Management of patent foramen ovale in embolic stroke of undetermined source patients: Malaysian experts' consensus.

INTRODUCTION: About 20 to 40% of ischaemic stroke causes are cryptogenic. Embolic stroke of undetermined source (ESUS) is a subtype of cryptogenic stroke which is diagnosed based on specific criteria. Even though patent foramen ovale (PFO) is linked with the risk of stroke, it is found in about 25% of the general population, so it might be an innocent bystander. The best way to treat ESUS patients with PFO is still up for discussion. MATERIALS AND METHODS: Therefore, based on current evidence and expert opinion, Malaysian expert panels from various disciplines have gathered to discuss the management of ESUS patients with PFO. This consensus sought to educate Malaysian healthcare professionals to diagnose and manage PFO in ESUS patients based on local resources and facilities. RESULTS: Based on consensus, the Malaysian expert recommended PFO closure for embolic stroke patients who were younger than 60, had high RoPE scores and did not require long-term anticoagulation. However, the decision should be made after other mechanisms of stroke have been ruled out via thorough investigation and multidisciplinary evaluation. The PFO screening should be made using readily available imaging modalities, ideally contrasttransthoracic echocardiogram (c-TTE) or contrasttranscranial Doppler (c-TCD). The contrast-transesophageal echocardiogram (c-TEE) should be used for the confirmation of PFO diagnosis. The experts advised closing PFO as early as possible because there is limited evidence for late closure. For the post-closure follow-up management, dual antiplatelet therapy (DAPT) for one to three months, followed by single antiplatelet therapy (APT) for six months, is advised. Nonetheless, with joint care from a cardiologist and a neurologist, the multidisciplinary team will decide on the continuation of therapy.

Lessons from antiarrhythmic trials involving class III antiarrhythmic drugs.

Beta-adrenergic blockers reduce mortality and sudden death in patients convalescing from myocardial infarction, and probably in patients with heart failure. However, the notion that class I antiarrhythmic drugs might save lives by suppressing the triggers of life-threatening ventricular arrhythmias was proved incorrect when the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients, whose ventricular ectopics were successfully suppressed by a number of class I antiarrhythmic drugs, died more readily than similar patients when treated with drugs rather than the placebo. Attention was diverted to class III antiarrhythmic drugs for patients with a poor ejection fraction who survived myocardial infarction and those with heart failure. A preliminary metaanalysis of 3 trials (Basel Antiarrhythmic Study of Infarct Survival [BASIS], Polish Amiodarone Trial [PAT], and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT]) suggested that amiodarone might reduce arrhythmic and all-cause mortality in high-risk post-myocardial-infarction (MI) patients. BASIS suggested that this was only true for patients with preserved ventricular function. Nevertheless, 2 major trials were instituted: the European Myocardial Infarct Amiodarone Trial (EMIAT) and the CAMIAT. Both reported similar results except that patients recruited because of high-density ventricular ectopy seemed to benefit a little more from amiodarone than did patients with poor ventricular function. Detailed analysis of these trials revealed important insights into the value of amiodarone.

Correlation of coronary angiography with "tombstoning" electrocardiographic pattern in patients after acute myocardial infarction.

BACKGROUND: It has been suggested that a specific pattern of electrocardiographic (ECG) changes following acute myocardial infarction (AMI), the so-called "tombstoning," predicts a poorer outcome, although the cause and associations of such changes are not known. To address the possible cause and implications, we correlated angiographic findings with tombstoning in patients following AMI. METHODS: The study investigated 124 patients with AMI, whose ECGs were taken within 24 h of onset of symptoms and who subsequently underwent angiography. In this population, 24 (19%) patients had a definite tombstoning pattern on their admission ECG. RESULTS: Compared with non-tombstoning ECGs, the significant differences in the tombstoning group are as follows: (1) All patients, including those with inferior infarction, had either total or partial occlusion of the left anterior descending (LAD) artery (100 vs. 44%, p < 0.0001); (2) LAD occlusions were significantly more severe and mostly proximal (100% occlusion: 50 vs. 20.5%, p = 0.02; <50% occlusion: 0 vs. 15.9% p = 0.039; proximal occlusion: 92 vs. 65%, p = 0.017); (3) patients with tombstoning ECGs had a significantly greater incidence of occlusion of all three coronary arteries (54.1 vs. 22%, p = 0.001); (4) tombstoning ECGs were more strongly associated with anterior than with inferior infarction (83.3 vs. 33%, p < 0.0001). CONCLUSIONS: The patients with a tombstoning pattern on the admission ECG, who underwent angiography, were associated with occlusion of a high-grade stenosis of the proximal LAD artery (usually with involvement of more than one artery) and were predominantly seen in association with anterior infarction.

Relation of ventricular repolarization to cardiac cycle length in normal subjects, hypertrophic cardiomyopathy, and patients with myocardial infarction.

BACKGROUND: Prolonged QT interval and QT dispersion have been reported to reflect an increased inhomogeneity of ventricular repolarization, which is believed to be responsible for the development of arrhythmic events in patients with long QT syndrome, coronary heart disease, and myocardial infarction, congestive heart failure, and hypertrophic cardiomyopathy (HC). HYPOTHESIS: This study was undertaken to determine whether an abnormal QT/RR dynamicity may reflect autonomic imbalance and may contribute to arrhythmogenesis in patients with heart disease. METHODS: The relation between QT, QTpeak (QTp), Tpeak-Tend (TpTe) intervals and cardiac cycle length was assessed in 70 normal subjects, 37 patients with HC, and 48 survivors of myocardial infarction (MI). A set of 10 consecutive electrocardiograms was evaluated automatically in each subject using QT Guard software (Marquette Medical Systems, Milwaukee, Wisc.). RESULTS: In patients with HC, all intervals were significantly prolonged compared with normals (p < 0.001 for QT and QTp; p < 0.04 for TpTc); in survivors of MI, this was true for the maximum QT and QTp intervals (p < 0.05). A strong linear correlation between QT, QTp, and RR intervals was observed in normals and in patients with MI and HC (r = 0.65-0.59, 0.82-0.77, 0.79-0.74, respectively, p < 0.0001). TpTe interval only showed a weak correlation with heart rate in normals (r = 0.24, p < 0.05) and was rate-independent in both patient groups (p = NS). Compared with normals, the slopes of QT/RR and QTp/RR regression lines were significantly steeper in patients with MI and HC (0.0990-0.0883, 0.1597-0.1551, 0.1653-0.1486, respectively). Regression lines were neither parallel nor identical between normals and patients (T > 1.96, Z > 3.07). There was no difference in steepness for TpTeR/RR lines between groups (0.0110, 0.0076, 0.0163, respectively). TpTe/QTp ratio was similar in normals and in patients with MI and HC (0.30 +/- 0.03, 0.31 +/- 0.07, 0.30 +/- 0.04, respectively), in the absence of any correlation between QTp and TpTe intervals, suggesting disproportional prolongation of both components of QT interval. CONCLUSION: Compared with normals, a progressive increase in QT and QTp intervals at slower heart rates in patients with MI and HC may indicate an enhanced variability of the early ventricular repolarization and may be one of the mechanisms of arrhythmogenesis.

The current cardiac safety situation with antihistamines.

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. The clinical interest of classical 'first generation' antihistamines is currently rather limited by their anticholinergic and sedative properties. The second generation of antihistamines, so-called non-sedating antihistamines, are free of these side-effects. However, since the 1990s, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe dysrhythmias. These drugs prolong the monophasic action potential and surface electrocardiographic QT interval and may lead to the development of early after-depolarization and possibly torsades de pointes through an inhibition of potassium channel repolarization. Concomitant administration with drugs that inhibit the hepatic cytochrome P-450 (imidazole antifungals, macrolide antibiotics) or those that prolong the QT interval by the same or other mechanism (e.g. antiarrhythmics, antipsychotics, tricyclic antidepressants) increases their effect on the cardiac repolarization. The cardiac safety profile of newer non-sedating antihistamines requires confirmation. Drugs with low or no potential to block the K + rectification channel (e.g. IKr channels) are likely to possess cardiac safety advantages. Other drug-related factors such as the physico-chemical properties of the antihistamines and its metabolic profile may also contribute to the cardiac response. Mizolastine is a new non-sedating antihistamine with antiallergic properties. It has a good bioavailability and a metabolism via the cytochrome P-450 oxidation accounting for only 35% of its hepatic clearance. In addition, mizolastine displays low lipophilicity and consequently low cardiac tissue fixation. In clinical studies, mizolastine has not shown any dose-related increase in QT intervals. Its clinical use has not been associated with ventricular dysrhythmias. Thus, although the post-marketing experience with mizolastine is still limited, mizolastine offers a safe alternative for the therapeutic management of allergic rhinitis and urticaria. However, more data are still needed on the cardiac safety of this and other non-sedating antihistamines.

Arrhythmogenic mechanisms of non-sedating antihistamines.

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. Recently, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe arrhythmias, namely torsades de pointes, particularly in overdosage, concomitant ingestion of imidazole or macrolide antibiotics and in patients with underlying cardiac or liver diseases. It has now been shown that the molecular target in human ventricle for the potassium channel blockade of antihistamine is HERG gene located in chromosome 7 that expresses the delayed rectifier IKr and appears to be involved in the congenital long QT syndrome. Mechanistic studies showed that blockade of IKr channels by these drugs leads to prolongation of the monophasic action potential (QT interval on surface electrocardiogram) which may then induce the development of early after-depolarization and dispersion of repolarisation leading to torsades de pointes through re-entry mechanism. There are still many questions that need to be answered such as the roles of other potassium channels (IKs, Ito, and Iped) and the relative expression of various potassium channels in different individuals which may be important in the pathogenesis of torsades de pointes with non-sedating antihistamines. There is also a lack of information on the cardiac actions of newer non-sedating antihistamines. It is hoped that with a better understanding of the arrhythmogenic mechanism of non-sedating antihistamines, one will be able to identify those at risk patients and prevent any cardiac toxicity associated with antihistamines and ultimately death.

What should we expect from the next generation of antiarrhythmic drugs?

Five drugs currently constitute approximately 70% of the world market for antiarrhythmic medications. Since the publication of studies documenting that certain Class I drugs may increase mortality in high-risk postinfarction patients, basic science and clinical studies have focused on Class III antiarrhythmic drugs. However, drugs that prolong repolarization and cardiac refractoriness are sometimes associated with potentially lethal torsades de pointes. Amiodarone, a multichannel blocker, may be the exception to this observation, but it nevertheless fails to reduce total mortality compared with placebo in high-risk patients following myocardial infarction. However, Class III agents remain the focus of drug development efforts because they lack the negative hemodynamic effects, affect both atrial and ventricular tissue, and can be administered as either parenteral or oral preparations. Developers of newer antiarrhythmic agents have focused on identifying antiarrhythmic medications with the following characteristics: appropriate modification of the arrhythmia substrate, suppression of arrhythmia triggers, efficacy in pathologic tissues and states, positive rate dependency, appropriate pharmacokinetics, equally effective oral and parenteral formulations, similar efficacy in arrhythmias and their surrogates, few side effects, positive frequency blocking actions, and cardiac-selective ion channel blockade. New and investigational agents that more closely approach these goals include azimilide, dofetilide, dronedarone, ersentilide, ibutilide, tedisamil, and trecetilide. In the near future, medications will increasingly constitute only part of an antiarrhythmic strategy. Instead of monotherapy, they will often be used in conjunction with an implanted device. Combination therapy offers many potential advantages. Long-term goals of antiarrhythmic therapy include upstream approaches, such as identification of the biochemical intermediaries of the process and, eventually, of molecular and genetic lesions involved in arrhythmogenesis.

QT dispersion does not represent electrocardiographic interlead heterogeneity of ventricular repolarization.

INTRODUCTION: QT dispersion (QTd, range of QT intervals in 12 ECG leads) is thought to reflect spatial heterogeneity of ventricular refractoriness. However, QTd may be largely due to projections of the repolarization dipole rather than "nondipolar" signals. METHODS AND RESULTS: Seventy-eight normal subjects (47+/-16 years, 23 women), 68 hypertrophic cardiomyopathy patients (HCM; 38+/-15 years, 21 women), 72 dilated cardiomyopathy patients (DCM; 48+/-15 years, 29 women), and 81 survivors of acute myocardial infarction (AMI; 63+/-12 years, 20 women) had digital 12-lead resting supine ECGs recorded (10 ECGs recorded in each subject and results averaged). In each ECG lead, QT interval was measured under operator review by QT Guard (GE Marquette) to obtain QTd. QTd was expressed as the range, standard deviation, and highest-to-lowest quartile difference of QT interval in all measurable leads. Singular value decomposition transferred ECGs into a minimum dimensional time orthogonal space. The first three components represented the ECG dipole; other components represented nondipolar signals. The power of the T wave nondipolar within the total components was computed to measure spatial repolarization heterogeneity (relative T wave residuum, TWR). QTd was 33.6+/-18.3, 47.0+/-19.3, 34.8+/-21.2, and 57.5+/-25.3 msec in normals, HCM, DCM, and AMI, respectively (normals vs DCM: NS, other P < 0.009). TWR was 0.029%+/-0.031%, 0.067%+/-0.067%, 0.112%+/-0.154%, and 0.186%+/-0.308% in normals, HCM, DCM, and AMI (HCM vs DCM: NS, other P < 0.006). The correlations between QTd and TWR were r = -0.0446, 0.2805, -0.1531, and 0.0771 (P = 0.03 for HCM, other NS) in normals, HCM, DCM, and AMI, respectively. CONCLUSION: Spatial heterogeneity of ventricular repolarization exists and is measurable in 12-lead resting ECGs. It differs between different clinical groups, but the so-called QT dispersion is unrelated to it.

Comparative reproducibility of QT, QT peak, and T peak-T end intervals and dispersion in normal subjects, patients with myocardial infarction, and patients with hypertrophic cardiomyopathy.

Abnormal repolarization is associated with arrhythmogenesis. Because of controversies in existing methodology, new computerized methods may provide more reliable tools for the noninvasive assessment of myocardial repolarization from the surface electrocardiogram (ECG). Measurement of the interval between the peak and the end of the T wave (TpTe interval) has been suggested for the detection of repolarization abnormalities, but its clinical value has not been fully studied. The intrasubject reproducibility and reliability of automatic measurements of QT, QT peak, and TpTe interval and dispersion were assessed in 70 normal subjects, 49 patients with acute myocardial infarction (5th day; MI), and 37 patients with hypertrophic cardiomyopathy (HC). Measurements were performed automatically in a set of 10 ECGs obtained from each subject using a commercial software package (Marquette Medical Systems, Milwaukee, WI, U.S.A.). Compared to normal subjects, all intervals were significantly longer in HC patients (P < 0.001 for QT and QTp; p < 0.05 for TpTe); in MI patients, this difference was only significant for the maximum QT and QTp intervals (P < 0.05). In both patient groups, the QT and QTp dispersion was significantly greater compared to normal subjects (P < 0.05) but no consistent difference was observed in the TpTe dispersion among all three groups. In all subjects, the reproducibility of automatic measurement of QT and QTp intervals was high (coefficient of variation, CV, 1%-2%) and slightly lower for that of TpTe interval (2%-5%; p < 0.05). The reproducibility of QT, QTp, and TpTe dispersion was lower (12%-24%, 18%-28%, 16%-23% in normal subjects, MI and HC patients, respectively). The reliability of automatic measurement of QT, QTp, and TpTe intervals is high but the reproducibility of the repeated measurements of QT, QTp and TpTe dispersion is comparatively low.

Comparison of formulae for heart rate correction of QT interval in exercise electrocardiograms.

The study investigated the differences in five different formulae for heart rate correction of the QT interval in serial electrocardiograms recorded in healthy subjects subjected to graded exercise. Twenty-one healthy subjects (aged 37+/-10 years, 15 male) were subjected to graded physical exercise on a braked bicycle ergometer until the heart rate reached 120 beats/min. Digital electrocardiograms (ECG) were recorded on baseline and every 30 seconds during the exercise. In each ECG, heart rate and QT interval were measured automatically (QT Guard package, Marquette Medical Systems, Milwaukee, WI, USA). Bazett, Fridericia, Hodges, Framingham, and nomogram formulae were used to obtain QTc interval values for each ECG. For each formula, the slope of the regression line between RR and QTc values was obtained in each subject. The mean values of the slopes were tested by a one-sample t-test and the comparison of the baseline and peak exercise QTc values was performed using paired t-test. Bazett, Hodges, and nomogram formulae led to significant prolongation of QTc intervals with exercise, while the Framingham formula led to significant shortening of QTc intervals with exercise. The differences obtained with the Fridericia formula were not statistically significant. The study shows that the practical meaning of QT, interval measurements depends on the correction formula used. In studies investigating repolarization changes (e.g., due to a new drug), the use of an ad-hoc selected heart rate correction formula is highly inappropriate because it may bias the results in either direction.

Consistency of multicenter measurements of heart rate variability in survivors of acute myocardial infarction.

Heart rate variability (HRV) analysis from 24-hour ambulatory ECG has been widely used in risk stratification of patients after myocardial infarction (MI). The accuracy of HRV assessment is known to potentially vary when different commercial systems are used. However, the consistency of HRV measurements has never been fully investigated. Twenty-six post-MI patients (mean age 59 +/- 8 years, 22 men) were studied, of whom 13 succumbed to sudden cardiac death (SCD) within 1 year and 13 remained alive for at least 3 years (MI survivors). Each patient had a 24-hour Holter ECG recorded before hospital discharge. HRV analysis was performed four times from the same recordings using three different Holter tape analysis systems (Marquette, Reynolds, and CardioData) by four independent operators (CardioData system was used twice, once in the United Kingdom and once in the United States). Mean normal-to-normal RR intervals (mNN) and 3 HRV parameters (SDNN, RMSSD, and HRV triangular index [HRVi]) were derived from each recording. The consistency of mNN and HRV measurements was evaluated by coefficient of variance (CV) and by the Bland-Altman method. The results demonstrated that (1) all indices measured by different systems were statistically similar (P = NS) except the measurement of RMSSD (P = 0.01), (2) the measurements of mNN were highly reproducible with a maximum mean difference of 1.8 +/- 13.8 ms and maximum limits of agreement from -14.6 to +15.6 ms. The maximum mean differences were--1.8 +/- 1.4 unit and 4.4 +/- 9.6 ms for HRVi and SDNN, respectively, and RMSSD was less reproducible with a maximum mean difference of--11.1 +/- 11.5 ms, and limits of agreement from -16.2 to +9.6 ms; and (3) the consistency of mNN (CV 0.9% +/- 0.9%) was significantly higher than that of HRVi, SDNN, and RMSSD (P < 0.0001). The consistency of HRVi was similar to that of SDNN (4.8% +/- 2.1% vs 5.7% +/- 4.8%, P = 0.4), and the consistency of RMSSD (26.6% +/- 13.3%) was significantly lower than that of the other measurements (P < 0.00001). In conclusion, the measurements of mNN by different analytical systems are the most consistent among the parameters studied. The global 24-hour measurements of HRV (SDNN and HRVi) are highly reproducible, whereas the measurement of short-term HRV components (RMSSD) is significantly less reproducible.