When was long qt syndrome discovered

The pregnancy was carried to term and a baby girl was delivered. The baby was noted to be persistently bradycardic. Her rhythm strip is shown in Figure 2. A diagnosis of long QT syndrome with pseudo-atrioventricular block was made. In the first few hours of life, she developed non-sustained ventricular tachycardia. She received a pacemaker and was started on beta-blockers.

She has been growing and developing normally since that time. She has not had further arrhythmias. Genetics and molecular biology. In the current era, no discussion of long QT syndrome is meaningful without familiarity with the molecular biology of the condition. Traditionally, the modes of inheritance were considered as autosomal dominant, as described by Romano [ 2] and Ward, [ 3] in which there is not usually any other phenotypic abnormality; and autosomal recessive, as in the Jervell and Lange-Nielsen [ 1] description.

The latter is characterized by the presence of sensorineural congenital deafness, due to the same ion channel abnormality.

Rather, LQTS is a so-called channelopathy , a disease due to abnormalities in the ion channels controlling the action potential in electrically active cells—in this case, the myocardial cells. Ion channels are large glycoprotein molecules spanning cell membrane and forming pores. These channels generally consist of several transmembrane regions and multiple subunits, which coassemble to give rise to the functional channel. Pores have permeability and selectivity, the control of which is maintained in highly preserved sequences of amino acids.

A simplified action potential is illustrated in Figure 3. The first phase phase 0 of the action potential is mediated by a rapid influx of sodium through sodium channels into the cell. This is followed by activation of a number of potassium currents, the function of which is to return the cell to its resting potential.

This is countered by the inflow of calcium ions resulting in the plateau phase of the action potential phase 2. Subsequently, as calcium currents subside, the cell is repolarized by the potassium currents phase 3 , giving rise to the T wave on ECG.

Several excellent descriptions of the cardiac action potential exist in the literature. In , a DNA marker was linked to the occurrence of long QT syndrome in a large family with several members affected by the disease. LQTS is considered in subgroups, according to the molecular biology of the ion channels Table 1.

The potassium channel defects result in a decrease in function, resulting in prolongation of the repolarization phase. In LQT3, the SCN5A mutation does not allow complete inactivation of sodium inflow, allowing continued entry into the cell, prolonging repolarization. At present, this is the only defect resulting in a gain of function in the LQTS, having implications for treatment options see below.

Another advance came when a patient with the Jervell and Lange-Nielsen syndrome, an autosomal recessive form of long QT syndrome, was found be homozygous for mutations ascribed to the autosomal dominant form of the disease. From genetic defect to clinical manifestations. The role of the autonomic nervous system in clinical events has long been recognized. Now we understand that the role of the autonomic nervous system in the development of clinical events is related to the effects it has on ion channels and currents.

Simplistically, the effect of the mutations identified thus far is to introduce an excess of positive charges into the cell. A rapid rate followed by a pause, such as is seen with a premature ventricular complex, favors the formation of early afterdepolarizations. This is believed to be the case with torsade de pointes in LQTS. Long QT syndrome is estimated to occur in 1 in to 10, individuals. Now, with a large number of patients genotyped, specific patterns are being related to the underlying mutations.

The clinical manifestations are broad and range from the asymptomatic carrier to sudden death. Typical symptoms include palpitations, syncope, and seizures, although cardiac arrest may be the initial presentation.

The occurrence of syncope during times of emotional excitement, physical exertion, or with auditory stimuli is very suggestive of long QT syndrome. Females have longer QT intervals and are more prone to torsade after puberty. Naturally, a family history of sudden death should be sought. Since prolongation of the QT interval can be observed in many conditions, including electrolyte disturbances—most notably hypocalcemia and hypomagnesemia, pharmacologic agents, central nervous system disorders, and heart disease Table 2 —a careful workup must exclude these causes.

In long QT syndrome, the T wave is more likely to be biphasic or notched, and certain ECG patterns have been associated with certain genotypes.

Due to the difficulty in making a diagnosis in some patients, Schwartz proposed a scoring system combining ECG and clinical data Table 3. In most patients a lead ECG suffices; however, in some patients additional testing will increase the likelihood of making the correct diagnosis. Normal values should be less than 0. Holter monitoring is sometimes useful in detecting prolongation of the QT interval and T wave changes.

The T wave may change in amplitude and in direction from beat to beat, a phenomenon known as T wave alternans. The Holter monitor is also an important test for detecting occult arrhythmias.

Sinus bradycardia is common, even without beta-blockade, and has been recognized in the fetus. The presentation may be that of profound bradycardia due to extreme prolongation of the QTc leading to pseudo heart block, such as that described in Case 2. Exercise testing is often used to document peak heart rate, inducibility of arrhythmias, and to determine the QT interval in the recovery phase of the test, where QT prolongation may be most marked.

Pharmacologic and electrolyte challenges are also done in some cases in the electrophysiology lab. At this point, genetic testing has not reached a clinical phase.

Arrangements can be made with some of the large research labs, particularly in the United States, but this testing has not evolved to a diagnostic service. Villain reported the outcomes of 15 selected newborns with QTc prolongation and found that in one-third the QTc normalized.

The authors have since described a case in which the clinical and molecular diagnosis of LQTS was made in a patient surviving a near-miss episode that had the features of SIDS. Presently, though, what proportion and, more importantly, how to pre-empt them, remain unknown.

While many drugs may prolong the QT interval, the vast majority are not associated with lethal ventricular arrhythmias. An example of this is the gastric motility agent cisapride, now off the market due to reported cardiac deaths. Most arrhythmias appear to relate to drug levels, often in the setting of medication interactions. The addition of the drug unmasks the molecular defect and results in clinical disease. It has been suggested that its relatively large pore size and structure allow the drug-channel interaction.

With treatment this figure is reduced approximately tenfold. Beta-blockers form the mainstay of therapy in long QT syndrome. The mortality has been significantly reduced using this modality of therapy alone. In some patients, pacing may be beneficial. This should be viewed as an adjunctive therapy and pacing these patients may require complex algorithms to eliminate the post-extrasystolic pauses that may lead to torsade de pointes.

Prior to the discovery of the channel defects underlying long QT syndrome, a prominent hypothesis was that sympathetic imbalance was at least partly responsible for the disease. Further, there are certain portions of the population who are at greater risk than others. Female gender conveys a substantially increased risk for drug induced LQTS [ 66 ],and QT prolonging drugs should be used with caution. The senior population, with reduced renal and hepatic function, eliminate QT prolonging drugs more slowly and are at increased risk for higher serum levels.

They often have multiple prescriptions and are further at risk for drug-drug interactions or altered metabolism. A disproportionate percentage of QT prolonging drugs are in the psychiatric arena, and patients with psychiatric needs are at increased risk of receiving such a drug, plus, may be more at risk for mistakes and errors in their use and administration. In the future, it may be easy to determine early in the course of drug development which compounds will have QT prolongation effect [ 67 ],thus preventing agents with this effect from reaching the market.

Acquired LQTS also occurs as a consequence of a number of acute and chronic neurologic disorders, such as subarachnoid hemorrhage and diabetic autonomic neuropathy [ 68 - 70 ], presumably due to effects of these diseases on the autonomic nervous system center [ 71 , 72 ].

Some of these cases probably have inherited LQTS. Others may be due to the immature autonomic nervous system of infants, with QT prolongation, but with death due to respiratory difficulties from the immature autonomic system. As is well known, electrolyte disturbances such as hypokalemia and hypomagnesemia also cause QT prolongation, T wave abnormalities, and arrhythmias.

The degree of prolongation which places patients at high risk is not well defined. A QTc of msec or greater has been suggested as cause for concern, but it is likely that some patients are at risk at shorter intervals, just as in inherited LQTS. Cessation of the drug is the primary treatment. Recognition of patients at risk is important. Physicians might consider obtaining an ECG within a few days of administration of a QT prolonging drug, assessing for prolongation, and should consider stopping the drug if QT prolongation is identified.

An ECG should be obtained any time a patient on one of the medications experiences palpitations, presyncope or syncope. The medication must be stopped upon recognition of TdP. Physicians should weigh the risk of a QT prolonging drug with the expected benefit and only prescribe the drug when alternatives are not available or not nearly as effective as the QT prolonging drug.

National Center for Biotechnology Information , U. Indian Pacing Electrophysiol J. Michael Vincent , MD. Author information Copyright and License information Disclaimer. Address for correspondence: Dr.

Michael Vincent, M. E-mail: moc. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Open in a separate window. Figure 1. Figure 2. Clinical Genetics Romano-Ward With autosomal dominant transmission, males and females are equally affected. Jervell, Lange-Nielsen Again, with autosomal genes, males and females are equally affected.

Figure 3. The Patient History Syncope, particularly vasovagal syncope, is common in the normal population, and occurs at the same rate in LQTS patients. The Family History A history of unexplained sudden death or repetitive syncope in young members of a family is certainly suspicious for LQTS.

QT interval The QTc ranges from about to over msec. Figure 4. T wave morphology Moss, et al first reported a T wave pattern characteristic for each genotype [ 25 ]. Clinical Course and Pathophysiology General Syncope is the predominant symptom, and patients may have one to several hundred episodes. Figure 5. Figure 6. Graph of QTc response during exercise in the three phenotypes. Figure 7. Figure 8. LQT4 This locus was identified by linkage analysis in one French family [ 5 ], but even now, a number of years later, the gene has not yet been reported.

Risk of syncope and sudden death The early publications emphasized a high risk of serious events. Prophylaxis It is important to note that sudden death may be the first manifestation of the disease.

Pacemakers Pacemakers play a role in some patients, particularly those with marked bradycardia or pauses, and those who can't tolerate beta-blockers [ 43 - 45 ]. ICDs Implantable cardiac defibrillators are being placed in a number of patients at the present time.

Investigational therapies LQT2 The paradoxical finding that increased extracellular potassium concentration improved IKr channel function [ 11 ] led to the idea that high dose potassium administration coupled with spironolactone to decrease excretion might be of benefit to LQT2 patients. LQT3 The early finding of repetitive openings of the sodium channel as the mechanism of APD and QT prolongation in LQT3 patients suggested that a sodium channel blocker may be of benefit in these patients.

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Quinidine syncope and the delayed repolarization syndromes. Mod Concepts Cardiovasc Dis. Current status of class III antiarrhythmic drug therapy. Open channel block by methanesulfonanilides. Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Torsades de pointes 'twisting of the points'. This is a life-threatening form of ventricular arrhythmia.

Your heart's two lower chambers ventricles beat fast and chaotically, making the waves on an ECG monitor look twisted. The heart pumps out less blood. The lack of blood to the brain causes you to faint suddenly and, often, without warning. If the episode lasts for a long time, fainting can be followed by a full-body seizure. If the dangerous rhythm does not correct itself, then a life-threatening arrhythmia called ventricular fibrillation follows.

Congenital long QT syndrome is caused by a genetic mutation. There is no known prevention. However, with proper treatment, you can prevent the dangerous heartbeats that can lead to long QT syndrome complications. You may be able to prevent the health conditions that lead to some types of acquired long QT syndrome with regular health checkups and good communication with your doctor. It is especially important to avoid medications that can affect your heart rhythm and cause prolongation of the QT interval.

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Chambers and valves of the heart A typical heart has two upper and two lower chambers. Share on: Facebook Twitter. Show references What is long QT syndrome?

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Waddell-Smith KE, et al. Pre-test probability and genes and variants of uncertain significance in familial long QT syndrome. Heart, Lung and Circulation. Significance of a long QT interval adult.

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