Efstathios Papatheodorou

BACKGROUND: Studies in ostensibly healthy male master athletes have revealed a greater prevalence of coronary artery calcification (CAC) and coronary plaques compared with relatively sedentary counterparts. In contrast, data relating to potentially adverse coronary remodelling in female master athletes is sparse and conflicting. We investigated the prevalence of coronary atherosclerosis in a cohort of predominantly post-menopausal female master athletes with a low atherosclerotic risk profile. METHODS: 196 female athletes with a mean age of 55±7 years-old and median exercise duration of 33 years (25-39) and 59 relatively sedentary females of similar age underwent cardiovascular investigations including a coronary computed tomogram angiography with assessment of CAC scores, coronary plaques, and pericoronary adipose tissue attenuation. 70% of the athletes and 68% of the control group were post-menopausal. RESULTS: Athletes and controls had a similarly low Framingham 10-year risk (1.49% versus 2.1%; P=0.68), but body mass index and blood pressure were lower and HDL-C was higher in the athletes. The prevalence of CAC score >0 Agatston units (AU) was low and did not differ between athletes and controls (21% versus 32%;P=0.073). Female athletes had a lower prevalence of a CAC score >50 ^th centile (19% versus 32%;P75 ^th centile (14% versus 25%;P=0.045) for age compared with controls, but the prevalence of a CAC score >100 AU did not differ between the groups (3.6% versus 8.5%;P=0.12). There were also no differences between the groups in the prevalence of individuals with coronary plaques (21% versus 32%;P=0.09), total plaque volume (16 mm ³ [IQR 3-56] versus 49 [5-142] mm ³ ;P=0.08), or plaque burden (10.8% [2.8-21] versus 15.4% [4.6-28];P=0.46). Coronary plaques were predominantly calcified in both athletes and controls (80% versus 63%;P=0.08). Age, blood pressure and HDL-C were independent predictors for a CAC score >0 AU among athletes. CONCLUSIONS: In contrast with previous studies in male master athletes, lifelong exercise in female counterparts does not appear to be associated with increased CAC score, coronary plaque burden or any qualitative differences in coronary plaque compared with relatively sedentary healthy counterparts. Coronary atherosclerosis in master female athletes is mainly driven by traditional risk factors.

Background: Homozygous truncating mutations located in the C-terminal region of the desmoplakin gene (DSP) are known to mainly cause Carvajal syndrome, an autosomal recessive syndromic form of arrhythmogenic cardiomyopathy with an extra-cardiac cutaneous phenotype. Case presentation: Here we describe a female proband with a documented arrhythmogenic left ventricular cardiomyopathy and a syncopal episode at the age of 13, who was found homozygous for the novel DSP variant: NM_004415.4:c.8586delC, p.(Ser2863Hisfs*20) at the extreme C-terminal region of the protein, just 8 amino acids upstream the stop codon. She did not have any of the typical dermatological symptoms that characterize Carvajal syndrome. Her brother had died suddenly at the age of 18 during exercise and was found homozygous for the same variant at the post-mortem, while their parents were heterozygous. The region of origin of both parents was the same geographic area of Greece, but they were not aware of any common ancestor. Detailed clinical examination revealed that the mother displayed a mild arrhythmic phenotype, while the father was asymptomatic. Conclusion: These observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein.

Background: Myocarditis is increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Purpose: The aim of our study was to define if a genetic predisposition exists in cases of myocarditis with suspicious findings of inherited cardiovascular disease (noise) in the family. Methods: Consecutive patients referred to our unit from 2010 to 2021, with a presentation of acute or clinically suspected myocarditis, as defined by current criteria, went through family screening of the first and second-degree relatives. Patients fulfilling typical criteria for definite ARVC upon presentation were excluded. Patients with suspicious familial findings (familial noise) including a. family history of sudden cardiac death, b. family history of myocarditis or cardiomyopathy or c. findings suggestive of cardiac disease in the relatives (ECG abnormalities, complex or frequent ventricular arrhythmias, conduction disease, troponemia, structural abnormalities suggestive of cardiomyopathy) went through genetic analysis for 90 genes associated with cardiomyopathy. Results: Fifty-five patients with myocarditis and familial noise were included (Table 1). In 49 (89%) patients ≥2 diagnostic criteria for clinically suspected myocarditis were fulfilled. In 50% of the patients, the noise in the family was revealed upon familial screening as there was no relevant family history. Myocardial inflammation was confirmed in 16 (29%) patients with histological findings on endomyocardial biopsy or ≥2 Lake Louise Criteria on cardiac magnetic resonance. Pathogenic or likely pathogenic variants were identified in 78% of the cases (figure 1). Desmoplakin (24%) followed by lamin A/C (13%) and titin (9%) were the most common genes identified. In cases with confirmed myocardial inflammation the genetic yield increased to 87%. Conclusions: A significant proportion of myocarditis patients with “familial noise” carry a pathogenic genetic variant in a cardiomyopathy related gene. These findings potentially affect the clinical management and need for family and genetic screening in patients with clinically suspected myocarditis. Funding Acknowledgement: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Greek Network for Precision Medicine in Cardiology and the Prevention of Sudden Cardiac Death in the Young, icardiacnet

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.

Aims: Marathon running is a popular ambition in modern societies inclusive of non-athletes. Previous studies have highlighted concerning transient myocardial dysfunction and biomarker release immediately after the race. Whether this method of increasing physical activity is beneficial or harmful remains a matter of debate. We examine in detail the real-world cardiovascular remodeling response following competition in a first marathon. Methods: Sixty-eight novice marathon runners (36 men and 32 women) aged 30 ± 3 years were investigated 6 months before and 2 weeks after the 2016 London Marathon race in a prospective observational study. Evaluation included electrocardiography, cardiopulmonary exercise testing, echocardiography, and cardiovascular magnetic resonance imaging. Results: After 17 weeks unsupervised marathon training, runners revealed a symmetrical, eccentric remodeling response with 3–5% increases in left and right ventricular cavity sizes, respectively. Blood pressure (BP) fell by 4/2 mmHg (P < 0.01) with reduction in arterial stiffness, despite only 11% demonstrating a clinically meaningful improvement in peak oxygen consumption with an overall non-significant 0.4 ml/min/kg increase in peak oxygen consumption (P = 0.14). Conclusion: In the absence of supervised training, exercise-induced cardiovascular remodeling in real-world novice marathon runners is more modest than previously described and occurs even without improvement in cardiorespiratory fitness. The responses are similar in men and women, who experience a beneficial BP reduction and no evidence of myocardial fibrosis or persistent edema, when achieving average finishing times.

Aim To investigate the accuracy of the recently published international recommendations for ECG interpretation in young athletes in a large cohort of white and black adolescent soccer players. Methods 11 168 soccer players (mean age 16.4±1.2 years) were evaluated with a health questionnaire, ECG and echocardiogram; 10 581 (95%) of the players were male and 10 163 (91%) were white. ECGs were retrospectively analysed according to (1) the 2010 European Society of Cardiology (ESC) recommendations, (2) Seattle criteria, (3) refined criteria and (4) the international recommendations for ECG interpretation in young athletes. Results The ESC recommendations resulted in a higher number of abnormal ECGs compared with the Seattle, refined and international criteria (13.2%, 4.3%, 2.9% and 1.8%, respectively). All four criteria were associated with a higher prevalence of abnormal ECGs in black athletes compared with white athletes (ESC: 16.2% vs 12.9%; Seattle: 5.9% vs 4.2%; refined: 3.8% vs 2.8%; international 3.6% vs 1.6%; pConclusions The 2017 international recommendations for ECG interpretation in young athletes can be applied to adolescent athletes to detect serious cardiac disease. These recommendations perform more effectively than previous ECG criteria in both white and black adolescent soccer players.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. Methods: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. Results: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54–13.68; P =0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39–51.24; P <0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. Conclusions: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.