No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Gleicher, N. & Elkayam, U. Peripartum cardiomyopathy, an autoimmune manifestation of allograft rejection? Autoimmun. Rev. 8, 384-387
Abstract
The timing of peripartum cardiomyopathy (PPCM) in association with pregnancy is typical of autoimmune conditions. This review addresses this fact by presenting PPCM as an organ specific autoimmune response (though not necessarily as an outright autoimmune condition), akin to autoimmune responses seen with complications of allogeneic organ transplantations. Since pregnancy represents a semi-allograft (representing paternal alloantigens), pregnancy and allogeneic organ transplants can be expected to be subject to similar allograft tolerance mechanisms, and also to share potential complications of normal allograft tolerance. This review suggests that PPCM represents a cardio-toxic autoimmune component within a more general immunological malfunction of tolerance of the fetal allograft by the maternal immune system. Treatment of PPCM with therapies, proven successful in graft versus host disease and organ rejection, may, therefore, be successful. Their success would also be confirmatory of such a concept.
... Although beta blockers are associated with low birth weight babies, they are not absolutely contraindicated in pregnancy.37,55 Both beta blockers and ACEI have been shown to suppress immune response in patients with PPCM.5,19,25,51 This may be beneficial considering the increased evidence for autoimmune etiology.2,5,25,28,56 ...
... Proper etiology of PPCM is unclear and several etiologies such as inflammation (myocarditis, cytokines), viral infection, autoimmunity, abnormal response to the hemodynamic stress of pregnancy, cytokine-mediated inflammation, Gq-related myocyte apoptosis, oxidative stress-induced Cathepsin D production which produces defective prolactin leading to endothelial damage and apoptosis of vascular cells, prolonged tocolysis, and selenium deficiency have been proposed.1-11,13,15,16,19,25,28-31,33,35-38,40,46-52 There is stronger literary evidence to support inflammation, viral infection, 16 kDa prolactin induced apoptosis and autoimmunity as possible etiology of PPCM.2,3,5,6,9,13,19,25,27,29-31,33,34,36,37,46-52 Thus, it is more likely that etiology is multifactorial.7,13,25,28,33 ...
... Proper etiology of PPCM is unclear and several etiologies such as inflammation (myocarditis, cytokines), viral infection, autoimmunity, abnormal response to the hemodynamic stress of pregnancy, cytokine-mediated inflammation, Gq-related myocyte apoptosis, oxidative stress-induced Cathepsin D production which produces defective prolactin leading to endothelial damage and apoptosis of vascular cells, prolonged tocolysis, and selenium deficiency have been proposed.1-11,13,15,16,19,25,28-31,33,35-38,40,46-52 There is stronger literary evidence to support inflammation, viral infection, 16 kDa prolactin induced apoptosis and autoimmunity as possible etiology of PPCM.2,3,5,6,9,13,19,25,27,29-31,33,34,36,37,46-52 ...
Peripartum cardiomyopathy (PPCM) is a rare entity, and anesthetic management for cesarean section of a patient with this condition can be challenging. We hereby present the anesthetic management of a patient with PPCM complicated with preeclampsia scheduled for cesarean section, along with a mini review of literature. A 24 year-old primigravida with twin gestation was admitted to our hospital with severe PPCM and preeclampsia for peripartum care, which finally required a cesarean section. Preoperative optimization was done according to the goal of managing left ventricular failure. Combined spinal epidural (CSE) anaesthesia with bupivacaine and sufentanil was used for cesarean section under optimal monitoring. The surgery was completed without event or complication. Postoperative pain relief was adequate and patient required only one epidural top up with sufentanil 6 hours after operation. To the best of our knowledge there is no report in literature of the use of sufentanil as a neuraxial opioid in the anesthetic management of cesarean section in a patient with PPCM. CSE with sufentanil may be a safer and more effective alternative in such cases.
... Several pathophysiological mechanisms have been proposed for the development of PPCM, including pregnancy-induced cardiac overload consisting of hypervolemia, elevated heart rate, and thrombophilia. But recent evidence suggests that some PPCM patients may have the same presentations as familial dilated cardiomyopathy (DCM) since HDP usually presents with LV diastolic dysfunction and may not lead to LV systolic dysfunction found in PPCM [2,[27][28][29]. ...
Peripartum cardiomyopathy (PPCM) is a diagnosis of exclusion and a heterogeneous disorder that presents during the last month of pregnancy or the first five months postpartum. It is a rare but potentially life-threatening illness. A lot of work has been done trying to discover the causes of this condition, and several risk factors have been identified, including hypertension during pregnancy (HDP), ethnicity, advanced age, and multiple gestations. HDP affects 40% of cases of PPCM, and the strength of the association increases with increasing severity of hypertension. Among PPCM patients, there is a 1.5 times higher prevalence of HDP and a four-fold higher prevalence of preeclampsia (PE). Besides, the risk of PPCM markedly increases among women with HDP (5-21 times) compared with normotensive women. The experimental work done in animal models has provided support for the angiogenic-imbalance theory proposed regarding the association between these two conditions. The presence of the same risk factors also supports the prevalence of the coexistence of PE and PPCM. During the last part of gestation, the placenta secretes more anti-angiogenic factors, which leads to the development of both PE and PPCM. However, not all patients with HDP develop PPCM. In fact, most PPCM patients do not show any signs of HDP. Further work in these patients elucidated that there is an underlying susceptibility in some women that predisposes them to develop this condition and results in a worse prognosis as compared with those PPCM patients who have HDP. Better provision of care, genetic variations, and association with HDP have been cited as some of the factors affecting prognosis. HDP has also been found to increase the risk of other forms of cardiomyopathies in the future. A lot of work still needs to be done to uncover all the pathologic mechanisms and genetic variations involved in this disorder. More intensive and focussed research may help in developing new therapies to better manage this condition and address all of its complications.
... The timing of the most common presentation in the early postpartum period suggests an autoimmune component, most likely related to the cessation of the need for fetal tolerance and the resetting of maternal cellular immunity. 167 Viral causes and nutritional deficiency could play a significant role, particularly in areas of the world such as those with very high incidence. 163 Genetic predisposition and familial syndromes have been recognized in women with PPCM, with a similar rate to that seen in other forms of primary nonischemic DCM. ...
DCM is an important cause of HF. Characterized by the common phenotype of ventricular dilation and depressed myocardial performance, its pathogenesis varies significantly, ranging from metabolic, endocrine,autoimmune, rheumatologic, infiltrative, genetic, and infectious causes to cardiotoxins. The rapidly expanding field of molecular genetics and diagnostic and biomarker strategies will likely allow us to capture an even better understanding of how cardiomyopathies develop.Demographics and treatment also vary significantly according to the cause. Treatment should be individualized and should target the underlying cause, in addition to the standard systolic HF therapies. In certain cases,with elimination of the cause and the appropriate treatment,reversal of myocardial remodeling and recovery of cardiac dysfunction can occur. Although current clinical research strategies usually target systolic HF as a group, future studies targeting specific cardiomyopathies will be critical for detection and treatment of specific cardiomyopathies.
... Autoimmune processes in the pathophysiology of PPCM have been a lingering matter of debate [1,11]. However, profound mechanistic and clinical evidence to support this concept are scarce. ...
Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related maternal heart failure that develops towards the end of pregnancy or in the months following delivery. In small retrospective case series, autoimmune responses in the pathogenesis of PPCM have been proposed upon identification of autoantibodies (AABs) to cardiac antigens. However, their clinical and prognostic relevance still remain unclear. In this study, we evaluated the presence of circulating AABs against cardiac sarcomeric myosin (MHC) and troponin I (TnI) in the sera of PPCM patients and in relation to clinical presentation. In this case-control study, 70 patients diagnosed with PPCM and 50 pregnancy-matched healthy women with normal cardiac function were enrolled. Clinical assessment, echocardiography and blood tests were performed at baseline and at 6 ± 2 months follow-up. The presence of serum AABs against MHC (anti-MHC) and TnI (anti-TnI) was determined with a custom-made enzyme-linked immunosorbent assay (ELISA). The seropositivity for these AABs was correlated with the severity of LV dysfunction and the occurrence of pericardial effusion indicative of perimyocardial inflammation at baseline. Potential impact of these AABs on disease progression was evaluated with regard to functional (left ventricular ejection fraction) and clinical improvement at follow-up. Either anti-MHC or anti-TnI or both AABs were detected in the serum of 46 % of PPCM patients and in 8 % of healthy controls. In PPCM the presence of either one of these AABs was associated with significantly lower baseline LVEF and lower rate of full cardiac recovery at follow-up. Patients who were seropositive for anti-TnI AABs showed more frequently pericardial effusion indicative of a more pronounced immune response of the peri-/myocardium in these patients. Further studies are required to clarify cellular and molecular circuits leading to elevated levels of AABs and their pathophysiological relevance for disease initiation and progression in PPCM.
... The clinical presentation is similar to that of other forms of nonischemic cardiomyopathy, with the onset in the later part of pregnancy or the first few months postpartum (7). Although the etiology remains uncertain, an autoimmune inflammatory pathogenesis triggered by fetal or placental antigens has been suspected (8,9). More recently, both genetic (10,11) and vascular (12) etiologies have been postulated to play a significant role. ...
Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality.
This study sought to prospectively evaluate recovery of the left ventricular ejection fraction (LVEF) and clinical outcomes in the multicenter IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study.
We enrolled and followed 100 women with PPCM through 1 year post-partum. The LVEF was assessed by echocardiography at baseline and at 2, 6, and 12 months post-partum. Survival free from major cardiovascular events (death, transplantation, or left ventricular [LV] assist device) was determined. Predictors of outcome, particularly race, parameters of LV dysfunction (LVEF), and remodeling (left ventricular end-diastolic diameter [LVEDD]) at presentation, were assessed by univariate and multivariate analyses.
The cohort was 30% black, 65% white, 5% other; the mean patient age was 30 ± 6 years; and 88% were receiving beta-blockers and 81% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The LVEF at study entry was 0.35 ± 0.10, 0.51 ± 0.11 at 6 months, and 0.53 ± 0.10 at 12 months. By 1 year, 13% had experienced major events or had persistent severe cardiomyopathy with an LVEF <0.35, and 72% achieved an LVEF ≥0.50. An initial LVEF <0.30 (p = 0.001), an LVEDD ≥6.0 cm (p < 0.001), black race (p = 0.001), and presentation after 6 weeks post-partum (p = 0.02) were associated with a lower LVEF at 12 months. No subjects with both a baseline LVEF <0.30 and an LVEDD ≥6.0 cm recovered by 1 year post-partum, whereas 91% with both a baseline LVEF ≥0.30 and an LVEDD <6.0 cm recovered (p < 0.00001).
In a prospective cohort with PPCM, most women recovered; however, 13% had major events or persistent severe cardiomyopathy. Black women had more LV dysfunction at presentation and at 6 and 12 months post-partum. Severe LV dysfunction and greater remodeling at study entry were associated with less recovery. (Investigations of Pregnancy Associated Cardiomyopathy [IPAC]; NCT01085955).
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
... Like Gleicher has pointed out in a number of publications, these unexplained conditions of pregnancy exhibit characteristics similar to immunological conditions observed in organ transplant rejection [28] and/or graft versus host disease (GVHD) [29], therefore ICP may represent the complications of normal tolerance of the fetal semi-allograft by the maternal immune system [30]. Herein, our microarray results revealed that genes associated with immune response, CXCL6, CXCL14 and IL-7R were up-regulated in mild ICP and further up-regulated in severe ICP, while CCL3 and CCL25 were only up-regulated in severe ICP, which suggest that abnormal immune response in patients’ placentas might be positively correlated to the severity of ICP. ...
Background
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP.
Methods
Thirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10–40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining.
Results
The core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas.
Conclusions
Our study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.
Objective
The relationship between anti-SSA/RO antibodies and pregnancy has been reported previously, and we aim to visualize the rates of maternal and infant outcomes with anti-SSA/RO.
Methods
We systematically searched records from Pubmed, Cochrane, Embase, and Web of Science databases, pooled incidence rates of adverse outcomes of pregnancy, and 95% confidence intervals (CIs) were performed with RStudio.
Results
A total of 890 records comprising 1675 patients and 1920 pregnancies were searched from the electronic databases. For maternal outcomes, the pooled estimate rates were 4% for termination of pregnancy, 5% for spontaneous abortion, 26% for preterm labor, and 50% for cesarean operation. While for fetal outcomes, the pooled estimate rates were 4% for perinatal death, 3% for intrauterine growth retardation, 6% for endocardial fibroelastosis, 6% for dilated cardiomyopathy, 7% for congenital heart block, 12% for congenital heart block recurrence, 19% for cutaneous neonatal lupus erythematosus, 12% for hepatobiliary disease and 16% for hematological manifestations. A subgroup analysis of congenital heart block prevalence was performed, diagnostic method and study region were found to affect heterogeneity to some extent.
Conclusion
Cumulative analysis of data from real-world studies confirmed adverse pregnancy outcomes of women with anti-SSA/RO, serves as a reference and a guide for the diagnosis and subsequent treatment of these women, thereby enhancing maternal and infant health. Additional studies with real-world cohorts are required to validate these results.
Clinical Case
• Download : Download full-size image
A 72-year-old female is referred for further management of heart failure with reduced ejection fraction (25%) secondary to nonischemic cardiomyopathy, which was diagnosed 2 years prior. The patient has a history of hypertension and obesity. Her blood pressure is 120/80 and her heart rate is 75 bpm. She has edema on her lower extremities but an otherwise normal cardiovascular exam. She complains of fatigue and dyspnea with activities of daily living and with ambulating around her home. Review of systems is also positive for depressive symptoms, including lack of energy, insomnia, and decreased interest in activities. Her medications include carvedilol 25 mg twice daily, lisinopril 40 mg daily, and spironolactone 12.5 mg daily. Laboratory studies including electrolyte panel are within normal limits. Her electrocardiogram shows normal sinus rhythm at a rate of 75 bpm with a left bundle branch block and QRS interval of 150 ms. A prior ischemic evaluation was negative, and a cardiac magnetic resonance imaging study confirmed dilated cardiomyopathy. How would you manage this patient? Would your management strategy be different if this was a 72-year-old man?
Abstract
Heart failure (HF) with reduced ejection fraction (HFrEF), defined as clinical signs and symptoms of volume overload and/or low cardiac output with an ejection fraction (EF) of ≤ 40%, affects an estimated 3.5 million patients in the United States. Women account for 36% of this population. Studies in the last decade have highlighted differences between women and men with HFrEF involving multiple aspects of the syndrome including epidemiology, pathophysiology, outcomes, and treatment. Women with HFrEF have fewer comorbidities, lower rates of hospitalization, and superior survival compared to men, but they also experience more symptoms, poorer functional status, and worse health-related quality of life (HRQOL). While disparities in the prescription of guideline-directed medical therapy (GDMT) have narrowed somewhat, women are still undertreated with diuretics and devices, and are less likely to be referred to disease management programs. Further, women remain significantly underrepresented in clinical HF trials, limiting available data guiding potential sex-specific clinical approaches. These differences in presentation, outcomes, and treatment are likely secondary to both biological and psychosocial factors. This chapter will outline important sex-specific differences in HFrEF while also addressing gaps in the literature and future directions.
This chapter details the etiologies and treatment for both viral and nonviral myocarditis. The pathogenesis of viral cardiomyopathies in murine models, and the typical clinical presentations are outlined. The role of antiviral therapy and immunosuppressive therapy are discussed, and previous clinical trials are reviewed. The emerging role of genetic background in predicting outcomes and targeting therapeutics is discussed.
Background
Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening complication of pregnancy. There is limited data regarding the predictors of persistent left ventricular (LV) systolic dysfunction. Recently, monocyte-to-high density lipoprotein (HDL) cholesterol ratio (MHR) has emerged as a novel indicator of inflammation and oxidative stress. We aimed to assess the predictive value of MHR on LV recovery in patients with PPCM.
Methods
A total of 64 patients with PPCM who admitted to our tertiary reference hospital between 2009 and 2017 were retrospectively analyzed in this study. Demographic and clinical data, laboratory parameters and echocardiographic findings were recorded. The duration of follow-up was at least 12 months after diagnosis for all participants. Recovery of LV systolic function was defined as the presence of LV ejection fraction (LV EF) > 45%. Univariate analysis was used to determine the significant predictors of persistent LV systolic dysfunction (non-recovery). A receiver operating characteristic (ROC) curve was used to establish the cut-off values for predictors.
Results
The mean follow-up duration was 72.1 ± 5.5 months. Of the 64 patients, 35 (55%) had persistent LVSD at their last follow-up while 29 (45%) showed LV EF improvement. The baseline MHR levels were significantly higher in the non-recovery group (P < 0.001). In univariate analysis, increased MHR levels (odds ratio:1.17; 95% confidence interval, 1.01–1.35; P < 0.001) significantly predicted LV non-recovery. Using a cut-off level of 9.73, MHR predicted persistent LV systolic dysfunction with a sensitivity of 89% and specificity of 79%. Besides, lower baseline LVEF increased WBC and CRP levels were identified as predictors of LV non-recovery.
Conclusions
Our data firstly indicated that elevated MHR was a significant predictor of persistent LV systolic dysfunction in PPCM. The MHR might contribute to determining high-risk patients with PPCM.
Peripartum cardiomyopathy (PPCM) is an uncommon complication of pregnancy. Early case reports identified overlap between familial dilated cardiomyopathy (DCM) and PPCM, although the degree of overlap is largely unknown. Other evidence supporting a contribution from gene mutations in PPCM includes familial occurrence, genome-wide association studies, variable prevalence among different regions and ethnicities, and more recent investigations of panels of genes for mutations among women with PPCM. Murine models implicate the role of altered metabolism and increased free radical stress to the heart during pregnancy, which seems to be involved in the pathogenesis of this condition. Although the true incidence of genetic cardiomyopathy is not yet known among women with PPCM, there is substantial evidence demonstrating that at least 10–15% of affected women have a clear genetic contribution to their condition. With this in mind, family counseling, cascade phenotypic screening, and clinical genetic testing should be considered among women with PPCM.
Peripartum cardiomyopathy (PPCM) is a rare, but life-threatening condition that occurs during the peripartum period in previously healthy women. Although its etiology remains unknown, potential risk factors include hypertensive disorders during pregnancy, such as preeclampsia, advanced maternal age, multiparity, multiple gestation, and African descent. Several cohort studies of PPCM revealed that the prevalence of these risk factors was quite similar. Clinically, approximately 40% of PPCM patients are complicated with hypertensive disorders during pregnancy. Because PPCM is a diagnosis of exclusion, heterogeneity is a common element in its pathogenesis. Recent genetic research has given us new aspects of the disease. PPCM and dilated cardiomyopathy (DCM) share genetic predisposition: 15% of PPCM patients were found to have genetic mutations that have been associated with DCM, and they showed a lower recovery rate. Other basic research using PPCM model mice suggests that predisposition genes related to both hypertensive and cardiac disorders via angiogenic imbalance may explain common elements of hypertensive disorders and PPCM. Furthermore, hypertensive disorders during pregnancy are now found to be a risk factor of not only PPCM, but also cardiomyopathy in the future. Understanding genetic variations allows us to stratify PPCM patients and to guide therapy.
An increased cardiovascular morbidity and mortality have been linked with overt and subclinical hyperthyroidism. These findings might be the consequence of the increased risk of atrial fibrillation, embolic events, heart failure, and coronary disease observed in the presence of thyroid hormone excess. A specific autoimmune cardiovascular involvement has been reported in patients with Graves’ disease. Pulmonary hypertension, cardiac valve disease, and dilated cardiomyopathy represent important risk factors, which may play an important role in determining the poor cardiovascular outcome reported in autoimmune hyperthyroidism. The correction of overt and subclinical hyperthyroidism should be the first step in improving the prognosis of hyperthyroid patients with cardiovascular complications.
Objective:
The objective of our study was to evaluate the prevalence of abnormal maternal echocardiographic findings in triplet pregnancies presenting with dyspnoea.
Study design:
Between 2003 and 2013, patients' records of 96 triplet pregnancies at our department were analysed including maternal and fetal outcome, echocardiographic parameters and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. After exclusion of triplet pregnancies with fetal demise before 23 + 0 weeks, selective feticide or missing outcome data, the study population consisted of 60 triplet pregnancies. All women with dyspnoea underwent echocardiography and measurement of NT-proBNP.
Results:
Dyspnoea towards the end of pregnancy was observed in 13.3 % (8/60) of all women with triplet pregnancies, and all of these women underwent echocardiography. The prevalence of abnormal echocardiographic findings in women with dyspnoea was 37.5 % (3/8) with peripartum cardiomyopathy in one woman. Median serum NT-proBNP was significantly higher in women with abnormal echocardiographic findings compared with those without (1779 ng/ml, range 1045-6076 ng/ml vs 172 ng/ml, range 50-311 ng/ml; p < 0.001 by Mann-Whitney-U Test).
Conclusion:
We conclude that triplet pregnancies presenting with dyspnoea show a high prevalence of abnormal echocardiographic findings. Since dyspnoea is a common sign in triplet pregnancies and is associated with a high rate of cardiac involvement, echocardiography and evaluation of maternal NT-proBNP could be considered to improve early diagnosis and perinatal management.
Women with cardiomyopathy are at risk for complications during and after pregnancy if they are unable to adapt to the hemodynamic changes of pregnancy. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients which can result in clinical decompensation with overt heart failure, arrhythmias, and even maternal death. A multidisciplinary approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Preconception planning, proper counseling, and accurate risk assessment are essential and should be offered to women of childbearing age. In this chapter, the risk assessment of pregnancy in women with cardiomyopathy will be reviewed. In addition, the management of pregnant women with cardiomyopathies and heart failure will be discussed including consideration of issues at the time of labor and delivery.
Current recommendations do not discourage pregnancy in stable, orthotopic heart transplant (OHT) recipients who are more than 1 year posttransplant, although a highly specialized level of care with a multidisciplinary team is recommended. These patients may incur significant risk to themselves, their allograft, and/or their fetuses. Recognition and treatment of posttransplant complications in pregnancy also may be difficult. Although the risk of recurrent pregnancies in patients with peripartum cardiomyopathy (PPCM) is well defined, the risk of pregnancy after a PPCM patient has undergone OHT is unknown. A case of severe allograft rejection in a woman with a history of PPCM who became pregnant nearly 3 years after OHT is presented and her subsequent management is described. The data available on pregnancy after transplant are based on case reports, registry data, and reviews. The decision to become pregnant should be preceded by an extensive discussion including the patient, her partner, her obstetrician, and the transplant team, reviewing potential risks to her health as well as to her allograft and the fetus. Providers should be clear that many questions pertaining to pregnancy after transplant remain unanswered, and the patient should be comfortable going forward in this situation.
Aim. To identify the most promising epitopes that simulate various sites ^1 -adrenergic and M2-cholinergic receptors, and to evaluate their possible contribution to the development and maintenance of cardiac arrhythmias, particularly idiopathic ventricular arrhythmia. Material and methods. Patients with ventricular arrhythmias without organic cardiovascular disease (the study group; n=70) were included in the study. The control group consisted of 20 healthy volunteers. Evaluation of levels of antibodies to antigenic determinants, modeling various sites в -adrenergic and M2-cholinergic performed in all patients. Causal treatment with clarithromycin and valacyclovir performed in part of patients. Results. Antibodies to different peptide sequences of в -adrenergic and M2-cholinergic receptors have been identified in 25% of main group patients. A direct correlation between the frequency of episodes of ventricular tachycardia and IgG levels to MRI-MRIV (p=0.02) revealed. Increase in titre of antibodies to в -adrenoceptors, to a peptide sequence |38 (p=0.02), and lower titers of antibodies to the M2 acetylcholine receptor - chimera MRI-MRIV IgM (p=0.06) and ARI-MRIV IgM (p=0.07) were observed when assessing the efficacy of the therapy in the causal dynamics in the group of "untreated" patients. IgG titer reduction of ARI-MRIV (p=0.02), which is 4 times out of 10 with reduction of ventricular ectopic activity, recorded after valacyclovir therapy. Clarithromycin therapy on the level of antibodies exerted no significant effect. Conclusion. Possible involvement of antibodies to |3 radrenoceptor and M2-cholinergic receptors in the development of idiopathic ventricular arrhythmias demonstrated. The relationship between the frequency of episodes of ventricular tachycardia and levels of antibody titers to ^-cholinergic receptors found. Attempt of causal treatment, depending on the possible mechanisms of the autoimmune process is executed. Further studies to confirm or refute the results to the larger sample of patients are needed.
Offspring of women with anti-SSA/Ro - SSB/La antibodies are believed at risk for congenital heart block (CHB). Whether this risk can be reduced, and what constitutes standard of care treatment is, however, unclear. Objective of this review therefore was to determine whether currently proposed standard of care treatments to avoid CHB in offspring of mothers at risk are evidence-based. To do so, we conducted a review of the literature under appropriate key words and phrases in Medline/PubMed and Google Scholar for years 2000-2013. Reference lists were further reviewed, and relevant manuscripts were pulled. We also reviewed www.clinicaltrials.gov for registered studies. In absence of randomized prospective clinical trials, a meta-analysis was not feasible. We, therefore, reviewed lower evidence level studies individually. Risk of CHB actually appears more closely associated with general autoimmunity than, specifically, with SSA/Ro - SSB/La antibodies. This and other observations raise questions whether CHB is caused by passively transferred maternal autoimmunity, as is currently widely believed. Observational studies suggest possible effectiveness of intravenous gamma globulin (IV-Ig) and hydroxychloroquine (Plaquenil) in reducing CHB-risk. Evidence for both is, however, inconclusive, and studies are biased in favor of hydroxychloroquine and against IV-Ig. Based on review of the literature, current evidence of effectiveness for any treatment has to be judged as insufficient. Amongst available treatment options, some considerations favor IV-Ig over hydroxychloroquine or, alternatively, suggest treatment with IV-Ig periconceptionally and into early gestation, with hydroxychloroquine added or replacing IV-Ig at approximately 10 weeks gestational age. Benefits for the utilization of steroid drugs are unclear. Since no treatment can be considered as established, prevention of CHB in offspring should be considered experimental, and performed under appropriate study conditions.
Left ventricular assist device (LVAD) support as bridge to recovery (BTR) is uncommon for subjects with chronic heart failure. Myocardial recovery is more evident in recent onset nonischemic cardiomyopathy (ROCM); however, the prevalence of BTR in this subset has not been addressed.
We examined the use of LVAD support for subjects with ROCM in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) study. The overall cohort (n = 373) was 38% female, 21% black, with a mean age of 45 ± 14 years. LVAD support was used in 3.8% (n = 14, 43% female, age 32 ± 10). Of LVAD subjects, 57% (8/14) were BTR, including 73% (8/11) of subjects with symptoms ≤4 months at the time of support. Left ventricular end-diastolic diameter (LVEDD) was smaller in BTR than nonrecovered (NR) subjects (P = .04). Myocardial inflammation was more common in BTR (75% versus 0%, P = .005), whereas fibrosis was less evident (25% versus 100%, P = .005). Of BTR subjects, 7/8 (87.5%) were alive and free of transplant with median follow-up of 19 months.
In a multicenter registry of ROCM, BTR was common and occurred in the majority of subjects requiring LVAD support. Histology and LVEDD may assist in predicting potential for BTR in ROCM.
Nearly 25% of patients with peripartum cardiomyopathy (PPCM) will require cardiac transplantation. Whether post-transplant outcomes differ among patients with PPCM compared with other recipients remains unsettled.
The United Network for Organ Sharing database was queried for cardiac transplants, comparing characteristics and outcomes for PPCM, other women, and all others.
Between 1987 and 2010, 42,406 patients (9,419 women and 32,987 men) received a heart transplant. Of these, 485 women who had PPCM as the indication were younger (p < 0.001), had higher sensitization (p < 0.001), required higher intensity of cardiovascular support pre-transplant (p = 0.026), and had higher listing status (p < 0.001). Those with PPCM had more post-transplant rejection during the index transplant hospitalization (p < 0.001) and during the first year (p = 0.003). Comparing PPCM with other women and all others, graft survival was inferior (p = 0.004 and p < 0.003, respectively) and age-adjusted survival was lower (p < 0.001 and p = 0.02, respectively).
This large report shows outcomes of graft failure and death are inferior for recipients with PPCM, which may be partly explained by younger age, higher allosensitization, higher pre-transplant acuity, and increased rejection. More research is needed to determine management strategies to improve outcomes in PPCM heart transplant recipients.
Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry.
IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002).
Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months.
To estimate the incidence, describe the mortality, and identify independent predictors of peripartum cardiomyopathy, a very serious cardiovascular complication of pregnancy associated with maternal morbidity and mortality among otherwise healthy women without prior heart disease.
We identified all cases of diagnosed heart failure that occurred among women within 1 month before to 5 months after delivery of a liveborn neonate in Kaiser Permanente Northern California delivery hospitals between 1995 and 2004. Incident peripartum cardiomyopathy was confirmed from medical records documenting dilated cardiomyopathy with reduced left ventricular systolic function after excluding women with prior heart failure or valvular disease. Data sources included medical records, electronic clinical databases, and state birth and death files.
Among 227,224 eligible women, we confirmed 110 recognized peripartum cardiomyopathy cases (incidence: 4.84 per 10,000 live births, 95% confidence interval 3.98-5.83). Independent predictors included maternal age of 25 years or older, non-Hispanic African American and Filipino groups, parity of 4 or greater, multiple gestation, severe anemia, pre-existing and pregnancy-related hypertensive disorders, and hemolysis, elevated liver enzymes, low platelets syndrome. Maternal death rate (per 1,000 person-years) was higher among cases (6.12) than noncases (0.23; P<.001). Neonates whose mothers developed peripartum cardiomyopathy experienced poorer clinical outcomes.
Within a large, diverse northern California population, 1 of every 2,066 women delivering a liveborn neonate had recognized, confirmed peripartum cardiomyopathy, which was associated with higher maternal and neonatal death rates and worse neonatal outcomes. Several readily available patient characteristics can be used to identify women at risk for this severe pregnancy complication.
II.
To varying extents, women with pre-existing cardiomyopathies have a limited cardiovascular reserve. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients, which can result in clinical decompensation with overt heart failure, arrhythmias, and rarely, maternal death. A multidisciplinary team approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Pre-conception planning and risk assessment are essential, and proper counseling should be offered to expectant mothers with regard to both the risks that pregnancy poses and the implications for future offspring. In this article, we will review the hemodynamic stressors that pregnancy places upon women with pre-existing cardiomyopathies and risk assessment and discuss what evidence exists with regard to the management of 2 forms of cardiomyopathy during pregnancy, labor, and delivery: dilated and hypertrophic cardiomyopathy.
There, likely, is no more controversial issue in reproductive medicine than the effects of autoimmunity on female reproductive success. Published studies are, therefore, often biased. We performed PubMed, Google Scholar and Medline searches for the years 2000-2010 under various key words and phrases, referring to effects of autoimmunity/autoimmune diseases on pregnancy/pregnancy outcomes/pregnancy rates/reproduction/reproductive outcomes/fertility/infertility/fertility treatments/infertility treatments, and a number of similar terms. Reference lists of selected manuscripts were evaluated for additional, potential references. All selected manuscripts were reviewed by at least one author (N.G.). Opinions were reached based on preferential review of only selected studies, which offered data, primarily developed in pursuit of unrelated scientific questions. Data from various medical fields point, surprisingly effectively, toward significant impacts of autoimmunity on female reproductive success. Autoimmunity not only increases miscarriage risks but also reduces female fecundity and infertility treatment success. A, likely, reason why differences of opinion have persisted is that effects are primarily observed in genetically predisposed women, with specific fragile X mental retardation 1 (FMR1) genotypes. This discovery coincides with recently increasing appreciation of the importance of the long arm of the X chromosome (Xq) in control of functional ovarian reserve (reflective of female fertility) and autoimmunity, with FMR1at Xq27.3, located at cross roads of both. Autoimmune effects on female reproductive success deserve recognition. Further investigations must not ignore patient stratification, based on ovarian FMR1 genotypes. Genetic definition of high-risk patients should lead to development of successful therapeutic interventions.
Background:
There has been no nationwide survey concerning peripartum cardiomyopathy (PPCM) among the Asian population, and clinical profiles of PPCM complicated with hypertensive disorders complicating pregnancy (HD) as the major risk factor of PPCM have not been characterized.
Methods and results:
A retrospective, nationwide survey of PPCM in 2007 and 2008 all over Japan was performed and the clinical characteristics were compared between patients with and without HD. We obtained data for 102 patients. HD during pregnancy occurred in 42 patients (41%). Patients with HD were older than those without HD (33.8 vs. 31.9 years old, P<0.05) and babies were delivered more frequently by Caesarean section (81% vs. 52%, P<0.01). Although cardiac parameters at diagnosis were similar in patients with and without HD, patients with HD were hospitalized for a shorter period and had better cardiac function after 7 months. Multivariate regression analysis revealed that HD was independently associated with a shorter hospital stay and a higher left ventricular ejection fraction at last follow up.
Conclusions:
PPCM complicated with HD had different clinical characteristics from those without HD. This condition might be a unique subset of PPCM that is characterized by relatively swift recovery except in the cases of death. In order to prevent severe heart failure and maternal death, peripartum women should be treated with HD cautiously and must immediately undergo a cardiac examination as needed.
Pregnancy represents a semi-allograft, subject to similar immune responses as allogeneic organ transplants. Tolerance of pregnancy appears best with maximal class II HLA heterogeneity between mother and father, while compatibilities are associated with increased pregnancy loss and maternal autoimmunity. Tolerance abnormalities often involve skin reactions. Abnormalities in tolerance of the fetal graft may do the same.
To define the characteristics of a newly described dermatosis in very early pregnancy.
Prospective case series of 7 couples/12 clinical episodes.
The dermatosis was observed in 7 out of 285 women undergoing in vitro fertilization (IVF; 2.5%; 95% CI 0.66-4.26%) and in 12 out of 277 total IVF cycles reaching embryo transfer (4.3%; 95% CI 1.93-6.73%). Prior to IVF all women reported autoimmune clinically significant allergies. All but 1 couple demonstrated class II HLA compatibility. Two of 4 pregnancies miscarried. All rashes erupted within days from embryo implantation.
The 'implantation rash' reported here is uncommon but not rare. It may be the consequence of abnormal maternal immune responses to embryo implantation in women with prior immune activation, associated with class II HLA compatibility between parents. Further prospective studies are required to better define this condition.
Autoimmune response against myocardial antigens is evident in numerous heart diseases. Both the induction of an autoimmune response and the pathogenesis of autoimmune heart diseases are not fully understood. The humoral immune response may play an important role via induction of cardiomyocyte apoptosis, alteration of myocardial mechanical and electrophysiological functions, and activation of the complement system and cell-mediated cytotoxicity. Anti-β-1 adrenergic receptor antibodies appear to contribute to the pathogenesis of dilated cardiomyopathy, heart failure, and Chagas disease. Herein, we review the current knowledge relating to anti-β-1 adrenergic receptor antibodies: their potential role in heart diseases and the potential benefits of a targeted therapy against their apparently destructive effects. Patients with dilated cardiomyopathy with circulating stimulatory anti-β-1 adrenergic receptor autoantibodies are probably at a higher risk for adverse outcome and should be treated with adrenergic receptor antagonists, and possibly with immunotherapy. Further research is required to determine which patients will gain additional clinical benefits from anti-autoantibody-targeted therapy.
Various clinical disorders can cause hyperthyroidism, the effects of which vary according to the patient's age, severity of clinical presentation and association with other comorbidities. Hyperthyroidism is associated with increased morbidity and mortality from cardiovascular disease, although whether the risk of specific cardiovascular complications is related to the etiology of hyperthyroidism is unknown. This article will focus on patients with Graves disease, toxic adenoma and toxic multinodular goiter, and will compare the cardiovascular risks associated with these diseases. Patients with toxic multinodular goiter have a higher cardiovascular risk than do patients with Graves disease, although cardiovascular complications in both groups are differentially influenced by the patient's age and the cause of hyperthyroidism. Atrial fibrillation, atrial enlargement and congestive heart failure are important cardiac complications of hyperthyroidism and are prevalent in patients aged > or = 60 years with toxic multinodular goiter, particularly in those with underlying cardiac disease. An increased risk of stroke is common in patients > 65 years of age with atrial fibrillation. Graves disease is linked with autoimmune complications, such as cardiac valve involvement, pulmonary arterial hypertension and specific cardiomyopathy. Consequently, the etiology of hyperthyroidism must be established to enable correct treatment of the disease and the cardiovascular complications.
La miocardiopatía periparto no es una patología frecuente; sin embargo, presenta una alta tasa de mortalidad, elevándose aún más cuando el diagnóstico y el tratamiento no se realizan en forma temprana. En el año 1937, se describe que la causa de la falla cardíaca en las pacientes con estas características se debía a una cardiopatía dilatada, diferente de la cardiopatía generada por el estrés del embarazo. Desde ese momento, se reconoce a la miocardiopatía periparto como una entidad distinta del resto de las cardiomiopatías. El objetivo de los autores de esta actualización es principalmente realizar una descripción de los mecanismos involucrados en la fisiopatología, las manifestaciones clínicas, el diagnóstico y el tratamiento de esta enfermedad.
Extensive research work over the past couple of decades has indicated a series of intricate relations between immune and reproductive systems. A range of reproductive immunology topics including the roles of adoptive and innate immunity in infertility and pregnancy, the immune system's role in induction of labor and preterm delivery, and immuno-modulatory effects of the female sex hormones will be discussed in this and the next issue of the Journal. The implications of this research on the development of novel therapeutic approaches are also addressed.
A recent review of the literature suggested that thyroid autoimmunity is statistically associated with preterm delivery. This observation raises a number of follow-up questions, among them whether autoimmune function, in general, predisposes to premature delivery. A review of the English literature for the last 10 years, via PubMed search, finds strong supportive evidence for such a hypothesis. Since the fetal-placental unit represents a (semi) allograft within a maternal (allograft) recipient, it is reasonable to assume that it is subject to similar immunologic tolerance (and failure thereof) as solid organ transplants. As autoimmune responses represent a normal feature of tolerance failure in organ transplantation, similar autoimmune responses can also be expected with failure of tolerance of the fetal-maternal graft. The association of premature (and possibly also term) labor with autoimmune function may, therefore, be the consequence of abnormalities in normal fetal-placental tolerance, leading to uterine activation and labor.
The objective was to determine whether the frequency of flare in systemic lupus erythematosus (SLE), patients is increased during pregnancy and the puerperium. Seventy-eight pregnancies in 68 SLE patients attending the lupus pregnancy clinic, at St. Thomas' Hospital, during the last 5 yr were included. The pregnancy period and 8 weeks post-delivery were considered. This group was compared with a control group of 50 consecutive, non-pregnant, age-matched SLE patients attending our weekly lupus clinic. Additionally, 43 of the pregnant patients carried on attending the lupus clinic for the year after puerperium, and their course was compared with themselves during pregnancy. SLE activity was assessed using the Lupus Activity Index (LAI) score. An increase > or = 0.26 in the score was considered as a flare of the disease. Pregnancy and control groups were homogeneous for age, race, disease duration and distribution of autoantibodies. Sixty-five per cent of the patients flared during pregnancy and/or the puerperium and 42% flared in the control group (P = 0.015). The rates of flare per patients/month were 0.082 +/- 0.004 for the pregnancy group and 0.039 +/- 0.003 for the control group (P < 0.001). The 43 patients whose course was controlled after the puerperium flared more frequently during pregnancy that thereafter (McNemar test, P = 0.003). The rates of flare per patient/month were 0.093 +/- 0.006 during pregnancy and the puerperium, and 0.049 +/- 0.004 after the puerperium (P = 0.0015). Kidney and central nervous system involvement was not different between the pregnancy and control groups. In terms of frequency of flares, there was no difference in any of the groups between patients taking and not taking steroids. We conclude that SLE tends to flare during pregnancy. Flares are maximal during the second and third trimester and the puerperium. Flares are not more severe than in non-pregnant patients, and most of the flares can be managed conservatively. Prednisolone does not prevent flares.
A 17-year-old male with AML FAB M4 relapsed 4 months after myeloablative conditioning and peripheral blood stem cell transplantation (PBSCT) from an HLA-identical unrelated donor. A second PBSC harvest was infused 2 days after completion of cytoreductive therapy with mitoxantrone 7 mg/m(2)/day i.v. for 3 days (total dose 21 mg/m(2)), fludarabine 30 mg/m(2)/day i.v. for 6 days (total dose 180 mg/m(2)) and Ara-C 125 mg/m(2)/day i.v. for 5 days (total dose 625 mg/m(2)). Neutrophil recovery occurred on day +10 and was associated with GVHD grade III of the skin which was treated with cyclosporin A (CsA) and prednisone. Because of fever of unknown origin and progressive fatigue combined with hypotension on day +15 after second PBSCT, echocardiography was performed which revealed a dramatic decrease in systolic function compared to the status pre-transplant. On the same day acute heart failure with consecutive ventricular fibrillation occurred. Although resuscitation was performed immediately the patient died. The autopsy revealed massive infiltration by donor CD8-positive lymphocytes with concomitant extensive damage of the heart tissue. Acute myocarditis of viral origin was excluded by in situ hybridization and nested PCR techniques. In this patient, myocardial involvement by acute GVHD seems to have triggered a fatal arrhythmia and heart failure.
Peripartum cardiomyopathy (PPCM) is a rare disorder in which left ventricular dysfunction and symptoms of heart failure occur in the peripartum period in previously healthy women. Incidence of PPCM ranges from 1 in 1300 to 1 in 15,000 pregnancies. The etiology of PPCM is unknown, but viral, autoimmune, and idiopathic causes may contribute. The diagnostic criteria are onset of heart failure in the last month of pregnancy or in first 5 months postpartum, absence of determinable cause for cardiac failure, and absence of a demonstrable heart disease before the last month of pregnancy. Risk factors for PPCM include advanced maternal age, multiparity, African race, twinning, gestational hypertension, and long-term tocolysis. The clinical presentation of patients with PPCM is similar to that of patients with dilated cardiomyopathy. Early diagnosis and initiation of treatment are essential to optimize pregnancy outcome. Treatment is similar to medical therapy for other forms of dilated cardiomyopathy. About half the patients of PPCM recover without complications. The prognosis is poor in patients with persistent cardiomyopathy. Persistence of disease after 6 months indicates irreversible cardiomyopathy and portends worse survival.
This paper summarizes recent evidence from transplantation, autoimmune and obstetrical literatures, suggesting that exposure to (allogeneic) donor cell traffic may be prerequisite for successful tolerance of allogeneic grafts in organ transplantation and pregnancy, where the fetus represents a semiallogeneic graft. It is based on a review of the literature utilizing PubMed and Medline searches. Donor cells can induce adverse effects, including graft-versushost disease, acute and/or chronic graft rejection and/or related autoimmune phenomena. Observations in the pre-eclampsia/eclampsia syndrome suggest that some still largely unexplained conditions of pregnancy, possibly including labor, may represent acute graftversus-host disease states. Abnormal clinical and laboratory responses may be the consequence of excessive histocompatibility (HLA) antigen dosaging, due to excessive fetal-maternal cell traffic. On other occasions, antigen dosaging may be appropriate, but maternal/paternal HLA may be too similar. Studies in habitually aborting patients have indicated that underexposure to HLA may induce (auto)immune abnormalities. All of these observations suggest that in a number of currently still poorly understood obstetrical conditions, immunologic treatment options deserve further careful investigation.
When the impact of abnormal autoimmune function on female fertility is objectively examined, an unexpectedly large contribution is (auto)immune related. This may be surprising since many authorities have been dismissive of (auto)immune-associated infertility. In this article, we therefore summarize the link between abnormal autoimmune function and female infertility, based on literature searches. Abnormal autoimmune function affects female fertility at numerous levels of the reproductive process. As with autoimmune conditions in general, abnormal autoimmune function affecting fertility is often difficult to diagnose since it frequently presents subclinically, without overt clinical symptoms. It also demonstrates other characteristics of abnormal autoimmunity, such as familial occurrence and genetic predisposition, environmental cofactors contributing to phenotypic expression of genetic risk and cyclicity of occurrence, often characterized by gestational exacerbation patterns. Proven treatments for autoimmune-associated infertility have not been established to date. This fact should, however, not preclude efforts to reach correct diagnoses, since only accurate diagnoses can lead to appropriately conducted clinical trials.
Part II of this article continues the presentation of evidence in support of the major impact of abnormal autoimmune function on human female reproduction. After concentrating on nonorgan-specific autoimmune conditions in Part I of this series, this article addresses organ-specific autoimmune conditions that cause female infertility. Based on literature searches, autoimmunity to endocrine organs appears to represent a significant cause of female infertility. This autoimmunity can be directed at both nonsteroid- and steroid-producing endocrine organs and can present as single-organ disease or in the form of multiple autoimmune endocrinopathies. As with nonorgan-specific autoimmunity, organ-specific autoimmunity demonstrates typical presentations, which include familial occurrence, genetic predisposition, commonality of occurrence with other autoimmune conditions and transition through pre-/subclinical stages on the way to overt clinical expression. In contrast to nonorgan-specific autoimmune conditions, organ-specific diseases often do not express a cyclical appearance pattern since glandular function, against which the autoimmune response is usually directed, has been exhausted. Particularly in cases where glandular function is affected by the autoimmune attack, the diagnosis of the condition is easier than in many nonorgan-specific autoimmune diseases, since it can be based on organ function and does not necessarily require autoimmune laboratory markers, which in nonorgan- and organ-specific diseases are often only poorly defined.
Evidence of bidirectional cell traffic between fetal and maternal departments is well established in pregnancy. The amount of cell traffic varies, however, with mode of delivery. Maternal-fetal traffic is highest with vaginal and lowest with cesarean section delivery. Fetal-maternal cell traffic follows opposite dynamics. Cell traffic has the potential to establish microchimerism of donor cells within the recipient. The presence of such microchimerism in recipients of cell traffic has been associated by some investigators with the occurrence of autoimmune diseases. Since this association between cell traffic, microchimerism and the development of autoimmune diseases has remained unproven, this article proposes that, if microchimerism is causally connected to the occurrence of autoimmune diseases, the prevalence of autoimmune diseases in offspring should correlate with their mode of delivery. The design of appropriate population studies would seem to be urgent because confirmation of this hypothesis would establish the mode of delivery as a controlling therapeutic modality in preventing autoimmune diseases in offspring.
Twenty-seven patients presented in the puerperium with cardiomegaly, abnormal `ECG, and congestive cardiac failure and were considered to have peripartum cardiomyopathy (PPCM). The incidence of PPCM was significantly higher in women over 30 years of age, in women in their third or subsequent pregnancy, and in the presence of twins or toxemia. Within 6 months, 14 patients had normal sized hearts (group A), and 13 patients maintained cardiomegaly (group B).
The 14 patients in group A have been followed for 3 to 21 years (average 10.7 years). Two have died of unrelated causes. Of the remaining 12, eight are functional class I and four are functional class II. Eight patients had 21 subsequent pregnancies, with no permanent deterioration of cardiac function. Of 13 patients in group B, 11 (85%) have died of congestive cardiac failure. Their average survival was 4.7 years; six of 11 were dead in 3 years. Their clinical course was punctuated by repeated admissions for congestive cardiac failure. Six had pulmonary emboli, one had a systemic embolus, and three of six patients with subsequent pregnancies deteriorated in the puerperium. Of the two surviving patients, one is functional class I and the other is functional class II.
Therefore, in those patients in whom cardiomegaly persisted, the prognosis was poor, and subsequent pregnancies were likely to lead to permanent deterioration. In those in whom the heart size returned to normal the prognosis was excellent.
This study was designed to investigate the organ and disease specificity of antiheart antibodies in patients with dilated cardiomyopathy.
Autoimmune disease is characterized by the presence of circulating autoantibodies, and autoimmune mechanisms may play a role in the pathogenesis of dilated cardiomyopathy.
An SDS-PAGE (sodium dodecylsulfate polyacrylamide gel electrophoresis) procedure followed by Western blotting was used to screen serum samples for antiheart antibodies of two immunoglobulin classes, IgM and IgG, from 52 patients with dilated cardiomyopathy and 48 patients with ischemic heart disease as control subjects. Use of two-dimensional gel electrophoresis followed by Western blotting and protein sequencing enabled us to identify the protein bands against which antiheart antibodies were produced in both groups of patients.
Strong IgG antiheart antibodies against myocardial proteins, cross-reacting with skeletal muscle proteins, were detected in significantly more patients with dilated cardiomyopathy (n = 24 [46%]) than with ischemic heart disease (n = 8 [17%]) (p = 0.001). Patients with dilated cardiomyopathy showed a significantly greater frequency and reactivity of IgG antiheart antibodies against six myocardial proteins (molecular weight 30, 35, 40, 60, 85 and 200 kD) than did patients with ischemic heart disease. These were identified as myosin light chain 1, tropomyosin, actin, heat shock protein (HSP)-60, an unidentified protein and myosin heavy chain, respectively.
We detected strong IgG antiheart antibodies in significantly more patients with dilated cardiomyopathy than with ischemic heart disease. The most immunogenic band was that corresponding to HSP-60. Antibodies against HSP-60 were found in 85% and 42% of patients with dilated cardiomyopathy and ischemic heart disease, respectively, confirming our hypothesis of an immune involvement in dilated cardiomyopathy.
Rheumatoid arthritis frequently remits during pregnancy, for unknown reasons. Since an immune response to paternally inherited fetal HLA can occur during normal pregnancy and since rheumatoid arthritis is an autoimmune disorder with a known HLA class II antigen association, we tested the hypothesis that maternal-fetal disparity in HLA alloantigens might be associated with the pregnancy-induced remission of rheumatoid arthritis.
We studied 57 pregnancies of 41 women with rheumatoid arthritis, 18 prospectively and 39 retrospectively. Serologic and DNA techniques were used to study HLA class I and II antigens. For newborns, typing was performed from cord-blood samples obtained at delivery. For four young children, typing was performed from DNA extracted from hair samples.
We found significantly more maternal-fetal disparity in HLA-DR and DQ antigens in pregnancies characterized by the remission or improvement of rheumatoid arthritis than in pregnancies characterized by active disease. Further studies using DNA-typing techniques to define allelic variants of HLA-DR and DQ antigens confirmed this observation. Maternal-fetal disparity in alleles of HLA- DRB1, DQA, and DQB occurred in 26 of 34 pregnancies characterized by remission or improvement (76 percent), as compared with 3 of 12 pregnancies characterized by active arthritis (25 percent) (odds ratio, 9.7; P = 0.003). The difference between the two groups was most marked for alleles of HLA-DQA.
Amelioration of rheumatoid arthritis during pregnancy is associated with a disparity in HLA class II antigens between mother and fetus. These findings suggest that the maternal immune response to paternal HLA antigens may have a role in the pregnancy-induced remission of rheumatoid arthritis.
Peripartum cardiomyopathy is a rare complication of pregnancy. Thirty percent of patients with this disorder are reported to recover baseline ventricular function within 6 months of delivery, but the ability of these ventricles to respond to hemodynamic stress is unknown. The aim of this investigation was to quantitatively assess the contractile reserve of patients with a history of peripartum cardiomyopathy and recovered left ventricular function.
Baseline left ventricular contractility was assessed by use of the load and heart rate-independent relationship between end-systolic stress and rate-corrected velocity of fiber shortening. Data were acquired from "recovered" patients (10.5 +/- 11.6 months after delivery) and compared with data from matched nonpregnant controls with use of two-dimensionally targeted M-mode echocardiography and calibrated subclavian pulse tracings that were recorded over a wide range of afterloads (end-systolic stress) generated by methoxamine (1 mg/min) infusion. Contractile reserve was assessed by a dobutamine challenge (5 micrograms/kg/min) and quantified as the vertical deviation of the dobutamine end-systolic stress minus the corrected velocity of fiber shortening data point from the baseline contractility line.
Patients with peripartum cardiomyopathy and matched controls had normal baseline heart rates, blood pressures, ventricular dimensions, and left ventricular function. Contractile reserve, however, was reduced in patients with recovered peripartum cardiomyopathy (0.30 +/- 0.12 vs 0.17 +/- 0.04 circ/sec, p < 0.03).
Women with a history of peripartum cardiomyopathy who have regained normal resting left ventricular size and performance have decreased contractile reserve revealed by the use of a dobutamine challenge test. Ventricles of these women may respond suboptimally to hemodynamic stress in spite of evidence of recovery by routine echocardiographic evaluation.
The aetiologies of accelerated or transplant-associated coronary artery disease (TxCAD) following cardiac transplantation and chronic rejection following renal transplantation remain ill-defined. Previous studies have used Western blotting to demonstrate an association between the formation of anti-endothelial (anti-EC) antibodies and TxCAD after heart transplantation. However, Western blotting favours detection of cytosolic proteins. The objectives of this study were to determine whether flow cytometry, a method which detects antigens on the cell surface, could be used to detect anti-EC antibodies and also whether the observations would extend to renal transplant patients with chronic rejection. Flow cytometry was used to look for antibodies reactive with the surface antigens of macrovascular and microvascular endothelial cell lines in sera from 44 cardiac and 35 renal transplant recipients before and after transplantation. In addition, sera from normals (n = 20), patients with nontransplant CAD (n = 50) and patients with unrelated diseases (n = 40) were investigated. Of 23 cardiac recipients who had developed TxCAD at one or two years post-transplant, 61% had IgM and 13% had IgG anti-EC antibodies post-transplantation. In contrast, in 21 cardiac recipients who had not developed TxCAD 14% had IgM and 14% IgG anti-EC antibodies. There was little evidence for the presence of anti-EC antibodies in cardiac recipients before transplantation. Of 26 renal transplant recipients whose transplants failed due to chronic rejection, 42% had IgG and 19% IgM anti-EC antibodies post-transplantation. Of nine renal recipients whose grafts were either functioning normally or who had acutely rejected, none had IgG or IgM anti-EC antibodies either pre- or post-transplantation. The anti-EC antibodies were not found in normals and were rare (less than 4%) in the other disease groups; they do not appear to be autoantibodies. In conclusion, these results suggest the FACS assay could be an informative and rapid test to provide more information on chronic rejection following cardiac and renal transplantation.
Detection of antimyosin antibodies in non-inflammatory cardiac disease undermines their disease specificity as a sensitive marker of damage in dilated cardiomyopathy (DCM) patients. Antibody subclass specificity could provide a more sensitive marker of disease and possibly discriminate the humoral autoimmune responses in different cardiac diseases. Frequency and reactivity of autoantibodies against alpha- and beta-isoforms of myosin heavy chain (mhc) were evaluated by ELISA for IgG, IgM, and subclasses IgG1, IgG2, and IgG3 in patients with DCM (NYHA III/IV, n = 82), end stage ischemic heart disease (E-IHD: NYHA III/IV, n = 62), mild ischemic heart disease (NYHA I/II, n = 27), and controls (n = 54). Autoantibodies against atrial and ventricular myosin were raised in heart failure patients compared to mild-IHD and controls but with different antigen affinities. Reactivity in E-IHD was significantly raised against (ventricular) beta-mhc compared with only mild-IHD patients, suggesting a relative increase in ventricular specific antibodies in IHD patients with a higher NYHA class. IgG subclass analysis for IgG1, IgG2, and IgG3 against alpha- and beta-mhc showed statistically raised levels of IgG3 only in DCM patients and a significantly higher reactivity of IgG2 in heart failure patients versus controls. The results demonstrate immunological heterogeneity of antimyosin antibodies developed in different clinical entities. Pro-inflammatory characteristics of IgG3 antibodies in a select group of patients with DCM may contribute to autoimmune mechanisms of injury in these patients.
Autoimmune thyroid disease (AITD) is suppressed during pregnancy and is exacerbated in the postpartum period. Studies indicate that new-onset AITD occurs in up to 10% of all women in the postpartum period and that up to 60% of Graves' patients in the reproductive years give a history of postpartum onset. Despite this extraordinary epidemiological evidence, the causes of these exacerbations are uncertain and have yet to be adequately investigated. Explaining these postpartum changes, therefore, remains hypothetical. Mechanisms invoked include the passage of fetal cells to the mother during pregnancy establishing maternal microchimerism, pregnancy-induced changes in the thyroid gland itself, and the role of prolactin as a consequence of breast-feeding. Once the disease onset or exacerbation, is established, then there have been considerable advances in our understanding of the immunopathology. Thyroid cell destruction (via apoptosis) or activation (via thyrotropin [TSH] receptor autoantibody induction) appear to be similar to nonpostpartum-related disease. The reasons for the transience in postpartum disease, particularly thyroiditis, is likely to be related to the induction of clonal suicide and the mechanisms for this phenomenon are beginning to be explored. While we have a number of clinical indicators that allow us to predict postpartum thyroid disease (such as autoantibody titers), at present, we have no treatment to prevent the disease. Furthermore, our predictions are not helpful in a high enough proportion of the population to warrant screening of all women before delivery. At this time, the best clinical approach is watchful waiting and postpartum thyroid function testing where suspected.
The study evaluates the clinical course and the development of systolic and diastolic left ventricular function in patients with chronic myocarditis with or without autoantibodies against cardiac myosin.
Patients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available.
Thirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation "tau" and the constant of myocardial stiffness "b" were determined at baseline and at follow-up.
In 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 +/- 10.1%) compared with antibody-positive patients (-0.1 +/- 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 +/- 31 ml; SVI: +10 +/- 17 ml) compared with antibody-positive patients (SV: -14 +/- 43 ml; SVI: -8 +/- 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation "tau" did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness "b" improved significantly in antibody-negative patients (-6.1 +/- 10.8) compared with antibody-positive patients (+7.3 +/- 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results.
Antimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.
To determine whether humoral autoimmune responses associated with dilated cardiomyopathy (DCM) influence the postoperative clinical course following cardiac transplantation.
ELISA levels of preformed cardiac myosin (CM) autoantibodies (Abs) in patients with a pretransplant diagnosis of dilated cardiomyopathy (DCM) (n=64) and ischemic heart disease (IHD, n=53) were correlated with cardiac rejection, immunosuppression, and the incidence of endocardial infiltrates after transplantation.
Alpha- and beta-CM autoantibody (IgG and IgM) levels were similar in DCM and IHD patients but were statistically higher than in controls. Distribution of preformed (beta-CM) IgM-Abs in patients with and without rejection in the first postoperative year differed in the two groups. DCM patients rejected earlier P=0.006, and the frequency of rejection at 3 months was statistically higher than in IHD patients. Frequency and reactivity of IgM-Abs in DCM patients with rejection [International Society for Heart and Lung Transplant (ISHLT) grade I and above] was 28% compared with 7% in rejection-free patients, P<0.05. IgM-positive patients had a greater frequency and severity of rejection episodes and required more immunosuppression. These patients had rejection earlier than Ab-negative patients, P<0.009. There was no correlation between antibody status and rejection in IHD patients or with IgG in either group. Distribution of IgG subclass differed in the two diseases. DCM patients had significantly higher IgG3 reactivity; 70% of this activity was present in patients who developed moderate rejection. IgG3-positive patients experienced more frequent rejections, as well as a greater incidence of grade 3A/B rejection as the first episode, than did Ab-negative patients (50% vs. 15%), P<0.05. Frequency of endocardial infiltrates was statistically higher in IgG3-positive patients.
Proinflammatory characteristics of preformed IgG3 and IgM antibodies in DCM patients may influence the frequency and severity of cardiac rejection after transplantation.
Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Certain categories in patients with dilated cardiomyopathy have shown the presence of humoral and cellular immunity activation suggesting a possible relation between myocarditis and dilated cardiomyopathy. Recent studies suggest a link between the circulating levels of cytokines (TNF alpha IL-1 et IL-6), the clinical status and prognostic. However, the mechanisms connecting heart failure and cytokine activation are unclear and the sites of cytokines production remain controversial. In the clinical setting, specific measurements of cytokines are not available. As tests of inflammation, erythrocyte sedimentation rate and C-reactive protein concentration appear to have interesting pronostic values. Current conventional therapy i.e. ACE inhibitors, type I angiotensin II antagonist and beta-blockers have shown some anti-cytokine properties. Recently, immunosuppressive therapies have shown their ability to improve symptoms and LV ejection in selected patients with dilated cardiomyopathy and clear sign of myocardium inflammation. Specific anti-cytokine therapy have been developed and showed interesting results in preliminary clinical studies. However large clinical trials testing this new therapy have been stoppel prematurely because of deterious effects.
We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and beta blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor-alpha (TNF-alpha) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-alpha, on clinical status, left ventricular function, and circulating plasma levels of TNF-alpha, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF-alpha determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P = 0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P = 0.03). Treatment with pentoxifylline (P = 0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.
Effector functions of an aberrant immune response have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The immunologic determinants of myocardial dysfunction, however, remain poorly understood. This study sought to determine the relation of different immunologic responses to hemodynamic dysfunction in DCM.
Immunoglobulin (Ig) G class/subclass response ELISA (enzyme-linked immunosorbent assay) against cardiac myosin heavy chain, histologic characteristics (DALLAS criteria), immunohistochemistry, plasma interleukin-4 and plasma interferon gamma (IFN-gamma) were determined in patients (n = 76) with clinically suspected myocarditis or DCM. Patients were prospectively evaluated, both clinically and hemodynamically, on admission (baseline) and at 6-month follow-up.
Indices of hemodynamic dysfunction (by cardiac catheterization and transthoracic echocardiography) correlated significantly with an Ig subclass response. IgG3 levels correlated with left ventricular ejection fraction (P =.02), pulmonary capillary wedge pressure (P <.0001), left ventricular end-systolic volume index (P =.002), left ventricular end-diastolic volume index (P =.033), left ventricular end-diastolic pressure (P =.04), right ventricular end-diastolic pressure (P =.039), and left ventricular end-systolic dimension and left ventricular end-diastolic dimension (P <.05). Patients positive for IgG3 (predominantly male, P =.01) had depressed left ventricular ejection fraction (< or =45%, relative risk 3.0, 95% CI 1.5-5.7, P =.005) at baseline and 6 months. Mitral-septal separation at follow-up improved in patients negative for IgG3 (P =.018), and the number of patients on conventional therapy in this group declined at 6-month follow-up (P <.05). Lymphocyte counts/high-power field; CD2, CD3, CD4, and CD8 (independent of IgG class/subclass response and left ventricular dysfunction) were significantly higher in patients positive for IFN-gamma (25%). A positive IFN-gamma response was higher in patients positive for IgG3. These patients, positive for IgG3 and IFN-gamma (10%), had significantly shorter duration of clinical symptoms: 0.17 years (0.12-2.36 y) versus 1.01 years (0.49-5.35 y, P =.04).
IgG3 reactivity correlated with depressed myocardial dysfunction. This may render this subclass Ig a surrogate target for therapeutic intervention in DCM. With IFN-gamma, IgG3 may reflect a more aggressive disease.
The etiology and mechanisms of pathogenesis of human peripartum cardiomyopathy (PPCM) remain unknown. The incidence and prevalence of this disease is rare in some parts of the world and more common in others. The purpose of this review is to summarize our current knowledge of the factors that have been entertained which may contribute to the pathogenesis of PPCM with special emphasis on more recent data from our laboratory that provide support to the view that this disease is an autoimmune disease with multiple contributing factors and effector mechanisms. This is supported by the fact that sera from PPCM patients contain high titers of auto-antibodies against normal human cardiac tissue proteins of 37, 33, and 25 kD that was not present in the sera of patients with idiopathic cardiomyopathy (IDCM), indicating for the first time that PPCM is distinct from IDCM. In addition to the autoantibodies, the PBMC's from PPCM patients demonstrate a heightened level of fetal microchimerism, an abnormal cytokine profile, decreased levels of CD4+ CD25lo regulatory T cells, and a significant reduction in the plasma levels of progesterone, estradiol and relaxin in PPCM patients as compared with other normal pregnant non-PPCM patients. A potential role for reduced plasma levels of selenium in the pathogenesis of select PPCM patients was also noted. These findings for the first time suggest that such abnormalities may in concert lead to the initiation and perpetuation of an autoimmune process, which leads to cardiac failure and disease. Identification of the precise nature of the cardiac tissue autoantigens (currently in progress) will pave the way for the delineation of mechanism of this autoimmune disease. A working model for the pathogenesis of this disease is also described herein.
Patients with severe heart failure have plasma cytokine concentrations that are more than twofold greater than those in patients with moderate heart failure. Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis factor-alpha (TNF-alpha) production, improves pump function in mild-to-moderate heart failure, its effects on advanced heart failure have not been determined. In a prospective, randomized, double-blind, placebo-controlled study we compared the effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) on left ventricular systolic function and dimensions as well as on plasma TNF-alpha (picograms per milliliter), interleukin-10 (IL-10), and the apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated cardiomyopathy and advanced heart failure. All patients had New York Heart Association functional class IV heart failure, required intravenous inotropic agents for >72 hours at the beginning of the study, and received diuretics, digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the study. Marked increases in TNF-alpha and Fas/Apo-1 concentrations were noted in the 18 patients compared with patients with functional class II to III heart failure and controls (p <0.001). Baseline characteristics were the same between the pentoxifylline and placebo groups. Pentoxifylline administration resulted in reduced TNF-alpha and Fas/Apo-1 concentrations, and an increase in ejection fraction at 1 month (p <0.05 compared with baseline and with placebo), effects that were not observed in the placebo-treated group. These data suggest that pentoxifylline may be a useful adjunct to conventional therapy in patients with severe heart failure.
Peripartum cardiomyopathy (PPCM) is a rare and serious heart disease that exclusively afflicts women during childbearing years. Symptoms include rapid onset of cardiovascular insufficiency occurring during pregnancy, initiated anytime between the third trimester until 5 months post-partum in the absence of any other signs or history of heart disease. The rare incidence of PPCM and the absence of any relevant animal models have limited research and understanding of the pathogenic mechanisms involved. Several compelling sets of data support the view that PPCM is a form of autoimmune IDCM. However, PPCM differs from autoimmune IDCM in that (a) it is associated with unique sets of autoantibodies and autoantigens, (b) it has a relatively rapid onset, and (c) it exclusively affects pregnant women. Furthermore, the etiology of PPCM is dependent on the interaction of pregnancy associated factors, e.g. increased hemodynamic stress, vasoactive hormones and fetal microchimerism, that co-operate in the context of essential immune and genetic environments for disease progression. Our model of PPCM attempts to represent how multiple factors, e.g. pregnancy, genetics, immune dysregulation, and fetal microchimerism are held in a complex dynamic balance that can co-operate towards the maintenance of cardiovascular health or disease in the mother (Fig. 1). A more thorough study of the precise nature of the cardiac tissue autoantigens may lead to the identification of the mechanisms of breakdown of self-tolerance and perhaps also the putative etiologic agent(s). Further studies of the precise nature of the cardiac tissue autoantigens and the specific factors governing the balance between tolerance and autoimmunity in the periphery, e.g. expression of PD-L1 on cardiac tissues and the role of regulatory T cells, may help to elucidate the autoimmune mechanisms of PPCM.
Prolactin (PRL) is a versatile hormone that is produced by the anterior pituitary gland and various extrapituitary sites including immune cells. Furthermore, PRL has widespread influences on proliferation and differentiation of a variety of cells in the immune system and is, in effect, a cytokine. PRL-receptors (PRL-R) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily. PRL-R signal transduction is mediated by a complex array of signaling molecules of which JAK2, Stat1 and Stat5 pathway have been well studied. In PRL-stimulated T cells, the transcription factor gene, interferon regulatory factor-1 provides a mechanism whereby PRL can regulate the immune response. The human PRL gene is situated on the short arm of chromosome 6 close to the major histocompatibility complex. Polymorphisms of the human PRL gene have implications for production of lymphocyte PRL in SLE. Mild and moderate hyperprolactinemia (HPRL) has been demonstrated in 20-30% of SLE patients and is associated with active disease. HPRL may have a role in lupus nephritis and central nervous system involvement of SLE patients. HPRL stimulated the production of autoantibodies. These evidences support the important role of PRL in autoimmunity and autoimmune diseases, mainly SLE.
Although an autoimmune mechanism has been postulated for myocarditis and dilated cardiomyopathy, immunosuppressive agents had not been shown to be effective. Potential benefits of intravenous immunoglobulin (IVIg) in the therapy of patients with myocarditis and recent onset of dilated cardiomyopathy were reported. Also, experimental studies showed that IVIg is an effective therapy for viral myocarditis by antiviral and anti-inflammatory effects. Accordingly, in the current study, the effects of IVIg in the patients were investigated with the analyses of inflammatory cytokines and oxidative stress. Nine patients (six in myocarditis, three in acute dilated cardiomyopathy) were treated with high-dose intravenous IVIg (1-2 g/kg, over 2 days). All were hospitalized with New York Heart Association (NYHA) class III to IV heart failure, left ventricular ejection fraction (LVEF) <40%, and symptoms for <6 months at the time of presentation. Five patients were diagnosed using endomyocardial biopsy. LVEF determined by echocardiography improved from 19.0+/-7.5% (mean+/-S.D.) at baseline to 35.4+/-9.1% at follow up (12.2+/-5.8 days after the treatment) (P<0.01). C-reactive protein and plasma inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) were decreased by this treatment. In addition, plasma level of thioredoxin, which regulates the cellular state of oxidative stress, was decreased by the treatment. All nine patients improved functionally to NYHA class I to II, and were discharged without side-effects. There have been no subsequent hospitalizations for heart failure during the course of follow-up (3 months-4.5 years). LVEF improved 16% of EF in the patients with myocarditis and acute dilated cardiomyopathy with the reduction of cytokines associated with improvement of oxidative stress state by high-dose of IVIg. Thus, IVIg seems to be a promising agent in the therapy of acute inflammatory cardiomyopathy in view of not only suppression of inflammatory cytokines but a reduction of oxidative stress.
The purpose this study was to investigate the relationship of anti-myosin and anti-heat shock protein immunoglobulin G (IgG) serum antibodies to the original heart disease of cardiac transplant recipients, and also to rejection and patient survival after cardiac transplantation.
Anti-myosin and anti-heat shock protein (anti-hsp) IgG antibodies were evaluated in pre-transplant sera from 41 adult cardiac allograft recipients and in sequential post-transplant serum samples from 11 recipients, collected at the time of routine endomyocardial biopsies during the first 6 months after transplantation. In addition, the levels of these antibodies were determined from the sera of 28 healthy blood donors.
Higher anti-myosin antibody levels were observed in pre-transplant sera than in sera from normal controls. Moreover, patients with chronic Chagas heart disease showed higher anti-myosin levels than patients with ischemic heart disease, and also higher levels, although not statistically significant, than patients with dilated cardiomyopathy. Higher anti-hsp levels were also observed in patients compared with healthy controls, but no significant differences were detected among the different types of heart diseases. Higher pre-transplant anti-myosin, but not anti-hsp, levels were associated with lower 2-year post-transplant survival. In the post-transplant period, higher anti-myosin IgG levels were detected in sera collected during acute rejection than in sera collected during the rejection-free period, whereas anti-hsp IgG levels showed no difference between these periods.
The present findings are of interest for post-transplant management and, in addition, suggest a pathogenic role for anti-myosin antibodies in cardiac transplant rejection, as has been proposed in experimental models of cardiac transplantation.
Prolactin is not only a lactigenic hormone but also an immunomodulator involved in lymphocyte survival, activation and proliferation. There is increasing data implicating prolactin in autoimmunity, and specifically in SLE. Increased serum prolactin levels have been reported in lupus patients of both genders, and have been associated with accelerated disease expression and early mortality in lupus-prone mice. Furthermore, suppression of prolactin secretion with bromocriptine provides beneficial effects in murine lupus, and perhaps in some SLE patients as well. Treatment with prolactin that causes mild to moderate hyperprolactinemia, similar to that present in SLE patients, breaks tolerance and induces a lupus-like illness in non-spontaneously autoimmune mice with a susceptible genetic background. These immuno stimulatory effects of prolactin are mediated by a decrease in negative selection and the maturation of autoreactive B cells to the follicular subset. Consistent with the fact that follicular B cells are T cell dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B cell tolerance. In mice, the effects of prolactin on the immune system are genetically determined, suggesting that only a subset of SLE patients are likely to have a prolactin-responsive disease. The manipulation of serum prolactin or, even more specifically, follicular B cells that are susceptible to the immuno stimulatory effects of prolactin, may provide novel therapeutic options for those SLE patients with a prolactin-modulated disease.
Carvedilol is known to decrease the severity of ventricular dysfunction, to increase the left ventricular ejection fraction (LVEF), and, consequently, to reduce morbidity and mortality in patients with dilated cardiomyopathy. There is accumulating evidence that inflammatory cytokines have an important role in the pathogenesis of heart failure.
To establish whether the addition of carvedilol has an additive beneficial effect on cytokines in patients with dilated cardiomyopathy who are already receiving treatment with angiotensin-converting enzyme (ACE) inhibitors, digoxin and diuretics.
In this single-centre, prospective, randomized study, 60 patients with dilated cardiomyopathy with an LVEF less than 40% and already receiving digoxin, ACE inhibitors and diuretics for six months as the standard therapy were randomly assigned to receive either carvedilol (n=30) or placebo (n=30). Patients received an initial dosage of 3.125 mg carvedilol or placebo twice daily for two weeks, which was then increased at two-week intervals (if tolerated), first to 6.25 mg, then to 12.5 mg, and, finally, to a target dosage of 25 mg twice daily. Clinical examinations, radionuclide studies, and determinations of plasma levels of tumour necrosis factor-alpha (TNF-a), interleukin (IL)-2 and IL-6 were performed at baseline and repeated four months after random assignment. Primary end points were New York Heart Association functional class, LV function and plasma cytokines levels. Eight patients died (seven in the placebo group, P=0.05). Patients treated with carvedilol had a significant improvement in functional class compared with the baseline values (P=0.001), with a decrease in the levels of cytokines (IL-6 [P=0.001] and TNF-a [P=0.001]). LVEF increased from 22.14+/-7.85% to 27.85+/-11.80% (P=0.002), but diastolic function did not change in the carvedilol group.
In patients with dilated cardiomyopathy, the addition of carvedilol to treatment with digoxin, ACE inhibitors and diuretics is associated with a significant improvement in symptoms and in LV function, and suppression of inflammatory cytokines.
Cardiomyopathy associated with pregnancy was first described more than half a century ago. However, because of its rare occurrence and geographical differences, the clinical profile of this condition has remained incompletely defined.
Data obtained from 123 women with a history of cardiomyopathy diagnosed during pregnancy or the postpartum period were reviewed. One hundred women met traditional criteria of peripartum cardiomyopathy; 23 were diagnosed with pregnancy-associated cardiomyopathy earlier than the last gestational month. Peripartum cardiomyopathy patients had a mean age of 31+/-6 years and were mostly white (67%). Common associated conditions were gestational hypertension (43%), tocolytic therapy (19%), and twin pregnancy (13%). Left ventricular ejection fraction at the time of diagnosis was 29+/-11% and improved to 46+/-14% (P< or =0.0001) at follow-up. Normalization of left ventricular ejection fraction occurred in 54% and was more likely in patients with left ventricular ejection fraction >30% at diagnosis. Maternal mortality was 9%. A comparison between the peripartum cardiomyopathy and early pregnancy-associated cardiomyopathy groups revealed no differences in age, race, associated conditions, left ventricular ejection fraction at diagnosis, its rate and time of recovery, and maternal outcome.
This study helps to define the clinical profile of patients with pregnancy-associated cardiomyopathy diagnosed in the United States. Clinical presentation and outcome of patients with pregnancy-associated cardiomyopathy diagnosed early in pregnancy are similar to those of patients with traditional peripartum cardiomyopathy. These 2 conditions may represent a continuum of a spectrum of the same disease.
Tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) are significantly elevated in patients with congestive heart failure (CHF). Pentoxifylline, a xanthin-derived agent, is known to inhibit the production of TNF-alpha and IL-6. Recent studies have shown that pentoxifylline produces an increase in ejection fraction, a decrease in left-ventricular chamber size and an improvement in clinical status in patients with idiopathic-dilated cardiomyopathy. Therefore, we studied the effects of pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy.
Primary endpoint was left-ventricular ejection fraction (LVEF) assessed by contrast 2D echocardiography. Secondary endpoints were concentrations of TNF-alpha, IL-6, brain natriuretic peptide, maximal oxygen uptake (VO(2 max)) assessed by cardiopulmonary exercise testing and Minnesota Living with Heart Failure Questionnaire score or New York Heart Association scale.
Forty-seven patients (31.9% ischemic, 21.3% hypertensive, 10.6% ischemic and hypertensive, 36.2% idiopathic-dilated cardiomyopathy) were randomly assigned to pentoxifylline 600 mg BID (n=23) or placebo (n=24) if they had a compensated CHF with a LVEF less than or equal to 40% and had taken their standard treatment consisting of angiotensin-converting enzyme inhibitors, diuretics and beta-blockers for at least 3 months. Baseline demographic and clinical characteristics of each group were similar. Forty-one patients completed the study protocol and were analysed for primary and secondary endpoints. After 6 months of treatment, LVEF was unchanged in the pentoxifylline group compared with placebo (29+/-7 to 33+/-10% vs. 27+/-9 to 34+/-9%, respectively, P=NS). Also the secondary endpoints did not significantly change during follow-up.
Additional treatment with pentoxifylline is neutral with regard to left-ventricular function, inflammatory cytokines and symptoms in patients with ischemic, hypertensive and idiopathic-dilated cardiomyopathy.
Peripartum cardiomyopathy (PPCM) is a rare disorder of dilated cardiomyopathy and left ventricular dysfunction occurring in the last month of pregnancy or within 5 months postpartum. Outcome of PPCM is highly variable, comprising clinical improvement and rapid deterioration unresponsive to medical treatment requiring heart transplantation or even death. In this study, we report the clinicopathologic findings of 10 patients with PPCM who were retrospectively identified in our cardiomyopathy registry. During a follow-up of 69+/-27 months, no patient died or required orthotopic heart transplantation. Left ventricular ejection fraction was 38+/-7% at the time of diagnosis and 53+/-7% during follow-up. While all patients had sinus rhythm at the time of diagnosis, three patients presented with left bundle branch block. We found no evidence of viral infection in endomyocardial biopsy samples of seven patients by PCR. Histopathologic findings revealed the presence borderline myocarditis in two of seven patients (29%). Circulating autoantibodies to cardiac tissue of any kind were observed in all patients. In conclusion, in our retrospective observational study, no patient diagnosed with PPCM died or received orthotopic heart transplantation. Improvement of left ventricular ejection fraction was present in eight patients (80%), while LV dysfunction persisted in four patients. Our findings support the hypothesis of an underlying autoimmune pathomechanism in this rare disease.
Peripartum cardiomyopathy (PPCM) is a disorder in which initial left ventricular systolic dysfunction and symptoms of heart failure occur between the late stages of pregnancy and the early postpartum period. It is common in some countries and rare in others. The causes and pathogenesis are poorly understood. Molecular markers of an inflammatory process are found in most patients. Clinical presentation includes usual signs and symptoms of heart failure, and unusual presentations relating to thromboembolism. Clinicians should consider PPCM in any peripartum patient with unexplained disease. Conventional heart failure treatment includes use of diuretics, beta blockers, and angiotensin-converting enzyme inhibitors. Effective treatment reduces mortality rates and increases the number of women who fully recover left ventricular systolic function. Outcomes for subsequent pregnancy after PPCM are better in women who have first fully recovered heart function. Areas for future research include immune system dysfunction, the role of viruses, non-conventional treatments such as immunosuppression, immunoadsorption, apheresis, antiviral treatment, suppression of proinflammatory cytokines, and strategies for control and prevention.
Peripartum cardiomyopathy is a rare and under recognized form of dilated cardiomyopathy, defined as a heart failure in the last month of pregnancy or in the first five months post-partum with absence of determinable cause for cardiac failure and absence of demonstrable heart disease. The incidence of peripartum cardiomyopathy ranges from 1 in 1300 to 1 in 15,000 pregnancy. Advanced maternal age, multiparity, twin births, preeclampsia and black race are known risk factors. The etiology of peripartum cardiomyopathy remains unknown but viral, autoimmune or idiopathic myocarditis are highly suggested. The clinical presentation on patients with peripartum cardiomyopathy is similar to that of patients with systolic heart failure. The treatment is based on drugs for sympyomatic control. Studies in graeter populations are need to determine the role of immunosupressive treatment. About half patients of peripartum cardiomyopathy recover. The left ventricular ejection fraction and the left ventricular end-diastolic diameter are statistically significant prognostic factors. The risk of developing peripartum cardiomyopathy in subsequent pregnancies remains high. The place of dobutamine stress test in counseling the patients who desire pregnancy must be more studied.
Preeclampsia-eclampsia (PE-E) is a poorly understood condition of human pregnancy, which can affect multiple organs and is a leading cause of maternal deaths worldwide. The etiology and pathophysiology remain enigmas, however, which hampers progress in prevention, diagnosis, and treatment of this condition. PE-E is characterized by many features typically seen in autoimmune diseases, or in association with autoimmune reactions. Although this does not mean that PE-E should be considered an autoimmune condition, it does suggest that abnormal autoimmune processes play an important part in the clinical presentation of PE-E. In that regard, PE-E mimics autoimmune responses also observed in situations of allograft rejection and graft-versus-host disease (GVHD). Indeed, PE-E shares many other clinical and laboratory characteristics with allograft rejection and GVHD. Recognizing PE-E as a clinical condition that is characterized by autoimmune abnormalities may facilitate earlier and more specific diagnosis, along with preventive and more specific therapies for women at risk.
Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.
Medical conditions with known etiology and typical peripartal/postpartal disease exacerbations are now, without exception, considered autoimmune in etiology. Postpartum psychiatric conditions, and especially postpartum depression, currently, however, are still not understood in their etiology. This paper suggests that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for (postpartum) depression. The high prevalence of (postpartum) depression led to its designation as a major public health problem. A better understanding of etiology and pathophysiology would greatly advance the, currently still inaccurate, diagnosis of the condition, and improve approaches towards prevention and treatment.
The autoimmune diseases are more common in females. The sex hormones have an important role in this gender bias, mainly estrogen and prolactin (PRL) which modulate the immune response. PRL is secreted from the pituitary gland and other organs and cells mainly the lymphocytes. PRL has an immunostimulatory effect and promotes autoimmunity: PRL impairs the negative selection of autoreactive B lymphocytes occurring during B cell maturation into fully functional B cells. PRL has an anti-apoptotic effect, enhances proliferative response to antigens and mitogens and enhances the production of immunoglobulins and autoantibodies. Hyperprolactinemia (HPRL) is observed in multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE) rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT) and multiple sclerosis (MS). There is no consistent correlation between PRL levels and disease activity. Murine models and small studies in SLE patients suggest some role of dopamine agonists in the therapy of those diseases. The genetic factor may have a role in humans as in animal models. The PRL isoform has an important effect on the bioactivity on prolactin receptors (PRL-Rs).
Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20-30%), viral, and/or immune. On endomyocardial biopsy there is chronic inflammation in 30-40% of cases. Mutations in genes encoding myocyte structural proteins, cardiotoxic noxae and infectious agents are known causes; due to high aetiologic and genetic heterogeneity, the gene defects identified so far account for a tiny proportion of the familial cases. In at least two thirds of patients, DCM remains idiopathic. Myocarditis may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Circulating heart-reactive autoantibodies are found in myocarditis/DCM patients and symptom-free relatives at higher frequency than in normal or noninflammatory heart disease control groups. These autoantibodies are directed against multiple antigens, some of which are expressed only in the heart (organ-specific); some autoantibodies have functional effects on cardiac myocytes in vitro as well as in animal models. Depletion of nonantigen-specific antibodies by extracorporeal immunoadsorption is associated with improved ventricular function and reduced cardiac symptoms in some DCM patients, suggesting that autoantibodies may also have a functional role in humans. Immunosuppression seems beneficial in patients who are virus-negative and cardiac autoantibody positive. Prospective family studies have shown that cardiac-specific autoantibodies are present in at least 60% of both familial and non familial pedigrees and predict DCM development among asymptomatic relatives, years before clinical and echocardiographic evidence of disease. Animal models have shown that autoimmune myocarditis/DCM can be induced by virus as well as reproduced by immunization with a well-characterized autoantigen, cardiac myosin. Thus, in a substantial proportion of patients, myocarditis and DCM represent different stages of an organ-specific autoimmune disease, that represents the final common pathogenetic pathway of infectious and noninfectious myocardial injuries in genetically predisposed individuals.
The antiphospholipid (Hughes) syndrome (APS) is a unique thrombotic disorder, causing both arterial and venous thrombosis, linked to the presence of antibodies directed against phospholipid-protein complexes. The first papers describing the syndrome were published in 1983 and, over the next two years, a series of publications described in detail the various clinical manifestations of the syndrome. Laboratory standardisation workshops were also set up and, in 1984, the first "world" symposium on APS was held. The international APS conferences have continued to grow in numbers and in stature. The APS has already had an impact in obstetrics, in medicine, in psychiatry, and in surgery. The approximate figure of 1 in 5 is a useful guide -- 1 in 5 of all young strokes, 1 in 5 recurrent miscarriages, 1 in 5 DVTs. More precise data will become available in the worlds of epilepsy, migraine, Alzheimer's, and MS. The advent of newer "biologic" immunosuppressives such as rituximab may offer help in selected cases. Intravenous immunoglobulin has proved successful, especially in the emergency setting.
N-terminal pronatriuretic peptide in patients with preeclampsia
- Dh Yang
- Lee
- Sh
- Tb Goo
- Hs Park
- Y Cho
- Chae
- Sc
Yang DH, Lee SH, Goo TB, Park HS, Cho Y, Chae SC, et al. N-terminal pronatriuretic peptide in patients with preeclampsia. J Am Coll Cardiol 2008;51:A337.
Graft-versus host disease and immunologic rejection: implications for diagnosis and treatments of pregnancy complications [14] Gleicher N. Pregnancy-related cell traffic, microchimerism and autoimmunity: the possibility of reducing autoimmune disease prevalence
- N Gleicher
Gleicher N. Graft-versus host disease and immunologic rejection: implications for diagnosis and treatments of pregnancy complications. Expert Rev Obstet Gynecol 2008;3:37–49. [14] Gleicher N. Pregnancy-related cell traffic, microchimerism and autoimmunity: the possibility of reducing autoimmune disease prevalence. Expert Rev Obstet Gynecol 2007;2:341–5.
Contractile reserve in patients with peripartum cardiomyopathy and recovered left ventricular function dysfunction
- Mb Lampert
- L Weinert
- J Hibbard
- C Korcarz
- M Lindheimer
- Rm Lang
Lampert MB, Weinert L, Hibbard J, Korcarz C, Lindheimer M, Lang RM.
Contractile reserve in patients with peripartum cardiomyopathy and
recovered left ventricular function dysfunction. Am J Obstet Gynecol
1997;176:189–95.
- D Hilfiker-Kleiner
- Gp Meyer
- E Schieffer
- B Goldmann
- E Podewski
- I Struman
Hilfiker-Kleiner D, Meyer GP, Schieffer E, Goldmann B, Podewski E,
Struman I, et al. J Am Coll Cardiol 2007;11(50):2354–5.
N-terminal pro-natriuretic peptide in patients with preeclampsia
- Yang
Contractile reserve in patients with peripartum cardiomyopathy and recovered left ventricular function dysfunction
- Lampert