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Publications (80)
Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere stru...
Introduction: Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by unexplained left ventricular (LV) hypertrophy (LVH). Genetic family screening of probands identifies mutation carriers (Gen+) without phenotype (Phen-), who require clinical follow-up.
Hypothesis: Identification of early phenotype signs may facilitate clinical...
Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomeric mutations which may affect myocardial mechano-energetic efficiency (MEE). We investigated the effects of sarcomeric mutations on MEE. A non-invasive pressure/volume (P/V) analysis was performed. We included 49 genetically screened HCM patients. MEEi was calculated as the ratio between...
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is identified in genes encoding sarcomere proteins....
Hypertrophic cardiomyopathy (HCM) is a genetic disease with heterogeneous clinical presentation and prognosis. Within the broad phenotypic expression of HCM, there is a subgroup of patients with a left ventricular (LV) apical aneurysm, which has an estimated prevalence between 2% and 5%. LV apical aneurysm is characterized by an area of apical dysk...
Left ventricular outflow obstruction (LVOTO) and diastolic dysfunction are the main pathophysiological characteristics of hypertrophic cardiomyopathy (HCM)LVOTO, may be identified in more than half of HCM patients and represents an important determinant of symptoms and a predictor of worse prognosis. This review aims to clarify the LVOTO mechanism...
The diffusion of Next Generation Sequencing (NGS)-based approaches has allowed the identification of cardiomyopathies and channelopathies pathogenic mutations in more than 200 different genes. Since also genes considered uncommon for a clinical phenotype are now included in molecular testing, the detection rate of disease-causing variants is increa...
Background: Mutations in Four and Half Lim domain 1 ( FHL1 ), an X-chromosome gene, have been described in rare cases of Hypertrophic Cardiomyopathy (HCM), mainly associated with myopathy. The current knowledge of the outcome of HCM caused by FHL1 mutations relies only on isolated case series.
Objective: We aim to establish the prevalence of FHL1 m...
The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has inc...
Background
Hypertrophic Cardiomyopathy (HCM) is mainly caused by sarcomeric mutations. In about 40% of cases the causal mutation is unknown. Myocardial mechano-energetic efficiency per unit of left ventricular (LV) mass (MEEi) is an echocardiographic parameter of LV pump performance. Sarcomeric mutations may affect energy efficiency.
Purpose
We in...
Background
Only one score for prediction of new-onset atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) has been developed in North America (HCM-AF North America score).
Purpose
To develop a new score (HCM-AF South Italy score) in an Italian derivation cohort and to test the new score with that from North America, in an I...
Background
Hereditary transthyretin (ATTRv) amyloidosis is a rare, autosomal dominant, and devastating disease. If untreated, the disease is fatal within 4–15 years from onset.
Thus, diagnosis in the early stages of ATTRv amyloidosis is crucial to start treatment and to prevent or delay disease progression. However, the diagnosis of symptomatic ATT...
Several treatments have demonstrated safety and effectiveness in the treatment of patients with hypertrophic cardiomyopathy; however, no drug has been shown to modify the natural history of the disease or to decrease maximal wall thickness. Improvement in our knowledge of the physiopathology of the disease has permitted the development of new thera...
Introduction: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed i...
FLNC truncating mutations (FLNCtv) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-C...
FLNC truncating mutations ( FLNCtv ) are prevalent causes of inherited dilated cardiomyopathy (DCM). Notably, carriers of truncating mutations in FLNC are at high risk of developing arrhythmogenic cardiomyopathy (ACM). We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific in...
This editorial aims to summarize the eight scientific papers published in the Special Issue “Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies” [...]
Aims
Arrhythmogenic cardiomyopathy (ACM) encompasses a genetically heterogeneous group of myocardial diseases whose manifestations are sudden cardiac death, cardiac arrhythmias, heart failure, and in a subset fibro-adipogenic infiltration of the myocardium. Mutations in the TMEM43 gene, encoding transmembrane protein 43 (TMEM43) are known to cause...
Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies ha...
Background
Mutations in the LMNA gene, encoding LMNA (lamin A/C), causes distinct disorders, including dilated cardiomyopathies, collectively referred to as laminopathies. The genes (coding and noncoding) and regulatory pathways controlled by LMNA in the heart are not completely defined.
Methods and Results
We analyzed cardiac transcriptome from w...
Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease characterized by fibrotic or fibrofatty myocardial replacement, associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Originally described as a disease of the right ventricle, ACM is currently recognized as a biventricular entity, due to the increasi...
We aim to validate echocardiographic left ventricular (LV) mass (echoLVM) in sixty-one patients with hypertrophic cardiomyopathy (HCM), using cardiac magnetic resonance measures (cmrLVM) as gold standard. cmrLVM was calculated using LV short-axis images, from base to apex, whereas echoLVM by LV epicardial minus LV endocardial volumes in 4 and 2 cha...
Background: Mutations in genes encoding intercalated disk/desmosome proteins, such as plakophilin 2 (PKP2), cause arrhythmogenic cardiomyopathy (ACM). Desmosomes are responsible for myocyte–myocyte attachment and maintaining mechanical integrity of the myocardium. Methods: We knocked down Pkp2 in HL-1 mouse atrial cardiomyocytes (HL-1Pkp2-shRNA) an...
Rationale:
Mutations in the LMNA gene, encoding lamin A/C (LMNA), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies.
Objective:
To gain insights into the molecular pathogenesis of DCM in laminopathies.
Methods and results:
We generated a tet-off bigenic mice expressing...
Lamin A/C (LMNA) is a major component of the nuclear membrane, involved in regulation of gene expression. Mutations in the LMNA gene cause a heterogeneous group of diseases, collectively referred to as laminopathies. Cardiac involvement is one of the most prominent feature of the laminopathies, presenting with dilated cardiomyopathy (DCM), conducti...
Rationale:
Mutations in theLMNAgene, encoding nuclear inner membrane protein lamin A/C, cause distinct phenotypes, collectively referred to as laminopathies. Heart failure, conduction defects, and arrhythmias are the common causes of death in laminopathies.
Objective:
The objective of this study was to identify and therapeutically target the res...
Rationale:
Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for...
Rationale:
PKP2, encoding plakophilin 2 (PKP2), is the most common causal gene for arrhythmogenic cardiomyopathy (AC).
Objective:
To characterize miRNAs expression profile in PKP2-deficient cells.
Methods and results:
Control and PKP2-knock down HL-1 (HL-1(Pkp2-shRNA)) cells were screened for 750 miRNAs using low-density microfluidic panels. F...
Rationale:
Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibro-adipocytes. Cellular origin(s) of fibro-adipocytes in AC is unknown.
Objective:
To identify the cellular origin of adipocytes in AC.
Methods and results:
Human and mouse cardiac cells were depleted from myocyt...
Introduction: A phenotypic characteristic of arrhythmogenic cardiomyopathy (AC) is a gradual replacement of cardiac myocytes by fibro-adipocytes, which leads to cardiac arrhythmias, dysfunction and sudden death.
Hypothesis: Differentially expressed miRNAs contribute to the pathogenesis of AC
Results: Control and plakophilin-2 (PKP2)-suppressed HL-1...
Arrhythmogenic cardiomyopathy (AC) is clinically characterized by arrhythmias, heart failure and sudden death and pathologically by replacement of cardiomyocytes by fibro-adipocytes. Mutations in desmosome genes are the main causes of AC. Desmosome proteins are known to be expressed only in cardiac myocytes. Cardiac progenitor cells (CPCs) expressi...
Introduction: Peak oxygen consumption (VO 2 ) has a strong and independent prognostic value in systolic heart failure; in contrast no data support its prognostic role in hypertrophic cardiomyopathy (HCM).
Hypothesis: We assess if peak VO 2 is a long-term predictor of outcome in HCM.
Methods: We studied 92 HCM patients (40±15 years). Peak VO 2 was e...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by excess fibro-adipocytes in the heart, cardiac arrhythmias and heart failure. Molecular genetic studies have identified mutations in several desmosome proteins as causes of ARVC. Our objective is to delineate the molecular links between the desmosomes and...
Mutations in the intercalated disc (ID) proteins, such as plakophilin 2 (PKP2) cause arrhythmogenic cardiomyopathy (AC). AC is characterized by the replacement of cardiac myocytes by fibro-adipocytes, cardiac dysfunction, arrhythmias and sudden death.
To delineate the molecular pathogenesis of AC.
Localization and levels of selected ID proteins inc...
Worldwide left ventricular (LV) twist is measured by 2D speckle tracking acquiring apical short axis at a LV level where papillary muscles are no longer visible; however, we hypothesized that this methodological recommendation is not enough accurate to obtain a reliable measurement of apical rotation.
We measured twist and untwist rate in 30 health...
Rationale: A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the Ubiquitin-Proteasome System (UPS).
Objectives: To determine the pathogenic r...
Aims:
The role of calcineurin protein phosphatase 2B (PP2B) in the pathogenesis of human hypertrophic cardiomyopathy (HCM) remains unsettled. We determined potential involvement of calcineurin in the pathogenesis of HCM caused by mutations in myozenin 2 (MYOZ2), an inhibitor of calcineurin.
Methods and results:
We generated multiple lines of tra...
Rationale:
A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS).
Objective:
To determine the pathogenic...
Aortic stenosis and mitral regurgitation, patent foramen ovale, interatrial septal defect, atrial fibrillation and perivalvular leak, are now amenable to percutaneous treatment. These percutaneous procedures require the use of Transthoracic (TTE), Transesophageal (TEE) and/or Intracardiac echocardiography (ICE). This paper provides an overview of t...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease of desmosome proteins characterized by fibroadipogenesis in the myocardium. We have implicated signaling properties of junction protein plakoglobin (PG) in the pathogenesis of ARVC.
To delineate the pathogenic role of PG in adipogenesis in ARVC.
We generated mice overexpressing PG,...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by fibro-fatty infiltration of the myocardium, particularly in the right ventricle. Molecular basis of adipocytic replacement of cardiac myocyte is not fully known. We have implicated suppression of the canonical Wnt signaling in the second heart field card...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon cardiomyopathy characterized by fibroadiposis replacing cardiac myocytes, predominantly in the right ventricle. The clinical phenotype is characterized by cardiac arrhythmias, sudden cardiac death, and heart failure. The molecular genetic basis of ARVC is partially known. Mutatio...
Metabolomics, the comprehensive profile of small-molecule metabolites found in biological specimens, has the potential to provide insights into the pathogenesis of disease states and lead to the identification of new biomarkers. Methods and
We analysed 451 plasma metabolites by liquid chromatography/mass spectroscopy and gas chromatography/mass spe...
Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy is a major determinant of risk of sudden death and morbidity in HCM. Treatment with statins reverses hypertrophy in animal models of HCM. Thus, statins may afford therapeutic benefits in HCM.
We performed a feasibility study with atorvastatin to gath...
To review recent developments in clinical aspects, molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC).
ARVC is a primary disease of the myocardium characterized by fibro-adipocytic replacement of myocytes, predominantly in the right ventricle. Phenotypic expression of ARVC is variable and a significant num...
Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and se...
List of Candidate Genes and Putative Functional SNPs.
The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage t...
Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are impli...
The pathological hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic disease of desmosomal proteins, is fibro-adipocytic replacement of cardiac myocytes. The cellular origin of adipocytes in ARVC is an enigma. In desmosomal ARVC the impetus has to instigate from cells that express the mutant protein. Cardiac myocytes are t...
Identification of myozenin-2 mutations (MYOZ2) has expanded the spectrum of causal mutations for hypertrophic cardiomyopathy (HCM) to include the Z disk proteins. The molecular mechanism(s) by which MYOZ2 mutations cause HCM are unknown. MYOZ2 is known to inhibit calcineurin phosphatase (PP2B). We posit mutant MYOZ2 lose their inhibitory effects on...
Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the...
Human hypertrophic cardiomyopathy, characterized by cardiac hypertrophy and myocyte disarray, is the most common cause of sudden cardiac death in the young. Hypertrophic cardiomyopathy is often caused by mutations in sarcomeric genes. We sought to determine arrhythmia propensity and underlying mechanisms contributing to arrhythmia in a transgenic (...
This study was conceived to assess associations between integrated backscatter signal at end diastole (IBS) and diastolic properties in patients with hypertrophic cardiomyopathy.
In 46 patients with hypertrophic cardiomyopathy, septal IBS was calculated by both applying an appropriate regression correction (IBSc) and by relating it to pericardial r...
Abnormal blood-pressure response during exercise occurs in about one third of patients with hypertrophic cardiomyopathy (HCM), and it has been associated with a high risk of sudden cardiac death. We assessed the hemodynamics of exercise in HCM patients with abnormal blood-pressure response by using ambulatory radionuclide monitoring (VEST) of left-...
Hypertrophic cardiomyopathy (HCM) is a disease of mutant sarcomeric proteins (except for phenocopy). Cardiac hypertrophy is the clinical diagnostic hallmark of HCM and a major determinant of morbidity and mortality in various cardiovascular diseases. However, there is remarkable variability in expression of hypertrophy, even among HCM patients with...
Active diastolePassive diastoleConclusions
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrop...
Background.
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric LV hypertrophy (LVH) and impairment in diastolic function. We assess the relationship between LVH and invasive indexes of diastolic function.
Methods.
21 HCM patients underwent cardiac catheterization to assess pulmonary capillary wedge pressure, LV end-diastolic pressure...
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA agai...
The objective was to determine the effects of antioxidant N-acetylcysteine (NAC) on reversal and attenuation of established interstitial fibrosis in the cardiac troponin T (cTnT) mouse model of human hypertrophic cardiomyopathy (HCM) mutation.
Interstitial fibrosis is a characteristic pathological feature of HCM and a risk factor for sudden cardiac...
Predictors of the development of atrial fibrillation (AF) in patients who have hypertrophic cardiomyopathy (HC) have not been extensively studied, although, in these patients, AF contributes to the exacerbation of symptoms and the development of heart failure. The present study determined the role of left atrial (LA) function in the development of...
Myocardial interstitial fibrosis is a characteristic of hypertrophic cardiomyopathy (HCM). This study evaluates the collagen turnover in HCM and its impact on left ventricular (LV) diastolic function.
Thirty-six HCM patients and 14 sex- and age-matched controls were studied. Collagen turnover was assessed as follows. By radioimmunoassay, a byproduc...
Hypertrophic cardiomyopathy is an autosomal dominant disease characterized by asymmetrical left ventricular hypertrophy, myocyte disarray, interstitial fibrosis, and small vessel disease. More than 100 mutations in 10 genes, all encoding for sarcomeric proteins, have been identified as responsible for this disease. While the etiology of hypertrophi...
We assessed the hemodynamic effects of isometric exercise by an ambulatory radionuclide monitoring device (VEST) that measured left ventricular function in patients who had hypertrophic cardiomyopathy (HCM), with and without significant left ventricular outflow-tract obstruction at rest, compared with control subjects.
We studied 10 patients with o...
Myocardial ischemia in the absence of coronary artery disease is common in patients with hypertrophic cardiomyopathy (HCM). Dobutamine stress echocardiography (DSE) induces left ventricular (LV) new wall motion abnormalities (NWMA) in some patients with HCM. We evaluated the effects of dobutamine on LV performance and hemodynamics in HCM.
Eighteen...
We sought to assess the hemodynamics of exercise in patients with hypertrophic cardiomyopathy (HCM), with and without an exercise-induced abnormal blood pressure (BP) response, by ambulatory radionuclide monitoring of left ventricular (LV) function with the VEST device (Capintec Inc., Ramsey, New Jersey).
Blood pressure fails to increase >20 mm Hg...
This study was designed to investigate whether, in patients with hypertrophic cardiomyopathy (HC), tilt-induced volume unloading triggers a peripheral reflex similar to that seen in patients with a history of vasovagal syncope or rather acts through an intrinsic cardiac mechanism secondary to diastolic dysfunction. Thirty-seven patients with HC (10...
The term hypertrophic cardiomyopathy is used to describe an autosomal dominant cardiac disorder, characterized by myocyte hypertrophy and disarray, interstitial fibrosis and small vessel disease, with or without macroscopic hypertrophy. More than 100 mutations in ten genes, all encoding sarcomeric proteins, have been identified as responsible for t...
Some studies have demonstrated that left ventricular (LV) diastolic function is the principal determinant of impaired exercise capacity in hypertrophic cardiomyopathy (HC). In this study we sought the capability of echocardiographic indexes of diastolic function in predicting exercise capacity in patients with HC. We studied 52 patients with HC whi...
