Effects of epinephrine on right ventricular monophasic action potentials in the LQT1 versus LQT2 form of long QT syndrome: preferential enhancement of "triangulation" in LQT1

AIMS: To explore effects of epinephrine and phenylephrine on the behavior of right ventricular monophasic action potentials (MAPs) in symptomatic LQT1 and LQT2 patients. METHODS AND RESULTS: We recorded endocardial MAPs from right interventricular septum at baseline and during epinephrine and phenylephrine infusions in six symptomatic DNA-verified LQT1 (QTc 528 +/- 83) and five LQT2 patients (QTc 527 +/- 72) and in five control patients (QTc 381 +/- 22). We measured MAP durations at 90% and at 50% levels of repolarization and their difference (MAP50 to MAP90, a measure of MAP morphologic "triangulation"), during atrial pacing to characterize rate dependence of MAPs and repolarization phase 3 durations, respectively. Restitution kinetics were determined during atrioventricular sequential pacing, using the approach of empirical restitution rate. Epinephrine prolonged MAP50-to-MAP90 duration and increased the rate dependence of MAP90 duration and increased restitution rate in type LQT1, but not in LQT2 patients nor in control subjects. Phenylephrine did not change MAP behavior. During epinephrine administration, both LQT1 and LQT2 patients had a ratio of the restitution rate of MAP to diastolic interval >1.0 at short diastolic intervals. CONCLUSION: Symptomatic LQT1 patients with prolonged baseline QTc intervals showed beta-adrenergic-induced changes in MAPs (triangulation) known to be arrhythmogenic, thus giving insight to the difference in clinical triggers of life-threatening arrhythmias between LQT1- and LQT2-affected individuals.     

Congenital Myocardial Sympathetic Dysinnervation (CMSD)—A Structural Defect of Idiopathic Long QT Syndrome

Concerning the pathogenetic mechanism of idiopathic long QT syndrome (LQTS), the hypothesis of a specific sympathetic imbalance has gained general acceptance, but its validity has never been proven. To test this hypothesis I-123-MIBG, an analogue of norepinephrine and guanethidine, was used to provide scintigraphic display of the efferent cardiac sympathetic innervation. Twelve members of four LQTS families (mean age 38.2 +/- 17.2 years, eight males) and eight healthy volunteers (mean age 48.2 +/- 13.3 years, five males) were studied by means of I-123-MIBG single photon emission computed tomography (SPECT). A quantitative analysis of all scans was performed. All scans of the healthy volunteers show a uniform tracer uptake with sometimes slightly decreased activity in the apex. (1) All patients with QTc greater than 440 msec (n = 5); (2) all, who had suffered from at least one episode of torsade de pointes, ventricular fibrillation (VF) or syncope (n = 5); and (3) all symptomatic patients with QTc prolongation (n = 4) have reduced or abolished (P less than 0.02) MIBG uptakes in the inferior and inferior septal parts of the left ventricle (congenital myocardial sympathetic dysinnervation [CMSD]). Additionally, one female without symptoms or QTc prolongation (LQT) shows an abnormal MIBG SPECT similar to the one of her daughter, who has LQT and symptoms. One male without LQT, who had suffered from VF shows CMSD similar to his father, who has LQT, but no symptoms. All members of the families with normal MIBG SPECTs have neither LQT nor symptoms. In all families CMSD fulfills the criteria of autosomal-dominant inheritance. Normal QTc-interval predicted only in 57% normal cardiac sympathetic innervation in the present LQTS families. Therefore, quantitative I-123-MIBG SPECT enables to identify myocardial sympathetic dysinnervation as structural defect in LQTS. CMSD is associated with and without LQT and presents a pattern of autosomal-dominant inheritance. LQT at rest or during exercise was specific (100%), but less sensitive (63%) in the assessment of CMSD than I-123-MIBG SPECT.     

Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome

OBJECTIVE: To determine the effect of epinephrine on the QT interval in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between May 1999 and April 2001, 37 patients (24 females) with genotyped LQTS (19 LQT1, 15 LQT2, 3 LQT3, mean age, 27 years; range, 10-53 years) from 21 different kindreds and 27 (16 females) controls (mean age, 31 years; range, 13-45 years) were studied at baseline and during gradually increasing doses of intravenous epinephrine infusion (0.05, 0.1, 0.2, and 0.3 microg x k(-1) x min(-1)). The 12-lead electrocardiogram was monitored continuously, and heart rate, QT, and corrected QT interval (QTc) were measured during each study stage. RESULTS: There was no significant difference in resting heart rate or chronotropic response to epinephrine between LQTS patients and controls. The mean +/- SD baseline QTc was greater in LQTS patients (500+/-68 ms) than in controls (436+/-19 ms, P<.001). However, 9 (47%) of 19 KVLQT1-genotyped LQT1 patients had a nondiagnostic resting QTc (<460 milliseconds), whereas 11 (41%) of 27 controls had a resting QTc higher than 440 milliseconds. During epinephrine infusion, every LQT1 patient manifested prolongation of the QT interval (paradoxical response), whereas healthy controls and patients with either LQT2 or LQT3 tended to have shortened QT intervals (P<.001). The maximum mean +/- SD change in QT (AQT [epinephrine QT minus baseline QT]) was -5+/-47 ms (controls), +94+/-31 ms (LQT1), and -87+/-67 ms (LQT2 and LQT3 patients). Of 27 controls, 6 had lengthening of their QT intervals (AQT >30 milliseconds) during high-dose epinephrine. Low-dose epinephrine (0.05 microg x kg(-1) x min(-1)) completely discriminated LQT1 patients (AQT, +82+/-34 ms) from controls (AQT, -7+/-13 ms; P<.001). Epinephrine-triggered nonsustained ventricular tachycardia occurred in 2 patients with LQTS and in 1 control. CONCLUSIONS: Epinephrine-induced prolongation of the QT interval appears pathognomonic for LQT1. Low-dose epinephrine infusion distinguishes controls from patients with concealed LQT1 manifesting an equivocal QTc at rest. Thus, epinephrine provocation may help unmask some patients with concealed LQTS and strategically direct molecular genetic testing.     

Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome

MOENNIG, G., et al. : Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome. Rate corrected QT interval (QTc) and QT dispersion (QTd) have been suggested as markers of an increased propensity to arrhythmic events and efficacy of therapy in patients with long QT syndrome (LQTS). To evaluate whether QTc and QTd correlate to genetic status and clinical symptoms in LQTS patients and their relatives, ECGs of 116 genotyped individuals were analyzed. JTc and QTc were longest in symptomatic patients (  n = 28  ). Both QTd and JTd were significantly higher in symptomatic patients than in asymptomatic (  n = 29  ) or unaffected family members (  n = 59  ). The product of QTd/JTd and QTc/JTc was significantly different among all three groups. Both dispersion and product put additional and independent power on identification of mutation carriers when adjusted for sex and age in a logistic regression analysis. Thus, symptomatic patients with LQTS show marked inhomogenity of repolarization in the surface ECG. QT dispersion and QT product might be helpful in finding LQTS mutation carriers and might serve as additional ECG tools to identify asymptomatic LQTS patients.     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

Holter monitoring in the evaluation of congenital long QT syndrome

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that affects one in 2,000 persons; causes syncope, seizures, and sudden death; and is both under‐ and overdiagnosed. LQTS diagnostic miscues have stemmed from assessment of ambulatory electrocardiographic monitoring (Holter) results. Objective: We sought to determine the prevalence of positive Holter monitor tests and its diagnostic significance in evaluating LQTS. Methods: We performed an institutional review board‐approved review of patients evaluated in our LQTS clinic from 2000 to 2009 who had Holter testing during their evaluation. Included patients (N = 473) were diagnosed with LQTS or dismissed as otherwise normal. Holters classified as positive had an episode of nonsustained ventricular tachycardia, supraventricular tachycardia, ≥4 couplets/day, ≥10 premature ventricular contractions/hour, or >5‐second sinus pause. Results: Among 209 patients dismissed as normal (128 females, average age 21 ± 15 years, average QTc 424 ± 39 ms), 27 (12.9%) had a positive Holter, while among 264 patients with LQTS (149 females, average age 22 ± 16 years, average QTc 472 ± 41 ms), 30 (11.3%) had a positive Holter (P = NS). Patients with LQT3 (5/23, 21%) and genotype‐negative LQTS (5/19, 26%) had a higher rate of positive Holter testing compared to LQT1 patients (7/124, 6%, P < 0.03). Among the 473 Holters, only one (0.2%) impacted clinical decision making. Conclusion: Routine Holter monitoring appears to be of minimal clinical utility from a diagnostic and prognostic perspective in evaluating LQTS, and may not be cost effective. Whether Holter monitoring aids in therapeutic decisions such as dosing or whether ambulatory QTc measurements, provided by some newer devices, might help in the diagnostic evaluation warrants further scrutiny. (PACE 2011; 34:1100–1104)     

Cardiac K+ channels and drug-acquired long QT syndrome

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.     

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.     

Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome

Macrovoltage T wave alternans (TWA) has been described in congenital long QT syndrome (LQTS). Microvoltage T wave alternans (microV-TWA) at low heart rate (HR) is a marker of arrhythmogenic risk in many conditions, but its significance in LQTS has not been established. Twenty-three genotypically heterogeneous patients with LQTS and 16 control subjects were studied at rest and during phenylephrine and dobutamine provocation. Genotyping was established by PCR amplification and DNA sequencing of the three most common LQTS genes; KCNQ1/KVLQT1 (LQT1), KCNH2/HERG (LQT2), and SCN5A (LQT3). microV-TWA was determined using Fast Fourier transform. Precluded by ectopy, microV-TWA could not be assessed in 8 of 23 patients with LQTS. In the remaining 15 patients with LQTS, microV-TWA occurred at lower HR in LQTS than in controls (117 +/- 49 vs 153 +/- 37 beats/min; P < 0.05). Patients with LQTS developed microV-TWA at HR < 150 beats/min more often than controls (10/15 vs 2/16; P = 0.003). However, microV-TWA was not detected in the 3 individuals with a history of out-of-hospital cardiac arrest including a 14-year-old male with an F339del-KVLQT1 mutation (LQT1) who had dobutamine-provoked polymorphic ventricular tachycardia requiring external defibrillation. Catecholamine-provoked microV-TWA occurs at lower HR in patients with LQTS than in healthy people but does not identify high risk subjects.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype-phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Molecular Biology of the Long QT Syndrome: Impact on Management

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions ofadrenergic activation. Recently, the genes for the LQTS linked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQTl) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQTl potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na⁺channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest thatLQT3 patients are more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cate-cholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na + channel blocker such as mexiletine for LQT3 patients and of interventions such as K⁺ channel openers or increases in the extracellular concentration of potassium for LQTl and LQT2 patients.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype–phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Electrocardiographic features in a patient with the coexistence of long QT syndrome and coronary vasospasm

A 20-year-old woman suffered from cardiopulmonary arrest due to ventricular fibrillation. The electrocardiogram after resuscitation showed prolonged QTc interval with bifid T wave. On the third hospital day, the QTc interval and the T-wave changes improved. However, the QTc interval was distinctively prolonged after administration of epinephrine, oral glucose load, and intracoronary acetylcholine (Ach) into the left coronary artery. Moreover, an injection of Ach into the right coronary artery provoked severe coronary spasm. This is a case of the coexistence of long QT syndrome (LQTS) and coronary vasospasm, which may give an important clinical implication for the treatment of LQTS.     

The Long QT Syndrome and Torsade De Pointes

The LQTS is a prime example of how molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available.     

Ventricular repolarization and heart rate responses during cardiovascular autonomic function testing in LQT1 subtype of long QT syndrome

Background: In the most prevalent LQT1 form of inherited long QT syndrome symptoms often occur during abrupt physical or emotional stress. Sympathetic stimulation aggravates repolarization abnormalities in experimental LQT1 models. We hypothesized that autonomic function tests might reveal the abnormal repolarization in asymptomatic LQT1 patients.
Methods: We measured heart rates (HRs) and QT intervals in nine asymptomatic carriers of a C-terminal KCNQ1 mutation and 8 unaffected healthy subjects using an approach of global QT values derived from 28 simultaneous electrocardiographic leads on beat-to-beat base during Valsalva maneuver, mental stress, sustained handgrip, and light supine exercise.
Results: LQT1 patients exhibited impaired shortening of both QTpeak and QTend intervals during autonomic interventions but exaggerated lengthening of the intervals—a QT overshoot—during the recovery phases. The number of tests with a QT overshoot was 2.4 ± 1.7 in LQT1 patients and 0.8 ± 0.7 in unaffected subjects (P = 0.02). Valsalva strain prolonged T wave peak to T wave end interval (TPE) in LQT1 but not in unaffected patients. LQT1 patients showed diminished HR acceleration in response to adrenergic challenge whereas HR responses to vagal stimuli were similar in both groups.
Conclusions: Standard cardiovascular autonomic provocations induce a QT interval overshoot during recovery in asymptomatic KCNQ1 mutation carriers. Valsalva maneuver causes an exaggerated fluctuation of QT and TPE intervals partly explaining the occurrence of cardiac events during abrupt bursts of autonomic activity in LQT1 patients.     

Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE: To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS: The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS: Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.     

Comparison of QT peak and QT end interval responses to autonomic adaptation in asymptomatic LQT1 mutation carriers

Background: LQT1 subtype of long QT syndrome is characterized by defective I_Ks, which is intrinsically stronger in the epicardium than in the midmyocardial region. Electrocardiographic QT peak and QT end intervals may reflect complete repolarization of epicardium and midmyocardial region of the ventricular wall, respectively. Repolarization abnormalities in LQT1 carriers may therefore be more easily detected in the QT peak intervals. Methods: Asymptomatic KCNQ1 mutation carriers (LQT1, n = 9) and unaffected healthy controls (n = 8) were studied during Valsalva manoeuvre, mental stress, handgrip and supine exercise. Global QT peak and QT end intervals derived from 25 simultaneous electrocardiographic leads were measured beat to beat with an automated method. Results: In unaffected subjects, the percentage shortening of QT peak was greater than that of QT end during mental stress and during the recovery phases of Valsalva and supine exercise. In LQT1 carriers, the percentage shortening of the intervals was similar. At the beginning of Valsalva strain under abrupt endogenous sympathetic activation, QT peak shortened in LQT1 but not in control patients yielding increased electrocardiographic transmural dispersion of repolarization in LQT1. Conclusions: In asymptomatic KCNQ1 mutation carriers, repolarization abnormalities are more evident in the QT peak than in the QT end interval during adrenergic adaptation, possibly related to transmural differences in the degree of I_Ks block.     

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome

OBJECTIVE: To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. SUBJECTS AND METHODS: Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS: Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). CONCLUSIONS: To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.     

超声心动图对左束支区域起搏电极定位及左心室收缩功能的评价

目的应用超声心动图对行左束支区域起搏（LBBP）患者的电极位置及左心室收缩功能进行评价。 方法选取2018年3月至2020年10月在中国科学院大学宁波华美医院行LBBP的患者64例。根据起搏电极位置将患者分为前室间隔组（17例）和后室间隔组（47例）;根据术前左心室收缩功能将患者分为左心室收缩功能正常组（44例）与左心室收缩功能减低组（20例）。所有患者均于术前3 d内及术后3个月行超声心动图检查,评估LBBP术起搏电极的定位,并对比分析LBBP术前、术后左心室收缩功能。 结果超声心动图显示前室间隔组、后室间隔组电极旋入深度分别为（10.6±1.6）mm、（10.3±1.6）mm,2组比较差异无统计学意义（P=0.72）;前室间隔组电极旋入点距主动脉右冠瓣距离为（23.9±5.5）mm,后室间隔组电极旋入点距三尖瓣隔瓣根部距离为（24.1±5.3）mm。左心室收缩功能正常组术前与术后3个月比较,左心室射血分数（LVEF）、左心室舒张末期容积（LVEDV）、左心室收缩末期容积（LVESV）差异均无统计学意义（P均＞0.05）。左心室收缩功能减低组术后3个月的LVEDV、LVESV均较术前明显减小,LVEF较术前明显增大,差异均有统计学意义（P均＜0.05）。64例患者中,2例可见电极尖端穿透室间隔左心室面,进入左心室心腔,余62例无并发症发生。 结论LBBP可改善患者左心室收缩功能。超声心动图可显示LBBP电极入室间隔的深度及位置,为临床精准定位起搏提供有价值的信息,并在LBBP术前、术后左心室收缩功能的随访评估中发挥重要作用。     

Cycle Length-Associated Modulation of the Regional Dispersion of Ventricular Repolarization in a Canine Model of Long QT Syndrome

CHINUSHI, M., et al. : Cycle Length‐Associated Modulation of the Regional Dispersion of Ventricular Repolarization in a Canine Model of Long QT Syndrome. Previous tridimensional activation mapping showed that the development of functional conduction block at the onset of torsades de pointes was regionally heterogeneous; conduction block was frequently observed in the LV and the interventricular septum (IVS) but not in the RV, in the canine anthopleurin‐A (AP‐A) model of long QT syndrome (LQTS). This may be related to the distribution of myocytes with M celllike electrophysiological characteristics. To better understand the regional difference of arrhythmogenicity in LQTS, the authors investigated cycle length related modulation of ventricular repolarization among three different layers: the endocardium (End), mid‐myocardium (Mid), and epicardium (Epi) of the LV and RV and at two different areas: the Epi and septum (Sep) in the IVS. The LQT3 model was produced by AP‐A in dogs. Using constant pacing and single premature stimulation (S₁S₂), the ventricular repolarization pattern was analyzed from 256 unipo2 lar electrograms. Activation‐recovery intervals (ARIs) were used to estimate local repolarization. In seven experiments, AP‐A increased regional ARI dispersion to 88.1 ± 36.0 ms in the LV, to 72.9 ± 35.7 ms in the IVS, and to 23.0 ± 8.7 ms in the RV at the pacing cycle length (CL) of 1,000 ms. Development of the large ARI dispersion was due to greater ARI prolongation at the Mid site in the LV and at Sep site in the IVS. As the S₁S₂ interval was shortened, regional ARI dispersion decreased gradually, and finally, ARI dispersion showed a reversal gradient of repolarization between the Mid and Epi sites in the LV and between the Sep and Epi sites in the IVS. Two factors contributed to create the reversal gradient of repolarization: (1) a difference in restitution kinetics at the Mid site in the LV and at the Sep site in the IVS, characterized by a larger Δ ARI and slower time constant (τ), and (2) a difference in diastolic intervals at each site resulting in different input to restitution at the same CL. However, the RV showed small alteration in the transmural dispersion of repolarization in the S₁S₂ protocol. S₂ created heterogeneous functional conduction block in the LV and IVS but not in the RV. In the LQT3 model, the arrhythmogenicity of torsades de pointes is primarily due to dispersion of repolarization in the LV and IVS because of prominent distribution of M cells. The RV seems to participate passively in reentrant excitation during torsades de pointes.