Sildenafil Citrate Does Not Affect QT Intervals and QT Dispersion: An Important Observation for Drug Safety

Background: Sildenafil is an effective and widely used therapeutic agent for erectile dysfunction. Deaths have been reported due to sildenafil use and most of them are attributed to concurrent use of nitrates. However, the effects of sildenafil on QT intervals, QT dispersion, and the possible risk of ventricular arrhythmia have not been studied before. Our aim in this study was to evaluate the effect of sildenafil citrate on QT intervals and QT dispersion. Methods: Thirty‐six patients with erectile dysfunction were included in this study. Twenty‐one patients had coronary artery disease whereas 12 of them also had accompanying diabetes mellitus. Standard 12‐lead electrocardiograms (ECG) were recorded three times: before, and at the first and fourth hours of 50 mg sildenafil citrate ingestion. All QT parameters were corrected for heart rate. Results: Mean age of the patients was 54 ± 12 years. The mean heart rate did not differ significantly between the three ECG examinations. The corrected and uncorrected maximum and minimum QT intervals were not significantly different between the three ECG examinations. The QT dispersion and corrected QT dispersion before and 1 hour and 4 hours after sildenafil ingestion were 31 ± 9 ms, 36 ± 10 ms; 32 ± 11 ms, 37 ± 14 ms; 27 ± 8 ms, 32 ± 9 ms, respectively (P > 0.05) . Conclusions: Sildenafil does not prolong QT intervals or increase QT dispersion in patients with erectile dysfunction. Our results suggest that the risk of ventricular arrhythmia does not increase with ingestion of 50 mg sildenafil.     

QT/RR Relationship in Patients after Remote Anterior Myocardial Infarction with Left Ventricular Dysfunction and Different Types of Ventricular Arrhythmias

Background: QT/RR relationship was found to be both rate‐dependent and rate‐independent, what suggests the influence of autonomic drive and other not‐autonomic related factors on it. The steeper QT/RR slope in patients after acute myocardial infarction (MI) was described, but the relationship to ventricular arrhythmias is unknown. The purpose of this study was to calculate differences in QT/RR relationship in patients after remote anterior MI with left ventricular dysfunction and different types of ventricular arrhythmias. Methods: The cohort of 95 patients (age: 63 ± 11 years, LVEF: 35 ± 9%) with previous anterior MI (mean 1.1 years) was divided into two well‐matched groups—50 patients without episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) (NoVT/VF: 39 males, 64 ± 12 years, LVEF 37 ± 8%) and 45 patients with VT and/or VF (all with ICD implanted) (VT/VF: 35 males, 62 ± 10 years, LVEF 34 ± 10%). No true antiarrhythmics were used. QT/RR slope was calculated from 24‐hour Holter ECG for the entire recording (E), daytime (D) and nighttime (N) periods. Results: Groups did not differ in basic clinical data (age, LVEF, treatment). QT/RR slopes were steeper in VT/VF than in NoVT/VF group in all analyzed periods: E ‐ 0.195 ± 0.03 versus 0.15 ± 0.03 (P < 0.001), N – 0.190 ± 0.03 versus 0.138 ± 0.03 (P < 0.001) and D ‐ 0.200 ± 0.04 versus 0.152 ± 0.03 (P < 0.001). No significant day‐to‐night differences were found in both groups. Conclusions: Steeper QT/RR slope and complete lack of day‐to‐night differences in VT/VF patients show inappropriate QT adaptation to the heart rate changes. The prognostic significance of this parameter needs prospective studies.     

Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men

The efficacy and safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, were evaluated in men with diabetes mellitus and erectile dysfunction (ED). Twenty-one men (aged 42–65 years) were enrolled in a double-blind, placebo-controlled, three-way crossover study conducted in two parts. In part I, the effect of a single dose (25 mg or 50 mg) of sildenafil or placebo on penile rigidity was assessed by penile plethysmography during visual sexual stimulation. In part II, daily diary records of erectile activity and a global efficacy question were used to evaluate once-daily dosing with 25 mg or 50 mg of sildenafil or placebo for 10 days. After a single 50 mg dose of sildenafil, the adjusted geometric mean duration (min) of penile rigidity >60 % at the base of the penis during visual sexual stimulation was significantly increased (10.1 min) compared with placebo (2.8 min; p = 0.0053). In part II, sildenafil significantly increased the number of erections considered sufficiently hard for vaginal penetration compared with placebo (p = 0.0005). Improved erections were reported by 50 % and 52 % of patients treated with 25 mg and 50 mg of sildenafil, respectively, compared with 10 % of those receiving placebo (p values < 0.05). Adverse events were mostly mild or moderate in nature and included muscular pains, headache, and dyspepsia. Sildenafil is a well-tolerated and potentially efficacious oral treatment for ED in men with diabetes mellitus. © 1998 John Wiley & Sons, Ltd.     

Left Ventricular Noncompaction Syndrome Masquerading or Misdiagnosed as Congenital Long QT Syndrome: Remember QT Prolongation Does Not Equal Long QT Syndrome

Distinguishing congenital long QT syndrome from QT prolongation caused by drugs or a different underlying disease process is essential for selecting the proper treatment. Herein, we present a case of a patient referred for left cardiac sympathetic denervation as a last resort treatment option for her 19‐year standing diagnosis of long QT syndrome with malignant ventricular fibrillation. However, based on her atypical clinical course and additional imaging studies, a diagnosis of left ventricular noncompaction, rather than long QT syndrome, was made. She left the clinic with a drastically different treatment plan and an improved quality of life. Because many cardiac and noncardiac diseases can demonstrate QT prolongation on electrocardiogram, all possible diagnoses should be considered before diagnosing a patient with congenital long QT syndrome especially with regard to the profound treatment implications and genetic follow‐up in family members.     

The Effect of Left Ventricular Function on QT Dispersion in Postmyocardial Infarction Patients with Previous Ventricular Tachyarrhythmias

Objectives: To determine if the presence of left ventricular dysfunction increases the QT and QT_c dispersion in postmyocardial infarction patients with ventricular tachyarrhythmias and to determine if left ventricular infarct location is associated with differences in QT and QT_c dispersion. Methods: The data was gathered from a retrospective electrophysiology (EP) database. All postinfarction patients (n = 87) with a past medical history of left ventricular myocardial infarction and ventricular tachyarrhythmia at baseline without bundle branch block or other intraventricular conduction abnormality were included. Patients were separated into those with an LVEF < 40% or < 40%. For secondary analysis, patients were separated into groups based on the location of the infarction. The QT and R‐R intervals were determined from each lead of a 12‐lead electrocardiogram (ECG) taken during the baseline EP study. The shortest QT and QT_c intervals were subtracted from the longest intervals on the 12‐lead ECG to give the QT and QT_c dispersions. Results: The QT and QT_c interval dispersions were significantly greater among patients with an LVEF < 40% than among those with an LVEF < 40% (57.3 ± 28.2 vs 47.4 ± 17.7, P = 0.05; 64.5 ± 32.1 vs 48.8 ± 18.2. P = 0.005, respectively). No differences in QT or QT_c dispersion were noted between patients with anterior or inferior myocardial infarctions. Conclusions: A higher QT dispersion can be predicted in patients with left ventricular dysfunction, but the location of the myocardial infarction does not predict the QT dispersion.     

QT Dispersion: Problems of Methodology and Clinical Significance

QT Dispersion. QT dispersion is defined as the difference in QT interval between the different leads of the surface 12-lead ECG. This may provide an indirect measure of the underlying inhomogeneity of myocardial repolarization, which is believed to be important in arrhylhmogenesis. Methodology for determining QT dispersion varies significantly between studies, and the results of these studies need to be interpreted in light of the methodology used. Although QT dispersion is developing into an important research tool, as yet it has no established role in clinical practice. Once standardization of methodology is achieved a clinical role may emerge, particularly in the assessment of patients before and after intervention aimed at reduction of arrhythmia risk.     

Precordial QT Dispersion does not Predict Inducibility of Ventricular Tachyarrhythmias at Post-Revascularization Electrophysiologic Study

Objectives: We tested the hypothesis that revascularization would decrease QT interval dispersion and that QT interval dispersion would predict the outcome of the electrophysiologic study following revascularization. Background: QT interval dispersion may be a measure of the inhomogeneity of ventricular repolarization. The value of the QT interval dispersion for predicting inducibility of ventricular tachyarrhythmias (VT) during electrophysiologic studies after coronary artery revascularization in patients with hemodynamically significant VT is unknown. Methods and Results: QT interval dispersions were measured from electrocardiograms recorded before and after coronary artery revascularization, but before an electrophysiologic study during the same hospitalization. Fifty-six patients (93% male, 65.1±9.6 years) were studied. QT interval dispersion decreased significantly following revascularization from 69±31 ms to 53±23 ms (p=0.002). Inducibility of VT could not be predicted by the QT interval dispersion following revascularization (50±30 ms in patients with VT induced vs. 58±25 ms in patients without VT induced at electrophysiologic study; p=0.2). The change in QT interval dispersion with revascularization (–15±33 ms vs. –17±46 ms; p=0.9) could not predict VT inducibility. Actuarial survival after 80 months follow-up was similar in the patients in whom VT was induced (82%) and those patients in whom VT was not induced (83%; p=NS). Conclusions: Coronary artery revascularization decreased QT interval dispersion in patients with hemodynamically significant VT, but QT interval dispersion was not predictive of inducibility of VT at follow-up electrophysiologic study. Actuarial survival was similar in patients in whom VT was induced and patients in whom VT was not induced.     

Dynamicity of Early and Late Phases of Repolarization in Patients with Remote Anterior Myocardial Infarction: The Interlead Differences

Background: Repolarization dynamicity (QT/RR) is supposed to be a prognostic marker in post‐MI patients. However, data on the relationships between early and late phases of QT and RR intervals (QT peak/RR and T peak–T end/RR) are insufficient, and which ECG lead should be used for the analysis is unclear. We analyzed repolarization dynamicity in patients after anterior MI with and without VT/VF history using two leads of Holter recordings‐ modified V₅ and V₃. The daytime and nighttime periods were also analyzed. Methods: Cohort of 88 patients after anterior MI (>6 months) consisted of 43 patients without VT/VF (33 males; 59 ± 12 years; LVEF: 41 ± 7%; NoVT/VF), and 45 patients with VT/VF history‐ ICD implanted as secondary prevention (40 males; 64 ± 10 years; LVEF: 32 ± 8%; VT/VF). QT/RR, QT peak/RR and T peak–T end/RR were calculated from 24‐hour ECG for the entire recording, daytime and nighttime periods, from V₅ and V₃ leads, respectively. Results: VT/VF patients had lower LVEF (P = 0.001). There were no differences in age and gender. VT/VF group had steeper QT/RR, QT peak/RR, and T peak–T end/RR in V₅: 0.233 ± 0.04 versus 0.150 ± 0.05, P = 0.0001, 0.181 ± 0.04 versus 0.120 ± 0.04, P = 0.0001, 0.052 ± 0.02 versus 0.030 ± 0.02, P = 0.0001, and in V₃: 0.201 ± 0.04 versus 0.149 ± 0.05, P = 0.0001, 0.159 ± 0.03 versus 0.118 ± 0.04, P = 0.0001, and 0.042 ± 0.02 versus 0.031 ± 0.02, P = 0.004; respectively. VT/VF patients had higher indices in V₅ than in V₃ lead (P = 0.001). QT/RR and QT peak/RR were steeper at daytime period in both leads. It was not found for T peak–T end/RR. Conclusions : Patients with VT/VF history are characterized by steeper relationships between repolarization duration and RR intervals. These findings are more evident in modified V₅ lead.     

QT Dispersion and Viable Myocardium in Patients with Prior Myocardial Infarction and Severe Left Ventricular Dysfunction

Background: QT dispersion (QTd) has been found to correlate to the amount of viable myocardium in patients with Q‐wave myocardial infarction and well‐preserved LV function. However, this relationship is unknown in patients with severe left ventricular dysfunction. Methods: Thirty‐four patients with prior large myocardial infarction and severe left ventricular dysfunction underwent Tc‐99m sestamibi single photon emission cardiac tomography (SPECT) and F‐18 fluorodeoxyglucose (FDG) SPECT. Viability was defined as a defect relative count density (DCD) of at least 20% greater on FDG SPECT. QTd, corrected QT dispersion (QTcd), and QT coefficient of variation (cv) in patients with viable myocardium was compared to those without viable mvocardium in the infarct area. Results: Thirteen patients were excluded from analysis for poor FDG images or inadequate ECG tracings. Of the remaining patients, 10 (48%) were found to have viability on FDG SPECT. QTd, QTcd, and QTcv in patients with viability were: 58 ± 22 ms, 61 ± 23 ms, and 4.81 ± 1.76%, respectively, which did not differ significantly from those in patients without viability (QTd = 56 ± 14 ms, QTcd = 70 ± 16 ms and Qtcv = 5.06 ± 1.20% (P = NS]). Moreover, neither FDG defect size, nor LVEF correlated with QTd. Conclusions: This study indicates no relationship between QTd and viability in patients with myocardial infarction and severe left ventricular dysfunction. A.N.E. 2002;7(1):53–59     

Comparison of QT/RR Relationship Using Two Algorithms of QT Interval Analysis for Identification of High Risk Patients for Life-Threatening Ventricular Arrhythmias

Objective: The purpose of this study was to evaluate the dynamic relationship between QT and RR intervals considering either the QTe interval (i.e., time between the onset of QRS and the end of the T wave) or the QTa interval (i.e., time between the onset of QRS and the apex of the T wave) from 30-second modules. Method: The Holter recordings in three groups of adult subjects (30 patients with malignant ventricular tachyarrhythmias [VT/VF patients], 40 patients with coronary artery disease [CAD], and 44 normal subjects) were analyzed using the ELATEC System. Results: In normal subjects the correlation coefficient between QTa and RR (QTa/RR) was significantly higher (0.87 ± 0.12) than those between QTe and RR (QTe/RR) (0.79 ± 0.17). In the other groups there was no significant difference between QTa/RR and QTe/RR: QTa/RR (CAD: 0.71 ± 0.3; VT/VF: 0.73 ± 0.19); and QTe/RR (CAD: 0.63 ± 0.33; VT/VF: 0.69 ± 0.21). The slope of QTe/ RR over 24 hours was significantly larger in VT/VF patients (0.23 ± 0.11) than in the other groups (control: 0.18 ± 0.08; CAD: 0.17 ± 0.1). Measuring the QTa/RR relation there was no difference between the three groups (VT/VF: 0.19 ± 0.09; CAD: 0.15 ± 0.09; normal: 0.19 ± 0.06). Conclusion: QTe/RR as well as QTa/RR analyses are methods of detecting a deranged rate dependence of QT intervals in high risk patients. An increased QTe/RR slope indicates a higher risk of life-threatening ventricular arrhythmias. Because there was no difference in QTa/RR we conclude that the end of the T wave gives important information about disorders in repolarization.     

Time dependent variability of QT dispersion after acute myocardial infarction and its relation to ventricular fibrillation: a prospective study

OBJECTIVE—To show whether increased QT dispersion on admission predicts ventricular fibrillation after acute myocardial infarction, and to determine the nature of time related changes in QT dispersion.
DESIGN—Prospective cohort study.
SETTING—Coronary care units of three teaching hospitals in Newcastle-upon-Tyne over an eight month period.
PATIENTS—All had acute myocardial infarction according to World Health Organization criteria.
INTERVENTIONS—For all patients, QT dispersion (QTd) and Bazett rate corrected QTc dispersion (QTcd) were measured from a high quality 12 lead ECG recorded on admission at a paper speed of 50 mm/s. In a subset, serial ECGs were recorded regularly to show time related changes in QTcd following acute myocardial infarction.
MAIN OUTCOME MEASURES—Occurrence of ventricular fibrillation within the first 24 hours after myocardial infarction.
RESULTS—Data collected from 201 patients, 12 of whom (6%) developed ventricular fibrillation within 24 hours. Neither QTd nor QTcd differed between those developing ventricular fibrillation and those who did not: QTd mean (SD), 74 (24) ms (95% confidence interval (CI) 59 to 89) v 66 (24) ms (95% CI 62 to 70), respectively; QTcd, 86 (26) ms^0.5 (95% CI 70 to 102) v 77 (29) ms^0.5 (95% CI 72 to 82), respectively. Significant QTcd changes occurred early after myocardial infarction.
CONCLUSIONS—Admission QTd and QTcd do not predict ventricular fibrillation after acute myocardial infarction. There are significant changes in QTcd with time, which may account for this measured lack of correlation.


Keywords: acute myocardial infarction; arrhythmia; ventricular fibrillation; QT dispersion     

Correction for Heart Rate Is Not Necessary for QT Dispersion in Individuals without Structural Heart Disease and Patients with Ventricular Tachycardia

Background: It remains controversial whether QT dispersion should be corrected for heart rate, especially when the limitations of rate correction formulae are considered. We investigated whether incremental atrial pacing affects QT dispersion and the rate‐corrected values according to Bazett's formula in individuals without structural heart disease and in patients with history of sustained ventricular tachycardia. Methods: We studied 32 individuals without structural heart disease (group A), and 16 patients with a history of sustained ventricular tachycardia (group B). QT dispersion and corrected for heart rate QT dispersion using Bazett's formula (QTc dispersion) were calculated in sinus rhythm, and during continuous right atrial pacing for one minute at 100 and 120 beats/min. Results: Interobserver variability was not significant (P ≧ 0.10). QT dispersion did not differ at rest between groups A and B and did not change significantly from baseline at any heart rate in both groups. However, QTc dispersion increased significantly with atrial pacing in a similar manner in group A and group B (42 ± 19 ms at rest vs 53 ± 23 ms at 120 beats/min, P < 0.001 for group A, 39 ± 16 ms at rest vs 60 ± 19 ms at 120 beats/min, P < 0.001 for group B). Conclusions: We conclude that QT dispersion remains unchanged during atrial pacing at heart rates up to 120 beats/min in both individuals without structural heart disease and in patients with a history of sustained ventricular tachycardia. Correction by Bazett's formula results in prolongation of QTc dispersion, yielding values which may be misleading. A.N.E. 2002;7(1):47–52     

Normalization of Ventricular Repolarization with Flecainide in Long QT Syndrome Patients with SCN5A:ΔKPQ Mutation

Background: The Long QT Syndrome (LQTS) is a genetic channelopathy with life‐threatening implications. The LQT3 form of this disease is caused by mutations of the SCN5A sodium‐channel gene. A specific mutation, SCN5A:ΔKPQ, is associated with repetitive reopenings of the sodium channel and prolonged inward current. This dominant inward current is manifest on the electrocardiogram as QT prolongation. Flecainide is a potent blocker of the open sodium channel. Methods and Results: The effect of flecainide on the duration of the QT‐interval and the T‐wave morphology was systematically evaluated in five male patients age 2–64 years having the SCN5A:ΔKPQ mutation. After baseline electrocardiograms were obtained, low‐dose oral flecainide was administered for 48 hours. Serial electrocardiograms and blood flecainide levels were obtained during flecainide therapy. The QTc interval decreased on average by 104 ms, from a baseline value of 565 ± 60 ms to 461 ± 23 ms (P < 0.04) at a mean flecainide level of 0.28 ± 0.08 mg/L, with shortening of the QTonset interval (P < 0.003) and normalization of T‐wave morphology. The effects of flecainide were compared with oral mexiletine in two patients, with flecainide showing greater QTc shortening and more complete normalization of repolarization. No adverse side effects or proarrhythmia were observed with flecainide in this study. Conclusion: Low‐dose, oral flecainide consistently shortened the QTc interval and normalized the repolarization T‐wave pattern in five LQT3 patients with SCN5A:ΔKPQ mutation. This preliminary study indicates that low‐dose flecainide is a promising therapeutic agent for LQTS patients with the SCN5A:ΔKPQ sodium channel mutation. A.N.E. 2001;6(2):153–158     

An Adolescent with Possible Arrhythmogenic Right Ventricular Dysplasia and Long QT Syndrome: Evaluation and Management

We describe a unique presentation of arrhythmogenic right ventricular dysplasia (ARVD) in a 14‐year‐old Caucasian male who was additionally diagnosed with long QT syndrome (LQTS). Genetic testing eventually confirmed the diagnosis of both ARVD and LQTS, which combined, to our knowledge, has not been reported in the literature.     

Asymptomatic Left Ventricular Dysfunction and Metabolic Syndrome: Results from an Italian Multicenter Study

Context:

Metabolic syndrome (MS) is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Although MS is associated with increased cardiovascular risk (CVR), its relationship with heart failure (HF) and left ventricular (LV) dysfunction is not fully understood.

Aims:

We sought to determine whether MS is associated to LV systolic and diastolic dysfunction in a sample of patients with MS and no symptoms for HF.

Subjects and Methods:

We enrolled 6422 consecutive asymptomatic patients admitted to echo-lab for a routine echocardiogram. We calculated LV systolic and diastolic function, by Simpson biplane method and validated Doppler parameters, respectively. MS was diagnosed if three or more CVR factors were found.

Results:

LV systolic function was evaluated in 6175 patients (96.2%). In the group of patients without MS (n = 5630), the prevalence of systolic dysfunction was 10.8% (n = 607) while in the group of patients with MS (n = 545) it was 12.5% (n = 87), (RR1.57; CI 95% 1.2-2.0; P < 0.001). Diastolic function was evaluated in 3936 patients (61.3%). In the group of patients without MS (n = 3566) the prevalence of diastolic dysfunction was 33.3% (n = 1187), while in patients with MS (n = 370) it was 45.7% (n = 169), (RR1.68; CI95% 1.3-2.0; P < 0.001). After adjustment for age and gender, MS proved to be an independent predictor of LV systolic and diastolic dysfunction.

Conclusions:

Our data show that asymptomatic LV systolic and diastolic dysfunction, is correlated with MS and demonstrate that echocardiography is a useful tool to detect patients at high risk for HF. Echocardiography in asymptomatic patients with MS may lead to a therapy initiation at early stages to prevent future cardiovascular events and HF.     

Impact of Left Ventricular Remodeling on Ventricular Repolarization and Heart Rate Variability in Patients after Myocardial Infarction Treated with Primary PCI: Prospective 6 Months Follow‐up

Background: The relation between postinfarction left ventricle remodeling (LVR), autonomic nervous system and repolarization process is unclear. Purpose of the study was to assess the influence of LVR on the early (QTpeak) and late (TpeakTend) repolarization periods in patients after myocardial infarction (MI) treated with primary PCI. The day‐to‐night differences of repolarization parameters and the relation between QT and heart rate variability (HRV) indices, as well left ventricle function were also assessed. Methods: The study cohort of 104 pts was examined 6 months after acute MI. HRV and QT indices (corrected to the heart rate) were obtained from the entire 24‐hour Holter recording, daytime and nighttime periods. Results: LVR was found in 33 patients (31.7%). The study groups (LVR+ vs LVR?) did not differ in age, the extent of coronary artery lesions and treatment. Left ventricle ejection fraction (LVEF) was lower (38%± 11% vs 55%± 11%, P < 0.001), both QTc (443 ± 26 ms vs 420 ± 20 ms, P < 0.001) and TpeakTendc (98 ± 11 ms vs 84 ± 12 ms, P < 0.005) were longer in LVR + patients, with no differences for QTpeakc. Trends toward lower values of time‐domain (SDRR, rMSSD) HRV parameters were found in LVR+ pts. Day‐to‐night difference was observed only for SDRR, more marked in LVR‐group. Remarkable relations between delta LVEF (6 months minus baseline), delta LVEDV and TpeakTendc were found, with no such relationships for QTpeakc. Conclusions: The patients with LVR have longer repolarization time, especially the late phase‐ TpeakTend, which represents transmural dispersion of repolarization. Its prolongation seems to be related to local attributes of myocardium and global function of the left ventricle but unrelated to the autonomic nervous influences. Remodeling with moderate LV systolic dysfunction is associated with insignificant decrease in HRV indices and preserved circadian variability.