The Cardiorenal Effects of Chronic Phosphodiesterase-V Inhibition in Preclinical Diastolic Dysfunction (Stage B Heart Failure).

OBJECTIVE: To determine whether chronic phosphodiesterase-V (PDEV) inhibition with tadalafil will improve urinary sodium excretion, glomerular filtration rate (GFR), plasma cyclic guanosine 3', 5'-monophosphate (cGMP), and urinary cGMP excretion in response to volume expansion (VE) in patients with preclinical diastolic dysfunction (PDD) or stage B heart failure. BACKGROUND: PDD is defined as abnormal diastolic function with normal systolic function, without clinical heart failure. PDD is predictive of development of heart failure and all-cause mortality. Impaired renal function and attenuated cGMP response to VE are hallmarks of PDD. METHODS: A double-blind, placebo-controlled, proof-of-concept study was conducted to compare 12 weeks of tadalafil 20 mg daily (n = 14) vs placebo (n = 7). Subjects underwent 2 study visits 12 weeks apart. Renal, neurohormonal and echocardiographic assessments were performed before and after intravascular VE (normal saline 0.25 mL/kg/min for 1 hour). RESULTS: Baseline characteristics were similar. There was no increase in GFR, plasma cGMP or urinary cGMP excretion in response to VE in either group at visit 1. At visit 2, tadalafil did not result in significant change in GFR but increased plasma cGMP and urinary cGMP excretion at baseline. In response to VE, tadalafil resulted in increased urine flow, urinary sodium excretion, GFR (7.00 [-1.0, 26.3] vs -9.00 [-24.5, 2.0] mL/min/1.73m2; P = 0.02) and plasma cGMP (0.50 [-0.1, 0.7] vs -0.25 [-0.6, -0.1] pmol/mL; P = 0.02). It did not improve urinary cGMP excretion after VE. CONCLUSION: In PDD, chronic PDEV inhibition with tadalafil improved renal response to VE through increased urine flow, urinary sodium excretion, GFR, and plasma cGMP. Further studies are required to determine whether this enhanced renal response can mitigate progression to clinical heart failure.

Student-run free clinic volunteers: who they are and what we can learn from them.

BACKGROUND: Initiatives employing medical students' volunteerism and idealism, such as the Student-Run Free Clinics (SRFC) program, are prevalent in US medical schools. Many studies evaluated various aspects of volunteering, sometimes resulting in conflicting evidence. This study simultaneously sought to identify the characteristics of volunteers vs. non-volunteers, and to characterize the volunteers' perception of the SRFC. METHODS: We administered a survey to the Long School of Medicine (LSOM) Class of 2018 before their third year of medical school. The authors compared and contrasted the findings of the SRFC volunteers with their non-volunteering counterparts by analyzing their demographics, volunteering history, academic performance, and clinical skills. The volunteers were also asked about their SRFC experiences. RESULTS: While most volunteers were female (62 %) and non-traditional students (67 %), the difference was not statistically significant (p = 0.15 and p = 0.38, respectively). Additionally, there were no statistically significant differences between the two groups in measures of academic performance (p = 0.25). Most of the volunteers learned about the SRFC program prior to starting medical school. Further, while SRFC volunteers were more likely to engage in additional local volunteering initiatives, the difference was not statistically significant (p = 0.03, prespecified  α= 0.006). Importantly, volunteers agreed/strongly agreed that SRFC volunteering emphasized aspects that were missing or underemphasized in the formal medical school curriculum. CONCLUSIONS: Medical students' age, gender, undergraduate major, and non-traditional status were not statistically different between volunteers vs. non-volunteers. However, there may be tendencies for volunteers to be female, non-traditional, and locally engaged. Further, the timing of knowledge of the SRFC program may not affect student involvement in the SRFC, either. Most importantly, however, while volunteering does not affect the students' academic performance, it may provide improvements in clinical competencies.

Annexin A1 is a Potential Novel Biomarker of Congestion in Acute Heart Failure.

OBJECTIVES: This study sought to identify the role of annexin A1 (AnxA1) as a congestion marker in acute heart failure (AHF) and to identify its putative role in predicting clinical outcomes. BACKGROUND: AnxA1 is a protein that inhibits inflammation following ischemia-reperfusion injury in cardiorenal tissues. Because AHF is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF. METHODS: In the Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a subanalysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into 3 tertiles based on their baseline AnxA1 levels. RESULTS: The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P < .007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (P< .05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (P = .03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (P = .03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (P < .05). CONCLUSIONS: Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels are associated with worse congestion, higher risk for further creatinine elevation, and higher rates of 60-day morbidity or all-cause mortality and 180-day all-cause mortality. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01132846.

Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes.

The incidence of diabetes mellitus (DM) is rising. DM is a risk factor for developing left ventricular (LV) dysfunction and adverse cardiovascular outcomes. Insulin, commonly used to treat DM, is associated with further worsening of such outcomes. Yet, the pathophysiology of the adverse properties of insulin on the heart remains poorly defined. Therefore, the objective of this study was to determine the biological effects of insulin on the heart in DM, which we tested in vivo in a diabetic rat model and in vitro on human cardiomyocytes and fibroblasts. Male Wistar rats were divided into 3 groups: controls (n = 17), untreated diabetics (UDM, n = 15), and insulin-treated diabetics (IDM, n = 9). Diabetes was induced with Streptozotocin. Insulin pumps in IDM and saline pumps in UDM and controls were implanted for 4 weeks before tissue collection. Separately, cultures of human cardiomyocytes (AC16) and human cardiac fibroblasts (HCF) were treated with insulin to assess apoptosis and fibrosis, respectively. In rats, insulin partially rescued the DM-associated weight loss while fully restoring euglycemia. However, IDM had 2 × the rate of LV fibrosis (p < 0.0001) compared to UDM, and triple the rate of cardiomyocyte apoptosis compared to controls (p < 0.05). Similarly, in vitro, insulin triggered apoptosis in a dose-dependent fashion in AC16 cells, and it increased fibrosis and upregulated SMAD2 in HCF to levels comparable to Transforming Growth Factor Beta 1. Therefore, we conclude that insulin therapy is associated with increased cardiomyocyte apoptosis and myocardial interstitial fibrosis. Longer studies are needed to explore the long-term effects of insulin on cardiac structure and function.

Cardiorenal Effects of Long-Term Phosphodiesterase V Inhibition in Pre-Heart Failure.

Background Phosphodiesterase V (PDEV) is upregulated in heart failure, leading to increased degradation of cGMP and impaired natriuresis. PDEV inhibition improves the renal response to B-type natriuretic peptide in animal models. We tested the hypothesis that long-term PDEV inhibition would improve renal function and cardiorenal response after short-term volume load in subjects with pre-heart failure. Methods and Results A total of 20 subjects with pre-heart failure (defined as an ejection fraction ≤45% without previous diagnosis of heart failure) and renal impairment were randomized in a 2:1 manner to tadalafil or placebo. Baseline echocardiography and renal clearance study were performed, followed by a short-term saline load and repeated echocardiography and renal clearance study. Subjects then received either tadalafil at a goal dose of 20 mg daily or placebo, and the study day was repeated after 12 weeks. Long-term tadalafil did not improve glomerular filtration rate (median increase of 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group; P=0.54). There was no difference in urinary sodium or cGMP excretion with PDEV inhibition following short-term saline loading. Conclusions Glomerular filtration rate and urinary sodium/cGMP excretion were not significantly different after 12 weeks of tadalafil compared with placebo. These results do not support the use of PDEV inhibition to improve renal response in patients with pre-heart failure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01970176.

Characteristics of Transgender Women Referred to Women's Heart Clinic.

INTRODUCTION: Transgender women have been reported to have a high burden of cardiovascular disease (CVD) and risk factors based largely on surveys. Our aim was to describe the prevalence of CVD and associated comorbidities among a cohort of older transgender women referred to cardiology as part of their gender-affirming care. METHODS: This was a retrospective, cross-sectional study of transgender women at a single institution from 2017 to 2019. RESULTS: Fifty-two consecutive patients were included. The most common reasons for referral were cardiac risk factor management (45%) and pre-operative cardiac risk stratification prior to gender-affirming surgery (35%). The mean age was 57 ± 10 years, 87% were white, and 92% had insurance coverage. Forty-eight patients (92%) were taking gender-affirming hormone therapy; 5 had undergone breast augmentation, 4 had undergone orchiectomy, and 2 had undergone vaginoplasty. The most common comorbidities were depression and/or anxiety (63%), obesity (58%), and hyperlipidemia (54%). Excluding aldosterone antagonists, 46% were on cardiac medications; changes were recommended for 25% of patients: new prescriptions in 9, dose adjustments in 5, and discontinuations in 4. According to the pooled cohort equation, the 10-year risk of atherosclerotic CVD was 9.4 ± 7.7% when the study population was calculated as male and 5.2 ± 5.1% when calculated as female (p <0.001). For patients who completed exercise testing, the functional aerobic capacity was fair (77.6 ± 21.4%) when calculated as male and average (99.5 ± 27.5%) as female (p < .0001); there was inconsistency in sex used for calculating the result on the formal report. CONCLUSIONS: Older transgender women may have an underestimated prevalence of CVD and its risk factors. More research is needed to identify cardiovascular health profiles, improve practice consistency, and establish normative values for transgender patients.

San Antonio refugees: Their demographics, healthcare profiles, and how to better serve them.

OBJECTIVE: The recent refugee crisis has resulted in the largest burden of displacement in history, with the US being the top resettlement country since 1975. Texas welcomed the second most US-bound refugees in 2016, with a large percentage arriving in San Antonio. Yet, the composition of the San Antonio refugees has not been described and their healthcare needs remain ill-defined. Through this study, we aim at elucidating their demographics and healthcare profiles, with the goal of devising recommendations to help guide refugee program development and guide other refugee resettlement programs. METHODS: Data from 731 charts belonging to 448 patients at the San Antonio Refugee Health Clinic (SARHC) were extracted and analyzed. Data included age, gender, country of origin, first language, interpretation need, health insurance status, medical history, vital signs, diagnoses, and prescribed medications. RESULTS: Women constituted the majority of patients (n = 267; 56.4%), and the median age of all patients was 39 (Q1:26, Q3:52). Nepali-speaking Bhutanese patients were the most represented group (n = 107, 43.1%), followed by Iraqi (n = 35, 14.1%), Burmese (n = 30, 12.1%), and Iranian (n = 19, 7.7%) refugees. Of those who responded, 200 (86.6%) did not have any form of health insurance. Additionally, 262 (50.9%) had a body-mass index (BMI) in the overweight or obese range. Further, 61.4% (n = 337) had blood pressures in the hypertensive range, while 9.3% (n = 51) had an elevated blood pressure. On average, each patient had 1.9 complaints, with abdominal pain, headaches, and cough being the predominant complaints. Allergic rhinitis, viral upper respiratory infections, and elevated blood pressure were the most common diagnoses. However, the list of common diagnoses differed per country of origin. CONCLUSION: The SARHC demographics were different from those of other Texas refugees. The rate of the uninsured and the burden of non-communicable diseases were high. Furthermore, each refugee subgroup had a different set of common problems. These findings reveal important considerations for refugee healthcare providers and the unique approach that may be required for different communities.