ESC Working Group on e-Cardiology Position Paper: accuracy and reliability of electrocardiogram monitoring in the detection of atrial fibrillation in cryptogenic stroke patients : In collaboration with the Council on Stroke, the European Heart Rhythm Association, and the Digital Health Committee.

The role of subclinical atrial fibrillation as a cause of cryptogenic stroke is unambiguously established. Long-term electrocardiogram (ECG) monitoring remains the sole method for determining its presence following a negative initial workup. This position paper of the European Society of Cardiology Working Group on e-Cardiology first presents the definition, epidemiology, and clinical impact of cryptogenic ischaemic stroke, as well as its aetiopathogenic association with occult atrial fibrillation. Then, classification methods for ischaemic stroke will be discussed, along with their value in providing meaningful guidance for further diagnostic efforts, given disappointing findings of studies based on the embolic stroke of unknown significance construct. Patient selection criteria for long-term ECG monitoring, crucial for determining pre-test probability of subclinical atrial fibrillation, will also be discussed. Subsequently, the two major classes of long-term ECG monitoring tools (non-invasive and invasive) will be presented, with a discussion of each method's pitfalls and related algorithms to improve diagnostic yield and accuracy. Although novel mobile health (mHealth) devices, including smartphones and smartwatches, have dramatically increased atrial fibrillation detection post ischaemic stroke, the latest evidence appears to favour implantable cardiac monitors as the modality of choice; however, the answer to whether they should constitute the initial diagnostic choice for all cryptogenic stroke patients remains elusive. Finally, institutional and organizational issues, such as reimbursement, responsibility for patient management, data ownership, and handling will be briefly touched upon, despite the fact that guidance remains scarce and widespread clinical application and experience are the most likely sources for definite answers.

Silent atrial fibrillation: epidemiology, diagnosis, and clinical impact.

Silent or subclinical asymptomatic atrial fibrillation (SAF) has currently gained wide interest in the epidemiologic, neurologic, and cardiovascular communities. It is well known that the electrophysiological and mechanical effects of symptomatic and silent atrial fibrillation (AF) are the same. It is probable that because "AF begets AF," progression from paroxysmal to persistent or permanent AF might be more rapid in patients with long-term unrecognized and untreated SAF, because no treatment is sought by or provided to such patients. Moreover, SAF is common and has significant clinical implications. The clinical consequences of SAF, which include emboli (silent or symptomatic), heart failure, and early mortality, are of paramount importance. Consequently, SAF should be considered in estimating the prevalence of the disease and its impact on morbidity, mortality, and quality of life. Several diagnostic methods of arrhythmia detection utilizing the surface electrocardiogram (ECG), subcutaneous ECG, or intracardiac devices have been utilized to seek meaningful arrhythmic markers of SAF. Whereas a wide range of clinical risk factors of SAF have been validated in the literature, there is an ongoing search for those arrhythmic risk factors that precisely identify and prognosticate outcome events in diverse populations at risk of SAF. Modern diagnostic modalities for the identification of SAF exist, but should be further explored, validated, and tailored to each patient needs. The scientific community should undertake the clinical challenge of identifying and treating SAF.

The antihypertensive treatment effect on left ventricular diastolic function is reflected in exercise electrocardiogram.

BACKGROUND/PURPOSE: Exercise electrocardiographic hump sign is associated with uncontrolled arterial hypertension (AH), left ventricular (LV) diastolic dysfunction, and false-positive exercise testing (ET). The aim of this prospective study was to evaluate the antihypertensive treatment effect on hump and on pseudoischemic ST-segment depression and potential correlations to LV diastolic function and mass changes. METHODS: The study comprised 59 non-coronary artery disease patients (45.9 years; 67.8% men) with never-treated arterial hypertension (143.2/95.1 mm Hg). Treadmill ET and echocardiography were performed at baseline and 6 months after pharmaceutical blood pressure normalization. Prevalence of hump and ST depression, transmitral (E/A) and tissue Doppler imaging (E'/A') early/late velocities ratios, E/E' ratio, and LV mass index (LVMI) were all defined. RESULTS: Prevalence of hump was reduced from 69.5% to 23.7% and false-positive ETs from 35.6% to 18.6% (P < .05). Significant improvement (P < .05) was found in E'/A' ratio (0.68 vs 0.84), E/E' ratio (9.3 vs 7.9), and LVMI (109.2 vs 99.8 g/m(2)). Changes in hump were related to ST-depression changes (r = 0.632, P < .001) and to LV diastolic indices changes; patients with hump only at first ET (54.2%) improved E/A and E'/A' ratios, whereas patients with hump only at second ET (8.5%) worsened diastolic indices with similar changes in blood pressure and LVMI. CONCLUSIONS: Antihypertensive treatment reduces the prevalence of hump and exercise ischemic-appearing ST depression probably through LV diastolic function improvement.

Right-sided chest leads in exercise testing for detection of coronary restenosis.

BACKGROUND: The incorporation of right-sided chest leads (V(3)R through V(5)R) into standard exercise testing has been reported to improve its diagnostic utility. HYPOTHESIS: The purpose of this study was to evaluate any improvement in the ability of exercise testing in detecting restenosis, using additional V(3)R through V(5)R leads, in asymptomatic patients undergoing percutaneous coronary intervention (PCI) in the right coronary artery (RCA) or/and left circumflex (LCX). METHODS: We studied 172 consecutive patients (54 +/- 7 years old, 106 males) undergoing PCI in RCA or/and LCX. A treadmill test had been performed before PCI. Six months later, all patients underwent a second treadmill test and arteriography in order to detect silent ischemia due to restenosis. Recordings during exercise were obtained with the standard 12-leads plus V(3)R through V(5)R. RESULTS: Out of 172 patients, 106 had stenosis in RCA, 35 in LCX, and 31 in both vessels while 6 months later, restenosis was detected in 8 (for RCA), 3 (for LCX), and 3 (for both vessels) patients respectively. Sensitivity, specificity, positive prognostic value, negative prognostic value, and accuracy of exercise testing performed post PCI were ameliorated using V(3)R through V(5)R (79% vs 57%, 97% vs 80%, 69% vs 21%, 98% vs 95%, and 95% vs 78% respectively, P < .05 for all except negative prognostic value). Maximal exercise-induced ST-segment deviation (in mm) was not changed post PCI in 12 leads (1.4 +/- 0.2 vs 1.5 +/- 0.2, P = NS) while it was decreased in V(3)R through V(5)R (0.2 +/- 0.2 vs 1.2 +/- 0.3, P < .01). CONCLUSIONS: The addition of V(3)R through V(5)R improves the diagnostic ability of standard exercise testing in detecting silent ischemia due to restenosis in patients undergoing PCI in RCA or/and LCX.

The aortic distensibility alteration is an index of influence of ischemic preconditioning to myocardial performance.

BACKGROUND: Ischemic preconditioning (IP) is a cardioprotective phenomenon, induced by brief episodes of myocardial ischemia, which is supposed to affect not only the myocardium, but also the entire cardiovascular system. Considering that patients with coronary artery disease (CAD) have also been described to present impaired aortic mechanical properties, we tried to investigate the possible influence of the late phase of IP on aortic distensibility in patients with CAD. METHODS: Fifty patients, aged 48 to 72 (mean, 57+/-6 years), with angiographically confirmed CAD and exercise-induced myocardial ischemia, underwent two treadmill exercise testings (ETs). The second ETs was performed the next day. Thallium-201 scintigraphy was performed during the first and the second ET. Aortic distensibility was evaluated before each exercise testing by a non-invasive technique, using two-dimensional guided M-mode transthoracic echocardiography and arterial pressure was measured simultaneously at the brachial artery by sphygmomanometry. RESULTS: The patients were divided in 2 groups according to the extent of myocardial ischemia at peak exercise of the second test, compared to the first test. In 35 (70%) of the studied patients ischemia signs were reduced during the second ET (Group A), while in the rest 15 (30%) of the patients (Group B) no improvement or even worsening of the observed ischemia signs was demonstrated by the studied exercise parameters and the extent of myocardial ischemia in thallium-scintigraphy. Increased aortic distensibility during the second measurement was found in 33 (94%) of the 35 patients of Group A but only in 1 (7%) of the 15 patients of Group B. Aortic distensibility was found to be significantly improved in patients of Group A, while it was found to be worsened in Group B patients. CONCLUSIONS: The aortic distensibility alteration could be used as an index of influence of ischemic preconditioning to exercise-induced myocardial ischemia, which could be considered indicative of the systemic effects of IP in humans.

Role of right-sided chest leads in the detection of multivessel coronary artery disease in patients with extended Q-wave anterior myocardial infarction.

OBJECTIVE: To evaluate the improvement of diagnostic ability of exercise testing to detect multivessel coronary artery disease in patients with extended Q-wave anterior myocardial infarction, using additional right-sided chest leads. METHODS: Fifty-two consecutive patients with Q-wave anterior myocardial infarction underwent exercise testing, using the standard 12 and the additional right-sided (V3R, V4R, V5R) chest leads, thallium-201 scintigraphy and coronary arteriography. RESULTS: Twenty-one (40%) patients had one-vessel disease, 18 (35%) had two-vessel disease and 13 (25%) had three-vessel disease. The sensitivities of the standard 12-lead exercise testing and its combination with the additional right-sided chest leads were 24% (5/21) versus 28% (6/21) for the detection of one-vessel disease (P: NS), 33% (6/18) versus 83% (15/18) for the detection of two-vessel disease (P<0.05) and 38% (5/13) versus 92% (12/13) for the detection of three-vessel disease (P<0.05), respectively. In thallium-201 scintigraphy, 29 of the 31 (94%) patients with multivessel coronary artery disease demonstrated reversible ischemia. The usual 12-lead exercise testing could detect ischemia in 11 (35%) of these 31 patients, while the addition of the right-sided chest leads could detect ischemia in 27 (87%) of them (P<0.05). CONCLUSIONS: The additional right-sided chest leads significantly improve the low sensitivity of the usual exercise testing to detect multivessel coronary artery disease in patients with previous extended Q-wave anterior myocardial infarction.

QRS score versus ST-segment changes in patients undergoing Tl-201 scintigraphy using dipyridamole infusion.

BACKGROUND: ST-segment changes after dipyridamole infusion followed by handgrip isometric stress lack diagnostic value, because of the low sensitivity for the detection of coronary artery disease (CAD). In addition, an abnormal QRS score during exercise had a greater diagnostic ability than ST-segment changes to detect CAD. This study was undertaken to compare QRS score values with ST-segment changes during thallium 201 scintigraphy via dipyridamole infusion. METHODS AND RESULTS: In this study 128 patients (101 men and 27 women), aged 53 to 72 years (mean, 59 +/- 8 years), underwent Tl-201 scintigraphy after dipyridamole infusion and handgrip isometric stress, as well as coronary angiography. QRS score values and ST-segment changes after dipyridamole infusion and handgrip isometric stress were also estimated. CAD was detected in 96 patients (75%), whereas normal coronary arteries were found in 32 (25%). According to scintigraphic data, 48 patients (37%) had no reversible perfusion defects whereas 80 (63%) had at least 1 reversible perfusion defect. Sensitivities for an abnormal QRS score and ST-segment deviation were 68% versus 18% ( P < .01) for detection of CAD and 75% versus 19% for detection of myocardial ischemia ( P < .01), respectively. Similar specificities were found ( P = not significant). CONCLUSIONS: An abnormal QRS score significantly improves the low sensitivity of ST-segment changes for the detection of myocardial ischemia and CAD by use of Tl-201 scintigraphy with dipyridamole infusion and handgrip isometric stress.

Molecular predictors of drug-induced prolongation of the QT interval.

One of the most common causes of drug withdrawal from the market is the prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsade de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Cardiac and non-cardiac drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general, and selectively blocking the rapidly activating delayed rectifier channel IKr. Co-assembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr, and the majority of mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital long-QT syndrome (LQTS). Current evidence suggests that 5 to 10% of persons in whom TdP develops on exposure to QT-interval prolonging drugs harbor mutations associated with the LQTS and can therefore be viewed as having a subclinical form of the congenital syndrome. This clinical observation is entirely consistent with the concept of reduced repolarization reserve arising from a mutation in an ion-channel gene, which predisposes the carrier to drug-induced TdP. This review centers on the possible molecular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.

A QRS score versus ST-segment changes during exercise testing: which is the most reliable ischaemic marker after myocardial revascularisation?

BACKGROUND: The diagnostic ability of exercise testing based on ST-segment changes is low for the detection of restenosis after percutaneous transluminal coronary angioplasty (PTCA) or ischaemia after bypass surgery (CABG). The aim of this study was to improve the diagnostic accuracy of exercise testing in patients with a history of PTCA or CABG, with the implementation of a QRS score. METHODS: We studied 128 post-PTCA patients (aged 49 +/- 8 years) and 104 post-CABG patients (aged 54 +/- 8 years), who had either positive exercise tests with or without angina, or negative exercise tests with continuing angina-like symptoms, and underwent cardiac catheterisation. RESULTS: The univariate risk ratio of exercise-induced ST-segment deviation to detect restenosis was 3.05 (p = 0.005) and 0.83 (p = 0.690) in group A and group B patients, respectively. The univariate risk ratios of abnormal QRS score values to detect restenosis were 32.1 (p < 0.001) and 18.8 (p < 0.001) for group A and group B patients, respectively. The univariate risk ratios of the combination of exercise-induced ST-segment changes and of abnormal QRS score values to detect restenosis was 9.43 (p < 0.001) and 3.77 (p < 0.044) for group A and group B patients, respectively. The value of the area under the ROC curves is higher for the QRS score in group A patients, group B patients and for the whole study population. CONCLUSIONS: QRS score values significantly improve the diagnostic ability of ST-segment change-based exercise testing, for the assessment of restenosis after PTCA or ischaemia after CABG.

Differences in the morphology and duration between premature P waves and the preceding sinus complexes in patients with a history of paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Experimental and human mapping studies have demonstrated that perpetuation of AF is due to the presence of multiple reentrant wavelets with various sizes in the right and left atria. HYPOTHESIS: Atrial fibrillation may be induced by atrial ectopic beats originating in the pulmonary veins, and premature P-wave (PPW) patterns may help to identify the source of firing. METHODS: To evaluate the morphology and duration of PPWs, 12-lead digital electrocardiogram (ECG) strips containing clearly definable PPWs not merging with the preceding T waves were obtained in 25 patients with AF history (9 men, mean age 59.5 +/- 2.2 years) and 25 subjects without any previous AF history (11 men, mean age 53.6 +/- 25 years). The polarity of PPWs was evaluated in all 12 ECG leads. Previously described indices, such as P maximum, P dispersion (= P maximum-P minimum), P mean, and P standard deviation were also calculated. RESULTS: Premature P-wave patterns were characterized by more positive P waves in lead V1. All P-wave analysis indices were significantly higher in patients with AF than in controls when calculated in the sinus beat, whereas they did not differ between the two groups when calculated in the PPW. P-wave indices did not differ between the PPW and the sinus either patients with AF or controls, except for P mean, which was significantly higher in the sinus (110.1 +/- 1.7 ms) than in the PPW (100 +/- 2 ms) only in patients with AF (p = 0.001). CONCLUSION: The evaluation of PPW patterns is only feasible in a small percentage of short-lasting digital 12-lead ECG recordings containing ectopic atrial beats. Premature P wave patterns characterized by more positive P waves in lead V1, which indicates a left atrial origin in the ectopic foci. The observed differences in P-wave analysis indices between patients with AF and controls and between sinus beats and PPWs may be attributed to the presence of electrophysiologic changes in the atrial substrate.

Improved myocardial performance during repetitive exercise testing: the role of extracellular superoxide dismutase activity in a model of exercise-induced myocardial preconditioning.

BACKGROUND: The aim of this study was to investigate whether endogenous antioxidant defense is involved in adaptation to myocardial ischemia in patients with coronary artery disease and severe exercise-induced myocardial ischemia. METHODS: Fifty patients, aged 50 to 72 years (mean, 58 +/- 6 years), with positive exercise test results underwent 4 treadmill exercise tests. Thallium-201 scintigraphy was performed during the first and the fourth testing. The second, the third, and the fourth tests were performed the next day. The time interval between the second and the third test was 15 minutes, and between the third and the fourth test, the interval was 45 minutes. Extracellular superoxide dismutase activity was measured just before and at the peak of the first and the fourth exercise test. RESULTS: The patients were divided in 2 groups according to the extent of myocardial ischemia at peak exercise of the fourth test compared with the first test. Most of the patients studied (37/50) showed improved myocardial performance during the last of the sequential exercise tests, as demonstrated with the studied exercise parameters and the extent of myocardial ischemia in thallium-scintigraphy. Extracellular superoxide dismutase activity before the last exercise test was found to be significantly increased only in the patients who had improved myocardial performance at the last of the sequential exercise tests. CONCLUSION: The beneficial effects of sequential episodes of exercise-induced myocardial ischemia seem to be strongly related to extracellular superoxide dismutase activity. Although there is still lack of direct evidence, our data support the theory that the favorable adaptation to repetitive exercise may represent an aspect of the clinical relevance of ischemic preconditioning in humans.

Significance of exercise-induced ST changes in leads aVR, V5, and V1. Discrimination of patients with single- or multivessel coronary artery disease.

BACKGROUND: It is known that exercise-induced ST-segment elevation in lead V1 (V1-E) detects left anterior descending (LAD) stenosis. It was also postulated that ST elevation in aVR and simultaneous ST depression in V5 (aVR-E + V5-D) is a marker of ischemia due to significant stenosis of the LAD in patients with single-vessel disease. HYPOTHESIS: This study was undertaken to investigate the significance of the concomitant appearance of both electrocardiographic (ECG) ischemic markers, and of each of them alone during exercise, to detect either LAD stenosis as single-vessel coronary artery disease (CAD), or multivessel CAD involving LAD stenosis. METHODS: A total of 196 consecutive patients (152 men and 44 women, mean age 54 +/- 7 years) with at least one of these ECG markers, who underwent treadmill exercise testing with the Bruce protocol and coronary arteriography, were studied. RESULTS: Patients were divided into three groups. In Group A (83 patients with V1-E + aVR-E & V5-D), 93% of patients with single-vessel disease had significant LAD stenosis (p<0.001), whereas 75% of patients with double-vessel disease had significant stenoses of the LAD and the left circumflex (LCx) coronary arteries (p<0.01). In Group B (97 patients with aVR-E & V5-D but without V1-E), 43% of patients with single-vessel disease had significant LAD stenosis (p<0.08), whereas 85% of patients with double-vessel disease had significant stenoses of the LAD and the right coronary artery (RCA) (p<0.01). In Group C (16 patients with only V1-E), 60% of patients with single-vessel disease had significant LAD stenosis (p<0.05), whereas 75% of patients with double-vessel disease had significant LAD and LCx stenoses (p<0.05). CONCLUSIONS: The concomitant appearance of exercise-induced ST elevation in lead V1, ST elevation in lead aVR, and ST depression in lead V5, as well as the isolated appearance of ST elevation in lead V1 detect significant LAD stenosis as single-vessel disease, or significant stenoses of LAD and LCx arteries in patients with double-vessel disease, whereas the appearance of ST elevation in aVR & ST depression in V5 but without ST elevation in V1 correlates strongly with significant LAD and RCA stenoses and usually indicates double-vessel disease.

P wave analysis indices in young healthy men: data from the digital electrocardiographic study in Hellenic Air Force Servicemen (DEHAS).

P wave analysis from the 12-lead ECG is a recent contribution of noninvasive electrocardiology. P wave analysis indices (maximum and minimum P wave duration, P wave dispersion [Pdis = Pmax-Pmin], adjusted P wave dispersion [APdis = Pdis/square root of measured leads], summated P wave duration [Psum], standard deviation of P wave duration [Psd], mean P wave duration [Pmean]) can predict atrial arrhythmias. However, the definitions of all these indices are based on few studies. The aim of this analysis was to define normal values of these indices and the examine possible associations between P wave indices and clinical variables. The study included 1,353 healthy men, 24 +/- 3 years of age, who answered a questionnaire and underwent a detailed physical examination and a digitized 12-lead surface ECG. All P wave indices were analyzed by two independent investigators. Mean values of the ECG indices were: Pmax: 96 +/- 11 ms, Pmin: 57 +/- 9 ms, Pdis: 38 +/- 10 ms, Psum: 924 +/- 96 ms, Psd: 12 +/- 3, APdis: 11 +/- 3 ms, and Pmean: 77 +/- 8 ms. Age was significantly related with Pmax (r = 0.277, P < 0.01), Pmin (r = 0.255, P < 0.001), Psum (r = 0.074, P < 0.01), and Pmean (r = 0.074, P < 0.01). All ECG indices were significantly associated with the R-R interval, and among each other. This study defined normal indices of wave duration and correlations among them. These markers may play an important predictive role in patients with atrial conduction abnormalities.

Future concepts in P wave morphological analyses.

The idea of analyzing P wave inscriptions to discriminate between patients with different diseases is not new. Whereas standard approaches deal mainly with an analysis of the duration of the P wave, there is an increasing interest for the P wave morphology. Detailed analysis of the low voltage P wave will require a hardware setup that enables high-quality signal acquisition with low noise interference in combination with an ECG subtraction technique. The feasibility of the surface ECG to detect the presence of an abnormal electrophysiological substrate in the atrial myocardium as well as to localize ectopic atrial rhythms will be enhanced by use of P wave morphological analysis.