In the past 25 years, major advances were achieved in the nosography of cardiomyopathies, influencing the definition and taxonomy of this important chapter of cardiovascular disease. Nearly, 50% of ...patients dying suddenly in childhood or adolescence or undergoing cardiac transplantation are affected by cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic, restrictive, and noncompacted) and added to update the World Health Organization classification. Myocarditis has also been named inflammatory cardiomyopathy. Extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed establishment of dilated cardiomyopathy as mostly cytoskeleton, force transmission disease; hypertrophic-restrictive cardiomyopathies as sarcomeric, force generation disease; and arrhythmogenic cardiomyopathy as desmosome, cell junction disease. Channelopathies (short and long QT, Brugada, and catecholaminergic polymorphic ventricular tachycardia syndromes) should also be considered cardiomyopathies because of electric myocyte dysfunction. Cardiomyopathies are easily diagnosed but treated only with palliative pharmacological or invasive therapy. Curative therapy, thanks to insights into the molecular pathogenesis, has to target the fundamental mechanisms involved in the onset and progression of these conditions.
In 1900, Fiedler first reported autopsy cases with peculiar inflammation of the myocardium, which he named interstitial myocarditis. He postulated an isolated cardiac inflammation of the myocardium ...in the absence of multiorgan involvement and with a poor prognosis due to invisible microorganisms, which years later would have been identified as viruses. The revision of original histologic sections by Schmorl showed cases with lymphocytes and others with giant-cell inflammatory histotypes. The in vivo diagnosis of myocarditis became possible thanks to right cardiac catheterization with endomyocardial biopsy (EMB). The gold standard for diagnosis was achieved with the employment of immunohistochemistry and molecular investigation by Polymerase Chain Reaction (PCR), which allows for the detection of viruses as causal agents. Both RNA and DNA were revealed to be cardiotropic, with a common receptor (CAR). A protease, coded by coxsackie virus, disrupts the cytoskeleton and accounts for cell death. Unfortunately, vaccination, despite having been revealed to be effective in animal experiments, has not yet entered the clinical field for prevention. Cardiac Magnetic Resonance turned out to be a revolutionary tool for in vivo diagnosis through the detection of edema (inflammatory exudate). Myocarditis may be fulminant in terms of clinical presentation but not necessarily fatal. The application of ExtraCorporeal Membrane Oxygenation (ECMO) allows for relieving the overloaded native heart.
Arrhythmogenic right ventricular cardiomyopathy Basso, Cristina, MD; Corrado, Domenico, MD; Marcus, Frank I, Prof ...
The Lancet (British edition),
04/2009, Volume:
373, Issue:
9671
Journal Article
Peer reviewed
Summary Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding ...desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.
The experience as a cardiovascular pathologist on sudden cardiac death (SCD) in the young and the impact that the findings had on in vivo diagnosis, treatment, and prevention are herein reported. The ...story dates back in the late 70s, when a series of juvenile sudden deaths occurred in the Veneto Region, North East of Italy. A successful application for a prospective study on young people dying suddenly (<35 years old, sudden infant death syndrome excluded) was submitted to the regional health authorities, thus implementing a network of collaboration with anatomic and forensic pathologists, to collect all such events and to gather epidemiological data. The project is still in progress, and since then we studied >650 hundreds consecutive juvenile SCD cases, allowing to identify the culprit diseases with abnormalities in the various cardiac structures (aorta, coronary arteries, myocardium, valves, and conduction system). The long standing Veneto Region experience clearly shows that autopsy still plays a pivotal role in the study and prevention of SCD and should be carried out regularly in the young. With time, the investigation of SCD necessarily moved from the classic postmortem study to molecular autopsy. In conclusion, SCD prevention in the young has to be faced by an interdisciplinary team, including pathologists, cardiologists, sport physicians, and geneticists, with a translational approach; the clinicopathologic correlation method still being the polar-star. In other words, the game in the fight against SCD is still played in the anatomical theater, the place where “death enjoys to save lives.”
Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, ...particularly in the young and athletes. Mutations in five genes that encode major components of the desmosomes, namely junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2, have been identified in approximately half of affected probands. AC is, therefore, commonly considered a 'desmosomal' disease. No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion. Caution in the interpretation of screening results is highly recommended because a 'pathogenic' mutation is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression.
Mitral valve prolapse (MVP) may present with ventricular arrhythmias and sudden cardiac death (SCD) even in the absence of hemodynamic impairment. The structural basis of ventricular electric ...instability remains elusive.
The cardiac pathology registry of 650 young adults (≤40 years of age) with SCD was reviewed, and cases with MVP as the only cause of SCD were re-examined. Forty-three patients with MVP (26 females; age range, 19-40 years; median, 32 years) were identified (7% of all SCD, 13% of women). Among 12 cases with available ECG, 10 (83%) had inverted T waves on inferior leads, and all had right bundle-branch block ventricular arrhythmias. A bileaflet involvement was found in 70%. Left ventricular fibrosis was detected at histology at the level of papillary muscles in all patients, and inferobasal wall in 88%. Living patients with MVP with (n=30) and without (control subjects; n=14) complex ventricular arrhythmias underwent a study protocol including contrast-enhanced cardiac magnetic resonance. Patients with either right bundle-branch block type or polymorphic complex ventricular arrhythmias (22 females; age range, 28-43 years; median, 41 years), showed a bileaflet involvement in 70% of cases. Left ventricular late enhancement was identified by contrast-enhanced cardiac magnetic resonance in 93% of patients versus 14% of control subjects (P<0.001), with a regional distribution overlapping the histopathology findings in SCD cases.
MVP is an underestimated cause of arrhythmic SCD, mostly in young adult women. Fibrosis of the papillary muscles and inferobasal left ventricular wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark and correlates with ventricular arrhythmias origin. Contrast-enhanced cardiac magnetic resonance may help to identify in vivo this concealed substrate for risk stratification.
The original designation of “Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy”(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac ...magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of “Arrhythmogenic Cardiomyopathy” (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed “Padua criteria” derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients.
•Fibro-fatty myocardial replacement is the distinctive phenotypic feature of Arrhythmogenic cardiomyopathy (ACM);•ACM can affect both the right and left ventricle;•The 2010 International Task Force diagnostic criteria lacked specific criteria for diagnosis of left-sided variants of ACM;•The proposed Padua diagnostic criteria encompass dominant-right, biventricular and dominant-left ACM.
In 1982 a nationwide program of pre-participation screening including 12-lead electrocardiography (ECG) was launched in Italy. The aim of this article is to examine whether this 25-year screening ...program should be considered a valid and advisable public health strategy. The analysis of data coming from the long-running Italian experience indicates that ECG screening has provided adequate sensitivity and specificity for detection of potentially lethal cardiomyopathy or arrhythmias and has led to substantial reduction of mortality of young competitive athletes by approximately 90%. Screening was feasible thanks to the Italian Health System, which is developed in terms of health care and prevention services, and because of the limited costs of cardiovascular evaluation in the setting of a mass program. On the basis of current scientific evidence the implementation of a mass-screening program aimed to prevent athletic-field sudden cardiac death should be at least carefully considered by public health administrators worldwide.
The ongoing COVID-19 pandemic has a major precedent almost exactly a century ago: the world-famous H1N1 influenza virus pandemic, sometimes known to the general public as the Spanish flu. From a ...history of medicine perspective, it is possible to underline many potential common traits between the two. In this article, hygiene and prophylaxis strategies are analyzed in a review of the most popular Italian general medical journals at the time of Spanish flu, Il Policlinico being the most representative of them. The analysis included 40 original journal articles as well as important references to the most influential coeval national manuals and international journals. The main issues in the context of public hygiene are prophylaxis with quinine and quinine derivatives, vaccinations, face masks, disinfection, and social distancing. We draw a comparison between these and the most recent international World Health Organization and Italian national guidelines on the topic. Sadly, little has changed since those times in terms of most of the prevention techniques, even with technical improvements, showing how shortsighted doctors and physicians can be when dealing with medical history. (Am J Public Health. 2021;111(10):1815–1823. https://doi.org/10.2105/AJPH.2021.306412 )
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