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Advances in the field of oncology have led to the advent of doxorubicin (DOX), an anthracycline chemotherapeutic agent, through which cancer survival rates have remarkably improved. There has, however, been a rise in adverse effects from the use of DOX, most notably cardiotoxicity. DOX-induced cardiotoxicity is thought to arise through the generation of reactive oxygen species (ROS), causing mitochondrial dysfunction in the cardiomyocytes. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards and focused on cancer patients undergoing DOX therapy. The research question addressed interventions aimed at preventing DOX-induced cardiotoxicity. Google Scholar, PubMed, and ScienceDirect databases were used to conduct a systematic search. Next, screening was carried out by reviewing the title and abstract of various articles to exclude irrelevant studies, followed by the retrieval of full-text articles. Scale for the assessment of narrative review articles 2 (SANRA 2) for narrative reviews, a measurement tool to assess systematic reviews (AMSTAR) checklist for systematic reviews, and the Cochrane risk of bias tool for randomized controlled trials (RCTs) were the tools employed for quality assessment. This systematic review provides convincing evidence about preventive interventions to counteract DOX-induced cardiotoxicity. Primary prevention strategies against DOX-induced cardiotoxicity include pharmacological and non-pharmacological measures. Dexrazoxane reduces cardiotoxicity without therapeutic compromise. Beta-blockers showed mixed results in preserving cardiac function. The research on renin-angiotensin-aldosterone system (RAAS) inhibitors suggests that most of these agents can reduce the risk of DOX-induced cardiotoxicity. The liposomal formulation of DOX decreases cardiotoxicity without sacrificing effectiveness. Chemotherapy regimens should be supplemented with cardioprotective medications to increase therapeutic efficacy and lower cardiac risks. Exercise is an essential non-pharmacological strategy for decreasing DOX-induced cardiotoxicity. It acts by lowering oxidative stress, maintaining mitochondrial function, and averting apoptosis. Other non-pharmacological interventions through antioxidative, anti-apoptotic, and mitochondrial protective mechanisms, such as resveratrol, vitamin E, curcumin, and visnagin, show promise in lowering DOX-induced cardiotoxicity and may be useful as supplementary therapy during cancer treatment. In conclusion, this review highlights the need for a multimodal strategy that incorporates different tactics, as well as the need for additional research and strong clinical trials, with the ultimate goal of protecting cardiac health in patients receiving chemotherapy with DOX.

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INTRODUCTION: Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin­converting enzyme inhibitors (ACEI) or angiotensin­receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD. METHODS: CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively. RESULTS: Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738-0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699-0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752-0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707-0.974, p = 0.023) among patients treated with ACEI/ARB. CONCLUSION: ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.

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What is the current knowledge on the topic? Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients, and patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients. ACEI/ARB are beneficial for greater survival among CAD patients, but the effect of ACEI/ARB therapy on long-term prognosis is unclear among CAD patients with advanced CKD.What does this study add to our knowledge? ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up.How might this change clinical pharmacology or translational science? CAD patients with advanced CKD are not only have worse outcomes but also limited in their choice of therapy strategies. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations.

Asunto(s)

Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Enfermedad de la Arteria Coronaria , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica , Humanos , Masculino , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Femenino , Antagonistas de Receptores de Angiotensina/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Persona de Mediana Edad , Anciano , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Estudios Longitudinales , Modelos de Riesgos Proporcionales , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Causas de Muerte

RESUMEN

BACKGROUND: Few data are available on long-term drug therapy and its potential prognostic impact after Takotsubo syndrome (TTS). Aim of the study is to evaluate clinical characteristics and long-term outcome of TTS patients on Renin Angiotensin system inhibitors (RASi). METHODS: TTS patients were enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry. Median follow-up was 31 (Interquartile range 12-56) months. Comparison of RASi treated vs. untreated patients was performed within the overall population and after 1:1 propensity score matching for age, sex, comorbidities, type of trigger and in-hospital complications. REGISTRATION: clinicaltrials.gov, NCT04361994, https://clinicaltrials.gov/study/NCT04361994 RESULTS: Of the 2453 TTS patients discharged alive, 1683 (68%) received RASi therapy. Patients with RASi were older (age 71±11 vs 69±13 years, p=0.01), with higher prevalence of hypertension (74%vs53%, p<0.01) and diabetes (19%vs15%, p=0.01), higher admission left ventricular ejection fraction (LVEF) (41±11% vs 39±12%, p<0.01) and lower rates of in-hospital complications (18.9% vs 29.6%, p<0.01). At multivariable analysis, RASi therapy at discharge was independently associated with lower mortality (HR 0.63, 95%CI 0.45-0.87, p<0.01). Survival analysis showed that at long term, patients treated with RASi had lower mortality rates in the overall cohort (log-rank p=0.001). However, this benefit was not found among patients treated with RASi in the matched cohort (log-rank p=0.168). Potential survival benefit of RASi were present, both in the overall and matched cohort, in two subgroups: patients with admission LVEF ≤40% (HR 0.54 95%CI 0.38-0.78, p=0.001; HR 0.59, 95%CI 0.37-0.95, p=0.030) and diabetes (HR 0.41, 95%CI 0.23-0.73, p= 0.002; HR 0.41, 95%CI 0.21-0.82, p=0.011). CONCLUSIONS: Long-term therapy with RASi after a TTS episode was not associated with lower mortality rates at propensity score analysis. However, potential survival benefit can be found among patients with admission LVEF ≤40% or diabetes.

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BACKGROUND: Atrial fibrillation (AFib) is a highly prevalent cardiac arrhythmia associated with increased mortality in affected persons. Renin-angiotensin system inhibitors (RASIs) have been suggested as potential therapeutic agents for cardiovascular and renal diseases. OBJECTIVES: However, the relationship between RASIs and mortality in AFib patients remains uncertain. Therefore, the present study was designed and implemented for this purpose. METHODS: We searched PubMed/MEDLINE, Embase, Web of Science (WOS), Cochrane Library, and Scopus databases for studies published until 12 February 2024 with relevant keywords. We included studies that reported mortality outcomes in AFib patients treated with RASIs and non-users. The data extraction and quality assessment processes were conducted, and subgroup analyses and sensitivity analyses were done. The data were analyzed by Stata 15 using statistical tests, such as Chi-square and I2 tests. RESULTS: A total of 15 studies (2007-2024; n=2,178,565 patients) examined the association between RASI drugs and mortality of patients with AFib. The results indicated that compared to the control group, the odds of AFib mortality in the group receiving RASIs were equal to 0.81(95% CI: 0.71-0.92; P-value ≤0.001). The study results did not indicate publication bias (Pvalue= 0.733). During the meta-regression analysis, none of the study variables demonstrated a significant relationship with the observed heterogeneity (P-value > 0.20). Cumulative OR results showed that from 2022 onwards, there was enough evidence to confirm the relationship using RASIs with mortality of patients with AFib. CONCLUSION: Therefore, this meta-analysis suggests that the use of RASI drugs is associated with reduced AFib mortality. However, the authors emphasize the need for further high-quality studies and large-scale randomized clinical trials to validate these findings.

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Objective: To investigate the effect of different single and combined pre-admission antihypertensive drug regimens on the prognosis of critically ill patients. Methods: We performed a retrospective cohort study using data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. All initial ICU admission records of patients with hypertension and previous antihypertensive exposure before ICU admission were included. Our primary outcome was 90-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance the distribution of baseline characteristics. Logistic regression analysis and subgroup analysis were performed to determine the independent effect of different single and combined antihypertensive drug regimens on 90-day mortality. Results: A total of 13,142 patients were included in the final analysis. The 90-day mortality rate in the combined groups is lower than that in the single therapy group (10.94% vs 11.12%), but no statistical significance was found in the original cohort (p = 0.742). After adjustment for potential confounders, the significantly decreased 90-day mortality rate was found in the combined groups (10.78% vs 12.65%, p = 0.004 in PSM; 10.34% vs 11.90%, p = 0.007). Patients who were exposed to either ACEIs or ARBs had a better prognosis than those not exposed (7.19% vs 17.08%, p < 0.001 in single antihypertensive groups; 8.14% vs18.91%, p < 0.001 in combined antihypertensive groups). The results keep robustness in the PSM and IPTW cohorts. In the logistic regression model analysis, combined therapy was associated with a 12%-20% reduced risk of 90-day death after adjusting potential confounders (OR 0.80-0.88, all p < 0.05), while exposure to ACEIs or ARBs was associated with the decreased risk of 90-day death by 52%-62% (OR 0.38-0.48, all p < 0.001) and 40%-62% (OR 0.38-0.60, all p < 0.001) in the single and combined therapy groups, respectively. The results were still robust to subgroup analysis. Conclusions: Pre-admission combined antihypertensive therapy is associated with a significantly lower risk of death than exposure to single antihypertensives in critically ill patients. Meanwhile, either ACEIs or ARBs seem to be the optimal candidates for both single and combined therapy. Further high-quality trials are needed to confirm our findings.

RESUMEN

Introduction: Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation. Methods: This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness. Results: Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28-3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings. Conclusion: ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

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Dysbiosis of the gut microbiota has been implicated in hypertension, and drug-host-microbiome interactions have drawn considerable attention. However, the influence of angiotensin receptor blocker (ARB)-shaped gut microbiota on the host is not fully understood. In this work, we assessed the alterations of blood pressure (BP), vasculatures, and intestines following ARB-modified gut microbiome treatment and evaluated the changes in the intestinal transcriptome and serum metabolome in hypertensive rats. Hypertensive patients with well-controlled BP under ARB therapy were recruited as human donors, spontaneously hypertensive rats (SHRs) receiving normal saline or valsartan were considered animal donors, and SHRs were regarded as recipients. Histological and immunofluorescence staining was used to assess the aorta and small intestine, and 16S rRNA amplicon sequencing was performed to examine gut bacteria. Transcriptome and metabonomic analyses were conducted to determine the intestinal transcriptome and serum metabolome, respectively. Notably, ARB-modified fecal microbiota transplantation (FMT), results in marked decreases in systolic BP levels, collagen deposition and reactive oxygen species accumulation in the vasculature, and alleviated intestinal structure impairments in SHRs. These changes were linked with the reconstruction of the gut microbiota in SHR recipients post-FMT, especially with a decreased abundance of Lactobacillus, Aggregatibacter, and Desulfovibrio. Moreover, ARB-treated microbes contributed to increased intestinal Ciart, Per1, Per2, Per3, and Cipc gene levels and decreased Nfil3 and Arntl expression were detected in response to ARB-treated microbes. More importantly, circulating metabolites were dramatically reduced in ARB-FMT rats, including 6beta-Hydroxytestosterone and Thromboxane B2. In conclusion, ARB-modified gut microbiota exerts protective roles in vascular remodeling and injury, metabolic abnormality and intestinal dysfunctions, suggesting a pivotal role in mitigating hypertension and providing insights into the cross-talk between antihypertensive medicines and the gut microbiome.

RESUMEN

The effect of pre-hospital use of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs)) on clinical outcomes of hypertensive patients with COVID-19 has been questioned due to conflicting reports on this issue. After applying exclusion criteria, 175 COVID-19 hospitalized patients admitted to the Tishreen Hospital from January 1 to July 31, 2021 were retrospectively enrolled in this study. Baseline characteristics and in-hospital mortality rate were assessed between hypertensive (N = 91, 52%) and non-hypertensive (N = 84, 48%) patients, as well as between patients taking ACEis/ARBs and non-ACEis/ARBs within the hypertensive group. A lower mortality rate (51.2 versus 31.9%, p = 0.009) was observed in the hypertensive group (mean age 64.6 years, 64.8% males) compared to the non-hypertensive (mean age 62.6 years, 66.7% males). Patients' mortality in the non-hypertensive group was associated with lower blood oxygen saturation (SPO2 = 75 versus 86%, p = 0.002), increased levels of inflammatory (CRP, white blood cell and neutrophils count), and tissue/renal injury markers (LDH, urea, and creatinine). In the hypertensive group, a lower mortality rate was noted in the ACEis/ARBs group compared to the non-ACEis/ARBs (24.1 versus 45.5%, p = 0.036), and this was associated with a decrease in D-DIMER levels, although not significant (1723 versus 2683 ng/mL, p > 0.05). Death in the non-ACEis/ARBs group was associated with decreased SPO2 and tissue/renal injury markers (LDH, CK, AST, urea, and creatinine). We concluded that hypertension is not a direct cause of poor prognosis in COVID-19 patients and that multi-organ damage is a significant indicator of death from COVID-19. RAS inhibitors could improve the survival of hypertensive COVID-19 patients.

RESUMEN

In recent years, regulatory agencies have raised concerns about the presence of potentially carcinogenic substances in certain formulations of Angiotensin Receptor Blockers (ARBs). Specifically, nitrosamines and azido compounds have been identified in some ARB products. Nitrosamines are known to have carcinogenic properties and are associated with an increased risk of neoplasms. Spontaneous safety reports from the EudraVigilance Data Analysis System (EVDAS) database were analyzed to investigate cases of neoplasms associated with ARBs. A disproportionality analysis was conducted, calculating the reporting odds ratio (ROR) and 95% confidence intervals (CIs) using a case/non-case approach for each ARB drug. The EVDAS database contained 68,522 safety reports related to ARBs (including Azilsartan, Candesartan, Irbesartan, Olmesartan, Losartan, Valsartan, and Telmisartan), among which 3,396 (5%) cases were associated with neoplasms. The majority of these cases were reported in Germany (11.9%), followed by France (9.7%). Approximately 70% of the reports were submitted by healthcare professionals such as physicians and nurses. Among the ARBs, valsartan had the highest ROR for neoplasm (ROR 1.949, 95% CI 1.857-2.046). This association remained significant when comparing ARBs with other classes of antihypertensive drugs, including ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics. Our study identifies a possible signal of an association between ARBs, particularly valsartan, and the risk of neoplasms. However, further observational and analytical studies are necessary to confirm these findings and elucidate the underlying mechanisms.

Asunto(s)

Antagonistas de Receptores de Angiotensina , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Antagonistas de Receptores de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Anciano , Valsartán , Adulto , Bases de Datos Factuales , Alemania/epidemiología

RESUMEN

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.

Asunto(s)

Antagonistas de Receptores de Angiotensina , Enzima Convertidora de Angiotensina 2 , Teoría Funcional de la Densidad , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Humanos , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , COVID-19/virología , Relación Estructura-Actividad , Estructura Molecular , Bencimidazoles/farmacología , Bencimidazoles/química , Tetrazoles/farmacología , Tetrazoles/química , Tetrazoles/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Tratamiento Farmacológico de COVID-19

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina , COVID-19 , Enfermedades Cardiovasculares , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Enfermedades Cardiovasculares/prevención & control , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/efectos adversos , Hipertensión/tratamiento farmacológico

RESUMEN

Background and Objectives: The efficacy and safety of a lower target dose of sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) for treating heart failure with reduced ejection fraction (HFrEF) in Chinese patients with moderate-to-severe chronic kidney disease (CKD) remain unknown. We performed a retrospective study to compare the efficacy of ARNI with that of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with HFrEF and moderate-to-severe CKD. Methods: This retrospective study included 129 patients. An inverse probability of treatment weighting (IPTW) analysis was performed to compare the baseline characteristics and outcomes between the 2 groups. The incidence of death due to cardiovascular disease, rehospitalization due to heart failure after treatment, and improvement in cardiac function symptoms (New York Heart Association [NYHA]) were assessed after 12 months. Improvements of ejection fraction (EF), N-terminal pro-brain natriuretic peptide (NT-proBNP) level, left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) were compared. Results: Compared with the ACEI/ARB group, the ARNI group, with 90.77% (59/65) in the lower target dose group, showed a lower rate of death due to cardiovascular disease (6.6% vs 0.9% after IPTW) and a lower incidence of rehospitalization (46.5% vs 30.4% after IPTW). NYHA class, estimated glomerular filtration rate, EF, NT-ProBNP levels, LVEDD, and LVESD improved in the ARNI group. None of the patients withdrew from treatment because of adverse drug reactions. Conclusion: Our study showed that ARNI resulted in a greater improvement in heart failure than ACEIs/ARBs in patients with HFrEF and moderate-to-severe CKD.

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Compuestos de Bifenilo , Combinación de Medicamentos , Insuficiencia Cardíaca , Neprilisina , Insuficiencia Renal Crónica , Volumen Sistólico , Valsartán , Función Ventricular Izquierda , Humanos , Aminobutiratos/efectos adversos , Aminobutiratos/uso terapéutico , Valsartán/uso terapéutico , Masculino , Femenino , Estudios Retrospectivos , Volumen Sistólico/efectos de los fármacos , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/diagnóstico , Anciano , Persona de Mediana Edad , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/efectos adversos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Neprilisina/antagonistas & inhibidores , Índice de Severidad de la Enfermedad , Tetrazoles/efectos adversos , Tetrazoles/uso terapéutico , Readmisión del Paciente , Factores de Tiempo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Péptido Natriurético Encefálico/sangre , China/epidemiología , Recuperación de la Función , Fragmentos de Péptidos/sangre

RESUMEN

OBJECTIVE: This study evaluates the 3-year clinical outcomes of high Killip grade (III/IV) acute myocardial infarction (AMI) patients treated with either ß-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI) or BB and angiotensin receptor blockers (ARB). METHODS: A total of 13,105 patients were registered at the Korea Acute Myocardial Infarction Registry at the National Institute of Health (KAMIR-NIH). Among them, 871 patients with high Killip classification AMI were divided into the BB + ACEI group (n = 489) and the BB + ARB group (n = 381). Following propensity score matching, 343 patients were selected in each group. All patients completed a 3-year follow-up period. RESULTS: The results indicate no significant differences between the BB + ACEI group and BB + ARB group in terms of cardiac death, recurrent myocardial infarction, and the rate of repeat percutaneous coronary intervention. However, the BB + ACEI group exhibited significantly lower risks in major adverse cardiac events (HR = 0.574, 95% CI: 0.421-0.783, p < .001), all-cause mortality (HR = 0.561, 95% CI: 0.404-0.778, p = .001), and non-cardiac death (HR = 0.365, 95% CI: 0.208-0.639, p < .001) compared to the BB + ARB group. CONCLUSION: Our results suggest that BB + ACEI treatment is more beneficial than BB + ARB for high Killip grade AMI patients. Additionally, the BB + ACEI group has a superior preventative effect on mortality compared to the BB + ARB group.

Asunto(s)

Antagonistas Adrenérgicos beta , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Infarto del Miocardio , Intervención Coronaria Percutánea , Sistema de Registros , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Masculino , Femenino , Antagonistas Adrenérgicos beta/uso terapéutico , Persona de Mediana Edad , Anciano , República de Corea , Infarto del Miocardio/mortalidad , Infarto del Miocardio/tratamiento farmacológico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Resultado del Tratamiento , Intervención Coronaria Percutánea/mortalidad , Intervención Coronaria Percutánea/efectos adversos , Factores de Riesgo , Factores de Tiempo , Quimioterapia Combinada , Recurrencia , Medición de Riesgo

RESUMEN

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.

Asunto(s)

Albúminas , Angiotensina II , Endocitosis , Células Epiteliales , Glucosa , Túbulos Renales Proximales , Receptor de Angiotensina Tipo 1 , Endocitosis/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/efectos de los fármacos , Angiotensina II/farmacología , Glucosa/metabolismo , Glucosa/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Animales , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Humanos , Albúminas/metabolismo , Porcinos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular , Losartán/farmacología

RESUMEN

Worldwide, hypertension is the leading risk factor for cardiovascular disease and death. An estimated 122 million people, per the American Heart Association in 2023, have been diagnosed with this common condition. It is generally agreed that the primary goal in the treatment of hypertension is to reduce overall blood pressure to below 140/90 mmHg, with a more optimal goal of 130/80 mmHg. Common medications for treating hypertension include calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics. CCBs are one of the most widely studied agents and are generally recommended as first-line therapy alone and in combination therapies. This is largely based on the vast knowledge of CCB mechanisms and their minimal side effect profile. CCBs can be separated into two classes: dihydropyridine and non-dihydropyridine. Non-dihydropyridine CCBs act on voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. Dihydropyridine CCBs act by vasodilating the peripheral vasculature. For many patients with only mild increases in systolic and diastolic blood pressure (e.g., stage 1 hypertension), the medical literature indicates that CCB monotherapy can be sufficient to control hypertension. In this regard, CCB monotherapy in those with stage 1 hypertension reduced renal and cardiovascular complications compared to other drug classes. Combination therapy with CCBs and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors has been shown to be an effective dual therapy based on recent meta-analyses. This article is a review of calcium channel blockers and their use in treating hypertension with some updated and recent information on studies that have re-examined their use. As for new information, we tried to include some information from recent studies on hypertensive treatment involving calcium channel blockers.

RESUMEN

BACKGROUND: The antihypertensive effects of angiotensin II receptor blockers (ARBs) are well recognized. However, conventional meta-analyses have reported inconsistent results on their efficacy and safety. AIM: This study aimed to evaluate the efficacy and safety of six ARBs (losartan, valsartan, irbesartan, telmisartan, candesartan, and olmesartan) commonly used to treat hypertension, using a network meta-analysis. METHOD: We retrieved randomized controlled trials on hypertension treatment using ARBs from the PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases. The efficacy outcomes included absolute changes in office systolic and diastolic blood pressure from baseline, and 24-h ambulatory blood pressure. Safety outcomes were assessed by the total number of adverse events (AEs) during treatment. We conducted the network meta-analysis using the 'bugsnet' and 'gemtc' packages in R. RESULTS: A total of 193 studies were included. Olmesartan had the highest surface under the cumulative ranking in reducing office systolic (91.4%) and diastolic blood pressure (87.2%). Candesartan has the highest ranking in lowering 24 h ambulatory systolic blood pressure (95.4%), while telmisartan reduced 24 h ambulatory diastolic blood pressure (83.4%). Olmesartan also ranked highest in safety (70.8%). CONCLUSION: Valsartan and losartan were less effective in lowering blood pressure than other drugs, with no significant differences. Olmesartan and telmisartan were associated with fewer AEs than losartan, although the incidence of adverse events was similar between the other blockers. Olmesartan and telmisartan demonstrated the best balance of antihypertensive efficacy and minimal adverse events. More research is needed to confirm whether telmisartan and olmesartan are optimal choices for controlling blood pressure in patients.

Asunto(s)

Antagonistas de Receptores de Angiotensina , Antihipertensivos , Hipertensión , Humanos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/administración & dosificación , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

RESUMEN

BACKGROUND: Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid. RESEARCH DESIGN AND METHODS: Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries. RESULTS: Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%-80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2). CONCLUSION: This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

Asunto(s)

Enzima Convertidora de Angiotensina 2 , Antivirales , Bencimidazoles , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Bencimidazoles/farmacología , Animales , Antivirales/farmacología , Humanos , Chlorocebus aethiops , Enzima Convertidora de Angiotensina 2/metabolismo , SARS-CoV-2/efectos de los fármacos , Células Vero , Conejos , Antagonistas de Receptores de Angiotensina/farmacología , Compuestos de Bifenilo/farmacología , Antihipertensivos/farmacología , Tetrazoles/farmacología , Masculino , Hipertensión/tratamiento farmacológico , COVID-19 , Losartán/farmacología , Resonancia por Plasmón de Superficie

RESUMEN

In India, around 234 million adults (one in three) suffer from hypertension (HTN). An average of 10% of these cases are likely to be resistant hypertension (RH). This load of 23 million patients is expected to expand further with revisions in diagnostic criteria. The treatment and control rates of hypertension in India average around 30% and 15%, respectively. Pharmacological management involves a stepwise approach starting with optimizing the A-C-D (angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide-like diuretics) triple-drug combination, followed by substitution with a thiazide-like diuretic and use of spironolactone as a next step (fourth drug). The subsequent steps are suggestions based on expert input and must be individualized. These include using a ß-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when target blood pressure (BP) values are not achieved. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are likely to be helpful in managing RH due to their renal and cardiovascular protection as well as mortality benefits. SGLT2i lowers BP independent of the dosage and concomitant anti-hypertensive medications. Patient education and tools to monitor BP and treatment compliance will improve outcomes with these medications. In addition to therapeutic intervention, a preventive approach for RH mandates a need to identify patients at risk and use appropriate preventive and optimal therapy to prevent uncontrolled hypertension in patients with cardiovascular disorders.

RESUMEN

Background: The limited efficacy of chemotherapy in improving survival in pancreatic ductal adenocarcinoma (PDAC) necessitates the exploration of novel strategies to overcome treatment resistance. Objectives: This study aimed to investigate the impact of combining renin-angiotensin system (RAS) blockers with chemotherapy on survival outcomes in patients with PDAC. Design: Patients with PDAC were enrolled in the retrospective study. Methods: We analyzed patients with PDAC (n = 384) at our institution between 2014 and 2021. Survival outcomes, including event-free survival (EFS) and overall survival (OS), were analyzed according to the concomitant use of RAS blockers. Results: Among the 384 patients in the study, 70 (18.2%) concomitantly received angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Patients in the ACEI/ARB group, characterized by older age and more comorbidities, displayed a significantly superior 12-month EFS rate (22.86% versus 13.69%, p = 0.008) compared to the non-ACEI/ARB group, while OS remained similar between the groups. In the multivariate analysis, the use of ACEI/ARB was associated with better 12-month EFS (hazards ratio = 0.71, 95% confidence interval: 0.52-0.96; p = 0.024). Poor performance, advanced disease status, and higher CA19-9 levels were associated with poor survival outcomes. Conclusion: Concomitant use of ACEIs/ARBs in patients with pancreatic cancer resulted in significantly better 12-month EFS. Age, performance status, disease status, and higher CA19-9 levels were independent predictors of survival. The combination strategy might provide better treatment outcomes in patients with PDAC.