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Study objective: Heart failure (HF) syndrome is associated with pulmonary system abnormalities that have a direct impact on mortality. Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct subtypes of HF with different pathophysiologies, clinical presentations, and treatment approaches. Obesity is highly prevalent in HFpEF and significantly contributes to its development. Importantly, obesity and high abdominal adiposity can have significant effects on pulmonary function. Therefore, HFpEF patients may have more pronounced pulmonary function impairment than HFrEF patients in part due to higher prevalence of upper body adiposity. Hypothesis: We hypothesized that lung volumes would be lower in patients with HFpEF compared to those with HFrEF and CTL. Further, we hypothesized that higher upper body adiposity (measured as trunk fat by dual-energy X-ray absorptiometry) would be associated with lower lung volumes in patients with HFpEF. Methods: HFpEF patients (n=26), HFrEF patients (n=26) and CTL (n=36) performed pulmonary function tests according to ATS/ERS guidelines. Total lung capacity (TLC), residual volume (RV), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were measured and absolute and % predicted values are reported. Dual-energy X-ray absorptiometry scans quantified % trunk fat. Absolute lung volumes were compared across groups using ANCOVA with age as a covariate and % predicted lung volumes were compared using one-way ANOVA. Results: HFpEF patients were older than HFrEF patients and CTL (HFpEF: 71±9 vs. HFrEF: 65±9 vs. CTL: 63±11 yrs, both p<0.05) while no differences were present among groups for sex, height, or BMI (all, p>0.05). HFpEF patients had higher % trunk fat than CTL (p<0.01), while no differences were present between HFrEF and HFpEF or CTL (p>0.05) (HFpEF: 46±11 vs. HFrEF: 42±8 vs. CTL: 38±11%). HFpEF patients had lower FVC (HFpEF: 3.0±0.7 vs. HFrEF: 3.7±1.0 vs. CTL: 3.8±0.8 L), FEV1 (HFpEF: 2.3±0.5 vs. HFrEF: 2.8±0.8 vs. CTL: 2.9±0.6 L), TLC (HFpEF: 5.5±1.3 vs. HFrEF: 6.3±1.4 vs. CTL: 6.4±1.1 L), and % predicted TLC than CTL (all, p<0.05). HFpEF and HFrEF patients had lower % predicted FVC and % predicted FEV1 than CTL (p<0.05). All other pulmonary function parameters were not different among groups (p>0.05). There was a negative relationship between % trunk fat and TLC for HFpEF patients (r= -0.51, p<0.05). There were negative relationships between % trunk fat and FVC for CTL (r= -0.37) and HFpEF patients (r= -0.50) (both, p<0.05), with statistically different y-intercepts (p<0.01). There were no other significant relationships (all, p>0.05). Conclusion: These findings demonstrate that patients with HF have smaller lung volumes than CTL. Further, our findings suggest that upper body adiposity may be an important contributing factor to these pulmonary system abnormalities in HFpEF. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objective We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL‐PAN). Methods Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease‐related damage, and survival were analyzed. Results Three hundred fifty‐eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty‐five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow‐up, relapse occurred in 48.5% of patients. One, 5‐ and 10‐year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. Conclusion The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN. image

Abstract Background Atrial fibrillation (AF) occurs more frequently in men, but women suffer more AF recurrence; mechanisms are not completely understood. Purpose To explore whether sex related differences in LA stiffness (LAstiffn) in patients with AF ablation could potentially explain differences in AF recurrence. Methods We screened patients with catheter ablation for AF, in sinus rhythm at 3 months post-ablation, with no significant mitral valve disease (&lt; moderate), and with prospectively measured LA volumes [maximum (LAVI) and minimum volume index] by echocardiography. LAStiffn index was estimated as (E/e’)/LA emptying fraction. Outcome endpoint was AF recurrence up to 14 years post ablation. Results A total of 591 patients with AF ablation were studied (mean age 60±10 years; 25% women; Table1). At 3 months post-ablation, LAVI was 36±10 mL/m2 and LAstiffn was 0.31±0.21 1/%. Compared to males, female patients were slightly older, had more frequently hypertension, congestive heart failure, prior stroke/TIA, higher CHA2DS2-VASc score; they less often had persistent AF, coronary artery disease, or dilated cardiomyopathy. Women also had higher LAstiffn (0.37±0.24 vs. 0.29±0.19, P &lt;.0001, Figure 1), despite similar indexed LA volumes (Table1). Rates of AF recurrence at follow-up (median 7.5 years; 347 patients with events) were higher in women vs. men (Figure 2, left; log-rank P&lt;.001) and persisted after adjustment for age, type and duration of AF, body mass index, cardiovascular risk factors and comorbidities, CHA2DS2-VASc score ≥2, LV ejection fraction, and LAVI (adjusted HR 1.58 [1.20-2.08], P=.001). Overall, LA volumes and LAstiffn were higher in patients with older age and more comorbidities (hypertension, congestive heart failure, coronary artery disease, persistent AF, CHA2DS2-VASc score ≥2, etc; P&lt;.01 for all). At multivariable regression analysis, LAVI and LAstiffn correlated with E/e’, LV size and mass, degree of mitral/tricuspid regurgitation, and LV stroke volume index (only LAVI). In addition, LAstiffn was higher in patients with elevated right ventricular systolic pressure (RVSP) &gt;35 mmHg and increase in RVSP more than 10 mmHg from pre-ablation (P&lt;.0001) (correlation R=0.44, P&lt;.0001). At follow-up, after adjusting for age and LAVI, higher LAstiffn remained associated with AF recurrence in women (P=.02, HR 2.82 per unit change, 95% CI, 1.08-6.72; Figure 2, right), but not in men (P=.30). Conclusions LAStiffn is higher in women vs. men and correlates with burden of comorbidities, aging, diastolic dysfunction and pulmonary hypertension, possibly reflecting more extensive LA myopathy, and potentially contributing to sex differences in AF recurrence.Figure 1Table 1

Introduction: Obesity and hypertension (HTN) are highly prevalent comorbid risk factors for heart failure with preserved ejection fraction (HFpEF). Obesity and HTN independently increase sympathetic nervous activity and impair muscle blood flow during exercise. Previous work has reported attenuated limb blood flow in patients with HFpEF; however, these findings were compared to controls with dissimilar comorbidities and during small muscle mass exercise. It is unclear if HFpEF alters muscle blood flow responses independent of the obesity- and HTN-mediated alterations. Hypothesis: We hypothesized the muscle blood flow response during cycling would be lower in HFpEF patients than age, sex, BMI, and HTN matched controls (CTL). Methods: HFpEF patients (n=14, 9M/5W, 71±7yrs, 32±4 kg/m 2 ) and CTL (n=12, 8M/4W, 69±7yrs, 31±4 kg/m 2 ) performed an incremental cycling test. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) by open-circuit acetylene wash-in technique, and systemic vascular resistance (SVR) was calculated. Vastus lateralis blood flow index (BFI) was measured by near-infrared spectroscopy and indocyanine green dye injections and venous norepinephrine concentration was measured. Changes from rest to 40 W of the incremental test are reported. Results: Resting Q, mean arterial pressure, SVR, and venous norepinephrine concentration were not statistically different between groups (p>0.18). From rest to 40 W, the increases in Q (CTL: 3.9±0.8 vs. HFpEF: 3.6±0.7 L/min), mean arterial pressure (CTL: 5.7±2.7 vs. HFpEF: 6.6±6.1 mmHg), and SVR (CTL: -7.3±2.1 vs. HFpEF: -6.0±2.0 mmHg/L/min) were not statistically different between groups (all, p>0.13). The HFpEF group had smaller increases in vastus lateralis BFI at 40 W compared to CTL (CTL: 7.2±3.6 vs. HFpEF: 4.2±2.6 fold-increase from rest) (p=0.02). The HFpEF group had greater increases in venous norepinephrine concentration from rest to 40 W than CTL (CTL: 164±216 vs. HFpEF: 377±247 pg/mL) (p=0.05). Conclusions: Our findings suggest that, compared to age, sex, BMI, and HTN matched controls, patients with HFpEF have an impaired locomotor muscle blood flow response during submaximal cycling exercise likely due to higher locomotor muscle vascular resistance.

ObjectiveDesign thinking is a creative problem‐solving process used to better understand users’ needs and experiences so that a product or service can be improved. Its emphasis on empathy, iterative prototyping, and participatory collaboration make it an ideal methodology for innovation in medical education. We apply this framework to the virtual rheumatology fellowship interview process so that interviews can become more applicant centered.MethodsThis educational quality improvement project uses a design‐thinking framework to identify opportunities and challenges for rheumatology fellowship applicants. The investigators use the 5‐step process (Empathize, Define, Ideate, Prototype, Test) and incorporate rapid qualitative analysis of semistructured interviews to innovate the interview experience. The iterative and collaborative nature of this process has empowered participants to codesign an applicant‐centered interview experience.ResultsInterviews with fellowship applicants (n = 9), fellow physicians (n = 4), and faculty members (n = 3) identified three major dynamics of the interview process: (1) Is it a safe environment to ask questions? (2) How do I exchange information effectively? and (3) How do I fit all these data into the bigger picture? Creative brainstorming techniques at a series of three workshops yielded four prototypes emphasizing customization, hybridization, facilitation, and preparation. A finalized applicant‐centered interview template was devised in preparation for the 2023‐2024 application season.ConclusionDesign thinking has yielded insights into three important dynamics that drive applicant experiences. These insights allow for a redesign of processes so that virtual interviews can be more applicant centered. This framework allows for further iterations and modifications as the needs of applicants and programs evolve over time.

ImportanceTesting new medical devices or procedures in terms of safety, effectiveness, and durability should follow the strictest methodological rigor before implementation.ObjectivesTo review and analyze studies investigating devices and procedures used in intracranial aneurysm (IA) treatment for methods and completeness of reporting and to compare the results of studies with positive, uncertain, and negative conclusions.Data SourcesEmbase, MEDLINE, Web of Science, and The Cochrane Central Register of Clinical Trials were searched for studies on IA treatment published between January 1, 1995, and the October 1, 2022. Grey literature was retrieved from Google Scholar.Study SelectionAll studies making any kind of claims of safety, effectiveness, or durability in the field of IA treatment were included.Data Extraction and SynthesisUsing a predefined data dictionary and analysis plan, variables ranging from patient and aneurysm characteristics to the results of treatment were extracted, as were details pertaining to study methods and completeness of reporting. Extraction was performed by 10 independent reviewers. A blinded academic neuro-linguist without involvement in IA research evaluated the conclusion of each study as either positive, uncertain, or negative. The study followed Preferring Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Main Outcomes and MeasuresThe incidence of domain-specific outcomes between studies with positive, uncertain, or negative conclusions regarding safety, effectiveness, or durability were compared. The number of studies that provided a definition of safety, effectiveness, or durability and the incidence of incomplete reporting of domain-specific outcomes were evaluated.ResultsOverall, 12 954 studies were screened, and 1356 studies were included, comprising a total of 410 993 treated patients. There was no difference in the proportion of patients with poor outcome or in-hospital mortality between studies claiming a technique was safe, uncertain, or not safe. Similarly, there was no difference in the proportion of IAs completely occluded at last follow-up between studies claiming a technique was effective, uncertain, or noneffective. Less than 2% of studies provided any definition of safety, effectiveness, or durability, and only 1 of the 1356 studies provided a threshold under which the technique would be considered unsafe. Incomplete reporting was found in 546 reports (40%).Conclusions and RelevanceIn this systematic review and meta-analysis of IA treatment literature, studies claiming safety, effectiveness, or durability of IA treatment had methodological flaws and incomplete reporting of relevant outcomes supporting these claims.

Background: Diastolic dysfunction (DD) is frequently present in patients with hypertrophic cardiomyopathy (HCM) due to abnormal left ventricular (LV) relaxation, wall hypertrophy, increased LV filling pressures and myocardial disarray and fibrosis, even though ejection fraction (EF) remains preserved until late stages. Our aim was to investigate in a large cohort whether contemporary markers of DD and increased filling pressures are associated with outcomes in these patients. Methods: We screened consecutive patients with HCM who had transthoracic echocardiography and no significant valvular heart disease. The associations of septal/lateral e’ velocity, E/e’, left atrial volume index (LAVi), and tricuspid regurgitant velocity (TR) with all-cause mortality were tested. A diastolic score (DS) was also calculated (1 point for each abnormality in e’, E/e’, TR, LAVi). Results: 1,496 patients with HCM were studied (mean age 52±15 yrs; 61% men; LV EF 69±7%; Table). Diastolic abnormalities were highly prevalent in these patients ( Table ). In the subset without septal reduction therapy (SRT; n=900), at a median followup of 9 years (IQR 7-11 yrs; n=78 deaths), increased E/e’ and DS were strongly associated with mortality (log-rank P <.0001 for both; Figure ). However, E/e’ did not remain significant in multivariable models after adjustment for known cardiac risk factors or other significant confounders ( Table ). In contrast, DS >2 remained independently associated with ~2-fold higher mortality risk (adjusted HR 1.91 [1.14-3.20, P =.01]; n=693; Table). In patients who underwent SRT (n=596), these associations showed the same trend but attenuated. Conclusion: In HCM patients who did not require SRT, the severity of DD was associated with mortality, independent of cardiac pump function or known cardiac risk factors. The composite score was more powerful than E/e’. Further studies are needed to fully understand the impact of DD in these patients with and without SRT.

Polycystic kidney disease (PKD) is the most common monogenic kidney disorder and an important cause of end stage renal disease. Vascular abnormalities are the most important non‐cystic complication and contribute to renal disease progression. Homocysteine (Hcy)‐mediated endothelial dysfunction (ED) and oxidative stress are evident early on, but the underlying mechanisms remain unknown. We hypothesized that abnormalities in Hcy metabolism are responsible for the increased levels, leading to Hcy‐induced ED from early stages of PKD. Methods We investigated the Hcy metabolic pathway (transulfuration/remethylation fig. 1) and downstream effects ‐main sources of renal tubular (RT) and endothelial cell (EC) reactive oxygen species (ROS), NADPH oxidase 4, (NOX4) and mitochondria‐ in 4‐week‐old PCK and Sprague‐Dawley (SD) control rats (n=12 each). Kidneys were harvested, frozen in liquid nitrogen, or preserved in formalin for metabolomics and ex‐vivo studies. Twenty‐four‐hour urine and terminal blood samples were collected for metabolite analysis and chemistries. Plasma folic acid, vitamin B12, and Hcy were determined by ELISA. Hcy pathway metabolites (betaine, dimethylglycine) were determined by 1 HNMR. Endothelial NO (eNOS) and oxidative stress were assessed by double immunofluorescence staining for CD31/eNOS and CD31/NOX4, respectively. RT and EC mitochondrial structure was assessed by electron microscopy. Results Serum creatinine and BUN remained unchanged, yet kidney weight/body weight ratio were increased in PCK. eNOS immunoreactivity was lower in PCK vs SD. Plasma Hcy and urine excretion of methyl donor betaine were elevated in PCK, and Hcy positively correlated with urine betaine. Plasma betaine was similar between the groups, but its tissue concentration was lower in PCK, which may lead to betaine insufficiency, impaired betaine dependent remethylation, and hyperhomocysteinemia. Contrarily, tissue glutathione concentration was higher in PCK vs SD, and plasma folate and vitamin B12 were similar, arguing against a defect in the transsulfuration or folate‐dependent remethylation pathways. RT NOX4 expression and immunoreactivity were increased in PCK compared to SD, in association with renal oxidative stress. PCK had increased number of CD31/NOX4 positive cells in peritubular capillaries, indicating increased EC ROS production. Collecting duct and EC mitochondria were swollen and showed cristae remodeling. Conclusion In PKD, early elevation in Hcy is likely related to betaine insufficiency and impaired betaine‐dependent remethylation may be responsible for the early elevation of Hcy. NOX4 and mitochondria abnormalities may be important contributors to oxidative stress and disease severity. Our data suggests these may not only be early vascular disease markers, but also play an important pathogenic role in vascular complications associated with PKD, and contribute to renal disease progression. Support or Funding Information R25‐DK101405, NIDDK P30 DK090728, NIDDK P30 DK 106912 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .