A rare case of discrete aortic coarctation in Williams-Beuren syndrome. Diagnostic and therapeutic considerations.

Williams-Beuren syndrome (WBS) is a genetic disorder caused by elastin gene deletions, and is characterized by cardiovascular malformations, primarily including supravalvular aortic stenosis and peripheral pulmonary stenosis. We report a case of a neonate who developed severe discrete aortic coarctation, underwent multiple surgical interventions, and was subsequently diagnosed with WBS. Severe discrete aortic coarctation is a rare event in WBS newborns. An abnormally thick aortic wall is present in these patients and is the basis of the failure of the classical approach towards coarctation repair, which consists of end-to-end anastomosis as first surgical choice. Our case, and a very few similar previously documented cases, have all demonstrated recoarctation, which only aortic patch implantation was able to successfully repair. In light of this, we would also like to underline the importance of early WBS diagnosis. Therefore, even in mild syndromic phenotype such as low birth weight or facial dysmorphism that raise the suspicion of a genetic syndrome, it is advisable to perform fluorescent in situ hybridization analysis rather than merely karyotypic one.

Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy.

BACKGROUND: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results. OBJECTIVES: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center. METHODS: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives. RESULTS: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis. CONCLUSIONS: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

Usefulness of cardiac magnetic resonance in assessing the risk of ventricular arrhythmias and sudden death in patients with hypertrophic cardiomyopathy.

AIMS: To assess the relationship between cardiovascular magnetic resonance (CMR) parameters and both spontaneous ventricular tachycardia (VT) and risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) patients. METHODS AND RESULTS: One hundred and eight consecutive HCM patients (mean age 42 +/- 15 years, 76% males) underwent CMR evaluation and risk assessment. Delayed contrast enhancement (DCE) was quantified with a specifically designed score. Endpoints were either the presence of clinical VT/ventricular fibrillation (VF) or of acknowledged risk factors for SCD. Compared to patients without arrhythmia, those with VT/VF (n = 33) had a higher DCE score [median 8 (2-13) vs. 11 (6-20); P = 0.01]; DCE score was also the only independent predictor of VT/VF in the multivariable model. DCE score [median 6 (1-10.5) vs. 12 (6-18); P = 0.001], mean and maximal left ventricular (LV) wall thickness (MaxLVWT), as well as LV mass index were significantly greater among patients at risk for SCD (n = 51) compared with the remaining 57 patients at low risk. DCE score and MaxLVWT were independent predictors of SCD risk. CONCLUSION: In HCM patients several CMR parameters are associated with risk for SCD. A semi-quantitative index of DCE is a significant multivariable predictor of both clinical VT/VF and of risk for SCD and may contribute to risk assessment in borderline or controversial cases.

Long-term left ventricular reverse remodelling with cardiac resynchronization therapy: results from the CARE-HF trial.

AIMS: The aim of the present study was to assess the long-term effects of cardiac resynchronization therapy (CRT) on the reverse remodelling of the left ventricle (LV). METHODS AND RESULTS: The effects of CRT compared with controls on LV dimensions and function were assessed at 3, 9, and 18 months and at the end of study (average 29 months) in 735 (90%) patients with adequate echocardiographic examinations, randomized in the CARE-HF trial. Echocardiographic recordings were submitted to a core laboratory to ensure consistent quantitative analysis. LV volume decreased and ejection fraction increased substantially in the CRT group by 3 months and improved further at each assessment when compared with the control group. Effects were less marked in patients with ischaemic heart disease and those with right ventricular dysfunction, but not in patients with a restrictive LV filling pattern. The extent of reverse remodelling at 18 months showed a modest relationship with baseline interventricular mechanical delay (IVMD). CONCLUSION: CRT induces sustained LV reverse remodelling with the most marked effects occurring within the first 3-9 months. The extent of remodelling in response to CRT is related to the aetiology of heart failure and, to a lesser extent, to the IVMD.

Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects.

BACKGROUND: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. AIMS: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. METHODS AND RESULTS: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and alphaB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. CONCLUSIONS: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.

Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects.

Mutations of the LMNA gene encoding the lamin A and C nuclear envelope proteins cause an autosomal dominant form of dilated cardiomyopathy (DCM) with atrioventricular block (AVB). The aim of this study was to investigate ultrastructural nuclear membrane changes by conventional electron microscopy and protein expression by immuno-electron microscopy in the heart of patients with DCM and AVB due to LMNA gene mutations. Four immunohistochemical techniques were used: pre-embedding and post-embedding in Epon-Araldite resin and London Resin White (LRW), with and without silver enhancement. Parallel light microscopy immunohistochemistry studies were performed. Conventional electron microscopy showed a loss of integrity of the myocyte nuclei with blebs of the nuclear membrane, herniations and delamination of the nuclear lamina and nuclear pore clustering. Post-embedding LRW was the most informative technique for morphology and immuno-labelling. Immuno-labelling was almost absent in the nuclear envelope of patients with LMNA gene mutations, but intensely present in controls. The loss of labelling selectively affected myocyte nuclei; the endothelial cell nuclei were immunostained in patients and controls. Light immunohistochemistry confirmed the results. These findings confirm the hypothesis that LMNA gene defects are associated with a loss of protein expression in the selective compartment of non-cycling myocyte nuclei.

Genetic predisposition to heart failure.

This review describes the numerous and complex molecular systems that are either known players or candidates in heart failure(HF). All systems whose genetic background has been investigated to date in HF are listed and discussed. Discussion also includes functional notes and known genetic polymorphisms already investigated in HF or candidates that have not yet been investigated. Despite substantial research on HF, relatively few coordinated studies have been conducted that assign precise risk to specific genetic polymorphisms. Identification of risk associated with genetic variations and subsequent translation of genetic knowledge into clinical practice will likely progress only in cases of large coordinated studies based on identical standards. The potential result will be a more accurate definition of HF identified as an evolving complex of cardiovascular diseases.

[Genetic diagnosis of familial dilated cardiomyopathy]. / Diagnosi genetica di cardiomiopatia dilatativa familiare.

The definition of familial dilated cardiomyopathy (DCM) is clinically based on the presence, in the same family, of at least two members proven as affected. The prevalence of familial forms is about 25-30%. The approach to define the prevalence of familial diseases and to identify asymptomatic subjects is based on a clinical, non-invasive screening of family members of consecutive index patients. Familial DCM is commonly inherited as autosomal dominant trait; less frequently it is autosomal recessive, X-linked or matrilinear. The disease is clinically and genetically heterogeneous. Genes causally linked to this phenotype include dystrophin, dystrophin-associated glycoproteins, actin, desmin, beta-miosin heavy chain, cardiac troponin T, and mitochondrial DNA genes, mostly transfer RNAs. A peculiar phenotype is DCM associated with atrioventricular block, an autosomal dominant disorder that is causally linked to lamin A/C gene defects in a high proportion of cases. Although the knowledge on molecular genetics of DCM is progressively increasing, at present, the number of molecular diagnoses that can be provided to patients is limited to a few X-linked, autosomal dominant and matrilinear DCMs (overall, about 10% of DCMs). The new clinical approach to familial DCM studies, based on the screening of family members, will bring to the cardiologist's attention both patients and relatives, with extension of the clinical evaluation to subjects who are still healthy. On the other hand, molecular genetists will face a complex molecular field, for both high heterogeneity and poor phenotypical specificity. Therefore, interdisciplinary clinical and research projects are especially needed, hopefully coordinated by scientific societies.

[Diseases associated with lamin A/C gene defects: what the clinical cardiologist ought to know]. / Malattie associate a difetti del gene della lamína A/C: quello che il cardiologo clinico deve sapere.

The nuclear lamina is a proteinaceous layer apposed to the inner nuclear membrane. It is composed of a family of polypeptides, the lamins, highly conserved in evolution. In mammals, 3 lamins, A, B and C have been described with molecular weights ranging from 60,000 to 78,000 Da. Lamins A and C have close sequence homology. Lamins can be classified with the intermediate filament polypeptides and consist of a central rod domain flanked by globular and carboxyl domains. Lamins are synthesized into the cytoplasm: lamins B and C are transported from the cytoplasm into the nucleus and their sequences are not cleaved but remain a permanent feature of the mature polypeptide. Vice versa, lamin A is not synthesized as a large precursor polypeptide. The lamin A/C gene (LMNA) is mapped to 1q21.2-q21.3. Lamins are expressed in a wide range of tissues, including adult heart and skeletal muscle. Naturally occurring mutations in LMNA have been shown to be responsible for distinct diseases called laminopathies, including dilated cardiomyopathy with or without conduction defect and with or without variable skeletal muscle involvement. In the cardiological setting, conduction defects associated with dilated cardiomyopathy are now a reliable marker for LMNA gene molecular screening.

Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure.

BACKGROUND: Reduced pulmonary arterial compliance (Ca) is a marker of poor prognosis in idiopathic pulmonary arterial hypertension. We tested the hypothesis that pulmonary arterial Ca could be a predictor of outcome in patients with chronic heart failure (CHF). METHODS: We enrolled 306 patients with CHF due to systolic left ventricular dysfunction (sLVD) who underwent a clinically driven right-sided heart catheterization. Pulmonary arterial Ca was measured by the ratio between stroke volume and pulse pressure (SV/PP). The primary end point was cardiovascular death; secondary end point was the composite of cardiovascular death, urgent heart transplantation, and appropriately detected and treated episode of ventricular fibrillation. RESULTS: An inverse relationship was observed between SV/PP and pulmonary vascular resistance, the mean resistance-compliance product (RC-time) being 0.30 ± 0.2 s. In patients with pulmonary capillary wedge pressure (PCWP) < 15 mm Hg, the mean RC-time was 0.34 ± 0.14 s, and in patients with PCWP ≥ 15 mm Hg it was 0.28 ± 0.22 s. Eighty-seven patients died in a follow-up period of 50 ± 32 months. At receiver operating characteristic curve analysis, the optimal prognostic cutoff point of SV/PP was 2.15 mL/mm Hg. An elevated (> 2.15) SV/PP was more strongly associated with survival than any other hemodynamic variable; it was associated with poor prognosis both in patients with high (P = .003) and in patients with normal pulmonary vascular resistance (P = .005). CONCLUSIONS: Pulmonary arterial Ca is a strong prognostic indicator in patients with CHF with sLVD. Most importantly, its prognostic role is retained in patients with normal pulmonary vascular resistance.

Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.

OBJECTIVES: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS: In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS: In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. CONCLUSIONS: Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

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.

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.

Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial.

AIMS: The GISSI-HF trial showed that n-3 polyunsaturated fatty acids (PUFA), but not rosuvastatin, reduce morbidity and mortality in patients with symptomatic heart failure (HF) of any cause. The aim of this echocardiographic substudy of GISSI-HF was to investigate the effects of n-3 PUFA and of rosuvastatin on left ventricular (LV) function in such patients. METHODS AND RESULTS: Six hundred and eight chronic HF patients were randomized to n-3 PUFA (n=312) or placebo (n=296); a second randomization was performed to rosuvastatin (n=212) or placebo (n=207). Echocardiographic examinations were recorded at baseline and at 1, 2, and 3 years; offline analysis was performed by a core laboratory to ensure consistent quantitative analysis. Baseline LV ejection fraction (EF) was 30% (95%CI 29-31). Left ventricular ejection fraction increased with n-3 PUFA by 8.1% at 1 year, 11.1% at 2 years, and 11.5% at 3 years vs. 6.3% at 1 year, 8.2% at 2 years, and 9.9% at 3 years in the placebo group (P=0.0050). No other echocardiographic parameter changed significantly. Rosuvastatin effects were not statistically significant. CONCLUSION: n-3 PUFA can provide a small but statistically significant advantage in terms of LV function in patients with symptomatic HF of any aetiology, already treated with recommended therapies.

Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: In patients with idiopathic pulmonary hypertension (IPAH) progression of the disease and survival are related to the capability of the right ventricle to adapt to the chronically elevated pulmonary artery pressure. Although several echocardiographic variables have been associated with outcome in previous studies, a comparative evaluation of all right ventricular (RV) function indices obtainable at echocardiography has never been performed. METHODS: 59 patients consecutively admitted in a tertiary referral centre because of IPAH (22 males, mean age 46.3+/-16.1 years, 68% in WHO class III/IV at referral) underwent right heart catheterization and echocardiography. During a median follow-up period of 52 months, 21 patients died and 2 underwent lung transplantation in emergency conditions. RESULTS: The following parameters were associated with survival: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, degree of tricuspid regurgitation, inferior vena cava collapsibility, superior vena cava flow velocity pattern, left ventricular diastolic eccentricity index. Patients with TAPSEor=1.7 had the highest event rate (51.7 per 100 person year); patients with TAPSE>15 mm and mild or no tricuspid regurgitation had the lowest event rate (2.6 per 100 person year). CONCLUSIONS: A comprehensive echocardiographic assessment of RV systolic and diastolic function based on TAPSE, left ventricular diastolic eccentricity index and degree of tricuspid regurgitation allows an accurate prognostic stratification of patients with IPAH.

Baseline and 6-month B-type natriuretic peptide changes are independent predictors of events in patients with advanced heart failure awaiting cardiac transplantation.

OBJECTIVE: To assess the prognostic role of B-type natriuretic peptide (BNP) measured at baseline and after 6 months in advanced heart failure patients, candidates for heart transplantation. METHODS: Ninety-nine patients with BNP evaluation (mean age 50.8 years, 85% men) were admitted in the heart transplantation waiting list; 39% were in New York Heart Association functional class IV; with hemodynamic patterns of severe heart failure, the cause was ischemic in 45% and idiopathic in 44%. In order to identify more severe patients, BNP values and changes at 6 months were dichotomized according to their upper tertile (>1100 and >or=70 pg/ml, respectively). RESULTS: Median baseline BNP was 719 pg/ml. After a median of 45 months, 40 events were observed (three cardiac assist device implants, 16 urgent heart transplantations, 13 sudden deaths and eight deaths from heart failure). The event rate was 10.0 and 32.3 per 100 person-years in patients with low and high BNP, respectively. In a bivariable Cox regression, BNP at entry in the list and change in BNP at 6 months were independent predictors of events, with hazard ratios of 4.10 (95% confidence interval 2.14-7.88, P<0.001) and 4.55 (95% confidence interval 2.36-8.80, P<0.001), respectively. Furthermore, the risk increased from neither BNP/BNP change, to one of them and to both of them present. CONCLUSION: Both high baseline and further increase in BNP levels during midterm follow-up are strong predictors of events in patients with advanced heart failure awaiting heart transplantation.

Regional abnormalities of myocardial deformation in patients with hypertrophic cardiomyopathy: correlations with delayed enhancement in cardiac magnetic resonance.

AIMS: Hypertrophic cardiomyopathy (HCM) is a genetic disease histologically characterized by a profound disarray of myocardial fibres and by local fibrosis. We sought to characterize regional left ventricular contractility in HCM patients using deformation analysis and to compare it with the presence or absence of delayed enhancement in cardiac magnetic resonance (CMR). METHODS AND RESULTS: We studied 58 HCM patients (mean age 41 years, 37 male). The control population comprised 15 normal subjects. Colour tissue-Doppler imaging was acquired in two-dimensional mode from apical four-chamber and two-chamber views; off-line analysis was performed in four basal and four middle left ventricular segments. Gadolinium-enhanced CMR was performed in 36 HCM patients. In HCM patients, peak systolic strain was not uniform across left ventricular segments; differences were not related to site or thickness of the segment analysed. Paradoxically, positive systolic strain values were measured in six middle segments. Delayed CMR enhancement was associated with lower peak systolic strain (P = 0.007). Regional non-uniformities in peak systolic strain were not observed in normal subjects. CONCLUSION: Areas of reduced left ventricular contractility in deformation analysis are associated with delayed CMR enhancement in patients with HCM.

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-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-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 > or =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-beta, 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 beta-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.