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New pathological insights into arrhythmogenic cardiomyopathy: implications for non-invasive diagnosis
No full textBackground
Arrhythmogenic cardiomyopathy (ACM) is a rare inherited heart muscle disease characterized by fibro-fatty or fibrous replacement of the ventricular myocardium. Our aims are: 1) to assess the transmural extent and pattern of distribution of fibro-fatty replacement in juvenile SCD and HTx with a pathologic diagnosis of ACM; 2) to correlate the pathology features with clinical findings; 3) to assess the burden of ACM as a cause of SCD in young competitive athletes; 4) to provide genotype-phenotype correlation.
Methods
The databases of SCD and HTx of the Cardiovascular Pathology Unit were inquired. All cases with a diagnosis of ACM at histopathological evaluation and availability of the whole heart for revision were included. A complete mid-ventricular transverse section was processed for histology. Ventricular segmentation was obtained dividing the right ventricle (RV), interventricular septum (IVS), and left ventricle (LV) in three portions (anterior, lateral, and posterior for each ventricle and anterior, mid, and posterior for the IVS); each ventricular portion was then partitioned in four layers (subepicardial, midmural, subendocardial, and trabecular) and every IVS sample in three layers (RV-side, mid-mural, and LV-side). The presence and extent of fibrous or fibro-fatty replacement was qualitative assessed, by excluding para-physiological fat infiltration. Clinical data were reviewed and genetic testing was performed.
Results
ACM was diagnosed in 97 out of 912 juvenile SCD (10.6%) and in 58 out of 1149 explanted hearts (5.0%). A total of 135 ACM cases fulfilled the inclusion criteria (91 SCD and 44 HTx). Mean age was 26.6±7.1 and 43.4±16.6 years respectively, with 6.6% and 43.2% of females. The segments most frequently involved in the SCD cohort were the LV lateral and posterior subepicardial, while in the HTx subgroup the whole RV (excluding the trabecular portions) and the LV lateral and posterior subepicardial. The interventricular septum (IVS) resulted affected in 40.7% of the SCD cases vs. 90.9% of the HTx. Isolated LV involvement was more frequent in SCD than HTx (29.6% vs 4.5%). Transmural scarring was almost constant in the RV in HTx (91%), less common in the RV in SCD (38.5%) and infrequent in the LV in both cohorts (7.7% SCD and 31.8% HTx). 54 competitive athletes were available for clinicopathologic correlations. ECG showed negative T waves in 23 cases (42.6%) and low QRS voltages in 16 (29.6%). The presence of negative T waves in the right precordial leads was associated with a higher prevalence of RV transmurality and biventricular involvement. The LV was more frequently involved compared to the RV (94.4% vs. 70.4%).
A P/LP genetic variant in a causative gene was identified in 47/106 cases (44.3%): 33.3% of the SCD, 62.9% of the HTx and 45.5% of the “extra” ACM cases. PKP2 (15 cases), DSP (6), DES (4), DSG2 (4), TTN (3), DSC2 (3), FLNC (3), SCN5A (2); MYBPC3 (1); LMNA (1). Six cases hosted two pathogenic variants. Desmosomal mutations and particularly PKP2, DSG2, and DSC2 were associated with a more frequent involvement of the RV and RV-side of the IVS. DSP and non-desmosomal mutations showed instead a variable RV involvement with a prevalent posterior and lateral subepicardial lesions in the LV, coupled with more frequent midmural IVS lesions.
Conclusions
Different patterns of scarring are identifiable in SCD and HTx with transmural lesions being almost constant in the RV in HTx and extremely rare in the LV, IVS more frequently involved in HTx and exclusive LV involvement almost unique to the SCD cohort. Genotype-phenotype correlations confirms that the classical RV ACM is mostly linked to PKP2, DSG2 and DSC2 mutations. Awareness of the morphologic variability can help the interpretation of ECGs, echocardiograms and magnetic resonance imaging
The missing pieces in the puzzle of arrhythmic mitral valve prolapse: papillary muscles, mitral anulus disjunction and myocardial scarring
No full textCauses of sudden death
No full textSudden cardiac death (SCD) pathophysiological point of view can be either mechanical or electrical. In case of mechanical SCD, the most frequent causes are pulmonary thromboembolism and cardiac tamponade due to intrapericardial rupture (aortic dissection, heart rupture). This distinction is important because cardiac arrest retains survival potential through cardiopulmonary resuscitation and defibrillators only if the rhythm is shockable. The heart diseases that can cause SCD vary according to the age of the individual. In young people, primary electrical diseases ('ion channel diseases') and cardiomyopathies (particularly hypertrophic and arrhythmogenic), both genetically determined and therefore potentially recurred in the proband's family, as well as myocarditis and coronary anomalies prevail; in adult-elderly populations, coronary atherosclerosis with its complications and degenerative valve diseases (aortic stenosis and mitral valve prolapse) predominate. In this short text, the main structural heart diseases characterized by electrical instability at risk of SCD will be recalled, with a focus on coronary, myocardial, and valvular diseases
The workup of ventricular arrhythmias: the ongoing search for a non-invasive tool to diagnose myocardial inflammation
No full textStorytelling of Hypertrophic Cardiomyopathy Discovery
No full textThe discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George’s Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. “Discrete” subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald–Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term “functional subaortic stenosis” was used in 1959 and “idiopathic hypertrophic subaortic stenosis” in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy’s Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989–1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled “HCM without hypertrophy”. Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death
Sudden cardiac death caused by Kawasaki coronary artery vasculitis in a child with Hodgkin's lymphoma. Case report and literature review
No full textCoronary artery vasculitis is a rare pathological condition and is often a manifestation of systemic vasculitis, such as Polyarteritis Nodosa, Kawasaki Disease, Takayasu Arteritis, and Giant Cell Arteritis, with Kawasaki Disease being the most common cause in children. We present the autopsy case of a 6-year-old boy with classic Hodgkin lymphoma who died of sudden cardiac death due to thrombosis caused by vasculitis, which exclusively affected the coronary arteries and was suggestive of Kawasaki Disease. To further investigate the histological features of Kawasaki Disease across all age groups, we conducted a literature review using the search terms “Kawasaki AND vasculitis AND histopathology” and “Kawasaki vasculitis histopathology” in Scopus, Google Scholar, and PubMed, covering the period from 1967 to 2023. The inclusion criteria were as follows: coronary histology (inflammation and/or aneurysm and/or thrombosis), postmortem studies, English language, free articles, all age groups, case reports, and case series
Radiofrequency Catheter Ablation of Atrial Flutter: Interventional Anatomy of the Cavo-Tricuspid Isthmus
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