Chronic obstructive pulmonary disease (COPD)
COPD is an independent risk factor for cardiovascular morbidity and mortality (Celli et al, 2010). Potential explanations for this association include: smoking, negative cardiac consequences of dynamic hyperinflation, exercise limitations and hypoxemia (Celli et al, 2010; Priori et al, 2001).
Carjea (Carjea, 2003) studied the prevalence and characteristics of late ventricular potentials in 90 patients with COPD compared to healthy subjects and found significant differences. The highest prevalence was noticed in moderate to severe cases.
Acromegaly
The heart is an end-organ of growth hormone action. A high prevalence of complex ventricular arrhythmias has been mentioned in patients with acromegaly, possible as a result of disordered left ventricular architecture and ventricular remodeling (Clayton, 2003).
The frequency of premature ventricular complexes increased with duration of acromegaly, and the severity of arrhythmia correlated with left ventricular mass but not with growth hormone levels (Kahaly et al, 1992). Structural heterogeneity in acromegalic heart is due to areas of hypertrophied myocytes, separated by fibrosis and cellular infiltrations (Clayton, 2003). Late ventricular potentials are frequently seen in active acromegaly, are associated with disease activity and may represent an early and sensitive parameter to detect myocardial injury (Herrmann et al, 2001). No association was found between presence of late ventricular potentials and left ventricular mass index. Longitudinal studies are needed to determine whether therapy changes the electrophysiological abnormalities. Earlier studies showed that arrhythmias were as frequent before and after treatment of acromegaly, implying that fibrous tissue infiltration caused irreversible scarring (Hayward et al, 1987; Rodrigues et al, 1989).
Thalassemia
Beta-thalassemia, the impaired production of the beta hemoglobin chain, is associated with significant changes in heterogeneity of cardiac ventricular repolarization and SCD (Russo et al, 2011). In the late stages, frequent premature ventricular contractions and sustained ventricular tachycardia have been mentioned, related to cardiac death. Thalassemia patients require intensive blood transfusions due to severe anemia, and an increase in body iron burden occurs both in patients who are or are not receiving transfusions (Lekawanvijit & Chattipakorn, 2009).
The role of iron overload in causing conduction delays in the thalassemic heart is well documented and iron overload thalassemic cardiomyopathy may explain the occurrence of LVPs (Isma’eel et al, 2007), as well as changes in QRS duration and RMS40 voltage. The patchy nature of cardiac iron deposition may provide substrates for re-entry and risk of fatal arrhythmias (Lekawanvijit & Chattipakorn, 2009). Iron-overloaded cardiomyocytes have a smaller overshoot potential and shorter action potential duration than iron-free cardiomyocytes in the same heart and reduced Na+ currents may be an underlying mechanism (Lekawanvijit & Chattipakorn, 2009). Further mechanisms related to tachyarrhythmias and SCD are changes in calcium homeostasis, elevated prostaglandin E2 to prostacyclin ratio, increased interleukin 1 level and lipid peroxidation. Future large populations, long-term follow-up studies are needed to demonstrate further clinical consequences in iron overload cardiomyopathy.
Connective tissue and systemic diseases
Cardiovascular involvement is common in connective tissue diseases (Lazzerini et al, 2006), but myocardial involvement is seldom recognized clinically (Stanescu & Dan, 1992). Ventricular arrhythmias represent a major cause of SCD in autoimmune rheumatic diseases (Sefarovic et al, 2006). The mechanisms are probably multiple and myocardial fibrosis seems to play a pivotal role (Lazzerini et al, 2006). Lazzerini et al (Lazzerini et al, 2007) concluded that anti-Ro/SSA positive patients have a particularly high risk of developing ventricular arrhythmias.
The heart is one of the major organs involved in scleroderma. Ventricular arrhythmias are common among asymptomatic patients with systemic sclerosis, especially: premature ventricular contractions and non-sustained VT (Sefarovic et al, 2006). Patchy myocardial fibrosis represents an ideal substrate for reentry tachyarrhythmias. LVPs occurred in patients with diffuse progressive systemic sclerosis; a lower myocardial involvement was noticed in the CREST syndrome (Paradiso et al, 1996). Diffuse abnormalities of the cardiac tissue detected by SAECG may be present in patients with systemic sclerosis without cardiac symptoms and higher skin scores correlated with the presence of LVPs (Paradiso et al, 2002). Pignone et al (Pignone et al, 1994) found no correlation between LVPs and immunologic patterns, cutaneous and pulmonary involvement in 26 patients with systemic sclerosis.
Myocardial lesions in systemic lupus erythematosus are characterized by an increase in interstitial connective tissue and myocardial scarring (Paradiso et al, 2001). The most important cardiac manifestations of systemic lupus erythematosus are: pericarditis, lesions of valves, myocardium and coronary artery disease (Gomez-Leon Manduiano & Amezcua-Guerra, 2008). Sinus and atrial arrhythmias are more prevalent, but QT interval prolongation, abnormalities in the autonomic tone and LVPs indicate high risk of developing life-threatening ventricular arrhythmias (Sefarovic et al, 2006). LVPs were recorded in patients with systemic lupus (Paradiso et al, 2001; Wranicz et al, 2001), and the depolarization abnormalities revealed by SAECG reflect a longer extent of myocardial fibrosis and echocardiography and SAECG alterations are markers of subclinical myocardial involvement. Increasing evidence suggest that anti-Ro/SSA antibodies may trigger rhythm disturbances due to an inhibiting cross-reaction with several cardiac calcium and potassium ionic channels (Lazzerini et al, 2010).
So far, the evidence related to electrocardiographic disturbances in this setting is restricted to studies with small number of patients (Teixeira, et al, 2010). The mechanisms of arrhythmias are related to the inflammatory process of pericarditis and myocarditis, atherosclerotic myocardial ischemia, increased sympathetic activity, vasculitis of small vessels with collagen deposits and anti-Ro/SSA antibodies (Lazzerini et al, 2010; Teixeira, et al, 2010).
Cardiac sarcoidosis affects the myocardium, pericardium and endocardium, and the disease may present with: atrioventricular and intraventricular conduction disturbances, ventricular arrhythmias and HF. Ventricular arrhythmias are among the main causes of SCD in cardiac sarcoidosis. LVPs on SAECG were mentioned and they were abolished after steroid therapy (Yodogawa et al, 2011).
Schizophrenia
Schizophrenia patients were also found to be positive for LVPs. Cardiac autonomic dysregulation in schizophrenia patients and use of psychiatric and/or non-psychiatric medications that affect conduction, may account for LVPs (Nashoni et al, 2010).
Influence of therapy on LVPs
LVPs are influenced by antiarrhythmic therapy, trombolytic drugs, anevrismectomy, percutaneous coronary interventions, coronary artery bypass surgery, statins, steroids. The effect on the prevalence of LVPs of modern pharmacologic therapy in patients with acute MI has been assessed in several studies (Santangeli et al, 2008). Class I, II and III antiarrhythmics may reduce the prevalence of LVPs. Class IV antiarrhythmics (Verapamil) do not influence LVPs. Some class III antiarrhythmic drugs are able to prolong SA-QRS and LAS40, and may be associated with the occurence of LVPs.
Freedman and Steinberg showed that sodium channel blockers (quinidine, procainamide, imipramide) have preferential effects on slowly conducting tissue in patients with a history of VT, causing an important prolongation of LVPs (Freedman & Steinberg, 1991). Santarelli et al, reported that LVPs were less frequent in acute MI patients treated with betablockers compared with those not treated with betablockers during hospitalization. This effect was found only in patients with a preserved LVEF (Santarelli et al, 1993). No significant SAECG changes have been observed after Sotalol.
Adrenergic stimulation with adrenaline and isoprenaline, and parasympatholytic agents such as atropine, lead to significant changes in the signal averaged electrocardiogram in healthy subjects (Goldberger et al, 1994). Beta-adrenergic stimulation with isoproterenol led to a significant shortening of SA-QRS, and epinephrine prolonged the QRS duration. Increased alfa-adrenergic stimulation with phenylephrine and parasympathetic stimulation did not affect the SAECG. Parasympathetic blockade caused a mild decrease in the QRS duration. Changes in the RMS40 and LAS40 paralleled those of the QRS duration (Goldberger et al, 1994).
Junker et al, found in a substudy of the CONSENSUS II trial, a reduced prevalence of LVPs after the angiotensin converting enzyme inhibitor enalapril (Junker et al, 1995). Lipid-lowering interventions reduce coronary events, VT/VF episodes, SCD and all-cause mortality (Liu et al, 2009). Recent studies have demonstrated that statins have antiarrhythmic properties in addition to their lipid-lowering effects (Abuissa et al, 2009; Chu et al 2007; Liu et al, 2009). Kayikcioglu et al. found a significant decrease of the prevalence of LVPs and ventricular arrhythmias in acute MI patients receiving pravastatin, irrespective of lipid level (Kayikcioglu et al, 2003). Pre-treatment with statin could reduce the reperfusion arrhythmias after acute myocardial infarction (Zhao et al, 2008). Most of the antiarrhythmic benefits after statin therapy observed in high cardiovascular risk patients might be explained by statins’ pleiotropic effects: anti-ischemia, anti-inflammation, antihypertrophy, angiogenic and sympathetic effects (Chu et al, 2007). Statins achieve their antiarrhythmic drug action in part by preventing or reversing electrophysiologic remodeling induced by hypercholesterolemia, but they also have an independent antiarrhythmic effect (Liu et al, 2009).
The ratio between QTc and QRS changes caused by several antiarrhythmic drugs identifies patients with sustained VT risk, which appear despite therapy (Cain et al, 1996). LVPs may disappear after coronary artery bypass surgery in acute MI patients (Bigger et al, 1997). Anevrisectomy is also known to reduce the prevalence of LVPs.
Corticosteroid therapy may be effective for ventricular arrhythmias in the early stage of cardiac sarcoidosis (Yodogawa et al, 2011).
Correlation and combination with other ECG methods
Several studies have mentioned correlations between surface standard 12-lead ECG and SAECG parameters. The relation between LVP and QT dispersion (QTd) (Ducceschi et al, 1996; Mozos, 2006), suggested that the existence of some slow conducting myocardial areas, related to positive LVPs, is associated with a higher inhomogeneity of ventricular repolarisation, expressed as a higher QTd. LAS40 and SA-QRS correlated with QT dispersion (Ducceschi et al, 1998).
QT intervals and Tpeak-Tend intervals were prolonged in post-infarction HF patients with LVPs. LVPs and SAECG parameters can be predicted using 12-lead ECG: QT intervals, QRS duration, T wave variables (Mozos et al, 2011). The significant association between SA-QRS and Tpeak-Tend interval and T wave amplitude was attributed to the extension of LVP into the ST segment.
Breithardt et al. (Breithardt et al, 1990) showed that the presence of LVPs was positively correlated with an ECG score based on R and Q wave duration and R/S ratio in MI patients with or without a history of sustained VT.
LVPs were not related to the frequency of ventricular ectopic activity and malignant premature ventricular contractions because each test assesses different components of arrhythmia susceptibility. The combination of the two abnormalities may identify a high-risk group for SCD (Middelkauff et al, 1990; Fauchier et al, 1991).
The combination of T wave alternans and SAECG, increases sensitivity, specificity, positive and negative predictive value for VT risk (Kondo et al, 2001).
SAECG and body surface mapping (BSM) provide complementary information in patients with an old MI, and an important, significant correlation was found between isointegral QRST maximum and LAS40 and RMS40 (Mozos et al, 2008). SAECG may be assessed using BSM, increasing its sensitivity in anterior and inferior MI (Ho, 1993). BSM may detect LVPs, undetected by SAECG, even if the underlying substrate is relative small or the electrodes are placed outside that area (Linnenbank et al, 2001). Analysis of isopotential maps of the terminal part of the QRS complex may provide additional information regarding LVPs distribution, slow conducting areas and VT origin (Faugere et al, 1986).
LVPs and other ventricular arrhythmia predictors
Despite the significant predictive value for arrhythmic events, LVPs show a low positive predictive accuracy, thus resulting in limited usefulness as a single variable to identify patients at high risk (Santangeli et al, 2008). Significantly impaired LVEF is an established predictor of SCD and is included in the current guidelines for primary prevention of SCD. But patients with a preserved LVEF are not included in the current guidelines (Liew, 2011).
Combination of LVPs with LVEF (Jain & Avasthi, 1992; Konta et al, Kudaiberdieva et al, 2003), ventricular volumes (Pollak et al, 1985), heart rate variability (Gomes et al, 2001), ventricular diskinezia (Olinic & Zdrenghea, 1998), programmed ventricular stimulation (Ho et al, 1996), atrial pacing (Steinbigler et al, 1999), a high Killip class (3 or 4) in a patient with a history of a MI, may improve the predictive value of LVPs for ventricular arrhythmias.
Kudaiberdieva et al (Kudaiberdieva et al, 2003) investigated incidence of ventricular tachycardia/ventricular fibrillation in relation with noninvasive arrhythmia risk markers in 54 patients with an old myocardial infarction. Logistic regression analysis revealed that the highest association with ventricular tachyarrhythmia had combination of LVPs and increased QT variability index, followed by combination of LVPs and left ventricular ejection fraction.
Standard methods fail to reveal late potentials in 20 to 30% of patients with ventricular arrhythmias after myocardial infarction (Steinbigler et al, 1999). Increase in heart rate may unmask late potentials in patients prone to malignant ventricular arrhythmias, because conduction in the arrhythmogenic area is critically slowed by an increased heart rate. Functional late potential analysis, with non-invasive clinical stress tests, should be performed in order to identify patients at risk of malignant ventricular arrhythmias, not identified with conventional late potential analysis (Steinbigler et al, 1999). Epicardial mapping has demonstrated that during sinus rhythm, activation of the tissue critical to ventricular tachycardia is completed before the end of the QRS complex and is not detectable within the ST segment (Steinbigler et al, 1999). A shift of septal mid-QRS potentials toward the terminal QRS complex by critical slowing of conduction during increased heart rate, could explain the appearance of new late ventricular potentials. Different findings may be due to myocardial infarction location: an increase of QRS duration in patients with anterior infarction and an increase of magnitude and LAS40 in patients after inferior infarctions (Steinbigler et al, 1999).
Combining electrocardiography methods with other methods may help to select the candidates for pharmacological therapy, defibrillator implantation and resynchronization, in order to reduce overall mortality and SCD.
Conclusions
Sudden cardiac death, caused mainly by fatal ventricular arrhythmias, can be predicted using a practical and low-cost tool: SAECG. LVPs represent slowed conduction through a diseased myocardium and may form the substrate for life-threatening ventricular arrhythmias in patients with cardiac and extracardiac pathology. SAECG is altered due to a variety of physiological and pharmacologic conditions. Antiarrhythmic therapy, trombolytic drugs, anevrismectomy, percutaneous coronary interventions, coronary artery bypass surgery, statins and steroid therapy are able to influence LVPs. Late ventricular potentials have a high negative predictive value. When positive, LVPs help better stratify the arrhythmic risk of patients, alone or in combination with other methods, in several clinical settings.
