Adel, Fadi

Introduction: The prevalence of diabetes mellitus (DM) is increasing, and it is associated with cardiorenal dysfunction. Natriuretic peptides (NPs) have cardiorenal protective actions and enhance insulin sensitivity. We designed a dual-action bispecific peptide (CRRL 094) that simultaneously activates the natriuretic peptide system and induces insulin secretion. Methods: To test the in vivo effects of the peptide, Wistar rats (male, 6-8-week-old) were made diabetic by intraperitoneal Streptozotocin (STZ) injection (65 mg/kg). One week after STZ injection, diabetes was confirmed (fasting blood glucose > 350 mg/dL). Rats were then divided into 2 groups: controls (Ctrl group, n=6) and treatment group (Tx group, n= 9). The peptide (1 pmol/kg/min) was infused in the Tx group for 150 min. Results: After 150 minutes of peptide infusion, plasma insulin (mean± standard deviation) increased more than 3.7x among the Tx group compared to the Ctrl group (0.294± 0.199 ng/mL vs 0.078± 0.021 ng/mL, p=0.01). Additionally, plasma glucose decreased among Tx group (405.3±96.4 mg/dL) compared to Ctrl group (545.6± 52.8 mg/dL, p=0.003). Furthermore, the rate of natriuresis increased significantly among the Tx group compared to controls (1.582±0.7 vs 0.639±0.21, p= 0.009), as did the rate of kaliuresis (3.1± 1.1 vs 2.0±0.6, p=0.045). Importantly, the glomerular filtration rate increased by 1.5x among the Tx group compared to the controls (1.6±0.5 vs 1.0±0.3, p= 0.03). There were no significant differences in mean arterial pressure or heart rate. Conclusions: The dual-action insulin-secreting natriuretic peptide (CRRL 094) was effective in increasing endogenous insulin secretion, enhancing natriuresis, and improving renal clearance. Further studies are warranted to assess its long-term safety and efficacy in diabetes.

Evaluating the Electrocardiographic Characteristics of Transgender Patients Undergoing Gender-affirming Hormone Therapy with Artificial Intelligence Introduction: An artificial intelligence (AI) electrocardiogram (ECG) algorithm has been demonstrated to identify a patient’s birth designated sex with 90.4% accuracy with an AUC = 0.97. However, the algorithm has not been evaluated in transgender and gender diverse individuals. We aimed to determine how the algorithm output varies among transgender individuals seen at the Mayo Clinic Transgender and Intersex Specialty Care Clinic (TISCC) who are undergoing gender-affirming hormonal treatment (GAHT). Methods: We applied the algorithm (which assessed the probability of “male” between 0 and 1, with < 0.5 considered as “female” and > 0.5 as “male”) to ECGs obtained from patients in the TISCC before and after the initiation of GAHT. GAHT frequently involves the use of testosterone in transgender men, and estrogen and anti-androgen agents in transgender women. Patient characteristics, including the date of the initiation of GAHT, were collected through chart review. Results: Among transgender women, the AI model probability of “male” decreased from 0.84± 0.25 (12/86 classified as males) to 0.59±0.36 (68/173 classified as male) with GAHT (p < 7.8e-10). Among transgender men, the AI model probability of “male” increased from 0.16 ± 0.28 (7/47 classified as male) to 0.41 ±0.38 (22/53 classified as male) with GAHT (p < 2.4e-4). Conclusion: After GAHT initiation, the Mayo Clinic AI ECG algorithm assigns a higher probability of being male among transgender men and a lower probability of being male among transgender women. These findings warrant further investigation into the electrocardiographic differences across genders and the effects of GAHT on the human heart.

Introduction: Stress echocardiography (SE) is a common functional imaging modality used for the detection of symptomatic coronary artery disease (CAD). Currently, the interpretation of SE relies on sex-based comparators for reporting parameters, including exercise time and functional aerobic capacity. These parameters are based on the cisgender male and female populations but have not been studied among transgender (TG) patients. Thus, we sought to characterize the SE parameters among a group of TG women. Methods: We designed a case-control study of TG women who underwent a SE at the Mayo Clinic. Each TG patient was age-matched with 2 cis-males and 2 cis-females. Demographics, medical history, and SE data were extracted. Conditional logistic regression analysis was performed to compare the TG cohort with each cisgender cohort separately. Results: Among the 43 TG females (age 57.7±9 years, 94.9% white), the prevalence of CAD was less than in cis-males (p=0.013) but similar to cis-females. For SE parameters, TG females had higher resting heart rates than cis-males (median [Q1, Q3]: 80 [71,93] vs 70 [64, 77]; p=0.002). Double product (24816 [21156, 27864] vs 26864 [22444, 30660]; p=0.016), exercise time (7.3 minutes [6,9] vs 8.5 [7.2, 9.5]; p=0.041), and metabolic equivalents (8.2 [7, 10] vs 9.5 [8.2, 10.5]; p=0.018), were all lower in TG females than cis-males. Exercise ejection fraction was higher in the transgender cohort than in cis-females (70 [70, 75] vs 70 [65, 70]; p=0.007). There was no difference in functional aerobic capacity or in the rest or stress wall motion score indices among the groups. Finally, there was no difference in the prevalence of positive electrocardiogram or SE studies. Conclusion: In conclusion, we report for the first time SE profiles for TG females which display an overall distinct phenotype compared to cis-males and cis-females. Larger prospective studies are warranted to further define these parameters for the TG population.

Introduction: The prevalence of metabolic syndrome (MS), and diabetes mellitus (DM) is increasing, and the use of biomarkers to identify subjects at risk of developing MS or DM may be useful for disease prevention. Natriuretic peptides (NPs) are well known for their role as biomarkers in heart failure (HF), but are increasingly being recognized for their favorable metabolic actions and potential role as risk modifiers for the development of DM and MS. To date, however, this risk relationship has not been well defined in the general population. Hypothesis: Adults in the general population with lower NP levels are at higher risk for developing DM or MS. Methods: A retrospective review of the Olmsted County Heart Function Study cohort, a population-based random sample of 2042 Olmsted County, MN residents aged ≥ 45 years. A subgroup of community-dwelling subjects without MS or DM at Visit 1 was identified and subjects returned for followup after 4 years (Visit 2). We compared the characteristics of subjects that developed MS or DM after 4 years to those that did not. Results: Of the 911 subjects who did not have MS or DM at visit 1, 93 (10.2%) developed either MS or DM at visit 2. Subjects who developed MS or DM at visit 2 were more likely to have higher baseline BMI (p <0.001), lower HDL (p<0.001), higher triglycerides (p < 0.001), higher insulin (p< 0.001), higher aldosterone (p < 0.001) levels, lower NT-proANP (p<0.001) and lower NT-proBNP levels (p < 0.01) compared to those that did not develop MS or DM. Those that developed MS or DM were also at higher risk for development of HF when controlling for age and sex (HR 2.73 CI 1.25-5.96). On univariate analysis, higher baseline levels of NT-proANP and NT pro-BNP had a significant negative association with developing new MS or DM (ORs per 1 SD increase: 0.64, CI 0.51-0.79 p < 0.0001 and 0.76, CI 0.62-0.95 p=0.016, respectively). Conclusions: Among adults aged ≥ 45 years in the community, low levels of NT- ANP and NT-proBNP are associated with increased risk of development of DM and MS. Further studies are warranted to determine if potentiating the natriuretic peptide system would delay the development of DM or MS.

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.

Background: Left atrial appendage occlusion with the Watchman device is an alternative strategy for stroke risk reduction in patients with non-valvular atrial fibrillation. There are rare case reports of Watchman associated infection. Currently, there is no formal study that evaluated the incidence and outcomes of Watchman-related infections. Methods: All patients who underwent Watchman implantation over a 14 year study period (July 2004 through December 2018) comprised our cohort. Baseline characteristics, procedural data, and post-implantation events were identified. Primary study outcomes included Watchman related infection, other cardiovascular device related infection, bacteremia, and mortality. Results: A total of 181 patients with an average age of 75, and a median CHA2DS2-VASc Score of 4 (interquartile range 2) and a median HAS-BLED Score of 3 (interquartile range 1), were included for analysis. A total of 534.7 patient years of follow up was accrued with an average of 2.9 years per patient. The most common indications for implantation included gastrointestinal bleeding (56 patients; 30.9%) and intracerebral bleeding (51 patients; 28.2%). During follow up, 38 patients (21%) died. Six developed evidence of bacteremia. Only one developed an implantable cardioverter defibrillator (ICD) infection that required complete system extraction. None of the cohort developed Watchman-related device infection during the study period. Conclusion: In a single center study spanning a 14 year period, we report no Watchman-related devices infections. This is despite the presence of patients with bacteremia, as well as an ICD infection requiring extraction. These data suggest that Watchman devices are extremely unlikely to become infected.