When Manual Analysis of 12-Lead ECG Holter Plays a Critical Role in Discovering Unknown Patterns of Increased Arrhythmogenic Risk: A Case Report of a Patient Treated with Tamoxifen and Subsequent Pneumonia in COVID-19.

Several medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another "safer" therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19.

Predictive value of unshielded magnetocardiographic mapping to differentiate atrial fibrillation patients from healthy subjects.

BACKGROUND: P-wave duration, its dispersion and signal-averaged ECG, are currently used markers of vulnerability to atrial fibrillation (AF). However, since tangential atrial currents are better detectable at the body surface as magnetic than electric signals, we investigated the accuracy of magnetocardiographic mapping (MCG), recorded in unshielded clinical environments, as predictor of AF occurrence. METHODS: MCG recordings, in sinus rhythm (SR), of 71 AF patients and 75 controls were retrospectively analyzed. Beside electric and magnetic P-wave and PR interval duration, two MCG P-wave subintervals, defined P-dep and P-rep, were measured, basing on the point of inversion of atrial magnetic field (MF). Eight parameters were calculated from inverse solution with "Effective Magnetic Dipole (EMD) model" and 5 from "MF Extrema" analysis. Discriminant analysis (DA) was used to assess MCG predictive accuracy to differentiate AF patients from controls. RESULTS: All but one (P-rep) intervals were significantly longer in AF patients. At univariate analysis, three EMD parameters differed significantly: in AF patients, the dipole-angle-elevation angular speed was lower during P-dep (p < 0.05) and higher during P-rep (p < 0.001) intervals. The space-trajectory during P-rep and the angle-dynamics during P-dep were higher (p < 0.05), whereas ratio-dynamics P-dep was lower (p < 0.01), in AF. At DA, with a combination of MCG and clinical parameters, 81.5% accuracy in differentiating AF patients from controls was achieved. At Cox-regression, the angle-dynamics P-dep was an independent predictor of AF recurrences (p = 0.037). CONCLUSIONS: Quantitative analysis of atrial MF dynamics in SR and the solution of the inverse problem provide new sensitive markers of vulnerability to AF.

Magnetocardiographic classification and non-invasive electro-anatomical imaging of outflow tract ventricular arrhythmias in recreational sport activity practitioners.

Ventricular arrhythmias (VAs) with left bundle-branch-block and inferior axis morphology (LBBB-IA), suggestive of outflow tract (OT) origin, are a challenge in sports medicine because they can be benign or expression of a silent cardiomyopathy. Non-invasive classification is essential to plan ablation strategy if required. We aimed to evaluating magnetocardiographic (MCG) discrimination of OT-VAs site of origin (SoO). MCG and ECG data of 26 sports activity practitioners, with OT-VAs were analyzed. OT-VAs-SoO was classified with discriminant analysis (DA) of 8 MCG parameters and with invasively-validated ECG algorithms. MCG inverse source-localization merged with magnetic resonance (CMR) provided three-dimensional electro-anatomical imaging (MCG 3D-EAI). ECG classification was univocal in 73%. MCG-DA differentiated right ventricular OT from aortic sinus cusp VAs, with 94.7% accuracy. MCG 3D-EAI confirmed OT-VAs-SoO in CMR images. In cases undergoing ablation, MCG 3D-EAI was confirmed by CARTO 3D-EAI. MCG-DA improves non-invasive classification of OT-VAs-SoO. Further comparison with interventional results is required.

Psychophysiological evaluation of patients with transient consciousness loss of uncertain origin.

BACKGROUND: Psychological profile (PsyP) of patients with transient loss of consciousness (TLoC) is evidence of high prevalence of anxiety and depression. However, the mechanistic link between abnormal PsyP and TLoC is still unclear. AIM: This study aimed to evaluate: 1) prevalence of abnormal PsyP in TLoC patients; 2) cardiac autonomic response to head-up tilt test (HUTT) in patients with (PsyP+) or without abnormal PsyP (PsyP-), developing syncope (HUTT+) or not (HUTT-). METHODS: Forty-one patients (66% female, mean age 36 ± 15 years), with history of TLoC, underwent PsyP before HUTT. Short-term heart rate variability analysis was carried out under baseline rest condition and at peak heart rate and/or onset of syncope induced by nitroglycerine (NTG), during HUTT. RESULTS: HUTT+ occurred in 17/41 patients, more frequently in females, who had higher levels of anxiety (p < 0.0001). PsyP+ was prevalent in 70.5% of HUTT+ patients (p < 0.05). Among PsyP+ patients HUTT+ had dominant sympathetic modulation (DSM) at rest, which increased at the onset of syncope, whereas in HUTT patients vagal modulation was prevalent at rest. Among NTG-induced HUTT+ patients, fourfold higher increases of very low frequency (VLF) power were found in PsyP- compared with PsyP+. CONCLUSIONS: 58% of patients with history of TLoC were PsyP+. In PsyP+ patients, DSM at rest correlates with higher prob-ability of NTG-induced syncope, which occurs with 60% increment of low frequency and 530% increment of VLF power. Conversely, in patients with prevalent vagal modulation at rest and a decrease in VLF power after NTG, syncope did not occur. This supports interpretation of VLF power as an index of stress-induced sympathetic activity.

Unshielded magnetocardiography: Repeatability and reproducibility of automatically estimated ventricular repolarization parameters in 204 healthy subjects.

BACKGROUND: Magnetocardiographic mapping (MCG) provides quantitative assessment of the magnetic field (MF) induced by cardiac ionic currents, is more sensitive to tangential currents, and measures vortex currents undetectable by ECG, with higher reported sensitivity of MCG ventricular repolarization (VR) parameters for earlier detection of acute myocardial ischemia. Aims of this study were to validate the feasibility of in-hospital unshielded MCG and to assess repeatability and reproducibility of quantitative VR parameters, considering also possible gender- and age-related variability. METHODS: MCG of 204 healthy subjects [114 males-mean age 43.4 ± 17.3 and 90 females-mean age 40.2 ± 15.7] was retrospectively analyzed, with a patented proprietary software automatically estimating twelve VR parameters derived from the analysis of the dynamics of the T-wave MF extrema (five parameters) and from the inverse solution with the effective magnetic dipole model giving the effective magnetic vector components (seven parameters). MCG repeatability was calculated as coefficient of variation (CV) ±standard error of the mean (SEM). Reproducibility was assessed as intraclass correlation coefficient (ICC). RESULTS: The repeatability of all MCG parameters was 16 ± 1.2 (%) (average CV ± SEM). Optimal (ICC > 0.7) reproducibility was found for 11/12 parameters (mean values) and in 8/12 parameters (single values). No significant gender-related difference was observed; six parameters showed a strong/moderate correlation with age. CONCLUSION: Reliable MCG can be performed into an unshielded hospital ambulatory, with repeatability and reproducibility of quantitative assessment of VR adequate for clinical purposes. Wider clinical use is foreseen with the development of multichannel optical magnetometry.

Heart rate variability analysis during head-up tilt test predicts nitroglycerine-induced syncope.

OBJECTIVE: The aim of this study was to determine whether or not heart rate variability (HRV) analysis during the first 20 min of head-up tilt testing could predict whether patients will develop syncope after nitroglycerine administration. DESIGN: 64 patients with previous loss of consciousness underwent head-up tilt testing with the Italian protocol, which involves the administration of nitroglycerine after 20 min of tilt. HRV parameters were analysed from 5 min intervals selected during pretest supine rest (phase 1), the first 5 min (phase 2) and the last 5 min (phase 3) of passive 20 min of tilting, prior to the administration of nitroglycerine. Differences in power (ms(2)) of the spectral components between the various phases of tilting were calculated for each patient and expressed as Δ. RESULTS: 20 patients (group 1, 9 women, mean age 43.2±24.5 years) had a syncope during tilt testing after nitroglycerine, while the other 44 (group 2, 24 women, mean age 41±20.5 years) did not. In group 1, the HRV spectral parameters high frequency (HF) and total power (TP) had a significant decrement from phases 2 to 3 (p=0.012 and 0.027, respectively), while in group 2 the average HF and TP values did not change. The Δ of spectral parameters between phases 2 and 3 were able to differentiate between the two groups and to predict syncope after nitroglycerine administration (p<0.05). CONCLUSIONS: HRV analysis within the first 20 min of passive tilting demonstrated that patients with nitroglycerine-induced syncope are characterised by a progressive decrement of parasympathetic activity, which does not occur in patients with a negative response to nitroglycerine. If confirmed on a wider population, HRV analysis could replace nitroglycerine administration and shorten the duration of the tilt test.

Cardiovascular autonomic nervous system evaluation in Parkinson disease and multiple system atrophy.

BACKGROUND: Autonomic nervous system dysfunction (ANSd) heralds or follows motor symptoms (MS) in Parkinson disease (PD), but may precede years and progress more rapidly in multiple system atrophy (MSA). Cardiac dysautonomia severity correlates with disabling symptoms thus a Cardiac Autonomic Nervous System Evaluation protocol (CANSEp) is useful to assess ANSd in PD and MSA patients. METHODS AND RESULTS: Consecutive patients with PD or MSA were studied. The severity of MS was quantified with UPDR III and Hoehn/Yahr scales. CANSEp consisted of the 5-test Ewing protocol (EP) and Heart Rate Variability analysis (HRVa), in time-domain (TD) and frequency-domain (FD). 36 patients with parkinsonian symptoms (23 PD, 13 MSA) and 40 healthy controls were studied. Parkinsonism was more severe in MSA, comparing UPDR III and Hoehn/Yahr scales (p<0.0001). Higher EP's scores were found in MSA (mean 5.1±1.98) compared to PD (mean 3.5±2) and controls (score 0.25±0.1). TD and FD-HRVa were abnormal in PD and MSA, compared to controls. In PD depression of vagal tone was predominant during sleep, whereas in MSA depression of sympathetic tone prevailed during daily activity. CONCLUSIONS: Whereas its specificity is very high, the sensitivity of the EP was only 43.5% in PD and 76.9% in MSA. HRVa improved diagnosis accuracy in 10 patients, unidentified by the EP alone, with overall sensitivity of 65.2% in PD and 92.3% in MSA. Thus CANSEp provides a better assessment of cardiovascular dysautonomia in parkinsonian syndromes, useful to differentiate PD from MSA and to address clinical and pharmacological management.

Prevalence of virulent Helicobacter pylori strains in patients affected by idiopathic dysrhythmias.

Helicobacter pylori virulent strains have been shown to affect cardiovascular diseases through molecular mimicry mechanisms. Silent autoimmune myocarditis has been hypothesized to be the cause of idiopathic dysrhythmias (IA). The aim of this study is to assess the prevalence of virulent H. pylori strains in patients affected by IA. In this study,54 patients (40 men, mean age 44 ± 17 years) affected by IA and 50 healthy subjects (34 men, mean age 45 ± 9) were evaluated. IA, defined as dysrhythmias with no evidence of other cardiac pathology, were either supraventricular (SVA, 23 patients; mean age 45 ± 15 years) or ventricular (VA, 31 patients; mean age 42 ± 18 years). H. pylori infection and gastrointestinal (GI) symptoms were evaluated. H. pylori strains expressing the cytotoxin-associated gene A (cagA) and the vacuolating-cytotoxin A (vacA) were also assessed through western blot. The prevalence of H. pylori is similar in IA patients and in controls (42 vs. 44%; p > 0.05); H. pylori infection is observed in 48 and 39% of the patients are affected by SVA and VA, respectively. The prevalence of CagA-positive strains is increased in IA patients compared to controls (65 vs. 42%; p < 0.01); similarly, the prevalence of VacA-positive strains is also increased in IA patients (74 vs. 46%; p < 0.006). Excluding belching, infected patients did not show any difference in GI symptoms, when compared to non-infected subjects. From this study it is concluded that there is an epidemiological link between CagA and VacA-positive H. pylori strains in IA patients.

Anti-ß-adrenoceptors autoimmunity causing 'idiopathic' arrhythmias and cardiomyopathy.

BACKGROUND: To determine the prevalence of anti-ß-adrenoceptors autoantibodies (aßAA) in patients with idiopathic arrhythmias (IA) and to assess whether aßAA are predictive markers for concealed cardiomyopathy in such patients. METHODS AND RESULTS: Sixty-seven patients (group 1) with IA [25 supraventricular (SVA) and 42 ventricular (VA)]; 14 patients (group 2) with suspected cardiomyopathy, 12 patients with definite cardiomyopathy (group 3); and 19 healthy controls (group 4) were tested with an enzyme immunoassay, using synthetic peptides corresponding to the second extracellular loop of the human ß1-and ß2-adrenoceptors. Endomyocardial biopsy was performed in 29 patients. As compared with group 4 [3/19 (15.7%)], anti-ß1-adrenoceptor autoantibodies (aß1AA) were more frequent in group-1 patients [38/67 (56.7%; P<0.01): 27/42 (64.2%; P<0.001) with VA and 11/25 (44%; P<0.05) with SVA]. 3 of the group 1 patients also had anti-ß2-adrenoceptor autoantibodies (aß2AA). 4 were positive for aß2AA only. Biopsy performed in 11/67 group 1 patients was abnormal in all. Of them, 7/8 (87.5%) with VA and 3/3 (100%) with SVA were positive for aß1AA. PCR analysis from paraffin blocks of the 11 group 1 biopsied patients was negative for EV, EBV, HCV, AV, PVB19, INF A/B,HSV1/2, HHV6 and HHV8 viral genomes. CONCLUSIONS: The second extracellular loop of the ß-adrenoceptor is the molecular target of specific autoantibodies. Positivity for aß1AA predicts abnormal histological findings in 90% of IA patients and suggests that autoimmunity might play an arrhythmogenic role.

Percutaneous method for single-catheter multiple monophasic action potential recordings during magnetocardiographic mapping in spontaneously breathing rodents.

To test the feasibility of a novel method to combine magnetocardiographic (MCG) estimate of ventricular repolarization (VR) and multiple monophasic action potential (MultiMAP) recording in spontaneously breathing rodents with percutaneous sub-xyphoid epicardial placement of a MCG-compatible amagnetic catheter (AC), ten Wistar rats (WRs) and ten guinea pigs (GPs) were studied. Under fluoroscopic control, the AC was moved until four stable MAPs were recorded (fixed inter-electrode distance of 1.2 mm). 36-channel DC-SQUID (sensitivity 20 fT Hz(-½)) were used for MCG mapping. MAPs, differentially amplified (BW: DC-500 Hz), were digitized at 1 kHz. AC pacing provided local ventricular effective refractory period (VERP) estimate. MAP duration (MAPd) was measured at 50% and 90% levels of repolarization. Simultaneous MCG mapping and MultiMAP recording were successful in all animals. Average MAPd50% and MAPd90% were shorter in WRs than in GPs (26.4 ± 2.9 ms versus 110.6 ± 14.3 ms and 60.7 ± 5.4 ms versus 127.7 ± 15.3 ms, respectively). VERP was 51 ± 4.8 ms in WRs and 108.4 ± 12.9 ms in GPs, respectively. The MAP amplitude was 16.9 ± 4.5 in WRs and 16.2 ± 4.2 in GPs. MAP and MCG parameters of VR were in good agreement. All animals survived the procedure. Two also survived a second invasive study; one was followed up until natural death at 52 months. Percutaneous MultiMAP recording is minimally invasive, usually avoids animal sacrifice, is compatible with simultaneous surface MCG mapping and might be used for experimental validation of MCG VR abnormality, to study the arrhythmogenic potential of new drugs and/or animal models of ventricular arrhythmias.

Ventricular activation is impaired in aged rat hearts.

Ventricular arrhythmias are frequently observed in the elderly population secondary to alterations of electrophysiological properties that occur with the normal aging process of the heart. However, the underlying mechanisms remain poorly understood. The aim of the present study was to determine specific age-related changes in electrophysiological properties and myocardial structure in the ventricles that can be related to a structural-functional arrhythmogenic substrate. Multiple unipolar electrograms were recorded in vivo on the anterior ventricular surface of four control and seven aged rats during normal sinus rhythm and ventricular pacing. Electrical data were related to morphometric and immunohistochemical parameters of the underlying ventricular myocardium. In aged hearts total ventricular activation time was significantly delayed (QRS duration: +69%), while ventricular conduction velocity did not change significantly compared with control hearts. Moreover, ventricular activation patterns displayed variable numbers of epicardial breakthrough points whose appearance could change with time. Morphological analysis in aged rats revealed that heart weight and myocyte transverse diameter increased significantly, scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium, and gap junction connexin expression decreased significantly in ventricular myocardium compared with control rats. Our results show that in aged hearts delayed total ventricular activation time and abnormal activation patterns are not due to delayed myocardial conduction and suggest the occurrence of impaired impulse propagation through the conduction system leading to uncoordinated myocardial excitation. Impaired interaction between the conduction system and ventricular myocardium might create a potential reentry substrate, contributing to a higher incidence of ventricular arrhythmias in the elderly population.

Susceptibility to ventricular arrhythmias in aged hearts.

Cardiac arrhythmias are frequent in the elderly population, perhaps secondary to an increased prevalence of hypertension and coronary artery disease as well as aging related changes resulting in loss of pacemaker cells and degenerative alteration of the conduction system. Independent from underlying structural heart disease, advanced age alone appears to be a risk factor for increased susceptibility to ventricular arrhythmia. However, the electrophysiological basis of this phenomenon is still unclear. Thus, it is important to assess and to define the underlying arrhythmogenic substrate. The aim of the present study was to identify a likely structural-functional ventricular arrhythmogenic substrate in aged hearts. For this purpose ventricular activation patterns were measured in control (n=4) and aged (n=10) in vivo rat hearts by recording unipolar electrograms with an epicardial, 1 mm resolution, 8x8 electrode array, during pacing and spontaneous or induced ventricular ectopic beats. Our results in aged hearts suggest that peripheral conduction system might be involved in perpetuating sequences of ventricular ectopic beats, regardless of their origin.

Longitudinal study of cardiac electrical activity in anesthetized guinea pigs by contactless magnetocardiography.

Guinea pigs (GPs) are used for preclinical evaluation of electrophysiologic effects of new drugs, because their myocytes have human-like action potentials and ventricular repolarization's (VR) ion currents. This study was aimed to assess the reliability of magnetocardiographic (MCG) mapping for longitudinal studies of GP cardiac electrical activity. Eighteen anesthetized GPs were investigated with an unshielded 36-channel MCG instrumentation, at the age of 5 months (268.1 +/- 19 g). Twelve GPs survived and were restudied when 14 months old (595.6 +/- 90.5 g). RR, PR, QRS, QT(peak), QT(end), JT(peak), JT(end) and T(peak-end) intervals were measured from MCG waveforms. Magnetic field (MF) maps, equivalent current dipole (ECD) parameters and current density imaging were also analyzed. A significant prolongation of the PR (p < 0.05) and QRS (p < 0.001) intervals was found at 14 months. Gender-related differences of VR intervals were not significant. P(peak) and QRS(peak) MFs were similar in all animals, while T(peak) MF varied interindividually at 5 months and showed a rotation in some animals, at 14 months. The ECD strengths, measured at the P(peak), QRS(peak) and T(peak) were stronger (p < 0.01) at the age of 14 months than at 5 months. In contrast to findings in Wistar rats, age-related and gender-related differences of MCG VR parameters were not significant in GPs. Further work is necessary to clarify the variability of VR MF observed in healthy GPs.

Magnetocardiography provides non-invasive three-dimensional electroanatomical imaging of cardiac electrophysiology.

OBJECTIVE: More than two decades of research work have shown that magnetocardiographic mapping (MCG) is reliable for non-invasive three-dimensional electroanatomical imaging (3D-EAI) of arrhythmogenic substrates. Magnetocardiographic mapping is now become appealing to interventional electrophysiologists after recent evidence that MCG-based dynamic imaging of atrial arrhythmias could be useful to classify patients with atrial fibrillation (AF) before ablation and to plan the most appropriate therapeutic approach. This article will review some key-points of 3D-EAI and discuss what is still missing to favor clinical applicability of MCG-based 3D-EAI. METHODS: Magnetocardiographic mapping is performed with a 36-channel unshielded mapping system, based on DC-SQUID sensors coupled to second-order axial gradiometers (pick-up coil 19 mm and 55-70 mm baselines; sensitivity of 20 fT/Sqrt[Hz] in above 1 Hz), as part of the electrophysiologic investigation protocol, tailored to the diagnostic need of each arrhythmic patient. More than 500 arrhythmic patients have been investigated so far. RESULTS: The MCG-based 3D-EAI has proven useful to localize well-confined arrhythmogenic substrates, such as focal ventricular tachycardia or preexcitation, to understand some causes for ablation failure, to study atrial electrophysiology including spectral analysis and localization of dominant frequency components of AF. However, MCG is still missing software tools for automatic and/or interactive 3D imaging, and multimodal data fusion equivalent to those provided with systems for invasive 3D electroanatomical mapping. CONCLUSION: Since there is an increasing trend to favor interventional treatment of arrhythmias, clinical application of MCG 3D-EAI is foreseen to improve preoperative selection of patients, to plan the appropriate interventional approach and to reduce ablation failure.

Noninvasive classification of ventricular preexcitation with unshielded magnetocardiography and transesophageal atrial pacing and follow-up.

BACKGROUND: Ventricular preexcitation (VPx) is usually localized noninvasively by means of electrocardiogram (ECG) algorithms, which vary in their concordance levels. Contactless magnetocardiography (MCG) has been used as an alternate 3-dimensional (3D) method of accessory pathways (AP) localization. The sensitivity of MCG can be increased for preoperative evaluations and planning of ablation procedures by combining it with transesophageal pacing (TEP) and electrophysiological (EP) studies. This study compared the accuracy of VPx localization with MCG with ECG algorithms, and examined the increment in diagnostic accuracy achievable with TEP. METHODS: Multisite mapping from the anterior chest wall was performed with a 36-channel MCG system. TEP allowed the evaluation of anterograde conduction properties and inducibility of arrhythmias. The reproducibility of the test and follow-up was examined in 88 patients with Wolff-Parkinson-White (WPW) syndrome. The accuracy of MCG localization was reevaluated during pacing-induced maximal VPx in 36 patients in whom, during MCG, the degree of VPx was highest during TEP. The gold standard for validation was effective ablation of the AP. RESULTS: The MCG classification of VPx was accurate in 94% of AP, versus 64% and 67% with ECG, during sinus rhythm and during pacing-induced maximal VPx, respectively. In 4.5% of cases with unclear ECG localization, MCG suggested a complex septal VPx. In all patients with successful ablations, the 3D MCG localization of the AP corresponded to the ablation site. CONCLUSIONS: MCG was more accurate than ECG for the classification of VPx and provided additional information in the non-invasive EP assessment of patients with WPW syndrome.