iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy.

BACKGROUND Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here, we set out to investigate genotype-phenotype relationships in 2 siblings with an extensive family history of HCM, both carrying a pathogenic truncating variant in the MYBPC3 gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations. METHODS We used a combination of induced pluripotent stem cell (iPSC)-based disease modeling and CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9)-mediated genome editing to generate patient-specific cardiomyocytes (iPSC-CMs) and isogenic controls lacking the pathogenic MYBPC3 variant. RESULTS Mutant iPSC-CMs developed impaired mitochondrial bioenergetics, which was dependent on the presence of the mutation. Moreover, we could detect altered excitation-contraction coupling in iPSC-CMs from the severely affected individual. The pathogenic MYBPC3 variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing of the mutant carriers identified a variant of unknown significance in the MYH7 gene (p.Ile1927Phe) uniquely present in the individual with severe HCM. We finally assessed the pathogenicity of this variant of unknown significance by functionally evaluating iPSC-CMs after editing the variant. CONCLUSIONS Our results indicate that the p.Ile1927Phe variant of unknown significance in MYH7 can be considered as a modifier of HCM expressivity when found in combination with truncating variants in MYBPC3. Overall, our studies show that iPSC-based modeling of clinically discordant subjects provides a unique platform to functionally assess the effect of genetic modifiers.The funding for this research was provided by the Spanish Ministry of Science and Innovation-MCIN (grants PID2021-123925OB-I00, PID2019-104776RB-I00, CB06/01/1056, and CB16/11/00399 financed by MCIN/AEI/10.13039/501100011033), AGAUR (2021-SGR-974), Fundació La Marató de TV3 (201534-30), Fundación BBVA (BIO14_298), Fundació Obra Social la Caixa, and CERCA Program/ Generalitat de Catalunya. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN, and the Pro CNIC Foundation. I. Lazis was partially supported by a predoctoral fellowship from MCIN (PRE2019-087901).S

Clinical phenotypes and prognosis of dilated cardiomyopathy caused by truncating variants in the TTN Gene.

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04–3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30–2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.pre-print1,66 M

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and males and females compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 male; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between males and females (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 males and 3 females; log-rank P35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator

none41siTo study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).Protonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry MProtonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry

Emery-Dreifuss Muscular Dystrophy 1 is associated with high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterise the cardiac complications of EMD variants. METHODS Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidence in male and female variant-carriers was determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared to consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers (mean [SD] ages 33.4 [13.3] and 43.3 [16.8] years, respectively). Nine (23.6%) males developed MVA and five (13.2%) developed ESHF during a median [IQR] follow-up of 65.0 [24.3, 109.5] months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median [IQR] age of 58.6 [53.2, 60.4] years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank p = 0.49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank p = 0.09). CONCLUSIONS Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.The work reported in this publication was funded by: a British Heart Foundation Clinical Research Training Fellowship to D.E.C. (FS/CRTF/ 20/24022); a British Heart Foundation Clinical Research Training fellowship to A.P. (FS/18/82/34024); The Ministry of Health, Italy, project RC-2022-2773270 to E.B.; the National Institutes of Health (NIH) (R01HL69071, R01HL116906, R01HL147064, NIH/NCATS UL1 TR002535, and UL1 TR001082) to L.M.; and support from the Rose Foundation for K.M.S

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P&lt;0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF &gt;35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P&lt;0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.</p

Predictores de riesgo en una cohorte española con cardiolaminopatías. Registro REDLAMINA

[Abstract] Introduction and objectives. According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) < 45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. Methods. The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. Results. We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF < 45% (P = .001) and NSVT (P < .001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF < 45% (P < .001). Conclusions. In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF < 45%. Therefore, female carriers of missense variants with either NSVT or LVEF < 45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.[Resumen] Introducción y objetivos. Según las guías de muerte súbita, se debe considerar un desfibrilador automático implantable (DAI) para los pacientes con miocardiopatía dilatada debida a variantes en el gen de la lamina (LMNA) con al menos 2 factores: varones, fracción de eyección del ventrículo izquierdo (FEVI) < 45%, taquicardia ventricular no sostenida (TVNS) y variantes no missense. Nuestro objetivo es describir las características clínicas de una cohorte española de pacientes con cardiolaminopatías (registro REDLAMINA) y evaluar los criterios de riesgo vigentes. Métodos. Se evaluó la relación entre factores de riesgo y eventos cardiovasculares en una cohorte de 140 portadores de variantes en LMNA (54 probandos, 86 familiares, edad ≥ 16 años). Se consideró: a) evento arrítmico mayor (EAM) si hubo descarga apropiada del DAI o muerte súbita, y b) muerte por insuficiencia cardiaca, incluidos los trasplantes. Resultados. Se identificaron 11 variantes nuevas y 21 previamente publicadas. La FEVI < 45% (p = 0,001) y la TVNS (p < 0,001) se relacionaron con los EAM, pero no el sexo o el tipo de variante (missense frente a no missense). La FEVI < 45% (p < 0,001) fue el único factor relacionado con la muerte por insuficiencia cardiaca. Conclusiones. En el registro REDLAMINA, los únicos 2 predictores asociados con EAM fueron la TVNS y la FEVI < 45%. No se debería considerar grupo de bajo riesgo a las portadoras de variantes missense con TVNS o FEVI < 45%. Es importante individualizar la estratificación del riesgo de los portadores de variantes missense en LMNA, porque no todas tienen el mismo pronóstico.This study received a grant from the Proyecto de investigación de la Sección de Insuficiencia Cardiaca 2017 from the Spanish Society of Cardiology and grants from the Instituto de Salud Carlos III (ISCIII) [PI14/0967, PI15/01551, AC16/0014] and ERA-CVD Joint Transnational Call 2016 (Genprovic). Grants from the ISCIII and the Ministerio de Economía y Competitividad de España (Spanish Department of Economy and Competitiveness) are supported by the Plan Estatal de I+D+i 2013-2016: Fondo Europeo de Desarrollo Regional (FEDER) “Una forma de hacer Europa”

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption. OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD. METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries. RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78). CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD

Association of Left Ventricular Systolic Dysfunction among Carriers of Truncating Variants in Filamin C with Frequent Ventricular Arrhythmia and End-stage Heart Failure

IMPORTANCE: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. OBJECTIVE: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTS: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTS: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCE: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction

Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P 35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.The project was partially funded by a grant from the Catalan Society of Cardiology (Barcelona, Spain). Hospital Universitario Virgen de la Arrixaca (Murcia, Spain) was supported by a grant from the Foundation Marató TV3 (218/C/2015) (Barcelona, Spain). Hospital Universitario y Politécnico La Fe (Valencia, Spain) was partially supported by Fondo Europeo de Desarrollo Regional (“Unión Europea, Una forma de hacer Europa”) (Madrid, Spain) and the Instituto de Salud Carlos III (La Fe Biobank PT17/0015/ 0043) (Madrid, Spain). Dr Guala was supported by funding from the Spanish Ministry of Science, Innovation and Universities (IJC2018-037349-I) (Madrid, Spain). Dr La Mura was supported by a research grant from the Cardiopath PhD program (Naples, Italy). Prof de la Pompa was supported by grants PID2019-104776RB-I00 and CB16/11/00399 (CIBER CV) from the Spanish Ministry of Science, Innovation and Universities. Dr Bayes-Genis was supported by grants from CIBER Cardiovascular (CB16/11/00403 and 16/11/00420) (Madrid, Spain) and AdvanceCat 2014-2020 (Barcelona, Spain); and has received advisory board and lecture fees from Novartis, Boehringer Ingelheim, Vifor, Roche Diagnostics, and Critical Diagnostics. Dr Pontone has received speaker honorarium and/or institutional research grants from GE Healthcare, Bracco, Boehringer Ingelheim, and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S