Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.

Antisense Oligonucleotide: A Potential Therapeutic Intervention for Chronic Kidney Disease

Chronic kidney disease (CKD) is a global public health issue that places an increasing burden on the healthcare systems of both the developed and developing countries. CKD is a progressive and irreversible condition, affecting approximately 10% of the population worldwide. Patients that have progressed to end-stage renal disease (ESRD) require expensive renal replacement therapy, i.e., dialysis or kidney transplantation. Current CKD therapy largely relies on the use of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs). However, these treatments by no means halt the progression of CKD to ESRD. Therefore, the development of new therapies is urgently needed. Antisense oligonucleotide (ASO) has recently attracted considerable interest as a drug development platform. Thus far, eight ASO-based drugs have been granted approval by the US Food and Drug Administration for the treatment of various diseases. Herein, we review the ASOs developed for the identification of CKD-relevant genes and/or the simultaneous development of the ASOs as potential therapeutics towards treating CKD.

Construction and Validation of a Risk Prediction Model for Acute Kidney Injury in Patients Suffering from Septic Shock

Background. Acute kidney injury (AKI) is an important complication in critically ill patients, especially in sepsis and septic shock patients. Early prediction of AKI in septic shock can provide clinicians with sufficient information for timely intervention so that improve the patients’ survival rate and quality of life. The aim of this study was to establish a nomogram that predicts the risk of AKI in patients with septic shock in the intensive care unit (ICU). Methods. The data were collected from the Medical Information Mart for Intensive Care III (MIMIC-III) database between 2001 and 2012. The primary outcome was AKI in the 48 h following ICU admission. Univariate and multivariate logistic regression analyses were used to screen the independent risk factors of AKI. The performance of the nomogram was evaluated according to the calibration curve, receiver operating characteristic (ROC) curve, decision curve analysis, and clinical impact curve. Results. A total of 2415 patients with septic shock were included in this study. In the training and validation cohort, 1091 (64.48%) of 1690 patients and 475 (65.52%) of 725 patients developed AKI, respectively. The predictive factors for nomogram construction were gender, ethnicity, congestive heart failure, diabetes, obesity, Simplified Acute Physiology Score II (SAPS II), angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), bilirubin, creatinine, blood urea nitrogen (BUN), and mechanical ventilation. The model had a good discrimination with the area under the ROC curve of 0.756 and 0.760 in the training and validation cohorts, respectively. The calibration curve for probability of AKI in septic shock showed optimal agreement between prediction by nomogram and actual observation. Decision curve and clinical impact curve analysis indicated that the nomogram conferred high clinical net benefit. Conclusion. The proposed nomogram can quickly and effectively predict the risk of AKI at an early stage in patients with septic shock in ICU, which can provide information for timely and efficient intervention in patients with septic shock in the ICU setting.

Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: An Italian Registry

Background: It is uncertain whether exposure to renin–angiotensin system (RAS) modifiers affects the severity of the new coronavirus disease 2019 (COVID-19) because most of the available studies are retrospective. Methods: We tested the prognostic value of exposure to RAS modifiers (either angiotensin-converting enzyme inhibitors [ACE-Is] or angiotensin receptor blockers [ARBs]) in a prospective study of hypertensive patients with COVID-19. We analyzed data from 566 patients (mean age 75 years, 54% males, 162 ACE-Is users, and 147 ARBs users) hospitalized in five Italian hospitals. The study used systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the primary outcome. Results: Sixty-six patients died during hospitalization. Exposure to RAS modifiers was associated with a significant reduction in the risk of in-hospital mortality when compared to other BP-lowering strategies (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.32 to 0.90, p = 0.019). Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers (OR: 0.66, 95% CI: 0.36 to 1.20, p = 0.172). Conversely, ARBs users showed a 59% lower risk of death (OR: 0.41, 95% CI: 0.20 to 0.84, p = 0.016) even after allowance for several prognostic markers, including age, oxygen saturation, occurrence of severe hypotension during hospitalization, and lymphocyte count (adjusted OR: 0.37, 95% CI: 0.17 to 0.80, p = 0.012). The discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515). Conclusions: This prospective study indicates that exposure to ARBs reduces mortality in hospitalized patients with COVID-19.

Intervention and in-hospital pharmacoterapies in octogenarian with acute coronary syndrome: a 10-year retrospective analysis of the Malaysian National Cardiovascular Database (NCVD) registry

Background Octogenarians and beyond have often been neglected in the populational study of disease despite being at the highest point of non-modifiable disease risk burden and the fastest-growing age group for the past decade. This study examined the characteristics and in-hospital management of octogenarian patients with acute coronary syndrome (ACS) in a multi-ethnic, middle-income country in South East Asia. Method This retrospective study utilised the Malaysian National Cardiovascular Disease- ACS (NCVD-ACS) registry. Consecutive patient data of those ≥80 years old admitted with ACS at 24 participating hospitals from 2008 to 2017 (n = 3162) were identified. Demographics, in-hospital intervention, and evidence-based pharmacotherapies over the 10-years were examined and compared across groups of interests using the Chi-square test. Multivariate logistic regression was used to calculate the adjusted odds ratio of receiving individual therapies according to patients’ characteristics. Results Octogenarians made up 3.8% of patients with ACS in the NCVD-ACS registry (mean age = 84, SD ± 3.6) from 2008 until 2017. The largest ethnic group was Chinese (44%). Most octogenarians (95%) have multiple cardiovascular risk factors, with hypertension (82%) being the main. Non-ST-elevation myocardial infarction (NSTEMI) predominated (38%, p < 0.001). Within the 10-year, there were positive increments in cardiovascular intervention and pharmacotherapies. Only 10% of octogenarians with ACS underwent percutaneous coronary intervention (PCI), the majority being STEMI patients (17.5%; p < 0.05). More than 80% were prescribed aspirin (91.3%) either alone or combined, dual antiplatelet therapy (DAPT) (83.3%), anticoagulants (89.7%) and statins (89.6%), while less being prescribed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (47.6%) and beta-blockers (43.0%). Men were more likely to receive PCI than women (adjusted Odds Ratio (aOR): 0.698; 95% CI: 0.490–0.993). NSTEMI (aOR = 0.402, 95% CI: 0.278–0.583) and unstable angina (UA) (aOR = 0.229, 95% CI: 0.143–0.366) were less likely to receive PCI but more likely given anticoagulants (NSTEMI, aOR = 1.543, 95% CI: 1.111–2.142; UA, aOR = 1.610, 95% CI: 1.120–2.314) than STEMI. The presence of cardiovascular risk factors and comorbidities influences management. Conclusion Octogenarians with ACS in this country were mainly treated with cardiovascular pharmacotherapies. As the number of octogenarians with ACS will continue to increase, the country needs to embrace the increasing use of PCI in this group of patients.

Korea hypertension fact sheet 2021: analysis of nationwide population-based data with special focus on hypertension in women

Background The Korean Society of Hypertension has published the Korea Hypertension Fact Sheet 2021 to provide an overview of the magnitude and management status of hypertension and their recent trends. Methods The Fact Sheets were based on the analyses of Korean adults aged 20 years or older of the 1998–2019 Korea National Health and Nutrition Examination Survey and the 2002–2019 National Health Insurance Big Data. Results Currently, the population average of systolic/diastolic blood pressure was 119/76 mmHg in Korean adults aged 20 years or older showing little change in the recent decade. It is estimated that 28% of the adult population aged 20 or older (33% of adults aged 30 or older) have hypertension. The estimated number of people with hypertension was 6.30 million for men and 5.77 million for women, and 1.96 million for men and 2.99 million for women among the population aged 65 or older. The number of people diagnosed with hypertension increased from 3.0 million in 2002 to 10.1 million in 2019. During the same period, the number of people using antihypertensive medication increased from 2.5 million to 9.5 million, and the number of people adherent to treatment increased from 0.6 million to 6.9 million. Among antihypertensive prescriptions, 40.6% of the patients received monotherapy, 43.4% received dual therapy, and 16.0% received triple or more therapy. The most commonly prescribed antihypertensive medication was angiotensin receptor blockers (ARB), followed by calcium channel blockers (CCB) and diuretics. In young women, angiotensin-converting enzyme inhibitors (ACEi), ARB and CCB are less frequently prescribed than in men, but 59.5% of hypertensive women aged 20–39 are prescribed ACEi or ARBs. Hypertensive disorders during pregnancy have been increasing over the past 10 years. In 2019, 5.4% of women who gave birth were diagnosed with chronic hypertension and 3.1% with pregnancy-induced hypertension. Conclusions To achieve further improvement in management of hypertension, we need to encourage awareness and treatment in young adults. It is required to develop tailored prevention and management strategies that are appropriate for and inclusive of various demographics.

Effect of a Perioperative Hypotension-Avoidance Strategy Versus a Hypertension-Avoidance Strategy on the Risk of Acute Kidney Injury: A Clinical Research Protocol for a Substudy of the POISE-3 Randomized Clinical Trial

Background: Most patients who take antihypertensive medications continue taking them on the morning of surgery and during the perioperative period. However, growing evidence suggests this practice may contribute to perioperative hypotension and a higher risk of complications. This protocol describes an acute kidney injury substudy of the Perioperative Ischemic Evaluation-3 (POISE-3) trial, which is testing the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy in patients undergoing noncardiac surgery. Objective: To conduct a substudy of POISE-3 to determine whether a perioperative hypotension-avoidance strategy reduces the risk of acute kidney injury compared with a hypertension-avoidance strategy. Design: Randomized clinical trial with 1:1 randomization to the intervention (a perioperative hypotension-avoidance strategy) or control (a hypertension-avoidance strategy). Intervention: If the presurgery systolic blood pressure (SBP) is <130 mmHg, all antihypertensive medications are withheld on the morning of surgery. If the SBP is ≥130 mmHg, some medications (but not angiotensin receptor blockers [ACEIs], angiotensin receptor blockers [ARBs], or renin inhibitors) may be continued in a stepwise manner. During surgery, the patients’ mean arterial pressure (MAP) is maintained at ≥80 mmHg. During the first 48 hours after surgery, some antihypertensive medications (but not ACEIs, ARBs, or renin inhibitors) may be restarted in a stepwise manner if the SBP is ≥130 mmHg. Control: Patients receive their usual antihypertensive medications before and after surgery. The patients’ MAP is maintained at ≥60 mmHg from anesthetic induction until the end of surgery. Setting: Recruitment from 108 centers in 22 countries from 2018 to 2021. Patients: Patients (~6800) aged ≥45 years having noncardiac surgery who have or are at risk of atherosclerotic disease and who routinely take antihypertensive medications. Measurements: The primary outcome of the substudy is postoperative acute kidney injury, defined as an increase in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of randomization or ≥50% within 7 days of randomization. Methods: The primary analysis (intention-to-treat) will examine the relative risk and 95% confidence interval of acute kidney injury in the intervention versus control group. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by preexisting chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate <60 mL/min/1.73 m2. Results: Substudy results will be analyzed in 2022. Limitations: It is not possible to mask patients or providers to the intervention; however, objective measures will be used to assess acute kidney injury. Conclusions: This substudy will provide generalizable estimates of the effect of a perioperative hypotension-avoidance strategy on the risk of acute kidney injury.

Perception of pharmacological prevention and subsequent non-adherence to medication in patients with ischaemic heart disease: a population-based cohort study

ObjectiveA patient-focused approach is advocated to embody risk of non-adherence to medication and subsequent adverse clinical outcomes following ischaemic heart disease (IHD). This study aimed to explore how patient perceived information on pharmacological prevention was associated with subsequent non-adherence to medication (measured by non-initiation, non-implementation and non-persistence) in patients with incident IHD.DesignCohort study.SettingDenmark.ParticipantsRegister-based cohort of 829 patients with incident IHD in 2013.MeasuresPerception covered whether patients’ experienced being adequately informed about their pharmacological prevention. Information on such was obtained from a survey and divided into ‘Well informed’, ‘Moderately informed’ and ‘Poorly informed’. Information on baseline characteristics, and reimbursed prescriptions of medication (antiplatelets, statins, ACE-inhibitors/angiotensin receptor blockers and β-blockers) during follow-up were obtained by linkage to nationwide public registers. Non-initiation and non-implementation of medication, measured as proportion of days covered, were analysed by Poisson regression. Non-persistence to medication, measured as risk of discontinuation, was analysed by multivariable Cox proportional hazard regression.Primary and secondary outcome measuresNon-implementation and non-persistence to medication up to 365 days of follow-up were primary outcomes. Secondary outcomes included non-initiation as well as non-implementation and non-persistence to medication at 180 days of follow-up.ResultsA dose–response association was in general found between perception of pharmacological prevention and risk of non-implementation and non-persistence. For example, the hazard of non-persistence to antiplatelets was 1.18 (95% CI 0.71 to 1.96) times higher for patients reporting 'Moderately informed' and 1.89 (95% CI 1.10 to 3.25) times higher for patients reporting 'Poorly informed', compared with patients reporting 'Well informed of perception of pharmacological prevention' up to 365 days of follow-up.ConclusionLower levels of perception of pharmacological prevention were associated with subsequent non-implementation and non-persistence to medication in patients with incident IHD.

Time to switch angiotensin-converting enzyme inhibitors/angiotensin receptor blockers to sacubitril/valsartan in patients with cancer therapy-related cardiac dysfunction

Advances in cancer therapy have resulted in more cancer therapy-related cardiac dysfunction (CTRCD), which is the main cause of death in older female survivors of breast cancer. Traditionally, guideline-recommended medications for heart failure, such as beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), are commonly used to prevent or attenuate CTRCD. However, sometimes their effectiveness is not satisfactory. Recently, the drug combination of sacubitril plus valsartan has been proven to be more beneficial for heart failure with reduced ejection fraction in the long term compared with an ACEI/ARB alone. However, there is a lack of evidence of the efficacy and safety of this drug combination in CTRCD. We report a case of worsening CTRCD, despite treatment with traditional medications, in which the patient improved after changing perindopril to sacubitril/valsartan. The patient’s heart function greatly improved after changing this ACEI to sacubitril/valsartan. Changing an ACEI/ARB to sacubitril/valsartan in patients with worsening chemotherapy-induced heart failure is appropriate. Further studies with a high level of evidence are required to assess the efficacy and safety of sacubitril/valsartan for CTRCD.