytes in diabetes transfer experiments. Our results suggest that the two Chromosome 6 susceptibility loci, Idd6 and Idd20, interact with the resistance locus Idd19 by regulating the activity of suppressor cells in the peripheral immune system.

The diabetes type 1 locus Idd6 modulates activity of CD4+CD25+ regulatory T-cells.

The genetic locus Idd6 confers susceptibility to the spontaneous development of type 1 diabetes in the NOD mouse. Our studies on disease resistance of the congenic mouse strain NOD.C3H 6.VIII showed that Idd6 influences T-cell activities in the peripheral immune system and suggest that a major mechanism by which the Idd6 locus modifies diabetes development is via modulation of regulatory T-cell activities. Our transfer experiments using total splenocytes and purified T-cells demonstrated that the locus specifically controls the efficiency of disease protection mediated by the regulatory CD4(+)CD25(+) T-cell subset. Our data also implicate the Idd6 locus in controlling the balance between infiltrating lymphocytes and antigen-presenting cells within the pancreatic islet.

GPX5 orthologs of the mouse epididymis-restricted and sperm-bound selenium-independent glutathione peroxidase are not expressed with the same quantitative and spatial characteristics in large domestic animals.

We report here on the cloning of cDNAs coding bovine and equine orthologs of mouse epididymis-restricted and sperm-bound glutathione peroxidase 5 (GPX5), a selenium-independent member of the multigenic GPX family in mammals. The complete sequence of bovine GPX5 as well as a partial sequence of the equine GPX5 were characterized, conceptually translated and aligned with other known mammalian GPX5 proteins. Using Northern blotting assays, we show that the level of expression of GPX5 is high in bovine but low in equine and that in both species the regionalization of GPX5 expression in epididymis is not totally identical to what was reported for rodent mouse GPX5. An antibody was produced against GPX5 and used in Western blot assays as well as in immunohistochemistry assays on bovine epididymis sections. It shows that the protein is essentially present in the cytoplasmic compartment of the caput segment 2 epithelium of the bovine epididymis. Unlike in the mouse model, bovine GPX5 seems to be poorly secreted and does not seem to be present on cauda epididymal spermatozoa.

Granulocyte-dendritic cell unbalance in the non-obese diabetic mice.

Several investigators, including ourselves, have reported lower yield of GM-CSF bone marrow-derived dendritic cells (DC) with altered MHC class II and co-stimulatory molecules expression in the non-obese diabetic (NOD) mice. However, whether this defect was intrinsic to the DC lineage and/or related to abnormal expansion of other cell types responding to GM-CSF remained an opened issue. We performed phenotypical and morphological analysis of cells from GM-CSF-supplemented-bone marrow-cultures and of freshly isolated bone marrow and blood cells from unmanipulated prediabetic NOD mice. The results show a heretofore undescribed bias towards generation of granulocytes in NOD mice, concomitant with quantitative and qualitative alterations of the DC lineage in both the bone marrow and the blood of this mouse strain. We propose that increased generation of granulocytes in NOD mice might contribute to autoimmunity. First, high numbers of granulocytes per se might favor inflammatory environment. Second, granulocytes, by interfering with DC development, might favor unbalanced antigen presenting cell function leading to T cell autoimmunity.

Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo.

Mast cells (MCs) are considered major players in IgE-mediated allergic responses, but have also recently been recognized as active participants in innate as well as specific immune responses. Recent work provided evidence that MCs are able to activate B and T lymphocytes through the release of vesicles called exosomes. Here we demonstrate that exosomes, which are located in the endocytic pathway, harbor exogenous Ags that associate with other molecules endowed with immunomodulatory functions, including 60- and 70-kDa heat shock proteins. Administration to naive mice of Ag-containing exosomes in the absence of conventional adjuvants elicits specific Ab responses across the MHC II haplotype barrier. We demonstrate that MC-exosomes induce immature dendritic cells (DCs) to up-regulate MHC class II, CD80, CD86, and CD40 molecules and to acquire potent Ag-presenting capacity to T cells. Uptake and processing of Ag-associated exosomes by endogenous DCs were also demonstrated. Finally, exosome-associated heat shock proteins are critical for the acquisition by DCs of the Ag-presenting function. This work demonstrates a heretofore unrecognized collaborative interaction between MCs and DCs leading to the elicitation of specific immune responses.

Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice.

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2-deficient 129 mice onto the NOD background along with 16 genetic markers (including I-A(g7) MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generation showed that proinsulin 2(-/-) mice develop accelerated insulitis and diabetes. The high prevalence of anti-insulin autoantibodies in proinsulin 2(-/-) mice indicates that diabetes acceleration relates to altered recognition of proinsulin. The prevalence of anti-glutamic acid decarboxylase autoantibodies and of sialitis is not increased in proinsulin 2(-/-) mice. We give evidence that proinsulin 2 expression leads to silencing of T cells specific for an epitope shared by proinsulin 1 and proinsulin 2. In the human, alleles located in the VNTR region flanking the insulin gene control beta cell response to glucose and proinsulin expression in the thymus and are key determinants of diabetes susceptibility. Proinsulin 2(-/-) NOD mice provide a model to study the role of thymic expression of insulin in susceptibility to diabetes.

Altered dendritic cells (DC) might be responsible for regulatory T cell imbalance and autoimmunity in nonobese diabetic (NOD) mice.

Nonobese diabetic (NOD) mice spontaneously develop diabetes, an auto-immune disease characterized by the destruction of insulin-secreting beta-cells by autoreactive T cells. Defects in development and/or functions of dendritic cells (DC) might be critical in eliciting the auto-immune reaction to beta cells in this model. In this paper, DC differentiation in NOD mice was investigated in vitro using bone marrow-derived progenitors (BM-DC) in the presence of GM-CSF and IL-4 or spleen-derived progenitors in the presence of GM-CSF and early acting cytokines such as Flt-3L and IL-6 (SPL-DC). In both culture systems, the absolute number of NOD DC generated was strongly reduced as compared to control strains. In addition, both BM-DC and SPL-DC from NOD mice show defective differentiation into mature DC in conventional culture conditions as indicated by low expression of MHC class II and CD80 molecules among CD11c positive cells and low capacity to stimulate allogeneic T cells. However, DC achieved full maturation when exposed to LPS, except for MHC class II expression that remained decreased. Ex vivo analysis confirmed an unusual phenotype of NOD DC. Both sets of results are thus consistent with a specific defect of DC maturation in these mice.