Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.

Background: Cardiac sequelae of past SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in health-care workers to report evidence of pericarditis and myocarditis after SARS-CoV-2 infection. Methods: We studied 139 health-care workers with confirmed past SARS-CoV-2 infection (103 diagnosed by RT-PCR and 36 by serology). Participants underwent clinical assessment, electrocardiography, laboratory tests including immune cell profiling and cardiac magnetic resonance (CMR). Pericarditis was diagnosed when classical criteria were present, and the diagnosis of myocarditis was based on the updated CMR Lake-Louise-Criteria. Results: Median age was 52 years (IQR 41–57), 100 (72%) were women, and 23 (16%) were previously hospitalized for Covid-19 pneumonia. At examination (10.4 [9.3–11.0] weeks after infection-like symptoms), all participants presented hemodynamic stability. Chest pain, dyspnoea or palpitations were observed in 58 (42%) participants; electrocardiographic abnormalities in 69 (50%); NT-pro-BNP was elevated in 11 (8%); troponin in 1 (1%); and CMR abnormalities in 104 (75%). Isolated pericarditis was diagnosed in 4 (3%) participants, myopericarditis in 15 (11%) and isolated myocarditis in 36 (26%). Participants diagnosed by RT-PCR were more likely to still present symptoms than participants diagnosed by serology (73 [71%] vs 18 [50%]; p=0.027); nonetheless, the prevalence of pericarditis or myocarditis was high in both groups (44 [43%] vs 11 [31%]; p=0.238). Most participants (101 [73%]) showed altered immune cell counts in blood, particularly decreased eosinophil (37 [27%]; p<0.001) and increased CD4 ^- CD8 ^-/lo Tαβ-cell numbers (24 [17%]; p<0.001). Pericarditis was associated with elevated CD4 ^- CD8 ^-/lo Tαβ-cell numbers (p=0.011), while participants diagnosed with myopericarditis or myocarditis had lower (p<0.05) plasmacytoid dendritic cell, NK-cell and plasma cell counts and lower anti-SARS-CoV-2-IgG antibody levels (p=0.027). Conclusions: Pericarditis and myocarditis with clinical stability are frequent long after SARS-CoV-2 infection, even in presently asymptomatic subjects. These observations will probably apply to the general population infected and may indicate that cardiac sequelae might occur late in association with an altered (delayed) innate and adaptative immune response. The trial is registered with ClinicalTrials.gov, number NCT04413071 Research in context: Evidence before this study: Very little evidence exists describing long cardiac sequelae after SARS-CoV-2 infection. Although pericarditis and myocarditis are the two most frequent cardiac manifestations observed after a viral infection, as of May 13, 2020, the peer-reviewed literature was limited to isolated case reports of myocarditis and pericarditis during the COVID-19 hospitalization phase and to a retrospective observation in 26 recovered patients with COVID-19 pneumonia presenting cardiac complaints during hospitalization, revealing the presence of myocardial oedema in 14 (54%) patients and late gadolinium enhancement in 8 (31%) patients. These small size case series, limited to hospitalized RT-PCR patients with COVID-19 pneumonia, are insufficient to generalize conclusions about the true prevalence of pericardial and myocardial long involvement after SARS-CoV-2 infection. In addition, no study has investigated the immunological consequences of SARS-CoV-2 infection in the settings of pericarditis and myocarditis. Added value of this study: To our knowledge, this is the largest cohort of subjects (N=139) —even for other common viruses— with clinical, electrocardiographic, laboratory and CMR imaging evaluations, to assess pericardial and myocardial involvements after SARS-CoV-2 infection. The strength of this study is the addition of non-hospitalized participants and also the inclusion of participants diagnosed of past SARS-CoV-2 infection through serology. Contrary to previous studies, women are well represented. We found a prevalence of pericarditis or myocarditis up to 40% cases; pericarditis coexisted with some degree of concurrent myocardial inflammation in 11% cases. Study participants who were previously hospitalized for COVID-19 pneumonia and patients who received antiviral (hydroxychloroquine, lopinavir-ritonavir) or anti-inflammatory (high-dose glucocorticoids and anti-interleukin treatments) treatments, and who were on chronic drug treatment with statins, were less likely to develop pericarditis or myocarditis. The clinical assessment of the participants showed clinical stability without any patient presenting severe pericardial effusion, heart failure or left ventricular dysfunction. We provide new data on seropositive subjects; although RT-PCR participants were more likely to still present symptoms than participants diagnosed by serology, the prevalence of pericarditis, myocarditis or myocarditis, almost three months after the initial viral prodrome, was high in both groups. In-depth investigation of the distribution of multiple major and minor populations of immune cells in blood showed high frequency of altered immune profiles after SARS-CoV-2 infection. The altered immune cell profiles identified partially mimic abnormalities previously reported during active infection together with others described here for the first time, with unique patterns associated with pericardial and/or myocardial injury. Nonetheless, we also described altered immune profiles in participants without pericardial and myocardial manifestations. Whether these later alterations are due to persistence of tissue damage in other organs affected by SARS-CoV-2, such as the lung, or they reflect normal post-infection immune recovery mechanisms, remains to be investigated. Implications of all the available evidence: At present, there is much interest in the long-term sequelae of COVID-19. It is intriguing that pericarditis and myocarditis were observed so long after SARS-CoV-2 infection and also in some presently asymptomatic subjects, in association with notably altered immune cell profiles in blood. These observations will probably apply to the general population infected and may indicate that cardiac sequelae might occur late, paving the way for a better understanding the immune mechanisms involved. Thus, our study may have health-care consequences given the widespread diagnosis of SARS-CoV-2 infection in population-based seroprevalence studies.

Iodinated contrast media (CM) are the leading cause of acute renal failure of toxic origin. Between 21% and 50% of patients that receive them develop contrast-induced nephropathy (CIN). All prophylactic measures used so far have failed to provide effective prevention. Since oxidative stress is involved in the damage, a possible preventive strategy could be the administration of antioxidant substances, such as quercetin. This compound has shown renoprotective effects in experimental studies. The aim of this study was to evaluate whether quercetin may be helpful in preventing CIN in patients undergoing coronary catheterization. A clinical phase II study was conducted. Patients were distributed in two groups, namely, CM (patients who only received contrast media) and CM+Q (patients who were pretreated with quercetin orally for 3–5 days). Results showed less incidence of CIN in the CM+Q group, possibly due to glomerular protection, evidenced by a lower increase in serum creatinine and albuminuria; and a lower decrease in the glomerular filtration rate (GFR). Furthermore, in this group, the relative risk of developing CIN observed in patients that received a high dose of contrast media was inferior. In conclusion, this is the first study that demonstrates that quercetin is a promising safe candidate in preventing CIN.

Introducción y objetivos: Las secuelas cardiacas tras la infección por SARS-CoV-2 todavía están poco documentadas. Se realizó un estudio transversal en trabajadores sanitarios para estudiar la prevalencia de afección pericárdica y miocárdica tras la infección por SARS-CoV-2. Métodos: Se estudió a 139 trabajadores sanitarios con infección previa por SARS-CoV-2 confirmada. Los participantes se sometieron a evaluación clínica, electrocardiograma, pruebas de laboratorio que incluyeron el perfil de células inmunitarias y resonancia magnética cardiaca (RMC). El diagnóstico clínico de pericarditis se realizó según los criterios clásicos y el diagnóstico clínico de miocarditis, ante la presencia de al menos 2 criterios en la RMC. Resultados: La mediana de edad fue 52 (intervalo, 41-57) años, el 71,9% eran mujeres y el 16,5% se había hospitalizado previamente por neumonía por COVID-19. En la evaluación (10,4 [9,3-11,0] semanas después de los síntomas de infección), todos los participantes presentaban estabilidad hemodinámica. El 41,7% tenía dolor torácico, disnea o palpitaciones; el 49,6%, alteraciones electrocardiográficas; el 7,9%, elevación de NT-proBNP; el 0,7%, elevación de troponina y el 60,4%, alteraciones en la RMC. El 30,9% de los participantes cumplían los criterios clínicos establecidos de pericarditis o miocarditis: pericarditis aislada en el 5,8%, miopericarditis en el 7,9% y miocarditis aislada en el 17,3%. La mayoría de los participantes (73,2%) mostraron recuentos alterados de células inmunitarias en sangre, en particular diminución de eosinófilos (27,3%; p < 0,001) y aumento del número de células T citotóxicas (17,3%; p < 0,001). La sospecha clínica de pericarditis se asoció (p < 0,005) particularmente con un elevado número de células T citotóxicas y recuento de eosinófilos disminuido, mientras que los participantes con sospecha clínica de miopericarditis o miocarditis tenían recuentos de neutrófilos, células natural killer y células plasmáticas más bajos (p < 0,05). Conclusiones: La afección pericárdica y miocárdica con estabilidad hemodinámica es frecuente después de la infección por SARS-CoV-2 y se asocia con perfiles de células inmunitarias específicas. Introduction and objectives The cardiac sequelae of SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in healthcare workers to report evidence of pericardial and myocardial involvement after SARS-CoV-2 infection. Methods We studied 139 healthcare workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, and laboratory tests, including immune cell profiling and cardiac magnetic resonance (CMR). Clinically suspected pericarditis was diagnosed when classic criteria were present and clinically suspected myocarditis was based on the combination of at least 2 CMR criteria. Results Median age was 52 (41-57) years, 71.9% were women, and 16.5% were previously hospitalized for COVID-19 pneumonia. On examination (10.4 [9.3-11.0] weeks after infection-like symptoms), participants showed hemodynamic stability. Chest pain, dyspnea or palpitations were present in 41.7% participants, electrocardiographic abnormalities in 49.6%, NT-proBNP elevation in 7.9%, troponin in 0.7%, and CMR abnormalities in 60.4%. A total of 30.9% participants met criteria for either pericarditis and/or myocarditis: isolated pericarditis was diagnosed in 5.8%, myopericarditis in 7.9%, and isolated myocarditis in 17.3%. Most participants (73.2%) showed altered immune cell counts in blood, particularly decreased eosinophil (27.3%; P < .001) and increased cytotoxic T cell numbers (17.3%; P < .001). Clinically suspected pericarditis was associated (P < .005) with particularly elevated cytotoxic T cells and decreased eosinophil counts, while participants diagnosed with clinically suspected myopericarditis or myocarditis had lower (P < .05) neutrophil counts, natural killer-cells, and plasma cells. Conclusions Pericardial and myocardial involvement with clinical stability are frequent after SARS-CoV-2 infection and are associated with specific immune cell profiles.

Background: Inclisiran is a novel lipid-lowering agent targeting PCSK9 via small interfering RNA (siRNA) technology. While clinical trials such as the ORION studies have demonstrated significant reductions in low-density lipoprotein cholesterol (c-LDL), real-world data (RWD) often differ due to variations in patient populations and clinical practices. Methods: This systematic review and meta-analysis adhered to PRISMA guidelines. A comprehensive search was conducted in MEDLINE for real-world studies evaluating inclisiran’s efficacy in reducing c-LDL. Articles meeting predefined inclusion criteria were assessed for quality and bias using RTI Item Bank. Data transformations were applied to harmonize median and IQR values to means and standard deviations for meta-analytic synthesis using RevMan 5.4. Results: A total of 3774 articles were identified, of which 7 studies comprising 1454 patients met the inclusion criteria. The meta-analysis revealed an average c-LDL reduction of 42.77% (95% CI: 37.42–48.12%). The subgroup analysis indicated greater reductions in patients receiving inclisiran alongside statins (45.67%; 95% CI: 36.64–54.71%) compared to monotherapy (37.53%; 95% CI: 29.91–45.15%). Discrepancies with clinical trials (e.g., 52% reduction in ORION studies) were attributed to baseline c-LDL differences and real-world adherence. Conclusions: Inclisiran demonstrates robust efficacy in real-world settings, achieving significant c-LDL reductions with a convenient dosing schedule. However, the observed discrepancies with clinical trials highlight the need for further RWD studies to bridge gaps in effectiveness and optimize therapeutic outcomes.