589 External validation of the increased wall thickness score for the diagnosis of cardiac amyloidosis

Abstract Aims This study aimed to validate the increased wall thickness (IWT) score, a multiparametric echocardiographic score to facilitate diagnosis of cardiac amyloidosis (CA), in an independent population of patients with increased LV wall thickness suspicious for CA. Methods and results Between January 2019 and December 2020, 152 consecutive patients with increased LV wall thickness suspicious for CA were included. For all patient, the multiparametric echocardiographic score (IWT score) was calculated. To validate the diagnostic accuracy of an IWT score ≥8 to predict the diagnosis of CA, sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy (PA) were calculated. Among the 152 patients included in the study, 50 (33%) were diagnosed as CA, 25 (16%) had severe aortic stenosis, 25 (16%) had hypertensive remodelling, and 52 (34%) had hypertrophic cardiomyopathy. Among the 50 and 102 patients with and without CA, 19 (38%) and 1 (1%) showed an IWT score ≥8, respectively. Overall, the diagnostic accuracy of an IWT score ≥8 for the diagnosis of CA in our population was the following: Se 38% (95% CI: 25–53%); Sp 99% (95% CI: 95–100%); PPV 95% (95% CI: 72–99%); NPV 77% (95% CI: 73–80%); PA 79% (95% CI: 72–85%). Conclusions This study reports the first external validation of the IWT score for the diagnosis of CA in patients with increased LV wall thickness. A score ≥8 showed a high Sp, PPV and PA, suggesting that the IWT score can be used to identify CA patients in those with increased LV wall thickness

Multimodality Imaging in Cardiomyopathies with Hypertrophic Phenotypes

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM

Clinical and Molecular Characteristics of Patients with PLN R14del Cardiomyopathy: State-of-the-Art Review

The deletion of the arginine 14 codon (R14del) in the phospholamban (PLN) gene is a rare cause of arrhythmogenic cardiomyopathy (ACM) and is associated with prevalent ventricular arrhythmias, heart failure, and sudden cardiac death. The pathophysiological mechanism which culminates in the ACM phenotype is multifactorial and mainly based on the alteration of the endoplasmic reticulum proteostasis, mitochondrial dysfunction and compromised Ca2+ cytosolic homeostasis. The symptoms of this condition are usually non-specific and consist of arrhythmia-related or heart failure-related manifestation; however, some peculiar diagnostic clues were detected, such as the T-wave inversion in the lateral leads, low QRS complexes voltages, mid-wall or epicardial fibrosis of the inferolateral wall of the left ventricle, and their presence should raise the suspicion of this condition. The risk stratification for sudden cardiac death is mandatory and several predictors were identified in recent years. However, the management of affected patients is often challenging due to the absence of specific prediction tools and therapies. This review aims to provide the current state of the art of PLN R14del cardiomyopathy, focusing on its pathophysiology, clinical manifestation, risk stratification for sudden cardiac death, and management

Medical treatment of patients with hypertrophic cardiomyopathy: An overview of current and emerging therapy

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 therapeutical approaches, including sarcomere modulators and gene therapy. A sarcomere modulator - mavacamten - has been shown to improve exercise capacity, left ventricular outflow tract obstruction, New York Heart Association functional class and health status in a phase 3 trial. Gene therapy - although still far from human experimentation - also has promising characteristics that may radically revolutionize the treatment of hypertrophic cardiomyopathy in the future. This therapy is currently approved for the treatment of select haematological malignancies, inherited retinal dystrophy and spinal muscular atrophy, and could potentially correct the genetic alterations of the most frequent sarcomeric forms of hypertrophic cardiomyopathy. This review provides an overview of current conventional therapies for the management of patients with hypertrophic cardiomyopathy, discusses emerging therapeutic approaches and presents future perspectives

Clinical and Molecular Characteristics of Patients with PLN R14del Cardiomyopathy: State-of-the-Art Review

The deletion of the arginine 14 codon (R14del) in the phospholamban (PLN) gene is a rare cause of arrhythmogenic cardiomyopathy (ACM) and is associated with prevalent ventricular arrhythmias, heart failure, and sudden cardiac death. The pathophysiological mechanism which culminates in the ACM phenotype is multifactorial and mainly based on the alteration of the endoplasmic reticulum proteostasis, mitochondrial dysfunction and compromised Ca2+ cytosolic homeostasis. The symptoms of this condition are usually non-specific and consist of arrhythmia-related or heart failure-related manifestation; however, some peculiar diagnostic clues were detected, such as the T-wave inversion in the lateral leads, low QRS complexes voltages, mid-wall or epicardial fibrosis of the inferolateral wall of the left ventricle, and their presence should raise the suspicion of this condition. The risk stratification for sudden cardiac death is mandatory and several predictors were identified in recent years. However, the management of affected patients is often challenging due to the absence of specific prediction tools and therapies. This review aims to provide the current state of the art of PLN R14del cardiomyopathy, focusing on its pathophysiology, clinical manifestation, risk stratification for sudden cardiac death, and management

Modified Body Mass Index as a Novel Nutritional and Prognostic Marker in Patients with Cardiac Amyloidosis

The nutritional assessment is gaining clinical relevance since cardiac cachexia and malnutrition are emerging as novel markers of functional status and prognosis in many cardiovascular disorders, including cardiac amyloidosis (CA). This study aimed to evaluate the prognostic role of different nutritional indices for cardiovascular mortality in patients with CA and subgroups. Fifty CA patients (26 AL and 24 ATTR wild-type) were retrospectively analyzed. All patients underwent a comprehensive clinical and laboratory evaluation. Conventional body mass index (cBMI), modified BMI (mBMI), new BMI (nBMI) and prognostic nutritional index (PNI) were analyzed. Multivariate regression analysis was performed to identify the association between nutritional and other clinical-laboratory parameters with cardiovascular death. Compared to ATTRwt patients, those with AL showed lower mBMI values. No significant difference was observed for the other nutritional indices. During a median follow-up of 11.2 months, a lower mBMI quartile was associated with worse survival, in both groups. In multivariate analysis, mBMI emerged as an independent predictor for cardiovascular death. This study showed that mBMI is a novel index of malnutrition and an independent risk factor for cardiovascular mortality in patients with CA in both AL and ATTRwt form

Diagnosis of Fabry Disease in a Patient with a Surgically Repaired Congenital Heart Defect: When Clinical History and Genetics Make the Difference

Fabry disease (FD) is a multiorgan disease, which can potentially affect any organ or tissue, with the heart, kidneys, and central nervous system representing the major disease targets. FD can be suspected based on the presence of specific red flags, and the subsequent evaluation of the α-Gal A activity and GLA sequencing, are required to confirm the diagnosis, to evaluate the presence of amenable GLA mutation, and to perform a cascade program screening in family members. An early diagnosis is required to start an etiological treatment and to prevent irreversible organ damage. Here, we describe a case of a 37-years-old patient, with a surgically repaired congenital heart defect in his childhood, who had a late diagnosis of FD based on the clinical history and targeted genetic evaluation. This case highlights the importance to perform a correct phenotyping and definite diagnosis of FD, to start an early and appropriate treatment in the index patient, and a cascade clinical and genetic screening to identify other family members at risk, which may benefit from specific treatment and/or a close follow-up

Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation

Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib

Diagnosis and Management of Rare Cardiomyopathies in Adult and Paediatric Patients. A Position Paper of the Italian Society of Cardiology (SIC) and Italian Society of Paediatric Cardiology (SICP)

Cardiomyopathies (CMPs) are myocardial diseases in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality. Thought for a long time to be rare diseases, it is now clear that most of the CMPs can be easily observed in clinical practice. However, there is a group of specific heart muscle diseases that are rare in nature whose clinical/echocardiographic phenotypes resemble those of the four classical morphological subgroups of hypertrophic, dilated, restrictive, arrhythmogenic CMPs. These rare CMPs, often but not solely diagnosed in infants and paediatric patients, should be more properly labelled as specific CMPs. Emerging consensus exists that these conditions require tailored investigation and management. Indeed, an appropriate understanding of these conditions is mandatory for early treatment and counselling. At present, however, the multisystemic and heterogeneous presentation of these entities is a challenge for clinicians, and time delay in diagnosis is a significant concern. The aim of this paper is to define practical recommendations for diagnosis and management of the rare CMPs in paediatric or adult age. A modified Delphi method was adopted to grade the recommendations proposed by each member of the writing committee

Cardiovascular involvement in mtDNA disease: diagnosis, management, and therapeutic options

: Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations