Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.

BACKGROUND: The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure. METHODS AND RESULTS: Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

Sodium Glucose Transporter 2 Inhibitors Versus Metformin on Cardiovascular and Renal Outcomes in Patients With Diabetes With Low Cardiovascular Risk: A Nationwide Cohort Study.

BACKGROUND: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes. METHODS AND RESULTS: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65. CONCLUSIONS: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

INTRODUCTION: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. AREAS COVERED: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. EXPERT OPINION: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.

Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study.

OBJECTIVE: To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. DESIGN: Population based matched cohort study. SETTING: Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. POPULATION: Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling. MAIN OUTCOME MEASURES: The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding. RESULTS: Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%). CONCLUSIONS: Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

[Cardiotoxicity risk assessment of anti-cancer drugs and future perspectives].

Cardiotoxicity is a serious adverse effect of anti-cancer drugs. Anti-cancer drug-induced cardiotoxicity are arrhythmia, cardiac contractile dysfunction, coronary artery disease, and hypertension, which affect to the quality of life in patients with cancer. In particular, cardiac contractile dysfunction is a life-threatening symptom leading to heart failure, suggesting that it is very important to predict the risk of developing the contractile dysfunction by anti-cancer drugs. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to assess the risk of drug-induced arrhythmias. This prompts us to evaluate other cardiotoxic effects such as contractility dysfunction and structural toxicity with hiPSC-CMs. Since anti-cancer drug-induced contractility dysfunction are considered to be induced by chronic exposure, we have developed a method to assess chronic contractility dysfunction by imaging analysis of hiPSC-CMs. BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound. We found that chronic exposure to BMS-986094 decreased the contraction and relaxation velocity in hiPSC-CMs. Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity.

Delayed cardiotoxicity following osimertinib therapy in non-small cell lung cancer: a unique case report.

This case report features a 62-year-old male with stage IB lung adenocarcinoma harboring an epidermal growth factor receptor exon 19 deletion, who underwent treatment with osimertinib following a left upper lobectomy and lymph node dissection. Despite a history of smoking and well-managed type 2 diabetes, the patient developed heart failure 18 months post-initiation of osimertinib therapy, marking one of the latest occurrences of heart failure following osimertinib treatment documented in limited literature. Cardiac MRI revealed significant left ventricular enlargement, lateral wall myocardial thinning, and localized myocardial fibrosis without perfusion defects, a finding not previously reported in literature. This case underscores the severe and unusual cardiac effects of osimertinib in patients with latent risk factors, highlighting the importance of vigilant cardiac monitoring and a multidisciplinary management approach.

PRDX6 alleviated heart failure by inhibiting doxorubicin-induced ferroptosis through the JAK2/STAT1 pathway inactivation.

Peroxiredoxin 6 (PRDX6) is a protective biomarker associated with ferroptosis in heart failure (HF). This study investigated the specific mechanism of PRDX6 on doxorubicin (DOX)-induced ferroptosis in HF. Wistar rats and H9c2 cells were induced by DOX to construct HF models. Pathological changes and collagen deposition in myocardium were investigated using HE and Masson staining. PRDX6 levels, indexes of ferroptosis, and JAK2/STAT1 pathway were detected by qRT-PCR, Western blot, and biochemical kits. DOX promoted heart weight/body weight, increased inflammation and collagen deposition, increased PTGS2 and MDA levels, and decreased SLC7A11, GPX4, FTH1, and PRDX6 levels in myocardium. PRDX6 overexpression reduced PTGS2, MDA, Fe2+, and LDH levels, inhibited JAK2 and STAT1 phosphorylation, and increased SLC7A11, GPX4, and FTH1 levels in DOX-added H9c2 cells. RO8191 and erastin reversed the inhibition of PRDX6 on ferroptosis through the JAK2/STAT1 pathway. Overall, PRDX6 alleviated HF by inhibiting DOX-induced ferroptosis through the JAK2/STAT1 pathway inactivation.

Acute High-Output Heart Failure with Pulmonary Hypertension and Severe Liver Injury Caused by Amlodipine Poisoning: A Case Report.

Acute high-output heart failure (HOHF) with pulmonary hypertension and liver injury caused by amlodipine poisoning is very rare. We report a 52-year-old woman who suffered from severe shock after an overdose of amlodipine. Hemodynamic monitoring showed that while her left ventricular systolic function and cardiac output were elevated, her systemic vascular resistance decreased significantly. At the same time, the size of her right heart, her central venous pressure, and the oxygen saturation of her central venous circulation all increased abnormally. The patient's circulatory function and right ventricular dysfunction gradually improved after large doses of vasopressors and detoxification measures. However, her bilirubin and transaminase levels increased significantly on hospital day 6, with a CT scan showing patchy, low-density areas in her liver along with ascites. After liver protective treatment and plasma exchange, the patient's liver function gradually recovered. A CT scan 4 months later showed all her liver abnormalities, including ascites, had resolved. The common etiologies of HOHF were excluded in this case, and significantly reduced systemic vascular resistance caused by amlodipine overdose was thought to be the primary pathophysiological basis of HOHF. The significant increase in venous return and pulmonary blood flow is considered to be the main mechanism of right ventricular dysfunction and pulmonary hypertension. Hypoxic hepatitis caused by a combination of hepatic congestion and distributive shock may be the most important factors causing liver injury in this patient. Whether amlodipine has other mechanisms leading to HOHF and pulmonary hypertension needs to be further studied. Considering the significant increase of right heart preload, aggressive fluid resuscitation should be done very cautiously in patients with HOHF and shock secondary to amlodipine overdose.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Exposure-response associations between chronic exposure to fine particulate matter and risks of hospital admission for major cardiovascular diseases: population based cohort study.

OBJECTIVE: To estimate exposure-response associations between chronic exposure to fine particulate matter (PM2.5) and risks of the first hospital admission for major cardiovascular disease (CVD) subtypes. DESIGN: Population based cohort study. SETTING: Contiguous US. PARTICIPANTS: 59 761 494 Medicare fee-for-service beneficiaries aged ≥65 years during 2000-16. Calibrated PM2.5 predictions were linked to each participant's residential zip code as proxy exposure measurements. MAIN OUTCOME MEASURES: Risk of the first hospital admission during follow-up for ischemic heart disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, valvular heart disease, thoracic and abdominal aortic aneurysms, or a composite of these CVD subtypes. A causal framework robust against confounding bias and bias arising from errors in exposure measurements was developed for exposure-response estimations. RESULTS: Three year average PM2.5 exposure was associated with increased relative risks of first hospital admissions for ischemic heart disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, and thoracic and abdominal aortic aneurysms. For composite CVD, the exposure-response curve showed monotonically increased risk associated with PM2.5: compared with exposures ≤5 µg/m3 (the World Health Organization air quality guideline), the relative risk at exposures between 9 and 10 µg/m3, which encompassed the US national average of 9.7 µg/m3 during the study period, was 1.29 (95% confidence interval 1.28 to 1.30). On an absolute scale, the risk of hospital admission for composite CVD increased from 2.59% with exposures ≤5 µg/m3 to 3.35% at exposures between 9 and 10 µg/m3. The effects persisted for at least three years after exposure to PM2.5. Age, education, accessibility to healthcare, and neighborhood deprivation level appeared to modify susceptibility to PM2.5. CONCLUSIONS: The findings of this study suggest that no safe threshold exists for the chronic effect of PM2.5 on overall cardiovascular health. Substantial benefits could be attained through adherence to the WHO air quality guideline.

Possible Digoxin-Related Toxic Effects in a Patient.

This case report describes a patient in their 70s with hypertension and heart failure presenting to the emergency department with chest discomfort, nausea, anorexia, and weakness.

Progression of Myocardial 18F-FDG Uptake in a Patient with Cardiotoxicity. / Evolução da Captação Miocárdica de 18F-FDG em Paciente com Diagnóstico de Cardiotoxicidade.

The objective of this case report was to present the progression of chemotherapy-induced cardiotoxicity in a patient with lymphoma, highlighting the importance of myocardial fluor-18-fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography coupled with computed tomography (PET/CT). 43-year-old female patient with uterine lymphoma, who underwent hysterectomy followed by three chemotherapy regimens and radiotherapy. The patient had episodes of acute heart failure two years after chemotherapy. Echocardiogram revealed a reduction in left ventricular ejection fraction (LVEF). A retrospective analysis of 18F-FDG PET/CT showed an increase in myocardial uptake in all tests performed during oncologic treatment. Despite disease remission, the patient developed heart failure with reduced LVEF. During chemotherapy, there was a diffuse, significant increase in myocardial 18F-FDG uptake, which preceded the decrease in myocardial performance and seemed to reflect metabolic changes in cardiomyocytes, related to cardiotoxicity. Would an analysis of myocardial 18F-FDG uptake yield a different cardiac outcome in this patient? This question is relevant, considering that other patients may benefit from the use of PET as an early marker of cardiotoxicity. Imaging tests are essential in the follow-up of patients at risk of cardiotoxicity. Although echocardiography remains the main imaging test in the diagnosis of cardiotoxicity, 18F-FDG PET/CT may be a powerful tool for the early diagnosis of this condition.

O objetivo deste relato é mostrar a evolução da cardiotoxicidade (CTX) por quimioterápicos em paciente com linfoma por exames de imagens, destacando a importância da captação miocárdica de flúor-18 fluordeoxiglicose (18F-FDG) pela tomografia por emissão de pósitrons, acoplada à tomografia computadorizada (PET/CT). Feminino, 43 anos, com linfoma uterino, submetida a histerectomia, três esquemas de quimioterapia (QT), sucessivamente, e radioterapia. Apresentou episódios de insuficiência cardíaca aguda dois anos após QT. Ecocardiograma mostrou redução da fração de ejeção do ventrículo esquerdo (FEVE). Análise retrospectiva do 18F-FDG PET/CT observou elevação da captação miocárdica em todos os exames durante o seguimento oncológico. Apesar da remissão oncológica, a paciente desenvolveu IC com FEVE reduzida. Durante a QT, ocorreu aumento difuso e significativo da captação miocárdica de 18F-FDG, que precedeu a queda do desempenho cardíaco, e pareceu refletir alterações metabólicas nos cardiomiócitos relacionadas à CTX. A análise da captação miocárdica de 18F-FDG modificaria o desfecho cardiológico da paciente? Esse questionamento é relevante, visto que outros pacientes podem se beneficiar desse método como marcador precoce de CTX. Os exames de imagem são imprescindíveis no acompanhamento de pacientes com risco de CTX. O ecocardiograma permanece como principal auxílio diagnóstico, porém o 18F-FDG PET/CT pode estar surgindo como uma poderosa ferramenta para um diagnóstico mais precoce dessa condição clínica.

Integrated miRNA-mRNA networks underlie attenuation of chronic ß-adrenergic stimulation-induced cardiac remodeling by minocycline.

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although ß-adrenergic receptor (ß-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the ß-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic ß-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome.

The added value of the HFA/ICOS score in the prediction of chemotherapy-related cardiac dysfunction in breast cancer.

BACKGROUND: The 2022 ESC Guidelines on Cardio-Oncology recommend baseline cardiovascular risk stratification before starting anticancer drugs, using the new risk assessment tools proposed by the Heart Failure Association (HFA) and the International Cardio-Oncology Society (ICOS).Our study aimed to assess the clinical application of HFA/ICOS risk score in breast cancer patients undergoing chemotherapy and its usefulness in predicting the development of chemotherapy-related cardiac dysfunction (CTRCD). METHODS: A prospective multicentric study enrolled 109 breast cancer patients treated with anthracyclines with or without trastuzumab. A cardiological evaluation, including ECG and echocardiogram at baseline (T0), 3 (T1), 6 (T2), and 12 months (T3) after starting treatment was performed. HFA/ICOS score was assessed in all patients. The population was divided into low, medium, high, and very-high risk.During follow-up, CTRCD and other cardiovascular events have been evaluated. RESULTS: 61 patients were low risk, 37 medium, 9 high, 2 very-high risk criteria. We found a significantly higher incidence of overall cardiotoxicity (CTRCD and other cardiovascular events) in the very-high risk group (100%) compared with the medium (29%) and low risk groups (13%). CTRCD incidence was also significantly higher in the high risk group (55%). CTRCD resulted as being associated with baseline arterial hypertension and baseline HFA/ICOS risk score of high ( p  = 0.006) or very-high ( p  < 0.0001). CONCLUSION: Our study confirms the HFA/ICOS score's ability to predict cardiovascular toxicity in breast cancer women and the need for close monitoring especially in high and very-high risk patients.

Association between secondhand smoke exposure and incident heart failure: The Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: There are no studies on the association between secondhand smoke (SHS) exposure and incident heart failure (HF). This cohort study aimed to examine the associations of self-reported and urinary cotinine-assessed SHS exposure with incident HF. METHODS AND RESULTS: This study included 5548 non-active smoking participants aged 45-84 years and free of known cardiovascular diseases and HF at baseline who self-reported SHS exposure time in the Multi-Ethnic Study of Atherosclerosis (MESA) at baseline (2000-2002). A cohort subset of 3376 non-active smoking participants underwent urinary cotinine measurements. HF events were verified by medical records or death certificates and ascertained from baseline through 2019. Multivariable Cox proportional hazards regression analysis was used with adjustment for demographic variables, traditional cardiovascular risk factors, physical activity, tobacco pack-years and medications. During a median follow-up of 17.7 years, 353 and 196 HF events were identified in the self-report cohort and cohort subset, respectively. In the self-report cohort, compared with the SHS unexposed group (0 h/week), the highest tertile of the SHS exposed group (7-168 h/week) was not associated with incident HF (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-1.00; p = 0.052). In contrast, in the cohort subset, participants with detectable urinary cotinine >7.07 ng/ml had a higher risk of incident HF than those with undetectable urinary cotinine ≤7.07 ng/ml (HR 1.45, 95% CI 1.03-2.06; p = 0.034). There were no significant heterogeneities in HF risk by age, sex, race/ethnicity, or past smoking status. CONCLUSION: Secondhand smoke exposure reflected by modestly increased urinary cotinine (>7.07 ng/ml) rather than self-report in non-active smokers was associated with a 40-50% higher risk of any HF event.

Bezlotoxumab during the first episode of Clostridioides difficile infection in patients at high risk of recurrence.

PURPOSE: To describe a cohort with a high risk of recurrence who received bezlotoxumab during the first episode of Clostridioides difficile infection (CDI) and to compare this cohort with patients with similar characteristics who did not receive the monoclonal antibody. METHODS: A prospective and multicentre study of patients with a high risk of recurrence (expected recurrence rate>35%) who were treated with bezlotoxumab during their first episode of CDI was conducted. A propensity score-matched model 1:2 was used to compare both cohorts that were weighed according to basal characteristics (hospital-acquisition, creatinine value, and fidaxomicin as a CDI treatment). RESULTS: Sixty patients (mean age:72 years) were prospectively treated with bezlotoxumab plus anti-Clostridioides antibiotic therapy. Vancomycin (48 patients) and fidaxomicin (12 patients) were prescribed for CDI treatment, and bezlotoxumab was administered at a mean of 4.2 (SD:2.1) days from the beginning of therapy. Recurrence occurred in nine out of 54 (16.7%) evaluable patients at 8 weeks. Forty bezlotoxumab-treated patients were matched with 69 non-bezlotoxumab-treated patients. Recurrence rates at 12 weeks were 15.0% (6/40) in bezlotoxumab-treated patients vs. 23.2% (16/69) in non-bezlotoxumab-treated patients (OR:0.58 [0.20-1.65]). No adverse effects were observed related to bezlotoxumab infusion. Only one of 9 patients with previous heart failure developed heart failure. CONCLUSION: We observed that patients treated with bezlotoxumab in a real-world setting during a first episode of CDI having high risk of recurrence, presented low rate of recurrence. However, a significant difference in recurrence could not be proved in comparison to the controls. We did not detect any other safety concerns.

Prostanoids in Cardiac and Vascular Remodeling.

Prostanoids are biologically active lipids generated from arachidonic acid by the action of the COX (cyclooxygenase) isozymes. NSAIDs, which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular adverse effects, including myocardial infarction, stroke, hypertension, and heart failure. While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less is known about the link between NSAIDs and heart failure risk. Current evidence indicates that NSAIDs may increase the risk for heart failure by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli. This review will summarize current knowledge of the role of the different prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

Paclitaxel-induced myocarditis presenting as new-onset heart failure.

Myocarditis with systolic dysfunction is not typically associated with paclitaxel use. Here, we present a case of paclitaxel-induced myocarditis with systolic dysfunction developing after two cycles of carboplatin/paclitaxel in a woman with uterine papillary serous carcinoma and no cardiac risk factors. Myocarditis was diagnosed by cardiac MRI. The management of paclitaxel-induced myocarditis includes intravenous diuresis and initiation of heart failure with reduced ejection fraction guideline-directed medical therapy. Cessation of paclitaxel is also recommended in these patients.