Mechanisms of ventricular arrhythmias and methods used to assess sudden cardiac risk in some extracardiac diseases
Electrocardiographic changes were mentioned in several noncardiac diseases, due to multiple mechanisms: changes of the position of the heart, autonomic imbalance, hormonal abnormalities, interposition of fluid or tissue between the heart and the electrodes, increased blood pressure, cardiomyopathy of systemic diseases, electrolyte imbalances, or due to therapy [1, 2].
A prolonged ECG
Besides a prolonged QT interval, longer than 450 ms in male and 460 ms in female ,
The aim of the present chapter was to provide a concise overview of available data regarding epidemiology and pathophysiology of ventricular arrhythmias in several noncardiac diseases, to mention the main methods used to assess arrhythmia risk, as well as to elucidate their relation to long-term outcome. Dyslipidemia, obesity, diabetes mellitus, liver, hematologic, neurologic and psychiatric disorders, are discussed.
3. Dyslipidaemia and ventricular arrhythmia risk
Elevated LDL cholesterol was associated with all manifestations of coronary artery disease including sudden cardiac death .
Several clinical and autopsy studies demonstrated an association between elevated cholesterol levels and sudden cardiac death [11, 12]. Gualdiero et al. reported a positive correlation between cholesterol level, QT dispersion and premature ventricular contractions in patients with isolated hypercholesterolemia, and normalization of serum cholesterol and QT dispersion and improvement of ventricular ectopic activity, with simvastatin . Szabo et al. found significant correlations of QT interval duration and QT dispersion with total and LDL cholesterol, triglycerides and apoplipoprotein B, respectively, in patients with
It was also hypothesized that hypercholesterolemia causes repolarization abnormalities, probably, by beta or IK channel phosphorylation mediated mechanisms . Hypercholesterolemia causes also endothelial dysfunction, with impaired microvascular vasodilatation, facilitating vasoconstriction, and electrical heterogeneity and extrasystolic activity . The increase in the QT interval duration in cholesterol fed rabbits was lesser if L-Arginine was supplemented, suggesting a beneficial role of L-Arginine (a nitric acid precusror) in hypercholesterolemia induced repolarization characteristics . L-Arginine increases endogenous nitric oxide, which may activate ATP dependent K channels, shortening the action potential .
Statins have antiarrhythmic properties, exhibiting a protective effect against the occurrence of ventricular arrhythmias and atrial fibrillation, in addition to their lipid-lowering and anti-atherogenic effects [5, 12, 13, 17, 18]. The main mechanisms explaining, probably, the antiarrhythmic properties of statins are as follows: prevention of ischemia-induced electrophysiological effects that predispose to ventricular arrhythmias and ischemia-induced oxidative stress, decrease in ischemia-induced myocyte hypertrophy, reverse of neural remodeling induced by hypercholesterolemia, increase of heart rate variability, decrease of QT interval duration and variability, reversion of electrophysiological remodeling induced by hypercholesterolemia, increase in parasympathetic tone, changes in transmembrane ion channel properties, decrease of the incidence of late ventricular potentials [10, 12].
4. Ventricular arrhythmias in obesity and eating disorders
Weight loss causes a shortening of the QT interval, correlated with diastolic blood pressure decrease, and changes in time and frequency domain parameters of heart rate variability, with recovery of the physiological autonomic control (increase in parasympathetic and reduction in sympathetic indices .
QT prolongation, signal averaged ECG abnormalities and late ventricular potentials were reported in
|Obesity||parasympathetic withdrawal, conduction abnormalities, cardiomyopathy of obesity, lipotoxicity of the myocardium induced by free fatty acids, structural heterogeneity due to fatty infiltration of the heart, focal myocardial disarray, fibrosis, mononuclear cell infiltration||SAECG|
|Hypercholesterolemia||autonomic imbalance, endothelial dysfunction, oxidative stress, impaired functionality of ion channels||QTc|
|electrolyte imbalances (hypokalemia)||QT, LVPs|
|Diabetes mellitus||autonomic imbalance, oxidative stress, increased cytosolic calcium, increased Na current, hyperinsulinemia, insulinresitance, hypokalemia||QT,|
|Liver cirrhosis||cirrhotic cardiomyopathy, cardiac ion channel remodeling, electrolyte imbalances, impaired autonomic function||QT|
|Stroke, Subarachnoid hemorrhage||cardiac autonomic imbalance, neural interventions, norepinephrine, calcium influx, myocytolysis, hypokalemia, concomitant myocardial ischemia and heart failure, risk factors for coronary heart disease, aging, inflammation, Takotsubo cardiomyopathy||QT|
VT, R/T, VF, Vf
|Intracranial hemorrhage||intraventricular blood, hydrocephalus||QTc|
|Neuromuscular disorders||cardiomyopathy, diffuse cardiac fibrosis and fatty acid infiltration, myocyte degeneration||QTcd, JTcd|
|Parkinson’s disease||autonomic disturbance (intrinsic or iatrogenic), cardiovascular comorbidities, electrolyte imbalances, degeneration of cardioselective neurons||QT|
|Epilepsy||sympathovagal imbalance, impaired cardiac repolarization, dysfunction of cortical networks, ictal hypoxemia and hypercapnia, stress hormones, cardiorespiratory interactions, fibrosis (perivascular, interstitial)||QT|
|Anemia||left ventricular hypertrophy, sympathetic nervous system activation, oxidative stress, chronic inflammation, decreased myocardial oxygen supply||QT|
5. Glucose metabolism disorders and ventricular arrhythmia risk
Several studies associate diabetes mellitus and hyperglycemia with sudden cardiac death, related to QT interval prolongation, appearance of late ventricular potentials, impaired depolarization and repolarization, enhanced sympathetic activity, oxidative stress, increased cytosolic calcium content, defective phosphoinositide 3-kinase signaling with increased persistent sodium current, premature and accelerated atherosclerosis, transient hypoglycemic episodes due to drug therapy, duration of diabetes, and renal failure, as target-organ damage, causing electrolyte imbalances [5, 33-36]. QT interval prolongation and increase of QT dispersion are predictive for sudden cardiac death in patients with
6. Liver diseases and ventricular arrhythmia risk
Several cardiac problems have been reported in patienst with
QT prolongation in liver pathology was first described in alcoholic liver diseases . Alcohol effects on life-threatening arrhythmias correlate directly with the amount and duration of alcohol intake; even small quantities are significant in susceptible individuals . Further studies reported prolonged QT intervals in patients with
Concluding, the mechanisms by which liver cirrhosis affects ventricular repolarization are as follows: electrolyte imbalances, impaired autonomic function, subclinical cardiomyopathy, reduced β-adrenoreceptor function, postreceptor pathway defects, altered physical properties of myocyte plasma membrane, elevated levels of cardiotoxins, ion channel remodeling, portosystemic shunting and systemic circulatory disturbances [46-48, 53, 54, 57].
The clinical significance of QT prolongation in liver cirrhosis is unclear, considering that sudden cardiac death and torsades de pointes are rare .
QTc interval was also measured in patients with
7. Cerebrogenic arrhythmias and ventricular arrhythmia risk in neurologic diseases
Cardiac diseases are a well-known
A concomitant myocardial ischemia or necrosis, elevated blood pressure and heart failure may be also considered . Autopsy of stroke patients, who developed repolarization abnormalities, revealed no obvious coronary artery atherosclerosis in most of them, and the only findings were petechial subendocardial hemorrhages and focal myofibrillar degeneration, reproducible with intravenous administration of catecholamines or electrical stimulation of the vagus nerve in laboratory animals . Sudden calcium influx, mediated by catecholamines, impairs myocardial relaxation, leads to myocytolysis, myofibrillar degeneration, coronary vasoconstriction, myocardial ischemia and ECG changes, and is proarrhythmic [61, 62]. Elevated serum uric acid, direct neural interventions, inflammation, reactive oxygen species, electrolyte imbalances, the structural and electrophysiological changes of a senescent heart and comorbities can increase sudden cardiac death risk in stroke [61, 66]. Stroke survivors with a prolonged QT in V6, were identified to have an increased sudden cardiac death risk . Prolonged QT intervals were associated with decreased survival rates and worse neurological outcomes at hospital discharge . The prevalence of cardiac arrhythmias after acute stroke may reach 28%, higher after subarachnoid hemorrhage (37.5%) and in right sided lesions . The most prevalent ECG findings were, besides atrial fibrillation, sinus tachycardia, atrio-ventricular block, repolarization changes, premature ventricular contractions, R on T phenomenon (R/T), non-sustained, sustained and polymorphic ventricular tachycardia (VT), ventricular fibrillation (VF) and flutter (Vf) [61, 62]. Independent risk factors for the development of ventricular arrhythmias in patients with aneurysmal subarachnoid hemorrhage were prolonged QTc and decreased heart rate, and therapy with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was protective . Literature data are insufficient to support the hypothesis that subarachnoid hemorrhage and stroke cause ventricular arrhythmias, considering that in most patients additional QT prolonging causes were mentioned, including hypokalemia, hypomagnesaemia, and congenital long QT syndrome, and patients with stroke usually have risk factors for coronary artery disease, such as hypertension, diabetes mellitus, and smoking, or advanced age, or left ventricular hypertrophy [61, 62, 75]. Several studies did not control pre-existing arrhythmias, were of short duration and did not explore the long-term consequences of ventricular arrhythmogenesis . Another important limitation of most of the studies is the use of single surface ECG, because it may underestimate arrhythmia incidence in the acute phase of a stroke . Holter monitoring revealed a higher incidence of ventricular arrhythmias after transient ischemic attacks, cerebral infarction and intracerebral hemorrhage compared to patients who were not continuously monitored (56% vs. 8%) .
It is also possible that in some cases, prolonged QTc actually existed before the development of stroke and it could be used as a
The ECG abnormalities observed in
It is uncertain whether ECG abnormalities are caused by the cerebrovascular event itself, considering that in the majority of studies patients' previous ECG data were unavailable . Current management after stroke focuses mostly on the neurological function . The QT interval and electrolyte levels should be monitored, and QT prolonging drugs should be avoided in patients with acute cerebrovascular events, especially for female patients with insular cortex lesions . Multiple studies recommend continuous ECG monitoring, however, others believe that only severely QTc interval prolongation predicts cardiac complications . Follow up studies with large sample sizes, considering previous arrhythmias and coronary heart disease, are needed, to establish the incidence of ventricular arrhythmias after stroke, and clear guidelines for clinicians approaching stroke patients with increased ventricular arrhythmia risk .
Goldberger et al. reported an unusual case of idiopathic acute
Two mechanisms connecting cardiomyopathies and neurological diseases have been described: cardiomyopathies may either secondarily cause neurological disease or may represent the cardiac manifestation of a neurological disease, especially neuromuscular disorders . Sudden cardiac death and ventricular arrhythmias occur mainly in neurological diseases causing hypertrophic cardiomyopathy (in adolescents and young adults), or dilated cardiomyopathy (among which syncope is a common clinical manifestation), or arrhythmogenic right ventricular dysplasia . Takotsubo cardiomyopathy ("the broken heart" syndrome) was reported after stroke, subarachnoid bleeding, spontaneous intracerebral bleeding,
Sudden unexpected death in
In order to reduce the risk of, or prevent, sudden cardiac death, 12-lead ECG should be performed in every patient with epilepsy, in order to identify those at high risk, and, therapy may include antiarrhythmic medication and implantation of cardiac combined pacemaker–defibrillator devices . Cardiogenic syncope is often a difficult differential diagnosis for seizures, and long QT with recurrent syncope has been mistaken for epilepsy, and, epileptic seizures, probably due to cerebral hypoperfusion, have been described in patients with congenital long QT [96, 104]. Mutations of ionic channels could affect both heart and brain function, thereby leading to a susceptibility to epilepsy and cardiac arrhythmias .
8. Hematologic diseases and ventricular arrhythmia risk
Anemia and red blood cells transfusions have been associated with arrhythmias. Several electrocardiographic changes were previously mentioned in patients with
Jaja et al  reported a blunted autonomic cardiovascular response to changes in posture in patients with
Athar et al. reported that packed red blood cells (PRBC)
A significant correlation was found between QT dispersion and
Anthracyclines, used in therapy of patients with
Sudden cardiac death, due to fatal ventricular arrhythmias, continues to be an important public health problem in developed countries. A high ventricular arrhythmia risk has been reported in several noncardiac diseases, including metabolic, liver, blood, neurological and psychiatric disorders. The most common mechanisms were: autonomic and electrolyte imbalances, ion channel remodeling, cardiomyopathies, increased oxidative stress and QT prolonging drugs. Most of the mentioned studies used standard 12-lead ECG and surrogate markers of ventricular arrhythmia risk (QT interval duration, QT dispersion and signal averaged ECG), but several papers reported ventricular arrhythmias, as well.
Considering that there are no guidelines for the prevention and therapy of arrhythmias appearing in most of extracardiac disorders, the present review highlighted important epidemiological and pathophysiological issues related to this topic.
Selected patients could benefit from electrocardiographic monitoring, specific therapy and avoidance of QT prolonging drugs, decreasing the burden of sudden cardiac death. Large follow up studies are needed, controlling for previous QT interval durations, arrhythmias, coronary heart disease and cardiovascular risk factors, in order to assess the prevalence of ventricular arrhythmias in noncardiac diseases, to identify further mechanisms and risk factors for arrhythmogenesis, and to elaborate clear guidelines for clinicians approaching the mentioned pathology.
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