Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. OBJECTIVES: The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis. METHODS: For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children). CONCLUSIONS: Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry.

BACKGROUND AND AIMS: Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS: Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS: A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS: The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.

Apoptosis, a useful marker in the management of hot-phase cardiomyopathy?

AIMS: 'Hot phases', characterized by chest pain and troponin release, may represent the first clinical presentation of arrhythmogenic cardiomyopathies. Differential diagnosis with acute myocarditis is an unmet challenge for the clinicians. We sought to investigate histological and genetic features in patients with cardiomyopathy presenting with hot phases. METHODS AND RESULTS: We evaluated a case series of consecutive patients hospitalized for suspected 'hot-phase cardiomyopathy' in two Italian centres from June 2017 to March 2022 (median follow-up 18 months) that underwent both endomyocardial biopsy (EMB) and genetic testing. Apoptosis was confirmed with TUNEL assay. Among the 17 enrolled patients (mean age 34 ± 15 years, 76% male), only six patients (35%) presented standard histological and immunohistochemical markers for significant cardiac inflammation at EMB. Conversely, apoptosis was found in 13 patients (77%). Genetic testing was positive for a pathogenic/likely pathogenic (P/LP) variant in genes involved in cardiomyopathies (most frequently in DSP) in eight patients (48%), rising to 62% among patients with apoptosis on EMB. Notably, all patients without apoptosis tested negative for P/LP disease-related variants. Left ventricular ejection fraction was lower in patients showing apoptosis at EMB compared to those without (p = 0.003). CONCLUSIONS: Apoptosis, rather than significant inflammation, was mostly prevalent in this case series of patients with 'hot-phase' presentation, especially in carriers of variants in cardiomyopathy-related genes. Detecting apoptosis on EMB might guide clinicians in performing genetic testing and in more tailored therapeutic choices in 'hot-phase cardiomyopathy'.

The role of genetic testing in Marfan syndrome.

PURPOSE OF REVIEW: This review aims to delineate the genetic basis of Marfan syndrome (MFS) and underscore the pivotal role of genetic testing in the diagnosis, differential diagnosis, genotype-phenotype correlations, and overall disease management. RECENT FINDINGS: The identification of pathogenic or likely pathogenic variants in the FBN1 gene, associated with specific clinical features such as aortic root dilatation or ectopia lentis, is a major diagnostic criterion for MFS. Understanding genotype-phenotype correlations is useful for determining the timing of follow-up, guiding prophylactic aortic root surgery, and providing more precise information to patients and their family members during genetic counseling. Genetic testing is also relevant in distinguishing MFS from other conditions that present with heritable thoracic aortic diseases, allowing for tailored and individualized management. SUMMARY: Genetic testing is essential in different steps of the MFS patients' clinical pathway, starting from the phase of diagnosis to management and specific treatment.

Left Ventricular Non-Compaction in Children: Aetiology and Diagnostic Criteria.

Left ventricular non-compaction (LVNC) is a heterogeneous myocardial disorder characterized by prominent trabeculae protruding into the left ventricular lumen and deep intertrabecular recesses. LVNC can manifest in isolation or alongside other heart muscle diseases. Its occurrence among children is rising due to advancements in imaging techniques. The origins of LVNC are diverse, involving both genetic and acquired forms. The clinical manifestation varies greatly, with some cases presenting no symptoms, while others typically manifesting with heart failure, systemic embolism, and arrhythmias. Diagnosis mainly relies on assessing heart structure using imaging tools like echocardiography and cardiac magnetic resonance. However, the absence of a universally agreed-upon standard and limitations in diagnostic criteria have led to ongoing debates in the scientific community regarding the most reliable methods. Further research is crucial to enhance the diagnosis of LVNC, particularly in early life stages.

[Clinical and genetic manifestations of left ventricular non-compaction in children]. / Caratteristiche cliniche e genetiche del ventricolo sinistro non compatto in età pediatrica.

Left ventricular non-compaction (LVNC) is a myocardial disease characterized by a two-layered structure typically seen at the apical and lateral left portions of the ventricular myocardium, distal to the papillary muscles. While considered a rare disease, its prevalence in children is increasing due to the increased awareness of this condition and improved resolution of imaging techniques. The etiology is heterogeneous, ranging from inherited conditions to acquired diseases. Although many patients are asymptomatic, some patients may experience adverse events, including heart failure, arrhythmias, or thromboembolic events. Several echocardiographic or cardiac magnetic resonance imaging diagnostic criteria have been proposed for diagnosing LVNC. However, their application in children is significantly limited. This review aims to describe the clinical and genetic characteristics of children with LVNC and discuss the role of the proposed diagnostic criteria.

Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: Role of age and heart failure phenotypes.

BACKGROUND: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes. METHODS: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments. RESULTS: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001). CONCLUSIONS: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes.

An atypical Aymé-Gripp phenotype detected by exome sequencing.

Aymé-Gripp Syndrome (AGS) is an ultra-rare syndrome characterized by peculiar facial traits combined with early bilateral cataracts, sensorineural hearing loss, and variable neurodevelopmental abnormalities. Only a few cases carrying a pathogenic variant in MAF have been described to date. A significant effort is then required to expand the genotypic and phenotypic spectrum of this condition. In this paper, we report the peculiar case of a 6-year-old girl carrying a de novo missense pathogenic variant in MAF, being the first case reported to show a milder phenotype with no cataracts and deafness displayed. Furthermore, we performed a systematic review of previously published cases, focusing on clinical manifestation and genotype.

Prediction of incident atrial fibrillation in hypertrophic cardiomyopathy.

BACKGROUND AND AIM: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with significant effects on outcome. We aim to compare the left atrial (LA) diameter measurement with HCM-AF Score in predicting atrial fibrillation (AF) development in HCM. METHODS: From the regional cohort of the Campania Region, Italy, 519 HCM patients (38% women, age45 ± 17 years) without history of AF, were enrolled in the study. The primary clinical endpoint was the development of AF, defined as at least 1 episode documented by ECG. RESULTS: During the follow-up (mean 8 ± 6, IQ range 2.5-11.2 years), 99 patients (19%) developed AF. Patients who developed AF were more symptomatic, had higher prevalence of ICD implantation, had larger LA diameter, greater left ventricular (LV) maximal wall thickness and LV outflow tract obstruction (p < 0.01). Both LA diameter and HCM-AF score were higher in patients who developed AF versus those who did not (LA diameter 49 ± 7 versus 43 ± 6 mm; HCM-AF score 22 ± 4 versus 19 ± 4; p < 0.0001); however, ROC curve analysis demonstrated that LA diameter had a significant greater area under the curve than HCM-AF Score (p < 0.0001). At 5 years follow-up, a LA diameter > 46 mm, showed a similar accuracy in predicting AF development of HCM-AF score ≥ 22, which identifies patients at high risk to develop AF. CONCLUSION: Our analysis shows that LA diameter, a worldwide and simple echocardiographic measure, is capable alone to predict AF development in HCM patients.

Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

Impact of GLA Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies.

BACKGROUND: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data. REGISTRATION: URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.

ECG/echo indexes in the diagnostic approach to amyloid cardiomyopathy: A head-to-head comparison from the AC-TIVE study.

BACKGROUND AND AIMS: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients. METHODS: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed. RESULTS: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007). CONCLUSIONS: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted.

Prognostic Implications of the Extent of Cardiac Damage in Patients With Fabry Disease.

BACKGROUND: There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD). OBJECTIVES: This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort. METHODS: Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m2); stage 3, ventricular impairment (LV ejection fraction <50% or E/e' ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke. RESULTS: A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy. CONCLUSIONS: In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification.

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.

Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.