Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome

Background: A novel familial arrhythmia syndrome, RyR2 calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2 , Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.

Ineffective Esophageal Motility: Need for Improvement in Diagnostic Criteria

Ineffective esophageal motility (IEM) is a hypomotility disorder with decreased contraction vigor and normally relaxing lower esophageal sphincter. Although IEM has been associated with poor esophageal clearance and gastroesophageal reflux, it is also seen in asymptomatic subjects and is often of unclear clinical significance. The Chicago classification version 4.0 updated the diagnostic threshold to require >70% weak or fragmented swallows or ≥50% failed swallows for a conclusive diagnosis of IEM. Provocation testing are recommended in borderline cases to assess clinical relevance. Prospective trials are needed to further refine the diagnostic criteria, understand the pathophysiology, and develop an effective treatment for IEM.

The Relevance of Ineffective Esophageal Motility to Surgical Practice

Foregut surgery is often complicated by postoperative dysphagia. Preoperative esophageal manometry has been used to counsel patients and to guide choice of operation to minimize dysphagia outcomes. Uncertainty surrounds the optimal surgical management of patients with disordered motility. While treatment protocols are generally accepted for the disorders of esophagogastric junction outflow, surgery choice in the presence of disorders of peristalsis, particularly ineffective esophageal motility (IEM), is less clear. With the diagnosis of IEM, provocation testing is being utilized to predict postoperative dysphagia and to guide management, though evidence is not yet sufficient to allow for strong recommendations.

The Importance of Nasal Provocation Testing in the Diagnosis of Dermatophagoides pteronyssinus-Induced Allergic Rhinitis

Background Allergen identification is the first step for allergen-specific immunotherapy (AIT) of allergic rhinitis (AR). Currently, the diagnosis of AR is based mainly on the positive results of the skin prick test (SPT) and/or serum specific immunoglobulin E (sIgE) measurement. However, the results of these two tests may not always directly correlate with AR. Objective To investigate the importance of nasal provocation testing (NPT) in the diagnosis of Dermatophagoides pteronyssinus (Der p)-induced AR. Methods Rhinitis patients willing to undergo AIT (n = 171) were enrolled. The correlations of Der p SPT, sIgE, NPT, and clinical symptom severity were assessed. Results NPT-positive responses were more common in patients with higher SPT and sIgE levels. The optimal cut-off value for a NPT-positive response for SPT was 5.5 mm and for sIgE was 2.77 kUA/L, based on the respective receiver operating characteristic (ROC) curves. The area under the curve (AUC) of the ROCs was 0.814 (SPT only) and 0.794 (sIgE only) and increased to 0.828 with the combination of SPT and sIgE. The Der p-NPT concentration was inversely correlated with SPT and sIgE levels ( r = −0.477, P < .001, and r = −0.461, P < .001, respectively), but none was correlated with the total nasal symptom score. Conclusion For patients who are willing to receive Der p AIT, NPT is a useful and safe test to confirm diagnosis prior to treatment initiation, especially in patients with lower levels of Der p SPT (< 5.5 mm) or sIgE (< 2.77 kUA/L).

How reliable is anamnestic data in predicting the clinical relevance of house dust mite sensitization?

Purpose For perennial inhalant allergens such as house dust mite (HDM), the German guideline on allergen-specific immunotherapy explicitly recommends provocation testing. This procedure is time-consuming, expensive, and potentially dangerous for the patient. Recently it has been discussed whether provocation tests are really necessary for diagnosing allergy to Dermatophagoides species. Thus, our study aimed to analyze the concordance between nasal provocation tests with Dermatophagoides species and anamnestic data. Methods We retrospectively analyzed the concordance between patients’ histories including self-reported symptom scores and the results of provocation testing in 471 individuals with proven sensitization to Dermatophagoides species. Results 248 patients had a positive nasal provocation test (NPT) result to Dermatophagoides species and 223 individuals a negative NPT result. Patients allergic to HSM suffered significantly more often from atopic dermatitis (14% vs. 7%, p = 0.046) and more from asthma (20% vs. 19%, p = 0.851). Moreover, individuals with clinically silent sensitization complained less about nasal secretion (37% vs. 45%, p = 0.244) but significantly more about nasal dryness (46% vs. 34%, p = 0.046) whereas rates of nasal airway obstruction, ocular complaints and sleep quality were comparable in both groups. Allergic patients reported more often perennial (34% vs. 30%, p = 0.374) and location-dependent (39% vs. 31%, p = 0.090) symptoms. However, the discrepant prevalence of atopic dermatitis was the only statistically significant difference between both groups. Conclusion Despite slight differences between both patient groups, clinical data are not sufficient to distinguish between silent sensitization and clinically relevant allergic rhinitis to HDM. Therefore, nasal provocation testing remains the gold standard for assessing clinical relevance in patients sensitized to Dermatophagoides species.

The role of computed tomography coronary angiography in multi-vessel coronary vasospasm: a case report

Background Coronary vasospasm can present like an acute coronary syndrome (ACS) with an intense vasoconstriction resulting in total or near-total occlusion of one or more of the coronary vessels. Definitive diagnosis can be made by intracoronary provocation testing. Case summary A 37-year-old Caucasian male and smoker was admitted with chest pain. Highly sensitive troponin-I was positive at 63 ng/L (99th percentile upper reference limit, &lt;15 ng/L) with a repeat value of 45 ng/L three and a half hours later which was of clinical significance. Serial electrocardiography (ECG) showed no ischaemic changes. Coronary angiography revealed several distal and side branch stenoses; however, angiographic appearances were atypical of coronary plaque. A differential diagnosis of spontaneous coronary artery dissection was suspected although the patient was pain free during the procedure. Computed tomography coronary angiography (CTCA) demonstrated normal coronary arteries, confirmed on repeat invasive coronary angiography. Cold pressor testing was unsuccessful in reproducing vasospasm. Acute coronary syndrome treatment was discontinued, he received smoking cessation advice and Amlodipine 5 mg daily was started. He has experienced no further episodes of cardiac chest pain on follow-up consultation 7 months later. Discussion This is an unusual case of persistent, extensive coronary vasospasm in a patient without ongoing chest pain or ischaemic ECG changes. Intracoronary nitrates are usually effective at relieving coronary spasm. Cold pressor testing has poor sensitivity for diagnosing vasospasm when compared to intracoronary provocation testing using either acetylcholine or ergonovine. Multi-slice CTCA may help to discriminate coronary plaque from coronary vasospasm when there is diagnostic uncertainty.

Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing (n = 1430), we selected patients in whom a type-1 BrS-ECG was evoked (n = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, p < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, p < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, p < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.