Is the right ventricular function affected by permanent pacemaker?

AIMS: The effect of right ventricular (RV) pacing on left ventricular (LV) function has been extensively evaluated, but the effect on RV function per se has not been evaluated systematically. We aimed to assess the effect of dual chamber pacemaker on RV function. METHODS AND RESULTS: All consecutive patients undergoing dual chamber pacemaker from January 2018 to March 2019 for AV block with a structurally normal heart were included. They underwent pre-procedure detailed echocardiography (including three-dimensional [3D] RV ejection fraction [RVEF]), a screening echocardiogram 2 days after pacemaker implantation and again a detailed echocardiogram at 6-month follow-up. We compared the baseline echocardiographic RV parameters with those 6 months after the pacemaker implantation. A total of 60 patients underwent successful pacemaker implantation. At 6 months, most of the patients were pacemaker dependent with pacing percentage of 98.9% ± 2.4%; there was a significant increase in TR and a mean drop in RVEF by 2.8 ± 5%, with 23 (38.3%) having at least a 5% decrease in RVEF. The drop in RVEF positively correlated with TR vena contracta at 6 months but did not correlate with pulmonary artery systolic pressure at 6 months. CONCLUSION: Our study shows the presence of demonstrable RV dysfunction as early as 6 months in a majority of patients who have undergone pacemaker implantation.

Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.

Estimating Myocardial Infarction Size With a Simple Electrocardiographic Marker Score.

Background Myocardial infarction (MI) size is a key predictor of prognosis in post-MI patients. Cardiovascular magnetic resonance (CMR) is the gold standard test for MI quantification, but the ECG is less expensive and more widely available. We sought to quantify the relationship between ECG markers and cardiovascular magnetic resonance infarct size. Methods and Results Patients with prior MI enrolled in the DETERMINE (Defibrillators to Reduce Risk by Magnetic Resonance Imaging Evaluation) and PRE-DETERMINE Trial and Registry were included. ECG leads were analyzed for markers of MI: Q waves, fragmented QRS, and T wave inversion. DETERMINE Score=number of leads with [Q waves×2]+[fragmented QRS]+[T wave inversion]. Left ventricular ejection fraction (LVEF) and infarct size as a percentage of left ventricular mass (MI%) were quantified by cardiovascular magnetic resonance. The Modified Selvester Score estimates MI size from 37 ECG criteria. In 551 patients (aged 62.1±10.9 years, 79% men, and LVEF=40.3±11.0%), MI% increased as the number of ECG markers increased (P<0.001). By univariable linear regression, the DETERMINE Score (range 0-26) estimated MI% (R2=0.18, P<0.001) with an accuracy approaching that of LVEF (R2=0.22, P<0.001) and higher than the Modified Selvester Score (R2=0.09, P<0.001). By multivariable linear regression, addition of the DETERMINE Score improved estimation of MI% over LVEF alone (P<0.001) and over Modified Selvester Score alone (P<0.001). Conclusions In patients with prior MI, a simple ECG score estimates infarct size and improves infarct size estimation over LVEF alone. Because infarct size is a powerful prognostic indicator, the DETERMINE Score holds promise as a simple and inexpensive risk assessment tool.

Reference values of ECG parameters derived from 906 echocardiographically confirmed healthy Indian children: A population-based study from Gujarat.

INTRODUCTION: There are few published studies on reference ranges of ECG parameters in children; some ethnic differences have been described. METHODS: We studied digital 12­lead ECGs (1000 samples/s) from 906 healthy rural Indian children (467 boys: 439 girls) aged 5-15 years. PR, QRS, and QT were measured using superimposed median beat. Age-wise normal limits (median, 2nd and 98th percentile) were defined. RESULTS: Heart rate decreased while PR interval and QRS duration increased with age. QTcB interval remained unchanged from 5 to 12 years and decreased thereafter due to QTcB shortening in boys but not in girls. "Juvenile T wave pattern" was seen in 95% of children aged 5-8 years in lead V1 and 55-60% in V2, V3; it decreased with age. RV dominance (R/S > 1) in lead V1 was seen in 13% at 5 years, 1% at 10 years and none at 14 years. CONCLUSION: Reference ranges in Indian children are similar to those in other ethnic groups.

A pilot study comparing two sites for incision during pacemaker implantation and their influence on the scar.

OBJECTIVE: There are two most common incisions that are used during most pacemaker implantation procedures, with the first type of incision being inferior and parallel to the clavicle (Group C) and the second type of incision along the deltopectoral groove (Group D). We evaluated the scars resulting from the two types of incision to objectively evaluate the degree of superiority in cosmetic outcomes, between these two types of incisions. METHODS: Seventy-six patients who underwent left pre-pectoral pacemaker insertion were evaluated, close to 6 months after the date of the pacemaker implantation, using a simple scoring system based on atrophy, contour and colour of the scar. The likelihood of reduced severity in scar scores were compared between the two groups and the number of patients with elevation or inversion of the scar and with keloid formation were quantified. RESULTS: Seventy-six patients, with 47 belonging to the 'Group C' and 29 belonging to the 'Group D' were evaluated. The average length (C: 25 ±â€¯2 mm; D: 24 ±â€¯3 mm) and thickness (C: 25 ±â€¯3 mm; D: 26 ±â€¯2 mm) of the scars were not significantly different. The mean cumulative total scores in 'Group C' (1.98 ±â€¯1.50) and 'Group D' (1.93 ±â€¯1.31) were comparable. The odds ratio (OR) estimate showed that outcomes for atrophy (OR:0.73), contour (OR:0.53) and the cumulative total scores (OR:0.72) were also comparable. CONCLUSION: This pilot study showed that the deltopectoral groove incision as a site of incision is comparable to the infraclavicular incision.

For neonatal ECG screening there is no reason to relinquish old Bazett's correction.

Aims: There is an almost endless controversy regarding the choice of the QT correction formula to be used in electrocardiograms (ECG) in neonates for screening for long QT syndrome (LQTS). We compared the performance of four commonly used formulae and a new formula derived from neonates. Methods and results: From a cohort of 44 596 healthy neonates prospectively studied in Italy between 2001 and 2006, 5000 ECGs including 17 with LQTS-causing mutation identified by genotyping were studied using four QT correction formulae [Bazett's (QTcB), Fridericia's (QTcF), Framingham (QTcL), and Hodges (QTcH)]. A neonate-specific exponential correction (QTcNeo) was derived using 2500 randomly selected ECGs and validated for accuracy in the remaining 2500 ECGs. Digital ECGs were recorded between the 15th and 25th day of life; QT interval was measured manually in leads II, V5, and V6. To assess the ability to provide heart rate (HR) independent QT correction, regression analysis of the QTc-HR plots for all 5000 ECGs with each correction formula was done. QTcB provided the most HR independent correction with a slope closest to zero (slope +0.086 ms/b.p.m.) followed by QTcF (slope -0.308 ms/b.p.m.), QTcL (slope -0.364 ms/b.p.m.), and QTcH (slope +0.962 ms/b.p.m.). The QTc-HR slope of QTcNeo (QT/RR0.467) was similar to QTcB. The ability to correctly identify neonates with LQTS was best with QTcB, QTcF, and QTcNeo (comparable areas under the receiver operating characteristic curves) with positive predictive value of 39-40% and sensitivity of 100%. Cut-off values were 460 ms for QTcB, 394 ms for QTcF, and 446 ms for QTcNeo. Conclusions: The Bazett's correction provides an effective HR independent QT correction and also accurately identifies the neonates affected by LQTS. It can be used with confidence in neonates, although other methods could also be used with appropriate cut-offs.

Individual-Specific QT Interval Correction for Drugs With Substantial Heart Rate Effect Using Holter ECGs Extracted Over a Wide Range of Heart Rates.

Although fixed QT correction methods are typically used to adjust for the effect of heart rate on the QT interval in thorough QT/QTc studies, individual-specific QT correction (QTcI = QT/RRI ) is advisable for drugs that increase the heart rate by >5 to 10 beats/minute (bpm). QTcI is traditionally derived using resting drug-free electrocardiograms (ECGs) collected at prespecified times. However, the resting heart rate range in healthy individuals is narrow, and extrapolation of inferences from these data to higher heart rates could be inappropriate. Accordingly, the QTcI derived from triplicate ECGs extracted at prespecified times (the traditional [T] method, yielding QTcIT) was compared with QTcIs obtained using ECGs with a wider heart rate range (alternative Holter [H] method, yielding QTcIH) from 24-hour Holter recordings from 40 healthy individuals selected from a central ECG laboratory database. For QTcIH, 10-second ECGs were extracted at stable heart rates in the ranges of 51-60, 61-70, 71-80, and 81-90 bpm (9 ECGs in each bin = 36 ECGs). An independent set of 40 ECGs with heart rates from 51 to 90 bpm was extracted from each individual to validate the accuracy of QTcI by the 2 methods. For the validation set, the QTcIH was a better QT correction method (slope of QTc vs heart rate closer to zero) than QTcIT. The mean difference between QTcIT and QTcIH increased from 3.1 milliseconds at 65 bpm to 10.0 milliseconds at 90 bpm (P < 0.01). The QTcIT exceeded QTcIH at heart rates > 60 bpm. Employment of the QTcIH may be more appropriate for studies involving drugs that increase heart rate.

Atypical Variants of Takotsubo Cardiomyopathy: Twin Case Reports.

Takotsubo cardiomyopathy (TTC) is a well-known entity. We present two rare presentations of the same. Our first patient was diagnosed to have hypertrophic cardiomyopathy with ventricular tachycardia (VT), for which an ICD had been implanted. He later developed acute TTC with a large left ventricular (LV) apical thrombus. Our second patient was a 59 year old lady diagnosed to have TTC 2 years ago, from which she had recovered completely. She recently developed a recurrence of the same.

Occult etiologies of complete atrioventricular block: Report of two cases.

In patients presenting with complete atrioventricular (AV) block, the common causes are degeneration of the conduction system, acute myocardial infarction, congenital and metabolic disorders (such as azotemia). However, at times, no cause can be ascribed and the label congenital or degenerative is applied depending on the patient's age and the QRS complex width. We present two cases of patients with complete AV block, who were subsequently found to have rare etiologies - sarcoidosis (with isolated feature of AV block) and non-Hodgkin's lymphoma.

Routine health check-ups: A boon or a burden?

Healthcare provider institutions in India now offer structured health check-up 'packages' for routine screening of common diseases. While some tests included within their ambit are in keeping with international and Indian recommendations, some are entirely unwarranted. Unnecessary and inappropriate screening tests may cause more harm than benefit. Besides financial and resource burden, there may be over-diagnosis and over-treatment, psychological distress due to false-positive test results, harm from invasive follow-up tests, and false reassurance due to false-negative test results. Clinicians must ensure a net benefit from tests and interventions in order to efficiently deliver preventive services. We reviewed current screening guidelines for cardiovascular disease and common cancers, and surveyed multiple 'packages' provided at 8 centres in Mumbai, India. We put forth our recommendations for routine health screening in asymptomatic adults in India.

Comparison of the spatial QRS-T angle derived from digital ECGs recorded using conventional electrode placement with that derived from Mason-Likar electrode position.

BACKGROUND: The spatial QRS-T angle is ideally derived from orthogonal leads. We compared the spatial QRS-T angle derived from orthogonal leads reconstructed from digital 12-lead ECGs and from digital Holter ECGs recorded with the Mason-Likar (M-L) electrode positions. METHODS AND RESULTS: Orthogonal leads were constructed by the inverse Dower method and used to calculate spatial QRS-T angle by (1) a vector method and (2) a net amplitude method, in 100 volunteers. Spatial QRS-T angles from standard and M-L ECGs differed significantly (57°±18° vs 48°±20° respectively using net amplitude method and 53°±28° vs 48°±23° respectively by vector method; p<0.001). Difference in amplitudes in leads V4-V6 was also observed between Holter and standard ECGs, probably due to a difference in electrical potential at the central terminal. CONCLUSION: Mean spatial QRS-T angles derived from standard and M-L lead systems differed by 5°-9°. Though statistically significant, these differences may not be clinically significant.

Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach.

BACKGROUND AND PURPOSE: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects. EXPERIMENTAL APPROACH: We used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo. KEY RESULTS: The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per µg(-1) mL(-1) ; at mean Cmax of 2.95 µg·mL(-1) , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean Cmax exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%. CONCLUSIONS AND IMPLICATIONS: Our study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability.

Comparison of two methods of estimating reader variability in QT interval measurements in thorough QT/QTc studies.

BACKGROUND: Two methods of estimating reader variability (RV) in QT measurements between 12 readers were compared. METHODS: Using data from 500 electrocardiograms (ECGs) analyzed twice by 12 readers, we bootstrapped 1000 datasets each for both methods. In grouped analysis design (GAD), the same 40 ECGs were read twice by all readers. In pairwise analysis design (PAD), 40 ECGs analyzed by each reader in a clinical trial were reanalyzed by the same reader (intra-RV) and also by another reader (inter-RV); thus, variability between each pair of readers was estimated using different ECGs. RESULTS: Inter-RV (mean [95% CI]) between pairs of readers by GAD and PAD was 3.9 ms (2.1-5.5 ms) and 4.1 ms (2.6-5.4 ms), respectively, using ANOVA, 0 ms (-0.0 to 0.4 ms), and 0 ms (-0.7 to 0.6 ms), respectively, by actual difference between readers and 7.7 ms (6.2-9.8 ms) and 7.7 ms (6.6-9.1 ms), respectively, by absolute difference between readers. Intra-RV too was comparable. CONCLUSIONS: RV estimates by the grouped- and pairwise analysis designs are comparable.

Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study.

Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebo-subtracted change from baseline in QTc corrected by Fridericia's method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies.

Cardiovascular safety monitoring during oncology drug development and therapy.

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.

Sudden Cardiac Death in India: A Growing Concern.

The incidence of sudden cardiac death (SCD) is based on studies from North America and Western Europe with very few countries in Asia having conducted robust studies evaluating the occurrence of SCD. This paper reviewed published data on SCD, with a focus on India. In recent years, varying methods of assessment such as verbal autopsies, questionnaires, and quantification of surrogate endpoints such as cardiovascular disease profiles have been used to estimate the incidence of SCD. These studies have shown that the incidence of SCD is on the rise, especially in the urban regions, which may be largely attributed to the increase in prevalence of coronary artery disease, diabetes and hypertension in India. These studies have shown that the risk stratification and management approach for SCD are conspicuously varied and there is a need for establishing a systematic approach for estimating the incidence and risk factors of SCD in India.

Reader variability in QT measurement due to measurement error and variability in leads selection: a simulation study comparing 2-way vs. 3-way interaction ANOVA model.

Reader variability (RV) results from measurement differences or variability in lead used for QT measurements; the latter is not reflected in conventional methods for estimating RV. Mean and SD of QT intervals in 12 leads of 100 ECGs measured twice were used to simulate data sets with inter-RV of 5, 10, 15, 20, and 25 ms and intra-RV of 3, 6, 9, 12, and 15 ms. Six hundred twenty-five data sets were simulated such that different leads were used in Read1 and Read2 in 0, 10%, 20%, 30%, 40% of ECGs by 25 readers. RV was estimated using ANOVA interaction models: three-way model using Reader, ECG and lead as factors, and 2-way model using reader and ECG as factors. Estimates from three-way model accurately matched inter- and intra-RV that were introduced during simulation regardless of percent of ECGs with lead selection variability. The two-way model provides identical estimates when both reads are in same leads, but higher, more realistically estimates when measurements are made in different leads.