Oral Co-Supplementation of Curcumin, Quercetin, and Vitamin D3 as an Adjuvant Therapy for Mild to Moderate Symptoms of COVID-19-Results From a Pilot Open-Label, Randomized Controlled Trial

Background: Curcumin, quercetin, and vitamin D3 (cholecalciferol) are common natural ingredients of human nutrition and reportedly exhibit promising anti-inflammatory, immunomodulatory, broad-spectrum antiviral, and antioxidant activities. Objective: The present study aimed to investigate the possible therapeutic benefits of a single oral formulation containing supplements curcumin, quercetin, and cholecalciferol (combinedly referred to here as CQC) as an adjuvant therapy for early-stage of symptomatic coronavirus disease 2019 (COVID-19) in a pilot open-label, randomized controlled trial conducted at Mayo Hospital, King Edward Medical University, Lahore, Pakistan. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed, mild to moderate symptomatic COVID-19 outpatients were randomized to receive either the standard of care (SOC) (n = 25) (control arm) or a daily oral co-supplementation of 168 mg curcumin, 260 mg quercetin, and 9 µg (360 IU) of cholecalciferol, as two oral soft capsules b.i.d. as an add-on to the SOC (n = 25) (CQC arm) for 14 days. The SOC includes paracetamol with or without antibiotic (azithromycin). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR test, acute symptoms, and biochemistry including C-reactive protein (CRP), D-dimer, lactate dehydrogenase, ferritin, and complete blood count were evaluated at baseline and follow-up day seven. Results: Patients who received the CQC adjuvant therapy showed expedited negativization of the SARS-CoV-2 RT-PCR test, i.e., 15 (60.0%) vs. five (20.0%) of the control arm, p = 0.009. COVID-19- associated acute symptoms were rapidly resolved in the CQC arm, i.e., 15 (60.0%) vs. 10 (40.0%) of the control arm, p = 0.154. Patients in the CQC arm experienced a greater fall in serum CRP levels, i.e., from (median (IQR) 34.0 (21.0, 45.0) to 11.0 (5.0, 16.0) mg/dl as compared to the control arm, i.e., from 36.0 (28.0, 47.0) to 22.0 (15.0, 25.0) mg/dl, p = 0.006. The adjuvant therapy of co-supplementation of CQC was safe and well-tolerated by all 25 patients and no treatment-emergent effects, complications, side effects, or serious adverse events were reported. Conclusion: The co-supplementation of CQC may possibly have a therapeutic role in the early stage of COVID-19 infection including speedy negativization of the SARS-CoV-2 RT-PCR test, resolution of acute symptoms, and modulation of the hyperinflammatory response. In combination with routine care, the adjuvant co-supplementation of CQC may possibly help in the speedy recovery from early-stage mild to moderate symptoms of COVID-19. Further research is warranted. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT0513067

The miRNA199a/SIRT1/P300/Yy1/sST2 signaling axis regulates adverse cardiac remodeling following MI.

Left ventricular remodeling following myocardial infarction (MI) is related to adverse outcome. It has been shown that an up-regulation of plasma soluble ST2 (sST2) levels are associated with lower pre-discharge left ventricular (LV) ejection fraction, adverse cardiovascular outcomes and mortality outcome after MI. The mechanisms involved in its modulation are unknown and there is not specific treatment capable of lowering plasma sST2 levels in acute-stage HF. We recently identified Yin-yang 1 (Yy1) as a transcription factor related to circulating soluble ST2 isoform (sST2) expression in infarcted myocardium. However, the underlying mechanisms involved in this process have not been thoroughly elucidated. This study aimed to evaluate the pathophysiological implication of miR-199a-5p in cardiac remodeling and the expression of the soluble ST2 isoform. Myocardial infarction (MI) was induced by permanent ligation of the left anterior coronary artery in C57BL6/J mice that randomly received antimiR199a therapy, antimiR-Ctrl or saline. A model of biomechanical stretching was also used to characterize the underlying mechanisms involved in the activation of Yy1/sST2 axis. Our results show that the significant upregulation of miR-199a-5p after myocardial infarction increases pathological cardiac hypertrophy by upregulating circulating soluble sST2 levels. AntimiR199a therapy up-regulates Sirt1 and inactivates the co-activator P300 protein, thus leading to Yy1 inhibition which decreases both expression and release of circulating sST2 by cardiomyocytes after myocardial infarction. Pharmacological inhibition of miR-199a rescues cardiac hypertrophy and heart failure in mice, offering a potential therapeutic approach for cardiac failure.This study was supported by a grant from the Seneca Foundation-Agency of Science and Technology of the Region of Murcia (20652/JLI/18) and a grant from the Instituto de Salud Carlos III (PI19/00519) which is cofinanced through the European Union's European Regional Development Fund (FEDER). Dr. Lax is a Ramon and Cajal researcher at the Department of Medicine, University of Murcia.S

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome.

Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.This work was supported by Fundación “la Caixa” (grant number LCF/PR/HR17/52150007 to VF, and JJF). JJF is supported by a Ramón y Cajal award (RYC2016–20026) from the Spanish Ministerio de Ciencia e Innovación (MICIN)/Agencia Estatal de Investigación (AEI)/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro”. VA’s lab is supported by MICIN/ AEI/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro” (grant number PID2019-108489RBI00), the Progeria Research Foundation (Award PRF 2019–77), and a donation from Asociación Progeria Alexandra Peraut. LBG is supported by The Progeria Research Foundation. MDD is supported by a predoctoral FPI fellowship from the Spanish MICIN/AEI/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro” (PRE2019-087463), and MA-P is supported by a predoctoral FPU contract from the Ministerio de Educación, Cultura y Deporte (FPU18/02913). The CNIC is supported by the MICIN, the Instituto de Salud Carlos III, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant number CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033).S

Influence of diabetes on sacubitril/valsartan titration and clinical outcomes in patients hospitalized for heart failure.

Diabetes mellitus is associated with worse outcomes and lower attainment of disease-modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co-morbidity. TRANSITION, a randomized, open-label study compared sacubitril/valsartan initiation pre-discharge vs. post-discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10-week and 26-week post-randomization. Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre-discharge or post-discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non-diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non-diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non-diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre-discharge or post-discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non-diabetes subgroups at 10 weeks, respectively: pre-discharge (7.5% vs. 7.1%) or post-discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT-proBNP (P < 0.005) and hs-TnT (P < 0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non-diabetes subgroups: 3.3% vs 4.0%; P = 0.438) and HF rehospitalization (diabetes vs. non-diabetes subgroups: 36.3% vs. 33.0%; P = 0.295) did not differ between the groups at 26 weeks. Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up-titration and tolerability as in those without diabetes.The study was funded by Novartis Pharma AG, Basel,Switzerland.S

Coronary Artery Disease and Prognosis of Heart Failure with Reduced Ejection Fraction.

Our aim was to determine the prognostic impact of coronary artery disease (CAD) on heart failure with reduced ejection fraction (HFrEF) mortality and readmissions. From a prospective multicenter registry that included 1831 patients hospitalized due to heart failure, 583 had a left ventricular ejection fraction of <40%. In total, 266 patients (45.6%) had coronary artery disease as main etiology and 137 (23.5%) had idiopathic dilated cardiomyopathy (DCM), and they are the focus of this study. Significant differences were found in Charlson index (CAD 4.4 ± 2.8, idiopathic DCM 2.9 ± 2.4, p < 0.001), and in the number of previous hospitalizations (1.1 ± 1, 0.8 ± 1.2, respectively, p = 0.015). One-year mortality was similar in the two groups: idiopathic DCM (hazard ratio [HR] = 1), CAD (HR 1.50; 95% CI 0.83-2.70, p = 0.182). Mortality/readmissions were also comparable: CAD (HR 0.96; 95% CI 0.64-1.41, p = 0.81). Patients with idiopathic DCM had a higher probability of receiving a heart transplant than those with CAD (HR 4.6; 95% CI 1.4-13.4, p = 0.012). The prognosis of HFrEF is similar in patients with CAD etiology and in those with idiopathic DCM. Patients with idiopathic DCM were more prone to receive heart transplant.This research was funded by CIBERCV I and supported by the Instituto de Salud Carlos III. L.V. is funded by the Instituto de Salud Carlos III, Spain (CM20/00104 and ).S

Critical warm ischemia time point for cardiac donation after circulatory death.

Donation after circulatory death (DCD) represents a promising opportunity to overcome the relative shortage of donors for heart transplantation. However, the necessary period of warm ischemia is a concern. This study aims to determine the critical warm ischemia time based on in vivo biochemical changes. Sixteen DCD non-cardiac donors, without cardiovascular disease, underwent serial endomyocardial biopsies immediately before withdrawal of life-sustaining therapy (WLST), at circulatory arrest (CA) and every 2 min thereafter. Samples were processed into representative pools to assess calcium homeostasis, mitochondrial function and cellular viability. Compared to baseline, no significant deterioration was observed in any studied parameter at the time of CA (median: 9 min; IQR: 7-13 min; range: 4-19 min). Ten min after CA, phosphorylation of cAMP-dependent protein kinase-A on Thr197 and SERCA2 decreased markedly; and parallelly, mitochondrial complex II and IV activities decreased, and caspase 3/7 activity raised significantly. These results did not differ when donors with higher WLST to CA times (≥9 min) were analyzed separately. In human cardiomyocytes, the period from WLST to CA and the first 10 min after CA were not associated with a significant compromise in cellular function or viability. These findings may help to incorporate DCD into heart transplant programs.Fundación Mutua Madrileña.S

Impact of dapagliflozin on cardiac remodelling in patients with chronic heart failure: The DAPA-MODA study.

AIMS Dapagliflozin improves the prognosis of patients with heart failure (HF), regardless of left ventricular ejection fraction (LVEF). However, its effect on cardiac remodelling parameters, specifically left atrial (LA) remodelling, is not well established. METHODS AND RESULTS The DAPA-MODA trial (NCT04707352) is a multicentre, single-arm, open-label, prospective and interventional study that aimed to evaluate the effect of dapagliflozin on cardiac remodelling parameters over 6 months. Patients with stable chronic HF receiving optimized guideline-directed therapy, except for any sodium-glucose cotransporter 2 inhibitor, were included. Echocardiography was performed at baseline, 30 and 180 days, and analysed by a central core-lab in a blinded manner to both patient and time. The primary endpoint was the change in maximal LA volume index (LAVI). A total of 162 patients (64.2% men, 70.5 ± 10.6 years, 52% LVEF >40%) were included in the study. At baseline, LA dilatation was observed (LAVI 48.1 ± 22.6 ml/m2 ) and LA parameters were similar between LVEF-based phenotypes (≤40% vs. >40%). LAVI showed a significant reduction at 180 days (-6.6% [95% confidence interval -11.1, -1.8], p = 0.008), primarily due to a decrease in reservoir volume (-13.8% [95% confidence interval -22.5, -4], p = 0.007). Left ventricular geometry improved with significant reductions in left ventricular mass index (-13.9% [95% confidence interval -18.7, -8.7], p < 0.001), end-diastolic volume (-8.0% [95% confidence interval -11.6, -4.2], p < 0.001) and end-systolic volume (-11.9% [95% confidence interval -16.7, -6.8], p < 0.001) at 180 days. N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed a significant reduction at 180 days (-18.2% [95% confidence interval -27.1, -8.2], p < 0.001), without changes in filling Doppler measures. CONCLUSION Dapagliflozin administration in stable out-setting patients with chronic HF and optimized therapy results in global reverse remodelling of cardiac structure, including reductions in LA volumes and improvement in left ventricular geometry and NT-proBNP concentrations.This study has been sponsored by Sociedad Española de Cardiología and has received funding by a non-conditional investigational grant from AstraZeneca Farmacéutica Spain.S

Indicadores de calidad en cardiología. Principales indicadores para medir la calidad de los resultados (indicadores de resultados) y parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). INCARDIO (Indicadores de Calidad en Unidades Asistenciales del Área del Corazón): Declaración de posicionamiento de consenso de SEC/SECTCV

ResumenLa práctica clínica cardiológica requiere una organización compleja que influya en los resultados globales y puede diferir sustancialmente entre distintos hospitales y comunidades. El objetivo de este documento de consenso es definir indicadores de calidad en cardiología, incluidos los indicadores para medir la calidad de los resultados (indicadores de resultados) y los parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). El documento está destinado principalmente al sistema de asistencia sanitaria de España y puede servir de base para documentos similares en otros países.AbstractCardiology practice requires complex organization that impacts overall outcomes and may differ substantially among hospitals and communities. The aim of this consensus document is to define quality markers in cardiology, including markers to measure the quality of results (outcomes metrics) and quality measures related to better results in clinical practice (performance metrics). The document is mainly intended for the Spanish health care system and may serve as a basis for similar documents in othe rcountries

Impact of ferric carboxymaltose for iron deficiency at discharge after heart failure hospitalization: a European multinational economic evaluation.

AIMS Iron deficiency (ID) is comorbid in up to 50% patients with heart failure (HF) and exacerbates disease burden. Ferric carboxymaltose (FCM) reduced HF hospitalizations and improved quality of life when used to treat ID at discharge in patients hospitalized for acute HF with left ventricular ejection fraction <50% in the AFFIRM-AHF trial. We quantified the effect of FCM on burden of disease and the wider pharmacoeconomic implications in France, Germany, Poland, Spain and Sweden. METHODS AND RESULTS The per country eligible population was calculated, aligning with the 2021 European Society of Cardiology (ESC) HF guidelines and the AFFIRM-AHF trial. Changes in burden of disease with FCM versus standard of care (SoC) were represented by disability-adjusted life years (DALYs), hospitalization episodes and bed days, using AFFIRM-AHF data. A Markov model was adapted to each country to estimate cost-effectiveness and combined with epidemiology data to calculate the impact on healthcare budgets. Between 335 (Sweden) and 13 237 (Germany) DALYs were predicted to be avoided with FCM use annually. Fewer hospitalizations and shorter lengths of stay associated with FCM compared to SoC were projected to result in substantial annual savings in bed days, from 5215 in Sweden to 205 630 in Germany. In all countries, FCM was predicted to be dominant (cost saving with gains in quality-adjusted life years), resulting in net savings to healthcare budgets within 1 year. CONCLUSIONS This comprehensive evaluation of FCM therapy highlights the potential benefits that could be realized through implementation of the ESC HF guideline recommendations regarding ID treatment.This work was supported by CSL Vifor, who provided support for model development, data analysis and medical writing for this study.S

Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial

Aims. The LION‐HEART study was a multicentre, double‐blind, randomised, parallel‐group, placebo‐controlled trial evaluating the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. Methods and results. Sixty‐nine patients from 12 centres were randomly assigned at a 2:1 ratio to levosimendan or placebo groups, receiving treatment by a 6‐hour intravenous infusion (0.2 μg/kg/min without bolus) every 2 weeks for 12 weeks. The primary endpoint was the effect on serum concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) throughout the treatment period in comparison with placebo. Secondary endpoints included evaluation of safety, clinical events and health‐related quality of life (HRQoL). The area under the curve (AUC, pg.day/mL) of the levels of NT‐proBNP over time for patients who received levosimendan was significantly lower than for the placebo group (344 × 103 [95% Confidence Interval (CI) 283 × 103−404 × 103] vs. 535 × 103 [443 × 103−626 × 103], p = 0.003). In comparison with the placebo group, the patients on levosimendan experienced a reduction in the rate of heart failure hospitalisation (hazard ratio 0.25; 95% CI 0.11-0.56; P = 0.001). Patients on levosimendan were less likely to experience a clinically significant decline in HRQoL over time (P = 0.022). Adverse event rates were similar in the two treatment groups. Conclusions. In this small pilot study, intermittent administration of levosimendan to ambulatory patients with advanced systolic heart failure reduced plasma concentrations of NT‐proBNP, worsening of HRQoL and hospitalisation for heart failure. The efficacy and safety of this intervention should be confirmed in larger trials