Clinical magnetocardiography: the unshielded bet-past, present, and future.

Magnetocardiography (MCG), which is nowadays 60 years old, has not yet been fully accepted as a clinical tool. Nevertheless, a large body of research and several clinical trials have demonstrated its reliability in providing additional diagnostic electrophysiological information if compared with conventional non-invasive electrocardiographic methods. Since the beginning, one major objective difficulty has been the need to clean the weak cardiac magnetic signals from the much higher environmental noise, especially that of urban and hospital environments. The obvious solution to record the magnetocardiogram in highly performant magnetically shielded rooms has provided the ideal setup for decades of research demonstrating the diagnostic potential of this technology. However, only a few clinical institutions have had the resources to install and run routinely such highly expensive and technically demanding systems. Therefore, increasing attempts have been made to develop cheaper alternatives to improve the magnetic signal-to-noise ratio allowing MCG in unshielded hospital environments. In this article, the most relevant milestones in the MCG's journey are reviewed, addressing the possible reasons beyond the currently long-lasting difficulty to reach a clinical breakthrough and leveraging the authors' personal experience since the early 1980s attempting to finally bring MCG to the patient's bedside for many years thus far. Their nearly four decades of foundational experimental and clinical research between shielded and unshielded solutions are summarized and referenced, following the original vision that MCG had to be intended as an unrivaled method for contactless assessment of the cardiac electrophysiology and as an advanced method for non-invasive electroanatomical imaging, through multimodal integration with other non-fluoroscopic imaging techniques. Whereas all the above accounts for the past, with the available innovative sensors and more affordable active shielding technologies, the present demonstrates that several novel systems have been developed and tested in multicenter clinical trials adopting both shielded and unshielded MCG built-in hospital environments. The future of MCG will mostly be dependent on the results from the ongoing progress in novel sensor technology, which is relatively soon foreseen to provide multiple alternatives for the construction of more compact, affordable, portable, and even wearable devices for unshielded MCG inside hospital environments and perhaps also for ambulatory patients.

Compliance in weight control reduces atrial fibrillation worsening: A retrospective cohort study.

BACKGROUND AND AIM: Obesity plays a dominant role in the etiology of atrial fibrillation (AF), and the maintenance of a normal body mass index (BMI) seems to prevent and even reduce the incidence of the arrhythmia's recurrence. We selected 270 patients (pts) to assess whether this therapeutic effect was statistically significant even in Mediterranean patients. METHOD AND RESULTS: In this retrospective cohort study, we analyzed every symptomatic AF relapse during a total follow-up of 657 patient-years. Clinical data, BMI variations, and pts' history were available in our clinical database. We divided the pts in four groups (Gs), according to their BMI variation during the follow-up: G1, normal weight pts, maintaining their weight; G2, overweight pts, losing weight; G3, overweight pts, maintaining their weight; G4, pts gaining weight. Their follow-up (in months) was normalized according to their AF relapses, thus obtaining a mean AF-free period for each patient. Among the overweight groups, G2 showed the best AF-free period (9.7 months). However, G3 and G4 showed a reduced AF-free interval (4.6 and 1.7 months, respectively). G1, predictably, had the longest AF-free period (10 months). CONCLUSION: The results of the present study confirm that simple non-invasive intervention aimed to normalize BMI and to control risk factors through appropriate lifestyle can be highly effective in reducing the AF burden, by acting on comorbidities and proarrhythmic mechanisms. Therefore, serious attempt should be made to correct risk factors before an ablation therapy is proposed.

From 3D to 4D imaging: is that useful for interventional cardiac electrophysiology?

Three-dimensional electroanatomical imaging is increasingly used in interventional cardiac electrophysiology, to guide catheter ablation of cardiac arrhythmias. At the same time, there is a growing interest for non-invasive methods, such as magnetocardiographic mapping (MCG), to localize the arrhythmogenic substrates, to test their reproducibility and to plan the most appropriate interventional approach. So far electroanatomical imaging has relayed on static mathematical modeling of the heart and more recently on direct merging with three-dimensional rendering of cardiac anatomy from multidetector computer tomography or magnetic resonance imaging. Merging electrophysiological information with static anatomical structures, can surely be a source of uncertainty for MCG-based pre-interventional localization of the arrhythmogenic substrate and causes mismatch between the real-time imaging of moving catheters and the static geometry of the cardiac chambers reconstructed with invasive electroanatomical imaging. The implementation of recent realistic numerical models of the beating heart in a breathing thorax can improve accuracy and fill the gap between non-invasive and interventional electroanatomical imaging.

Non-invasive electrophysiologic study with amagnetic transesophageal pacing during unshielded multichannel magnetocardiographic mapping.

UNLABELLED: Multichannel magnetocardiographic (MCG) mapping is a non-invasive method, which can provide reproducible three-dimensional (3D) localization of accessory pathways (AP) and ventricular arrhythmias, before ablation procedures. More recently MCG imaging of intra-atrial reentry circuits has also been reported. So far, reported cases of MCG localization and imaging of arrhythmias were investigated during spontaneous rhythm only, although more relevant information can be obtained during dynamic electrophysiologic study (EPS). For cardiac pacing one could use an amagnetic intracardiac catheter; but this, however, would add invasivity to a non-invasive method. The aim of this study was to validate a novel approach for dynamic non-invasive EPS based on MCG in combination with amagnetic transesophageal pacing (TEP). METHOD: A tetrapolar 7 French amagnetic catheter was developed, which provides effective TEP (with an average stimulation threshold of 10-15 mA) and simultaneous recording of two esophageal atrial electrograms. MCG data were acquired at rest, with a 36-channel MCG system (sensitivity of 20 fT/Hz(1/2)), for 90 to 300 seconds (sampling rate of 1 KHz; bandwidth of DC Hz to 100 Hz), as a function of the type of pacing procedure. 10 patients were investigated, during both continuous and programmed TEP. RESULTS AND CONCLUSIONS: MCG during TEP was feasible and reproducible. It provided: 1) more accurate localization of AP during pacing-induced maximal preexcitation; 2) inducibility of supraventricular AR and imaging of atrial reentry circuits, not spontaneously present; 3) stabilization of the heart rate to improve the accuracy of quantitative estimate of ventricular repolarization parameters.

Magnetocardiographic study of ventricular repolarization in hypertensive patients with and without left ventricular hypertrophy.

UNLABELLED: Previous studies in magnetically shielded rooms have shown that magnetocardiographic (MCG) mapping can be useful to detect early signs of left ventricular hypertrophy (LVH). The aim of this study was to evaluate ventricular repolarization parameters in patients with essential hypertension, associated or not with LVH, by means of unshielded multichannel MCG mapping. METHODS: 31 patients with pharmacologically treated essential hypertension (average BP systolic: 147.8+/-11.2, diastolic: 92.2+/-4.9) since 6.5+/-5.6 years, 13 without and 18 with evidence of LVH (4 by ECG, 11 by echocardiography, and 3 at both), were studied with a 36-channel MCG system (sensitivity of 20 fT/square root of Hz1/2) and with 12-lead ECG, in an unshielded hospital setting. To assess ventricular repolarization, HR-corrected, QTend, JTpeak, JTend, Tpeak-end intervals and QT dispersion (QTd) were measured from both MCG and ECG waveforms. The magnetic field gradient orientation (alpha angle) during the ST interval and at the Tpeak was also computed. 20 normal age-matched volunteers were used for comparison. RESULTS: As compared to normal volunteers, MCG JTend, QTend, Tpeak-end and QTd were significantly longer in hypertensive patients. The difference was not significant, if only patients with essential hypertension but no LVH were considered. The magnetic field alpha angle during the ST was significantly abnormal in patients with essential hypertension (p < 0.01). CONCLUSIONS: In patients with essential hypertension, MCG detects alterations of ventricular repolarization, not evidenced by 12-lead ECG.

Magnetocardiographic differences of ventricular repolarization parameters between Wistar rats and guinea pigs.

UNLABELLED: The morphology and range of duration of the action potential (AP) in normal Wistar rat's (WR) myocyte markedly differ from those of guinea pigs (GP), whose plateau (phase 2) duration is longer. Thus a clear-cut T wave can be easy defined in GP but not in WR. Aim of this study was to differentiate magnetocardiographic (MCG) ventricular repolarization (VR) parameters of healthy adult WR and GP. METHODS: 10 female animals (5 Guinea pigs and 5 Wistar rats) were studied with a 36-channel MCG system (sensitivity of 20 fT/square root of Hz1/2) and with one ECG lead, in an unshielded hospital room. To assess VR, HR-corrected, JTpeak, JTend, Tpeak-end and QTend, intervals were measured from both MCG waveforms. Timing was improved by MCG maps analysis. Magnetic field orientation (MFO), its dynamics (MFD) and stability (JTS) during the JT interval, were also automatically computed from MCG maps. RESULTS: All repolarization intervals were significantly shorter in WR than in GP, except the Tpeak-end, which was longer. MFO and MFD also differed. CONCLUSIONS: MCG estimate of VR parameters, in adult WR and GP, is precise enough to evidence breed-related differences, consistent with physiological heterogeneity of duration during phases 2 and 3 of the AP, and with an higher degree of transmural dispersion of repolarization in WR.

Effects of filtering on computer-aided analysis for detection of chronic ischemic heart disease with unshielded rest magnetocardiographic mapping.

UNLABELLED: Recent studies have reported better sensitivity of magnetocardiographic (MCG) mapping, as compared to ECG, in detecting ventricular repolarization (VR) abnormalities due to myocardial ischemia in patients (pts) with Ischemic Heart Disease (IHD). For quick data reduction, automatic analysis of MCG mapping is mostly used. The aim of our study was to evaluate if filtering modality could alter automatic analysis of MCG. METHOD: 39 subjects were studied: 20 normals and 19 IHD pts, with angiography-documented >70% coronary stenosis, positive stress/SPECT and ischemic 12-lead ECG in 12/19 (63%). Rest MCG was recorded with a 36-channel system (at 1 kHz; bandwidth DC-100 Hz). To assess VR, Hänninen's STalpha angle and three magnetic field dynamics parameters, [i.e. +/- poles: angle (A), distance (D) and ratio (R)] during the T-wave interval, were computed from the same MCG maps: 1) after digital 20 Hz low-pass filtering (LPF) and 2) after digital 50 Hz adaptive filtering (AF). The baseline was unchanged. Three quantitative MCG scores of the T-wave (EXT, ML, Q) were automatically calculated (with 20 Hz LPF only). RESULTS: Whereas the filtering modality didn't affect the predictivity of the STalpha angle, the predictive values of A, D, and R were different and partially contradicting. Automatic MCG scores had a predictive values ranging between 73% and 92%. CONCLUSIONS: The diagnostic power of unshielded MCG for detection of chronic IHD, with T-wave parameters (A, D and R) might be affected by LPF. The STalpha angle is not affected by LPF. Automatic EXT, ML and Q scores have better predictivity than ECG.

Dynamical MCG mapping with an atomic vapor magnetometer.

We have developed a magnetometer based on magnetic resonance in cesium vapor optically pumped by resonant laser radiation, which has the sensitivity and bandwidth to record human magnetocardiograms. The device is operated as a first-order gradiometer in a weakly shielded environment and allows us to record 2-dimensional field maps by shifting the subject with respect to a single sensor and making time-sequential measurements. We discuss the magnetometer technique and its performance as well as obtained results, which include a comparison of MCG data recorded with our single channel optical magnetometer with SQUID measurements from a commercial multi-channel device as well as from SQUID reference data. The results obtained so far in the detection of cardiomagnetic signals using the optical magnetometer make us confident that the technique has a high potential to serve as an alternative to SQUID detection.

Clinical multichannel MCG in unshielded hospital environment.

UNLABELLED: From November 5th, 2001 to May 19th, 2004, 545 patients (177 with arrhythmias, 67 with WPW syndrome, 60 with Ischemic Heart Disease (IHD), 129 with different kinds of cardiomyopathy, 106 normals, 6 FMCG) have been consecutively investigated at the Catholic University of Rome, with unshielded Multichannel Magnetocardiographic Mapping (MMCG): 20 with the 9-channel system only and 525 with the 36-channel system (207 of them with both systems). 107 patients were investigated also after physical stress, carried out with a standard bicycle ergometer. In all patients MMCG was recorded at least three times, to check for reproducibility and/or for clinical follow-up, for a total of more than 1600 recordings. METHOD: MMCG was performed, with both the 9-channel and the 36-channel systems, at 1 kHz in the bandwidth DC-100 Hz. In the last 200 pts, 12-lead ECG was simultaneously recorded with amagnetic electrodes. On each patient file, post-processing and signal analysis for the quantitative assessment of ventricular repolarization and for 3D localization and electroanatomical imaging of cardiac arrhythmias, were carried out independently with two different approaches and software programs developed by CMI and by Neuromag (Finland). RESULTS: The results with the two methods have been compared. For 3D electroanatomical integration of MMCG localization results, 3D cardiac models have been used, constructed from patient MRI and/or from orthogonal fluoroscopic images taken at the moment of MCG recording. CONCLUSIONS: Qualitative reproducibility of MMCG was satisfactory. However the estimate of quantitative parameters has shown a certain degree of variability, which deserves further evaluation.

The effect of geometric and topologic differences in boundary element models on magnetocardiographic localization accuracy.

This study was performed to evaluate the changes in magnetocardiographic (MCG) source localization results when the geometry and the topology of the volume conductor model were altered. Boundary element volume conductor models of three patients were first constructed. These so-called reference torso models were then manipulated to mimic various sources of error in the measurement and analysis procedures. Next, equivalent current dipole localizations were calculated from simulated and measured multichannel MCG data. The localizations obtained with the reference models were regarded as the "gold standard." The effect of each modification was investigated by calculating three-dimensional distances from the gold standard localizations to the locations obtained with the modified model. The results show that the effect of the lungs and the intra-ventricular blood masses is significant for deep source locations and, therefore, the torso model should preferably contain internal inhomogeneities. However, superficial sources could be localized within a few millimeters even with nonindividual, so called standard torso models. In addition, the torso model should extend long enough in the pelvic region, and the positions of the lungs and the ventricles inside the model should be known in order to obtain accurate localizations.

Cardiovascular adaptation during action pistol shooting.

BACKGROUND: Action Pistol Shooting, implies high degree of physical and psychological stress, however cardiovascular adaptation during competition has not been studied so far. METHODS: We studied six healthy males athletes, during the Italian National Dynamic Pistol Shooting Championship. ECG was monitored and blood pressure (BP) manually measured along the match. RESULTS: Mean heart rate (HR) was close to 100 bpm per minute in all but one shooters. Marked tachycardia, above 180 beats per minute was recorded in four shooters, during "field course" stages. In two cases the heart rate under stress reached about 200 bpm, for the occurrence of paroxysmal atrial arrhythmias. BP behavior was different among the six shooters with mean systolic values ranging between 140 and 170 mmHg and maximal systolic values between 160 e 240 mmHg. CONCLUSIONS: Action Pistol Shooting induces acute elevation of HR and BP, which may reach abnormal values and can be associated with impaired performance and score. Further study is warranted in shooters undergoing combat-like tournaments to evaluate unperceived cardiovascular stress and their coping capability.

Bioelectromagnetic localization of a pacing catheter in the heart.

The accuracy of localizing source currents within the human heart by non-invasive magneto- and electrocardiographic methods was investigated in 10 patients. A non-magnetic stimulation catheter inside the heart served as a reference current source. Biplane fluoroscopic imaging with lead ball markers was used to record the catheter position. Simultaneous multichannel magnetocardiographic (MCG) and body surface potential mapping (BSPM) recordings were performed during catheter pacing. Equivalent current dipole localizations were computed from MCG and BSPM data, employing standard and patient-specific boundary element torso models. Using individual models with the lungs included, the average MCG localization error was 7+/-3 mm, whereas the average BSPM localization error was 25+/-4 mm. In the simplified case of a single homogeneous standard torso model, an average error of 9+/-3 mm was obtained from MCG recordings. The MCG localization accuracies obtained in this study imply that the capability of multichannel MCG to locate dipolar sources is sufficient for clinical purposes, even without constructing individual torso models from x-ray or from magnetic resonance images.

Nonfluoroscopic localization of an amagnetic stimulation catheter by multichannel magnetocardiography.

This study was performed to: (1) evaluate the accuracy of noninvasive magnetocardiographic (MCG) localization of an amagnetic stimulation catheter; (2) validate the feasibility of this multipurpose catheter; and (3) study the characteristics of cardiac evoked fields. A stimulation catheter specially designed to produce no magnetic disturbances was inserted into the heart of five patients after routine electrophysiological studies. The catheter position was documented on biplane cine x-ray images. MCG signals were then recorded in a magnetically shielded room during cardiac pacing. Noninvasive localization of the catheter's tip and stimulated depolarization was computed from measured MCG data using a moving equivalent current-dipole source in patient-specific boundary element torso models. In all five patients, the MCG localizations were anatomically in good agreement with the catheter positions defined from the x-ray images. The mean distance between the position of the tip of the catheter defined from x-ray fluoroscopy and the MCG localization was 11 +/- 4 mm. The mean three-dimensional difference between the MCG localization at the peak stimulus and the MCG localization, during the ventricular evoked response about 3 ms later, was 4 +/- 1 mm calculated from signal-averaged data. The 95% confidence interval of beat-to-beat localization of the tip of the stimulation catheter from ten consecutive beats in the patients was 4 +/- 2 mm. The propagation velocity of the equivalent current dipole between 5 and 10 ms after the peak stimulus was 0.9 +/- 0.2 m/s. The results show that the use of the amagnetic catheter is technically feasible and reliable in clinical studies. The accurate three-dimensional localization of this multipurpose catheter by multichannel MCG suggests that the method could be developed toward a useful clinical tool during electrophysiological studies.

Nonfluoroscopic localization of an amagnetic catheter in a realistic torso phantom by magnetocardiographic and body surface potential mapping.

This study was performed to evaluate the accuracy of multichannel magnetocardiographic (MCG) and body surface potential mapping (BSPM) in localizing three-dimensionally the tip of an amagnetic catheter for electrophysiology without fluoroscopy. An amagnetic catheter (AC), specially designed to produce dipolar sources of different geometry without magnetic disturbances, was placed inside a physical thorax phantom at two different depths, 38 mm and 88 mm below the frontal surface of the phantom. Sixty-seven MCG and 123 BSPM signals generated by the 10 mA current stimuli fed into the catheter were then recorded in a magnetically shielded room. Non-invasive localization of the tip of the catheter was computed from measured MCG and BSPM data using an equivalent current dipole source in a phantom-specific boundary element torso model. The mean 3-dimensional error of the MCG localization at the closer level was 2 +/- 1 mm. The corresponding error calculated from the BSPM measurements was 4 +/- 1 mm. At the deeper level, the mean localization errors of MCG and BSPM were 7 +/- 4 mm and 10 +/- 2 mm, respectively. The results showed that MCG and BSPM localization of the tip of the AC is accurate and reproducible provided that the signal-to-noise ratio is sufficiently high. In our study, the MCG method was found to be more accurate than BSPM. This suggests that both methods could be developed towards a useful clinical tool for nonfluoroscopic 3-dimensional electroanatomical imaging during electrophysiological studies, thus minimizing radiation exposure to patients and operators.

Magnetocardiographic pacemapping for nonfluoroscopic localization of intracardiac electrophysiology catheters.

The purpose of the study was to validate, in patients, the accuracy of magnetocardiography (MCG) for three-dimensional localization of an amagnetic catheter (AC) for multiple monophasic action potential (MAP) with a spatial resolution of 4 mm2. The AC was inserted in five patients after routine electrophysiological study. Four MAPs were simultaneously recorded to monitor the stability of endocardial contact of the AC during the MCG localization. MAP signals were band-pass filtered DC-500 Hz and digitized at 2 KHz. The position of the AC was also imaged by biplane fluoroscopy (XR), along with lead markers. MCG studies were performed with a multichannel SQUID system in the Helsinki BioMag shielded room. Current dipoles (5 mm; 10 mA), activated at the tip of the AC, were localized using the equivalent current dipole (ECD) model in patient-specific boundary element torso. The accuracy of the MCG localizations was evaluated by: (1) anatomic location of ECD in the MRI, (2) mismatch with XR. The AC was correctly localized in the right ventricle of all patients using MRI. The mean three-dimensional mismatch between XR and MCG localizations was 6 +/- 2 mm (beat-to-beat analysis). The co efficient of variation of three-dimensional localization of the AC was 1.37% and the coefficient of reproducibility was 2.6 mm. In patients, in the absence of arrhythmias, average local variation coefficients of right ventricular MAP duration at 50% and 90% of repolarization, were 7.4% and 3.1%, respectively. This study demonstrates that with adequate signal-to-noise ratio, MCG three-dimensional localizations are accurate and reproducible enough to provide nonfluoroscopy dependant multimodal imaging for high resolution endocardial mapping of monophasic action potentials.

Reproducibility of transesophageal pacing in patients with Wolff-Parkinson-White syndrome.

The purpose of this study was to assess, in patients with ventricular preexcitation, the time dependent physiological variation of antegrade conduction properties in the AV node and in accessory pathways (Aps) as a function of autonomic tone variation induced by posture and physical effort, using noninvasive transesophageal atrial pacing. In 74 WPW patients (mean age 21.31 +/- 9.46 yrs), AV node and Kent antegrade effective refractory periods (at pacing cycle lengths 600, 400, and 320 ms), Wenckebach point, shortest preexcited RR intervals during sustained atrial fibrillation (AF) or atrial pacing, as well as the inducibility of AV reentry tachycardia (AVRT) and AF/flutter (AFL) were assessed. All measurements were carried out at rest, in supine and upright positions, and during effort. A second study was carried out approximately 3 months after the first study. The coefficient of variation (CVs) and reproducibility (CRs) were calculated. For each parameter, the differences between the mean of the two studies were not statistically significant. The CVs and CRs ranged between 0.4% and 4% and between 2 and 28 ms, respectively. AF was induced in 40 (54%) of 74 patients at the first study and in 30 (40.5%) of 74 patients at the second study. AVRT was induced in 33 (45%) of 74 patients at the first study and in 38 (51.3%) of 74 patients at the second study. The reproducibility was 45% for AF/AFL and 65% for reentry tachycardia. Transesophageal atrial pacing is a reliable method for noninvasive reproducible evaluation of antegrade electrophysiological properties of both the AV node and APs in WPW patients. However, the effect of autonomic balance variation has to be taken into account and precisely defined because it may significantly affect the inducibility of supraventricular arrhythmias and the estimation of the absolute values of the vulnerable parameters.

Malignant cardiac involvement in a family with myotonic dystrophy.

BACKGROUND: In patients with myotonic dystrophy, histopathological and electrophysiologic abnormalities of cardiac conduction system may lead to sudden cardiac death due to atrioventricular block or to ventricular electrical instability. METHODS: Four members of a family affected by myotonic dystrophy are reported, which underwent a cardiological examination including invasive electrophysiological study and prolonged follow-up. Other 3 members of the same family had died suddenly. No clinical data are available for 2 of these patients, while paroxysmal atrial flutter and non sustained ventricular tachycardia had been detected at Holter in the third one. RESULTS: Signs of atrioventricular conduction impairment, poorly predictable with non invasive electrocardiography, were found in the 4 patients undergoing intracardiac electrophysiologic study. In 2/4 patients, both having dizzy spells and the most impaired atrioventricular conduction, a pace-maker was implanted. Polymorphic, non sustained ventricular response was induced in 2/4 patients, 1 of them with spontaneous high grade ventricular arrhythmias. CONCLUSIONS: The respective role of atrioventricular conduction impairment and ventricular vulnerability in determining sudden death has not been stated so far in these patients. The observed polymorphic non sustained response should not be "a priori" disregarded as aspecific, since it could be the electrophysiological counterpart of a peculiar anatomic arrhythmogenic substrate. A comprehensive study, including invasive electrophysiology, is advisable in all patients with myotonic dystrophy whenever a member of their family presents with cardiac involvement, to assess the most probable life-threatening arrhythmogenic mechanism.

Recurrent perimyocarditis following a non penetrating chest trauma. A case report.

A young man, after a non penetrating chest trauma, developed recurrent episodes of fever, chest pain, pleural and pericardial effusion, without laboratory evidence of viral infections, or positivity for conventional autoimmunity markers. A clearcut positivity for more specific cardiac autoantibodies, against Beta 1 adrenoceptors (AB1AA), was found (at all dilutions from 1:20 to 1:160). A full dosage of Prednisone rapidly relieved all symptoms, whereas antibiotic therapy had been previously uneffective. At a follow-up control after three months, the patient was healed and AB1AA were positive only at dilutions 1:20 and 1:40. As silent viral myocarditis was apparently ruled out by serological negativity for viral infections, it is possible that autoimmunity could have played a primary pathogenetic role for the development of pericarditis in this patient. Further work is needed to ascertain whether or not AB1AA detection could be a specific marker of cardiac autoimmunity phenomena.