Cardiotrophin-1 plasma levels are associated with the severity of hypertrophy in hypertrophic cardiomyopathy

AIMS: Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P /=30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm). CONCLUSIONS: These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy

Negative screening of Fabry disease in patients with conduction disorders requiring a pacemaker.

Identification of Fabry disease (FD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Conduction problems are frequent in FD and could precede other manifestations, offering a possible earlier diagnosis. We studied the prevalence of FD in 188 patients < 70 years with conduction problems requiring pacemaker implantation. Although classical manifestations of FD were not rare, no patient with FD was identified. Screening efforts should not be conducted in this population.post-print523 K

A cost-effectiveness analysis of hypertrophic cardiomyopathy sudden cardiac death risk algorithms for implantable cardioverter defibrillator decision-making

AIMS: To conduct a contemporary cost-effectiveness analysis examining the use of implantable cardioverter defibrillators (ICD) for primary prevention in patients with hypertrophic cardiomyopathy (HCM). METHODS: A discrete-time Markov model was used to determine the cost-effectiveness of different ICD decision-making rules for implantation. Several scenarios were investigated including the reference scenario of implantation rates according to observed real world practice. A 12-year time horizon with an annual cycle length was used. Transition probabilities used in the model were obtained using Bayesian analysis. The study has been reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Using a 5-year SCD risk threshold of 6% was cheaper than current practice and has marginally better total quality adjusted life years (QALYs). This is the most cost-effective of the options considered, with an incremental cost effectiveness ratio of £834 per QALY. Sensitivity analyses highlighted that this decision is largely driven by what health related quality of life (HRQL) is attributed to ICD patients and time horizon. CONCLUSION: We present a timely new perspective on HCM ICD cost-effectiveness, using methods reflecting real-world practice. While we have shown that a 6% 5-year SCD risk cut-off provides the best cohort stratification to aid ICD decision-making, this will also be influenced by the particular values of costs and HRQL for subgroups or at a local level. The process of explicitly demonstrating the main factors which drive conclusions from such an analysis will help to inform shared decision-making in this complex area for all stakeholders concerned

Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits

Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations

Utilidad clínica del estudio genético en pacientes con miocardiopatía dilatada

[Abstract] Introduction and objectives: Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation. The prevalence of familial disease can reach 50%. Our objective was to describe the genetic basis of DCM in a cohort with a high proportion of transplanted patients. Methods: We included patients with DCM and genetic testing performed using next-generation sequencing (NGS) that included at least 80 genes. Clinical data, family history and genetic results were retrospectively analysed. When possible, assessment of first-degree relatives was carried out. Results: Eighty-seven DCM patients and 308 relatives from 70 families were evaluated. Clinical prevalence of familial disease was 37% (32 patients). Forty-four percent of patients (38 patients) had required heart transplantation. A relevant variant was found in 43 patients (49%), 25 patients (29%) carried variants of unknown significance and in 19 patients (22%) the study was negative. Most genetic variants were found in sarcomeric genes and the yield of genetic testing was higher in patients with familial DCM. Conclusions: The yield of genetic testing in our DCM cohort was high, reaching 69% in familial cases. Mutational spectrum was heterogeneous and the identification of the specific aetiology of the disease often provided prognostic information.[Resumen] Introducción y objetivos. La miocardiopatía dilatada (MCD) es la causa más frecuente de trasplante cardiaco. Se considera que es familiar hasta en el 50% de los casos. Nuestro objetivo es describir los resultados genéticos obtenidos en una cohorte de pacientes con MCD, de los cuales una elevada proporción había acabado en trasplante cardiaco. Métodos. Se incluyeron pacientes con MCD a los que se realizó next-generation sequencing (NGS, «secuenciación de nueva generación») de al menos 80 genes relacionados con la enfermedad. Se analizaron retrospectivamente los datos clínicos de los pacientes, la historia familiar y los resultados del estudio genético. En los casos en los que fue posible, se realizó una evaluación de sus familiares de primer grado. Resultados. Fueron evaluados 87 pacientes con MCD y 308 familiares de 70 familias distintas. La prevalencia clínica de enfermedad familiar fue del 37% (32 pacientes) y el 44% (38 pacientes) habían precisado un trasplante cardiaco. En 43 pacientes (49%) se encontró al menos una variante relevante, en 25 pacientes (29%) se identificaron variantes de significado incierto y en 19 pacientes (22%) el estudio fue negativo. La mayoría de las mutaciones se encontraron en genes sarcoméricos y la rentabilidad del estudio fue mayor en los pacientes con MCD familiar. Conclusiones. El estudio genético NGS en nuestra población de pacientes con MCD tuvo una elevada rentabilidad, alcanzando el 69% en los casos familiares. El espectro mutacional fue heterogéneo y con frecuencia la identificación de la etiología específica de la enfermedad aportó información pronóstica

Prognostic Implications of Pathogenic Truncating Variants in the TTN Gene

[Abstract] Introduction and objectives: TTN gene truncating variants (TTNtv) are a frequent cause of dilated cardiomyopathy (DCM). However, there are discrepant data on the associated prognosis. Our objectives were to describe the prevalence of TTNtv in our cohort and to compare the clinical course with that described in the literature. Methods: We included patients with DCM and genetic testing performed using next-generation sequencing. Through a systematic literature research, we collected information about carriers and affected relatives with TTNtv. We compared the cumulative percentage of affected carriers and the survival free of cardiovascular death. Results: One hundred and ten DCM patients were evaluated. A total of 13 TTNtv distributed in 14 probands were identified (12.7%). We found a 21.4% prevalence in familial cases. No significant differences in the relation between age and clinical disease expression were identified. Survival free of cardiovascular death curves constructed from data in the literature seems not to overestimate the risk in our population. Conclusions: The identification of TTNtv in patients with DCM is frequent and provides relevant information about the disease prognosis. The risk of cardiovascular death should not be underestimated. Age related penetrance need to be considered in the familial evaluation

Amiloidosis cardiaca por cadenas ligeras y por transtirretina: características clínicas, historia natural y predictores pronósticos

[Abstract] Introduction and objectives. Light-chain amyloidosis (AL-CA) and transthyretin amyloidosis (ATTR-CA) are the most common types of cardiac amyloidosis (CA). We sought to study the clinical characteristics and prognosis of both diseases. Methods. We conducted a single-centre, retrospective review of all patients diagnosed with CA between 1998 and 2018. Clinical characteristics, complementary tests, survival and other adverse clinical events were studied. Results. We identified 105 patients with CA, 65 ATTR-CA and 40 AL-CA. Mean age was 74.4 years; 24.8% were women. In both groups, heart failure was the most frequent clinical presentation (55.2%). The most prevalent electrocardiographic findings were the pseudoinfarct pattern (68.5%) and a Sokolow-Lyon index <1.5 mV (67.7%), with no differences between the two subtypes of CA. One-year, 3-year, and 5-year survival was 43.3%, 40.4% and 35.4%, respectively, in AC-AL patients, and 85.1%, 57.3% and 31.4% in AC-ATTR patients (p = .004). AL-CA subtype (HR 3.41, CI95% 1.45−8.06, p = .005), previous admission for heart failure (HR 4.25, 95% CI 1.63−11.09, p = .003) and a NYHA class III-IV (HR 2.76, 95% CI 1.09−7.03, p = .033) were independent predictors of mortality, while beta-blocker therapy was associated with longer survival (HR .23, 95% CI .09–.59, p = .002). Conclusions. Differences exist between the clinical presentation of AL-CA and ATTR-CA patients. Both diseases, particularly AL-CA, are associated with poor life prognosis.[Resumen] Antecedentes y objetivos. La amiloidosis cardiaca (AC) por cadenas ligeras (AC-AL) y por transtirretina (AC-ATTR) son los dos subtipos más frecuentes de la enfermedad. Nos propusimos caracterizar clínicamente estas entidades y analizar su pronóstico. Material y métodos. Realizamos una revisión retrospectiva de todos los pacientes diagnosticados de AC entre 1998 y 2018 en un centro español. Además de recoger las características clínicas y los resultados de las pruebas complementarias al diagnóstico, analizamos la supervivencia y la incidencia de desenlaces clínicos adversos. Resultados. Identificamos 105 pacientes con AC, 65 AC-ATTR y 40 AC-AL. La edad media era de 74,4 años; el 24,8% eran mujeres. En ambos grupos la insuficiencia cardiaca (IC) fue la forma de presentación clínica más frecuente (55,2%). Los hallazgos electrocardiográficos más prevalentes fueron el patrón de pseudoinfarto (68,5%) y un índice de Sokolow-Lyon <1,5 mV (67,7%), sin diferencias entre los dos subtipos. La supervivencia a 1, 3 y 5 años fue del 43,3%, 40,4% y 35,4%, respectivamente, en pacientes con AC-AL y de 85,1%, 57,3% y 31,4% en pacientes con AC-ATTR (p = 0,004). El subtipo AC-AL (HR 3,41, IC95% 1,45-8,06, p = 0,005), el ingreso previo por IC (HR 4,25, IC95% 1,63-11,09, p = 0,003) y una clase NYHA III-IV (HR 2,76, IC95% 1,09-7,03, p = 0,033) fueron predictores independientes de mortalidad, mientras que el tratamiento betabloqueante se asoció con una mayor supervivencia (HR 0,23, IC95% 0,09-0,59, p = 0,002). Conclusiones. Existen ciertas diferencias en la presentación clínica de los pacientes con AC-AL y AC-ATTR. Ambas entidades, y muy especialmente la AC-AL, presentan un pobre pronóstico vital

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