Udi Nussinovitch

The Clinical Significance of Anti-Beta-1 Adrenergic Receptor Autoantibodies in Cardiac Disease

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.

Glucocorticoids and the Cardiovascular System: State of the Art

Glucocorticoids (GC) are drugs commonly used, by approximately 1% of the total adult population as anti-inflammatory and immunosuppressive therapies for asthma, inflammatory bowel disease, dermatological, ophthalmic, neurological, and rheumatic autoimmune diseases. Supporting evidence exists of GC use in both immune mediated and non-immune mediated heart disease. The molecular mechanisms by which GC induces immune-modulation and direct cardioprotection, are complex and not fully understood. We review herein, the current knowledge of GC use in various immune-mediated or non-immune mediated cardiovascular conditions. GC have been investigated in autoimmune, inflammatory and idiopathic heart diseases such as atrio-ventricular conduction abnormalities, rheumatic fever, myocarditis, dilated cardiomyopathy, Churg-Strauss syndrome, Kawasaki disease and sarcoidosis. GC therapy has been studied in non-autoimmune and non-inflammatory indications such as acute myocardial infarction, angina, postpericardiotomy syndrome and other pericardial diseases, endocarditis and cardiac amyloidosis, as well as in invasive cardiology, coronary interventions, and cardiopulmonary-bypass surgery. Despite GCs role as natural, physiologic regulators of the immune system, cardiovascular adverse outcomes may occur. Some of the well-known side effects of GC therapy involve bone, metabolic, and cardiovascular systems and include osteoporosis, fractures, dyslipidemia, diabetes, obesity, and hypertension.

The Diagnostic and Clinical Significance of Anti-Muscarinic Receptor Autoantibodies

The role of autoimmunity in cardiovascular diseases has become one of the focal points of research studies. Autoimmune response and autoreactive autoantibodies have been found in dilated cardiomyopathy, heart failure, rheumatic fever, myocarditis, atherosclerosis, and other diseases. Autoantibodies may appear due to tissue injury and exposure of autoantigens, in addition to molecular mimicry and cross-reactivity with antigens found in infectious agents in predisposed individuals. In the early 1990s, autoantibodies reacting with the M2 muscarinic receptor were found in patients with dilated cardiomyopathy and subsequently, in patients with Chagas heart disease and arrhythmic disorders. Immunization of animals with the corresponding antigen triggered cardiac abnormalities also appearing in dilated cardiomyopathy of humans. It has been suggested that antibodies against M2 muscarinic receptors play a role in the pathogenesis of cardiac diseases and may also alter the electrophysiological properties of cardiac tissue. Herein, we review the current knowledge of antibodies against M2 muscarinic receptors and the possible use of a targeted therapy against these autoantibodies.

Cerebrospinal fluid lactate dehydrogenase isoenzymes in children with bacterial and aseptic meningitis.

Differentiation of bacterial from aseptic meningitis may be difficult. Our aim was to determine the pattern of distribution of lactate dehydrogenase (LDH) isoenzymes in the cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis. One hundred and fifty-seven patients with suspected meningitis were enrolled in the study. They were divided into 3 groups according to the culture- or bacterial antigen assay-proven diagnosis and CSF findings: bacterial meningitis (n = 31), aseptic meningitis (n = 65), and non-meningitis (n = 61). Total LDH level and percentages of LDH isoenzymes in the CSF were measured in each patient. Each group showed a distinct LDH isoenzyme distribution pattern, with a statistically significant difference among the groups in the percentages of the various isoenzymes. Compared with the non-meningitis group, total LDH activity in the CSF was high in the aseptic meningitis group (49.82+/-35.59 U/L, P < 0.001) and exaggerated in the bacterial meningitis group (944.53+/-112.3 U/L, P < 0.001). Low LDH-2 levels were unique to bacterial meningitis (P < 0.01), whereas high LDH-3 levels were characteristic of aseptic meningitis (P < 0.05). Both groups had low levels of LDH-1 and high levels of LDH-4 and LDH-5. In conclusion, the LDH isoenzyme pattern may be of clinical diagnostic value in meningitis, particularly when culture results are pending.

QT dispersion in amyloidosis due to familial Mediterranean fever.

Cardiac amyloid deposition in FMF may cause increased QT dispersion (QTd), a marker for cardiac arrhythmias. The aim of this study was to further evaluate repolarization dispersion in familial Mediterranean fever (FMF) with amyloidosis. Findings on 12-lead electrocardiography were compared between 18 patients with FMF-amyloidosis and 18 age- and sex-matched control subjects. Repolarization and dispersion parameters were computed with designated computer software, and results of the 5 beats were subsequently averaged. There were no statistically significant differences between the groups as to average corrected QT interval length, average QTd interval, average QT corrected dispersion, or QT dispersion ratio. JT dispersion and JT corrected dispersion were also similar in both groups. In conclusion, patients with FMF-amyloidosis seem to have QT and JT dispersion parameters similar to those of healthy subjects. Future research and longer follow-ups should be conducted in order to evaluate the prognostic importance of repolarization dispersion parameters in amyloidosis of FMF.

Echocardiographic Abnormalities in Familial Dysautonomia

Sudden death accounts for up to 43% of all deaths in patients with familial dysautonomia (FD). The classic features of FD, namely, autonomic dysfunction, high blood pressure, and blood pressure labiality, are all risk factors for cardiac remodeling and hypertrophy. Myocardial remodeling and hypertrophy are independent risk factors for arrhythmias, cardiovascular events, and sudden death. An extensive review of the medical literature found no documentation of structural heart defects or myocardial remodeling in patients with FD. Sixteen patients with FD underwent physical examination, in-clinic blood pressure measurements, and echocardiographic study. On the basis of the findings, the patients were categorized by left ventricular geometric pattern. Twenty-four-hour ambulatory blood pressure monitoring was recommended to all participants. The majority of FD patients were found to have very high blood pressure values both during in-clinic measurements and during ambulatory blood pressure monitoring. Echocardiographic abnormalities were found in 43.75% of the study group; 18.75% of the study group had concentric hypertrophy, among which severe hypertrophy was found in 2 patients. Unknown previously, cardiac remodeling or hypertrophy is common in FD. We recommend that routine cardiac echocardiography be performed in this population, and attempts to treat high blood pressure should begin earlier in life.

P-wave dispersion in systemic AA amyloidosis of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary disease characterized by attacks of fever and polyserositis. Recent studies differ as to whether FMF is associated with an abnormally high P-wave duration and P-wave dispersion, markers for supraventricular arrhythmogenicity. The aim of our study was to further evaluate atrial dispersion in FMF patients with amyloidosis. The study groups consisted of 16 patients with FMF and amyloidosis, and 16 age- and sex-matched control subjects. All participants underwent 12-lead electrocardiography under strict standards. P-wave length and P-wave dispersion in each individual patient were computed from a randomly selected beat and an averaged beat constructed from 7 to 12 beats, included in a 10-s electrocardiogram. No statistically significant differences were found between the groups for minimal, maximal, and average P-wave duration and P-wave dispersion, calculated either from a random beat or averaged beats. In conclusion, although a small difference cannot be excluded because of the small study groups, FMF patients with amyloidosis appear to have atrial conduction parameters similar to those of healthy controls, and therefore apparently do not have an increased electrocardiographic risk for developing supraventricular arrhythmias.

Distinguishing a heart attack from the "broken heart syndrome" (Takotsubo cardiomyopathy).

Takotsubo cardiomyopathy (TC) is a neurocardiological disorder presumed to be triggered by stress, which may cause reversible heart failure, usually in postmenopausal women. It may mimic an acute myocardial infarction, accompanied by minimal elevation of cardiac enzymes, usually without evidence of obstructive coronary artery disease. Most clinicians are unfamiliar with this disorder. Therefore, some TCs are misdiagnosed as acute myocardial infarction. The modified Mayo Clinic criteria usually confirm a diagnosis, although the diagnostic criteria for TC remain controversial. Enhanced awareness by clinicians is important when encountering patients with chest pain and elevated cardiac enzymes. Takotsubo cardiomyopathy is usually associated with a favorable prognosis, although in rare instances it may be associated with life-threatening complications. Supportive care is especially important in the TC management. Our aim was to describe TC, characterize its clinical features, and extensively review the relevant literature.

Normal autonomic nervous system responses in uncomplicated familial Mediterranean fever: a comparative case–control study

There is a paucity of knowledge regarding the autonomic nervous system function in patients with familial Mediterranean fever (FMF). Therefore, our aim was to evaluate autonomic responses in patients with FMF using complementary tests. The study groups included 33 patients with uncomplicated FMF and 39 control subjects. Autonomic function was evaluated by measuring responses to metronomic breathing, the Valsalva maneuver, and the Ewing maneuver. Autonomic parameters were computed from electrocardiograms with designated computer software. There were no statistically significant differences in any of the measured parameters of autonomic function between the patient and control group. The measured autonomic parameters of both groups were similar to those previously reported in healthy individuals. In conclusion, patients with FMF who did not develop amyloidosis due to continuous colchicine treatment appeared to have normal autonomic function, as reflected by the normal response to physiological autonomic stimuli.

Pattern of cerebrospinal fluid lactic dehydrogenase during treatment of bacterial meningitis.

Bacterial and aseptic meningitis are characterized by distinctive lactic dehydrogenase isoenzyme patterns. No studies have quantified the dynamics of lactic dehydrogenase isoenzyme distribution during treated bacterial meningitis. We used a retrospective case-series design, and reviewed files of all neonates with bacterial meningitis who attended our pediatric tertiary medical center for 8 years period. We identified neonates in whom a repeated lumbar puncture was indicated. Findings of cerebrospinal fluid analysis, including levels of lactic dehydrogenase isoenzymes, were compared with an age-matched reference group. In two patients with meningitis, lumbar puncture with cerebrospinal fluid analysis was repeated because of inadequate response to treatment or initially obscure etiologic pathogens. Both patients had initially low levels of lactic dehydrogenase-1 and lactic dehydrogenase-2 and high levels of lactic dehydrogenase-4 and lactic dehydrogenase-5, similar to other patients with bacterial meningitis. The distribution pattern of lactic dehydrogenase isoenzyme normalized after adequate antibiotic treatment. In light of the encouraging results in these two patients, further studies are warranted regarding the value of lactic dehydrogenase isoenzyme measurements for follow-up purposes and for evaluations of response to treatment.