拘束型心筋症

BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare, severe cardiac disease with a heterogeneous genetic basis. Both genetic and nongenetic factors contribute to RCM pathogenesis. Identifying the underlying molecular causes is important for diagnosis and family screening. In this study, we investigated the genetic basis of RCM in a 52-year-old woman with a family history of RCM and heart disease. METHODS: Genetic predisposition was evaluated using whole-exome sequencing (WES). Candidate variants identified in the proband were validated by Sanger sequencing and interpreted using bioinformatics tools and the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Two heterozygous missense variants were identified: a novel DES c.262C > A (p.Leu88Met) variant and a previously reported MYH7 c.2360G > A (p.Arg787His) variant. The DES variant was absent from population databases and was classified as a variant of uncertain significance, whereas the MYH7 variant has been reported in the cardiomyopathy spectrum, primarily in hypertrophic cardiomyopathy. Although both variants may be relevant to the participant's phenotype, their contribution remains uncertain without segregation and functional studies. CONCLUSION: These findings expand the spectrum of DES and MYH7 variants observed in cardiomyopathy and highlight the need for further segregation and functional analyses to clarify their clinical significance in RCM. Identifying the genetic basis of RCM in this family may improve screening strategies and guide clinical management.

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) widely used in human heart failure and has demonstrated potential cardiorenal and neurohormonal effects in experimental canine studies. Hydrochlorothiazide is a thiazide diuretic that acts at a more distal segment of the nephron than furosemide. Its addition to loop diuretic therapy may enhance sodium and fluid excretion through sequential nephron blockade and thereby improve the diuretic response in cases of refractory congestion. However, information regarding the combination of these two drugs in cats with congestive heart failure is lacking. This report describes the long-term clinical outcome of a cat with recurrent cardiogenic pleural effusion treated with sacubitril/valsartan and hydrochlorothiazide. A 14-year-old spayed female Persian-cross cat was referred for severe respiratory distress caused by recurrent pleural effusion. Echocardiography identified advanced cardiomyopathy with a nonspecific phenotype and overlapping hypertrophic and restrictive features, including focal basal septal hypertrophy, biatrial enlargement, atrial fibrillation and spontaneous echocardiographic contrast. Despite conventional treatment, which included pimobendan, torasemide, and antithrombotic medications, the cat experienced multiple episodes of pleural effusion over the following months, requiring repeated thoracocentesis. Consequently, the treatment regimen was expanded to include sacubitril/valsartan and hydrochlorothiazide. According to the owner, all other cardiac medications were discontinued approximately one week later without veterinary consultation. At long-term follow-up approximately two years after sacubitril/valsartan and hydrochlorothiazide therapy initiation, the cat remained clinically stable, with no further episodes of respiratory distress. Echocardiography revealed persistent severe structural heart disease, although improved left ventricular systolic indices were observed. This case report describes prolonged clinical stabilization in a cat with advanced cardiomyopathy and recurrent congestive heart failure following the administration of sacubitril/valsartan and hydrochlorothiazide over a two-year period. Whether this outcome reflects a specific effect of sacubitril/valsartan, the addition of hydrochlorothiazide, or a combination of both cannot be determined from a single observation. Nonetheless, the duration and completeness of the response observed here warrant prospective evaluation of combination of ARNI therapy and hydrochlorothiazide in cats with refractory congestive heart failure. Further studies are needed to assess the safety and effectiveness of this approach in feline cardiomyopathy.

Atrial fibrillation or flutter (AF/AFL) affects approximately 56% to 71% of patients with transthyretin amyloid cardiomyopathy (ATTR-CM), with prevalence rising in more advanced disease. AF usually arises on a background of amyloid atrial cardiomyopathy: atrial infiltration, increased stiffness, impaired reservoir and contractile mechanics, and a prothrombotic milieu present even in sinus rhythm. Whether AF contributes independently to mortality remains unsettled. Unadjusted analyses show higher mortality or event rates with AF, inconsistently significant; the association attenuates once amyloid severity is accounted for in single-center and trial datasets. The largest dataset, reported only as a conference abstract, is the exception: an association with a composite including cardiovascular hospitalization persisted after adjustment for stage. Its clinical relevance may lie less in mortality prediction than in symptoms, heart failure events, and thromboembolism. Conventional risk stratification performs poorly: CHA2DS2-VASc does not discriminate left atrial appendage thrombus, thrombus occurs during therapeutic anticoagulation, and in a large propensity-matched cohort stroke rates were comparable with and without AF, suggesting thromboembolic risk reflects the underlying atrial myopathy rather than rhythm status alone. Rate control is constrained by restrictive physiology; catheter ablation has been associated with favorable outcomes in observational cohorts, in selected patients and with clinically meaningful periprocedural decompensation. No disease-modifying therapy has prevented AF or reduced AF burden in a prospectively adjudicated trial. Throughout, we separate published evidence from expert practice. The data support a cross-sectional association between AF and greater ATTR-CM severity but do not establish that incident AF identifies biological progression in an individual patient.

Filamin C (FLNC) contributes to 1%-8% of adult-onset cardiomyopathy (CMP), with a high prevalence of end-stage heart failure and sudden cardiac death, particularly for FLNC truncating variants (FLNCtv), rendering it one of the high-risk CMP genes. Outcome data and genotype-phenotype correlation in children are scarce. We conducted a retrospective cohort study of children (< 18 years) with CMP features and a (likely) pathogenic FLNC variant, identified via literature search or in the Belgian Pediatric Cardiology Registry (BePCaR), to evaluate cardiovascular outcomes and genotype-phenotype correlations. Seventy-four individuals (56.8% male, median age 4.5 years) from 57 families were included. Restrictive CMP was the most prevalent phenotype. Half of the patients experienced major adverse cardiovascular events, including heart transplantation (20.3%) and death (13.5%). Hypertrophic CMP was exclusively associated with ROD2 domain variants. Mortality was significantly higher in FLNCtv carriers versus non-truncating carriers (26.9% vs. 6.3%, p = 0.019), and multivariate analysis identified FLNCtv as an independent predictor of adverse outcome (OR = 6.4, 95% CI: [1.36, 29.80]). Extracardiac manifestations occurred in 32.4%, predominantly in RCM patients, with myopathy-associated variants clustering in exons 21 and 41. Pathogenic FLNC variants associate with early-onset CMP and poor prognosis, underscoring the need for early genetic screening, risk stratification, and personalized follow-up to improve outcome.