Cardiovascular magnetic resonance insights into anomalies of the mitral valve apparatus in Fabry cardiomyopathy and hypertrophic cardiomyopathy.

Background and aims: Despite different etiopathogenesis, Fabry Disease cardiomyopathy (FDc) and sarcomeric hypertrophic cardiomyopathy (HCM) share a similar hypertrophic phenotype, including anomalies of the mitral valve apparatus (AMVA). Some of these anomalies have also been described in the pre-hypertrophic stage of both diseases. This cardiovascular magnetic resonance (CMR) study aimed to: (i) compare AMVA between FDc and HCM with a similar degree of left ventricular hypertrophy (LVH), to add new insights into differential diagnosis; (ii) assess whether AMVA represent an early and progressive alteration in FDc; (iii) propose simple and potentially reproducible measurements of AMVA. Methods: This observational, retrospective study enrolled: (i) 80 Fabry patients, divided into three groups with increasing severity of cardiac phenotype (20 patients LVH-/normal T1, 20 patients LVH-/low T1 and 40 patients LVH+), and (ii) 40 patients with HCM. All patients underwent CMR. The LVH + FDc and the HCM groups were matched for age, sex, body surface area and left ventricular (LV) mass. The following AMVA were measured on cine images: papillary muscles (PMs) hypertrophy (maximal diameter (Dmax) of anterolateral (Al) and posteromedial (Pm) PM), apical displacement, anteriorization of Al PM and anterior mitral valve leaflet (AMVL) elongation. Reference values for defining AMVA were derived from a matched healthy control group (n = 40). Results: Both HCM and FDc LVH + patients showed PMs hypertrophy, with a greater degree in the FDc LVH + group [Dmax Al PM 16 ± 3.4 vs. 15 ± 3.1 mm, p 0.017; Dmax Pm PM 14 ± 4.0 vs.12 mm (10.0-14.0), p 0.039] As compared to controls, both HCM and FDc LVH + patients showed PMs apical displacement (HCM 83% vs. healthy volunteers 8%, p < 0.001; FDc LVH + 65% vs. healthy volunteers 8%, p < 0.001), with a greater prevalence in HCM. Anteriorization of Al PM was only evident in HCM (15 ± 6.2 vs. healthy controls 21 ± 5.3 mm, p < 0.001). Elongation of AMVL was detected both in HCM and FDc with LVH + (HCM 29 ± 4.0 vs. healthy volunteers 24 ± 2.9 mm, p < 0.001; FDc LVH + 27 ± 4.0 vs. healthy volunteers 24 ± 2.9 mm, p < 0.001) without significant differences between the two phenocopies. The prevalence of myocardial crypts was higher among HCM patients than in FDc LVH + patients (75% vs. 48%, p 0.012). Conclusions: we report greater PMs hypertrophy in FDc and a higher prevalence of PMs positional alterations (anterior and apical displacement) and myocardial crypts in HCM. All these AMVA became more pronounced with the progression of the FDc phenotype. We suggest the systematic inclusion of the analysis of AMVA by simple linear measurements on cine images in the CMR assessment of hypertrophic cardiomyopathies, to help in the differential diagnosis between HCM and FDc and to facilitate early detection of cardiac involvement in FDc.

When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review.

PRKAG2 cardiomyopathy is a rare genetic disorder that manifests early in life with an autosomal dominant inheritance pattern. It harbors left ventricular hypertrophy (LVH), ventricular pre-excitation and progressively worsening conduction system defects. Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition. We report the association of the PRKAG2 missense variant c.1006G>A p. (Val336Ile) with LVH, conduction abnormalities (short PR interval and incomplete right bundle branch bock) and early-onset arterial hypertension (AH) in a 44-year-old Caucasian patient. While cardiac magnetic resonance (CMR) showed a mild hypertrophic phenotype with maximal wall thickness of 17 mm in absence of tissue alterations, the electric phenotype was relevant including brady-tachy syndrome and recurrent syncope. The same variant has been detected in the patient's sister and daughter, with LVH + early-onset AH and electrocardiographic (ECG) alterations + lipothymic episodes, respectively. Paying close attention to the coexistence of LVH and ECG alterations in the proband has been helpful in directing genetic tests to exclude primary cardiomyopathy. Hence, identifying the genetic basis in the patient allowed for familial screening as well as a proper follow-up and therapeutic management of the affected members. A review of the PRKAG2 cardiomyopathy literature is provided alongside the case report.

Delayed identification of monoclonal protein is associated with early death in isolated cardiac AL amyloidosis.

BACKGROUND: Early identification of immunoglobulin light-chain amyloidosis (AL) is crucial due to its rapid progression. Monoclonal light-chain (M-LC) testing is the first step in the diagnostic workup for patients with suspected cardiac amyloidosis (CA). We aimed to determine whether the time interval between the first CA suspicion and M-LC testing can be related to AL amyloidosis survival outcomes. METHODS: All patients (n = 94) with isolated cardiac AL amyloidosis diagnosed at our center between 2016 and 2020 were included. Those with pre-existing known monoclonal protein (monoclonal gammopathy of undetermined significance or smoldering multiple myeloma) were excluded. Time intervals to diagnostic tests and diagnosis were calculated and assessed for their survival prediction ability. RESULTS: The time interval between first CA suspicion (on echocardiography) and M-LC testing correlated with early mortality, and the best cutoff predicting survival, was 6 weeks. The 26 patients (∼28% of entire cohort) who underwent M-LC-studies >6 weeks after first suspicion more frequently presented Mayo stage IIIb (65% vs. 35%, p = .008), showing poorer overall survival than those (n = 68, 72%) referred for early M-LC studies (median 3 vs. 14 months, p = .039). CONCLUSIONS: Monoclonal protein testing should be the first-step in the diagnostic workup for patients with echocardiographic/other instrumental red flags raising CA suspicion.

A real-life study of daratumumab combinations in newly diagnosed patients with light chain (AL) amyloidosis.

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.

Predictive value of unshielded magnetocardiographic mapping to differentiate atrial fibrillation patients from healthy subjects.

BACKGROUND: P-wave duration, its dispersion and signal-averaged ECG, are currently used markers of vulnerability to atrial fibrillation (AF). However, since tangential atrial currents are better detectable at the body surface as magnetic than electric signals, we investigated the accuracy of magnetocardiographic mapping (MCG), recorded in unshielded clinical environments, as predictor of AF occurrence. METHODS: MCG recordings, in sinus rhythm (SR), of 71 AF patients and 75 controls were retrospectively analyzed. Beside electric and magnetic P-wave and PR interval duration, two MCG P-wave subintervals, defined P-dep and P-rep, were measured, basing on the point of inversion of atrial magnetic field (MF). Eight parameters were calculated from inverse solution with "Effective Magnetic Dipole (EMD) model" and 5 from "MF Extrema" analysis. Discriminant analysis (DA) was used to assess MCG predictive accuracy to differentiate AF patients from controls. RESULTS: All but one (P-rep) intervals were significantly longer in AF patients. At univariate analysis, three EMD parameters differed significantly: in AF patients, the dipole-angle-elevation angular speed was lower during P-dep (p < 0.05) and higher during P-rep (p < 0.001) intervals. The space-trajectory during P-rep and the angle-dynamics during P-dep were higher (p < 0.05), whereas ratio-dynamics P-dep was lower (p < 0.01), in AF. At DA, with a combination of MCG and clinical parameters, 81.5% accuracy in differentiating AF patients from controls was achieved. At Cox-regression, the angle-dynamics P-dep was an independent predictor of AF recurrences (p = 0.037). CONCLUSIONS: Quantitative analysis of atrial MF dynamics in SR and the solution of the inverse problem provide new sensitive markers of vulnerability to AF.

Magnetocardiographic classification and non-invasive electro-anatomical imaging of outflow tract ventricular arrhythmias in recreational sport activity practitioners.

Ventricular arrhythmias (VAs) with left bundle-branch-block and inferior axis morphology (LBBB-IA), suggestive of outflow tract (OT) origin, are a challenge in sports medicine because they can be benign or expression of a silent cardiomyopathy. Non-invasive classification is essential to plan ablation strategy if required. We aimed to evaluating magnetocardiographic (MCG) discrimination of OT-VAs site of origin (SoO). MCG and ECG data of 26 sports activity practitioners, with OT-VAs were analyzed. OT-VAs-SoO was classified with discriminant analysis (DA) of 8 MCG parameters and with invasively-validated ECG algorithms. MCG inverse source-localization merged with magnetic resonance (CMR) provided three-dimensional electro-anatomical imaging (MCG 3D-EAI). ECG classification was univocal in 73%. MCG-DA differentiated right ventricular OT from aortic sinus cusp VAs, with 94.7% accuracy. MCG 3D-EAI confirmed OT-VAs-SoO in CMR images. In cases undergoing ablation, MCG 3D-EAI was confirmed by CARTO 3D-EAI. MCG-DA improves non-invasive classification of OT-VAs-SoO. Further comparison with interventional results is required.

Unshielded magnetocardiography: Repeatability and reproducibility of automatically estimated ventricular repolarization parameters in 204 healthy subjects.

BACKGROUND: Magnetocardiographic mapping (MCG) provides quantitative assessment of the magnetic field (MF) induced by cardiac ionic currents, is more sensitive to tangential currents, and measures vortex currents undetectable by ECG, with higher reported sensitivity of MCG ventricular repolarization (VR) parameters for earlier detection of acute myocardial ischemia. Aims of this study were to validate the feasibility of in-hospital unshielded MCG and to assess repeatability and reproducibility of quantitative VR parameters, considering also possible gender- and age-related variability. METHODS: MCG of 204 healthy subjects [114 males-mean age 43.4 ± 17.3 and 90 females-mean age 40.2 ± 15.7] was retrospectively analyzed, with a patented proprietary software automatically estimating twelve VR parameters derived from the analysis of the dynamics of the T-wave MF extrema (five parameters) and from the inverse solution with the effective magnetic dipole model giving the effective magnetic vector components (seven parameters). MCG repeatability was calculated as coefficient of variation (CV) ±standard error of the mean (SEM). Reproducibility was assessed as intraclass correlation coefficient (ICC). RESULTS: The repeatability of all MCG parameters was 16 ± 1.2 (%) (average CV ± SEM). Optimal (ICC > 0.7) reproducibility was found for 11/12 parameters (mean values) and in 8/12 parameters (single values). No significant gender-related difference was observed; six parameters showed a strong/moderate correlation with age. CONCLUSION: Reliable MCG can be performed into an unshielded hospital ambulatory, with repeatability and reproducibility of quantitative assessment of VR adequate for clinical purposes. Wider clinical use is foreseen with the development of multichannel optical magnetometry.