ABSTRACT
BACKGROUND: Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation. METHODS: Consecutively referred adult (aged ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m2 in men and ≥95 g/m2 in women). RESULTS: From a cohort of 393 patients, 214 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45-4.62) g/m2/year in males and +1.38 (IQR 0.09-2.85) g/m2/year in females (p<0.001). CONCLUSIONS: Approximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.
Subject(s)
Fabry Disease , Hypertrophy, Left Ventricular , Humans , Fabry Disease/complications , Fabry Disease/epidemiology , Fabry Disease/physiopathology , Hypertrophy, Left Ventricular/epidemiology , Hypertrophy, Left Ventricular/etiology , Hypertrophy, Left Ventricular/diagnosis , Hypertrophy, Left Ventricular/physiopathology , Male , Female , Adult , Incidence , Risk Factors , Middle Aged , Prospective Studies , Young Adult , Sex Factors , Time FactorsABSTRACT
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.
Subject(s)
Myocarditis , Humans , Myocarditis/genetics , Myocarditis/epidemiology , Acute Disease , Prevalence , Cardiomyopathies/genetics , Cardiomyopathies/epidemiologyABSTRACT
Hypertrophic cardiomyopathy (HCM) is a common myocardial disease defined by increased left ventricular wall thickness unexplained by loading conditions. HCM frequently is caused by pathogenic variants in sarcomeric protein genes, but several other syndromic, metabolic, infiltrative, and neuromuscular diseases can result in HCM phenocopies. This review summarizes the current understanding of these HCM mimics, highlighting their importance across the life course. The central role of a comprehensive, multiparametric diagnostic approach and the potential of precision medicine in tailoring treatment strategies are emphasized.
Subject(s)
Cardiomyopathy, Hypertrophic , Humans , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/therapy , Cardiomyopathy, Hypertrophic/genetics , Diagnosis, Differential , PhenotypeABSTRACT
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; 10â 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62â 050 patients screened), 0.7% in stroke (25 studies; 15â 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; 11â 108â 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.
Subject(s)
Fabry Disease , Stroke , Humans , Infant, Newborn , Fabry Disease/diagnosis , Fabry Disease/epidemiology , Fabry Disease/genetics , alpha-Galactosidase/genetics , Prevalence , Hypertrophy, Left VentricularABSTRACT
BACKGROUND: Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. METHODS: Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. RESULTS: Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). CONCLUSIONS: For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.
Subject(s)
Cardiomyopathy, Dilated , Cardiomyopathy, Hypertrophic , Metabolism, Inborn Errors , Male , Humans , Adult , Infant , Methylmalonic Acid , Metabolism, Inborn Errors/geneticsABSTRACT
INTRODUCTION: We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). METHODS: We studied 129 consecutive patients (23.7⯱â¯20.9â¯years, range 0-74â¯years; male/female 68%/32%). Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography; imaging; and laboratory. Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and predictive accuracy of RF were analyzed in the genotyped population. RESULTS: In the overall cohort of 129 patients, 169 RF were identified in 62 patients (48%). Prevalence of RF was higher in infants (78%) and in adults >55â¯years old (58%). Following targeted genetic and clinical evaluation, 94 patients (74%) had a definite diagnosis (sarcomeric HCM or specific causes of HCM). We observed 14 RF in 13 patients (21%) with sarcomeric gene disease, 129 RF in 34 patients (97%) with other specific causes of HCM, and 26 RF in 15 patients (45%) with idiopathic HCM (pâ¯<â¯0.0001). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo andâ¯>â¯55yo. Se, Sp, PPV, NPV and PA of RF were 97%, 70%, 55%, 98% and 77%, respectively. Single and clinical combination of RF (clusters) had an high specificity, NPV and predictive accuracy for the specific etiologies (syndromes/metabolic/infiltrative disorders associated with HCM). CONCLUSIONS: An extensive diagnostic work up, focused on analysis of specific diagnostic RF in patients with unexplained LVH facilitates a clinical diagnosis in 74% of patients with HCM.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/epidemiology , Adolescent , Adult , Aged , Cardiomyopathy, Hypertrophic/blood , Child , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Prevalence , Young AdultABSTRACT
Hypertrophic cardiomyopathy (HCM) is the most common known inherited heart disorder, with a prevalence of 1:500 of the adult population. Etiology of HCM can be heterogeneous, with sarcomeric gene disease as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%-15% of the patients. Early diagnosis of storage and infiltrative disorders, particularly those with specific treatments (i.e., Fabry disease and/or amyloidosis), means early management and treatment, with a significant impact on patients prognosis. Here, we report on four different cases of HCM, highlighting difficulties to make differential diagnosis of different forms of cardiomyopathies, and their potential impact on the management.
ABSTRACT
AIM: Anderson-Fabry disease (AFD) is a hereditary disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A which causes dysfunctions in multiple organ systems. Cardiac manifestation includes left ventricular hypertrophy, thickening of the valves, conduction disturbances and in the late phase, extensive areas of myocardial fibrosis with increased risk of sudden cardiac death. Case example: A case of AFD with exclusive cardiac involvement is described. During follow-up, due to the high risk of life-threatening arrhythmic events, implantation of an implantable cardioverter defibrillator is performed. CONCLUSION: AFD patients with advanced cardiac disease might represent a subgroup of patients who may require an implantable cardioverter defibrillator for primary prevention of sudden cardiac death.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/therapy , Death, Sudden, Cardiac/prevention & control , Fabry Disease/complications , Multimodal Imaging/methods , alpha-Galactosidase/therapeutic use , Cardiomyopathy, Hypertrophic/etiology , Defibrillators, Implantable , Echocardiography/methods , Electrocardiography/methods , Fabry Disease/diagnosis , Follow-Up Studies , Humans , Isoenzymes/therapeutic use , Magnetic Resonance Imaging, Cine/methods , Male , Middle Aged , Rare Diseases , Risk Assessment , Severity of Illness Index , Treatment OutcomeSubject(s)
Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/therapy , Death, Sudden, Cardiac/prevention & control , Algorithms , Arrhythmias, Cardiac/complications , Death, Sudden, Cardiac/epidemiology , Decision Trees , Heart Diseases/diagnosis , Heart Diseases/therapy , Heart Failure/etiology , Heart Failure/prevention & control , Heart Ventricles , HumansSubject(s)
Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/therapy , Cardiology/standards , Catheter Ablation/standards , Death, Sudden, Cardiac/prevention & control , Defibrillators, Implantable/standards , Electric Countershock/standards , Anti-Arrhythmia Agents/adverse effects , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/mortality , Catheter Ablation/adverse effects , Catheter Ablation/mortality , Combined Modality Therapy , Death, Sudden, Cardiac/epidemiology , Drug Therapy, Combination , Electric Countershock/adverse effects , Electric Countershock/instrumentation , Electric Countershock/mortality , Humans , Risk Assessment , Risk Factors , Treatment OutcomeSubject(s)
Arrhythmias, Cardiac/therapy , Death, Sudden, Cardiac/prevention & control , Acute Disease , Aged , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/genetics , Autopsy/methods , Cardiac Resynchronization Therapy/methods , Cardiomyopathies/complications , Cardiomyopathies/therapy , Cardiotonic Agents/therapeutic use , Catheter Ablation/methods , Child , Coronary Artery Disease/complications , Coronary Artery Disease/therapy , Defibrillators , Drug Therapy, Combination , Early Diagnosis , Emergency Treatment/methods , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/therapy , Heart Transplantation/methods , Heart Valve Diseases/complications , Heart Valve Diseases/therapy , Humans , Mental Disorders/complications , Myocardial Infarction/complications , Myocardial Infarction/therapy , Myocarditis/complications , Myocarditis/therapy , Nervous System Diseases/complications , Nervous System Diseases/therapy , Out-of-Hospital Cardiac Arrest/therapy , Pregnancy , Pregnancy Complications, Cardiovascular/therapy , Primary Prevention/methods , Quality of Life , Risk Assessment , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/therapy , Sports/physiology , Stroke Volume/physiology , Terminal Care/methods , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/therapyABSTRACT
The physiological importance of the right ventricle (RV) has been underestimated over the past years. Finally in the early 1950s through the 1970s, cardiac surgeons recognized the importance of RV function. Since then, the importance of RV function has been recognized in many acquired cardiac heart disease. RV can be mainly or together with left ventricle (LV) affected by inherited or acquired cardiomyopathy. In fact, RV morphological and functional remodeling occurs more common during cardiomyopathies than in ischemic cardiomyopathies and more closely parallels LV dysfunction. Moreover, there are some cardiomyopathy subtypes showing a predominant or exclusive involvement of the RV, and they are probably less known by cardiologists. The clinical approach to right ventricular cardiomyopathies is often challenging. Imaging is the first step to raise the suspicion and to guide the diagnostic process. In the differential diagnosis, cardiologists should consider athlete's heart, congenital heart diseases, multisystemic disorders, and inherited arrhythmias. However, a multiparametric and multidisciplinary approach, involving cardiologists, experts in imaging, geneticists, and pathologists with a specific expertise in these heart muscle disorders is required.
Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Cardiomyopathy, Restrictive/diagnosis , Diagnostic Imaging/methods , Heart Defects, Congenital/diagnosis , Sarcoidosis/diagnosis , Ventricular Dysfunction, Right/diagnosis , Cardiac Catheterization/methods , Diagnosis, Differential , Echocardiography, Doppler/methods , Endomyocardial Fibrosis/diagnosis , Female , Humans , Magnetic Resonance Imaging, Cine/methods , Male , Tomography, X-Ray Computed/methods , Ventricular Function, Right/physiologyABSTRACT
OBJECTIVES: Aortoseptal angulation (AoSA) can predict provocable left ventricular outflow tract obstruction (LVOTO) in patients with symptomatic hypertrophic cardiomyopathy (HCM). Lack of a standardised measurement technique in HCM without the need for complex three-dimensional (3D) imaging limits its usefulness in routine clinical practice. This study aimed to validate a simple measurement of AoSA using 2D echocardiography and cardiac MR (CMR) imaging as a predictor of LVOTO. METHODS: We retrospectively assessed 160 patients with non-obstructive HCM, referred for exercise stress echocardiography. AoSA was measured using resting 2D echocardiography in all patients, and CMR in 29. Twenty-five controls with normal echocardiograms were used for comparison. RESULTS: Patients with HCM had a reduced AoSA compared with controls (113°±12 vs 126°±6), p<0.0001. Sixty (38%) patients had provocable LVOTO, with smaller angles than non-obstructive patients (108°±12 vs 116°±12, p<0.0001). AoSA, degree of mitral valvular regurgitation and incomplete systolic anterior motion (SAM) were associated with peak left ventricular outflow tract gradient (r=0.508, p<0.0001). An angle ≤100° had 27% sensitivity, 91% specificity and 59% positive predictive value for predicting provocable LVOTO. When combined with SAM, specificity was 99% and positive predictive value 88%. Intraclass correlation coefficient of AoSA measured by two observers was 0.901 (p<0.0001). Bland-Altman analysis of echocardiographic AoSA showed good agreement with the CMR-derived angle. CONCLUSIONS: Measurement of AoSA using echocardiography in HCM is easy, reproducible and comparable to CMR. Patients with provocable LVOTO have reduced angles compared with non-obstructive patients. AoSA is highly specific for provocable LVOTO and should prompt further evaluation in symptomatic patients without resting obstruction.
ABSTRACT
Takotsubo cardiomyopathy (TTC) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Recent experimental and clinical observation has suggested a role for genetics in the pathogenesis of TTC. Ethnic as well as seasonal variation in the prevalence of TTC is well described, but it is only recently that familial cases of TTC have been reported. In recent years technological advances in exome capture and DNA sequencing have offered clinicians a new opportunity to discover genetics-related disease. This article explores the role of genetic mechanisms that might explain or modulate the pathogenesis of TTC.
Subject(s)
Takotsubo Cardiomyopathy/genetics , Animals , Female , Humans , Mice , Polymorphism, Genetic/genetics , Takotsubo Cardiomyopathy/etiology , Takotsubo Cardiomyopathy/physiopathologySubject(s)
Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Cardiomyopathies/physiopathology , Diagnostic Imaging , Genetic Predisposition to Disease , Genetic Testing , Heart Function Tests , Heredity , Humans , Medical History Taking , Pedigree , Phenotype , Physical Examination , Predictive Value of Tests , PrognosisABSTRACT
Systematic clinical assessment and careful monitoring of patients with hypertrophic cardiomyopathy (HCM) can be used to identify a cohort of patients that benefit from medical intervention and almost certainly improve long-term outcomes. One of the major limitations of the current approach is a lack of predictive power of individual risk factors, which means that many patients receive therapy. The aim of this review is to highlight other aspects of the disease, assessed using old and new medical technologies, that appear to provide new prognostic information. The hope for the future is that their incorporation in new risk algorithms will improve treatment for all HCM patients with the disease, irrespective of their vulnerability to adverse complications.