Iacopo Olivotto

• Azienda Ospedaliero Universitaria Careggi

Background Cardiac myosin inhibitors were recently developed to address the underlying pathophysiology of hypertrophic cardiomyopathy and to improve symptoms and quality of life. In this review, we evaluated the pharmacologic profile and clinical outcomes for mavacamten and aficamten, 2 cardiac myosin inhibitors investigated in symptomatic hypertro...

Early surgery and improved medical care have led to the increased survival of neonates with congenital heart disease (CHD), who now commonly reach adulthood. Among adults with CHD, a growing subgroup is represented by middle-aged and even elderly patients. In this elderly population, acquired cardiac and extracardiac comorbidities represent the mai...

Background and Aims The European Society of Cardiology guidelines recommend a systematic search for diagnostic clues or ‘red flags’ (RFs) in patients with hypertrophic cardiomyopathy (HCM) to better tailor disease management. To date, the prevalence and clinical significance of RF associated with HCM phenotypes in different clinical settings are un...

Background The left ventricular (LV) hypercontractile phenotype (HP) plays a critical role in hypertrophic cardiomyopathy (HCM) and is usually identified with the left ventricular outflow tract gradient (LVOTG). Purpose To assess the systemic and coronary hemodynamic profile associated with HP identified with increased LV elastance (also known as...

Background Hemodynamic force (HDF) analysis allows non-invasive measurement of intraventricular pressure gradients, portraying cyclic spatial-temporal interaction between blood and tissues. Impaired HDFs have been implicated in early detecting of adverse cardiac remodelling and treatment response in various cardiovascular disorders, providing insig...

BACKGROUND Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Reg...

Introduction Heart failure (HF) is a complex clinical syndrome. Accurate risk stratification and early diagnosis of HF are challenging as its signs and symptoms are non-specific. We propose to address this global challenge by developing the STRATIFYHF artificial intelligence-driven decision support system (DSS), which uses novel analytical methods...

ESC Guidelines provide best practice, evidence-based recommendations for diagnosing and treating patients with cardiovascular diseases. It is not always possible for best practices to be followed, however, particularly in low-resource settings. To address this issue, a set of guideline-related documents were created to identify key priorities for u...

Gene panels represent a widely used strategy for genetic testing in a vast range of Mendelian disorders. While this approach aids reliable bioinformatic detection of short coding variants, it fails to detect most larger variants. Recent studies have recommended the adoption of pangenomes to augment detection of large variants from targeted sequenci...

Introduction: In patients with obstructive hypertrophic cardiomyopathy (oHCM), the SEQUOIA-HCM trial demonstrated that aficamten, a next-in-class cardiac myosin inhibitor, improved exercise capacity, heart failure symptoms and hemodynamics compared with placebo. Aficamten’s impact on overall quality-of-life (QoL) in oHCM has not been reported. Hypo...

Background: Mavacamten, a cardiac myosin inhibitor, is approved across 5 continents for the treatment of obstructive hypertrophic cardiomyopathy (HCM). Long-term data of mavacamten are available from multiple studies, providing the opportunity to further understand mavacamten long term safety, including adverse events (AEs) of clinical interest. Ai...

Introduction: Area-based social determinants of health (SDOH) are associated with higher risk for acquired heart disease. However, the impact of area-based SDOH on clinical outcomes in patients with hypertrophic cardiomyopathy (HCM) has not been previously studied. Hypothesis: Residing in an area with lower median household income and a higher soci...

Background: The impact of genotype on the risk of arrhythmia and heart failure in dilated and arrhythmogenic cardiomyopathy (DCM/ACM) is not well defined. Better understanding of genetic risk factors is needed to improve patient risk stratification, management, and outcomes. Methods: In this observational study, we leveraged the international Sarco...

Objective: Atrial cardiomyopathy is closely associated with atrial fibrillation (AF), and some patients exhibit no dysfunction at rest but demonstrate evident changes in left atrial (LA) function and LA volume during exercise. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rh...

Aims Left ventricular (LV) ring-like scar on cardiac magnetic resonance (CMR) has been linked to malignant arrhythmias in patients with non-ischemic cardiomyopathy. This study aimed to perform a comprehensive evaluation of this phenotype and to identify risk factors for life-threatening arrhythmic events (LAEs), a composite of sudden cardiac death...

Introduction Mavacamten safety and efficacy in patients with obstructive hypertrophic cardiomyopathy (HCM) was demonstrated in the phase 3 EXPLORER-HCM trial. Long-term safety and efficacy of mavacamten in patients with obstructive HCM is being studied in the MAVA-Long-Term Extension (LTE) study (NCT03723655). Purpose To present long-term safety a...

Background Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease that has progressively gained attention due to the availability of specific therapeutic options. Heart involvement is of critical prognostic significance and differential diagnosis with Hypertrophic Cardiomyopathy (HCM) is as challenging as it is crucial to provide the...

Background Anderson Fabry disease (AFD) is an X-linked lysosomal storage disorder leading to a deficiency in α-galactosidase A and globotriasylceramide (Gb3) deposition in different organs. Cardiac involvement is extremely common. It has been shown that the ECG abnormalities are directly correlated with the progressive accumulation of glycosphingol...

Background Hemodynamic force (HDF) analysis allows non-invasive measurement of intraventricular pressure gradients, portraying cyclic spatial-temporal interaction between blood and tissues. Impaired HDFs have been implicated in early detecting of adverse cardiac remodelling and treatment response in various cardiovascular disorders, providing insig...

Introduction Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions. Purpose We developed and validate a...

The tenet of cardiac amyloidosis (CA) as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has come under scrutiny. Thus, we aimed to evaluate the prevalence and clinical significance of left ventricular (LV) systolic dysfunction versus restriction in a large real-world cohort with CA, assessed at t...

Background Mobile health technologies are revolutionizing cardiovascular (CV) medicine. However, more than 80% of heart disease related deaths occur in low-income settings, that are unable to take advantage of such technologies for healthcare awareness and prevention. Purpose To assess the feasibility of a pilot telemedicine-based CV screening cam...

Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic...

Background Cardiac Magnetic Resonance Imaging (CMR) is crucial for diagnosing and stratifying cardiac disease, but up to 10% of patients face challenges due to claustrophobia. Conventional methods for overcoming claustrophobia have limited success. The metaverse, an immersive 3D environment using virtual and augmented reality, is under investigatio...

Background Patients with hypertrophic cardiomyopathy (HCM) are generally restricted regarding participation in competitive sports based on the potential risk of sudden cardiac death and malignant arrhythmias. As a result, they are often inactive and experience the negative consequences of a sedentary lifestyle. Hence, the need arises to strike the...

BACKGROUND Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined. METHODS Data from 13 high clinical volume HCM centers from the international SHA...

Background and Aims Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have...

Importance Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardi...

Background and Aims The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) an...

Background and Aims Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Methods Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE u...

Most acquired and inherited cardiomyopathies are characterized by regional left ventricular involvement and nonischemic myocardial scars, often with a disease-specific pattern. Irrespective of the etiology and pathophysiological mechanisms, myocardial disorders are invariably associated with cardiac fibrosis, which contributes to dysfunction and el...

Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in...

Hemodynamic forces (HDFs), which represent the forces exchanged between blood and surrounding tissues, are critical in regulating the structure and function of the left ventricle (LV). These forces can be assessed on cardiac magnetic resonance or transthoracic echocardiography exams using specialized software, offering a non-invasive alternative fo...

Transthyretin cardiac amyloidosis (ATTR-CA) predominantly affects older adults with multiple chronic conditions, leading to significant physical, cognitive, and emotional challenges. New disease-modifying drugs are effective in early stages, prompting a shift toward comprehensive assessments, including functional capacity and quality of life. Howev...

Background and Aims Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have prove...

Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of...

Aims: The Italian Fabry Disease Cardiovascular Registry (IFDCR) comprises 50 Italian centres with specific expertise in managing cardiovascular manifestations and complications of patients with Fabry disease (FD). The primary aim of the IFDCR is to examine and improve the clinical care and outcomes of patients with FD by addressing several knowled...

Aim Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO 2 ) in patients with non‐obstructive HCM. Methods and res...

Background In patients with Hypertrophic Cardiomyopathy (HCM) S-ICD is usually the preferred option as pacing is generally not indicated. However, limited data are available on its current practice adoption and long term follow-up. Purpose The present study was designed to examine in a multicenter, open-label, long-term study, the patient’s select...

Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM‐Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM‐Thin to better understand the natural history and...

Background: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract...

Introduction: Cardiac magnetic resonance imaging (CMR) is vital, but claustrophobia affects 10% of patients. The metaverse, an immersive virtual and augmented reality environment, has healthcare potential. We present a metaverse-based CMR simulation for claustrophobic patients. Methods: Three cardiomyopathy patients, initially CMR-refusing due to c...

Background Advancements in cardiac imaging have revolutionized our understanding of ventricular contraction. While ejection fraction (EF) is still the gold standard parameter to assess left ventricle (LV) function, strain imaging (SI) has provided valuable insights into ventricular mechanics. The lack of an integrative method including SI parameter...

Background The prognostic impact of catheter ablation (CA) of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients has not yet been satisfactorily elucidated. Objectives The aim of the study was to assess the impact of CA of AF on clinical outcomes in a large cohort of HCM patients. Methods In this retrospective multicenter stud...

Background Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown. Aims To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA. Methods Consecut...

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhy...

BACKGROUND Assessing myocardial strain by cardiac magnetic resonance feature tracking (FT) has been found to be useful in patients with overt hypertrophic cardiomyopathy (HCM). Little is known, however, of its role in sarcomere gene mutation carriers without overt left ventricular hypertrophy (subclinical HCM). METHODS Thirty-eight subclinical HCM...

In this chapter, we will discuss cardiac disorders that share the same hypertrophic pattern as cardiac amyloidosis (CA) but differ in clinical and epidemiological pathognomonic aspects. Left ventricular hypertrophy is a phenotype rather than a diagnosis, which results from a number of myocardial diseases, some of which exclusively involve the heart...

Anderson–Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differ...

Background Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives The purpose of this study was to characterize...

We report a case of successful implantation of a subcutaneous implantable cardioverter-defibrillator in a young patient with severe pectus excavatum presenting with out-of-hospital ventricular fibrillation arrest who was recently surgically repaired with a MIRPE–Nuss procedure. No complications in lead positioning were observed, and the device was...

Background and Aims Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC....

The aim of this study was to evaluate the effectiveness and safety of the anti-IL-1 receptor anakinra in patients with chronic active myocarditis refractory to standard therapy. In this retrospective, observational study, we enrolled 6 patients with chronically active myocarditis treated with anakinra on-top-of standard treatment. Response to treat...

Background and aims In the EXPLORER‐HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real‐world (RW) HOCM patients with those enrolled in EXPLORER‐H...

Background: Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history...

Restrictive cardiomyopathy (RCM) is characterized by restrictive ventricular pathophysiology determined by increased myocardial stiffness. While suspicion of RCM is initially raised by clinical evaluation and supported by electrocardiographic and echocardiographic findings, invasive hemodynamic evaluation is often required for diagnosis and managem...

Background: Pseudonormal T waves may be detected on stress electrocardiograms (ECGs) in hypertrophic cardiomyopathy (HCM). Either myocardial ischaemia or purely exercise-induced changes have been hypothesised to contribute to this phenomenon, but the precise electrophysiological mechanisms remain unknown. Methods: Computational models of human HCM...

As a slowly progressive form of hypertrophic cardiomyopathy (HCM), Anderson-Fabry disease (FD) resembles the phenotype of the most common sarcomeric forms, although significant differences in presentation and long-term progression may help determine the correct diagnosis. A variety of electrocardiographic and imaging features of FD cardiomyopathy h...

Background Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size. Purpose To discover novel genetic loci, genes and mechanisms implicated in HCM using a lar...

Introduction: In patients with obstructive hypertrophic cardiomyopathy (HCM), blood flow changes from left ventricular outflow tract (LVOT) obstruction can lead to hemolysis and release of red blood cell proteins into circulation. Increased cell-free plasma hemoglobin (Hb) and reduced haptoglobin (Hp) are biomarkers of intravascular hemolysis. Mava...

Background: Approximately 40% of cases of dilated (DCM) and arrhythmogenic cardiomyopathy (AC) are caused by rare genetic variants of large-effect. Sex-based differences in the penetrance of genetic DCM and AC have been described, however, findings have been inconsistent. Age at the time of diagnosis can be used as an indicator of age-related penet...

Background: Extensive late gadolinium enhancement (LGE) is now recognized as a risk factor for sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). However, risk for SCD is very low in older (≥60 years) HCM patients, and therefore utility of assessing LGE for risk stratification in this subgroup of patients is uncertain. O...