Karen M. Sliwa

The Task Force on Sports Cardiology and Exercise in Patients with Cardiovascular Disease of the European Society of Cardiology recommends that ‘it would be reasonable to permit intensive exercise and competitive sports in most individuals with pathogenic variants implicated in dilated cardiomyopathy (DCM) in the absence of overt clinical features of the disease’.1 Although the natural history of most pathogenic variants is unknown, special consideration is given to individuals with pathogenic variants that are associated with an increased risk of life-threatening arrhythmias such as lamin A/C or filamin C mutations.1 Individuals with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal variants also have a similar recommendation.2 In these individuals, exercise may have an adverse effect on cardiac function that could potentially result in fatal arrhythmias.3 They should therefore not engage in any competitive sports or recreational exercise of high or very high intensity irrespective of the severity of left ventricular (LV) dysfunction and dilatation.4 However, the Task Force did not make such specific recommendations for carriers of truncated Titin variants (TTNtv).1 TTN is the largest known protein in biology, spanning half the cardiac sarcomere.5 It is therefore a critical component of the cardiac sarcomere that is essential for its mechanical and regulatory functions. TTNtv have been implicated as major disease alleles, responsible for more than 25% of familial cases of DCM, but these variants are also found in 2–3% of the apparently healthy general population.6 It has been postulated that once the TTNtv gets incorporated into the sarcomere, it is unable to function normally, thus leading to gain-of-function/dominant negative phenotypes, resulting in DCM.7 In this edition of the Journal, Savonitto et al.8 have explored, perhaps for the first time, the relationship between lifelong exercise intensity and the development of cardiac manifestations in subjects carrying a TTNtv’.8 This was a retrospective cohort study that included all carriers of TTNtv enrolled in the Familial Cardiomyopathy Registry of Cardiovascular Department of the University of Trieste, Italy. The patient population comprised both the probands (the first family members diagnosed with TTN cardiomyopathy) and their relatives; both the affected (phenotype-positive) and the healthy (phenotype-negative) carriers of the TTNtv. The primary end-point of the study was the development of LV systolic dysfunction, defined as the occurrence of LV ejection fraction below 45%, either at baseline or during the follow-up. The secondary end-points were the occurrence of life-threatening or non-life-threatening arrhythmias, or specifically of atrial fibrillation or flutter, during follow-up. Each patient was evaluated using multiple electrocardiograms (ECGs) and Holter ECGs during follow-up. The study subjects were then grouped into athletes and non-athletes, based on their engagement in a minimum of 4 h of higher-intensity sports (≥6 METs) per week for at least 6 years. The investigators recruited a total of 117 subjects, 27% females and 66% probands, and followed them up for a median of 7.2 years. The results showed that vigorous exercise was not associated with the primary or any of the secondary end-points. Thus, the investigators concluded that, intensive physical activity did not appear to have a significant impact on the development of LV systolic dysfunction or arrhythmias in carriers of TTNtv. The authors also discussed the limitation of the study, including the retrospective study design, the small sample size from a single-centre, and the possibility of social desirability bias, given that the subjects could have altered their responses to align with perceived societal expectations. However, the most important limitation was the selection bias, given that deceased patients with TTNtv in the Familial Cardiomyopathy Registry were excluded from the analysis. The deceased patients could have developed LV dysfunction and died of arrhythmic or heart failure complications. Therefore, by design, the study failed to determine the true impact of intensive exercise on the study end-points. Hence the study conclusion should have been ‘Among the survivors of subjects carrying TTNtv in the Registry, intensive physical activity did not appear to have a significant impact on the development of LV systolic dysfunction or arrhythmias’. As suggested by the authors, the subject is important and should be explored further in a large, multi-ethnic, and multi-centre prospective study.

Background: COVID-19 can cause acute and chronic cardiovascular complications. Acute complications include heart failure, coronary syndrome, arrhythmias, myocarditis, pulmonary embolism, etc. These complications are linked to pre-existing cardiovascular disease (CVD) and increase the risk of adverse outcomes. We characterized acute cardiovascular complications in COVID-19 patients from 32 countries. Methods: This cohort study combined two prospective, multicenter studies of hospitalized adults with COVID-19: the CARDIO COVID 19-20 registry and the WHF COVID-19 CVD study. We performed descriptive and multivariate analyses to assess the incidence of cardiovascular complications, associated factors, and their correlation with mortality. Results: We included 8045 patients from the Americas, Africa, Asia, and Europe. Median age was 59 years (IQR 47-69), and 60.9 % were male. Cardiovascular complications occurred in 1072 patients (13.3 %), most commonly arrhythmias (448, 5.5 %), acute heart failure (441, 5.4 %), and pulmonary embolism (227, 2.8 %). Patients with CVD had higher complication rates (33.1 % vs. 10.2 %), more ICU admissions (56 % vs. 36.7 %), and higher in-hospital mortality (40.4 % vs. 13.2 %). The incidence of complications was highest in the Americas (18.4 %) and Europe (14.9 %). Risk factors included age and cardiometabolic comorbidities. Regression analysis showed that having ≥1 cardiovascular complication increased the risk of in-hospital mortality (aRR 2.32, 95 % CI 2.10-2.55, p < 0.001). Conclusions: Cardiovascular complications affected over 10 % of hospitalized patients, with regional variations. These events were associated with higher mortality and were highly prevalent among those with CVD.

Background: Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (tBil) may reflect congestion and liver dysfunction in acute heart failure (AHF), while lower ALT also associates with sarcopenia. Objective: The purpose of this study was to assess ALT, AST, and tBil levels in AHF patients during high-intensity care (HIC) vs usual care (UC) follow-up. Methods: ALT, AST, and tBil were measured 1 to 2 days predischarge in 1,062 AHF patients, and again after 90 days of either HIC or UC according to the STRONG-HF (Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP testinG, of Heart Failure therapies) protocol. The primary endpoint was 180-day all-cause death or HF hospitalization. Results: Median (Q1-Q3) baseline ALT, AST, and tBil were 21 (15-32) U/L, 23 (17-32) U/L, and 14(10-21) umol/L, respectively. Patients with lower ALT had lower body mass index. Patients with lower ALT, but not tBil or AST, were more likely to have edema, elevated jugular venous pressure, and orthopnea, and use more diuretics prerandomization. A nonsignificant inverse association between ALT and the primary outcome (HR: 0.82 [95% CI: 0.66-1.01] per log-unit, P = 0.06) was observed. Greater reductions of ALT, AST, and tBil to 90 days were associated with greater improvement of edema, rales, NYHA functional class, and N-terminal pro-B-type natriuretic peptide. After 90 days, the HIC group had a greater reduction in AST and tBil than the UC group, while nonsignificant for ALT. The treatment effect of HIC over UC on the primary outcome was consistent across the baseline ALT, AST, and tBil range (all P interaction >0.10), but patients with lower ALT experienced greater health status improvement from HIC. Conclusions: Lower ALT was associated with lower body mass index and more congestion in AHF, supporting previous studies suggesting ALT as a sarcopenia marker. The beneficial effect of HIC on health status was greater in low baseline ALT patients. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201).

The numerical calculation of the theoretically predicted cross sections in Fig. 2 in the Letter were incorrect due to a coding error. As a result, the lower limits on the dyon mass, reported in Table I in the Letter, were overestimated by ∼10–1400  GeV. This error has been corrected now, and the amended cross-section curves and mass bounds are given in Fig. 1 and Table I, respectively. The theoretical cross sections presented in Supplemental Material [1] have been corrected, too. FIG. 1. Corrected version of the original Fig. 2 in the Letter. Cross-section upper limits at 95% CL for DY spin-0, ½, and 1 dyon-pair production, with magnetic charge 1⁢𝑔𝐷 and multiple electric charges, in 13 TeV 𝑝⁢𝑝 collisions. The solid lines are leading-order cross-section calculations. TABLE I. Corrected version of the original Table I in the Letter. 95% CL mass limits found in a Drell-Yan production model for spin-0, spin- ½, and spin-1 dyon-pair direct production in LHC collisions, assuming -independent couplings. Electric charge Magnetic charge Spin 0 1 2 3 4 5 6 10 15 20 25 50 75 100 125 150 175 200 95% CL mass limits (GeV) 1⁢𝑔D 0 870 750 750 750 750 750 750 760 780 790 810 920 970 1010 1010 1000 950 840 2⁢𝑔D 0 1240 1110 1110 1110 1110 1110 1110 1120 1120 1110 1110 1100 1070 1050 1020 950 870 770 3⁢𝑔D 0 1300 1170 1170 1170 1170 1170 1160 1170 1170 1160 1160 1130 1070 1020 940 850 4⁢𝑔D 0 1200 1060 1060 1060 1060 1060 1060 1060 1060 1040 1030 970 900 1⁢𝑔D ½ 1410 1270 1270 1270 1270 1270 1260 1280 1300 1310 1330 1400 1450 1460 1420 1370 1310 2⁢𝑔D ½ 1810 1660 1660 1660 1660 1660 1650 1650 1650 1640 1640 1600 1550 1500 1420 1350 3⁢𝑔D ½ 1840 1700 1700 1690 1690 1680 1680 1670 1670 1650 1640 1580 1500 1420 1330 1280 4⁢𝑔D ½ 1680 1560 1550 1550 1540 1540 1540 1530 1520 1510 1480 1420 1340 1280 1210 5⁢𝑔D ½ 1460 1300 1300 1300 1300 1300 1310 1300 1290 1290 1290 1220 1⁢𝑔D 1 1460 1340 1340 1350 1350 1350 1340 1360 1390 1420 1450 1550 1620 1670 1670 1650 1610 2⁢𝑔D 1 1930 1790 1790 1790 1790 1790 1790 1800 1800 1790 1790 1780 1770 1740 1710 1640 1590 1520 3⁢𝑔D 1 2040 1910 1910 1910 1900 1900 1900 1900 1890 1890 1890 1840 1790 1730 1670 1600 4⁢𝑔D 1 1990 1860 1850 1850 1840 1840 1840 1840 1830 1820 1810 1750 1690 1620 1570 5⁢𝑔D 1 1820 1690 1680 1680 1670 1660 1670 1650 1660 1640 1640 1570 1500 1480 The upper limits on the dyon production cross sections are not affected by this programming lapse. The magnetic-monopole ones have also been amended and match the originally calculated mass limits. The monopole cross-section limits are considerably stronger than their dyon counterparts, even for low electric charges. The reason is that for dyons only the negative charges are (conservatively) considered in the detection efficiency, unlike monopoles where both pair-produced particles are taken into account in the MMT acceptance calculation. The conclusions are modified quantitatively, yet the spirit remains the same, with the dyon mass bounds now ranging from 750 to 1910 GeV, continuing to be the strongest attained in collider experiments.

Objective: Pregnancy in women with a prosthetic heart valve is considered high risk, primarily due to the need for effective anticoagulation. However, data on the relationship between anticoagulation practices and pregnancy outcomes are very limited. Methods: The Registry of Pregnancy and Cardiac disease is a global registry that prospectively enrolled pregnancies in women with a prosthetic heart valve between January 2018 and April 2023. Detailed data on anticoagulation, including dosage and monitoring, and cardiovascular, pregnancy, and perinatal outcomes were collected. Results: In total, 613 pregnancies were included of which 411 pregnancies were in women with a mechanical valve and 202 were in women with a biological valve. The chance of an uncomplicated pregnancy with a live birth in women with a mechanical valve was 54%, compared with 79% in women with a biological valve (P < .001). Thromboembolic and haemorrhagic complications most frequently occurred when low-molecular weight heparin (LMWH)-based regimens were used. Valve thrombosis occurred in 24 (6%) women, and a prosthetic valve in mitral position was associated with valve thrombosis (odds ratio 3.3; 95% confidence interval 1.9-8.0). A thromboembolic event occurred in 12 (10%) women with anti-Xa monitoring and in 9 (21%) women without (P = .060). Foetal death occurred in 20% of all pregnancies. Conclusions: More favourable outcomes were found in women with a biological valve compared with a mechanical valve. In women with a mechanical valve, the use of LMWH was associated with an increased risk of thromboembolic complications. A mitral prosthetic valve was identified as a predictor for valve thrombosis. The benefit could not be confirmed nor refuted, in terms of reduced thromboembolic events, from using anti-Xa level monitoring in women on LMWH.