Re-analysis of Next-generation Sequencing Data in Patients with Hypertrophic Cardiomyopathy: Contribution of Spliceogenic MYBPC3 Variants in an Italian Cohort.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Biventricular Hypertrophic Cardiomyopathy in a 26-year-old Nigerian Woman with Noonan Syndrome.

BACKGROUND: Cardiac disorders are found in about half of cases of Noonan syndrome (NS). The most common congenital heart diseases in this syndrome include pulmonary valvular stenosis obstructive or nonobstructive hypertrophic cardiomyopathy (17%). Biventricular hypertrophic cardiomyopathy (HCM) is very rare in this condition. OBJECTIVE: The objective is to report a case of biventricular hypertrophic cardiomyopathy in a 26-year-old Nigerian female with the phenotype. METHODS: This is a descriptive case report. RESULTS: The patient presented with dyspnoea on exertion which started at the age of 7 years and has progressively worsened. There was associated precordial chest pain and palpitation. Clinical examination revealed a young woman, who is small for her age. She had some dysmorphic features such as a webbed neck, lowset ears, low posterior hairline, crowded teeth, high arched palate, a small and asymmetric chin and a high carrying angle at the elbows. The pulses were synchronous and there was no radio-radial or radiofemoral delay and her blood pressures were within normal limits. Cardiac auscultation was unremarkable. The 12-lead ECG showed biventricular hypertrophy with a strain pattern. The echocardiogram showed features in keeping with biventricular hypertrophic cardiomyopathy. CONCLUSION: Biventricular HCM is relatively uncommon in Noonan syndrome. Patients with typical dysmorphia should have a full cardiac evaluation to look for these anomalies.

CONTEXTE: Des troubles cardiaques sont présents chez environ la moitié des patients atteints du syndrome de Noonan. Les cardiopathies congénitales les plus fréquentes dans ce syndrome incluent la sténose valvulaire pulmonaire (60 %), la communication interauriculaire (25 %) et la cardiomyopathie hypertrophique obstructive ou non obstructive (17 %). La cardiomyopathie hypertrophique (HCM) biventriculaire est très rare dans ces conditions. OBJECTIF: L'objectif est de rapporter un cas de cardiomyopathie hypertrophique biventriculaire chez une femme nigériane de 26 ans présentant le phénotype. MÉTHODES: Il s'agit d'un rapport de cas descriptif. RÉSULTATS: La patiente s'est présentée avec une dyspnée à l'effort, débutant à l'âge de 7 ans et s'aggravant progressivement. Il y avait des douleurs précordiales associées ainsi que des palpitations. L'examen clinique a révélé une jeune femme, petite pour son âge, avec quelques traits dysmorphiques tels qu'un cou palmé, des oreilles basses, une implantation basse des cheveux à l'arrière, des dents serrées, un palais ogival, un menton petit et asymétrique et un angle de port élevé au niveau des coudes. Les pouls étaient synchrones, sans retard radio-radial ou radiofémoral, et la tension artérielle était dans les limites normales. L'auscultation cardiaque n'a révélé aucune anomalie. L'électrocardiogramme à 12 dérivations a montré une hypertrophie biventriculaire avec un pattern de strain. L'échocardiogramme a révélé des caractéristiques compatibles avec une cardiomyopathie hypertrophique biventriculaire. CONCLUSION: La cardiomyopathie hypertrophique biventriculaire est relativement rare dans le syndrome de Noonan. Les patients présentant une dysmorphie typique devraient subir une évaluation cardiaque complète afin de détecter ces anomalies. MOTS CLÉS: Syndrome de Noonan, Dysmor phie, Cardiomyopathie hypertrophique.

Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. OBJECTIVES: The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. METHODS: In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate <0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling. RESULTS: The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings. CONCLUSIONS: The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.

Family Screening in Hypertrophic Cardiomyopathy: Identification of Relatives With Low Yield From Systematic Follow-Up.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease, and clinical and genetic family screening is recommended by guidelines. OBJECTIVES: This study sought to investigate the diagnostic yield of screening relatives of HCM patients and identify predictive factors for HCM development during long-term follow-up in relatives from gene-elusive families. METHODS: This was a retrospective cohort study of families screened at clinics for inherited cardiomyopathies in Eastern Denmark, from 2006 to 2023. RESULTS: We included 1,230 relatives (55% female; age: 42 ± 17 years) from 531 families. The combined clinical and genetic yield at baseline was 26% (n = 321). After 7 years (mean) of follow-up (6,762 person-years), 43 (4%) additional relatives developed HCM. The strongest predictors of developing HCM were carrying a likely pathogenic/pathogenic variant (HR: 4.58; 95% CI: 2.50-8.40; P < 0.001) and larger left ventricular maximum wall thickness (MWT) (HR: 2.21 per mm; 95% CI: 1.76-2.77 per mm; P < 0.001). In gene-elusive families, we found that an MWT of ≥10 mm represented the optimal classification threshold for developing HCM (area under the curve: 0.80), with only 2 (0.4%) relatives from gene-elusive families with an MWT of <10 mm developing HCM during follow-up. CONCLUSIONS: In HCM, the diagnostic yield of a single screening visit was 1 in 4, and the additional yield during 7 years of follow-up was 4%. Gene carriers and relatives from gene-elusive families with a baseline MWT of ≥10 mm were at the highest risk of developing HCM during follow-up. These findings may inform future recommendations on the management of relatives of HCM patients.

Hypertrophic cardiomyopathy and left ventricular non-compaction: Distinct diseases or variant phenotypes of a single condition?

Hypertrophic cardiomyopathy (HCM) is a genetically determined myocardial disease characterized by an increased thickness of the left ventricle (LV) wall that cannot be solely attributed to abnormal loading conditions. HCM may present with an intraventricular or LV outflow tract obstruction, diastolic dysfunction, myocardial fibrosis and/or ventricular arrhythmias. Differentiating HCM from other diseases associated with LV hypertrophy, such as hypertension, aortic stenosis, or LV non-compaction (LVNC), can at times be challenging. LVNC is defined by excessive LV trabeculation and deep recesses between trabeculae, often accompanied by increased LV myocardial mass. Previous studies indicate that the LVNC phenotype may be observed in up to 5% of the general population; however, in most cases, it is a benign finding with no impact on clinical outcomes. Nevertheless, LVNC can occasionally lead to LV systolic dysfunction, manifesting as a phenotype of dilated or non-dilated left ventricular cardiomyopathy, with an increased risk of thrombus formation and arterial embolism. In extreme cases, where LVNC is associated with a very thickened LV wall, it can even mimic HCM. There is growing evidence of an overlap between HCM and LVNC, including similar genetic mutations and clinical presentations. This raises the question of whether HCM and LVNC represent different phenotypes of the same disease or are, in fact, two distinct entities.

Efficacy and safety of mavacamten for the treatment of hypertrophic cardiomyopathy: an updated systematic review and meta-analysis of randomized controlled trials.

The efficacy and safety profile of mavacamten, a cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy (HCM) is not well-established, prompting the need for an updated meta-analysis. The authors conducted an extensive search across multiple electronic databases, including Embase, MEDLINE (via Pubmed), and CENTRAL, to identify randomized controlled trials (RCTs) assessing the efficacy and safety of mavacamten in HCM. Review Manager 5.4 (Revman) was employed to pool risk ratios (RR) and mean differences (MD). Our literature search yielded 4 RCTs with a total of 503 patients. Mavacamten was found to be associated with higher rates of greater than or equal to 1 New York Heart Association (NYHA) class improvement (RR 2.20, 95% CI: 1.48-3.28; I2=51%) and change from baseline in the Kansas City Cardiomyopathy Questionnaire- Clinical Summary Score (KCCQ-CSS) (MD 7.50, 95% CI: 3.44-11.55; I2 =50%). Mavacamten was also associated with improved resting left ventricular outflow tract (LVOT) gradient (MD -38.33, 95% CI: -49.38 to -27.28; I2 =75%), Valsalva LVOT gradient (MD -48.08, 95% CI: -62.21 to -33.96; I2 =78%), post-exercise LVOT gradient (MD -37.1, 95% CI: -44.37 to -29.84; I2 =0%), LVMI (MD -16.91, 95% CI: -28.29 to -5.54; I2 =88%), and lower rates of septal reduction therapy (SRT) (RR 0.30, 95% CI: 0.22-0.40; I2 =0%). There were no significant differences between mavacamten and placebo regarding the composite functional outcome, greater than or equal to 1 treatment-emergent adverse event, greater than or equal to 1 serious adverse event, and atrial fibrillation. The authors; findings suggest that mavacamten contributes to improvements in NYHA class, KCCQ-CSS scores, and LVOT gradients while reducing the incidence of SRT in patients with HCM.

Clinical utility of electrocardiographic voltage parameters for the diagnosis of hypertrophic cardiomyopathy.

Background: While electrocardiographic parameters of hypertensive left ventricular hypertrophy (H-LVH) are well known, limited data are available regarding hypertrophic cardiomyopathy (HCM). This study was to assess the diagnostic value of electrocardiographic voltage parameters in HCM. Methods: Included patients with HCM treated between March 2015 and May 2023. Voltage parameters (S-L, Cornell, Cornell product, Lewis, Peguero, and modified Cornell voltages) and echocardiography were evaluated. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of electrocardiogram in HCM. The multiple linear regression was conducted to analyze the correlation between electrocardiogram indicators and cardiac diastolic function. Results: The highest sensitivity for HCM was Peguero voltage (70.4%; 88.6% specificity). The Peguero voltage had high sensitivity in male (63.8%) and female patients (84.9%), those aged <65 years (71.6%) and ≥65 years (68.3%), with non-apical HCM (AHCM) (76.7%), obstructive HCM (82.1%), and non-obstructive HCM (66.9%). The sensitivity of the S-L voltage was high in AHCM (72.2%). The sensitivity for HCM reached 88.7% when the S-L and Peguero voltages were combined. The modified Cornell index had the highest area under the curve (0.88, 95% CI: 0.84-0.91), and its optimal cutoff value was 2.05 mV in males (77.6% sensitivity and 74% specificity) and 1.935 mV in females (90.6% sensitivity and 91.4% specificity). Peguero voltage (beta = 0.154, P = 0.034) and SD (beta = 0.223 P = 0.004) were independently correlated with E/e', an index of left ventricular diastolic function. Conclusion: The Peguero voltage had high sensitivity and specificity for detecting the presence of HCM. It was positively correlated with E/e' in patients with HCM. For AHCM, the S-L voltage was more advantageous. Combining the S-L voltage with the Peguero voltage further improves the sensitivity for HCM and thus could be used to improve the screening of HCM in clinical practice. The SD and modified Cornell voltage also had good diagnostic performance, especially in females.

Clinical features and postoperative outcomes in elderly patients undergoing septal myectomy for hypertrophic cardiomyopathy.

BACKGROUND: Surgical septal reduction is sometimes avoided in older adults due to anticipated high operative risk. OBJECTIVE: To compare the clinical and echocardiographic characteristics of young and older patients undergoing septal myectomy for oHCM and assess differences in early and late postoperative outcomes. METHODS: 2663 patients with oHCM underwent transaortic septal myectomy between 2000 and 2021 and were categorized by age: 18-64, 65-74, and ≥75 years. RESULTS: Median age at the time of surgery increased over the study interval. Female sex (p<0.001), hypertension p<0.001), and diabetes (p=0.004) were more prevalent in older patients, but extent of functional limitation (NYHA) was similar (p=0.092). Elderly patients had thinner septal and posterior walls (p<0.001, p=0.006) and less prominent asymmetry (p<0.001). They are less likely to have positive genetic testing. Hospital mortality was 0.2%, 0.5%, and 1.3% in patients <65, 65-74, and ≥75 (p=0.06), and five-year survival rates were 97%, 93%, and 91%. Septal-to-posterior wall thickness ratio significantly correlated with increased mortality in patients >65, but not in patients <65 (p=0.92). Most of the patients reported improved quality of life following myectomy. CONCLUSION: Clinical characteristics of oHCM in older patients differ from those in younger ones. More symmetric but less extensive ventricular hypertrophy and less positive genetic testing suggests that HCM has distinct clinical and morphological variants in the elderly. Septal myectomy is safe in older patients, but the presence of LV wall asymmetry portends a poorer prognosis.

Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.

Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder of the heart characterized by hypercontractility at the molecular scale that leads to diverse clinical phenotypes. While the clinical aspects of hypertrophic cardiomyopathy have been extensively studied, the molecular mechanisms of missense mutations in cardiac muscle α-actin that cause the disease remain largely elusive. Here we used cryo-electron microscopy to reveal the structures of hypertrophic cardiomyopathy-associated actin mutations M305L and A331P in the filamentous state. We show that the mutations have subtle impacts on the overall architecture of the actin filament with mutation-specific changes in the nucleotide binding cleft active site, interprotomer interfaces, and local changes around the mutation site. This suggests that structural changes induced by M305L and A331P have implications for the positioning of the thin filament protein tropomyosin and the interaction with myosin motors. Overall, this study supports a structural model whereby altered interactions between thick and thin filament proteins contribute to disease mechanisms in hypertrophic cardiomyopathy.

Vigorous exercise and sports participation in individuals with hypertrophic cardiomyopathy.

Historically, individuals with HCM have been restricted from vigorous competitive sports due to concerns for risk of sudden death. More recently, prospective data are emerging that individuals with HCM who participate in vigorous sports do not have increased arrhythmic risk compared to the less active, and series of athletes with HCM continuing to compete, while small, have not shown high risk. Guidelines are evolving, and while differences exist, all now recommend an individualized approach and shared decision-making for athletes with HCM wishing to return to play.

Cardiopulmonary Fitness and Personalized Exercise Prescription in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are generally restricted regarding participation in competitive sports based on the potential risk of sudden cardiac death and malignant arrhythmias. As a result, they are often inactive and experience the negative consequences of a sedentary lifestyle. Hence, the need arises to strike the right balance between these 2 extremes through personalized exercise prescription. The aims of this study were (1) to assess the characteristics of patients with HCM practicing regular aerobic physical activity compared with sedentary patients; (2) to perform a personalized moderate-intensity exercise prescription and evaluate its effects. METHODS AND RESULTS: Patients with HCM were evaluated through clinical assessment, ECG, ambulatory ECG monitoring, echocardiography, and cardiopulmonary testing. A personalized moderate-intensity exercise prescription was performed, and the same investigations were repeated. Physically active patients with HCM demonstrated better cardiopulmonary functional capacity than sedentary patients (oxygen consumptionpeak/kg 32.9±7.4 versus 25.2±7.4 mL/min per kg P≤0.0001, ventilation/carbon dioxide production slope 26.7±4.3 versus 29.9±5.2 P=0.004), with similar prevalence of ventricular arrhythmias (P=0.43). Sedentary subjects showed a borderline higher prevalence of obesity (P=0.07) than physically active subjects. Moderate-intensity exercise prescription led to improved cardiopulmonary fitness without occurrence of adverse events. CONCLUSIONS: Patients with HCM practicing regular aerobic exercise have a better functional capacity in the absence of relevant events than sedentary patients. Conversely, a sedentary lifestyle led to a deterioration of cardiopulmonary functional capacity and fitness. The tailored moderate-intensity personalized exercise prescription appears to be a feasible approach in carefully selected patients with HCM to counterbalance the negative effects of sedentary behavior without significant major events.

Deep learning of echocardiography distinguishes between presence and absence of late gadolinium enhancement on cardiac magnetic resonance in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can cause myocardial fibrosis, which can be a substrate for fatal ventricular arrhythmias and subsequent sudden cardiac death. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) represents myocardial fibrosis and is associated with sudden cardiac death in patients with HCM, CMR is resource-intensive, can carry an economic burden, and is sometimes contraindicated. In this study for patients with HCM, we aimed to distinguish between patients with positive and negative LGE on CMR using deep learning of echocardiographic images. METHODS: In the cross-sectional study of patients with HCM, we enrolled patients who underwent both echocardiography and CMR. The outcome was positive LGE on CMR. Among the 323 samples, we randomly selected 273 samples (training set) and employed deep convolutional neural network (DCNN) of echocardiographic 5-chamber view to discriminate positive LGE on CMR. We also developed a reference model using clinical parameters with significant differences between patients with positive and negative LGE. In the remaining 50 samples (test set), we compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus the DCNN-derived probability and the reference model. RESULTS: Among the 323 CMR studies, positive LGE was detected in 160 (50%). The reference model was constructed using the following 7 clinical parameters: family history of HCM, maximum left ventricular (LV) wall thickness, LV end-diastolic diameter, LV end-systolic volume, LV ejection fraction < 50%, left atrial diameter, and LV outflow tract pressure gradient at rest. The discriminant model combining the reference model with DCNN-derived probability significantly outperformed the reference model in the test set (AUC 0.86 [95% confidence interval 0.76-0.96] vs. 0.72 [0.57-0.86], P = 0.04). The sensitivity, specificity, positive predictive value, and negative predictive value of the combined model were 0.84, 0.76, 0.78, and 0.83, respectively. CONCLUSION: Compared to the reference model solely based on clinical parameters, our new model integrating the reference model and deep learning-based analysis of echocardiographic images demonstrated superiority in distinguishing LGE on CMR in patients with HCM. The novel deep learning-based method can be used as an assistive technology to facilitate the decision-making process of performing CMR with gadolinium enhancement.

Clinical Outcomes of Concomitant Coronary Artery Bypass Grafting During Ventricular Septal Myectomy.

BACKGROUND: The clinical characteristics and survival outcomes of patients who underwent concomitant coronary artery bypass grafting during septal myectomy have not been well studied. METHODS AND RESULTS: We reviewed patients who underwent both septal myectomy and coronary artery bypass grafting from 2009 to 2020. Causes of concomitant grafting and their impact on survival were analyzed. The median follow-up period was 5.1 years. A total of 320 patients underwent both grafting and myectomy. Of these, 69.7% and 28.1% underwent grafting attributed to atherosclerotic coronary artery disease and myocardial bridging, respectively. Patients who underwent grafting for coronary artery disease tended to be older, had a longer bypass time, and required more grafts compared with patients undergoing procedures because of myocardial bridging (all P<0.05). Postoperatively, the left ventricular outflow gradient significantly decreased from 85.4 mm Hg to 12.8 mm Hg (P<0.001) without perioperative death. The cumulative survival rates were 96.2% and 97.6% at 5 years in the coronary artery disease and myocardial bridging groups, respectively, and they were comparable to that of general myectomy cohort (hazard ratio [HR], 1.06 [95% CI, 0.47-2.36], P=0.895 and HR 0.75 [95% CI, 0.23-2.46], P=0.636, respectively). Sudden death accounted for 45.5% (5 of 11) of postoperative mortality. Analysis of composite end point events showed decreased morbidity with at least one arterial graft in the overall cohort (HR, 0.47 [95% CI, 0.23-0.94], P=0.034). CONCLUSIONS: Concomitant grafting in septal myectomy was found to be a safe procedure. Patients who underwent such surgery experienced favorable postoperative outcomes comparable to those who underwent septal myectomy alone, with a 5-year survival rate of >95% and improved functional class of >90%.

Evaluation of potential novel biomarkers for feline hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy in cats. The diagnosis can be difficult, requiring advanced echocardiographic skills. Additionally, circulating biomarkers (N-terminal pro-B type natriuretic peptide and cardiac troponin I) have several limitations when used for HCM screening. In previous work, we identified interleukin 18 (IL-18), insulin-like growth factor binding protein 2 (IGFBP-2), brain-type glycogen phosphorylase B (PYGB), and WNT Family Member 5 A (WNT5A) as myocardial genes that show significant differential expression between cats with HCM and healthy cats. The products of these genes are released into the circulation, and we hypothesized that IL-18, IGFBP-2, PYGB, and WNT5A serum RNA and protein concentrations differ between healthy cats, cats with subclinical HCM, and those with HCM and congestive heart failure (HCM + CHF). Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) and enzyme-linked immunosorbent assay (ELISA) were applied to evaluate gene and protein expression, respectively, in the serum of eight healthy controls, eight cats with subclinical HCM, and six cats with HCM + CHF. Serum IGFBP-2 RNA concentrations were significantly different among groups and were highest in cats with subclinical HCM. Compared to healthy controls, serum IL-18 and WNT5A gene expression were significantly higher in cats with HCM + CHF, and WNT5A was higher in cats with subclinical HCM. No differences were observed for PYGB. These results indicate that further investigation via large scale clinical studies for IGFBP-2, WNT5A, and IL-18 may be valuable in diagnosing and staging feline HCM.

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.