Bundgaard, Henning

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Abstract Background Cardiac troponin (cTn) levels exceeding the 99th percentile upper reference limit and a rise/fall pattern are key for diagnosing myocardial injury and infarction. Macrotroponins, formed by patient anti-cTn antibodies targeting cTn, can cause persistently elevated cTn levels without ongoing myocardial injury. The frequency and impact of macrotroponin interference on cTn 99th percentiles are unclear. This study compares sex-specific 99th percentiles for 2 cTn assays, before and after excluding macrotroponin-positive samples, focusing on the top 10% of cTn levels. Methods We examined 1058 plasma samples from healthy individuals previously used for Danish cTn 99th percentiles. Following International Federation of Clinical Chemistry and Laboratory Medicine educational recommendations, macrotroponin presence was assessed in the top 10% cTn samples using immunoglobulin G (IgG) depletion screening and a reference sucrose gradient, confirming macrotroponin when both methods concurred. Due to analytical dilution constraints, [the highest] 88 of 135 Siemens Atellica high-sensitivity cTnI (hs-cTnI) samples were analyzed with both methods. All 106 Roche hs-cTnT samples were negative using IgG depletion, and sucrose analysis was limited to the highest 70 samples. Results Macrotroponin was found in 76% (67/88) of Siemens samples but in none of the Roche samples (0/70). Excluding macrotroponin-affected samples lowered the Siemens 99th percentiles from 117 ng/L to 22 ng/L in men and from 37 ng/L to 9 ng/L in women. The 99th/50th percentile ratio for Siemens decreased from 12- to 29-fold to 3- to 7-fold, approaching the Roche ratios. Conclusions Macrotroponin significantly influenced the Siemens Atellica hs-cTnI 99th percentiles, suggesting important clinical implications that warrant further prospective studies. The 99th/50th percentile ratio may help evaluate macrotroponin interference in troponin assays.

BACKGROUND: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans. METHODS: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays. RESULTS: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0–6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180–679 mL) autologous plasma, the concentration of cTn in participants’ blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8–168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7–295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0–44.9) to 52.7 mL/min (95% CI, 42.2–57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2–95.0). CONCLUSIONS: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury.

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1′). Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1′ after maximal exercise (43 [interquartile range, 25–58] versus 25 [interquartile range, 19–34] beats/min; P <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1′ had an odds ratio of 3.4 (95% CI, 1.6–7.4) of being symptomatic before diagnosis ( P <0.001). In addition, ΔHRR1′ was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22–48] versus 27 [interquartile range, 20–36] beats/min; P =0.01). After diagnosis, patients with a ΔHRR1′ in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles ( P =0.045). Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.