The new 2023 ESC guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions.

In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as 'myocardial disorders 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'. They are morpho-functionally classified as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy with the addition of the left ventricular non-dilated cardiomyopathy that describes intermediate phenotypes not fulfilling standard disease definitions despite the presence of myocardial disease on cardiac imaging or tissue analysis. The new ESC guidelines provide 'a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations'. The recommendations and suggestions included in the document provide the tools to build up pathways tailored to specific cardiomyopathy (phenotype and cause) and define therapeutic indications, including target therapies where possible. The impact is on clinical cardiology, where disease-specific care paths can be assisted by the guidelines, and on genetics, both clinics and testing, where deep phenotyping and participated multi-disciplinary evaluation provide a unique tool for validating the pathogenicity of variants. The role of endomyocardial biopsy remains underexploited and confined to particular forms of restrictive cardiomyopathy, myocarditis, and amyloidosis. New research and development will be needed to cover the gaps between science and clinics. Finally, the opening up to disciplines such as bioinformatics, bioengineering, mathematics, and physics will support clinical cardiologists in the best governance of the novel artificial intelligence-assisted resources.

Spontaneous coronary artery dissection: an unpredictable event.

Spontaneous coronary artery dissection (SCAD) is an under-recognized cause of acute coronary syndrome that predominantly affects women in adulthood and is the leading cause of acute myocardial infarction in pregnancy. The most common clinical presentation is ST-segment elevation myocardial infarction (STEMI) or non-STEMI, followed by cardiogenic shock (∼2%), sudden cardiac death (0.8% in autopsy series), cardiac arrest, ventricular arrhythmias (∼5%), and Takotsubo syndrome. The prevalence of SCAD in the general population is largely uncertain due to underdiagnosis. Oral contraceptives, post-menopausal therapy, and infertility treatments are recognized associated factors. The pathological substrates (fibromuscular dysplasia) and triggers (especially emotional stress) are commonly present in affected women. The few cases with a precise genetic aetiology occur in the context of syndromic and non-syndromic connective tissue diseases. The only true certainty in SCAD is the overwhelming prevalence in women. The first event as well as the recurrence (up to 30%, which varies depending on the definition) is largely unpredictable. The treatment strategy is highly individualized and requires extensive additional study in order to optimize outcomes and prevent major adverse cardiovascular events in affected individuals. We have known about SCAD for nearly a century, but we still do not know how best to prevent, diagnose, and treat it, making SCAD a highly important and unmet clinical need.

Prevalence and Complications of Aberrant Subclavian Artery in Patients With Heritable and Nonheritable Arteriopathies.

BACKGROUND: An aberrant subclavian artery (ASA) (or lusoria) is the most common congenital anomaly of the aortic arch (0.5%-2.2%; female-to-male ratio 2:1 to 3:1). ASA can become aneurysmal and result in dissection, involving Kommerell's diverticulum when present and the aorta. Data of its significance in genetic arteriopathies are not available. OBJECTIVES: The purpose of this study was to assess the prevalence and complications of ASA in gene-positive and -negative nonatherosclerotic arteriopathies. MATERIALS: The series includes 1,418 consecutive patients with gene-positive (n = 854) and gene-negative arteriopathies (n = 564) diagnosed as part of institutional work-up for nonatherosclerotic syndromic and nonsyndromic arteriopathies. Comprehensive evaluation includes genetic counseling, next-generation sequencing multigene testing, cardiovascular and multidisciplinary assessment, and whole-body computed tomography angiography. RESULTS: ASA was found in 34 of 1,418 cases (2.4%), with a similar prevalence in gene-positive (n = 21 of 854, 2.5%) and gene-negative (n = 13 of 564, 2.3%) arteriopathies. Of the former 21 patients, 14 had Marfan syndrome, 5 had Loeys-Dietz syndrome, 1 had type-IV Ehlers-Danlos syndrome, and 1 had periventricular heterotopia type 1. ASA did not segregate with genetic defects. Dissection occurred in 5 of 21 patients with genetic arteriopathies (23.8%; 2 Marfan syndrome and 3 Loeys-Dietz syndrome), all with associated Kommerell's diverticulum. No dissections occurred in gene-negative patients. At baseline, none of the 5 patients with ASA dissection fulfilled criteria for elective repair according to guidelines. CONCLUSIONS: The risk of complications of ASA is higher in patients with genetic arteriopathies and is difficult to predict. In these diseases, imaging of the supra-aortic trunks should enter baseline investigations. Determination of precise indications for repair can prevent unexpected acute events such as those described.

Genetics and clinics: together to diagnose cardiomyopathies.

The diagnostic paths of hereditary cardiomyopathies (CMPs) include both clinical and molecular genetics. The first step is the clinical diagnosis that guides the decisions about treatments, monitoring, prognostic stratification, and prevention of major events. The type of CMP [hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy (ARVC)] is defined by the phenotype, and the genetic testing may identify the precise cause. Furthermore, genetic testing provides a pre-clinical diagnosis in unaffected family members and the basis for prenatal diagnosis. It can contribute to risk stratification (e.g. LMNA) and can be a major diagnostic criterion (e.g. ARVC). The test can be limited to a single gene when the pre-test diagnostic hypothesis is based on proven clinical evidence (e.g. GLA for Fabry disease). Alternatively, it can be expanded from a multigene panel to a whole exome or whole genome sequencing when the pre-test hypothesis is a genetically heterogeneous disease. In the last decade, the study of larger genomic targets led to the identification of numerous gene variants not only pathogenic (clinically actionable) but also of uncertain clinical significance (not actionable). For the latter, the pillar of the genetic diagnosis is the correct interpretation of the pathogenicity of genetic variants, which is evaluated using both bioinformatics and clinical-genetic criteria about the patient and family. In this context, cardiologists play a central role in the interpretation of genetic tests, performing the deep-phenotyping of variant carriers and establishing the co-segregation of the genotype with the phenotype in families.

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.

Long COVID: long-term effects?

The term Long COVID (or Post COVID) describes a condition characterized by persistence of symptoms for at least 12 weeks after the onset of COVID-19. It may last several months but the duration is still matter of observation. The symptoms and the clinical manifestations are clinically heterogeneous and suggesting involvement of multi-organs/systems, including the cardiovascular system. The general recurrent symptoms include fatigue, breathlessness, myalgia, headache, loss of memory, and impaired concentration. Patients report loss of their previous psychophysical performance. Cardiovascular involvement manifests with common symptoms such as palpitations and chest pain, and, less commonly, with events such as late arterial and venous thromboembolisms, heart failure episodes, strokes or transient ischaemic attack, 'myo-pericarditis'. The diagnostic criteria are mainly based on the narrative of the patients. Measurable biomarkers or instrumental findings or clinical events are not yet framed in a shared diagnostic framework. The open question for clinicians and researchers is whether biomarkers, electrocardiogram, non-invasive imaging, and clinical monitoring should be included in a shared diagnostic protocol aimed at defining the diagnostic path and protecting patients at risk of unexpected events.

Pathologic substrate of gastropathy in Anderson-Fabry disease.

In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.

Myths to debunk: the non-compacted myocardium.

Left ventricular non-compaction (LVNC) is defined by the triad: prominent trabecular anatomy, thin compacted layer, and deep inter-trabecular recesses. No person, sick or healthy, demonstrates identical anatomy of the trabeculae; their configuration represents a sort of individual dynamic 'cardiac fingerprinting'. LVNC can be observed in healthy subjects with normal left ventricular (LV) size and function, in athletes, in pregnant women, as well as in patients with haematological disorders, neuromuscular diseases, and chronic renal failure; it can be acquired and potentially reversible. When LVNC is observed in patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, restrictive cardiomyopathy, or arrhythmogenic cardiomyopathy, the risk exists of misnaming the cardiomyopathy as 'LVNC cardiomyopathy' rather than properly describe, i.e. a 'DCM associated with LVNC'. In rare infantile CMPs (the paradigm is tafazzinopathy or Barth syndrome), the non-compaction (NC) is intrinsically part of the cardiac phenotype. The LVNC is also common in congenital heart disease (CHD) as well as in chromosomal disorders with systemic manifestations. The high prevalence of LVNC in healthy athletes, its possible reversibility or regression, and the increasing detection in healthy subjects suggest a cautious use of the term 'LVNC cardiomyopathy', which describes the morphology, but not the functional profile of the cardiac disease. Genetic testing, when positive, usually reflects the genetic causes of an underlying cardiomyopathy rather than that of the NC, which often does not segregate with CMP phenotype in families. Therefore, when associated with LV dilation and dysfunction, hypertrophy, or CHD, the leading diagnosis is cardiomyopathy or CHD followed by the descriptor LVNC.

Cardiac Phenotypes in Hereditary Muscle Disorders: JACC State-of-the-Art Review.

Hereditary muscular diseases commonly involve the heart. Cardiac manifestations encompass a spectrum of phenotypes, including both cardiomyopathies and rhythm disorders. Common biomarkers suggesting cardiomuscular diseases include increased circulating creatine kinase and/or lactic acid levels or disease-specific metabolic indicators. Cardiac and extra-cardiac traits, imaging tests, family studies, and genetic testing provide precise diagnoses. Cardiac phenotypes are mainly dilated and hypokinetic in dystrophinopathies, Emery-Dreifuss muscular dystrophies, and limb girdle muscular dystrophies; hypertrophic in Friedreich ataxia, mitochondrial diseases, glycogen storage diseases, and fatty acid oxidation disorders; and restrictive in myofibrillar myopathies. Left ventricular noncompaction is variably associated with the different myopathies. Conduction defects and arrhythmias constitute a major phenotype in myotonic dystrophies and skeletal muscle channelopathies. Although the actual cardiac management is rarely based on the cause, the cardiac phenotypes need precise characterization because they are often the only or the predominant manifestations and the prognostic determinants of many hereditary muscle disorders.

Common presentation of rare diseases: Aortic aneurysms & valves.

The concept "common presentation of rare diseases" implies that rare diseases are masked by common phenotypic manifestations. This concept applies to both aneurysmal and valvular diseases that can be syndromic and non-syndromic. Syndromic disorders include genetic connective tissue diseases and chromosomal disorders that are diagnosed independently from the aneurysm or valve disease. Non-syndromic diseases, on the other hand, are defined by the presence of aneurysm or valve disease or both. The reasons for suspecting these rare diseases include young age, the absence of risk factors, a positive family history for aortic or valvular disease/event, and extra-cardiovascular traits for syndromes. The probands should receive genetic counseling, genetic testing [single gene in case of precise phenotyping addressing the gene to be tested, or multigene panels, in case of diseases with genetic heterogeneity], post-test counseling, clinical family screening and cascade genetic testing in relatives after the identification of a causative mutation. Segregation studies are essential in case of novel mutations, in particular non-truncation predicting variants. Clinical family screening of syndromic diseases is facilitated by the evaluation of non-cardiovascular traits; this supports early diagnosis and geno-phenotype correlation. Vice versa, family screening studies in non-syndromic aneurysmal and valvular diseases exclusively relies on CV imaging screening of relatives. In this context, conditions such as BAV and related aortopathy are easy to diagnose because BAV is present at birth while aortopathy usually develops during the life course.

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy.

Current clinical treatment regimens, including many emergent immune strategies (e.g., checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA. FUS methods can non-invasively generate mechanical and/or thermal effects that capitalize on the unique oncogenomic/proteomic signature of a tumor. Potential benefits of FUS therapy for PDA include: (1) emulsification of targeted tumor into undenatured antigens in situ, increasing dendritic cell maturation, and increasing intra-tumoral CD8+/ T regulatory cell ratio and CD8+ T cell activity; (2) reduction in intra-tumoral hypoxic stress; (3) modulation of tumor cell membrane protein localization to enhance immunogenicity; (4) modulation of the local cytokine milieu toward a Th1-type inflammatory profile; (5) up-regulation of local chemoattractants; (6) remodeling the tumor stroma; (7) localized delivery of exogenously packaged immune-stimulating antigens, genes and therapeutic drugs. While not all of these results have been studied in experimental PDA models to date, the principles garnered from other solid tumor and disease models have direct relevance to the design of optimal FUS protocols for PDA. In this review, we address the pertinent limitations in current and emergent immune therapies that can be improved with FUS therapy for PDA.