A case series of patients with filamin-C truncating variants attending a specialized cardiac genetic clinic.

Background: FLNC encodes for filamin-C, a protein expressed in Z-discs of cardiac and skeletal muscle, involved in intracellular signalling and mechanical stabilization. Variants can cause diverse phenotypes with skeletal (myofibrillar or distal myopathy) and/or cardiac (hypertrophic, restrictive, and arrhythmogenic cardiomyopathies) manifestations. Truncating variants have recently been implicated in arrhythmogenic cardiomyopathy (ACM) without skeletal disease. Case summary: Retrospective review of medical records, including cardiac investigations, was performed for families attending a specialized clinic with a FLNC truncating variant (FLNCtv). Variants were classified according to accepted variant interpretation criteria. Of seven families identified, six had primary cardiac phenotypes with one nonsense and five frameshift variants (nonsense-mediated decay competent) identified. One family had no cardiac phenotype, with a pathogenic variant (p.Arg2467Alafs*62) identified as secondary genetic finding. Of the six with cardiac phenotypes, proband age at diagnosis ranged 27-35 years (four females). Five families experienced sudden cardiac death (SCD) of a young relative (age range: 30-43 years), and one patient listed for cardiac transplant. Left ventricular (LV) ejection fraction ranged from 13 to 46%, with LV fibrosis (late gadolinium enhancement) on cardiac imaging or on postmortem histology seen in three families. Two families had one genotype-positive/phenotype-negative relative. Discussion: The FLNCtv causes a left-sided ACM phenotype with a high risk of severe cardiac outcomes including end-stage heart failure and SCD. Incomplete penetrance is observed with implications for reporting secondary genetic findings.

Prevalence and determinants of tricuspid regurgitation after repair of tetralogy of Fallot.

BACKGROUND: The prevalence and determinants of tricuspid regurgitation (TR) in patients with repaired Tetralogy of Fallot (rTOF) remain incompletely understood. OBJECTIVES: To explore the prevalence of and factors associated with TR in patients with rTOF, specifically, the relationship of right ventricular (RV) dilatation with TR severity. METHODS: Patients (≥17 yrs) with rTOF referred to our service (2000-2019) were identified. Those with severe pulmonary stenosis, significant shunt, or previous tricuspid valve surgery were excluded. Using standard cardiac MRI protocols, RV, right atrial (RA) and tricuspid valve (TV) parameters were measured and compared. RESULTS: 68 consecutively eligible patients with rTOF were included in the study (27 ± 9 yrs., 35% female). Despite substantial RV volume overload (mean RVEDVi 153 mL/m2), the majority of the cohort (78%) had no or only mild TR. RA volumes, tenting height/area and annular diameter were normal (4.9 ± 2.0 mm, 1.1 ± 1.0 cm2 and 32.4 ± 6.2 mm, respectively). There was no significant correlation of TR fraction with RVEDVi (r = 0.13; p = 0.30), RVEF (r = 0.09; p = 0.44) or tricuspid annular diameter (r = 0.07; p = 0.62). Only RAVi showed a weak but significant correlation with TR fraction (0.29; p = 0.03). In a pooled cohort analysis, including both rTOF patients and adults with a dilated RV from pre-tricuspid shunt lesions, only rTOF was independently associated with higher TR fraction (p = 0.017). CONCLUSION: Despite substantial RV dilatation in a cohort with rTOF, there was surprisingly little TR. We found poor correlation between RVEDVi, RA volumes, tricuspid annular dilatation and the presence of significant TR. These findings question commonly held notions regarding the pathophysiology of functional TR in these patients.

Right ventricular volume and its relationship to functional tricuspid regurgitation.

BACKGROUND: Significant right ventricular (RV) dilatation has long been considered integral to the pathogenesis of functional tricuspid regurgitation (FTR). OBJECTIVES: To explore the relationship of RV dilatation and FTR in patients with 'pure' RV volume overload. METHODS: Patients (>17yrs) with RV dilatation due to pre-tricuspid shunts (atrial septal defect; ASD and/or partial anomalous pulmonary venous drainage; PAPVD) referred to our service (2000-2019) were retrospectively identified. Those with pulmonary hypertension, primum ASD or left-heart disease were excluded. Using standard cardiac MRI protocols, RV, right atrial and TV parameters were measured and compared. RESULTS: Of 52 consecutively eligible patients (42 ± 15yrs, 25 males), 25 had ASDs, 13 had PAPVD and 14 had both conditions. All were in sinus rhythm and none had pulmonary regurgitation. Left and right ventricular ejection fractions were normal (LVEF 63 ± 8%, RVEF 56 ± 8%). Indexed RV end-diastolic volumes (RVEDVi) were moderately increased (males 148 ± 33 mL/m2 and females 141 ± 42 mL/m2, range 95-267 mL/m2). Despite substantial RV volume overload, no patients had severe tricuspid regurgitation (TR). Only two had > mild TR. There was a weak correlation between tricuspid annular diameter and both degree of RV dilatation (r = 0.37; p = 0.01) and degree of TR (r = 0.38; p = 0.006). There was a similarly poor correlation between right atrial dimensions and the degree of TR (r = 0.34; p = 0.02). CONCLUSION: When RV dilatation is simply due to volume overload, we find that significant TR is extremely rare. This gives an important and novel insight; that RV dilatation per se does not result in FTR.

Intra- and inter-observer reproducibility of multilayer cardiac magnetic resonance feature tracking derived longitudinal and circumferential strain.

BACKGROUND: Multilayer strain measurement with cardiac magnetic resonance feature tracking (CMR-FT) allows independent assessment of endocardial and epicardial strain. This novel method of layer-specific quantification of myocardial deformation parameters provides greater insight into contractility compared to whole-layer strain analysis. The clinical utility of this technique is promising. The aim of this study is to investigate the intra- and inter- observer reproducibility of CMR-FT derived multilayer global longitudinal strain (GLS) and global circumferential strain (GCS) parameters in the setting of normal cardiac function, cardiac pathology, and differing MRI field strengths. METHODS: We studied 4 groups of 20 subjects, comprising of patients with dilated cardiomyopathy, ischemic heart disease, and patients without cardiac pathology at both 1.5 and 3 T. Quantitative measures of whole-layer and multi-layer longitudinal and circumferential strain were calculated using CMR-FT software. RESULTS: Intraclass correlation coefficients (ICC) for intraobserver reproducibility of endocardial, epicardial, and whole-layer measurements of GLS were 0.979, 0.980, and 0.978 respectively, and those for GCS were 0.986, 0.977, and 0.985. ICCs for inter-observer reproducibility of endocardial, epicardial, and whole-layer measurements of GLS were 0.976, 0.970, and 0.976, and those for GCS were 0.982, 0.969, and 0.981. Bland Altman analysis showed minimal bias and acceptable limits of agreement (LOA) within each patient subgroup and the overall cohort. Circumferential and longitudinal strain parameters were equally reproducible in the overall cohort. CONCLUSIONS: CMR-FT derived multilayer measurements of longitudinal and circumferential strain demonstrate high intra- and inter- observer reproducibility, with suitability for use in clinical practice.

Prevalence of Anderson-Fabry disease in a cohort with unexplained late gadolinium enhancement on cardiac MRI.

INTRODUCTION: Fabry disease is a rare X-linked genetic disorder in which cardiac manifestations include LVH, contractile dysfunction, and fibrosis, visible on cardiac MRI (cMRI) as late gadolinium enhancement (LGE) of the myocardium. Fabry's disease is an important diagnosis to make as treatment is available as lifelong replacement of the deficient enzyme. AIM: To define the prevalence of Fabry disease in a cohort of patients with unexplained LGE on cMRI. METHODS: The study population was recruited from patients aged >16 years who had cMRI performed between 2010 and 2018 to investigate LVH, idiopathic LV dysfunction and/or idiopathic ventricular arrhythmia. Patients with 'unexplained' LGE i.e. without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid, were tested for Fabry disease by either genetic testing or the Dried Blood Spot test (Sanofi-Genzyme). RESULTS: Of the 79 patients with unexplained LGE on cMRI, 2 patients tested positive for Fabry disease, both using genetic sequencing techniques. The prevalence of Fabry disease in this selected cohort was 2.5%. Specifically, 1 patient was a 65 year old male and the other patient a 75 year old female. In both cases, the pattern and distribution of LGE on cMRI was of patchy mid-wall enhancement in the inferoseptum. CONCLUSION: Unexplained LGE on cMRI may be an isolated manifestation of late-onset Fabry disease. This finding should prompt testing for Fabry disease given this is a potentially treatable condition.

RETRACTED: Right to left ventricular volume ratio: A novel marker of disease severity in chronic thromboembolic pulmonary hypertension.

[This retracts the article DOI: 10.1016/j.ijchv.2013.10.001.].

Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology.

BACKGROUND: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). METHODS: Eleven Fontan subjects (32+/-2 years, mean+/-SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET); six underwent 20 weeks of high-intensity resistance training; others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. RESULTS: In the trained state, muscle strength increased by 43% (p=0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p<0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, p<0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p=0.01) and during moderate-intensity exercise (by 16 ml, p=0.04); inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). CONCLUSIONS: Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation.