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Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Syncope, defined as a transient loss of consciousness secondary to global cerebral hypoperfusion, is common in the general population. The single most helpful "test" in the evaluation of patients with syncope is a thoughtful history, with recent evidence that structured histories are remarkably effective in arriving at a diagnosis. In addition to the history, physical examination, and electrocardiogram, arriving at a diagnosis of syncope can involve monitoring and provocative strategies. The majority of patients with syncope have neurally mediated syncope and a favourable prognosis. The management of neurally mediated syncope continues to largely revolve around education, avoidance of triggers, reassurance, and counter-pressure maneuvers. The evidence surrounding medical therapy in vasovagal syncope is not strong to date. Pacemaker therapy is reasonable in older patients with recurrent, unpredictable syncope with pauses, but should be considered as a last resort in younger patients.

ObjectiveThe natural history of frequent premature ventricular complexes (PVCs) in association with preserved left ventricular ejection fraction (LVEF) is uncertain. The optimal management of this population is thus undefined. We studied the outcomes of untreated patients with frequent PVCs and preserved LVEF.MethodsThis cohort study prospectively evaluated consecutive patients from 2012 to 2017, with asymptomatic or minimally symptomatic frequent idiopathic PVCs (≥5% PVCs in 24 hours; normal LVEF; no cause identified on comprehensive evaluation). No suppressive therapy (ablation or antiarrhythmic drugs) were used and patients were followed with serial ambulatory ECG monitoring and echocardiography. The primary arrhythmic outcome was reduction in PVC burden to ResultsOne hundred patients met inclusion criteria (mean age 51.8 years, 57% female) with a median PVC burden of 18.4%. Reduction to ConclusionsA strategy of active surveillance is appropriate for the majority of patients with frequent idiopathic PVCs in association with preserved LVEF, owing to the low risk of developing left ventricular systolic dysfunction and the high rate of spontaneous resolution.

There has been a resurgent interest in frequent premature ventricular contractions (PVCs) led by the novel concept that they may be a potential cause of, or at least contribute to, cardiomyopathy. This review evaluates recent advances in our understanding of PVC-induced cardiomyopathy.Recent studies have focused on identifying the predictors of PVC-induced cardiomyopathy, with the most consistent predictors being PVC burden and PVC QRS duration. Multiple studies have investigated the effect of catheter ablation on PVC burden and resultant left ventricular function, with the efficacy of catheter ablation and the overall PVC response rates varying between 60 and 88%. After successful ablation, the rates of improvement in left ventricular ejection fraction have varied between 47 and 100%. A recent study raises the question that perhaps even a lower PVC burden could result in PVC cardiomyopathy and adverse outcomes.There is an increasing body of literature supporting a causal role of frequent PVCs in the development of left ventricular dysfunction. Effective therapy for PVCs exists; however, the optimal indications for therapy have yet to be determined.

This study examined the mechanisms for force and power reduction during and up to 48 h after maximal eccentric contractions of the knee extensor muscles in young men and women. 13 men (22.8 ± 2.6 years) and 13 women (21.6 ± 2.2 years) performed 150 maximal effort eccentric contractions (5 sets of 30) with the knee extensor muscles at 60° s−1. Maximal voluntary isometric contractions (MVIC) and maximal voluntary concentric contractions (MVCC) were performed before and after the 150 eccentric contractions. The MVCCs involved a set of two isokinetic contractions at 60° s−1 and sets of isotonic contractions performed at seven different resistance loads (1 N m, 10, 20, 30, 40, 50, and 60% MVIC). Electrical stimulation was used during the MVICs and at rest to determine changes in voluntary activation and contractile properties. At baseline, men were stronger than women (MVIC: 276 ± 48 vs. 133 ± 37 N m) and more powerful (MVCC: 649 ± 77 vs. 346 ± 78 W). At termination of the eccentric contractions, voluntary activation, resting twitch amplitude, and peak power during concentric contractions at the seven loads and at 60° s−1 decreased (P 0.05) with no sex differences. Central mechanisms were primarily responsible for the depressed maximal force production up to 48 h after repeated eccentric contractions of the knee extensors and these mechanisms were similar in men and women.

Relative myocardial perfusion imaging may underestimate severity of coronary disease (CAD), particularly in cases of balanced ischemia. Can quantification of peak left (LV) and right (RV) ventricular Rb-82 uptake measurements identify patients with left main or 3 vessel disease? Patients (N = 169) who underwent Rb-82 PET MPI and coronary angiography were categorized as having no significant coronary stenosis (n = 60), 1 or 2 vessel disease (n = 81), or left main disease/3 vessel disease (n = 28), based on angiography. Maximal LV and RV ventricular myocardial Rb-82 uptake was measured during stress and rest. Failure to augment LV uptake by ≥ 8500 Bq/cc at stress, predicted left main or 3 vessel disease with a sensitivity of 93% and specificity of 61% (area under curve = 0.83). A ≥10% increase in RV: LV uptake ratios with stress over rest was 93% specific (area under curve = 0.74) for left main or 3 vessel disease. These indices incrementally predicted left main or 3 vessel disease compared to models including age, gender, cardiac risk factors, and summed stress and difference scores. Quantifying maximal rest and stress LV and RV uptake with PET myocardial perfusion imaging may independently and incrementally identify patients with left main or 3 vessel disease.

ObjectivesThe aim of this study was to compare treadmill exercise (TEX) and dipyridamole stress on the uptake and retention of N-13 ammonia.BackgroundSize and severity of stress-induced myocardial perfusion defects are clinically important. Because ammonia uptake and retention seems to be related to perfusion, viability, and metabolism, exercise stress might induce larger perfusion defects than dipyridamole stress.MethodsTwenty-six patients underwent TEX and dipyridamole stress N-13 ammonia positron emission tomography (PET). Images were assessed with a 17-segment model and a five-point score. Summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated. Left ventricular (LV) defect sizes were measured quantitatively with a 70% threshold for abnormal perfusion.ResultsCompared with dipyridamole stress, TEX yielded larger SSS (9.1 ± 5.7 vs. 6.9 ± 5.9; p < 0.01), SDS (5.8 ± 4.7 vs. 3.7 ± 4.6; p < 0.02), and percentage of LV stress defect (19.3 ± 11.5% vs. 13.8 ± 13.6%; p < 0.02).ConclusionsIn patients achieving adequate exercise, TEX N-13 ammonia PET myocardial perfusion imaging (MPI) yields larger stress perfusion defects than dipyridamole stress and might reflect the true myocardial ischemic burden. Treadmill exercise might be the preferred method of stress for routine N-13 ammonia PET MPI.

Computed tomographic coronary angiography (CTCA) is an effective non-invasive tool for the detection and risk stratification of patients with suspected coronary artery disease (CAD) [1–5]. Many previous studies have focused upon a biased population already referred to invasive coronary angiography (ICA). As such, operating characteristics measured in these studies may not reflect diagnostic accuracy in the routine clinical CTCA population. To account for such bias, the normalcy rate (NR) has been employed to estimate the true specificity of a diagnostic test in clinical practice [2]. We sought to assess the NR of CTA in a clinical CTCA patient populationwith low pretest probability (≤4%) for CAD. Consecutive patients underwent clinical CTA studies were enrolled in a cardiac CT registry. Each patient's pretest probability for obstructive CADwas calculated using age, gender, and symptoms [1,2]. 601 patients with a very low pretest probability (≤4%) and had an imaging heart rate ≤70 beats/min and BMI≤40 kg/m were retrospectively analyzed. The study was approved by the institutional human research ethics board. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Our institutional CTA protocol has been previously described [1,2,5]. In brief, images were acquired with a triphasic protocol (100% contrast, 40%/60% contrast/saline, and 40 cc saline (Visipaque 320 or Omnipaque 350, GE Healthcare, Milwaukee, Wis) and infusion rates were individualized according to scan time and patient body habitus [1,2,5]. Prospective ECG-triggered or retrospective ECG-gated data sets were acquired with the GE Volume CT (GE Healthcare) with 64×0.625 mm slice collimation and a gantry rotation of 350 ms (mA=300 to 800, kV=120). Images were processed using the GE Advantage Volume Share Workstation (GE Healthcare) and visually interpreted by expert observers blinded to all clinical data. A 17 segment model of the coronary arteries and 4 point grading score (normal, mild [b50%], moderate [50% to 69%], severe [≥70%]) was used for the evaluation of coronary stenosis [1,2]. Normal CTCA was defined as the absence of obstructive CAD (b50%), and the normalcy rate was calculated using 2 definitions for obstructive CAD (≥50% and ≥70% coronary artery diameter stenosis), as defined by Diamond-Forrester and the CASS Registry [1,2]. All patients referred to ICA had their reports reviewed. Results were categorized as normal if there was no significant obstructive CAD (diameter stenosis b50%) or abnormal if there was ≥1 coronary segment with diameter stenosis ≥50% [1,2,5]. Statistical analyses were performed using SAS (version 9.1.3, SAS Institute Inc, Cary, NC), and statistical significance was defined as pb0.05. Continuous variables are presented as means and standard deviations, and categorical variables are presented as frequencies with percentages. The Fisher exact test was used to compare categorical variables. Using those patients referred to ICA, the operating characteristics of CTCAwere calculated on a per-patient basis and were reported with 95% CIs [1,2,5]. A total of 601 patients (age=42.8±9.5 years, men=181 (30.1%), mean pretest probability (2.7±1.0 %)were analysed. 35 (5.8%) patients had evidence of obstructive CAD (≥50% stenosis) with 19 patients having moderate (50–69%) diameter stenoses and 16 with severe (≥70%) stenoses. Of the remaining 566 patients, 157 (26.1%) had evidence of non-obstructive coronary atherosclerosis. Using thresholds of≥50% and≥70% stenoses, the normalcy rate CTCAwas 94% (CI: 92%– 96%) and 97% (CI: 96%–99%), respectively. A total of 22 patients underwent ICA. The prevalence of obstructive CAD in those who underwent ICA was 45.5%. CTCA correctly detected obstructive CAD in 9 patients and correctly excluded disease in 10 patients with an overall accuracy of 86.3%. Based upon this small population, CTCA had per-patient sensitivity of 90% (CI: 54%–100%), positive predictive value of 82% (CI: 48%–97%) and negative predictive value of 91% (CI: 57%–100%) for CAD. As expected, the specificity was lower (83% (CI: 51%–97%)). This analysis confirms, in a large population of patients with a very low pretest probability of obstructive CAD, the high normalcy rate (94– 97%) of CTCA. It is widely known that once a test becomes accepted into clinical practice, a decline in specificity is observed. Since the reduction in specificity is attributed to verification and referral bias ICA is typically be performed in patients with abnormal CTA and uncommonly in patients without obstructive CAD. Therefore, to account for such bias, the notion of NR has been developed. Though it is desirable to attain high NR, the NR should not be 100%. By screening large populations with a pretest probability N0% for obstructive CAD, one would expect to diagnose patients with CAD. Because our study population had a mean pretest probability of 2.7%, it was not unexpected to have made the diagnosis of obstructive CAD in some patients. In summary, the normalcy rate of CTA is very good (94–97%) in patients with a low pretest probability (≤4%) of CAD.