Abstract Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predic tive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser,p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses.

Abstract Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall.The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS.

Abstract Background: Variants in the desmoplakin (DSP) gene have been recognized in associa tion with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhyth mogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovas cular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP,nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were preva lent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.

Abstract Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predic tive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser,p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses.

Abstract Hypertension and atherosclerosis are debilitating diseases that affect millions each year.Long-term consequences include but are not limited to stroke, myocardial infarction, and kidney failure. Platelet-activating factor (PAF) is a proinflammatory mediator synthesized from a subclass of phosphatidylcholines that increases platelet activation, leukocyte adhesion, infiltration of macrophages, and intracellular lipid accumulation, thereby contributing to atherosclerosis. Magnesium, a key micronutrient and free radical scavenger, is a water-soluble mineral that regulates peripheral vasodilation and calcium, phosphate, and hydroxyapatite homeostasis. Magnesium’s antihypertensive ability stems from its role as a natural calcium antagonist and promoter of vasodilatory mediators, such as nitric oxide. Platelet-activating factor and magnesium share an inverse relationship, and elevated magnesium levels have been shown to have protective effects against plaque formation as well as antihypertensive and antiarrhythmic effects, all of which allow for healthier aging. The purpose of this literature review is to investigate the role of platelet-activating factor and magnesium in the pathophysiology of hypertension, atherosclerosis, cardiovascular disease, stroke, and aging. Since the pathophysiology of the platelet-activating factor biomolecule is underexplored, further research studies are warranted in order to navigate the putative signaling pathways involved in the cardioprotective effects of dietary magnesium as a natural anti-PAF agent.

Abstract Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD.

Abstract In thelast few decades, the roles of cardio-oncology and cardiovascular geneticsgained more and more attention in research and daily clinical practice, shaping a new clinical approach and management of patients affected by cancer and cardiovascular disease. Genetic characterization of patients undergoing cancer treatment can support a better cardiovascular risk stratification beyond the typical risk factors, suchas contractile function and QT interval duration, uncovering a possible patient’s concealed predisposition to heart failure, life threatening arrhythmias and sudden death. Specifically, an integrated cardiogenetic approach in daily oncological clinical practice can ensure the best patient-centered healthcare model, suggesting, also the adequate cardiac monitoring timing and alternative cancer treatments, reducing drug-related complications. We report the case of a 14-month-old girl affected by neuroblastoma, treated by cisplatin, complicated by cardiac arrest. We described the genetic characterization of a Ryanodine receptor 2 (RYR2) gene mutation and subsequent pharmacogenomic approach to better shape the cancer treatment.

Abstract Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur requently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population.

Abstract 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.

Abstract 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.

Abstract Cardiomyopathies (CMPs) are a heterogeneous group of diseases, frequently genetic, affecting the heart muscle. The symptoms range from asymptomatic to dyspnea, arrhythmias, syncope, and sudden cardiac death. This study is focused on MYH7 (beta-myosin heavy chain), as this gene is commonly mutated in cardiomyopathy patients. Due to the high combined prevalence of MYH7 variants and severe health outcomes, it is one of the most frequently tested genes in clinical settings. We analyzed the clinical presentation and natural history of 48 patients with MYH7- related cardiomyopathy belonging to a cohort from a tertiary center at Helsinki University Hospital, Finland. We made special reference to three age subgroups (0–1, 1–12, and >12 years). Our results characterize a clinically significant MYH7 cohort, emphasizing the high variability of the CMP phenotype depending on age. We observed a subgroup of infants (0–1 years) with MYH7 associated severe DCM phenotype. We further demonstrate that patients under the age of 12 years have a similar symptom burden compared to older patients.