Valentina Favalli

Long-Term Outcome and Risk Stratification in Dilated Cardiolaminopathies

OBJECTIVES The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies. BACKGROUND Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases. METHODS Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype. RESULTS Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for >or=10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death. CONCLUSIONS Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

The MOGE(S) Classification for a Phenotype–Genotype Nomenclature of Cardiomyopathy: Endorsed by the World Heart Federation

In 1956, Blankerhorn and Gall (1) proposed the term myocarditis for inflammatory heart muscle disease, and myocardiosis for other heart muscle diseases. A year thereafter, Brigden (2) defined cardiomyopathies as uncommon, non-coronary heart muscle diseases. Subsequently, Goodwin and Oakley (3) defined cardiomyopathies as myocardial diseases of unknown origin, and proposed categorization of the disorders as dilated (DCM), hypertrophic (HCM), and restrictive (or obliterative) (RCM) cardiomyopathies. In 1980, the World Health Organization (WHO) and International Society and Federation of Cardiology (ISFC) established the definition of cardiomyopathies as myocardial diseases of unknown etiology, reflecting the general lack of information about the mechanism(s) of disease (4). Although WHO-ISFC retained the 3 morphological types of cardiomyopathies proposed by Goodwin and Oakley, it also introduced the term specific heart muscle disease, where the cause of myocardial dysfunction was known. The WHO-ISFC classification subsequently expanded the definition of cardiomyopathies by adding the functional component and defined cardiomyopathy as the diseases of myocardium associated with myocardial dysfunction. Two additional classes, arrhythmogenic right ventricular cardiomyopathy (ARVC) and unclassified cardiomyopathy, were introduced during the revision, and the category of the specific heart muscle disease was excluded (5). The ISFC changed its name to the World Heart Federation (WHF) in 1998 (6), and did not indulge in further revision of the recommendations for either diagnosis or management of cardiomyopathies. A substantial increase in the knowledge of the genetic basis of cardiomyopathy has occurred, and noninvasive phenotypic characterization has become significantly more sophisticated. Therefore, the American Heart Association (AHA) (7) and the European Society of Cardiology (ESC) (8) in the last decade have proposed revisions to the classification of cardiomyopathic disorders. Whereas both systems have substantial similarities and have made important recommendations, the former has described cardiomyopathies starting from the genetic basis of the etiology followed by the phenotypic description of myocardial involvement. Conversely, the ESC has retained the description in original morphofunctional categories with further subclassification into genetic (familial) and nongenetic (nonfamilial) groups. Both classifications continue to exclude specific heart muscle disease (resulting from coronary, hypertensive, valvular, and congenital heart disease) from consideration as a cardiomyopathic disorder. There is no denying the fact that most cardiomyopathies are genetic diseases, which in the real life are brought to clinical attention (and diagnosed and managed) based on a phenotypic diagnosis. More than 60 disease genes have been identified to date (9); genes such as MYBPC3 may be associated with different phenotypes (HCM, RCM, DCM), and genes such as DYS may cause a unique phenotype (DCM only). The penetrance of the genetic mutation is variable, and phenotypic manifestations are often age dependent. Most genetic cardiomyopathies are inherited as autosomal dominant traits, with a minority of families demonstrating autosomal recessive, X-linked recessive or dominant (rare), and matrilineal inheritance. Cascade family screening and follow-up have become mandatory (10). It has become necessary for a more descriptive nosology to be developed that may encompass either all attributes of the individual patient cardiomyopathy or allow a common platform for collaborative research efforts. A number of experts, including clinical cardiologists, heart failure–transplantation physicians, geneticists, and cardiovascular imagers, have proposed a systematic nomenclature endorsed by the WHF Scientific Committee. The proposed classification is a descriptive presentation of the cardiomyopathic process, which is flexibly modifiable and expandable. This nosology is inspired from the TNM staging of tumors and is being simultaneously published by the Journal of the American College of Cardiology and the official journal of the WHF, Global Heart.

Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations.

Background The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-β (TGF-β), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-β blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-β effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. β-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation β-adrenergic blocker nebivolol retains the β-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS. Methods The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score ≥2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-β, quantitative assessment of the expression of the mutated gene (FBN1, both 5′ and 3′), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48. Conclusion The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding β-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

The MOGE(S) Classification of Cardiomyopathy for Clinicians

Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries.

Diagnostic work-up and risk stratification in X-linked dilated cardiomyopathies caused by dystrophin defects.

OBJECTIVES We sought to describe the diagnostic work-up, phenotype, and long-term evolution of dilated cardiomyopathy (DCM) associated with Dystrophin (DYS) defects. BACKGROUND X-linked DCM associated with DYS defects can be clinically indistinguishable from other types of DCM. METHODS The series comprises 436 consecutive male patients diagnosed with DCM. Patients underwent endomyocardial biopsy (EMB). Genetic testing employed multiplex polymerase chain reaction and multiple ligation dependent probe assay for deletions and direct sequencing of the 79 exons and flanking regions of the gene for point mutations or small rearrangements. RESULTS We identified DYS defects in 34 of 436 patients (7.8%) (onset age 34 ± 11 years, age range 17 to 54 years); 30 had proven X-linked inheritance. The 2 phenotypes included DCM with mild skeletal myopathy and/or increased serum creatine phosphokinase (n = 28) or DCM only (n = 6). The EMB showed defective dystrophin immunostain. The DYS defects consisted of 21 in-frame deletions and 11 out-of-frame deletions as well as 1 stop and 1 splice-site mutation. During a median follow-up of 60 months (interquartile range: 11.25 to 101.34 months) we observed 17 events, all related to heart failure (HF) (median event-free survival: 83.5 months). Eight patients (23%) underwent transplantation, and 9 (26%) died of HF while waiting for transplantation. Eight patients received an implantable cardioverter-defibrillator, although none had device intervention during a median follow-up of 14 months (interquartile range: 5 to 25 months). No patient died suddenly, suffered syncope, or developed life-threatening ventricular arrhythmias. CONCLUSIONS DYS-related DCM should be suspected in male patients with increased serum creatine phosphokinase (82%) and X-linked inheritance. The disease shows a high risk of end-stage HF but a lower risk of life-threatening arrhythmias.

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)

Objective To evaluate the prevalence and phenotype of smooth muscle alpha-actin (ACTA2) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD). Design Observational study of ACTA2 mutations in TAAD. Setting Centre for Inherited Cardiovascular Diseases. Patients A consecutive series of 100 patients with TAAD. Exclusion criteria included genetically confirmed Marfan syndrome, Loeys–Dietz type 2, familial bicuspid aortic valve and Ehlers–Danlos type IV syndromes. Interventions Multidisciplinary clinical and imaging evaluation, genetic counselling and testing of ACTA2, and family screening. Main outcome measures Prevalence of ACTA2 mutations and corresponding phenotypes. Results TAAD was familial in 43 cases and sporadic in 57 cases. Five mutations in the familial TAAD group (12%) were identified that were absent in controls. The known p.Arg149Cys and the novel p.Asp82Glu, p.Glu243Lys and p.Val45Leu mutations affected evolutionarily conserved residues. The IVS4+1G>A mutation was novel. Of 14 affected relatives, 13 were carriers of the mutation identified in the corresponding proband while one deceased relative had no genetic test. Type A dissection was the first manifestation of aortic aneurysm in four probands and occurred unexpectedly in five relatives. The aortic aneurysm was age dependent and absent in mutated children. Of nine patients who had acute dissection, five died following surgery. At dissection, the size of the aortic aneurysm ranged from 40 mm to 95 mm. Extravascular, ocular, skeletal, nervous and pulmonary traits were variably associated with TAAD, with iris flocculi being most common. Conclusions Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections.

Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

Background—Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. Methods and Results—We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Conclusions—Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

The need to modify patient selection to improve the benefits of implantable cardioverter-defibrillator for primary prevention of sudden death in non-ischaemic dilated cardiomyopathy

Left ventricular ejection fraction (LVEF) ≤35% is a major determinant for implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death (SD) in patients with non-ischaemic dilated cardiomyopathy (DCM). However, as a risk marker for SD, low LVEF has limited sensibility and specificity. Selecting patients according to the current guidelines shows that most DCM patients do not actually benefit from ICD implantation and may suffer collateral effects and that many patients who are at risk of SD are not identified because a large proportion of SD patients exhibit only mildly depressed LVEF. Identifying patients who are at risk of SD on the sole basis of LVEF appears to be an over-simplification which does not maximize the benefit of ICD therapy. Owing to the complexity of the substrates underlying SD, multiple risk factors used in combination could probably predict the risk of SD better than any individual risk marker. Among non-invasive tests, microvolt T-wave alternans and cardiac magnetic resonance with late gadolinium enhancement may contribute to a better SD risk stratification by their high negative predictive value. Genetics may further contribute because approximately one-third of DCM patients have evidence of familial disease, and mutations in some known disease genes, including LMNA, have been associated with a high risk of SD. In this review, we critically analyse the current indications for ICD implantation and we explore existing knowledge about potentially predicting markers for selecting DCM patients who are at high and low risk of SD.

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies.

Dilated cardiomyopathy (DCM) is a condition whereby the normal muscular function of the myocardium is altered by specific or multiple aetiologies. About 25-35% of DCM patients show familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins. Most of the DCM-related mutations fall in the Lamin AC gene, in particular in the Coil2B domain of the encoded protein. In this context, we focussed our studies on the crystal structures of two lamin Coil2B domain mutants (R335W and E347K). Both R335 and E347 are higly conserved residues whose substitution has little effects on the Coil2B domain three-dimensional structure; we can thus hypothesize that the mutations may interfere with the binding of components within the nuclear lamina, or of nuclear factors, that have been proposed to interact/associate with lamin A/C.

Aortic root 3D parametric morphological model from 2D-echo images

The gold standard for the study of the macro-anatomy of the aortic root are multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging. Both technologies have major advantages and limitations. Although 4D echo is entering the study of the aortic root, 2D echo is the most commonly used diagnostic tool in daily practice. We designed and developed an algorithm for 3D modeling of the aortic root based on measures taken routinely at 2D echocardiography from 20 healthy individuals with normal aortic root. The tool was then translated in 12 patients who underwent both echo and MDCT. The results obtained with the 3D modeling program were quantitatively and qualitatively compared with 3D reconstruction from MDCT. Ad hoc ratios describing the morphology of the aortic root in MDCT and in the 3D model were used for comparison. In 12 patients with aortic root dilatation, the ratios obtained with our model are in good agreement with those from MDCT. Linear correlation for both long axis and short axis ratios was strong. The 3D modeling software can be easily adopted by cardiologists routinely involved in clinical evaluation of the pathology of the aortic root. The tool is easy to apply, does not require additional costs, and may be used to generate a set of data images for monitoring the evolution of the morphology and dimension of the aortic root, flanking the 3D MDCT and MR that remain the gold standard tools.