Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
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Άγιος Νικόλαος Κρήτη 72100
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Τετάρτη 3 Απριλίου 2019

Neurotherapeutic potential of erythropoietin after ischemic injury

 of the central nervous system
Florian Simon, Nicolaos Floros, Wiebke Ibing, Hubert Schelzig, Artis Knapsis

Neural Regeneration Research 2019 14(8):1309-1312

Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors. 

QT interval

REVIEW ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 71-79
QT interval – Its measurement and clinical significance

Sita Ram Mittal DM (Cardiology) 
Department of Cardiology, Mittal Hospital and Research Centre, Ajmer, Rajasthan, India

Date of Web Publication 3-Apr-2019
        
Correspondence Address:
Sita Ram Mittal
Xi/101, Brahmpuri, Ajmer - 305 001, Rajasthan 
India
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Source of Support: None, Conflict of Interest: None

Crossref citations Check

DOI: 10.4103/JCPC.JCPC_44_18

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  Abstract

QT interval extends from the beginning of QRS complex to the end of T wave. Thus, it includes the duration of ventricular depolarization (QRS) and repolarization (J point to end of T wave). It corresponds to the duration of cellular action potential. "long-" and "short"-QT intervals are considered as risk markers for cardiac arrhythmias and sudden death. In the last decade, there have been significant advances in our understanding about measurement and significance of QT interval. We have made an attempt to review the literature to find the limitations and queries surrounding the present status of measurement of QT interval and its significance as a risk marker for cardiac arrhythmias and sudden death.

Keywords: Arrhythmias, electrocardiography, repolarization heterogeneity, sudden cardiac death, torsades de pointes


How to cite this article:
Mittal SR. QT interval – Its measurement and clinical significance. J Clin Prev Cardiol 2019;8:71-9

How to cite this URL:
Mittal SR. QT interval – Its measurement and clinical significance. J Clin Prev Cardiol [serial online] 2019 [cited 2019 Apr 4];8:71-9. Available from: http://www.jcpconline.org/text.asp?2019/8/2/71/255378




  Introduction
Top



QT interval extends from the beginning of QRS complex to the end of T wave. It corresponds to the duration of action potential.[1]


  (A) Measurement
Top


(a) Current understanding

At present, available electrocardiogram (ECG) machines can automatically measure QT interval and corrected QT (QTc) interval. Machines computing data from multiple leads give more accurate information than those which analyze only single lead. Automated measurement by ECG machines should, however, be confirmed by manual measurement, especially if there is difference between automated measurement and visual impression.[2] Such problem is likely to occur when T wave is notched, biphasic, or relatively flat.[3],[4],[5] QT interval is measured from the beginning of QRS to the end of T wave irrespective of whether the QRS complex begins with "Q" wave or "R" wave.[6] It is measured from the lead in which it is longest (usually leads V2 or V3).[1],[7] This is necessary because in some leads initial part of QRS and/or terminal part of T wave may be isoelectric[2] resulting in false shortening of QT interval. Mean of at least three beats is taken[8] in the same lead. Accurate measurement can be made only after a series of regular equal cycles[9] during stable sinus rhythm.[8]

At times, end of T wave and its junction with T-P segment is not sharp producing difficulty in defining exact end of T wave. In such situation, end of T wave is taken as the point where a tangent drawn from the steep portion of the downslope of T wave touches the isoelectric line.[10],[11]

(b) Controversies

(i) Measurement of end of T wave is not clear

There is no consensus regarding measuring of QT interval when a "U" wave fuses with the end of T wave masking the exact point of end of T wave. Some authors feel that the point where a tangent extending from the downslope of T wave touches the baseline should be taken as the end of T wave.[12] However, this might underestimate the QT interval.[2] Al-Akehar and Siddique[13] suggested that the "U" wave should be included in the QT measurement. However, this is likely to result in overestimation of QT interval. Further, there are no accepted reference values for the "normal" and prolonged QU interval.[8] Some authors have suggested measuring QT interval in leads in which a prominent U wave is absent (usually lead aVR and aVL).[1] However, this QT interval may not be the longest. Most of the authors feel that the point of notch between "T" and "U" wave can be taken as the end of T wave.[8],[9],[14],[15] This is not the true end-point of the T wave, but it does for practical purposes.[14]

If T wave is notched or bifid, end of the terminal wave can be taken to measure the QT interval. In tachycardia, end of T wave may fuse with the beginning ofPwave. In such a situation, junction of T andPwaves can be taken as the end of T wave for practical purposes.[9] However, there is no evidence that this is the true QT interval.

Due to above-mentioned differences in opinion, there can be considerable interobserver variability in manual measurement of QT interval.[16] Therefore, if the end of T wave is not clear, method used to determine the end of T wave should be mentioned in the report.

(ii) Measurement in the presence of broad QRS

There is currently no agreed consensus on how to measure the QT interval in patients with broad QRS, paced ventricular rhythm, or atrial fibrillation.[17] Measurement of J-T interval has been suggested for detection of prolonged repolarization in ventricular conduction defect. However, its use has not been validated. Further, J-T interval has strong correlation with ventricular rate.[18] Normal limits for rate adjusted J-T interval have not been established for ventricular conduction defect or for normal ventricular conduction. J-T interval, therefore, does not give correct information about QT interval in the presence of ventricular conduction defect. Bogossian et al.[19] suggested that in the presence of left bundle branch block (LBBB), native QT interval (QT interval before development of LBBB) can be calculated as measured QT interval −50% of LBBB duration. However, it can cause overcorrection of QT interval.[20] Further, this formula does not tell the correct QT interval in the presence of LBBB. This is especially important because factors that lead to the development of LBBB (e.g. myocardial ischemia) may also prolong QT. Finding native QT interval does not have much clinical significant once LBBB has developed. We should be able to determine QT interval after the development of LBBB. There is no literature on measurement of QT interval in patients of right bundle branch block, fascicular blocks, nonspecific intraventricular conduction defects, and paced rhythm.


  (B) Correction for Heart Rate
Top


With increasing heart rate, repolarization shortens so that myocardium is excitable when the next impulse comes. QT interval, therefore, shortens with increasing heart rate. Therefore, exact significance of QT interval can be judged only after correcting it for heart rate. QTc interval is called "QTc."

(a) Formulae for correction

(i) Current understanding

Several formulae have been proposed for correction of QT interval.[8],[21]

Bazett's formula[22] is most commonly used.[2] It is as follows:





R-R is the preceding R-R interval. QT is measured in milliseconds and RR is measured in seconds. It works best between heart rate of 60–100 beats/min. It may give erroneous results at both slower (overcorrection) and faster heart rates (undercorrection).[8]

Linear Framingham method for correction of QT interval is as follows:

QTC = QT + 0.154 (1-RR)

It may give more uniform rate correction over wider range of heart rates.[15]

Fridericia formula for QT interval correction is as follows:[23]

QTc = QT/(R-R)0.33

This formula fails at high heart rates.[24]

Another formula suggested for rate correction is as follows:

QTc = QT + 1.75 (HR-60).[1]

HR is heart rate. Intervals are measured in milliseconds. It has been shown to be relatively insensitive to heart rate.[21]

(ii) Limitations

All formulae have some or other shortcoming.[8] For a given ECG, there can be significant difference in the results of various formulae. Therefore, the formula used for correction should be mentioned in the report.[2] Bazett's formula is easy to use and gives reasonably working information in most of the patients with normal heart rates. Most of the studies on QT interval have used this formula. It is most commonly used.[8]

(b) Heart rate-QT interval nomogram

(i) Current understanding

One heart rate-QT interval nomogram has been described for stratification of risk of torsades de pointes in drug-induced QT prolongation.[25] QT interval is measured manually and then plotted against the heart rate on the QT nomogram. Nomogram takes heart rate rather than R-R interval. Higher is the QT– heart rate pair above the nomogram, greater is the risk of drug-induced torsades de pointes.[4]

(ii) Limitations

The nomogram does not correct the QT interval for heart rate. It only gives some impression about risk of torsades de pointes of a given QT interval and heart rate. It is important to remember that several other factors contribute to the risk of drug-induced torsades de pointes at a given QT interval. Further, there is substantial intersubject variability in the relation between heart rate and QT interval[26]
Nomogram has been validated only for evaluation of drug-induced QT prolongation. It has not been validated in other causes of QT prolongation. The relationship between QT interval, heart rate, and risk is uncertain at rapid heart rate. Therefore, an interrupted nomogram line has been used for heart rates above 104/min.[21] Therefore, nomogram cannot be used reliably at fast heart rate.


Thus, no formula or nomogram provides an ideal rate correction for a given subject in a particular clinical setting.[3] This is especially true when assessing the minor changes of QT interval induced by drugs.[27]

(c) Correction in irregular rhythm

(i) Current understanding

It is not possible to measure correct QT interval in irregular rhythm, for example, in sinus arrhythmia, atrial fibrillation, or frequent ectopic beats. QT interval may be prolonged in ectopic and postectopic beat. Although it is not the correct QT, such phenomena may suggest increased risk of arrhythmias in patients with long QT.[8]

(ii) Limitations

Musat et al.[28] correlated QT interval correction methods during atrial fibrillation and sinus rhythm. They observed that Fridericia method most closely approximates the QTc interval during atrial fibrillation to QTc during sinus rhythm. Patients were being treated with dofetilide. They studied the last ECG in atrial fibrillation to the first ECG in sinus rhythm. Therefore, their observation cannot be extrapolated to a routine case of atrial fibrillation.


  (C) Normal Value of Qtc
Top


(i) Current understanding

Previously, normal upper limit of QTc was considered as 460 ms for women and 450 ms for male.[2] Subsequently, valves of 470 ms for male and 480 ms for female were suggested as limits of normality.[29] Later, values of 440–450 ms in men and 440–470 ms in women were considered as borderline.[27] Recent European guidelines for the management of patients with ventricular arrhythmias and prevention of sudden cardiac death have, however, suggested that QTc normally ranges between 360 ms and 480 ms.[30]

(ii) Limitations

QTc interval is affected by age, sex, sympathetic tone, posture, meals, heart rate, and diurnal pattern.[31],[32],[33] Therefore, minor fluctuations should not be given undue importance and a rigid cut of value is not justified. A tip that helps identify normal QT interval on visual ECG examination is that it is less than half of the preceding R-R interval.[13] QTc >500 ms predisposes to torsades de pointes.[3],[27],[31]


  (D) Qt Dispersion
Top


(i) Current understanding

Onset of QRS and end of T wave do not occur simultaneously in every lead. QT interval, therefore, varies from lead to lead. This variation in QT interval is known as dispersion of QT interval (QTD). Initially, it was considered as an indicator of arrhythmogenicity.[34],[35]

(ii) Limitations

Subsequent studies did not confirm initial impression of relation with arrhythmogenicities
Reported normal values vary widely (10–71 ms)[36]
Main cause of QT dispersion is, in fact, the unreliable localization of the end of T wave[37]
Depending on QRS vector, initial part of QRS may be isoelectric in some leads. This results in incorporation of q wave in the P-R segment.[14] It also contributes to QTD
QT dispersion is sensitive to age, time of day, season of year, and even body position[38]
QTD per se does not represent underlying heterogeneity in repolarization and does not itself confer increased cardiovascular risk[37]
It has not been found to be a clinically useful parameter[24] and is no longer used.[39]



  (E) Significance of Variations in Qt Interval
Top


(1) Prolonged QT

Initially, prolonged QT interval per se was considered to be a very important risk factor for cardiac arrhythmias and sudden death. Over the past two decades, there has been significant advancement in our understanding of significance of prolonged QT interval. Following conclusions can be drawn from the literature.

(a) Congenital or familial prolongation of QT

(i) Current understanding

Congenital prolongation of QT interval is caused by mutation in ion channels (potassium, calcium, or sodium). More than 15 mutations have been identified.[13] Hereditary long QT syndromes (Jervell Lange–Nielson syndrome, Romano–Ward syndrome, Andersen–Tawil syndrome, and Timothy syndrome) are associated with high risk of cardiac events.[40] Other mutations in long QT susceptibility genes may or may not manifest QT prolongation on a resting 12-lead surface ECG[41],[42] and are mostly without consequence.[41]

(ii) Controversies

Triggers such as exertion, swimming, emotion, auditory stimuli, and postpartum period can rarely increase electrical instability of heart resulting in potentially life-threatening arrhythmias.[41],[43] In these cases, a normal QT interval does not exclude the risk
Some gene suggestive electrocardiographic findings have been suggested.[44] LQT1 is frequently associated with broad-based T wave. LQT2 is usually associated with low amplitude, notched, or biphasic T wave. Long isoelectric ST segment followed by a narrow-based T wave is common in LQT3. However, exceptions to these relative gene-specific T wave patterns exist.[41] These T wave patterns can only raise suspicion of type of long QT syndrome from among the three common types in the absence of genetic testing (primarily due to cost issues). These T wave changes can give clue to propensity for syncopal attacks due to torsades de pointes in patients with long QT syndrome.[45] Significance of these T wave patterns in general population is also not clear
T wave alternans is defined as beat-to-beat change in amplitude or polarity of the T wave. It may be present at rest or may appear during emotional or physical stress or with drug-induced QT prolongation.[12] It has been observed as a precursor to torsades de pointes in some cases.[46] Independent significance of this finding in persons without other risk factors is not clear
It has been suggested that in patients with strong clinical suspicion, abnormal QT interval may be unmasked by sudden standing[47],[48] or during recovery from exercise stress test.[49],[50] However, there is no documentation that these findings correlate with risk of future cardiovascular events. Intravenous pharmacologic provocation testing (e.g. with epinephrine) can unmask inappropriate prolongation of the QTc interval. However, there is risk of induction of arrhythmias. It is also not clear if epinephrine-induced QT prolongation correlates with risk of arrhythmias in day-to-day life. As for today, the risk in such mutations with normal QTc interval in resting ECG can be evaluated confidently only be genetic study and not by the QT interval alone.[13],[27],[51] However, genetic testing is limited by cost and is recommended only when there is strong clinical index of suspicion
Many patients with unexplained congenital prolongation of QT interval never experience torsades de pointes.[17] Reason is not clear. At present, there is no method to find which patients of congenitally prolonged QT interval are immune to life-threatening arrhythmias.


(b) Acquired prolongation of QT

Several acquired conditions are known to cause QT prolongation. Risk of serious arrhythmias is, however, variable.

(i) Heart failure, myocardial diseases, or coronary artery disease


  Controversy
Top


Risk of serious cardiovascular events in patients with cardiac disease depends on severity of underlying disease, magnitude of left ventricular dysfunction, electrolyte imbalance, presence of high degree or complete atrioventricular block, presence of bradycardia or pauses,[3] frequent ventricular premature beats with compensatory pause,[3] sustained ventricular tachycardia, and instability of repolarization and genetic susceptibility,[52] rather than on QT interval prolongation alone.[53] It is, therefore, not clear as to which patients with cardiac disease and prolonged QT interval will benefit from prophylaxis against life-threatening arrhythmias.

(ii) Electrolyte imbalance

Hypokalemia, hypomagnesemia, and hypocalcemia prolong QT interval.


  Controversy
Top


The risk correlates with magnitude of electrolyte imbalance, disturbance of other electrolytes, and concomitant cardiac status in addition to magnitude of QT interval prolongation.

(iii) Drug-induced QT prolongation

There is a long list of drugs that prolong QT interval. Common drugs include quinidine, piscarnomed, disopyramide, flecainide, sotalol, ibutilide, and cisapride. However, several other factors control occurrence of fatal arrhythmias.

Controversies

In patients with drug-induced prolongation of QT interval, conclusions about the risk of torsades de pointes based solely on prolongation of QTc interval may turn out to be highly flawed.[27] Risk is dependent on several factors as follows:

Magnitude of QT prolongation[53]


Patients who develop drug-induced torsades de pointes usually have QTc interval >500 ms[3],[54] or there is more than 60–70 ms increase from baseline value.[29] However, only a small subset of these patients develop torsades de pointes.[55] Other factors contribute to the risk of torsades de pointes.[55]

Drug responsible for QT prolongation


List of drugs that can prolong QT interval is extensive.[56] However, there is no documentation of torsades de pointes in most of the case reports.[4] Some drugs rarely produce arrhythmias although they prolong QT interval, for example, amiodarone, dronedarone, ranolazine, lithium, terfenadine, astemizole, antibiotics, and antipsychotics.[4],[52],[55] For some drugs as dofetilide, the risk of torsades de pointes is much higher.[57]

Dose, route, and rate of administration, drug metabolism, and excretion[55]


Risk of sotalol-induced torsades de pointes is dose dependent.[58] Risk of torsades de pointes with haloperidol is usual after intravenous injection.[59]

Concomitant use of other drugs prolonging QT[51]
Concomitant electrolyte imbalance, for example, hypokalemia, hypocalcemia, and hypomagnesemia[52],[55]
Underlying cardiac status, for example, heart failure, myocardial infarction, and active ischemia
Genetic predisposition: Genetically determined reduced repolarization reserve[60] or rate of drugs metabolism or excretion[61]
Subclinical mutations in congenital LQTS genes[60],[62],[63]
Renal and/or hepatic failure in patients being treated with drugs requiring renal elimination (e.g. sotalol)[55] or hepatic metabolism (e.g. methadone).[55]


In the absence of other factors, drug-induced QT prolongation alone rarely produces torsades de pointes and subsequent sudden death.[41]

(iv) QT prolongation associated with intracerebral or subarachnoid hemorrhage and myxedema

QT prolongation in these conditions is usually not associated with increased risk of cardiac arrhythmias.[64] Reason is not clear.

(2) Short QT interval

Definition

Current understanding

Short QT interval is considered as a risk factor for cardiac arrhythmias and sudden death. Normal lower limit is suggested as 390 ms.[2]

Controversies

Some authorities feel that QT interval <320 ms should be considered as "short."[41] It is considered realistic to prevent overdiagnosis and excessive investigations.[41],[65] However, the definition of a lower limit of QTc in short QT interval syndrome and its association with serious cardiac arrhythmias is less clear.[50] QT interval <300 ms may not be associated with serious cardiac arrhythmias.[66] It is possible that very short QTc (200–260 ms) may be associated with an increased cardiac risk.[51] Markers other than QTc interval are needed to identify patients at risk.[51]

(a) Congenital or familial short QT syndrome

Current understanding

It is due to mutation in some specific ion channels. Several specific genotypes have been identified.[67] There is no structural heart disease. It has been observed that congenital short QT interval may be associated with increased risk of paroxysmal atrial fibrillation, syncope, or cardiac arrest.[68] Episodes occur most often during periods of rest or sleep.[41]

Controversy

Some ECG findings have been suggested to be associated with congenital short QT syndrome. These include no or short ST segment and tall peaked T waves.[41] Recent studies have, however, shown that there are no diagnostic electrocardiographic findings[64] and risk is related to genetic mutation.[51],[69]

(b) In general population

Short QT interval is rare and is not associated with increased cardiac risk.[65],[66],[70]

(c) Early repolarization

It may be associated with short QT interval.[71] Some patients with early repolarization syndrome (J wave syndromes) may be associated with increased risk of arrhythmias.[72] However, increased risk is not related to shortening of QT interval.[71],[73]

(d) Hypercalcemia, hypermagnesemia, and acidosis

These can shorten QT interval. Risk is related to magnitude of abnormality and severity of underlying disease rather than to shortening of QT interval.

(e) Digitalis

Magnitude of shortening of QT interval in digitalis overdose has no relation to digitalis-induced arrhythmias which depend on concomitant electrolyte imbalance and underlying cardiac status.

(f) Other drugs

Clinical significance of QT shortening induced by other drugs is still under evaluation.[74]


  (F) Subanalysis of Qt Interval
Top


Failure of QTc to reliably predict the risk of arrhythmias[75] has resulted in evaluation of other electrocardiographic parameters to evaluate repolarization heterogeneity.[25] Following parameters have been evaluated.

(1) J point to peak of T wave

(a) Current understanding

Normally, it is around 200 ms.[10] In the presence of prolonged QT interval, it can exceed 300 ms. In setting of short QT interval, it can be as short as 100 ms. It is less sensitive to changes in posture and respiration-related changes in T wave morphology.[76] It is affected by heart rate.

(b) Controversies

It has not been evaluated in detail in normal population and patients at high risk of cardiac arrhythmias. It is not clear if this parameter alone has any independent significance over other electrocardiographic parameters.

(2) Interval from peak of T wave to its end

(a) Current understanding

Most typically lead V5 is used for this measurement.[77] Difficulties can arise in measurement particularly with low T wave amplitude or when T waves are notched or biphasic.[17] It is less sensitive to changes in posture and respiration-related changes in T wave morphology.[76] Control subjects have been shown to have a value of <90 ms.[78],[79] Some authors feel that this interval provides some measure of repolarization heterogeneity independently associated with sudden cardiac death.[37],[80],[81] It has been suggested that the peak of T wave to its end (Tp-Te) interval may serve as an index of total dispersion of repolarization (transmural, apicobasal, and global). This interval has been used in predicting arrhythmias and sudden cardiac death in some cardiac channelopathies.[82],[83] Tp-Te >100 ms has been shown to predict malignant ventricular arrhythmias within 24 h of ST-segment elevation myocardial infarction.[84]

(b) Controversies

Genesis of arrhythmias and sudden death in the setting of acute coronary syndrome is also dependent on several other factors, for example, electrolyte imbalance, extent of infarction, left and right ventricular functions, extent of underlying coronary artery disease, and persistence of ischemia. Further, all patients with prolonged Tp-Te interval do not develop malignant arrhythmias. Therefore, it is difficult to determine additional independent prognostic significance of this interval in patients with acute coronary syndrome
This interval has also been found to be prolonged in conditions such as coronary ectasia,[78] nondipper blood pressure pattern in patients with metabolic syndrome,[79] and patients with coronary slow flow.[85] These conditions are not known to be associated with high risk of malignant arrhythmias and sudden death
Arrhythmogenic risk of this parameter has not been evaluated in context of various drug, other conditions predisposing to arrhythmias, and patients without cardiovascular disease or risk factors.


Large randomized controlled trials with long-term follow-up are needed to find if this parameter alone has any independent clinical significance.

(3) Interval from peak of T wave to its end/QT ratio

(a) Current understanding

Normal range of this ratio is very wide (0.15–0.25).[86] It remains relatively constant between the heart rate from 60 to 100 beats/min.[87] Higher ratio (>0.30) has been linked to increased risk of arrhythmias in patients with long QT syndrome, Brugada syndrome, short QT syndrome, and acute myocardial infarction.[84],[86],[87],[88]

(b) Controversies

This interval has also been found to be prolonged in conditions such as coronary ectasia,[78] nondipper blood pressure pattern in patients with metabolic syndrome,[79] and patients with coronary slow flow.[85] These conditions are not known to be associated with risk of malignant arrhythmias and sudden death.
Arrhythmogenic risk of this parameter has not been evaluated in context of various drug, other conditions predisposing to malignant arrhythmias, and patients without cardiovascular disease or risk factors.


Large randomized controlled trials with long-term follow-up in "normal" population and in patients with other conditions known to prolong QT interval or associated with risk of malignant arrhythmias and sudden death are needed to find actual independent significance of this parameter.

(4) Status of various components of QT interval

(a) Current understanding

Different etiological factors affect different components of QT interval. Flecainide causes broadening of QRS.[64] Tricyclic antidepressants also produce QRS widening without lengthening of J-T interval.[4] Long QT3 syndrome is associated with long ST segment and late-onset T wave.[44] Sotalol produces broad T wave with increased Tp-Te interval.[37] ST elevation myocardial infarction also prolongs Tp-Te interval.[80],[86] In hypokalemia, it is the Q-U interval that is prolonged.

(b) Queries

There is no literature regarding following issues:

Duration of different components of QT interval in normal population
Effect of age, gender, ethnic group, posture, and diurnal variation on
various components of QT interval
Effect of heart rate on various components of QT interval and method to correct them for given heart rate
Abnormality of which channel affects which part of the QT interval?
What is the clinical significance of prolongation of different components in normal population and in patients known to have high risk of arrhythmias and sudden death?
Correlation of arrhythmogenic risk of various drugs and other factors to various parts of QT interval
Will the management differ depending on prolongation of different components of QT interval?


Well-designed prospective studies with long-term follow-up are needed to answer these queries.

Controversies regarding QT interval are summarized in [Table 1].
Table 1: Controversies/limitations regarding QT interval

Click here to view



  (H) Conclusion
Top


Manual measurement of QT interval is associated with interindividual variability. Automated measurement and heart rate correction by ECG machine can give working information unless the ECG is abnormal. There is no consensus regarding measurement of QT interval if T wave is bifid or fuses with U orPwave, QRS is broad or rhythm is irregular
There can be significant difference in the results of various formulae recommended for correction of QT interval for heart rate. Therefore, the formula used for rate correction should be mentioned in the report for proper follow-up of patient. Bazzett's formula is easy to use and gives reasonably working information in most of the patients
Normal QTc interval has a wide range – 360–480 ms. QTc is also affected by sympathetic tone, posture, meals, and diurnal pattern. Therefore, undue significance should not be given to minor changes
QT dispersion alone does not correlate with risk of arrhythmias
Hereditary long QT syndromes are associated with increased risk of arrhythmias and sudden death. Other genetic mutations are mostly without consequences. In acquired prolonged QT interval, risk depends more on genetic predisposition, underlying cardiac status, and electrolyte or metabolic disturbances. All drugs prolonging QTc interval do not carry similar risk
Hereditary short QT syndromes carry some risk of paroxysmal atrial fibrillation, syncope, or cardiac arrest. Most of the other cases do not have any risk
Independent significance of various parts of QT interval is not clear.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Hypertension and sleep duration and water intake

Association between hypertension and sleep duration and water intake in Indian young adults
Umeshwar Pandey, Tanu Midha, Yashwant Kumar Rao

Journal of Clinical and Preventive Cardiology 2019 8(2):50-55

Context: The prevalence of hypertension is on the rise in developing countries like India. Physiological parameters such as sleep duration and water intake may be associated with hypertension in young adults. Aims: The aim is to study the association between hypertension and day and nighttime sleep duration and water intake among young adults. Setting and Design: The study was a cross-sectional study, conducted among 596 students of Government Medical College, Kannauj, aged between 17 and 22 years. Materials and Methods: Participants were classified using the diagnostic criteria of the American Heart Association. Data were recorded on a pre-designed and pretested questionnaire. Data analysis was performed using SPSS 22.0. Receiver operator characteristic curve analysis and multiple logistic regression analysis were applied. Results: The prevalence of hypertension was 34.9&#37;, 35.9&#37; among boys, and 33.5&#37; among girls, respectively. Less water intake and shorter sleep duration at nighttime were found to be independent predictors of hypertension. Cutoff of sleep duration at nighttime for predicting hypertension was &#8804;7.6 h among boys and &#8804;7.1 h among girls. The sensitivity and specificity of the cutoff for sleep duration at night time in boys was 79.3&#37; and 74.2&#37;, respectively, and that in girls was 81.5&#37; and 75.6&#37;, respectively. The cutoff for water intake for predicting hypertension was &#8804;2.1 L for boys and &#8804;1.5 L for girls, respectively. The sensitivity and specificity of the cutoff for water intake in boys was 74.8&#37; and 70.3&#37;, and in girls was 78.3&#37; and 71.5&#37;, respectively. Conclusions: Young adults with longer duration of sleep during night time and more water intake had a lesser risk of hypertension. 

Ankle–brachial pressure index/carotid intima-media thickness ratio in predicting presence and severity of coronary artery disease

Utility of ankle–brachial pressure index/carotid intima-media thickness ratio in predicting presence and severity of coronary artery disease: A study from major center in Northeastern India
Farhin Iqbal, Amol Vasantrao Patil, Jogesh Chandra Barkataki

Journal of Clinical and Preventive Cardiology 2019 8(2):44-49

Background: Studies have shown that carotid intima-media thickness (CIMT) and ankle&#8211;brachial pressure index (ABI) can be used as surrogate markers of coronary artery disease (CAD). However, whether studying the ratio of ABI and CIMT has any added value in predicting CAD when compared to either of them alone, has not been studied. Aims: The aim of the study is to compare CIMT and ABI as surrogate markers for the presence and extent of CAD and to investigate whether studying the ratio of ABI and CIMT has any incremental value in predicting CAD than either of them. Methods: We prospectively enrolled 235 stable, non-ACS patients who underwent CIMT and ABI measurements followed by diagnostic coronary angiography. Results: The mean age of the study population was 56.32 &#177; 10.14 years. CIMT was significantly higher in the CAD group compared to non-CAD group (0.91 &#177; 0.22 vs. 0.66 &#177; 0.15, P &#8804; 0.0001). ABI was significantly lower in the CAD group compared to non-CAD group (1.07 &#177; 0.19 vs. 1.18 &#177; 0.14, P &#8804; 0.0001). At an optimal cutoff value of &#8805;0.75 mm, CIMT showed better predictive values (sensitivity and specificity &#8211;72.3&#37; and 79&#37;, respectively) compared to ABI &#8804;0.9 (sensitivity and specificity &#8211; 21.53&#37; and 96.19&#37;, respectively). CIMT was the strongest independent predictor of CAD (P &#60; 0.0001) followed by ABI (P &#61; 0.006) by multiple regression. ABI/CIMT ratio of &#8804;1.55 had better predictive value (sensitivity and specificity &#8211;75.4&#37; and 78.1&#37;, respectively) and stronger correlation with CAD severity (R &#61; 0.42), than either of them. Conclusion: CIMT is a better surrogate marker of CAD compared to ABI. Studying ABI/CIMT ratio has an incremental value in predicting CAD. 

Neural Regeneration Research

Tandem pore TWIK-related potassium channels and neuroprotection
J Antonio Lamas, Diego Fern&#225;ndez-Fern&#225;ndez

Neural Regeneration Research 2019 14(8):1293-1308

TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notwithstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications. 


Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system
Florian Simon, Nicolaos Floros, Wiebke Ibing, Hubert Schelzig, Artis Knapsis

Neural Regeneration Research 2019 14(8):1309-1312

Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30&#37; and improvement of neurobehavioral outcome by nearly 40&#37;. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors. 


Dendritic shrinkage after injury: a cellular killer or a necessity for axonal regeneration?
An Beckers, Lieve Moons

Neural Regeneration Research 2019 14(8):1313-1316

Dendrites form an essential component of the neuronal circuit have been largely overlooked in regenerative research. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. This mini-review aims to discuss an intriguing hypothesis, which postulates that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon central nervous system damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve injury. Strikingly, inhibiting dendritic pruning upon damage perturbed axonal regeneration. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature, as summarized in this short narrative. In addition, the review discusses a plausible underlying mechanism for the observed antagonistic axon-dendrite interplay, which is based on energy restriction inside neurons. Axonal injury indeed leads to a high local energy demand in which efficient axonal energy supply is fundamental to ensure regrowth. At the same time, axonal lesion is known to induce mitochondrial depolarization, causing energy depletion in the axonal compartment of damaged neurons. Mitochondria, however, become mostly stationary after development, which has been proposed as a potential underlying reason for the low regenerative capacity of adult mammals. Per contra, upon reduced neuronal activity, mitochondrial mobility enhances. In this view, dendritic shrinkage after axonal injury in zebrafish could result in less synaptic input and hence, a release of mitochondria within the soma-dendrite compartment that then translocate to the axonal growth cone to stimulate axonal regeneration. If this hypothesis proofs to be correct, i.e. dendritic remodeling serving as fuel for axonal regeneration, we envision a major shift in the research focus within the neuroregenerative field and in the potential uncovering of various novel therapeutic targets. 


Regenerative biomarkers for Duchenne muscular dystrophy
Simon Guiraud, Kay E Davies

Neural Regeneration Research 2019 14(8):1317-1320

Skeletal muscle has an extraordinary capacity to regenerate after injury and trauma. The muscle repair mechanism is a complex process orchestrated by multiple steps. In neuromuscular disorders such as Duchenne muscular dystrophy (DMD), the pathological consequences of the lack of dystrophin and the loss of the dystrophin-associated protein complex are dramatic, with a progressive cascade of events, such as continual influx of inflammation, repeated cycles of degeneration and impaired regeneration. Thus, muscle regeneration is a hallmark of the disease and careful monitoring of regenerative processes with robust markers should provide useful information to the field. Since decades, several indices of regeneration such as centronucleation and fibre size have been commonly used. In the present review, we discuss the impaired regenerative process in DMD, the common and new indices of regeneration and their associated methodologies. We notably highlight the regenerative marker embryonic myosin as a robust indicator of muscle regeneration. We also describe new quantitative methodologies offering the possibility of using a panel of translational regenerative biomarkers to obtain a more complete view of the regeneration processes. Upregulation of utrophin, an autosomal and functional paralogue of dystrophin, is one of the most promising therapeutic strategies as it targets the primary cause of the disease and is applicable to all DMD patients regardless their genetic defects. As utrophin is a regeneration associated protein increased in dystrophic muscle, we discuss the correlation of utrophin levels after drug treatment with regeneration markers. The recent advances in technologies and complementary markers of muscle regeneration described in this review, provide an unprecedented opportunity to develop more robust utrophin DMD based strategies for all DMD patients. 


Exploring the efficacy of natural products in alleviating Alzheimer's disease
Prajakta Deshpande, Neha Gogia, Amit Singh

Neural Regeneration Research 2019 14(8):1321-1329

Alzheimer&#8217;s disease (hereafter AD) is a progressive neurodegenerative disorder that affects the central nervous system. There are multiple factors that cause AD, viz., accumulation of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles, generation of reactive oxygen species due to mitochondrial dysfunction and genetic mutations. The plaques and tau tangles trigger aberrant signaling, which eventually cause cell death of the neurons. As a result, there is shrinkage of brain, cognitive defects, behavioral and psychological problems. To date, there is no direct cure for AD. Thus, scientists have been testing various strategies like screening for the small inhibitor molecule library or natural products that may block or prevent onset of AD. Historically, natural products have been used in many cultures for the treatment of various diseases. The research on natural products have gained importance as the active compounds extracted from them have medicinal values with reduced side effects, and they are bioavailable. The natural products may target the proteins or members of signaling pathways that get altered in specific diseases. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target for AD, and to address questions about how these natural products can rescue AD or other neurodegenerative disorders. Some of these products are in clinical trials and results are promising because of their neuroprotective, anti-inflammatory, antioxidant, anti-amyloidogenic, anticholinesterase activities and easy availability. This review summarizes the use of animal model systems to identify natural products, which may serve as potential therapeutic targets for AD. 


Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease
Daisuke Tanokashira, Wataru Fukuokaya, Akiko Taguchi

Neural Regeneration Research 2019 14(8):1330-1334

Type 2 diabetes&#8212;associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)&#8212;is a risk factor for cognitive impairment and dementia including Alzheimer&#8217;s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid &#946; accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline. 


Role of macrophages in peripheral nerve injury and repair
Ping Liu, Jiang Peng, Gong-Hai Han, Xiao Ding, Shuai Wei, Gang Gao, Kun Huang, Feng Chang, Yu Wang

Neural Regeneration Research 2019 14(8):1335-1342

Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabilitation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe peripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration. 


Therapeutic strategies for peripheral nerve injury: decellularized nerve conduits and Schwann cell transplantation
Gong-Hai Han, Jiang Peng, Ping Liu, Xiao Ding, Shuai Wei, Sheng Lu, Yu Wang

Neural Regeneration Research 2019 14(8):1343-1351

In recent years, the use of Schwann cell transplantation to repair peripheral nerve injury has attracted much attention. Animal-based studies show that the transplantation of Schwann cells in combination with nerve scaffolds promotes the repair of injured peripheral nerves. Autologous Schwann cell transplantation in humans has been reported recently. This article reviews current methods for removing the extracellular matrix and analyzes its composition and function. The development and secretory products of Schwann cells are also reviewed. The methods for the repair of peripheral nerve injuries that use myelin and Schwann cell transplantation are assessed. This survey of the literature data shows that using a decellularized nerve conduit combined with Schwann cells represents an effective strategy for the treatment of peripheral nerve injury. This analysis provides a comprehensive basis on which to make clinical decisions for the repair of peripheral nerve injury. 


Role and prospects of regenerative biomaterials in the repair of spinal cord injury
Shuo Liu, Yuan-Yuan Xie, Bin Wang

Neural Regeneration Research 2019 14(8):1352-1363

Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regeneration of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some regenerative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness. 


The "Brain Stress Timing" phenomenon and other misinterpretations of randomized clinical trial on aneurysmal subarachnoid hemorrhage
Rafael Martinez-Perez, Natalia Rayo, Agust&#237;n Montivero, Jorge Marcelo Mura

Neural Regeneration Research 2019 14(8):1364-1366

Clipping and coiling are currently the two alternatives in treatment of ruptured cerebral aneurysms. In spite of some meritorious analysis, further discussion is helpful to understand the actual state of art. Retreatment and rebleeding rates clearly favors clipping, although short-term functional outcome seems to be beneficial for clipping, while this different is not such if we perform the comparison at a longer follow up. Long-term follow ups and cost analysis are mandatory to have a clear view of the current picture in treatment of subarachnoid hemorrhage. Treatment strategy should be made by a multi-disciplinary team in accredited centers with proficient experience in both techniques.