Structure and function of anticoagulation clinics in the United States: an AC forum membership survey.

Many anticoagulation clinics have adapted their services to provide care for patients taking direct oral anticoagulants (DOAC) in addition to traditional warfarin management. Anticoagulation clinic scope of service and operations in this transitional environment have not been well described in the literature. A survey was conducted of United States-based Anticoagulation Forum members to inquire about anticoagulation clinic structure, function, and services provided. Survey responses are reported using summary or non-parametric statistics, when appropriate. Unique clinic survey responses were received from 159 anticoagulation clinics. Clinic structure and staffing are highly variable, with approximately half of clinics (52%) providing DOAC-focused care in addition to traditional warfarin-focused care. Of those clinics managing DOAC patients, this accounts for only 10% of their clinic volume. These clinics commonly have a DOAC follow up protocol (75%). Clinics assign a median of 190.5 (interquartile range 50-300) patients per staff full-time-equivalent, with more patients assigned in phone-based care clinics than in face-to-face based care clinics. Most clinics (68.5%) report receiving reimbursement, which occur either through a combination of patient and insurance provider billing (78.2%), insurance reimbursement only (19.5%) or patient reimbursement only (2.3%). There is wide heterogeneity in anticoagulation clinic structure, function, and services provided. Half of all survey-responding anticoagulation clinics provide care for DOAC-treated patients. Understanding how changes in healthcare policy and reimbursement have impacted these clinics remains to be explored.

The Associations between Neighborhood Characteristics and Childhood Overweight and Obesity in a National Dataset.

BACKGROUND: National child obesity rates continue to climb. While neighborhood factors are known to influence childhood weight, more work is needed to further our understanding of these relationships and inform intervention and policy approaches reflective of complex real-world contexts. METHODS: To evaluate the associations between neighborhood components and childhood overweight/obesity, we analyzed sequential, cross-sectional data from the National Survey of Children's Health collected annually between 2016 and 2021. To characterize the complexity of children's neighborhood environments, several interrelated neighborhood factors were examined: amenities, detractions, support, and safety. We used ordinal logistic regression models to evaluate the associations between these exposures of interest and childhood weight status, adjusting for potential confounders. RESULTS: Our analytic sample contained 96,858 children representing a weighted population of 28,228,799 children ages 10-17 years. Child weight status was healthy in 66.5%, overweight in 16.8%, and obese in 17.2%. All four neighborhood factors were associated with child weight status. The odds of overweight or obesity generally increased with a decreasing number of amenities and increasing number of detractions, with the highest adjusted odds ratio seen with no amenities and all three possible detractions (1.71; 95% confidence interval [1.31, 2.11]). CONCLUSIONS: Multiple factors within a child's neighborhood environment were associated with child weight status in this sample representative of the US population aged 10-17 years. This suggests the need for future research into how policies and programs can support multiple components of a healthy neighborhood environment simultaneously to reduce rates of childhood overweight/obesity.

A Narrative Review of Public Health Interventions for Childhood Obesity.

PURPOSE OF REVIEW: Public health interventions that intervene on macrolevel systems hold the promise of reducing childhood obesity at the population level through prevention. The purpose of this review is to highlight some of the recent and best scientific evidence related to public health interventions for the prevention of childhood obesity. We provide a narrative review of scientific evidence for six categories of public health interventions and their impact on childhood obesity: federal nutrition assistance programs, programs implemented in early care and education centers, interventions to support healthy nutrition and physical activity in schools, community-based programs and policies, labeling policies and marketing to children, and taxes on sugar sweetened beverages (SSB). RECENT FINDINGS: Federal nutrition assistance programs have the strongest evidence to support reduction in childhood obesity and serve populations with the highest prevalence of childhood obesity. Other interventions including SSB taxes, community-wide interventions, and interventions at schools and early care and education centers also show significant improvements in child weight status. Overall public health interventions have strong evidence to support widespread implementation in service of reducing childhood obesity rates at the population level. To effectively address the recalcitrant childhood obesity epidemic, multi-pronged solutions are needed. The current evidence for public health obesity interventions is consistent with the paradigm that recognizes the importance of macrolevel systems influences on childhood obesity: interventions that are most effective intervene at macrolevels.

Language Disparities in Caregiver Satisfaction with Physician Communication at Well Visits from 0-2 Years.

OBJECTIVE: This study aimed to describe caregiver satisfaction with physician communication over the first two years of life and examine differences by preferred language and the relationship to physician continuity. METHODS: Longitudinal data were collected at well visits (2 months to 2 years) from participants in a randomized controlled trial to prevent childhood obesity. Satisfaction with communication was assessed using the validated Communication Assessment Tool (CAT) questionnaire. Changes in the odds of optimal scores were estimated in mixed-effects logistic regression models to evaluate the associations between satisfaction over time and language, interpreter use, and physician continuity. RESULTS: Of 865 caregivers, 35% were Spanish-speaking. Spanish-speaking caregivers without interpreters had lower odds of an optimal satisfaction score compared with English speakers during the first 2 years, beginning at 2 months [OR 0.64 (95% CI: 0.43, 0.95)]. There was no significant difference in satisfaction between English-speaking caregivers and Spanish-speaking caregivers with an interpreter. The odds of optimal satisfaction scores increased over time for both language groups. For both language groups, odds of an optimal satisfaction score decreased each time a new physician was seen for a visit [OR 0.82 (95% CI: 0.69, 0.97)]. CONCLUSION: Caregiver satisfaction with physician communication improves over the first two years of well-child visits for both English- and Spanish-speakers. A loss of physician continuity over time was also associated with lower satisfaction. Future interventions to ameliorate communication disparities should ensure adequate interpreter use for primarily Spanish-speaking patients and address continuity issues to improve communication satisfaction.

Prostate effect in dogs with the aldosterone receptor blocker eplerenone.

Eplerenone (Inspra) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not.

Feasibility evaluation of the Reaching Out to Kids with Emotional Trauma (ROcKET) intervention in an elementary school: a single-arm, single-centre, feasibility study based on the RE-AIM framework.

OBJECTIVE: The study purpose was to describe feasibility of implementation of the Reaching Out to Kids with Emotional Trauma (ROcKET) intervention. We hypothesised that the ROcKET Intervention would be feasible in a poor resource school. DESIGN: We performed a single-arm, single-centr feasibility study of an intervention pilot, based on the RE-AIM framework. SETTING: The intervention was delivered in a single K-4th elementary charter school in the Nashville, TN area, in a low-resource community. PARTICIPANTS: 57 elementary school children attending our partner school and reporting exposure to at least one adverse childhood experience (ACE) and their parents. INTERVENTIONS: The Reaching Out to Kids with Emotional Trauma (ROcKET) intervention is a school-based multilevel intervention (individual child, family and school) that promotes positive health behaviours in children who have been exposed to ACEs. OUTCOMES: Outcomes were gathered qualitatively via focus groups. The primary outcome was feasibility. The secondary outcomes were implementation outcomes according to the RE-AIM framework, including Reach, Effectiveness, Adoption and Implementation. RESULTS: Of 105 eligible children, 57 children and their parents participated (54%) with 31 (54%) girls, 47 (82%) Black/African American, 5 (9%) Hispanic and 5 (9%) white. The school staff implemented all planned ROcKET sessions with >90% fidelity in each session, and 52 (91%) of children who completed the final intervention session went on to complete 6 month follow-up assessments. The average attendance at the in-school child sessions was 57 students (87%), and 35 (61%) of parents attended at least one family session, with 25 (44%) of parents attending at least half of the family sessions. 13 (23%) parents participated in the focus groups. Qualitative data suggested high parent participant satisfaction, uptake of positive health behaviours targeted by the intervention and increased quality of life. CONCLUSIONS: Our study suggests that the ROcKET intervention was feasible and acceptably delivered in a local elementary school with high reach to low-income and minority populations. These data suggest that schools, especially those serving low-income and minority children, can be an appropriate avenue for interventions designed to address health disparities. Data from this study will be used to advise a pilot study of the intervention.

18-year-old with Abdominal Pain Due to Congenital Bowel Malrotation: A Case Report.

INTRODUCTION: Congenital bowel malrotation resulting in midgut volvulus is traditionally regarded as a diagnosis of infancy. Rarely, congenital bowel malrotation is diagnosed in adolescents or adults and requires a high index of suspicion. Presentations can be acute or chronic, and physical examination findings are nonspecific. Diagnosis is primarily achieved through abdominal computed tomography (CT) or during exploratory laparotomy. The pathophysiology in late-onset malrotation is similar to neonatal malrotation, with a division of Ladd's bands - peritoneal fibrous bands that connect the cecum to the right lower quadrant retroperitoneum - as the definitive treatment. We present a case of congenital bowel malrotation in an adolescent with persistent and worsening migratory abdominal pain. CASE REPORT: An 18-year-old female presented to the emergency department with two days of poorly localized abdominal pain and nausea. Initial evaluation was unremarkable and she was discharged home with a diagnosis of constipation. She returned two days later with worsening abdominal pain and new onset emesis. Given her persistent and worsening symptoms an abdominal CT was performed, which revealed malrotation of the bowel. Taken together, her CT findings and abdominal symptoms were concerning for symptomatic congenital bowel malrotation and she underwent a Ladd procedure. She remained asymptomatic both at discharge and at two-week postoperative follow-up. CONCLUSION: Symptomatic congenital bowel malrotation is more common in older children and adults than has traditionally been thought. Physicians must consider this diagnosis in their differential when working up a patient for acute or chronic intermittent abdominal pain to prevent potentially severe sequelae.

Effects of handling and storage on potassium concentration in plasma and serum samples obtained from cats.

OBJECTIVE: To compare potassium concentrations in feline plasma and serum samples analyzed promptly after collection or after 20 to 28 hours of refrigerated storage. ANIMALS: 41 cats. PROCEDURES: A venous blood sample was obtained from each cat. Aliquots were placed in 2 tubes without anticoagulant (blood was allowed to clot to derive serum) and 2 tubes with heparin (to derive plasma). One serum and 1 plasma sample were kept at room temperature and analyzed within 60 minutes after collection (baseline); the other serum and plasma samples were analyzed after 20 to 28 hours of refrigerated storage. At both time points, serum and plasma potassium concentrations were measured. RESULTS: Median baseline serum potassium concentration (4.3 mmol/L) was significantly higher than median baseline plasma potassium concentration (4.1 mmol/L). The median difference between those values was 0.4 mmol/L (95% CI, 0.2 to 0.5 mmol/L). Compared with their respective baseline measurements, the median serum plasma concentration (4.8 mmol/L) and median plasma potassium concentration (4.6 mmol/L) were higher after 20 to 28 hours of refrigeration. CLINICAL RELEVANCE: Results indicated that with regard to potassium concentration in feline blood samples, clotting or refrigerated storage for 20 to 28 hours results in a significant artifactual increase. Detection of an unexpectedly high potassium concentration in a cat may represent pseudohyperkalemia, especially if the blood sample was placed in a no-additive tube, was stored for 20 to 28 hours prior to analysis, or both.

Barriers to integrating direct oral anticoagulants into anticoagulation clinic care: A mixed-methods study.

BACKGROUND: Outpatient anticoagulation clinics were initially developed to care for patients taking vitamin K antagonists such as warfarin. There has not been a systematic evaluation of the barriers and facilitators to integrating direct oral anticoagulant (DOAC) care into outpatient anticoagulation clinics. METHODS: We performed a mixed methods study consisting of an online survey of anticoagulation clinic providers and semi-structured interviews with anticoagulation clinic leaders and managers between March and May of 2017. Interviews were transcribed and coded, exploring for themes around barriers and facilitators to DOAC care within anticoagulation clinics. Survey questions pertaining to the specific themes identified in the interviews were analyzed using summary statistics. RESULTS: Survey responses were collected from 159 unique anticoagulation clinics and 20 semi-structured interviews were conducted. Three primary barriers to DOAC care in the anticoagulation clinic were described by the interviewees: (a) a lack of provider awareness for ongoing monitoring and services provided by the anticoagulation clinic; (b) financial challenges to providing care to DOAC patients in an anticoagulation clinic model; and (c) clinical knowledge versus scope of care by the anticoagulation staff. These themes linked to three key areas of variation, including: (a) the size and hospital affiliation of the anticoagulation clinic; (b) the use of face-to-face versus telephone-based care; and (c) the use of nurses or pharmacists in the anticoagulation clinic. CONCLUSIONS: Anticoagulation clinics in the United States experience important barriers to integrating DOAC care. These barriers vary based on the clinic size, model for warfarin care, and staff credentials (nursing or pharmacy).

Out-of-range INR results lead to increased health-care utilization in four large anticoagulation clinics.

BACKGROUND: The impact on health-care costs and utilization of a single out-of-range (OOR) INR value not associated with bleeding or thromboembolic complication among chronic warfarin-treated patients is not well described. METHODS: At four large phone-based anticoagulation clinics (total 14 948 patients), warfarin-treated patients with atrial fibrillation (AF) or venous thromboembolism were retrospectively propensity matched into an OOR INR group (n = 116) and a control group (n = 58). Types and frequency of contacts (eg, phone, voicemail, facsimile) and personnel involved were identified. A prospective time study analysis of 59 OOR and 92 control patients was performed over 8.5 days to record the time required to care for these patients. 2016 USD cost estimates were generated from average salaries. RESULTS: OOR and in-range INR patients experienced an average of 4.2 and 3.2 (P < .001) INR lab draws until two sequential tests were in range. OOR INR patients required an average of 5.3 interactions with the anticoagulation clinic vs 3.7 for in-range INR patients (P < .001). OOR INR patients more often required phone calls, fewer mailed letters, and more often required multiple types of contact than in-range INR patients. In the prospective analysis, total median time involved for each OOR INR value was 5.1 minutes (IQR 3.7-9.5) vs 2.9 minutes (IQR 1.8-5.8) for control INR values (P < .001). At the clinic level, OOR INR values were associated with a yearly staff cost of $17 938 (IQR $8969-$31 391). CONCLUSIONS: We quantified the amount of extra anticoagulation staff effort required to manage warfarin-treated patients who experience a single OOR INR value without bleeding or thromboembolic complications, which leads to higher healthcare utilization costs.

Protein 4.1R Exon 16 3' Splice Site Activation Requires Coordination among TIA1, Pcbp1, and RBM39 during Terminal Erythropoiesis.

Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion. This element also activates an internal exon when placed in a corresponding intronic position in a heterologous reporter. The impact of these two factors is further enhanced by high levels of RBM39, whose expression rises during erythroid differentiation as exon 16 inclusion increases. TIA1 and Pcbp1 associate in a complex containing RBM39, which interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point. Our results provide a mechanism for exon 16 3' splice site activation in which a coordinated effort among TIA1, Pcbp1, and RBM39 stabilizes or increases U2 snRNP recruitment, enhances spliceosome A complex formation, and facilitates exon definition through RBM39-mediated splicing regulation.

Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure.

BACKGROUND: In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. METHODS AND RESULTS: HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis. CONCLUSIONS: Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone.

Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRA), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.

Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart.

We studied the role of aldosterone (aldo) in myocardial injury in a model of angiotensin (Ang) II-hypertension. Wistar rats were given 1% NaCl (salt) to drink and randomized into one of the following groups (n = 10; treatment, 21 d): 1) vehicle control (VEH); 2) Ang II infusion (25 ng/min, sc); 3) Ang II infusion plus the selective aldo blocker, eplerenone (epl, 100 mg/kg.d, orally); 4) Ang II infusion in adrenalectomized (ADX) rats; and 5) Ang II infusion in ADX rats with aldo treatment (20 micro g/kg.d, sc). ADX rats received also dexamethasone (12 micro g/kg.d, sc). Systolic blood pressure increased with time in all treatment groups except the VEH group (VEH, 136 +/- 6; Ang II/NaCl, 203 +/- 12; Ang II/NaCl/epl, 196 +/- 10; Ang II/NaCl/ADX, 181 +/- 7; Ang II/NaCl/ADX/aldo, 236 +/- 8 mm Hg). Despite similar levels of hypertension, epl and ADX attenuated the increase in heart weight/body weight induced by Ang II. Histological examination of the hearts evidenced myocardial and vascular injury in the Ang II/salt (7 of 10 hearts with damage, P < 0.05 vs. VEH) and Ang II/salt/ADX/aldo groups (10 of 10 hearts with damage, P < 0.05). Injury included arterial fibrinoid necrosis, perivascular inflammation (primarily macrophages), and focal infarctions. Vascular lesions were associated with expression of the inflammatory mediators cyclooxygenase 2 (COX-2) and osteopontin in the media of coronary arteries. Myocardial injury, COX-2, and osteopontin expression were markedly attenuated by epl treatment (1 of 10 hearts with damage, P < 0.05 vs. Ang II/salt) and adrenalectomy (2 of 10 hearts with damage, P < 0.05 vs. Ang II/salt). Our data indicate that aldo plays a major role in Ang II-induced vascular inflammation in the heart and implicate COX-2 and osteopontin as potential mediators of the damage.

Eplerenone, a new selective aldosterone blocker.

Activation of the renin-angiotensin-aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and heart failure in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin converting enzyme inhibitors (ACEi) and the angiotensin receptor blockers (ARB), unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the last few years strongly supports the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone blocker, eplerenone, has been shown to produce significant cardioprotective and renoprotecive effects in experimental models of cardiovascular disease. Early clinical studies suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure post-myocardial infarction (post-MI).

The evolution of aldosterone antagonists.

Since the isolation and purification of aldosterone from adrenal extracts 50 years ago (Experientia 9 (1953) 33), scientists have learned a great deal about how and where aldosterone acts, the factors that control its release, what is its role in the pathophysiology of cardiovascular disease, how to make and study aldosterone antagonists, and for what medical purposes these agents are useful. In this paper, we will discuss the evolution of aldosterone antagonists from the relatively nonselective spironolactone (Aldactone), to the highly selective eplerenone (Inspra). Eplerenone represents a molecule with improved steroid receptor selectivity and pharmacokinetic properties in man compared to spironolactone. Recent clinical results have demonstrated that these improvements translate into tolerability and efficacy in patients with cardiovascular disease.

Aldosterone target organ protection by eplerenone.

The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant effect of this hormone. However, there is convincing evidence for additional extrarenal actions of aldosterone that are mediated via activation of mineralocorticoid receptors (MRs) in the heart, vasculature and brain. It is now postulated that many of the detrimental effects of aldosterone are mediated through MR activation in these nonclassical target organs. The selective aldosterone blocker, eplerenone (Inspra), is under development for human therapeutic use for treatment of hypertension and heart failure post-myocardial infarction (MI). Clinical and preclinical studies have linked elevated aldosterone to hypertension, left ventricular and vascular remodeling, cardiac, renal, and cerebral vascular inflammation and injury, and increased risk of mortality in heart failure patients. Multiple studies in experimental models of hypertension and heart failure demonstrate that selective blockade of aldosterone by eplerenone effectively preserves cardiac function, attenuates maladaptive left ventricular remodeling and tissue and vascular injury in part by reducing vascular inflammation in aldosterone target organs.

Emerging therapies for heart failure.

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.