Ida S. Leren

High prevalence of exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia mutation-positive family members diagnosed by cascade genetic screening

AIM Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease predisposing to life-threatening arrhythmias. We aimed to determine the prevalence of arrhythmias and efficacy of beta-blocker treatment in mutation-positive family members diagnosed by cascade genetic screening. METHODS AND RESULTS Relatives of six unrelated CPVT patients were tested for the relevant mutation in the ryanodine receptor-2 gene. Mutation carriers underwent an exercise test at inclusion time and 3 months after the initiation of beta-blocker therapy in the highest tolerable dose. The occurrence of ventricular premature beats, couplets, and non-sustained ventricular arrhythmias (nsVT) were recorded in addition to the heart rate at which they occurred. Thirty family members were mutation carriers and were followed for 22 (13-288) months. Previous undiagnosed CPVT-related symptoms were reported by eight subjects. Exercise test induced ventricular arrhythmias in 23 of the 30 mutation carriers. On beta-blocker treatment, exercise-induced arrhythmias occurred at a lower heart rate (117 +/- 17 vs. 135 +/- 34 beats/min, P = 0.02) but at similar workload (P = 0.78). Beta-blocker treatment suppressed the occurrence of exercise-induced nsVT in three of the four patients, while less severe arrhythmias were unchanged. One patient died during follow-up. CONCLUSION Exercise test revealed a high prevalence of arrhythmias in CPVT mutation carriers diagnosed by cascade genetic screening. beta-Blocker therapy appeared to suppress the most severe exercise-induced arrhythmias, while less severe arrhythmias occurred at a lower heart rate.

Strain echocardiography is related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy

Aims Hypertrophic cardiomyopathy (HCM) patients are at risk of ventricular arrhythmias (VAs). We aimed to explore whether systolic function by strain echocardiography is related to VAs and to the extent of fibrosis by cardiac magnetic resonance imaging (CMR). Methods and results We included 150 HCM patients and 50 healthy individuals. VAs were defined as non-sustained and sustained ventricular tachycardia and aborted cardiac arrest. Left ventricular function was assessed by ejection fraction (EF) and by global longitudinal strain (GLS) assessed by speckle tracking echocardiography. Mechanical dispersion was calculated as standard deviation (SD) of time from Q/R on ECG to peak longitudinal strain in 16 left ventricular segments. Late gadolinium enhancement (LGE) was assessed by CMR. HCM patients had similar EF (61 ± 5% vs. 61 ± 8%, P = 0.77), but worse GLS (−15.7 ± 3.6% vs. −21.1 ± 1.9%, P < 0.001) and more pronounced mechanical dispersion (64 ± 22 vs. 36 ± 13 ms, P < 0.001) compared with healthy individuals. VAs were documented in 37 (25%) HCM patients. Patients with VAs had worse GLS (−14.1 ± 3.6% vs. −16.3 ± 3.4%, P < 0.01), more pronounced mechanical dispersion (79 ± 27 vs. 59 ± 16 ms, P < 0.001), and higher %LGE (6.1 ± 7.8% vs. 0.5 ± 1.4%, P < 0.001) than patients without VAs. Mechanical dispersion correlated with %LGE (R = 0.52, P < 0.001) and was independently associated with VAs (OR 1.6, 95% CI 1.1–2.3, P = 0.02) and improved risk stratification for VAs. Conclusion GLS, mechanical dispersion, and LGE were markers of VAs in HCM patients. Mechanical dispersion was a strong independent predictor of VAs and related to the extent of fibrosis. Strain echocardiography may improve risk stratification of VAs in HCM.

Arrhythmogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis.

This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy is mainly an autosomal dominant inherited disease linked to mutations in genes encoding desmosomes or desmosome-related proteins. Classic symptoms include palpitations, cardiac syncope, and aborted cardiac arrest due to ventricular arrhythmias. Heart failure may develop in later stages. Diagnosis is based on the presence of major and minor criteria from the Task Force Criteria revised in 2010 (TFC 2010), which includes evaluation of findings from six different diagnostic categories. Based on this, patients are classified as having possible, borderline, or definite ARVC. Imaging is important in ARVC diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting structural and functional abnormalities, but importantly these findings may occur after electrical alterations and ventricular arrhythmias. Electrocardiograms (ECGs) and signal-averaged ECGs are analysed for depolarization and repolarization abnormalities, including T-wave inversions as the most common ECG alteration. Ventricular arrhythmias are common in ARVC and are considered a major diagnostic criterion if originating from the RV inferior wall or apex. Family history of ARVC and detection of an ARVC-related mutation are included in the TFC 2010 and emphasize the importance of family screening. Electrophysiological studies are not included in the diagnostic criteria, but may be important for differential diagnosis including RV outflow tract tachycardia. Further differential diagnoses include sarcoidosis, congenital abnormalities, myocarditis, pulmonary hypertension, dilated cardiomyopathy, and athletic cardiac adaptation, which may mimic ARVC.

Strain echocardiographic assessment of left atrial function predicts recurrence of atrial fibrillation

Aims We evaluated if a dispersed left atrial (LA) contraction pattern was related to atrial fibrillation (AF) in patients with normal left ventricular (LV) function, and normal or mildly enlarged left atrium. Methods and results We included 61 patients with paroxysmal AF (PAF). Of these, 30 had not while 31 had recurrence of AF after radiofrequency ablation (RFA). Twenty healthy individuals were included for comparison. Echocardiography was performed in patients in sinus rhythm the day before RFA. LA volume was calculated. Peak negative longitudinal strain was assessed in 18 LA segments during atrial systole. Contraction duration in 18 LA segments was measured as the time from peak of the P wave on electrocardiogram to maximum myocardial shortening in each segment. The standard deviation of contraction durations was defined as LA mechanical dispersion (LA MD). LA size was rather preserved in patients with PAF (LA volume 25 ± 10 mL/m2). LA MD was more pronounced in patients with recurrence of AF after RFA compared with those without recurrence and controls (38 ± 14 ms vs. 30 ± 12 ms vs. 16 ± 8 ms, both P < 0.001). LA MD was a predictor of PAF [OR 7.84 (95%CI 2.15–28.7), P < 0.01, per 10 ms increase] adjusted for age, LA volume, e’, and LA function. LA function by strain was reduced in both patients with and without recurrent AF after RFA compared with controls (−14 ± 4% vs. −16 ± 3% vs. −19 ± 2%, both P < 0.05). Conclusion LA MD was pronounced, and LA deformation was reduced in patients with PAF with apparently normal LV structure and function, and normal or mildly enlarged LA. LA MD may be useful as a predictor of AF recurrence after RFA.

Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. OBJECTIVE We aimed to explore the incidence and severity of ventricular arrhythmias in patients with CPVT before the initiation of β-blocker treatment, when treated with β1-selective β-blockers, and when treated with nadolol. METHODS In this study, 34 patients with CPVT were included (mean age 34 ± 19 years; 15 (44%) women; 30 (88%) ryanodine receptor 2 variant positive). We performed 3 bicycle exercise stress tests in each patient: (1) before the initiation of β-blocker treatment, (2) after >6 weeks of treatment with β1-selective β-blockers and (3) after >6 weeks of treatment with nadolol. We recorded resting and maximum heart rates and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. RESULTS Resting heart rate was similar during treatment with nadolol and β1-selective β-blockers (54 ± 10 beats/min vs 56 ± 14 beats/min; P = .50), while maximum heart rate was lower during treatment with nadolol compared with β1-selective β-blockers (122 ± 21 beats/min vs 139 ± 24 beats/min; P = .001). Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with during treatment with β1-selective β-blockers (arrhythmic score 1.6 ± 0.9 vs 2.5 ± 0.8; P < .001) and before the initiation of β-blocker treatment (arrhythmic score 1.6 ± 0.9 vs 2.7 ± 0.9; P = .001); however, no differences were observed during treatment with β1-selective β-blockers compared with before the initiation of β-blocker treatment (arrhythmic score 2.5 ± 0.8 vs 2.7 ± 0.9; P = .46). CONCLUSION The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with β1-selective β-blockers. β1-Selective β-blockers did not change the occurrence or severity of arrhythmias compared with no medication.

Comparison of patients with early-phase arrhythmogenic right ventricular cardiomyopathy and right ventricular outflow tract ventricular tachycardia

Aims Differentiation between early-phase arrhythmogenic right ventricular cardiomyopathy (ARVC) and right ventricular outflow tract (RVOT)-ventricular tachycardia (VT) can be challenging, and correct diagnosis is important. We compared electrocardiogram (ECG) parameters and morphological right ventricular (RV) abnormalities and investigated if ECG and cardiac imaging can help to discriminate early-phase ARVC from RVOT-VT patients. Methods and results We included 44 consecutive RVOT-VT (47 ± 14 years) and 121 ARVC patients (42 ± 17 years). Of the ARVC patients, 77 had definite ARVC and 44 had early-phase ARVC disease. All underwent clinical examination, ECG, and Holter monitoring. Frequency of premature ventricular complexes (PVC) was expressed as percent per total beats/24 h (%PVC), and PVC configuration was recorded. By echocardiography, we assessed indexed RV basal diameter (RVD), indexed RVOT diameter, and RV and left ventricular (LV) function. RV mechanical dispersion (RVMD), reflecting RV contraction heterogeneity, was assessed by speckle-tracking strain echocardiography. RV ejection fraction (RVEF) was assessed by cardiac magnetic resonance imaging (CMR). Patients with early-phase ARVC had lower %PVC by Holter and PVC more frequently originated from the RV lateral free wall (both P < 0.001). RVD was larger (21 ± 3 vs. 19 ± 2 mm, P < 0.01), RVMD was more pronounced (22 ± 15 vs. 15 ± 13 ms, P = 0.03), and RVEF by CMR was decreased (41 ± 8 vs. 49 ± 4%, P < 0.001) in early-phase ARVC vs. RVOT-VT patients. Conclusion Patients with early-phase ARVC had structural abnormalities with lower RVEF, increased RVD, and pronounced RVMD in addition to lower %PVC by Holter compared with RVOT-VT patients. These parameters can help correct diagnosis in patients with unclear phenotypes.

Prognostic Value of Left Ventricular Deformation Parameters in Patients with Severe Aortic Stenosis: A Pilot Study of the Usefulness of Strain Echocardiography

Background: In patients with aortic stenosis, subtle alterations in myocardial mechanics can be detected by speckle‐tracking echocardiography before reduction of left ventricular ejection fraction (LVEF). Methods: In this prospective study, 162 patients with aortic stenosis with an average aortic valve area of 0.7 ± 0.2 cm2 and a mean LVEF of 60 ± 11% were included. Global longitudinal strain (GLS) and mechanical dispersion (SD of time from Q/R on the electrocardiogram to peak strain in 16 left ventricular segments) were assessed using echocardiography, and all‐cause mortality (n = 37) was recorded during 37 ± 13 months of follow‐up. Results: Overall, nonsurvivors had more pronounced mechanical dispersion and worse GLS compared with survivors (74 ± 24 vs 61 ± 18 msec [P < .01] and −14.5 ± 4.4% vs −16.7 ± 3.6% [P < .01], respectively). In the 42 conservatively treated patients without surgical aortic valve replacement, a similar pattern was observed in nonsurvivors versus survivors (mechanical dispersion, 80 ± 24 vs 57 ± 14 msec [P < .01]; GLS, −14.0 ± 4.9% vs −17.1 ± 3.8% [P = .04], respectively). Mechanical dispersion was significantly associated with mortality (hazard ratio per 10‐msec increase, 1.23; 95% CI, 1.07–1.42; P < .01) in a Cox model adjusted for LVEF and with aortic valve replacement treatment as a time‐dependent covariate. Continuous net reclassification improvement showed that mechanical dispersion was incremental to LVEF, GLS, and valvulo‐arterial impedance when adjusting for aortic valve replacement treatment in the total population. Conclusion: Increased mechanical dispersion may be a risk marker providing novel prognostic information in patients with aortic stenosis. Graphical abstract Figure. No caption available. HighlightsStrain echocardiography can detect altered myocardial mechanics in patients with AS.Pronounced mechanical dispersion is associated with worse prognosis in patients with AS.Mechanical dispersion adds incremental prognostic value to LVEF, atrioventricular impedance, and global longitudinal strain.Mechanical dispersion predicts mortality independently of LVEF and AVR surgery status.

Echocardiographic comparison between left ventricular non-compaction and hypertrophic cardiomyopathy

BACKGROUND Modern imaging technology has improved detection of left ventricular non-compaction cardiomyopathy (LVNC). Hypertrophic cardiomyopathy (HCM) shares morphological features with LVNC, but prognosis and treatment strategies differ between LVNC and HCM. METHODS AND RESULTS We aimed to compare global and regional LV myocardial function in LVNC and HCM. We hypothesized that apical function is reduced in LVNC due to the embryonic reduced compaction of the apex. We studied 25 patients with LVNC (47±14years) according to current criteria, 50 with HCM (47±14years) and 50 healthy individuals (49±19years). By echocardiography, we assessed maximal wall thickness (MWT) and LV ejection fraction (EF). Numbers of trabeculations were counted from 3 apical views. Global longitudinal strain by speckle tracking echocardiography was calculated from a 16 LV segments model. LV basal (6 segments) and apical (4 segments) longitudinal strains were averaged. MWT was thinner, EF lower and trabeculations were more pronounced in LVNC compared to HCM (all p<0.001) but with no significantly differences in LV global longitudinal strain (-15.1±6.1 vs. -16.8±3.7, p=0.14). Function by longitudinal strain increased significantly from base to apex in HCM (-14.9±4.3% vs. -19.5±4.7%, p<0.001) and in healthy controls (-20.0±1.9% vs. -21.8±2.9%, p<0.001), but not in LVNC (-14.7±6.4% vs. -15.7±7.2%, p=0.35). CONCLUSIONS Increased number of trabeculations, thinner MWT and lower EF were characteristics of LVNC. Myocardial function was homogeneously reduced in LVNC, while an apical to basal gradient with relatively preserved apical function was present in HCM. These characteristics may help to discriminate between LVNC and HCM.

Soluble ST2 is associated with disease severity in arrhythmogenic right ventricular cardiomyopathy

Abstract Purpose: Diagnostic and prognostic evaluation remains challenging in arrhythmogenic right ventricular cardiomyopathy (ARVC). We measured plasma concentration of soluble ST2 (sST2) and assessed its association with right ventricular (RV) function and ventricular arrhythmias in patients with ARVC. Methods: We included patients with ARVC and genotype positive relatives. Soluble ST2 was determined by ELISA. We assessed myocardial function by echocardiography including strain by speckle tracking technique. Results: We included 44 subjects (age 41 ± 15 years, 21 (48%) female). Soluble ST2 was associated with RV global strain (r = 0.44; p = 0.008), as well as with left ventricular (LV) function. Plasma levels of sST2 were higher in patients with ventricular arrhythmias than in patients without ventricular arrhythmias (35 ± 13 ng/mL vs. 26 ± 7 ng/mL, p = 0.009). The association between sST2 and ventricular arrhythmias remained significant even after adjusting for RV function (Wald = 5.2; p = 0.02). Conclusions: Soluble ST2 is associated with RV and LV function in patients with ARVC. Soluble ST2 may aid in the determination of disease severity in ARVC.

Catecholaminergic polymorphic ventricular tachycardia

BACKGROUND CPVT (catecholaminergic polymorphic ventricular tachycardia) is a condition characterized by syncopes and cardiac arrest that was first described in 1975. CPVT has later been classified as a genetic disease with a great risk for life-threatening arrhythmias that are mainly caused by mutations in the ryanodine receptor 2 gene. Starting with a case report, we present an overview of CPVT. MATERIAL AND METHODS The literature reviewed was identified through a non-systematic search in PubMed. RESULTS Diagnosing CPVT may be difficult, as resting ECG is normal and the syncopes may be misdiagnosed as epilepsy. Information about syncopes related to physical or emotional stress and occurrence of unexplained syncopes or cardiac arrest among family members, is important in the diagnostic evaluation. An exercise stress test often reveals the classical pattern of ventricular arrhythmias at heart rates above 100 beats/min. The diagnosis can be confirmed by genetic testing. By beta-blocker treatment and, if necessary, an ICD (implantable cardioverter defibrillator) the prognosis can be improved. INTERPRETATION CPVT is a serious disease with a poor prognosis when left untreated. It is a rare but important differential diagnosis in young individuals with syncopes or cardiac arrest. Genetic screening of relatives has made it possible to identify mutation carriers in affected families in order to provide them with preventive therapy.