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Colorectal cancer is the second most common cause of cancer death in the United States, and up to half of patients develop colorectal liver metastases (CRLMs). Notably, somatic genetic mutations, such as mutations in RAS, BRAF, mismatch repair (MMR) genes, TP53, and SMAD4, have been shown to play a prognostic role in patients with CRLM. This review summarizes and appraises the current literature regarding the most relevant somatic mutations in surgically treated CRLM by not only reviewing representative studies, but also providing recommendations for areas of future research. In addition, advancements in genetic testing and an increasing emphasis on precision medicine have led to a more nuanced understanding of these mutations; thus, more granular data for each mutation are reviewed when available. Importantly, such knowledge can pave the way for precision medicine with the ultimate goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Little evidence exists about the comparative effects of first‐line antihypertensive medications (i.e., renin‐angiotensin‐aldosterone converting enzyme inhibitors (RAASi), amlodipine, or thiazide diuretics) in older adults with limited life expectancy. We compared the rates of injurious falls and short‐term cardiovascular events between different first‐line antihypertensive medication classes in adults receiving care in nursing homes (NH). Methods: This was a retrospective cohort of Medicare fee‐for‐service beneficiaries receiving care in NHs. Patients newly dispensed first‐line antihypertensive medications were identified using Part D claims (2015–2018) and linked with clinical assessments (i.e., Minimum Data Set). Fall‐related injuries (FRI), hip fractures, and major adverse cardiac events (MACE) outcomes were identified using hospitalization claims. Patients were followed from the date of antihypertensive dispensing until the occurrence of outcomes, death, disenrollment, or 6‐month follow‐up. Inverse‐probability‐of‐treatment‐weighted (IPTW) cause‐specific hazards regression models were used to compare outcomes between patients who were new users of RAASi, amlodipine, or thiazides. Results: Our cohort included 16,504 antihypertensive users (RAASi, n = 9574; amlodipine, n = 5049; thiazide, n = 1881). Mean age was 83.5 years (± 8.2), 70.6% were female, and 17.2% were non‐white race. During a mean follow‐up of 5.3 months, 326 patients (2.0%) experienced an injurious fall, 1590 (9.6%) experienced MACE, and 2123 patients (12.9%) died. The intention‐to‐treat IPTW hazard ratio (HR) for injurious falls for amlodipine (vs RAASi) use was 0.85 (95% confidence interval (CI) 0.66–1.08) and for thiazides (vs RAASi) was 1.22 (95% CI 0.88–1.66). The rates of MACE were similar between those taking anti‐hypertensive medications. Thiazides were discontinued more often than other classes; however, inferences were largely unchanged in as‐treated analyses. Subgroup analyses were generally consistent. Conclusions: Older adults with limited life expectancy experience similar rates of injurious falls and short‐term cardiovascular events after initiating any of the first‐line antihypertensive medications. [ABSTRACT FROM AUTHOR]

Liver disease is often associated with dysfunctional potassium homeostasis but is not a well-established risk factor for hyperkalemia. This retrospective cohort study examined the potential relationship between liver disease and recurrent hyperkalemia. Patients with ≥1 serum potassium measurement between January 2004 and December 2018 who experienced hyperkalemia (serum potassium >5.0 mmol/L) were identified from the United States Veterans Affairs database. A competing risk regression model was used to analyze the relationship between patient characteristics and recurrent hyperkalemia. Of 1,493,539 patients with incident hyperkalemia, 71,790 (4.8%) had liver disease (one inpatient or two outpatient records) within 1 year before the index hyperkalemia event. Recurrent hyperkalemia within 1 year after the index event occurred in 234,807 patients (15.7%) overall, 19,518 (27.2%) with liver disease, and 215,289 (15.1%) without liver disease. The risk of recurrent hyperkalemia was significantly increased in patients with liver disease versus those without (subhazard ratio, 1.34; 95% confidence interval, 1.32–1.37; p < 0.0001). Aside from vasodilator therapy, the risk of recurrent hyperkalemia was not increased with concomitant medication. In this cohort study, liver disease was an independent risk factor strongly associated with recurrent hyperkalemia within 1 year, independent of concomitant renin–angiotensin–aldosterone system inhibitor or potassium-sparing diuretic use. [ABSTRACT FROM AUTHOR]

Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors. The recommendation for use of GDMT is based on the results of multiple major randomized controlled trials demonstrating improved clinical outcomes in patients with HFrEF who are maintained on this therapy. The effect is most beneficial when medications from the four main drug classes are used in conjunction. Despite this, there is an underutilization of GDMT, partially due to lack of awareness of how to safely and effectively initiate and titrate these medications. In this review article, we describe the different drug classes included in GDMT and offer an approach to initiation and effective titration in both the inpatient as well as outpatient setting. [ABSTRACT FROM AUTHOR]

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in Ace2 knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity. [ABSTRACT FROM AUTHOR]

Purpose. To assess whether renin-angiotensin system inhibitor (RASI) utilization is associated with age-related macular degeneration (AMD) prevalence among hypertensive patients. Methods. A US population-based, cross-sectional study was conducted. 3,023 hypertensive participants aged 40 years and older with gradable retinal images and ascertained RASI usage in the National Health and Nutrition Examination Survey (NHANES), 2005–2008, were finally enrolled into the study. RASI usage was obtained by interview, and AMD was determined through retinal image assessment. We performed multivariable analyses to assess the relationship between utilization of RASIs and AMD prevalence. We also took drug treatment duration into account, in order to better understand the effects of RASIs. Results. Multivariable logistic regression analyses revealed that AMD prevalence had no significant association with RASI usage but was inversely correlated with RASI treatment duration (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78–0.98, p = 0.02). Long-term usage (>5 years) of RASIs was significantly associated with not only reduced overall risk of AMD (OR = 0.23, 95% CI = 0.14–0.38, p < 0.001) but also lower propensity to have early (OR = 0.23, 95% CI = 0.14–0.37, p < 0.001) and late (OR = 0.25, 95% CI = 0.07–0.87, p = 0.03) AMD. Furthermore, long-term RASI users were less prone to develop soft drusen (OR = 0.67, 95% CI = 0.45–0.99, p = 0.04) and geographic atrophy (GA) (OR = 0.39, 95% CI = 0.22–0.71, p = 0.003). Conclusions. Evidence supporting that RASI utilization could directly protect against AMD in hypertensive patients was still insufficient, but long-term RASI treatment seemed to be beneficial for both early and late AMD, implicating a promising therapeutic approach that RASIs might offer for AMD prevention and management. [ABSTRACT FROM AUTHOR]

Background: Overactivation of renin-aldosterone-angiotensin system (RAS) is part of the pathogenesis of obesity-associated hypertension. Evidences have shown that weight loss can result in reduction in blood pressure and RAS. This study was aim to investigate changes of plasma aldosterone concentration (PAC) after bariatric surgery. Methods: A prospective study was done in 14 morbidly obese patients undergoing bariatric surgery. Patients who were taking medications that can interfere with PAC and renin levels were excluded. Collection of blood samples were done at baseline and at 3 and 6-month post-bariatric surgery. Results: Four out of 14 patients had hypertension at baseline. Mean body mass index (BMI) was 56.7 ± 13.5 kg/m2. PAC were significantly decreased at 3-and 6-month post-bariatric surgery from 14.3 ± 8.0 to 7.5 ± 5.5 [reduction of 36% from baseline (P < 0.01)] and 8.0 ± 6.6 ng/dl [reduction of 32% from baseline (P < 0.05)] respectively. The reduction of PAC at 3-month post-surgery was correlated with the reduction of body weight (r = 0.46, P < 0.05), waist circumference (r = 0.73, P < 0.05) and percent of body fat (r = 0.58, P < 0.05). Conclusions: Maximal reduction of PAC in obese patients underwent bariatric surgery occurred during the first 3 months after bariatric surgery. The reduction of PAC was associated with the reduction of body weight, waist circumference and percent of body fat suggesting the link between RAS and obesity-mediated hypertension. [ABSTRACT FROM AUTHOR]

Background: Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives. Methods: In a retrospective cohort study (2007–2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs). Findings: Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (OR) = 0.942 (CI: 0.899–0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794–0.892, p<0.001), ARB+pravastatin OR = 0.794 (CI: 0.748–0.843, p<0.001), ARB+rosuvastatin OR = 0.818 (CI: 0.765–0.874, p<0.001). ARBs combined with atorvastatin and simvastatin are associated with smaller reductions in risk, and ACEI with no risk reduction, compared to when combined with pravastatin or rosuvastatin. Among Hispanics, no combination of statins and RAS-acting AHTs reduces risk relative to combinations of statins and non-RAS-acting AHTs. Among blacks using ACEI+rosuvastatin, ADRD odds were 33% lower compared to blacks using other statins combined with non-RAS-acting AHTs (OR = 0.672 (CI: 0.548–0.825, p<0.001)). Conclusion: Among older Americans, use of pravastatin and rosuvastatin to treat hyperlipidemia is less common than use of simvastatin and atorvastatin, however, in combination with RAS-acting AHTs, particularly ARBs, they may be more effective at reducing risk of ADRD. The number of Americans with ADRD may be reduced with drug treatments for vascular health that also confer effects on ADRD. [ABSTRACT FROM AUTHOR]

Background: In 2012, Medicare incorporated medication adherence targeting oral antidiabetic medications, renin-angiotensin system (RAS) antagonists, and statins as highly weighted components in its Star Ratings Program. In the same year, health plans began receiving quality bonus payments for higher star ratings.Objective: We aimed to assess how these policy changes affected adherence to targeted and other chronic disease medications in the United States.Methods: We performed interrupted time series analyses to assess monthly changes in medication adherence from 2010 to 2016 using health plans' Medicare claims submitted to a large pharmacy benefits manager. We conducted 2 sets of analyses. The first examined whether policy changes affected adherence to the 3 targeted therapy classes, and the second assessed the association between policy changes and adherence to 5 chronic disease classes not targeted by star ratings. For the second analysis, we further compared adherence between members who concomitantly used and did not use targeted medications.Results: For star-ratings analyses, we studied 240 811 members on oral antidiabetic medications, 500 958 on RAS antagonists, and 471 135 on statins. Adherence for all star rating-targeted and nontargeted medications increased after 2012 (P < .001). Oral antidiabetic, statin, and RAS antagonist adherence was, respectively, 11.2%, 3.7%, and 8.1% higher than adherence without policy changes (P < .001). Nontargeted antihypertensive and antihyperlipidemic adherence trends were higher among those concomitantly on star rating-targeted medications compared with those who were not (P < .001).Conclusions: As policy makers strive to identify optimal quality measures for improving healthcare delivery, it is important to consider that incentives can promote improved performance in both targeted measures and related outcomes. [ABSTRACT FROM AUTHOR]

Introduction: angiotensin II, a major effector protein of the renin angiotensin system (RAS), induces bone loss under certain conditions. Drugs that block the RAS may therefore reduce bone loss and fracture incidence. The fracture incidence in older hypertensive men with long-term use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) were compared with the incidence in users of calcium channel blockers (CCBs) and non-users. Methods: a total of 5,994 US men aged 65 years or older who had bone mineral density measured at baseline in the Osteoporotic Fractures in Men Study (MrOS) were followed for fracture incidence for an average of 6.8 years. Men with follow-up dual-energy X-ray absorptiometry bone mineral density data and who reported hypertension at any visit, or use of antihypertensive medications at any visit among those with non-missing mediation data were included in the study (N = 2,573). Results: six hundred and nineteen men had taken ACE inhibitors, while 182 took ARBs for at least 4 years. Using Cox regression for the incidence of non-vertebral fractures, we found that long-term users of ACE inhibitors and ARBs each had a significantly lower fracture incidence than non-users. The hazard ratio of non-vertebral fractures was three times lower in ARB users than ACE inhibitor users (Hazard ratio (95% confidence interval): 0.194 (0.079-0.474) versus 0.620 (0.453-0.850), P = 0.0168). There was a trend of greater fracture risk reduction with longer duration of ARB use, but not for ACE inhibitor use. Conclusions: in older hypertensive men, ARBs use was associated with lower incidence of non-vertebral fracture than ACE inhibitors or CCBs. [ABSTRACT FROM AUTHOR]

Background: Heart failure is the leading cause for 30-day all-cause readmission, the reduction of which is a goal of the Affordable Care Act. There is a growing interest in understanding the impact of evidence-based heart failure therapy on 30-day all-cause readmission. In the current study, we examined the impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI-ARBs) on 30-day all-cause readmission in heart failure.Methods: Of the 1384 hospitalized Medicare beneficiaries with heart failure and left ventricular ejection fraction <45% discharged alive from 106 Alabama hospitals (1998-2001) without prior ACEI-ARB use and without known contraindications to ACEI-ARB use; 734 received new predischarge prescriptions for these drugs. Using propensity scores for ACEI-ARB initiation, we assembled a matched cohort of 477 pairs of patients balanced on 32 baseline characteristics (mean age 75 years, 46% women, 26% African American).Results: Thirty-day all-cause readmissions occurred in 18% and 24% of matched patients receiving and not receiving ACEI-ARBs, respectively (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.56-0.97; P = .030). ACEI-ARB use was also associated with lower risk of 30-day all-cause mortality (HR 0.56; 95% CI, 0.33-0.98; P = .041) and of the combined endpoint of 30-day all-cause readmission or 30-day all-cause mortality (HR 0.73; 95% CI, 0.56-0.94; P = .017). All associations remained significant at 1 year post discharge.Conclusions: Among hospitalized patients with heart failure and reduced ejection fraction, the use of ACEI-ARBs was associated with a significantly lower risk of 30-day all-cause readmission and 30-day all-cause mortality; both beneficial associations persisted during long-term follow-up. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the leading causes for hospitalization in the United States and Europe, and is accompanied by high mortality. Current pharmacological therapy of chronic heart failure with reduced ejection fraction is largely based on compounds that inhibit the detrimental action of the adrenergic and the renin–angiotensin–aldosterone systems on the heart. More than one decade after spironolactone, two novel therapeutic principles have been added to the very recently released guidelines on heart failure therapy: the HCN-channel inhibitor ivabradine and the combined angiotensin and neprilysin inhibitor valsartan/sacubitril. New compounds that are in phase II or III clinical evaluation include novel non-steroidal mineralocorticoid receptor antagonists, guanylate cyclase activators or myosine activators. A variety of novel candidate targets have been identified and the availability of gene transfer has just begun to accelerate translation from basic science to clinical application. This review provides an overview of current pharmacology and pharmacotherapy in chronic heart failure at three stages: the updated clinical guidelines of the American Heart Association and the European Society of Cardiology, new drugs which are in clinical development, and finally innovative drug targets and their mechanisms in heart failure which are emerging from preclinical studies will be discussed. [ABSTRACT FROM AUTHOR]

The average salt intake of people in Canada, the United States, and Europe is about 3,400mg of sodium per day, which exceeds the recommended intake levels set by various health organizations. The World Health Organization recommends a worldwide reduction of sodium intake to less than 2,000mg per day. Most research to date has focused on the negative effects of high-sodium intake; however, little information is available on the metabolic effects of low-sodium intakes. This review focuses on the hormonal changes associated with low-sodium diets, specially the hormones involved in metabolism and cardiovascular and renal function. Based largely on rodent studies, low-sodium diets have been associated with changes in glycemic control, energy metabolism, cardiovascular disease risk, cholesterol concentrations, inflammation, and functioning of the renin-angiotensin-aldosterone system. Overall, research has revealed mixed results regarding the impact of dietary sodium intake on various hormones. Further research is required to assess the effects of sodium reduction on hormones and their associated pathways in order to determine the likelihood of any unintended effects. [ABSTRACT FROM AUTHOR]

Purpose: Antihypertensive drugs are prescribed to patients with chronic kidney disease (CKD) for their cardioprotective and renoprotective effects. Nationally representative information on the use of antihypertensive drugs among CKD patients is limited. The purpose of this study was to assess the utilization patterns of antihypertensive drugs among the CKD population (stages I-IV) in the United States. Methods: We conducted a retrospective crosssectional analysis of the National Health and Nutrition Examination Survey (NHANES) panels from 2005-2006, 2007-2008, and 2009-2010. The estimated glomerular filtration rate was calculated and kidney damage was assessed to identify participants with CKD. The demographic and clinical characteristics of the participants with CKD were reported, as were the antihypertensive drugs they used. Findings: A total weighted sample of 116,231,361 participants representative of the CKD population in the United States (stages I-IV) was identified. Less than one half of the participants with CKD in the NHANES were using antihypertensive drugs. β- blockers were the most commonly used and angiotensin II receptor blockers were the least used antihypertensive agents among participants with CKD. Age (Z70 years), awareness of hypertension or diabetes, and higher stage of CKD were associated with an increased likelihood of antihypertensive drug use among participants with CKD. Implications: The results of our analyses suggest that antihypertensive drugs are underused in the CKD population, and the use of preferred agents (ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) is low. Efforts should be directed toward emphasizing the importance of using antihypertensive drugs in the CKD population. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease. [ABSTRACT FROM AUTHOR]

The incidence of metabolic syndrome is rapidly increasing in the United States and worldwide. The metabolic syndrome is a complex metabolic and vascular disorder that is associated with inappropriate activation of the renin–angiotensin–aldosterone system (RAAS) in the cardiovascular (CV) system and increased CV morbidity and mortality. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes nitric oxide (NO) production in the endothelium and glucose uptake in insulin-sensitive tissues. Angiotensin (Ang) II inhibits insulin-mediated PI3K pathway activation, thereby impairing endothelial NO production and Glut-4 translocation in insulin-sensitive tissues, which results in vascular and systemic insulin resistance, respectively. On the other hand, Ang II enhances insulin-mediated activation of the mitogen-activated protein kinase (MAPK) pathway, which leads to vasoconstriction and pathologic vascular cellular growth. Therefore, the interaction of Ang II with insulin signaling is fully operative not only in insulin-sensitive tissues but also in CV tissues, thereby linking insulin resistance and CV disease. This notion is further supported by an increasing number of experimental and clinical studies indicating that pharmacological blockade of RAAS improves insulin sensitivity and endothelial function, as well as reduces the incidence of new-onset diabetes in high-risk patients with CV disease. This article reviews experimental and clinical data elucidating the physiological and pathophysiological role of the interaction between insulin and RAAS in the development of insulin resistance as well as CV disease. [ABSTRACT FROM AUTHOR]

Hispanics are the fastest growing ethnic minority in the USA. Among Hispanics, lack of hypertension awareness and lack of effective blood pressure (BP) control are problematic, as are higher incidence rates of hypertension-related co-morbidities compared with non-Hispanic populations. Moreover, there are currently no hypertension treatment guidelines that address the unique characteristics of this ethnic group. This article discusses ethnic differences in hypertension and cardiovascular risk factors and reviews the literature on the efficacy of antihypertensive agents in Hispanic patients, with a focus on the role of renin-angiotensin-aldosterone system (RAAS) inhibition in the management of hypertension in these patients. Hypertension in Hispanic patients can be challenging to manage, in part because this population has a higher prevalence of obesity, diabetes, and metabolic syndrome compared with non-Hispanic whites. The presence of these comorbidities suggests that RAAS-inhibitor-based therapies may be particularly beneficial in this population. However, few studies have evaluated the efficacy of antihypertensive treatments in Hispanic patients. Two outcomes studies in hypertensive patients have shown the benefits of treating Hispanic patients with antihypertensive therapy and included RAAS inhibitors as part of the treatment regimen. In addition, BP-lowering trials have shown the antihypertensive efficacy of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors, although data on the latter are more limited. Additional studies are needed to more thoroughly evaluate the effects of RAAS inhibitors (and other drug classes) on outcomes and BP lowering in the Hispanic hypertensive population. [ABSTRACT FROM AUTHOR]

Hypertension is prevalent in adult and pediatric end-stage renal disease patients on hemodialysis. Volume overload is a primary factor contributing to hypertension, and attaining true dry weight remains a priority for nephrologists. Other contributing factors to hypertension include activation of the sympathetic and renin-angiotensin-aldosterone systems, endothelial cell dysfunction, arterial stiffness, exposure to hypertensinogenic drugs, and electrolyte imbalances during hemodialysis. Epidemiologic studies in adults show that uncontrolled hypertension results in cardiovascular morbidity, but reveal increased mortality risk at low blood pressure, so that it remains unclear what the target blood pressure should be. Despite the lack of a definitive BP target, gradual dry weight reduction should be the first intervention for BP control. Renin-angiotensin-aldosterone system inhibitors have been shown to improve cardiovascular morbidity and mortality and are recommended as the initial pharmacologic therapy for hypertensive hemodialysis patients. Short-daily or nocturnal hemodialysis are also good therapeutic options for these patients. It is already established that hypertension in pediatric hemodialysis patients is associated with adverse cardiovascular outcomes, and there is emerging evidence that the mechanisms causing hypertension are similar to adults. Hypertension in adult and pediatric hemodialysis patients warrants aggressive management, although clinical trial evidence of a target BP that improves mortality does not currently exist. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined temporal changes in diabetic kidney disease (CKD) prevalence in the U.S. It notes that about 40% of people with diabetes develop DKD. It attributes DKD prevalence to the increasing size of the diabetes population and the widespread application of diabetes therapies. Results showed that prevalence was 2.2% in the National Health and Nutrition Examination Survey (NHANES) III and 2.8% in NHANES 1999-2004. The study found that the use of glucose-lowering medications rose to 74.2% in NHANES 2005-2008 and that the use of renin-angiotensin-aldosteronne system inhibitors increased to 40.6%.

Hypertension in African Americans is a major clinical and public health problem because of the high prevalence and premature onset of elevated blood pressure (BP) as well as the high burden of co-morbid factors that lead to pharmacological treatment resistance (obesity, diabetes mellitus, depressed glomerular filtration rate, and albuminuria). BP control rates are lower in African Americans, especially men, than in other major race/ethnicity-sex groups; overall control rates are 29.9% for non-Hispanic Black men. Optimal antihypertensive treatment requires a comprehensive approach that encompasses multifactorial lifestyle modifications (weight loss, salt and alcohol restriction, and increased physical activity) plus drug therapy. The most important initial step in the evaluation of patients with elevated BP is to appropriately risk stratify them to allow determination of whether they are truly hypertensive and also to determine their goal BP levels. The overwhelming majority of African American hypertensive patients will require combination antihypertensive drug therapy to maintain BP consistently below target levels. The emphasis is now appropriately on utilizing the most effective drug combinations for the control of BP and protection of target-organs in this high-risk population. When BP is >15/10mmHg above goal levels, combination drug therapy is recommended. The preferred combination is a calcium antagonist/angiotensin-converting enzyme inhibitor or, alternatively, in edematous and/or volume overload states, a thiazide diuretic/angiotensin-converting inhibitor. [ABSTRACT FROM AUTHOR]

Background: Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin- aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB. Objective: To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension. Methods: Patients (aged ≥18 years) initiated on either combination therapy were identified in the Market- Scan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period. Results: Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95%CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242) [2008 values]. Conclusion: In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARBversusACEI plusARB, despite the increased prescription costs associated with aliskiren plusARBtherapy. [ABSTRACT FROM AUTHOR]

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration—time curve (AUCτ) was 22% lower and the peak aliskiren plasma concentration (Cmax) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUCτ(r = 0.005; P = .917); AUC τwas negatively correlated with body weight (r = −0.235; P < .0001) and LBW (r = −0.295; P < .0001). Results were similar for Cmax. Adjusting individual aliskiren AUC τand Cmax values for overall mean body weight or LBW abolished gender differences. Based on r2 values, LBW variation accounted for 8.9% of aliskiren AUCτ variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren. [ABSTRACT FROM PUBLISHER]

The article discusses the effects of Renin-Angiotensin system-blocking therapy for the hypertensive chronic kidney disease (CKD) of African Americans in the U.S. According to the authors, CKD is a major public health problem in the country, especially among the black subjects. They said that 4.5 million Americans have hypertensive CKD, and another 110,000 persons have end-stage renal diseases (ESRD) due to hypertension. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and a low blood pressure goal stabilize the glomerular filtration rate and prevent ESRD during 4.5 years.

Abstract: The first oral direct renin inhibitor, aliskiren, recently received approval for the treatment of hypertension. This article addresses the premise, promise, and potential limitations of this new class of renin-angiotensin system inhibitor. Although aliskiren adds to a list of more than 100 drugs approved for the treatment of hypertension, its introduction into clinical medicine is of particular interest because of the novel mechanism of action: inhibition of renin’s catalytic activity, the most proximal and rate-limiting step in renin-angiotensin system activation. By producing more complete renin-angiotensin system inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications. Other potential advantages include additional blood pressure reduction when used in combination therapy, a placebo-like side-effect profile, avid renal concentration, and long duration of action. Potential limitations include modest levels of blood pressure reduction that are equivalent to but not greater than angiotensin receptor blockers, reduced gastrointestinal absorption with a high-fat meal, and large reactive increases in renin secretion—the functional importance of which is under intense investigation. The results of outcomes trials are eagerly awaited. [Copyright &y& Elsevier]

Aliskiren (Tekturna®) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was getter ally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowenng effects when combined with HCTZ 12.5-25 mg/day. ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-hased therapies in lowering BP after 6 months, and was similarly well tolerated. The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) reductions with agents that block the renin-angiotensin system are regarded as less effective as monotherapy in African Americans than other ethnic groups. This practice-based study compares the efficacy of an angiotensin receptor blocker-based regimen in African-American and Caucasian patients. Included in the 10-week study were 173 African- American and 1296 Caucasian patients. Efficacy was based on differences in 24-hour ambulatory BP. After baseline ambulatory BP monitoring and office BPs were obtained, all patients were started or switched to the angiotensin receptor blocker telmisartan, 40-80 mg daily, plus hydro-chlorothiazide 12.5 mg daily (if needed for office BP control: <140/90 mm Hg). More African Americans required the addition of a low-dose thiazide diuretic than Caucasians (47.3% vs. 34.9%; p=0.021). Once patients with white coat hypertension were excluded (i.e., those with baseline ambulatory BP monitoring <130/80 mm Hg), ambulatory BP monitoring changes were similar between groups. A greater proportion of African Americans than Caucasians without white coat hypertension also needed combination therapy (52.1% vs. 39.5%; p=0.04). While achievement of BP goal was similar between groups by office criterion (<140/90 mm Hg), differences were noted by ambulatory BP monitoring (<130/80 mm Hg) (48.0% in African American vs. 63.2% in Caucasians; p=0.01) despite the same BP reductions, reflecting higher baseline values in African Americans. We conclude that an angiotensin receptor blocker as part of a BP-lowering strategy is effective in previously untreated African-American patients, although a higher proportion will require the use of a diuretic compared with Caucasians. [ABSTRACT FROM AUTHOR]

This roundtable discussion, held in December 2003, was convened to discuss the impact of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure's (JNC 7) challenging blood pressure goal objectives for the clinical management of hypertensive patients. The discussion was moderated by Michael Weber, MD, of the State University of New York Downstate College of Medicine in New York City. Participants included leading experts in the field Joseph Izzo, Jr., MD, of the School of Medicine and Biomedical Sciences at the State University of New York at Buffalo; Suzanne Oparil, MD, of the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham; and Jan Basile, MD, of the Ralph H. Johnson VA Medical Center and Department of General Internal Medicine/Geriatrics, Medical University of South Carolina in Charleston. The primary intention of this roundtable is to educate physicians about the importance of achieving the blood pressure goals agreed upon by the JNC 7 Committee and to present practical ways for the attainment of such goals in clinical practice. [ABSTRACT FROM AUTHOR]

The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling. [ABSTRACT FROM AUTHOR]

Approximately 132,000 patients per year undergo anterior cervical discectomy and fusion (ACDF) in the United States. Although the utilization of instrumentation and bone graft alternatives has enhanced fusion rates, pseudarthrosis remains a problem, with incidence rates up to 56%. Renin-angiotensin system (RAS) modulators are typically used to treat arterial hypertension, which affects 50-80% of spinal fusion patients. Recent evidence suggests an association between RAS blockers and bone metabolism, particularly in the context of bone healing. In addition, preclinical and clinical studies have suggested a potential correlation between the use of RAS blockers and reduced osteoporotic fracture risk. We aimed to determine whether there was a correlation between the use of antihypertensive medication, particularly angiotensin-II type-1 receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), and outcomes in anterior cervical discectomy and fusion (ACDF) surgery. Retrospective observational study. Degenerative disc disease patients who underwent ACDF. Spinal fusion status and neurological function (modified Japanese Orthopaedic Association [mJOA] and Nurick grading scales. A cohort of adult patients with symptomatic cervical degenerative disc disease who were operated upon using an allograft implant, and with a 1-year minimum follow-up was considered eligible. Information on demographic data, comorbidities (especially hypertension status), antihypertensive medication, neurological examination and fusion status were collected. Fusion criteria in static radiographs were increased opacification and bridging trabecular bone at the margins of the graft. In dynamic radiographs, fusion criteria were interspinous motion of < 1 mm and superjacent interspinous motion of < 4 mm. For CT scans, fusion was defined as solid bridging of bone across the disc space of the intended fusion. A total of 178 patients with cervical degenerative disc disease who underwent ACDF, with a median age of 53.7 (range 24-90) years, were included in the analysis. Median follow-up was 21.7 months. Out of the 82 hypertensive patients who were identified, 77 (93.9%) were taking antihypertensive drugs (28 [36.4%] received ARBs and 27 [35.1%] received ACEIs). The overall pooled fusion rate was 69.5%. Patients treated with ARBs exhibited a higher fusion rate compared to those who were untreated (88.9% vs 69.7%, respectively, p=.04). By contrast, patients treated with ACEIs displayed a lower fusion rate than untreated patients (45.8% vs 69.7%, respectively, p=.02). Comparisons between successful fusion and failed fusion groups identified treatment with ACEIs as risk factors for the development of pseudarthrosis. Treatment with ARBs displayed a trend towards being a favorable factor for fusion (RR=1.2, 95% CI 1.0, 1.5). In the multivariate nominal logistic analysis, ARB (p=.02) treatment remained an independent risk and beneficial factor, respectively, for fusion. In our retrospective study of a cohort of ACDF patients, treatment with ARBs was associated with an increased fusion rate, while treatment with ACEIs identified as risk factor for failed fusion. Further preclinical and clinical studies are needed to verify the beneficial effects of ARBs and deleterious influence of ACEIs on spinal fusion. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. Renin-angiotensin-aldosterone system (RAAS) blockers are thought to have a specific renoprotective effect in diabetes. Hirst et al. report the results of randomized clinical trials assessing the effects of RAAS inhibitors on urinary albumin excretion levels in diabetic patients. Although reductions in urinary albumin excretion were observed, whether RAAS inhibitors offer additional protection over other antihypertensive agents is unclear. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editors discuss various papers within the issue on topics including the role of angiotensin converting enzyme 2 (ACE2), the therapeutic use of ACE2/Ang-(1-7)/ Mas, G-protein coupled receptor, axis in cardiovascular function, and its effect in hypertension.

Focuses on the role of aldosterone blockade in managing heart failure. Social and economic impact of heart failure in the U.S.; Role of neurohormonal mediators in renin-angiotensin-aldosterone and sympathetic nervous system in heart failure.

Editorial. Comments on the therapeutic value of the renin-angiotensin system in the progression delay of chronic renal diseases in the United States. Contribution of angiotensin II type 1 (AT1) in the process of renal fibrosis; Role of hemodynamic factors in the genesis of the fibrotic response; Importance of AT1 receptor alterations in hemodynamic activity.

The article focuses on a research related to the impact of taking lisinopril, a drug of the angiotensin-converting enzyme (ACE) inhibitor, to losartan drug on kidney in type 2 diabetes and proteinuria as of March 2014. Topics discussed include the use of combined angiotensin inhibition for treating diabetic nephropathy, decline in glomerular filtration rate (eGFR) and the reason for developing hyperkalemia due to the two drugs.

The article reports that Novartis AG has obtained the approval of Food and Drug Administration (FDA) for Valturna, a pill that combines valsartan and aliskeren. It notes that Valturna is a therapy that targets two-points within the renin-angiotensin-aldosterone system and offers greater blood pressure (BP) reduction. It cites that the drug was approved with a suggestion to treat hypertension in patients who are not adequately controlled by either aliskiren or angiotensin receptor blocker.

The article informs that the U.S. Food and Drug Administration (FDA) has announced the approval of aliskiren tablets for the treatment of hypertension. It has been stated that the medicine, that acts directly on the renin-angiotensin system, has mild and brief side effects and should not be used during pregnancy.